VA Class:AM700
Amphotericin B, a macrocyclic polyene, is an antifungal agent.201, 202, 417
Conventional IV amphotericin B (formulated with sodium desoxycholate) is used for the treatment of potentially life-threatening fungal infections including aspergillosis, blastomycosis, systemic candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioidomycosis†, sporotrichosis, and zygomycosis.126, 211, 268, 292, 417, 423, 424, 425, 426, 427, 428, 429, 436, 440, 441 The drug also has been used IV for empiric antifungal therapy in febrile neutropenic patients†126, 211, 248, 277, 279, 287, 376, 422, 452 or for prevention of fungal infections in other immunocompromised individuals† (e.g., cancer patients, bone marrow or solid organ transplant recipients).126, 249, 276, 277, 286, 287, 290, 375 In addition, conventional IV amphotericin B is used for the treatment of certain protozoal infections, including leishmaniasis102, 103, 104, 105, 106, 108, 109, 126, 381, 382, 417, 430, 440, 442, 443, 501, 502 and primary amebic meningoencephalitis caused by Naegleria fowleri †.119, 126, 269, 292, 442, 511, 512, 513
Conventional IV amphotericin B should be used principally in patients with progressive, potentially life-threatening fungal infections and should not be used to treat noninvasive fungal infections (e.g., oral thrush, vaginal candidiasis, esophageal candidiasis) in immunocompetent patients with normal neutrophil counts.126, 269, 292, 417 When necessary, conventional amphotericin B has been administered intrathecally† or intraventricularly† (either alone or in conjunction with systemic antifungal therapy) for the treatment of CNS infections caused by susceptible fungi.126, 211, 426, 440, 455, 457 Conventional amphotericin B also has been administered by bladder irrigation† for the treatment of Candida cystitis,251, 260, 262, 293, 425 administered intraperitoneally† for the treatment of fungal peritonitis,211 and given intrabronchially† or by nebulization† for the treatment or prophylaxis of pulmonary fungal infections.211, 261, 276, 370, 460, 463
Amphotericin B lipid complex (Abelcet®) is labeled for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional IV amphotericin B.201
Amphotericin B liposomal (AmBisome®) is labeled for the treatment of infections caused by Aspergillus , Candida , or Cryptococcus that are refractory to conventional IV amphotericin B and for the treatment of these infections in patients who cannot receive conventional amphotericin B because of renal impairment or unacceptable toxicity.202 Amphotericin B liposomal also is labeled for the treatment of cryptococcal meningitis in patients with human immunodeficiency virus (HIV) infection, for empiric therapy of presumed fungal infections in febrile, neutropenic patients, and for the treatment of visceral leishmaniasis.202
IV amphotericin B is considered a drug of choice for the treatment of many systemic infections caused by susceptible fungi, especially for initial treatment in patients with severe infections.126, 209, 211, 219, 229, 230, 231, 269, 283, 336, 436, 440, 448 Although clinical experience with lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B liposomal) has been obtained principally from small, open-label studies and case reports,201, 202, 230, 235, 377, 424, 436 the lipid formulations of amphotericin B generally appear to be better tolerated (e.g., lower incidence of acute infusion reactions and adverse hematologic and renal effects) and may be preferred for some infections.215, 216, 423, 424, 425, 428, 429, 436, 440, 441, 448 Additional study is needed to determine the relative efficacy of these lipid formulations of amphotericin B compared with conventional IV amphotericin B for the treatment of severe, potentially life-threatening fungal infections.201, 202, 219, 230, 231, 244, 250, 346, 377
Conventional IV amphotericin B,211, 236, 243, 248, 268, 269, 288, 292, 417, 420, 423, 436, 440, 458, 459 amphotericin B lipid complex,201, 207, 235, 237, 238, 239, 396 and amphotericin B liposomal202, 230, 231, 232, 236, 240, 241, 242, 379, 459 are used for the treatment of invasive aspergillosis caused by Aspergillosis .
The Infectious Diseases Society of America (IDSA) and other clinicians consider voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients, including HIV-infected patients.423, 436, 440 These experts state that IV amphotericin B liposomal or isavuconazonium sulfate (prodrug of isavuconazole) are the preferred alternatives for primary treatment of aspergillosis;423 IV amphotericin B lipid complex is another alternative.423 For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IV amphotericin B (a lipid formulation), an IV echinocandin (caspofungin, micafungin), oral or IV posaconazole, or itraconazole oral suspension are recommended.423 IDSA states that conventional IV amphotericin B and lipid formulations of amphotericin B are appropriate options for initial and salvage treatment of invasive aspergillosis when voriconazole cannot be used; however, conventional IV amphotericin B should be reserved for use in resource-limited settings when no alternative agents are available.423
For the treatment of invasive aspergillosis in HIV-infected adults and adolescents, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend voriconazole as the drug of choice;440 IV amphotericin B (conventional or lipid formulation), IV echinocandins (anidulafungin, caspofungin, micafungin), and oral posaconazole are recommended as alternatives.440
Invasive aspergillosis (especially in immunocompromised patients) is difficult to diagnose and treat, and the overall response rate of invasive aspergillosis to conventional IV amphotericin B has been highly variable ranging from 14-83%.236, 238, 243, 268, 420, 458 In a controlled study in immunocompromised adults and adolescents 12 years of age or older with invasive aspergillosis, patients were randomized to receive voriconazole (6 mg/kg IV twice daily on day 1, then 4 mg/kg IV twice daily for at least 7 days, followed by oral voriconazole 200 mg twice daily) or conventional amphotericin B (1-1.5 mg/kg IV once daily).458 A successful outcome (complete and partial responses) at week 12 in the modified intention-to-treat population (ITT) was achieved in 53% of those treated with voriconazole compared with 32% of those treated with amphotericin B.458 In addition, the survival rate at 12 weeks was 71% in the voriconazole group compared with 58% in the amphotericin B group.458
In several studies involving patients with invasive aspergillosis, the response rates to amphotericin B lipid complex207 or amphotericin B liposomal209, 231, 232, 236, 379, 459 have ranged from 32-69%.
Although conventional IV amphotericin B has been used in conjunction with other antifungals (e.g., flucytosine) for salvage therapy in some patients with invasive aspergillosis (e.g., CNS, endocarditis) that did not respond to conventional IV amphotericin B alone, it is unclear whether these combination regimens offer any benefit over use of IV amphotericin B alone and there are concerns related to possible drug interactions between amphotericin B and flucytosine.211, 236, 243, 268, 269, 346 (See Flucytosine under Drug Interactions: Anti-infective Agents.)
For additional information on management of aspergillosis, the current clinical practice guidelines from IDSA available at [Web]423 and the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440 should be consulted.
IV amphotericin B is used for the treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis .211, 267, 269, 288, 292, 319, 321, 322, 417, 424, 436, 448
While both oral itraconazole and IV amphotericin B are considered drugs of choice for the treatment of blastomycosis, IV amphotericin B is preferred for initial treatment of severe blastomycosis, especially infections involving the CNS,269, 288, 292, 319, 320, 321, 322, 424, 436, 448 and for initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.267, 424 Oral itraconazole is the drug of choice for the treatment of nonmeningeal, non-life-threatening blastomycosis, including mild to moderate pulmonary blastomycosis or mild to moderate disseminated blastomycosis (without CNS involvement) and also is recommended for follow-up therapy in patients with more severe infections after an initial response has been obtained with IV amphotericin B.291, 424, 436
When amphotericin B is used for the treatment of blastomycosis, conventional IV amphotericin B or a lipid formulation of amphotericin B can be used.424 However, IDSA and others state that a lipid formulation of amphotericin B (e.g., amphotericin B liposomal) may be preferred for the treatment of CNS blastomycosis since higher CSF concentrations may be obtained.424, 448
For additional information on management of blastomycosis, the current clinical practice guidelines from IDSA available at [Web] should be consulted.424
IV amphotericin B is used for the treatment of disseminated or invasive infections caused by Candida , including candidemia, cardiovascular infections (endocarditis, pericarditis, myocarditis), and meningitis, and for the treatment of other serious infections caused by Candida , including osteoarticular infections (osteomyelitis, septic arthritis), peritonitis, intra-abdominal abscesses, urinary tract infections (symptomatic cystitis, pyelonephritis, urinary fungus balls), and endophthalmitis.126, 211, 222, 223, 224, 225, 248, 254, 283, 292, 417, 425, 436 The drug also is used for the treatment of certain severe or refractory mucocutaneous Candida infections (e.g., esophageal candidiasis†, oropharyngeal candidiasis†).425, 436, 440
Amphotericin B generally is effective against infections caused by C. albicans , C. glabrata , C. krusei , C. parapsilosis , or C. tropicalis ,223, 254, 425 and is a drug of choice for many infections caused by fluconazole-resistant Candida .425 Fluconazole-resistant C. albicans are being isolated with increasing frequency from patients who have received prior fluconazole therapy (especially in HIV-infected patients) and some Candida infections (e.g., candidemia) are increasingly caused by strains that are intrinsically resistant to fluconazole (e.g., C. krusei ) or likely to have resistance or reduced susceptibility to fluconazole (e.g., C. glabrata ).224, 294, 425
For the treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis† in nonneutropenic patients in intensive care units (ICUs), IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) for initial therapy.425 IDSA states that fluconazole (IV or oral) is an acceptable alternative for initial therapy in selected patients, including those who are not critically ill and are unlikely to have infections caused by fluconazole-resistant Candida .425 If echinocandin- and azole-resistant Candida are suspected, IV amphotericin B (a lipid formulation) is recommended;425 IV amphotericin B (a lipid formulation) also is a reasonable alternative when echinocandins and fluconazole cannot be used because of intolerance, limited availability, or resistance.425 IDSA states that transition from the echinocandin (or amphotericin B) to fluconazole can be considered (usually within 5-7 days) in patients who are clinically stable, have isolates susceptible to fluconazole (e.g., C. albicans ), and have negative repeat blood cultures after initial antifungal treatment.425
For the treatment of candidemia in neutropenic patients, IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) or, alternatively, IV amphotericin B (a lipid formulation) for initial therapy.425 Fluconazole is an alternative for initial therapy in those who are not critically ill or have had no prior exposure to azole antifungals and also can be used for step-down therapy during neutropenia in clinically stable patients who have fluconazole-susceptible isolates and documented bloodstream clearance.425 Voriconazole can be used as an alternative for initial therapy when broader antifungal coverage is required and also can be used as step-down therapy during neutropenia in clinically stable patients who have voriconazole-susceptible isolates and documented bloodstream clearance.425 For infections known to be caused by C. krusei , an echinocandin, amphotericin B (a lipid formulation), or voriconazole is recommended.425
For the treatment of chronic disseminated (hepatosplenic) candidiasis, IDSA recommends initial treatment with IV amphotericin B (a lipid formulation) or an IV echinocandin (anidulafungin, caspofungin, micafungin) followed by oral fluconazole therapy.425
For the treatment of CNS candidiasis, IDSA recommends initial treatment with IV amphotericin B liposomal (with or without oral flucytosine) and step-down treatment with fluconazole.425 Infected CNS devices (e.g., ventriculostomy drains, shunts, stimulators, prosthetic reconstructive devices, biopolymer wafers that deliver chemotherapy) should be removed if possible.425 If a ventricular device cannot be removed, IDSA states that conventional amphotericin B can be administered through the device.425 Conventional amphotericin B has been administered intrathecally† as an adjunct to systemic antifungal treatment in patients with Candida meningitis.126, 211, 455
For the treatment of neonatal candidiasis, including CNS infections, conventional IV amphotericin B usually is the drug of choice for initial treatment.292, 425 Although not routinely recommended in neonates, concomitant use of flucytosine can be considered as salvage therapy if CNS infections do not respond to initial therapy with IV amphotericin B alone.292, 425 The IDSA and American Academy of Pediatrics (AAP) state that fluconazole can be considered for step-down treatment after an initial response has been obtained with IV amphotericin B.292, 425 Fluconazole also is a reasonable alternative for initial treatment of neonatal candidiasis (without CNS involvement), provided the patient had not been receiving fluconazole prophylaxis and the causative agent is susceptible.292, 425 Although lipid formulations of IV amphotericin B can be considered as alternatives for the treatment of neonatal candidiasis, these formulations should be used with caution in this age group, particularly in the presence of urinary tract involvement.292, 425
For the treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida , IDSA recommends initial treatment with a lipid formulation of IV amphotericin B (with or without oral flucytosine) or an IV echinocandin (anidulafungin, caspofungin, micafungin) and step-down treatment with fluconazole.425 If the isolate is susceptible, long-term suppressive or maintenance therapy (secondary prophylaxis) with fluconazole is recommended to prevent recurrence in those with native valve endocarditis who cannot undergo valve replacement and in those with prosthetic valve endocarditis.425
Mucocutaneous or noninvasive Candida infections, such as esophageal, oropharyngeal, or vaginal candidiasis, usually can be adequately treated with an appropriate oral or topical antifungal;147, 269, 283, 292, 425, 436, 440 however, severe or refractory mucocutaneous infections (e.g., esophageal candidiasis†, oropharyngeal candidiasis†) caused by azole-resistant Candida or infections that fail to respond to such therapy may require IV amphotericin B therapy.292, 425, 436, 440 In addition, IV amphotericin B has been recommended as an alternative for the treatment of esophageal candidiasis† in patients who cannot tolerate oral therapy.425, 440
Amphotericin B has been used for the treatment of urinary tract infections caused by Candida .126, 211, 232, 251, 260, 262, 292, 293, 425, 432, 433, 434, 435, 436, 466, 467, 468, 469, 470, 471, 472, 473, 474 IDSA states that antifungal treatment is not usually indicated in patients with asymptomatic cystitis, unless there is a high risk of disseminated candidiasis (e.g., neutropenic patients, low birthweight infants [less than 1.5 kg], patients undergoing urologic manipulations).425 For the treatment of symptomatic cystitis, pyelonephritis, or fungus balls likely to be caused by fluconazole-susceptible Candida , fluconazole is the drug of choice.425 If symptomatic cystitis is caused by fluconazole-resistant Candida , IDSA recommends conventional IV amphotericin B or oral flucytosine for infections caused by C. glabrata and conventional IV amphotericin B for infections caused by C. krusei .425 If pyelonephritis is caused by fluconazole-resistant Candida , conventional IV amphotericin B (with or without oral flucytosine) is recommended for C. glabrata and conventional IV amphotericin B is recommended for C. krusei .425 Although conventional amphotericin B has been administered by bladder irrigation† for the treatment of candiduria (funguria),126, 211, 232, 251, 260, 262, 292, 293, 425, 432, 433, 434, 435, 466, 467, 468, 469, 470, 471, 472, 473, 474 such therapy has been controversial since candiduria may be self-limited in some patients (e.g., after changing or removing indwelling catheters) and the risks and benefits of bladder irrigation versus systemic antifungal treatment have not been clearly identified.293, 434, 467, 468, 469, 471, 472, 473, 474 IDSA states that bladder irrigation† with conventional amphotericin B is not generally recommended, but may be useful for patients with refractory, symptomatic cystitis caused by fluconazole-resistant Candida (e.g., C. glabrata , C. krusei ) or as an adjunct to systemic antifungal therapy for the treatment of urinary fungus balls.425
IDSA states that IV amphotericin B liposomal (with or without oral flucytosine) is the regimen of choice for the treatment of endophthalmitis caused by fluconazole- and voriconazole-resistant Candida .425 In patients with macular involvement, intravitreal† administration of conventional amphotericin B also is recommended to ensure prompt high levels of antifungal activity.425 Decisions regarding antifungal treatment and surgical intervention should be made jointly by an ophthalmologist and an infectious disease clinician.425
Amphotericin B lipid complex has been effective when used in pediatric cancer patients with chronic disseminated candidiasis337 or other Candida infections.235 Liposomal amphotericin B has been used effectively for the treatment of disseminated Candida infections,230, 231, 232 and the overall response rate in patients with candidiasis who received the lipid formulation has been reported to be 56-70%.231, 232, 348
IV amphotericin B has been used for the treatment of infections caused by C. auris , an emerging pathogen that has been associated with potentially fatal candidemia or other invasive infections.506, 507, 509
C. auris , first identified in 2009, has now been reported as the cause of serious invasive infections (including fatalities) in multiple countries worldwide (e.g., Japan, South Korea, India, Kuwait, South Africa, Pakistan, United Kingdom, Venezuela, Columbia, US).504, 505, 506, 507, 509 As of May 2017, a total of 77 clinical cases of C. auris had been reported to CDC from 7 different states in the US.504 C. auris may be difficult to identify using standard in vitro methods and has been misidentified as C. haemulonii , C. famata , or Rhodotorula glutinis .507, 508 A large percentage of C. auris clinical isolates are resistant to fluconazole and multidrug-resistant isolates with reduced susceptibility or resistance to all 3 major classes of antifungal agents (azoles, polyenes, echinocandins) have been reported.505, 507, 508, 509
Pending further accumulation of data, CDC has issued interim recommendations regarding laboratory diagnosis, treatment, and infection control measures for suspected or known C. auris infections.510 Based on limited data available to date, CDC recommends that an IV echinocandin (anidulafungin, caspofungin, micafungin) be used for initial treatment of invasive C. auris infections (e.g., bloodstream or intra-abdominal infections) in adults.510 CDC states that a switch to IV amphotericin B (a lipid formulation) could be considered if the patient is clinically unresponsive to the echinocandin or fungemia persists longer than 5 days.510 Consultation with an infectious disease specialist is highly recommended.510
Unless there is evidence of infection, CDC does not currently recommend antifungal treatment when C. auris is isolated only from noninvasive body sites (e.g., urine, external ear, wounds, respiratory secretions).510 Some individuals are colonized with C. auris in the axilla, groin, nose, external ear canal, oropharynx, urine, wounds, rectum, and stool;504, 510 however, data are limited and the duration of C. auris colonization is unclear.510 Therefore, CDC recommends that infection control measures be observed for all patients with cultures yielding C. auris , including those with positive cultures only from noninvasive body sites.510
Whenever C. auris infection is suspected, clinicians should immediately contact state or local public health authorities and the CDC ([email protected]) for guidance.510 For additional information on diagnosis and management of C. auris infections, the interim recommendations and most recent information from CDC available at [Web] should be consulted.510
IV amphotericin B is used for the treatment of coccidioidomycosis caused by Coccidioides immitis or C. posadasii .126, 248, 269, 285, 288, 292, 417, 426, 436, 440, 441
IDSA states that antifungal treatment is not considered necessary in patients with newly diagnosed, uncomplicated coccidioidal pneumonia who have mild or nondebilitating symptoms, including those with an asymptomatic pulmonary nodule or cavity due to coccidioidomycosis and no overt immunocompromising conditions.426 However, antifungal treatment is recommended for patients with symptomatic chronic cavitary coccidioidal pneumonia, ruptured coccidioidal cavities, extrapulmonary soft tissue coccidioidomycosis, bone and joint coccidioidomycosis, or coccidioidal meningitis.426 Antifungal treatment of coccidioidomycosis also is usually recommended for patients who are immunocompromised or debilitated (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).426, 440, 441
IDSA and others state that an oral azole (fluconazole or itraconazole) usually is recommended for initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis.426, 436, 440, 441 However, IV amphotericin B is recommended as an alternative and is preferred for initial treatment of severely ill patients who have rapidly progressing or extrathoracic disseminated disease, for immunocompromised individuals, or when azole antifungals cannot be used (e.g., pregnant women).426, 440, 441
For the treatment of clinically mild coccidioidomycosis (e.g., focal pneumonia) in HIV-infected adults, adolescents, or children, CDC, NIH, and IDSA recommend initial therapy with oral fluconazole or oral itraconazole.440, 441 Although clinical data are limited, oral voriconazole or oral posaconazole may be used as alternatives in HIV-infected adults or adolescents for the treatment of clinically mild coccidioidomycosis† that has not responded to fluconazole or itraconazole.440
For the treatment of severe (nonmeningeal) coccidioidomycosis (e.g., diffuse pulmonary or extrathoracic disseminated infections) in HIV-infected adults, adolescents, or children, CDC, NIH, and IDSA recommend initial therapy with IV amphotericin B (conventional or lipid formulation) followed by oral azole therapy.440, 441 Alternatively, some experts recommend initial therapy with IV amphotericin B used in conjunction with an oral azole (fluconazole or itraconazole) followed by the oral azole alone.440, 441
For the treatment of coccidioidal meningitis, the regimen of choice in HIV-infected adults, adolescents, or children or other individuals is IV or oral fluconazole (with or without intrathecal† conventional amphotericin B).292, 426, 440, 441 Other oral azoles (itraconazole, posaconazole, voriconazole) are considered alternatives for the treatment of coccidioidal meningitis in adults and adolescents.426, 440 Patients who do not respond to fluconazole or itraconazole alone may be candidates for intrathecal† conventional amphotericin B (with or without continued azole therapy) or IV amphotericin B used in conjunction with intrathecal† conventional amphotericin B.292, 426, 440, 441 Consultation with an expert who has experience in treating coccidioidal meningitis is recommended.292, 440
HIV-infected adults, adolescents, or children who have been adequately treated for coccidioidomycosis should receive long-term (usually life-long) secondary prophylaxis to prevent recurrence or relapse.440, 441 Although oral fluconazole or oral itraconazole are the drugs of choice recommended by CDC, NIH, and IDSA for secondary prophylaxis to prevent recurrence or relapse of coccidioidomycosis in HIV-infected adults, adolescents, or children,440, 441 these experts state that oral posaconazole or oral voriconazole can be used as an alternative for secondary prophylaxis of coccidioidomycosis in HIV-infected adults or adolescents who did not initially respond to fluconazole or itraconazole.440
While data regarding use of lipid formulations of amphotericin B in the treatment of coccidioidomycosis are limited to date, amphotericin B lipid complex has been used with some success in a limited number of patients for the treatment of this infection.394, 396 Some experts state that there is no evidence that lipid formulations of IV amphotericin B are more effective than conventional IV amphotericin B for the treatment of coccidioidomycosis.441
For additional information on management of coccidioidomycosis, the current clinical practice guidelines from IDSA available at [Web]426 and the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440, 441 should be consulted.
IV amphotericin B is used for the treatment of infections caused by Cryptococcus neoformans ,126, 145, 153, 158, 162, 169, 170, 177, 182, 183, 184, 188, 189, 196, 197, 201, 202, 211, 213, 214, 215, 216, 230, 231, 269, 292, 393, 417, 427, 436, 440, 441, 449 and generally is considered a drug of choice, especially for the treatment of cryptococcal meningitis.126, 145, 153, 158, 162, 169, 170, 177, 182, 183, 184, 196, 197, 211, 213, 214, 269, 292, 393, 427, 436, 440, 441 Because of reported in vitro and in vivo synergism, IDSA and other clinicians recommend concomitant use of amphotericin B and flucytosine for initial treatment of cryptococcal infections,197, 211, 213, 214, 292, 346, 427, 436, 440 especially in HIV-infected patients.145, 169, 172, 182, 183, 185, 192, 292, 427, 440 Addition of flucytosine to the regimen appears to reduce the time required for sterilization of the CSF in those with CNS involvement and may decrease the risk of subsequent relapse and improve survival.145, 169, 171, 183, 197, 214, 292, 346, 393, 427, 440
Conventional IV amphotericin had been the preferred amphotericin B formulation for the treatment of cryptococcosis, but IV amphotericin B liposomal may now be preferred, especially in patients who have or are predisposed to renal dysfunction.436, 440, 441 Conventional IV amphotericin B can be used if cost is an issue and the risk of renal dysfunction is low.440 Although data are limited, IV amphotericin B lipid complex is considered an alternative to IV amphotericin B liposomal or conventional IV amphotericin B for the treatment of cryptococcosis.440, 441
For the treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, IDSA, and other clinicians state that the preferred regimen is initial (induction) therapy with IV amphotericin B (liposomal or conventional formulation) given in conjunction with flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral fluconazole given for at least 8 weeks, followed by long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to complete at least 1 year of azole therapy.427, 436, 440, 441
For the initial (induction) phase of treatment of cryptococcal meningitis in HIV-infected adults and adolescents, IV amphotericin B (liposomal or conventional formulation) in conjunction with oral flucytosine is the preferred regimen.440, 441 Alternative regimens for initial (induction) treatment of cryptococcal meningitis in HIV-infected adults and adolescents who cannot receive the preferred regimen are IV amphotericin B lipid complex given in conjunction with oral flucytosine; IV amphotericin B (liposomal or conventional formulation) given in conjunction with oral or IV fluconazole; IV amphotericin B (liposomal or conventional formulation) alone; oral or IV fluconazole given in conjunction with oral flucytosine; or oral or IV fluconazole alone.440 Alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.427, 440 IDSA states that use of intrathecal† or intraventricular† conventional amphotericin B in the treatment of cryptococcal meningitis generally is discouraged and is rarely necessary.427
For the treatment of cryptococcal CNS infections in organ transplant recipients, IDSA recommends initial (induction) therapy with IV amphotericin B liposomal or IV amphotericin B lipid complex given in conjunction with oral flucytosine for at least 2 weeks, then follow-up (consolidation) therapy with oral fluconazole given for 8 weeks.427 If the induction regimen does not include flucytosine, it should be continued for at least 4-6 weeks.427 Conventional IV amphotericin B is not usually recommended for first-line treatment of cryptococcosis in transplant recipients because of the risk of nephrotoxicity.427 For organ transplant recipients with mild to moderate pulmonary cryptococcosis (without diffuse pulmonary infiltrates) or other mild to moderate cryptococcal infections not involving the CNS, IDSA recommends fluconazole given for 6-12 months.427
In adults and children who do not have HIV infection and are not transplant recipients, IDSA states that the preferred regimen for the treatment of cryptococcal meningitis is initial (induction) therapy with conventional IV amphotericin B given in conjunction with oral flucytosine for at least 4 weeks (a 2-week period of induction therapy can be considered in those who are immunocompetent, are without uncontrolled underlying disease, and are at low risk for therapeutic failure), then follow-up (consolidation) therapy with oral fluconazole administered for an additional 8 weeks or longer.427
For the treatment of mild to moderate pulmonary cryptococcosis (nonmeningeal) in immunocompetent or immunosuppressed adults or children, IDSA states that the regimen of choice is oral fluconazole given for 6-12 months.427 However, severe pulmonary cryptococcosis, cryptococcemia, and disseminated cryptococcal infections in immunocompetent or immunosuppressed adults, adolescents, or children should be treated using regimens recommended for cryptococcal meningitis.427, 440, 441
In a randomized, multicenter study comparing conventional IV amphotericin B (mean dose of 0.4-0.5 mg/kg daily for 10 weeks with or without concomitant flucytosine) with oral fluconazole (400 mg on day 1 followed by 200-400 mg daily for 10 weeks) in HIV-infected patients with cryptococcal meningitis, therapy was effective in 40% of patients receiving amphotericin B and in 34% of those receiving fluconazole. Although overall mortality between patients receiving conventional amphotericin B and patients receiving fluconazole was similar (14% in patients receiving amphotericin B versus 18% in patients receiving fluconazole), mortality was higher during the first 2 weeks of therapy in patients receiving fluconazole (15% versus 8% in those receiving amphotericin B).192 CSF cultures were positive for an average of about 42 or 64 days in patients receiving conventional amphotericin B or fluconazole, respectively.192 In a double-blind multicenter trial in patients with AIDS-associated cryptococcal meningitis, the relative efficacy of initial therapy with conventional IV amphotericin B (0.7 mg/kg daily) given with flucytosine (100 mg/kg daily) or placebo for 2 weeks followed by oral fluconazole (800 mg daily for 2 days, then 400 mg daily for 8 weeks) or oral itraconazole (600 mg daily for 3 days, then 400 mg daily for 8 weeks) was evaluated.214 At 2 weeks, CSF cultures were negative in 60% of those who received amphotericin B with concomitant flucytosine compared with 51% of those who received amphotericin B alone.214 The clinical response to oral fluconazole or oral itraconazole for follow-up therapy was similar, but the rate of CSF sterilization at 10 weeks was higher in those who received fluconazole (72%) compared with those who received itraconazole (60%).214
In a study evaluating safety and efficacy of IV amphotericin B lipid complex for the treatment of cryptococcal meningitis in HIV- infected patients, the lipid formulation was at least as effective as conventional IV amphotericin B for initial therapy in these patients and was associated with less hematologic and renal toxicity than the conventional formulation.216 An initial clinical response was obtained in 86% of patients who received amphotericin B lipid complex (5 mg/kg once daily during weeks 1 and 2, and 3 times weekly during weeks 3-6) and in 65% of those who received conventional IV amphotericin (0.7 mg/kg during weeks 1 and 2, and 1.2 mg/kg 3 times weekly during weeks 3-6); all patients received follow-up therapy with oral fluconazole for an additional 12 weeks).216 The overall response rate (resolution of all signs and symptoms and conversion of CNS, blood, and urine cultures to negative) was 38% in those who received amphotericin B lipid complex and 41% in those who received conventional IV amphotericin B.216
Amphotericin B liposomal was compared with conventional amphotericin B for empiric treatment of cryptococcal meningitis in HIV-infected patients in a randomized, double-blind study in 267 patients (study 94-0-013).202 Patients were randomized to receive 11-21 days of IV amphotericin B liposomal (3 or 6 mg/kg daily) or conventional IV amphotericin B (0.7 mg/kg daily); this induction regimen was followed by oral fluconazole (400 mg daily for adults and 200 mg daily in a pediatric patient younger than 13 years of age) given to complete 10 weeks of protocol-directed therapy.202 At 2 weeks, the success rate (defined as CSF culture conversion) for mycologically evaluable patients (defined as all randomized patients who received at least 1 dose of study drug, had positive baseline CSF culture, and at least 1 follow-up culture) was 47.5% in those who received conventional amphotericin B and 58.3 or 48% in those who received amphotericin B liposomal in a dosage of 3 or 6 mg/kg daily, respectively.202 At 10 weeks, the success rate (defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10) in those with documented cryptococcal meningitis at baseline was 53% in those who received conventional amphotericin B and 49% in those who received amphotericin B liposomal in a dosage of 6 mg/kg daily; the success rate was only 37% in those who received the lower dosage of amphotericin B liposomal.202 The survival rate at 10 weeks was similar in those receiving conventional amphotericin B (89%) or the higher dosage of amphotericin B liposomal (90%); the incidence of adverse effects (infusion reactions or adverse cardiovascular or renal effects) was lower in those receiving amphotericin B liposomal than in those receiving conventional amphotericin B.202 In another randomized study in HIV-infected patients with cryptococcal meningitis who received a 3-week course of liposomal amphotericin B (4 mg/kg daily) or a 3-week course of conventional IV amphotericin B (0.7 mg/kg daily) followed by a 7-week course of oral fluconazole (400 mg daily), the median time to negative CSF cultures was 7-14 days in those receiving amphotericin B liposomal compared with more than 21 days in those receiving conventional IV amphotericin B.215
Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis
HIV-infected adults, adolescents, or children who have been adequately treated for cryptococcosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence.427, 440, 441 Oral fluconazole is the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected patients and other individuals who have had documented, adequately treated cryptococcal meningitis;427, 440, 441 some experts suggest that oral itraconazole is an alternative in those who cannot tolerate fluconazole, but the drug may be less effective than fluconazole in preventing relapse of cryptococcosis.427, 440, 441
Although conventional IV amphotericin B has been used or recommended as an alternative for secondary prophylaxis to prevent relapse of cryptococcal meningitis† (e.g., in patients who could not receive azole antifungals),155, 160, 169, 177, 185, 197, 213, 427, 436 it is less effective and is associated with IV catheter-related infections.427 Results of a multicenter study comparing safety and efficacy of conventional IV amphotericin B (1 mg/kg once weekly) or oral fluconazole (200 mg once daily) for prevention of relapse of the disease in HIV-infected patients with negative cryptococcal cultures after initial adequate amphotericin B therapy indicate that the fluconazole regimen is more effective (in terms of preventing relapse of culture-positive meningitis) and better tolerated than the amphotericin B regimen for maintenance therapy in these patients.175, 193
Cryptococcus gattii Infections
Although data are limited, CDC, NIH, and IDSA state that recommendations for the treatment of CNS, pulmonary, or disseminated infections caused by Cryptococcus gattii and recommendations for long-term suppressive or maintenance therapy (secondary prophylaxis) of C. gattii infections are the same as the recommendations for C. neoformans infections.427, 440 IDSA states that single, small cryptococcoma may be treated with oral fluconazole; however, induction therapy with a regimen of conventional IV amphotericin B and flucytosine given for 4-6 weeks, followed by consolidation therapy with fluconazole given for 6-18 months should be considered for very large or multiple cryptococcomas caused by C. gattii .427 Regimens that include amphotericin B (conventional or liposomal formulations), flucytosine, and fluconazole have been effective in a few patients with CNS infections known to be caused by C. gattii .450, 451, 454
For additional information on management of cryptococcosis, the current clinical practice guidelines from IDSA available at [Web]427 and the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440, 441 should be consulted.
