RAT-BITE FEVER

RAT-BITE FEVER

Current Diagnosis

• Exposure to rats is the major risk factor. Transmission can occur with simple contact with infected animals or excreta.

• A maculopapular rash and septic arthritis following initial symptoms of fever and/or sepsis should raise the suspicion of rat- bite fever.

• Clinicians must maintain a high index of suspicion for this diagnosis.

• Notify microbiology laboratory of clinical suspicion (slow growth, 5%–10% CO2  microaerophilic conditions, 20% normal rabbit serum media supplementation, and avoidance of sodium polyanethol sulfonate when collecting blood cultures from the patient).

Current Therapy

Bite Site

• Clean and disinfect the bite site.

• Administer tetanus toxoid (tetanus-diphtheria toxoids, Td), if indicated.

• Postexposure rabies prophylaxis (Imovax Rabies) for animal bites should be considered in consultation with local public health authorities, though there are no reports of rat-to-human transmission of the rabies virus.

Established and Suspected Cases

• Give intravenous penicillin G at a dose of 1.2 million U/day for 5 to 7 days, followed by oral penicillin (PenVK)1 or ampicillin (Omnipen)1 500 mg qid for an additional 7 days.

• For penicillin-allergic patients, consider doxycycline (Vibramycin)1 100 mg IV/PO twice daily or tetracycline (Achromycin)1 500 mg PO four times daily.

• S. moniliformis can be resistant to gentamicin (Garamycin),1 tobramycin (Nebcin),1 ciprofloxacin (Cipro),1 and levofloxacin (Levaquin).1

1 Not FDA approved for this  indication.

Rat-bite fever (RBF) is a systemic, febrile disease caused by infection with Streptobacillus moniliformis or Spirillum minus. As the name implies, this infection is transmitted by a rat bite. However, the bacteria can also be transmitted by simple contact with infected rats or even through ingestion of food contaminated with rat excreta. Diagnosis can be difficult, and a high degree of suspicion is necessary to make a correct diagnosis. Recognition and early treatment are crucial, because case fatality is as high as 25% in untreated cases.

Epidemiology

S. moniliformis is part of the normal respiratory flora of the rat. From 50% to 100% of healthy wild, laboratory, and pet rats harbor moniliformis in the nasopharynx. S. moniliformis is also excreted in the urine. S. minus causes rat-bite fever mostly in Asia, but this organism is found worldwide. S. minus has been demonstrated in rat conjunctival secretions and blood. Thus, rat-bite fever can be transmitted not only from a bite but also through scratches, handling of dead rats, handling litter material, or by contamination of rat excreta.

Although the rat is the natural reservoir and major vector of the disease, S. moniliformis has also been found in other rodents such as mice, squirrels, gerbils, and weasels. No precise data are available on the true incidence of rat-bite fever because it is not a reportable disease. It appears to be unusual in Western countries, a rarity that might reflect failed diagnosis, empiric treatment of infected bites and scratches caused by animals, or spontaneous recovery.

Risk Factors

The major risk factor is exposure to rats, either as an occupational hazard for persons such as laboratory workers, veterinarians, or pet shop employees, or for persons who have rats for pets or feed rats to snakes, especially children. Classically, homelessness and lower socioeconomic status were described as major factors, but most cases reported in the last few years have involved pet rats. Thirty percent of patients with rat-bite fever do not report any exposure to rats or other rodents. Therefore, the lack of documented exposure does not exclude this diagnosis.

Pathophysiology

Very little is known about the pathophysiology of S. moniliformis infections. Presumably, the failure of local control by dendritic cells, tissue macrophages, neutrophils, and other components of the innate immune system results in deeper infection, leading to bacteremia.

Studies using histologic analysis have revealed intravascular thrombosis near the port of entry.

Prevention

The role of prophylactic antibiotics is unknown, but some authors recommend the use of oral penicillin V (PenVK)1 after documented exposure to rats and a break in the skin. Penicillin V should be given for 3 days at a dose of 2 g per day for adults. Primary prevention should be encouraged for patients with occupational risk by using protective gloves to handle animals or cages.

Clinical Manifestations

Rat-bite fever is a systemic febrile disease. Classically, following a rat bite and a short incubation of 2 to 10 days, systemic dissemination of the organism is associated with an abrupt onset with intermittent relapsing fever, rigors, myalgias, arthralgias, headache, sore throat, malaise, and vomiting. These symptoms are followed within the first week by the development of a maculopapular rash in 75% of patients. The rash can be pustular, purpuric, or petechial, and it typically involves the extremities, in particular the palms and soles. The bite site typically heals promptly, with minimal inflammation and no significant regional lymphadenopathy.

