Jpn. J. Infect. Dis., 73, 85–87, 2020

Laboratory and Epidemiology Communications Rat-Bite Fever Due to Streptobacillus moniliformis in a Patient without Bite History: an Unexpected Cause of Consciousness Disturbance Hiroshi Onodera1*, Hironori Uekita1, Tatsuya Watanabe1, Kayano Taira1, Chisa Watanabe2, Hiroko Saito2 , Junji Seto3 , Yu Suzuki3**, and Koichi Imaoka4 1Department of Cardiology and 2Division of Clinical Laboratory, Yonezawa City Hospital, Yamagata; 3Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata; and 4Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan Communicated by Masayuki Saijo

Rat-bite fever (RBF) is a zoonotic disease caused Whole-body computed tomography, head magnetic by direct contact with rats harboring Streptobacillus resonance imaging, and transthoracic echocardiography moniliformis, Streptobacillus notomytis, or Spirillum revealed no explainable causes of consciousness minus (1,2). Few studies have reported RBF cases. disturbance, such as cerebrovascular lesions. However, Therefore, the incidence of RBF is not well understood mild signs of pneumonia were found in the right lung. in Japan. The mortality rate is approximately 10% in On hospitalization day 3, gram-negative filamentous undertreated RBF cases (1,3). Of the 3 bacterial causes, bacilli were detected from aerobic and anaerobic S. moniliformis infection typically presents as a triad blood cultures (Fig. 1). The bacillus, unidentifiable of relapsing fever, polyarthralgia, and skin rash along using automatic analyzer (VITEC 2 compact, with severe diseases, including pneumonia, meningitis, bioMérieux, Marcy-l'Étoile, France) showed small and endocarditis (3). Generally, a history of rat bite white colonies under aerobic condition at 35°C for is an important clue for RBF diagnosis. However, we 48 h on sheep blood agar (Pourmedia Sheep Blood encountered a case of RBF caused by S. moniliformis Agar M58, EIKEN CHEMICAL CO., LTD, Tokyo, infection without rat bite. Japan). The results of 16S ribosomal RNA (rRNA) In September 2016, a 76-year-old Japanese male gene sequencing of the bacillus (Genbank accession patient living in a rural area in Okitama district, no. LC192962) were identical with those of S. Yamagata Prefecture, Japan, was referred to our hospital moniliformis DSM12112T (CP001779). In addition, the because of consciousness disturbance. He had a history sequence showed similarities of 98.5% (1,420/1,441 of diabetes mellitus treated with oral antidiabetic agents. bp) and 97.9% (1,411/1,441 bp) with the strains of Upon physical examination, the patient was febrile (37.3°C) S. notomytis AHL370-1T (KR001919) and S. ratti and disoriented (Glasgow Coma Scale 14; E4V4M6). OGS16T (KR001922), respectively. On hospitalization His blood pressure, heart rate, and percutaneous oxygen day 5, tazobactam/piperacillin (4.5 grams every 8 saturation in room air were 161/104 mmHg, 92 bpm, h) was empirically prescribed for mild pneumonia and 95%, respectively. He complained of right elbow and bacteremia. After treatment, the consciousness and left hip joint pain without evidence of bruises or disturbance of the patient gradually improved and his abrasions and no limitation of movement. He had no body temperature became normal on hospitalization day skin rash or other findings suggestive of meningitis or 7. His arthralgia nearly disappeared on hospitalization cerebral apoplexy such as headache, nuchal rigidity, and day 11. He was discharged on hospitalization day 16 extremity paralysis. His cardiovascular and respiratory findings were normal. Hematological assessment revealed white blood cell count and C-reactive protein level of 18,690/μL and 5.5 mg/dL, respectively. Renal and thyroid functions as well as levels of liver enzymes, electrolytes, blood glucose, and serum ammonia were within normal ranges. Antinuclear antibody tests were negative whereas semi- quantitative procalcitonin protein was 1+ (Table 1).

Accepted November 8, 2019. J-STAGE Advance Publication December 25, 2019. DOI: 10.7883/yoken.JJID.2019.271 * Corresponding author: Mailing address: Department of Cardiology, Yonezawa City Hospital, 6-36 Aioi-cho, Yonezawa, Yamagata 992-8502, Japan. Tel: +81-238-22- 2450, Fax: +81-238-22-2876, E-mail: bufbills@yahoo. co.jp **Present address: Yamagata Prefectural Central Hospital, Fig. 1. Gram-stained sample of blood culture showed pleomorphic, Yamagata, Japan. filamentous gram-negative bacilli (×1,000).

85 Table 1. Laboratory data on admission Peripheral blood Arterial blood gas (room air) White blood cell count 18,690 /μL pH 7.432 Hemoglobin 14.9 g/dL PaO2 73.8 Torr 4 Platelet count 38.1×10 / μL PaCO2 34.5 Torr

HCO3 22.6 mmol/L Biochemistry Lactic acid 1.9 mmol/L Total protein 8.0 g/dL Total bilirubin 2.1 mg/dL Serological test Aspartate aminotransferase 32 IU/L Antinuclear antibodies ×40 Alanine aminotransferase 22 IU/L Anti DS-DNA IgG < 10 IU/ml Lactic dehydrogenase 237 IU/L Anti Jo-1 antibody < 1.0 U/ml Urea nitrogen 19 mg/dL Semi-quantitative procalcitonin (1+) Creatinine 1.53 mg/dL Uric acid 6.2 mg/dL Creatine phosphokinase 107 IU/L Glucose 176 mg/dL C-reactive protein 5.5 mg/dL Myoglobin 138.7 ng/mL Sodium 138 mmol/L Potassium 3.9 mmol/L Chloride 102 mmol/L Calcium 10.1 mg/dL Ammonia 27 μg/dL

