Introduction ⬇
VA Class:AM900
VA Class:AP100
AHFS Class:
Generic Name(s):
Associated Monographs
Co-trimoxazole is a synergistic fixed combination of sulfamethoxazole (an intermediate-acting antibacterial sulfonamide), and trimethoprim; both sulfamethoxazole and trimethoprim are synthetic folate-antagonist anti-infectives.
Uses ⬆ ⬇
Acute Otitis Media 
Co-trimoxazole is used in adults† and children for the treatment of acute otitis media (AOM) caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae 186,272,273,274,278 when the clinician makes the judgment that the drug offers some advantage over use of a single anti-infective.186 Data are limited to date regarding safety of repeated use of co-trimoxazole in pediatric patients younger than 2 years of a the drug should not be administered prophylactically or for prolonged periods for the treatment of otitis media in any age group.186
Various anti-infectives, including oral amoxicillin, oral amoxicillin and clavulanate potassium, various oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), IM ceftriaxone, oral co-trimoxazole, oral erythromycin-sulfisoxazole, oral azithromycin, oral clarithromycin, and oral loracarbef, have been used in the treatment of AOM.272,273,278,286,291,292,293,294,295,296,297,298,299,300,301,302,321 The AAP, CDC, and other clinicians state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, and is well tolerated and inexpensive.278,286,295,300,301,302,303,304,305,321
Co-trimoxazole is not considered a first-line agent for treatment of AOM, but is recommended as an alternative for individuals with type I penicillin hypersensitivity.321 Because S. pneumoniae resistant to amoxicillin also frequently are resistant to co-trimoxazole, clarithromycin, and azithromycin, these drugs may not be effective in patients with AOM who fail to respond to amoxicillin.302,321 For additional information regarding treatment of AOM and information regarding prophylaxis of recurrent AOM, treatment of persistent or recurrent AOM, and treatment of otitis media with effusion (OME), see Uses: Otitis Media in the Aminopenicillins General Statement 8:12.16.08.
GI Infections
Travelers' Diarrhea
Oral co-trimoxazole is used in adults and children† for the treatment of enteritis caused by enterotoxigenic Escherichia coli that occurs during or soon after travel to developing countries or other areas where hygiene is poor (travelers' diarrhea).112,114,115,159,181,182,183,184,185,186,242,256 Travelers' diarrhea is a condition characterized by a twofold or greater increase in the frequency of unformed bowel movements; other manifestations may include abdominal cramps, nausea, bloating, urgency, fever, and malaise.114,159,181,182,183,184,185,187,256 The principal cause of travelers' diarrhea is infection with enterotoxigenic E . coli , but other infectious agents (e.g., Shigella , Salmonella , Campylobacter spp.) have also been associated with the disease.112,114,159,180,181,182,183,256,257,288
Treatment of the condition depends on severity of the illness; travelers' diarrhea is usually a mild, self-limited disorder.114,159,180,242,256,257 In individuals with mild to moderate disease, replacement therapy with oral fluids and electrolytes may be sufficient,114,115,159,180,181,242,256,257 although therapy with nonspecific or antimotility agents (e.g., bismuth subsalicylate, loperamide) may be useful for temporary relief of associated symptoms (e.g., abdominal cramps and diarrhea).114,115,159,180,181,182,187,190,191,242,256,257 Travelers who develop diarrhea with at least 3 loose stools in an 8-hour period, especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in the stools, may benefit from short-term treatment with an anti-infective agent.114,115,159,180,242,259,306 Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin ofloxacin) usually are considered the drugs of choice when treatment of travelers' diarrhea is indicated.159,180,242,306 Co-trimoxazole can be used as an alternative in children who cannot receive fluoroquinolones; however, resistance to co-trimoxazole has been reported in many areas.159,242,306
Efficacy of anti-infective therapy may depend on the etiologic agent and its susceptibility to antibiotics.159 In several controlled studies, therapy for 3-5 days with oral co-trimoxazole112,182,183,184,185 or trimethoprim alone112,183,184 substantially reduced the duration of abdominal pain and nausea and the number of unformed stools in individuals with the disease; mild rash occurred infrequently with both therapies.112,181,183,184,185 In another controlled study, concomitant therapy with co-trimoxazole and loperamide for 3 days provided more rapid relief of travelers' diarrhea than therapy with either drug alone, and co-trimoxazole given alone as a single dose† (320 mg of trimethoprim given as co-trimoxazole) was also more effective than placebo in treating the condition.181 However, because of the development of resistance to co-trimoxazole in many areas, other anti-infective agents (e.g., ciprofloxacin, levofloxacin, ofloxacin), which also have been used with success in the treatment of travelers' diarrhea, may be considered first.159,180,242,306 Nausea and vomiting without diarrhea should not be treated with anti-infectives.114,159 Individuals with persistent diarrhea and severe fluid loss, fever, and blood or mucus in the stools should seek medical attention.114,159
Oral co-trimoxazole also has been used effectively to prevent travelers' diarrhea† in individuals traveling for relatively short periods to areas where enterotoxigenic E. coli and other causative bacterial pathogens (e.g., Shigella ) are known to be susceptible to the drug.113,159,242 Because travelers' diarrhea is a relatively nonthreatening illness that is usually mild and self-limiting and can be effectively treated and because of the risks of widespread use of anti-infective agents prophylactically (i.e., potential adverse drug reactions, selection of resistant organisms and increased susceptibility to infections caused by these or other organisms), the US Centers for Disease Control and Prevention (CDC) and most experts recommend that anti-infectives not be used prophylactically by most individuals traveling to areas of risk.114,159,180,193,242,256,257,280 In addition, although controlled studies have indicated that various anti-infectives when taken prophylactically have been 52-95% effective in preventing travelers' diarrhea in several developing areas of the world, efficacy depends on resistance patterns of pathogenic bacteria in each travel area, and such information seldom is available.159 While fluoroquinolone resistance for bacteria causing travelers' diarrhea currently is least common, this could change as use of these drugs increases worldwide.159 The CDC states that although use of anti-infective agents for prophylaxis of travelers' diarrhea in certain high-risk groups, such as travelers with immunosuppression or immunodeficiency, may seem reasonable, there currently are no specific data to support such prevention in these populations.159 (For information on prophylaxis of travelers' diarrhea in HIV-infected individuals, see Travelers' Diarrhea under Uses: GI Infections, in Ciprofloxacin 8:12.18.) Anti-infectives that have been used for prophylaxis of travelers' diarrhea are not effective in preventing diarrhea caused by viral or parasitic infections, and use of such prophylaxis may give a false sense of security to the traveler about the risk associated with consuming certain local foods and beverages.159 The principal preventive measure is prudent dietary practices.114,159,256,257 If prophylaxis is used, ciprofloxacin, levofloxacin, ofloxacin, or norfloxacin can be given for a maximum of 3 weeks.180
Shigella Infections
Co-trimoxazole is used IV or orally for the treatment of enteritis caused by susceptible strains of Shigella flexneri or S. sonnei. 135,186 Choice of anti-infective therapy should be based on drug susceptibility of the isolated organism. Although therapy may be initiated based on local susceptibility patterns pending results of susceptibility testing, some clinicians currently state that, when the susceptibility of the isolate is unknown, fluoroquinolones are the anti-infectives of choice with co-trimoxazole as an alternate, especially in areas where ampicillin-resistant strains of Shigella have been reported. Fluoroquinolones are the drugs of choice and co-trimoxazole an alternate for the treatment of shigellosis when the organism is resistant to ampicillin or the patient is allergic to ampicillin.
Escherichia coli Infections
Co-trimoxazole has been used in the treatment of GI infections caused by Escherichia coli †.286
Optimal therapy for diarrhea caused by enterotoxigenic E. coli † (ETEC) is not established and resistance is common.286 AAP states that if diarrhea caused by ETEC is suspected in a traveler to a resource-limited country, use of co-trimoxazole, azithromycin, or ciprofloxacin should be considered if diarrhea is severe or intractable and if in vitro testing indicates that the causative organism is susceptible.286 A parenteral regimen should be used if systemic infection is suspected.286
For the treatment of dysentery caused by enteroinvasive E. coli † (EIEC), the AAP suggests than an oral anti-infective (e.g., co-trimoxazole, azithromycin, ciprofloxacin) can be used if in vitro tests indicate the causative organism is susceptible.286
The role of anti-infectives in patients with hemorrhagic colitis caused by shiga toxin-producing Escherichia coli (STEC; formerly known as enterohemorrhagic E. coli †) is unclear and most experts do not recommend use of anti-infectives for treatment of children with enteritis caused by E. coli 0157:H7.286
Respiratory Infections
Co-trimoxazole is used in adults for treatment of acute exacerbation of chronic bronchitis caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae 135 when the clinician makes the judgment that the drug offers some advantage over use of a single anti-infective.186 Co-trimoxazole is considered by many clinicians to be the drug of choice for the treatment of upper respiratory tract infections and bronchitis caused by H. influenzae .121 The drug also is used as an alternative to penicillin G or penicillin V for the treatment of respiratory tract infections caused by Streptococcus pneumoniae .121 Co-trimoxazole is as effective as amoxicillin, ampicillin, erythromycin, or tetracycline in the treatment of acute exacerbations of chronic bronchitis.
Many clinicians consider co-trimoxazole an alternative for the treatment of infections caused by Legionella micdadei † ( L. pittsburgensis ) or L. pneumophila †.121
Co-trimoxazole should not be used in the treatment of pharyngitis caused by S. pyogenes (group A β-hemolytic streptococci); results of clinical studies indicate that co-trimoxazole therapy is associated with a higher bacteriologic failure rate (as evidenced by failure to eradicate S. pyogenes from the tonsillopharyngeal area) than penicillin therapy.186
Urinary Tract Infections
Co-trimoxazole is used for the treatment of urinary tract infections (UTIs) caused by susceptible strains of E. coli, Proteus (indole-positive or -negative), Klebsiella , Morganella morganii , or Enterobacter. 135,186
Co-trimoxazole, given in single doses, as 3-day therapy, or for 7-10 days, is effective in the treatment of acute uncomplicated UTIs. Some clinicians consider a 3-day regimen of co-trimoxazole the treatment of choice for the empiric treatment of acute uncomplicated UTIs.121,163 Co-trimoxazole also is used for the treatment of acute complicated UTIs (e.g., UTIs associated with abnormalities of the urinary tract or neurogenic bladder), but other anti-infectives are preferred by most clinicians. For the treatment of acute pyelonephritis, some clinicians recommend anti-infective treatment for 7-14 days.163 Mild cases of pyelonephritis in women can be treated with an oral fluoroquinolone or with co-trimoxazole (if the causative organism in known to be susceptible).163 If the infection is likely to be caused by gram-positive bacteria, amoxicillin or amoxicillin and clavulanate potassium may be used.163 Patients with more severe infections should be hospitalized and therapy should be initiated using a parenteral regimen.163 Some clinicians recommend that acute pyelonephritis be treated with a parenteral fluoroquinolone or, alternatively, an aminoglycoside with or without ampicillin or an extended-spectrum cephalosporin; an aminoglycoside with or without ampicillin sodium and sulbactam sodium is recommended if the infection is likely to be caused by gram-positive bacteria.163 When treating acute uncomplicated UTI, the causative organism should be cultured and susceptibility tests conducted prior to initiation of co-trimoxazole therapy; co-trimoxazole may be initiated, however, before obtaining the results of these tests. Some clinicians also recommend obtaining follow-up urine cultures after discontinuance of anti-infective therapy to determine whether the bacteria have been eliminated.
Most clinicians reserve co-trimoxazole for the treatment of chronic or recurrent UTIs. In chronic or recurrent UTIs, the drug suppresses fecal and vaginal flora and usually does not select out resistant coliforms. For the treatment of chronic or recurrent UTIs resulting from reinfection or relapse in women, low doses of co-trimoxazole (e.g., 40 mg of trimethoprim and 200 mg of sulfamethoxazole given nightly or 3 times weekly) are as effective as other anti-infectives (e.g., methenamine mandelate, nalidixic acid, nitrofurantoin) and are preferred by many clinicians. Men with prostatitis-associated recurrent UTIs usually respond poorly to anti-infectives. Although 14-day courses of co-trimoxazole in such patients reportedly are associated with failure rates of greater than 60%, efficacy of the drug appears to be increased markedly with treatment courses of 3-6 months.
Brucellosis
Oral co-trimoxazole is considered an alternative to tetracyclines for the treatment of brucellosis† when tetracyclines are contraindicated, including brucellosis in pediatric patients.121,286 To decrease the incidence of relapse, many clinicians recommend that rifampin be used in conjunction with co-trimoxazole or a tetracycline.121,286 For treatment of serious brucellosis or when there are complications, including endocarditis, meningitis, or osteomyelitis, some clinicians recommend that an aminoglycoside (streptomycin or gentamicin) be used concomitantly with co-trimoxazole or a tetracycline for the first 7-14 days of therapy; rifampin can also be included in the regimen to reduce the risk of relapse.286
Burkholderia Infections
Co-trimoxazole is used for the treatment of infections caused by Burkholderia cepacia †.121 Co-trimoxazole is considered the drug of choice and ceftazidime, chloramphenicol, or imipenem are alternatives for these infections.121
Co-trimoxaozle is used for the treatment of melioidosis† caused by susceptible B. pseudomallei , usually in a multiple-drug regimen with chloramphenicol and doxycycline.121 Ceftazidime or imipenem monotherapy is recommended as the drug of choice for these infections.121 B. pseudomallei is difficult to eradicate and relapse of melioidosis is common.
