Rat bite fever

OVERVIEW: What every practitioner needs to know

Are you sure your patient has rat bite fever? What are the typical findings for this disease?

Symptoms of rat bite fever depend on the microbial etiology and route of infection. Both
Streptobacillus moniliformis and Spirillum minus are causes of illnesses termed rat bite fever.

Streptobacillary rat bite fever (due to Streptobacillus moniliformis)

Acute onset of fever, shaking chills, headache, and vomiting (near 100% of cases).
Maculopapular rash, often involving the palms and soles (75% of cases; may also be petechial, pustular, or purpuric, and may desquamate in 20% of cases).
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Migratory arthralgias or arthritis with or without joint effusions (50% of cases).
Typically, the bite (or site of inoculation) is well-healed with no evidence of inflammation or regional adenopathy.

Haverhill fever (variant of Streptobacillary rat bite fever associated with ingestion of S. moniliformis)

Acute onset of fever, chills, rash, and arthritis.
Rash is typically smaller in distribution and more uniform than with parenteral inoculation.
Upper respiratory and gastrointestinal symptoms are common.
Recurrences of fever are uncommon.

Spirillary rat bite fever (due to Spirillum minus)

The illness begins with fever and chills accompanied by induration at the site of inoculation. The bite lesion may become ulcerated with associated regional adenopathy and lymphangitis. Initial rapid defervescence may be followed by multiple periodic relapses of high fever (2-4 days) interspersed with afebrile periods (3-7 days).

Myalgia, headache, and vomiting is commonly associated with febrile episodes.

Rash (50% of patients) typically consists of large macules and may also include indurated plaques or urticarial lesions.

Arthritis and arthralgia are rare.

What other disease/condition shares some of these symptoms?

Infectious diseases that may be confused with rat bite fever include meningococcemia, disseminated gonococcal infection, Rocky Mountain spotted fever, ehrlichiosis, leptospirosis, Lyme disease, relapsing fever (Borrelia recurrentis), syphilis, brucellosis, and viral infections (adenovirus, parvovirus, Chikungunya, dengue, and others).

Non-infectious illnesses that may present in a manner that is similar to rat bite fever include juvenile idiopathic arthritis (JIA) and other collagen-vascular disorders, drug reactions, and serum sickness.

What caused this disease to develop at this time?

Symptoms of streptobacillary rat bite fever typically manifest within 3-10 days of inoculation with S. moniliformis.
For spirillary rat bite fever, the incubation period is more variable (average 14-18 days, range 1-36 days).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Definitive diagnosis requires direct detection of the organism in blood or other body fluid (e.g., joint, pericardial, abscess, meninges, autopsy tissues).

Culture diagnosis

S. monliformisis fastidious and requires special handling and culture conditions.

Culture is optimally performed using tripticase soy agar or broth supplemented with 20% horse or rabbit serum and incubation at 35°-37°C with 8%-10% carbon dioxide.

Sodium polyanethol sulfonate (SPS), a common additive to aerobic blood culture bottles, will inhibit growth of S. moniliformis. Anaerobic culture bottles do not contain SPS and are suitable for growth of S. moniliformis.

S. minus does not grow well in any artificial medium and requires non-culture methods to confirm infection.

PCR diagnosis

Polymerase chain reaction (PCR)-based methods for detection of S. moniliformis have been described but are not widely available.

PCR detection of S. minus has not been described.

Microscopic detection

S. moniliformis, a pleomorphic Gram-negative bacillus, may be seen by Giemsa stain of blood or body fluid.

S. minus spirochetes may be seen rarely on peripheral blood smear or darkfield examination of ulcer exudate. Otherwise, animal inoculation (intraperitoneally into guinea pigs or mice) with blood or wound aspirates may allow detection of organisms in the animal’s bloodstream after 5-15 days. However, this method is inefficient and not widely available.

Would imaging studies be helpful? If so, which ones?

Ultrasound, CT, or MRI may help to identify fluid collections (e.g., joint effusions and soft tissue and solid organ abscesses) for sampling and culture of S. moniliformis.

Confirming the diagnosis

Laboratory abnormalities consistent with (but not diagnostic for) rat bite fever include elevated WBC up to 30,000/mm³ with a left shift, mild to moderate anemia, and false positive test for syphilis (25% of patients with S. moniliformis infection and 50% of patients with S. minus infection).

If you are able to confirm that the patient has rat bite fever, what treatment should be initiated?

Table I shows antibiotic therapy options for the treatment of rat bite fever.

Table I.

Clinical manifestation	First-line therapy	Alternative therapies
Rat bite fever without endocarditis	Penicillin G (PCN G) 20,000-50,000 IU/kg/day IV or IM (maximum of 1.2 million IU/day) for 7-10 daysS. minus is more sensitive to PCN than S. moniliformis and may require shorter duration therapy with lower doses. However, it may be difficult to distinguish spirillary rat bite fever from streptobacillary rat bite fever, and the two organisms may cause co-infection.	• 5-7 days of IV PCN G followed by 1 week of oral PCN VK 1-2 g/day in divided doses has been successful.• Oral PCN VK may be considered at the outset of therapy in children not requiring hospitalization.• For patients with PCN allergy, consider doxycycline or streptomycin as 2nd-line alternatives.• Limited successful experience exists with ampicillin, cefuroxime, and cefotaxime (or ceftriaxone).
Rat bite fever with endocarditis	PCN G 160,000-240,000 IU/kg/day IV (maximum 20 million IU/day) for at least 4 weeksAntibiotic susceptibility should be determined, and a goal peak serum bactericidal titer of at least 1:8 recommended. Consider combination therapy with gentamicin or streptomycin.	Successful treatment with ceftriaxone and gentamicin has been reported.
Haverhill fever	PCN G as for rat bite fever without endocarditisOutpatient therapy is appropriate for most individuals.

