Spirillum minus
Authors: Luis F. Guzman Vinasco, M.D. and Mark E. Rupp, M.D.
GENERAL DESCRIPTION
Spirillum minus is the principal cause of rat bite fever in the Eastern hemisphere, but only rarely causes disease in the United States. The organism, first described by Dr. Henry Van Dyke Carter in 1887, was previously known as Spirocheta morus muris, Sporozoa muris, Spirochaeta laverani, Spironema minor, Leptospira morsus minor, Spirochaeta muris and Spirochaeta petit (8). The organism was named S. minus in 1924 (14).The first case description of rat bite fever due to S. minus in the United States was described by Shattuck and Theiller in 1924 (16). In Japan, infection caused by S. minus is known as Sodoku from So = Rat and Doku = Poison.
Microbiology
S. minus is a gram-negative, tightly coiled spirochete measuring 0.2 - 0.5 μm by 3-5 μm, which possesses 2-6 regular spirals (9). The organism is motile by means of bipolar flagella. S. minus has not been cultivated on laboratory media. The taxonomic position of S. minus will remain unclear until appropriate nucleic acid based phylogenetic studies have been performed (8).
Epidemiology
The epidemiology of S. minus infection is similar to that of Streptobacillus moniliformis. Rats are frequently colonized by S. minus (2, 9) and infection in humans is usually acquired through the bite of a rat. Spirillum minus is found in a wide variety of tissues and fluids of infected rodents including blood, peritoneal fluid, conjunctival fluid, muscle, tongue, and lung tissues (17). It also infects cats and other carnivores that feed on infected rodents (4). In contrast to S. moniliformis, S. minus has not been described to cause disease via oral ingestion.
Clinical Manifestations
Inoculation of S. minus occurs through the bite of a colonized rat. Generally, the bite wound heals during the 1 to 3 week incubation period. However, as the systemic phase of the illness begins; characterized by fever, chills, malaise, and headache, the bite wound becomes swollen and indurated and is often associated with regional adenopathy. The bite site may ulcerate and progress to a chancre-like lesion (4, 6). A macular violaceous rash may occur involving the extremities, face, and trunk. Joint manifestations are rare (1, 7). Laboratory studies reveal a leukocytosis and up to 50% of patients have a false-positive serologic test for syphilis (9). Without antimicrobial therapy, the fever abates over 3 to 5 days only to recur at regular intervals of 3 to 10 days. Although relapses have been described to occur for years (18), spontaneous resolution usually occurs in 1 to 2 months. Without treatment mortality is approximately 10% (5).
Complications of S. minus infection are rare. The most serious complication is endocarditis which usually occurs in the setting of pre-existing valvular abnormality (20). However, cases of spirillar endocarditis in previously normal valves have been described (13). Other complications include myocarditis, meningitis, hepatitis, pleural effusions, conjunctivitis, epididymitis, and anemia (20). The differential diagnoses include Borrelia spp, malaria, lymphoma, and other relapsing infections (4).
Laboratory Diagnosis
S. minus can be directly visualized in blood and infected tissues using Giemsa stain, Wright stain, or darkfield microscopy. The diagnosis of S. minus infection can be proven by recovery of organisms from mice or guinea pigs, 1 to 3 weeks after intraperitoneal inoculation of infectious material from the index patient. A means of propagation of the organism in laboratory media has not been established, nor are specific serologic tests available. Half of patients infected by S minus have a positive serology for syphilis (4). S. minus bacterial DNA should be amplified through use of broad range bacterial 16S rRNA gene primers (8).
Pathogenesis
Infection due to S. minus is a multisystem disorder characterized by dissemination of organisms via the bloodstream. Granulomatous inflammation and regional adenopathy is evident at the initial site of inoculation. In fatal cases, autopsy reveals hemorrhagic necrosis in various tissues including liver, kidney, spleen, myocardium, and meninges (9).
SUSCEPTIBILITY IN VITRO AND IN VIVO
Single Drug
In Vitro Studies
Because S. minus has not been cultivated on synthetic media there are no in vitro data regarding the susceptibility of S. minus to antimicrobial agents.