Cholera
Co-trimoxazole is used in the treatment of cholera† when anti-infective therapy is indicated as an adjunct to fluid and electrolyte replacement.121,231,286 Tetracyclines usually are considered the drugs of choice for the treatment of cholera, and co-trimoxazole, a fluoroquinolone, erythromycin, or furazolidone (no longer commercially available in the US) is recommended when tetracyclines are contraindicated or when the infection is caused by tetracycline-resistant Vibrio cholerae .121,231,286 V. cholerae serogroup 0139 Bengal may not be susceptible to co-trimoxazole or furazolidone.286
Cyclospora Infections
The CDC and others consider co-trimoxazole the treatment of choice for cyclosporiasis infection† caused by Cyclospora cayetanensis ,119,159,320 a coccidian parasite that causes severe, generally self-limiting, diarrhea.286,288,320
Granuloma Inguinale (Donovanosis)
Co-trimoxazole is used for the treatment of granuloma inguinale (donovanosis) caused by Calymmatobacterium granulomatis †.116,286 The CDC recommends that donovanosis be treated with a regimen of oral co-trimoxazole or oral doxycycline or, alternatively, a regimen of oral ciprofloxacin, oral erythromycin, or oral azithromycin.116 Anti-infective treatment of donovanosis should be continued until all lesions have healed completely; a minimum of 3 weeks of treatment usually is necessary.116 If lesions do not respond within the first few days of therapy, the CDC recommends that addition of a parenteral aminoglycoside (e.g., 1 mg/kg of gentamicin IV every 8 hours) to the regimen be considered.116 Erythromycin should be used to treat donovanosis in pregnant and lactating women; addition of a parenteral aminoglycoside (e.g., gentamicin) to the regimen should be strongly considered in these women.116 Anti-infective treatment appears to halt progressive destruction of tissue, although prolonged duration of therapy often is required to enable granulation and reepithelialization of ulcers.116 Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.116
Individuals with HIV infection should receive the same treatment regimens recommended for other individuals with donovanosis; however, the CDC suggests that addition of a parenteral aminoglycoside (e.g., gentamicin) to the regimen should be strongly considered in HIV-infected patients.116
Any individual who had sexual contact with a patient with donovanosis should be examined and treated if they had sexual contact with the patient during the 60 days preceding the onset of symptoms in the patient and they have clinical signs and symptoms of the disease.116
Isosporiasis
Many clinicians consider co-trimoxazole the drug of choice for the treatment of isosporiasis† caused by Isospora belli .119,120,199
Listeria Infections
Co-trimoxazole has been used successfully in the treatment of meningitis caused by Listeria monocytogenes †,232,233,234,235,236,237 and some clinicians consider the drug the preferred alternative for the treatment of listeria infections (except endocarditis) in penicillin-allergic patients.118,121,286
Mycobacterial Infections
Co-trimoxazole has been used in the treatment of cutaneous infections caused by Mycobacterium marinum † and is considered an alternative to minocycline.121
Nocardia Infections
Co-trimoxazole has been used in the treatment of infections caused by Nocardia †, including N. asteroides, N. brasiliensis , and N. caviae. Co-trimoxazole121,286 or a sulfonamide alone (e.g., sulfisoxazole, sulfamethoxazole)286 are considered drugs of choice for the treatment of nocardiosis. Alternative anti-infectives for the treatment of nocardiosis include a tetracycline (should not be used in pregnant women or children younger than 8 years of age), amoxicillin and clavulanate potassium, imipenem, meropenem, amikacin, cycloserine, or linezolid.121,286 Amikacin and cycloserine generally should be reserved for use in the treatment of severe infections when other drugs are ineffective.121,286 Some clinicians suggest that in patients with nocardiosis involving the CNS or when the infection is disseminated or overwhelming, amikacin be included during the first 4-12 weeks of therapy or until there is clinical improvement.286 In vitro susceptibility testing, if available, is recommended to guide selection of an anti-infective agent for the treatment of severe nocardiosis or for the treatment of patients unable to tolerate a sulfonamide.286
Nocardiosis in immunocompetent patients with lymphocutaneous disease usually responds after 6-12 weeks of appropriate anti-infective therapy.286 Immunocompromised patients and those with invasive disease require 6-12 months of anti-infective therapy and, because of the possibility of relapse, therapy should be continued for at least 3 months after apparent cure; nocardiosis in patients with human immunodeficiency virus (HIV) infection may require even longer therapy.286 Drainage of abscesses may be beneficial, especially in immunocompromised patients.286
Pertussis
Although efficacy of the drug remains to be fully determined, the CDC and other experts currently consider co-trimoxazole an alternative to erythromycin for the treatment of the catarrhal stage of pertussis† to potentially ameliorate the disease and reduce its communicability.121,164,165,166,168,169,286 Co-trimoxazole also is considered an alternative to erythromycin for the prevention of pertussis† in household and other close contacts (e.g., day-care facility attendees) of patients with the disease.164,165,166,167,168,255
Plague
Co-trimoxazole has been used for postexposure prophylaxis of plague†.159,283,286 Although recommended by the CDC and other clinicians as an alternative agent for such prophylaxis in infants and children younger than 8 years of age,159,283,286 efficacy of the drug for prevention of plague is unknown.286 Most experts (e.g., CDC, AAP, US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend oral ciprofloxacin or doxycycline for postexposure prophylaxis in adults and most children.159,309,310 Postexposure prophylaxis with anti-infectives is recommended after high-risk exposures to plague, including close exposure to individuals with naturally occurring plague, during unprotected travel in active epizootic or epidemic areas, or laboratory exposure to viable Yersinia pestis .159,283,286,309,310
Co-trimoxazole also has been used in the treatment of plague†, but appears to be less effective than other anti-infectives used for treatment of the disease (e.g., streptomycin, gentamicin).309,311 Because of lack of efficacy, some experts state that co-trimoxazole should not be used for the treatment of pneumonic plague.309
For more information on the management of plague exposure, see Uses: Plague, in Streptomycin 8:12.02.
Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Treatment
Co-trimoxazole is used for the treatment of Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP).119,135,186,286 When given IV or orally, the drug has a cure rate of 70-80% in patients with PCP. Because co-trimoxazole has excellent tissue penetration and therapy with the agent is associated with rapid clinical response (i.e., 3-5 days in patients with mild to moderate infection),170 co-trimoxazole currently is considered the initial drug of choice for most patients with this infection.119,170,286 Co-trimoxazole also is considered the drug of choice for the treatment of PCP in patients with acquired immunodeficiency syndrome (AIDS);100,104,105,148,149,150,151,152,153,170,241 however, in patients with AIDS, co-trimoxazole is associated with an increased incidence of adverse reactions (especially fever and adverse dermatologic and hematologic reactions).101,102,103,109,117,135,136,137,138,149,150,151,152,153,160,161,247,248,250,251,252,253 In patients who are intolerant of co-trimoxazole, treatment alternatives include pentamidine isethionate (IV), trimetrexate glucuronate, trimethoprim and dapsone, clindamycin and primaquine, or atovaquone.119,170
Prevention
Co-trimoxazole is used for the prophylaxis of PCP, both for the prevention of initial episodes ( primary prevention ) and for the prevention of recurrence ( secondary prevention or chronic maintenance therapy) following an initial episode, in immunosuppressed individuals considered to be at increased risk of developing PCP.119,186,280,286 Some clinicians consider HIV-infected patients, patients with cancer (especially children with acute lymphocytic leukemia receiving maintenance chemotherapy), or renal transplant recipients with active cytomegalovirus infections to be candidates for co-trimoxazole prophylaxis.
Co-trimoxazole is used for prophylaxis of PCP in patients with HIV infection,138,148,149,150,151,152,153,155,156,157,172,186,199,200,201,202,203,204,220,227,228,239,240,241,261,262,280 although an increased risk of toxicity in these patients has been reported.104,138,148,149,150,151,152,153,155,156,157 Some evidence indicates that co-trimoxazole may be better tolerated in HIV-infected children than adults.101,102,155,202,205,206,266 In addition, patients receiving the drug for prophylaxis of PCP appear to tolerate the drug better than those patients receiving it for treatment of PCP.186 In a placebo-controlled study in adults with AIDS and newly diagnosed Kaposi's sarcoma but no history of opportunistic infections, no cases of PCP were observed in patients receiving co-trimoxazole ( primary prevention ) for a mean survival period of about 2 years; such pneumonia occurred in 53% of patients receiving placebo and developed within 5 months in 80% of patients who discontinued co-trimoxazole because of toxicity.155
Data from a study of 2 cohorts of HIV-positive men whose cases were followed for more than 9 years demonstrated that the largest increase in survival time from the development of a helper/inducer (CD4+, T4+) T-cell count of 200 cells/ mm3 was in patients diagnosed with PCP, suggesting that the combination of prophylaxis and antiretroviral therapy was a more important factor than antiretroviral therapy alone in prolonging survival.265 In another cohort of HIV-infected men, such prophylaxis was associated with a decreased incidence of PCP as the initial AIDS-related illness and, because of this beneficial effect and resultant delays in the onset of initial AIDS-related illness, was associated with increases in the rates of other less common opportunistic infections as the initial AIDS-related illness, including Mycobacterium avium complex, wasting syndrome, esophageal candidiasis, and cytomegalovirus infection.269 It was suggested that PCP prophylaxis may delay the development of the first AIDS-defining illness by 6-12 months. Although the generalizability of these data to other HIV-positive populations (e.g., women) is unclear, they suggest that PCP prophylaxis may have a role in prolonging survival and/or in delaying the development of AIDS-related illness in HIV-infected patients.265,269
Primary Prophylaxis
The Prevention of Opportunistic Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) recommends primary prophylaxis against PCP in HIV-infected adults and adolescents with CD4+ T-cell counts less than 200/ mm3 or a history of oropharyngeal candidiasis.280 HIV-infected adults and adolescents with a CD4+ T-cell percentage of less than 14% or a history of an AIDS-defining illness who do not otherwise qualify for prophylaxis also should be considered for primary prophylaxis.280 If CD4+ T-cell counts are monitored less frequently than every 3 months, individuals with CD4+ T-cell counts of greater than 200 but less than 250/ mm3 also should be considered for primary prophylaxis.280
The USPHS/IDSA recommends oral co-trimoxazole as the drug of choice for primary prophylaxis of PCP in HIV-infected individuals.280 When co-trimoxazole is used for the primary prevention of PCP in adults and adolescents, the preferred dosage regimen is 160 mg of trimethoprim (as co-trimoxazole) daily.280 This regimen also provides prophylaxis against Toxoplasma gondii and some common respiratory bacterial infections.280 Alternatively, 80 mg of trimethoprim (as co-trimoxazole) daily or 160 mg of trimethoprim (as co-trimoxazole) 3 times a week can be used.280 For individuals who experience an adverse reaction to co-trimoxazole that is not life-threatening, the USPHS/IDSA recommends that the drug be continued if feasible; for individuals who have discontinued the drug because of an adverse effect, reinstitution of co-trimoxazole should be considered once the adverse effect has resolved.280 Patients who have experienced adverse effects, especially fever and rash, may tolerate reintroduction of co-trimoxazole better with a gradual increase in dose (desensitization) or reintroduction of the drug at a reduced dose or frequency of administration.280 Alternative regimens that can be used in patients who cannot tolerate co-trimoxazole include dapsone, dapsone with pyrimethamine and leucovorin, aerosolized pentamidine, or atovaquone.280
Current evidence indicates that primary PCP prophylaxis can be discontinued in adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4+ T-cell counts from less than 200/ mm3 to greater than 200/ mm3.199,280,281,287,312,313,314,315,316 Patients included in studies evaluating discontinuance of prophylaxis generally were receiving primary prophylaxis and antiretroviral regimens that included HIV protease inhibitors; median follow-up ranged from 6-16 months and median CD4+ T-cell count at the time prophylaxis was discontinued exceeded 300/ mm3.199,280,281,287,312,313,314,315,316 In addition, at the time prophylaxis was discontinued, most patients had CD4+ T-cell counts exceeding 200/ mm3 for at least 3 months and many patients had sustained plasma HIV-1 RNA levels below the detection limits of the available assays.199,280,281,287,312,313,314,315,316 The USPHS/IDSA states that discontinuance of primary PCP prophylaxis is recommended in patients who have sustained a CD4+ T-cell count exceeding 200/ mm3 for at least 3 months because such prophylaxis appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.280 However, the USPHS/IDSA states that primary PCP prophylaxis should be restarted if the CD4+ T-cell count decreases to less than 200/ mm3.280
Prevention of Recurrence
The USPHS/IDSA recommends long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in HIV-infected adults and adolescents who have a history of PCP to prevent recurrence.280 The same regimens recommended for primary prophylaxis are used for suppressive therapy.280 Secondary prophylaxis generally is administered for life, unless immune recovery has occurred as a result of potent antiretroviral therapy.280
Current evidence indicates that secondary PCP prophylaxis can be discontinued in HIV-infected adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4+ T-cell counts from less than 200/ mm3 to greater than 200/ mm3.280,316,317,318 Patients in studies evaluating discontinuance of secondary prophylaxis had responded to potent antiretroviral therapy with an increase in CD4+ T-cell count to greater than 200/ mm3 for at least 3 months.280,312,316,317,318 Most patients were receiving an antiretroviral regimen that included HIV protease inhibitors; the median CD4+ T-cell count at the time prophylaxis was discontinued was greater than 300/ mm3 and most patients had sustained plasma HIV-1 RNA levels below the detection limits of the available assays.280,312,316,317,318 The longest follow-up was 13 months.280 The USPHS/IDSA states that discontinuance of secondary PCP prophylaxis in adults and adolescents who have a sustained (3 months or longer) increase in CD4+ T-cell counts to greater than 200/ mm3 is recommended because such prophylaxis appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.280 However, in patients who had PCP episodes when they had CD4+ T-cell counts exceeding 200/ mm3, it probably is prudent to continue secondary PCP prophylaxis for life regardless of how high the CD4+ T-cell count increases in response to potent antiretroviral therapy.280
If secondary PCP prophylaxis is discontinued in HIV-infected adults or adolescents meeting the recommended criteria, the USPHS/IDSA recommends that it be restarted if the CD4+ T-cell count decreases to less than 200/ mm3 or if PCP recurs at a CD4+ T-cell count exceeding 200/ mm3.280
Prophylaxis in HIV-Infected Children