IV amphotericin B is used for the treatment of histoplasmosis caused by Histoplasma capsulatum .126, 269, 288, 417, 428, 436, 440, 441
The drugs of choice for the treatment of histoplasmosis, including histoplasmosis in HIV-infected individuals, are IV amphotericin B and oral itraconazole.227, 248, 269, 283, 292, 318, 428, 436, 440, 441 IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection.126, 197, 227, 269, 283, 288, 292, 318, 428, 436, 440, 441 Oral itraconazole generally is used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up therapy in the treatment of severe infections after a response has been obtained with IV amphotericin B.227, 283, 288, 292, 318, 428, 436, 440, 441 Other azole antifungals (fluconazole, posaconazole, voriconazole) are considered second-line alternatives to itraconazole, but can be considered in patients who have less severe disease and cannot tolerate itraconazole.428, 436, 440, 441
For the treatment of moderately severe to severe acute pulmonary histoplasmosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend initial (induction) treatment with IV amphotericin B liposomal and follow-up treatment with oral itraconazole.440 Alternatively, if necessary because of cost or tolerability, IV amphotericin B lipid complex can be used.440
For the treatment of progressive disseminated histoplasmosis in children, IDSA states that conventional IV amphotericin B or an initial regimen of conventional IV amphotericin B and follow-up treatment with oral itraconazole can be used.428 IDSA states that conventional amphotericin B usually is well tolerated in children, but a lipid formulation may be substituted if necessary.428
For the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B liposomal and follow-up treatment with oral itraconazole;441 conventional IV amphotericin B can be used as an alternative to the lipid formulation for initial treatment in these children.441 Although oral itraconazole may be used alone for the treatment of mild to moderate progressive disseminated histoplasmosis in children, including HIV-infected infants and children, this regimen is not recommended for more severe infections.428, 441
For the treatment of meningitis caused by H. capsulatum in HIV-infected adults, adolescents, or children and other individuals, CDC, NIH, and IDSA recommend initial (induction) treatment with IV amphotericin B liposomal and follow-up treatment with oral itraconazole.428, 440, 441 The liposomal formulation of amphotericin B generally is preferred for the treatment of CNS histoplasmosis428, 440, 441 since CSF concentrations may be higher with the liposomal formulation than with some other formulations.428, 441 Conventional IV amphotericin B has been administered alone or in conjunction with intrathecal† administration of the drug for the treatment of meningitis caused by H. capsulatum .126, 211
HIV-infected adults, adolescents, or children who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis.440, 441 Oral itraconazole is the drug of choice for secondary prophylaxis of histoplasmosis in HIV-infected patients.436, 440, 441
For additional information on management of histoplasmosis, the current clinical practice guidelines from IDSA available at [Web]428 and the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440, 441 should be consulted.
IV amphotericin B is used for the treatment of paracoccidioidomycosis† (South American blastomycosis) caused by Paracoccidioides brasiliensis .126, 221, 282, 288, 292, 436
IV amphotericin B is the drug of choice for initial treatment of severe paracoccidioidomycosis.126, 221, 282, 292, 436 Oral itraconazole is the drug of choice for the treatment of less severe or localized paracoccidioidomycosis and for follow-up therapy in more severe infections after initial treatment with IV amphotericin B.126, 288, 292
IV amphotericin B is used in the treatment of penicilliosis† caused by Penicillium marneffei .406, 407, 408, 410, 440
Although oral itraconazole can be used alone for the treatment of mild penicilliosis, an initial regimen of IV amphotericin B is recommended for the treatment of severe or disseminated P. marneffei infections†.406, 407, 410, 440
For the treatment of severe, acute penicilliosis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B liposomal followed by oral itraconazole.440 These experts state that a voriconazole regimen (IV initially, then oral) can be used as an alternative in patients with severe penicilliosis, including those who fail to respond to a regimen of IV amphotericin B followed by itraconazole.440
HIV-infected patients who have been treated for penicilliosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse.407, 408, 440
For additional information on management of penicilliosis, the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web] should be consulted.440
IV amphotericin B is used in the treatment of disseminated, pulmonary, osteoarticular, and meningeal sporotrichosis caused by Sporothrix schenckii .126, 211, 269, 288, 289, 291, 292, 417, 436, 429, 436
IV amphotericin B is the drug of choice for initial treatment of severe, life-threatening sporotrichosis and whenever sporotrichosis is disseminated or has CNS involvement.126, 288, 289, 291, 292, 346, 429, 436 Oral itraconazole is the drug of choice for the treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up treatment of severe infections after a response has been obtained with IV amphotericin B.288, 289, 291, 292, 429, 436
Since sporotrichosis in immunocompromised patients (e.g., HIV-infected individuals) is particularly aggressive and difficult to treat, IV amphotericin B usually is the drug of choice for initial therapy in these patients; however, treatment failures occur.288, 289 IDSA and other clinicians state that a lipid formulation of amphotericin B is preferred for the treatment of sporotrichosis since the lipid formulations generally are associated with fewer adverse effects.429, 436
For additional information on management of sporotrichosis, the current clinical practice guidelines from IDSA available at [Web] should be consulted.429
Amphotericin B has been used for the treatment of infections known or suspected to be caused by Exserohilum rostratum †.476, 477, 487, 489, 490, 491, 492
Exserohilum is a common mold found in soil and on plants, especially grasses, and thrives in warm and humid climates.477, 478, 481, 482E. rostratum is considered an opportunistic human pathogen and rarely has been involved in human infections, including cutaneous and subcutaneous infections or keratitis, typically as the result of skin or eye trauma.478, 480, 481, 482, 487 More invasive infections (e.g., infections involving the sinuses, heart, lungs, or bones) and life-threatening infections also have been reported rarely, usually in immunocompromised individuals.478, 480, 481, 482, 487 In addition, E. rostratum was identified as the predominant pathogen in the 2012-2013 multistate outbreak of fungal meningitis and other fungal infections that occurred in the US in patients who received contaminated preservative-free methylprednisolone acetate injections prepared by a compounding pharmacy.477, 478, 488, 490, 491 Exserohilum infections cannot be transmitted person-to-person.478
Although data are limited and the clinical relevance of in vitro testing remains uncertain,477, 480 in vitro studies indicate that Exserohilum is inhibited by some triazole antifungals (e.g., voriconazole, itraconazole, posaconazole) and amphotericin B.477, 480, 481, 482, 489 Echinocandins (e.g., caspofungin, micafungin) have variable in vitro activity480, 481, 482 and fluconazole has poor in vitro activity against the fungus.481
Exserohilum Infections Related to Contaminated Injections
In September 2012, the CDC and US Food and Drug Administration (FDA) initiated investigations in response to fungal CNS infections (including some fatalities) reported in patients who received epidural injections of contaminated extemporaneously prepared methylprednisolone acetate injections from the New England Compounding Center (NECC).477, 479 Subsequently, there were reports of joint infections and osteomyelitis in some patients who received intra-articular injections of methylprednisolone acetate from NECC, as well as infections possibly related to other NECC products.477, 479
Out of an abundance of caution at that time, the FDA recommended that health-care professionals and consumers not use any product that was produced by NECC, and the company recalled all products that were compounded at and distributed from its facility in Framingham, Massachusetts.479
E. rostratum was one of the predominant pathogen identified in samples taken from patients who received contaminated products from NECC;477, 478, 488, 490, 491Aspergillus also was identified in an index patient and Cladosporium cladosporioides was recovered from several other patients.477 The presence of E. rostratum was confirmed in recalled lots of the contaminated products.477 Other organisms identified in unopened vials from recalled lots of corticosteroid products were A. fumigatus , A. tubingensis , various Bacillus species (including Bacillus subtilis ), Cladosporium , Paenibacillus , and Penicillium .477
CDC data indicate that, as of October 30, 2015, there were a total of 753 cases of fungal infections (including 64 deaths) reported in 20 states that have been linked to specific lots of contaminated methylprednisolone acetate injections.477 Although the majority of initial cases involved fungal meningitis (some with stroke),477, 483, 486, 488, 490, 491, 492 subsequent reports involved localized spinal or paraspinal infections (e.g., epidural abscess).477, 483, 486, 491 More than 6 months after the outbreak related to contaminated products was first identified, CDC continued to receive reports of patients presenting with localized spinal and paraspinal infections (e.g., epidural abscess, phlegmon, discitis, vertebral osteomyelitis, arachnoiditis, or other complications at or near the site of injection).477, 483, 486 These localized infections occurred in patients with or without a diagnosis of fungal meningitis.483 In some patients being treated for fungal meningitis who had no previous evidence of localized infections, such infections were found at the site of injection using magnetic resonance imaging (MRI) studies.483 Some cases occurred in patients without any previous evidence of infection or in those with persistent, worsening, or new symptoms.483
Patients with meningitis generally presented 1-4 weeks or longer after receiving contaminated methylprednisolone acetate injections; the greatest risk for development of fungal meningitis appeared to be during the first 6 weeks after an epidural or paraspinal injection.489 Data from one group of patients indicated that the median time from the last injection with contaminated product to the date of the first MRI finding indicative of infection was 50 days (range 12-121 days) for all patients with a spinal or paraspinal infection, and the median time from the first positive lumbar puncture finding to the first positive MRI finding was 21 days for those with meningitis and spinal or paraspinal infections.483
Clinicians treating fungal infections in patients who received contaminated methylprednisolone acetate injections from NECC should consult an infectious disease expert to assist with diagnosis, management, and follow-up, which may be complex and prolonged.477 A clinical consultant network for clinicians can be reached by calling CDC at 800-232-4636.477
Because of evidence of latent disease, CDC cautions clinicians to continue to remain vigilant for the possibility of infections in patients who received injections of NECC products and to consider such infections in the differential diagnosis when evaluating symptomatic patients who received such products.477, 483, 486 CDC recommends routine laboratory and microbiologic tests, including bacterial and fungal cultures, as necessary;477 MRI evaluations should be considered if clinically warranted.483, 486
CDC released interim treatment guidance documents containing recommendations for empiric antifungal treatment of CNS and parameningeal infections and osteoarticular infections associated with the contaminated methylprednisolone acetate products.477 These recommendations were based on evidence that E. rostratum was the predominant pathogen in the outbreak and consultation with experts.477
For the treatment of CNS infections (including meningitis, stroke, and arachnoiditis) and/or parameningeal infections (epidural or paraspinal abscess, discitis or osteomyelitis, and sacroiliac infection) in adults who received contaminated corticosteroid injections, CDC recommends voriconazole.477 Use of IV amphotericin B liposomal in addition to voriconazole should be strongly considered in patients who present with severe disease and in patients who do not improve or experience clinical deterioration or manifest new sites of disease activity while receiving voriconazole monotherapy.477 IV amphotericin B liposomal also is recommended as an alternative in patients who unable to tolerate voriconazole.477 IV amphotericin B liposomal is preferred over other lipid formulations of amphotericin B because of better CNS penetration.477 Because of limited data and associated toxicities, routine use of intrathecal conventional amphotericin B is not recommended in these patients.477
For the treatment of osteoarticular infections (discitis, vertebral osteomyelitis, and epidural abscess or osteoarticular infections not involving the spine) in adults who received intra-articular injections of contaminated corticosteroid products, CDC recommends voriconazole.477 Use of a lipid formulation of IV amphotericin B in addition to IV voriconazole should be considered in patients with severe osteoarticular infection and/or clinical instability.477 A lipid formulation of IV amphotericin B, posaconazole, or itraconazole are recommended as alternatives in patients who cannot tolerate voriconazole.477 Expert consultation is advised when making decisions regarding alternative regimens.477
Adequate duration of antifungal treatment for infections associated with the contaminated corticosteroid injections is unknown, but prolonged therapy is required.477 (See Exserohilum Infections under Dosage: Amphotericin B Liposomal (AmBisome®), in Dosage and Administration.) In addition, close follow-up monitoring after completion of treatment is essential in all patients to detect potential relapse.477
The CDC website at [Web] should be consulted for the most recent information regarding the contaminated NECC products and associated infections, including specific information regarding diagnosis and treatment of these infections.477
Amphotericin B has been used for the treatment of serious fungal infections caused by Fusarium ,57 and a lipid formulation of amphotericin B is recommended as a drug of choice for the treatment of these fungal infections.436
For the treatment of fusariosis, the most appropriate antifungal should be selected based on in vitro susceptibility testing.57 Amphotericin B may be preferred for infections caused by F. solani or F. verticillioides ;57 either voriconazole or amphotericin B are recommended for infections caused by other Fusarium .57 Some clinicians suggest that concomitant use of amphotericin B and voriconazole should be considered in patients with severe infections or immunosuppression.436
IV amphotericin B is used for the treatment of zygomycosis, including mucormycosis, caused by susceptible species of Lichtheimia (formerly Absidia ), Mucor , or Rhizopus and for the treatment of infections caused by susceptible species of Conidiobolus or Basidiobolus .126, 269, 324, 417 IV amphotericin B generally has been considered the drug of choice for these infections.269, 324 However, in several cases of GI basidiobolomycosis caused by Basidiobolus ranarum , the response to amphotericin B (e.g., amphotericin B liposomal) was poor.413, 414, 415, 416 Most cases of GI basidiobolomycosis reported to date have been successfully treated with oral itraconazole after partial surgical resection of the GI tract.413, 415, 416
While most experience to date in treating zygomycosis has involved use of conventional IV amphotericin B, lipid formulations (amphotericin B lipid complex,366, 368, 396 amphotericin B liposomal126, 231, 232, 369, 384 ) also have been used to treat these infections, including rhinocerebral and pulmonary mucormycosis in some patients who did not respond to conventional amphotericin B or had to discontinue conventional amphotericin B because of adverse renal effects.
Empiric Therapy in Febrile Neutropenic Patients
Conventional IV amphotericin B†, 126, 248, 252, 273, 277, 290, 374, 376, 422, 452 amphotericin B lipid complex†, 422, 452 and amphotericin B liposomal195, 202, 252, 372, 374, 422, 452 are used for empiric therapy of presumed fungal infections in febrile, neutropenic patients who have not responded to empiric treatment with broad-spectrum antibacterial agents.
Because systemic fungal infections (e.g., Candida , Aspergillus ) are present in up to one-third of neutropenic patients who remain febrile after a 7-day course of empiric broad-spectrum anti-infective therapy, IDSA and other clinicians recommend that consideration be given to administering empiric antifungal therapy (with or without a change in the antibacterial regimen) to neutropenic patients who have persistent or recurrent fever after 4-7 days of antibacterial therapy.279, 290, 422 Conventional IV amphotericin B historically has been considered the drug of choice for empiric antifungal treatment in such patients; however, lipid formulations of amphotericin B or other antifungals (e.g., caspofungin, voriconazole) also have been used.422
Empiric therapy with conventional IV amphotericin B has been used in patients undergoing bone marrow transplantation (BMT) who have persistent fever despite 3-7 days of broad-spectrum antibacterial therapy,277, 290, 346 and such therapy was included in the Eastern Cooperative Oncology Group (ECOG) guidelines for the management of autologous and allogeneic BMT patients.277 If conventional IV amphotericin B is used for empiric antifungal therapy in febrile, neutropenic allogeneic BMT patients who are receiving cyclosporine, the potential for additive nephrotoxic effects should be considered before initiating such therapy.277, 346 (See Drug Interactions: Nephrotoxic Drugs.)
Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric anti-infective regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.422 In addition, consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients is advised.422
The relative efficacy of conventional IV amphotericin B and amphotericin B liposomal for empiric therapy in febrile, neutropenic patients has been evaluated in a randomized, double-blind, multicenter study that involved 687 adult and pediatric cancer patients 2-80 years of age who were febrile despite having received at least 5 days of empiric therapy with broad spectrum anti-infectives.252 The overall therapeutic success rate (defined as resolution of fever during the neutropenic period, successful treatment of any baseline fungal infections, absence of emergent fungal infections during therapy or within 7 days after completion of study drug, patient survival for at least 7 days after empiric therapy, and use of study drug without premature discontinuance because of toxicity or lack of efficacy) was 50.1% for amphotericin B liposomal and 49.4% for conventional amphotericin B.252 Emergent fungal infections were mycologically confirmed in 3.2% of those receiving amphotericin B liposomal and in 7.8% of those receiving conventional amphotericin B.252 While the overall success rate was similar in both groups, the group receiving amphotericin B liposomal had a lower incidence of documented emergent fungal infections and also had a lower incidence of acute infusion reactions and adverse renal effects than those receiving conventional amphotericin B.252 Amphotericin B liposomal also appeared to be as effective as conventional IV amphotericin B for empiric therapy of presumed fungal infections in several randomized, open label, multicenter studies that involved febrile neutropenic adults and pediatric patients undergoing chemotherapy for hematologic malignancy or as part of bone marrow transplantation.202, 374, 375
Prevention of Fungal Infections in Transplant Recipients, Cancer Patients, or Other Patients at High Risk
Conventional IV amphotericin B†126, 211, 249, 277, 286, 287, 375, 422 and amphotericin B liposomal†274, 358, 371, 372 have been used prophylactically in an attempt to reduce the incidence of fungal infections (e.g., aspergillosis, candidiasis) in neutropenic cancer patients† or patients undergoing BMT† or solid organ transplantation†. IV amphotericin B also has been used to prevent Candida infections in patients undergoing urologic procedures†.425
Use of primary antifungal prophylaxis in cancer patients undergoing myelosuppressive therapy or patients undergoing BMT or solid organ transplantation has been controversial, particularly since such prophylaxis may predispose the patient to colonization with resistant fungi and/or result in the emergence of highly resistant organisms.277, 278, 287, 298, 422 Some clinicians discourage primary prophylaxis with antifungals except in certain carefully selected high-risk patients in whom potential benefits are expected to justify possible risks (e.g., patients in institutions that have a high incidence of fungal infections or circumstances where the frequency of systemic Candida infections is high).422 When primary antifungal prophylaxis is warranted in cancer patients or BMT or solid organ transplant recipients, IDSA and other clinicians generally prefer use of an oral azole antifungal.277, 422, 423
For postoperative antifungal prophylaxis in recipients of solid organ transplants† at high risk for invasive candidiasis (i.e., liver, pancreas, or small bowel transplant recipients), IDSA recommends fluconazole or IV amphotericin B liposomal.425 IDSA states that the risk of invasive candidiasis in recipients of other solid organ transplants (e.g., kidney, heart) appears to be too low to warrant routine antifungal prophylaxis.425
For high-risk patients undergoing urologic procedures†, IDSA states that fluconazole or conventional IV amphotericin B can be used for several days before and after the procedure to prevent Candida infections.425
Conventional amphotericin B,211, 243, 261, 276, 286, 287, 460, 463 amphotericin B lipid complex,460, 461 and amphotericin B liposomal460, 462, 464 have been administered by nasal instillation† or nebulization† in an attempt to prevent aspergillosis in immunocompromised patients, including solid organ transplant recipients† (e.g., lung transplant recipients) and neutropenic chemotherapy patients†.
For additional information on prevention of fungal infections in neutropenic patients, the current clinical practice guidelines from IDSA available at [Web] should be consulted.422, 423, 425
When used for antifungal prophylaxis in cancer patients or patients undergoing BMT, conventional amphotericin B has been administered in usual IV dosages or, more frequently, as low-dose IV therapy (i.e., 0.1-0.25 mg/kg daily).249, 277, 287, 375 Safety and efficacy of low-dose conventional IV amphotericin B for prophylaxis in neutropenic patients undergoing BMT have been evaluated in a prospective, randomized, placebo-controlled study.375 Patients undergoing autologous BMT were randomized to receive low-dose conventional IV amphotericin B (0.1 mg/kg daily) or placebo; any patient with persistent neutropenia and fever despite prophylaxis with low-dose amphotericin B and broad-spectrum antibacterial agent therapy was withdrawn from the study and given empiric therapy with a higher dosage of conventional IV amphotericin B (0.6 mg/kg daily).375 During the study, 8.8% of those receiving low-dose amphotericin B and 14.3% of those receiving placebo had mycologically confirmed fungal infections ( Candida , Aspergillus ); 6-week mortality was higher in those receiving placebo (11 deaths in those receiving placebo compared with 3 deaths in those receiving amphotericin B), but this difference did not appear to be related to fungal infections.375 Because there is some evidence that administration of low-dose conventional IV amphotericin B therapy to BMT patients can decrease the incidence posttransplant fungal infections,249, 277, 287 some clinicians suggest that secondary prophylaxis with low-dose conventional IV amphotericin B be considered for all transplant patients with a history of documented invasive aspergillosis since these patients are at risk for reactivation of the disease.126 However, there is evidence that prophylaxis with low-dose conventional IV amphotericin B may be ineffective in preventing posttransplant fungal infections in liver transplant patients since candidemia and invasive aspergillosis have been reported in liver transplant recipients receiving prophylaxis with conventional IV amphotericin B (0.5 mg/kg daily).370
Data are accumulating regarding use of amphotericin B liposomal for antifungal prophylaxis in neutropenic cancer patients or BMT or transplant patients.274, 358, 371, 372 Safety and efficacy of amphotericin B liposomal (2 mg/kg 3 times weekly) for antifungal prophylaxis in patients undergoing chemotherapy or BMT have been evaluated in a double-blind, placebo-controlled study.358 Systemic or superficial fungal infections were suspected in 42 or 46% of those receiving amphotericin B liposomal or placebo, respectively; however, while there were mycologically confirmed fungal infections in 3.4% of those receiving placebo, there were none in those receiving amphotericin B liposomal prophylaxis.358 There was fungal colonization of at least one site (fungal pathogen isolated but not associated with clinical or other evidence of disease) in 20 or 40% of those receiving amphotericin B liposomal or placebo, respectively.358 The mortality rate was similar in both groups (14-15%).358 In a limited placebo-controlled study in liver transplant recipients, there was no evidence of posttransplant fungal infections in those who received 5 days of amphotericin B liposomal prophylaxis (1 mg/kg daily initiated at the time of transplantation); 16% of patients who received placebo developed C. albicans infections posttransplant.274 However, in another study in liver transplant recipients who received amphotericin B liposomal for antifungal prophylaxis (1 mg/kg daily initiated after transplant and continued for 7 days), the regimen appeared to effectively prevent Candida infections but several patients developed posttransplant Aspergillus infections that were fatal.371
Conventional IV amphotericin B,102, 103, 104, 105, 106, 107, 108, 109, 115, 116, 117, 126, 269, 271, 381, 417, 430, 440, 442, 443 amphotericin B lipid complex†, 246, 381, 430, 440, 443 and amphotericin B liposomal have been used for the treatment of leishmaniasis.202, 380, 381, 430, 440, 442, 443, 444
Leishmaniasis is caused by more than 15-20 different species of Leishmania that are transmitted to humans by the bite of infected sand flies.108, 430, 493, 494, 495, 499 Leishmania also can be transmitted via blood (e.g., blood transfusions, needles shared by IV drug abusers) and transmitted perinatally from mother to infant.108, 430, 493, 499 In the Eastern Hemisphere, leishmaniasis is found most frequently in parts of Asia, the Middle East, Africa, and southern Europe;499 in the Western Hemisphere, the disease is found most frequently in Mexico and Central and South America and has been reported occasionally in Texas and Oklahoma.499 Leishmaniasis has been reported in short-term travelers to endemic areas and in immigrants and expatriates from such areas,108, 494, 495, 499 and also has been reported in US military personnel and contract workers serving or working in endemic areas (e.g., Iraq, Afghanistan).108, 499
Leishmania infection in humans may cause uncomplicated cutaneous leishmaniasis, diffuse cutaneous leishmaniasis, mucosal leishmaniasis, visceral leishmaniasis, or post-kala-azar leishmaniasis and may be termed Old World (Eastern Hemisphere) or New World (Western Hemisphere).108, 430, 493, 494, 495, 496, 497, 499 The specific form of leishmaniasis and disease severity depend on the Leishmania species involved, geographic area of origin, location of sand fly bite, and patient factors (e.g., nutritional and immune status).108, 430, 493, 494, 495, 496, 497 Treatment of leishmaniasis (e.g., drug, dosage, duration of treatment) must be individualized based on the region where the disease was acquired, likely infecting species, drug susceptibilities reported in the area of origin, form of the disease, and patient factors (e.g., age, pregnancy, immune status).108, 430, 493, 494, 496, 497, 499 No single treatment approach is appropriate for all possible clinical presentations.108, 430 Consultation with clinicians experienced in management of leishmaniasis is recommended.430, 493, 499
For assistance with diagnosis or treatment of leishmaniasis in the US, clinicians can contact CDC Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after business hours and on weekends and holidays.500 CDC Drug Service should be contacted at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in the US.500
Cutaneous and Mucocutaneous Leishmaniasis
Conventional IV amphotericin B is used for the treatment of American cutaneous leishmaniasis, including infections caused by Leishmania braziliensis or L. mexicana , and for mucocutaneous leishmaniasis, including infections caused by L. braziliensis .102, 103, 104, 105, 106, 107, 108, 109, 126, 269, 271, 381, 417, 430, 442, 443
Although some cases of cutaneous leishmaniasis (usually Old World) may subside or resolve spontaneously over months or years, treatment of cutaneous leishmaniasis is recommended if there are multiple or large lesions, lesions are disabling or disfiguring or fail to heal within 6 months, the patient is immunocompromised, or dissemination to mucosal leishmaniasis is likely (e.g., New World disease caused by L. braziliensis or L. panamensis ).430, 493, 494, 495, 496 Local treatment (e.g., topical paromomycin [not commercially available in the US], thermotherapy, intralesional pentavalent antimonials [not commercially available in the US], cryotherapy) may be appropriate in selected cases.108, 430, 440, 442, 495, 496 For systemic treatment of cutaneous leishmaniasis, pentavalent antimonials (i.e., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US, but may be available from CDC]) usually are used.440, 442, 493, 494, 495, 496 Other treatment options for cutaneous leishmaniasis include amphotericin B, miltefosine, pentamidine, and ketoconazole,108, 430, 440, 442, 493, 495, 496 especially when antimonials cannot be used because of tolerance or resistance.494, 495
Data are limited regarding use of lipid formulations of amphotericin B in the treatment of cutaneous leishmaniasis, but amphotericin B lipid complex† and amphotericin B liposomal† have been used in a limited number of patients for the treatment of cutaneous leishmaniasis.380, 381 At least one patient with cutaneous leishmaniasis unresponsive to meglumine antimonate therapy was successfully treated with a 2-week regimen of IV amphotericin B liposomal (1.5 mg/kg daily) followed by a 4-week regimen of conventional IV amphotericin B (3 mg/kg once weekly).380
IV amphotericin B liposomal is used in the treatment of visceral leishmaniasis (also known as kala-azar)187, 202, 247, 253, 382, 383, 404, 442, 443, 444 and is recommended by some clinicians as a drug of choice, especially for immunocompromised patients.430, 442 Conventional IV amphotericin B†108, 115, 116, 117, 126, 430, 442, 443 and amphotericin B lipid complex†246, 430, 443 also have been used for the treatment of visceral leishmaniasis.
