Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV

Epidemiology

Bartonella species cause infections that include cat scratch disease (CSD), retinitis, trench fever, relapsing bacteremia, culture-negative endocarditis, bacillary angiomatosis (BA), and bacillary peliosis hepatis.¹ The latter two manifestations occur almost exclusively in individuals who are immunocompromised. Thirty-seven species and three subspecies of Bartonella have been described and are officially recognized (https://www.bacterio.net/genus/bartonella);¹⁴Bartonella species have been implicated in human infections.

BA most often occurs late in HIV infection,² in patients with median CD4 T lymphocyte (CD4 cell) counts <50 cells/mm³. In patients with HIV, bartonellosis is often a chronic illness, lasting for months to more than a year, with bacillary angiomatosis (BA) lesions and intermittent bacteremia. Development of BA lesions caused by B. henselae is statistically linked to cat exposure in patients with HIV.² In contrast, BA caused by B. quintana is associated with body louse infestation and homelessness.² The body louse serves as the vector of B. quintana to humans. To avoid exposure to B. quintana, people with HIV should avoid body lice exposure and have prompt eradication of lice if infestation occurs. The cat flea is the vector of B. henselae in cats. Cats are the most common vector (via a scratch) responsible for transmitting B. henselae to humans, most likely when their 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%;³ infection is more common among kittens and feral cat populations. Control of cat flea infestation and avoidance of cat scratches are therefore critical strategies for preventing B. henselae infections in people with HIV.

Clinical Manifestations

BA lesions have been associated with nearly every organ system, but cutaneous lesions are the most readily identified. These lesions can be clinically indistinguishable from Kaposi sarcoma, pyogenic granuloma, and other skin conditions. BA also can cause subcutaneous nodules. Osteomyelitis is usually caused by B. quintana, and only B. henselae causes bacillary peliosis hepatis.² 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 patients with advanced HIV and should be considered in the differential diagnosis of patients with CD4 counts <100 cells/mm³ and fever.⁴ Bartonella is a frequent cause of culture-negative endocarditis in immunocompetent and immunocompromised humans and is most commonly caused by B. quintana, less frequently by B. henselae, and rarely by other Bartonella species.⁵ Immune complex disease (such as glomerulonephritis) may complicate endocarditis or other systemic Bartonella infections; assessment for immune complex formation may be warranted in such cases, so that nephrotoxic agents can be avoided.

Diagnosis

Diagnosis of BA can be confirmed by histopathologic examination of biopsied tissue.⁶ BA lesions are characterized by vascular proliferation, and a modified silver stain (such as Warthin-Starry stain) usually demonstrates numerous bacilli. Tissue Gram staining and acid-fast staining are negative.

A well-characterized indirect fluorescent antibody (IFA) serologic test was developed at the Centers for Disease Control and Prevention (CDC)⁷ (https://www.cdc.gov/laboratory/specimen-submission/detail.html?CDCTestCode=CDC-10486) and is available at some state health laboratories. In addition, several private laboratories offer serological testing, but the performance characteristics of these tests have not been validated for patients with HIV. 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 with Bartonella for months or even >1 year. However, as many as 25% of Bartonella culture-positive patients never develop antibodies in the setting of advanced HIV infection.⁴ In those patients who do develop anti-Bartonella antibodies, monitoring of antibody levels can be useful in following treatment response of Bartonella infection to antibiotics, reflecting resolution⁸ or recrudescence. Because of interlaboratory variability, longitudinal testing should be conducted at the same laboratory, to enable direct comparison of titers over time.

Because of their fastidious nature, Bartonella organisms can be isolated only with difficulty from blood (drawn into ethylenediaminetetraacetic acid [EDTA] tubes, centrifuged, and then plated directly onto chocolate agar), and they have been cultured directly from tissue in only a few laboratories.² Removing samples from blood culture bottles after 8 days of incubation, followed by staining with acridine orange, has facilitated identification and subsequent culture of Bartonella species.⁹ Additionally, polymerase chain reaction (PCR) amplification methods (using universal and/or specific primers) for tissue samples are increasingly available through private laboratories, as well as the CDC (https://www.cdc.gov/laboratory/specimen-submission/detail.html?CDCTestCode=CDC-10365) and may aid in diagnosis of Bartonella in freshly biopsied tissue samples (such as BA skin lesions, lymph node biopsies, cardiac valves, or other vascular lesions) or whole blood.^8,10 Clinicians should be aware that results from the CDC may take longer (several weeks to months) for serologic and molecular testing, respectively, compared with some private laboratories.

In summary, diagnosis of bartonellosis may require multiple testing modalities, including serologic testing (which is the most accessible test, and helpful both for diagnosis and subsequent monitoring, when positive), histopathology, and molecular testing for biopsied or resected tissue (e.g., BA lesion tissue or heart valve tissue).