The CDC,172,202,227,239,280,281,282 American Academy of Pediatrics (AAP),163,286 USPHS/IDSA,280 and most clinicians202,203,206,221,266,268 recommend antimicrobial prophylaxis for PCP in selected HIV-infected children.186 This recommendation is based on the high mortality rate associated with PCP in infants and children and the established efficacy of prophylaxis in HIV-infected adults; it is unlikely that placebo-controlled studies will ever be performed in HIV-infected children.202,206 PCP is the most common serious HIV-associated opportunistic infection among children, occurring in more than 50% of those with perinatally acquired HIV infection that progresses to AIDS within the first year of life, and in about 40% of pediatric AIDS cases overall.202,268 In children with perinatally acquired HIV infection, PCP occurs most often at 3-6 months of age.282,286 Despite the availability of effective anti-infectives for the treatment of P. jiroveci infections, the median survival from the first episode in infants and children is 1-4 months;202,206 among AIDS cases reported to CDC, 35% of children with PCP died within 2 months of diagnosis.202 Overall, about 90% of children with PCP died and 70% survived for less than 6 months in one retrospective study despite active treatment with co-trimoxazole and/or pentamidine.206 Therefore, current strategies should be aimed at preventing initial and subsequent infection with the protozoa in children at high risk for HIV infection by initiating early prophylactic therapy.202,206,221,268
The CDC, USPHS/IDSA, AAP, and other experts recommend that all infants born to HIV-infected women receive primary PCP prophylaxis starting at 4-6 weeks of age, regardless of their CD4+ T-cell count.280,282,286 Infants who are first identified as being HIV-exposed after 6 weeks of age should receive prophylaxis beginning at the time of identification.282 Because of the potential for adverse drug effects in neonates and the low incidence of P. jiroveci infection in this age group, primary but not secondary prophylaxis should be delayed until 1 month of age.202,282 Prophylaxis can be discontinued in children who are found not to be infected with HIV.280,282 All HIV-infected infants and infants whose infection status has not yet been determined should continue prophylaxis until 12 months of age.280,282
The need for subsequent prophylaxis should be based on age-specific CD4+ T-cell count thresholds.280,282 In HIV-infected children 1-5 years of age, primary prophylaxis against PCP should be initiated if CD4+ T-cell counts are less than 500/ mm3 or the CD4+ percentage is less than 15%.280,282 In HIV-infected children 6-12 years of age, primary prophylaxis against PCP should be initiated if CD4+ T-cell counts are less than 200/ mm3 or the CD4+ percentage is less than 15%.280,282
The USPHS/IDSA recommends oral co-trimoxazole as the drug of choice for the primary and secondary (suppressive or chronic maintenance therapy) prevention of PCP in HIV-infected infants and children.280 When co-trimoxazole is used for the primary or secondary prevention of PCP, the preferred dosage regimen is 150 mg/m2 of trimethoprim (as co-trimoxazole) daily in 2 divided doses for 3 consecutive days each week.280 Alternatively, this dose can be administered as a single dose for 3 consecutive days each week, in 2 divided doses daily, or in 2 divided doses 3 times a week on alternate days.280 Alternative regimens that can be used in HIV-infected infants and children include dapsone, aerosolized pentamidine, or atovaquone.280
The safety of discontinuing primary or secondary PCP prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.280 Children who have a history PCP should receive life-long suppressive therapy to prevent recurrence.280
Toxoplasmosis
Prevention
Primary Prophylaxis
The USPHS/IDSA recommends that, shortly after being diagnosed with HIV infection, all HIV-infected individuals be tested for IgG antibody to Toxoplasma to detect latent infection with T. gondii .280 HIV-infected individuals (particularly those seronegative for Toxoplasma antibody) should be counseled concerning the various sources of toxoplasmic infection and how best to avoid these sources, including avoiding raw or undercooked meat, washing raw vegetables, hand washing after contact with raw meat or soil, and hand washing after changing cat litter boxes.280 The USPHS/IDSA recommends that all HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and who have CD4+ T-cell counts less than 100/ mm3 receive primary prophylaxis against toxoplasmic encephalitis.280 Primary prophylaxis against toxoplasmosis encephalitis generally is recommended for HIV-infected infants and children with severe immunosuppression who are seropositive for Toxoplasma IgG antibody.280 Co-trimoxazole is the drug of choice for primary prophylaxis against toxoplasmosis encephalitis and dosages of the drug recommended for prophylaxis against PCP appear to be effective against toxoplasmosis encephalitis.280 When co-trimoxazole is used for primary prevention of toxoplasmosis encephalitis in adults and adolescents, the preferred dosage regimen is 160 mg of trimethoprim (as co-trimoxazole) daily.280 In patients who cannot tolerate co-trimoxazole, regimens used for primary prophylaxis of PCP that consist of dapsone with pyrimethamine and leucovorin also provide protection against toxoplasmosis encephalitis.280 Atovaquone with or without pyrimethamine and leucovorin also can be used for primary prophylaxis against toxoplasmosisencephalitis.280 However, aerosolized pentamidine does not provide protection against toxoplasmosis encephalitis and regimens consisting of dapsone, pyrimethamine, azithromycin, or clarithromycin used alone cannot be recommended for prophylaxis against toxoplasmosis encephalitis based on current data.280
HIV-infected individuals who are seronegative for Toxoplasma antibody and who are not currently receiving primary PCP prophylaxis with a regimen known to be active against toxoplasmosis encephalitis should be retested for Toxoplasma antibody if their CD4+ T-cell count falls below 100/ mm3 to determine whether they have seroconverted, are now at risk for toxoplasmosis encephalitis, and have become candidates for primary prophylaxis against the infection.280
Current evidence indicates that primary prophylaxis can be discontinued with minimal risk of developing toxoplasmic encephalitis in HIV-infected adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4+ T-cell counts from less than 200/ mm3 to greater than 200/ mm3.280,312,313,316,319 Patients included in these studies generally were receiving primary prophylaxis and antiretroviral regimens that included HIV-protease inhibitors; median follow-up ranged from 7-22 months and median CD4+ T-cell count at the time prophylaxis was discontinued exceeded 300/ mm3.280,312,313,316,319 At the time prophylaxis was discontinued, many patients had sustained plasma HIV-1 RNA levels below the detection limits of the available assays.280 While patients with CD4+ T-cell counts below 100/ mm3 are at greatest risk for toxoplasmic encephalitis, the risk in patients whose CD4+ T-cell counts have increased to 100-200/ mm3 has not been studied as extensively as in those whose CD4+ T-cell counts have increased to greater than 200/ mm3.280 Therefore, the recommendation to discontinue primary toxoplasmosis prophylaxis specifies that prophylaxis can be discontinued when the CD4+ T-cell count exceeds 200/ mm3.280 The USPHS/IDSA states that discontinuation of primary toxoplasmosis prophylaxis is recommended in adults and adolescents who have a sustained (3 months or longer) increase in CD4+ T-cell counts to greater than 200/ mm3 because such prophylaxis appears to add little benefit in terms of disease prevention for toxoplasmosis, and discontinuance reduces the pill burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.280
If primary toxoplasmosis prophylaxis is discontinued in adults and adolescents meeting the recommended criteria, the USPHS/IDSA states that it should be restarted if the CD4+ T-cell count decreases to less than 100-200/ mm3.280
The safety of discontinuing primary toxoplasmosis prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.280
Prevention of Recurrence
The USPHS/IDSA recommends that HIV-infected individuals who have had toxoplasmic encephalitis receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent relapse.280 Secondary toxoplasmosis prophylaxis generally is administered for life, unless immune recovery has occurred as a result of potent antiretroviral therapy.280
The USPHS/IDSA states that the regimen of choice for secondary prophylaxis to prevent relapse of toxoplasmosis in HIV-infected adults, adolescents, infants, and children is a regimen of sulfadiazine and pyrimethamine (with leucovorin).280 In patients who cannot tolerate sulfonamides, a regimen of clindamycin and pyrimethamine (with leucovorin) is recommended; a regimen of atovaquone with or without pyrimethamine (with leucovorin) also is an alternative in adults and adolescents;280 Co-trimoxazole is not recommended for secondary toxoplasmosis prophylaxis.280
For information on USPHS/IDSA recommendations regarding secondary prophylaxis of toxoplasmosis in HIV-infected individuals, including when to initiate or discontinue such prophylaxis, see Uses: Toxoplasmosis, in Pyrimethamine 8:30.08.
Wegener's Granulomatosis
Co-trimoxazole has reportedly produced beneficial responses in a limited number of patients with Wegener's granulomatosis†, but further study is needed.122,123,133,146,147,207 Prolonged remissions have been observed in many of these patients,123,133,146,147,207 including some whose disease relapsed while receiving conventional therapy (e.g., cyclophosphamide),122,123,146 and co-trimoxazole therapy may reduce or eliminate the need for cytotoxic (e.g., cyclophosphamide) and corticosteroid therapy.122,123,146,147,207 Relapse has occurred occasionally during co-trimoxazole therapy146,207 but may respond to supplemental dosages of trimethoprim or the addition of small dosages of cytotoxic therapy.146 The precise role of co-trimoxazole in the management of Wegener's granulomatosis and the drug's effect on long-term morbidity and mortality remain to be determined,146,147,207 but the drug appears to be a useful alternative to more toxic drugs (e.g., cyclophosphamide) in some patients.122,123,133,146,147,207
Whipple's Disease
Co-trimoxazole is used in the treatment of Whipple's disease† caused by Tropheryma whippelii .121
Dosage and Administration ⬆ ⬇
Reconstitution and Administration
Co-trimoxazole is administered orally or by IV infusion. When oral therapy is not feasible or for severe infections, the drug may be administered IV. The drug should not be injected IM.
Co-trimoxazole for injection concentrate must be diluted prior to IV infusion. For IV infusion, each 5 mL of the concentrate for injection containing 80 mg of trimethoprim is usually diluted with 125 mL of 5% dextrose. In patients in whom fluid intake is restricted, each 5 mL of the concentrate may be diluted in 75 mL of 5% dextrose.
Dosage
Dosage of co-trimoxazole is expressed in terms of the trimethoprim content of the fixed combination containing 5 mg of sulfamethoxazole to 1 mg of trimethoprim.
Acute Otitis Media
For the treatment of acute otitis media in children 2 months of age or older, the usual oral dosage of co-trimoxazole is 8 mg/kg of trimethoprim (as co-trimoxazole) daily in 2 divided doses every 12 hours. The usual duration of treatment is 10 days.
GI Infections
Shigella Infections
For the treatment of enteritis caused by S. flexneri or S. sonnei , the usual adult oral dosage of co-trimoxazole is 160 mg of trimethoprim (as co-trimoxazole) administered every 12 hours. The usual oral dosage for children 2 months of age or older is 8 mg/kg daily of trimethoprim (as co-trimoxazole), administered in 2 divided doses every 12 hours for 5 days.
For enteritis caused by S. flexneri or S. sonnei in children 2 months of age or older and in adults, the usual IV dosage of co-trimoxazole is 8-10 mg/kg of trimethoprim (as co-trimoxazole) daily, administered in 2-4 equally divided doses every 6, 8, or 12 hours for 5 days.
Travelers' Diarrhea
For the treatment of travelers' diarrhea in adults, co-trimoxazole has been given in a dosage of 160 mg of trimethoprim (as co-trimoxazole) every 12 hours for 3-5 days.112,114,115,182,183,184,185,186,242,256,257,306 A single oral dose of 320 mg of trimethoprim (as co-trimoxazole) has also been used for the treatment of travelers' diarrhea.242,306
Although the use of anti-infectives for prophylaxis of travelers' diarrhea† generally is discouraged,114,159,180,193,256,257 an adult oral dosage of trimethoprim 160 mg (as co-trimoxazole) once daily during the period of risk has been used.113,115,256,257
Respiratory Tract Infections
For the treatment of bronchitis, the usual adult oral dosage of co-trimoxazole is 160 mg of trimethoprim (as co-trimoxazole) administered every 12 hours for 14 days.
Urinary Tract Infections
For the treatment of chronic or recurrent urinary tract infections (UTIs) or prostatitis†, the usual adult oral dosage of co-trimoxazole is 160 mg of trimethoprim (as co-trimoxazole) administered every 12 hours. Most clinicians recommend continuing co-trimoxazole treatment for 10-14 days for chronic or recurrent UTIs or for 3-6 months in men with prostatitis†. For the prophylaxis† of chronic or recurrent UTIs, co-trimoxazole doses of 40-80 mg of trimethoprim (as co-trimoxazole) have been administered daily or 3 times weekly for 3-6 months. For the treatment of chronic or recurrent UTIs in children 2 months of age or older, the usual oral dosage is 8 mg/kg daily of trimethoprim (as co-trimoxazole), administered in 2 divided doses every 12 hour for 10 days.
For severe UTIs in children 2 months of age or older and in adults, the usual IV dosage of trimethoprim is 8-10 mg/kg (as co-trimoxazole) daily, administered in 2-4 equally divided doses every 6, 8, or 12 hours for up to 14 days.
Brucellosis
For the treatment of brucellosis†, some clinicians recommend that pediatric patients receive a dosage of oral trimethoprim (as co-trimoxazole) of 10 mg/kg daily (maximum 480 mg/daily) in 2 divided doses for 4-6 weeks.286
Cholera
For the treatment of cholera†, the usual oral dosage of trimethoprim (as co-trimoxazole) is 4-5 mg/kg twice daily for 3 days in children or 160 mg twice daily for 3 days in adults, in conjunction with fluid and electrolyte replacement.231,286
Cyclospora Infections
For the treatment of cyclosporiasis†, the usual oral dosage of co-trimoxazole is 160 mg of trimethoprim (as co-trimoxazole) twice daily for 7-10 days in adults or 5 mg/kg twice daily for 7-10 days in children.119 However, HIV-infected patients may require higher dosage and more prolonged therapy.119
Granuloma Inguinale (Donovanosis)
For the treatment of granuloma inguinale (donovanosis) caused by Calymmatobacterium granulomatis †, the CDC recommends that oral trimethoprim (as co-trimoxazole) be given in a dosage of 160 mg twice daily for at least 3 weeks.116 If lesions do not respond within the first few days, addition of a parenteral aminoglycoside (1 mg/kg of gentamicin IV every 8 hours) to the regimen should be considered; addition of the aminoglycoside should be strongly considered when treating donovanosis in patients with human immunodeficiency virus (HIV) infection and in pregnant and lactating women.116 Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.116
Isosporiasis
For the treatment of isosporiasis†, some clinicians recommend that adults receive an oral co-trimoxazole dosage of 160 mg of trimethoprim (as co-trimoxazole) twice daily for 10 days and that children receive an oral co-trimoxazole dosage of trimethoprim (as co-trimoxazole) of 5 mg/kg twice daily for 10 days.119 However, immunocompromised patients may require higher dosage and more prolonged therapy.119
Nocardia Infections
For the treatment of nfections caused by Nocardia †, an average adult oral dosage of trimethoprim (as co-trimoxazole) of 640 mg daily has been administered for an average of 7 months.
Pertussis
Although the optimum dosage and duration of co-trimoxazole for the treatment or prevention of pertussis† have not been established, an oral dosage of 8 mg/kg of trimethoprim and 40 mg/kg of sulfamethoxazole daily in 2 divided doses has been recommended for children164,286 and a dosage of 320 mg daily in 2 divided doses has been recommended for adults.164,166,168 Because of reports of prophylaxis failures and delays or failure in eradication with shorter courses of anti-infective therapy in this infection, the US Public Health Service Advisory Committee on Immunization Practices (ACIP),164 American Academy of Pediatrics (AAP),286 and some clinicians222,223,224,225,226 recommend that a 14-day course of therapy be employed for the treatment or prevention of pertussis.
