Antimicrobial use

Backgrounders

Policy

Reports

Miscellaneous

= AVMA/SAVMA  Members Only

Some files on this page require Adobe Acrobat Reader software. Click on the image above to download it for free from the Adobe site.

Owing to recent advances in our knowledge of the zoonotic potential of Bartonella spp, the designations "cat-scratch disease" and "cat-scratch fever" may be appropriate only when considering human disease manifestations from a historical perspective. Henceforth, the disease should be known as bartonellosis.

During July 1994, a 51-year-old woman experienced a flu-like illness characterized by headache, myalgia, lethargy, and mild transient fever. In September, the patient was examined by the family physician when both eyes had become swollen and slightly painful. Swelling in the right eye resulted in near complete closure of the eyelids. These symptoms resolved spontaneously, and were presumed to be associated with allergy or viral infection. On Oct 31, 1994, the patient was examined by an ophthalmologist at a tertiary care center because of a discernible decrease in visual acuity in the right eye. Retinitis and optic neuritis were diagnosed. After obtaining additional history, it was established that the patient volunteered at a local animal shelter and had adopted four 2-week-old orphaned kittens in July. Bartonellosis was diagnosed, on the basis of history of numerous scratches while bottle-feeding the kittens, compatible disease manifestations, and a reciprocal antibody titer of 8,192 to Bartonela henselae antigen. After treatment with ciprofloxacin, there was rapid resolution of lethargy and gradual improvement in visual acuity. On Dec 20, 1994, we isolated B henselae from the blood of all 4 kittens. A reciprocal antibody titer to B henselae antigen was 64 in 1 kitten and 256 in 3 kittens.

Q: What is bartonellosis?

A: Although predated by a considerable body of important observations, reports^1,2 published in 1990 in the same issue of the New England Journal of Medicine set the stage for a scientific revolution in our understanding of Bartonella (previously, Rochalimaea) infections. Relman et at¹ used polymerase chain reaction (PCR) to amplify bacterial DNA from lesions of acquired immunodeficiency syndrome (AIDS) patients with bacillary angiomatosis. When compared with known eubacterial sequences, the uncultured organisms were most closely related to Rochalimaea quintana, the cause of trench fever. Independently, Slater et al² described isolation of a fastidious gram-negative organism in blood cultures from immunocompromised and nonimmunocompromised febrile patients. The organisms described in these 2 reports were subsequently characterized as B quintana or a newly defined species B henselae. In 1993, Brenner et al³ provided convincing evidence to justify reclassification of the 4 species in the genus Rochalimaea. Previously designated Rochalimaea species were united with the genus Bartonella, and named B quintana, B vinsonii, B henselae, and B elizabethae. This reclassification removed the family Bartonellaceae from the order Rickettsiales and resulted in the transfer of these organisms from the family Rickettsiaceae to the family Bartonellaceae. In effect, this reclassification eliminated the previous genus designation Rochalimaea. Of potential importance, research from our laboratory⁴ and others⁵ indicates that additional species and sub-species, for which the pathogenic potential has yet to be defined, will be added to the genus Bartonella in the future.

Q: What disease manifestations are associated with Bartonella infections in people?

A: In 1992, Schwartzman⁶ summarized the rapidly expanding clinical spectrum of human illness caused by infections attributable to Bartonella organisms. The list of recognized clinical entities has expanded considerably since Schwartzman's review. In recent years, infection with Bartonella species has been associated ith several distinct clinical syndromes in people, including bacillary (pertaining to bacilli or rodlike forms) angiomatosis,^7,8 bacillary peliosis (extravasation of blood) hepatis,^8,9 relapsing fever with bacteremia,^2,10 cat-scratch disease (CSD),^11-13 endocarditis,^14-16 granulomatous hepatosplenic syndrome,¹⁷ retinitis and swelling of the optic nerve,¹⁸ osteolytic lesions,^19,20 and pulmonary granulomas.²¹ A role for B henselae in the pathogenesis of AIDS encephalopathy also has been proposed.²²

It was reported for the first time in 1993, that B quintana, B elizabethae, and B henselae cause endocarditis in people--just 1 example that illustrates the rapid recognition of new clinical entities associated with Bartonella infections. Subsequent to these reports, we isolated and characterized a novel Bartonella subspecies from a dog with endocarditis.⁴ The importance of members of the genus Bartonella as canine pathogens or the role of dogs as a reservoir for human infection awaits additional study.