Pentavalent antimonials (i.e., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US, but may available from CDC]) have historically been considered the drugs of first choice for initial treatment of visceral leishmaniasis;108, 493, 497, 498 however, drug resistance and treatment failures have become a major concern in some areas (e.g., India, Nepal).497, 498 Other treatment options for visceral leishmaniasis include amphotericin B, miltefosine, or paromomycin.440, 493, 497, 498 Relapse of visceral leishmaniasis is common in immunocompromised patients (e.g., HIV-infected patients), regardless of the treatment regimen.381, 382, 440, 497
In a group of patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed L. infantum , amphotericin B liposomal was associated with an overall success rate (clearance with no relapse during a follow-up period of 6 months or longer) of 96.5% in immunocompetent patients.202 In patients who were immunocompromised, amphotericin B liposomal therapy was able to initially clear the infection in 94.7% of patients; however, the overall success rate was only 11.8% and there was a high rate of relapse in these patients.202 The manufacturer states that data are inconclusive regarding efficacy of IV amphotericin B liposomal for the treatment of infections caused by L. donovani or L. chagasi .202
Leishmaniasis in HIV-infected Individuals
Based on data from individuals who are not infected with HIV, CDC, NIH, and IDSA state that the drugs of choice for the treatment of cutaneous leishmaniasis in HIV-infected adults or adolescents are amphotericin B liposomal† or sodium stibogluconate (not commercially available in the US, but may be available from CDC).440 Possible alternatives are miltefosine, topical paromomycin (not commercially available in the US), intralesional pentavalent antimony (not commercially available in the US), or local heat therapy.440
For the treatment of visceral leishmaniasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend amphotericin B liposomal as the drug of choice since the drug appears to have similar efficacy but is better tolerated in these patients than conventional amphotericin B or pentavalent antimony compounds.440 Alternatives for the treatment of visceral leishmaniasis in HIV-infected adults and adolescents include amphotericin B lipid complex†, conventional amphotericin B†, sodium stibogluconate (not commercially available in the US, but may be available from CDC), or miltefosine.440
CDC, NIH, and IDSA recommend long-term suppressive or maintenance therapy (secondary prophylaxis)† to decrease the risk of relapse in HIV-infected adults and adolescents who have been treated for visceral leishmaniasis and have CD4+ T-cell counts less than 200/mm3.440 Although data are limited, these experts state that long-term suppressive or maintenance therapy (secondary prophylaxis) also should be offered to those who have been adequately treated for cutaneous leishmaniasis but are immunocompromised and have had multiple relapses.440 If secondary prophylaxis against leishmaniasis is indicated in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend use of amphotericin B liposomal† or amphotericin B lipid complex†;440 the alternative is sodium stibogluconate (not commercially available in the US, but may be available from CDC).440 The manufacturer of amphotericin B liposomal states that, while the drug may have a role for long-term suppressive therapy to prevent relapse of visceral leishmaniasis in HIV-infected individuals, the efficacy and safety of repeated courses of amphotericin B liposomal or maintenance therapy with the drug in immunocompromised individuals have not been evaluated to date.202
If secondary prophylaxis against leishmaniasis is initiated in HIV-infected adults and adolescents, some experts state that consideration can be given to discontinuing such prophylaxis if CD4+ T-cell counts remain greater than 200-350/mm3 for at least 3-6 months in response to antiretroviral therapy.440 However, others suggest that such prophylaxis should be continued indefinitely.440
Primary Amebic Meningoencephalitis
Conventional IV amphotericin B has been used for the treatment of primary amebic meningoencephalitis caused by Naegleria fowleri †, a free-living ameba.119, 126, 292, 442, 511, 512, 513
CNS infections caused by free-living ameba have a high mortality rate, and only a very limited number of cases have been successfully treated.292, 511, 512, 513 Early diagnosis and aggressive treatment of these infections may increase the chance of survival.292, 511, 512, 513 Although data are limited, most reported cases of N. fowleri have been treated empirically with multiple-drug regimens.511, 512, 513 Treatment regimens used or recommended for the treatment of N. fowleri infections include several anti-infectives (e.g., amphotericin B, azole antifungals [fluconazole], flucytosine, macrolides [azithromycin, clarithromycin], miltefosine, rifampin) and other therapies (e.g., dexamethasone, phenytoin, therapeutic hypothermia).292, 442, 511, 512, 513
Based on multiple-drug regimens used to date in documented survivors, CDC recommends an anti-infective regimen that includes conventional amphotericin B (administered IV and intrathecally†), azithromycin, fluconazole, miltefosine, and rifampin for treatment of primary amebic meningoencephalitis caused by N. fowleri .511 Because there is some evidence that amphotericin B liposomal may be less effective than conventional amphotericin B in mice for the treatment of primary amebic meningoencephalitis caused by N. fowleri , the conventional formulation is preferred if amphotericin B is used for the treatment of primary amebic meningoencephalitis.442, 511
For assistance with diagnosis or treatment of patients with suspected free-living ameba infections, clinicians should contact the CDC Emergency Operation Center at 770-488-7100.511
Reconstitution and Administration
Conventional amphotericin B is administered by IV infusion.345, 417 The drug also has been given intra-articularly†, 456 intrapleurally†, 475 intrathecally†, 126, 211, 426, 440, 441, 455, 457 by nasal instillation† or nebulization†, 211, 243, 261, 276, 286, 287, 460, 463 and by bladder irrigation†.126, 211, 232, 251, 260, 262, 292, 293, 425, 432, 433, 434, 435, 466, 467, 468, 469, 470, 471, 472, 473, 474
Commercially available conventional amphotericin B for IV infusion must be reconstituted and diluted prior to administration.417 The drug must not be prepared with any diluents other than those specified below since precipitation may occur. 417 Strict aseptic technique must be observed. 417
Conventional amphotericin B should be reconstituted to a concentration of 5 mg/mL by rapidly adding 10 mL of sterile water for injection without bacteriostatic agent to a vial labeled as containing 50 mg of drug.417 The sterile water diluent should be added to the vial using a sterile syringe (minimum needle size of 20 gauge) and the vial should be immediately shaken until the colloidal dispersion is clear.417 For IV infusion, the colloidal dispersion is further diluted, usually to a concentration of 0.1 mg/mL, with 500 mL of 5% dextrose injection (the dextrose injection must have a pH exceeding 4.2).417 Although the pH of commercially available 5% dextrose injection usually exceeds 4.2, the pH of each container of 5% dextrose injection should be determined and, if the pH is low, it may be adjusted with 1 or 2 mL of sterile buffer solution in accordance with the instructions provided by the manufacturers of conventional amphotericin B.417
Reconstituted conventional amphotericin B or dilutions of the drug must not be used if precipitation or foreign matter is evident.417 An inline membrane filter may be used during IV administration of conventional amphotericin B; however, the mean pore diameter of the filter should not be less than 1 µm to ensure passage of the amphotericin B colloidal dispersion.417 IV infusions of conventional amphotericin B containing a drug concentration of 0.1 mg/mL or less should be used promptly after preparation.417
IV infusions of conventional amphotericin B are given slowly over a period of approximately 2-6 hours, depending on the dose being administered.345, 360, 417
Although IV infusions of conventional amphotericin B have been well tolerated in some patients when given over 1-2 hours,345, 346, 359, 360, 361, 362 the manufacturers and many clinicians state that rapid IV infusions of conventional amphotericin B should be avoided since potentially serious adverse effects (e.g., hypotension, hypokalemia, arrhythmias, shock) may occur.264, 359, 360, 362, 417
Amphotericin B Lipid Complex (Abelcet®)
Amphotericin B lipid complex is administered by IV infusion.201 The drug also has been administered by nasal inhalation† or nebulization†.460, 461
Commercially available amphotericin B lipid complex injectable suspension concentrate must be diluted prior to IV infusion. 201 The injectable suspension concentrate must be diluted in 5% dextrose injection to a concentration of 1 mg/mL; a concentration of 2 mg/mL may be appropriate for pediatric patients and patients with cardiovascular disease.201 Solutions containing sodium chloride or bacteriostatic agents should not be used to dilute amphotericin B lipid complex, and the drug should not be mixed with other drugs or with electrolytes.201
To prepare IV infusions of amphotericin B lipid complex, vials labeled as containing 5 mg/mL should be shaken gently until there is no evidence of yellow sediment on the bottom of the vial.201 The appropriate dose should be withdrawn from the required number of vials into one or more sterile 20-mL syringes using an 18-gauge needle.201 The needle should be removed from the filled syringe and replaced with the 5-µm filter needle provided by the manufacturer; each filter needle may be used to filter the contents of up to four 100-mg vials of the drug.201 The filter needle should then be inserted into an IV container of 5% dextrose injection and the contents of the syringe injected into the container.201
Prior to initiation of the infusion, the IV container of diluted drug should be shaken until the contents are thoroughly mixed; the infusion container should then be shaken every 2 hours if the infusion time exceeds 2 hours.201 Amphotericin B lipid complex diluted in 5% dextrose injection should not be used if there is any evidence of foreign matter in the solution.201
The drug should be administered using a separate infusion line; if an existing IV line is used, it should be flushed with 5% dextrose injection before amphotericin B lipid complex is infused.201 An inline membrane filter should not be used during administration of amphotericin B lipid complex.201
IV infusions of diluted amphotericin B lipid complex should be infused at a rate of 2.5 mg/kg per hour.201
Amphotericin B Liposomal (AmBisome®)
Amphotericin B liposomal is administered by IV infusion.202 The drug also has been administered by nasal inhalation† or nebulization†.460, 462, 464
Amphotericin B liposomal must be reconstituted by adding 12 mL of sterile water for injection to a vial labeled as containing 50 mg of amphotericin B to provide a solution containing 4 mg/mL.202 Other diluents (e.g., diluents containing sodium chloride or a bacteriostatic agent) should not be used to reconstitute amphotericin B liposomal, and reconstituted solutions should not be admixed with other drugs.202 The appropriate amount of reconstituted amphotericin B liposomal should be withdrawn into a sterile syringe.202 The 5-µm sterile, disposable filter provided by the manufacturer should then be attached to the syringe and the syringe contents injected through the filter into the appropriate volume of 5% dextrose injection to provide a final concentration of 1-2 mg/mL.202 Lower concentrations (0.2-0.5 mg/mL) may be appropriate for infants and small children.202
Amphotericin B liposomal may be infused through an in-line membrane filter provided the mean pore diameter of the filter is not less than 1 µm.202 The drug may be administered through an existing IV line; however, the line must be flushed with 5% dextrose injection prior to infusion of the antifungal.202 If this is not feasible, amphotericin B liposomal must be administered through a separate line.202
IV infusions of amphotericin B liposomal should be given over a period of approximately 2 hours using a controlled infusion device.202 If the infusion is well tolerated, infusion time may be reduced to approximately 1 hour; however, the duration of infusion should be increased in patients who experience discomfort during infusion.202
Dosage of amphotericin B varies depending on whether the drug is administered as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B lipid complex, or amphotericin B liposomal. 201, 202, 417Dosage recommendations for the specific formulation being administered should be followed. 201, 202, 417
Dosage of conventional amphotericin B must be individualized and adjusted according to the patient's tolerance and clinical status (e.g., site and severity of infection, etiologic agent, cardiopulmonary and renal function status).417
The manufacturers caution that under no circumstances should the total daily dose of conventional amphotericin B exceed 1.5 mg/kg .417 Overdosage can result in potentially fatal cardiac or cardiopulmonary arrest.417 (See Acute Toxicity.)
Prior to initiation of conventional IV amphotericin B therapy, a single test dose of the drug (1 mg in 20 mL of 5% dextrose injection) should be administered IV over 20-30 minutes and the patient carefully monitored (i.e., pulse and respiration rate, temperature, blood pressure) every 30 minutes for 2-4 hours.417 In patients with good cardiorenal function who tolerate the test dose, the manufacturers recommend that therapy be initiated with a daily dosage of 0.25 mg/kg (0.3 mg/kg in those with severe or rapidly progressing fungal infections) given as a single daily dose.417 In patients with impaired cardiorenal function and in patients who have severe reactions to the test dose, the manufacturers recommend that therapy be initiated with a smaller daily dosage (i.e., 5-10 mg).417 Depending on the patient's cardiorenal status, dosage may gradually be increased by 5-10 mg daily to a final daily dosage of 0.5-0.7 mg/kg.417
The manufacturers state that the optimal dosage of conventional amphotericin B is unknown and data are insufficient to define total dosage and duration of treatment for eradication of specific fungal infections.417 Dosage up to 1 mg/kg daily or up to 1.5 mg/kg when given on alternate days is recommended by the manufacturers.417 When converting a daily IV dosage schedule to alternate-day therapy, dosage must be increased gradually every other day until it is twice the previous daily dosage.
If conventional amphotericin B therapy is discontinued for longer than 1 week, the manufacturers recommend that administration of the drug be resumed at the usual initial dosage of 0.25 mg/kg daily, and dosage should again be gradually increased.417
For the treatment of invasive aspergillosis, conventional IV amphotericin B has been administered in a dosage of 0.5-1.5 mg/kg daily.211, 417, 236, 243, 248, 268, 279, 346 The duration of treatment is based on the degree and duration of immunosuppression, disease site, and clinical response.423, 440 The Infectious Diseases Society of America (IDSA) recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6-12 weeks.423
If conventional IV amphotericin B is used as an alternative for the treatment of invasive aspergillosis in HIV-infected adults or adolescents, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend a dosage of 1 mg/kg daily.440 The optimal duration of therapy in these patients has not been established, but antifungal therapy should be continued at least until CD4+ T-cell counts exceed 200/mm3 and there is evidence of resolution of aspergillosis.440
For the treatment of blastomycosis, the usual dosage of conventional IV amphotericin B is 0.7-1 mg/kg once daily.424
For the treatment of moderately severe to severe pulmonary or disseminated extrapulmonary blastomycosis (without CNS involvement), IDSA recommends that adults (including immunocompromised individuals) receive initial therapy with conventional IV amphotericin B in a dosage of 0.7-1 mg/kg once daily for 1-2 weeks or until improvement occurs, followed by oral itraconazole therapy.424 The total treatment duration should be 6-12 months for pulmonary blastomycosis or at least 12 months for disseminated extrapulmonary blastomycosis or for immunocompromised individuals.424
For the treatment of severe blastomycosis in children, IDSA recommends initial therapy with conventional IV amphotericin B in a dosage of 0.7-1 mg/kg once daily, followed by oral itraconazole therapy for a total treatment duration of 12 months.424
For the treatment of disseminated or invasive Candida infections, the usual dosage of conventional IV amphotericin B in adults or pediatric patients is 0.5-1 mg/kg daily.223, 254, 292, 307, 436 The recommended duration of antifungal treatment for candidemia (without persistent fungemia or metastatic complications) is 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.425
For the treatment of neonatal candidiasis, including CNS infections, IDSA recommends that conventional IV amphotericin B be given in a dosage of 1 mg/kg daily.425 The recommended duration of antifungal treatment for uncomplicated neonatal candidiasis is 2 weeks after documented clearance of Candida from the bloodstream and resolution of candidemia symptoms.425 If neonatal candidiasis involves the CNS, antifungal treatment should be continued until resolution of all signs, symptoms, and CSF and radiologic abnormalities (if present).425
If conventional IV amphotericin B is used as an alternative for the treatment of esophageal candidiasis† in adults who cannot tolerate oral therapy or have fluconazole-refractory infections, IDSA recommends a dosage of 0.3-0.7 mg/kg daily for 21 days.425 If conventional IV amphotericin B is used as an alternative for the treatment of esophageal candidiasis†, including fluconazole-refractory infections, in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 0.6 mg/kg daily for 14-21 days.440 If used as an alternative for the treatment of esophageal candidiasis† in HIV-infected infants and children, CDC, NIH, and IDSA recommend that conventional IV amphotericin B be given in a dosage of 0.3-0.7 mg/kg once daily for at least 3 weeks and for at least 2 weeks after resolution of symptoms.441
If conventional IV amphotericin B is used as an alternative for the treatment of severe or refractory oropharyngeal candidiasis† (e.g., caused by fluconazole-resistant strains), IDSA recommends a dosage of 0.3 mg/kg daily.425
For the treatment of symptomatic cystitis caused by fluconazole-resistant Candida (e.g., C. glabrata , C. krusei ), IDSA recommends that conventional IV amphotericin B be given in a dosage of 0.3-0.6 mg/kg daily for 1-7 days.425 For the treatment of pyelonephritis caused by fluconazole-resistant Candida , conventional IV amphotericin B should be given in a dosage of 0.3-0.6 mg/kg daily (with or without oral flucytosine) for 1-7 days.425 The same regimen can be used for the treatment of urinary tract infections associated with fungus balls.425
For the treatment of candiduria, conventional amphotericin B has been administered by bladder irrigation†.126, 211, 232, 251, 260, 262, 292, 293, 425, 432, 433, 434, 435, 466, 467, 468, 469, 470, 471, 472, 473, 474 The optimal concentration of conventional amphotericin B for bladder irrigation†, method of irrigation (continuous or intermittent), and duration of therapy have not been established.251, 260, 262, 466, 468, 469, 470, 471 For use as a continuous bladder irrigant†, conventional amphotericin B for injection has been reconstituted with sterile water for injection to a concentration of 50 mg/L and administered at a rate of 42 mL/hour for up to 15 days.260, 432, 433, 467, 468, 470 Some clinicians suggest that lower concentrations (5-10 mg/L) may be acceptable based on usual susceptibilities of Candida and potential toxicity.468, 471 IDSA states that a 5-day regimen of conventional amphotericin B administered by bladder irrigation† as a 50-mg/L solution in sterile water may be useful for treatment of symptomatic cystitis caused by fluconazole-resistant Candida (e.g., C. glabrata , C. krusei ).425 For treatment of Candida urinary tract infections associated with fungus balls, IDSA states that 25-50 mg of conventional amphotericin B in 200-500 mL of sterile water administered by irrigation† through nephrostomy tubes (if present) is recommended.425
For the treatment of coccidioidomycosis, the usual dosage of conventional IV amphotericin B is 0.5-1.5 mg/kg daily.211, 245, 436 For the treatment of severe and/or rapidly progressive acute pulmonary or disseminated coccidioidomycosis (nonmeningeal), IV amphotericin B usually is used initially with follow-up therapy with oral fluconazole or oral itraconazole.426 The total duration of treatment usually is at least 1 year.426
For the treatment of diffuse pulmonary or extrathoracic disseminated coccidioidomycosis (nonmeningeal) in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend initial therapy with conventional IV amphotericin B given in a dosage of 0.7-1 mg/kg daily until improvement occurs, then follow-up treatment with oral fluconazole or oral itraconazole.440
For the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial therapy with conventional IV amphotericin B given in a dosage of 0.5-1 mg/kg once daily until improvement occurs, then follow-up treatment with oral fluconazole or oral itraconazole.441 The total duration of treatment should be 1 year.441
HIV-infected adults, adolescents, or children who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole to prevent recurrence or relapse.440, 441
If conventional IV amphotericin B is used for initial (induction) therapy in HIV-infected adults or adolescents with cryptococcal meningitis, CDC, NIH, and IDSA recommend a dosage of 0.7-1 mg/kg daily in conjunction with oral flucytosine (25 mg/kg 4 times daily) given for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral or IV fluconazole alone given for at least 8 weeks.427, 440
If conventional IV amphotericin B is used for the treatment of cryptococcal meningitis in HIV-infected adults and adolescents who cannot receive flucytosine, CDC, NIH, and IDSA recommend initial (induction) therapy with a dosage of 0.7-1 mg/kg daily in conjunction with oral or IV fluconazole (800 mg daily) given for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral or IV fluconazole alone given for at least 8 weeks.427, 440 Alternatively, if necessary, IDSA states that conventional IV amphotericin B can be given alone in a dosage of 0.7-1 mg/kg daily for 4-6 weeks for initial (induction) therapy followed by the usual consolidation therapy.427
For the treatment of cryptococcal meningitis in immunocompetent adults without HIV infection who are not transplant recipients, IDSA recommends a regimen than includes induction therapy with conventional IV amphotericin B in a dosage of 0.7-1 mg/kg daily and oral flucytosine (25 mg/kg 4 times daily) given for at least 4 weeks (6 weeks in those with neurologic complications), then consolidation therapy with oral fluconazole alone given for 8 weeks.427 If the patient is immunocompetent without uncontrolled, underlying disease and is at low risk for therapeutic failure, IDSA states that the induction regimen can be given for only 2 weeks, followed by consolidation therapy with oral fluconazole alone for 8 weeks.427 In those who cannot receive flucytosine, induction therapy with IV amphotericin B can be given in a dosage of 0.7-1 mg/kg daily alone for at least 6 weeks, then consolidation therapy with oral fluconazole alone given for 8 weeks.427
For the treatment of CNS and disseminated cryptococcal infections in children, IDSA recommends a regimen that includes induction therapy with conventional IV amphotericin B in a dosage of 1 mg/kg daily and oral flucytosine (25 mg/kg daily 4 divided doses) given for 2 weeks, then consolidation therapy with oral fluconazole alone given for at least 8 weeks.427 In children without HIV infection who are not transplant recipients, the induction phase should be continued for at least 4 weeks (6 weeks in those with neurologic complications) before initiating the consolidation regimen.427
For the treatment of cryptococcal meningitis in HIV-infected infants and children, CDC, NIH, and IDSA recommend a regimen that includes induction therapy with conventional IV amphotericin B in a dosage of 1 mg/kg once daily in conjunction with oral flucytosine (25 mg/kg 4 times daily) given for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with IV or oral fluconazole given alone for at least 8 weeks.441 In HIV-infected infants and children who cannot receive flucytosine, CDC, NIH, and IDSA recommend induction therapy with conventional IV amphotericin B in a dosage of 1-1.5 mg/kg once daily alone or in conjunction with fluconazole for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with IV or oral fluconazole alone for at least 8 weeks.441
For the treatment of severe pulmonary or disseminated cryptococcosis (nonmeningeal) in HIV-infected infants and children, CDC, NIH, and IDSA recommend that conventional IV amphotericin B be given in a dosage of 0.7-1 mg/kg daily (with or without oral flucytosine).441 The same dosage can be used without flucytosine for localized disease (e.g., isolated pulmonary disease).441 The treatment duration depends on the patient's response and the site and severity of infection.441
Severe pulmonary cryptococcosis, cryptococcemia, or disseminated cryptococcosis in immunocompetent or immunocompromised adults, adolescents, or children should be treated using a regimen recommended for cryptococcal meningitis.427, 440, 441
HIV-infected adults, adolescents, or children who have been adequately treated for cryptococcosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to prevent recurrence or relapse.440, 441
If conventional IV amphotericin B is used as an alternative to oral fluconazole for long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent recurrence or relapse of cryptococcosis in HIV-infected adults and adolescents or other adults and adolescents who were adequately treated for cryptococcal meningitis, IDSA recommends a dosage of 1 mg/kg once weekly.427
If conventional IV amphotericin B is used for the treatment of moderately severe to severe acute pulmonary histoplasmosis or progressive disseminated histoplasmosis, IDSA recommends that adults receive an initial regimen of 0.7-1 mg/kg daily for 1-2 weeks, followed by oral itraconazole.428 The total duration of treatment should be 12 weeks in those with acute pulmonary disease or at least 12 months in those with progressive disseminated disease.428
For the treatment of progressive disseminated histoplasmosis in children, IDSA states that conventional IV amphotericin B can be given in a dosage of 1 mg/kg daily for 4-6 weeks or, alternatively, an initial regimen of 1 mg/kg daily can be given for 2-4 weeks followed by oral itraconazole for a total treatment duration of 3 months.428
If conventional IV amphotericin B is used as an alternative for the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants or children, CDC, NIH, and IDSA recommend an initial regimen of 0.7-1 mg/kg once daily for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for 12 months.441
HIV-infected adults, adolescents, or children and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse.428, 440, 441
For the treatment of paracoccidioidomycosis†, conventional IV amphotericin B has been given in a dosage of 0.4-0.5 mg/kg daily, although higher dosages (i.e., 1 mg/kg daily or, rarely, 1.5 mg/kg daily) have been used for the treatment of rapidly progressing, potentially fatal infections. Prolonged therapy usually is required.221 In severely ill patients, some clinicians recommend that conventional IV amphotericin B be given in a dosage of 0.7-1 mg/kg daily for initial treatment followed by oral itraconazole therapy.436
For the treatment of sporotrichosis, the manufacturers state that conventional IV amphotericin B has been given for up to 9 months with a total dose of up to 2.5 g.417
For the treatment of osteoarticular sporotrichosis, severe or life-threatening pulmonary sporotrichosis, or disseminated sporotrichosis, IDSA recommends that adults receive conventional IV amphotericin B in a dosage of 0.7-1 mg/kg daily until a response is obtained, followed by oral itraconazole (200 mg twice daily) given for a total treatment duration of at least 12 months.429 IDSA and other clinicians state that a lipid formulation of amphotericin B may be preferred for the treatment of disseminated sporotrichosis.429
For the treatment of meningeal sporotrichosis, IDSA recommends that adults receive conventional IV amphotericin B in a dosage of 0.7-1 mg/kg daily for at least 4-6 weeks, followed by oral itraconazole (200 mg twice daily) for a total treatment duration of at least 12 months.429 IDSA and other clinicians state that a lipid formulation of amphotericin B may be preferred (rather than conventional amphotericin B) for the treatment of meningeal sporotrichosis.429
For the treatment of disseminated sporotrichosis in children, IDSA recommends that conventional IV amphotericin B be given in a dosage of 0.7 mg/kg daily until a response is obtained, followed by oral itraconazole for a total treatment duration of at least 12 months.429
For the treatment of zygomycosis, including mucormycosis, the usual dosage of conventional IV amphotericin B is 1-1.5 mg/kg daily for 2-3 months.126, 211, 248 For the treatment of rhinocerebral phycomycosis, the manufacturer recommends a total treatment dose of at least 3 g.417 Although a total treatment dose of 3-4 g can cause lasting renal impairment, the manufacturer states that this is a reasonable minimum dosage if there is clinical evidence of invasion of deep tissue since such infections usually are rapidly fatal and an aggressive therapeutic approach is necessary.417
Adjunctive Therapy in CNS Fungal Infections
For the treatment of CNS fungal infections (e.g., candidal, coccidioidal, or cryptococcal meningitis), intracisternal†, intraventricular†, or intrathecal† injection of conventional amphotericin B has been used in conjunction with IV administration.245, 292, 455 For intrathecal† administration, amphotericin B has been reconstituted with sterile water for injection to a concentration of 0.25 mg/mL. The usual initial dose is 0.025 mg (0.1 mL of the reconstituted injection diluted with 10-20 mL of CSF and administered by barbotage) 2 or 3 times per week.245 The dose is gradually increased until the maximum dose is reached that can be given without causing severe discomfort.245 This dose usually is 0.5-1 mg, although 0.2-0.3 mg may be effective in some infections and others (e.g., coccidioidal meningitis) may require up 1.5 mg;211, 245 corticosteroids (10-15 mg of hydrocortisone in adults) usually are added to relieve headache.211, 346 (See Drug Interactions: Corticosteroids.)
