Sage Journals: Discover world-class research

Abstract

A syndrome of fever, malaise, and regional lymphadenopathy in people that was frequently associated with contact with kittens or cats was called Cat Scratch Disease (CSD) for decades (Debre et al 1950). A novel organism, Rochalimaea henselae, was recognized (Regnery et al 1992a,b) and then was associated with CSD shortly thereafter (Zangwill et al 1993). A proposal to unify the genera Rochalimaea and Bartonella was made in 1993 and the organism was renamed Bartonella henselae (Brenner et al 1993). Since that time, over 2500 manuscripts regarding B henselae or related organisms have been published and there have been many notable discoveries concerning the diagnosis, treatment, and prevention of Bartonella spp. infections in both cats and people.

At the 2004 Fall Forum of The American Association of Feline Practitioners (AAFP) in San Francisco, two lectures and a roundtable discussion were presented on zoonotic diseases of cats in general (Brown et al 2002) and Bartonella spp. associated diseases in specific. It was noted at that time that an obvious consensus had not been reached for many issues concerning Bartonella spp. infections of cats. Subsequently, in the summer of 2005, the AAFP Guidelines Committee decided to convene a panel of interested individuals to develop a Panel Report on the topic. The panelists completed the first draft of this Panel Report in November 2005. The project was announced and a brief outline was presented on November 14, 2005 at the AAFP Meeting in Chicago. After approval of the document by the panelists, the Panel Report was distributed to select external reviewers that were considered experts in the field (see Acknowledgements). In addition, AAFP Fellows were contacted and given the opportunity to provide comments. After the comments of the external reviewers and AAFP Fellows were incorporated, the Panel Report was approved by the Guidelines Committee members and the AAFP Board in April 2006. The panel members felt that presentation of the materials would be best in a question and answer format; we used the questions that were commonly presented to us as veterinary clinicians or Bartonella spp. researchers. We have attempted to formulate consensus viewpoints when possible, using evidence-based medicine and thus have provided pertinent references for most statements. This Panel Report will be amended as indicated as new published data become available.

1. How are Bartonella Spp. Currently Classified?

Bartonella spp. are gram-negative, hemotropic, bacterial organisms that infect people and a number of domestic and wild mammals (Brenner et al 1993, Breitschwerdt and Kordick 2000, Chomel et al 2004, Boulouis et al 2005, Guptill 2005).

2. Which Bartonella Spp. Infect Cats?

By use of culture or DNA amplification techniques, cats are known to be infected by Bartonella henselae (Regnery et al 1992b, Koehler et al 1994, Breitschwerdt and Kordick 2000, Chomel et al 2004, Boulouis et al 2005, Guptill 2005), B clarridgeiae (Clarridge et al 1995, Kordick et al 1997b, Gurfield et al 1997, Heller et al 1997, Maruyama et al 2000), B koehlerae (Avidor et al 2004, Droz et al 1999, Rolain et al 2003a), B quintana (La et al 2005) and B bovis (Regnery et al 2000, Bermond et al 2002). Cats are thought to be the main reservoir hosts for B henselae and B clarridgeiae and probably are the reservoir for B koehlerae (Boulouis et al 2005). There is limited information about other Bartonella spp. infections of cats and the role of cats in the ecology of other Bartonella spp. is unknown. In serological studies, antibodies against B quintana (Al-Majali 2004) and B elizabethae (Hjelm et al 2002) have been detected in some cats. Because of serological cross reactivity among Bartonella spp., results of prevalence estimates based on serology should be interpreted cautiously.

3. Which of the Bartonella spp. known to Infect Cats are Associated with CSD or other Human Syndromes?

The large majority of people with CSD, bacillary peliosis, or bacillary angiomatosis have been infected by B henselae or B quintana (Koehler et al 1992, 1997, Breitschwerdt and Kordick 2000, Chomel et al 2003a, 2004, Boulouis et al 2005). Persistent fever has also been detected in people infected by B henselae (Jacobs and Schutze 1998). Based on serological test results, B clarridgeiae has been suspected as a cause of CSD-like illness in people (Clarridge et al 1995, Kordick et al 1997b). Bartonella koehlerae DNA was recently amplified from the blood of a person with endocarditis (Avidor et al 2004). Bartonella quintana infection is the cause of trench fever, endocarditis, bacillary angiomatosis and other clinical conditions (Slater and Welch 2004). However, B quintana is transmitted to people by lice; cats are not thought to be an important factor in transmission to people.

4. Are there Multiple Variants of B Henselae?

There is marked genetic diversity among B henselae isolates from cats. Two 16S rRNA genotypes, genotype I (Houston) and genotype II (Marseille) of B henselae exist and other methods of genetic classification define additional differences. Prevalence of Type I and Type II genotypes in cats or people has been most widely reported on and results varied in different studies which may relate to geographical or other factors (Gurfield et al 1997, Heller et al 1997, Koehler et al 1997, Sander et al 1998, Maruyama et al 2000, Guptill et al 2004, Fabbi et al 2004). Results of multilocus sequence typing (MLST) suggest that the type II genotype is ancestral with the type I appearing later and that horizontal gene transfer occurs with Bartonella (Iredell et al 2003). Most studies suggest that strains that infect humans are less genetically diverse than those that infect cats (Arvand et al 2001, Dillon et al 2002, Iredell et al 2003). Genetic variations between isolates may also relate to virulence in people (Bergmans et al 1996, Chang et al 2002, Dillon et al 2002, Iredell et al 2003, Woestyn et al 2004).

5. How Common are Bartonella spp. Infections of Cats Around the World?

Bartonella spp. infections of cats have been documented by culture or amplification of DNA by PCR assay in multiple countries within Europe, Asia, Oceania, and the Americas; an extensive review is available (Boulouis et al 2005). Prevalence rates vary dramatically, but bacteremia is commonly detected in greater than 20% of cats tested. For example, in cats between 3 months and 2 years of age residing in Florida, 33% were culture positive for a Bartonella spp. in blood at the time of sampling (Guptill et al 2004). Overall, B henselae and B clarridgeiae are the most common Bartonella infections detected in studies of cats throughout the world, and prevalence rates vary among countries (Chomel et al 2004, Boulouis et al 2005). Depending on the population tested, serological evidence of exposure can be extremely common; 93% of feral cats in North Carolina, USA had antibodies against Bartonella spp. (Nutter et al 2004). In general, the seroprevalence rate by study is generally about twice the rate of bacteremia in the same population. For example, in one study of 271 cats, 65 (24%) cats had B henselae bacteremia and 138 (51%) cats were seropositive for B henselae antibodies (Guptill et al 2004). In the United States, increased risk for seropositivity parallels increasing warmth and precipitation (Jameson et al 1995), which are also factors important for increased exposure to potential arthropod vectors.

6. Where does Bartonella Henselae Reside in Infected Cats?

Bartonella henselae mainly infects erythrocytes and endothelial cells but can also be found in a variety of tissues and in some cases has been documented extracellularly (Kordick and Breitschwerdt 1995, Kordick et al 1999, Mehock et al 1998, Guptill et al 2000, Rolain et al 2001).

7. What Cats are Most Likely to Acquire Bartonellosis?

In most surveys, likelihood of B henselae or B clarridgeiae bacteremia of cats is greatest in young cats and cats infested with fleas (Chomel et al 1995, Foley et al 1998, Gurfield et al 2001, Guptill et al 2004, Boulouis et al 2005). Other risk factors include being allowed outdoors or being otherwise associated with multiple cats.

8. How are Bartonella spp. Transmitted between Cats?

In experimental studies, cats have successfully been infected with Bartonella spp. by intradermal, subcutaneous, intramuscular, intravenous, and oral inoculation of plate grown bacteria or blood derived from infected cats (Greene et al 1996, Regnery et al 1996, Abbott et al 1997, Guptill et al 1997, 1998, 1999, Kordick et al 1997a,b, 1999), exposure to Ctenocephalides felis (Chomel et al 1996), and by intradermal injection of infected flea feces (Foil et al 1998). Bartonella henselae is ingested by fleas while they are ingesting cat blood, the infection is amplified in the flea hindgut, and live B henselae is present in flea feces for at least 9 days (Higgins et al 1996, Foil et al 1998, Finkelstein et al 2002). Based on these results and those of epidemiological studies linking Bartonella spp. infection or exposure to cats allowed outdoors or exposed to fleas, it is the consensus opinion that exposure to fleas or flea feces is the most important consideration for transmission of Bartonella spp. between cats. However, Bartonella spp. DNA has also been detected in ticks and biting flies and so the role of other blood-feeding parasites in the transmission of bartonellosis should be further explored (Chang et al 2001, Chung et al 2004). In contrast to these successful or possible means of spread, B henselae was not transmitted from infected queens to kittens during gestation, by milk, or from infected queens to toms during breeding (Abbott et al 1997, Guptill et al 1998).