Plague
For anti-infective prophylaxis of individuals with close exposure to pneumonic plague or an exceptionally high risk of exposure to plague, the CDC recommends an oral trimethoprim (as co-trimoxazole) dosage of 320-640 mg daily in 2 equally divided doses for 7 days or a dosage of 8 mg/kg daily in 2 equally divided doses for 7 days in children at least 2 months of age.283
Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
For the treatment of Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP) in adults and children older than 2 months of age, the usual oral or IV dosage of trimethoprim (as co-trimoxazole) is 15-20 mg/kg daily, given in 3 or 4 equally divided doses.119,135,170,186 An IV dosage of 10-15 mg/kg daily has also been suggested for the treatment of PCP in adults with normal renal function.135 The usual duration of co-trimoxazole for treatment of PCP is 14-21 days.119,135,156,286
For both primary and secondary prevention of PCP in HIV-infected adults and adolescents, the Prevention and Opportunistic Infections Working Group of the US Public Health Service and the Infectious Disease Society of America (USPHS/IDSA) and other experts recommend an oral trimethoprim (as co-trimoxazole) dosage of 160 mg once daily;116,119,172,186,199,200,201,204,220,227,239,240,241,243,262,280 alternatively, an oral trimethoprim (as co-trimoxazole) dosage of 80 mg once daily also is recommended.119,280 In patients with acute lymphocytic leukemia undergoing induction and maintenance chemotherapy, co-trimoxazole therapy given on 3 consecutive days (e.g., Monday, Tuesday, and Wednesday) weekly appears to be as effective as daily therapy for the prevention of PCP and may be associated with a lower frequency of systemic fungal infections.125
For primary or secondary prophylaxis of PCP in children, including HIV-infected children, the USPHS/IDSA and other clinicians recommend an intermittent regimen of trimethoprim 150 mg/m2 daily (as co-trimoxazole) in 2 divided doses for 3 consecutive days each week is recommended.119,186,280 Alternatively, the USPHS/IDSA and AAP state that 150 mg/m2 can be administered as a single daily dose for 3 consecutive days each week, in 2 divided doses daily 7 days each week, or in 2 divided daily doses given 3 times each week on alternate days.280,286 AAP states that these dosages can be used in children 4 weeks of age† or older.286
Toxoplasmosis
For primary prophylaxis against toxoplasmosis† in HIV-infected adults and adolescents, the USPHS/IDSA recommends an oral trimethoprim dosage of 160 mg (as co-trimoxazole) once daily.280 Alternatively, an oral dosage of trimethoprim of 80 mg once daily (as co-trimoxazole) may be used.280 For primary prophylaxis against toxoplasmosis in HIV-infected children, the dosage recommended by USPHS/IDSA is trimethoprim 150 mg/m2 (as co-trimoxazole) daily in 2 divided doses.280
Dosage in Renal Impairment
In patients with impaired renal function, doses and/or frequency of administration of co-trimoxazole must be modified in response to the degree of renal impairment, severity of the infection, susceptibility of the causative organism, and serum concentrations of the drug. The manufacturers recommend that the usual adult daily dosage of co-trimoxazole be reduced 50% in patients with creatinine clearances of 15-30 mL/minute. Although the manufacturers recommend not using the drug in patients with creatinine clearances less than 15 mL/minute, some clinicians suggest using the drug in reduced dosages in these patients.
Cautions ⬆ ⬇
The most frequent adverse effects of co-trimoxazole are adverse GI effects (nausea, vomiting, anorexia) and sensitivity skin reactions (e.g., rash, urticaria), each reportedly occurring in about 3.5% of patients. The incidence and severity of these adverse reactions are generally dose related, and adverse reactions may occasionally be obviated by a reduction in dosage. Hypersensitivity and hematologic reactions are the most serious adverse effects of co-trimoxazole, reportedly occurring in less than 0.5% of patients. Fatal hypersensitivity reactions, including Stevens-Johnson syndrome and erythema multiforme, have occurred in several children who received co-trimoxazole. Deaths associated with hypersensitivity reactions, fulminant hepatocellular necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias have occurred with the administration of sulfonamides.
The frequency of some co-trimoxazole-induced adverse effects, including rash (usually diffuse, erythematous, and maculopapular),100,101,102,103,109,117,135,136,137,138,139,140,141,154,155,160,186,220,247,248,250,251,252,253 fever,100,101,102,109,135,136,139,140,141,154,155,160,186,247,248,251 leukopenia (neutropenia),100,101,102,103,109,117,135,136,138,154,155,186,248,250 thrombocytopenia,101,102,103,117,138 hyperkalemia,186 hyponatremia,186 and increased serum aminotransferase concentrations,102,109,117,138,139,154,186,251,253 is substantially higher in patients with acquired immunodeficiency syndrome (AIDS) than in other patients.100,101,102,103,109,117,135,136,137,138,149,150,151,152,153,155,160,161,162,186 Such adverse effects have occurred in up to 80% of AIDS patients receiving the drug,102,103,109,117,137,138,151,152,154 usually during the second week of therapy,101,102,109,117,136,138,139,141 but generally have been reversible following discontinuance of co-trimoxazole therapy.101,102,109,117,136,137,138,247,248 The exact mechanism(s) of this increased risk of co-trimoxazole toxicity has not been determined,101,102,103,136,138,142,247,248,254 but may be immunologically based.101,102,103,135,136,138,247,248 While it has been suggested that glutathione deficiency in HIV-infected patients and resultant accumulation of reactive hydroxylamine metabolites of sulfamethoxazole may be involved in this increased risk, this hypothesis requires confirmation.217,254 These adverse effects usually recur following rechallenge with the drug,101,102,109,138,160,247,248,251 although cautious desensitization has been performed successfully in some patients in whom continued co-trimoxazole therapy was considered necessary.139,140,141,161,162 Limited evidence suggests that white AIDS patients may be at greater risk of these adverse effects than black AIDS patients,142,143,144 indicating that genetic factors may also be important.142 Some evidence also indicates that co-trimoxazole may be better tolerated in HIV-infected children than adults.101,102,155,202,205,206 Adverse effects usually are less severe in patients receiving the drug for prophylaxis of Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia compared with those receiving co-trimoxazole for treatment of the disease.241
Sensitivity Reactions
Epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, serum sickness, and allergic myocarditis are the most severe allergic reactions reported with sulfonamides alone or co-trimoxazole. Other reported allergic and anaphylactoid reactions include anaphylaxis, arthralgia, erythema multiforme, Schönlein-Henoch purpura, pruritus, urticaria, periorbital edema, corneal ring infiltrates, conjunctival and scleral injection, and photosensitivity. Mild to moderate rashes, when they occur, usually appear within 7-14 days after initiation of co-trimoxazole. Rashes are generally erythematous, maculopapular, morbilliform, and/or pruritic. Generalized pustular dermatosis124 and fixed drug eruption179 also have been reported. Patients with AIDS appear to be at particular risk of developing rash (usually diffuse, erythematous, and maculopapular) during co-trimoxazole therapy.100,101,102,103,109,117,135,136,137,138,139,140,141,149,150,151,152,153,155,160,161,162,220,247 (See the opening discussion in Cautions.)
Hematologic Effects
Co-trimoxazole-induced hematologic toxicity has resulted rarely in aplastic anemia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, eosinophilia, megaloblastic and/or hemolytic anemia, methemoglobinemia, pancytopenia, hypoprothrombinemia, and/or purpura. Hematologic toxicity may occur with increased frequency in folate-depleted patients including geriatric, malnourished, alcoholic, pregnant, or debilitated patients; in patients receiving folate antimetabolites (e.g., phenytoin) or diuretics; in patients with hemolysis or impaired renal function; and in patients receiving co-trimoxazole in high dosages and/or for prolonged periods (e.g., longer than 6 months). In geriatric patients receiving some diuretics (principally thiazides) and co-trimoxazole concomitantly, an increased incidence of thrombocytopenia with purpura has been reported. The risk of leukopenia, neutropenia, and thrombocytopenia also appear to be increased in patients with AIDS.100,101,102,103,109,117,135,136,138
Folic acid may be administered during co-trimoxazole therapy and will not interfere with the drug's antibacterial effect. Megaloblastic anemia and occasionally neutropenia and thrombocytopenia can be reversed by administration of leucovorin (folinic acid). If signs of bone marrow suppression occur in patients receiving co-trimoxazole, leucovorin should be administered; some clinicians recommend a leucovorin dosage of 5-15 mg daily until normal hematopoiesis is restored.
GI Effects
Nausea, vomiting, and anorexia are the most frequent GI reactions to co-trimoxazole, but glossitis, stomatitis, abdominal pain, pancreatitis (sometimes fatal), pseudomembranous enterocolitis, and diarrhea also have been reported.
Local Effects
Pain, local irritation, inflammation, and rarely thrombophlebitis may occur with IV co-trimoxazole, especially if extravascular infiltration of the drug occurs.
Nervous System Effects
Adverse nervous system effects of co-trimoxazole include headache, insomnia, fatigue, apathy, nervousness, muscle weakness, ataxia, vertigo, tinnitus, peripheral neuritis, mental depression, aseptic meningitis, seizures, and hallucinations. Tremor and other neurologic manifestations (e.g., ataxia, ankle clonus, apathy) developed during co-trimoxazole therapy in several patients with AIDS; although such manifestations also have been associated with the underlying disease process, they resolved in these patients within 2-3 days after discontinuing the drug.158
Other Adverse Effects
Other adverse effects reported with co-trimoxazole therapy include drug fever, chills, myalgia, hepatitis (including cholestatic jaundice and hepatic necrosis), increased serum aminotransferase and bilirubin concentrations, renal failure, interstitial nephritis, increased BUN and serum creatinine concentrations, crystalluria and stone formation, toxic nephrosis with oliguria and anuria, pulmonary infiltrates, cough, shortness of breath, hypotension, periarteritis nodosa, and a positive lupus erythematosus phenomenon. Rhabdomyolysis has been reported rarely in patients receiving co-trimoxazole, mainly in HIV-infected patients.186 Sulfonamides chemically resemble some goitrogens, diuretics (acetazolamide, thiazides), and oral hypoglycemic agents, and cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have been reported rarely in patients receiving sulfonamides.
Precautions and Contraindications
Co-trimoxazole shares the toxic potentials of sulfonamides and trimethoprim, and the usual precautions associated with therapy with these drugs should be observed. (See Cautions in the Sulfonamides General Statement 8:12.20 and see Cautions in Trimethoprim 8:36.) Fatalities, although rare, have occurred in patients receiving sulfonamides, secondary to severe reactions induced by the drugs, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Such fatal reactions also have been reported when sulfonamides were used in fixed combination with other drugs (e.g., with trimethoprim or erythromycin).134 Although probably rare, the precise incidence of severe dermatologic, hematologic, and hepatic effects with these combinations, including co-trimoxazole, is not known.134 Patients receiving co-trimoxazole should be monitored appropriately for the possible occurrence of such potentially severe reactions, and the drug should be discontinued at the first sign of such a reaction. The development of rash, sore throat, fever, pallor, arthralgia, cough, shortness of breath, purpura, or jaundice may be an early sign of a serious adverse reaction.
Co-trimoxazole should be used with caution in patients with impaired renal or hepatic function, possible folate deficiency (e.g., geriatric individuals, chronic alcoholics, patients receiving anticonvulsants, malnourished patients, those with malabsorption syndrome), with severe allergy or bronchial asthma, or with possible folate or glucose-6-phosphate-dehydrogenase (G-6-PD) deficiency. Patients should be warned to report any early signs and symptoms of a serious hematologic disorder, including fever, sore throat, pallor, jaundice, or purpura. The manufacturers recommend that a complete blood count be obtained frequently in patients receiving co-trimoxazole, especially if signs and symptoms of blood disorders occur. The drug should be discontinued at the first appearance of rash or if any reduction in formed blood elements occurs. Leucovorin (folinic acid) should be administered if bone marrow depression occurs, especially if megaloblastic anemia, neutropenia, or thrombocytopenia occurs. Patients with acquired immunodeficiency syndrome (AIDS) who receive co-trimoxazole should be carefully monitored, since they appear to have a particularly high incidence of adverse reactions to the drug (especially fever and adverse dermatologic and hematologic reactions).101,102,103
Urinalysis and careful microscopic examination of the urine should be performed in patients receiving co-trimoxazole, especially patients with impaired renal function. Patients receiving co-trimoxazole should be cautioned to maintain adequate fluid intake to prevent crystalluria and stone formation.
Co-trimoxazole should be used with caution in geriatric patients, particularly when complicating conditions (e.g., impaired renal and/or hepatic function, concomitant use of other drugs) are present, since these patients may have an increased risk of severe adverse reactions to the drug. Severe adverse dermatologic reactions, generalized bone marrow suppression, and a specific decrease in platelets (with or without purpura) are the most frequently reported severe adverse effects of the drug in geriatric patients. Co-trimoxazole also should be used with caution in patients with a history of hypersensitivity to sulfonamide-derivative drugs (e.g., acetazolamide, thiazides, tolbutamide), since cross-sensitivity may exist with these agents.
Commercially available formulations of co-trimoxazole for injection concentrate contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.132 The overall prevalence of sulfite sensitivity in the general population is unknown and probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.132
Co-trimoxazole is contraindicated in patients with known hypersensitivity to trimethoprim or sulfonamides, with marked hepatic damage or severe renal impairment when renal function status cannot be monitored, or with documented megaloblastic anemia secondary to folate deficiency. However, cautious desensitization has been performed in some hypersensitive patients in whom co-trimoxazole therapy was considered necessary.139,140,141,161,162 The manufacturers recommend that the drug not be used in patients with creatinine clearances less than 15 mL/minute.
Pediatric Precautions
The manufacturers of co-trimoxazole recommend that the drug not be used in infants younger than 2 months of age. Commercially available co-trimoxazole injections contain benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.174,175,176,177,178 Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates.174,175,176,177,178 Safety and efficacy of repeated courses of co-trimoxazole therapy in children younger than 2 years of age, except those with documented Pneumocystis infections, have not been fully evaluated. Co-trimoxazole should be used with caution in children who have the fragile X chromosome associated with mental retardation, because folate depletion may worsen the psychomotor regression associated with the disorder.
Mutagenicity and Carcinogenicity
Bacterial mutagenic studies have not been performed with co-trimoxazole. Trimethoprim did not exhibit mutagenic activity in the Ames test. No chromosomal damage was observed in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma concentrations, but a low level of chromosomal damage was observed in some studies at concentrations approximately 1000 times human plasma concentrations. No chromosomal abnormalities were observed in human leukocytes cultured in vitro at trimethoprim concentrations up to 20 times human steady-state plasma concentrations. In addition, no chromosomal abnormalities were found in peripheral lymphocytes of patients receiving 320 mg of trimethoprim in combination with up to 1600 mg of sulfamethoxazole daily for as long as 112 weeks.
Long-term studies in animals to evaluate the carcinogenic potential of co-trimoxazole have not been performed.
Pregnancy, Fertility, and Lactation
Pregnancy
Trimethoprim and sulfamethoxazole, alone and in combination, have produced teratogenic effects, manifested principally as cleft palate, in some (but not all) studies in rats receiving dosages exceeding the usual human dosages. In addition, in some rabbit studies, an overall increase in fetal loss was associated with trimethoprim doses 6 times the usual human dose. Although there are no adequate and controlled studies to date in humans, studies in pregnant women suggest that the incidence of congenital abnormalities in those who received co-trimoxazole was similar to that in those who received a placebo; there were no abnormalities in 10 children whose mothers had received the drug during the first trimester. In one report, there were no congenital abnormalities in 35 children whose mothers had received co-trimoxazole at the time of conception or shortly thereafter. Because co-trimoxazole crosses the placenta and may interfere with folic acid metabolism, the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Because sulfonamides may cause kernicterus in neonates, the manufacturers state that use of co-trimoxazole in pregnant women is contraindicated.