Preventing Exposure

People with HIV, specifically those who are severely immunocompromised (CD4 counts <100 cells/mm³), are at high risk of severe disease when infected by B. quintana or B. henselae. The major risk factors for acquisition of B. henselae are contact with cats infested with fleas and receiving cat scratches. Immunocompromised individuals should consider the potential risks of cat ownership (AIII). Patients who want cats should acquire animals that are older than 1 year of age 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 individuals with HIV should avoid rough play with cats and situations in which scratches are likely (AII). Patients should avoid contact with flea feces (i.e., flea dirt), and any cat-associated wound should be washed promptly with soap and water (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 (BII). The major risk factor for B. quintana infection is body lice infestation. Patients who are homeless or in marginal housing 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). Regardless of CD4 count, patients with HIV and solid organ transplantation may be at risk of developing more severe Bartonella infections, similar to transplant recipients without HIV.¹¹

Preventing Disease

Primary chemoprophylaxis for Bartonella-associated disease is not recommended (BIII). However, note that in a retrospective case-control study, use of a macrolide (such as for Mycobacterium avium complex prophylaxis) was protective against developing Bartonella infection.²

Treating Disease

All patients with HIV and Bartonella infection should receive antibiotic treatment (AII). No randomized, controlled clinical trials have evaluated antimicrobial treatment of bartonellosis in patients with HIV. Erythromycin and doxycycline have been used successfully to treat BA, peliosis hepatis, bacteremia, and osteomyelitis; either drug is considered first-line treatment for bartonellosis on the basis of reported experience in case series (AII).^1,2 Anecdotal and limited published case reports¹² suggest that other macrolide antibiotics (such as azithromycin or clarithromycin) are effective in treating Bartonella infections in patients with HIV and may be better tolerated than erythromycin; either of these can be an alternative therapy for Bartonella infections (except for endocarditis or central nervous system [CNS] infections) (BIII). Therapy should be administered for at least 3 months (AII). Doxycycline, preferably in combination with a rifamycin class antibiotic, is the treatment of choice for bartonellosis infection involving the CNS (AIII). For severe Bartonella infections (i.e., patients with multifocal disease or evidence of clinical decompensation), combination therapy using erythromycin or doxycycline with a rifamycin class antibiotic is recommended (BIII); intravenous therapy may be needed initially (AIII). Treatment of Bartonella endocarditis should include doxycycline with the addition of a rifamycin class antibiotic for a minimum of 6 weeks (BII). Doxycycline for 6 weeks plus gentamicin for the first 2 weeks may also be considered but is less preferred, due to the intrinsic nephrotoxicity of gentamicin and the frequency of vasculitis-induced renal dysfunction complicating Bartonella endocarditis (BII).¹³

Penicillins and first-generation cephalosporins have no in vivo activity and should not be used for treatment of bartonellosis (AII).¹⁴ Quinolones and trimethoprim-sulfamethoxazole (TMP-SMX) have variable in vitro activity and an inconsistent clinical response in case reports and are not recommended (AIII).

Special Consideration with Regard to Starting ART

The potential exists for immune reconstitution inflammatory syndrome (IRIS) in association with bartonellosis and antiretroviral therapy (ART) in persons with HIV. In ART-naive patients, ART generally can be initiated at the same time as Bartonella-directed treatment; however, patients with Bartonella CNS or ophthalmic lesions probably should be treated with doxycycline and a rifamycin class antibiotic for 2 to 4 weeks before instituting ART (CIII).

Monitoring of Response to Therapy and Adverse Effects (Including IRIS)

Because of the propensity for relapse of Bartonella infection, patients should have anti-Bartonella IgG antibody titers checked at the time of diagnosis (diluted to endpoint) and, if positive, should be followed with sequential titers every 6 to 8 weeks during treatment, preferably until a fourfold decrease is documented (CIII).⁸ Patients treated with oral doxycycline should be cautioned about pill-associated esophagitis and photosensitivity. Adverse effects associated with macrolides include nausea, vomiting, abdominal pain, and elevations of liver transaminase levels; potential QT interval prolongation also should be considered. Serious side effects can occur during treatment with rifamycin class antibiotics, including hypersensitivity reactions (thrombocytopenia, interstitial nephritis, and hemolytic anemia) and hepatitis. Administration of rifamycin class antibiotics strongly induces the cytochrome P450 enzyme system, which is an important consideration when other medications, including many antiretroviral (ARV) drugs, are taken simultaneously.

Managing Treatment Failure

Relapse of Bartonella infections occurs frequently, especially in patients with BA. Among patients who fail to respond to initial treatment, switching to a different preferred regimen (for example, from doxycycline to erythromycin) may be considered, again with treatment duration of ≥3 months (AIII). For severe infections, the addition of a rifamycin class antibiotic is indicated (AIII). For patients with positive or increasing antibody titers, but with clinical improvement, treatment should continue until a fourfold decrease in the antibody titers is documented (CIII).⁸

Preventing Recurrence

After a primary course of treatment (minimum of 3 months), treatment may be discontinued, with close monitoring for evidence of relapse (e.g., symptoms, increase in antibody titers).