9. How Common are Bartonella spp. Infections in Cat Fleas?

Bartonella spp. have been identified in C felis culture or result of PCR assay in many countries, including France (La Scola et al 2002, Rolain et al 2003b), Thailand (Parola et al 2003), USA (Koehler et al 1994, Chomel et al 1996, Lappin et al 2006), New Zealand (Kelly et al 2005), Japan (Ishida et al 2001), and the United Kingdom (Shaw et al 2004). In one study of fleas collected from 92 client-owned cats residing in Alabama, Maryland, or Texas in the USA, the prevalence rates for B henselae and B clarridgeiae DNA were 22.8% and 19.6%, respectively (Lappin et al 2006).

10. Do Blood-feeding Arthropods Transmit Bartonella Spp. Infection to People?

Many people with B henselae-associated illnesses have a history of close contact with kittens (Zangwill et al 1993, Tappero et al 1993, Breitschwerdt and Kordick 2000, Chomel et al 2004, Slater and Welch 2004, Boulouis et al 2005, Guptill 2005). Most people with Bartonella infections are believed to have been scratched and therefore likely to have had Bartonella spp. inoculated into their skin by a cat. Infected flea feces or infected cat blood are likely to contaminate cat claws during grooming, ultimately contaminating cat scratches with Bartonella spp. (Foil et al 1998). It is also possible that Bartonella-infected flea feces could enter the body through any broken skin. In Parinaud's oculoglandular syndrome, it is possible that flea feces containing the organism contaminate the conjunctiva, starting the syndrome (Cunningham and Koehler 2000). Some people with Bartonella spp. antibodies or Bartonella-associated illness have not been in contact with cats. In these individuals, transmission by contact with flea feces in the environment, flea (or other arthropod) bite, or contact with other reservoirs may be have been the source of infection.

11. Are Bartonella Spp. New Infections of Cats?

Recently DNA of B henselae was amplified from the dental pulp of cats that lived over 800 years ago (La et al 2004). Thus, the organisms are not new to cats, but are newly recognized. Factors associated with the emergence of zoonotic Bartonellae were recently reviewed (Boulouis et al 2005). Factors cited included recent use of advanced diagnostic tools allowing for increased sensitivity of detection, increasing populations of immune deficient individuals predisposed to disease, presence of co-infections that might amplify disease, increases in outdoor activity, or rural housing that may increase risk for exposure, and spread of the organisms around the world by transport of infected reservoir hosts (Boulouis et al 2005).

12. What are the Clinical Manifestations of Bartonella Henselae Infections of People?

In people, B henselae infection is most commonly associated with CSD, peliosis hepatis, bacillary angiomatosis, endocarditis, bacteremia, neuroretinitis, and encephalopathy (Carithers 1985, Margileth 1987, Koehler et al 1992, Rolain et al 2004). Immunocompetent people are more likely than immunodeficient people to develop classical CSD. After cat scratch transmission, a papule followed by a pustule develops at the site of inoculation within 14 days. Regional lymphadenopathy usually develops within weeks after inoculation; abscessed nodes are common (Carithers 1985, Margileth 1987). Most cases of uncomplicated CSD are self-limiting, may take several months to completely resolve, and have minimal to no response to antimicrobial treatment (Rolain et al 2004). However, complicated cases like those with central nervous system disease, visceral involvement, or retinitis are frequently prescribed antimicrobial agents; the combination of doxycycline with rifampin is common (Rolain et al 2004). Bacillary angiomatosis and peliosis hepatis are most common in immunocompromised people. In contrast to CSD, these syndromes nearly always respond to antimicrobial therapy (Rolain et al 2004) and occasionally may be fatal without antibiotic treatment.

13. How Common is CSD?

In the United States, the incidence of CSD was estimated at 9.3 cases per 100,000 people per year (Jackson et al 1993). In 2000, it was estimated that hospitalization rates for treatment of CSD were 0.60/100,000 children under 18 years of age and 0.86/100,000 children under 5 years of age (Reynolds et al 2005). In that study, it was also noted by the authors that while cat ownership has increased dramatically, the prevalence rates of CSD detected in 2000 were similar to those detected in the 1980s (Reynolds et al 2005). In the Netherlands, the incidence of CSD was estimated at 12.5 cases per 100,000 people per year (Bergmans et al 1997).

14. Does Exposure of People to Bartonella Spp. Always Result in Illness?

Bartonella spp. infection does not always result in recognized illness; clinically healthy, seropositive people have been detected in a number of studies (Noah et al 1997, Sander et al 2001, Massei et al 2004, McGill et al 2005).

15. How do Bartonella Spp. Cause Disease in People?

There are many possible mechanisms for Bartonella-associated illness. As discussed in Question 4, pathogenic potential may vary among different Bartonella spp., genotypes within a species, individual isolates, and host species that is infected. In people, disease associated with Bartonella spp. varies according to the immune status of the host. For those who become ill, pathological changes include a focal suppurative reaction seen in classical CSD of immunocompetent people, an angioproliferative response to infection seen with bacillary angiomatosis in immune suppressed people, an endovascular proliferation of the organism seen with endocarditis, or an exaggerated inflammatory response to the organism as occurs with meningoencephalitis (Chomel et al 2003b, Resto-Ruiz et al 2003, Rolain et al 2004, Dehio 2005).

Intradermal inoculation of four cats with B koehlerae led to bacteremia but no detectable clinical abnormalities (Yamamoto et al 2002). Results of studies in which B henselae or B clarridgeiae were inoculated into cats experimentally have given variable clinical results but the studies cannot be compared directly because of differences in isolates used and study design (Regnery et al 1996, Abbott et al 1997, Kordick and Breitschwerdt 1997, Guptill et al 1997, 1998, 1999, Kordick et al 1999, O'Reilly et al 1999, Mikolajczyk and O'Reilly 2000, Powell et al 2002, Yamamoto et al 2002, 2003). Fever, loss of appetite, transient mild anemia, red swellings at the injection site, lymphadenopathy, exaggerated or diminished response to stimuli, aggressive behavior, focal seizures, nystagmus, and generalized tremors were detected transiently in some cats.

16. What Abnormalities have been Detected in Cats Experimentally Inoculated with Bartonella Spp.?

Histopathological lesions have been detected in some cats experimentally inoculated with B henselae or B clarridgeiae (Guptill et al 1997, Kordick et al 1999). Peripheral lymph node hyperplasia, splenic follicular hyperplasia, splenic microabscesses and hepatic abscess, lymphocytic cholangitis/pericholangitis, lymphocytic hepatitis, lymphoplasmacytic myocarditis, and interstitial lymphocytic or pyogranulomatous nephritis were detected in some cats (Guptill et al 1997, Kordick et al 1999). In addition, Bartonellae were detected in multiple tissues from experimentally inoculated cats. The results of these studies suggest that Bartonella spp. infection could be considered on the differential list for a number of medical problems in cats. However, the panel believes that further work is needed to determine what actual causal associations may exist among Bartonella spp. infections and any clinical syndromes in cats (see discussion of Question 17).

17. Do Studies of Naturally Infected Cats Suggest an Association between Bartonella Spp. Infection and Illness?

The consensus opinion of the panel and external reviewers is that much more work will be required to determine the spectrum of Bartonella spp. associated illness in cats since most naturally infected cats exhibit no clinical signs. There have been only a few peer-reviewed reports documenting Bartonella spp. associated illness in naturally exposed cats. One fatal case of B henselae-associated endocarditis was reported in a cat (Chomel et al 2003b). Several case reports provide evidence of Bartonella spp. exposure in cats with ocular disease and subsequent response to therapy with drugs with presumed Bartonella activity (Lappin and Black 1999, Ketring et al 2004). Peer-reviewed seroepidemiologic studies have been published from the United States (Breitschwerdt et al 2005), Japan (Ueno et al 1996) and Switzerland (Glaus et al 1997). In the study from Switzerland, prevalence rates were similar in ill and clinically healthy cats but the ill B henselae seropositive cats were more likely than the ill seronegative cats to have stomatitis and diseases of the urinary system. In the study from Japan, coinfection of cats with feline immunodeficiency virus and Bartonella spp. was associated with an increased risk of lymphadenopathy and gingivitis. In the study from the United States, ill B henselae seropositive cats were more likely than ill seronegative cats to have hematuria. Local production of Bartonella spp. antibodies and Bartonella spp. DNA have been detected in aqueous humor of cats previously presumed to have idiopathic uveitis but a cause and effect was not established (Lappin et al 2000). Many of the studies are based on serological test results and such results document exposure but not necessarily active infection. In addition, because serological test results do not confirm the Bartonella spp. associated with the infection (Question 2), the role each Bartonella spp. that infects cats plays in the induction of clinical disease is unknown. Many chronic conditions may be the result of multiple factors acting together, or else just coincidental occurrence and thus, clearly linking a syndrome with an organism like Bartonella, which has a long history of association with its reservoir host, will be challenging (See Question 22).