Fertility
The effect of co-trimoxazole on fertility in humans is not known. Reproduction studies in rats using oral trimethoprim (as co-trimoxazole) dosages up to 70 mg/kg daily have not revealed evidence of impaired fertility.
Lactation
Co-trimoxazole is distributed into milk. Because co-trimoxazole may interfere with folic acid metabolism, the drug should be used in nursing women only if the potential benefits justify the possible risks to the infant. Because sulfonamides may cause kernicterus in infants younger than 2 months of age, a decision should be made whether to discontinue nursing or co-trimoxazole or to use an alternative drug, taking into account the importance of co-trimoxazole to the woman.
Drug Interactions ⬆ ⬇
Warfarin
Co-trimoxazole may prolong the prothrombin time (PT) of patients receiving concomitant warfarin by inhibiting metabolic clearance of warfarin. If co-trimoxazole is used with warfarin, dosage of warfarin and PT must be monitored carefully.
Other Drugs
Because co-trimoxazole possesses anti-folate properties, the drug could theoretically increase the incidence of folate deficiencies induced by other drugs such as phenytoin when used concomitantly. Co-trimoxazole inhibits the metabolism of phenytoin.135,186 Concomitant administration of usual dosages of co-trimoxazole and phenytoin can increase the half-life of phenytoin by 39% and decrease metabolic clearance rate of phenytoin by 27%.135,186 If the drugs are administered concomitantly, the possibility of an increase in effects associated with phenytoin should be considered.135,186
Co-trimoxazole should be used with caution in patients receiving methotrexate, since sulfonamides can displace methotrexate from plasma protein-binding sites resulting in increased free methotrexate concentrations.
Marked but reversible nephrotoxicity has been reported in renal transplant recipients receiving co-trimoxazole together with cyclosporine.186
Increases in serum digoxin concentrations can occur in patients receiving co-trimoxazole; this interaction is more likely to occur in geriatric patients.186 Serum digoxin concentrations should be monitored in patients receiving digoxin and co-trimoxazole.186
Increased plasma sulfamethoxazole concentration may occur in patients receiving indomethacin.186
Megaloblastic anemia has been reported in patients receiving co-trimoxazole and pyrimethamine dosages exceeding 25 mg weekly (for malaria prophylaxis).186
Concomitant administration of tricyclic antidepressants and co-trimoxazole may decrease the efficacy of the antidepressant.186
Like other sulfonamides, co-trimoxazole potentiates the effect of oral hypoglycemic agents.186
Toxic delirium has been reported in one individual following administration of co-trimoxazole and amantadine.186
Other Information ⬆ ⬇
Acute Toxicity
Manifestations
Overdosage with co-trimoxazole may produce symptoms of nausea, vomiting, diarrhea, mental depression, confusion, facial swelling, headache, bone marrow depression, and slight elevations of serum aminotransferases (transaminases).
Treatment
In acute overdosage with oral co-trimoxazole, the stomach should be emptied immediately by inducing emesis or by lavage. Supportive and symptomatic treatment should be initiated. Patients should be monitored with blood counts and other appropriate laboratory studies (e.g., serum electrolyte concentrations). Hemodialysis may remove only moderate amounts of the drug; peritoneal dialysis is not effective in enhancing the elimination of co-trimoxazole.
Mechanism of Action
Co-trimoxazole usually is bactericidal. Of its components, sulfamethoxazole is bacteriostatic and trimethoprim usually is bactericidal. Co-trimoxazole acts by sequentially inhibiting enzymes of the folic acid pathway; sulfamethoxazole inhibits the formation of dihydrofolic acid from p -aminobenzoic acid and, by inhibiting dihydrofolate reductase, trimethoprim inhibits the formation of tetrahydrofolic acid from dihydrofolic acid. By inhibiting synthesis of tetrahydrofolic acid, the metabolically active form of folic acid, co-trimoxazole inhibits bacterial thymidine synthesis.
Sequential inhibition by co-trimoxazole of two steps in the folic acid pathway appears to be responsible for the antibacterial synergism of the trimethoprim-sulfamethoxazole combination. For most organisms, optimum synergistic antibacterial action occurs in vitro at a trimethoprim:sulfamethoxazole ratio of about 1:20, which is also the approximate peak serum concentration ratio of the 2 drugs achieved following oral or IV administration of co-trimoxazole. Synergistic activity also has been observed in vitro at trimethoprim:sulfamethoxazole ratios of 1:1-1:40.
Susceptibility of organisms to trimethoprim usually is more critical to the efficacy of co-trimoxazole than is susceptibility to sulfamethoxazole. Many organisms that are resistant to sulfamethoxazole but susceptible or only moderately susceptible to trimethoprim will show synergistic antibacterial response to co-trimoxazole. However, for Neisseria gonorrhoeae , susceptibility to sulfamethoxazole is required for antibacterial response to co-trimoxazole.
Spectrum
In Vitro Susceptibility Testing
For most organisms, inoculum size may influence the result of in vitro co-trimoxazole susceptibility tests. Accurate in vitro susceptibility testing requires that thymidine not be present in the growth medium or that the medium be supplemented with thymidine phosphorylase to inactivate any thymidine that might be present.
The Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to co-trimoxazole, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.270 If results indicate that a clinical isolate has intermediate susceptibility to co-trimoxazole, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.270 Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used.270 This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.270 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to co-trimoxazole, the strain is not inhibited by systemic concentrations of the drug achievable with normal dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.270
Disk Susceptibility Tests
When the disk-diffusion procedure is used for susceptibility testing, a 1.25-mcg trimethoprim/23.75-mcg sulfamethoxazole disk should be used.270
When the disk-diffusion susceptibility test is performed according to CLSI standardized procedures, Enterobacteriaceae, Pseudomonas aeruginosa , Acinetobacter , or Staphylococci with growth inhibition zones of 16 mm or greater are susceptible to co-trimoxazole, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.270
When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 16 mm or greater are susceptible to co-trimoxazole, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.270
When testing susceptibility of S. pneumoniae according to CLSI standardized procedures using Mueller-Hinton agar (supplemented with 5% defibrinated sheep blood), S. pneumoniae with growth inhibition zones of 19 mm or greater are susceptible to co-trimoxazole, those with zones of 16-18 mm have intermediate susceptibility, and those with zones of 15 mm or less are resistant to the drug.270
When the disk diffusion procedure is performed according to CLSI standardized procedures, Vibrio cholerae with growth inhibition zones of 16 mm or greater are susceptible to co-trimoxazole, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.270
Dilution Susceptibility Tests
When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures, Enterobacteriaceae, Ps. aeruginosa , other non-Enterobacteriaceae gram-negative bacilli (e.g., Acinetobacter , Stenotrophomonas maltophilia , other Pseudomonas spp), or Staphylococcus with MICs equal to or less than 2 mcg/mL of trimethoprim and 38 mcg/mL of sulfamethoxazole are susceptible to co-trimoxazole and those with MICs equal to or greater than 4 mcg/mL of trimethoprim and 76 mcg/mL of sulfamethoxazole are resistant to the drug.270
When dilution susceptibility testing for Haemophilus is performed according to CLSI standardized procedures using HTM, Haemophilus with MICs equal to or less than 0.5 mcg/mL of trimethoprim and 9.5 mcg/mL of sulfamethoxazole are susceptible to co-trimoxazole and those with MICs equal to or greater than 4 mcg/mL of trimethoprim and 76 mcg/mL of sulfamethoxazole are resistant to the drug.270 Haemophilus with an MIC of 1-2 mcg/mL of trimethoprim and 19-38 mcg/mL of sulfamethoxazole have intermediate susceptibility to co-trimoxazole.270 These same interpretive criteria are used when dilution susceptibility testing for S. pneumoniae is performed according to CLSI standardized procedures using cation-adjusted Mueller-Hinton broth (with 2-5% lysed horse blood).270
When dilution susceptibility testing is performed according to CLSI standardized procedures, V. cholerae with MICs equal to or less than 2 mcg/mL of trimethoprim and 38 mcg/mL of sulfamethoxazole are susceptible to co-trimoxazole and those with MICs of 4 mcg/mL or greater of trimethoprim and 76 mcg/mL or greater are resistant to the drug.270
Gram-positive Aerobic Bacteria
In vitro, when the optimum 1:20 synergistic ratio of trimethoprim:sulfamethoxazole is used, trimethoprim concentrations of 0.05-0.15 mcg/mL and sulfamethoxazole concentrations of 0.95-2.85 mcg/mL inhibit most strains of Streptococcus pneumoniae. Many strains of Staphylococcus aureus , group A β-hemolytic streptococci ( Streptococcus pyogenes ), and Nocardia also are susceptible to co-trimoxazole. Some strains of enterococci, including some E. faecalis (formerly Streptococcus faecalis ), are not susceptible to the drug; to accurately determine susceptibility of enterococci to co-trimoxazole, the growth medium must be free of thymidine and other sources of exogenous folate. Some group A β-hemolytic streptococci may not respond to co-trimoxazole in tonsillopharyngeal infections, possibly because of inadequate concentrations of the drug in this area.
Bacillus anthracis strains with in vitro resistance to sulfamethoxazole or trimethoprim have been reported, and these anti-infectives should not be used in the treatment of B. anthracis infections (i.e., anthrax).307,308
Gram-negative Aerobic Bacteria
Co-trimoxazole is active in vitro against common gram-negative bacteria associated with urinary tract infections, including most Enterobacteriaceae. The drug is not active against Pseudomonas aeruginosa.
Generally, co-trimoxazole is active in vitro against most of the following Enterobacteriaceae: Acinetobacter , Enterobacter , Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Salmonella , and Shigella . When the optimum 1:20 synergistic ratio of trimethoprim:sulfamethoxazole is used in vitro, the MIC for most of these organisms is 1.5 mcg/mL or less of trimethoprim; for sulfamethoxazole, MICs for P. mirabilis, Shigella , and Salmonella generally are 2.85 mcg/mL or less, for E. coli are 9.5 mcg/mL or less, and for Klebsiella and Enterobacter are 28.5 mcg/mL or less. Co-trimoxazole also is active in vitro against Haemophilus influenzae (including ampicillin-resistant strains), H. ducreyi , and Neisseria gonorrhoeae. Approximately 70% of indole-positive Proteus and 50% of Providencia and Serratia strains are susceptible to co-trimoxazole.
Anaerobic Bacteria
Co-trimoxazole generally is considered inactive against most strains of Bacteroides , and appears to have no activity against strict anaerobes (e.g., Clostridium ).
Protozoa
Co-trimoxazole is active in vitro106,107,108 and in vivo100,101,102,103,104,105,109 against Pneumocystis jiroveci (formerly Pneumocystis carinii ).
Resistance
In vitro, resistance develops more slowly to co-trimoxazole than to trimethoprim or sulfamethoxazole alone.
Use of sulfamethoxazole alone results in rapid selection of sulfonamide-resistant fecal coliforms. As many as 50% of hospital-isolated and 20% of community-isolated Escherichia coli are resistant to sulfonamides, including sulfamethoxazole. Resistance to sulfamethoxazole in gram-negative bacteria is usually plasmid mediated. In many organisms (e.g., E. coli , Neisseria meningitis , Streptococcus pneumoniae , Plasmodium falciparum ), point mutations in conserved regions of dihydropteroate synthase (DHPS), an essential enzyme for folate biosynthesis, confer sulfonamide resistance.289,290 Mutations in DHPS also have been identified in Pneumocystis carinii isolates obtained from HIV-infected patients, including some patients who had not previously received a sulfonamide, and these mutations are being reported with increasing frequency in this organism.289 It is unclear whether DHPS mutations in P. carinii are associated with resistance to co-trimoxazole since P. carinii pneumonia has been effectively treated with co-trimoxazole in some patients despite the presence of DHPS mutants.298 However, there is some evidence from a study in HIV-infected patients with P. carinii pneumonia that presence of strains with DHPS mutations may be associated with decreased survival.289 Resistance to trimethoprim has been shown to occur by several mechanisms, most often chromosomally mediated, but also rarely involving mutation of bacteria to thymidine-dependent strains or plasmid-mediated resistance involving altered production or sensitivity of bacterial dihydrofolate reductase. Plasmid-mediated resistance to trimethoprim has been shown to be transferable among some bacterial strains; plasmid-mediated resistance to trimethoprim usually results in concomitant coding for sulfonamide resistance. Thymidine-dependent strains account for less than 1% of trimethoprim resistance, and chromosomal- and plasmid-mediated resistance accounts for approximately 90% and 10% of reported resistant strains, respectively.
Resistant strains of Enterobacteriaceae, especially E. coli, Klebsiella , and Proteus , have occurred during therapy with co-trimoxazole. Strains of Klebsiella and Proteus that are only moderately susceptible to co-trimoxazole in vitro at the beginning of therapy appear to be especially likely to develop resistance during therapy. The incidence of trimethoprim resistance among Enterobacteriaceae in fecal flora and associated with urinary tract infections has been reported to range from 8-38% in some hospitals and to range from 30-100% among fecal Enterobacteriaceae following 2 weeks of co-trimoxazole therapy. In a study in Mexico, more than 95% of fecal E. coli resistant to trimethoprim also were resistant to sulfamethoxazole, but the resistant strains were not associated with clinical infection. Strains of Enterobacteriaceae and S. pneumoniae resistant to trimethoprim, but sensitive to sulfonamides and penicillin, respectively, have been reported.
Although co-trimoxazole previously was considered nearly uniformly active against H. influenzae , resistant strains have been reported rarely.145 In a national collaborative study of H. influenzae isolates from 1986, the incidence of co-trimoxazole resistance was about 1%, including several strains that also were resistant to ampicillin (β-lactamase mediated), chloramphenicol, and tetracycline.145
Pharmacokinetics
Absorption
The fixed-combination preparation containing trimethoprim and sulfamethoxazole (co-trimoxazole) is rapidly and well absorbed from the GI tract. Peak serum concentrations of 1-2 mcg/mL of trimethoprim and 40-60 mcg/mL of unbound sulfamethoxazole are reached 1-4 hours after a single oral dose of co-trimoxazole containing 160 mg of trimethoprim and 800 mg of sulfamethoxazole. Following multiple-dose oral administration, steady-state peak serum concentrations usually are 50% greater than those obtained after single-dose administration of the drug. Following oral administration of the fixed-ratio combination preparation, the trimethoprim:sulfamethoxazole ratio of mean steady-state serum concentrations usually is about 1:20.