Following the rash, approximately 50% of infected patients develop an asymmetric migrating polyarthritis, which appears to be exceedingly painful and affects large and middle-sized joints. Joint effusion appears more common in adults. Infection can occur in any tissue. Although most cases of rat-bite fever resolve spontaneously, there have been reports of complications. These include meningitis, endocarditis (including prosthetic valve endocarditis), myocarditis, pericarditis, pneumonia, brain abscess, septic arthritis, DIC (disseminated intravascular coagulation), and infarcts of the spleen and kidneys. The mortality rate in untreated cases is around 10% to 15%, and it rises to more than 50% in the rare cases with cardiac involvement.

Two closely related variants have been described. In Havervill fever, the organism is transmitted by ingestion of contaminated food.

Havervill fever tends to occur in epidemics and also causes rashes and arthritis, but upper respiratory tract symptoms and vomiting appear more prominent. It is important to note that these patients do not provide a history of exposure to rodents. Sodoku is a rat-bite fever caused by S. minus; it is common in Japan. The course is more subacute, arthritic symptoms are rare, and if the bite initially heals, it then ulcerates and is associated with regional lymphadenopathy and a distinctive rash. S. minus cannot be grown using synthetic media, and thus microbiologic diagnosis rests on visualization of these organisms in infected tissues.

Diagnosis

Diagnosis is difficult and requires a high clinical index of suspicion. The initial symptoms of rat-bite fever are nonspecific, triggering a broad differential diagnosis. Additionally, the fastidious nature of this organism makes isolation from blood cultures difficult. Clinicians should ask about rodent exposure when compatible symptoms are seen in patients. Rat-bite fever should not be ruled out in the absence of bite history, because transmission can occur without a bite, and pet owners or laboratory workers can minimize the significance of the bite, especially in the absence of a local reaction.

No reliable serologic test is available, and the definitive diagnosis requires isolation of S. moniliformis from the wound, blood, or synovial fluid in patients with septic arthritis. The microbiology laboratory should be specifically notified of any clinical suspicion to enhance the chances of recovering the pathogen.

S. moniliformis is a highly pleomorphic, nonencapsulated, nonmotile, gram-negative rod, which can stain positively on Gram stain (Figure 1). It is often dismissed as proteinaceous debris because of its numerous bulbous swellings with occasional clumping (moniliformis = “necklace-like”). It grows slowly and requires a microaerophilic environment with 5% to 10% CO2 or anaerobic conditions and media supplementation with 20% normal rabbit serum. Cultures can take up to 7 days to turn positive. Some experts recommend holding blood cultures for 21 days to permit sufficient time to grow this organism. S. moniliformis is also inhibited by sodium polyanethol sulfonate, a common adjunct in most commercial blood culture media at a concentration as low as 0.0125%. S. moniliformis has been identified using polymerase chain reaction amplification and 16S ribosomal ribonucleic acid (rRNA) sequencing, which shows great promise though it is available at reference laboratories. Fatty acid profiles obtained by gas-liquid chromatography can also be used for identification.

FIGURE 1    Gram stain of Streptobacillus moniliformis. Gram stain  of growth from anaerobic bottle, × 100 magnification  [microphotography].

(Reprinted with permission from Partners’ Infectious Disease Images; accessed on August 11, 2016, from http://www.idimages.org/images/detail/?imageid=373.)

S. minus, the other etiologic agent of rat-bite fever, is a short, thick, gram negative, tightly coiled spiral rod that measures 0.2 to 0.5 µm and has two to six helical turns.

Differential Diagnosis

Differential diagnosis for fever, rash, and polyarthritis is broad. Malaria, typhoid fever, and neoplastic disease can cause relapsing fevers, and the presence of a rash and polyarthritis might suggest viral and rickettsial diseases including Rocky Mountain spotted fever. An asymmetric oligoarthritis suggests disseminated gonococcal and meningococcal diseases in the context of cutaneous lesions on the palms and soles. Lyme disease, leptospirosis, or secondary syphilis can have a similar clinical presentation. Finally, when classic infectious symptoms such as fever or rash are missing, any causes of polyarthritis, from crystal-induced arthropathies to rheumatoid arthritis, should be considered.

Treatment

All established cases of rat-bite fever should be treated with antibiotics because of the associated mortality and potential for complications. Intravenous penicillin G at a dose of 1.2 million units per day should be initiated as soon as the clinical diagnosis is made.

