- Rickettsial Infections
- Chlamydial Infections
- Nongonococcal Urethritis
- Granuloma Inguinale (Donovanosis)
- Pelvic Inflammatory Disease
- Gram-Negative Bacterial Infections
- Gram-Positive Bacterial Infections
- Acne
- Respiratory Tract Infections
- Spirochetal Infections
- GI Infections
- Malaria
- Mycobacterial Infections
- Ehrlichiosis and Anaplasmosis
- Periodontitis
- Rheumatoid Arthritis
- Syndrome of Inappropriate Antidiuretic Hormone Secretion
- Pericardial and Pleural Effusions
- Diagnostic Uses
- Prophylaxis in Victims of Sexual Assault
Tetracyclines are used principally in the treatment of infections caused by susceptible Rickettsia , Chlamydia , Mycoplasma , and a variety of uncommon gram-negative and gram-positive bacteria. Because of the development of resistance, tetracyclines are rarely used for the treatment of infections caused by common gram-negative or gram-positive bacteria unless other appropriate anti-infectives are contraindicated or are ineffective and in vitro susceptibility tests indicate that the causative organisms are susceptible to the drugs.
Generally, given a susceptible organism, the currently available tetracyclines are all equally effective when administered in appropriate dosages. Because minocycline and, to a lesser extent, doxycycline penetrate most body tissues and fluids better than do other currently available tetracyclines, some clinicians prefer these derivatives in the treatment of infections of the CNS, eye, or prostate. Because of poor CNS penetration, none of the currently available tetracyclines should be used in the treatment of meningitis. Doxycycline generally is the preferred derivative when a tetracycline is indicated in patients with impaired renal function. Because of its low renal clearance, doxycycline may not be as effective as other currently available tetracyclines for the treatment of urinary tract infections in patients with normal or impaired renal function.
Tetracyclines are used for the treatment of rickettsial infections.234,239,241,305,393,497,500,502,507,508 The US Centers for Disease Control and Prevention (CDC) and other clinicians state that doxycycline is the preferred tetracycline for the treatment of most rickettsial infections, including spotted fevers (Rocky Mountain spotted fever [ RMSF], Mediterranean spotted fever, African tick-bite fever, Queensland tick typhus, North Asian tick fever, oriental spotted fever, rickettsialpox, cat flea typhus), typhus fever (e.g., epidemic typhus, murine typhus) and the typhus group, Q fever, rickettsialpox, ehrlichiosis, Sennetsu fever, and other tick fevers caused by rickettsiae. 239,240,305,307,386,469,500,505 Although tetracyclines are not usually used in children younger than 8 years of age, doxycycline is recommended by the CDC and American Academy of Pediatrics (AAP) as the drug of choice for presumed or confirmed Rickettsial infections (including RMSF) in children of any age.469,500 (See Cautions: Pediatric Precautions.)
Because a delay in treatment can result in severe disease and fatal outcome, treatment of patients with suspected rickettsial disease should be initiated promptly based on clinical and epidemiologic evidence pending laboratory confirmation.239,500,502 An infectious disease or tropical medicine specialist should be consulted.239 IV therapy generally is indicated for hospitalized patients and oral therapy generally is appropriate for those with early disease, outpatients, or hospitalized patients who are not vomiting or obtunded.500,502 Treatment usually is continued for at least 5-10 days and until the patient is afebrile for 3 days or more and clinically improved.500,502,507 Severe illness may require a longer duration of therapy.469,500
Although doxycycline alone usually is the drug of choice for the treatment of acute Q fever caused by Coxiella burnetii ,492,239 doxycycline has been used in conjunction with hydroxychloroquine or a fluoroquinolone (e.g., levofloxacin, ofloxacin) for the treatment of Q fever endocarditis.490,491,492 In one limited study in patients with confirmed C. burnetii infection and chronic endocarditis, a regimen of doxycycline and hydroxychloroquine was associated with a lower relapse rate than a regimen of doxycycline and ofloxacin.490 Although both regimens require long-term therapy, the mean duration of therapy for cured patients was 55 months for those who received the doxycycline/quinolone regimen compared with 31 months for those who received the doxycycline/hydroxychloroquine regimen.490 Prolonged therapy (at least 18 months) with the doxycycline and hydroxychloroquine regimen is necessary to prevent relapse.490 The CDC recommends a 2- to 3-week regimen of doxycycline for the treatment of acute Q fever, a 1-year regimen of doxycycline and hydroxychloroquine for the treatment of acute Q fever in patients with preexisting valvular heart disease (to prevent progression of acute disease to endocarditis), and a 1.5- to 3-year regimen of doxycycline and hydroxychloroquine for the treatment of chronic Q fever.239,492
It has been suggested that tetracycline may be effective as prophylaxis against Q fever† and may prevent clinical disease if initiated 8-12 days after exposure; however, such prophylaxis is not effective and may only prolong the onset of disease if given immediately (1-7 days) after exposure.240
Tetracyclines are highly effective in the treatment of most chlamydial infections, including urogenital infections caused by Chlamydia trachomatis , respiratory tract infections caused by Chlamydophila pneumoniae (formerly Chlamydia pneumoniae ), respiratory tract infections caused by C. psittaci (psittacosis), and lymphogranuloma venereum caused by invasive serovars of C. trachomatis .213,394,469
Urogenital Chlamydial Infections in Adults and Adolescents
For the treatment of urogenital chlamydial infections in adults and adolescents, the CDC and other clinicians recommend a single dose of oral azithromycin or a 7-day regimen of oral doxycycline.213,216 Alternatively, adults and adolescents with urogenital chlamydial infections can receive a 7-day oral regimen of tetracycline, erythromycin base, erythromycin ethylsuccinate, ofloxacin, levofloxacin, or amoxicillin.213,216 Results of clinical studies indicate that the single-dose azithromycin and multi-dose doxycycline regimen are equally effective for the treatment of urogenital chlamydial infections when patients are compliant and follow-up encouraged; however, if poor compliance or inability to provide follow-up are a concern, azithromycin may be more cost-effective since the single-dose regimen can be administered under direct supervision.213 Erythromycin is less effective than either azithromycin or doxycycline and GI effects associated with the drug may discourage patient compliance with the regimen.213,216 To maximize compliance with 7-day regimens, the CDC recommends that the drugs be dispensed on site and that the first dose be taken under supervision.213 Since the azithromycin and doxycycline regimens are highly effective, a test of cure probably is unnecessary in patients who receive one of these regimens unless symptoms persist or reinfection is suspected; however, a test of cure should be considered 3 weeks after completion of an erythromycin regimen.213 Some studies have demonstrated high rates of infection among women retested for chlamydia after treatment, presumably because of reinfection.213 In some populations (e.g., adolescents), rescreening women several months after treatment might be effective for detecting further morbidity.213
Patients being treated for chlamydial infection should be instructed to refer their sexual partner(s) for evaluation and treatment, and to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen.213 In addition, to minimize the risk of reinfection, patients should be instructed to abstain from sexual intercourse until after all their sexual partners are cured.213 Although the CDC acknowledges that the exposure intervals are somewhat arbitrary, they recommend that individuals who had sexual contact with the chlamydia patient within 60 days before the onset of symptoms or diagnosis in the patient should be evaluated and treated.213 If the patient reports that the last sexual contact occurred more than 60 days prior to the onset of symptoms or diagnosis, their most recent sexual partner should be treated.213
Individuals with HIV infection who also are infected with chlamydia should receive the same treatment regimens recommended for other individuals with chlamydial infections.213
Urogenital Chlamydial Infections in Children
For the treatment of urogenital chlamydial infections in children who weigh less than 45 kg, the CDC recommends a 14-day regimen of oral erythromycin base or ethylsuccinate.213 For the treatment of urogenital chlamydial infections in children younger than 8 years of age who weigh at least 45 kg, the CDC recommends a single dose of oral azithromycin; for those 8 years of age and older, the CDC recommends either a single dose of azithromycin or a 7-day regimen of oral doxycycline.213
Presumptive Treatment of Chlamydial Infections in Patients with Gonorrhea
Patients infected with N. gonorrhoeae frequently also have coexisting chlamydial and mycoplasmal infection; however, cephalosporins, spectinomycin, and most quinolone regimens used for the treatment of gonorrhea are ineffective for the treatment of these infections.213 Because of the risks associated with untreated coexisting chlamydial infection, the CDC and most clinicians recommend that patients being treated for uncomplicated gonorrhea or disseminated gonococcal infection also receive an anti-infective regimen effective for presumptive treatment of uncomplicated urogenital chlamydial infection.213,216,469 For presumptive treatment of chlamydia in adults and adolescents being treated for uncomplicated or disseminated gonococcal infections, the CDC and others recommend use of a single dose of oral azithromycin or a 7-day regimen of oral doxycycline.213,216
The strategy of routine administration of a regimen effective against chlamydia in patients being treated for gonococcal infection has been recommended by the CDC for more than 10 years and appears to have resulted in substantial decreases in the prevalence of urogenital chlamydial infection in some populations.213 In addition, since most N. gonorrhoeae isolated in the US are susceptible to doxycycline and azithromycin, dual therapy possible may delay the development of resistance in N. gonorrhoeae .213 Since the cost of presumptive treatment of chlamydia is less than the cost of testing for presence of chlamydia, routine dual therapy without chlamydial testing can be cost-effective for populations in which coinfection with chlamydia has been reported in 10-30% of patients with N. gonorrhoeae infection.213 In areas where the rate of coinfection with chlamydia is low and chlamydial testing is widely available, some clinicians may prefer to test for chlamydia rather than treat presumptively; however, presumptive treatment is indicated for patients who may not return for test results.213
Trachoma and Inclusion Conjunctivitis
An oral tetracycline (with or without a topical tetracycline, topical erythromycin, or topical sulfacetamide) is used for the treatment of trachoma and inclusion conjunctivitis caused by C. trachomatis in adults and children older than 8 years of a 386 however, anti-infective therapy may not eliminate C. trachomatis in all cases of chronic trachoma. Inclusion conjunctivitis and trachoma in younger children and neonates and chlamydial infections in pregnant women generally are treated with oral or IV erythromycin.213,216,386,469
Doxycycline generally is considered the drug of choice for the treatment of lymphogranuloma venereum caused by invasive serotypes of C. trachomatis (serovars L1, L2, L3), and oral erythromycin is considered an alternative regimen for the treatment of the disease.213,216,469 Some clinicians suggest that tetracycline can be used as an alternative to doxycycline.216 Erythromycin is the preferred regimen for the treatment of lymphogranuloma venereum in pregnant and lactating women.213 Effective treatment cures the infection and prevents ongoing tissue damage, although tissue reaction can result in scarring.213 Aspiration of buboes or incision and drainage may be necessary to prevent the formation of inguinal/femoral ulcerations.213
The CDC recommends that individuals who had sexual contact with the lymphogranuloma venereum patient should be examined, tested for urethral or cervical chlamydial infection, and treated with a standard chlamydia regimen (single 1-g dose of azithromycin or 7-day regimen of oral doxycycline 100 mg twice daily) if they had sexual contact with the patient within 60 days prior to onset of symptoms in the patient.213
While HIV-infected individuals with lymphogranuloma venereum should receive the same treatment regimens recommended for other patients, there is some evidence that HIV-infected patients may require more prolonged therapy and resolution may be delayed.213
Tetracyclines are the drugs of choice for the treatment of C. psittaci infections (psittacosis, ornithosis);284,386,394,469 erythromycin or chloramphenicol is recommended for the treatment of psittacosis when tetracyclines are contraindicated.284,386,394,469 The CDC states that most individuals with psittacosis respond to an oral regimen of doxycycline or tetracycline hydrochloride.394 A regimen of IV doxycycline hyclate may be indicated for initial treatment of severely ill patients.394 Remission of symptoms usually is evident within 48-72 hours, but treatment should be continued for at least 10-14 days after fever abates since relapse can occur.394
While C. trachomatis is a frequent cause of nongonococcal urethritis, these infections can be caused by Ureaplasma urealyticum or Mycoplasma genitalium ; Trichomonas vaginalis and herpes simplex virus (HSV) also are possible causes of nongonococcal urethritis.213 The CDC currently considers a single oral dose of azithromycin or a 7-day regimen of oral doxycycline the regimens of choice for the treatment of nongonococcal urethritis.213 Alternative regimens recommended by the CDC are a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or levofloxacin.213 Patients with persistent or recurrent urethritis who were not compliant with the treatment regimen or were reexposed to untreated sexual partner(s) should be retreated with the initial regimen.213 If the patient has recurrent and persistent urethritis, was compliant with the anti-infective regimen, and reexposure can be excluded, the CDC recommends retreatment with a single 1-g dose of oral azithromycin and a 2-g dose of oral metronidazole or oral tinidazole.213
Granuloma Inguinale (Donovanosis) 
Tetracyclines are drugs of choice for the treatment of granuloma inguinale (donovanosis), caused by Klebsiella granulomatis (formerly Calymmatobacterium granulomatis ).213,225 The CDC recommends that donovanosis be treated with a regimen of oral doxycycline or, alternatively, a regimen of oral azithromycin, oral ciprofloxacin, oral erythromycin, or oral co-trimoxazole.213 Anti-infective treatment of donovanosis should be continued until all lesions have healed completely; a minimum of 3 weeks of treatment usually is necessary.213,225 If lesions do not respond within the first few days of therapy, the CDC recommends that a parenteral aminoglycoside (e.g., 1 mg/kg of gentamicin IV every 8 hours) be added to the regimen.213 Erythromycin is recommended for the treatment of donovanosis in pregnant and lactating women;213,225 addition of a parenteral aminoglycoside (e.g., gentamicin) to the regimen should be strongly considered in these women.213 Anti-infective treatment appears to halt progressive destruction of tissue, although prolonged duration of therapy often is required to enable granulation and re-epithelization of ulcers.213 Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.213
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 to the regimen should be strongly considered in HIV-infected patients.213
Doxycycline is used in conjunction with other anti-infectives for the treatment of acute pelvic inflammatory disease† (PID).213,216
One parenteral regimen recommended by the CDC and other clinicians for the treatment of PID in adults and adolescents is a 2-drug regimen of IV cefoxitin or IV cefotetan given in conjunction with oral or IV doxycycline.213,216,469 The parenteral regimen may be discontinued 24 hours after there is clinical improvement and oral doxycycline is then continued to complete 14 days of therapy.213,216 Because oral and IV doxycycline have similar bioavailabilities, the CDC states that either may be used for the initial phase of treatment.213 When tubo-ovarian abscess is present, some clinicians use clindamycin or metronidazole in addition to oral doxycycline to complete 14 days of therapy since this provides more effective anaerobic coverage.213
In another parenteral regimen recommended by the CDC and others for the treatment of PID, an initial regimen of IV clindamycin and IV or IM gentamicin is given.213,216 The parenteral regimen is discontinued 24 hours after there is clinical improvement and oral doxycycline is used to complete 14 days of therapy; however, if tubo-ovarian abscess is present, some clinicians substitute oral clindamycin instead of oral doxycycline for follow-up after the initial parenteral regimen.213,216 An alternative parenteral regimen recommended by the CDC for the treatment of PID is IV ampicillin and sulbactam given in conjunction with oral or IV doxycycline; this regimen has good coverage against C. trachomatis , N. gonorrhoeae , and anaerobes and is effective for patients with tubo-ovarian abscess.213,216
When an oral regimen is used for the treatment of PID in adults or adolescents, the CDC and many clinicians recommend use of a single IM dose of ceftriaxone, cefoxitin (with oral probenecid), or an equivalent second or third generation cephalosporin (e.g., cefotaxime) followed by a 14-day regimen of oral doxycycline with or without a 14-day regimen of oral metronidazole.213,216 The addition of metronidazole to this regimen provides coverage against bacterial vaginosis, which is frequently associated with PID.213
For further information on the treatment of PID, see Uses: Pelvic Inflammatory Disease, in the Cephalosporins General Statement 8:12.06.
