Bartonella species

Bartonella species

Updated January, 2010

Jane E. Koehler, M.D., David A. Relman, M.D.

GENERAL DESCRIPTION

Bacteria belonging to the Bartonella genus are extremely fastidious, slow-growing gram-negative rods that are dependent on blood or blood products for growth. There are currently sixteen known species of Bartonella, five of which have been isolated from humans: B. henselae, B. quintana, B. elizabethae, B. bacilliformis and B. vinsonii subsp. arupensis. Bartonella henselae, B. quintana, B. vinsonii and B. elizabethae were previously classified in the genus Rochalimaea and considered rickettsiae, but were moved to the genus Bartonella in 1993 (3).

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Epidemiology Guided Medline Search

Bartonellae alternate between two niches: the gut of obligately hematophagous arthropod vectors and the bloodstream of the mammalian reservoir (18). Bartonella species usually have both arthropod and mammalian host specificity, e.g., the domestic cat is the host for B. henselae and the cat flea is the vector, whereas the human is believed to be the definitive reservoir for B. quintana and the body louse is the arthropod vector. In one study of human immunodeficiency virus (HIV)-infected patients with concomitant Bartonella infection (22), patients with B. henselae infection were statistically significantly more likely to have a cat and to have received cat scratches, whereas those with B. quintana were homeless and had exposure to body lice. B. henselae is now known to be the primary agent of cat scratch disease, and the cat serves as the reservoir and vector for transmission of the bacterium to humans. It has become evident that numerous mammalian species have persistent bloodstream infection with their own cognate Bartonella species (2).

Clinical Manifestations Guided Medline Search

The spectrum of disease caused by Bartonella species includes cat scratch disease (B. henselae), bacillary angiomatosis (B. henselae and B. quintana), bacillary peliosis (B. henselae), endocarditis (B. henselae, B. quintana, B. elizabethae), relapsing bacteremia (B. henselae and B. quintana), bacteremia (B. vinsonii subsp. arupensis), trench fever (B. quintana), Oroya fever (B. bacilliformis) and verruga peruana (B. bacilliformis) (17). Infections occur in both immunocompromised and immunocompetent individuals, but the manifestations and response to treatment are dramatically different, depending on the immune status of the patient. Cat scratch disease, a benign, self-limited granulomatous lymphadenitis caused by B. henselae, occurs in immunocompetent individuals. The primary cat scratch disease lesion occurs at the site of a cat scratch, 3-10 days after the inoculation. Lymphadenopathy develops two weeks after the scratch and regresses spontaneously over the ensuing 2-4 months (26).

Bacillary angiomatosis and bacillary peliosis are vascular proliferative manifestations of Bartonella infection that occur in immunocompromised patients (35), especially those co-infected with HIV. Bacillary angiomatosis infections occur most commonly late in HIV infection; in one series, the median CD₄ cell count of patients at the time of bacillary angiomatosis diagnosis was 22/mm³ (29). B. quintana and B. henselae cause bacillary angiomatosis; these lesions are usually noted in the skin, but also can occur in the brain, bones, subcutaneous tissues, lymph nodes, gastrointestinal and respiratory tracts. Peliosis is a closely related vascular proliferative lesion caused by B. henselae infection in the liver and spleen of immunocompromised patients (31). More than half of patients with focal bacillary angiomatosis are bacteremic with the corresponding Bartonella species, emphasizing the systemic nature of this disease (21).

B. bacilliformis infections occur exclusively in South America, most commonly in the Peruvian Andes at an altitude of between 2,500 and 8,000 feet (45). The acute infection, Oroya fever, can cause a severe, potentially fatal hemolytic anemia that is often followed by a chronic phase, verruga peruana, or Peruvian warts (11). These cutaneous lesions may be clinically indistinguishable from those of bacillary angiomatosis and persist for months to years, causing few symptoms.

