Streptobacillus moniliformis (Rat Bite Fever)

Authors: Luis F. Guzman Vinasco, M.D., Mark E. Rupp, M.D.

Author, 1st Edition (1997) and 2nd Edition (2002): Mark E. Rupp, M.D.

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History

Microbiology

Streptobacillus moniliformis, the only species in the genus, is a pleomorphic gram-negative, non-motile, non-spore-forming, non-encapsulated microaerophilic bacillus. Although the morphology of the organism is dependent on the age of the culture and growth conditions, it characteristically appears as long filamentous organisms with fusiform swellings.

Epidemiology

Approximately two million animal bites occur each year in the United States, most of which are due to cats and dogs, while rats are responsible for 1% of these bites (Khatchadourian). It has been known for thousands of years that a febrile illness can follow the bite of a rat. In the Western hemisphere most cases of rat-bite fever are due to Streptobacillus moniliformis. The natural habitat of S. moniliformis is the respiratory passage of rodents - especially rats; the organism can also be recovered from the urine of rats (19). The organism is carried by healthy rats, both wild and laboratory, with colonization rates reported as high as 50% to 100% (39, 40). S. moniliformis occasionally causes disease in rats resulting in otitis media, conjunctivitis, and pneumonia (65).

Infection with S. moniliformis in humans occurs most commonly in persons living in crowded, rat-infested urban dwellings. Children appear to be at greater risk, with about 50% of cases occurring in persons under age 12 (47). Also, laboratory personnel working with rodents are at an increased risk of contracting rat-bite fever (1, 10, 27). Infection generally results from rat bite, but has also resulted from bites or scratches due to animals that feed or have close contact with rats, such as cats, dogs, pigs, and ferrets (21). Infection may also result from handling dead rats without an apparent breach of the skin (38). In addition, a case has been described in which it was hypothesized that S. moniliformis was inoculated across non-intact skin from an inanimate object that was colonized with the organism (20). Oral ingestion ofS. moniliformis can cause epidemics of an illness resembling rat-bite fever which is known as Haverhill Fever or Erythema Arthriticum Epidemicum. Sources of such outbreaks have been linked to contaminated milk and water (37, 43).

Clinical Manifestations

As many as 10% of persons bitten by a rat who do not receive antibiotic prophylaxis develop rat-bite fever (48). Rat bite fever should be in the differential diagnosis anytime a patient presents with classic symptoms of fever, rash, and joint involvement, especially if there is a history of rodent exposure or rat bite. Clinicians should consider rat bite fever in the differential diagnosis of an unexplained febrile illness, especially in patients with relapsing or intermittent fever (33). If significant rodent exposure is documented in the patient history, the differential diagnosis should include rat bite fever, plague, lymphocytic choriomeningitis, hantavirus pulmonary syndrome, tularemia, Pasteurella infections and leptospirosis (29).

Typically, the incubation period for rat bite fever lasts less than 10 days and is followed by the abrupt onset of fever, chills, headaches, vomiting, myalgias, and arthralgias. At the time of presentation, the bite wound is often completely healed, and unless the history of rat bite is elicited, the diagnosis may remain obscure. A rash often develops within several days of the onset of fever and is usually macular, maculopapular or petechial, although pustular lesions have been described (12). The rash is most prominent on the extremities and may involve the palms and soles. Desquamation has been described (58). This presentation in a child may lead to an erroneous diagnosis of Kawasaki disease and delay effective antibiotic treatment (2). About 50% of patients develop septic polyarticular arthritis. The joints involved, in decreasing order of frequency, are the knees, ankles, elbows, wrists, shoulders, hips, and sternoclavicular (34, 52). Laboratory tests often reveal an elevated white blood cell count with an increased number of band-form neutrophils on the differential count. Approximately 25% of patients develop a falsely-positive serologic test for syphilis (62).

Haverhill fever (erythema arthriticum epidemicum), refers to outbreaks of epidemic disease resulting from ingestion of S. moniliformis. The first reports originated in Haverhill MA in 1926 and were thought to be due to contaminated milk (40). Subsequent outbreaks, sometimes numbering in the hundreds of patients, have usually been associated with ingestion of raw milk or contaminated water (17). Patients develop signs and symptoms identical to those of rat bite fever. However, the absence of rat exposure and the presence of a large number of patients with common temporal and geographic exposure, should suggest Haverhill fever. Initial resolution of symptoms (fever, headache, nausea, vomiting), followed in 3-4 days by the recurrence of fever and development of polyarthralgias and polyarthritis, as well as a rubellifom rash, has been described (17). Polyarthritis the most common persistent clinical feature can persist for months (17).

