Rat-Bite Fever: Diagnosis, Treatment & Prevention

RAT-­BITE FEVER
Method of
Jatin M. Vyas, MD, PhD
CURRENT DIAGNOSIS
• Exposure to rats is the major risk factor. Transmission can
occur with simple contact with infected animals or excreta.
• A maculopapular rash and septic arthritis after initial symptoms
of fever or sepsis should raise the suspicion of rat-­bite fever.
• Clinicians must maintain a high index of suspicion for this
diagnosis.
• Notify microbiology laboratory of clinical suspicion (slow
growth, 5%–10% CO2 microaerophilic conditions, 20% normal rabbit serum media supplementation, and avoidance of
sodium polyanethol sulfonate when collecting blood cultures
from the patient).
CURRENT THERAPY
available on the true incidence of rat-­bite fever because it is not a
reportable disease. It appears to be unusual in Western countries,
a rarity that might reflect failed diagnosis, empiric treatment of
infected bites and scratches caused by animals, or spontaneous
recovery.
Risk Factors
The major risk factor is exposure to rats, either as an occupational
hazard for persons such as laboratory workers, veterinarians, or
pet shop employees, or for persons who have rats for pets or feed
rats to snakes, especially children. Classically, homelessness and
lower socioeconomic status were described as major factors, but
most cases reported in the last few years have involved pet rats.
Thirty percent of patients with rat-­bite fever do not report any
exposure to rats or other rodents. Therefore the lack of documented exposure does not exclude this diagnosis.
Pathophysiology
Very little is known about the pathophysiology of S moniliformis
infections. Presumably, the failure of local control by dendritic
cells, tissue macrophages, neutrophils, and other components of
the innate immune system results in deeper infection, leading to
bacteremia. Studies using histologic analysis have revealed intravascular thrombosis near the port of entry.
Prevention
Established and Suspected Cases
• Give intravenous penicillin G at a dose of 1.2 million U/day for
5 to 7 days, followed by oral penicillin (PenVK)1 or ampicillin
(Omnipen)1 500 mg qid for an additional 7 days.
• For penicillin-­allergic patients, consider doxycycline (Vibramycin)1 100 mg IV/PO twice daily or tetracycline (Achromycin)1
500 mg PO four times daily.
• S. moniliformis can be resistant to gentamicin (Garamycin),1
tobramycin (Nebcin),1 ciprofloxacin (Cipro),1 and levofloxacin
(Levaquin).1
1Not FDA approved for this indication.
Rat-­bite fever (RBF) is a systemic, febrile disease caused by infection with Streptobacillus moniliformis or Spirillum minus. As the
name implies, this infection is transmitted by a rat bite. However, the bacteria can also be transmitted by simple contact with
infected rats or even through ingestion of food contaminated with
rat excreta. Diagnosis can be difficult, and a high degree of suspicion is necessary to make a correct diagnosis. Recognition and
early treatment are crucial, because case fatality is as high as 25%
in untreated cases.
Epidemiology
S moniliformis is part of the normal respiratory flora of the rat.
From 50% to 100% of healthy wild, laboratory, and pet rats
harbor S moniliformis in the nasopharynx. S moniliformis is also
excreted in the urine. S minus causes rat-­bite fever mostly in Asia,
but this organism is found worldwide. S minus has been demonstrated in rat conjunctival secretions and blood. Thus rat-­bite
fever can be transmitted not only from a bite but also through
scratches, handling of dead rats, handling litter material, or by
contamination of rat excreta.
Although the rat is the natural reservoir and major vector of
the disease, S moniliformis has also been found in other rodents
such as mice, squirrels, gerbils, and weasels. No precise data are
The role of prophylactic antibiotics is unknown, but some
authors recommend the use of oral penicillin V (PenVK)1 after
documented exposure to rats and a break in the skin. Penicillin V
should be given for 3 days at a dose of 2 g per day for adults. Primary prevention should be encouraged for patients with occupational risk by using protective gloves to handle animals or cages.