Mean peak steady-state serum concentrations of approximately 9 and 105 mcg/mL of trimethoprim and sulfamethoxazole, respectively, are reached after IV infusion of 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 8 hours in adults with normal renal function. Steady-state trough concentrations reached with this IV dose are approximately 6 mcg/mL of trimethoprim and 70 mcg/mL of sulfamethoxazole.
Distribution
Both trimethoprim and sulfamethoxazole are widely distributed into body tissues and fluids, including sputum, aqueous humor, middle ear fluid, prostatic fluid, vaginal fluid, bile, and CSF; trimethoprim also distributes into bronchial secretions. Trimethoprim has a larger volume of distribution (Vd) than does sulfamethoxazole. In adults, apparent Vds of 100-120 and 12-18 L have been reported for trimethoprim and sulfamethoxazole, respectively. In patients with uninflamed meninges, trimethoprim and sulfamethoxazole concentrations in CSF are about 50 and 40%, respectively, of concurrent serum concentrations of the drugs. Trimethoprim and sulfamethoxazole concentrations in middle ear fluid are approximately 75 and 20%, respectively, and in prostatic fluid are approximately 200 and 35%, respectively, of concurrent serum concentrations of the drugs.
Trimethoprim is approximately 44% and sulfamethoxazole is approximately 70% bound to plasma proteins.
Both trimethoprim and sulfamethoxazole readily crosses the placenta. Amniotic fluid concentrations of trimethoprim and sulfamethoxazole are reported to be 80 and 50%, respectively, of concurrent maternal serum concentrations. Both trimethoprim and sulfamethoxazole is distributed into milk. Trimethoprim and sulfamethoxazole concentrations in milk are approximately 125 and 10%, respectively, of concurrent maternal serum concentrations.
Elimination
Trimethoprim and sulfamethoxazole have serum half-lives of approximately 8-11 and 10-13 hours, respectively, in adults with normal renal function. In adults with creatinine clearances of 10-30 and 0-10 mL/minute, serum half-life of trimethoprim may increase to 15 and greater than 26 hours, respectively. In adults with chronic renal failure, sulfamethoxazole half-life may be 3 times that in patients with normal renal function. Trimethoprim serum half-lives of about 7.7 and 5.5 hours have been reported in children less than 1 year of age and between 1 and 10 years of age, respectively.
Both trimethoprim and sulfamethoxazole are metabolized in the liver. Trimethoprim is metabolized to oxide and hydroxylated metabolites and sulfamethoxazole is principally N -acetylated and also conjugated with glucuronic acid. Both drugs are rapidly excreted in urine via glomerular filtration and tubular secretion. In adults with normal renal function, approximately 50-60% of a trimethoprim and 45-70% of a sulfamethoxazole oral dose are excreted in urine within 24 hours. Approximately 80% of the amount of trimethoprim and 20% of the amount of sulfamethoxazole recovered in urine are unchanged drug. In adults with normal renal function, urinary concentrations of active trimethoprim are approximately equal to those of active sulfamethoxazole. Urinary concentrations of both active drugs are decreased in patients with impaired renal function.
Only small amounts of trimethoprim are excreted in feces via biliary elimination. Trimethoprim and active sulfamethoxazole are moderately removed by hemodialysis.
Chemistry and Stability
Chemistry
Co-trimoxazole is a fixed combination of sulfamethoxazole and trimethoprim. Sulfamethoxazole is an intermediate-acting antibacterial sulfonamide. Both sulfamethoxazole and trimethoprim are synthetic folate-antagonist anti-infectives. Co-trimoxazole contains a 5:1 ratio of sulfamethoxazole to trimethoprim. Potency of co-trimoxazole is expressed in terms of the trimethoprim content.
Trimethoprim occurs as white to cream-colored, bitter-tasting, odorless crystals or crystalline powder and sulfamethoxazole occurs as a white to off-white, practically odorless, crystalline powder. Sodium hydroxide is added during manufacture of co-trimoxazole for injection concentrate to adjust pH to 10. Co-trimoxazole oral suspension has a pH of 5-6.5.
Stability
Co-trimoxazole for injection concentrate should be stored at 15-25°C or 15-30°C, depending on the formulation (the manufacturers' recommendations should be followed) and should not be refrigerated. Oral suspensions of the drug should be stored in tight, light-resistant containers at 15-25 or 15-30°C, depending on the formulation (the manufacturers' recommendations should be followed), and the tablets should be stored in well-closed, light-resistant containers at 15-30°C.
Co-trimoxazole for injection concentrate is physically and chemically compatible with IV solutions of 5% dextrose; admixed solutions of co-trimoxazole in 5% dextrose that are cloudy or contain a precipitate should be discarded. Because of the potential for incompatibility, the manufacturers state that co-trimoxazole IV solutions should not be admixed with other drugs or solutions other than 5% dextrose. Specialized references should be consulted for specific compatibility information.
Co-trimoxazole solutions containing 0.64 mg of trimethoprim and 3.2 mg of sulfamethoxazole per mL of 5% dextrose (1:25 dilution) are stable for 6 hours at room temperature. Co-trimoxazole solutions containing 0.64-0.8 mg of trimethoprim and 3.2-4 mg of sulfamethoxazole per mL of 5% dextrose (1:20 dilution) are stable for 4 hours at room temperature. Co-trimoxazole solutions containing 0.8-1.1 mg of trimethoprim and 4-5.3 mg of sulfamethoxazole per mL of 5% dextrose (1:15 dilution) are stable for 2 hours at room temperature. Co-trimoxazole solutions in 5% dextrose should not be refrigerated. Prior to infusion, solutions of the drug should be inspected visually and discarded if there is evidence of crystallization or cloudiness.
Following initial entry into a multiple-dose vial of co-trimoxazole for injection concentrate, the manufacturers recommend that the contents be used within 48 hours.
Preparations ⬆ ⬇
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.
Co-trimoxazole
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions January 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References ⬆
Only references cited for selected revisions after 1984 are available electronically.
100. Murray JF, Felton CP, Garay SM et al. Pulmonary complications of the acquired immunodeficiency syndrome. Report of a National Heart, Lung, and Blood Institute Workshop. N Engl J Med . 1984; 310:1682-9. [PubMed 6328301]
101. Jaffe HS, Abrams DI, Ammann AJ et al. Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet . 1983; 2:1109-11. [PubMed 6138645]
102. Gordin FM, Simon GL, Wofsy CB et al. Adverse reactions to trimethoprim-sulfamethoxazole in patients with acquired immunodeficiency syndrome. Ann Intern Med . 1984; 100:495-9. [PubMed 6230976]
103. Kovacs JA, Hiemenz JW, Macher AM et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med . 1984; 100:663-71. [PubMed 6231873]
104. Wong B. Parasitic diseases in immunocompromised hosts. Am J Med . 1984; 76:479-86. [PubMed 6608268]
105. Haverkos HW. Assessment of therapy for Pneumocystis carinii pneumonia: PCP Therapy Project Group. Am J Med . 1984; 76:501-8. [PubMed 6367458]
106. Pesanti EL. In vitro effects of antiprotozoan drugs and immune serum on Pneumocystis carinii . J Infect Dis . 1980; 141:775-80. [PubMed 6156221]
107. Pesanti EL, Cox C. Metabolic and synthetic activities of Pneumocystis carinii in vitro. Infect Immun . 1981; 34:908-14. [PubMedCentral][PubMed 6174453]
108. Pifer LL, Pifer DD, Woods DR. Biological profile and response to anti-pneumocystis agents of Pneumocystis carinii in cell culture. Antimicrob Agents Chemother . 1983; 24:674-8. [PubMedCentral][PubMed 6607029]
109. Small CB, Harris CA, Friedland GH et al. The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med . 1985; 145:837-40. [PubMed 3873229]
110. Kluge RM, Spaulding DM, Spain AJ. Combination of pentamidine and trimethoprim-sulfamethoxazole in the therapy of Pneumocystis carinii pneumonia in rats. Antimicrob Agents Chemother . 1978; 13:975-8. [PubMedCentral][PubMed 307941]
111. Shelhamer JH, Ognibene FP, Macher AM et al. Persistence of Pneumocystis carinii in lung tissue of acquired immunodeficiency syndrome patients treated for pneumocystis pneumonia. Am Rev Respir Dis . 1984; 130:1161-5. [PubMed 6334462]
112. DuPont HL, Reves RR, Galindo E et al. Treatment of travelers' diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone. N Engl J Med . 1982; 307:841-4. [PubMed 7050714]
113. DuPont HL, Galindo E, Evans DG et al. Prevention of travelers' diarrhea with trimethoprim-sulfamethoxazole and trimethoprim alone. Gastroenterology . 1983; 84:75-80. [PubMed 6336616]
114. National Institutes of Health Office of Medical Applications of Research. Consensus conference: travelers' diarrhea. JAMA . 1985; 253:2700-4. [PubMed 2985834]
115. DuPont HL, Ericsson CD, Johnson PC. Chemotherapy and chemoprophylaxis of travelers' diarrhea. Ann Intern Med . 1985; 102:260-1. [PubMed 3966763]
116. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep . 2002; 51(No. RR-6):1-78. [Fulltext MMWR]
117. Wharton JM, Coleman DL, Wofsy CB et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med . 1986; 105:37-44. [PubMed 3521428]
118. Lorber B. Listeriosis. Clin Infect Dis . 1997; 24:1-11. [PubMed 8994747]
119. Anon. Drugs for parasitic infections. Med Lett Drugs Ther . Aug 2004. From the Medical Letter website. [Web]
120. DeHovitz JA, Pape JW, Boncy M et al. Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med . 1986; 315:87-90. [PubMed 3487730]
121. Anon. The choice of antibacterial drugs. Med Lett Drugs Ther . 2001; 43:69-78. [PubMed 11518876]
122. DeRemee RA, McDonald TJ, Weiland LH. Wegener's granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin Proc . 1985; 60:27-32. [PubMed 3871238]
123. West BC, Todd JR, King JW. Wegener granulomatosis and trimethoprim-sulfamethoxazole: complete remission after a twenty-year course. Ann Intern Med . 1987; 106:840-2. [PubMed 3495214]
124. MacDonald KJS, Green CM, Kenicer KJA. Pustular dermatosis induced by co-trimoxazole. BMJ . 1986; 293:1279-80. [PubMedCentral][PubMed 3096466]
125. Hughes WT, Rivera GK, Schell MJ et al. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med . 1987; 316:1627-32. [PubMed 3495732]
126. Marchant CD, Shurin PA, Johnson CE et al. A randomized controlled trial of amoxicillin plus clavulanate compared with cefaclor for treatment of acute otitis media. J Pediatr . 1986; 109:891-6. [PubMed 3534203]
127. Van Hare GF, Shurin PA, Marchant CD et al. Acute otitis media caused by Branhamella catarrhalis : biology and therapy. Rev Infect Dis . 1987; 9:16-27. [PubMed 3493519]
128. Odio CM, Kusmiesz H, Shelton S et al. Comparative treatment trial of Augmentin versus cefaclor for acute otitis media with effusion. Pediatrics . 1985; 75:819-26. [PubMed 4039433]
129. Van Hare GF, Shurin PA. The increasing importance of Branhamella catarrhalis in respiratory infections. Pediatr Infect Dis J . 1987; 6:92-4. [PubMed 3547295]
130. Bluestone CD. Otitis media and sinusitis in children: role of Branhamella catarrhalis . Drugs . 1986; 31(Suppl 3):132-41. [PubMed 3732081]
131. Centers for Disease Control. Antibiotic-resistant strains of Neisseria gonorrhoeae : policy guidelines for detection, management, and control. MMWR Morb Mortal Wkly Rep . 1987; 36(Suppl 5S):1-18S. [PubMed 3099157]
132. Food and Drug Administration. Sulfiting agents; labeling for human use; warning statements. [21 CFR Part 201] Fed Regist . 1986; 51:43900-5.
133. Axelson JA, Clark RH, Ancerewicz S. Wegener granulomatosis and trimethoprim-sulfamethoxazole. Ann Intern Med . 1987; 107:600. [PubMed 3498420]
134. Food and Drug Administration. Serious adverse reactions with sulfonamides. FDA Drug Bull . 1984; 14:5-6. [PubMed 6734993]
135. Glaxo Wellcome. Septra® I.V. infusion prescribing information. Research Triangle Park, NC; 1997 Apr.
136. Cohn DL, Penley KA, Judson RN et al. The acquired immunodeficiency syndrome and a trimethoprim-sulfamethoxazole adverse reaction. Ann Intern Med . 1984; 100:311.
137. Mitsuyasu R, Groopman J, Volberding P. Cutaneous reaction to trimethoprim-sulfamethoxazole in patients with AIDS and Kaposi's sarcoma. N Engl J Med . 1983; 308:1535-6. [PubMed 6222258]
138. Wofsy CB. Use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome. Rev Infect Dis . 1987; 9(Suppl 2):S184-94. [PubMed 3554457]
139. Smith RM, Iwamoto GK, Richerson HB et al. Trimethoprim-sulfamethoxazole desensitization in the acquired immunodeficiency syndrome. Ann Intern Med . 1987; 106:335-6. [PubMed 3492167]
140. Hughes TE, Almgren JD, McGuffin RW et al. Co-trimoxazole desensitization in bone marrow transplantation. Ann Intern Med . 1986; 105:148. [PubMed 3521426]
141. Gibbons RB, Lindauer JA. Successful treatment of Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole in hypersensitive AIDS patients. JAMA . 1985; 253:1259-60. [PubMed 3871490]
142. Colebunders R, Izaley L, Bila K et al. Cutaneous reactions to trimethoprim-sulfamethoxazole in African patients with acquired immunodeficiency syndrome. Ann Intern Med . 1987; 107:599-600. [PubMed 2957947]
143. Hazel E, Sethi N, Jacquette G et al. Diminished sulfa-trimethoprim(ST) toxicity in Blacks treated for Pneumocystis carinii pneumonia (PCP). III International Conference on Acquired Immunodeficiency Syndrome (AIDS); 1987 June 1-5, Washington, DC. Washington, DC: US Department of Health and Human Services and the World Health Organization; 1987:F.3.2. Abstract.
144. DeHovitz JA, Johnson WD Jr, Pape JW. Cutaneous reactions to trimethoprim-sulfamethoxazole in Haitians. Ann Intern Med . 1985; 103:479-80. [PubMed 3161443]
145. Doern GV, Jorgensen JH, Thornsberry C et al. National collaborative study of the prevalence of antimicrobial resistance among clinical isolates of Haemophilus influenzae . 1988; 32:180-5.
