key: cord-0040246-9x7sfl7i
authors: Pressler, Barrak
title: Bartonellosis
date: 2009-05-15
journal: Consultations in Feline Internal Medicine
DOI: 10.1016/b0-72-160423-4/50007-x
sha: ecd106f4fb36a44a5c8fcbc2a2bc7f86ce5fd7cb
doc_id: 40246
cord_uid: 9x7sfl7i

nan

Although more than 100 years old, Robert Koch's postulates still are used as standards for establishing that a given microorganism is an agent of disease. 1 However, we now know that because of the complex interaction of genetics, microbes, and the host's immune system, disease development is not always as simple as Koch believed. The postulates are easy to fulfill for an organism that is nearly universally pathogenic. But what of a microbe that causes disease only in an individual with a particular genetic make-up, who must have been exposed previously to a second microorganism, and only when the host is exposed to the microbe at a time of mucosal injury? In such a scenario the pathogen may never even be suspected if in the absence of the other precipitating factors it is part of the normal host flora. Many conditions we consider to be "idiopathic" or "immune-mediated" may truly have an infectious etiology but require more than Koch's postulates to identify the causative organisms.

Feline bartonellosis is the prototypical example of this challenge in infectious disease research. Cats rarely develop the same Bartonella spp.-induced disease syndromes as other species, but what particular feline or microbial factors are protective? The majority of naturally infected cats appear to be asymptomatic reservoirs, so why do experimentally infected cats exhibit clinical abnormalities more commonly? After 15 years of research, we are still not even sure what cells Bartonella spp. infect in cats. Given these gaps in our knowledge, it is unlikely that Koch's postulates will be fulfilled for Bartonella spp.-induced disease in the near future. However, our knowledge of this genus is increasing rapidly, which facilitates educated approaches to diagnosis and treatment of infected animals.

Bartonella spp. are facultatively intracellular, gram-negative bacilli that infect a variety of animals. 2 Bartonella spp. are within the alpha-2 Proteobacteria; closely related bacteria of veterinary importance are Brucella spp. and the Rickettsiae. The genus Bartonella has undergone major reorganization as molecular techniques have defined genetic relationships between known species and improved the detection of new species. The previously separate genera Rochalimaea and Grahamella were merged into Bartonella in the early 1990s. 2, 3 Approximately 20 species of Bartonella are recognized currently; however, new species have been defined as recently as 2002, and further changes in the classification of Bartonella undoubtedly will occur in the coming years. 2, 4 Most Bartonella spp. have animal reservoir hosts, but only a minority of these infect dogs and cats (Table 4 -1). 4 The four species that have been isolated from cats are B. henselae, B. clarridgeiae, B. koehlerae, and B. bovis (weissii). B. henselae is classified further into two genotypes, B. henselae I and B. henselae II, previously known as B. henselae Houston I strain and B. henselae Marseilles strain, respectively. 5 These genotypes are differentiated by the 16S ribosomal RNA gene sequences. 5 Differences in other proteins also have been demonstrated, and these are likely responsible for the variation in antibody responses in infected cats. 5, 6 Coinfection with both genotypes of B. henselae can occur in cats, as can coinfection with either B. henselae genotype and B. clarridgeiae. [7] [8] [9] [10] [11] [12] 