Empiric Therapy in Febrile Neutropenic Patients
For the empiric treatment of presumed fungal infections in febrile neutropenic patients†, conventional IV amphotericin B has been given in a dosage of 0.5-1 mg/kg daily.452
Empiric antifungal therapy should be discontinued when neutropenia resolves.422 In those with prolonged neutropenia, IDSA suggests that such therapy may be discontinued after 2 weeks if the patient is clinically well and no discernible lesions are found by clinical evaluation, chest radiographs, or CT scans of abdominal organs.422 If the patient appears ill or is at high risk, consideration can be given to continuing empiric antifungal treatment throughout the neutropenic episode.422
Prevention of Fungal Infections in Transplant Recipients, Cancer Patients, or Other Individuals at High Risk
For prophylaxis of fungal infections in neutropenic cancer patients† or patients undergoing bone marrow transplantation† (BMT), conventional IV amphotericin B has been administered in a dosage of 0.1 mg/kg daily.126, 287, 375
For high-risk patients undergoing urologic procedures†, IDSA states that conventional IV amphotericin B can be given in a dosage of 0.3-0.6 mg/kg daily for several days before and after the procedure.425
For the treatment of American cutaneous leishmaniasis caused by Leishmania braziliensis or L. mexicana or the treatment of mucocutaneous leishmaniasis caused by L. braziliensis , conventional IV amphotericin B has been given in a dosage of 0.25-0.5 mg/kg daily,102, 103, 104, 105, 109 with dosage gradually increased until 0.5-1 mg/kg daily was reached,104, 105, 107, 108, 109, 126, 442 at which time the drug was given on alternate days.107, 108, 126, 442 Duration of therapy depends on the severity of disease and response to the drug, but is generally 3-12 weeks102, 103, 105 and the total dose generally ranges from 1-3 g.102, 105, 106, 107, 108, 109
For the treatment of mucosal disease, some clinicians recommend that conventional IV amphotericin B be given in a dosage 0.5-1 mg/kg daily or every other day for 4-8 weeks.442
Visceral leishmaniasis (also known as kala-azar) in adults and children has been treated with 0.5-1 mg/kg of conventional IV amphotericin B† administered on alternate days for 14-20 doses.126, 257 Some clinicians recommend that adults and children with visceral leishmaniasis receive a total treatment dosage of 15-20 mg/kg of conventional IV amphotericin B† given as 1 mg/kg daily for 15-20 days or 1 mg/kg every second day for 4-8 weeks.442, 443
If conventional IV amphotericin B† is used as an alternative to amphotericin B liposomal in HIV-infected adults and adolescents with visceral leishmaniasis, CDC, NIH, and IDSA recommend a dosage of 0.5-1 mg/kg daily for a total treatment dosage of 1.5-2 g.440 Long-term suppressive or maintenance therapy (secondary prophylaxis) with amphotericin B liposomal may be indicated.440 (See Leishmaniasis under Dosage: Amphotericin B Liposomal [Ambisome®], in Dosage and Administration.)
Primary Amebic Meningoencephalitis
If conventional IV amphotericin B is used for the treatment of primary amebic meningoencephalitis caused by Naegleria fowleri †, a dosage of 1.5 mg/kg daily in 2 divided doses for 3 consecutive days, then 1 mg/kg IV once daily for 11 consecutive days, has been recommended.511 If conventional amphotericin B is administered intrathecally† for the treatment of primary amebic meningoencephalitis, a dosage of 1.5 mg once daily for 2 days, then 1 mg every other day for 8 days, has been recommended.511 If conventional amphotericin B is administered by both routes in the same patient, some clinicians state that the maximum total dosage in adults and children is 1.5 mg/kg daily.442 Amphotericin B should be used in conjunction with other anti-infectives.292, 442, 511, 512, 513 Consultation with a specialist at CDC is recommended.511 (See Primary Amebic Meningoencephalitis under Uses: Protozoal Infections.)
Amphotericin B Lipid Complex (Abelcet®)
For the treatment of invasive fungal infections in adults and children, the manufacturer of amphotericin B lipid complex recommends a dosage of 5 mg/kg IV once daily.201
If IV amphotericin B lipid complex is used as an alternative for the treatment of invasive aspergillosis, IDSA recommends a dosage of 5 mg/kg daily.423 The duration of treatment is based on the degree and duration of immunosuppression, disease site, and clinical response.423, 440 IDSA recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6-12 weeks.423
If a lipid formulation of amphotericin B is used as an alternative for the treatment of invasive aspergillosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 5 mg/kg IV once daily.440 The optimal duration of therapy in these patients has not been established, but antifungal therapy should be continued at least until CD4+ T-cell counts exceed 200/mm3 and there is evidence of resolution of aspergillosis.440
If a lipid formulation of IV amphotericin B is used for the treatment of moderate to severe pulmonary or disseminated extrapulmonary blastomycosis (without CNS involvement), IDSA recommends that adults (including immunocompromised individuals) receive initial therapy with a dosage of 3-5 mg/kg once daily for 1-2 weeks or until improvement occurs, followed by oral itraconazole therapy.424 Total treatment duration should be 6-12 months for pulmonary blastomycosis or at least 12 months for disseminated extrapulmonary blastomycosis or for immunocompromised individuals.424
If a lipid formulation of IV amphotericin B is used for the treatment of severe blastomycosis in children, IDSA recommends initial therapy with a dosage of 3-5 mg/kg daily, followed by oral itraconazole therapy for a total treatment duration of 12 months.424
For the treatment of CNS blastomycosis, IDSA recommends that adults receive initial therapy with a lipid formulation of IV amphotericin B given in a dosage of 5 mg/kg daily for 4-6 weeks, followed by an oral azole (fluconazole, itraconazole, voriconazole) given for at least 12 months and until resolution of CSF abnormalities.424
If a lipid formulation of amphotericin B is used for initial treatment of candidemia or other invasive Candida infections in nonneutropenic or neutropenic adults, IDSA recommends a dosage of 3-5 mg/kg daily.425 These experts state that a transition to fluconazole can be considered (usually within 5-7 days) in nonneutropenic patients who are clinically stable, have isolates susceptible to fluconazole (e.g., C. albicans ), and have negative repeat blood cultures after initial antifungal treatment.425 IDSA recommends that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.425
If a lipid formulation of amphotericin B is used for the treatment of chronic disseminated (hepatosplenic) candidiasis, IDSA recommends initial treatment with a dosage of 3-5 mg/kg daily for several weeks followed by oral fluconazole.425 Antifungal treatment should be continued until lesions resolve on repeat imaging (usually several months).425
If a lipid formulation of amphotericin B is used for initial treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida , IDSA recommends a dosage of 3-5 mg/kg daily given with or without oral flucytosine.425 If the infection is caused by fluconazole-susceptible Candida , treatment can be transitioned to fluconazole after the patient is stabilized and Candida has been cleared from the bloodstream.425
If a lipid formulation of amphotericin B is used as an alternative for the treatment of esophageal candidiasis†, including fluconazole-refractory infections, in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 3-4 mg/kg IV once daily for 14-21 days.440
If a lipid formulation of amphotericin B is used for the treatment of invasive C. auris infections (e.g., bloodstream or intra-abdominal infections) in adults (see Candida auris Infections under Uses: Candida Infections), CDC recommends a dosage of 3-5 mg/kg IV daily.510
If a lipid formulation of IV amphotericin B is used for the treatment of diffuse pulmonary or extrathoracic disseminated coccidioidomycosis (nonmeningeal) in HIV-infected adults of adolescents, CDC, NIH, and IDSA recommend a dosage of 4-6 mg/kg daily until improvement occurs, then follow-up treatment with oral fluconazole or oral itraconazole.440
If a lipid formulation of IV amphotericin B is used for the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) in HIV-infected infants and children, CDC, NIH, and IDSA recommend a dosage of 5 mg/kg once daily until improvement occurs, then follow-up treatment with oral fluconazole or oral itraconazole.441 The total duration of treatment should be 1 year.441
HIV-infected adults, adolescents, or children who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole to prevent recurrence or relapse.440, 441
If amphotericin B lipid complex is used for initial (induction) therapy in HIV-infected adults and adolescents with cryptococcal meningitis, CDC, NIH, and IDSA recommend a dosage of 5 mg/kg daily in conjunction with oral flucytosine (25 mg/kg 4 times daily) given for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral or IV fluconazole given for at least 8 weeks.427, 440 Alternatively, if necessary, IDSA states that IV amphotericin B lipid complex can be given alone in a dosage of 5 mg/kg daily for 4-6 weeks for initial (induction) therapy followed by the usual consolidation therapy.427
For the treatment of CNS cryptococcosis in adult organ transplant recipients, IDSA recommends induction therapy with IV amphotericin B lipid complex in a dosage of 5 mg/kg daily and oral flucytosine (100 mg/kg daily in 4 divided doses) given for at least 2 weeks, then consolidation therapy with oral fluconazole given for 8 weeks followed by a maintenance regimen of oral fluconazole given for 6-12 months.427 If flucytosine cannot be used in the induction regimen, consideration should be given to continuing induction therapy with IV amphotericin B lipid complex for at least 4-6 weeks before initiating consolidation therapy with oral fluconazole.427
For the treatment of cryptococcal meningitis in immunocompetent adults without HIV infection who are not transplant recipients and when conventional IV amphotericin B cannot be used (e.g., patients who have or are predisposed to renal dysfunction), IDSA recommends a regimen than includes induction therapy with IV amphotericin B lipid complex in a dosage of 5 mg/kg daily given with oral flucytosine (100 mg/kg daily in 4 divided doses) for at least 4 weeks (6 weeks in those with neurologic complications), then consolidation therapy with oral fluconazole given for 8 weeks.427 If the patient is immunocompetent without uncontrolled, underlying disease and is at low risk for therapeutic failure, IDSA states that the induction regimen can be given for only 2 weeks, followed by consolidation therapy with oral fluconazole for 8 weeks.427 In those who cannot receive flucytosine, induction therapy with IV amphotericin B lipid complex can be given in a dosage of 5 mg/kg daily alone for at least 6 weeks, then consolidation therapy with oral fluconazole given for 8 weeks.427
If amphotericin B lipid complex is used for the treatment of cryptococcal meningitis in HIV-infected infants and children, CDC, NIH, and IDSA recommend induction therapy with 5 mg/kg once daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.427, 441
For the treatment of CNS and disseminated cryptococcal infections in children who cannot receive conventional IV amphotericin B, IDSA recommends a regimen that includes induction therapy with IV amphotericin B lipid complex in a dosage of 5 mg/kg daily given with oral flucytosine (100 mg/kg daily in 4 divided doses) for 2 weeks, then consolidation therapy with oral fluconazole given for at least 8 weeks.427 In children without HIV infection who are not transplant recipients, the induction phase should be continued for at least 4 weeks (6 weeks in those with neurologic complications) before initiating the consolidation regimen.427
If amphotericin B lipid complex is used in HIV-infected infants and children with severe pulmonary or disseminated cryptococcosis (nonmeningeal), CDC, NIH, and IDSA recommend a dosage of 5 mg/kg once daily (with or without oral flucytosine).441 The same dosage can be used without flucytosine for localized disease (e.g., isolated pulmonary disease).441 The treatment duration depends on the patient's response and site and severity of infection.441
HIV-infected adults, adolescents, or children who have been adequately treated for cryptococcosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to prevent recurrence or relapse.440, 441
If IV amphotericin B lipid complex is used for the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend an initial (induction) regimen of 3 mg/kg daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for at least 12 months.440
HIV-infected adults, adolescents, or children and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse.428, 440, 441
Empiric Therapy in Febrile Neutropenic Patients
For the empiric treatment of presumed fungal infections in febrile neutropenic patients†, amphotericin B lipid complex has been given in a dosage of 3-5 mg/kg daily.452
Empiric antifungal therapy should be discontinued when neutropenia resolves.422 In those with prolonged neutropenia, IDSA suggests that such therapy may be discontinued after 2 weeks if the patient is clinically well and no discernible lesions are found by clinical evaluation, chest radiographs, or CT scans of abdominal organs.422 If the patient appears ill or is at high risk, consideration can be given to continuing empiric antifungal treatment throughout the neutropenic episode.422
For the treatment of visceral leishmaniasis† (kala-azar), amphotericin B lipid complex has been given in a dosage of 1-3 mg/kg once daily for 5-10 days.246, 430, 443
If amphotericin B lipid complex is used for the treatment of cutaneous leishmaniasis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 2-4 mg/kg daily for a total treatment dosage of 20-60 mg/kg.440 Alternatively, a dosage of 4 mg/kg daily on days 1-5, 10, 17, 24, 31, and 38 for a total treatment dosage of 20-60 mg/kg can be used.440
If amphotericin B lipid complex is used for long-term suppressive or maintenance therapy (secondary prophylaxis)† in HIV-infected adults and adolescents who have been adequately treated for visceral leishmaniasis, CDC, NIH, and IDSA recommend a dosage of 3 mg/kg once every 21 days.440 Some experts state that consideration can be given to discontinuing secondary prophylaxis against leishmaniasis in HIV-infected individuals who have CD4+ T-cell counts that have remained greater than 200-350/mm3 for 3-6 months or longer.440 Other clinicians suggest that secondary prophylaxis against leishmaniasis should be continued indefinitely in HIV-infected individuals.440
Amphotericin B Liposomal (AmBisome®)
For the treatment of systemic fungal infections, the usual dosage of IV amphotericin B liposomal for adults or children 1 month of age or older is 3-5 mg/kg once daily.202, 231, 232
For the treatment of aspergillosis, the usual dosage of IV amphotericin B liposomal for adults or children 1 month of age or older is 3-5 mg/kg once daily.202, 423 In the treatment of invasive aspergillosis, use of higher dosage (10 mg/kg daily) does not result in improved efficacy and is associated with an increased incidence of adverse effects (e.g., nephrotoxicity).423, 459
The duration of treatment is based on the degree and duration of immunosuppression, disease site, and clinical response.423 IDSA recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6-12 weeks.423 In published studies, the median duration of amphotericin B liposomal therapy for the effective treatment of aspergillosis has ranged from 15-29 days.230, 231, 232, 379
If a lipid formulation of IV amphotericin B is used as an alternative for the treatment of invasive aspergillosis in HIV-infected adults, CDC, NIH, and IDSA recommend 5 mg/kg IV once daily.440 The optimal duration of therapy in these patients has not been established, but antifungal therapy should be continued at least until CD4+ T-cell counts exceed 200/mm3 and there is evidence of resolution of aspergillosis.440
If a lipid formulation of IV amphotericin B is used for the treatment of moderate to severe pulmonary or disseminated extrapulmonary blastomycosis (without CNS involvement), IDSA recommends that adults (including immunocompromised individuals) receive initial therapy with a dosage of 3-5 mg/kg once daily for 1-2 weeks or until improvement occurs, followed by oral itraconazole therapy.424 The total treatment duration should be 6-12 months for pulmonary blastomycosis or at least 12 months for disseminated extrapulmonary blastomycosis or for immunocompromised individuals.424
If a lipid formulation of IV amphotericin B is used for the treatment of severe blastomycosis in children, IDSA recommends initial therapy with a dosage of 3-5 mg/kg once daily, followed by oral itraconazole therapy for a total treatment duration of 12 months.424
For the treatment of CNS blastomycosis, IDSA recommends that adults receive initial therapy with a lipid formulation of IV amphotericin B given in a dosage of 5 mg/kg once daily for 4-6 weeks, followed by oral azole therapy (fluconazole, itraconazole, voriconazole).424 The total duration of treatment should be at least 12 months and until CSF abnormalities resolve.424
For the treatment of systemic Candida infections, the usual dosage of IV amphotericin B liposomal for adults and children 1 month of age or older is 3-5 mg/kg once daily.202, 231, 232 In published studies, the median duration of amphotericin B liposomal therapy for the effective treatment of candidiasis has ranged from 15-29 days,230, 231, 232 although some Candida infections were effectively treated with a median duration of therapy of 5-7 days.230, 231, 232
If a lipid formulation of IV amphotericin B is used for initial treatment of candidemia or other invasive Candida infections in nonneutropenic or neutropenic adults, IDSA recommends a dosage of 3-5 mg/kg daily.425 These experts state that a transition to fluconazole can be considered (usually within 5-7 days) in nonneutropenic patients who are clinically stable, have isolates susceptible to fluconazole (e.g., C. albicans ), and have negative repeat blood cultures after initial antifungal treatment.425 IDSA recommends that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.425
If a lipid formulation of amphotericin B is used for the treatment of chronic disseminated (hepatosplenic) candidiasis, IDSA recommends initial treatment with a dosage of 3-5 mg/kg daily for several weeks followed by oral fluconazole.425 Antifungal treatment should be continued until lesions resolve on repeat imaging (usually several months).425
If IV amphotericin B liposomal is used for treatment of CNS candidiasis, IDSA recommends a dosage of 5 mg/kg daily (with or without oral flucytosine).425 After a response is attained, transition to fluconazole can be considered.425 Antifungal treatment should be continued until signs and symptoms, CSF abnormalities, and radiologic abnormalities have resolved.425
If a lipid formulation of IV amphotericin B is used for initial treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida , IDSA recommends a dosage of 3-5 mg/kg daily given with or without oral flucytosine.425 If the infection is caused by fluconazole-susceptible Candida , treatment can be transitioned to fluconazole after the patient is stabilized and Candida has been cleared from the bloodstream.425
If a lipid formulation of IV amphotericin B is used as an alternative for the treatment of esophageal candidiasis†, including fluconazole-refractory infections, in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 3-4 mg/kg IV once daily for 14-21 days.440
If IV amphotericin B liposomal is used for treatment of endophthalmitis caused by fluconazole- and voriconazole-resistant Candida , IDSA recommends a dosage of 3-5 mg/kg daily (with or without oral flucytosine).425 In patients with macular involvement, intravitreal administration of conventional IV amphotericin B† also is recommended to ensure prompt high levels of antifungal activity.425
If a lipid formulation of IV amphotericin B is used for the treatment of invasive C. auris infections (e.g., bloodstream or intra-abdominal infections) in adults (see Candida auris Infections under Uses: Candida Infections), CDC recommends a dosage of 3-5 mg/kg IV daily.510
If a lipid formulation of IV amphotericin B is used for the treatment of diffuse pulmonary or extrathoracic disseminated coccidioidomycosis (nonmeningeal) in HIV-infected adults of adolescents, CDC, NIH, and IDSA recommend a dosage of 4-6 mg/kg daily until improvement occurs, then follow-up treatment with oral fluconazole or oral itraconazole.440
If a lipid formulation of IV amphotericin B is used for the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) in HIV-infected infants and children, CDC, NIH, and IDSA recommend a dosage of 5 mg/kg daily until improvement occurs, then follow-up treatment with oral fluconazole or oral itraconazole.441 The total duration of treatment should be 1 year.441
HIV-infected adults, adolescents, or children who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole to prevent recurrence or relapse.440, 441
For empiric treatment of cryptococcosis in adults and children 1 month of age or older, the manufacturer recommends that IV amphotericin B liposomal be given in a dosage of 3-5 mg/kg daily.202 For the treatment of cryptococcal meningitis in HIV-infected adults and children 1 month of age or older, the manufacturer recommends that IV amphotericin B liposomal be given in a dosage of 6 mg/kg daily.202
For the treatment of cryptococcal meningitis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a regimen than includes initial (induction) therapy with IV amphotericin B liposomal in a dosage of 3-4 mg/kg daily in conjunction with oral flucytosine (25 mg/kg 4 times daily) given for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral or IV fluconazole given for at least 8 weeks.427, 440
For the treatment of cryptococcal meningitis in HIV-infected adults and adolescents who cannot receive flucytosine, CDC, NIH, and IDSA recommend initial (induction) therapy with IV amphotericin B liposomal given in a dosage of 3-4 mg/kg once daily in conjunction with oral or IV fluconazole (800 mg daily) for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral or IV fluconazole alone given for at least 8 weeks.440 Alternatively, if necessary, a regimen of IV amphotericin B liposomal alone given in a dosage of 3-4 mg/kg once daily can be used for initial (induction) therapy followed by the usual consolidation therapy.440
For the treatment of CNS cryptococcosis in adult organ transplant recipients, IDSA recommends induction therapy with IV amphotericin B liposomal in a dosage of 3-4 mg/kg daily and oral flucytosine (100 mg/kg daily in 4 divided doses) given for at least 2 weeks, then consolidation therapy with oral fluconazole given for 8 weeks followed by a maintenance regimen of oral fluconazole given for 6-12 months.427 Alternatively, if flucytosine cannot be used in the induction regimen, consideration should be given to using a regimen of IV amphotericin B liposomal in a dosage of 6 mg/kg daily given for at least 4-6 weeks followed by the usual consolidation therapy with oral fluconazole.427
For the treatment of cryptococcal meningitis in immunocompetent adults without HIV infection who are not transplant recipients and when conventional IV amphotericin B cannot be used (e.g., patients who have or are predisposed to renal dysfunction), IDSA recommends a regimen than includes induction therapy with IV amphotericin B liposomal in a dosage of 3-4 mg/kg daily with oral flucytosine (100 mg/kg daily in 4 divided doses) given for at least 4 weeks (6 weeks in those with neurologic complications), then consolidation therapy with oral fluconazole given for 8 weeks.427 If the patient is immunocompetent without uncontrolled, underlying disease and is at low risk for therapeutic failure, IDSA states that the induction regimen can be given for only 2 weeks, followed by consolidation therapy with oral fluconazole for 8 weeks.427 In those who cannot receive flucytosine, induction therapy with IV amphotericin B liposomal alone given in a dosage of 3-4 mg/kg daily for at least 6 weeks can be used, followed by consolidation therapy with oral fluconazole given for 8 weeks.427
For the treatment of CNS and disseminated cryptococcal infections in children who cannot receive conventional IV amphotericin B, IDSA recommends a regimen that includes induction therapy with IV amphotericin B liposomal in a dosage of 5 mg/kg daily with oral flucytosine (100 mg/kg daily in 4 divided doses) given for 2 weeks, then consolidation therapy with oral fluconazole given for at least 8 weeks.427 In children without HIV infection who are not transplant recipients, the induction phase should be continued for at least 4 weeks (6 weeks in those with neurologic complications) before initiating the consolidation regimen.427
For the treatment of cryptococcal meningitis in HIV-infected infants and children, CDC, NIH, and IDSA recommend a regimen that includes induction therapy with IV amphotericin B liposomal in a dosage of 6 mg/kg once daily in conjunction with oral flucytosine (25 mg/kg 4 times daily) given for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with IV or oral fluconazole given alone for at least 8 weeks.441 In HIV-infected infants and children who cannot receive flucytosine, CDC, NIH, and IDSA recommend induction therapy with IV amphotericin B liposomal in a dosage of 6 mg/kg once daily alone or in conjunction with IV fluconazole for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with IV or oral fluconazole alone for at least 8 weeks.441
If amphotericin B liposomal is used in HIV-infected infants and children with severe pulmonary or disseminated cryptococcosis (nonmeningeal), CDC, NIH, and IDSA recommend a dosage of 3-5 mg/kg once daily (with or without oral flucytosine).441 The same dosage can be used without flucytosine for localized disease (e.g., isolated pulmonary disease).441 The treatment duration depends on the patient's response and site and severity of infection.441
HIV-infected adults, adolescents, or children who have been adequately treated for cryptococcosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to prevent recurrence or relapse.440, 441
For the treatment of moderately severe to severe acute pulmonary histoplasmosis, IDSA recommends that adults receive an initial regimen of IV amphotericin B liposomal given in a dosage of 3-5 mg/kg daily for 1-2 weeks, followed by oral itraconazole for a total treatment duration of 12 weeks.428 For the treatment of moderately severe to severe progressive disseminated histoplasmosis, IDSA recommends that adults receive an initial regimen of IV amphotericin B liposomal given in a dosage of 3 mg/kg daily for 1-2 weeks, followed by oral itraconazole for a total treatment duration of at least 12 months.428
For the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected adults or adolescents, CDC, NIH, and IDSA recommend an initial (induction) regimen of IV amphotericin B liposomal in a dosage of 3 mg/kg once daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for at least 12 months.440 In HIV-infected infants or children, CDC, NIH, and IDSA recommend an initial (induction) regimen of IV amphotericin B liposomal in a dosage of 3-5 mg/kg once daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for 12 months.441
For the treatment of CNS histoplasmosis in HIV-infected adults, adolescents, or children or other adults, CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B liposomal given in a dosage of 5 mg/kg once daily for 4-6 weeks and follow-up treatment with oral itraconazole given for a total treatment duration of at least 12 months and until abnormal CSF findings resolve and histoplasmal antigen is undetectable.428, 440, 441
HIV-infected adults, adolescents, or children and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse.428, 440, 441
If IV amphotericin B liposomal is used for the treatment of CNS and/or parameningeal infections known or suspected to be caused by Exserohilum rostratum † in adults who received injections of a contaminated corticosteroid product (see Uses: Exserohilum Infections), CDC recommends a dosage of 5-6 mg/kg daily.477 Higher dosage (7.5 mg/kg daily) may be considered in patients who are not improving, but the increased risk of nephrotoxicity should be considered.477 Administration of 1 L of 0.9% sodium chloride injection prior to IV infusion of amphotericin B liposomal may be considered to minimize risk of nephrotoxicity.477
If IV amphotericin B liposomal is used for the treatment of osteoarticular infections known or suspected to be caused by E. rostratum † in adults who received intra-articular injections of a contaminated corticosteroid product (see Uses: Exserohilum Infections), CDC recommends a dosage of 5 mg/kg daily.477
Adequate duration of antifungal treatment for infections related to contaminated corticosteroid products is unknown, but prolonged treatment is required and should be based on disease severity and clinical response.477 A treatment duration of 6-12 months is probably necessary in patients who have severe CNS disease with complications (arachnoiditis, stroke), persistent CSF abnormalities, or underlying immunosuppression.477 In those with parameningeal infection, a minimum treatment duration of 3-6 months should be considered, and at least 6 months or longer probably is required for more severe disease (e.g., discitis, osteomyelitis) and in those with underlying immunosuppression or complications not amenable to surgical treatment.477 In those with osteoarticular infections, a minimum treatment duration of 3 months should be considered, and longer than 3 months is probably necessary in those with severe disease, bone infections, or underlying immunosuppression.477 After completion of treatment, close follow-up monitoring is essential in all patients to detect potential relapse.477
An infectious disease expert and the most recent guidelines from CDC should be consulted for information regarding the management of infections in patients who received injections of potentially contaminated products.477 Clinicians should consult the CDC website at [Web] for the most recent recommendations regarding the drugs of choice, dosage, and duration of treatment of these infections.477
For the treatment of severe, acute penicilliosis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend that IV amphotericin B liposomal be given in a dosage of 3-5 mg/kg daily for 2 weeks, followed by oral itraconazole (200 mg twice daily) for 10 weeks.440
After the patient has been adequately treated, long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole is recommended to prevent recurrence or relapse.407, 408, 440
Empiric Therapy in Febrile Neutropenic Patients
For the empiric treatment of presumed fungal infections in febrile neutropenic patients 1 month of age or older, the usual dosage of amphotericin B liposomal is 3 mg/kg once daily.202 In one limited study, the median duration of empiric therapy was 10.8 days.252
Empiric antifungal therapy should be discontinued when neutropenia resolves.422 In those with prolonged neutropenia, IDSA suggests that such therapy may be discontinued after 2 weeks if the patient is clinically well and no discernible lesions are found by clinical evaluation, chest radiographs, or CT scans of abdominal organs.422 If the patient appears ill or is at high risk, consideration can be given to continuing empiric antifungal treatment throughout the neutropenic episode.422
Prevention of Fungal Infections in Transplant Recipients, Cancer Patients, or Other Individuals at High Risk
For postoperative prophylaxis in liver, pancreas, or small bowel transplant recipients† at high risk of candidiasis, IDSA states that IV amphotericin B liposomal can be given in a dosage of 1-2 mg/kg daily for at least 7-14 days.425
For the treatment of visceral leishmaniasis (also known as kala-azar) in immunocompetent adults and children 1 month of age or older, the manufacturer recommends that amphotericin B liposomal be given in a dosage of 3 mg/kg once daily on days 1-5, then 3 mg/kg should be given once daily on days 14 and 21; a second course of the drug may be useful if the parasitic infection is not completely cleared with a single course.202 For the treatment of visceral leishmaniasis in immunocompromised adults and children 1 month of age or older, the manufacturer recommends that amphotericin B liposomal be given in a dosage of 4 mg/kg once daily on days 1-5, then 4 mg/kg once daily on days 10, 17, 24, 31, and 38; however, if the parasitic infection is not completely cleared after the first course or if relapses occur, an expert should be consulted regarding further treatment.202 Various other dosage regimens have been used, including 5-7.5 mg/kg or 10 mg/kg once daily for 2 consecutive days.443, 444
If amphotericin B liposomal is used for the treatment of cutaneous leishmaniasis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 2-4 mg/kg daily for a total treatment dosage of 20-60 mg/kg.440 Alternatively, a dosage of 4 mg/kg daily on days 1-5, 10, 17, 24, 31, and 38 for a total treatment dosage of 20-60 mg/kg can be used.440
If amphotericin B liposomal is used for the treatment of visceral leishmaniasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 2-4 mg/kg daily for a total treatment dosage of 20-60 mg/kg.440 Alternatively, a dosage of 4 mg/kg daily on days 1-5, 10, 17, 24, 31, and 38 for a total treatment dosage of 20-60 mg/kg can be used.440
If amphotericin B liposomal is used for long-term suppressive or maintenance therapy (secondary prophylaxis)† in HIV-infected adults and adolescents who have been adequately treated for visceral leishmaniasis and have CD4+ T-cell counts less than 200/mm3, CDC, NIH, and IDSA recommend a dosage of 4 mg/kg once every 2-4 weeks.440 Some experts state that consideration can be given to discontinuing secondary prophylaxis against leishmaniasis in HIV-infected adults and adolescents who have CD4+ T-cell counts that have remained greater than 200-350/mm3 for 3-6 months or longer.440 Other clinicians suggest that secondary prophylaxis against leishmaniasis should be continued indefinitely in HIV-infected individuals.440
Conventional IV amphotericin B is associated with a high incidence of adverse effects, and most patients who receive the drug experience potentially severe adverse effects at some time during the course of therapy.264, 417 Acute infusion reactions (e.g., fever, shaking chills, hypotension, headache, anorexia, nausea, vomiting, tachypnea) and nephrotoxicity are common adverse reactions to conventional IV amphotericin B.264, 417
Although clinical experience with amphotericin B lipid complex (Abelcet®) and amphotericin B liposomal (AmBisome®) is limited to date, these drugs appear to be better tolerated than conventional IV amphotericin B.201, 202, 216, 219, 244, 265 As with conventional IV amphotericin B, the most frequent adverse reactions to amphotericin B lipid complex201, 207 or amphotericin B liposomal303 are acute infusion reactions; however, data accumulated to date indicate that lipid formulations of amphotericin B may be associated with a lower overall incidence of adverse effects and a lower incidence of hematologic and renal toxicity than the conventional formulation of the drug.201, 202, 207, 216, 244, 265, 333
Acute infusion reactions consisting of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea may occur 1-3 hours after initiation of IV infusions of conventional amphotericin B,211, 264, 341, 417 amphotericin B lipid complex,201, 207 or amphotericin B liposomal.202 These reactions are most severe and occur most frequently with initial doses and usually lessen with subsequent doses.264, 341, 417 Fever (with or without shaking chills) usually occurs within 15-20 minutes after IV infusions of conventional amphotericin B are started.417 The majority of patients receiving conventional IV amphotericin B (50-90%) exhibit some degree of intolerance to initial doses of the drug, even when therapy is initiated with low doses.211, 264, 417
In a study designed to evaluate the incidence of infusion reactions occurring in patients receiving conventional IV amphotericin B, 71% of patients had at least one infusion-related reaction during the first 7 days of therapy; fever and chills occurred in 28-51% and nausea and headache occurred in 9-18% of patients.341 In patients receiving amphotericin B lipid complex, chills and fever have been reported in 14-18% of patients and nausea, vomiting, and hypotension have been reported in 8-9% of patients.201 In a large, double-blind study in adults and pediatric febrile neutropenic patients, infusion reactions (i.e., fever, chills/rigors, nausea, vomiting) occurred in 4-20% of those receiving the first dose of amphotericin B liposomal and 7-56% of those receiving the first dose of conventional IV amphotericin B.202 In a randomized study in HIV-infected patients with cryptococcal meningitis, infusion reactions (i.e., fever, chills/rigors, nausea, vomiting) occurred in 6-16% of those receiving amphotericin B liposomal (3 or 6 mg/kg daily) and 18-48% of those receiving conventional amphotericin B.202 There have been reports of flushing, back pain (with or without chest tightness), and chest pain occurring within a few minutes after initiation of IV infusions of amphotericin B liposomal; these reactions occasionally were severe but disappeared when the infusion was stopped.202 These symptoms do not occur with every dose and usually do not recur with subsequent doses given at a slower IV infusion rate.202
Although the precise mechanism for these infusion reactions is not known, limited evidence indicates that amphotericin-induced increases in prostaglandin (e.g., PGE2) synthesis may be involved.136, 211, 341 Aspirin, antipyretics (e.g., acetaminophen), antiemetics, meperidine, antihistamines (e.g., diphenhydramine), or corticosteroids have been used for the treatment or prevention of acute infusion reactions in patients receiving conventional IV amphotericin or other formulations of the drug.136, 201, 202, 211, 341, 417 It has been suggested that meperidine (25-50 mg IV) may decrease the duration of shaking chills and fever occurring in association with IV infusion of amphotericin B.211, 341, 417 There is some evidence that IV administration of small doses of corticosteroids just prior to or during IV infusion of conventional amphotericin B may help decrease the severity of febrile and other systemic reactions;417 however, corticosteroids should be used only when necessary using minimal dosage for as short a period as possible.341, 417 (See Drug Interactions: Corticosteroids.) Use of a premedication regimen (e.g., acetaminophen and diphenhydramine; acetaminophen, corticosteroid, and diphenhydramine) is not routinely recommended prior to the initial dose of any amphotericin B formulation, but can be administered promptly to treat a reaction if it occurs and then as pretreatment prior to subsequent doses.341, 346
Rapid IV infusion of conventional IV amphotericin B has been associated with a more severe reaction consisting of hypotension, hypokalemia, arrhythmias, and shock.417 Some of these adverse effects also have been reported rarely with amphotericin B lipid complex201 or amphotericin B liposomal.202 It may be difficult to determine whether these severe reactions indicate intolerance or hypersensitivity to the drug.