Gram-Negative Bacterial Infections
Tetracyclines are the drugs of first or second choice for the treatment of many infections caused by uncommon gram-negative bacteria.
Doxycycline is used in the treatment of infections caused by Bartonella quintana † (formerly Rochalimaea quintana ).386,516 B. quintana , a gram-negative bacilli, can cause cutaneous bacillary angiomatosis, trench fever, bacteremia, endocarditis, and chronic lymphadenopathy.258,260,267,516 B. quintana infections have been reported most frequently in immunocompromised patients (e.g., individuals with HIV infection), homeless individuals in urban areas, and chronic alcohol abusers.258,260 Optimum anti-infective regimens for the treatment of infections caused by B. quintana have not been identified,258,260,267 and various drugs have been used to treat these infections, including doxycycline, erythromycin, azithromycin, chloramphenicol, or cephalosporins.260,267,386,516 There is evidence that these infections tend to persist or recur and prolonged therapy (several months or longer) usually is necessary.258,260
Doxycycline has been used in the treatment of infections caused by Bartonella henselae (formerly Rochalimaea henselae ) (e.g., cat scratch disease, bacillary angiomatosis, peliosis hepatitis);257,516 however, the possible role of tetracyclines in the treatment of these infections has not been determined. Cat scratch disease generally is a self-limited illness in immunocompetent individuals and may resolve spontaneously in 2-4 months; however, some clinicians suggest that anti-infective therapy be considered for acutely or severely ill patients with systemic symptoms, particularly those with hepatosplenomegaly or painful lymphadenopathy, and probably is indicated in immunocompromised patients.300,301,302,469 Anti-infectives also are indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud's oculoglandular syndrome.300,301,302,469,516 While the optimum anti-infective regimen for the treatment of cat scratch disease or other B. henselae infections has not been identified, some clinicians recommend use of erythromycin, azithromycin, doxycycline, ciprofloxacin, rifampin, co-trimoxazole, gentamicin, or third generation cephalosporins.257,300,301,302,469,516
HIV-infected individuals (especially severely immunosuppressed individuals) are at unusually high risk for severe disease caused by Bartonella and relapse or reinfection sometimes occurs following initial treatment of these infections.250,496 The CDC, NIH, and Infectious Diseases Society of America (IDSA) suggest that the drug of choice for treatment of bartonellosis in HIV-infected patients is erythromycin or doxycycline, but that doxycycline is preferred for CNS bartonellosis.496 In addition, although data are insufficient to make firm recommendations, these experts and the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) suggest that use of doxycycline or erythromycin for long-term suppressive therapy (secondary prophylaxis) to prevent recurrence of Bartonella infection be considered in HIV-infected adults or adolescents with relapse or reinfection.250,496
Tetracyclines (doxycycline, tetracycline hydrochloride) generally are considered the drugs of choice for brucellosis.328,331,386,469 Limited data suggest that combined anti-infective therapy may reduce the likelihood of disease relapse, and some clinicians recommend that another anti-infective (e.g., streptomycin or gentamicin and/or rifampin) be used in conjunction with a tetracycline for the treatment of brucellosis.328,329,331,386,469 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 the tetracycline for the first 7-14 days of therapy; rifampin can also be used in the regimen to reduce the risk of relapse.469 Some experts recommend a 3-drug regimen that includes a tetracycline, an aminoglycoside, and rifampin for the treatment of brucellosis in patients with meningoencephalitis or endocarditis.240 Although data are limited, alternative regimens that have been suggested for the treatment of brucellosis include co-trimoxazole with or without gentamicin or rifampin (recommended for use in children when tetracyclines are contraindicated); ciprofloxacin (or ofloxacin) and rifampin; and chloramphenicol with or without streptomycin.230,240,386,469
Postexposure prophylaxis with anti-infectives is not generally recommended after possible exposure to endemic brucellosis; however, use of an anti-infective regimen recommended for the treatment of brucellosis (e.g., doxycycline and rifampin) should be considered following a high-risk exposure to Brucella .240,469 These high-risk exposures include needle-stick injuries involving the brucella vaccine available for veterinary use (a brucella vaccine for use in humans is not available); inadvertent laboratory exposure to the organism; or confirmed exposure in the context of biologic warfare or bioterrorism.240
Tetracyclines (usually doxycycline) are used in the treatment of melioidosis† caused by Burkholderia pseudomallei .240,386 Doxycycline alone or in conjunction with co-trimoxazole may be effective for the treatment of localized or mild melioidosis.240 However, severe illness requires an initial parenteral regimen of ceftazidime, imipenem, or meropenem (with or without concomitant co-trimoxazole or doxycycline), followed by a prolonged maintenance regimen of oral anti-infectives (e.g., co-trimoxazole with or without doxycycline).240,517,518
Although only limited experience is available regarding the treatment of human cases of glanders† caused by B. mallei ,240,517 some clinicians suggest that, pending results of in vitro susceptibility tests, regimens used for the treatment of severe melioidosis also can be used for initial empiric treatment of glanders.240
Some experts (e.g., US Army Medical Research Institute of Infectious Diseases [USAMRIID], European Commission's Task Force on Biological and Chemical Agent Threats [BICHAT]) state that the same treatment regimens recommended for naturally occurring melioidosis or glanders should be used if these Burkholderia infections occur in the context of biologic warfare or bioterrorism.240,517 Although the benefits of postexposure prophylaxis† are unknown, USAMRIID states that adults can receive oral doxycycline in conjunction with oral rifampin for postexposure prophylaxis if exposure occurs in the context of biologic warfare or bioterrorism.240 The CDC recommends that laboratory workers with high-risk exposure to melioidosis be offered postexposure prophylaxis with oral doxycycline.519 The optimum duration of postexposure prophylaxis is unknown, but a duration of at least 10 days is recommended.240,519
Gonorrhea and Associated Infections
Some manufacturers state that oral doxycycline234 or oral tetracycline hydrochloride can be used as alternatives for the treatment of uncomplicated gonorrhea. However, tetracyclines are considered inadequate therapy for the treatment of gonorrhea and are not recommended by the CDC for the treatment of uncomplicated or disseminated gonorrhea.213 The CDC and many clinicians currently recommend use of tetracyclines for presumptive treatment of coexisting chlamydial infections in patients being treated for gonococcal infections.213,216 (See Presumptive Treatment of Chlamydial Infections in Patients with Gonorrhea under Uses: Chlamydial Infections.)
For the treatment of epididymitis most likely caused by gonococcal or chlamydial infection, the CDC recommends a single 250-mg IM dose of ceftriaxone given in conjunction with a 10-day regimen of oral doxycycline (100 mg twice daily).213,216 For epididymitis most likely to be caused by enteric bacteria (e.g., Escherichia coli ), for those allergic to tetracyclines and/or cephalosporins, or for patients older than 35 years of age, the CDC recommends a 10-day regimen of oral ofloxacin or oral levofloxacin.213 Empiric treatment of epididymitis is indicated before in vitro culture results are available.213 As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided.213 Although most patients can be treated as outpatients, hospitalization should be considered when severe pain suggests other diagnoses (e.g., torsion, testicular infarction, abscess) or when patients are febrile or might be noncompliant.213
For the treatment of proctitis likely to be caused by N. gonorrhoeae or C. trachomatis , the CDC recommends a single 125-mg IM dose of ceftriaxone (or another anti-infective effective against rectal and genital gonorrhea) given in conjunction with a 7-day regimen of oral doxycycline (100 mg twice daily).213
Tetracyclines (doxycycline, tetracycline) are used for the treatment of plague caused by Yersinia pestis .234,238,239,240,386,469 Streptomycin (or gentamicin) with or without a tetracycline generally is considered the drug of choice for the treatment of plague.238,239,386,469 Alternative drugs recommended when aminoglycosides are not used include doxycycline (or tetracycline), chloramphenicol, or co-trimoxazole (may be less effective than other alternatives).239,386,469 Based on results of in vitro and animal testing, ciprofloxacin (or other fluoroquinolones) also is recommended as an alternative for the treatment of plague.238,240 Chloramphenicol generally is considered the drug of choice for the treatment of plague meningitis239,240,469 or other conditions that require high anti-infective tissue concentrations (e.g., plague pleuritis, endophthalmitis, or myocarditis).239 An infectious diseases specialist should be consulted regarding management of patients with plague.239
Anti-infective regimens recommended for the treatment of naturally occurring or endemic bubonic, septicemic, or pneumonic plague also are recommended for the treatment of plague that occurs following exposure to Y. pestis in the context of biologic warfare or bioterrorism.238 These exposures would most likely result in primary pneumonic plague.238 Prompt initiation of anti-infective therapy (within 18-24 hours of onset of symptoms) is essential in the treatment of pneumonic plague.238,240 Some experts (e.g., the US Working Group on Civilian Biodefense, USAMRIID) recommend that treatment of plague in the context of biologic warfare or bioterrorism should be initiated with a parenteral anti-infective regimen of streptomycin (or gentamicin) or, alternatively, doxycycline, ciprofloxacin, or chloramphenicol, although an oral regimen (doxycycline, ciprofloxacin) may be substituted when the patient's condition improves or if parenteral therapy is unavailable.238,240
Postexposure prophylaxis† with anti-infectives is recommended after high-risk exposures to plague, including close exposure to individuals with naturally occurring plague or laboratory exposure to viable Y. pestis .242 In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, USAMRIID) recommend that asymptomatic individuals with exposure to plague aerosol or asymptomatic individuals with household, hospital, or other close contact (within about 2 m) with an individual who has pneumonic plague should receive postexposure anti-infective prophylaxis; however, any exposed individual who develops a temperature of 38.5°C or higher or new cough should promptly receive a parenteral anti-infective for treatment of the disease.240 An oral regimen of doxycycline or ciprofloxacin usually is recommended for such prophylaxis.238,240 Alternatives suggested for postexposure prophylaxis include oral tetracycline,240,242 co-trimoxazole,242 or oral chloramphenicol (an oral preparation is not commercially available in the US).240 Although plague vaccine (no longer commercially available in the US) was previously recommended to provide protection against Y. pestis infection, the vaccine was effective for preventing or ameliorating bubonic plague but was not effective for prophylaxis against exposure to aerosolized Y. pestis and therefore did not provide protection against pneumonic plague.240,238
Individuals with unavoidable exposures to plague in active epizootic or epidemic areas (e.g., mainly in rural mountainous or upland areas of most countries in Africa, Asia, and the Americas) during travel are at high risk for plague and should be advised to consider chemoprophylaxis during periods of exposure.239 CDC recommends tetracycline or doxycycline for prophylaxis against plague† in such travelers;239 co-trimoxazole is an acceptable alternative for infants and children younger than 8 years of age who should not receive tetracyclines.239 In addition, personal protective measures should be employed, including using insect repellents containing DEET on skin and clothing, avoiding sick or dead animals or rodent nests and burrows, and avoiding areas where recent plague epidemics or epizootics have been reported.239 Individuals staying in modern accommodations while in active plague epizootic or epidemic areas are unlikely to be at high risk of exposure.239
Tetracyclines (usually doxycycline) are used as alternative agents for the treatment of tularemia caused by Francisella tularensis .234,240,386 Streptomycin (or gentamicin) generally are considered the drugs of choice for this infection.240,243,386,469 Alternatives for the treatment of tularemia include tetracyclines (doxycycline), chloramphenicol, or ciprofloxacin.240,243,386,469 Anti-infective regimens recommended for the treatment of naturally occurring or endemic tularemia also are recommended for the treatment of tularemia that occurs following exposure to F. tularensis in the context of biologic warfare or bioterrorism.243 However, the fact that a fully virulent streptomycin-resistant strain of F. tularensis was developed in the past for use in biologic warfare should be considered.240,243 Exposures to F. tularensis in the context of biologic warfare or bioterrorism would most likely result in inhalational tularemia with pleuropneumonitis, although the organism also can infect humans through the skin, mucous membranes, and GI tract.243
Postexposure prophylaxis† with anti-infectives usually is not recommended after possible exposure to natural or endemic tularemia (e.g., tick bite, rabbit or other animal exposure) and is unnecessary in close contacts of tularemia patients since human-to-human transmission of the disease is not known to occur.240 However, postexposure prophylaxis is recommended following a high-risk laboratory exposure to F. tularensis (e.g., spill, centrifuge accident, needlestick injury).243 In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend that asymptomatic individuals with exposure to F. tularensis receive postexposure anti-infective prophylaxis; however, any individual who develops an otherwise unexplained fever or flu-like illness within 14 days of presumed exposure should promptly receive a parenteral anti-infective for treatment of the disease.240,243 Oral doxycycline (or oral tetracycline) or oral ciprofloxacin usually is recommended for postexposure prophylaxis following such exposures.240,243
Other Gram-Negative Bacterial Infections
When the drugs of choice are contraindicated or are ineffective, tetracyclines are used as alternatives to erythromycins, ceftriaxone, or co-trimoxazole in the treatment of Campylobacter fetus infections.
Tetracyclines are used as alternatives to penicillin G in the treatment of infections caused by Leptotrichia buccalis (Vincent's infection).386
Although doxycycline has been used for the treatment of chancroid caused by Haemophilus ducreyi ,234 tetracyclines are not included in current CDC recommendations for the treatment of chancroid.213 (For information on treatment of chancroid, see Uses: Chancroid in Ceftriaxone 8:12.06.12.)
