Rat bite fever

INTRODUCTION — Rat bite fever (RBF) is a rarely diagnosed, systemic illness caused by infection with Streptobacillus moniliformis, Streptobacillus notomytis, or Spirillum minus. This topic will review the clinical manifestations, diagnosis, and treatment of patients with RBF. The topic that discusses the management of animal bites is presented separately. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management".)

EPIDEMIOLOGY — In the United States, RBF is typically caused by S. moniliformis. The disease is rare, with only several cases documented each year. As an example, between 2000 and 2012, only 17 cases were identified in California [1]. However, its actual incidence is unknown because RBF is not a nationally notifiable disease, and many cases go undiagnosed since these bacteria are difficult to identify and are likely to respond to empiric antibiotic therapy. (See 'Treatment' below.)

The risk of RBF due to S. moniliformis after a rat bite is reported to be 10 percent [2], and an estimated 20,000 rat bites occur in the United States each year [2]. Historically, over 50 percent of reported cases occurred in children, and RBF was most likely to be seen in those living in poverty [3]. However, the demographics have changed to include pet store workers and laboratory technicians as rats have become popular pets and research subjects [4,5]. A nation-wide survey in the United States found that 0.33 in one million persons visited the emergency department for rat bite fever and 0.20 in one million were hospitalized; the true incidence of rat bite fever in the United States is probably even lower because this study utilized coding data to identify cases and did not require microbiologic confirmation of the illness [6].

In Asia, RBF is known as sodoku (so: rat; and doku: poison) and it is primarily caused by S. minus [2]. S. notomytis has also been reported in Japan. This species was originally isolated from a spinifex hopping mouse in 1979 and was described genetically in 2015 [7].

MICROBIOLOGY — S. moniliformis and S. notomytis can be grown in culture, although they are difficult to grow. By contrast, S. minus is unable to be cultured.

●S. moniliformis – S. moniliformis is a pleomorphic, fastidious, branching gram-negative bacillus (picture 1). It stains irregularly and can be mistaken for gram-positive pleomorphic rods. The bacteria are microaerophilic; they require specific media for isolation (10 to 20% serum) and incubation in a 5 to 10% CO₂ environment. Sodium polyanethol sulfonate (SPS), an anticoagulant added to most aerobic blood culture bottles, inhibits growth of S. moniliformis. This limitation may be overcome by inoculating each bottle with 10 mL of blood [8]. Anaerobic culture bottles, resin bead culture systems, and trypticase soy agar and broth may demonstrate growth if they do not contain SPS.

S. moniliformis grows slowly. As a result, the clinical microbiology laboratory should be notified if there is clinical suspicion for the disease so that cultures can be held for up to seven days to allow identification. On solid agar plates, pinpoint colonies representing cell wall-defective variants (L-forms) may surround larger gray-white colonies [9]. Inoculation into thioglycolate broth enriched with serum produces growth in typical "puff-ball" or "cotton ball" colonies [10].

S. moniliformis can be identified by a characteristic fatty acid profile on gas chromatography [11]. In contrast, biochemical testing is often difficult, and results may be inaccurate because of the fastidious nature of the organism. Identification by 16S rDNA sequencing is feasible although this method is specific to the genus (ie, Streptobacillus) and may not distinguish certain rare species such as S. felis and S. hongkongensis [12]. Mass spectrometry-based identification methods have also been used on direct clinical specimens when clinical suspicion is high, bypassing the need for culture [13].

●S. notomytis – S. notomytis can be grown in culture similar to S. moniliformis and is distinguishable by 16S rDNA sequencing.

●S. minus – S. minus, previously known as Spirocheta morsus or Sporozoa muris, is a short, thick, nonmotile gram-negative tightly coiled spiral that has 2 to 6 helical turns spanning 0.2 to 0.5 micrometers. This organism cannot be cultured on synthetic media but may be seen with Giemsa or Wright stain or with dark-field microscopy [2].

TRANSMISSION

S. moniliformis — S. moniliformis is commonly found in the nasal and oropharyngeal flora of rats and probably other rodents. Most rats are asymptomatic; however, on occasion, they may demonstrate signs of disease [2]. The rate of nasopharyngeal carriage of S. moniliformis by rats (even healthy laboratory rats) is quite variable, reportedly being as high as 100 percent [14,15].