146. Israel HL. Sulfamethoxazole-trimethoprim therapy for Wegener's granulomatosis. Arch Intern Med . 1988; 148:2293-5. [PubMed 3263099]
147. Spiera H, Lawson W, Weinrauch H. Wegener's granulomatosis treated with sulfamethoxazole- trimethoprim: report of a case. Arch Intern Med . 1988; 148:2065-6. [PubMed 3261974]
148. Kaplan LD, Wofsy CB, Volberding PA. Treatment of patients with acquired immunodeficiency syndrome and associated manifestations. JAMA . 1987; 257:1367-74. [PubMed 3546745]
149. Hughes WT. Pneumocystis carinii pneumonitis. N Engl J Med . 1987; 317:1021-3. [PubMed 2958709]
150. Anon. Treatment of Pneumocystis carinii pneumonia. Med Lett Drugs Ther . 1987; 29:103-4. [PubMed 2959845]
151. Kovacs JA, Masur H. Pneumocystis carinii pneumonia: therapy and prophylaxis. J Infect Dis . 1988; 158:254-9. [PubMed 2969023]
152. Glatt AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med . 1988; 318:1439-48. [PubMed 3285211]
153. Rankin JA, Collman R, Daniele RP. Acquired immunodeficiency syndrome and the lung. Chest . 1988; 94:155-64. [PubMed 3289833]
154. Sattler FR, Cowan R, Nielsen DM et al. Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective, noncrossover study. Ann Intern Med . 1988; 109:280-7. [PubMed 3260759]
155. Fischl MA, Dickinson GM, La Voie L. Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS. JAMA . 1988; 259:1185-9. [PubMed 3257532]
156. Anon. Prevention of Pneumocystis carinii pneumonia. Med Lett Drugs Ther . 1988; 30:94-5. [PubMed 3050408]
157. Kaplan LD, Abrams DI, Wofsy CB et al. Trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis carinii pneumonia in acquired immunodeficiency syndrome (AIDS). Clin Res . 1986; 33:406A.
158. Borucki MJ, Matzke DS, Pollard RB. Tremor induced by trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1988; 109:77-8. [PubMed 2967659]
159. Centers for Disease Control and Prevention. Health information for international travel, 2003-2004. Atlanta, GA: US Department of Health and Human Services; 2003:13-39,99-116,227,231-5,249-50. Updates available from CDC website. [Web]
160. Arnold PA, Guglielmo BJ, Hollander H. Severe hypersensitivity reaction upon rechallenge with trimethoprim-sulfamethoxazole in a patient with AIDS. Drug Intell Clin Pharm . 1988; 22:43-5. [PubMed 2965002]
161. Greenberger PA, Patterson R. Management of drug allergy in patients with acquired immunodeficiency syndrome. J Allergy Clin Immunol . 1987; 79:484-8. [PubMed 3819229]
162. Papakonstantinou G, Fuessel H, Hehlmann R. Trimethoprim-sulfamethoxazole desensitization in AIDS. Klin Wochenschr . 1988; 66:351-3. [PubMed 3260637]
163. Warren JW, Abrutyn E, Hebel JR et al. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin Infect Dis . 1999; 29:745-58. [PubMed 10589881]
164. US Public Health Service Immunization Practices Advisory Committee (ACIP). Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures. MMWR Morb Mortal Wkly Rep . 1991; 40(Suppl RR-10):1-28. [PubMed 1898620]
165. Cullen AS, Cullen HB. Whooping-cough: prophylaxis with co-trimoxazole. Lancet . 1978; 1:556. [PubMed 76096]
166. Arneil GC, McAllister TA. Whooping-cough in infants: antimicrobial prophylaxis? Lancet . 1977; 2:33-4. Letter. (IDIS 75690)
167. Rabo E. Drug prophylaxis in pertussis. Lancet . 1977; 2:707-8. [PubMed 71510]
168. Arneil GC, McAllister TA. Drug prophylaxis in pertussis. Lancet . 1977; 2:708. [PubMed 71511]
169. Adcock KJ, Reddy S, Okubadejo OA et al. Trimethoprim/sulphamethoxazole in pertussis: comparison with tetracycline. Arch Dis Child . 1972; 47:311-3. [PubMedCentral][PubMed 4336846]
170. Fishman JA. Treatment of infection due to Pneumocystis carinii. Antimicrob Agents Chemother . 1998; 42:1309-14. [PubMedCentral][PubMed 9624465]
171. Pierone G, Masci JR, Nicholas P. Pentamidine and hypoglycaemia. Lancet . 1989; 2:864. [PubMed 2571784]
172. US Public Health Service Task Force on Antipneumocystis Prophylaxis for Patients with Human Immunodeficiency Virus Infection. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep . 1992; 41(No. RR-4):1-11.
173. Masur H, Lane HC, Kovacs JA et al. Pneumocystis pneumonia: from bench to clinic. Ann Intern Med . 1989; 111:813-26. [PubMed 2683916]
174. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics . 1983; 72:356-8. [PubMed 6889041]
175. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull . 1982; 12:10-1. [PubMed 7188569]
176. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep . 1982; 31:290-1. [PubMed 6810084]
177. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med . 1982; 307:1384-8. [PubMed 7133084]
178. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol . 1984; 1:288-92. [PubMed 6440575]
179. Bharija SC, Singh M, Belhaj MS. Fixed drug eruption in an 8-month-old infant. Dermatologica . 1988; 176:108. [PubMed 2967210]
180. Anon. Advice for travelers. Med Lett Treat Guid . 2004; 2:33-40.
181. Ericsson CD, DuPont HL, Mathewson JJ et al. Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA . 1990; 263:257-61. [PubMed 2403603]
182. Ericsson CD, Johnson PC, DuPont HL et al. Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea. Ann Intern Med . 1987; 106:216-20. [PubMed 3541724]
183. DuPont HL, Ericsson CD, Reves RR et al. Antimicrobial therapy for travelers' diarrhea. Rev Infect Dis . 1986; 8(Suppl 2):S217-22. [PubMed 3523718]
184. DuPont HL, Ericsson CD, Galindo E et al. Antimicrobial therapy of traveler's diarrhea. Scand J Gastroenterol . 1983; 18(Suppl 84):99-105.
185. Ericsson CD, Johnson PC, DuPont HL et al. Role of a novel antidiarrheal agent, BW942C, alone or in combination with trimethoprim-sulfamethoxazole in the treatment of travelers' diarrhea. Antimicrob Agents Chemother . 1986; 29:1040-6. [PubMedCentral][PubMed 3524436]
186. Roche. Bactrim® (trimethoprim and sulfamethoxazole) tablets, double-strenth tablets, pediatric suspension prescribing information. Nutley, NJ; 1998 Aug.
187. Johnson PC, Ericsson CD, DuPont HL et al. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA . 1986; 255:757-60. [PubMed 3944976]
188. Wiström J, Jertborn M, Hedström SA et al. Short-term self-treatment of travellers' diarrhoea with norfloxacin; a placebo-controlled study. J Antimicrob Chemother . 1989; 23:905-13. [PubMed 2668252]
189. Anon. Quinolones in acute non-travelers' diarrhoea. Lancet . 1990; 336:282.
190. Steffen R. Worldwide efficacy of bismuth subsalicylate in the treatment of travelers' diarrhea. Clin Infect Dis . 1990; 12(Suppl 1):S80-6.
191. Ericsson CD, DuPont HL, Johnson PC. Nonantibiotic therapy for travelers' diarrhea. Rev Infect Dis . 1986; 8(Suppl 2):S202-6.
192. Sack RB, Froehlich JL, Orskov F et al. Doxycycline is an effective treatment for travellers' diarrhoea. J Diarrhoeal Dis Res . 1986; 4:144-8. [PubMed 3584904]
193. Pavia AT, Tauxe RU. Travel to the Soviet Union: is diarrhea a risk? JAMA . 1987; 258:1661.
194. Young FE, Nightingale SL. FDA's newly designated treatment INDs. JAMA . 1988; 260:224-5. [PubMed 2838651]
195. Nightingale SL. From the Food and Drug Administration. JAMA . 1988; 259:2064.
196. Anon. Treatment IND for AIDS drug. FDA Drug Bull . 1988; 18:2.
197. Allegra CJ, Chabner BA, Tuazon CU et al. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med . 1987; 317:978-85. [PubMed 2958710]
198. AIDS Program, Treatment Branch, National Institute of Allergy and Infectious Diseases and Warner-Lambert Company. A treatment protocol for the use of trimetrexate with leucovorin rescue for AIDS patients with Pneumocystis carinii pneumonia and serious intolerance to approved therapies. No. TX 301. Bethesda, MD; 1988 Jun 7.
199. Schneider MME, Borleffs JCC, Stolk RP et al. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1 infected patients treated with highly active antiretroviral therapy. Lancet . 1999; 353:201-3. [PubMed 9923876]
200. Doepel LK. HHS news regarding an inexpensive drug (co-trimoxazole) used to treat Pneumocystis carinii pneumonia (PCP) has been found to be superior to the only drug (pentamidine) currently approved for PCP prophylaxis in preventing a second episode of PCP. US Department of Health and Human Services Public Health Service. 1991 Sep 6.
201. National Institute of Allergy and Infectious Diseases backgrounder: questions and answers about ACTG protocol 021 and PCP prevention. Bethesda, MD: National Institutes of Health Office of Communications; 1991 Sep 6.
202. Working Group on PCP Prophylaxis in children. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep . 1991; 40(Suppl RR-2):1-13. [PubMed 1898620]
203. Anon. Guidelines established for PCP prophylaxis in infants and children infected with HIV. NIAID AIDS Agenda . 1991; (Mar/Apr):6.
204. Castellano AR, Nettleman MD. Cost and benefit of secondary prophylaxis for Pneumocystis carinii pneumonia. JAMA . 1991; 266:820-4. [PubMed 1907671]
205. McSherry G, Wright M, Oleska J et al. Frequency of serious adverse reactions (SAR) to trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine (P) among children with human immunodeficiency virus 1 (HIV-1) infection. Proceedings of ICAAC Los Angeles 1988. Abstract No. 1357.
206. Connor E, Bagarazzi M, McSherry G et al. Clinical and laboratory correlates on Pneumocystis carinii pneumonia in children infected with HIV. JAMA . 1991; 265:1693-7. [PubMed 1672168]
207. Valeriano-Marcet J, Spiera H. Treatment of Wegener's granulomatosis with sulfamethoxazole-trimethoprim. Arch Intern Med . 1991; 151:1649-52. [PubMed 1872670]
208. Kovacs A, Frederick T, Church J et al. CD4 T-lymphocyte counts and Pneumocystis carinii pneumonia in pediatric HIV infection. JAMA . 1991; 265:1698-1703. [PubMed 1672169]
209. Ruskin J, La Riviere M. Low-dose co-trimoxazole for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus disease. Lancet . 1991; 337:468-71. [PubMed 1671479]
210. Freedberg KA, Tosteson ANA, Cohen CJ et al. Inhaled pentamidine and prevention of pneumocystis pneumonia. N Engl J Med . 1991; 325:735. [PubMed 1908059]
211. Bender BS. Inhaled pentamidine and prevention of pneumocystis pneumonia. N Engl J Med . 1991; 325:736.
212. Falloon J, Masur H. The era of aerosol pentamidine prophylaxis: the beginning or the end? Am J Med . 1991; 90:415-7. Editorial.
213. Fitzpatrick JE, Tyler H, Gramstad ND. Treatment of chancroid: comparison of sulfamethoxazole-trimethoprim with recommended therapies. JAMA . 1981; 246:1804-5. [PubMed 7024580]
214. Naamara W, Plummer FA, Greenblatt RM et al. Treatment of chancroid with ciprofloxacin. A prospective, randomized clinical trial. Am J Med . 1987; 82(Suppl 4A):317-20. [PubMed 3555055]
215. Schmid GP. The treatment of chancroid. JAMA . 1986; 255:1757-62. [PubMed 3512872]
216. Fransen L, Nsanze H, Jo-Ndinya-Achola et al. A comparison of single-dose spectinomycin with five days of trimethoprim-sulfamethoxazole for the treatment of chancroid. Sex Transm Dis . 1987; 14:98-101. [PubMed 2956702]
217. van der Ven AJAM, Koopmans PP, Vree TB et al. Adverse reactions to co-trimoxazole in HIV infection. Lancet . 1991; 338:431-3. [PubMed 1678095]
218. Wormser GP, Horowitz HW, Duncanson FP et al. Low-dose intermittent trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. Arch Intern Med . 1991; 151:688-92. [PubMed 1901482]
219. Reviewers' comments (personal observations).
220. National Institute of Allergy and Infectious Diseases Division of AIDS. Note to physicians: important therapeutic information on prevention of recurrent Pneumocystis carinii pneumonia in persons with AIDS. Bethesda, MD: National Institutes of Health; 1991 Oct 11.
221. Allen UD, Read SE. Pneumocystis carinii pneumonia [PCP] prophylaxis for HIV-infected infants: a decision analysis. Proceedings of ICAAC Chicago 1991. Abstract No. 627.
222. Bass JW. Erythromycin for pertussis: probable reason for past failures. Lancet . 1985; 2:147. [PubMed 2862331]
223. Bass JW. Erythromycin for treatment and prevention of pertussis. Pediatr Infect Dis . 1986; 5:154-7. [PubMed 2868449]
224. Steketee RW, Wassilak SGF, Adkins WN et al. Evidence for a high attack rate and efficacy of erythromycin prophylaxis in a pertussis outbreak in a facility for the developmentally disabled. J Infect Dis . 1988; 157:434-40. [PubMed 3257783]
225. Halsey NA, Welling MA, Lehman RM. Nosocomial pertussis: a failure of erythromycin treatment and prophylaxis. Am J Dis Child . 1980; 134:421-2.
226. Bass JW. Use of erythromycin in pertussis outbreaks. Pediatrics . 1983; 72:748-9. [PubMed 6356008]
227. Anon. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with HIV. JAMA . 1992; 267:2294-9. [PubMed 1348788]
228. Kovacs JA, Masur H. Prophylaxis for Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus. Clin Infect Dis . 1992; 14:1005-9. [PubMed 1350925]
229. Carr A, Tindall B, Brew BJ et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med . 1992; 117:106-11. [PubMed 1351371]
230. Beaman MH, Luft BJ, Remington JS. Prophylaxis for toxoplasmosis in AIDS. Ann Intern Med . 1992; 117:163-4. [PubMed 1605431]
231. Swerdlow DL, Ries AA. Cholera in the Americas: guidelines for the clinician. JAMA . 1992; 267:1495-9. [PubMed 1371570]
232. Scheld WM. Evaluation of rifampin and other antibiotics against Listeria monocytogenes in vitro and in vivo. Rev Infect Dis . 1983; 5(Suppl 3):S593-9.
233. Levitz RE, Quintiliani R. Trimethoprim-sulfamethoxazole for bacterial meningitis. Ann Intern Med . 1984; 100:881-90. [PubMed 6372565]
234. Berenguer J, Solera J, Diaz MD et al. Listeriosis in patients infected with human immunodeficiency virus. Rev Infect Dis . 1991; 13:115-9. [PubMed 2017609]
235. Friedrich LV, White RL, Reboli AC. Pharmacodynamics of trimethoprim-sulfamethoxazole in Listeria meningitis: a case report. Pharmacotherapy . 1990; 10:301-4. [PubMed 2117750]
236. Overturf GD. Use of trimethoprim-sulfamethoxazole in pediatric infections: relative merits of intravenous administration. Rev Infect Dis . 1987; 9(Suppl 2):S168-76.