Clinical Manifestations
Rat-­bite fever is a systemic febrile disease. Classically, following
a rat bite and a short incubation of 2 to 10 days, systemic dissemination of the organism is associated with an abrupt onset
with intermittent relapsing fever, rigors, myalgias, arthralgias,
headache, sore throat, malaise, and vomiting. These symptoms
are followed within the first week by the development of a maculopapular rash in 75% of patients. The rash can be pustular,
purpuric, or petechial, and it typically involves the extremities,
in particular the palms and soles. The bite site typically heals
promptly, with minimal inflammation and no significant regional
lymphadenopathy.
Following the rash, approximately 50% of infected patients
develop an asymmetric migrating polyarthritis, which appears
to be exceedingly painful and affects large and middle-­sized
joints. Joint effusion appears more common in adults. Infection can occur in any tissue. Although most cases of rat-­bite
fever resolve spontaneously, there have been reports of complications. These include meningitis, endocarditis (including
prosthetic valve endocarditis), myocarditis, pericarditis, pneumonia, brain abscess, septic arthritis, DIC (disseminated intravascular coagulation), and infarcts of the spleen and kidneys.
The mortality rate in untreated cases is around 10% to 15%,
and it rises to more than 50% in the rare cases with cardiac
involvement.
Two closely related variants have been described. In Havervill
fever, the organism is transmitted by ingestion of contaminated
food. Havervill fever tends to occur in epidemics and also causes
rashes and arthritis, but upper respiratory tract symptoms and
vomiting appear more prominent. It is important to note that
these patients do not provide a history of exposure to rodents.
Sodoku is a rat-­bite fever caused by S minus; it is common in
Japan. The course is more subacute, arthritic symptoms are rare,
and if the bite initially heals, it then ulcerates and is associated
with regional lymphadenopathy and a distinctive rash. S minus
1Not FDA approved for this indication.
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Rat-­Bite Fever
Bite Site
• Clean and disinfect the bite site.
• Administer tetanus toxoid (tetanus-­diphtheria toxoids, Td), if
indicated.
• Postexposure rabies prophylaxis (Imovax Rabies) for animal
bites should be considered in consultation with local public
health authorities, though there are no reports of rat-­to-­
human transmission of the rabies virus.
713
cannot be grown using synthetic media, and thus microbiologic
diagnosis rests on visualization of these organisms in infected
tissues.
VIII Infectious Diseases
Diagnosis
714
Diagnosis is difficult and requires a high clinical index of suspicion. The initial symptoms of rat-­bite fever are nonspecific, triggering a broad differential diagnosis. Additionally, the fastidious
nature of this organism makes isolation from blood cultures difficult. Clinicians should ask about rodent exposure when compatible symptoms are seen in patients. Rat-­bite fever should not be
ruled out in the absence of bite history, because transmission can
occur without a bite, and pet owners or laboratory workers can
minimize the significance of the bite, especially in the absence of
a local reaction.
No reliable serologic test is available, and the definitive diagnosis requires isolation of S moniliformis from the wound, blood, or
synovial fluid in patients with septic arthritis. The microbiology
laboratory should be specifically notified of any clinical suspicion
to enhance the chances of recovering the pathogen.
S moniliformis is a highly pleomorphic, nonencapsulated,
nonmotile, gram-­negative rod, which can stain positively on
Gram stain (Figure 1). It is often dismissed as proteinaceous
debris because of its numerous bulbous swellings with occasional clumping (moniliformis=“necklace-­like”). It grows slowly
and requires a microaerophilic environment with 5% to 10%
CO2 or anaerobic conditions and media supplementation with
20% normal rabbit serum. Cultures can take up to 7 days to
turn positive. Some experts recommend holding blood cultures
for 21 days to permit sufficient time to grow this organism. S
moniliformis is also inhibited by sodium polyanethol sulfonate,
a common adjunct in most commercial blood culture media at a
concentration as low as 0.0125%. S moniliformis has been identified using polymerase chain reaction amplification and 16S
ribosomal ribonucleic acid (rRNA) sequencing, which shows
great promise though it is available at reference laboratories.
Fatty acid profiles obtained by gas-­liquid chromatography can
also be used for identification.
S minus, the other etiologic agent of rat-­bite fever, is a short,
thick, gram-­negative, tightly coiled spiral rod that measures 0.2
to 0.5 μm and has two to six helical turns.