In Vivo Studies
Although S. minus can be propagated in mice or guinea pigs, there is little data regarding treatment of S. minus using this system. However, Heilman and Hermel clearly demonstrated the efficacy of penicillin by treating one-half of 50 infected mice with penicillin (10). Blood smears from the treated mice were negative within 2 days of starting treatment. Blood smears from all but one of the untreated mice remained positive for S. minus for the 30-day observation period. Tani and Takano reported treating experimentally infected mice with a variety of antimicrobial agents to determine the dosage required to prevent transmission of disease through transfusion (19). The 100% preventive dose (PD100) for penicillin was 1000 units, while the PD100 for tetracycline, oxytetracycline, chloramphenicol, and streptomycin was 100 μg, 100 μg, >200 μg, and >100 μg respectively.
Combination Drugs
No published studies regarding combination therapy against S. minus are available.
ANTIMICROBIAL THERAPY
Drug of Choice
There are no prospective trials concerning the treatment of S. minus. Data are derived from anecdotal reports of treatment of single or small groups of patients.
Wheeler is credited with reporting the first use of penicillin against S. minus (22). Currently, penicillin is the drug-of-choice for the treatment of spirillar rat bite fever. The organism appears to be exquisitely susceptible to penicillin and it has been stated that only 2 doses of procaine penicillin or 1 dose of repository penicillin is adequate for cure (5). However, most authorities recommend treatment of 10 to 14 days. Initially, patients should be treated with 2.4 to 4.8 million units of penicillin G daily delivered intravenously in 4 evenly timed doses. Following defervescence, patients can be switched to oral ampicillin or penicillin V (500 mg po every 6 hours) to finish a 10 to 14 days course. Although there are no studies to guide one, patients with relatively mild disease and no evidence of complications such as endocarditis or meningitis, can probably be treated with an oral regimen for the entire treatment course. Jarisch-Herxheimer reactions may occur during the initial stages of therapy (15). Prior to the availability of penicillin, arsenicals were frequently used to treat patients infected with S. minus, apparently, with some degree of success (21). Streptomycin and tetracycline derivatives have also reportedly been used successfully to treat S. minus infection (2, 11, 15). Alternate therapies include oral amoxicillin-clavulanate, 875 mg/100 mg twice daily (for 10–14 days), or oral or intravenous doxycycline, 100 mg twice daily (4).
Pediatric Patients
Penicillin remains the drug-of-choice for pediatric patients. The dosage is 25,000 units/kg per day divided into 4 doses. Tetracyclines should be avoided due to their association with tooth enamel agenesis and tooth staining.
Special Infections
Endocarditis and Central Nervous System Infection
Complications of spirillar rat bite fever are rare. Although optimal therapy for endocarditis or meningitis is unknown, high-dose penicillin is indicated at a dosage of approximately 20 million units per day divided evenly every 4 hours. Although the optimum duration of therapy is unknown, based on limited data, treatment of meningitis for 10 - 14 days and endocarditis for 28 days should be sufficient.
Underlying Diseases
No published studies indicate that specific underlying conditions predispose one to infection or complication due to S. minus or necessitate a change in treatment recommendations.
Alternate Therapy
Serious Beta-Lactam Allergy
In the event of serious penicillin allergy, a tetracycline derivative should be employed in the treatment of S. minus infection. The recommended dosage would be 500 mg either p.o. or intravenously every 6 hours or doxycycline 100 mg p.o. or intravenously every 12 hours.
ADJUNCTIVE THERAPY
No data is available regarding non-antimicrobial drug therapy or other adjunctive treatment.
ENDPOINTS FOR MONITORING THERAPY
Endpoints for monitoring therapy have not been established.
VACCINES
No vaccine is commercially available for prevention of S. minus infection.
PREVENTION OR INFECTION CONTROL
In the event of a rat bite, the wound should be thoroughly cleaned and tetanus prophylaxis administered if appropriate. Although the efficacy of prophylaxis is not proven, a prudent course-of-action would dictate administration of amoxacillin/clavulanate at a dosage of 500 mg p.o. every 8 hours for 3 days. In addition to S. minus, this regimen would cover S. moniliformis and other commonly encountered pathogens in bite wounds.
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