The domestic cat is the reservoir host for B. henselae, and B. henselae is the Bartonella spp. isolated most commonly from cats. 2 The natural history of B. henselae infection has been deduced largely from experimental studies, because naturally infected cats usually are asymptomatic and thus not identified routinely in clinical practice. Although B. henselae is adapted for infection of cats, its larger genome and numerous potential vectors indicate it is less specialized than other members of the genus. 13, 14 In addition to the domestic cat, wild felids also can be infected, but the clinical implications in these species are still unknown. 15, 16 The prevalence of B. henselae and B. clarridgeiae in cats has been studied throughout the world (Figure 4-1 comparison of prevalence studies between countries is difficult because each report uses different techniques for diagnosing infection or seropositivity. Regardless, significant regional differences exist in the overall prevalence of Bartonella spp. in addition to the relative prevalence of the different Bartonella spp. within populations of cats. Regional prevalence throughout the world of both Bartonella spp. exposure and bacteremia increases as yearly average temperature and precipitation increase. 10, 17 This combination of climatic variables is the most suitable for fleas, the insect vector for B. henselae and presumptively B. clarridgeiae. 18, 19 Regions unsuitable for fleas (as a result of severe winters, such as in Norway and Alaska, or low precipitation, such as the southwestern United States) have a low prevalence of Bartonella spp.-positive cats. 17, 20 Conversely, regions with mild year-round weather (such as the southeastern United States, California, central Europe, the Middle East, southern Africa, and the Philippines) have a higher number of exposed and infected cats. 9, 17, [21] [22] [23] [24] [25] For unknown reasons, large regional variations exist between the relative prevalence of B. henselae genotype I versus genotype II, and B. henselae versus B. clarridgeiae. For example, less than 10 per cent of B. henselae cases in Japan are genotype I, whereas most cases of B. henselae are genotype II in the Philippines. 9,10 B. henselae genotype II predominates in northern and central Europe, but western Europe has an approximately equal number of both genotypes. 7,12,26-29 Regional differences within the United States also exist for B. henselae genotype distribution. 25 As with B. henselae, the seroprevalence and infection rate for B. clarridgeiae vary throughout the world.* Many studies have identified factors associated with B. henselae infection in cats. Some results are conflicting; however, most support an increased risk of bacteremia in feral cats, shelter cats, young cats, cats with partial or complete outdoor lifestyles, cats with fleas, and cats in multicat environments. † Cat gender, retroviral infection, Toxoplasma gondii serostatus, and illness in general are not associated with bacteremia or exposure. ‡ Risk factors for seropositivity are the same as for bacteremia, except that prevalence of seropositivity increases with cat age as the prevalence of bacteremia decreases. 25, 33, 38, 39 Other factors that have been studied less often but appear to have no association with infection or exposure include visits to veterinarians, declawing, presence of dogs in the same household, and attendance at cat shows. 33, 34 Factors that have been reported once as possibly significant but have not been confirmed in other reports include presence of antibodies against coronavirus, spumavirus, or Borrelia burgdorferi. 26, 39 Less is known of the natural epidemiology of the non-B. henselae Bartonella species that infect cats. As with B. henselae, cats are the only identified reservoir of B. clarridgeiae; however, rate of exposure to and infection with B. clarridgeiae usually is much lower than for B. henselae. § Because fleas from cats have been found to carry B. clarridgeiae, the route of infection in cats is presumed to be similar to B. henselae. 19, 40 Identified risk factors for B. clarridgeiae exposure and infection are similar to those of B. henselae.

Natural infection with B. koehlerae has been reported in three cats (two in California and one in France). 41, 42 Because cats infected experimentally with B. koehlerae fail to demonstrate the same relapsing bacteremia as cats infected with other Bartonella spp., the prevalence of infection likely is underestimated by these rare reports. 43 B. bovis (originally reported as B. weissii) has been cultured from only four cats, all in the United States. 44 Cats reported with B. koehlerae or B. bovis infection did not have obvious environmental or historical findings different from other Bartonella spp.-infected cats. 41, 42, 44 Although seropositivity to B. elizabethae and B. quintana has been reported in cats, infection has not been demonstrated. 21, 24, 38 Whether these results represent true exposure or cross-reactivity between Bartonella spp. is unclear. B. henselae antibodies are known to cross-react with B. quintana; however, B. quintana has been isolated from cat fleas. 19, 21 Regardless of whether exposure to these Bartonella spp. indeed occurs, they are of unknown clinical significance in cats.

Although not proven definitively, current thought assumes that after inoculation B. henselae and B. clarridgeiae enter the bloodstream, infect erythrocytes, and cause bacteremia. Initial bacteremia in experimental cats lasts from 2 to 32 weeks, beginning 1 to 2 weeks after inoculation. [45] [46] [47] [48] [49] [50] [51] [52] [53] Bartonella spp. DNA often can be amplified from cat blood for several weeks after blood cultures become negative. 52 Recurrent episodes of bacteremia follow at unpredictable intervals, with the frequency of bacteremia decreasing with age. 48, [52] [53] [54] The site of persistent Bartonella spp. infection during periods of abacteremia is still unknown. However, suspected sites include vascular endothelial cells, erythrocytes, lymph nodes, and cells of the central nervous system. [55] [56] [57] [58] [59] [60] No definitive proof exists that cats ever become free of infection.

The antibody response to acute experimental B. henselae or B. clarridgeiae infection is similar to other diseases. Anti-Bartonella spp. IgM is first detected within 1 week of inoculation followed by a rise in IgG 1 to 2 weeks later. 47, 50, 51 The IgG titer peaks after 5 to 10 weeks and remains persistently elevated for months to years. 18, [47] [48] [49] [50] [51] 53, 54 Rare naturally infected bacteremic but seronegative cats have been identified. 7,25,31,61 These cats may have had positive titers that declined to extremely low concentrations over time, or a subset of infected cats may never seroconvert. Although some studies suggest that antibody titer may correlate with bacteremia, this association is too unreliable to be clinically useful. 33, 54 After experimental infection with one genotype or species of Bartonella, subsequent challenge with the identical genotype or species results in a protective rise in anti-Bartonella spp. IgG, preventing illness or bacteremia. 62, 63 However, challenge with a different genotype or species does not result in crossprotection, and bacteremia with the second Bartonella spp. occurs. 62, 63 The exception to this is in cats first infected with B. henselae genotype I and then challenged with B. henselae genotype II; these cats appear immune to both genotypes, although the reverse order of infection does not confer the same immunity. 63 Natural infection with multiple genotypes and species of Bartonella has been reported several times. [7] [8] [9] [10] [11] [12] Anti-Bartonella spp. antibodies develop against many bacterial proteins. 5, 64 Considerable overlap exists in antibody targets between species, and thus cross-reactivity between the antibodies against different Bartonella spp. occurs. 21, 40, 43 Antibodies against the different proteins develop over a period of several weeks. 64