18. What Bartonella Spp. Tests are Available for Use with Cats?

Culture of blood or tissues, amplification of Bartonella DNA by PCR assay of tissue and body fluids, and detection of antibodies in serum, aqueous humor, or CSF can be used to assess individual cats for Bartonella infection and are commercially available in the United States and some other countries.

19. How can Culture Results be Used to Aid in the Diagnosis of Feline Bartonellosis?

Proving the presence of Bartonella spp. in blood or tissues indicates current infection and it is our consensus opinion that culture is the gold standard technique for proving infection. The major limitations are the requirement for a specialized laboratory and the length of time for return of results because of the slow growth of the organisms. There are many seropositive, culture result-negative cats; it has often been assumed these cats had eliminated the infection. However, other possibilities are: the bacteremia was intermittent (Kordick and Breitschwerdt 1997) and not present in the sample cultured; the number of organisms were below the sensitivity limit of the assays; the organism died in transport to the laboratory; the culture was not held long enough; or the serological test result was falsely positive. New media to support the growth of Bartonella spp. in culture have recently been reported and may improve the ability to culture Bartonella spp. from blood or other tissues of cats (Maggi et al 2005). Although positive blood culture results prove Bartonella spp. infection in cats, they do not prove the cat is clinically ill from the infection.

20. How can PCR Assay Results be Used to Aid in the Diagnosis of Feline Bartonellosis?

Amplification of Bartonella spp. DNA from feline blood in EDTA, other fluids, or tissues has been used in many studies (Lappin et al 2000, 2006, Jensen et al 2000, Maggi and Breitschwerdt 2005). There are several gene targets that have been used. PCR assays targeting the 16S–23S rRNA intergenic spacer region can be designed to amplify different species resulting in different product sizes so that a single assay can also be used to determine the species of the infecting organism(s) that was amplified (Jensen et al 2000, Maggi and Breitschwerdt 2005). PCR assays require specialized laboratories, require stringent quality control to avoid both false-positive and false-negative results, can be expensive to perform, and are currently not standardized among laboratories. However, results can be obtained more rapidly than from culture. True positive PCR assay results document presence of microbial DNA but do not prove the organism was alive or prove that the cat was clinically ill from the infection. False-negative PCR assay results could occur because of intermittent bacteremia, previous use of antibiotics, lack of microbial DNA in the sample tested, or inhibitory or interfering substances in biologic specimens. Bartonella spp. DNA can also be amplified from tissue, CSF, and aqueous humor; however, any blood contamination of the fluid or tissue being tested could give a positive test result. For example, even though B henselae DNA was amplified from the aqueous humor of some cats with uveitis, the DNA could have been present from hemorrhage associated with aqueous paracentesis or from the breakdown of the blood ocular barrier from another cause of uveitis (Lappin et al 2000).

21. How Well do Serological Test Results Correlate with Bartonella Spp. Infection in Cats?

Antibodies against Bartonella spp. have been detected in serum of cats and humans primarily by use of immunofluorescent antibody assay (IFA), enzyme linked immunosorbent assay (ELISA), or Western blot immunoassay. Use of IFA slides or ELISA plates coated with different Bartonella spp. have been used to attempt to determine the prevalence of exposure to different infecting species. Western blot immunoassay has the advantage of determining the immunodominant antigens recognized by the immune response (Haimerl et al 1999, Freeland et al 1999, Chenoweth et al 2004). Many assays used for cats use whole B henselae organisms (IFA) or antigens (ELISA and Western blot immunoassay) for antibody detection. Antibodies against B henselae generally cross react with B clarridgeiae and other Bartonella spp. so a positive test result cannot discriminate the infective species. Serum antibody tests can be performed quickly and are inexpensive but there is currently no standardization among laboratories in the United States. A positive antibody test result suggests exposure to a Bartonella spp. but it does not prove current infection and a negative test result does not exclude infection (Pretorius et al 1999). The reported positive predictive values of IFA or ELISA (anti-IgG) serologic tests for B henselae or B clarridgeiae bacteremia are 32–46%, and the reported negative predictive values are 85–97% (Chomel et al 1995, Gurfield et al 2001, Fabbi et al 2004, Guptill et al 2004). Therefore, less than half of antibody result-positive cats may be actively infected and 3–15% of antibody result-negative cats may be bacteremic.

22. Can Bartonella Spp. Antibody Tests be Used to Prove Clinical Disease in Cats?

Because of the difficulty in proving clinical bartonellosis in cats, sensitivity, specificity, and predictive values of Bartonella spp. antibody tests for Bartonella-associated illness in cats have not been determined. There is no antibody class response (IgM or IgG), no antibody titer magnitude, and no antigen recognition pattern by Western blot immunoassay that consistently correlates with the presence or absence of clinical disease. While increasing antibody titers can be detected in some cats, this only indicates active infection, not clinical illness resulting from infection. Results of a Bartonella spp. antibody test that detects antibodies against B henselae and B clarridgeiae were compared between groups of cats with and without clinical syndromes potentially associated with Bartonella spp. infection (uveitis, neurological disease, and stomatitis) while controlling for age and geographical location (Pearce et al 2005, Fontenelle et al 2005, Dowers and Lappin 2005). Clinically healthy and ill cats could not be differentiated on the basis of antibody test results. Even detection of antibody production in aqueous humor does not prove clinical bartonellosis. In one study, local production of Bartonella spp. antibodies by the ocular tissues of cats with uveitis was documented in some cats but local antibody production also occurred transiently in healthy cats after experimental inoculation (Lappin et al 2000).

23. How can I Make a Clinical Diagnosis of Feline Bartonellosis?

It is the consensus of our panel that there is no single test result that can prove clinical bartonellosis in cats. The combination of all of the following findings may aid in the diagnosis:

presence of a syndrome reported to be associated with Bartonella spp. infection;

exclusion of other causes of the clinical syndrome;

detection of a positive Bartonella spp. test (culture, PCR assay, or serology); and

response to administration of a drug with presumed anti-Bartonella activity.

However, as discussed in Question 22, results of serological tests alone do not prove current infection. In addition, because the antibiotics used for the treatment of bartonellosis in cats generally have a broad spectrum and are effective for other infecting organisms which can cause syndromes resembling bartonellosis, even when these criteria are fulfilled, the diagnosis of clinical feline bartonellosis is not definitive.

24. What Antibiotics are Most Likely to be Effective for Treatment of Cats with a Clinical Illness Attributable to Bartonellosis?

Because the diagnosis of feline bartonellosis is difficult and has not been standardized, optimal anti-microbial protocols for clinical feline bartonellosis are unknown. Much of the information concerning treatment of bartonellosis in cats was derived from studies of people. In vitro, Bartonella spp. are susceptible to many antibiotics (Maurin et al 1995, Kordick et al 1997b, Rolain et al 2004) but antibiotic susceptibilities do not correlate with clinical efficacy in people. Even in people for whom well-defined clinical syndromes are recognized, a consensus on optimal use of antibiotic therapy is not always reached (Rolain et al 2004). Antibiotic failure or success may relate to the pathogenesis of the individual syndrome and the immune status of the host. For example, in immunocompetent people with classical CSD, the organism is often present in low numbers in lymph nodes by the time of biopsy. In this situation, the clinical manifestations of disease may relate to the immune-mediated clearance of the organism, not organism replication explaining antimicrobial failure. Failure of antibiotic treatment may be related to the intracellular location of the Bartonella organism and replication rates (Schulein et al 2001, Seubert et al 2002). In studies of B tribocorum infection of rat erythrocytes, it was shown that after a brief period of intraerythrocytic replication, the organism persisted in a non-replicating state (Schulein et al 2001). While many of the drugs used to treat CSD in people penetrate cells very well, each is primarily dependent on bacterial replication. In individual case reports in cats, therapeutic responses have been reported with doxycycline or azithromycin (Lappin and Black 1999, Ketring et al 2004). Both of these antibiotics have extensive anti-bacterial spectrums and also modulate immune responses, therefore apparent therapeutic responses may be related to anti-inflammatory effects (Culic et al 2002, Lee et al 2004). However, the extent of these anti-inflammatory effects in cats is unknown. In a double-blind, placebo controlled trial of children with CSD, administration of azithromycin led to a more rapid decrease in lymph node volume, but not other clinical parameters, when compared to placebo (Bass et al 1998). The panel recommends consulting the AVMA and AAFP statements (www.avma.org/scienact/jtua/default.asp) on judicious use of antimicrobial agents prior to antibiotic selection. It is the consensus opinion of the panel that in general, drugs commonly used for humans (ie, fluoroquinolones and azithromycin), should not be prescribed for routine bacterial infections of cats if an alternate choice is available. Doxycycline administered at 10 mg/kg, PO, q12–24 h or amoxicillin–clavulanate at 22 mg/kg, PO, q12 h for 7 days may be appropriate first choices for Bartonella-positive cats for which a definitive diagnosis is not known. If there is a positive response, treatment should be continued. If the cats have persistent clinical signs after 7 days and a further exhaustive search for an etiology has not yielded a definitive diagnosis, switching to azithromycin (10 mg/kg, PO, daily for 1 week followed by q48 h) or a fluoroquinolone may be indicated. Optimal duration of therapy for any drug has not been determined, however, because the organisms are intracellular, continuation of treatment for a minimum of 2 weeks and at least 1 week past resolution of clinical illness may be prudent. Because cats with clinical bartonellosis are likely bacteremic, extreme care should be taken to avoid being bitten or scratched while administering drugs. Precautions should be used when administering doxycycline to help minimize esophageal irritation and stricture (Melendez et al 2000).