Empiric therapy is necessary and should not be delayed for laboratory confirmation of this bacterial infection. The intravenous treatment should continue for 5 to 7 days. After treatment with IV penicillin and suitable clinical response, therapy should be continued with oral penicillin (PenVK)1 or ampicillin (Omnipen)1 at a dose of 500 mg qid for an additional 7 days. For patients allergic to penicillin, intravenous doxycycline (Vibramycin)1 at a dose of 100 mg every 12 hours or oral tetracycline (Achromycin)1 at a dose of 500 mg four times a day can be used.

Streptomycin1 and cephalosporins including cefotamxine (Claforan)1 have been reported to be potentially useful. Other antibiotics including azithromycin (Zithromax),1 erythromycin,1 carbapenems,1 aztreonam (Azactam),1 clindamycin (Cleocin),1 vancomycin (Vancocin),1 and nitrofurantoin (Macrodantin)1 have shown efficacy in vitro, but they lack good clinical correlation to recommend them for routine use. Erythromycin has been associated with treatment failures. Trimethoprim-sulfamethoxazole (Bactrim),1 polymyxin B,1 gentamicin (Garamycin),1 tobramycin (Nebcin),1 ciprofloxacin (Cipro),1 and levofloxacin (Levaquin)1 should not be used because in vitro resistance has been demonstrated.

Typically, the bite site heals promptly. It should be cleaned and disinfected, as is typical for management of other wounds. Tetanus prophylaxis (tetanus-diphtheria toxoids, Td) administration is indicated as required by the patient’s immunization record. Rabies prophylaxis (Imovax Rabies) is usually not required for rodent bite, but consultation with local public health authorities is encouraged. There are no reports of transmission of the rabies virus from rats to humans.

References

1.     Adam J.K., et al. Notes from the field: fatal rat-bite Fever in a child – San Diego County, California, 2013. MMWR Morb Mortal Wkly Rep. 2014;63(50):1210–1211.

2.    Chen P.L., Lee N.Y., Yan J.J., et al. Prosthetic valve endocarditis caused by Streptobacillus moniliformis: A case of rat bite fever. J Clin Microbiol. 2007;45:3125–3126.

3.     Crews J.D., Palazzi D.L., Starke J.R. A teenager with fever, rash, and arthralgia. Streptobacillus moniliformis infection. JAMA Pediatr. 2014;168(12):1165–1166.

4.    Elliott S.P. Rat bite fever and Streptobacillus moniliformis. Clin Microbiol Rev. 2007;20:13–22.

5.     Fenn D.W., et al. An unusual tale of rat-bite fever endocarditis. BMJ Case Rep. 2014;2014:.

6.      Gaastra W., Boot R., Ho H.T., Lipman L.J. Rat bite fever. Vet Microbiol. 2009;133:211–228.

7.    Graves M.H., Janda J.M. Rat-bite fever (Streptobacillus moniliformis): A potential emerging disease. Int J Infect Dis. 2001;5:151–155.

8.    Holroyd K.J., Reiner A.P., Dick J.D. Streptobacillus moniliformis polyarthritis mimicking rheumatoid arthritis: An urban case of rat bite fever. Am J Med. 1988;85:711–714.

9.       Lambe Jr. D.W., McPhedran A.M., Mertz J.A., Stewart P. Streptobacillus moniliformis isolated from a case of Haverhill fever: Biochemical characterization and inhibitory effect of sodium polyanethol sulfonate. Am J Clin Pathol. 1973;60:854– 860.

10.       Miura Y., Nei T., Saito R., Sato A., Sonobe K., Takahashi K. Streptobacillus moniliformis bacteremia in a rheumatoid arthritis patient without a rat bite: a case report. BMC Res Notes. 2005 Nov 19;8(1):694. doi:10.1186/s13104-015-1642-6.

11.    Schachter M.E., Wilcox L., Rau N., et al. Rat-bite fever, Canada. Emerg Infect Dis. 2006;12:1301–1302.

12.     Stehle P., Dubuis O., So A., Dudler J. Rat bite fever without fever. Ann Rheum Dis. 2003;62:894–896.

13.     Trucksis M. Rat Bite Fever. UpToDate. http://www.uptodate.com/contents/rat-bite-fever; [accessed July 9, 2015].

14.    Washburn R.G. Streptobacillus moniliformis (rat−bite fever). In: Mandell G.L., Bennett J.E., Dolin R., eds. Principles and Practice of Infectious Diseases, vol 2. 6th ed Philadelphia: Elsevier; 2005:2708–2710.

1  Not FDA approved for this  indication.

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