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Bartonellosis
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Epidemiology

Bartonella species cause infections that include cat scratch disease, trench fever, relapsing bacteremia, endocarditis, bacillary angiomatosis (BA), and bacillary peliosis hepatis (506Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am 1998;12:137-55.). The latter two manifestations occur only in immunocompromised persons. BA is caused by either B. quintana or B. henselae (506Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am 1998;12:137-55., 507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). Nineteen species of Bartonella have been identified, and five have been isolated from humans. However, only B. henselae and B. quintana infections have been identified in HIV-infected persons (507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). BA most often occurs late in HIV infection, in patients with a median CD4+ count of <50 cells/µL (507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). In HIV-infected patients, bartonellosis is often a chronic illness, lasting for months to years, with BA lesions and intermittent bacteremia.

Development of BA lesions caused by B. henselae is statistically linked to cat exposure in patients with HIV infection (507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). In contrast, BA caused by B. quintana is associated with body louse infestation and homelessness (507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). The body louse serves as the vector of B. quintana among humans. The cat flea is the vector of B. henselae among cats. However, the cat is the most common vector (via a scratch) that is responsible for transmitting B. henselae to humans, most likely when claws become contaminated with feces from B. henselae-infected fleas. In some areas of the United States, the prevalence of B. henselae bacteremia in pet cats approaches 50% (508Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae infection. A new zoonosis with the domestic cat as reservoir. JAMA 1994;271:531-5.). Control of cat flea infestation and avoidance of cat scratches are therefore critical strategies for prevention of B. henselae infections in HIV-infected persons. To avoid exposure to B. quintana, HIV-infected patients should avoid and treat infestation with body lice.

Clinical Manifestations

BA lesions have been associated with nearly every organ system, but cutaneous lesions are the most readily identified. BA lesions can be clinically indistinguishable from KS. BA also can cause subcutaneous nodules. Osteomyelitis is usually caused by B. quintana, and only B. henselae can cause bacillary peliosis hepatis. Although isolated organs can appear to be the principal focus of disease, BA represents a hematogenously disseminated infection, and systemic symptoms of fever, night sweats, and weight loss often accompany BA. Bartonella infection is a major cause of unexplained fever in late-stage AIDS patients and should be considered in the differential diagnosis of patients with fever and a CD4+ count of <100 cells/µL (509Koehler J, Sanchez M, Tye S, et al. Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever. Clin Infect Dis 2003;37:559-66.).

Diagnosis

Diagnosis can be confirmed by histopathologic examination of biopsied tissue (510LeBoit PE, Berger TG, Egbert BM, et al. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Pathol 1989;13:909-20.). BA lesions are characterized by vascular proliferation, and a modified silver stain (e.g., Warthin-Starry stain) usually demonstrates numerous bacilli. Tissue Gram staining and acid-fast staining are negative.

A well-characterized serologic test was developed at CDC (511Regnery RL, Olson JG, Perkins BA, Bibb W. Serological response to Rochalimaea henselae antigen in suspected cat-scratch disease. Lancet 1992;339:1443-5.) and is also available at some state health labs. In addition, several private laboratories offer serological testing, but none of these private laboratory tests has been evaluated for sensitivity or specificity with sera from HIV-infected patients. In immunocompetent patients, anti-Bartonella antibodies might not be detectable for 6 weeks after acute infection; in contrast, by the time Bartonella infection is suspected in patients with late-stage HIV infection, they usually have been infected for months or even >1 year. Note that as many as 25% of Bartonella culture-positive patients might never develop antibodies in the setting of advanced HIV infection (509Koehler J, Sanchez M, Tye S, et al. Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever. Clin Infect Dis 2003;37:559-66.). In those patients who do develop anti-Bartonella antibodies, monitoring of antibody levels might correlate with resolution and recrudescence of Bartonella infection.

Bartonella species can be isolated (with difficulty) from blood, using EDTA tubes. The organisms have been isolated from tissue in only a few laboratories because of the fastidious nature of Bartonella (507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). PCR methods have been developed for identification and speciation of Bartonella, but are not widely available.

