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Original Report

Rat-Bite (Streptobac8dlu.s monilnjiormh) : A Potential Emerging Disease Margot H. Graves, BS;” and J. Michael Janda, PhD*

ABSTRACT Two distinct clinical have been identified in association with S. moniliformis . One, Haver- Objectives: To determine the relative prevalence of human infec- hill fever, originally recognized in 1926, is an infection tions attributable to Streptobacillus moniliformis in California transmitted to humans through the consumption of con- over the past 3 decades. taminated water, milk, or food previously in contact with Methods: A retrospective analysis of all the data collected was rats.‘,* The disease is characterized by a high incidence conducted on S. moniliformis cultures identified by the Micro- of pharyngitis and pronounced vomiting. bial Diseases Laboratory (MDL) from January 1970 to Decem- The more common associated with S. ber 1998. moniliformis infection, however, is rat-bite fever @RF). This illness is characterized by abrupt onset of high , Results: Information on a total of 45 S. moniliformis isolates , severe migratory , vomiting, and a was analyzed. Overall, 91% of the isolates were from human (2-4 days later). The petechial rash develops over sources; 58% were received since 1990. These strains were the extremities, in particular the palms and the soles.’ The divided almost equally between males and females, with 50% onset of symptoms typically occurs 10 or more days after of the isolates from patients 9 years old or younger. In 75% of the cases of human where a diagnosis was given, exposure. Any related wound has usually healed by the rat-bite fever (RBF) was suspected; 83% of these suspected time symptoms develop. 1-4Estimates of the mortality rate cases involved either a known rat bite or exposure to . associated with untreated cases of streptobacilliosis approach 13/o.o *z5x6Fatality is most often associated with Conclusions: As crowding becomes an increasing environ- cases in infants and patients with endocarditis.‘,5 mental reality, humans are more frequently being exposed to To date, most of the information regarding S. monil- zoonotic diseases as a result of encounters with “wild” ani- zjiwmis infection, and in particular RBF, stems from indi- mals. Domesticated animals also are exposed more frequently vidual case reports. In light of the increasing incidence to wild animals; thus, increasing human exposure to once rare of human contact with animals, including the care and zoonotic illnesses. Rat-bite fever is a disease that seems to be handling of unusual or exotic pets,’ a retrospective easily recognizable by clinicians, easily identified in the clinical review of the incidence of streptobacilliosis in California laboratory (if suspected), and successfully treated when the appropriate therapy is administered. Physicians should con- over the past 3 decades was conducted and serves as the sider RBF as a possible diagnosis when fever, rash, and expo- basis of this report. sure to rats are part of the patient’s history. MATERIALS AND METHODS Key Words: rat-bite fevel; Streptobacillus moniliformis, zoonotic infections The Microbial Diseases Laboratory (MDL) is the refer- ence laboratory for the state of California. The laboratory Int J Infect Dis 2001; 5151-154. is responsible for the isolation and identification of bac- A seldom encountered zoonotic pathogen seen by clini- terial, fungal, and parasitic pathogens of public health sig- cal laboratories is Streptobacillus moniliformis. This pleo- nificance throughout the state. A system of 39 county morphic, facultatively anaerobic, gram-negative bacterium public health laboratories serves as the conduit for the is traditionally associated with direct or indirect expo- submission of unusual, unidentified, or reportable isolates sure to rats, the for S. moniliformis. Its from clinical laboratories to the MDL. distribution is worldwide. I-3 The MDL identifies or confirms S monilz@m& isolates using four tests: (1) a growth requirement of 10 to 20% *State of California, Department of Health Services, Microbial Diseases ; (2) the presence of typical gram-negative bacilli Laboratory, Berkeley, California. (sometimes in chains) and filaments with bulbous swellings Address correspondence to Dr. J. Michael Janda, California Department in a Gram stain (Figure 1); (3) growth in broth (thiogly- of Health Services, Microbial Diseases Laboratory, 2 15 1 Berkeley Way, collate medium) with “puff ball”-colony formation (Figure Berkeley, CA 94704. E-mail: [email protected]. 2); and (4) a positive direct fluorescent test using

151 152 International Journal of Infectious Diseases / Volume 5, Number 3,200l

Figure 2. Thioglycollate broth with “puff ball” colonies.