Bacillary angiomatosis, also called epithelioid angiomatosis, is a vascular proliferative disease of the skin that is characterized by multiple, blood-filled, cystic tumors.^7,8 When visceral parenchymal organs are involved, the condition is referred to as bacillary peliosis hepatis, splenic peliosis, or systemic bacillary angiomatosis. These conditions, now recognized to be infectious manifestations of B henselae or B quintana, have been more frequently documented in immunocompromised individuals, particularly AIDS patients, but also have been reported in immunocompetent individuals. Historically, bacillary angiomatosis has been reported in association with tuberculosis or advanced cancer, presumably a reflection of coexisting Bartonella infection. In a study from the Greater San Francisco Bay region of northern California, B henselae was isolated from the blood of 7 cats belonging to 4 patients with bacillary angiomatosis.⁵ An important observation in this study, which has been expanded by findings from our laboratory, is that B henselae bacteremia can persist in apparently healthy cats for periods of at least 18 months.

Persistent or relapsing fever, accompanied by malaise, anorexia, and weight loss has been documented frequently in immunocompromised individuals with Bartonella infections.^2,8,21 Acute febrile illness with bacteremia, bacillary angiomatosis, bacillary splenitis, and other chronic disease manifestations associated with Bartonella infections are being recognized with increasing frequency in immunocompetent people.^10,23 Persistent B henselae bacteremia, of potentially 3 months' duration, was identified in an immunocompetent man, who was potentially infected by tick exposure.²³ This report suggests that, similar to the situation in cats, people can experience prolonged illness with persistent bacteremia.

Q: How prevalent is B henselae infection in cats?

A: For nearly a century, regional lymphadenopathy has been associated with animal contact, particularly cat scratches.^6,24 Over the years, numerous microorganisms have been implicated as the cause of CSD. In 1983, small, argyrophilic (easily impregnated with silver), gram-negative, pleomorphic bacteria were seen within blood vessel walls and macrophages in lymph nodes of patients with CSD.²⁵ In 1988, a bacterium, later designated Afipia felis, was isolated from lymph nodes of patients with CSD.²⁶ In the same year, Cockerell et al²⁷ proposed possible association between epithelioid angiomatosis and CSD in a letter to Lancet. In 1992, Regnery et al at the Centers for Disease Control,¹¹ identified seroreactivity to B henselae antigens in 88% of 41 patients with suspected CSD, compared with 3% of controls. Similarly, a case-controlled study of CSD patients and their cats in Connecticut,²⁸ identified a strong association with cats 12 months of age or younger, a history of a scratch or bite, contact with fleas, and seroreactivity to B henselae antigen. Additional support that B henselae is the predominant cause of CSD was provided when DNA was amplified from lymph node samples of 21 (84%) of 25 patients with suspected CSD, using a PCR assay.¹³ We have isolated B henselae from 19 of 21 cats owned by 14 patients with CSD.^a It appears that B henselae is the predominant but, presumably, not the only cause of CSD. In 1994, Groves and Harrington provided a detailed review of Rochalimaea henselae infections as newly recognized zoonoses transmitted by domestic cats.²⁴

Although CSD is considered a benign, self-limiting disease in people, approximately 10% of previously recognized CSD cases were accompanied by atypical manifestations, including tonsillitis, encephalitis, cerebral arteritis, transverse myelitis, granulomatous hepatitis, and/or splenitis, osteolysis, pneumonia, pleural effusion, and thrombocytopenic purpura. Until recently, physicians would not have considered Bartonella infection in the differential diagnosis for patients with atypical CSD manifestations, particularly if a history of lymphadenopathy or animal contact was not obtained. As evidenced by reports in the past 3 years, the spectrum of human disease associated with the genus Bartonella is likely to expand, requiring periodic reassessment as new information becomes available.

Q: Are Bartonella species pathogenic for cats?