●Contact with infected rat – Infection with S. moniliformis can result from a bite or scratch from an infected or colonized rat or from handling rats at home or the workplace (eg, laboratories or pet stores). The risk of infection after a rat bite has been reported to be as high as 10 percent [2]. Transmission can also result from oral contact, such as kissing pet rats [16,17]. Approximately 30 percent of patients with rat bite fever do not report having been bitten or scratched [10,15,18].

●Ingestion of food or water – Infection with S. moniliformis can also occur after ingestion of food or water contaminated with infected rat feces [19,20]. When infection occurs through this route, it is known as "Haverhill Fever"; this was named after an outbreak in 1926 when 86 persons in Haverhill, Massachusetts developed a febrile illness following the consumption of contaminated unpasteurized milk [20,21]. A similar outbreak occurred in 1983 among 304 boarding school children in Chelmsford, England [22].

S. minus, S. notomytis — The modes of transmission of S. minus, S. notomytis, and S. moniliformis are similar; however, infections with S. minus and S. notomytis have not been associated with contaminated food or water.

CLINICAL MANIFESTATIONS — The clinical manifestations of RBF depend on the causative organism (S. moniliformis or S. minus).

S. moniliformis — The clinical manifestations of RBF due to S. moniliformis can range from a mild flu-like illness to fulminant sepsis in children and adults [19,23,24]. The mortality rate of RBF is approximately 13 percent in untreated patients [2,19].

Initial presentation — For individuals with infection due to S. moniliformis, the incubation period is typically fewer than seven days following exposure. (See 'S. moniliformis' above.)

Symptoms start abruptly with fever, myalgias, migratory arthralgias, vomiting, pharyngitis, and headache. By the time symptoms develop due to a bite or scratch, the wound has usually resolved and there is no regional adenopathy [2]. Individuals who acquire RBF through ingestion have more severe vomiting and an increased incidence of pharyngitis compared with those who acquire disease through a bite.

The initial symptoms are frequently followed by a maculopapular rash on the extremities [19,25], which is then followed by polyarthritis in up to 50 percent of patients [26,27]:

●The rash is typically seen on the extensor surface of the extremities and may involve the palms and soles [28]. Although usually maculopapular, it can be petechial, purpuric, or present with hemorrhagic vesicles.

●The arthritis typically involves the knees, followed by ankles, elbows, wrists, shoulders, and hips. The presentation of arthritis can vary, but the majority of cases are polyarticular, and in some, the distribution is asymmetric [29-32].

A case series found that only one-third of children presented with the classical triad of fever, rash, and joint involvement; children more commonly presented with only one or two of these features [32]. Although symptoms may resolve spontaneously without antibiotic therapy, in some cases, the fever can have a relapsing course and the arthritis may persist for several years. In a case report of a child with knee swelling, pathogenic bacteria were found to persist in joints for months despite clearance of the organisms from blood and other sites [13]. However, arthritis may also be due to an immune-mediated mechanism rather than actual infection with the organism [29,30].

Complications — Endocarditis (including prosthetic valve endocarditis) is the best-described complication of RBF [33-36]. Individuals often have a history of valvular disease, and symptoms are similar to endocarditis due to other causes, including the presence of anemia, Osler nodes, and hepatosplenomegaly. In one case series, the mortality associated with S. moniliformis endocarditis was 53 percent [33].

Case reports have also illustrated a variety of other complications. Bacteremia was the most common complication during the Chelmsford and Haverhill outbreaks [20,37]. Other serious complications include meningitis [24,38], myocarditis, pneumonia [23], focal abscesses in the brain, prostate, spleen, liver, or kidney [9], vasculitis [39], septic arthritis [29,30], osteomyelitis [40], hemophagocytic lymphohistiocytosis [41], and multiorgan failure [19,34]. Two cases of fulminant sepsis and death in previously healthy adults were reported in the United States in 2003, one from a rat bite in a pet store and the other most likely from a sick pet rat [19].

S. minus — In contrast to infection with S. moniliformis, RBF caused by S. minus has a longer incubation period (one to three weeks). In addition, the initial wound may reappear at the onset of the systemic illness or persist with edema and ulceration with associated regional adenopathy [42]. Fever, chills, headache, and malaise are common presenting signs, whereas arthritis and myalgia are infrequent. Approximately 50 percent develop a red-brown macular rash [2,43].

S. notomytis — Cases of RBF due to S. notomytis have rarely been described. In one report, S. notomytis was reported to cause fever, rash, and polyarthritis in a woman from Japan following a rat bite on her finger [44]. In another report, S. notomytis was found to cause arthritis and meningitis [38].