Complications of rat-bite fever include endocarditis (33, 52), myocarditis (59), pericarditis (5, 50), meningitis (23, 55), pneumonia (38, 55), amnionitis and pelvic abscess (18, 42), brain abscess (15), splenic abscess (9), liver abscess and kidney abscess (62), and prostatitis and pancreatitis (65). Mortality in untreated cases of infection due to S. moniliformis is approximately 10%, but with appropriate antimicrobial treatment mortality is rare.

Laboratory Diagnosis

S. moniliformis is difficult to recover with traditional bacteriological techniques because this fastidious bacterium requires enriched media and is inhibited by sodium polyanetholsulfonate, an additive present in many commercial blood culture bottles. Optimal recovery is achieved using an enriched liquid media such as trypticase soy broth supplemented with rabbit or horse serum, incubated at 37o C in a 10% CO2 atmosphere (13). Sodium-polyanethol sulfonate inhibits the growth of S. moniliformis at concentrations as low as 0.0125% (32, 56). When grown in thioglycolate broth, S. moniliformis produces characteristic "puff ball" or "bread crumb" colonies. Cell wall-deficient colonies, which have a characteristic "fried-egg" appearance on solid media, arise spontaneously, were first described by Klienberger, and named L-forms in honor of the Lister Institute (30).

At the biochemical level, S. moniliformis is an inactive species with negative reactions for oxidase, catalase, nitrate reduction, urea, phenylalanine deamination, and gelatin liquefaction. Acid with gas formation is produced from glucose, maltose, fructose, galactose, glycogen, mannose, and starch (66). There is a high degree of conformity when testing strains of S. moniliformisderived from a variety of animal sources (65). Fatty-acid profile analysis, obtained via gas liquid chromatography, has been reported as a rapid identification method (53) and analysis of protein banding patterns by high-resolution SDS-PAGE can be used to type organisms for epidemiologic purposes (11). For humans currently no validated serological test is available although ELISA and EIA assays are available for veterinary use to detect S. moniliformis antibiodies and have been utilized to monitor rodent colonies for infection (3, 21). PCR-based detection using broad-range 16s rRNA gene primers has been successfully used to identify the pathogen when cultures are negative (2, 7, 8, 21). False positive results for S. moniliformis PCR, due to the presence of Leptotrichia sp. were recently reported (4, 64), so sequencing of PCR amplicons may be necessary.

Pathogenesis

Very little is known about potential virulence factors of S. moniliformis. Clinical disease occurs when local cutaneous host defense mechanisms are overwhelmed resulting in bacteremia and metastatic disease. Two mechanisms for the development of arthritis in streptobacillary infection have been proposed. One is immunological in origin and occurs in cases where joint effusions are sterile, the other is due to direct infection of the joint resulting in suppurative arthropathy (14). In fatal cases, autopsies reveal focal infiltrations of mononuclear cells in involved tissues.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drugs

A large number of studies have reported the susceptibility of single strains of S. moniliformis using a variety of techniques. There is a paucity of studies examining multiple strains.

Edwards and Finch examined the susceptibility of 7 strains of S. moniliformis to 9 antimicrobial agents using an agar dilution method (16). The mean MIC in μg/ml were as follows: penicillin < 0.015, ampicillin < 0.06, cefuroxime < 0.125, cefotaxime < 0.05, tetracycline < 0.5, ciprofloxacin < 2.0, gentamicin < 4.0, erythromycin < 4.0, chloramphenicol = 8.0. Wullenweber tested the susceptibility of 13 strains of S. moniliformis of human, murine, and avian origin using a breakpoint microtiter assay (Radiometer, Copenhagen) (65). The organisms were susceptible to a wide variety of antibiotics including beta-lactams, monobactams, carbapenems, macrolides, lincosamides, glycopeptides, rifampin, and tetracyclines. Indeterminate sensitivity or resistance was observed with aminoglycosides, fluoroquinolones, chloramphenicol, trimethoprim/ sulfamethoxazole, and fusidic acid. The specific agents tested and a summary of results are shown in Table 1. Other studies testing single strains are generally in agreement with the 2 studies discussed above (1, 20, 23, 25, 27, 28, 32, 35, 36, 41, 44, 46, 52, 54, 56, 57). Antibiotics examined in one or more of the studies utilizing single strains of S. moniliformis that were not examined in the 2 larger studies are summarized in Table 2.