Differential Diagnosis
Differential diagnosis for fever, rash, and polyarthritis is broad.
Malaria, typhoid fever, and neoplastic disease can cause relapsing
fevers, and the presence of a rash and polyarthritis might suggest
viral and rickettsial diseases including Rocky Mountain spotted
fever. An asymmetric oligoarthritis suggests disseminated gonococcal and meningococcal diseases in the context of cutaneous
lesions on the palms and soles. Lyme disease, leptospirosis, or secondary syphilis can have a similar clinical presentation. Finally,
when classic infectious symptoms such as fever or rash are missing, any causes of polyarthritis, from crystal-­induced arthropathies to rheumatoid arthritis, should be considered.
Treatment
All established cases of rat-­bite fever should be treated with antibiotics because of the associated mortality and potential for complications. Intravenous penicillin G at a dose of 1.2 million units
per day should be initiated as soon as the clinical diagnosis is
made. Empiric therapy is necessary and should not be delayed for
laboratory confirmation of this bacterial infection. The intravenous treatment should continue for 5 to 7 days. After treatment
with IV penicillin and suitable clinical response, therapy should be
continued with oral penicillin (PenVK)1 or ampicillin (Omnipen)1
at a dose of 500 mg qid for an additional 7 days. For patients
allergic to penicillin, intravenous doxycycline (Vibramycin)1 at a
dose of 100 mg every 12 hours or oral tetracycline (Achromycin)1
at a dose of 500 mg four times a day can be used.
Streptomycin1 and cephalosporins including cefotamxine (Claforan)1 have been reported to be potentially useful. Other antibiotics including azithromycin (Zithromax),1
erythromycin,1
carbapenems,1
aztreonam
(Azactam),1
clindamycin (Cleocin),1 vancomycin (Vancocin),1 and nitrofurantoin (Macrodantin)1 have shown efficacy in vitro, but they
lack good clinical correlation to recommend them for routine
use. Erythromycin has been associated with treatment failures.
Trimethoprim-­sulfamethoxazole (Bactrim),1 polymyxin B,1
gentamicin (Garamycin),1 tobramycin (Nebcin),1 ciprofloxacin (Cipro),1 and levofloxacin (Levaquin)1 should not be used
because in vitro resistance has been demonstrated.
Typically, the bite site heals promptly. It should be cleaned
and disinfected, as is typical for management of other wounds.
Tetanus prophylaxis (tetanus-­diphtheria toxoids, Td) administration is indicated as required by the patient’s immunization record.
Rabies prophylaxis (Imovax Rabies) is usually not required for
rodent bite, but consultation with local public health authorities
is encouraged. There are no reports of transmission of the rabies
virus from rats to humans.
1Not FDA approved for this indication.
References
Figure 1 Gram stain of Streptobacillus moniliformis. Gram stain of
growth from anaerobic bottle, ×100 magnification [microphotography].
Reprinted with permission from Partners’ Infectious Disease Images; accessed on August 11, 2016, from http://www.idimages.org/images/detail
/?imageid=373.
Abusalameh M, Mahankali-­Rao P, Earl S, et al: Discitis caused by rat bite fever
in a rheumatoid arthritis patient on tocilizumab-­first ever case, Rheumatology
(Oxford) 57:1118–1120, 2018.
Adam JK, et al: Notes from the field: fatal rat-­bite Fever in a child -­San Diego County, California, 2013, MMWR Morb Mortal Wkly Rep 63(50):1210–1211, 2014.
Chen PL, Lee NY, Yan JJ, et al: Prosthetic valve endocarditis caused by Streptobacillus moniliformis: A case of rat bite fever, J Clin Microbiol 45:3125–3126, 2007.
Crews JD, Palazzi DL, Starke JR: A teenager with fever, rash, and arthralgia.
Streptobacillus moniliformis infection, JAMA Pediatr 168(12):1165–1166, 2014.
Elliott SP: Rat bite fever and Streptobacillus moniliformis, Clin Microbiol Rev
20:13–22, 2007.
Fenn DW, et al: An unusual tale of rat-­bite fever endocarditis, BMJ Case Rep. 2014,
2014.
Giorgiutti S, Lefebvre N: Rat bite fever, N Engl J Med 381(18):1762, 2019.
