Information for Healthcare Workers

Etiologic Agent

In North America, RBF is caused primarily by Streptobacillus moniliformis. These bacteria have the following microbiological features:

  • Fastidiously growing bacteria
  • Gram-negative, pleomorphic, non-sporulating, non-encapsulated rod
  • Facultative anaerobes, except isolates from guinea pigs, which are obligate anaerobes.
  • Non-motile
  • Frequently in chains and tangled filaments with bulbous or “Monilia”-like swellings

Spirillum minus more often cause RBF infections in Asia and are characterized as:

  • Short, thick, motile spirochetes, having bipolar flagellar tufts

Transmission

Streptobacillus moniliformis and Spirillum minus are commensal organisms that are part of the normal respiratory flora of rodents. Bacteria can be found in the oral, nasal, and conjunctival secretions, as well as animal urine. Either organism may be transmitted to humans through broken skin, bites, or scratches. Infection can also result from close contact with an infected rodent (without a reported bite or scratch), or ingestion of food or drink that have been contaminated with these bacteria. Infection that occurs as a result of ingestion is known as Haverhill fever, after a large bacterial outbreak that occurred in Haverhill, Massachusetts, in 1926, linked to contaminated unpasteurized milk products. Without early diagnosis and appropriate treatment, RBF can cause severe infections and death.

Clinical Features

Initial symptoms of S. moniliformis are non-specific and include fever, chills, myalgia, headache, and vomiting. Patients may develop a maculopapular rash on the extremities around 2 to 4 days after fever onset, followed by polyarthritis in approximately 50% of patients. The incubation period for S. moniliformis typically ranges from 3 to 10 days. The signs and symptoms of Haverhill fever can differ slightly from Streptobacillary cases of RBF. Haverhill fever can be associated with more severe nausea, vomiting, and pharyngitis.

Symptoms caused by Spirillum minus infection usually occur 7 to 21 days after exposure to an infected animal. Patients are likely to have a history of travel outside of the United States and to Asia in particular. Following partial healing of a rat bite, common signs and symptoms include fever, ulceration at the bite site, lymphangitis, lymphadenopathy, and a distinct rash of purple or red plaques.

If untreated or not appropriately treated, RBF infections may result in soft tissue and solid-organ abscesses, septic arthritis, pneumonia, hepatitis, nephritis, meningitis, and endocarditis, myocarditis, or pericarditis. Complications involving endocarditis carry the highest risk for mortality.

Diagnostics and Laboratory Testing

RBF should be suspected in patients with fever, nausea, vomiting, joint pain, and rash, as well as a known or suspected history of rodent exposure.

S. moniliformis

  • RBF is diagnosed by conducting culture isolation of S. moniliformis from blood, synovial fluid, other body fluids, affected tissues such as abscessed organs, or primary lesions. S. moniliformis may be isolated in the synovial fluid of patients with septic arthritis, but will be sterile in most. The organism is difficult to grow in culture and requires specific media and incubation conditions.
  • In the absence of a positive culture, Gram stain identification of pleomorphic gram-negative bacilli in appropriate specimens supports a preliminary diagnosis.
  • Historically, serological assays were used for diagnostic purposes; however, validated serological tests for RBF determination in humans are currently not available.

S. minus

  • S. minusdoes not grow in artificial media. For this reason, diagnosis is made by identifying characteristic spirochetes in appropriate specimens using darkfield microscopy or differential stains.

If RBF is suspected in a severe illness or death, but a diagnosis has not been made, physicians can consider requesting diagnostic assistance from their state public health laboratories or CDC (see Specimen Processing and Submission).

Specimen Processing and Submission

Whole blood and joint aspirate fluid are specimens of choice for S. moniliformis diagnosis. Specimens should be collected before initiating antimicrobial therapy.

Collect blood specimen in EDTA, lavender-top tubes. Do not use blood culture bottles to collect whole blood specimens. Most blood culture bottles contain Sodium Polyanethole Sulfonate (SPS), a compound which will inhibit the growth of S. moniliformis. DO NOT refrigerate collected specimens. Specimens should be stored at room temperature after collection, as refrigeration at cold temperatures will inhibit bacterial growth.

For culture isolation of S. moniliformis, overlay HIA agar plates (with 5% rabbit blood) with sterile rabbit or horse serum. Allow the plates to dry before inoculating with specimen and streaking for isolation. For liquid media, adding drops of sterile serum to thioglycolate or heart infusion broth can enhance bacterial growth. This should be cultivated at 37°C in 5-10% CO2 with the supplementation described above. S. moniliformis are fastidious, slow-growing organisms, and it can take up to 7 days for recovery of the organism. Frequent subcultures of the organism may be needed to maintain viability.

CDC requests isolates for RBF testing. Contact BSPB if you are unable to send an isolate. All specimens should be submitted at room temperature for optimal testing conditions upon arrival at CDC.

For detailed information on how to submit specimens for testing at CDC, visit the Special Bacteriology Reference Laboratory website.

Treatment

There is limited research on the effectiveness of specific antibiotics to treat RBF. Intravenous penicillin G given for 7 or more days, then oral penicillin, is usually recommended for the treatment of RBF. However, patients can develop Jarisch-Herxheimer reactions, which can complicate penicillin treatment. Patients usually improve quickly once antibiotics are started. Without appropriate treatment, the mortality rate is about 10%.

In patients allergic to penicillin, doxycycline or streptomycin are alternative choices.

RBF can present similarly to other febrile rash illnesses such as Rocky Mountain Spotted Fever (RMSF). If RBF and RMSF are both in differential diagnosis, doxycycline should be considered as first-line treatment given the need for rapid treatment and limited diagnostics for both diseases. This consideration applies to pediatric patients <8 years old as dental staining is not a risk when using doxycycline for less than 14 days.

Endocarditis is a rare complication and may require combination therapy with both intravenous penicillin G and streptomycin or gentamicin for effective treatment; however, this is based on older studies and no recent studies have been done to evaluate the effectiveness of combination treatment.

References

  • Dendle C, Woolley IJ, Korman TM. Rat-bite fever septic arthritis: illustrative case and literature review. Eur J Clin Microbiol Infect Dis. 2006;25(12):791-797.
  • Elliott SP. Rat bite fever and Streptobacillus moniliformis. Clin Microbiol Rev. 2007;20(1):13-22.
  • Gaastra W, Boot R, Ho HT, Lipman LJ. Rat bite fever. Vet Microbiol. 2009;133(3):211-228.
  • Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted FeverExternal. J Pediatr. 2015;166(5):1246-1251.
  • Washburn RG. Rat-Bite Fever. In: Bennett, Dolin, Blaser, editors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, Pennsylvania: Elsevier, Inc.; 2015. p. 2629-32.

Epidemiology

RBF is known to be fairly rare in the United States; however, it may be underdiagnosed due to the difficulty in culturing the organism for confirmatory diagnostic testing and an underrepresentation of rodent exposure in the patient’s clinical history.

Currently, rat bite fever is not reportable in any U.S. state or territory and is not nationally notifiable.

Recent case reports have highlighted the risk for RBF among persons, particularly infants, children, and adolescents, having contact with rodents in the home. As pet rats and rodents increase in popularity, this population of pet owners is likely to be an emerging risk group. Occupationally-acquired cases in pet stores or animal research laboratories have also been reported.

S. moniliformis is usually susceptible to several antibiotics, including:
  • penicillins
  • cephalosporins
  • carbapenems
  • aztreonam
  • clindamycin
  • erythromycin
  • nitrofurantoin
  • bacitracin
  • doxycycline
  • tetracycline
  • teicoplanin
  • vancomycin