Two cases of infection due to S. moniliformis resistant to penicillin have been reported (57, 60). Both reports are somewhat suspect as to their validity by current standards. In the report by Stokes the organism was identified by morphology but no biochemical tests were reported. The organism was freeze-dried but when the investigators attempted to further characterize the organism, it was no longer viable. Susceptibility testing was performed by disc diffusion in which the discs were manufactured by the authors by impregnating filter paper with the antibiotics. In the paper by Toren et al, the isolate was again identified by morphology without supporting biochemical data. The methodology by which antibiotic susceptibility was determined is not clear and MIC values were not reported. Penicillin susceptibility was simply reported as negative. Therefore, until penicillin-resistance is better documented, isolates of S. moniliformis can be regarded as uniformly susceptible to penicillin.

Combination Drugs

Although antibiotics are occasionally used in combination to treat infection due to S. moniliformis, there is scant data to indicate additive or synergistic activity.

In-vivo Studies

There have been no in-vivo studies of the efficacy of antibiotic treatment, singly or in combination, against S. moniliformis.

ANTIMICROBIAL THERAPY

General

It should first be noted that there are no prospective trials concerning the treatment of infection due to S. moniliformis. All data regarding this subject are derived from anecdotal reports of the treatment of single or small numbers of patients.

Robbins is credited with reporting the first use of penicillin against S. moniliformis (49), and penicillin remains the drug-of-choice . The patient was a 70 year-old man with a leg abscess and positive blood cultures for S. moniliformis who failed treatment with sulfathiazole. The patient responded favorably to penicillin at a total dosage of approximately 2 million units. Watkins reported 16 cases of rat-bite fever observed in St. Louis over a 8 year period and reviewed the literature with regard to antibiotic therapy (63). He concluded that "Penicillin is indicated early in the treatment of rat-bite fever after correct diagnostic procedures have been employed." Despite over 50 years of experience since this advice was printed, it should not be significantly altered in caring for patients today. In a paper by Roughgarden in 1965 in which 62 cases of streptobacillary rat-bite fever, occurring between 1918 and 1958, were reviewed, including 27 cases in which penicillin therapy was used, it was concluded that "a consistently effective regimen for streptobacillary disease consists of a daily dosage of not less than 400,000 to 600,000 units continued for not less than seven days (50). If no response is obtained in two days with this program, the dosage should be raised to 1,200,000 units daily" (50). This recommendation was for procaine penicillin G given intramuscularly. Currently, intravenous penicillin G is thought to be more appropriate. For uncomplicated disease, low-to-moderate doses should be effective (2.4 million units per day to 4.8 million units per day, split evenly every 6 hours). Most patients improve rapidly and, for individuals who appear well after 5 to 7 days, treatment can be switched to oral ampicillin or penicillin V (500 mg po every 6 hours) to finish 10 to 14 days of therapy. Although there are no studies to guide one, based on the in-vitro susceptibility of S. moniliformis to penicillin, patients with mild disease can probably be treated with an oral regimen for the entire treatment course.

A number of antibiotics, other than penicillin, have been used to successfully treat patients with infection due to S. moniliformis. These agents include the following: cefazolin, cephalothin, cephradine, flucloxacillin, oxacillin, nafcillin, ampicillin, amoxacillin/clavulanate, ticarcillin, ceftriaxone, tetracycline, clindamycin, erythromycin, and chloramphenicol. Often these agents have been combined with one another, or one of these agents has been combined with an aminoglycoside. However, there is no in-vivo or in-vitro data to indicate that there is synergistic activity associated with combination therapy. These cases are summarized in Table 3.

Therefore, based on the data available, the drug of choice for treatment of infections due to S. moniliformis is penicillin. Alternative agents for patients who are allergic to penicillin include cephalosporins (1st, 2nd, or 3rd generation agents appear to be effective), tetracyclines, erythromycin, clindamycin, or chloramphenicol. It should be noted that several in-vitro studies have shown that S. moniliformis is resistant tosulfonamides (1, 23, 24, 54, 65) and therapy with sulfonamides has been associated with clinical failure (23, 56). Therefore, sulfonamides are not recommended as alternatives to penicillin.

L-forms, cell wall-deficient variants, spontaneously arise in culture and have been isolated from human blood. Because L-form cells lack a cell wall, they are resistant to antibiotics that act upon the cell wall, ie, beta-lactams . Although there is little supporting evidence, it has been postulated that persisting penicillin-resistant L-form cells may cause relapse of infection after therapy has ceased. Some authors have recommended addition of streptomycin or other aminoglycosides to enhance activity against L-forms (33). Others have followed intravenous penicillin therapy with a short course of oral tetracycline (52).