Tetracyclines have been effective in the treatment of rat-bite fever† caused by Spirillum minus and Haverhill fever† caused by Streptobacillus moniliformis ; however, penicillin G generally is preferred for the treatment of these infections.386
Tetracyclines are considered alternatives to penicillin G for the treatment of infections caused by Pasteurella multocida †.386
Some clinicians recommend minocycline as an alternative to co-trimoxazole for the treatment of infections caused by Stenotrophomonas maltophilia .386
Tetracyclines, with or without rifampin, have been used in the treatment of Legionnaires' disease† caused by Legionella pneumophila .247 Macrolides or fluoroquinolones generally are considered the drugs of choice for the treatment of pneumonia caused by L. pneumophila and doxycycline and co-trimoxazole are alternatives.247,249,284,386,469 A parenteral regimen usually is necessary for the initial treatment of severe Legionnaires' disease and the addition of oral rifampin is recommended during the first 3-5 days of macrolide or doxycycline therapy in severely ill and/or immunocompromised patients; after a response is obtained, rifampin can be discontinued and therapy changed to an oral regimen.247,249,469
Although minocycline has been used to eliminate meningococci from the nasopharynx of asymptomatic N. meningitidis carriers in situations in which the risk of meningococcal meningitis is high,393 adverse CNS effects (e.g., vestibular symptoms) are reported occasionally with minocycline393 and the CDC and AAP currently recommend other anti-infective agents (i.e., rifampin, ceftriaxone, ciprofloxacin) for the treatment of carriers of N. meningitidis .391,392,469 Minocycline is not indicated for the treatment of infections caused by N. meningitidis .393
Tetracyclines have been used for the treatment of infections caused by susceptible Acinetobacter , Bacteroides , Enterobacter aerogenes , Escherichia coli , and Shigella ; respiratory tract infections caused by H. influenzae ; and respiratory tract and urinary tract infections caused by K. pneumoniae. However, many strains of these gram-negative bacteria have been shown to be resistant to tetracyclines and the drugs generally should not be used empirically in infections suspected to be caused by these organisms. Tetracyclines should be used in the treatment of infections caused by common gram-negative bacteria only when other appropriate anti-infectives (e.g., aminoglycosides) are contraindicated or are ineffective and when results of in vitro susceptibility tests indicate that the organisms are susceptible.
Gram-Positive Bacterial Infections
Doxycycline and tetracycline hydrochloride are used in the treatment of anthrax200,201,204,234,469 and for postexposure prophylaxis following a suspected or confirmed exposure to aerosolized anthrax spores (inhalational anthrax).200,201,202,204,222,234,236,286 Doxycycline is the preferred tetracycline for inhalational anthrax based on efficacy data in monkey studies and ease of administration.200
Parenteral penicillin generally has been considered the drug of choice for the treatment of naturally occurring or endemic anthrax caused by susceptible strains of Bacillus anthracis , including clinically apparent inhalational, GI, or meningeal anthrax and anthrax septicemia, although IV ciprofloxacin or IV doxycycline also are recommended.201,204,222,236,240,298,386,469 However, B. anthracis strains with natural resistance to penicillins have been reported and there are published reports of B. anthracis strains that have been engineered to have tetracycline and penicillin resistance as well as resistance to other anti-infectives (e.g., macrolides, chloramphenicol, rifampin).200,297 Therefore, it has been postulated that exposures to B. anthracis that occur in the context of biologic warfare or bioterrorism may involve bioengineered resistant strains and this concern should be considered when selecting initial therapy for treatment of anthrax that occurs as the result of bioterrorism-related exposures or when selecting anti-infective agents for postexposure prophylaxis following such exposures.200,222 For additional information on treatment of anthrax and recommendations for postexposure prophylaxis following exposure to anthrax spores, see Uses: Anthrax in Ciprofloxacin 8:12.18.
Doxycycline is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized B. anthracis spores.200,204,234,236,240 Ciprofloxacin or doxycycline are considered initial drugs of choice for postexposure prophylaxis following exposure to aerosolized anthrax spores that occurs in the context of biologic warfare or bioterrorism.200,240,290,289 There is no evidence to date that ciprofloxacin is more or less effective than doxycycline for such postexposure prophylaxis.290 During the bioterrorism-related exposures to B. anthracis spores during September and October 2001, the CDC initially recommended postexposure prophylaxis with either ciprofloxacin or doxycycline,236 but later revised these recommendations because of the large number of exposed individuals.289,290 At that time, the CDC suggested that use of doxycycline for postexposure prophylaxis was preferable since widespread use of any anti-infective agent can promote resistance to that drug and because many common pathogens already are resistant to tetracycline but still susceptible to fluoroquinolone and this tactic might preserve effectiveness of ciprofloxacin against these common pathogens.289,290 The US Working Group on Civilian Biodefense currently recommends use of ciprofloxacin as the initial drug of choice for postexposure prophylaxis and recommend use of doxycycline as an alternative if the organism is found to be susceptible.200 These experts also state that in vitro studies suggest that oral tetracycline hydrochloride could be substituted for doxycycline, if necessary.200 Ultimately, selection of an anti-infective agent for postexposure prophylaxis should be based on the clinical setting, susceptibility of the strain involved, and reported adverse effects associated with the drugs and either doxycycline or ciprofloxacin may be preferable for an individual patient.289,290
Anti-infective prophylaxis should be continued until exposure to B. anthracis has been excluded.204 If exposure is confirmed, postexposure vaccination with anthrax vaccine (if available) may be indicated in conjunction with prophylaxis.200,204 Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, the CDC and other experts recommend that postexposure prophylaxis be continued for at least 60 days after exposure.200,204,236,240,419 Because of potential adverse effects from prolonged use of doxycycline in infants and children, amoxicillin is an alternative to complete the postexposure prophylaxis regimen when susceptibility to penicillin is known.369
The CDC states that anti-infective prophylaxis is not necessary for workers in contaminated environments who wear appropriate personal protective equipment and who have received the complete vaccine series, unless a breach of respiratory protection occurs. However, remediation workers involved in clean up and decontamination of B. anthracis -contaminated sites who have not been vaccinated with the complete 6-dose recommended regimen of anthrax vaccine should receive anti-infective prophylaxis, regardless of other methods being used to protect these individuals from exposure.419 This recommendation also applies to workers entering areas that already have been remediated but have not yet been cleared for general occupancy.419 Unvaccinated or incompletely vaccinated remediation workers should begin anti-infective prophylaxis at the time of first entry into the contaminated area, and such prophylaxis should be continued until at least 60 days after last entry into the area419 for unvaccinated workers. Remediation workers who have received all or part of the 6-dose vaccine regimen should continue anti-infective prophylaxis for at least 30 days and should complete the vaccination regimen. In addition, it might be prudent to continue anti-infective prophylaxis until 7-14 days after the third vaccine dose is administered.
Remediation workers with repeated entries into contaminated sites over a prolonged period of time could require anti-infective prophylaxis for considerably longer than the 60 days recommended for individuals with a single exposure.419 To date, some remediation workers have received anti-infective prophylaxis for more than 6 months.419 If anthrax vaccine is administered to an individual while their risk of exposure to anthrax spores continues, the CDC recommends concomitant anti-infective prophylaxis throughout the period of risk and for 60 days after the risk of exposure has ended, unless the 6-dose series of anthrax vaccine has been completed and annual boosters are up-to-date.419
Although controlled studies evaluating doxycycline for aerosolized anthrax exposure have not been conducted for ethical reasons, the drug has been evaluated in a rhesus monkey model of inhalational anthrax.200,218 In this study, mortality due to anthrax was significantly lower in monkeys that received doxycycline compared with those that received placebo.218 Peak serum concentrations of doxycycline associated with survival in this rhesus monkey model were within the range usually observed with usual dosages of the drug.220
Treatment of Inhalational Anthrax
The rapid course of symptomatic inhalational anthrax and high mortality rate make early initiation of anti-infective therapy essential.200,204,236 While monotherapy with IV penicillin G, ciprofloxacin, or doxycycline has been recommended for the treatment of anthrax that occurs as the result of natural or endemic exposures,201,240,386,469 the CDC and other experts (e.g., US Working Group on Civilian Biodefense) recommend that treatment of clinically apparent inhalational anthrax that occurs as the result of exposure to anthrax spores in the context of biologic warfare or bioterrorism should be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 other anti-infectives predicted to be effective.200,222 Drugs to be included in the initial treatment regimen with ciprofloxacin or doxycycline should be selected based on in vitro susceptibility, possibility of efficacy, adverse effects, and cost.290 Based on in vitro data, drugs that have been suggested as possibilities to augment ciprofloxacin and doxycycline in such multiple-drug regimens include chloramphenicol, clindamycin, rifampin, vancomycin, clarithromycin, imipenem, penicillin, or ampicillin.200,222 If meningitis is established or suspected, some clinicians suggest a multiple-drug regimen that includes ciprofloxacin (rather than doxycycline) and chloramphenicol, rifampin, or penicillin.222
Because of the difficulty in making a rapid microbiologic diagnosis of anthrax, high-risk individuals who develop fever or other evidence of systemic infection should promptly receive therapy for possible anthrax infection while waiting for results of laboratory studies.200 If large numbers of individuals require treatment in mass casualty settings, IV therapy with a multiple-drug parenteral regimen may not be possible.200 In these circumstances, oral therapy with a regimen recommended for postexposure prophylaxis of inhalational anthrax is an option.200
Because of the possible persistence of anthrax spores in lung tissue, anti-infective therapy for the treatment of inhalational anthrax that occurs as the result of exposure to aerosolized spores in the context of biologic warfare or bioterrorism should be continued for at least 60 days.200,240 Oral anti-infective therapy can be substituted for IV therapy as soon as the patient's clinical condition improves.200,240
Although tetracyclines are not usually used in children younger than 8 years of age, doxycycline can be used in infants and children for the initial treatment of anthrax if considered necessary.200,234 (See Cautions: Pediatric Precautions.) If infants and children with inhalational anthrax have clinical improvement while receiving the initial parenteral regimen, an oral regimen of 1 or 2 anti-infectives (including either doxycycline or ciprofloxacin) may be used to complete the first 14-21 days of therapy.369 Because of potential adverse effects from prolonged use of doxycycline in infants and children, amoxicillin is an option for completion of therapy but is not recommended for initial therapy.369
For the treatment of inhalational anthrax in pregnant women, the benefits of doxycycline therapy outweigh the risks and the CDC and other experts (e.g., US Working Group on Civilian Biodefense) state that doxycycline can be used when necessary for the treatment of inhalational anthrax.200,222 (See Cautions: Pregnancy, Fertility, and Lactation.)
Recommendations for the treatment of anthrax in immunocompromised patients are the same as those for patients who are immunocompetent.200
Treatment of Cutaneous Anthrax
Natural penicillins (e.g., oral penicillin V, IM penicillin G benzathine, IM penicillin G procaine) generally have been considered drugs of choice for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible strains of B. anthracis that occurs as the result of naturally occurring or endemic exposure to anthrax, although some clinicians suggest use of oral fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin), oral amoxicillin, or oral doxycycline if in vitro tests indicate susceptibility.201,298 For the treatment of cutaneous anthrax† that occurs following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, the CDC and other experts (e.g., US Working Group on Civilian Biodefense) recommend use of oral ciprofloxacin or oral doxycycline for initial therapy.200,222 Therapy may be changed to oral amoxicillin if results of in vitro testing indicate that the organism is susceptible to the drug and the patient is improving.222 Recommendations for treatment of cutaneous anthrax in immunocompromised patients are the same as those for patients who are immunocompetent.222 Use of a multiple-drug parenteral anti-infective regimen is recommended for the initial treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or lesions on the head and neck.200,201,222
Whether infants and young children are at increased risk for systemic dissemination of cutaneous anthrax infections is not known; however, a child 7 months of age infected following a bioterrorism-related exposure developed systemic illness after onset of cutaneous anthrax.369 Therefore, the CDC recommends that a parenteral regimen be used for the initial treatment of cutaneous anthrax in children younger than 2 years of age and use of a combination regimen should be considered.369 If a parenteral regimen is indicated for the treatment of cutaneous anthrax and if infants and children have clinical improvement while receiving the parenteral regimen, an oral regimen of 1 or 2 anti-infectives (including either doxycycline or ciprofloxacin) may be used to complete the first 7-10 days of therapy.369 Because of potential adverse effects from prolonged use of doxycycline in infants and children, amoxicillin is an option for completion of therapy, but is not recommended for initial therapy.369
Although 5-10 days of anti-infective therapy usually is recommended for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of natural or endemic exposures to anthrax, the CDC and other experts recommend that therapy be continued for at least 60 days if the cutaneous infection occurred as the result of exposure to aerosolized anthrax spores since the possibility of inhalational anthrax would also exist.200,222 Anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, but the lesion will still progress through the black eschar stage despite effective treatment.200,298
Other Gram-Positive Bacterial Infections
Tetracyclines are used as alternatives to penicillin G or metronidazole for the treatment of Clostridium tetani infections.386
When penicillin G is ineffective or is contraindicated, tetracyclines are used in the treatment of actinomycosis caused by Actinomyces israelii .386 Some clinicians recommend that long-term tetracycline hydrochloride therapy be used as follow-up treatment after penicillin G in severe cases of the disease.
Tetracyclines are considered alternatives to co-trimoxazole for the treatment of nocardiosis†.284,386 Some clinicians recommend a regimen of a sulfonamide and either minocycline or amikacin as an alternative to co-trimoxazole; although doxycycline or minocycline are also recommended alone as alternative regimens for the treatment of nocardiosis.284
Because of increasing resistance, tetracyclines are not considered drugs of choice for infections caused by gram-positive cocci (e.g., Staphylococcus or Streptococcus and should not be used empirically in infections suspected to be caused by these organisms. Tetracyclines should be used in the treatment of infections caused by Staphylococcus or Streptococcus only when other appropriate anti-infectives (e.g., penicillins, cephalosporins, erythromycin, clindamycin, vancomycin) are ineffective or are contraindicated and when results of in vitro susceptibility tests indicate that the organisms are susceptible to the drugs. If tetracyclines are used in infections caused by β-hemolytic streptococci, therapy should be continued for at least 10 days.
Tetracyclines are used orally in the treatment of moderate to severe inflammatory acne vulgaris.370,393 The drugs are not indicated in the treatment of noninflammatory acne. Therapy of acne vulgaris must be individualized and frequently modified depending on the types of acne lesions that predominate and the response to therapy. Oral minocycline may be effective in patients with inflammatory acne unresponsive to oral tetracycline hydrochloride or oral erythromycin. Although it has been suggested that failure to respond to anti-infective therapy may be caused by the development of resistance by P. acnes to the drug being administered, resistance is rare in this organism and failure to respond to anti-infective therapy appears to be more frequently caused by other factors (e.g., poor patient compliance, emotional or psychological factors, use of comedogenic cosmetic products, the presence of deep nodular or cystic lesions, sinus tract formation).