What are the adverse effects associated with each treatment option?

Penicillin and cephalosporins may cause hypersensitivity reactions, nausea, diarrhea. Long-term use of cepalosporins may be associated with beta-lactam drug reaction (hepatotoxicity and bone marrow suppression).

Use of gentamicin or streptomycin should be accompanied by serum drug level monitoring due to risk of ototoxicity and nephrotoxicity.

Use of doxycycline for children < 8 years old should be considered carefully due to the potential risk of permanent tooth discoloration.

What are the possible outcomes of rat bite fever?

Proper antibiotic therapy of streptobacillary rat bite fever typically results in full recovery, with a case fatality rate of less than 1.5%. Untreated infection may be associated with persistent or recurrent episodes of fever and arthralgias and a case fatality rate of 7%-13%. Infants younger than 3 months are more likely to experience severe infection with increased risk of mortality, even with proper antibiotic therapy.

Spirillary rat bite fever typically resolves spontaneously even without antibiotic therapy, although persistent infections and relapses may occur for more than one year following the initial presentation. Untreated infection is associated with a case fatality rate of 6.5%. Complications of prolonged untreated cases include endocarditis, myocarditis, meningitis, hepatitis, nephritis and chronic anemia, severe diarrhea, and weight loss.

What causes this disease and how frequent is it?

Detailed epidemiology: Rat bite fever is a zoonosis with worldwide distribution. Streptobacillary rat bite fever (due to Streptobacillus moniliformis) is the most commonly seen form in the United States; approximately 200 cases have been reported in the literature, but the true incidence is unknown because it is not a reportable disease. Children account for > 50% of cases in the United States, followed by laboratory personnel and pet shop employees.

Spirillary rat bite fever (due to Spirillum minus) is more common in Asia, with only one American case reported in the past 40 years.

Transmission of disease: The causative organisms are common nasopharyngeal colonizers of rats and are also excreted in their urine (10%-100% of rats carry S. moniliformis, and approximately 25% of rats in S. minus endemic areas carry
S. minus). Rat bites are the most common source of inoculation, although transmission may also occur following scratches or simple handling of rats without noticeable trauma.

Children living in rat-infested housing are at increased risk of transmission and may become infected without known history of contact.

The risk of disease following a documented rat bite is probably between 4%-11%.

Transmission to humans has also occurred from mice, squirrels, weasels, and gerbils and from rat-eating carnivores such as cats, dogs, and pigs.

Haverhill fever occurs following transmission of S. moniliformis by ingestion of food or water contaminated by rats.

There are no known genetic factors that predispose individuals to rat bite fever or particular complications.

How do these pathogens/genes/exposures cause the disease?

The pathogenesis of rat bite fever, including organism-specific virulence factors, is not well understood. Common pathologic features of streptobacillary rat bite fever include ulcerative endocarditis with presumed secondary septic embolization to the liver, spleen, lungs, and joints.

With spirillary rat bite fever, edema, mononuclear leukocyte infiltration, and necrosis occur at the site of inoculation. Bloodstream invasion by the organism is associated with symptoms of relapse.

What complications might you expect from the disease or treatment of the disease?

Complications of streptobacillary rat bite fever include endocarditis, myocarditis, septic arthritis, soft tissue and solid organ abscess, meningitis, and pneumonia.

Untreated spirillary rat bite fever may be associated with endocarditis, myocarditis, meningitis, hepatitis, nephritis and chronic anemia, severe diarrhea, and weight loss.

How can rat bite fever be prevented?

Rat bite fever is best prevented through limiting exposure to rats by controlling rodent populations in urban areas, taking precautions to avoid bites and scratches when handling rats, and avoiding consumption of unpasteurized milk (to prevent outbreaks of Haverhill fever).

Antibiotic prophylaxis with amoxicillin or amoxicillin-clavulanic acid may be considered following documented bites in young infants (< 3 months), who are at increased risk of severe disease and mortality. However, this is not routinely recommended, and the optimal prophylactic regimen is unknown.

What is the evidence?

Antibiotic treatment regimens are based on expert opinion arising from case reports and case series.

Shackelford, P, Kaplan, SL. “Rat-bite fever.”. vol. 235. 1993.

“Rat-bite fever–New Mexico, 1996”. JAMA. vol. 279. 1998. pp. 740-1.

Cunningham, BB, Paller, AS, Katz, BZ. “Rat bite fever in a pet lover”. J Am Acad Dermatol. vol. 38. 1998. pp. 330-2.

Hagelskjaer, L, Sorensen, I, Randers, E. “Streptobacillus moniliformis infection: 2 cases and a literature review”. Scand J Infect Dis. vol. 30. 1998. pp. 309-11.

Rupp, ME. “Streptobacillus moniliformis endocarditis: case report and review”. Clin Infect Dis. vol. 14. 1992. pp. 769-72.

Rordorf, T, Züger, C, Zbinden, R. “Streptobacillus moniliformis endocarditis in an HIV-positive patient”. Infection. vol. 28. 2000. pp. 393-4.

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