Cell-mediated immunity against Bartonella spp. has not been studied extensively. Peripheral blood CD4:CD8 lymphocyte ratio remains within reference range during acute infection despite marked hyperplasia of lymphoid organs. 47, 53 B. henselae-specific lymphocytes that proliferate in response to B. henselae-derived proteins are detectable within spleens from experimentally infected cats. 47, 49 Delayed-type hypersensitivity in B. henselae-infected kittens causes mild local reactions after intradermal inoculation of bacterial lysates. 49 

The vector for B. henselae is the cat flea. 18 Transmission is thought to occur by intradermal inoculation of infected flea feces or regurgitation of flea saliva into the bite wound during feeding. 18 ,65 Ingestion of infected fleas or their feces does not result in infection. 65 Experimentally infected flea-free cats do not transmit B. henselae to co-housed cats despite fighting and playing behavior that includes traumatic injuries. 18, 53 B. henselae is not transmitted transplacentally or transmammary to kittens from bacteremic queens. 43, 49, 53 Kittens born to infected mothers acquire maternal anti-Bartonella spp. antibodies from colostrum that is first detectable at 2 weeks of age and then wanes to undetectable concentrations by 10 weeks. 49 

Illness in general (defined as a cat brought to a veterinarian for any reason other than preventive care) is not associated with bartonellosis. 12, 25, 26, 34 However, when specific disease syndromes are compared between Bartonella spp.-positive and Bartonella spp.-negative cats, stomatitis twice has been associated with B. henselae. 26, 35 Anecdotally, some cats with intractable oral disease respond to appropriate anti-Bartonella spp. treatment. Other conditions that may be more prevalent in Bartonella spp.-infected cats are lymphadenopathy and renal or urological disease. 26, 35 Bartonella spp. are the most common cause of culturenegative endocarditis in dogs and human beings. 66 Patients present typically with the same history, physical examination, and cardiac-related abnormalities as with non-Bartonella spp. endocarditis; however, no bacteria are isolated by routine aerobic blood cultures. 62 One case of B. henselae endocarditis has been reported in a cat. 67 Although Bartonella spp.-specific blood cultures were negative, light microscopic examination of the aortic valve revealed intraendothelial organisms consistent with a Bartonella spp., and B. henselae DNA was amplified from valve tissue. 67 Several reports have identified Bartonella spp. as a possible cause of uveitis in cats 68-70 (see Chapter 3). Bartonella spp. infection is a well-recognized cause of uveitis in people and was suspected to be a cause of anterior uveitis and choroiditis in one dog. 4, 71 Cats with inflammatory ocular disease have a high prevalence of anti-Bartonella spp. antibodies; however, seropositivity was not statistically significant in the one study that compared cats with uveitis to a control population. 68, 70 The aqueous humor versus serum anti-Bartonella spp. antibody titer ratio may be used as an aid in the diagnosis of Bartonella spp.-induced uveitis; local antibody production in the eye supports the diagnosis of ocular bartonellosis. 69, 70 As with serum anti-Bartonella spp. antibodies, the prevalence of B. henselae DNA within aqueous humor of cats with uveitis is not significantly different from seropositive healthy cats. However, antibodies may decrease the number of viable organisms below the level of detection by PCR, or inflammation may be a chronic process that progresses despite the clearance of infection. 70