A: Whether members of the genus Bartonella are pathogenic for cats or contribute to previously described instances of argyrophilic bacteria in lymph nodes of cats with persistent lymphadenopathy²⁹ or to peliosis hepatis³⁰ remains to be determined. Bartonella henselae bacteremia can be documented in 25 to 41% of healthy cats.⁵,^a We have observed self-limiting febrile illness of 48 to 72 hours' duration and transient neurologic dysfunction in 2 cats experimentally infected with B henselae by blood transfusion. Owing to the high percentage of chronically bacteremic healthy cats in the United States, establishing a cause-and-effect relation between disease manifestations and bacteremia in cats will be difficult.

Q: How do you culture or detect Bartonella species?

A: Bartonella henselae and B bacilliformis are intraerythrocytic bacteria, whereas B quintana maintains an epicellular location on the erythrocyte.³¹ Therefore cell lysis, using a lysis centrifugation technique, greatly facilitates bacterial isolation from blood. Although organisms within the genus Bartonella, are fastidious and slow-growing, they can be cultured successfully, using agar plates containing 5% defibrinated rabbit or sheep blood that are maintained at 35 C in a high-humidity chamber with 5% CO2 concentration. In our experience, bacterial colonies may not be visible until 10 to 56 days after inoculation of the agar plate. Because members of the order Rickettsiales are cultivable only in their host cells or living tissues, cultivation of Bartonella species on bacteriologic media, in conjunction with DNA divergence studies, provided justification for removal of members of the genus Bartonella from the order Rickettsiales. Bartonella organisms are small curved gram-negative rods. In tissues, the organisms stain positive with silver stains, such as Warthin-Starry, and can be detected by using primers to amplify Bartonella DNA.⁴

Q: How is bartonellosis diagnosed?

A: The diagnosis of Bartonella infection should be confirmed by isolating the organism or amplifying DNA from tissues using PCR. Seroconversion, using an immunofluorescent antibody assay or ELISA, can be documented in people with acute disease and in cats after experimentally induced infection. Although incompletely characterized, the kinetics of the serologic response to Bartonella antigen in chronically infected cats is highly variable. A seroepidemiologic survey, incorporating 577 samples from throughout North America, identified an overall prevalence of 28%, with range from a low of 4 to 76 in the Midwest and Great Plains region to 60% in the Southeast.^b High seroprevalence appeared to correlate with warm, humid climates. A seroepidemiologic study of 592 cats in Baltimore, Md, identified overall seroprevalence of 14.7%, with a much higher prevalence (44.4%) in feral cats, compared with pet cats donated to the City Municipal Animal Shelter (12.2%).³² A regional serosurvey of 518 sick cats examined at our veterinary teaching hospital identified 109 (21%) cats seropositive to B henselae. Serologic test results may provide some useful epidemiologic information, but will be of limited clinical use because we have been unable to detect B henselae-specific antibodies in some bacteremic cats and were unable to isolate Bartonella organisms from some cats in which antibodies are detectable. It appears that numerous cats have persistent bacteremia, generally in conjunction with low antibody titers.^a

Q: How are Bartonella infections treated?

A: Because of disparate results among studies and an overall lack of microbiologic data in clinical therapeutic trials, numerous issues related to treatment of human Bartonella infection remain controversial. In contrast to the apparent lack of response to antimicrobial treatment in human CSD patients,^33,34 bacillary angiomatosis, parenchymal bacillary peliosis, and acute Bartonella bacteremia appear to respond to antimicrobial treatment, particularly in immumocompromised individuals.³⁵ Doxcycline, erythromycin, and rifampin are recommended antibiotics,³⁶ but clinical improvement has been reported after the use of penicillin, gentamicin, ceftriaxone, ciprofloxacin, and azithromycin. Treatment for 2 weeks in immunocompetent individuals and for 6 weeks in immunocompromised people is generally recommended. Relapses, associated with bacteremia, have been reported in immunocompromised people despite treatment for 6 weeks. Antimicrobial efficacy has not been established for any antibiotic for eliminating B henselae bacteremia in cats.