Laboratory abnormalities — There are no specific lab abnormalities in patients with RBF. Moderately elevated white blood cell counts and sedimentation rates have been reported in some patients [2].

The findings in the joint fluid can vary. One case report described a four-year-old patient with rat bite fever and polyarticular arthritis in his distal radioulnar and knee joints [45]. Fluid from the distal radioulnar joint had a leukocyte count of only 31/microL, whereas the knee joint had a leukocyte count of 75,250/microL; both specimens were culture positive for S. moniliformis.

DIAGNOSIS — RBF is most commonly diagnosed empirically because growing S. moniliformis or S. notomytis is difficult and S. minus is unable to be cultured. (See 'Empiric diagnosis' below.)

However, analysis of the 16S rDNA gene sequence has been used for diagnosis on appropriate specimens [18,46,47]. (See 'Definitive diagnosis' below.)

Other diagnostic modalities, such as serologic testing, are not available.

Empiric diagnosis — An empiric diagnosis of RBF is made in the patient with an unexplained febrile illness or sepsis and a history of rat exposure. This is particularly true in patients with a relapsing or intermittent fever pattern, a maculopapular rash, and/or polyarthritis or polyarthralgia (typically involving the knees and ankles).

Definitive diagnosis — Confirming a diagnosis of RBF is extremely difficult. If S. moniliformis or S. notomytis is felt to be the causative agent:

●Specimens of blood, synovial fluid, or aspirates from abscesses should be inoculated into bacteriologic media without sodium polyanethol sulfonate (SPS), since SPS inhibits the growth of the organism. Although SPS is present in most aerobic blood culture media, it is not present in some anaerobic culture bottles. The microbiology laboratory should be alerted so that specific media and culture conditions can be used to optimize isolation of the organism. (See 'Microbiology' above.)

Even with appropriate diagnostic testing, synovial fluid cultures can be negative in cases of uncomplicated disease as the etiology of the arthritis may be due to an immune-mediated mechanism rather than actual infection with the organism [29,30].

●Real time qPCR testing has been developed and can detect Streptobacillus in tissue samples including blood, synovial fluid, and urine with high sensitivity, if the testing is available [48,49].

●16S rDNA testing (if available) on appropriate specimens such as tissue (heart valve, bone) or synovial fluid may be useful for diagnosis of S. moniliformis or S. notomytis. However, the sensitivity and clinical utility of such testing have not been proven. This type of testing is not available on routine blood samples.

S. minus is unable to be cultured, and a microbiologic diagnosis is made through demonstration of the organisms on examination of blood, exudate, or tissues using Giemsa or Wright stains or darkfield microscopy.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for a patient presenting with some combination of fever, maculopapular rash, and/or polyarthritis is broad and involves a wide variety of infectious organisms. These agents can usually be diagnosed through readily available culture, serologic, and molecular techniques. It is important to obtain a recent travel and/or exposure history to help prioritize the likely infectious organisms. Detailed discussions of how to diagnose these infections are presented separately in appropriate topic reviews.

●Fever and rash – A general approach to the patient with fever and rash is discussed separately (see "Fever and rash in the immunocompetent patient"). However, in the patient presenting with a fever and rash characteristic of RBF, the following alternative infectious organisms should be considered:

•Viral – There are a number of viral etiologies that should be considered in a patient with fever and a maculopapular rash. These principally include enterovirus, measles, parvovirus, HIV, dengue, lymphocytic choriomeningitis virus, and Epstein-Barr virus. Infection with these viruses should be considered in the patient with a history of appropriate activity and/or exposure. As an example, enterovirus infection should be considered in the patient who works with children. These infections are most commonly diagnosed via serology or polymerase chain reaction (PCR) testing. (See "Fever and rash in the immunocompetent patient", section on 'Epidemiology and etiology'.)

•Bacterial – Bacterial causes presenting with a petechial rash include endocarditis from Staphylococcus aureus or Streptococcus pyogenes, as well as disseminated gonorrhea and meningococcemia. These infections are usually diagnosed via positive blood or fluid cultures. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Clinical manifestations of meningococcal infection" and "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents".)

Unlike the rash associated with RBF, patients with typhoid fever due to Salmonella typhi present with faint macules ("rose spots"), and those with toxic shock syndrome due to S. aureus or Streptococcus species infection are more likely to have a diffuse erythroderma. (See "Staphylococcal toxic shock syndrome" and "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Other extraintestinal manifestations'.)