Figure 1. Typical bacilli (some in chains) and filaments with bulbous 41 S. monilzjbrmis infections were from southern Cali- swellings (oil immersion; original magnification X1000). fornia (n = 14) the San Francisco Bay area (n = 11) the San Joaquin valley (n = 9), North San Francisco Bay area an in-house produced polyclonal antibody. The polyclonal (n = 3) Monterey Bay area (n = 3) and Sierra Foothills antibody was prepared from whole cell antigens of S. (n = 1). The male to female ratio was 1.0:1.2 with 19 monilzjbrmis strain MDL 56-3. Formalized whole cell anti- (46%) male and 22 (54%) female patients. The age ranged gen was washed and used to immunize rabbits. Rabbits from 6 weeks to 92 years (mean, 46 y) (Figure 4). The were immunized five times over a 2-week period by intm- average age was just under 19 years. venous injection through the marginal vein. Serum was The most common isolate source of S. moniliformis collected and fluorescein isothiocyanate @ITC) conjugated. in human infections was blood (78%) followed by aspi- Quality control was performed on the conjugate by test- rates (12%) and wounds (10%). Common media used to ing it against various S.monz’ZziformB strains at several work- isolate S. moniliformis from blood included pediatric ing dilutions. Original laboratory reports were reviewed BACTECTM Plus blood culture bottles (BD Diagnostics, and data from these were compiled to produce the results. Sparks, MD) (n = 5) trypticase soy blood culture bottles, with or without supplementation (n = 4) anaerobic blood RESULTS culture bottles (type not specified, n = 3) and thiogly- collate broth (n = 1). For nonblood isolates (e.g., wounds) Since 1970, the MDL has received 45 isolates of S. monil- blood agar was the most common media used to recover iform&. Forty-one (91%) isolates were from human S. moniliformis. Some of the histories included the num- sources; of these, 24 (58%) have been received since ber of times S. moniliformis was isolated from the blood 1990 (Figure 3). These 41 isolates were received from 19 per patient (n = 28); the results were as follows: 17 (61%) different local (county) jurisdictions, with a majority of were isolated once, eight (29%) were isolated twice, and strains (61%) received from four county and one city three (10%) were isolated three or more times. From the public health laboratories: Sacramento (n = 8) Los Ange- other sources with this information (n = 5) four (80%) les (n = 6) Santa Clara (n = 5) San Diego and San Fran- were isolated only once per patient, and the remaining cisco (n = 3 each). Most infections were centered around wound isolate was positive by culture more than three densely populated areas and no infections were reported times. The range of onset times (n = 9) was 2 to 7 days, from northern California counties. Geographically, the with four (44%) patients exhibiting symptoms within 3 Rat-BiteFever / Graves and Janda 153

Table 1. Selected Characteristics of Patients with S. moni/i~omis Infections Percentage of Characteristic* Patients*+ Presenting diagnosis (n = 32) Rat-bite fever 63 RBFILeptospirosis or Kawasaki or septic 9 Streptobacillus bacteremia/ 3 Arthritis (reactive or rheumatoid) 9 Fever 6 Sepsis 3 Tendinitis 3 Wound infection 3 Presenting symptoms (n = 34) Fever 88 Arthritis/arthralgia 73 Rash 65 / 20 18 Chills 15 Animal exposure (n = 35) Pet rat 54 Figure 3. Prevalence of S. moniliformis infections by year in Califor- School rat 14 nia, 1970-98. Other rat exposure 11 Wild rat 9 days of exposure. Table 1 lists selected characteristics of Mouse 3 the patients in this study. Squirrel 3 Exposure not known 6 When patients presented with at least two of the three Rat exposure (n = 31) classic symptoms (fever, rash, arthritis) and a history of rat Bite 61 exposure, clinicians suspected RBF in 44% of the cases. Other rat association 26 Scratch 10 Another 19% were diagnosed with RBF if there was an Kiss 3 exposure to rats but only one of the three classic symp Therapy (n = 25) toms. One astute practitioner diagnosed RBF in a patient alone 44 Penicillin along with other 12 with no history of exposure to rats or any of the three Ampicillin or or clavulanic acid 12 major symptoms. In patients presenting with at least two Other antibiotics 32 of the major symptoms and having a history of a different *Based on 41 cases: r? In column one denotes the number of cases in which animal exposure (to a mouse and a squirrel, respectively), data were available. +Age range, 6 weeks to 92 years (mean, 46 y); male to female ratio of 41 two clinicians suspected RBF Several authors have reported patients was 1 .0:1.2. RBF following exposures to animals other than rats.‘,x Symptom combinations varied greatly in the cases included in this study. The greatest percentage of the In the present study, exposure to pet rats accounted patients exhibited fever with rash (28%), followed by for the greatest risk. All the pet rat exposures except one patients having all three classic symptoms: fever, rash, and took place in the owner’s or a friend’s home. The excep- arthritis (22%). Several histories showed fever with arthri- tion occurred in a pet store. This source of exposure is tis (17%). Only one patient had a rash with arthritis and not commonly acknowledged in the current literature as no fever. Four of the cases (11%) had fever without rash the greatest risk. Three of the school rat exposures were or arthritis. to adults in school and could more accurately be classi- fied laboratory exposures. All four other rat exposures were rat bites with the “source” of the rat not recorded in the exposure history. Data confirm that of S. monilzjiwmis to humans by rats takes place not only after a bite.‘-‘x5 Thirty- nine percent of the cases received the pathogen as the result of exposure other than a bite that included scratches, kissing, or unknown mode of transmission. In two of the patients treated with ampicillin-amox- icillin or ampicillin and clavulanic acid, gentamicin was also part of the regime. The “other antibiotics” category in Table 1 includes six patients treated with a variety of antibiotics, including erythromycin--clin- Figure 4. Prevalence of S. moniliformis infections by age in Califor- damycin, , cephalosporins, cephalothin- nia, 1970-98. cephalexin, , and gentamicin. 154 International Journal of Infectious Diseases / Volume 5, Number 3,2001