237. Günther G, Philipson A. Oral trimethoprim as follow-up treatment of meningitis caused by Listeria monocytogenes . Rev Infect Dis . 1988; 10:53-5. [PubMed 3258438]
238. Hardy WD, Feinberg J, Finkelstein DM et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: AIDS Clinical Trials Group Protocol 021. N Engl J Med . 1992; 327:1842-8. [PubMed 1448121]
239. US Public Health Service Task Force on Antipneumocystis Prophylaxis in Patients with Human Immunodeficiency Virus Infection. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. J Acquir Immune Defic Syndr . 1993; 6:46-55. [PubMed 8417174]
240. Schneider MME, Hoepelman AIM, Eeftinck Schattenkerk JKM et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med . 1992; 327:1836-41. [PubMed 1360145]
241. Masur H. Prevention and treatment of pneumocystis pneumonia. N Engl J Med . 1992; 327:1853-60. [PubMed 1448123]
242. Caeiro JP, Du-Pont HL. Management of travellers' diarrhoea. Drugs . 1998; 56:73-81. [PubMed 9664200]
243. Blum RN, Miller LA, Gaggini LC et al. Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr . 1992; 5:341-7. [PubMed 1548570]
244. Coker RJ, Nieman R, McBride M et al. Co-trimoxazole versus dapsone-pyrimethamine for prevention of Pneumocystis carinii pneumonia. Lancet . 1992; 340:1099. [PubMed 1357487]
245. Stein DS, Stevens RC, Terry D et al. Use of low-dose trimethoprim-sulfamethoxazole thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother . 1991; 35:1705-9. [PubMedCentral][PubMed 1952835]
246. Martin MA, Cox PH, Beck K et al. A comparison of the effectiveness of three regimens in the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Arch Intern Med . 1992; 152:523-8. [PubMed 1546914]
247. Marinas JS, Stanford JF. A severe hypersensitive reaction to trimethoprim-sulfamethoxazole in a patient infected with human immunodeficiency virus. Clin Infect Dis . 1993; 16:178-9. [PubMed 8448304]
248. Kelly JW, Dooley DP, Lattuada CP et al. A severe, unusual reaction to trimethoprim-sulfamethoxazole in patients infected with human immunodeficiency virus. Clin Infect Dis . 1992; 14:1034-9. [PubMed 1600003]
249. Jost R, Stey C, Salomon F. Fatal drug-induced pancreatitis in HIV. Lancet . 1993; 341:1412. [PubMed 7684478]
250. Harb GE, Jacobson MA. Human immunodeficiency virus (HIV) infection: does it increase susceptibility to adverse drug reactions? Drug Safety . 1993; 9:1-8.
251. Martin GJ, Paparello SF, Decker CF. A severe systemic reaction to trimethoprim-sulfamethoxazole in a patient infected with the human immunodeficiency virus. Clin Infect Dis . 1993; 16:175-6. [PubMed 8448303]
252. Coopman SA, Johnson RA, Platt R et al. Cutaneous disease and drug reactions in HIV infection. N Engl J Med . 1993; 328:1670-4. [PubMed 8487826]
253. Lee BL, Safrin S. Interactions and toxicities of drugs used in patients with AIDS. Clin Infect Dis . 1992; 14:773-9. [PubMed 1314104]
254. Pozniak A, Weinberg J, Macleod G. HIV and co-trimoxazole toxicity. Lancet . 1991; 338:760-1. [PubMed 1679894]
255. Centers for Disease Control and Prevention. Pertussis outbreaks—Massachusetts and MD, 1992. MMWR Morb Mortal Wkly Rep . 1993; 42:197-200. [PubMed 8446095]
256. DuPont HL, Ericsson CD. Prevention and treatment of traveler's diarrhea. N Engl J Med . 1993; 328:1821-7. [PubMed 8502272]
257. Ericsson CD, DuPont HL. Travelers' diarrhea: approaches to prevention and treatment. Clin Infect Dis . 1993; 16:616-26. [PubMed 8507751]
258. National Institute of Allergy and Infectious Diseases, Bethesda, MD: Personal communication.
259. DuPont HL. Travellers' diarrhoea: which antimicrobial? Drugs . 1993; 45:910-7.
260. U.S. Bioscience, Inc. Neutrexin® (trimetrexate glucuronate) for injection prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 48th ed. Oradell, NJ: Medical Economics Company Inc; 1994(Suppl A):A44-7.
261. May T, Beuscart C, Reynes J et al. Trimethoprim-sulfamethoxazole versus aerosolized pentamidine for primary prophylaxis of Pneumocystis carinii pneumonia: a prospective, randomized, controlled clinical trial. J Acquir Immune Defic Syndr . 1994; 7:457-62. [PubMed 8158539]
262. Gallant JE, Moore RD, Chaisson RE. Prophylaxis for opportunistic infections in patients with HIV infection. Ann Intern Med . 1994; 120:932-44. [PubMed 8172439]
263. Smith GH. Treatment of infections in the patient with acquired immunodeficiency syndrome. Arch Intern Med . 1994; 154:959-73.
264. Rowe JM, Ciobanu N, Ascensao J 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]
265. Osmond D, Charlebois E, Lang W et al. Changes in AIDS survival time in two San Francisco cohorts of homosexual men, 1983 to 1993. JAMA . 1994; 271:1083-7. [PubMed 7908703]
266. Rigaud M, Pollack H, Leibovitz E et al. Efficacy of primary chemoprophylaxis against Pneumocystis carinii pneumonia during the first year of life in infants infected with human immunodeficiency virus type 1. J Pediatr . 1994; 125:476-80. [PubMed 7915306]
267. National Institutes of Health Combined Clinical Staff Conference. Consensus conference: recent advances in the management of AIDS-related opportunistic infections. Ann Intern Med . 1994; 120:945-55. [PubMed 7909657]
268. Kovacs JA, Kovacs AAS. PCP prophylaxis in paediatric HIV infection: time for a change? Lancet . 1994; 344:5-6. Letter.
269. Hoover DR, Saah AJ, Bacellar H et al. Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. N Engl J Med . 1992; 329:1992-6.
270. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing: eleventh informational supplement. NCCLS document M100-S12. NCCLS: Wayne, PA; 2002 Jan.
272. Anon. Drugs for treatment of acute otitis media in children. Med Lett Drugs Ther . 1994; 36:19-21. [PubMed 8107649]
273. Pichichero ME. Assessing the treatment alternatives for acute otitis media. Pediatr Infect Dis J . 1994; 13:S27-34. [PubMedCentral]
274. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J . 1993; 12:973-5. [PubMed 8108222]
275. Bluestone CD, Stephenson JS, Martin LM. Ten-year review of otitis media pathogens. Pediatr Infect Dis J . 1992; 11:S7-11. [PubMed 1513611]
276. Rosenfeld RM, Vertrees JE, Carr J et al. Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr . 1994; 124:355-67. [PubMed 8120703]
277. Del Beccaro MA, Mendelman PM, Inglis AF et al. Bacteriology of acute otitis media: a new perspective. J Pediatr . 1992; 120:81-4. [PubMed 1731029]
278. Giebink GS, Canafax DM, Kempthorne J. Antimicrobial treatment of acute otitis media. J Pediatr . 1991; 119:495-500. [PubMed 1880671]
280. US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons with human immunodeficiency virus. From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website. [Web]
281. Furrer H, Egger M, Opravil M et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1 infected adults treated with combination antiretroviral therapy. N Engl J Med . 1999; 340:1301-6. [PubMed 10219064]
282. Centers for Disease Control and Prevention. 1995 revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR Morb Mortal Wkly Rep . 1995; 44(No. RR-4):1-11. [Fulltext MMWR][PubMed 7799912]
283. Centers for Disease Control and Prevention. Prevention of plague: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1996;45(No. RR-14):1-15. [Fulltext MMWR]
284. Butler T. Yersinia species (including plague). In: Mandell GL, Bennett JE, Dolan R, eds. Principles and practices of infectious diseases. 4th ed. New York: Churchill Livingstone; 1995:2070-76.
285. Centers for Disease Control and Prevention. Human plague—India, 1994. MMWR Morb Mortal Wkly Rep . 1994; 43:689-91. [PubMed 8084331]
286. Committee on Infectious Diseases, American Academy of Pediatrics. 2000 Red book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000:192-3,226,243-7,254-62,411-2,435-8,450-2,460-5,638-40.
287. Weverling GS, Mocroft A, Ledergerber B et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection, Euro SIDA study group. Lancet . 1999; 353:1293-8. [PubMed 10218526]
288. Centers for Disease Control and Prevention. Outbreak of cyclosporiasis—Northern Virginia-Washington, DC.-Baltimore, MD, metropolitan area, 1997. MMWR Morb Mortal Wkly Rep . 1997; 46:689-91. [PubMed 9256053]
289. Helweg-Larsen J, Benfield TL, Eugen-Olsen J et al. Effects of mutations of Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia. Lancet . 1998; 354:1347-51.
290. Meshnick S. Drug-resistant Pneumocystis carinii. Lancet . 1999; 354:1318-19. [PubMed 10533856]
291. Klein JO. Selection of oral antimicrobial agents for otitis media and pharyngitis. Infect Dis Clin Pract . 1995; 4(Suppl 2):S88-94.
292. Pichichero ME, Cohen R. Shortened course of antibiotic therapy for acute otitis media, sinusitis and tonsillopharyngitis. Pediatr Infect Dis J . 1997; 16:680-95. [PubMed 9239773]
293. McCracken GH. Treatment of acute otitis media in an era of increasing microbial resistance. Pediatr Infect Dis J . 1998; 17:576-9. [PubMed 9655564]
294. Klein JO. Otitis media. Clin Infect Dis J . 1994; 19:823-33.
295. Klein JO. Clinical implications of antibiotic resistance for management of acute otitis media. Pediatr Infect Dis J . 1998; 17:1084-9. [PubMed 9850003]
296. Gooch WM, Philips A, Rhoades R et al. Comparison of the efficacy, safety and acceptability of cefixime and amoxicillin/clavulanate in acute otitis media. Pediatr Infect Dis J . 1997; 16(Suppl):21-4.
297. Kafetzis DA. Multi-investigator evaluation of the efficacy and safety of cefprozil, amoxicillin-clavulanate, cefixime and cefaclor in the treatment of acute otitis media. Eur J Clin Microbiol Infect Dis . 1994; 13:857-65. [PubMed 7889960]
298. Adler M, McDonald PJ, Trostmann U et al. Cefdinir versus amoxicillin/clavulanic acid in the treatment of suppurative acute otitis media in children. Eur J Clin Microbiol Dis . 1997; 16:214-9.
299. Gooch WM, Adelglass J, Kelsey DK et al. Loracarbef versus clarithromycin in children with acute otitis media with effusion. Clin Ther . 1999; 21:711-21. [PubMed 10363736]
300. Hoppe HL, Johnson CE. Otitis media: focus on antimicrobial resistance and new treatment options. Am J Health-Syst Pharm . 198; 55:1881-97.
301. Bluestone CD. Ear and mastoid infections. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia, PA: WB Saunders; 1998:530-9.
302. Dowell SF, Butler JC, Giebink GS et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the drug-resistant Streptococcus pneumoniae Working Group. Pediatr Infect Dis J . 1999; 18:1-9. [PubMed 9951971]
303. Blumer JL. Pharmacokinetics and pharmacodynamics of new and old antimicrobial agents for acute otitis media. Pediatr Infect Dis J . 1998; 17:1070-5. [PubMed 9850001]
304. Jacobs MR. Antibiotic-resistant Streptococcus pneumoniae in acute otitis media: overview and update. Pediatr Infect Dis J . 1998; 17:947-52. [PubMed 9802651]
305. Poole MD. Implications of drug-resistant Streptococcus pneumoniae for otitis media. Pediatr Infect Dis J . 1998; 17:953-6. [PubMed 9802652]
306. Adachi JA, Ostrosky-Zeichner L, Dupont HL et al. Empirical antimicrobial therapy for travelers' diarrhea. Clin Intect Dis . 2000; 31:1079-83.
307. Onderstepoort J. The antibiotic sensitivity patterns of Bacillus anthracis isolated from Kruger National Park. J Vet Res . 1991; 58:17-9.
308. Inglesby TV, Henderson DA, Bartlett JG et al. Anthrax as a biologic weapon: medical and public health management. JAMA . 1999; 281:1735-45. [PubMed 10328075]
309. Inglesby TV, Dennis DT, Henderson DA for the Working Group on Civilian Biodefense. Plague as a biological weapon: medical and public health management. JAMA . 2000; 283:2281-90. [PubMed 10807389]
310. US Army Medical Research Institute of Infectious Disease. USAMRIID's medical management of biologic casualties handbook. 4th ed. USAMRIID: Fort Detrick, MD; 2001 Feb.
311. Butler T, Levin J, Linh NN et al. Yersinia pestis infection in Vietnam: II Quantiative blood cultures and detection of endotoxin in the cerebrospinal fluid of patients with meningitis. J Infect Dis . 1976; 133:493-9. [PubMed 1262715]
312. Dworkin MS, Hanson DL, Kaplan JE et al. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis . 2000; 182:611-5. [PubMed 10915098]
313. Mussini C, Pezzotto P, Govoni A et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficient virus type 1-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis . 2000; 181:1635-42. [PubMed 10823763]
314. Lopez Bernaldo de Quiros JC, Miro JM, Pena JM et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection: Grupo de Estudio del SIDA 04/98. N Engl J Med . 2001; 344:159-67. [PubMed 11172138]
315. Furrer H, Opravil M, Rossi M et al. Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study. AIDS . 2001; 15:501-7. [PubMed 11242147]
316. Kirk O, Lundgren JD, Pedersen C et al. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS . 1999; 13:1647-51.
317. Soriano V, Dona C, Rodriguez-Rosado R et al. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS . 2000; 14:383-6. [PubMed 10770540]
318. Ledergerber B, Mocroft A, Reiss P et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. N Engl J Med . 2001; 344:168-74. [PubMed 11188837]
319. Furrer H, Opravil M. Bernasconi E et al. Stopping primary prophylaxis in HIV-1-infected patients at high risk of toxoplasma encephalitis: Swiss HIV cohort study. Lancet . 2000; 355:2217-8. [PubMed 10881897]
320. Centers for Disease Control and Prevention. Fact sheet for health professionals, Cyclospora infection: information for health care providers. From CDC website. [Web]
321. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics . 2004: 113:1451-65.