Preliminary studies using topical clindamycin, topical erythromycin, and topical tetracycline hydrochloride (a topical solution is no longer commercially available in the US) indicate that topical anti-infectives are as effective as oral tetracycline hydrochloride or oral erythromycin in the treatment of mild to moderate inflammatory acne. Some clinicians recommend that oral anti-infective therapy be used initially in the treatment of moderate to severe inflammatory acne vulgaris since the response to topical therapy may be delayed. A topical anti-infective is then used concomitantly after a few weeks, and the oral anti-infective is slowly discontinued. However, further controlled studies are needed to determine when each route of administration is preferred and when combined topical and oral administration of anti-infectives is indicated in the treatment of inflammatory acne vulgaris. For information on the topical use of tetracyclines in acne, see Tetracyclines 84:04.04.
Tetracyclines are used in the treatment of respiratory tract infections caused by M. pneumoniae , Haemophilus influenzae , Klebsiella , and Streptococcus pneumoniae .234,386,393,509 Tetracycline should only be used for treatment of infections caused by these bacteria when in vitro susceptibility tests indicate the organism is susceptible.509
Tetracyclines are used in the treatment of atypical pneumonia caused by Mycoplasma pneumoniae. Available data suggest that erythromycin and tetracycline are equally effective in shortening the duration of clinical symptoms and hastening radiographic improvement in adults with mycoplasma pneumonia, despite failure to eradicate the pathogen from nasopharyngeal or sputum cultures. Although conflicting data regarding the efficacy of antibiotic therapy of mycoplasma pneumonia in children have been reported, some clinicians suggest that erythromycin is preferred for treating children with the disease. The optimal duration of antibiotic therapy for mycoplasma pneumonia has not been established; however, because of the persistence of the pathogen, some clinicians recommend that such therapy be continued for 2-4 weeks to minimize the possibility of relapse.
Tetracyclines are used in the treatment of community-acquired pneumonia (CAP).272,284
Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens; therapy may then be changed (if possible) to a pathogen-specific regimen based on results of in vitro culture and susceptibility testing, especially in hospitalized patients.272,284 The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation and whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., penicillin- or multidrug-resistant S. pneumoniae , enteric gram-negative bacilli, Ps. aeruginosa ).272,284 For both outpatients and inpatients, most experts recommend that an empiric regimen for the treatment of CAP include an anti-infective active against S. pneumoniae since this organism is the most commonly identified cause of bacterial pneumonia and causes more severe disease than many other common CAP pathogens.272,284,285
When used in empiric regimens for the treatment of CAP, tetracyclines provide coverage against C. pneumoniae , M. pneumoniae , Haemophilus influenzae , and Legionella .272 Although tetracyclines may also provide some coverage for S. pneumoniae , many isolates of this organisms are resistant to tetracyclines.272,284 Doxycycline generally is the tetracycline recommended for empiric treatment of CAP because of good oral bioavailability, convenient twice-daily regimen, and tolerability.284 In most situations, either doxycycline or a macrolide is included in outpatient empiric CAP regimens.272,284 Although the IDSA doesn't make a distinction between macrolides and doxycycline,284 the ATS states that use of a macrolide is preferred (rather than doxycycline) because S. pneumoniae may be resistant to tetracyclines and recommends use of doxycycline as an alternative in patients hypersensitive or intolerant of macrolides.272 Tetracyclines are not usually recommended for empiric CAP regimens in patients with severe infections admitted to an intensive care unit (ICU), but doxycycline may be used as an alternative to macrolides in inpatient CAP regimens in patients hospitalized in a non-ICU setting.272,284
The duration of CAP therapy depends on the causative pathogen, illness severity at the onset of anti-infective therapy, response to treatment, comorbid illness, and complications.272,284 CAP secondary to S. pneumoniae generally can be treated for 7-10 days272 or 72 hours after the patient becomes afebrile.284 CAP caused by bacteria that can necrose pulmonary parenchyma generally should be treated for at least 2 weeks.284 Patients chronically treated with corticosteroids also may require at least 2 weeks of therapy.272 CAP caused by M. pneumoniae or C. pneumoniae probably should be treated for at least 10-14 days.272,284 CAP caused by Legionella in immunocompetent patients also probably should be treated for at least 10-14 days, although some clinicians recommend 21 days.272,284
Pathogens most frequently involved in outpatient CAP include S. pneumoniae , M. pneumoniae , C. pneumoniae , respiratory viruses, and H. influenzae (especially in cigarette smokers).272 Therefore, for empiric outpatient treatment of acute CAP in immunocompetent adults, the IDSA recommends monotherapy with an oral macrolide (azithromycin, clarithromycin, erythromycin), oral doxycycline, or an oral fluoroquinolone active against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin).284 Some experts prefer macrolides or doxycycline in patients younger than 50 years of age who have no comorbidities and fluoroquinolones for other individuals.284 The IDSA states that alternative empiric outpatient regimens include oral amoxicillin and clavulanate or certain oral cephalosporins (cefpodoxime, cefprozil, cefuroxime axetil).284
For outpatient treatment of CAP in immunocompetent adults without cardiopulmonary disease or other modifying factors that would increase the risk of multidrug-resistant S. pneumoniae or gram-negative bacteria, the American Thoracic Society (ATS) recommends an empiric regimen of monotherapy with azithromycin or clarithromycin or, alternatively, doxycycline.272 However, for the outpatient treatment of immunocompetent adults with cardiopulmonary disease (congestive heart failure or chronic obstructive pulmonary disease [ COPD]) and/or other modifying factors that increase the risk for multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends a 2-drug empiric regimen consisting of a β-lactam anti-infective (e.g. oral cefpodoxime, oral cefuroxime axetil, high-dose amoxicillin, amoxicillin and clavulanate, parenteral ceftriaxone followed by oral cefpodoxime) and a macrolide or doxycycline or, alternatively, monotherapy with a fluoroquinolone active against S. pneumoniae (e.g., ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin).272 The CDC suggests that use of these oral fluoroquinolones in the outpatient treatment of CAP be reserved for when other anti-infectives are ineffective or cannot be used or when highly penicillin-resistant S. pneumoniae (i.e., penicillin MICs 4 mcg/mL or greater) are identified as the cause of infection.285
In addition to S. pneumoniae , other pathogens often involved in inpatient CAP are H. influenzae , enteric gram-negative bacilli, S. aureus , Legionella , M. pneumoniae , C. pneumoniae , and viruses.272 Patients with severe CAP admitted into the ICU may have Ps. aeruginosa infections (especially those with underlying bronchiectasis or cystic fibrosis) and Enterobacteriaceae often are involved.272 In addition, anaerobic infection should be suspected in patients with aspiration pneumonia or lung abscess.284
Inpatient treatment of CAP is initiated with a parenteral regimen, although therapy may be changed to an oral regimen if the patient is improving clinically, is hemodynamically stable, and is able to ingest drugs.272,284 CAP patients usually have a clinical response within 3-5 days after initiation of therapy and failure to respond to the initial empiric regimen generally indicates an incorrect diagnosis, host failure, inappropriate anti-infective regimen (drug selection, dosage, route), unusual pathogen, adverse drug reaction, or complication (e.g., pulmonary superinfection, empyema).284
For empiric inpatient treatment of CAP in immunocompetent adults who require hospitalization in a non-ICU setting, the IDSA recommends a 2-drug regimen consisting of a parenteral β-lactam anti-infective (e.g., cefotaxime, ceftriaxone, ampicillin and sulbactam, piperacillin and tazobactam) and a macrolide (e.g., azithromycin, clarithromycin, erythromycin) or monotherapy with a fluoroquinolone active against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin).284 The IDSA does not recommend use of doxycycline for inpatient empiric regimens.284
For empiric inpatient treatment of CAP in immunocompetent adults who are hospitalized in a non-ICU setting and have cardiopulmonary disease (congestive heart failure or chronic obstructive pulmonary disease [ COPD]) and/or other modifying factors that increase the risk for multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends a 2-drug regimen consisting of a parenteral β-lactam anti-infective (cefotaxime, ceftriaxone, ampicillin and sulbactam, high-dose ampicillin) and an oral or IV macrolide (azithromycin or clarithromycin; doxycycline can be used in those with macrolide sensitivity or intolerance) or, alternatively, monotherapy with an IV fluoroquinolone active against S. pneumoniae .272 If anaerobes are documented or lung abscess is present, clindamycin or metronidazole should be added to the regimen.272 For CAP patients admitted to a non-ICU setting who do not have cardiopulmonary disease or other modifying factors, the ATS suggests an empiric regimen of monotherapy with IV azithromycin; for those with macrolide sensitivity or intolerance, a 2-drug regimen of doxycycline and a β-lactam or monotherapy with a fluoroquinolone active against S. pneumoniae can be used.272
For information on empiric regimens for the inpatient treatment of CAP in patients who require hospitalization in an ICU, see Inpatient Regimens for CAP under Respiratory Tract Infections: Community-Acquired Pneumonia, in Uses in the Erythromycin General Statement 8:12.12.04.
Tetracyclines (doxycycline, tetracycline hydrochloride) are used as alternative agents for the treatment of syphilis caused by Treponema pallidum .213,216,234 Parenteral penicillin G is the treatment of choice for all stages of syphilis.213,216 Although efficacy is not well documented, the CDC and others state that use of oral doxycycline or tetracycline hydrochloride can be considered to treat primary, secondary, latent, or tertiary syphilis (not neurosyphilis) in nonpregnant adults and adolescents hypersensitive to penicillin if compliance and follow-up serologic testing can be ensured.213,216 Although there is less clinical experience with doxycycline than tetracycline hydrochloride for the treatment of syphilis, compliance probably is better with doxycycline since it may be better tolerated.213 If compliance and follow-up with nonpenicillin regimens cannot be ensured, patients with primary, secondary, latent, or tertiary syphilis who are hypersensitive to penicillin should be desensitized, if necessary, and treated with penicillin.213
Patients with neurosyphilis who are hypersensitive to penicillin should be desensitized, if necessary, and treated with penicillin or, alternatively, treated in consultation with the CDC or other clinicians who have expertise in the treatment of neurosyphilis.213
Although the AAP states that doxycycline or tetracycline hydrochloride can be used to treat primary, secondary, or latent syphilis (not tertiary or neurosyphilis) in children 8 years of age or older with penicillin hypersensitivity,469 the CDC states that infants and children with syphilis who are hypersensitive to penicillin should be desensitized, if necessary, and treated with penicillin.213
Tetracyclines should not be used to treat syphilis in pregnant women hypersensitive to penicillin.213 There are no proven alternatives to penicillin for the treatment of syphilis during pregnancy, and pregnant women with a history of penicillin hypersensitivity should be desensitized, if indicated, and treated with penicillin.213
There is little information on use of penicillin alternatives for the treatment of syphilis in HIV-infected patients.213 The CDC states that HIV-infected patients with primary or secondary syphilis should be managed according to the recommendations for HIV-negative, penicillin-hypersensitive patients.213 However, if compliance and follow-up cannot be assured, HIV-infected individuals with latent syphilis who are hypersensitive to penicillin should be desensitized and treated with penicillin.213
For information on current recommendations regarding treatment and follow-up for all stages and forms of syphilis, see Spirochetal Infections: Syphilis, under Uses in the Natural Penicillins General Statement 8:12.16.04.