25. What Antibiotics can be Used to Clear Bartonella Spp. Bacteremia in Cats?

Duration of bacteremia without treatment has varied dramatically in studies of naturally infected or experimentally infected cats. In some cats, bacteremia was present for weeks and in other cats bacteremia was present for months (Kordick and Breitschwerdt 1995, Guptill et al 1997, Greene et al 1996, Kordick and Brietschwerdt 1998). Duration of bacteremia may relate to the immune status of the host as well as the Bartonella spp. or genotype involved with the infection. There have been several attempts to eliminate bacteremia in cats naturally infected or experimentally infected with B henselae or B clarridgeiae (Koehler et al 1994, Greene et al 1996, Regnery et al 1996, Kordick et al 1997b). Drugs evaluated have included doxycycline, amoxicillin, amoxicillin–clavulanate, enrofloxacin, erythromycin, tetracycline HCl, and rifampin. Results of the studies were variable with bacteremia apparently being eliminated in some cats but not others. In some cats, blood culture results were initially negative after treatment but then positive at a later date. Follow-up times were limited in some studies, and clearance of Bartonella infection cannot truly be documented. Taken together, it is the consensus opinion of the panel that the available data indicate that the most appropriate antibiotic treatment regimens for feline Bartonella infections are unknown, and the optimal follow-up time for repeat testing has not been established. However, we believe that if treatment is attempted, it should be prolonged and combined with eradication of fleas on all animals in the household and the premises in an attempt to avoid re-infection.

26. Is there any Indication for Repeating Bartonella Spp. Tests in Cats?

Occasionally, repeated antibody testing might be indicated. For example, a changing antibody titer might indicate active or recently cleared infection. However, the diagnostic utility of repeated antibody testing to determine active infection or to determine clearance of bacteremia has not been documented in a peer-reviewed publication. Repeated blood culture or PCR assays can be used to document persistent infection if initial results are positive, but negative test results do not document Bartonella elimination (see Question 19).

27. Should Clinically Healthy Cats be Tested for Bartonella Spp. Infection?

Different authors have made varying recommendations on whether to test clinically healthy cats for Bartonella spp. infection. However, The Guidelines for Preventing Opportunistic Infections Among HIV-Infected Persons, jointly authored by the United States Public Health Service and the Infectious Diseases Society of America, states “No evidence indicates any benefits to cats or their owners from routine culture or serologic testing of the pet for Bartonella infection” (Kaplan et al 2002). It is the consensus opinion of this panel that there are currently not enough data concerning the benefit of performing Bartonella spp. tests on healthy cats to make a definitive recommendation for all cats. We believe it is prudent to discuss the advantages and disadvantages of Bartonella testing with each individual cat owner and document the discussion and outcome of the discussion in the medical record (Tannenbaum 1991). The following are some advantages and disadvantages concerning routine Bartonella spp. testing of healthy cats.

Potential Advantages

Cats with positive Bartonella spp. test results can be avoided, for example, for selection as blood donors or breeding animals.

Cats with negative Bartonella spp. test results are less likely to be harboring the organism and so may be a safer pet than a cat with Bartonella spp. positive test results.

Testing cats for Bartonella spp. may allow the veterinarian to avoid claims or litigation.

Potential Disadvantages

Bartonella spp. test results (particularly PCR and serology) can be falsely positive.

Cats with positive Bartonella spp. serological test results are often considered dangerous but may have eliminated the infection and may be partially immune to re-infection.

Detection of negative Bartonella spp. test results will lead to a false sense of security. ○

Cats with negative Bartonella spp. test results at one point in time may be falsely negative.

○

Cats with negative Bartonella spp. test results at one point in time can be infected and become bacteremic within 2 weeks if preventative measures are not taken.

Detection of positive Bartonella spp. test results in some situations may lead to needless euthanasia.

The expense of Bartonella spp. testing will lead to some owners avoiding ownership of an individual cat.

Redistribution of limited funds to cover the expense of Bartonella spp. testing will result in some owners forgoing other needed and relevant health care like flea control.

28. What is the Best Way to Prove a Cat is not Infected by a Bartonella Spp.?

As discussed in the sections regarding diagnostic testing, documentation of true Bartonella-negative status is difficult to impossible with current testing modalities. It is the consensus of our panel that cats that are culture- or PCR-negative, and antibody-negative, are very unlikely to be a source of flea, cat, or human infection.

29. Should Healthy Cats be Treated for Bartonella spp. Infection?

Because of the difficulty in eliminating Bartonella spp. infection and because some cats that eliminate Bartonella spp. infection can be reinfected, there is no proven benefit to treating Bartonella-positive (based on any test result), healthy cats. Administration of antibiotics that fail to clear a chronic intracellular infection may result in antimicrobial resistance. Treatment may result in a false sense of security to the owner leading to less stringent avoidance of bites or scratches and maintenance of flea control. Antibiotics can be expensive and have potential for toxicity. In addition, the increased risk to the owner from administration of the drug versus the poorly documented benefit to treatment should also be considered. In one study, the authors stated “given current concern about the development of antimicrobial resistance, we would reserve recommendation for treatment to cats owned by an immunocompromised individual or as an alternative to euthanasia of a pet” (Kordick et al 1997b). It is the consensus opinion of the panel that whether or not anti-microbial therapy is prescribed, it is imperative to also prescribe flea control measures.

30. What is the Potential for Development of a Bartonella Vaccine for Cats?

Naturally exposed cats have been infected with B clarridgeiae and B henselae or both genotypes of B henselae concurrently (Gurfield et al 2001, 2004). Results of experimental studies have demonstrated variable protection for cats from heterologous or homologous challenge (Greene et al 1996, Regnery et al 1996, Yamamoto et al 1998, 2003). Thus, available data indicate that to be effective a Bartonella vaccine will need to be multivalent (Yamamoto et al 1998).

31. Is Bartonellosis an Occupational Risk Factor for Veterinary Health Care Professionals?

Because veterinary health care providers commonly handle cats with previous or current flea infestation, exposure to Bartonella spp. infected cats is common. In one survey of 351 veterinary health care professionals in the USA, 7.1% were seropositive for B henselae or B quintana antibodies. The number of years of experience correlated to risk of seropositivity suggesting an increased risk of exposure over time (Noah et al 1997). These findings emphasize that veterinary health care professionals should avoid scratches and bites, use caution to avoid contact with flea excreta when handling flea-infested cats, immediately clean wounds thoroughly, and wash their hands immediately after every physical examination or other procedure (Brown et al 2002).

32. What is the AAFP Recommendation for Avoiding Zoonotic Bartonellosis and Bartonella Spp. Infections of Cats?

The AAFP Panel recommendations that follow were adapted from Guidelines for Preventing Opportunistic Infections Among HIV-Infected Persons (Kaplan et al 2002) and the AAFP Panel Report on Zoonoses (Brown et al 2002).

Flea control should be initiated and maintained year-round.

If a family member is immunocompromised and a new cat is to be acquired, adopt a healthy cat >1 year of age and free from fleas.

Discuss the advantages and disadvantages of testing healthy cats for Bartonella spp. infections.

Immunocompromised individuals should avoid contact with cats of unknown health status.

Cat claws should be trimmed regularly, but declawing of cats is generally not required.

Scratches and bites should be avoided (including rough play with cats).

Cat-associated wounds should be washed promptly and thoroughly with soap and water and medical advice sought.

While Bartonella spp. have not been shown to be transmitted by saliva, cats should not be allowed to lick open human wounds.

The AAFP Panel recommendations for decreasing the likelihood of pet cats becoming infected with Bartonella spp.:

Maintain an appropriate flea-control program year-round.

Be cautious about adding stray cats or cats from shelters to the household without controlling fleas.

Keep cats indoors to minimize hunting and exposure to fleas and other possible vectors.