Most experimentally infected cats have no apparent clinical signs during the chronic, relapsing bacteremia stage of Bartonella spp. infection. However, a transient febrile illness can occur immediately after inoculation of specific pathogen-free cats. 47, 48, 50, 51 Between 1 and 3 days after intradermal inoculation, cats develop a localized inflammatory lesion that progresses and resolves spontaneously over 2 weeks. 50, 51 The inoculation site typically is erythematous and firm, and pustules may form. 50, 51 Approximately 1 week after infection, kittens become lethargic and anorexic with fever, pale mucous membranes, peripheral lymphadenopathy, and a stiff gait. 47, 48, 50, 51 Lymph node and splenic enlargement develop secondary to marked lymphoid hyperplasia. 47, 50 The time between inoculation and development of clinical signs is proportional to the number of bacteria used in the inoculum; smaller doses result in slower development of illness. 47 Recovery from the initial transient illness corresponds to resolution of the first bacteremic episode. 47, 48, 51 In all cats, lymphadenopathy regresses, skin lesions heal, and fever resolves without incidence. 47, 51 Later episodes of bacteremia do not cause recurrence of clinical signs, and no correlation exists between bacteremia and antibody titer. 54 Clinicopathological abnormalities during acute and chronic infection are rare, although eosinophilia has been reported. 48, 50, 54, 72 Several additional abnormalities have been reported more rarely in experimental cats. Behavioral changes and signs of central neurological disease including star-gazing, obtundation, and postural deficits with decreased conscious proprioception may occur in cats infected as kittens. 48, 51 These episodes last from 1 to 4 days, occur 1 week to 4 months after inoculation, and coincide with periods of bacteremia. 48, 51 Nystagmus and whole-body tremors developed in two queens infected as adults. 73 Cataracts or vitreal degeneration developed in several cats infected as kittens. 48, 70 Finally, B. henselae infection may prevent conception or cause fetal resorption in infected queens. 73 Some reports suggest that clinical signs in experimentally infected cats may be related to the species or strain of Bartonella used. 31 Although the presence and severity of complications in people with cat scratch disease may be associated with B. henselae genotype, studies of naturally infected cats do not support this difference in pathogenicity. 52, 54, 63, 74 Other Species Unlike in cats, Bartonella spp. are considered pathogens in human beings and dogs. Familiarity with the disease syndromes and clinical signs associated with bartonellosis in these species may allow recognition of unusual Bartonella spp.-induced diseases in cats. Endocarditis and uveitis are discussed earlier in this chapter. Cat scratch disease, proliferative vascular diseases, Oroya fever, and trench fever are diseases induced by Bartonella spp. in people that may have analogous conditions in animals. Several other clinical signs and diseases have been associated with Bartonella spp. infection in dogs, although definitive proof of causation is lacking (see Table 4 -1).

Cat scratch disease is a chronic, localized, suppurative lymphadenitis in people that usually follows traumatic injury by a cat. 4 Lymphadenopathy lasts several months, is nonpainful, and usually is not accompanied by systemic signs of illness. 4 However, some patients develop systemic complications, including fever, myalgia/arthralgia, splenomegaly, and central nervous system or ocular disease. 4 Although the typical lymphadenitis of cat scratch disease has not been reported in animals, granulomatous lymphadenopathy in dogs and transient lymphadenopathy after acute infection in cats do occur. 47, 50, 75 As reviewed previously, some of these complications occur in acute (fever, arthralgia/myalgia, splenomegaly) or chronic (CNS or ocular disease) B. henselae infections in cats.* Bacillary angiomatosis, peliosis hepatis, and verruga peruana are angioproliferative lesions that affect various organs in people. 4 Several Bartonella spp. have been implicated, including B. henselae, B. quintana, and B. bacilliformis. 4 Peliosis hepatis associated with B. henselae has been reported in a dog. 76 No reports of angioproliferative diseases exist in cats. The pathogenesis of these vascular lesions is unknown, but is related presumptively to the presence of intraendothelial organisms. 4, 57 Oroya fever is an acute febrile disease in human beings caused by B. bacilliformis. 4 Severe intravascular hemolysis secondary to erythrocyte invasion by organisms occurs; mortality is high in untreated patients. 4 No analogous disease has been reported in animals, although anemia has been associated with B. elizabethae infection in a dog. 77 Trench fever was described initially as an acute, transient febrile illness caused by B. quintana in people. 4 It is now diagnosed more commonly as a cause of chronic asymptomatic bacteremia, analogous to natural bartonellosis in cats. 4

Given the diverse manifestations of Bartonella spp. infections, the differential diagnoses for infection in cats are extensive. The transient fever and lymphadenopathy seen in acute infection should be differentiated from acute viral infections (particularly FeLV and feline immunodeficiency virus [FIV]), bacterial sepsis, toxoplasmosis, and systemic fungal diseases. Noninfectious diseases, particularly lymphoma, also should be considered in any cat with these vague signs of illness.

More specific syndromes ascribed to Bartonella spp. infection in cats have differential diagnoses that are reviewed thoroughly elsewhere. In general, causes of uveitis in cats include viral, protozoal, fungal, and neoplastic diseases. The more ubiquitous bacteria, particularly the enteric bacteria, should be considered in cats with endocarditis. Calicivirus (see Chapter 1), feline odontoclastic resorptive lesions (see Chapter 9), and hypersensitivity reactions are common causes of oral inflammation or stomatitis that should be excluded before consideration of bartonellosis.

In cats, asymptomatic Bartonella spp. infection must be differentiated from Bartonella spp.-induced disease. The former is relatively straightforward to diagnose: positive blood culture or successful amplification of Bartonella spp. DNA by PCR is diagnostic for infection. However, no single diagnostic test can be used to diagnose clinical bartonellosis in cats. Clinicians must always keep in mind that disease in cats secondary to Bartonella spp. infection is rare. Because cats are natural reservoirs for B. henselae and B. clarridgeiae, exclusion of differential diagnoses and response to therapy are just as important for diagnosing clinical bartonellosis as is demonstration of seroreactivity or documenting presence of organisms. Several diagnostic tests are commercially available, and others are offered at research or specialty laboratories (Table 4 -2).