Nephrotoxicity is the major dose-limiting toxicity reported with conventional IV amphotericin B, and nephrotoxicity occurs to some degree in the majority of patients receiving the drug.126, 211, 269, 292, 417, 436 Adverse renal effects in patients receiving conventional IV amphotericin B include decreased renal function and renal function abnormalities such as azotemia, hypokalemia, hyposthenuria, renal tubular acidosis, and nephrocalcinosis.126, 417 Increased BUN and serum creatinine concentrations417 have been reported. Hypokalemia and hypomagnesemia develop in a large proportion of patients,269, 417, 436 and hypocalcemia has been reported.417 Uric acid excretion is increased and nephrocalcinosis can occur.269 Renal tubular acidosis may be present without concurrent systemic acidosis.269 It has been suggested that hydration and sodium repletion prior to administration of IV amphotericin B may decrease the risk of nephrotoxicity, and supplemental alkali therapy may decrease complications related to renal tubular acidosis.101, 417 Nephrotoxicity associated with conventional IV amphotericin B appears to involve several mechanisms, including a direct vasoconstrictive effect on renal arterioles that reduces glomerular and renal tubular blood flow and a lytic action on cholesterol-rich lysosomal membranes of renal tubular cells.126, 211 On biopsy, juxtamedullary glomerulitis and intratubular and interstitial calcium deposits in the distal nephron are found. Although renal function usually improves within a few months after discontinuance of conventional amphotericin B therapy, some degree of permanent impairment may remain in some patients, especially in patients who received a large cumulative dose of the drug (exceeding 5 g) or concomitant therapy with other nephrotoxic drugs.269, 417 Patients with higher serum low-density lipoprotein (LDL) concentrations appear to be more susceptible to amphotericin B-induced renal toxicity than those with lower concentrations.340
Increased BUN and/or serum creatinine,201, 202 hypokalemia,201, 202 hypomagnesemia,202 and hypocalcemia202 also have been reported in patients receiving amphotericin B lipid complex201 or amphotericin B liposomal.202 While these formulations appear to be associated with a lower risk of nephrotoxicity than conventional IV amphotericin B and have been used in patients with preexisting renal impairment (in most cases resulting from prior therapy with conventional IV amphotericin B),201, 202, 207, 216, 219, 244, 265, 333 additional experience with the drugs is necessary to more accurately determine the extent of nephrotoxicity that occurs with these formulations.201 In several studies when amphotericin B lipid complex was substituted for conventional IV amphotericin B in patients who developed nephrotoxicity while receiving the conventional formulation and had baseline serum creatinine concentrations of 2 mg/dL or greater, serum creatinine concentrations generally declined during therapy with the lipid formulations.201 In a randomized, double-blind study comparing safety and efficacy of amphotericin B liposomal or conventional IV amphotericin B for antifungal prophylaxis in febrile, neutropenic patients, nephrotoxicity occurred in about 19 or 34% of patients, respectively.202 In a randomized study in HIV-infected patients with cryptococcal meningitis, serum creatinine concentrations twofold higher than baseline concentrations were reported in 14-21% of those receiving amphotericin B liposomal (3 or 6 mg/kg daily) and in 33% of those receiving conventional amphotericin B.202
Other adverse renal effects that have been reported in patients receiving conventional IV amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal202 include anuria,201, 417 oliguria,201, 417 dysuria,201, 202, 417 decreased renal function,201 hematuria,202 urinary incontinence,202 renal tubular acidosis,201 and acute renal failure.201, 202, 417 Nephrogenic diabetes insipidus has been reported in patients receiving conventional IV amphotericin B.417
Patients receiving conventional IV amphotericin B may develop normocytic, normochromic anemia.126, 211, 417 The anemia develops gradually and may not occur until after 10 weeks of therapy; it may be related either to a direct inhibition of erythrocytes or erythropoietin production or may be secondary to renal toxicity.211 The hematocrit rarely decreases below 20-25%126 and generally returns to baseline within several months following discontinuance of the drug.211 Anemia also has been reported rarely in patients receiving amphotericin B lipid complex201 or amphotericin B liposomal.202
Other hematologic effects, including agranulocytosis,417 coagulation disorders,201, 202, 417 decreased or increased prothrombin,202 thrombocytopenia,201, 202, 417 leukopenia,417 eosinophilia,201, 417 or leukocytosis,201, 417 have been reported rarely in patients receiving conventional IV amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal.202
Cardiopulmonary and Sensitivity Reactions
Various adverse cardiopulmonary effects, including hypotension,417 tachypnea,417 cardiac failure,417 cardiac arrest,417 cardiomyopathy,263 shock,417 pulmonary edema,417 hypersensitivity pneumonitis,417 arrhythmias (including ventricular fibrillation),417 dyspnea,211, 417 and hypertension,417 have been reported in individuals receiving conventional IV amphotericin B.
Bronchospasm,201, 417 wheezing,201, 417 angioedema,202 and anaphylaxis or anaphylactoid reactions201, 202, 417 have been reported in patients receiving conventional IV amphotericin B or the lipid formulations of amphotericin B. If severe respiratory distress, anaphylaxis, or an anaphylactoid reaction occurs in a patient receiving amphotericin B, the drug should be discontinued immediately and the patient given appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.201, 202 The manufacturer of amphotericin B lipid complex states that the drug is contraindicated in patients who have experienced severe respiratory distress after receiving a prior dose of the drug.201
Cardiac enlargement with congestive heart failure occurred in a few patients receiving conventional IV amphotericin B with 20-40 mg of hydrocortisone sodium succinate added to each infusion. Congestive heart failure was considered to be due to amphotericin B-induced hypokalemic cardiopathy and corticosteroid-induced salt and fluid retention. (See Drug Interactions: Corticosteroids.) Following discontinuance of hydrocortisone and administration of oral potassium supplements, cardiac status returned to normal although conventional amphotericin B therapy was continued.
In addition to the nausea and vomiting reported as part of acute infusion reactions to the drugs, other adverse GI effects have been reported in patients receiving conventional IV amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal.202 These adverse effects include anorexia and weight loss,201, 417 diarrhea,201, 202, 417 dyspepsia,201, 417 cramping,201, 417 epigastric pain,201, 202, 417 hemorrhagic gastroenteritis,417 GI hemorrhage,201, 202 and melena.201, 417 Alternate-day therapy may decrease the incidence of anorexia.417
IV administration of conventional amphotericin B,211, 417 amphotericin B lipid complex,201 or amphotericin B liposomal202 may cause erythema, pain, or inflammation at the injection site.201, 202, 417 Phlebitis417 or thrombophlebitis211, 417 has been reported with conventional IV amphotericin B. The manufacturers of conventional IV amphotericin B and some clinicians suggest that the addition of 500-1000 units of heparin to the amphotericin B infusion, the use of a pediatric scalp-vein needle, or alternate-day therapy may decrease the incidence of thrombophlebitis.211, 417 Extravasation of the drug causes local irritation.417
Adverse neurologic effects that have been reported in patients receiving conventional IV amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal202 include malaise,201 depression,202 confusion,202 dizziness,202 insomnia,202 somnolence,202 coma,202 anxiety,202 agitation,202 nervousness,202 abnormal thinking,202 hallucinations,202 tremor,202 seizures,201, 202 myasthenia,201 hearing loss,201, 417 tinnitus,201, 417 transient vertigo,201, 417 visual impairment,201, 417 diplopia,201, 417 peripheral neuropathy,201, 417 encephalopathy,201, 417 cerebrovascular accident,201 and extrapyramidal syndrome.201 Leukoencephalopathy has been reported following use of amphotericin B; literature reports suggest that total body irradiation may be a predisposition.417
Adverse musculoskeletal effects, including generalized pain,201, 417 dystonia,202 and muscle,201, 202, 417 bone,201, 202 or joint pain,201, 202, 417 have been reported in patients receiving conventional IV amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal.202
Rash (including maculopapular or vesiculobullous rash),201, 202, 417 purpura,202 pruritus,201, 202, 417 urticaria,202 sweating,201, 202 exfoliative dermatitis,201, 417 erythema multiforme,201 toxic epidermal necrolysis,417 Stevens-Johnson syndrome,417 alopecia,202 dry skin,202 skin discoloration, and ulcer202 have been reported in patients receiving amphotericin B.417
Increased serum concentrations of AST (SGOT),201, 202, 357, 417 ALT (SGPT),201, 202, 357, 417 alkaline phosphatase,201, 202, 357, 417 bilirubin,201, 202, 417γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP),417 and LDH201, 202 have been reported in patients receiving conventional IV amphotericin B,357, 417 amphotericin B lipid complex,201 or amphotericin B liposomal.202 Acute liver failure,417 hepatotoxicity,357 hepatitis,201, 417 jaundice,201, 417 hyperglycemia,201, 202 and hypoglycemia201 have been reported rarely.
Intrathecal† administration of conventional amphotericin B has produced headache, nausea and vomiting, urinary retention, pain along lumbar nerves, paresthesia, vision changes, and arachnoiditis.
Precautions and Contraindications
Initial doses of conventional IV amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal202 should be administered under close clinical observation by medically trained personnel. The fact that acute infusion reactions (e.g., fever, chills, hypotension, nausea, vomiting, headache, dyspnea, and tachypnea) often occur 1-3 hours after initiation of amphotericin B IV infusions (especially after the first few doses) and that severe reactions including anaphylaxis have been reported rarely should be considered.201, 202, 417 Conventional IV amphotericin B is associated with a high incidence of adverse effects and should be reserved principally for the treatment of progressive, potentially life-threatening fungal infections caused by susceptible organisms when the potential benefits of the drug outweigh its untoward and dangerous side effects.417
Renal, hepatic, and hematologic function should be monitored in patients receiving conventional IV amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal.201, 202, 417 Some clinicians suggest that renal function be monitored at least 2-3 times weekly during initial amphotericin B therapy and that hepatic and hematologic function be monitored 1-2 times weekly.346 Serum electrolytes (especially potassium and magnesium) and complete blood cell counts (CBCs) also should be monitored in patients receiving any of these drugs.201, 202, 417 Because of the drug's nephrotoxic potential, conventional IV amphotericin B should be used with caution in patients with reduced renal function and patients receiving any amphotericin B formulation concomitantly with a nephrotoxic drug should be closely monitored.201, 202, 417 (See Drug Interactions: Nephrotoxic Drugs.)
Conventional amphotericin B, amphotericin B lipid complex, and amphotericin B liposomal are contraindicated in patients who are hypersensitive to amphotericin B or any other component in the respective formulation.201, 202, 417 The manufacturers of conventional amphotericin B417 and amphotericin B liposomal202 suggest that use of these drugs can be considered in patients with hypersensitivity if the clinician determines that the benefits of such therapy outweigh the risks;201, 202, 417 however, they are contraindicated in patients who have had severe respiratory distress or a severe anaphylactic reaction while receiving the drugs.201, 202
Although safety and efficacy of conventional IV amphotericin B in pediatric patients have not been established through adequate and well-controlled studies, the drug has been used effectively to treat systemic fungal infections in pediatric patients without unusual adverse effects.417 The manufacturers state that the lowest effective dosage of the drug should be employed whenever conventional IV amphotericin B is used in pediatric patients.417
IV amphotericin B lipid complex generally is well tolerated in pediatric patients, and has been used for the treatment of invasive fungal infections in children 3 weeks to 16 years of age without unusual adverse effects.201, 398 Acute infusion reactions (fever, chills, rigors) and anaphylaxis have been reported in pediatric patients receiving amphotericin B lipid complex and have necessitated discontinuance of the drug in these patients.398
IV amphotericin B liposomal has been administered to pediatric patients 1 month to 16 years of age without any unusual adverse effects.202, 247, 404 Although safety and efficacy of the drug in neonates younger than 1 month of age have not been established to date,202 amphotericin B liposomal has been used in a limited number of neonates† for the treatment of severe fungal infections without any unusual adverse effects.401, 403 Transient hypokalemia that responded to potassium supplementation was the only adverse effect reported in a group of neonates who received amphotericin B liposomal in a dosage of 1-5 mg/kg given by IV infusion over 0.5-1 hours.401 In a large, double-blind study comparing the safety and efficacy of amphotericin B liposomal and conventional IV amphotericin B, the incidence of chills, vomiting, hypokalemia, or hypertension in patients 16 years of age or younger ranged from 10-37% in those receiving amphotericin B liposomal and from 21-68% in those receiving the conventional formulation of the drug.202
While safety and efficacy of conventional IV amphotericin B, amphotericin B lipid complex,201 and amphotericin B liposomal202 have not been studied specifically in geriatric patients, no unusual age-related adverse effects have been reported when the drugs were used in patients 65 years of age or older.
Although clinical experience to date indicates that dosage modification is unnecessary when amphotericin B liposomal is used in geriatric patients, the manufacturer recommends that these patients be carefully monitored while receiving the drug.202
Mutagenicity and Carcinogenicity
There have been no long-term studies to date to evaluate the carcinogenic potential of conventional amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal.202
The mutagenic potential of conventional amphotericin B417 or amphotericin B liposomal has not been evaluated to date.202 There was no evidence of mutagenicity when amphotericin B lipid complex was evaluated using in vitro studies (e.g., bacterial reverse mutation assay, mouse lymphoma forward mutation assay, CHO chromosomal aberration assay) or in vivo studies (e.g., mouse bone marrow micronucleus assay) with or without metabolic activation.201
Pregnancy, Fertility, and Lactation
Safe use of amphotericin B during pregnancy has not been established. Conventional IV amphotericin B has been used to treat systemic fungal infections or visceral leishmaniasis in a limited number of pregnant women without obvious adverse effects to the fetus.417 While reproduction studies in rats and rabbits using conventional amphotericin B,417 amphotericin B lipid complex,201 or amphotericin B liposomal202 have not revealed evidence of harm to the fetus, rabbits receiving amphotericin B liposomal dosages equivalent to 0.5-2 times the usual human dosage experienced a higher rate of spontaneous abortions than the control group.202 However, animal reproduction studies are not always predictive of human response.201, 417 There are no adequate or controlled studies to date using any amphotericin B formulation in pregnant women, and these drugs should be used during pregnancy only when clearly needed.201, 202, 417
There have been no studies to date to determine whether conventional amphotericin B affects fertility.417 Studies in male and female rats using amphotericin B lipid complex at doses up to 0.32 times the usual human dose (based on body surface area) indicate that the drug does not affect fertility.201 When liposomal amphotericin was administered to rats in 10- or 15-mg/kg doses (equivalent to human doses of 1.6 or 2.4 mg/kg based on body surface area), there was evidence of an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in female rats receiving the higher dosage but no effect on fertility or days to copulation; there were no effects on male reproductive function.202
It is not known whether amphotericin B is distributed into human milk.201, 202, 417 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to amphotericin B in nursing infants if it were distributed, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.201, 202, 417
Systematic drug interaction studies have not been performed to date using amphotericin B lipid complex201 or amphotericin B liposomal.202 The fact that drug interactions reported with conventional IV amphotericin B could also occur with these lipid formulations of the drug should be considered.201, 202
Since nephrotoxic effects may be additive, the concurrent or sequential use of IV amphotericin B and other drugs with similar toxic potentials (e.g., aminoglycosides, cyclosporine, pentamidine) should be avoided, if possible.201, 202, 417 Great caution and intensive monitoring of renal function is recommended if any amphotericin B formulation is used concomitantly with a nephrotoxic agent.201, 202, 417
There is evidence from a prospective study in patients undergoing bone marrow transplantation (BMT) that concurrent initiation of cyclosporine and amphotericin B lipid complex therapy may be associated with increased nephrotoxicity.201 In a renal transplant recipient who was receiving cyclosporine and had stable whole blood cyclosporine concentrations, blood cyclosporine concentrations in the days after initiation of amphotericin B lipid complex therapy were more than twice those reported prior to initiation of antifungal therapy; however, this increase was transient and did not necessitate adjustment of cyclosporine dosage.368
Acute, reversible renal failure occurred in at least 4 patients with human immunodeficiency virus (HIV) infection who received IV amphotericin B concomitantly with IV or IM pentamidine;365 there was no evidence of adverse renal effects in patients who received IV amphotericin B concomitantly with pentamidine administered by oral inhalation.365
Drugs Affected by Potassium Depletion
Because amphotericin B may induce hypokalemia, the drug may predispose patients receiving cardiac glycosides to glycoside-induced cardiotoxicity and may enhance the effects of skeletal muscle relaxants (e.g., tubocurarine).201, 417 Serum potassium concentrations should be monitored closely in patients receiving any amphotericin B formulation concomitantly with a cardiac glycoside or skeletal muscle relaxant.201, 202, 417
In some in vitro studies, the combination of flucytosine and amphotericin B resulted in synergistic inhibition417 of strains of Cryptococcus neoformans , Candida albicans , and C. tropicalis . The suggested mechanism of the synergism is that the binding of amphotericin B to sterols in cell membranes increases the permeability of the cytoplasmic membrane, thus allowing greater penetration of flucytosine into the fungal cell. However, in a study evaluating the antifungal effects of the drugs in the presence of serum, the combination of amphotericin B and flucytosine was not additive or synergistic against C. albicans .305
There is some evidence that concomitant use of amphotericin B and flucytosine may increase the toxicity of flucytosine, possibly by increasing cellular uptake and/or by decreasing renal excretion of the drug.201, 417 Flucytosine and amphotericin B should be used concomitantly with caution.201 If flucytosine is used in conjunction with amphotericin B, especially in HIV-infected patients, serum flucytosine concentrations and blood cell counts should be monitored carefully.169, 182, 197, 346 In addition, it has been suggested that flucytosine be initiated at a low dosage (i.e., 75-100 mg/kg daily) and subsequent dosage adjusted based on serum flucytosine concentrations.126, 346, 436
Imidazole and Triazole Antifungal Agents
Although the clinical importance is unclear, results of in vitro studies evaluating the antifungal effects of amphotericin B used concomitantly with imidazole- or triazole-derivative antifungals (e.g., clotrimazole, fluconazole, itraconazole, ketoconazole) against C. albicans , C. pseudotropicalis , C. glabrata , or Aspergillus fumigatus indicate that antagonism can occur with these combinations.312, 336 Since amphotericin B exerts its antifungal activity by binding to sterols in the fungal cell membrane and imidazoles and triazoles act by altering the cell membrane, antagonism is theoretically possible; however, it is unclear whether such antagonism actually would occur in vivo.309 Results of studies evaluating combined use of amphotericin B and fluconazole, ketoconazole, or itraconazole in animal models of aspergillosis, candidiasis, or cryptococcosis have been conflicting.309, 314, 336 While antagonism occurred in some models ( A. fumigatus infection in mice, rabbits, or rats treated with amphotericin B and fluconazole or itraconazole), these combinations resulted in additive or indifferent effects in other models (e.g., C. albicans or C. neoformans infection in mice or rabbits treated with amphotericin B and fluconazole).309, 314, 336 In a few studies evaluating the drugs in murine cryptococcosis or candidiasis, sequential use of an initial large dose of amphotericin B followed by an azole antifungal (e.g., fluconazole) was uniformly effective in prolonging survival and decreasing fungal burden.336 Because further study is needed regarding the interaction between amphotericin B and imidazole- or triazole-derivative antifungals (e.g., fluconazole, itraconazole, or ketoconazole), such combination therapy should be used with caution, particularly in immunocompromised patients.202, 336, 417
Results of an in vitro study indicate that the combination of amphotericin B and fluconazole or itraconazole may be synergistic, additive, or indifferent against Pseudallescheria boydii ; there was no evidence of antagonism.315
Norfloxacin may enhance the antifungal activity of some antifungals (e.g., amphotericin B, flucytosine, ketoconazole, nystatin).142 There are conflicting reports on this interaction, however, and in at least one in vitro study norfloxacin had no effect on the antifungal activity of amphotericin B.143 Further study is needed to evaluate the antifungal effect when norfloxacin is used in conjunction with an antifungal.143
Results of an in vitro study indicate that the combination of rifabutin and amphotericin B may be additive or synergistic against Aspergillus fumigatus , A. flavus , Fusarium solani , F. moniliforme , F. pallidoroseum (formerly F. semitectum ), and F. proliferatum ; there was no evidence of antagonism with this combination.364 While rifabutin has no in vitro antifungal activity against Aspergillus or Fusarium when used alone, an antifungal effect was evident when the drug was used in combination with amphotericin B.364
Results of a study in dogs indicate that concomitant administration of zidovudine and conventional amphotericin B (at 0.5 times the recommended human dosage) or amphotericin B lipid complex (at 0.16 or 0.5 times the recommended human dosage) for 30 days was associated with increased myelotoxicity and nephrotoxicity.201 Although the clinical importance of this animal study is unclear, renal and hematologic function should be closely monitored in patients receiving zidovudine concomitantly with amphotericin B.201
The manufacturers state that antineoplastic agents (e.g., mechlorethamine) may enhance the potential for renal toxicity, bronchospasm, and hypotension in patients receiving amphotericin B and such concomitant therapy should be used only with great caution.201, 202, 417
Corticosteroids reportedly may enhance the potassium depletion caused by conventional amphotericin B.417 The manufacturers state that concomitant use of corticosteroids should be avoided, unless necessary to control adverse effects of conventional amphotericin B.417 In such cases, the corticosteroid should be administered using minimal dosage for as short a duration as possible.417
If corticosteroids are used concomitantly with any amphotericin B formulation, serum electrolytes and cardiac function should be monitored closely.201, 202, 417
IV infusion of conventional amphotericin B during or shortly after leukocyte transfusions has rarely been associated with acute pulmonary reactions199, 417 characterized by acute dyspnea, tachypnea, hypoxemia, hemoptysis, and diffuse interstitial infiltrates.199 The most severe pulmonary reactions have been reported when amphotericin B was administered within the first 4 hours after a leukocyte transfusion; respiratory deterioration appeared to contribute to death in at least 5 patients with such reactions.199
It has been recommended that amphotericin B be used with caution in patients receiving leukocyte transfusions, especially in those with gram-negative septicemia.199 The manufacturer of amphotericin B lipid complex states that the drug should not be used concurrently with leukocyte transfusions.201 The manufacturers of conventional amphotericin B recommend that doses of the drug be separated in time as much as possible from leukocyte transfusions and that pulmonary function be monitored in patients receiving both therapies.417
Acute overdosage of conventional amphotericin B may result in potentially fatal cardiac or cardiorespiratory arrest.417 Adverse cardiovascular effects, including hypotension, bradycardia, and cardiac arrest, have been reported in several pediatric patients who inadvertently received overdosage of conventional amphotericin B.363 One child who received conventional amphotericin B in a dosage of 4.6 mg/kg given by IV infusion over 2 hours experienced vomiting, followed by seizures, and cardiac arrest immediately after the infusion.363, 202
In patients who received 1 or more amphotericin B lipid complex doses of 7-13 mg/kg., serious acute reactions did not occur.201
Information on acute toxicity of amphotericin B liposomal is not available.202 There was no reported dose-related toxicity following repeated daily doses up to 15 mg/kg in adult patients or up to 10 mg/kg in pediatric patients.202
In the event of overdosage with any amphotericin B formulation, therapy with the drug should be discontinued and the patient's clinical status (e.g., cardiorespiratory, renal, and liver function, hematologic status, serum electrolytes) monitored.201, 417, 417 Supportive therapy should be administered as required.201, 202, 417 Amphotericin B is not removed by hemodialysis.201, 417 The manufacturers of conventional amphoteric B state that the patient's condition should be stabilized, including correction of electrolyte abnormalities, prior to reinstituting the drug.417
Amphotericin B usually is fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms.308, 313, 417 Amphotericin B exerts its antifungal activity principally by binding to sterols (e.g., ergosterol) in the fungal cell membrane.201, 202, 269, 417 As a result of this binding, the cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs.417 Cell death occurs in part as a result of permeability changes,417 but other mechanisms also may contribute to the in vivo antifungal effects of amphotericin B against some fungi.141, 326, 327, 346 Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (e.g., bacteria).
Binding to sterols in mammalian cells (such as certain kidney cells and erythrocytes) may account for some of the toxicities reported with conventional amphotericin B therapy.201, 202, 417 At usual therapeutic concentrations of amphotericin B, the drug does not appear to hemolyze mature erythrocytes, and the anemia seen with conventional IV amphotericin B therapy may result from the action of the drug on actively metabolizing and dividing erythropoietic cells.
Amphotericin B is active against most pathogenic fungi, including yeasts, and also is active against some protozoa.312, 315, 339, 417 Amphotericin B is inactive against bacteria, rickettsiae, or viruses.417
In vitro, amphotericin B concentrations of 0.03-1.0 mcg/mL usually inhibit Aspergillus fumigatus ,392 A. flavus ,392 Coccidioides immitis ,417 C. posadasii ,446, 447 Cryptococcus neoformans ,385, 391, 417 C. gattii ,453 Exophiala castellanii ,258 E. spinifera ,258 Histoplasma capsulatum ,417 Rhodotorula ,417 and Sporothrix schenckii .417 Blastomyces dermatitidis may require slightly higher drug concentrations for inhibition.