•Spirochetal – Spirochetal infections presenting as rash can be maculopapular or petechial, as seen in secondary syphilis, leptospirosis, and relapsing fever due to Borrelia recurrentis. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations' and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Clinical features, diagnosis, and management of relapsing fever".)

•Other tick-borne illnesses – Tick-borne pathogens can cause a macular, maculopapular, or petechial rash as seen in infection due to Rickettsia rickettsia (the agent causing Rocky Mountain Spotted fever), Rickettsia typhi (murine typhus), and less commonly, Anaplasma phagocytophilum and Ehrlichia chaffeensis. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Human ehrlichiosis and anaplasmosis".)

●Relapsing fever – For patients presenting with relapsing fever, B. recurrentis and typhoid fever must be considered [2]. (See "Clinical features, diagnosis, and management of relapsing fever" and "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)

●Polyarthritis – Parvovirus and disseminated gonococcal infection are possibilities in patients who present with polyarthritis plus fever and rash. For patients with more localized joint findings, septic arthritis due to staphylococcal and streptococcal species should be considered. (See "Septic arthritis in adults" and "Viral arthritis: Causes and approach to evaluation and management".)

TREATMENT — The management of patients with RBF includes both local care of the wound in those reporting a bite, as well as appropriate antibiotics for individuals with clinical symptoms. (See 'Clinical manifestations' above.)

There are no prospective trials concerning the treatment of infection due to S. moniliformis. All data regarding treatment are based on anecdotal reports of the treatment of single or small numbers of patients. (See 'Antibiotic therapy' below.)

Management of an animal bite — Treatment of RBF associated with an animal bite should begin with appropriate management of the bite wound, such as copious irrigation. Patients should also be assessed to see if tetanus or rabies post-exposure is warranted, although rats and other small rodents are rarely infected with rabies. More detailed discussions of the management of animal bites are presented elsewhere. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management" and "Indications for post-exposure rabies prophylaxis".)

Antibiotic therapy — Empiric therapy for RBF should be started immediately in patients with a compatible clinical presentation and exposure history. Laboratory confirmation is difficult and may take several days. If the organism is detected, therapy can be modified based upon antimicrobial susceptibility, which can be determined using standard testing (eg, disk diffusion, broth microdilution). (See 'Microbiology' above and 'Diagnosis' above.)

In untreated patients, the mortality rate of RBF has been reported to be as high as 13 percent [2,19]. Although some patients may recover spontaneously, lack of effective antibiotic treatment is highly associated with an increased risk of death.

Given the rarity of the illness, therapy for RBF is mostly guided by case reports and modest clinical experience. Penicillin is the traditional treatment of choice for RBF since most of the published experience has been with the use of this agent. However, in the absence of clear evidence to the contrary, many experts prefer ceftriaxone when intravenous (IV) therapy is indicated since it appears to be effective in treating RBF in case reports [41,50], is effective in treating other known serious penicillin-susceptible infections, and is more easily administered.

The dose and duration of antibiotic therapy for RBF depend upon the clinical presentation (uncomplicated versus serious invasive disease). (See 'Uncomplicated disease' below and 'Serious invasive infections' below.)

Uncomplicated disease — Cases of RBF typically present as uncomplicated disease, which consists of fever, myalgias, polyarthritis, polyarthralgias, vomiting, headache, and/or rash. (See 'Clinical manifestations' above.)

In most patients with uncomplicated disease we initiate IV therapy and then transition to oral treatment after five to seven days. However, given the possibility that a patient can develop serious invasive disease, the response to treatment must be carefully assessed, and more aggressive treatment (eg, higher or prolonged doses of IV antibiotics) should be considered in those who do not show clinical improvement or if there is concern for complicated disease. (See 'Serious invasive infections' below.)

Adults — The preferred agents for initial therapy of uncomplicated disease in adults are penicillin or ceftriaxone.

●If IV penicillin G is initiated, case reports suggest a low dose (1.2 million units per day divided in six equally divided doses) is sufficient for treatment of uncomplicated disease [2,51]. However, if there is uncertainty about the severity of disease, clinicians may prefer to initiate a higher dose (eg, 12 to 18 million units per day in four or six equally divided doses), prior to transitioning to the oral regimen.

●If ceftriaxone is used, a dose of 1 g once daily is reasonable, although there are no data to guide dosing for uncomplicated disease.