The most widely available tests for Bartonella spp. detect the presence of anti-Bartonella spp. antibodies. These tests include the immunofluorescent antibody test (IFA), which detects the presence of antibodies against whole organisms, and the Western blot, which detects antibodies against proteins from bacterial lysates. Most The high prevalence of seroreactivity to B. henselae and B. clarridgeiae makes antibody testing a poor method for diagnosing Bartonella spp.-induced disease. As with any serological test, the presence of antibodies merely means that a patient has been exposed to the organism. In general, the long lifespan of plasma cells and long half-life of IgG ensure that antibodies persist in circulation long after organisms have been cleared. For cats in particular, a poor correlation exists between the presence of anti-Bartonella spp. antibodies and illness. 7, 25, 31, 33 Other limitations to the antibody tests include inability to discriminate between different Bartonella spp. because of antibody cross-reactivity, and lack of correlation between titer magnitude and bacteremia, time since infection, or presence of clinical signs.* Antibody testing in cats may be useful in two situations. First, the high negative predictive value (>90 per cent) of the IFA test allows rapid screening of cats. 25, 31 Although positive results do not always imply infection, absence of anti-Bartonella spp. antibodies is likely to mean that a patient is not infected. However, because a small number of infected cats remain seronegative, this screening method does not identify all infected cats reliably. 7,25,31,61 Second, a fourfold or greater increase in antibody titer may imply recent infection. This likewise should be interpreted with caution, because naturally and experimentally infected cats may have titers that fluctuate widely over time. 54 A large increase in antibody titer should be accompanied by clinical signs to be supportive of Bartonella spp.-induced disease.

Definitive diagnosis of Bartonella spp. infection requires isolation by blood culture or DNA amplification by PCR. Collection of blood for either of these tests is best done before initiation of antibiotic therapy. Laboratories should be notified that Bartonella spp. are suspected when submitting blood for culture because samples require special processing and a variety of culture media should be used. 25, 27 Most Bartonella spp. cultures are positive within 2 weeks of plating, although some isolates may take up to 2 months to grow. 78 Alternatively, PCR of blood may offer a more rapid method of diagnosing Bartonella spp. infection than culture. Theoretically the sensitivity of PCR is equal to or greater than that of culture; however, this test may vary between laboratories and few studies have been published using this diagnostic test. 54 As with antibody testing, clinicians should not assume that positive culture or PCR results mean that a cat's clinical signs are due to Bartonella spp. infection. The majority of culture-and PCRpositive cats are asymptomatic.

The previous discussion implies the diagnosis of Bartonella spp.-induced disease in cats may be impossible. However, despite the less-than-perfect tests available, a practical approach to diagnosis can be used. Because Bartonella spp. infection in cats is asymptomatic in the vast majority of cases clinical bartonellosis should be considered a "rule-out" diagnosis. Testing should be considered only after more likely differential diagnoses have been excluded in patients that have clinical signs potentially associated with Bartonella spp.

Cats with clinical syndromes that have a strong association with Bartonella spp. infection (such as endocarditis) should be tested earlier in the diagnostic work-up. In cats, this includes endocarditis and possibly uveitis. Patients with clinical signs rarely attributed to bartonellosis (such as lymphoplasmacytic stomatitis, anemia, or fever) also may be tested for Bartonella spp., although testing in these cases likely should occur later in the diagnostic plan. Once the decision has been made to test for Bartonella spp., antibody testing can be an appropriate initial screen. Paired titers may be considered in acutely ill cats; single resting titers are sufficient in patients with chronic illnesses. Negative titers can be considered adequate for excluding bartonellosis in chronically ill cats, whereas positive titers can be followed by blood culture, PCR, or antibiotic trials as appropriate. Culture of blood is recommended in all cases of endocarditis because this disease is always presumed to be secondary to bacteremia. Serial antibody titers likely are not useful for monitoring response to treatment, although some laboratories do claim to see a decrease in titer after antibiotic therapy. Repeat culture or PCR can be performed if desired, but because of the relapsing nature of Bartonella spp. bacteremia, negative results may be transient.