Amphotericin B is active in vitro against most strains of Candida .312, 385, 388, 389, 391 In vitro, C. albicans ,385, 388, 391 C. dubliniensis ,389 C. glabrata (formerly Torulopsis glabrata ),385, 391 C. krusei ,385 C. parapsilosis ,385, 391 and C. tropicalis 385, 391 usually are inhibited by amphotericin B concentrations of 0.03-1 mcg/mL.312, 388, 389, 391 In a study evaluating in vitro susceptibility of clinical isolates of C. dubliniensis obtained from patients with or without human immunodeficiency virus (HIV) infection, these strains were inhibited by amphotericin B concentrations of 0.03-0.125 mcg/mL.389 While some strains of C. lusitaniae are inhibited in vitro by amphotericin B concentrations of 0.06-0.5 mcg/mL,386 other strains appear to be resistant to the drug.343, 399, 402 Clinical isolates of C. auris (often misidentified as C. haemulonii , C. famata , or Rhodotorula glutinis ) generally have been inhibited in vitro by amphotericin B concentrations of 0.5-1 mcg/mL.506, 508, 509
Some Penicillium marneffei isolates have been inhibited in vitro by amphotericin B concentrations of 0.002-4 mcg/mL,409, 445 but other strains required concentrations as high as 32 mcg/mL for in vitro inhibition.409
Many zygomycetes, including Lichtheimia (formerly Absidia ),418, 419 Mucor ,417, 418, 419 Rhizopus ,418, 419 Rhizomucor ,418, 419 Apophysomyces elegans ,368, 418, 419 and Cunninghamella ,418, 419 are inhibited in vitro by amphotericin B concentrations of 0.003-2 mcg/mL.418, 419 Some clinical isolates of Basidiobolus , including B. ranarum , have amphotericin B MICs of 0.5-4 mcg/mL;414, 415, 419, 421 however, other isolates are resistant to the drug.414, 415 Conidiobolus coronatus has been inhibited in vitro by amphotericin B concentrations of 0.5-4 mcg/mL.421
While some strains of Pseudallescheria boydii are inhibited in vitro by amphotericin B concentrations of 0.5 mcg/mL or less,315 most strains are resistant to the drug.417 Amphotericin B concentrations of 1-16 mcg/mL were necessary for in vitro inhibition of clinical isolates of Scedosporium apiospermum or S. prolificans , and these filamentous fungi probably are resistant to the drug.392
Amphotericin B is active against Exserohilum ,480, 481, 482 and E. rostratum has been inhibited in vitro by amphotericin B concentrations of 0.03-0.5 mcg/mL.480, 481 In vitro studies of E. rostratum obtained from patients with infections related to injections of contaminated methylprednisolone acetate preparations (see Uses: Exserohilum Infections) indicate that the MIC of amphotericin B was 0.032-2 mcg/mL for these strains.477 However, the clinical relevance of MIC testing for E. rostratum remains uncertain, and MIC values indicating susceptibility have not been identified.477
While many strains of Fusarium are resistant to amphotericin B,417 some strains of F. solani , F. oxysporum , and F. verticillioides have been inhibited in vitro by amphotericin B concentrations of 2-8 mcg/mL.57 Some strains of Scopulariopsis , including some strains of S. acremonium and S. brevicaulis , are inhibited in vitro by amphotericin B concentrations of 1-4 mcg/mL; other strains are resistant to the drug.405
In one in vitro study, MICs of conventional amphotericin B reported for B. dermatitidis , C. immitis , H. capsulatum , P. brasiliensis , C. albicans , C. tropicalis , C. parapsilosis , and C. neoformans ranged from 0.125-2 mcg/mL.385 C. glabrata or A. fumigatus were inhibited in vitro by conventional amphotericin B concentrations of 1-2 mcg/mL;385 A. flavus was inhibited in vitro by conventional amphotericin B concentrations of 4 mcg/mL.385 In a study that evaluated the in vitro susceptibility of C. albicans , C. parapsilosis , C. tropicalis , and C. glabrata to several different amphotericin B formulations, MICs reported for conventional amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal were 0.1-0.78, 0.2-0.78, or 0.2-6.25 mcg/mL, respectively.339 When C. krusei was tested, the MICs of conventional amphotericin B or amphotericin B lipid complex were 0.78-1.56 or 3.13-6.25 mcg/mL, respectively; however, MICs of amphotericin B liposomal reported for this organism were greater than 50 mcg/mL.339
Amphotericin B is active in vitro102 and in vivo102, 103, 104, 105, 106, 107, 108, 109 against Leishmania braziliensis . The drug also is active in vitro111, 112, 113, 114 and in vivo107, 108, 109, 115, 116, 117 against L. mexicana 107, 108, 109, 111 and L. donovani ,108, 111, 112, 113, 114, 115, 116, 117 including antimony-resistant strains of the organisms.107, 108, 109, 111, 112, 113, 114, 115, 116, 117 In vitro, amphotericin B concentrations of 1 mcg/mL result in complete elimination of L. donovani amastigotes in human monocyte-derived macrophages and L. donovani promastigotes in cell-free media.114 The drug also is active in vitro against L. tropica .111, 114
Amphotericin B is active in vitro118, 119, 120, 121, 124, 125 and apparently in vivo118, 119, 122, 123, 124 against Naegleria spp., particularly N. fowleri . The drug has variable and limited activity in vitro against Acanthamoeba castellanii and A. polyphaga .121, 125
Resistance to amphotericin B has been produced in vitro by serial passage of fungi in the presence of increasing concentrations of the drug,201, 202 and resistant strains of some fungi (e.g., Candida ) have been isolated from patients who received long-term therapy with conventional amphotericin B.201, 202, 269, 294, 299, 343 Amphotericin B-resistant Candida are reported relatively infrequently; however, primary resistance to the drug occurs in some strains of C. lusitaniae 343 and also occurs in C. guilliermondii .343, 346 Some clinical isolates of C. auris have reduced susceptibility or resistance to amphotericin B in vitro (i.e., MIC 2 mcg/mL or greater).504, 505, 508, 509
While the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised individuals, including leukemia patients387 and patients with human immunodeficiency virus (HIV) infection.218 In addition, a few isolates of Cryptococcus neoformans resistant to fluconazole also have been resistant to amphotericin B.349
Fungi resistant to conventional amphotericin B also may be resistant to amphotericin B lipid complex and amphotericin B liposomal.201, 202
The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B lipid complex, or amphotericin B liposomal, and pharmacokinetic parameters reported for one amphotericin B formulation should not be used to predict the pharmacokinetics of any other amphotericin B formulation.201, 202, 205, 210, 332, 417
In general, usual dosages of amphotericin B lipid complex result in lower serum concentrations of amphotericin B and greater volumes of distribution than those reported for the conventional formulation of the drug.201, 206, 207, 210, 265, 333 Plasma drug concentrations attained after administration of amphotericin B liposomal generally are higher and the volume of distribution is lower than those reported for similar doses of conventional amphotericin B.202, 205, 209, 210, 269, 332 The clinical importance of differences in pharmacokinetics of the various amphotericin B formulations has not been elucidated, and interpretation of serum or tissue concentrations of amphotericin B reported in published studies is complicated by the fact that many assays used to measure the drug do not differentiate between free amphotericin B and amphotericin B that is lipid-complexed, liposome-encapsulated, or protein-bound.205, 233 It has been suggested that differences in the distribution and clearance of amphotericin B following administration of lipid-complexed or liposomal-encapsulated formulations relative to those reported following administration of conventional amphotericin B (i.e., increased uptake by the liver and spleen and decreased kidney concentrations) are one of several factors that may contribute to the improved toxicity profiles reported for these formulations; however, how these pharmacokinetic differences affect the therapeutic efficacy of the various formulations is unclear.205, 209, 210, 233, 234, 332, 338 The manufacturers' literature and specialized references should be consulted for information regarding the absorption, distribution, or elimination of amphotericin B administered as amphotericin B lipid complex or amphotericin B liposomal.201, 202, 205, 207, 332
After an initial IV infusion of 1-5 mg of amphotericin B daily, with dosage gradually increased to 0.4-0.6 mg/kg daily, plasma concentrations ranging from approximately 0.5-2 mcg/mL were reported.417 Following a rapid initial decrease, plasma concentrations plateau at about 0.5 mcg/mL.417
In one study, immediately after completion of IV infusion of 30 mg of amphotericin B (administered as conventional amphotericin B over a period of several hours), average peak serum concentrations were about 1 mcg/mL; when the dose was 50 mg, average peak serum concentrations were approximately 2 mcg/mL. Immediately after infusion, no more than 10% of the amphotericin B dose can be accounted for in serum. Average minimum serum concentrations (recorded just prior to the next drug infusion) of approximately 0.4 mcg/mL have been reported when 30-mg doses of conventional amphotericin B were given once daily or 60-mg doses were given every other day.
Information on the distribution of amphotericin B is limited.417
The volume of distribution of the drug following administration of conventional amphotericin B has been reported to be 4 L/kg.
Amphotericin B concentrations attained in inflamed pleura, peritoneum, synovium, and aqueous humor following IV administration of conventional amphotericin B reportedly are about 60% of concurrent plasma concentrations.417 Penetration into vitreous humor is low.417
Following IV administration of conventional amphotericin B, CSF concentrations of the drug rarely exceed 2.5% of concurrent serum concentrations.417 To achieve fungistatic CSF concentrations, the drug must usually be administered intrathecally†.126, 211, 426, 440, 441, 455, 457 In patients with meningitis, intrathecal† administration of 0.2-0.3 mg of conventional amphotericin B via a subcutaneous reservoir has produced peak CSF concentrations of 0.5-0.8 mcg/mL; 24 hours after the dose, CSF concentrations were 0.11-0.29 mcg/mL. Amphotericin B is removed from the CSF by arachnoid villi and appears to be stored in the extracellular compartment of the brain, which may act as a reservoir for the drug.
Low concentrations of amphotericin B are attained in amniotic fluid.417
It is not known whether amphotericin B is distributed into milk.201, 202, 417
Amphotericin B is more than 90% bound to plasma proteins.417
The metabolic fate of amphotericin B in humans has not been fully elucidated.417
Following IV administration of conventional amphotericin B in patients whose renal function is normal prior to therapy, the initial plasma half-life is approximately 24 hours.417 After the first 24 hours, the rate at which amphotericin B is eliminated decreases and an elimination half-life of approximately 15 days has been reported.417
Conventional amphotericin B is eliminated very slowly (over weeks to months) by the kidneys;417 slow release of the drug from the peripheral compartment may account for the long elimination half-life. Over a 7-day period, the cumulative urinary excretion of a single dose of conventional amphotericin B is about 40% of the administered drug. It has been estimated that only about 2-5% of a total dose of amphotericin B is excreted in urine unchanged.417 When conventional IV amphotericin B therapy is discontinued, the drug can be detected in blood for up to 4 weeks and in urine for up to 4-8 weeks.
Amphotericin B is not hemodialyzable.201, 417
Amphotericin B is an antifungal antibiotic produced by Streptomyces nodosus .201, 202, 417 The drug is an amphoteric polyene macrolide which occurs as a yellow to orange, odorless or practically odorless powder and is insoluble in water and in anhydrous alcohol. Each mg of amphotericin B contains not less than 750 mcg of anhydrous drug, and amphotericin A (a contaminant of amphotericin B) may be present in a concentration of not more than 5%. Because amphotericin B is amphoteric, it can form salts in acidic or basic media. Although the salts are more water soluble, they have less antifungal activity.
Various amphotericin B preparations are commercially available for parenteral administration.201, 202, 417 Amphotericin B formulated with sodium desoxycholate (conventional amphotericin B) was the first parenteral amphotericin B preparation to become commercially available.205, 211, 269, 333, 417 Because conventional amphotericin B is associated with certain dose-limiting toxicities (principally nephrotoxicity), various other formulations have been investigated with the goal of increasing the tolerability of amphotericin B without compromising the antifungal effects of the drug.205, 207, 210, 211, 269 As a result, amphotericin B now also is commercially available as amphotericin B lipid complex and amphotericin B liposomal.201, 202 These formulations contain novel lipid-based drug delivery systems that may affect the pharmacokinetics and functional properties of amphotericin B and improve the toxicity profile of the drug.206, 207, 208, 210, 211, 233, 234
Conventional amphotericin B for injection contains amphotericin B and sodium desoxycholate.417 Amphotericin B is insoluble in water; presence of sodium desoxycholate in the formulation solubilizes amphotericin B during reconstitution with sterile water providing a colloidal dispersion of the drug.205, 334, 417 Commercially available conventional amphotericin B occurs as a sterile, yellow to orange lyophilized cake which may partially reduce to powder following manufacture.417 Each vial labeled as containing 50 mg of amphotericin B contains 41 mg of sodium desoxycholate and is buffered with 20.2 mg of sodium phosphates; at the time of manufacture, air in the vial is replaced with nitrogen.417
Extemporaneous lipid emulsions of conventional IV amphotericin B have been prepared by diluting the drug in 20% fat emulsion (Intralipid®) in an attempt to provide a vehicle for amphotericin B that would decrease the nephrotoxicity of the drug;328, 329, 330, 331, 334, 335, 351, 352, 353, 354 however, because of limited information on the safety and efficacy of these admixtures, lack of standardization, and the commercial availability of lipid formulations of amphotericin B, these extemporaneous lipid emulsions are not recommended.328, 330, 346, 352, 353
Amphotericin B lipid complex (ABLC; Abelcet®) consists of a 1:1 molar ratio of amphotericin B complexed to a phospholipid vehicle composed of a 7:3 molar ratio of L-α-dimyristoylphosphatidylcholine (DMPC) to L-α-dimyristoylphosphatidylglycerol (DMPG).201, 206, 210, 333 The amphotericin B-phospholipid complex has a microscopic, ribbon-like structure with a diameter of about 2-11 µm.205, 206, 210, 333 Each mL of commercially available amphotericin B lipid complex suspension contains 5 mg of amphotericin B, 3.4 mg of DMPC, 1.5 mg of DMPG, and 9 mg of sodium chloride.201 The suspension occurs as a yellow, opaque liquid with a pH of 5-7.201
Commercially available amphotericin B liposomal (L-AmB; AmBisome®) is a lyophilized powder containing amphotericin B intercalated into a unilamellar bilayer liposomal membrane.202, 206 Liposomes are microscopic vesicles composed of a phospholipid bilayer capable of encapsulating drugs; the lipid bilayer separates the internal aqueous core from the external environment.202, 205, 206 The liposomal membranes used in commercially available amphotericin B liposomal have a diameter of less than 100 nm and consist of hydrogenated soy phosphatidylcholine (HSPC), cholesterol, distearoylphosphatidylglycerol, and alpha tocopherol.202, 209 Commercially available amphotericin B liposomal also contains sucrose for isotonicity and disodium succinate hexahydrate as a buffer.202 Because of the amphophilic substances used in the membrane and the lipophilic nature of amphotericin B, the drug is an integral part of the overall structure of the liposomes.202 Reconstitution of commercially available amphotericin B liposomal with sterile water for injection results in a yellow, translucent suspension with a pH of 5-6.202
Conventional amphotericin B powder for injection should be stored at 2-8°C and protected from light.417
Following reconstitution with sterile water for injection, colloidal solutions of conventional amphotericin B containing 5 mg/mL should be protected from light and are stable for 24 hours at room temperature or 1 week when refrigerated.417
Reconstituted colloidal solutions of conventional amphotericin B must be diluted only with 5% dextrose in water having a pH greater than 4.2 since the colloidal particles of the drug tend to coagulate quickly at pH less than 5.417 (See Reconstitution and Administration: Conventional Amphotericin B, in Dosage and Administration.) IV solutions of the drug containing 0.1 mg/mL or less should be used promptly after dilution.417 Although the manufacturers state that IV infusions of amphotericin B should be protected from light during administration,417 potency is unaffected if reconstituted dispersions or IV infusions of the drug are exposed to light for less than 8-24 hours.346
Dilutions of amphotericin B apparently are compatible with limited amounts of heparin sodium and hydrocortisone sodium succinate or methylprednisolone sodium succinate. Specialized references should be consulted for specific compatibility information.
Commercially available amphotericin B lipid complex (Abelcet®) suspension for IV infusion should be refrigerated at 2-8°C and protected from light.201 Following dilution in 5% dextrose injection, amphotericin B lipid complex is stable for up to 48 hours at 2-8°C and for an additional 6 hours at room temperature.201 Amphotericin B lipid complex suspension and dilutions of the drug should not be frozen; any unused solutions of the drug should be discarded.201
Commercially available lyophilized amphotericin B liposomal (AmBisome®) should be stored at 25°C or lower.202 Following reconstitution with sterile water for injection, liposomal amphotericin B solutions containing 4 mg/mL may be stored for up to 24 hours at 2-8°C and should not be frozen.202 IV infusions of amphotericin B liposomal should be initiated within 6 hours after dilution in 5% dextrose injection.202 Any partially used vials of the drug should be discarded.202
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 50 mg* | Amphotericin B for Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
57. Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev . 2007; 20:695-704. [PubMedCentral][PubMed 17934079]
100. Peterson LR, Hall WH, Kelty RH et al. Therapy of Candida peritonitis: penetration of amphotericin B into peritoneal fluid. Postgrad Med J . 1978; 54:340-2. [PubMedCentral][PubMed 673990]
101. Heidemann HT, Gerkens JF, Spickard WA et al. Amphotericin B nephrotoxicity in humans decreased by salt repletion. Am J Med . 1983; 75:476-81. [PubMed 6614033]
102. Furtado TA. Clinical results in the treatment of American leishmaniasis with oral and intravenous amphotericin. Antibiot Annu . 1959-1960:631-7.
103. Sampaio SAP, Godoy JT, Paiva L et al. The treatment of American (mucocutaneous) leishmaniasis with amphotericin B. Arch Dermatol . 1960; 82:627-35. [PubMed 13745957]
104. Sampaio SAP, Castro RM, Dillon NL et al. Treatment of mucocutaneous (American) leishmaniasis with amphotericin B: report of 70 cases. Int J Dermatol . 1971; 10:179-81. [PubMed 5116171]
105. Crofts MAJ. Use of amphotericin B in mucocutaneous leishmaniasis. J Trop Med Hyg . 1976; 79:111-3. [PubMed 933229]
106. Singer C, Armstrong D, Jones TC et al. Imported mucocutaneous leishmaniasis in New York City: report of a patient treated with amphotericin B. Am J Med . 1975; 59:444-7. [PubMed 1163553]
107. Chulay JD. Cutaneous leishmaniasis of the new world. In: Strickland GT, ed. Hunter's tropical medicine. 6th ed. Philadelphia: WB Saunders; 1984:589-93.
108. World Health Organization. Control of leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniasis, Geneva, 22-26 March 2010. Who Technical Report Series No. 949. Geneva: World Health Organization; 2010.
109. Kerdel-Vegas F. American leishmaniasis. Int J Dermatol . 1982; 21:291-303. [PubMed 6749711]
111. Berman JD. in vitro susceptibility of antimony-resistant Leishmania to alternative drugs. J Infect Dis . 1982; 145:279. [PubMed 6274970]
112. McMillan B. The inhibition of leptomonads of the genus Leishmania in culture by antifungal agents. Ann Trop Med Parasitol . 1960; 54:293-300.
113. Ghosh BK, Ghosh A. The effects of antibiotics on Leishmania donovani . Dermatol Int . 1967; 6:154-60. [PubMed 5590117]
114. Berman JD, Wyler DJ. An in vitro model for investigation of chemotherapeutic agents in leishmaniasis. J Infect Dis . 1980; 142:83-6. [PubMed 6249874]
115. Prata A. Treatment of kala-azar with amphotericin B. Trans R Soc Trop Med Hyg . 1963; 57:266-8. [PubMed 14047022]
116. Yesudian P, Thambiah AS. Amphotericin B therapy in dermal leishmanoid. Arch Dermatol . 1974; 109:720-2. [PubMed 4828540]
117. Chulay JD, Manson-Bahr PEC. Visceral leishmaniasis (kala-azar). In: Strickland GT, ed. Hunter's tropical medicine. 6th ed. Philadelphia: WB Saunders Company; 1984:578-85.
118. Carter RF. Sensitivity to amphotericin B of a Naegleria sp. isolated from a case of primary amoebic meningoencephalitis. J Clin Pathol . 1969; 22:470-4. [PubMedCentral][PubMed 5798635]
119. Duma RJ, Rosenblum WI, McGehee RF et al. Primary amoebic meningoencephalitis caused by Naegleria : two new cases, response to amphotericin B, and a review. Ann Intern Med . 1971; 74:861-9. [PubMed 5580636]
120. Schuster FL, Rechthand E. In vitro effects of amphotericin B on growth and ultrastructure of the amoeboflagellates Naegleria gruberi and Naegleria fowleri. Antimicrob Agents Chemother . 1975; 8:591-605.
121. Duma RJ, Finley R. In vitro susceptibility of pathogenic Naegleria and Acanthamoeba species to a variety of therapeutic agents. Antimicrob Agents Chemother . 1976; 10:370-6. [PubMedCentral][PubMed 984777]
122. Anderson K, Jamieson A. Primary amoebic meningoencephalitis. Lancet . 1972; 1:902-3. [PubMed 4111856]
123. Apley J, Clarke SKR, Roome APCH et al. Primary amoebic meningoencephalitis in Britain. Br Med J . 1970; 1:596-9. [PubMedCentral][PubMed 5440234]
124. Seidel JS, Harmatz P, Visvesvara GS et al. Successful treatment of primary amebic meningoencephalitis. N Engl J Med . 1982; 306:346-8. [PubMed 7054710]
125. Nagington J, Richards JE. Chemotherapeutic compounds and Acanthamoebae from eye infections. J Clin Pathol . 1976; 29:648-51. [PubMedCentral][PubMed 185240]
126. Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone Inc; 1995:2300-9,2316-23,2336-8,2350-1,2371,2388-9,2413,2428-36,2714-9.
127. Ezdinli EZ, O'Sullivan DD, Wasser LP et al. Oral amphotericin for candidiasis in patients with hematologic neoplasms: an autopsy study. JAMA . 1979; 242:258-60. [PubMed 376883]
128. Dekker AW, Rozenberg-Arska M, Sixma JJ et al. Prevention of infection by trimethoprim-sulfamethoxazole plus amphotericin B in patients with acute nonlymphocytic leukaemia. Ann Intern Med . 1981; 95:555-9. [PubMed 6794406]
129. Guiot HF, van der Meer JW, van Furth R. Selective antimicrobial modulation of human microbial flora: infection prevention in patients with decreased host defense mechanisms by selective elimination of potentially pathogenic bacteria. J Infect Dis . 1981; 143:644-54. [PubMed 7017019]
130. Hann IM, Prentice HG, Corringham R et al. Ketoconazole versus nystatin plus amphotericin B for fungal prophylaxis in severely immunocompromised patients. Lancet . 1982; 1:826-9. [PubMed 6122057]
131. Kay HEM, Watson JG, Jameson B et al. Infection after bone marrow transplantation using cyclosporine. Transplantation . 1983; 36:491-5. [PubMed 6314614]
132. Wolff LJ. Supportive care for children with cancer. Guidelines of the Children's Cancer Study Group. Use of prophylactic antibiotics. Am J Pediatr Hematol Oncol . 1984; 6:267-76. [PubMed 6393790]
133. Meunier-Carpentier F. Chemoprophylaxis of fungal infections. Am J Med . 1984; 76:652-6. [PubMed 6324589]
134. Simor AE, Goswell G, Louis L et al. Antifungal susceptibility testing of yeast isolates from blood cultures by microbroth dilution and the E test. Eur J Clin Microb Infect Dis . 1997; 16:693-7.
136. Gigliotti F, Shenep JL, Lott L et al. Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B. J Infect Dis . 1987; 156:784-9. [PubMed 3309074]
137. Scott EN, Kaufman L, Brown AC et al. Serologic studies in the diagnosis and management of meningitis due to Sporothrix schenckii . N Engl J Med . 1987; 317:935-40. [PubMed 3306388]
138. Gullberg RM, Quintanilla A, Levin ML et al. Sporotrichosis: recurrent cutaneous, articular, and central nervous system infection in a renal transplant recipient. Rev Infect Dis . 1987; 9:369-75. [PubMed 3296101]
139. Freeman JW, Ziegler DK. Chronic meningitis caused by Sporotrichum schenckii . Neurology . 1977; 27:989-92. [PubMed 561914]
140. Klein RC, Ivens MS, Seabury JH et al. Meningitis due to Sporotrichum schenckii . Arch Intern Med . 1966; 118:145-9. [PubMed 5329613]
141. Mozaffarian N, Berma JW, Casadevall A. Enhancement of nitric oxide synthesis by macrophages represens an additional mechanism of amphotericin B. Antimicrob Agents Chemother . 1997; 41:1825-9. [PubMedCentral][PubMed 9257771]
142. Holmes B, Brogden RN, Richards DM. Norfloxacin: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs . 1985; 30:1-11.
143. Overbeek BP, Rozenberg-Arska M, Verhoef J. Do quinolones really augment the antifungal effect of amphotericin B in vitro? Drugs Exp Clin Res . 1985; 11:745-6.
144. Zuger A, Schuster M, Simberkoff MS et al. Maintenance amphotericin B for cryptococcal meningitis in acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1988; 109:592-3. [PubMed 3421567]
145. Zuger A, Louie E, Holzman RS et al. Cryptococcal disease in patients with the acquired immunodeficiency syndrome: diagnostic features and outcome of treatment. Ann Intern Med . 1986; 104:234-40. [PubMed 3946951]
147. National Institutes of Health Office of Medical Applications of Research. Consensus development conference statement: Oral complications of cancer therapies: diagnosis, prevention, and treatment. 1989:7.
150. Li PK, Lai KN. Amphotericin B induced ocular toxicity in cryptococcal meningitis. Br J Ophthalmol . 1989; 73:397-8. [PubMedCentral][PubMed 2730866]
151. Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new triazoles. Antimicrob Agents Chemother . 1988; 32:1-8. [PubMedCentral][PubMed 2831809]
152. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern Med . 1988; 109:177-9. [PubMed 2839058]
153. Foulds G, Brennan DR, Wajszczuk C et al. Fluconazole penetration into cerebrospinal fluid in humans. J Clin Pharmacol . 1988; 28:363-6. [PubMed 2839557]
155. Sugar AM, Saunders C. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med . 1988; 85:481-9. [PubMed 2845779]
156. Dupont B, Drouhet E. Cryptococcal meningitis and fluconazole. Ann Intern Med . 1987; 106:778. [PubMed 3032037]
157. Byrne WR, Wajszczuk CP. Cryptococcal meningitis in the acquired immunodeficiency syndrome (AIDS): successful treatment with fluconazole after failure of amphotericin B. Ann Intern Med . 1988; 108:384-5. [PubMed 2829678]
158. Esposito R, Foppa CU, Antinori S. Fluconazole for cryptococcal meningitis. Ann Intern Med . 1989; 110:170. [PubMed 2535777]
159. Stern JJ, Hartman BJ, Sharkey P et al. Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med . 1988; 85:477-80. [PubMed 2845778]
160. Tozzi V, Bordi E, Galgani S et al. Fluconazole treatment of cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med . 1989; 87:353. [PubMed 2549790]
161. Larsen RA, Bozzette S, McCutchan A et al. Persistent Cryptococcus neoformans infection of the prostate after successful treatment of meningitis. The California Collaborative Treatment Group. Ann Intern Med . 1989; 111:125-8. [PubMed 2545124]
162. Glatt AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med . 1988; 318:1439-48. [PubMed 3285211]
163. De Wit S, Weerts D, Goossens H et al. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet . 1989; 1:746-8. [PubMed 2564563]
164. Jacobson CE (Roerig, New York, NY): Personal communication; 1989 Feb 28.
165. Mau S, Salamone FR, Muller RJ et al. Trimetrexate, ganciclovir, foscarnet and fluconazole: investigational drugs used in the management of AIDS. Hosp Pharm . 1989; 24:209-15.
166. Jones PD, Marriott D, Speed BR. Efficacy of fluconazole in cryptococcal meningitis. Diagn Microbiol Infect Dis . 1989; 12:235S-8S. [PubMed 2556240]
167. Warnock DW. Itraconazole and fluconazole: new drugs for deep fungal infection. J Antimicrob Chemother . 1989; 24:275-80. [PubMed 2553654]
168. Washton H. Review of fluconazole: a new triazole antifungal agent. Diagn Microbiol Infect Dis . 1989; 12:229S-33S. [PubMed 2556239]
169. Dismukes WE. Cryptococcal meningitis in patients with AIDS. J Infect Dis . 1988; 157:624-8. [PubMed 3279135]
170. Dismukes WE, Cloud G, Gallis HA et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med . 1987; 317:334-41. [PubMed 3299095]
171. Panther LA, Sande MA. Cryptococcal meningitis in the acquired immunodeficiency syndrome. Semin Respir Infect . 1990; 5:138-45. [PubMed 2247708]
172. Eng RHK, Bishburg E, Smith SM et al. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med . 1986; 81:19-23. [PubMed 3524224]
173. Walsh TJ, Pizzo A. Treatment of systemic fungal infections: recent progress and current problems. Eur J Clin Microbiol Infect Dis . 1988; 7:460-75. [PubMed 2846299]
174. Sugar AM, Stern JJ, Dupont B. Overview: treatment of cryptococcal meningitis. Clin Infect Dis . 1990; 12(Suppl 3):S338-48.