If a relapse occurs, an additional course of treatment is recommended, followed by long-term suppression of infection with doxycycline or a macrolide (AIII).

Long-term suppression can be discontinued after the patient has received at least 3–4 months of therapy and when the CD4 count remains >200 cells/mm³ on effective ART for ≥6 months (CIII).⁸ Some specialists would discontinue therapy only if the Bartonella titers also have decreased fourfold (CIII).

Special Considerations During Pregnancy

Infection with B. bacilliformis in immunocompetent patients during pregnancy has been associated with increased complications and risk of death, but no data are available on the effect of B. quintana or B. henselae infection during pregnancy.

The approach to diagnosis of Bartonella infections in pregnant women is the same as in non-pregnant women. Erythromycin treatment (or an alternative macrolide) should be used as first-line therapy (AIII) rather than tetracyclines (such as doxycycline) during pregnancy, because of the increased risk of hepatotoxicity and the accumulation of tetracycline in fetal teeth and bones, resulting in dark, permanent staining of fetal teeth. Third-generation cephalosporins, such as ceftizoxime¹⁵ or ceftriaxone, may have efficacy against Bartonella in pregnant women with HIV, but it 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 (AII).

References

1. Rose SR, Koehler JE. Chapter 236: Bartonella, including cat-scratch disease. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease. 9th ed. Philadelphia, PA: Elsevier Press; 2020.
2. Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med.1997;337:1876-1883. Available at http://www.ncbi.nlm.nih.gov/pubmed/9407154.
3. Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae A new zoonosis with the domestic cat as reservoir. JAMA. 1994;271:531-535. Available at http://www.ncbi.nlm.nih.gov/pubmed/8301768.
4. Koehler JE, Sanchez MA, Tye S, et al. Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever. Clin Infect Dis. 2003;37:559-566. Available at http://www.ncbi.nlm.nih.gov/pubmed/12905141.
5. Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis. 2010;51:131-40. Available at http://www.ncbi.nlm.nih.gov/pubmed/20540619.
6. LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TS, Stoler MH. Bacillary angiomatosis. The histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Path. 1989;13:909-920. Available at http://www.ncbi.nlm.nih.gov/pubmed/2802010.
7. Regnery RL, Olson JG, Perkins BA, Bibb W. Serological response to "Rochalimaea henselae" antigen in suspected cat-scratch disease. 1992;339:1443-1445. Available at http://www.ncbi.nlm.nih.gov/pubmed/1351130.
8. Lee SA, Plett SK, Luetkemeyer AF, et al. Bartonella quintana aortitis in a man with AIDS, diagnosed by needle biopsy and 16S rRNA gene amplification. J Clin Microbiol. 2015;53:2773-2776. Available at http://www.ncbi.nlm.nih.gov/pubmed/26063867.
9. Larson AM, Dougherty MJ, Nowowiejski DJ, et al. Detection of Bartonella (Rochalimaea) quintana by routine acridine orange staining of broth blood cultures. J Clin Microbiol 1994;32:1492-14. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC264025/.
10. Dumler JS, Carroll KC, Patel R. Bartonella. In: Carroll KC, Pfaller MA, Landry M, et al, eds. Manual of Clinical Microbiology. 12th ed. Washington, DC: American Society for Microbiology; 2019.
11. Psarros G, Riddell J 4th, Gandhi T, Kauffman CA, Cinti SK. Bartonella henselae infections in solid organ transplant recipients: report of 5 cases and review of the literature. Medicine (Baltimore). 2012;91:111-121. Available at http://www.ncbi.nlm.nih.gov/pubmed/22391473.
12. Guerra LG, Neira CJ, Boman D, et al. Rapid response of AIDS-related bacillary angiomatosis to azithromycin. Clin Infect Dis. 1993;17:264-266. Available at https://www.ncbi.nlm.nih.gov/pubmed/8399879.
13. Raybould JE, Raybould AL, Morales MK, et al. Bartonella endocarditis and pauci-immune glomerulonephritis: A case report and review of the literature. Infect Dis Clin Pract (Baltim Md). 2016;24:254-260. Available at https://www.ncbi.nlm.nih.gov/pubmed/27885316.
14. Koehler JE, LeBoit PE, Egbert BM, Berger TG. Cutaneous vascular lesions and disseminated cat-scratch disease in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med. 1988;109:449-55. Available at https://pubmed.ncbi.nlm.nih.gov/3415105.
15. Riley LE, Tuomala RE. Bacillary angiomatosis in a pregnant patient with acquired immunodeficiency syndrome. Obstet Gynecol. 1992;79:818-819. Available at http://www.ncbi.nlm.nih.gov/pubmed/1565376.