The Bartonella infections most frequently encountered by physicians in the United States and Europe are bacillary angiomatosis and cat scratch disease (the latter is by far the more common, with greater than 22,000 cases annually in the United States (14)). Treatment of bacillary angiomatosis has not been studied prospectively or systematically. The aggregate of anecdotal cases of cat scratch disease treatment do not demonstrate clearly that treatment affects outcome, and virtually all patients recover fully regardless of whether they receive antibiotic treatment or not. In contrast, bacillary angiomatosis and bacillary peliosis can be fatal if not treated (7), and the response to antibiotic treatment is often dramatic. This difference in treatment response may be due to the number of Bartonella bacilli present in lesions (fewer in cat scratch disease, more numerous in bacillary angiomatosis) or the immune status of the infected individual, or both.

Maman E, et al. Musculoskeletal Manifestations of Cat Scratch Disease. Clin Infect Dis. 2007 Dec 15;45:1535-40.

Breitschwerdt EB, et al. Bartonella sp. Bacteremia in Patients with Neurological and Neurocognitive Dysfunction. J Clin Microbiol 2008;46:2856-2861.

Angelakis E, et al. Human Case of Bartonella alsatica lymphadenitis. Emerg Infect Dis 2008;14:1951-1952.

Laboratory Diagnosis Guided Medline Search

Focal Bartonella infection (cat scratch disease, bacillary angiomatosis) can be diagnosed from biopsied tissue samples using the Warthin-Starry silver stain. Bartonella species can be isolated from human blood (EDTA (4) or Wampole isolator tubes (37)) and tissue using solid agar containing blood or using endothelial cell co-cultivation (21, 24). However, these methods are too laborious for most diagnostic microbiology laboratories. The indirect fluorescence antibody test (9) provides a more accessible means of diagnosing Bartonella infections. This test is performed at the U.S. Centers for Disease Control and Prevention and at some U.S. State Public Health laboratories.

Pathogenesis Guided Medline Search

Very little is known about the pathogenesis in host response between immunocompromised and immunocompetent humans to Bartonella infection. Patients with immunocompromise develop BA whereas patients with normal immune function develop a granulomatous response devoid of vascular proliferation. Finally, it was recently demonstrated in an animal model (36) that the Bartonella bacilli circulate within red blood cells (RBC) for prolonged periods of time, but the mechanism of RBC entry and persistence has not been determined.

[Mege JL, Meghari S, Honstettre A, Capo C, Raoult D. The Two faces of interleukin 10 in human infectio Guided Medline Searchus diseases. Lancet Infectious Diseases 2006:7;557-569.]

Susceptibility in vitro and in vivo Guided Medline Search In Vitro and In Vivo

In Vitro Susceptibilities

As for many other fastidious organisms, in vitro susceptibility testing for Bartonella species is not standardized. Additionally, there is a striking discrepancy between some of the in vitro and in vivo antibiotic susceptibility patterns obtained for Bartonella species. This discrepancy is especially notable for antibiotics that affect cell wall synthesis, e.g., penicillins. Most in vitro susceptibility testing reveals MIC₉₀ values of approximately <0.05 µg/ml for penicillin (27), yet clinical failures and even dramatic disease progression have been frequently noted during treatment with this drug (20, 23). The clinical utility of MICs derived from in vitro susceptibility testing has therefore not been established, and we do not recommend routine susceptibility testing of Bartonella isolates to guide patient therapy.