175. National Institute of Allergy and Infectious Diseases, Division of AIDS. A note to physicians: important information on results of a control clinical trial of fluconazole vs. amphotericin B for suppression of cryptococcal meningitis. Bethesda, MD: 1990 April 30.
176. Roerig, New York, NY: Personal communication.
177. Anon. Fluconazole. Med Lett Drugs Ther . 1990; 32:50-2. [PubMed 2185400]
179. Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs . 1990; 39:877-916. [PubMed 2196167]
180. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Ann Intern Med . 1990; 113:183-7. [PubMed 2197908]
181. McKinsey DS, Gupta MR, Riddler SA et al. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). Ann Int Med . 1989; 111:655-9. [PubMed 2802421]
182. Larsen RA, Leal MAE, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS: a randomized trial. Ann Int Med . 1990; 113:183-7. [PubMed 2197908]
183. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med . 1989; 321:794-9. [PubMed 2671735]
184. Wong RD, Goetz MB. Treatment of cryptococcal meningitis in AIDS. Ann Int Med . 1990; 113:992.
185. Bozzette SA, Larsen RA, Chiu J et al. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med . 1991; 324:580-4. [PubMed 1992319]
186. Bozzette SA, Larsen RA, Chiu J et al. Fluconazole treatment of persistent Cryptococcus neoformans prostatic infection in AIDS. Ann Intern Med . 1991; 115:285-6. [PubMed 1854112]
187. Davidson RN, Croft SL, Scott A et al. Liposomal amphotericin B in drug-resistant visceral leishmaniasis. Lancet . 1991; 337:1061-2. [PubMed 1673494]
188. Schürman D, De Matos Marques B, Grünewald T et al. Safety and efficacy of liposomal amphotericin B in treating AIDS-associated disseminated cryptococcus. J Infect Dis . 1991; 1164:620-2.
189. Coker R, Horner J. Short-course treatment and response to liposomal amphotericin B in AIDS-associated cryptococcus. J Infect Dis . 1992; 11165:593.
190. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food Drug and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to November 30, 1991. Rockville, MD; 1992 Sep.
191. Bristol-Myers Squibb, Princeton, J: Personal communication.
192. Saag MS, Powderly WG, Cloud GA et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med . 1992; 326:83-9. [PubMed 1727236]
193. Powderly WG, Saag M, Cloud GA et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med . 1992; 326:793-8. [PubMed 1538722]
194. Coker R, Tomlinson D, Harris J. Successful treatment of cryptococcal meningitis with liposomal amphotericin B after failure of treatment with fluconazole and conventional amphotericin B AIDS . 1991; 5:231-2.
195. Fisher NC, Singhal S, Miller SJ et al. Fungal infection and liposomal amphotericin B (AmBisome) therapy in liver transplantation: a 2 year review. J Antimicrob Chemother . 1999; 43:597-600. [PubMed 10350395]
196. de Lalla F, Pellizzer G, Vaglia A et al. Amphotericin B as primary therapy for cryptococcoses in patients with AIDS: reliability of relatively high doses administered over a relatively short period. Clin Infect Dis . 1995; 20:263-6. [PubMed 7742427]
197. American Thoracic Society. Fungal infection in HIV-infected persons. Am J Respir Crit Care Med . 1995; 152:816-22. [PubMed 7633749]
199. Wright DG, Robichaud KJ, Pizzo PA et al. Lethal pulmonary reactions associated with the combined use of amphotericin b and leukocyte transfusions. N Engl J Med . 1981; 304:1185-9. [PubMed 7219459]
201. Sigma-Tau Pharmaceuticals, Inc. ABELCET® (amphotericin B lipid complex injection) prescribing information. Gaithersburg, MD; 2013 Mar.
202. Astellas Pharma US, Inc. AmBisome® (amphotericin B liposome) powder for injection prescribing information. Northbrook, IL; 2012 May.
205. Janknegt R, de Marie S, Bakker-Woudenberg IAJM et al. Liposomal and lipid formulations of amphotericin B: clinical pharmacokinetics. Clin Pharmacokinet . 1992; 23:279-91. [PubMed 1395361]
206. Heimez JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis . 1996; 22(Suppl 2):S135-44. [PubMed 8722841]
207. Rapp RP, Gubbins PO, Evans ME. Amphotericin B lipid complex. Ann Pharmacother . 1997; 31:1174-86. [PubMed 9337444]
208. Stevens DA. Overview of amphotericin B colloidal dispersion (Amphocil). J Infect . 1994; 28(Suppl 1):45-9. [PubMed 8077690]
209. Hay RJ. Liposomal amphotericin B, AmBisome. J Infect . 1994; 28(Suppl 1):35-43. [PubMed 8077689]
210. Szoka FC, Tang. Amphotericin B formulated in liposomes and lipid based systems: a review. J Liposome Res . 1993; 3:363-75.
211. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Clin Infect Dis . 1990; 12:308-29.
213. Powderly WG. Recent advances in the management of cryptococcal meningitis in patients with AIDS. Clin Infect Dis . 1996; 22(Suppl 2):S119-23.
214. Van der Horst CM, Saag MS, Cloud GA et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med . 1997; 337:15-21. [PubMed 9203426]
215. Leenders ACAP, Reis P, Portegies P et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associate cryptococcal meningitis. AIDS . 1997; 11:1463-71. [PubMed 9342068]
216. Sharkey PK, Graybill JR, Johnson ES et al. Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis . 1996; 22:315-21. [PubMed 8838189]
217. Joly V, Aubry P, Ndayiragide A et al. Randomized comparison of amphotericin B deoxycholate dissolved in dextrose or intralipid for the treatment of AIDS-associated cryptococcal meningitis. Clin Infect Dis . 1996; 23:556-62. [PubMed 8879780]
218. Kelly SL, Lamb DC, Kelly DE et al. Resistance to fluconazole and amphotericin in Candida albicans from AIDS patients. Lancet . 1996; 348:1523-4. [PubMed 8942815]
219. Oppenheim BA, Herbrecht R, Kusne S. The safety and efficacy of amphotericin B colloidal dispersion in the treatment of invasive mycoses. Clin Infect Dis . 1995; 21:1145-53. [PubMed 8589134]
220. Valero G, Graybill JR. Successful treatment of cryptococcal meningitis with amphotericin B colloidal dispersion: report of four cases. Antimicrob Agents and Chemother . 1995; 39:2588-90.
221. Goldani LZ, Sugar A. Paracoccidioidomycosis and AIDS: an overview. Clin Infect Dis . 1995; 21:1275-81. [PubMed 8589154]
222. Barson WJ, Marcon MJ. Successful therapy of Candida albicans arthritis with a sequential intravenous amphotericin B and oral fluconazole regimen. Pediatr Infect Dis J . 1996; 15:1119-22. [PubMed 8970223]
223. Rex JH, Bennett JE, Sugar AM et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med . 1994; 331:1325-30. [PubMed 7935701]
224. Meunier F. Management of candidemia. N Engl J Med . 1994; 331:1371-2. [PubMed 7935710]
225. Graybill JR. Editorial response: can we agree on the treatment of candidiasis? Clin Infect Dis . 1997; 25:60-2.
227. Kauffman CA. Role of azoles in antifungal therapy. Clin Infect Dis . 1996; 22(Suppl 2:S148-53. [PubMed 8722843]
228. Dromer F, Mathoulin S, Dupont B et al. Comparison of the efficacy of amphotericin B and fluconazole in the treatment of cryptococcosis in human immunodeficiency virus-negative patients: retrospective analysis of 83 cases. Clin Infect Dis . 1996; 22(Suppl 2:S154-60. [PubMed 8722844]
229. Meunier F, Sculier JP, Coune A et al. Amphotericin B encapsulated in liposomes administered to cancer patients. Ann NY Acad Sci . 1988; 544:598-610. [PubMed 2850759]
230. Ringdén O, Meunier F, Tollemar J et al. Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother . 1991; 28(Suppl B):73-82. [PubMed 1778894]
231. Ng TTC, Dening DW. Liposomal amphotericin B (AmBisome) therapy of invasive fungal infections: evaluation of United Kingdom compassionate use data. Arch Intern Med . 1995; 155:1093-8. [PubMed 7748054]
232. Lopez-Berestein G, Bodey GP, Fainstein V et al. Treatment of systemic fungal infections with liposomal amphotericin B. Arch Intern Med . 1989; 149:2533-6. [PubMed 2818111]
233. de Marie S, Janknegt R, Bakker-Woudenberg IAJM. Clinical use of liposomal and lipid-complexed amphotericin B. J Antimicrob Chemother . 1993; 33:907-16.
234. Wieb VJ, DeGregorio W. Liposome-encapsulated amphotericin B: a promising new treatment for disseminated fungal infections. Rev Infect Dis . 1988; 10:1097-101. [PubMed 3060940]
235. Oravcova E, Mistrik M, Sakalova A et al. Amphotericin B lipid complex to treat invasive fungal infections in cancer patients: report of efficacy and safety in 20 patients. Chemotherapy . 1995; 41:473-6. [PubMed 8529439]
236. Denning DW. Treatment of invasive aspergillosis. J Infect . 1994; 28(Suppl 1):25-33. [PubMed 8077688]
237. Kline MW, Bocobo FC, Paul ME et al. Successful medical therapy of Aspergillus . osteomyelitis of the spine in an 11-year-old boy with chronic granulomatous disease. Pediatrics . 1994; 93:830-5. [PubMed 8165091]
238. Hospenthal DR, Byrd JC, Weiss RB. Successful treatment of invasive aspergillosis complicating prolonged treatment-related neutropenia in acute myelogenous leukemia with amphotericin B lipid complex. Med Pediatr Oncol . 1995; 25:119-22. [PubMed 7603397]
239. Jones RS, Barman A, Suh B et al. Successful treatment of Aspergillus vertebral osteomyelitis with amphotericin B lipid complex. Infect Dis Clin Pract . 1998; 237-9.
240. Richard EM, Apperley JF, Marchus RE. Successful use of liposome encapsulated amphotericin to treat invasive aspergillosis following failure of conventional amphotericin. Clin Lab Haematol . 1992; 14:127-30. [PubMed 1633682]
241. Khan AU, Gopalakrishnan G, Al-Awadi K et al. Renal aspergilloma due to Aspergillus flavus . Clin Infect Dis . 1995; 21:210-2. [PubMed 7578735]
242. Polo JM, Fabrega E, Casafont F et al. Treatment of cerebral aspergillosis after liver transplantation. Neurology . 1992; 42:1817-9. [PubMed 1513474]
243. Bodey GP, Vartivarian S. Aspergillosis. Eur J Clin Microbiol Infect Dis . 1989; 8:413-37. [PubMed 2502407]
244. White MH, Anaissie EJ, Kusne S et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis . 1997; 24:635-42. [PubMed 9145737]
245. Pappagianis D. Coccidioidomycosis. Semin Dermatol . 1993; 12:301-9. [PubMed 8312146]
246. Sundar S, Agrawal NK, Sinha PR et al. Short-course, low-dose amphotericin B lipid complex therapy for visceral leishmaniasis unresponsive to antimony. Ann Intern Med . 1997; 127:133-7. [PubMed 9230003]
247. di Martino L, Davidson RN, Giacchinno R et al. Treatment of visceral leishmaniasis in children with liposomal amphotericin B. J Pediatr . 1997; 131:271-7. [PubMed 9290615]
248. Hibberd PL, Rubin RH. Clinical aspects of fungal infection in organ transplant recipients. Clin Infect Dis . 1994; 19(Suppl 1):S33-40. [PubMed 7948569]
249. Riley DK, Pavia AT, Beatty PG et al. The prophylactic use of low-dose amphotericin B in bone marrow transplant patients. Am J Med . 1994; 97:509-14. [PubMed 7985709]
250. Bowden RA, Cays M, Gooley T et al. Phase I study of amphotericin B colloidal dispersion for the treatment of invasive fungal infections after marrow transplant. J Infect Dis . 1996; 173:1208-15. [PubMed 8627074]
251. Leu HS, Huang CT. Clearance of funguria with short-course antifungal regimens: a prospective randomized, controlled study. Clin Infect Dis . 1995; 20:1152-7. [PubMed 7619991]
252. Walsh TJ, Finberg RW, Arndt C et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med . 1999; 340:764-71. [PubMed 10072411]
253. Davidson RN, di Martino L, Gradoni L et al. Short-course treatment of visceral leishmaniasis with liposomal amphotericin B (AmBisome). Clin Infect Dis . 1996; 22:938-43. [PubMed 8783690]
254. Donowitz LG, Hendley JO. Short-course amphotericin B therapy for candidemia in pediatric patients. Pediatrics . 1995; 95:888-91. [PubMed 7761216]
255. Driessen M, Ellis JB, Cooper PA et al. Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: a prospective randomized trial. Pediatr Infect Dis J . 1996; 15:1107-12. [PubMed 8970221]
257. Mishra M, Biswas UK, Jha AM et al. Amphotericin versus sodium stibogluconate in first-line treatment of Indian kala-azar. Lancet . 1994; 344:1599-600. [PubMed 7983993]
258. Gold WL, Vellend H, Salit IE et al. Successful treatment of systemic and local infections due to Exophiala species. Clin Infect Dis . 1994; 19:339-41. [PubMed 7986913]
260. Fan-Havard P, O'Donovan C, Smith SM et al. Oral fluconazole versus amphotericin B bladder irrigation for treatment of candidal funguria. Clin Infect Dis . 1995; 21:960-5. [PubMed 8645847]
261. Cross CE. Amphotericin B aerosol for transiently immunocompromised hosts: reasonably safe, but does it matter? Chest . 1995; 108:599-601. Editorial.
262. Hsu CCS, Chang RH. Two-day continuous bladder irrigation with amphotericin B. Clin Infect Dis . 1995; 20:1570-1. [PubMed 7548519]
263. Arsura EL, Ismail Y, Freedman S et al. Amphotericin B-induced dilated cardiomyopathy. Am J Med . 1994; 97:560-2. [PubMed 7985716]
264. Gales MA, Gales BJ. Rapid infusion of amphotericin B in dextrose. Ann Pharmacother . 1995; 29:523-9. [PubMed 7655137]
265. Kline S, Larsen TA, Fieber L et al. Limited toxicity of prolonged therapy with high doses of amphotericin B lipid complex. Clin Infect Dis . 1995; 21:1154-8. [PubMed 8589135]
267. Pappas PG, Pottage JC, Powderly WG et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med . 1992; 116:847-53. [PubMed 1567099]
268. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review or 2,121 published cases. Clin Infect Dis . 1990; 12:1147-201.
269. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 31st ed. London: The Pharmaceutical Press; 1996:383-402.
271. Despommier DD, Gwadz RW, Hotez PJ. Parasitic Diseases. 3rd ed. New York: Springer-Verlag; 1995:203-9.
273. Pizzo A. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med . 1993; 328:1323-32. [PubMed 8469254]
274. Tollemar J, Hockerstedt K, Ericzon BG et al. Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. A randomized, placebo-controlled study. Transplantation . 1995; 59:45-50. [PubMed 7839427]
276. Schwartz S, Behre G, Heinemann V et al. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood . 1999; 93:3654-61. [PubMed 10339471]
277. Rowe JM, Ciobanu N, Ascensao J et al et al. Recommended guidelines for the management of autologous and allogeneic bone marrow transplantation: a report from the Eastern Cooperative Oncology Group (ECOG). Ann Intern Med . 1994; 120:143-58. [PubMed 8256974]
278. Perfect JR. Antifungal prophylaxis: to prevent or not. Am J Med . 1993; 92:233-4.
279. Shelhamer JH, Toews GB, Masur H et al. Respiratory disease in the immunosuppressed patients. Ann Intern Med . 1992; 117:85-8. [PubMed 1596052]
280. Yancey RW, Perlino CA, Kaufman L. Asymptomatic blastomycosis of the central nervous system with progression in patients given ketoconazole therapy: a report of two cases. J Infect Dis . 1991; 164:807-10. [PubMed 1894941]
281. Pitrak DL, Anderson BR. Cerebral blastomycoma after ketoconazole therapy for respiratory tract blastomycosis. Am J Med . 1989; 86:713-4. [PubMed 2729325]
282. Nishioka S. Paracoccidioidomycosis and AIDS. Clin Infect Dis . 1996; 22:1132. [PubMed 8783743]
283. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med . 1994; 220:263-72.
284. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis . 1993; 16:677-88. [PubMed 8507760]
285. Galgiani JN, Ampel NM. Coccidioidomycosis in human immunodeficiency virus—infected patients. J Infect Dis . 1990; 162:1165-9. [PubMed 2230241]
286. Rubin RH, Tolkoff-Rubin NE. Antimicrobial strategies in the care of organ transplant recipients. Antimicrob Agents Chemother . 1993; 37:619-24. [PubMedCentral][PubMed 8494357]
287. Walsh TJ, Lee JW. Prevention of invasive fungal infections in patients with neoplastic diseases. Clin Infect Dis . 1993; 17(Suppl 2):S468-80. [PubMed 8274613]
288. Klein NC, Cunha BA. New antifungal drugs for pulmonary mycoses. Chest . 1996; 110:525-32. [PubMed 8697859]
289. Kauffman CA. Old and new therapies for sporotrichosis. Clin Infect Dis . 1995; 21:981-5. [PubMed 8645851]
290. McWhinney PH, Kibbler CC, Hamonn MD et al. Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years' experience. Clin Infect Dis . 1993; 17:397-404. [PubMed 8218680]
291. Mangino JE, Pappas PG. Itraconazole for the treatment of histoplasmosis and blastomycosis. Int J Antimicrob Agents . 1995; 5:219-25. [PubMed 18611672]
292. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.
293. Jacobs LG, Skidmore EA, Freeman K et al. Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients. Clin Infect Dis . 1996; 22:30-5. [PubMed 8824962]
294. Nguyen MH, Peacock JE, Morris AJ et al. The changing face of candidemia: emergence of non- C. albicans species and antifungal resistance. Am J Med . 1996; 100:617-23. [PubMed 8678081]
295. Anaissie E, Bodey GP, Kantarjiann H et al. Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior amphotericin B therapy. Am J Med . 1991; 91:142-50. [PubMed 1867240]
296. Colville A, Wale MCJ. Fluconazole or amphotericin for candidaemia in non-neutropenic patients. Lancet . 1991; 337:1605-6. [PubMed 1675729]
297. Soutar RL. Fluconazole or amphotericin for candidosis in neutropenic patients. Lancet . 1991; 337:181. [PubMed 1670824]
298. Winston DJ, Chanrasekar PH, Lazarus HM et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind multicenter trial. Ann Intern Med . 1993; 118:495-503. [PubMed 8442620]
299. Powderly WG, Kobayashi GS, Herzig GP et al. Amphotericin B-resistant yeast infection in severely immunocompromised patients. Am J Med . 1988; 84:826-32. [PubMed 3284339]
300. Menichetti F, Del Favero A, Martino P et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. Ann Intern Med . 1994; 120:913-8. [PubMed 8172437]
301. Sanguineti A, Carmichael K, Campbell K. Fluconazole-resistant Candida albicans after long-term suppressive therapy. Arch Intern Med . 1993; 153:1122-4. [PubMed 8481078]
302. Pavia AT, Riley DK. Fluconazole prophylaxis in patients with leukemia. Ann Intern Med . 1993; 119:951. [PubMed 8215009]
303. Akiyama H, Sakamaki H, Onozawa Y. Fluconazole prophylaxis in patients with leukemia. Ann Intern Med . 1993; 119:951. [PubMed 8215008]
304. Galgiani JN, Catanzaro A, Cloud GA et al. Fluconazole therapy for coccidioidal meningitis. Ann Intern Med . 1993; 119:28-35. [PubMed 8498760]
305. Martin E, Maier F, Bhakdi S. Antagonistic effects of fluconazole and 5-fluorocytosine on candidacidal action of amphotericin B in human serum. Antimicrob Agents Chemother . 1994; 28:1331-8.
306. Berry AJ, Rinaldi G, Graybill JR. Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS. Antimicrob Agents Chemother . 1992; 36:690-2. [PubMedCentral][PubMed 1622188]
307. Anaissie EJ, Darouiche RO, Abi-Said D et al. Management of invasive candidal infections: results of a prospective, randomized multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis . 1996; 23:964-72. [PubMed 8922787]
308. Klepser ME, Wolfe EJ, Jones RN et al. Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans . Antimicrob Agents Chemother . 1997; 41:1392-5. [PubMedCentral][PubMed 9174207]
309. Sanati H, Ramos CF, Bayer AS et al. Combination therapy with amphotericin B and fluconazole against invasive candidiasis in neutropenic-mouse and infective-endocarditis rabbit models. Antimicrob Agents Chemother . 1997; 41:1345-8. [PubMedCentral][PubMed 9174196]
310. Maenza JR, Merz WG, Romagnoli MJ et al. Infection due to fluconazole-resistant Candida in patients with AIDS: prevalence and microbiology. Clin Infect Dis . 1997; 24:28-34. [PubMed 8994752]
311. Marins MD, Lozano-Chiu M, Rex JH. Point prevalence of oropharyngeal carriage of fluconazole-resistant Candida in human immunodeficiency virus-infected patients. Clin Infect Dis . 1997; 25:843-6. [PubMed 9356799]
312. van Ettenn EWM, van de Rhee NE, van Kampen KM et al. Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans . Antimicrob Agents Chemother . 1991; 35:2275-81. [PubMedCentral][PubMed 1804000]
313. Witt MD, Imhoff T, Li C et al. Comparison of fluconazole and amphotericin B for treatment of experimental Candida endocarditis caused by non- C. albicans strains. Antimicrob Agents Chemother . 1993; 37:2030-2. [PubMedCentral][PubMed 8239628]
314. Sugar A, Hitchcock CA, Troke PF et al. Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother . 1995; 39:598-601. [PubMedCentral][PubMed 7793858]
315. Walsh TJ, Peter J, McGough DA et al. Activities of amphotericin B and antifungal azoles alone and in combination against Pseudallescheria boydii . Antimicrob Agents Chemother . 1995; 39:1361-4. [PubMedCentral][PubMed 7574531]
316. National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard. NCCLS document M27-A. Wayne, PA; NCCLS:1997 Jun.
317. Pfaller A, Rex JH, Rinaldi MG. Antifungal susceptibility testing: technical advances and potential clinical applications. Clin Infect Dis . 1997; 24:776-84. [PubMed 9142769]
318. Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore) . 1997; 76:339-54. [PubMed 9352737]
319. Chao D, Steier KJ, Gomila R. Update and review of blastomycosis. J Am Osteopath Assoc . 1997; 97:525-32. [PubMed 9313349]
320. Bradsher RW. Therapy of blastomycosis. Semin Respir Infect . 1997; 12:263-7. [PubMed 9313298]
321. Varkey B. Blastomycosis in children. Semin Respir Infect . 1997; 12:235-42. [PubMed 9313295]
322. Chapman SW, Lin AC, Hendricks KA et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect . 1997; 12:219-28. [PubMed 9313293]
323. Henequin C, Benailly N, Silly C et al. In vitro susceptibilities to amphotericin B, itraconazole, and miconazole of filamentous fungi isolated from patients with cystic fibrosis. Antimicrob Agents Chemother . 1997; 41:2064-6. [PubMedCentral][PubMed 9303420]
324. Hopkins MA, Treloar DM. Mucormycosis in diabetes. Am J Crit Care . 1997; 6:363-7. [PubMed 9283673]
325. Law D, Moore CB, Denning DW. Amphotericin B resistance testing of Candida spp.: a comparison of methods. J Antimicrob Chemother . 1997; 40:109-12. [PubMed 9249212]
326. Osaka K, Ritov VB, Bernardo JF et al. Amphotericin B protects cis -parinaric acid against peroxyl radical-induced oxidation: amphotericin B as an antioxidant. Antimicrob Agents Chemother . 1997; 41:743-7. [PubMedCentral][PubMed 9087481]
327. Tohyama M, Kawakami K, Saito A. Anticryptococcal effect of amphotericin B is mediated through macrophage production of nitric oxide. Antimicrob Agents Chemother . 1996; 40:1919-23. [PubMedCentral][PubMed 8843304]
328. Kintzel PE. Amphotericin B in fat emulsion. Am J Health-Syst Pharm . 1996; 53:2701. [PubMed 8931810]
329. Lopez RM, Ayestara A, Pou L et al. Stability of amphotericin B in a extemporaneously prepared i.v. fat emulsion. Am J Health-Syst Pharm . 1996; 53:2724-7. [PubMed 8931814]
330. Heide PE. Precipitation of amphotericin B from i.v. fat emulsion. Am J Health-Syst Pharm . 1997; 54:1449. [PubMed 9194992]
331. Owes D, Fleming RA, Restino MS et al. Stability of amphotericin B 0.05 and 0.5 mg/mL in 20% fat emulsion. Am J Health-Syst Pharm . 1997; 54:683-6. [PubMed 9075499]
332. Heinemann V, Bosse D, Jehn U et al. Pharmacokinetics of liposomal amphotericin B (AmBisome) in critically ill patients. Antimicrob Agents Chemother . 1997; 41:1275-80. [PubMedCentral][PubMed 9174183]
333. Kan VL, Bennett JE, Amantea MA et al. Comparison of safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers. J Infect Dis . 1991; 164:418-21. [PubMed 1856491]
334. Ayestaran A, Lopez R, Montoro JB et al. Pharmacokinetics of conventional formulation versus fat emulsion formulation of amphotericin B in a group of patients with neutropenia. Antimicrob Agents Chemother . 1996; 40:609-12. [PubMedCentral][PubMed 8851579]
335. Heinemann V, Kahny B, Jehn U et al. Serum pharmacology of amphotericin B applied in lipid emulsions. Antimicrob Agents Chemother . 1997; 41:728-32. [PubMedCentral][PubMed 9087478]
336. Sugar AM. Use of amphotericin B with azole antifungal drugs: what are we doing? Antimicrob Agents Chemother . 1995; 39:1907-12.
337. Walsh TJ, Whitcomb P, Piscitelli S et al. Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis. Antimicrob Agents Chemother . 1997; 41:1944-8. [PubMedCentral][PubMed 9303390]
338. Amantea A, Bowden RA, Forrest A et al. Population pharmacokinetics and renal function-sparing effects of amphotericin B colloidal dispersion in patients receiving bone marrow transplants. Antimicrob Agents Chemother . 1995; 39:2042-7. [PubMedCentral][PubMed 8540713]
339. Mitsutake K, Kohno S, Miyazaki Y et al. In vitro and in vivo antifungal activities of liposomal amphotericin B, and amphotericin B lipid complex. Mycopathologia . 1994; 128:13-7. [PubMed 7708087]
340. Wasan KM, Conklin JS. Enhanced amphotericin B nephrotoxicity in intensive care patients with elevated levels of low-density lipoprotein cholesterol. Clin Infect Dis . 1997; 24:78-80. [PubMed 8994768]
341. Goodwin SD, Cleary JD, Walawander CA et al. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin Infect Dis . 1995; 20:755-61. [PubMed 7795069]
342. Kingo ARM, Smyth JA, Waisman D. Lack of evidence of amphothericin B toxicity in very low birth weight infants treated for systemic candidiasis. Pediatr Infect Dis J . 1997; 16:1002-3. [PubMed 9380454]
343. Alexander BD, Perfect JR. Antifungal resistance trends towards the year 2000. Implications for therapy and new approaches. Drugs . 1997; 54:657-78. [PubMed 9360056]
344. White MH, Bowden RA, Sandler E et al. Amphotericin colloidal dispersion (ABCD) vs. amphotericin B (AmB) in the empiric treatment of febrile neutropenic patients. Blood . 1996; 88(Suppl 1):302a.