Other issues concerning bartonellosis discussed in this document should also be considered with each individual family, for example, the complexities of diagnostic testing and the uncertainty of antimicrobial treatment efficacy. While Bartonella spp. are significant zoonotic agents, veterinary clinicians and their teams should focus on the entire cat and emphasize prevention of all zoonotic diseases (Brown et al 2002).

Footnotes

Acknowledgements

The Panel thanks the following experts and AAFP Fellows for their extensive reviews of the document; Drs. M Arvand, RJ Birtles, HJ Boulouis, H Carney (AAFP Fellow), BB Chomel, EB Breitschwerdt, CE Greene, A Johns (AAFP Fellow), LK Jarboe (AAFP Fellow), J Koehler, BA Nanton (AAFP Fellow), RL Regnery, and SE Shaw.

The document was also reviewed and approved (April 4, 2006) by the AAFP Guidelines committee; Drs. H Carney, TH Elston, N Hird, LK. Jarboe, A Johns, MR Lappin, J Levy, DS Manley, C McManis, LM Miller, J Richards, I Rodan (Chair), F Slack (2nd Chair), E Sundahl, N Suska, and H Tuzio.

References

Abbott

R.C.

Chomel

B.B.

Kasten

R.W.

Floyd-Hawkins

K.A.

Kikuchi

Koehler

J.E.

Pedersen

N.C.

Experimental and natural infection with Bartonella henselae in cats, Comparative Immunology, Microbiology and Infectious Diseases 20, 1997, 41–57.

Al-Majali

A.M.

Seroprevalence and risk factors for Bartonella henselae and Bartonella quintana among pet cats in Jordan, Preventive Veterinary Medicine 64, 2004, 63–71.

Arvand

Klose

A.J.

Schwartz-Porshe

Hahn

Wendt

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, Journal of Clinical Microbiology 39, 2001, 743–746.

Avidor

Graidy

Efrat

Leibowitz

Shapira

Schattner

Zimhony

Giladi

Bartonella koehlerae, a new cat-associated agent of culture-negative human endocarditis, Journal of Clinical Microbiology 42, 2004, 3462–3468.

Bass

J.W.

Freitas

B.C.

Freitas

A.D.

Sisler

C.L.

Chan

D.S.

Vincent

J.M.

Person

D.A.

Claybaugh

J.R.

Wittler

R.R.

Weisse

M.E.

Regnery

R.L.

Slater

L.N.

Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease, The Pediatric Infectious Disease Journal 17, 1998, 447–452.

Bergmans

A.M.

de Jong

C.M.

van Amerongen

Schot

C.S.

Schouls

L.M.

Prevalence of Bartonella species in domestic cats in the Netherlands, Journal of Clinical Microbiology 35, 1997, 2256–2261.

Bergmans

A.M.

Schellekens

J.F.

van Embden

J.D.

Schouls

L.M.

Predominance of two Bartonella henselae variants among cat-scratch disease patients in the Netherlands, Journal of Clinical Microbiology 34, 1996, 254–260.

Bermond

Boulouis

H.-J.

Heller

Van Laere

Monteil

Chomel

B.B.

Sander

Dehio

Piemont

Bartonella bovis sp. nov. and Bartonella capreoli sp. nov., isolated from European ruminants, International Journal of Systematic and Evolutionary Microbiology 52, 2002, 383–390.

Boulouis

H.J.

Chang

Henn

J.B.

Kasten

R.W.

Chomel

B.B.

Factors associated with the rapid emergence of zoonotic Bartonella infections, Veterinary Research 36, 2005, 383–410.

10.

Breitschwerdt

E.B.

Kordick

D.L.

Bartonella infection in animals: carriership, reservoir potential, pathogenicity, and zoonotic potential for human infection, Clinical Microbiology Reviews 13, 2000, 428–438.

11.

Breitschwerdt

E.B.

Levine

J.F.

Radulovic

Hanby

S.B.

Kordick

D.L.

La Perle

K.M.D.

Bartonella henselae and Rickettsia seroreactivity in a sick cat population from North Carolina, International Journal of Applied Research in Veterinary Medicine 3, 2005, 287–302.

12.

Brenner

D.J.

O'Connor

S.P.

Winkler

H.H.

Steigerwalt

A.G.

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, International Journal of Systematic Bacteriology 43, 1993, 777–786.

13.

Brown

R.R.

Elston

T.H.

Evans

Glaser

Gulledge

M.L.

Jarboe

Lappin

M.R.

Marcus

L.C.

Feline zoonoses guidelines from the American Association of Feline Practitioners, Compendium on Continuing Education for the Practicing Veterinarian 25, 2002, 936–965.

14.

Carithers

H.A.

Cat-scratch disease. An overview based on a study of 1,200 patients, American Journal of Diseases of Children 139, 1985, 1124–1133.

15.

Chang

C.C.

Chomel

B.B.

Kasten

R.W.

Romano

Tietze

Molecular evidence of Bartonella spp. in questing adult Ixodes pacificus ticks in California, Journal of Clinical Microbiology 39, 2001, 1221–1226.

16.

Chang

C.C.

Chomel

B.B.

Kasten

R.W.

Tappero

J.W.

Sanchez

M.A.

Koehler

J.E.

Molecular epidemiology of Bartonella henselae infection in human immunodeficiency virus-infected patients and their cat contacts, using pulsed-field gel electrophoresis and genotyping, The Journal of Infectious Diseases 186, 2002, 1733–1739.

17.

Chenoweth

M.R.

Greene

C.E.

Krause

D.C.

Gherardini

F.C.

Predominant outer membrane antigens of Bartonella henselae, Infection and Immunity 72, 2004, 3097–3105.

18.

Chomel

B.B.

Abbott

R.C.

Kasten

R.W.

Floyd-Hawkins

K.A.

Kass

P.H.

Glaser

C.A.

Pedersen

N.C.

Koehler

J.E.

Bartonella henselae prevalence in domestic cats in California: risk factors and association between bacteremia and antibody titers, Journal of Clinical Microbiology 33, 1995, 2445–2450.

19.

Chomel

B.B.

Kasten

R.W.

Floyd-Hawkins

Chi

Yamamoto

Roberts-Wilson

Gurfield

A.N.

Abbott

R.C.

Pedersen

N.C.

Koehler

J.E.

Experimental transmission of Bartonella henselae by the cat flea, Journal of Clinical Microbiology 34, 1996, 1952–1956.

20.

Chomel

B.B.

Boulouis

H.J.

Breitschwerdt

E.B.

Cat scratch disease and other zoonotic Bartonella infections, Journal of the American Veterinary Medical Association 224, 2004, 1270–1279.

21.

Chomel

B.B.

Kasten

R.W.

Sykes

J.E.

Boulouis

H.J.

Breitschwerdt

E.B.

Clinical impact of persistent Bartonella bacteremia in humans and animals, Annals of the New York Academy of Science 990, 2003a, 267–278.

22.

Chomel

B.B.

Wey

A.C.

Kasten

R.W.

Stacy

B.A.

Labelle

Fatal case of endocarditis associated with Bartonella henselae type I infection in a domestic cat, Journal of Clinical Microbiology 41, 2003b, 5337–5339.

23.

Chung

C.Y.

Kasten

R.W.

Paff

S.M.

Van Horn

B.A.

Vayssier-Taussat

Boulouis

H.J.

Chomel

B.B.

Bartonella spp. DNA associated with biting flies from California, Emerging Infectious Diseases 10, 2004, 1311–1313.

24.

Clarridge

J.E.

3rd Raich

T.J.

Pirwani

Simon

Tsai

Rodriquez-Barradas

M.C.

Regnery

Zollo

Jones

D.C.

Rambo

Strategy to detect and identify Bartonella species in routine clinical laboratory yields Bartonella henselae from human immunodeficiency virus-positive patient and unique Bartonella strain from his cat, Journal of Clinical Microbiology 33, 1995, 2107–2113.

25.

Culic

Erakovic

Cepelak

Barisic

Brajsa

Ferencic

Galovic

Glojnaric

Manojlovic

Munic

Novak-Mircetic

Pavicic-Beljak

Sucic

Veljaca

Zanic-Grubisic

Parnham

M.J.

Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects, European Journal of Pharmacology 450, 2002, 277–289.

26.

Cunningham

E.T.

Koehler

J.E.

Ocular bartonellosis, American Journal of Ophthalmology 130, 2000, 340–349.

27.

Debre

Lamy

Jammet

M.L.

La maladie des griffes de chat, Bulletins et memories de la Societe medicale des hopitaux de Paris 66, 1950, 76–79.

28.

Dehio

Bartonella-host-cell interactions and vascular tumour formation, Nature Reviews in Microbiology 3, 2005, 621–631.

29.

Dillon

Valenzuela

Don

Blanckenberg

Wigney

D.I.

Malik

Morris

A.J.

Robson

J.M.