Doxycycline is considered a drug of choice in the treatment of early Lyme disease†.276,280,386,460,462,463,464,465,466,467,468,469,473,478,487,488
Lyme disease (Lyme borreliosis) is a spirochetal disease caused by Borrelia burgdorferi and currently is the most common tick-borne infection in the US,261,263,265,462,463,464,478 although the disease has a worldwide distribution.462,464 In the US, Lyme disease is transmitted by the bite of Ixodes scapularis (also called I. dammini ) and I. pacificus ticks.244,251,255,265,266,462,463,464,465,488 In addition to B. burgdorferi , I. scapularis may be simultaneously infected with and transmit Anaplasma phagocytophilum (causative agent of human granulocytotropic anaplasmosis [HGA, formerly known as human granulocytic ehrlichiosis]) and/or Babesia microti (causative agent of babesiosis).460 Because coinfection with A. phagocytophilum and/or B. microti can occur in patients with Lyme disease in geographic areas where these other pathogens are endemic, these diseases should be considered in the differential diagnosis of patients being evaluated for Lyme disease.460 Concurrent infection with A. phagocytophilum and B. burgdorferi has been reported, and diagnosing such a mixed infection is critical to ensure appropriate anti-infective therapy.500 In areas where both Lyme disease and HGA are reported, discerning between the diseases in the early stages of illness may be difficult.500 Although doxycycline may be effective for the treatment of HGA (see Uses: Ehrlichiosis and Anaplasmosis), other anti-infectives used in the treatment of Lyme disease are ineffective for the treatment of HGA and babesiosis.460 Therefore, diagnosing such coinfections is critical to ensure that appropriate anti-infectives are used for treatment.460
Lyme disease generally occurs in 3 stages that typically occur in sequence, with different clinical manifestations at each stage.268,462,469,488 However, the disease, like syphilis, can have a variable presentation, and in individual patients the 3 stages can occur alone or may overlap.268,462,488 The 3 stages of Lyme disease usually are early localized, early disseminated, and late disease).268,462,469
Early localized (stage 1) Lyme disease, which may appear days to weeks after transfer of the spirochete to the human host, usually is manifested by a characteristic skin lesion, erythema migrans (erythema chronicum migrans).463,465,469,487,488 Current data suggest that erythema migrans develops in at least 80-90% of patients470,488 and typically begins as an erythematous macule or papule at the site of the tick bite that expands circularly to form a large (e.g., up to 70 cm in diameter) annular lesion, sometimes with partial central clearing.244,245,248,263,268,288,462,463,464,469,478,478 Some patients with Lyme disease develop secondary multiple skin lesions, which may resemble the primary lesion somewhat but generally are smaller and migrate less.263,266,269,288,462,463,469 Erythema migrans often is accompanied by fever, flu-like constitutional symptoms (e.g., chills, malaise, fatigue, headache), or regional lymphadenopathy.244,245,248,268,464,465,469,488
Early disseminated (stage 2) infection, which may be manifested days to months after the initial infection, is associated with hematogenous and lymphatic dissemination of the infection and characteristic symptoms in various organ systems, principally the skin, nervous system, musculoskeletal system, and/or heart.263,268,270,462,463,469,488 Severe headache and neck stiffness, generally transient, and meningitis with cranial (e.g., facial nerve [Bell's] palsy) or peripheral (e.g., radiculoneuropathy of the limbs or trunk) neuropathy are nervous system manifestations that can occur in the early stages of the disease.268,270,288,462,463,464,465 Optic nerve involvement, which may occur as a result of inflammation or increased intracranial pressure, has been reported principally in children and may lead to blindness.259,488 Manifestations of acute neuroborreliosis may develop in about 15% of untreated patients within weeks after the period of early disseminated infection.487,488 Acute neurologic abnormalities typically resolve or improve within weeks or months even in untreated patients, although a small percentage (5%) of untreated patients may exhibit chronic neurologic manifestations.488 Symptoms of musculoskeletal involvement, which generally are variable and intermittent and occur in about 60% of untreated patients in the US, may include migratory pain in the joints, bursae, tendons, muscle, and bone and, rarely, a deep myositis; brief episodes of arthritis, principally involving one or only a few large joints (particularly the knee), also may occur during the early stages of the disease.268,462,463,469,488 Cardiac involvement appears to occur in approximately 4-10% of untreated patients with Lyme disease, usually within 1-3 months after infection.462,463,465,466,488 The most frequently occurring cardiac abnormality is AV block of varying degrees (first-degree, Wenckebach, or complete heart block), which is usually of short duration but potentially may require temporary insertion of a pacemaker.268,460,462,463,464,466,469,488
Late Lyme disease (stage 3), which occurs months to years following the tick bite, generally is manifested by intermittent episodes of arthritis, which may become chronic (defined as continuous joint inflammation for 1 year or longer) but eventually resolves even in untreated patients (i.e., the number of patients with recurrent episodes of arthritis decreases by approximately 10-20% each year).462,463,464,467,469 Some evidence suggests that chronic arthritis, which occurs in a small percentage of patients despite recommended anti-infective treatment for Lyme disease, may be related to certain immunogenetic or immune factors (e.g., presence of HLA-DR4 haplotype).462,464,467,473,488 Other manifestations of late Lyme disease include subtle central or peripheral neurologic abnormalities such as mild subacute encephalopathy (e.g., characterized by memory loss, behavioral changes, somnolence) and/or polyneuropathy (e.g., characterized by intermittent paresthesias, radicular pain).268,462,463,469,488 Resolution of late neurologic manifestations of Lyme disease may occur very slowly and, in some patients, may be incomplete.462,463,468,488 Acrodermatitis chronica atrophicans, a chronic skin lesion characterized by inflammation and subsequent atrophy, is a late manifestation of Lyme disease that has been reported in Europe464,474 but only rarely in the United States.462,464,488
Diagnosis of Lyme disease is based principally on clinical findings, and treating patients with early disease solely on the basis of objective signs and a known exposure often is appropriate.424,460,469,488 The IDSA states that clinical findings are sufficient for the diagnosis of erythema migrans, but clinical findings alone are not sufficient for diagnosis of extracutaneous manifestations of Lyme disease or for diagnosis of HGA or babesiosis.460 Individuals with known endemic exposure to B. burgdorferi and physician-diagnosed erythema migrans can receive treatment for Lyme disease without serologic testing;434,436,448,450,460,465,469,478,488 however, erythema migrans should be clinically differentiated from similar rashes that are not caused by B. burgdorferi infection.424,448 In areas of low or no endemic risk, the likelihood of Lyme disease in a patient with a rash resembling erythema migrans is low.430,460 Serologic testing can provide valuable supportive diagnostic information in patients with endemic exposure and objective clinical findings that indicate later stage disseminated Lyme disease.424,465,469,488 Negative test results are useful in ruling out Lyme disease in patients with clinical findings compatible with disseminated or late-stage infection.429,430,469 Since the proportion of false-positive test results increases when the pretest probability of Lyme disease is low, the use of testing to make a diagnosis of Lyme disease in individuals without endemic exposure is not recommended.424,430,449,450,469
When serologic testing is indicated to aid in diagnosis, the CDC, Association of State, Territorial, and Public Health Laboratory Directors (ASTPHLD), and other clinicians recommend initial testing with a sensitive screening test, either an enzyme-linked immunosorbent assay (ELISA) or an indirect fluorescent antibody (IFA) test, followed by testing with the more specific Western blot (immunoblot) test to corroborate equivocal or positive results obtained with the initial test.424,425,426,430,433,449,450,465,469,488 Although anti-infective treatment in early localized disease may blunt or abrogate the antibody response, patients with early disseminated or late-stage disease usually have strong serologic reactivity and demonstrate expanded IgG Western blot banding patterns to diagnostic B. burgdorferi antigens.424,425,426,430,431,432,434,448,478,488 Antibodies often persist for months or years following successfully treated or untreated infection.424,428,431,432,465 Therefore, seroreactivity alone cannot be used as a marker of active disease.424,428,465,488 Repeated infection with B. burgdorferi has been reported,424,426,427,428,452 and neither a positive serologic test result and/or a history of prior Lyme disease ensures that an individual has protective immunity.424,452
The CDC, IDSA, and National Institute of Allergy and Infectious Diseases (NIAID) state that clinicians should be familiar with current recommendations for diagnosis and treatment of Lyme disease and should be alert for and know how to minimize potential complications associated with therapy for the disease.410,411,414,460
Postexposure Prophylaxis after Tick Bite
There is some evidence from a controlled study in adults that a single dose of oral doxycycline may be effective in preventing Lyme disease when given within 72 hours after a documented I. scapularis tick bite.458 Some clinicians suggest that this single-dose antibiotic regimen may be useful for individuals in Lyme-disease endemic areas who are bitten by an I. scapularis tick (particularly a nymphal tick) that is at least partially engorged with blood.475,488 However, the accurate and timely identification of tick species or stage of development and infection status of the tick as well as assessment of the degree of tick engorgement are often difficult,460,475 and postexposure antibiotic prophylaxis appears unlikely to have a substantial effect on disease incidence since most ticks that are recognized are removed within 48 hours (i.e., usually before transmission of infection).475,461 In addition, I. scapularis ticks may transmit other infections such as babesiosis ( B. microti ) for which doxycycline may not be appropriate therapy.460
The CDC, IDSA, AAP, and other clinicians currently do not recommend routine anti-infective prophylaxis or serologic testing for individuals after a tick bite.424,460,469,478 However, the IDSA states that postexposure prophylaxis with a single oral dose of doxycycline (200 mg in adults or 4 mg/kg in children 8 years of age or older) can be offered to individuals in Lyme disease-endemic areas who are bitten by an I. scapularis tick when all of the following circumstances exist: the attached tick can be reliably identified as an adult or nymphal I. scapularis tick, the estimated duration of tick attachment has been at least 36 hours based on the degree of engorgement of the tick or certainty about the time of exposure to the tick, the doxycycline dose can be given within 72 hours of tick removal, the local rate of infection of I. scapularis with B. burgdorferi is 20% or greater, and doxycycline is not contraindicated.460 Prophylaxis after I. pacificus bites generally is not necessary since rates of infection with B. burgdorferi in these ticks is low.460
The best currently available method for preventing B. burgdorferi infection and other Ixodes -transmitted infections is avoidance of tick exposure; if exposure is unavoidable, the risk of infection can be reduced through use of protective clothing and tick repellents, daily checking of the entire body for ticks, and prompt removal of attached ticks before transmission of B. burgdorferi infection.460 Individuals from whom attached ticks are removed should be closely monitored for 30 days; those who develop a skin lesion at the site of the tick bite, a temperature exceeding 38°C, or other illness within 1 month after removal of an attached tick should receive a prompt assessment for tick-borne diseases, including Lyme disease, HGA,395,396,469,500,503,504 or babesiosis.460 Current evidence suggests that the infected tick usually must be attached for at least 24-48 hours to transmit B. burgdorferi .462,463,464,478,488 Patients who have received Lyme disease vaccine (no longer commercially available in the US) have a reduced risk of developing the disease but should be assessed in a similar manner as those who have not been vaccinated against the disease.460,488
In a double-blind, placebo-controlled study, individuals 12-82 years of age who resided in a hyperendemic area and who had within the previous 72 hours removed an attached tick that was entomologist-verified as I. scapularis were randomized to receive a single oral dose of doxycycline 200 mg or placebo.458 At baseline and at 3 and 6 weeks, these individuals were examined for manifestations of B. burgdorferi infection, including erythema migrans; serum antibody levels and blood cultures also were obtained at these time points.458 Erythema migrans at the site of the tick bite (the primary end point) occurred in 1 of 235 individuals (0.4%) who had received doxycycline versus 8 of 247 individuals (3.2%) who received placebo, representing 87% efficacy for this prophylactic regimen.458 However, extrapolation of the findings of this study to other clinical settings should take into account that this efficacy rate is based on a relatively small number of individuals who developed Lyme disease and that identification of I. scapularis ticks by patients and/or clinicians may not be presumed to be as accurate as that by the medical entomologists in this study.458
Treatment of Early Localized or Disseminated Lyme Disease
Anti-infective therapy usually is effective in all stages of Lyme disease, and appropriate treatment of early disease shortens the duration of symptoms and generally prevents the development of late sequelae.424,460,469,478,487 The IDSA, AAP, and other clinicians currently recommend oral doxycycline, oral amoxicillin, or oral cefuroxime axetil as first-line therapy for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree atrioventricular (AV) heart block.460,469,478,487,488 Although the optimal duration of therapy has not been established, most clinicians treat early Lyme disease for 14-21 days.460,469,478,487,488 The IDSA states that a 14-day regimen (range 14-21 days) of any of these oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) may be used for initial treatment of early Lyme disease since all 3 drugs have been shown to be effective for the treatment of erythema migrans and associated symptoms in prospective clinical studies.460 Oral doxycycline, amoxicillin, or cefuroxime axetil usually are preferred to other drugs such as oral tetracycline hydrochloride, oral penicillin G, or oral penicillin V, particularly in patients with early disseminated infection, because of improved microbiologic activity, better GI absorption and tolerance, and/or higher CSF drug concentrations.261,271,280,288,462,463 Macrolide antibiotics (e.g., erythromycin, azithromycin, clarithromycin) also have been used for the treatment of early Lyme disease, 460,462,465,487,488 although limited evidence suggests that erythromycin or azithromycin may not be as effective as other recommended agents.460,462,465,487,488 (See Lyme Disease in Uses: Spirochetal Infections, in the Erythromycins General Statement 8:12.12.04.) The IDSA and other clinicians state that macrolide antibiotics are not recommended as first-line therapy for early Lyme disease; these agents should be reserved for patients who are intolerant of amoxicillin, doxycycline, and cefuroxime axetil,460,469,478 and patients treated with macrolides should be monitored closely.460
Most patients with erythema migrans who received oral doxycycline, amoxicillin, or cefuroxime axetil in multicenter studies had satisfactory outcomes; although subjective symptoms persisted in some patients after treatment, objective evidence of persistent infection or relapse was rare and retreatment usually was unnecessary.211,291,488 In a randomized, controlled study, doxycycline 100 mg twice daily or amoxicillin 500 mg 3 times daily (plus probenecid 500 mg 3 times daily) for 21 days showed similar efficacy in preventing late complications (e.g., meningitis, myocarditis, arthritis) in patients with early Lyme disease (erythema migrans); mild fatigue or arthralgia occurred infrequently following antibiotic therapy but resolved in all cases within the 6-month follow-up period.291 In a multicenter study, oral therapy with doxycycline 100 mg 3 times daily or cefuroxime 500 mg twice daily for 20 days resulted in cure or improvement in about 90% of patients, and even those considered to have failed therapy did not show objective evidence of continuing infection.211,460 Although effective, ceftriaxone is not superior to recommended oral drugs for the treatment of early Lyme disease and is not a recommended first-line agent in the absence of neurologic manifestations or third-degree atrioventricular block.460
While doxycycline has the advantage of also being effective for the treatment of HGA (see Uses: Ehrlichiosis and Anaplasmosis), which may occur concurrently in patients with early Lyme disease,386,395,396,460,469,487,488,500,503,504 tetracyclines are not usually recommended for pregnant or lactating women or for children younger than 8 years of age.405,408,460,478,487,488 However, the CDC, IDSA, and AAP state that the use of tetracyclines (e.g., doxycycline) may be warranted in pregnant women with presumed or confirmed Rickettsial infections (including RMSF) or ehrlichiosis (including HGA and HME) or other life-threatening illness.222,500 Transplacental transmission of B. burgdorferi appears to occur rarely, if at all,488 and epidemiologic studies in pregnant women have not documented an association between exposure to Lyme disease prior to conception or during pregnancy and subsequent fetal death, congenital malformations, or prematurity.462,470 The IDSA, AAP, and other clinicians state that pregnant or nursing women need not be treated differently than other patients with Lyme disease, except that they should not receive tetracyclines (unless coinfection with A. phagocytophilum is suspected).462,469,460,488,469
Limited evidence in patients with early disseminated Lyme disease (e.g., multiple erythema migrans lesions and/or objective evidence of organ involvement [e.g., arthritis, heart block, facial nerve palsy]) who did not have meningitis suggests that oral doxycycline is a cost-effective alternative to ceftriaxone for preventing late manifestations of the disease.405,406,407 In a randomized, comparative study, clinical cure (resolution of objective clinical findings of Lyme disease) was reported in 88 or 85% of patients receiving oral doxycycline (100 mg twice daily for 21 days) or ceftriaxone (2 g IV or IM daily for 14 days), respectively, and both regimens were well tolerated.406 Although further study is needed to determine the relative safety and efficacy of oral versus IV antibiotic therapy in the treatment of Lyme disease, oral therapy is easier to administer than IV therapy, is associated with fewer serious complications, and is more economical.412,413,414,460 Patients with facial nerve palsy alone or uncomplicated Lyme arthritis usually respond adequately to prolonged therapy (e.g., 28 days) with oral anti-infectives (e.g., oral doxycycline, oral amoxicillin, oral cefuroxime axetil).460,478 However, more severe or late complications of Lyme disease generally require higher dosages and more prolonged therapy and/or parenteral anti-infectives (e.g., ceftriaxone or alternatively, cefotaxime or IV penicillin G for 14-28 days).255,460,261,462,463,465,466,467,468,469,471,472,478,487,488 (See Lyme Disease in Uses: Spirochetal Infections, in the Natural Penicillins General Statement 8:12.16.04 and see Lyme Disease in Uses: Spirochetal Infections, in Ceftriaxone 8:12.06.12.)