The earliest in vitro susceptibility testing for Bartonella species was reported by Myers et al. in 1984 (30). They tested two B. quintana strains, the Fuller strain (type strain ATCC VR358) and Heliodoro strain using the agar dilution method (antibiotics diluted with agar composed of GC agar base with IsoVitaleX supplementation). They found a MIC₅₀/MIC₉₀ for penicillin of 0.024/0.035 µg/ml and 0.024/0.044 µg/ml for the 2 strains, respectively. The Fuller and Heliodoro strains were susceptible to erythromycin (MIC₅₀/MIC₉₀ 0.026/0.036 µg/ml and 0.033/0.040 µg/ml, respectively), doxycycline (MIC₅₀/MIC90 0.021/0.036 µg/ml and 0.095/0.115 µg/ml) and tetracycline (MIC₅₀/MIC₉₀ 0.040/0.068 µg/ml and 0.35/0.82 µg/ml). Maurin and colleagues (27) reported MICs for 28 antibiotics with 14 Bartonella isolates, also using an agar dilution method, but using Columbia agar supplemented with 5% horse blood. They also observed susceptibility to penicillin G (MIC₉₀ range of 0.015-0.06 µg/ml) for all Bartonella species: B. quintana (9 strains), B. vinsonii (1), B. elizabethae (1) and B. henselae (3). All 14 Bartonella species and strains tested were susceptible to erythromycin, doxycycline and rifampin. Additionally, they noted susceptibility of all Bartonella isolates to azithromycin and clarithromycin. Sobraques et al. (38) tested the in vitro susceptibility of four strains of B. bacilliformis and found similar susceptibilities to other Bartonella species, including susceptibility to erythromycin (MIC 0.06 µg/ml), azithromycin (MIC 0.015 µg/ml), clarithromycin (MIC 0.015 to 0.03 µg/ml), doxycycline (MIC 0.03 to 0.06 µg/ml), rifampin (MIC 0.003 µg/ml) and streptomycin (MIC 4 µg/ml). In another study, the susceptibility of B. henselae and B. quintana to five macrolides was tested using in vitro cultivation with Vero cell monolayers: all five macrolide antibiotics demonstrated activity against both these Bartonella species (13). All human Bartonella isolates tested to date have been susceptible in vitro to erythromycin and tetracycline except one that was resistant to erythromycin on one testing (MIC >256 µg/ml), but on retesting was susceptible (MIC 0.06 µg/ml) (8). A subsequent relapse isolate from the same patient also was susceptible at an MIC of 0.06 µg/ml.

The E-test (AB Biodisk, Solna, Sweden) was utilized to test the erythromycin, azithromycin, doxycycline, ciprofloxacin, rifampin and vancomycin susceptibilities of 10 B. henselae isolates grown on chocolate agar (47). The susceptibilities for doxycycline, erythromycin, azithromycin and rifampin correlated with those from agar dilution methods. Use of E-test strips with Bartonella isolates streaked on fresh chocolate agar is the susceptibility testing method most accessible to a clinical microbiology lab, and may be useful in the specific situation of comparing initial and relapse isolates for changes in susceptibility. Susceptibility testing with combination drugs has not been performed.

In Vivo Susceptibilities

Animal data substantiate the role of macrolides or a tetracycline in the treatment of Bartonella infection. Regnery and colleagues experimentally infected 25 cats with B. henselae and then treated groups of 5 cats for two weeks with one of four different antibiotics: tetracycline, amoxicillin, erythromycin or enrofloxacin, a fluoroquinolone (34). They cultured the blood of each animal at intervals after experimental infection, and determined that only tetracycline or erythromycin treatment resulted in a significant decrease in the titer of B. henselae bacilli in the blood at any time during the period after infection. There were no significant differences among the four antibiotics with regard to the apparent frequency at which bacteremia resolved. However, the duration of bacteremia did differ: bacteremia resolved at day 71 for tetracycline- and erythromycin-treated cats, at day 83 for control cats and at days 98 and 127 for those treated with enrofloxacin and amoxicillin, respectively.

Antimicrobial therapy Guided Medline Search Smart search

Bartonella Infection in the Immunocompromised Patient

Bacillary Angiomatosis and Bacillary Peliosis: Stoler et al. described the first patient with bacillary angiomatosis in 1983, and although neither the disease had been named nor the infecting bacillus identified, they treated the patient successfully with erythromycin (41). In 1987, we treated the cutaneous and osseous bacillary angiomatosis lesions of the first prospectively identified patient at San Francisco General Hospital with erythromycin; the lesions resolved completely (20). We have now treated more than 65 patients with biopsy-proven bacillary angiomatosis, and from our experience and from reviewing the published literature on treatment of anecdotal bacillary angiomatosis cases (summarized in (23) and (28)), either one of two drugs can be confidently recommended for first line therapy: erythromycin or doxycycline. The response to treatment appears to be equivalent whether erythromycin or doxycycline is prescribed and whether the bacillary angiomatosis is caused by B. henselae or B. quintana.