Iredell

Limited diversity among human isolates of Bartonella henselae, Journal of Clinical Microbiology 40, 2002, 4691–4699.

30.

Dowers

K.D.

Lappin

M.R.

The association of Bartonella spp. infection in cats with chronic stomatitis (abstract), Journal of Veterinary Internal Medicine 19, 2005, 471.

31.

Droz

Chi

Horn

Steigerwalt

A.G.

Whitney

A.M.

Brenner

D.J.

Bartonella koehlerae sp. nov., isolated from cats, Journal of Clinical Microbiology 37, 1999, 1117–1122.

32.

Fabbi

De Giuli

Tranquillo

Bragoni

Casiraghi

Genchi

Prevalence of Bartonella henselae in Italian stray cats: evaluation of serology to assess the risk of transmission of Bartonella to humans, Journal of Clinical Microbiology 42, 2004, 264–268.

33.

Finkelstein

J.L.

Brown

T.P.

O'Reilly

K.L.

Wedincamp

Jr. Foil

L.D.

Studies on the growth of Bartonella henselae in the cat flea (Siphonaptera: Pulicidae), Journal of Medical Entomology 39, 2002, 915–919.

34.

Foil

Andress

Freeland

R.L.

Roy

A.F.

Rutledge

Triche

P.C.

O'Reilly

K.L.

Experimental infection of domestic cats with Bartonella henselae by inoculation of Ctenocephalidies felis (Siphonaptera: Pulicidae) feces, Journal of Medical Entomology 35, 1998, 625–628.

35.

Fontenelle

J.P.

Hill

Powell

C.C.

Lappin

M.R.

The association of Bartonella henselae antibodies and uveitis in cats (abstract), Journal of Veterinary Internal Medicine 19, 2005, 436.

36.

Foley

J.E.

Chomel

Kikuchi

Yamamoto

Pedersen

N.C.

Seroprevalence of Bartonella henselae in cattery cats: association with cattery hygiene and flea infestation, The Veterinary Quarterly 20, 1998, 1–5.

37.

Freeland

R.L.

Scholl

D.T.

Rohde

K.R.

Shelton

L.J.

O'Reilly

K.L.

Identification of Bartonella-specific immunodominant antigens recognized by the feline humoral immune system, Clinical and Diagnostic Laboratory Immunology 6, 1999, 558–566.

38.

Glaus

Hofmann-Lehmann

Greene

Glaus

Wolfensberger

Lutz

Seroprevalence of Bartonella henselae infection and correlation with disease status in cats in Switzerland, Journal of Clinical Microbiology 35, 1997, 2883–2885.

39.

Greene

C.E.

McDermott

Jameson

P.H.

Atkins

C.L.

Marks

A.M.

Bartonella henselae infection in cats: evaluation during primary infection, treatment, and rechallenge infection, Journal of Clinical Microbiology 34, 1996, 1682–1685.

40.

Guptill

Feline Bartonellosis. Greene

C.E.

Infectious Diseases of the Dog and Cat, 3rd edn, 2005, Saunders-Elsevier: St. Louis, MO, 511–518.

41.

Guptill

Slater

C.C.

Lin

T.L.

Glickman

L.T.

Welch

D.F.

HogenEsch

Experimental infection of young specific pathogen-free cats with Bartonella henselae, The Journal of Infectious Diseases 176, 1997, 206–216.

42.

Guptill

Slater

C.C.

Glickman

L.T.

Lin

T.L.

Welch

D.F.

Crippen

J.T.

HogenEsch

Immune response of neonatal specific pathogen-free cats to experimental infection with Bartonella henselae, Veterinary Immunology and Immunopathology 71, 1999, 233–243.

43.

Guptill

Slater

L.N.

C.C.

Lin

T.L.

Glickman

L.T.

Welch

D.F.

Tobolski

HogenEsch

Evidence of reproductive failure and lack of perinatal transmission of Bartonella henselae in experimentally infected cats, Veterinary Immunology and Immunopathology 65, 1998, 177–189.

44.

Guptill

C.C.

Glickman

Turek

Slater

HogenEsch

Extracellular Bartonella henselae and artifactual intraerythrocytic pseudoinclusions in experimentally infected cats, Veterinary Microbiology 76, 2000, 283–290.

45.

Guptill

C.C.

HogenEsch

Slater

L.N.

Glickman

Dunham

Syme

Glickman

Prevalence, risk factors, and genetic diversity of Bartonella henselae infections in pet cats in four regions of the United States, Journal of Clinical Microbiology 42, 2004, 652–659.

46.

Gurfield

A.N.

Boulouis

H.J.

Chomel

B.B.

Heller

Kasten

R.W.

Yamamoto

Piemont

Coinfection with Bartonella clarridgeiae and Bartonella henselae and with different Bartonella henselae strains in domestic cats, Journal of Clinical Microbiology 35, 1997, 2120–2123.

47.

Gurfield

A.N.

Boulouis

H.J.

Chomel

B.B.

Kasten

R.W.

Heller

Bouillin

Gandoin

Thibault

Chang

C.C.

Barrat

Piemont

Epidemiology of Bartonella infection in domestic cats in France, Veterinary Microbiology 80, 2001, 185–198.

48.

Haimerl

Tenter

A.M.

Simon

Rommel

Hilger

Autenrieth

I.B.

Seroprevalence of Bartonella henselae in cats in Germany, Journal of Medical Microbiology 48, 1999, 849–856.

49.

Heller

Artois

Xemar

De Briel

Gehin

Jaulhac

Monteil

Piemont

Prevalence of Bartonella henselae and Bartonella clarridgeiae in stray cats, Journal of Clinical Microbiology 35, 1997, 1327–1331.

50.

Higgins

J.A.

Radulovic

Jaworski

D.C.

Azad

A.F.

Acquisition of the cat scratch disease agent Bartonella henselae by cat fleas (Siphonaptera: Pulicidae), Journal of Medical Entomology 33, 1996, 490–495.

51.

Hjelm

McGill

Blomqvist

Prevalence of antibodies to Bartonella henselae, B. elizabethae and B. quintana in Swedish domestic cats, Scandinavian Journal of Infectious Disease 34, 2002, 192–196.

52.

Iredell

Blanckenberg

Arvand

Grauling

Feil

E.J.

Birtles

R.J.

Characterization of the natural population of Bartonella henselae by multilocus sequence typing, Journal of Clinical Microbiology 41, 2003, 5071–5079.

53.

Ishida

Tsuneoka

Iino

Murakami

Inokuma

Ohnishi

Tsukahara

Bartonella henselae infection in domestic cat and dog fleas, Kansenshogaku Zasshi – The Journal of the Japanese Association for Infectious Disease 75, 2001, 133–136.

54.

Jackson

L.A.

Perkins

B.A.

Wenger

J.D.

Cat scratch disease in the United States: an analysis of three national databases, American Journal of Public Health 83, 1993, 1707–1711.

55.

Jacobs

R.F.

Schutze

G.E.

Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children, Clinical Infectious Diseases 26, 1998, 80–84.

56.

Jameson

Greene

Regnery

Dryden

Marks

Brown

Cooper

Glaus

Greene

Prevalence of Bartonella henselae antibodies in pet cats throughout regions of North America, The Journal of Infectious Diseases 172, 1995, 1145–1149.

57.

Jensen

W.A.

Fall

M.Z.

Rooney

Kordick

D.L.

Breitschwerdt

E.B.

Rapid identification and differentiation of Bartonella species using a single-step PCR assay, Journal of Clinical Microbiology 38, 2000, 1717–1722.

58.

Kaplan

J.E.

Massur

Holmes

K.K.

Guidelines for preventing opportunistic infections among HIV-infected persons, Morbidity and Mortality Weekly Report 51 (RR08), 2002, 1–46.

59.

Kelly

Roberts

Fournier

P.E.

A review of emerging flea-borne bacterial pathogens in New Zealand, The New Zealand Medical Journal 118, 2005, 1257.

60.

Ketring

K.L.

Zuckerman

E.E.

Hardy

W.D.

Jr.

Bartonella: a new etiological agent of feline ocular disease, Journal of the American Animal Hospital Association 40, 2004, 6–12.

61.

Koehler

J.E.

Glaser

C.A.

Tappero

J.W.

Rochalimaea henselae infection. A new zoonosis with the domestic cat as reservoir, Journal of the American Medical Association 16, 1994, 553–554.

62.

Koehler

J.E.

Quinn

F.D.

Berger

T.G.

LeBoit

P.E.

Tappero

J.W.

Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis, New England Journal of Medicine 327, 1992, 1625–1631.

63.

Koehler

J.E.

Sanchez

M.A.

Garrido

C.S.

Whitfeld

M.J.

Chen

F.M.

Berger

T.G.

Rodriguez-Barradas

M.C.

LeBoit

P.E.

Tappero

J.W.

Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-peliosis, New England Journal of Medicine 337, 1997, 1876–1883.

64.

Kordick

D.L.

Breitschwerdt

E.B.

Intraerythrocytic presence of Bartonella henselae, Journal of Clinical Microbiology 33, 1995, 1655–1656.

65.

Kordick

D.L.

Breitschwerdt

E.B.

Relapsing bacteremia after blood transmission of Bartonella henselae to cats, American Journal of Veterinary Research 58, 1997, 492–497.

66.

Kordick

D.L.

Brietschwerdt

E.B.

Persistent infection of pets within a household with three Bartonella species, Emerging Infectious Diseases 4, 1998, 325–328.

67.

Kordick

D.L.

Brown

T.T.

Shin

Breitschwerdt

E.B.

Clinical and pathologic evaluation of chronic Bartonella henselae or Bartonella clarridgeiae infection in cats, Journal of Clinical Microbiology 37, 1999, 1536–1547.

68.

Kordick

D.L.

Hilyard

E.J.

Hadfield

T.L.

Wilson

K.H.

Steigerwalt

A.G.

Brenner

D.J.

Breitschwerdt

E.B.

Bartonella clarridgeiae, a newly recognized zoonotic pathogen causing inoculation papules, fever, and lymphadenopathy (cat scratch disease), Journal of Clinical Microbiology 35, 1997a, 1813–1818.

69.

Kordick

D.L.

Papich

M.G.

Breitschwerdt

E.B.

Efficacy of enrofloxacin or doxycycline for treatment of Bartonella henselae or Bartonella clarridgeiae infection in cats, Antimicrobial Agents and Chemotherapy 41, 1997b, 2448–2455.

70.

Kordick

D.L.

Wilson

K.H.

Sexton

D.J.

Hadfield

T.L.

Berkhoff

H.A.

Breitschwerdt

E.B.

Prolonged Bartonella bacteremia in cats associated with cat-scratch disease patients, Journal of Clinical Microbiology 33, 1995, 3245–3251.

71.

V.D.

Clavel

Lepetz

Aboudharam

Raoult

Drancourt

Molecular detection of Bartonella henselae DNA in the dental pulp of 800-year-old French cats, Clinical Infectious Diseases 39, 2004, 1391–1394.

72.

V.D.

Tran-Hung

Aboudharam

Raoult

Drancourt

Bartonella quintana in a domestic cat, Emerging Infectious Diseases 11, 2005, 1287–1289.

73.

Lappin

M.R.

Griffin

Brunt

Riley

Burney

Hawley

Brewer

M.M.

Jensen

W.A.

Prevalence of Bartonella spp., Mycoplasma spp., Ehrlichia spp., and Anaplasma phagocytophilum DNA in the blood of cats and their fleas in the United States, Journal of Feline Medicine and Surgery 8, 2006, 85–90.

74.

Lappin

M.R.

Jensen

Kordick

D.L.

Karem

Breitschwerdt

E.B.

Bartonella spp. antibodies and DNA in aqueous humor of cats, Journal of Feline Medicine and Surgery 2, 2000, 61–68.

75.

Lappin

M.R.

Black

J.C.

Bartonella spp. associated uveitis in a cat, Journal of the American Veterinary Medical Association 214, 1999, 1205–1207.

76.

La Scola

Davoust

Boni

Raoult

Lack of correlation between Bartonella DNA detection within fleas, serological results, and results of blood culture in a Bartonella-infected stray cat population, Clinical Microbiology and Infection 8, 2002, 345–351.

77.

Lee

J.Y.

Lee

Y.M.

Shin

S.Y.

Seol

Y.J.

Rhyu

I.C.

Chung

C.P.

Han

S.B.

Effect of subantimicrobial dose doxycycline as an effective adjunct to scaling and root planing, Journal of Periodontology 75, 2004, 1500–1508.

78.

Maggi

R.G.

Breitschwerdt

E.B.

Potential limitations of the 16S–23S rRNA intergenic region for molecular detection of Bartonella species, Journal of Clinical Microbiology 43, 2005, 1171–1176.

79.

Maggi

R.G.

Duncan

A.W.

Breitschwerdt

E.B.

Novel chemically modified liquid medium that will support the growth of seven bartonella species, Journal of Clinical Microbiology 43, 2005, 2651–2655.

80.

Margileth

A.M.

Cat scratch disease. A therapeutic dilemma, Veterinary Clinics of North America Small Animal Practice 17, 1987, 91–103.

81.

Maruyama

Nakamura

Kabeya

Tanaka

Sakai

Katsube

Prevalence of Bartonella henselae, Bartonella clarridgeiae and the 16S rRNA gene types of Bartonella henselae among pet cats in Japan, The Journal of Veterinary Medical Science 62, 2000, 273–279.

82.

Massei

Messina

Gori

Macchia

Maggiore

High prevalence of antibodies to Bartonella henselae among Italian children without evidence of cat scratch disease, Clinical Infectious Diseases 38, 2004, 145–148.

83.

Maurin

Gasquet

Ducco

Raoult

MICs of 28 antibiotic compounds for 14 Bartonella (formerly Rochalimaea) isolates, Antimicrobial Agents and Chemotherapy 39, 1995, 2387–2391.

84.

McGill

Wesslen

Hjelm

Holmberg

Auvinen

M.K.

Berggren

Grandin-Jarl

Johnson

Wikstrom

Friman

Bartonella spp. seroprevalence in healthy Swedish blood donors, Scandinavian Journal of Infectious Diseases 37, 2005, 723–730.

85.

Mehock

J.R.

Greene

C.E.

Gherardini

F.C.

Hahn

T.W.

Krause

D.C.

Bartonella henselae invasion of feline erythrocytes in vitro, Infection and Immunity 66, 1998, 3462–3466.

86.

Melendez

L.D.

Twedt

D.C.

Wright

Suspected doxycycline-induced esophagitis with esophageal stricture formation in three cats, Feline Practice 28, 2000, 10–12.

87.

Mikolajczyk

M.S.

O'Reilly

K.L.

Clinical disease in kittens inoculated with a pathogenic strain of Bartonella henselae, American Journal of Veterinary Research 61, 2000, 375–379.

88.

Noah

D.L.

Kramer

C.M.

Verbsky

M.P.

Rooney

J.A.

Smith

K.A.

Childs

J.E.

Survey of veterinary professionals and other veterinary conference attendees for antibodies to Bartonella henselae and B quintana, Journal of the American Veterinary Medical Association 210, 1997, 342–344.

89.

Nutter

F.B.

Dubey

J.P.

Levine

J.F.

Breitschwerdt

E.B.

Ford

R.B.

Stoskopf

M.K.

Seroprevalences of antibodies against Bartonella henselae and Toxoplasma gondii and fecal shedding of Cryptosporidium spp., Giardia spp., and Toxocara cati in feral and domestic cats, Journal of the American Veterinary Medical Association 235, 2004, 1394–1398.

90.

O'Reilly

K.L.

Bauer

R.W.

Freeland

R.L.

Foil

L.D.

Hughes

K.J.

Rohde

K.R.

Roy

A.F.

Stout

R.W.

Triche

P.C.

Acute clinical disease in cats following infection with a pathogenic strain of Bartonella henselae (LSU16), Infection and Immunity 67, 1999, 3066–3072.

91.

Parola

Sanogo

O.Y.

Lerdthusnee

Zeaiter

Chauvancy

Gonzalez

J.P.

Miller

R.S.

Telford

S.R.

3rd Wongsrichanalai

Raoult

Identification of Rickettsia spp. and Bartonella spp. in fleas from the Thai–Myanmar border, Annals of the New York Academy of Sciences 990, 2003, 173–181.

92.

Pearce

Radecki

S.V.

Brewer

M.M.

Lappin

M.R.

Prevalence of Bartonella spp. antibodies in cats with and without central nervous system disease (abstract), Journal of Veterinary Internal Medicine 19, 2005, 460.

93.

Pretorius

A.M.

Kelly

P.J.

Birtles

R.J.

Raoult

Isolation of Bartonella henselae from a serologically negative cat in Bloemfontein, South Africa, Journal of the South African Veterinary Association 70, 1999, 154–155.

94.

Powell

C.C.

Kordick

D.L.

Lappin

M.R.

Inoculation with Bartonella henselae followed by feline herpesvirus 1 fails to activate ocular toxoplasmosis in chronically infected cats, Journal of Feline Medicine and Surgery 4, 2002, 107–110.

95.

Regnery

Marano

Jameson

2000. A fourth Bartonella species, Bartonella weissii, species nova, isolated from domestic cats (abstract). In: Proceedings of the 15th Sesquiannual Meeting. American Society of Rickettsiology 15.

96.

Regnery

R.L.

Anderson

B.E.

Clarridge

J.E.

3rd Rodriguez-Barradas

M.C.