Pediatric Patients

As previously mentioned, children appear to be at increased risk for infection due to S. moniliformis because of their increased propensity to suffer rat bite. Penicillin G remains the drug-of-choice for these infections, at a dose of 25,000 units per kg per day divided evenly every 6 hours. Tetracyclines should be avoided as a secondary choice due to their association with tooth discoloration and tooth enamel agenesis. Reasonable secondary choices include cephalosporins, erythromycin, and clindamycin.

Pregnant Patients

S. moniliformis has rarely been reported to cause infection in pregnant women and has not been reported to cause transplacental infection of the fetus (18). Penicillins have been used extensively in pregnant women and neonates and are generally safe (22). Therefore, penicillin remains the drug-of-choice in treating S. moniliformis infections in pregnant patients. Cephalosporins, which have demonstrated activity against S. moniliformis in vitro, could be used in women allergic to penicillin. However, these agents should be used with extreme caution in women with a history of anaphylactic reaction to penicillins. For the reasons discussed above, tetracyclines should be avoided in the treatment of pregnant women. Erythromycin is generally safe for use in pregnancy, although the estolate form should be avoided due to the risk for cholestatic hepatitis (22). Clindamycin has also been used safely in pregnant women (22). There is little change, associated with pregnancy, in the pharmacokinetics of this agent and the drug crosses the placenta, reaching levels approximately one-half of those in maternal serum (22). Chloramphenicol use should generally be avoided in pregnant women and children due to hematologic toxicity and the "gray baby syndrome," a syndrome of neonates characterized by vomiting, abdominal distension, flaccidity, and circulatory collapse.

Special Infections

Endocarditis and Central Nervous System Infections

Endocarditis as a complication of rat bite fever due to S. moniliformis occurs very rarely. Reviews on this topic document very few cases described in the medical literature (33, 52). Although optimal therapy is not known, high dose penicillin treatment is recommended (> 20 million units per day divided evenly every 4 hours) particularly if the isolate is resistant to penicillin at a level of > 0.1 μg/ml (35). In patients allergic to penicillin, vancomycin with gentamicin may be used (33).

Similar to endocarditis, meningitis or brain abscess has been described exceedingly rarely. There is no data regarding optimal therapy, but high-dose penicillin therapy is the treatment of choice. An attractive alternative, based on limited in-vitro data and their excellent penetration into the cerebrospinal fluid, are the 3rd generation cephalosporins, cefotaxime and ceftriaxone.

Streptobacillus moniliformis infections in veterinary practice

S. moniliformis causes infection in a wide variety of animals including rats, mice, spinifex hopping mice, guinea pigs, dogs, turkeys, cattle, non-human primates and koalas (21, 65). There is little information regarding therapy in animals and this topic is beyond the scope of this chapter. The interested reader is referred to the review by Wullenweber (65).

Underlying Diseases

There is no indication that specific diseases or underlying conditions predispose one to infection or complication due to S. moniliformis. Environmental or occupational conditions making contact with rodents and rat bite more likely will also increase the likelihood of infection due to S. moniliformis.

Alternative Therapy

Although penicillin is the drug-of-choice for treatment of rat-bite fever, a wide range of alternative agents are available for individuals who are allergic to beta-lactam agents, including macrolides and tetracyclines. For penicillin-allergic patients, both streptomycin and tetracycline appear to be effective (44, 52), vancomycin combined with gentamicin has also been recommended (33), but erythromycin use has been associated with treatment failures (24). Cephalosporins have also been used successfully (6, 12) and may be considered if cross-allergenicity with penicillin is felt to be unlikely (17).

VACCINES

No vaccine preparation is available for prevention of illness due to S. moniliformis.

ENDPOINTS FOR MONITORING THERAPY

Endpoints for monitoring therapy have not been established.

ADJUNCTIVE THERAPY

S. moniliformis has rarely been described to cause discrete abscesses (9, 15, 42, 62). In these instances, surgical drainage is recommended.

PREVENTION OR INFECTION CONTROL

In the event of a rodent bite, the wound should be thoroughly cleansed and tetanus prophylaxis administered, if warranted. Although the efficacy of antibiotic prophylaxis for rat bite is unknown, a prudent course-of-action would dictate administration of amoxicillin/clavulanate at a dosage of 500 mg p.o. every 8 hours for 3 days. Other common sense precautions one should take to avoid infection with include using caution and wearing gloves while handling laboratory rodents, eradicating rats from human dwellings, and avoiding potentially contaminated water and unpasteurized milk.

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