For treatment of Bartonella infection in the immunocompromised patient, the drug of first choice is either erythromycin 500 mg Q6H PO or IV, or doxycycline 100 mg Q12H PO or IV. We usually initiate therapy for bacillary angiomatosis with oral erythromycin, but favor oral doxycycline over erythromycin in several situations: when poor patient compliance dictates twice daily dosing, to achieve potentially superior CNS antibiotic delivery for focal CNS Bartonella infection, or when severe gastrointestinal symptoms are present that could be exacerbated by oral erythromycin therapy. Rifampin also appears to have in vivo activity in patients with bacillary angiomatosis lesions, but because in general, bacteria spontaneously develop rifampin resistance at a high rate, we do not recommend use of this antibiotic alone.

Combination therapy, with the addition of rifampin to either erythromycin or doxycycline is recommended for immunocompromised patients with acute, life-threatening Bartonella infection, including bacillary peliosis, endocarditis or CNS disease. Failure to respond to antibiotic treatment after 7-10 days should prompt change of drug therapy to the other first line drug, addition of rifampin, change of route of antibiotic administration to intravenous, or all of these. The intravenous route is especially important in those patients with severe Bartonella infection of the gastrointestinal tract who may have inadequate absorption of the antibiotic and symptom exacerbation by oral erythromycin therapy.

Penicillins and first generation cephalosporins lack efficacy and should not be used to treat Bartonella infection in immunocompromised patients (20, 23). Although some anecdotal reports describe a response of Bartonella infection to ciprofloxacin, we have observed progression of bacillary angiomatosis lesions in patients treated with ciprofloxacin (43). In addition, we have isolated Bartonella species from immunocompromised patients treated with gentamicin or trimethoprim/sulfamethoxazole and would therefore not recommend treatment of patients with bacillary angiomatosis infection with either of these antibiotics.

It is evident that the majority of patients with cutaneous bacillary angiomatosis have systemic disease, and a short duration of treatment is frequently associated with relapse. At least three months antibiotic treatment is recommended for patients with cutaneous bacillary angiomatosis, and four months for patients with bacillary peliosis (23). For patients with bacillary angiomatosis of the bone or CNS, treatment should continue for at least four months. After discontinuation of antibiotic therapy, patients should be monitored carefully for relapse of Bartonella infection in the same organ or at a new site. If relapse occurs, the patient should receive treatment and lifelong secondary prophylaxis with either doxycycline or a macrolide (15).

Alternative Therapy

For patients unable to tolerate erythromycin or doxycycline, alternative antibiotics include minocycline (100 mg PO Q12H), used to treat bacillary angiomatosis successfully in an immunocompetent adult (44) or tetracycline (500 mg PO Q6H), used to treat an HIV-infected patient with bacillary angiomatosis successfully (21). There also is very limited experience with azithromycin; this antibiotic could be considered if a patient is incapable of complying with BID doxycycline. Azithromycin (500 mg PO Q24H) for 28-90 days was used to treat five of the ten immunocompetent patients with B. quintana bacteremia reported by Spach et al. (40), and one immunocompromised patient with bacillary angiomatosis was successfully treated with 1 gm PO Q24H (12).

Bartonella Infection in the Immunocompetent Patient

Uncomplicated Cat Scratch Disease: The only prospective, double-blind, placebo-controlled study of treatment of immunocompetent patients with uncomplicated cat scratch disease was reported by Bass et al (1). They treated patients with 5 days of azithromycin or placebo and found no statistically significant difference between the two groups in the duration of lymphadenopathy. However, they did find a statistically significant difference between the number of patients achieving 80% reduction of lymph node volume (by sonography) at 30 days after initiation of treatment in the azithromycin group. Because the natural course of cat scratch disease is relatively benign, self-limited and extremely variable, the data for treating uncomplicated CSD are not currently compelling. More important, as antibiotic resistance of many bacteria is increasing dramatically, treatment of uncomplicated cat scratch disease does not appear to be justified either from the standpoint of the individual patient who is likely to experience little benefit yet would be exposed to potential antibiotic side effects, or from a public health standpoint.