In vitro susceptibility testing of Bartonella species thus far has failed to predict susceptibility in vivo. 4 Bartonella spp. tested on standard culture media are susceptible to most antibiotics; however, these results do not take into account the intraerythrocytic location of Bartonella spp. organisms in infected animals. Susceptibility testing of Bartonella spp. cocultivated with whole cells has shown that most antibiotics are only bacteriostatic, although aminoglycosides hold the most promise for killing intracellular organisms. 4, 72 Trials in naturally and experimentally infected cats are few. A definitive treatment has not been established at this time, and published studies contradict one another. Enrofloxacin and doxycycline have been reported to reduce or eliminate circulating B. henselae in naturally infected cats when administered at standard doses for 2 to 4 weeks. 72 However, most cats that did not have organisms isolated by blood culture during or soon after treatment were bacteremic again weeks to months after cessation of therapy. 72 In experimentally infected cats, one study reported no benefit from treatment of B. henselae-infected cats with amoxicillin or enrofloxacin; however, erythromycin or tetracycline depressed the number of circulating organisms without decreasing the length of bacteremia. 46 Another study showed reduction or clearance of B. henselae with doxycycline or amoxicillin with or without clavulanic acid, whereas enrofloxacin treatment was ineffective in all cases. 45 Although not evaluated in any controlled study, the current recommended drug for treatment of Bartonella spp.-induced disease in cats is azithromycin. The regimen used is usually 5 to 10 mg/kg PO q24h for 5 days, then q48h for 40 days. No studies have been reported on the efficacy of this drug in cats for treatment of any disease, and this dosage is based solely on pharmacological data, human literature, and anecdotal reports.

As with cats, optimal treatment of bartonellosis of human beings has not been studied systematically. In the only randomized prospective double-blind study in people with cat scratch disease resulting from B. henselae, azithromycin was shown to decrease lymph node size by 80 per cent in half of all treated patients, versus 7 per cent of placebo-treated controls. 4 However, no beneficial effect was observed for prevention of complications such as endocarditis. Doxycycline and rifampin combination therapy is the treatment of choice in patients with complicated cat scratch disease infections. 4 Vascular proliferative diseases in people caused by Bartonella spp. are treated with erythromycin or doxycycline. 4 Studies on Bartonella spp. endocarditis support the use of gentamicin with doxycycline, with rifampin to be substituted if renal function precludes the use of aminoglycosides. 4 Interestingly, for all Bartonella spp. infections in people, overtly immunosuppressed patients have a more dramatic response to antibiotic therapy than immunocompetent individuals. 4 Routine treatment of asymptomatic Bartonella spp.infected cats is not recommended. True incidence of Bartonella spp.-induced disease is low, and indiscriminate antibiotic use may lead to resistance. In those cats with clinical signs suspected to be secondary to Bartonella spp., improvement or resolution of illness should be used to determine duration of therapy in conjunction with serial culture or PCR tests. Lack of response to appropriate anti-Bartonella spp. therapy should prompt clinicians to question whether the diagnosis of Bartonella spp.-induced disease is correct.

The only natural route of infection currently known is transmission by fleas during feeding. 18 Inoculation of flea feces into the bite lesion occurs either during feeding by the flea, or secondary to scratching or biting by the cat. 18 Based on studies of ectoparasites collected from dogs and nondomestic animals, ticks also are suspected to be capable of Bartonella spp. transmission. 2, 79 Therefore, ectoparasite control is the most important method for preventing infection of naïve cats. Flea baths of seropositive cats immediately before introduction to a cattery without infected animals prevented seroconversion of the uninfected cats. 34 Limiting cat exposure to other animals, particularly stray cats or cats with access to the outdoors, is logical. However, unidentified factors may contribute to or prevent infection in cats; persistently infected animals within the same household may harbor different Bartonella spp. without cross-infection despite the presence of fleas. 80

Many of the syndromes caused by Bartonella spp. in human beings traditionally have been diseases of high-density populations with substandard hygiene or have been limited geographically by the distribution of the vector insect. 2, 4 However, the increase in immunocompromised people throughout the world undoubtedly has contributed to the emergence of Bartonella spp. as an important zoonosis. Unfortunately the risk of transmission of bartonellosis from an infected cat to a person is unknown. At least one study showed that B. henselae seropositivity in human patients with a variety of conditions was not related to pet ownership. 81 Based on identified risk factors for Bartonella spp. infection in cats, the ideal pet cat for an immunocompromised person is one raised in a clean, ectoparasite-free environment. Epidemiological studies have shown that cats greater than 1 year of age and cats that have been pets their entire lives are less likely to be seropositive or infected with Bartonella spp.* Therefore owners seeking a new pet should be counseled to adopt an adult cat from a private, cattery environment. Because the absence of anti-Bartonella spp. antibodies has a high negative predictive value, adoption of a seronegative cat is the best option. Owners should be warned however that even the use of antibody testing as a negative screening process will not completely eliminate infected cats, as a small number of cats are infected but seronegative. Blood culture or PCR can be used to confirm lack of infection if desired.

Any seropositive but non-bacteremic cat must be considered possibly infected, as bacteremia is cyclic. Theoretically, ownership of a seropositive or bacteremic cat with stringent ectoparasite control may decrease the risk of zoonotic transmission of Bartonella spp., because human infection also may require inoculation of flea feces. Treating seropositive or culture-positive cats with courses of antibiotics is of questionable value because elimination of the carrier state in cats has not been demonstrated definitively. Ultimately the decision on whether to recommend ownership of a Bartonella spp. seropositive or confirmed infected cat to an immunocompromised person is best left in the hands of a physician.