Because CSD generally denotes a self-limiting illness characterized by fever and lymphadenopathy, and because the recognized spectrum of human disease manifestations associated with Bartonella infections (which, as illustrated in our introductory case, may not include persistent fever or lyphadenopathy) has expanded considerably in recent years, it has become obvious that the designation CSD lacks clinical, microbiologic, and zoonotic utility. Although cats are a major reservoir for B henselae, some patients deny the possibility of a cat scratch or bite wound, or indicate no contact with cats. Transmission from other environmental sources or animal hosts is probable and the more inclusive term, bartonellosis, may facilitate enhanced future understanding of diseases caused by members of the genus Bartonella.

Q: What are the zoonotic implications of Bartonella infections?

A: The zoonotic implications of Bartonella infections in dogs and cats appear to be substantial for immunocompromised and immunocompetent people. Although it is well established that the human body louse transmits B quintana, the reservoir and mode of transmission that results in B quintana-induced bacillary angiomatosis in the United States has not been established. The mode of transmission, the role of insect vectors such as fleas and ticks, and potential reservoir hosts for other Bartonella species also remain largely undetermined. Bartonella henselae has been isolated from fleas obtaining blood meals from naturally infected cats,⁵ but vector competence has not been reported. Although recent research findings have substantially improved our understanding of the clinical and zoonotic aspects of diseases caused by Bartonella species, information related to potential environmental and animal reservoirs, insect, animal and mechanical modes of transmission, and the spectrum of animal and human illnesses caused by these organisms is obviously incomplete.

Footnotes

(a) Kordick DL, Wilson KH, Hegarty BC, et al. Bartonella (Rochalimaea) bacteremia in three feline populations, in Proceedings. Interscience Conf on Antimicrobial Agents and Chemotherapy, (abst) 1994;199.

(b) Jameson PH, Greene CE, Regnery RL. Seroprevalence of Rochalimaea henselae in cats throughout North America, in Proceedings. 12th Annu Forum Am Coll Vet Intem Med (abst) 1994;1006.

References

1. Relman DA, Loutit JS, Schmidt TM, et al. The agent of bacillary angiomatosis: an approach to the identification of uncultured pathogens. N Engl J Med 1990;323:1573-1580.

2. Slater LN, Welch DF, Hensel D, et al. A newly recognized fastidious gram-negative pathogen as a cause of fever and bacteremia. N Engl J Med 1990;323:1587-1593.

3. Brenner DJ, O'Connor SP, Winkler HH, et al. 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. Int J Syst Bacteriol 1993;43:777-786.

4. Breitschwerdt, EB, Kordick DL, Malarkey DE, et al. Endocarditis in a dog due to infection with a novel Bartonella subspecies. J Clin Microbiol 1995;33:154-160.

5. Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae infection: a new zoonosis with the domestic cat as a reservoir.JAMA 1994;271:531-535.

6. Schwartzman WA. Infections due to Rochalimaea: the expanding clinical spectrum. Clin Infect Dis 1992;15:893-902.

7. Cockerell CJ, Tierno PM, Friedman-Kien AE, et al. Clinical, histologic, microbiologic, and biochemical characterization of the causative agent of bacillary (epithelioid) angiomatosis: a rickettsial illness with features of bartonellosis. J Invest Dermatol 1991;97:812-817.

8. Koehler JE, Tapero JW. Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1993;17:612-624.

9. Reed JA, Brigati DJ, Flynn SD, et al. Immunocytochemical identification of Rochalimaea henselae in bacillary (epithelioid) angiomatosis, parenchymal bacillary peliosis, and persistent fever with bacteremia. Am J Surg Pathol 1992;16:650-657.

10. Welch DF, Hensel DM, Pickett DA, et al. Bacteremia due to Rochalimaea henselae in a child: practical identification of isolates in the clinical laboratory.J Clin Microbiol 1993;31:2381-2386.

11. Regnery RL, Olson JG, Perkins BA, et al. Serological response to Rochalimaea henselae antigen in suspected cat-scratch disease. Lancet 1992;339:1443-1445.

12. Dolan MJ, Wong MT, Regnery RL, et al. Syndrome of Rochalimaea henselae adenitis suggesting cat scratch disease. Ann Intern Med 1993;118:331-336.

13. Anderson B, Sims K, Regnery R, et al. Detection of Rochalimaea henselae DNA in specimens from Cat Scratch Disease patients by PCR. J Clin Microbiol 1994;32:942-948.