Jones

D.C.

Carr

J.H.

Characterization of a novel Rochalimaea species, R. henselae sp. nov., isolated from blood of a febrile, human immunodeficiency virus-positive patient, Journal of Clinical Microbiology 30, 1992a, 265–274.

97.

Regnery

Martin

Olson

Naturally occurring “Rochalimaea henselae” infection in domestic cat, Lancet 340, 1992b, 557.

98.

Regnery

R.L.

Rooney

J.A.

Johnson

A.M.

Nesby

S.L.

Manzewitsch

Beaver

Olson

J.G.

Experimentally induced Bartonella henselae infections followed by challenge exposure and antimicrobial therapy in cats, American Journal of Veterinary Research 57, 1996, 1714–1719.

99.

Resto-Ruiz

Burgess

Anderson

B.E.

The role of the host immune response in pathogenesis of Bartonella henselae, DNA and Cell Biology 22, 2003, 431–440.

100.

Reynolds

M.G.

Holman

R.C.

Curns

A.T.

O'Reilly

McQuiston

J.H.

Steiner

C.A.

Epidemiology of cat-scratch disease hospitalizations among children in the United States, Pediatric Infectious Disease Journal 24, 2005, 700–704.

101.

Rolain

J.M.

Fournier

P.E.

Raoult

Bonerandi

J.J.

First isolation and detection by immunofluorescence assay of Bartonella koehlerae in erythrocytes from a French cat, Journal of Clinical Microbiology 41, 2003a, 4001–4002.

102.

Rolain

J.M.

Frank

Davoust

Raoult

Molecular detection of Bartonella quintana, B. koehlerae, B. henselae, B. clarridgeiae, Rickettsia felis, and Wolbachia pipientis in cat fleas, France, Emerging Infectious Disease 9, 2003b, 338–342.

103.

Rolain

J.M.

Brouqui

Koehler

J.E.

Maguina

Dolan

M.J.

Raoult

Recommendations for treatment of human infections caused by Bartonella species, Antimicrobial Agents and Chemotherapy 48, 2004, 1921–1933.

104.

Rolain

J.M.

La Scola

Liang

Davoust

Raoult

Immunofluorescent detection of intraerythrocytic Bartonella henselae in naturally infected cats, Journal of Clinical Microbiology 39, 2001, 2978–2980.

105.

Sander

Ruess

Deichmann

Bohm

Bredt

Two different genotypes of Bartonella henselae in children with cat-scratch disease and their pet cats, Scandinavian Journal of Infectious Diseases 30, 1998, 387–391.

106.

Sander

Berner

Ruess

Serodiagnosis of cat scratch disease: response to Bartonella henselae in children and a review of diagnostic methods, European Journal of Clinical Microbiology and Infectious Diseases 20, 2001, 392–401.

107.

Seubert

Schulein

Dehio

Bacterial persistence within erythrocytes: a unique pathogenic strategy of Bartonella spp., International Journal of Medical Microbiology 291, 2002, 555–560.

108.

Schulein

Seubert

Gille

Lanz

Hansmann

Piemont

Dehio

Invasion and persistent intracellular colonization of erythrocytes. A unique parasitic strategy of the emerging pathogen Bartonella, Journal of Experimental Medicine 193, 2001, 1077–1086.

109.

Shaw

S.E.

Kenny

M.J.

Tasker

Birtles

R.J.

Pathogen carriage by the cat flea Ctenocephalides felis (Bouché) in the United Kingdom, Veterinary Microbiology 102, 2004, 183–188.

110.

Slater

L.N.

Welch

D.F.

Bartonella species, including cat-scratch disease. Mandell

G.L.

Bennett

J.E.

Dolin

Principles and Practice of Infectious Diseases, 6th edn, 2004, Churchill Livingstone-Harcourt: Philadelphia, PA, 2733–2748.

111.

Tannenbaum

Medical–legal aspects of veterinary public health in private practice, Seminars in Veterinary Medicine and Surgery 6, 1991, 175–185.

112.

Tappero

J.W.

Mohle-Boetani

Koehler

J.E.

Swaminathan

Berger

T.G.

LeBoit

P.E.

Smith

L.L.

Wenger

J.D.

Pinner

R.W.

Kemper

C.A.

The epidemiology of bacillary angiomatosis and bacillary peliosis, Journal of the American Medical Association 269, 1993, 770–775.

113.

Ueno

Hohdatsu

Muramatsu

Koyama

Morita

Does coinfection of Bartonella henselae and FIV induce clinical disorders in cats?, Microbiology and Immunology 40, 1996, 617–620.

114.

Woestyn

Olive

Bigaignon

Avesani

Delmee

Study of genotypes and virB4 secretion gene of Bartonella henselae strains from patients with clinically defined cat scratch disease, Journal of Clinical Microbiology 42, 2004, 1420–1427.

115.

Yamamoto

Chomel

B.B.

Kasten

R.W.

Chang

C.C.

Tseggai

Decker

P.R.

Mackowiak

Floyd-Hawkins

K.A.

Pedersen

N.C.

Homologous protection but lack of heterologous-protection by various species and types of Bartonella in specific pathogen-free cats, Veterinary Immunology and Immunopathology 65, 1998, 191–204.

116.

Yamamoto

Chomel

B.B.

Kasten

R.W.

Hew

C.M.

Weber

D.K.

Lee

W.I.

Droz

Koehler

J.E.

Experimental infection of domestic cats with Bartonella koehlerae and comparison of protein and DNA profiles with those of other Bartonella species infecting felines, Journal of Clinical Microbiology 40, 2002, 466–474.

117.

Yamamoto

Chomel

B.B.

Kasten

R.W.

Hew

C.M.

Weber

D.K.

Lee

W.I.

Koehler

J.E.

Pedersen

N.C.

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, Veterinary Microbiology 92, 2003, 73–86.

118.

Zangwill

Hamilton

Perkins

Regnery

Plikaytis

Hadler

Cartter

Wenger

Cat scratch disease in Connecticut. Epidemiology, risk factors, and evaluation of a new diagnostic test, New England Journal of Medicine 329, 1993, 8–13.

American Association of Feline Practitioners 2006 Panel report on diagnosis,treatment,and prevention of Bartonella spp. infections

Abstract

1. How are Bartonella Spp. Currently Classified?

2. Which Bartonella Spp. Infect Cats?

3. Which of the Bartonella spp. known to Infect Cats are Associated with CSD or other Human Syndromes?

4. Are there Multiple Variants of B Henselae?

5. How Common are Bartonella spp. Infections of Cats Around the World?

6. Where does Bartonella Henselae Reside in Infected Cats?

7. What Cats are Most Likely to Acquire Bartonellosis?

8. How are Bartonella spp. Transmitted between Cats?

9. How Common are Bartonella spp. Infections in Cat Fleas?

10. Do Blood-feeding Arthropods Transmit Bartonella Spp. Infection to People?

11. Are Bartonella Spp. New Infections of Cats?

12. What are the Clinical Manifestations of Bartonella Henselae Infections of People?

13. How Common is CSD?

14. Does Exposure of People to Bartonella Spp. Always Result in Illness?

15. How do Bartonella Spp. Cause Disease in People?

16. What Abnormalities have been Detected in Cats Experimentally Inoculated with Bartonella Spp.?

17. Do Studies of Naturally Infected Cats Suggest an Association between Bartonella Spp. Infection and Illness?

18. What Bartonella Spp. Tests are Available for Use with Cats?

19. How can Culture Results be Used to Aid in the Diagnosis of Feline Bartonellosis?

20. How can PCR Assay Results be Used to Aid in the Diagnosis of Feline Bartonellosis?

21. How Well do Serological Test Results Correlate with Bartonella Spp. Infection in Cats?

22. Can Bartonella Spp. Antibody Tests be Used to Prove Clinical Disease in Cats?

23. How can I Make a Clinical Diagnosis of Feline Bartonellosis?

24. What Antibiotics are Most Likely to be Effective for Treatment of Cats with a Clinical Illness Attributable to Bartonellosis?

25. What Antibiotics can be Used to Clear Bartonella Spp. Bacteremia in Cats?

26. Is there any Indication for Repeating Bartonella Spp. Tests in Cats?

27. Should Clinically Healthy Cats be Tested for Bartonella Spp. Infection?

Potential Advantages

Potential Disadvantages

28. What is the Best Way to Prove a Cat is not Infected by a Bartonella Spp.?

29. Should Healthy Cats be Treated for Bartonella spp. Infection?

30. What is the Potential for Development of a Bartonella Vaccine for Cats?

31. Is Bartonellosis an Occupational Risk Factor for Veterinary Health Care Professionals?

32. What is the AAFP Recommendation for Avoiding Zoonotic Bartonellosis and Bartonella Spp. Infections of Cats?

Footnotes

Acknowledgements

References