345. Nicholl TA, Nimmo CR, Shepherd JD et al. Amphotericin B infusion-related toxicity: comparison of two- and four-hour infusions. Ann Pharmacother . 1995; 29:1081-7. [PubMed 8573948]
346. Reviewers' comments (personal observations).
347. Sequus Pharmaceuticals, Menlo Park, CA: Personal communication.
348. Noskin GA, Pietrelli L, Coffey G et al. Amphotericin B colloidal dispersion for treatment of candidemia in immunocompromised patients. Clin Infect Dis . 1998; 26:461-7. [PubMed 9502471]
349. Venkateswarlu K, Taylor M, Manning NJ et al. Fluconazole tolerance in clinical isolates of Cryptococcus neoformans . Antimicrob Agents Chemother . 1997; 41:748-51. [PubMedCentral][PubMed 9087482]
350. Wingard JR. Infections due to resistant Candida species in patients with cancer who are receiving chemotherapy. Clin Infect Dis . 1994; 19(Suppl 1):S49-53. [PubMed 7948571]
351. Walker S, Tailor SA, Lee M et al. Amphotericin B in lipid emulsion: stability, compatibility, and in vitro antifungal activity. Antimicrob Agents Chemother . 1998; 42:762-6. [PubMedCentral][PubMed 9559779]
352. Schoffski P, Freund M, Wunder R et al. Safety and toxicity of amphotericin B in glucose 5% or intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study. BMJ . 1998; 317:379-84. [PubMedCentral][PubMed 9694753]
353. Nath CE, Shaw PJ, Gunning R et al. Amphotericin B in children with malignant disease: a comparison of the toxicities and pharmacokinetics of amphotericin B administered in dextrose versus lipid emulsion. Antimicrob Agents Chemother . 1999; 43:1417-23. [PubMedCentral][PubMed 10348763]
354. Nucci M, Loureiro M, Silveira F et al. Comparison of the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in fat emulsion in a randomized trial with cancer patients. Antimicrob Agents Chemother . 1999; 43:1445-8. [PubMedCentral][PubMed 10348768]
355. Kauffman CA, Wiseman SW. Anaphylaxis upon switching lipid-containing amphotericin B formulations. Clin Infect Dis . 1998; 26:1237-8. [PubMed 9597266]
356. Cronin JE, Barron RL. Anaphylaxis upon switching lipid-containing amphotericin B formulations. Clin Infect Dis . 1999; 28:1342. [PubMed 10451192]
357. Gill J, Sprenger HR, Ralph ED et al. Hepatotoxicity possibly caused by amphotericin B. Ann Pharmacother . 1999; 33:683-5. [PubMed 10410179]
358. Kelsey SM, Goldman JM, McCann S et al. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Bone Marrow Transplantation . 1999; 23:163-8. [PubMed 10197802]
359. Ellis ME, Al-Hokail AA, Clink HM et al. Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother . 1992; 36:172-9. [PubMedCentral][PubMed 1590686]
360. Drutz DJ. Rapid infusion of amphotericin B: is it safe, effective, and wise? Am J Med . 1992; 93:119-21.
361. Bowler WA, Weiss PJ, Hill HE et al. Risk of ventricular dysrhythmias during 1-hour infusions of amphotericin B in patients with preserved renal function. Antimicrob Agents Chemother . 1992; 36:2542-3. [PubMedCentral][PubMed 1489202]
362. Cruz JM, Peacock JE, Loomer L et al. Rapid intravenous infusion of amphotericin B: a pilot study. Am J Med . 1992; 93:123-30. [PubMed 1497007]
363. Cleary JD, Hayman J, Sherwood J et al. Amphotericin B overdose in pediatric patients with associated cardiac arrest. Ann Pharmacother . 1993; 27:715-9. [PubMed 8329789]
364. Clancy CJ, Yu YC, Lewin A et al. Inhibition of RNA synthesis as a therapeutic strategy against Aspergillus and Fusarium : demonstration of in vitro synergy between rifabutin and amphotericin B. Antimicrob Agents Chemother . 1998; 42:509-13. [PubMedCentral][PubMed 9517924]
365. Antoniskis D, Larsen RA. Acute, rapidly progressive renal failure with simultaneous use of amphotericin B and pentamidine. Antimicrob Agents Chemother . 1990; 34:470-2. [PubMedCentral][PubMed 2334159]
366. Strasser MD, Kennedy RJ, Adam RD. Rhinocerebral mucormycosis: therapy with amphotericin B lipid complex. Arch Intern Med . 1996; 156:337-9. [PubMed 8572846]
367. Moses AE, Rahav G, Barenholz Y et al. Rhinocerebral mucormycosis treated with amphotericin B colloidal dispersion in three patients. Clin Infect Dis . 1998; 26:1430-3. [PubMed 9636875]
368. Naguib MT, Huycke MM, Pederson JA et al. Apophysomyces elegans infection in a renal transplant recipient. Am J Kidney Dis . 1995; 26:381-4. [PubMed 7645546]
369. Maury S, Leblanc T, Feuilhade M et al. Successful treatment of disseminated mucormycosis with liposomal amphotericin B and surgery in a child with leukemia. Clin Infect Dis . 1998; 26:200-2. [PubMed 9455544]
370. Singh N, Mieles L, Yu VL et al. Invasive aspergillosis in liver transplant recipients: association with candidemia and consumption coagulopathy and failure of prophylaxis with low-dose amphotericin B. Clin Infect Dis . 1993; 17:906-8. [PubMed 8286639]
371. Lorf T, Braun F, Ruchel R et al. Systemic mycoses during prophylactical use of liposomal amphotericin B (Ambisome®) after liver transplantation. Mycoses . 1999; 42:47-53. [PubMed 10394848]
372. Ringden O, Andstrom EE, Remberger M et al. Prophylaxis and therapy using liposomal amphotericin B (AmBisome) for invasive fungal infections in children undergoing organ or allogeneic bone-marrow transplantation. Pediatr Transplantation . 1997; 1:124-9.
373. Noskin G, Pietrelli L, Gurwith M et al. Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients. Bone Marrow Transplantation . 1999; 23:697-703. [PubMed 10218847]
374. Gotzsche PC, Johansen HK. Meta-analysis of prophylactic or empirical antifungal treatment versus placebo or no treatment in patients with cancer complicated by neutropenia. BMJ . 1997; 314:1238-44. [PubMedCentral][PubMed 9154027]
375. Perfect JR, Klotman ME, Gilbert CC et al. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis . 1992; 165:891-7. [PubMed 1569339]
376. Malik IA, Moid I, Aziz Z et al. A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia. Am J Med . 1998; 105:478-83. [PubMed 9870832]
377. Karp JE, Merz WG. Editorial response: randomized trial of lipid-based amphotericin B for invasive aspergillosis in neutropenic hosts is an important step forward. Clin Infect Dis . 1998; 27:1413-4. [PubMed 9868652]
378. Severens JL, Donnelly JP, Meis JF et al. Two strategies for managing invasive aspergillosis: a decision analysis. Clin Infect Dis . 1997; 25:1148-54. [PubMed 9402374]
379. Ellis M, Spence D, de Pauw B et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis . 1998; 27:1406-12. [PubMed 9868651]
380. Torre-Cisneros J, Prada JL, Vilanueva JL et al. Successful treatment of antimony-resistant cutaneous leishmaniasis with liposomal amphotericin B. Clin Infect Dis . 1994; 18:1024-5. [PubMed 8086540]
381. Davidson RN. Practical guide for the treatment of leishmaniasis. Drugs . 1998; 56:1009-18. [PubMed 9878989]
382. Laguna F, Lopez-Velez R, Pulido F et al. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. AIDS . 1999; 19:1063-9.
383. Boletis JN, Pefanis A, Stathakis C et al. Visceral leishmaniasis in renal transplant recipients: successful treatment with liposomal amphotericin B (AmBisome). Clin Infect Dis . 1999; 28:1308-9. [PubMed 10451172]
384. Coukell AJ, Brogden RN. Liposomal amphotericin B: therapeutic use in the management of fungal infections and visceral leishmaniasis. Drugs . 1998; 55:585-612. [PubMed 9561346]
385. Brogden RN, Goa KL, Coukell AJ. Amphotericin-B colloidal dispersion: a review of its use against systemic fungal infections and visceral leishmaniasis. Drugs . 1998; 56:365-83. [PubMed 9777313]
386. Favel A, Michel-Nguyen A, Chastin C et al. In-vitro susceptibility pattern of Candida lusitaniae and evaluation of the Etest method. J Antimicrob Chemother . 1997; 39:591-6. [PubMed 9184357]
387. Nolte FS, Parkinson T, Falconer DJ et al. Isolation and characterization of fluconazole- and amphotericin b-resistant Candida albicans from blood of two patients with leukemia. Antimicrob Agents Chemother . 1997; 44:196-9.
388. Lopez-Ribot JL, McAtee RK, Perea S et al. Multiple resistant phenotypes of Candida albicans coexist during episodes of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother . 1999; 43:1621-30. [PubMedCentral][PubMed 10390213]
389. Moran GP, Sullivan DJ, Henman MC et al. Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro. Antimicrob Agents Chemother . 1997; 41:617-23. [PubMedCentral][PubMed 9056003]
390. Sullivan D, Coleman D. Candida dubliniensis : characteristics and identification. J Clin Microbiol . 1998; 36:329-34. [PubMedCentral][PubMed 9466736]
391. Hoban DJ, Zhanel GG, Karlowsky JA. In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients. Antimicrob Agents Chemother . 1999; 43:1463-4. [PubMedCentral][PubMed 10348771]
392. Hennequin C, Benailly N, Silly C et al. In vitro susceptibilities to amphotericin B, itraconazole, and miconazole of filamentous fungi isolated from patients with cystic fibrosis. Antimicrob Agents Chemother . 1997; 41:2064-6. [PubMedCentral][PubMed 9303420]
393. Robinson PA, Bauer M, Leal MAE et al. Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clin Infect Dis . 1999; 28:82-92. [PubMed 10028076]
394. Koehler AP, Cheng AFB, Chu KC et al. Successful treatment of disseminated coccidioidomycosis with amphotericin B lipid complex. J Infect . 1998; 36:113-5. [PubMed 9515680]
395. Walsh TJ, Yeldandi V, McEvoy M et al. Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients. Antimicrob Agents Chemother . 1998; 42:2391-8. [PubMedCentral][PubMed 9736569]
396. Walsh TJ, Hiemenz JW, Seibel NL et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis . 1998; 26:1383-96. [PubMed 9636868]
397. Denning DW, Marinus A, Cohen J et al. An EORTC multicentre prospective survey of invasive aspergillosis in haematological patients: diagnosis and therapeutic outcome. J Infect . 1998; 37:173-80. [PubMed 9821093]
398. Walsh TJ, Seibel JL, Arndt C et al. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J . 1999; 18:702-8. [PubMed 10462340]
399. Yoon SA, Vazquez JA, Steffan PE et al. High-frequency, in vitro reversible switching of Candida lusitaniae clinical isolates from amphotericin B susceptibility to resistance. Antimicrob Agents Chemother . 1999; 43:836-45. [PubMedCentral][PubMed 10103188]
400. Gumbo T, Isada CM, Hall G et al. Candida glabrata fungemia: clinical features of 139 patients. Medicine (Baltimore) . 1999; 78:220-7. [PubMed 10424204]
401. Scarcella A, Pasquariello MB, Giugliano B et al. Liposomal amphotericin B treatment for neonatal fungal infections. Pediatr Infect Dis J . 1998; 17:146-8. [PubMed 9493812]
402. Pfaller MA, Messer SA, Hollis RJ. Strain delineation and antifungal susceptibilities of epidemiologically related and unrelated isolates of Candida lusitaniae. Diagn Microbiol Infect Dis . 1994; 20:127-33. [PubMed 7874879]
403. Arishi HA, Frayha HH, Kalloghlian A et al. Liposomal amphotericin B in neonates with invasive candidiasis. Am J Perinatol . 1997; 14:573-6. [PubMed 9394170]
404. Catania S, Aiassa C, Tzahtzoglou S et al. Visceral leishmaniasis treated with liposomal amphotericin B. Pediatr Infect Dis J . 1999; 18:73-4. [PubMed 9951989]
405. Aguilar C, Pujol I, Guarro J. In vitro antifungal susceptibilities of Scopulariopsis isolates. Antimicrob Agents Chemother . 1999; 43:1520-2. [PubMedCentral][PubMed 10348787]
406. Sirisanthana T, Supparatpinyo K, Perriens J et al. Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients. Clin Infect Dis . 1998; 26:1107-10. [PubMed 9597237]
407. Supparatpinyo K, Perriens J, Nelson KE et al. A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the human immunodeficiency virus. N Engl J Med . 1998; 339:1739-43. [PubMed 9845708]
408. Wu TC, Chan JW, Ng CK et al. Clinical presentations and outcomes of Penicillium marneffei infections: a series from 1994 to 2004. Hong Kong Med J . 2008; 14:103-9. [PubMed 18382016]
409. Sar B, Boy S, Keo C et al. In vitro antifungal-drug susceptibilities of mycelial and yeast forms of Penicillium marneffei isolates in Cambodia. J Clin Microbiol . 2006; 44:4208-10. [PubMedCentral][PubMed 16971649]
410. Lin JN, Lin HH, Lai CH et al. Renal transplant recipient infected with Penicillium marneffei. Lancet Infect Dis . 2010; 10:138. [PubMed 20113983]
411. Aberg JA, Price RW, Heeren DM et al. A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy. J Infect Dis . 2002; 185:1179-82. [PubMed 11930330]
412. Mussini C, Pezzotti P, Miró JM et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis . 2004; 38:565-71. [PubMed 14765351]
413. Centers for Disease Control and Prevention. Gastrointestinal basidiobolomycosis—Arizona. MMWR Morb Mortal Wkly Rep . 1999; 48:710-3. [PubMed 21033182]
414. Basidiobolus ranarum as an etiologic agent of gastrointestinal zygomycosis. J Clin Microgiol . 2001; 39:2360-3.
415. Lyon GM, Smilack JD, Komatsu KK et al. Gastrointestinal basidiobolomycosis in Arizona: clinical and epidemiological characteristics and review of the literature. Clin Infect Dis . 2001; 32:1448-55. [PubMed 11317246]
416. Zavasky DM, Samowitz W, Loftus T et al. Gastrointestinal zygomycotic infection caused by Basidiobolus ranarum : case report and review. Clin Infect Dis . 1999; 28:1244-8. [PubMed 10451160]
417. X-Gen Pharmaceuticals, Inc. Amphotericin B for injection prescribing information. Big Flats, NY; 2009 Dec.
418. Almyroudis NG, Sutton DA, Fothergill AW et al. In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents. Antimicrob Agents Chemother . 2007; 51:2587-90. [PubMedCentral][PubMed 17452481]
419. Dannaoui E, Meletiadis J, Mouton JW et al. In vitro susceptibilities of zygomycetes to conventional and new antifungals. J Antimicrob Chemother . 2003; 51:45-52. [PubMed 12493786]
420. Bowden R, Chandrasekar P, White MH et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis . 2002; 35:359-66. [PubMed 12145716]
421. Guarro J, Aguilar C, Pujol I. In-vitro antifungal susceptibilities of Basidiobolus and Conidiobolus spp. strains. J Antimicrob Chemother . 1999; 44:557-60. [PubMed 10588321]
422. Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Disease Society of America. Clin Infect Dis . 2011; 52:e56-93. Updates may be available at IDSA website at www.idsociety.org.
423. Patterson TF, Thompson GR, Denning DW et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis . 2016; 63:e1-e60. Updates may be available at IDSA website at www.idsociety.org.
424. Chapman SW, Dismukes WE, Proia LA et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis . 2008; 46:1801-12. Updates may be available at IDSA website at www.idsociety.org. [PubMed 18462107]
425. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis . 2016; 62:e1-50. Updates may be available at IDSA website at www.idsociety.org.
426. Galgiani JN, Ampel NM, Blair JE et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin Infect Dis . 2016; 63:e112-46. Updates may be available at IDSA website at www.idsociety.org.
427. Perfect JR, Dismukes WE, Dromer F et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis . 2010; 50:291-322. Updates may be available at IDSA website at www.idsociety.org. [PubMed 20047480]
428. Wheat LJ, Freifeld AG, Kleiman MB et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis . 2007; 45:807-25. Updates may be available at IDSA website at www.idsociety.org. [PubMed 17806045]
429. Kauffman CA, Bustamante B, Chapman SW et al. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis . 2007; 45:1255-65. Updates may be available at IDSA website at www.idsociety.org. [PubMed 17968818]
430. Aronson N, Herwaldt BL, Libman M et al. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis . 2016; 63:1539-1557. [PubMed 27941143]
432. Wise GJ, Kozinn PJ, Goldberg P. Amphotericin B as a urologic irrigant in the management of noninvasive candiduria. J Urol . 1982; 128:82-4. [PubMed 7109077]
433. Paladino JA, Crass RE. Amphotericin B and flucytosine in the treatment of candidal cystitis. Clin Pharm . 1982 Jul-Aug; 1:349-52.
434. Fisher JF, Chew WH, Shadomy S et al. Urinary tract infections due to Candida albicans. Rev Infect Dis . 1982 Nov-Dec; 4:1107-18.
435. Gross MH, Pickard WW, Perfect JR. Retrospective review of amphotericin B use in a tertiary-care medical center. Am J Hosp Pharm . 1987; 44:1353-7. [PubMed 3618612]
436. . Antifungal drugs. Treat Guidel Med Lett . 2012; 10:61-8; quiz 69-70. [PubMed 22825657]
440. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (September 17, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
441. Panel on Opportunistic Infection in HIV-exposed and HIV-infected children, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics (December 15, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
442. Anon. Drugs for parasitic infections. Treat Guidel Med Lett . 2013; 11 (suppl). From the Medical Letter website. [Web]
443. Murray HW, Berman JD, Davies CR et al. Advances in leishmaniasis. Lancet . 2005 Oct 29-Nov 4; 366:1561-77.
444. Bern C, Adler-Moore J, Berenguer J et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis . 2006; 43:917-24. [PubMed 16941377]
445. Imwidthaya P, Thipsuvan K, Chaiprasert A et al. Penicillium marneffei: types and drug susceptibility. Mycopathologia . 2001; 149:109-15. [PubMed 11307592]
446. Ramani R, Chaturvedi V. Antifungal susceptibility profiles of Coccidioides immitis and Coccidioides posadasii from endemic and non-endemic areas. Mycopathologia . 2007; 163:315-9. [PubMed 17484074]
447. Cordeiro RA, Brilhante RS, Rocha MF et al. In vitro activities of caspofungin, amphotericin B and azoles against Coccidioides posadasii strains from Northeast, Brazil. Mycopathologia . 2006; 161:21-6. [PubMed 16389480]
448. Bariola JR, Perry P, Pappas PG et al. Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. Clin Infect Dis . 2010; 50:797-804. [PubMed 20166817]
449. Hamill RJ, Sobel JD, El-Sadr W et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis . 2010; 51:225-32. [PubMed 20536366]
450. Okamoto K, Hatakeyama S, Itoyama S et al. Cryptococcus gattii genotype VGIIa infection in man, Japan, 2007. Emerg Infect Dis . 2010; 16:1155-7. [PubMedCentral][PubMed 20587194]
451. Grosse P, Tintelnot K, Söllner O et al. Encephalomyelitis due to Cryptococcus neoformans var gattii presenting as spinal tumour: case report and review of the literature. J Neurol Neurosurg Psychiatry . 2001; 70:113-6. [PubMedCentral][PubMed 11118259]
452. Goldberg E, Gafter-Gvili A, Robenshtok E et al. Empirical antifungal therapy for patients with neutropenia and persistent fever: Systematic review and meta-analysis. Eur J Cancer . 2008; 44:2192-203. [PubMed 18706808]
453. Gomez-Lopez A, Zaragoza O, Dos Anjos Martins M et al. In vitro susceptibility of Cryptococcus gattii clinical isolates. Clin Microbiol Infect . 2008; 14:727-30. [PubMed 18558948]
454. Galanis E, Hoang L, Kibsey P et al. Clinical presentation, diagnosis and management of Cryptococcus gattii cases: Lessons learned from British Columbia. Can J Infect Dis Med Microbiol . 2009; 20:23-8. [PubMedCentral][PubMed 20190892]
455. Glick JA, Graham RS, Voils SA. Candida meningitis post Gliadel wafer placement successfully treated with intrathecal and intravenous amphotericin B. Ann Pharmacother . 2010; 44:215-8. [PubMed 20028954]
456. Zmierczak H, Goemaere S, Mielants H et al. Candida glabrata arthritis: case report and review of the literature of Candida arthritis. Clin Rheumatol . 1999; 18:406-9. [PubMed 10524556]
457. Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect . 2001; 16:263-9. [PubMed 11740828]
458. Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med . 2002; 347:408-15. [PubMed 12167683]
459. Cornely OA, Maertens J, Bresnik M et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis . 2007; 44:1289-97. [PubMed 17443465]
460. Marino E, Gallagher JC. Prophylactic antifungal agents used after lung transplantation. Ann Pharmacother . 2010; 44:546-56. [PubMed 20179260]
461. Borro JM, Solé A, de la Torre M et al. Efficiency and safety of inhaled amphotericin B lipid complex (Abelcet) in the prophylaxis of invasive fungal infections following lung transplantation. Transplant Proc . 2008; 40:3090-3. [PubMed 19010204]
462. Monforte V, Ussetti P, López R et al. Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety. J Heart Lung Transplant . 2009; 28:170-5. [PubMed 19201343]
463. Monforte V, Roman A, Gavalda J et al. Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors. J Heart Lung Transplant . 2001; 20:1274-81. [PubMed 11744410]
464. Monforte V, Ussetti P, Gavaldà J et al. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant . 2010; 29:523-30. [PubMed 20061165]
465. Herbrecht R, Letscher-Bru V, Bowden RA et al. Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis . 2001; 20:460-6. [PubMed 11561801]
466. Kauffman CA, Vazquez JA, Sobel JD et al. Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis . 2000; 30:14-8. [PubMed 10619726]
467. Nesbit SA, Katz LE, McClain BW et al. Comparison of two concentrations of amphotericin B bladder irrigation in the treatment of funguria in patients with indwelling urinary catheters. Am J Health Syst Pharm . 1999; 56:872-5. [PubMed 10344610]
468. Gubbins PO, McConnell SA, Penzak SR. Current management of funguria. Am J Health Syst Pharm . 1999; 56:1929-35; quiz 1936. [PubMed 10554910]
469. Drew RH, Arthur RR, Perfect JR. Is it time to abandon the use of amphotericin B bladder irrigation?. Clin Infect Dis . 2005; 40:1465-70. [PubMed 15844069]
470. Trinh T, Simonian J, Vigil S et al. Continuous versus intermittent bladder irrigation of amphotericin B for the treatment of candiduria. J Urol . 1995; 154:2032-4. [PubMed 7500451]
471. Sanford JP. The enigma of candiduria: evolution of bladder irrigation with amphotericin B for management--from Anecdote to Dogma and a lesson from Machiavelli. Clin Infect Dis . 1993; 16:145-7. [PubMed 8448292]
472. Jacobs LG, Skidmore EA, Cardoso LA et al. Bladder irrigation with amphotericin B for treatment of fungal urinary tract infections. Clin Infect Dis . 1994; 18:313-8. [PubMed 8011810]
473. Tuon FF, Amato VS, Penteado Filho SR. Bladder irrigation with amphotericin B and fungal urinary tract infection--systematic review with meta-analysis. Int J Infect Dis . 2009; 13:701-6. [PubMed 19155184]
474. Wise GJ. Do not abandon amphotericin B as an antifungal bladder irrigant. Clin Infect Dis . 2005; 41:1073-4; author reply 1074. [PubMed 16142684]
475. Kfoury AG, Smith JC, Farhoud HH et al. Adjuvant intrapleural amphotericin B therapy for pulmonary mucormycosis in a cardiac allograft recipient. Clin Transplant . 1997; 11:608-12. [PubMed 9408694]
476. Centers for Disease Control and Prevention (CDC). Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy - United States, 2012. MMWR Morb Mortal Wkly Rep . 2012; 61:839-42. [PubMed 23076093]
477. Centers for Disease Control and Prevention. Multistate outbreak of fungal meningitis and other infections. From CDC website. Accessed 2017 Jul 21. [Web]
478. Centers for Disease Control and Prevention. Exserohilum rostratum . From CDC website. Accessed 2013 Aug 12. [Web]
479. Food and Drug Administration. Multistate outbreak of fungal meningitis and other infections. 2012 Dec 12. From FDA website. Accessed 2013 Aug 12. [Web]
480. da Cunha KC, Sutton DA, Gené J et al. Molecular identification and in vitro response to antifungal drugs of clinical isolates of exserohilum. Antimicrob Agents Chemother . 2012; 56:4951-4. [PubMedCentral][PubMed 22733074]
481. DoctorFungus.org. The Official Website of the Mycoses Study Group. Exserohilum spp. From [Web]. Accessed 2013 Aug 12.
482. Revankar SG, Sutton DA. Melanized fungi in human disease. Clin Microbiol Rev . 2010; 23:884-928. [PubMedCentral][PubMed 20930077]
483. Centers for Disease Control and Prevention (CDC). Spinal and paraspinal infections associated with contaminated methylprednisolone acetate injections - Michigan, 2012-2013. MMWR Morb Mortal Wkly Rep . 2013; 62:377-81. [PubMedCentral][PubMed 23677044]
486. Centers for Disease Control and Prevention. Notice to clinicians: continued vigilance urged for fungal infections among patients who received contaminated steroid injections. From cdc website. Accessed 2013 Aug 12. [Web]
487. Adler A, Yaniv I, Samra Z et al. Exserohilum: an emerging human pathogen. Eur J Clin Microbiol Infect Dis . 2006; 25:247-53. [PubMed 16511679]
488. Ritter JM, Muehlenbachs A, Blau DM et al. Exserohilum Infections Associated with Contaminated Steroid Injections: A Clinicopathologic Review of 40 Cases. Am J Pathol . 2013; :. [PubMedCentral]
489. Pappas PG, Kontoyiannis DP, Perfect JR et al. Real-time treatment guidelines: considerations during the Exserohilum rostratum outbreak in the United States. Antimicrob Agents Chemother . 2013; 57:1573-6. [PubMedCentral][PubMed 23384532]
490. Kerkering TM, Grifasi ML, Baffoe-Bonnie AW et al. Early clinical observations in prospectively followed patients with fungal meningitis related to contaminated epidural steroid injections. Ann Intern Med . 2013; 158:154-61. [PubMed 23183583]
491. Smith RM, Schaefer MK, Kainer MA et al. Fungal Infections Associated with Contaminated Methylprednisolone Injections - Preliminary Report. N Engl J Med . 2012; :. [PubMedCentral]
492. Kainer MA, Reagan DR, Nguyen DB et al. Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med . 2012; 367:2194-203. [PubMedCentral][PubMed 23131029]
493. Centers for Disease Control and Prevention. Leishmaniasis - resources for health professionals. From CDC website. Accessed 2015 Sep 22. [Web]
494. Murray HW. Leishmaniasis in the United States: treatment in 2012. Am J Trop Med Hyg . 2012; 86:434-40. [PubMedCentral][PubMed 22403313]
495. Mitropoulos P, Konidas P, Durkin-Konidas M. New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. J Am Acad Dermatol . 2010; 63:309-22. [PubMed 20303613]
496. Monge-Maillo B, López-Vélez R. Therapeutic options for old world cutaneous leishmaniasis and new world cutaneous and mucocutaneous leishmaniasis. Drugs . 2013; 73:1889-920. [PubMed 24170665]
497. Monge-Maillo B, López-Vélez R. Therapeutic options for visceral leishmaniasis. Drugs . 2013; 73:1863-88. [PubMedCentral][PubMed 24170666]
498. Olliaro PL, Guerin PJ, Gerstl S et al. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980-2004. Lancet Infect Dis . 2005; 5:763-74. [PubMed 16310148]
499. Centers for Disease Control and Prevention. Health information for international travel, 2016. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website. [Web]
500. Centers for Disease Control and Prevention. Clinical management advice for confirmed or suspected cases of parasitic diseases. From CDC website. Accessed 2014 Jun 6. [Web]
501. Berman J. Amphotericin B formulations and other drugs for visceral leishmaniasis. Am J Trop Med Hyg . 2015; 92:471-3. [PubMedCentral][PubMed 25510726]
502. van Griensven J, Carrillo E, López-Vélez R et al. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect . 2014; 20:286-99. [PubMed 24450618]
503. Steimbach LM, Tonin FS, Virtuoso S et al. Efficacy and safety of amphotericin B lipid-based formulations-A systematic review and meta-analysis. Mycoses . 2017; 60:146-154. [PubMed 27878878]
504. Tsay S, Welsh RM, Adams EH et al. Notes from the Field: Ongoing Transmission of Candida auris in Health Care Facilities - United States, June 2016-May 2017. MMWR Morb Mortal Wkly Rep . 2017; 66:514-515. [PubMedCentral][PubMed 28520710]
505. Larkin E, Hager C, Chandra J et al. The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation. Antimicrob Agents Chemother . 2017; 61 [PubMedCentral][PubMed 28223375]
506. Lee WG, Shin JH, Uh Y et al. First three reported cases of nosocomial fungemia caused by Candida auris. J Clin Microbiol . 2011; 49:3139-42. [PubMedCentral][PubMed 21715586]
507. Vallabhaneni S, Kallen A, Tsay S et al. Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus - United States, May 2013-August 2016. MMWR Morb Mortal Wkly Rep . 2016; 65:1234-1237. [PubMed 27832049]
508. Kathuria S, Singh PK, Sharma C et al. Multidrug-Resistant Candida auris Misidentified as Candida haemulonii: Characterization by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and DNA Sequencing and Its Antifungal Susceptibility Profile Variability by Vitek 2, CLSI Broth Microdilution, and Etest Method. J Clin Microbiol . 2015; 53:1823-30. [PubMedCentral][PubMed 25809970]
509. Lockhart SR, Etienne KA, Vallabhaneni S et al. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis . 2017; 64:134-140. [PubMed 27988485]
510. Centers for Disease Control and Prevention. Candida auris interim recommendations for healthcare facilities and laboratories. From CDC website. Accessed 2017 May 30. [Web]
511. Centers for Disease Control and Prevention. Naegleria fowleri — primary amebic meningoencephalitis (PAM) — amebic encephalitis. From CDC website. Accessed 2017 Jun 12. [Web]
512. Linam WM, Ahmed M, Cope JR et al. Successful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis. Pediatrics . 2015; 135:e744-8. [PubMedCentral][PubMed 25667249]
513. Grace E, Asbill S, Virga K. Naegleria fowleri: Pathogenesis, Diagnosis, and Treatment Options. Antimicrob Agents Chemother . 2015; 59:6677-81. [PubMedCentral][PubMed 26259797]