14. Spach DH, Callis KP, Paauw DS, et al. Endocarditis caused by Rochalimaea quintana in a patient infected with human immunodeficiency virus. J Clin Microbiol 1993;31:692-694.

15. Daly JS, Worthington MG, Brenner DJ, et al. Rochalimaea elizabethae sp. nov. isolated from a patient with endocarditis. J Clin Microbiol 1993;31:872-881.

16. Hadfield TL, Warren R, Kass M, et al. Endocarditis caused by Rochalimaea henselae. Hum Pathol 1994;24:1140-1141.

17. Golden SE. Hepatosplenic cat-scratch disease associated with elevated anti-Rochalimaea antibody titers. Pediatr Infect Dis J 1993;12:868-871.

18. Golnik KC, Marotto ME, Fanous MM, et al. Ophthalmic manifestations of Rochalimaea species. Am J Ophthalmol 1994;118:145.

19. Koehler JE, Quinn FD, Berger TG, et al. Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis. N Engl J Med 1992;327:1625-1631.

20. Waldvogel K, Regnery RL, Anderson B E, et al. Disseminated cat-scratch disease: detection of Rochalimaea henselae in affected tissue. Eur J Pediatr 1994;153:23-27.

21. Caniza MA, Granger DL, Wilson KH, et al. Bartonella (Rochalimaea) henselae: etiology of pulmonary nodules in a patient with depressed cell-mediated immunity. Clin Infect Dis 1995 (in press).

22. Schwartzman WA, Patnaik M, Barka NE, et al. Rochalimaea antibodies in HlV-associated neurologic disease. Neurology 1994;144:1312-1316

23. Lucey D, Dolan MJ, Moss CW, et al. Relapsing illness due to Rochalimaea henselae in immunocompetent hosts: implication of therapy and new epidemiological associations. Clin Infect Dis 1992;14:683-688.

24. Groves MG, Harrington KS. Rochalimaea henselae infections: newly recognized zoonoses transmitted by domestic cats. J Am Vet Med Assoc 1993;204:267-271.

25. Wear DJ, Margileth AM, Hadfield TL, et al. Cat scratch disease. A bactenal infection. Science 1983;221:1403-1405.

26. English CK, Wear DJ, Margileth AM, et al. Cat-scratch disease. Isolation and culture of the bactenal agent.JAMA 1988; 259: 1347-1352.

27. Cockerell CJ, Fnedman-Kien AE. Epithelioid angiomatosis and cat scratch disease bacillus (lett). Lancet 1988; 1:1334-1335.

28. Zangwill KM, Hamilton DH, Perkins BA, et al. Cat Scratch Disease in Connecticut. Epidemiology, risk factors, and evaluation of a new diagnostic test. N Engl J Med 1993;329:8-13.

29. Kirkpatnck CE, Moore FM, Patnaik AK, et al. Argyrophilic, intracellular bacteria in some cats with idiopathic peripheral lymphadenopathy. J Comp Path 1989;101:341-349.

30. Brown PJ, Henderson JP, Galloway P, et al. Peliosis hepatis and telangiectasis in 18 cats. J Small Anim Pract 1994; 35:73-77.

31. Kordick DL, Breitschwerdt EB. Intraerythrocytic presence of Bartonella henselae. J Clin Microbiol 1994 (in press).

32. Childs JE, Rooney JA, Cooper JL, et al. Epidemiologic observations on infection with Rochalimaea species among cats living in Baltimore, Md. J Am Vet Med Assoc 1994;204:1775- 1778.

33. Carithers HA. Cat-scratch disease: an overview based on a study of 1,200 patients. Am J Dis Child 1985;139:1124- 1133.

34. Margileth AM. Antibiotic therapy for cat-scratch disease: clinical study of therapeutic outcome in 268 patients and a review of the literature. Pediatr Infect Dis J 1992;11:474-478.

35. Guerra LG, Neira CJ, Boman D, et al. Rapid response of AIDS-related bacillary angiomatosis to azithromycin. Clin Infect Dis 1993;17:264-266.

36. Maurin M, Raoult D. Antimicrobial susceptibility of Rochalimaea quintana, Rochalimaea vinsonfi, and the newly recognized Rochalimaea henselae. J Antimicrob Chemother 1993;32:587-594.