Treatment of Late or Persistent Manifestations of Lyme Disease
- Neurologic Manifestations. Patients with early Lyme disease who have acute neurologic involvement manifested by facial nerve palsy alone should receive antibiotic therapy to prevent further sequelae; antibiotic therapy has not been shown to accelerate resolution of palsy.460,469,488 Neurologic examination, including lumbar puncture, should be performed in patients in whom neurologic disease is strongly suspected on clinical grounds.460The IDSA states that patients with negative CSF examinations may be treated with the same antibiotic regimens recommended for patients with erythema migrans (i.e., oral doxycycline, oral amoxicillin, or oral cefuroxime axetil);460 those with clinical and laboratory evidence of CNS involvement should be treated with regimens effective against meningitis.460,478,488 The IDSA states that while evidence from studies in Europe suggests that IV penicillin G and ceftriaxone or cefotaxime have similar efficacy in treating acute neurologic manifestations of Lyme disease,212,217,460 ceftriaxone often is used because its once-daily administration schedule allows outpatient management of therapy.460For adults with acute neurologic disease manifested by meningitis or radiculopathy, the IDSA and other clinicians recommend ceftriaxone for 14-28 days; alternatively, IV penicillin G or cefotaxime may be used.460,478,487,488 Some clinicians suggest that oral or IV doxycycline for 14-28 days may be adequate therapy in adults with acute neurologic manifestations who are intolerant of cephalosporins and penicillin, although experience in the US with such a regimen for Lyme meningitis is limited.280,281,460 Children younger than 8 years of age with acute neurologic manifestations of meningitis or radiculopathy should receive ceftriaxone460,469,478,488 or cefotaxime for 14-28 days;460,478,488 IV penicillin G may be used as an alternative in such children.460,469,478,488
- Cardiac Manifestations. Cardiac involvement in Lyme disease usually manifests as atrioventricular (AV) heart block and generally occurs during the first few weeks of infection in conjunction with erythema migrans.460 The IDSA states that patients with first- or second-degree AV heart block associated with early Lyme disease should be treated with the same antibiotic regimens (i.e., oral doxycycline, amoxicillin, or cefuroxime axetil) as patients with erythema migrans who do not have carditis.460,469,478,488 However, some clinicians recommend use of IV regimens (e.g., ceftriaxone, cefotaxime, or penicillin G) in patients with first-degree AV block and a PR-interval exceeding 0.3 seconds.478,488 The IDSA and other clinicians recommend that patients with third-degree AV heart block be hospitalized for cardiac monitoring because of the potential for life-threatening complications.460 While evidence supporting the superiority of IV versus oral therapy currently is unavailable,460 most clinicians recommend that patients with severe cardiac involvement receive ceftriaxone, penicillin G, or cefotaxime IV for 14-28 days.460,469,478,488 Patients with third-degree AV block may require a temporary pacemaker.460,478,488
- Lyme Arthritis. Patients with uncomplicated Lyme arthritis generally can be treated with a prolonged course (e.g., 28 days) of oral anti-infectives (i.e., doxycycline, amoxicillin, or cefuroxime axetil).460,462,464,468,469,478,487,488 While oral regimens are easier to administer, associated with fewer serious adverse effects, and less expensive than IV regimens, some patients with Lyme arthritis treated with oral regimens have subsequently developed overt neuroborreliosis, which may require IV therapy for successful treatment.460,488 When Lyme arthritis is accompanied by neurologic disease documented by CSF analysis, the IDSA and other clinicians recommend that adults receive ceftriaxone for 14-28 days; alternative therapy is cefotaxime or IV penicillin G.460,469,478,488 Ceftriaxone or cefotaxime is recommended in children with coexisting Lyme arthritis and neurologic manifestations; alternatively, IV penicillin G may be given.460 Long-acting penicillin G benzathine preparations are not recommended for treatment of these patients because of the low serum penicillin G concentrations attained after administration of such preparations.460
- Treatment of Late or Persistent Manifestations of Lyme Disease. Late manifestations of Lyme disease may include oligoarticular arthritis, encephalopathy (principally memory deficit, irritability, and somnolence), and neuropathy (principally distal paresthesias or radicular pain).460 Comparative studies evaluating different antibiotic regimens in patients with late Lyme disease generally are lacking.478 Response to therapy for late manifestations of Lyme disease may be slow and improvement may take weeks or months, although most appropriately treated patients eventually recover.408,460,488
- Persistent Arthritis. In patients who have persistent or recurrent joint swelling after receiving recommended antibiotic regimens, the IDSA and other clinicians recommend another 28-day course of a recommended oral antibiotic or 14-28 days of ceftriaxone, cefotaxime, or IV penicillin G.408,460,462,467,478,488 However, the IDSA states that clinicians should consider allowing several months for joint inflammation to resolve after initial treatment before an additional course of antibiotic therapy is given.460 Many clinicians also suggest that the initial diagnosis of Lyme disease be reevaluated in patients who appear not to respond to recommended anti-infective therapy (e.g., 21-28 days of oral and/or IV antibiotics).462,465,472 Patients with persistent arthritis who have received 2 courses of recommended oral antibiotic therapy or a single course of IV antibiotics should receive symptomatic treatment with a nonsteroidal anti-inflammatory agent (NSAIA); treatment with intra-articular corticosteroids also may be considered.408,460,462,467,471,473,488 Arthroscopic synovectomy may be indicated and may decrease time to recovery in patients with persistent synovitis who report substantial pain or limited function.408,460,467,473,478,488
- Late Neuroborreliosis Affecting the CNS or Peripheral Nervous System. Patients with late neurologic disease affecting the CNS or peripheral nervous system (e.g., encephalopathy, neuropathy) should receive 14-28 days of ceftriaxone; alternative therapy is cefotaxime or IV penicillin G.460 Clinical response to these regimens is typically gradual and may be incomplete.460,478,488 However, additional courses of antibiotic therapy are not recommended unless reliable objective measures substantiate relapse of neurologic disease.460 For children with late CNS or peripheral nervous system manifestations, ceftriaxone for 14-28 days is recommended; alternatively, cefotaxime or IV penicillin G may be given.460,469
Chronic Lyme Disease or Post-Lyme Disease Syndrome
After receiving recommended antibiotic therapy for Lyme disease, some patients manifest a post-infectious syndrome, which some clinicians have referred to as chronic Lyme disease or post- Lyme disease syndrome.459,460,488 Some evidence suggests that this syndrome occurs more frequently in patients who have symptoms of early dissemination of the infection, particularly if there is a delay in treatment.488 Patients with this syndrome are a diverse group and report various persistent subjective complaints including arthralgia, fatigue, and/or myalgia;459,460,488 some clinicians categorize such symptoms as chronic Lyme disease or a post- Lyme disease syndrome similar to chronic fatigue syndrome or fibromyalgia.459,460,488 Patients with residual B. burgdorferi infection (or possibly reinfection) have been reported rarely in Europe; however, residual infection has not been reliably documented to date in a large series of patients in Europe or North America who received appropriate treatment for Lyme disease.460 The IDSA states that currently available evidence is insufficient to consider chronic Lyme disease a separate diagnostic entity.460
Although case reports and uncontrolled studies have reported benefit from prolonged antibiotic therapy in patients with chronic Lyme disease, symptom recurrence after discontinuance of therapy is common; in addition, the prevalence of fatigue and/or arthralgias in the general population reportedly is greater than 10%.209,210,460,488 In a small percentage of patients appropriately treated for Lyme disease, persistent symptoms may be explained by coinfection with A. phagocytophilum or B. microti .395,396,460,469,500,503,504 Although studies of treatment of patients with Lyme disease who remain unwell after standard courses of antibiotic therapy currently are in progress,460 the IDSA states that no controlled clinical studies currently support the efficacy of repeated or prolonged courses of oral and/or IV antibiotics in such patients.412,413,414,459,460,488,489 In addition, serious complications (e.g., biliary disease leading to cholecystectomy), including at least one death, have been reported in patients receiving such empiric therapy.412,413,414,459,460,488,489 (See Lyme Disease in Uses: Spirochetal Infections, in Ceftriaxone 8:12.06.12.) The American College of Rheumatology and IDSA state that the risks and costs of treating suspected Lyme disease empirically with IV antibiotics (e.g., ceftriaxone) exceed the benefits in patients with a positive antibody titer for B. burgdorferi and only nonspecific complaints of myalgia or fatigue;415,422 such patients are best managed symptomatically rather than with prolonged courses of antibiotics.488
Two double-blind, placebo-controlled studies evaluating prolonged antibiotic therapy (IV ceftriaxone followed by oral doxycycline for a total of 90 days) in patients with persistent symptoms of Lyme disease after appropriate initial therapy were discontinued after interim analysis revealed no difference in clinical benefit between prolonged antibiotic therapy and placebo.459,488 In these 2 studies, patients were randomized to receive IV ceftriaxone 2 g daily for 30 days followed by oral doxycycline 100 mg twice daily for 60 days, or matching IV and oral placebos.459 Patients were enrolled in the 2 studies based on their seropositivity or seronegativity for antibodies to B. burgdorferi antigen on Western blot assay.459 All patients included in the studies had one or more of the following diagnoses: a history of single or multiple erythema migrans skin lesions, early neurologic or cardiac symptoms attributed to Lyme disease, radiculoneuropathy, or Lyme arthritis; seronegative patients were required to have a documented history of erythema migrans by an experienced clinician.459 These patients were experiencing profound fatigue, widespread musculoskeletal pain, cognitive impairment, radicular pain, paresthesias, and/or dysesthesias that had begun within 6 months of the initial documented diagnosis of US-acquired acute Lyme disease and had persisted for at least 6 months but less than 12 years.459
Most patients in these studies previously had received oral antibiotic therapy for a median of 50 days; 33% had received IV antibiotic therapy for an average of 30 days.459 Baseline evaluation included a complete review of patient medical history, physical examination, neuropsychologic testing, CSF analysis, and phlebotomy; cultures and molecular analysis by polymerase chain reaction (PCR) of blood and CSF at baseline or during the studies did not detect any evidence of persistent infection by B. burgdorferi in these patients.459 A planned interim analysis of data from the combined studies at 180 days did not reveal a significant difference in the efficacy of prolonged antibiotic therapy compared with that of placebo based on summary scores for the mental and physical components of a health-related quality of life survey instrument (Medical Outcomes Study 36-item Short-Form General Health Survey); separate analysis of data from the seropositive and the seronegative studies also failed to show any benefit of the prolonged antibiotic regimen compared to placebo.459
In an observational study of patients diagnosed as having chronic Lyme disease (i.e., manifesting symptoms for greater than 3 months from at least 2 out of the following 3 groups of symptoms: fatigue, neurologic complaints [e.g., paresthesias, cognitive dysfunction, radicular pain], musculoskeletal complaints [e.g., arthralgias, myalgias, weakness]), 70% of patients reported improvement and 20% reported resolution of symptoms following long-term therapy (generally 3-6 months) with tetracycline hydrochloride (500 mg 3 times daily).423 In this study, patients with a longer duration of Lyme disease symptoms prior to receiving tetracycline therapy had a slower onset of improvement following initiation of therapy.423 Additional study is needed to establish the value of prolonged (e.g., 3-6 months) anti-infective therapy in patients with persistent manifestations of Lyme disease.423,460
Tetracyclines are used in the treatment of leptospirosis† caused by Leptospira .239,306,386 Some clinicians state that penicillin G is the drug of choice for treatment of leptospirosis and tetracyclines and ceftriaxone are alternatives.386 The CDC recommends that leptospirosis be treated with penicillin, amoxicillin, ampicillin, or doxycycline;239,306 IV penicillin G or ampicillin is indicated in patients with severe disease.306
Doxycycline has been recommended for chemoprophylaxis in individuals exposed to Leptospira †.239 Travelers participating in recreational water activities (e.g., whitewater rafting, adventure racing, or kayaking) in areas where leptospirosis is endemic or epidemic may be at increased risk for the disease, especially during periods of flooding.239 Individuals considered at an increased risk for leptospirosis should practice personal preventive measures including wearing protective clothing and minimizing contact with potentially contaminated water.239 Based on limited data, the CDC recommends that travelers at increased risk for leptospirosis be advised to consider doxycycline chemoprophylaxis initiated 1-2 days before exposure and continued through the period of exposure.239 Travelers who may be at increased risk for leptospirosis and who are also in need of malaria chemoprophylaxis may consider using doxycycline for both indications.239 (See Prevention of Malaria under Malaria, in Uses.)
Tetracyclines are considered the drugs of choice for the treatment of tick-borne (endemic) or louse-borne (epidemic) relapsing fever caused by Borrelia .386 The drugs also appear to be effective in the treatment of yaws, pinta, and bejel and are used as alternatives to penicillin G for the treatment of these diseases.386
Helicobacter pylori Infection and Duodenal Ulcer Disease
Tetracycline hydrochloride is used in combination with metronidazole, bismuth subsalicylate, and an H2-receptor antagonist for the treatment of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ) infection in patients with an active duodenal ulcer.386,400 Tetracycline hydrochloride also has been used successfully in other multiple-drug regimens (with or without bismuth salts, metronidazole, and/or an H2-receptor antagonist) for the treatment of H. pylori infection† in patients with peptic ulcer disease.330,333,334,335,336,337,338,339,340,341,342,343,344,345,346,348,373,374,376,378,379,385,435,437,438,439,440,441,442,443,477,479,481,482,483,484,485,486 Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers;330,333,336,339,349,350,351,352,353,354,435,374,376,378,387,438,479,482 long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.333,352,355,356,357,358,359,360,361,362,363,435,479,482 For additional information on the association of this infection with these and other GI conditions, see Helicobacter pylori Infection, under Uses, in Clarithromycin 8:12.12.92.