Preventing Exposure

HIV-infected persons, specifically those who are severely immunocompromised (CD4+ counts <100 cells/µL), are at high risk for severe disease caused by B. quintana and B. henselae. The major risk factors for acquisition of B. henselae are contact with cats infested with fleas and receiving cat scratches. Immunocompromised persons should consider the potential risks of cat ownership (AIII). Persons who acquire a cat should acquire an animal aged >1 year and in good health (BII). Cats should be acquired from a known environment, have a documented health history, and be free of fleas. Stray cats and cats with flea infestation should be avoided. Declawing is not advised, but HIV-infected persons should avoid rough play with cats and situations in which scratches are likely (AII). Patients should avoid contact with flea feces ("flea dirt"), and any cat-associated wound should be washed promptly (BIII). Care of cats should include a comprehensive, ongoing flea-control program under the supervision of a veterinarian (BIII). No evidence indicates any benefits to cats or their owners from routine culture or serologic testing of the pet for Bartonella infection or from antibiotic treatment of healthy, serologically positive cats (DII). The major risk factor for B. quintana infection is body lice infestation. Homeless or marginally housed persons should be informed that body louse infestation can be associated with serious illness and provided with appropriate measures to eradicate body lice, if present (AII).

Preventing Disease

Primary chemoprophylaxis for Bartonella-associated disease is not recommended (DIII). However, note that in a retrospective case-control study, MAC prophylaxis using a macrolide or rifamycin was protective against developing Bartonella infection (507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.).

Treatment of Disease

Guidelines for treatment of Bartonella infections have been published (512Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother 2004;48:1921-33.). No randomized, controlled clinical trials have evaluated antimicrobial treatment of bartonellosis in HIV-infected patients. Erythromycin and doxycycline have been used successfully to treat BA, peliosis hepatis, bacteremia, and osteomyelitis and are considered first-line treatment for bartonellosis, on the basis of reported experience in case series (AII) (506Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am 1998;12:137-55., 507Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.). Therapy should be administered for ≥3 months (AII). Doxycycline, with or without RIF, is the treatment of choice for bartonellosis infection involving the central nervous system (CNS) and other severe bartonellosis infections (AIII).

Clarithromycin or azithromycin treatment has been associated with clinical response and either of these can be an alternative for Bartonella treatment (BIII). Azithromycin is recommended for patients who are less likely to comply with the more frequent dosing schedule for doxycycline or erythromycin. Penicillins and first-generation cephalosporins have no in vivo activity and should not be used for treatment of bartonellosis (DII). Quinolones and TMP-SMX have variable in vitro activity and an inconsistent clinical response in case reports and are not recommended (DIII).

IRIS has not been described in association with Bartonella infection, but patients with Bartonella CNS or ophthalmic lesions should probably be treated with doxycycline and RIF for 2-4 weeks before instituting ART.

Monitoring and Adverse Effects, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Patients treated with oral doxycycline should be cautioned about pill-associated ulcerative esophagitis that occurs most often when a dose is taken with only a small amount of liquid or at night just before retiring (AIII) (513Kikendall JW, Friedman AC, Oyewole MA, Fleischer D, Johnson LF. Pill-induced esophageal injury: case reports and review of the medical literature. Dig Dis Sci 1983;28:174-82.).

No immune inflammatory response syndrome has been described in association with Bartonellosis and treatment with ART in HIV-infected persons.

Management of Treatment Failure

Among patients who fail to respond to initial treatment, one or more of the second-line alternative regimens should be considered (AIII).

Preventing Recurrence

Relapse can occur after a course of primary treatment. In this setting, long-term suppression of infection with doxycycline or a macrolide is recommended, as long as the CD4+ count remains <200 cells/µL (AIII).

Long-term suppression can be discontinued after the patient has received 3-4 months of therapy and when the CD4+ count remains >200 cells/µL for ≥6 months (CIII). Certain specialists would discontinue therapy only if the Bartonella titers have also decreased by fourfold (CIII).