DISCUSSION Although it cannot be unequivocally established that the increase in S. monilifomnis infections observed in Cal- The MDL has confirmed 41 cases of S. moniliformis asso- ifornia over the past 8 years is attributable to these fac- ciated with RBF between 1970 and 1998. Because this tors, the twofold increase suggests that this may be the disease is not reportable, 8,9 the incidence is difficult to case. Regardless of the reason for the increase, prevention measure. Overall numbers (1.5 cases/y), however, coincide of serious disease is dependent upon early clinical recog- with one report citing an incidence of one to two cases nition, alerting the laboratory of the potential diagnosis, per year.6 Twenty-four isolates were received since 1990 use of appropriate laboratory procedures, methods and (3.0 cases/y), suggesting a twofold increase and a possi- media to recover and identify S. monilifrmis from blood ble rise in the incidence of RBE Potential reasons for this or other body fluids and tissues,‘* and institution of appro increase include more pet and other animal exposure, priate antimicrobial therapy (penicillin, tetracycline).‘~3~* better isolation and identification procedures, a higher Measures to decrease the number of RBF cases can level of suspicion on the part of clinicians, or some com- be instituted. Extermination of rats in urban areas, where bination of these three. unintended exposure is highest, can be undertaken. Peo- Most RBF infections in California occur in younger ple can be educated to avoid potentially contaminated people (under 12 y) and are associated with septic, febrile food (including unpasteurized milk) and water. Finally, episodes. In addition, a large percentage of patients (67%) most laboratory infections can be avoided if laboratory presented with signs of arthritis. Although S. monilzjixmis workers are gloved and cautious when handling labora- was more often isolated from blood than any other site, tory rodents (alive or dead). in four cases S. moniltjiwnais was recovered from wounds or lesions. This is somewhat unusual in that classic descriptions suggest that wounds usually have healed by REFERENCES the time symptoms appear and the RBF diagnosis is enter- tained.‘-* Depending on whether or not a rash or poly- 1. Washburn RG. Streptobacillus moniliformis (rat-bite fever). arthritis accompany febrile episodes of RBF, the In: Mandell GL, Bennett JE, Dolin R, eds. Principles of infec- tious diseases. 4th ed. New York: Churchill Livingstone, can also include , lep- 1995:2084-2086. tospirosis, Rocky Mountain spotted fever, Lyme disease, 2. Rupp ME. Rat-bite fever. In: Hoeprich PD, Jordan MC, Ronald viral exanthems, disseminated sexually-transmitted dis- AR, eds. Infectious diseases; a treatise of infectious processes. eases, and a variety of other infective or vascular 5th ed. Philadelphia:JB Lippincott, 1994:1317-1320. processes. I,3 Whenever a history of exposure to rats is 3. Wilson ME. A world guide to infections; diseases, distribu- tion, diagnosis. New York: Oxford University Press, revealed, RBF is highly suggested. 1991:653-654. Several findings from this retrospective study are 4. Mutters R. Actinobacillus, Capnocytophaga, Eikenella, noteworthy. Two cases of RBF were associated with expo- Kingella, and other fastidious or rarely encountered gram- sure to animals other than rats (squirrel, mice). This illus- negative rods. 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