Complicated Cat Scratch Disease: Retinitis, CNS Infection and Granulomatous Hepatitis: Treatment of complicated cat scratch disease, including retinitis, granulomatous hepatitis and encephalitis with a number of different antibiotics has been reported by a number of authors. As with cat scratch disease, however, it is not clear that antibiotics have any efficacy in the treatment of these manifestations in immunocompetent patients. Wong et al. (48) report one patient with stellate neuroretinitis from whose blood B. henselae was isolated. However, despite receiving doxycycline and rifampin for one month and experiencing resolution of ophthalmologic symptoms, B. henselae could still be cultured from the blood of this patient. Many clinicians elect to administer oral antibiotics to patients with visual impairment or to give intravenous antibiotics to those ill enough to require hospitalization. Clinical experience with doxycycline and rifampin in immunocompromised patients makes this combination a reasonable choice if treatment of these immunocompetent patients is elected.

Relapsing Bacteremia: Clinical experience with treatment of isolated Bartonella bacteremia also is limited. Historically, soldiers with B. quintana relapsing bacteremia (trench fever) during World War I cleared the infection in the absence of antibiotic treatment. In contemporary times, one immunocompetent patient with B. henselae bacteremia and meningitis was treated with amoxicillin for five days, then doxycycline for two weeks, and finally ceftriaxone for ten days, but had positive blood cultures for the subsequent six weeks, despite resolution of symptoms (25). Although treatment did not eliminate the bacteremia in this patient, patients with Bartonella bacteremia should be treated, probably with doxycycline for 2-4 weeks. An important caveat should be kept in mind: the patient must first be evaluated carefully for endocarditis because this will change the duration and follow-up of antibiotic treatment.

Endocarditis: Spach et al. (39) described four patients with Bartonella endocarditis, all of whom received antibiotic therapy with multiple drugs, three of whom had valve replacement and all of whom were cured. The one patient who did not require valve replacement received treatment with ceftriaxone, doxycycline and erythromycin. The other three patients who required valve replacement did not receive treatment with a first line antibiotic against Bartonella species prior to valve replacement, and whether surgery was required due to ineffective antibiotic treatment or the natural course of Bartonella endocarditis in these three patients is not known. In these three patients, valve replacement may have been curative.

In a series of 33 Bartonella endocarditis patients (32), only one surviving patient did not require valve replacement, and this patient was treated with ceftriaxone and doxycycline. The remainder of the patients received numerous other antibiotics before and after valvular surgery. B. henselae was isolated from one patient after completion of a course of amoxicillin and gentamicin, and we have isolated Bartonella species from a patient receiving similar treatment. Thus, the culture-negative endocarditis regimen using gentamicin plus penicillin or amoxicillin is unlikely to treat Bartonella endocarditis adequately. Patients with Bartonella endocarditis should receive six weeks of antibiotic therapy, probably with two drugs (doxycycline plus rifampin or erythromycin plus rifampin), because neither first line drug is bactericidal.

Oroya Fever and Verruga Peruana: Antibiotic treatment of patients infected with B. bacilliformis has been documented to decrease the morbidity and mortality associated with both acute and chronic stages of infection with this pathogen. Mortality due to Oroya fever was estimated to be 40% prior to the era of antibiotics and is now estimated to be approximately 8% (11). Some patients who survive the acute anemia succumb to intercurrent infection with intracellular pathogens such as Salmonella, Toxoplasma and Mycobacterium because of an immunodeficient state that may develop during Oroya fever (11). Thus, although penicillin treatment can attenuate the lysis of erythrocytes during the acute phase, patients in the endemic regions of South America often are treated with chloramphenicol to reduce the mortality from intercurrent Salmonella infection. Antibiotic treatment of Oroya fever may not prevent subsequent development of verrugae (45), and once verruga peruana develops, the currently favored treatment is streptomycin (38). Macrolides have also been used successfully, but with much less experience (38).

Bartonella elizabethae: Only one human infection with B. elizabethae has been reported, in a patient with endocarditis (10). This patient defervesced during treatment with nafcillin and gentamicin but developed progressive congestive heart failure and required valve replacement.

Bartonella vinsonii subsp. Arupensis: This species has been isolated from only one human, a cattle rancher, with bacteremia and fever (46). The patient defervesced after a single dose of ceftriaxone and did not appear to have endocarditis by cardiac echocardiography.