Graves MH, Janda JM: Rat-­bite fever (Streptobacillus moniliformis): A potential
emerging disease, Int J Infect Dis 5:151–155, 2001.
Hall CW, Al Hammadi A, Hasan, MR, Kapoor AK: Recognising rat-bite fever—
a rare metastatic infection with Streptobacillus moniliformis, Lancet Infect Dis
24(1):e69, 2024.
Holroyd KJ, Reiner AP, Dick JD: Streptobacillus moniliformis polyarthritis mimicking
rheumatoid arthritis: An urban case of rat bite fever, Am J Med 85:711–714, 1988.
King HY. Rat Bite Fever. UpToDate. http://www.uptodate.com/contents/rat-­
bitefever; [accessed April 21, 2018].
Lambe DW Jr, McPhedran AM, Mertz JA, Stewart P: Streptobacillus moniliformis
isolated from a case of Haverhill fever: Biochemical characterization and inhibitory effect of sodium polyanethol sulfonate, Am J Clin Pathol 60:854–860, 1973.
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RELAPSING FEVER
Method of
Diego Cadavid, MD
CURRENT DIAGNOSIS
• There are two forms of relapsing fever: epidemic and endemic.
• Epidemic relapsing fever is transmitted from person to person
by the body louse Pediculus humanus.
• Endemic relapsing fever is transmitted from rodent reservoirs
to humans exposed to endemic areas by soft-­bodied ticks of
the genus Ornithodoros.
• The hallmark of relapsing fever is two or more febrile episodes separated by periods of relative well-­being.
• The diagnosis is confirmed by visualization of the etiologic
spirochetes in thin peripheral blood smears prepared at times
of febrile peaks by phase-­contrast or darkfield microscopy or
light microscopy after Wright or Giemsa staining.
CURRENT THERAPY
• The antibiotic of choice for treatment of relapsing fever is
doxycycline except in children or pregnant women. In children <8 years of age, erythromycin1 or oral penicillin is used
instead of tetracycline (Table 3).
• Relapsing fever, if severe or complicated with neuroborreliosis, requires treatment with the intravenous antibiotics
ceftriaxone or penicillin G (Table 3).
• The louse-­borne epidemic form is treated with a single dose,
whereas the endemic tick-­borne form is treated with multiple
doses for at least 1 week (Table 3).
• Antibiotic treatment of relapsing fever results in the Jarisch-­
Herxheimer reaction (JHR) in as many as 60% of cases,
more often in the epidemic than in the endemic forms. It is
characterized by the sudden onset of tachycardia, hypotension, chills, rigors, diaphoresis, and high fever. To reduce the
risk of JHR, antibiotics should be started between but not at
times of febrile peaks.
1Not FDA approved for this indication.
Relapsing fever is one of several diseases caused by spirochetes.
Other human spirochetal diseases are syphilis, Lyme disease, and
leptospirosis. Notable features of spirochetes are wavy and helical
shapes, length-­to-­diameter ratios of as much as 100 to 1, and flagella that lie between the inner and outer cell membranes. The spirochetes that cause relapsing fever are in the genus Borrelia. Other
Borrelia species cause Lyme disease, avian spirochetosis, and epidemic bovine abortion. Table 1 shows the main Borrelia species of
relapsing fever, their vectors, and an estimate of their geographic
ranges. In the United States, relapsing fever was considered a disease
endemic only in the West. However, the recent finding of relapsing
fever–like Borrelia in ticks and dogs in the eastern United States
suggests that the risk of relapsing fever may extend into the East.
Epidemiology
There are two forms of relapsing fever: epidemic transmitted
to humans by the body louse Pediculus humanus (louse-­borne
relapsing fever [LBRF]) and endemic transmitted to humans by
soft-­bodied ticks of the genus Ornithodoros (tick-­borne relapsing
fever [TBRF]). In LBRF, itching caused by skin infestation with
lice leads to scratching, which may result in crushing of lice and
release of infected hemolymph into areas of skin abrasion. Louse
infestation is associated with cold weather and a lack of hygiene.