Conventional antiulcer therapy with H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori , and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year).330,339,354,374,376,479,482 Several useful therapeutic regimens for H. pylori -associated peptic ulcer disease have been identified,330,333,334,337,340,341,342,343,344,345,346,375,376,377,378,380,381,382,383,384,435,437,440 and the American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.374,376,378,445,479
The optimum regimen for treatment of H. pylori infection has not been established; however, combined therapy with 3 drugs that have activity against H. pylori (generally a bismuth salt, metronidazole, and tetracycline or amoxicillin) has been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori -associated peptic ulcer disease.330,333,334,336,337,338,348,353,364,365,366,374,376,378,379,381,387,388,400,435,438,439,479,482,486 Although such 3-drug regimens typically have been administered for 10-14 days, current evidence principally from studies in Europe suggests that 1 week of such therapy provides H. pylori eradication rates comparable to those of longer treatment periods.376,378,479 Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, H2-receptor antagonist) also have been used successfully for H. pylori eradication,330,333,334,342,343,344,345,346,366,367,374,376,378,385,435,440,441,442,443,444,446,447,477,479,482,483 and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.376,388,445,479,480,482 Current data suggest that eradication of H. pylori infection using regimens consisting of 1 or 2 anti-infective agents with a bismuth salt and/or an H2-receptor antagonist or proton-pump inhibitor (e.g., omeprazole, lansoprazole) is cost effective compared with intermittent or continuous maintenance therapy with an H2-receptor antagonist (considering the costs associated with ulcer recurrence, including endoscopic or other diagnostic procedures, physician visits, and/or hospitalization).389,390,402,403
Although high eradication rates have been achieved with standard 3-drug, bismuth-based regimens (e.g., bismuth-metronidazole-tetracycline or bismuth-metronidazole-amoxicillin), such regimens typically involve administration of many tablets/capsules and have been associated with a relatively high (although variable) incidence of adverse effects.376,378,379,479 In addition, the efficacy of these regimens generally is unacceptable in patients with H. pylori strains resistant to the imidazole anti-infective (e.g., metronidazole) component.376,378,379,400,479 Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti- H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.376,479 Therefore, the ACG and many clinicians379,385,479 currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.479,385,482 Although few comparative studies have been performed, such regimens appear to provide high (e.g., 85-90%) H. pylori eradication rates, are well tolerated, and may be associated with better patient compliance than more prolonged therapy.385,390,479 The ACG states that in a cost-sensitive environment, an alternative regimen consisting of a bismuth salt, metronidazole, and tetracycline for 14 days is a reasonable choice in patients who are compliant and in whom there is a low expectation of metronidazole resistance (no prior exposure to the drug and a low regional prevalence of resistance).479
Rapid development of resistance by H. pylori to certain drugs (e.g., metronidazole, clarithromycin and other macrolides, quinolones) has occurred when these drugs were used as monotherapy or as the only anti-infective agent in anti- H. pylori regimens.334,336,372,374,404,435,476 Resistance commonly emerges during therapy with clarithromycin or metronidazole when eradication of H. pylori is not achieved; therefore, prior exposure to these anti-infectives predicts resistance in individual patients and should be considered when selecting anti- H. pylori treatment regimens.374,400,476,479 Regimens containing metronidazole or clarithromycin should not be used to treat H. pylori infection in patients with known or suspected metronidazole- or clarithromycin-resistant isolates because of reduced efficacy in such patients.400,476,479
For additional discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, see Helicobacter pylori Infection, under Uses, in Clarithromycin 8:12.12.92.
Tetracyclines (doxycycline, tetracycline hydrochloride) usually are considered the drugs of choice when anti-infective therapy is indicated as an adjunct to fluid and electrolyte replacement in patients with cholera caused by Vibrio cholerae .203,331,332,386,469,509 Although some clinicians recommend use of co-trimoxazole for the treatment of cholera in children younger than 8 years of age, the AAP states that in cases of severe cholera, the benefits of tetracyclines may outweigh the risks in this age group.469 Tetracycline therapy reduces the duration of excretion of Vibrio cholerae and, since it decreases the volume and duration of diarrhea, may decrease requirements for fluid replacement.469 Adjunctive anti-infective therapy should be considered in patients with moderately to severe disease.469 When the infection is caused by strains of V. cholerae resistant to tetracyclines, alternative agents include co-trimoxazole, fluoroquinolones, or furazolidone.386,469
Vibrio parahaemolyticus Infections
Tetracyclines (doxycycline, tetracycline hydrochloride) are one of several alternatives recommended for the treatment of severe cases of Vibrio parahaemolyticus † infection when anti-infective therapy is indicated in addition to supportive care.203,331 V. parahaemolyticus infection is a relatively rare foodborne illness than can occur as the result of ingestion of contaminated, undercooked or raw fish or shellfish; the incubation period usually is 2-48 hours.331 The signs and symptoms of V. parahaemolyticus infection are watery diarrhea, abdominal cramps, and nausea and vomiting lasting 2-5 days.331 Although supportive care usually is sufficient, some clinicians recommend use of tetracycline, doxycycline, gentamicin, or cefotaxime in severe cases.331
Although optimum anti-infective therapy has not been identified, a tetracycline or third generation cephalosporin (e.g., cefotaxime, ceftazidime) is recommended for the treatment of infections caused by Vibrio vulnificus †.203,331,386 V. vulnificus , a gram-negative aerobic bacteria that can cause potentially fatal septicemia, wound infections, or gastroenteritis, generally is transmitted through ingestion of contaminated raw or undercooked seafood (especially raw oysters) or through contamination of a wound with seawater or seafood drippings.203,206,235,331 V. vulnificus is naturally present in marine environments, thrives in warm ocean water, and frequently is isolated from oysters and other shellfish harvested from the Gulf of Mexico and from US coastal waters along the Pacific and Atlantic ocean.203,235 Individuals with preexisting liver disease are at high risk for developing fatal septicemia following ingestion of seafood contaminated with V. vulnificus and debilitated or immunocompromised individuals (e.g., those with chronic renal impairment, cancer, diabetes mellitus, steroid-dependent asthma, chronic GI disease) or individuals with iron overload states (e.g., thalassemia and hemochromatosis) also are at increased risk for fatal infections.203,206,331 In immunocompromised individuals, fever, nausea, myalgia, and abdominal cramps may occur as soon as 24-48 hours after ingestion of seafood contaminated with V. vulnificus and sepsis and cutaneous bullae may be present within 36 hours of the onset of symptoms.203
Because the case fatality rate for V. vulnificus septicemia exceeds 50% in immunocompromised individuals or those with preexisting liver disease, these individuals should be informed about the health hazards of ingesting raw or undercooked seafood (especially oysters), the need to avoid contact with seawater during the warm months, and the importance of using protective clothing (e.g., gloves) when handling shellfish.203,206 V. vulnificus should be considered in the differential diagnosis of fever of unknown etiology, and individuals who present with fever (especially when bullae, cellulitis, or wound infection is present) and who have preexisting liver disease or are immunocompromised should be questioned regarding a history of raw oyster ingestion or seawater contact.203 Because the high fatality rate associated with V. vulnificus infections, anti-infective therapy should be initiated promptly if indicated.203,206
Tetracyclines (usually doxycycline) are suggested as possible choices for the treatment of GI infections caused by Yersinia enterocolitica or Y. pseudotuberculosis .331,332 (For information on treatment of Y. pestis infections, see Plague under Uses: Gram-Negative Bacterial Infections.)
Y. enterocolitica and Y. pseudotuberculosis GI infections usually are self-limited and anti-infective therapy unnecessary; however, the AAP, IDSA, and others recommend use of anti-infectives in immunocompromised individuals or for the treatment of severe infections or when septicemia or other invasive disease occurs.331,332,469 GI infections caused by Y. enterocolitica or Y. pseudotuberculosis can occur as the result of ingesting undercooked pork, unpasteurized milk, or contaminated water; infection has occurred in infants whose caregivers handled contaminated chitterlings (raw pork intestines) or tofu.331 Use of co-trimoxazole, an aminoglycoside (amikacin, gentamicin, tobramycin), a fluoroquinolone (e.g., ciprofloxacin), doxycycline, cefotaxime, or ceftizoxime has been recommended when treatment is considered necessary;331,332,386 combination therapy may be necessary.332 Some clinicians suggest that the role of oral anti-infectives in the management of enterocolitis, pseudoappendicitis syndrome, or mesenteric adenitis caused by Yersinia needs further evaluation.469
Although doxycycline has been used in the past for the treatment of travelers' diarrhea†,420,421 other anti-infective agents (i.e., ciprofloxacin, levofloxacin, norfloxacin, ofloxacin, azithromycin) are preferred if anti-infective therapy is indicated in individuals whose diarrhea is severe or associated with fever or bloody stools.239,299 The CDC and other experts no longer recommend use of anti-infectives for prophylaxis of travelers' diarrhea in most individuals traveling to areas of risk.239,299
Tetracycline hydrochloride is considered the treatment of choice for balantidiasis† caused by Balantidium coli ; metronidazole and iodoquinol are considered alternative agents.293,469
Although the manufacturers state that tetracyclines may be useful as an adjunct to amebicides in the treatment of acute intestinal amebiasis,234,241,393 tetracyclines are not generally recommended for the treatment of amebiasis caused by Entamoeba .293,469
Tetracycline is considered a drug of choice for the treatment of infections caused by Dientamoeba fragilis †.293 Many clinicians recommend iodoquinol, paromomycin, tetracycline, or metronidazole for the treatment of D. fragilis infections293
Tetracycline hydrochloride is used in conjunction with folic acid in the treatment of tropical sprue† (postinfectious tropical malabsorption).347 Although treatment with folic acid alone can improve symptoms of tropical sprue, it does not cure the diarrhea; combination therapy appears to be most effective in resolving symptoms (including diarrhea) and promoting weight gain.347
For the treatment of Whipple's disease† caused by Tropheryma whippelii , some clinicians suggest that co-trimoxazole is the drug of choice and penicillin G and tetracyclines are alternatives.386
Doxycycline is used for prevention of malaria in individuals traveling to areas where chloroquine-resistant Plasmodium falciparum has been reported.234,239,293,299,409 The CDC and many clinicians recommend use of the fixed combination of atovaquone and proguanil hydrochloride (Malarone®), doxycycline, or mefloquine for prevention of malaria in individuals traveling to malarious areas where chloroquine-resistant P. falciparum has been reported.239,293,299 Doxycycline (unless contraindicated) or the fixed combination of atovaquone and proguanil can be used for prophylaxis in individuals traveling to areas of risk where mefloquine resistance has been confirmed. 239,293,299
Although chloroquine is the drug of choice for travelers to areas where chloroquine-resistant P. falciparum malaria has not been reported, the CDC states that doxycycline, mefloquine, or the fixed combination of atovaquone and proguanil can be used as alternatives for prophylaxis in individuals traveling to these areas who are unable to take chloroquine or hydroxychloroquine.239
Doxycycline is the preferred tetracycline for prevention of malaria.239,293,299 Efficacy of other tetracyclines (e.g., minocycline) for prevention of malaria has not been fully determined.239 Therefore, CDC recommends that individuals receiving long-term minocycline therapy (e.g., for acne) who also require doxycycline malaria prophylaxis should discontinue minocycline 1-2 days prior to travel and initiate doxycycline for such prophylaxis;239 minocycline therapy can be reinitiated after doxycycline prophylaxis is finished.239
Because doxycycline is active only against the asexual erythrocytic forms of plasmodia,234,399,401,417 the drug provides substantial, but not complete, suppressive action for P. falciparum .399,401,417 In addition, doxycycline cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species since they have exoerythrocytic stages.239,293 Therefore, terminal prophylaxis with primaquine phosphate may be indicated in addition to doxycycline prophylaxis if exposure occurred in areas where P. ovale or P. vivax are endemic.239,293,299 For additional information on the treatment and prevention of P. ovale or P. vivax , see Primaquine Phosphate 8:30.08.
Specific references, including those most recently published by the CDC and World Health Organization (WHO), should be consulted to determine in which countries a risk of acquiring malaria exists, to determine whether prophylaxis against malaria is indicated in these countries, and to aid in selecting the appropriate antimalarial agent(s).239 The choice of an antimalarial agent(s) for suppression or chemoprophylaxis depends on the specific malarious area as well as the duration of exposure.239 Detailed recommendations for prevention of malaria are available from CDC 24 hours a day from the voice information service (877-394-8747) or at [Web].239
No drug regimen is completely effective in preventing malaria,299 and travelers should be informed that, regardless of the prophylactic regimen used, it is still possible to contract malaria.239 Travelers should be advised of the importance of taking measures to reduce contact with mosquitoes (e.g., using appropriate insect repellents, wearing clothes that cover most of the body, remaining in air-conditioned or well-screened areas, using mosquito nets [e.g., bed nets] between dusk and dawn, using aerosolized insecticides in rooms where mosquitoes are found).239 For information on protective measures, see [Web].
Travelers to countries with malaria should be instructed to seek prompt medical attention as soon as possible if they develop symptoms of malaria, including fever with chills and headache or other influenza-like illness, while traveling or after return (especially during the first 2 months).239,293,299 Malaria symptoms can develop as early as 6 days after initial exposure or can appear months after departure from a malarious area, after chemoprophylaxis is discontinued.239 Travelers should understand that malaria can be effectively treated early in the course of the disease, but that delays before initiation of therapy can have serious or even fatal consequences.239
Presumptive Self-treatment of Malaria
CDC and other experts recommend use of malaria prophylaxis for travel to malarious areas.239,293 However, travelers who elect not to take prophylaxis and travelers who require or choose to use a prophylaxis regimen that may not have optimal efficacy (e.g., chloroquine prophylaxis in areas with chloroquine-resistant P. falciparum ) are at greater risk of acquiring malaria and may need prompt treatment.239 In addition, long-term travelers who are taking effective prophylaxis but who will be in very remote areas may decide, in consultation with their health-care provider, to take along an appropriate antimalarial for presumptive self-treatment.239 The antimalarial regimen provided for presumptive self-treatment should be different than the regimen that the traveler uses for prophylaxis.293 Travelers should be advised to initiate self-treatment promptly in the event of an influenza-like illness (e.g., fever, chills) if professional medical care will not be available within 24 hours.239 Use of presumptive self-treatment is only a temporary measure and these travelers should be advised to seek medical advice as soon as possible.239
CDC recommends the fixed combination of atovaquone and proguanil (Malarone®) for presumptive self-treatment of malaria in travelers not taking the drug for prophylaxis and states that the CDC Malaria Hotline (770-488-7788) should be consulted regarding other potential options for self-treatment if atovaquone and proguanil cannot be used.239 There have been several reports of P. falciparum resistant to atovaquone and proguanil in isolated locations in Africa.293 Some clinicians also suggest that a regimen of oral doxycycline in conjunction with oral quinine sulfate or, alternatively, mefloquine alone may be used for presumptive self-treatment of malaria† in travelers.293
Treatment of Uncomplicated Malaria
Doxycycline or tetracycline hydrochloride is used in conjunction with quinine sulfate for the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum †.293,493 For the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum and for the treatment of uncomplicated malaria when the plasmodial species has not been identified, CDC recommends the fixed combination of oral atovaquone and proguanil (Malarone®); the fixed combination of oral artemether and lumefantrine (Coartem®); or a regimen that includes oral quinine sulfate in conjunction with oral doxycycline, tetracycline, or clindamycin.520 Although mefloquine is an alternative, it has been associated with adverse effects (e.g., severe neuropsychiatric reactions) and the CDC recommends that it be used only if the recommended treatment regimens cannot be used.520
When a quinine sulfate regimen is used for treatment of uncomplicated, chloroquine-resistant P. falciparum malaria, concomitant use with doxycycline or tetracycline generally is preferable to use with clindamycin because more efficacy data exist regarding regimens that include tetracyclines.493 However, for pregnant women with uncomplicated malaria caused by chloroquine-resistant P. falciparum , prompt treatment with quinine sulfate and clindamycin is recommended.493 Although tetracyclines generally are contraindicated in pregnant women, in rare circumstances (e.g., if other treatment options are not available or not tolerated) quinine sulfate may be used in conjunction with doxycycline or tetracycline if the benefits outweigh the risks.493
Doxycycline is used in conjunction with quinine sulfate and primaquine for the treatment of uncomplicated, chloroquine-resistant P. vivax malaria†.293,493 For the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax , the CDC recommends a regimen of oral quinine sulfate in conjunction with oral doxycycline or tetracycline; the fixed-combination of oral atovaquone and proguanil; or a regimen of oral mefloquine.520 Because all of these regimens are active only against asexual erythrocytic forms of plasmodia (not exoerythrocytic stages) and cannot prevent delayed primary attacks or relapse of P. vivax malaria or provide a radical cure, a 14-day regimen of oral primaquine is indicated in addition to these regimens to eradicate hypnozoites and prevent relapse in patients treated for P. vivax malaria.293,493
For additional information on treatment of uncomplicated malaria, see Uses: Malaria, in Quinine Sulfate 8:30.08.