If the patient has improved clinically after five to seven days, the patient can be transitioned to oral penicillin V (500 mg four times per day), ampicillin (500 mg four times per day), or amoxicillin (500 mg three times per day) to complete a 14-day course of therapy. For those who are allergic to penicillin but can tolerate cephalosporins, cephalexin is an alternative. In one case report, oral cephalexin (1 g three times daily) was used to treat osteomyelitis due to S. moniliformis [52].

In nonpregnant adults who are allergic to penicillin and cephalosporins, doxycycline (100 mg orally or IV twice per day) can be used. The decision to use doxycycline during pregnancy must be decided on a case-by-case basis. Although most tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother and adverse effects on fetal bone and teeth [53-55], these events are rare with short courses of doxycycline. (See "Tetracyclines", section on 'Pregnant or breastfeeding women' and "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

Streptomycin and gentamicin are also alternative agents; however, their use is limited because other treatment options with less toxicity are available.

Children — For children, initial treatment options typically include IV penicillin G (100,000 to 150,000 units per kg per day divided in four doses, maximum 8 million units per day) or ceftriaxone (50 mg/kg once daily, maximum 2 g/day). Similar to adults, IV therapy is usually administered for five to seven days. Patients who have improved clinically can be transitioned to oral penicillin V (25 to 50 mg/kg per day orally in three or four divided doses, maximum 2 g per day) to complete a 14-day course. For those who are allergic to penicillin but can tolerate cephalosporins, oral cephalexin can be used (eg, 50 mg/kg/day divided every eight hours), although there is no published experience to support a specific dose.

For children who are allergic to penicillin and cephalosporins, we administer a 14-day course of doxycycline. Although tetracyclines can cause dental staining when administered to children, the risk of dental staining with doxycycline is minimal if a short course is administered. Children weighing more than 45 kg should receive the adult dose; smaller children should receive 2 to 4 mg/kg per day IV or orally in two divided doses (maximum 200 mg per day).

Serious invasive infections — Serious invasive infections complicating RBF are rare. These include endocarditis (including prosthetic valve endocarditis), meningitis, myocarditis, pneumonia, focal abscesses, bacteremia, pyogenic arthritis, and multiple organ failure. Although death has been reported in up to approximately 50 percent, the majority of these occurred in the absence of effective antimicrobial therapy [2,33].

IV penicillin G and ceftriaxone are the preferred agents. The optimal dose of these agents is unclear, as there are no adequately controlled clinical trials. We favor giving doses adequate to treat other serious penicillin-susceptible infections (eg, streptococcal endocarditis).

For patients with native valve endocarditis, we administer either IV penicillin G or ceftriaxone for four weeks:

●IV penicillin G – For adults, the dosing of IV penicillin G is 12 to 18 million units per day either continuously or in four or six equally divided doses. For individuals whose isolate is not highly susceptible to penicillin (minimum inhibitory concentration [MIC] >0.1 mcg/mL), the dose can be increased to 24 million units per day.

For children, the dosing of IV penicillin G is 200,000 to 300,000 units per kg per day divided in four doses (maximum of 24 million units per day).

●Ceftriaxone – For adults, the dose of IV ceftriaxone is 2 g once daily. In children, the dose is 100 mg/kg divided every 12 hours (maximum 2 g/dose).

For patients with prosthetic valve involvement, an aminoglycoside should be considered, similar to the management of prosthetic valve endocarditis due to other streptococcal species [2,56]. In addition, if penicillin G is used, we prefer the higher dose (eg, 24 million units per day in adults). More detailed recommendations for dosing in adults and children with prosthetic valve endocarditis are discussed elsewhere. (See "Antimicrobial therapy of prosthetic valve endocarditis", section on 'Streptococci'.)

For other conditions, the dose and duration may need to be further modified. As an example, for adults with meningitis, the dose of IV ceftriaxone should be 2 g twice daily. In those with osteomyelitis, the 2 g daily dose can be used, but the duration may need to be extended. (See "Nonvertebral osteomyelitis in adults: Treatment", section on 'Duration of therapy'.)

In both adults and children with complicated disease who are allergic to penicillin and cephalosporins, desensitization to a beta-lactam is generally preferred (see "Penicillin allergy: Immediate reactions"). If this is not possible, treatment decisions should be made in conjunction with an infectious diseases specialist.

PREVENTION — In persons who have exposure to rats, preventing severe RBF involves increasing their awareness of the signs and symptoms of the infection. (See 'Clinical manifestations' above.)