A consensus statement on appropriate screening of animals to be used as blood donors has been published by a panel of veterinary infectious disease experts within the American College of Veterinary Internal Medicine. 82 I recommend that practitioners or veterinary practices that are planning to establish their own cat blood donor pool follow these guidelines. Regardless, institutions that rely upon privately-owned volunteered cats for blood donors disagree on screening for Bartonella spp. infection. Given the high prevalence of infected cats, exclusion of seropositive or bacteremic animals significantly limits the available pool of blood donors. However, because experimentally infected cats are most likely to show clinical signs immediately after inoculation, it may be desirable to avoid transfusion of naïve ill patients as they may be unable to tolerate further insult. Maintenance of a Bartonella spp. seronegative donor pool may be feasible only in geographical regions of low seroprevalence.

Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates

Bartonella infection in animals: carriership, reservoir potential, pathogenicity, and zoonotic potential for human infection

Proposals to unify the genera Bartonella and Rochalimaea, with descriptions of Bartonella quintana comb. nov., Bartonella vinsonii comb. nov., Bartonella henselae comb. nov., and Bartonella elizabethae comb. nov., and to remove the family Bartonellaceae from the order Rickettsiales

Recommendations for treatment of human infections caused by Bartonella species

Genotypic characteristics of two serotypes of Bartonella henselae

Predominant outer membrane antigens of Bartonella henselae

Prevalence of Bartonella species in domestic cats in the Netherlands

Coinfection with Bartonella clarridgeiae and Bartonella henselae and with different Bartonella henselae strains in domestic cats

Bartonella henselae and Bartonella clarridgeiae infection in domestic cats from the Philippines

Prevalence of Bartonella henselae, Bartonella clarridgeiae and the 16S rRNA gene types of Bartonella henselae among pet cats in Japan

Prevalence of Bartonella species and 16S rRNA gene types of Bartonella henselae from domestic cats in Thailand

Prevalence of Bartonella species causing bacteraemia in domesticated and companion animals in the United Kingdom

The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae

Genomic diversity of Bartonella henselae isolates from domestic cats from Japan, the USA and France by pulsed-field gel electrophoresis

Seroprevalence of Bartonella infection in American free-ranging and captive pumas (Felis concolor) and bobcats (Lynx rufus)

Prevalence of Bartonella infection in wild African lions (Panthera leo) and cheetahs (Acinonyx jubatus)

Prevalence of Bartonella henselae antibodies in pet cats throughout regions of North America

Experimental transmission of Bartonella henselae by the cat flea

Molecular detection of Bartonella quintana, B. koehlerae, B. henselae, B. clarridgeiae, Rickettsia felis, and Wolbachia pipientis in cat fleas

Low prevalence of Bartonella henselae infections in Norwegian domestic and feral cats

Comparative seroreactivity to Bartonella henselae and Bartonella quintana among cats from Israel and North Carolina

Bartonella (Rochalimaea) henselae in Southern Africa-evidence for infections in domestic cats and implications for veterinarians

Genetic variability and prevalence of Bartonella henselae in cats in Berlin, Germany, and analysis of its genetic relatedness to a strain from Berlin that is pathogenic for humans

AM: Seroprevalence of and risk factors for Bartonella henselae and Bartonella quintana infections among pet cats in Jordan

Prevalence, risk factors, and genetic diversity of Bartonella henselae infections in pet cats in four regions of the United States

Seroprevalence of Bartonella henselae infection and correlation with disease status in cats in Switzerland

Prevalence of Bartonella henselae and Bartonella clarridgeiae in stray cats

Prevalence of Bartonella infection in domestic cats in Denmark

Prevalence of Bartonella henselae in young, healthy cats in Sweden

Prevalence of Bartonella henselae and Bartonella clarridgeiae in an urban Indonesian cat population

Epidemiology of Bartonella infection in domestic cats in France

A serological survey of rural dogs and cats on the southwestern Canadian prairie for zoonotic pathogens

Bartonella henselae prevalence in domestic cats in California: risk factors and association between bacteremia and antibody titers

Seroprevalence of Bartonella henselae in cattery cats: association with cattery hygiene and flea infestation

Does coinfection of Bartonella henselae and FIV induce clinical disorders in cats?