Special Considerations During Pregnancy

Infection with B. bacilliformis in immunocompetent patients during pregnancy has been associated with increased complications and risk for death (514Maguina C, Garcia PJ, Gotuzzo E, Cordero L, Spach DH. Bartonellosis (Carrin's disease) in the modern era. Clin Infect Dis 2001;33:772-9.). No data are available on the effect of B. henselae or B. quintana infections in pregnant women with concomitant HIV infection.

The approach to diagnosis of Bartonella infections in pregnant women is the same as in nonpregnant women. Erythromycin treatment should be used (AIII) rather than tetracyclines (EII) during pregnancy because of the increased risk for hepatotoxicity and the accumulation of tetracycline in fetal teeth and bones, resulting in dark, permanent staining of fetal teeth. Third-generation cephalosporins (e.g., ceftizoxime (515Riley LE, Tuomala RE. Bacillary angiomatosis in a pregnant patient with acquired immunodeficiency syndrome. Obstet Gynecol 1992;79:818-9.) or ceftriaxone) might have efficacy against Bartonella in the pregnant HIV-infected woman, but should be considered second-line therapy after a macrolide. First- and second-generation cephalosporins are not recommended because of their lack of efficacy against Bartonella (EII).

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Bartonella infections
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Definitions of abbreviations: DS = double strength; PO = by mouth; SS = single strength; bid = twice daily; tiw = 3 times weekly; SQ = subcutaneous; IM = intramuscular; qid = 4 times daily; q12h = once every 12 hours
Preferred therapy for bacillary angiomatosis, peliosis hepatis, bacteremia, and osteomyelitis
transparent gifgrey bulletErythromycin 500 mg PO or IV qid (AII); or
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transparent gifgrey bulletDoxycycline 100 mg PO or IV q12h (AII)
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Duration of therapy: at least 3 months (AII)
Alternative therapy for bacillary angiomatosis infections, peliosis hepatis, bacteremia, and osteomyelitis
transparent gifgrey bulletAzithromycin 500 mg PO daily (BIII)
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transparent gifgrey bulletClarithromycin 500 mg PO bid (BIII)
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Severe Jarisch-Herxheimer-like reaction can occur in the first 48 hours of treatment
CNS infections and severe infections
transparent gifgrey bulletDoxycycline 100 mg PO or IV q12h +/- rifampin 300 mg PO or IV q12h (AIII)
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Duration of therapy: 4 months (AII)
Long-term suppression
transparent gifgrey bulletWith a macrolide or doxycycline for patients with relapse or reinfection as long as the CD4+ count remains <200 cells/µL (AIII)
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References

506. Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am 1998;12:137-55.
507. Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997;337:1876-83.
508. Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae infection. A new zoonosis with the domestic cat as reservoir. JAMA 1994;271:531-5.
509. Koehler J, Sanchez M, Tye S, et al. Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever. Clin Infect Dis 2003;37:559-66.
510. LeBoit PE, Berger TG, Egbert BM, et al. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Pathol 1989;13:909-20.
511. Regnery RL, Olson JG, Perkins BA, Bibb W. Serological response to Rochalimaea henselae antigen in suspected cat-scratch disease. Lancet 1992;339:1443-5.
512. Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother 2004;48:1921-33.
513. Kikendall JW, Friedman AC, Oyewole MA, Fleischer D, Johnson LF. Pill-induced esophageal injury: case reports and review of the medical literature. Dig Dis Sci 1983;28:174-82.
514. Maguina C, Garcia PJ, Gotuzzo E, Cordero L, Spach DH. Bartonellosis (Carrin's disease) in the modern era. Clin Infect Dis 2001;33:772-9.
515. Riley LE, Tuomala RE. Bacillary angiomatosis in a pregnant patient with acquired immunodeficiency syndrome. Obstet Gynecol 1992;79:818-9.
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