In addition, following a rat bite, we suggest a three-day course of oral penicillin V (adults: 500 mg four times per day; children: 25 to 50 mg/kg per day in three or four divided doses, maximum 2 g per day). Doxycycline is a reasonable alternative. However, the efficacy of antimicrobial prophylaxis is unknown. A more general discussion of antimicrobial therapy after an animal bite is presented separately. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Bites from mammals other than dogs and cats'.)

Other measures to limit the incidence of RBF include eradication of rats in urban areas, avoidance of unpasteurized milk and potentially contaminated water, and the use of gloves by laboratory workers when handling rodents or cleaning rat cages. Individuals with pet rats should not kiss or lick them, and they should wash their hands after handling the animals.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Rat bite fever (RBF) is a rarely diagnosed, systemic illness caused by infection with Streptobacillus moniliformis, Streptobacillus notomytis, or Spirillum minus. S. moniliformis causes most cases of the disease in the United States. S. minus causes RBF primarily in Asia, although it is probably present worldwide. Infection with S. notomytis has only rarely been reported. (See 'Epidemiology' above.)

●Microbiology – S. moniliformis is a pleomorphic, fastidious, branching gram-negative bacillus (picture 1); S. notomytis is similar. Both require specific media for isolation and must be incubated in a 5 to 10% CO₂ environment. S. minus is a tightly coiled spiral, gram-negative rod. It can be identified by darkfield examination but cannot be cultured on artificial media. (See 'Microbiology' above.)

●Transmission – Infection with S. moniliformis, S. notomytis, or S. minus can result from a bite or scratch from an infected or colonized rat, or from handling rats at home or the workplace (eg, laboratories or pet stores). Infection with S. moniliformis can also occur after ingestion of food or water contaminated with infected rat feces. (See 'Transmission' above.)

●Clinical manifestations

•S. moniliformis or S. notomytis – For individuals with infection due to S. moniliformis or S. notomytis, symptoms start abruptly with fever, myalgias, migratory arthralgias, vomiting, pharyngitis, and headache. The incubation period is typically fewer than seven days following exposure. By the time symptoms develop due to a bite or scratch, the wound has usually resolved and there is no regional adenopathy. (See 'S. moniliformis' above and 'S. notomytis' above.)

A variety of complications of RBF due to these organisms have also been reported, including meningitis, endocarditis, and bacteremia. (See 'Complications' above.)

•S. minus – Infection with S. minus has a longer incubation period (one to three weeks) and is characterized by fever, chills, headache, and malaise. In addition, the initial wound may reappear at the onset of the systemic illness or persist with edema and ulceration with associated regional adenopathy. (See 'S. minus' above.)

●Diagnosis – RBF is most commonly diagnosed clinically because growing S. moniliformis is difficult and no serologic test is available. However, culture yield may be improved if grown in culture bottles without sodium polyanethol sulfonate (eg, certain anerobic culture bottles); in addition, analysis of the 16S rDNA gene sequence has been used for diagnosis on appropriate specimens. (See 'Diagnosis' above.)

●Management of infection

•Local wound care – The management of patients with RBF includes local care of the wound in those reporting a bite and antibiotics. The need for tetanus and/or rabies vaccine should also be assessed. (See 'Management of an animal bite' above and 'Antibiotic therapy' above.)

•Antimicrobial therapy – Patients with suspected RBF require immediate antibiotic treatment to reduce the mortality associated with this infection. Empiric therapy should be initiated in patients with a compatible clinical presentation and exposure history since laboratory confirmation is difficult and may take several days. (See 'Treatment' above.)

For most patients, we suggest initial therapy with intravenous (IV) penicillin G or ceftriaxone (Grade 2C). The dose and duration depend upon the clinical presentation (uncomplicated versus serious invasive therapy).

For those with uncomplicated disease, IV therapy is typically administered for five to seven days. Patients who have improved clinically can be transitioned to oral therapy to complete a 14-day course. By contrast, for those with serious invasive disease (eg, endocarditis), higher doses of IV therapy are administered for an extended duration (eg, four weeks). (See 'Antibiotic therapy' above.)

●Preventive therapy – To prevent infection following a rat bite, we suggest a three-day course of oral penicillin V (Grade 2C). For adults, we administer 500 mg four times per day; for children, the dose is 25 to 50 mg/kg per day in three or four divided doses (maximum 2 g per day). However, the efficacy of antimicrobial prophylaxis is unknown. (See 'Prevention' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michele Trucksis, PhD, MD, who contributed to an earlier version of this topic review.