(Printable Version of Antimicrobial Therapy for Bartonella)

ADJUNCTIVE THERAPY Guided Medline Search

The majority of patients with Bartonella endocarditis require valve replacement, in addition to antimicrobial therapy. However, the contribution of valve replacement to the cure of Bartonella infection has not been studied prospectively, and most patients reported in the literature received no treatment or were treated with an inadequate regimen before diagnosis of Bartonella endocarditis.

Endpoints for monitoring therapy Guided Medline Search

Patients with cutaneous bacillary angiomatosis lesions should be evaluated for presence of Bartonella infection at other sites that would alter therapy duration, e.g., for osseous lesions or endocarditis. Cutaneous lesions usually improve in the first several weeks of antibiotic therapy and resolve completely in one to two months, depending on the size and number of lesions. Patients with peliosis hepatitis can be monitored by abdominal CT scanning, and those with osseous lesions by ^99mtechnetium bone scans. Patients in whom antibiotic therapy has been stopped should be followed closely for recurrence of Bartonella infection at the original site as well as at new sites, e.g., a patient treated for osteomyelitis may recur with bacteremia (21).

A Jarisch-Herxheimer-like reaction has been described in immunocompromised patients after receiving the first several doses of antibiotics (21). Physicians should advise patients of this possible treatment complication, and patients with severe respiratory and/or cardiovascular compromise should be monitored carefully following institution of antimicrobial therapy. This reaction has occasionally been mistaken for an adverse drug reaction.

An additional concern is the propensity for doxycycline to cause pill-associated ulcerative esophagitis (16). This complication is most frequently reported when a dose is taken with only a small amount of liquid or at night just before retiring, and can be prevented by taking doxycycline several hours before bedtime with copious amounts of water.

VACCINES Guided Medline Search

There are no vaccines available for prevention of Bartonella infection in either humans or animals.

PREVENTION AND PROPHYLAXIS Guided Medline Search Smart search

Prevention of Bartonella Infection

Bartonella species are vector borne, and control of the associated vector may help decrease incidence of these infections. The cat flea efficiently transmits B. henselae from cat to cat (6), and this is hypothesized to facilitate creation of the large reservoir of infected cats (as many as 41% of cats are infected in the San Francisco Bay area (19)). Fleas could potentially transmit B. henselae directly to humans, but this has not been documented to date, and the vast majority of human B. henselae infections occur following a cat scratch or bite (26). Control of cat flea infestation is recommended, especially for the pets of immunocompromised patients (33). This strategy may reduce the transmission of B. henselae by decreasing feline infection, reducing contamination of cat claws due to scratching, and reducing the potential of direct transmission to humans via fleas. Additional recommendations for decreasing risk of B. henselae infection include acquiring a mature cat, which is less likely to scratch and less likely to be bacteremic (5, 19), washing cat wounds immediately with soap and water and avoiding rough play with the cat (15, 33).

Antibiotic treatment of cats belonging to immunocompromised individuals has been proposed, but it is not evident that Bartonella infection can be permanently eradicated from the feline reservoir (34). In addition, treatment usually involves orally force-feeding antibiotics to the cat, which incurs substantial risk of cat scratches and bites and is likely to increase risk of transmission of B. henselae to the humans involved.

Bartonella quintana is transmitted from human to human by the body louse (42); homeless individuals are at increased risk for infestation with the body louse and thus for infection with B. quintana. Avoiding infestation with and exposure to the body louse is the only current recommendation for prevention of B. quintana infection. For B. bacilliformis, the substantial decrease of infection in endemic regions of the Peruvian Andes has been attributed not only to antibiotic treatment of humans but also to reduction of the sandfly vector for this Bartonella species (45). For B. elizabethae and B. vinsonii subsp. arupensis, the reservoirs are apparently rodents (46), but the vectors are as yet unknown. There currently are no recommendations about prevention of infection with these two species.

Antibiotic Prophylaxis

Antibiotics of the macrolide, tetracycline and rifamycin classes have shown good in vivo activity against Bartonella species. Treatment with macrolide antibiotics was protective against B. henselae and B. quintana infection in HIV-infected patients in one study (22). It is therefore likely that Mycobacterium avium complex prophylaxis or treatment regimens that include an antibiotic of the macrolide, rifamycin or tetracycline class will provide adequate prophylaxis against Bartonella infection.

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