Doxycycline or tetracycline hydrochloride is used in conjunction with IV quinidine gluconate (followed by oral quinine sulfate) for the treatment of severe P. falciparum malaria†.493 The CDC recommends that severe P. falciparum malaria be treated with IV quinidine gluconate therapy in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin administered orally or IV as tolerated.493 After parasitemia is reduced to less than 1% and the patient can tolerate oral therapy, IV quinidine gluconate therapy can be discontinued and oral quinine sulfate therapy initiated to complete 3 or 7 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (3 days if malaria was acquired in Africa or South America or 7 days if acquired in Southeast Asia).493
Clinicians who desire assistance with diagnosis and treatment of malaria may consult with experts at the CDC Malaria Epidemiology Branch by calling the CDC Malaria Hotline at 770-488-7788from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays and request that the individual on call for the Malaria Epidemiology Branch be paged.239
For additional information on treatment of severe malaria, see Uses: Malaria, in Quinidine 24:04.04.04.
Minocycline is used as an alternative agent in multiple-drug regimens used for the treatment of multibacillary leprosy†453,455 and also is used in a single-dose rifampin-based multiple-drug regimen for the treatment of single-lesion paucibacillary leprosy†.453,454,455,456,457
For the treatment of multibacillary leprosy (i.e., more than 5 lesions or skin smear positive for acid-fast bacteria), the World Health Organization (WHO) currently recommends a multiple-drug regimen that includes rifampin, clofazimine, and dapsone.453 Minocycline is recommended as an alternative for use in antileprosy regimens in patients with multibacillary leprosy who will not accept or cannot tolerate clofazimine,453,455 or when rifampin cannot be used because of adverse effects, intercurrent disease (e.g., chronic hepatitis), or infection with rifampin-resistant Mycobacterium leprae .453,455
For the treatment of paucibacillary leprosy (i.e., 2-5 skin lesions), the WHO usually recommends a 6-month multiple-drug regimen that includes rifampin and dapsone.453,455 However, patients with single-lesion paucibacillary leprosy (i.e., a single skin lesion with definite loss of sensation but without nerve trunk involvement) have been effectively treated with a single-dose rifampin-based multiple-drug regimen (ROM) that includes a single dose of rifampin, a single dose of ofloxacin, and single dose of minocycline.453,455,456,457 The single-dose ROM regimen may be an acceptable and cost-effective alternative regimen in antileprosy programs that have detected a large number of patients (e.g., more than 1000 annually) with single-lesion paucibacillary leprosy;453,454,455,456,457 however, the WHO states that the single-dose ROM regimen should not be used in antileprosy programs that have detected few single-lesion paucibacillary leprosy patients since it involves additional logistic and informational problems for these programs.455
For additional information on the treatment of leprosy, see Rifampin 8:16.04, Dapsone 8:16.92, and Clofazimine 8:16.92.
Other Mycobacterial Infections
Minocycline or doxycycline are considered drugs of choice for the treatment of cutaneous infections caused by Mycobacterium marinum .368
Doxycycline is considered the drug of choice in adults for the treatment of human granulocytotropic anaplasmosis† (HGA; formerly human granulocytic ehrlichiosis [HGE]) caused by Anaplasma phagocytophilum (formerly Ehrlichia phagocytophila , E. equi , agent of HGE),386,395,396,469,500,503,504 human monocytotropic (or monocytic) ehrlichiosis† (HME) caused by E. chaffeensis ,386,469,500,502 and ehrlichiosis† caused by E. ewingii or E. canis. 386,469,500 Doxycycline is recommended by the CDC and AAP as the drug of choice for presumed or confirmed rickettsial infections (including RMSF) or ehrlichiosis† (including HGA and HME) in children of any age.469,500
Treatment of suspected ehrlichiosis,† should be initiated promptly since a delay in treatment while awaiting laboratory confirmation of the diagnosis may increase the risk for severe disease and fatal outcomes.395,396,469,500 IV therapy generally is indicated for hospitalized patients, and oral therapy generally is appropriate for patients with early disease, outpatients, or hospitalized patients who are not vomiting or obtunded.469,500 The optimum duration of therapy has not been established;469,502,500 however, therapy is usually continued at least 5-10 days and until the patient is afebrile for 3 days or longer and clinically improved.469,502,500 A longer duration of therapy may be required for severe illness.469 The CDC recommends a treatment duration of 10-14 days in those with HGA since this provides an appropriate duration of therapy for adequate treatment of possible concurrent early Lyme disease.500 (See Lyme Disease under Uses: Spirochetal Infections.)
As alternatives to doxycycline, some clinicians suggest chloramphenicol for the treatment of infections caused by E. chaffeensis and rifampin as an alternative for the treatment of infections caused by A. phagocytophilum .386
Oral doxycycline (administered as 20-mg tablets) is used as an adjunct to scaling and root planing to promote attachment level gain and to reduce pocket depth in adults with periodontitis.207,208,219 Doxycycline (administered subgingivally as a controlled-release preparation)371 or minocycline (administered subgingivally as sustained-release microspheres)227 is used in conjunction with scaling and root planing for the reduction of pocket depth in adults with periodontitis. (See Doxycycline Hyclate 52:04.04 and see Minocycline Hydrochloride 52:04.04.)
Minocycline is used in the treatment of rheumatoid arthritis†.252,253,254,256 Results of one study indicate that minocycline is at least as effective as hydroxychloroquine in the management of rheumatoid arthritis in adults.253 Minocycline is one of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.252 (For further information on the treatment of arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.)
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Demeclocycline (but not other currently available tetracyclines) has been effective when used in the treatment of the syndrome of inappropriate antidiuretic hormone secretion† (SIADH). Because it takes several days for diuresis to occur after initiation of demeclocycline therapy, the drug is of limited value in patients with acute water intoxication caused by excess ADH secretion. However, demeclocycline is effective in inhibiting the action of ADH in patients with the chronic form of the disease, and most clinicians advocate the use of the drug instead of lithium. Further studies are needed to compare the safety and efficacy of demeclocycline and other forms of therapy for SIADH. Demeclocycline has also been used to treat hyponatremia and water retention† in patients with congestive heart failure or cirrhosis. However, use of demeclocycline in these conditions has been associated with a high incidence of renal failure, and the drug probably should not be used in these patients.
Pericardial and Pleural Effusions
Tetracycline hydrochloride (no longer commercially available as a parenteral formulation in the US) has been used by intracavitary injection as a sclerosing agent to control pleural effusions† caused by metastatic tumors. Doxycycline also has been administered in a limited number of patients by intracavitary injection†308,309,311,312,316,319,326,416,418 or via lavage drainage†310,316,319 for the management of malignant pleural effusions, and minocycline has been administered by intracavitary injection† for malignant pleural effusions and concurrent postoperative air leaks in a few patients.317,319,416
Patients with malignant pleural effusions frequently have symptoms of dyspnea, cough, and chest pain and heaviness.308,311,313,318 Although thoracentesis may provide temporary relief of such symptoms, the effusion often reaccumulates rapidly,308,309,311,318 and surgical insertion of a thoracostomy tube with subsequent intrapleural instillation of a sclerosing agent generally is considered the treatment of choice for such effusions in patients with neoplasms unresponsive to systemic antineoplastic or radiation therapy.288,313,318,324,327 When instilled into the pleural space, tetracyclines and other effective sclerosing agents cause inflammation that results in fibrosis and adherence of serosal surfaces (pleurodesis), thereby obliterating the pleural space and reducing the chance of fluid reaccumulation;288,311,312,318,325,326 however, most current pleurodesis procedures for malignant pleural effusion appear to be associated with a substantial risk of recurrence.288,327 Some clinicians recommend removal of the sclerosing fluid after 0.5-4 hours,288 although it has been suggested that dispersal of the sclerosing agent and pleurodesis may occur within minutes after instillation of tetracycline.288,316 Further studies are needed to elucidate fully the optimum length of time that the drug should remain in the pleural cavity.288,316 Pleurodesis appears to be most effective when drainage from the thoracostomy tube does not exceed 100 mL/hour and is unlikely to be successful if the patient's underlying disease prevents complete expansion of the lung following drainage of the effusion.311,313,318,324
The most common adverse effects reported with intracavitary administration of tetracyclines into the pleural space are chest pain and fever.308,309,311,319,325,416,418 Opiate analgesics may be administered prior to the procedure to relieve pain associated with pleurodesis;309,311,313,316,319,325 lidocaine also has been instilled into the chest tube prior to pleurodesis to help alleviate discomfort.311,313,317,325,418 Although adverse effects attributable to systemic absorption of doxycycline or minocycline appear to be minimal with currently used intrapleural doses of these drugs, therapeutic serum concentrations of tetracycline and lidocaine have been achieved in some patients following intrapleural administration.325
Doxycycline or minocycline has been suggested as an alternative to tetracycline hydrochloride for the management of malignant pleural effusions when intrapleural therapy is indicated.308,309,316,319,326,416 Data in a limited number of patients suggest that intrapleural doxycycline prevents pleural fluid reaccumulation in most patients with metastatic pleural effusions, at least in the short term (e.g., 1 month) and appears to be associated with relatively few adverse effects (e.g., chest pain, fever).288,309,310,316 Another agent, bleomycin, has been reported in at least one controlled study to be more effective and possibly better tolerated but more expensive than tetracycline hydrochloride for the management of such effusions.288,311,313,316,320,321,322,324,327,416 The efficacy and safety of intrapleural doxycycline or minocycline compared with intrapleural administration of bleomycin or other potentially more toxic and/or complicated therapies (e.g., thoracostomy, talc insufflation, nitrogen mustard) for the management of malignant pleural effusions remains to be determined.288
Tetracycline hydrochloride and doxycycline also have been administered by intrapericardial injection† in a limited number of patients with malignant pericardial effusions and associated cardiac tamponade†.314,315,323
Because tetracyclines have an affinity for and localize in tumors and necrotic or ischemic tissue, the drugs have been used to detect malignant cells† in gastric washings, pleural fluid, and ascitic fluid. After several days of oral tetracycline therapy, appropriate specimens are obtained and examined under ultraviolet light; malignant cells in the samples exhibit a bright yellow-gold fluorescence. In addition, radiolabeled tetracycline hydrochloride has been used to detect tumors†, especially in the chest, and to detect and measure the extent of ischemia following myocardial infarcts†.
Prophylaxis in Victims of Sexual Assault
Oral doxycycline is used in conjunction with oral metronidazole and IM ceftriaxone for empiric anti-infective prophylaxis in adult or adolescent victims of sexual assault†; postexposure hepatitis B vaccination also is recommended for susceptible victims.213 Many experts recommend routine empiric prophylactic therapy after a sexual assault, and use of such prophylaxis probably benefits most patients since follow-up of assault victims can be difficult and such prophylaxis allays the patient's concerns about possible infection.213 Trichomoniasis, genital chlamydial infection, gonorrhea, and bacterial vaginosis are the sexually transmitted diseases most commonly diagnosed in women following sexual assault; however, the prevalence of these infections is substantial among sexually active women and their presence after assault does not necessarily indicate that the infections were acquired during the assault.213 Chlamydial and gonococcal infections among females are of special concern because of the possibility of ascending infection.213 When empiric anti-infective prophylaxis is indicated in adult or adolescent sexual assault victims, the CDC recommends administration of a single 125-mg IM dose of ceftriaxone given in conjunction with a single 2-g oral dose of metronidazole and a single 1-g oral dose of azithromycin or a 7-day regimen of oral doxycycline (100 mg twice daily).213 This 3-drug regimen provides coverage against gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, but efficacy in preventing these infections after sexual assault has not been specifically evaluated.213 Because of possible adverse GI effects with the 3-drug regimen, the CDC suggests that the patient be counseled regarding the possible benefits, as well as the possibility of toxicity of such prophylaxis.213 Alternative regimens may be required for some patients because of the likelihood of transmission of other sexually transmitted diseases from the assailant.213 CDC states that a recommendation concerning the appropriateness of antiretroviral prophylaxis against HIV cannot be made based on currently available information, and the decision to offer such prophylaxis should be individualized taking into account the probability of HIV transmission from a single act of intercourse and the nature of the assault (e.g., extent of physical trauma and exposure to ejaculate).213 (See Guidelines for Use of Antiretroviral Agents: Antiretroviral Agents for Postexposure Prophylaxis following Sexual Assault or Nonoccupational Exposure to HIV, in the Antiretroviral Agents General Statement 8:18.08.)
There are few data available to establish the risk of a child acquiring a sexually transmitted disease as a result of sexual assault or abuse.213 The risk is believed to be low in most circumstances, although documentation to support this position is inadequate.213 The CDC currently states that presumptive treatment for children who have been sexually assaulted or abused is not widely recommended because girls appear to be at lower risk for ascending infection than adolescent or adult women and regular follow-up usually can be ensured.213 Even if the risk is perceived by the health-care provider to be low, some children or their parents or guardians may have concerns about the possibility of the child contracting a sexually transmitted disease as a result of the assault and these concerns may be an appropriate indication for presumptive treatment in some settings.213
For topical uses of tetracyclines, see Minocycline Hydrochloride 52:04.04 and Tetracyclines 84:04.04.