Migrant workers and soldiers at war are particularly susceptible to
this infection. Historically, massive outbreaks of LBRF occurred
in Eurasia, Africa, and Latin America, but currently the disease
is found only in Ethiopia and neighboring countries. However,
immigrants can spread LBRF to other parts of the world.
The main risk factor for TBRF is exposure to endemic areas
(Table 1). The risk of infection increases with outdoor activities
in areas where rodents nest, like entering caves or sleeping in rustic cabins. Ornithodoros ticks are soft-­bodied and feed for short
periods of time (minutes), usually at night. They can live many
years between blood meals and may transmit spirochetes to their
offspring transovarially. Infection is produced by regurgitation of
infected tick saliva into the skin wound during tick feeding. There
are several natural vertebrate reservoirs for TBRF, but most common are rodents (deer mice, chipmunks, squirrels, and rats). In
contrast, the body louse Pediculus humanus is a strict human parasite, living and multiplying in clothing. Hard-­tick-­borne relapsing fever (HTBRF) is an emerging infectious disease throughout
the temperate zone caused by Borrelia miyamotoi. Borrelia miyamotoi is a spirochete closely related to the bacteria that cause
TBRF. It is more distantly related to the bacteria that cause Lyme
disease. First identified in 1995 in ticks from Japan, B miyamotoi
has since been detected in two species of North American ticks,
the black-­legged or “deer” tick (Ixodes scapularis) and the western black-­legged tick (Ixodes pacificus). These ticks are already
known to transmit Lyme disease, anaplasmosis, and babesiosis.
Clinical Diagnosis
Relapsing fever should be suspected in any patient presenting
with two or more episodes of high fever and constitutional symptoms spaced by periods of relative well-­being. The index of suspicion increases if the patient has been exposed to endemic areas for
TBRF or to countries where LBRF still occurs (Table 1). Whereas
LBRF is usually associated with a single febrile relapse, TBRF
usually has multiple relapses (up to 13). Only about 10% of cases
of HTBRF have febrile relapses. In LBRF the second episode of
fever is typically milder than the first; in TBRF the multiple febrile
periods are usually of equal severity. The febrile periods last from
1 to 3 days, and the intervals between fevers last from 3 to 10
days. During the febrile periods, numerous spirochetes are circulating in the blood. This is called spirochetemia and is sometimes
unexpectedly detected during routine blood smear examinations.
Between fevers, spirochetemia is not observed because the numbers are low. The fever pattern and recurrent spirochetemia are
the consequences of antigenic variation of abundant outer membrane lipoproteins of relapsing fever Borrelia species that are the
target for serotype-­specific antibodies.
The mean latency between exposure to ticks in the endemic form
or to lice in the epidemic form and onset of symptoms is 6 days
(range, 3–18 days). Because Ornithodoros ticks feed briefly and
painlessly at night, patients with TBRF may not be able to recall
having been bitten by a tick. The clinical manifestations of TBRF
and LBRF are similar, although some differences do exist. Table 2
lists the frequency of the most common manifestations of TBRF.
The usual initial presentation is sudden onset of chills followed by
high fever, tachycardia, severe headache, vomiting, myalgia and
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Relapsing Fever
Miura Y, Nei T, Saito R, Sato A, Sonobe K, Takahashi K: Streptobacillus moniliformis bacteremia in a rheumatoid arthritis patient without a rat bite: a case
report, BMC Res Notes 8(1):694, 2005 Nov 19, https://doi.org/10.1186/s13104-­
015-­1642-­6.
Schachter ME, Wilcox L, Rau N, et al: Rat-­bite fever, Canada, Emerg Infect Dis
12:1301–1302, 2006.
Stehle P, Dubuis O, So A, Dudler J: Rat bite fever without fever, Ann Rheum Dis
62:894–896, 2003.
Torres-­Miranda D, Moshgriz M, Siegel M: Streptobacillus moniliformis mitral valve
endocarditis and septic arthritis: the challenges of diagnosing rat-­bite fever endocarditis, Infect Dis Rep 10(2):7731, 2018.
Washburn RG: Streptobacillus moniliformis (rat−bite fever). In Mandell GL, Bennett JE, Dolin R, editors: Principles and Practice of Infectious Diseases, vol 2, 6th
ed, Philadelphia, 2005, Elsevier, pp 2708–2710.
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