Seroprevalence of Bartonella henselae and Toxoplasma gondii infections among pet cats in Kanagawa and Saitama prefectures

Seroprevalence of Bartonella henselae, Toxoplasma gondii, FIV and FeLV infections in domestic cats in Japan

Prevalence of antibodies to Bartonella henselae, B. elizabethae and B. quintana in Swedish domestic cats

Evidence of Bartonella henselae infection in cats and dogs in the United Kingdom

Lack of correlation between Bartonella DNA detection within fleas, serological results, and results of blood culture in a Bartonella-infected stray cat population

Bartonella koehlerae sp. nov., isolated from cats

First isolation and detection by immunofluorescence assay of Bartonella koehlerae in erythrocytes from a French cat

Experimental infection of domestic cats with Bartonella koehlerae and comparison of protein and DNA profiles with those of other Bartonella species infecting felines

A fourth Bartonella species, Bartonella weissii, species nova, isolated from domestic cats (abstract)

Bartonella henselae infection in cats: evaluation during primary infection, treatment, and rechallenge infection

Experimentally induced Bartonella henselae infections followed by challenge exposure and antimicrobial therapy in cats

Experimental infection of young specific pathogen-free cats with Bartonella henselae

Relapsing bacteremia after blood transmission of Bartonella henselae to cats

Immune response of neonatal specific pathogen-free cats to experimental infection with Bartonella henselae

Acute clinical disease in cats following infection with a pathogenic strain of Bartonella henselae (LSU16)

Clinical disease in kittens inoculated with a pathogenic strain of Bartonella henselae

Evaluation and use of a nested polymerase chain reaction assay in cats experimentally infected with Bartonella henselae genotype I and Bartonella henselae genotype II

Experimental and natural infection with Bartonella henselae in domestic cats

Clinical and pathologic evaluation of chronic Bartonella henselae or Bartonella clarridgeiae infection in cats

Extracellular Bartonella henselae and artifactual intraerythrocytic pseudoinclusions in experimentally infected cats

Infection of feline brain cells in culture with Bartonella henselae

The VirB type IV secretion system of Bartonella henselae mediates invasion, proinflammatory activation and antiapoptotic protection of endothelial cells

Argyrophilic, intracellular bacteria in some cats with idiopathic peripheral lymphadenopathy

Bartonella henselae invasion of feline erythrocytes in vitro

Immunofluorescent detection of intraerythrocytic Bartonella henselae in naturally infected cats

Isolation of Bartonella henselae from domestic cats in Japan

Homologous protection but lack of heterologous protection by various species and types of Bartonella in specific pathogen-free cats

Infection and re-infection of domestic cats with various Bartonella species or types: B. henselae type I is protective against heterologous challenge with B. henselae type II

Identification of Bartonella-specific immunodominant antigens recognized by the feline humoral immune system

Experimental infection of domestic cats with Bartonella henselae by inoculation of Ctenocephalides felis (Siphonaptera: Pulicidae) feces

Bartonella vinsonii subsp. berkhoffi and related members of the alpha subdivision of the Proteobacteria in dogs with cardiac arrhythmias, endocarditis, or myocarditis

Fatal case of endocarditis associated with Bartonella henselae type I infection in a domestic cat

Bartonella: a new etiological agent of feline ocular disease

Bartonella spp infection as a possible cause of uveitis in a cat

Bartonella spp antibodies and DNA in aqueous humour of cats

Bartonella vinsonii subspecies berkhoffi as a possible cause of anterior uveitis and choroiditis in a dog

Efficacy of enrofloxacin or doxycycline for treatment of Bartonella henselae or Bartonella clarridgeiae infection in cats

Evidence of reproductive failure and lack of perinatal transmission of Bartonella henselae in experimentally infected cats

Study of genotypes and virB4 secretion gene of Bartonella henselae strains from patients with clinically defined cat scratch disease

Granulomatous disease associated with Bartonella infection in two dogs

Peliosis hepatis in a dog infected with Bartonella henselae

Bartonella henselae and Bartonella elizabethae as potential canine pathogens

Prolonged Bartonella bacteremia in cats associated with cat scratch disease patients

Coinfection with multiple tick-borne pathogens in a Walker Hound kennel in North Carolina

Persistent infection of pets within a household with three Bartonella species

Cat or dog ownership and seroprevalence of ehrlichiosis, Q fever, and cat-scratch disease

Canine and feline blood donor screening for infectious disease

Aortic valve endocarditis in a dog due to Bartonella clarridgeiae

Detection of Bartonella henselae and Bartonella clarridgeiae DNA in hepatic specimens from two dogs with hepatic disease

Isolation of Bartonella washoensis from a dog with mitral valve endocarditis

A prospective study of canine infective endocarditis in northern California (1999-2001): emergence of Bartonella as a prevalent etiologic agent

Prevalence of antibody to Rochalimaea henselae among Austrian cats

Prevalence of antibodies to Rochalimaea species (cat-scratch disease agent) in cats

Prevalence of Bartonella henselae bacteremia, the causative agent of cat scratch disease, in an Australian cat population

Bartonella henselae bacteraemia in domestic cats from Auckland

Ease of isolation and semiquantitative culture of Bartonella henselae from cats in Melbourne

Seroprevalence of Bartonella henselae in cats in Germany

Prevalence of Bartonella henselae immunoglobulin G antibodies in Singaporean cats

Prevalence of Bartonella henselae in cats in the UK

Prevalence of Bartonella henselae in Italian stray cats: evaluation of serology to assess the risk of transmission of Bartonella to humans