Table 2. Result of antibiotic susceptibility test for Streptobacillus patient’s symptoms. moniliformis isolated from blood samples in a case of A medical interview of the patient’s living consciousness disturbance environment is useful in making an appropriate Antibiotic MIC, μg/mL diagnosis and treatment for RBF. In the present case, Penicillin G ≤ 0.03 repeated medical interviews showed that the patient had a dog, lived in poor hygienic conditions, and sometimes Ampicillin 0.12 witnessed rats in the kitchen. He had no history of Ceftizoxime ≤ 2 contact with unsanitary water or soil. Moreover, RBF Ceftazidime ≤ 1 can develop without rat bite because S. moniliformis from rat urine can be transmitted to humans via the oral Cefepime ≤ 1 route (4). Indeed, Elliott showed that 22 (34%) of 65 Cefmetazole ≤ 1 RBF cases were not caused by rat bite or rat exposure (3). Flomoxef ≤ 1 Thus, our patient, who had no history of direct contact Imipenem ≤ 0.25 with rats, including rat bites, was orally infected with S. moniliformis via contaminated food, drinking water, or Meropenem ≤ 0.25 rat feces. Clavulanic Amoxicillin ≤ 2 The classical triad is not an essential symptom for Sulbactam Cefoperazone 16 streptobacillary RBF. In case of RBF, the sensitivity of fever, polyarthralgia, and skin rash is 92%, 66%, and Sulbactam Ampicillin ≤ 4 61%, respectively (3). In our patient, no skin rashes Tazobactam Piperacillin ≤16 and swelling or reddening of the joints were observed Clindamycin 0.25 during the course of the disease. Consciousness Minocycline ≤ 0.25 disturbance has been rarely reported as an atypical symptom of RBF (5). Streptobacillary bacteremia may Chloramphenicol 8 have caused consciousness disturbance but we did not Sparfloxacin > 1 completely rule out the effects of meningitis and aging Levofloxacin 0.5 due to lack of cerebrospinal fluid examination and electroencephalogram findings. MIC, minimum inhibitory concentration. Despite RBF often being underdiagnosed, several cases have been reported in humans suggesting that RBF may have been treated as a fever of unknown origin (3,6). after consciousness and joints normalized. Therefore, physicians should consider the possibility The antibiotic susceptibility test result showed that of RBF even if atypical symptoms of RBF have been the S. moniliformis isolate was susceptible to penicillin confirmed in patients living or spending time in rat- G and minocycline (Table 2). RBF is potentially fatal. infested areas. However, it can be easily treated with a simple course Because it is difficult to identify S. moniliformis of penicillin or tetracycline (1,3). The administration bacteremia using the findings of various clinical imaging of tazobactam/piperacillin remarkably improved the techniques and blood tests, performing blood cultures

86 and identifying the isolated are essential. The REFERENCES genus Streptobacillus has recently been subdivided 1. Washburn RG. Rat-bite fever: Streptobacillus moniliformis and into several new species such as S. notomytis and S. Spirillum minus. In: Bennett JE, Dolin R, Blaser MJ, editors. ratti (7,8). Streptobacillus spp. have been identified Mandell, Douglas, and Bennett’s Principles and Practice of by sequencing 16S rRNA gene (6). In addition, we Infectious Diseases. 8th ed. Philadelphia: Elsevier; 2014. P. 2629- identified Streptobacillus spp. using 16S rRNA gene 32. sequencing. However, establishing a simple method to 2. Fukushima K, Yanagisawa N, Imaoka K, et al. Rat-bite fever due to Streptobacillus notomytis isolated from a human specimen. J Infect differentiate Streptobacillus spp. is necessary for the Chemother. 2018;24:302-4. early diagnosis of RBF. 3. Elliott SP. Rat bite fever and Streptobacillus moniliformis. Clin In the present study, we encountered a sporadic Microbiol Rev. 2007;20:13-22. case of RBF. RBF can be caused via food or water 4. Fordham JN, Mckay-Ferguson E, Davies A, et al. Rat bite fever contamination (9). In Japan, 92 of feral brown rat without the bite. Ann Rheum Dis. 1992;51:411-2. % 5. Kiefer H, Fröscher W, Mohr HP. Rat bite disease with (Rattus norvegicus) and 58% of feral black rat (Rattus meningoencephalitic involvement. Med Klin. 1981;76:653-5. rattus) harbored S. moniliformis or S. notomytis (7,10). German. Accordingly, healthcare providers including physicians 6. Eisenberg T, Ewers C, Rau J, et al. Approved and novel strategies in and public health employees should pay special attention diagnostics of rat bite fever and other Streptobacillus infections in humans and animals. Virulence. 2016;7:630-48. to RBF. 7. Eisenberg T, Glaeser SP, Ewers C, et al. Streptobacillus notomytis In conclusion, we report a case of RBF without typical sp. nov., isolated from a spinifex hopping mouse (Notomys alexis symptoms and epidemiological background. Thus, Thomas, 1922), and emended description of Streptobacillus Levaditi awareness of the possibilities of sepsis and zoonosis in et al. 1925, Eisenberg et al. 2015 emend. Int J Syst Evol Microbiol. identifying the cause of consciousness disturbance in 2015;65:4823-9. 8. Eisenberg T, Imaoka K, Kimura M, et al. Streptobacillus ratti clinical practice is essential in cases where the patient sp. nov., isolated from a black rat (Rattus rattus). Int J Syst Evol lives or spends time in rat-infested areas. Microbiol. 2016;66:1620-6. 9. Parker F, Hudson NP. The etiology of (erythema Conflict of interest None to declare. arthriticum epidemicum). Am J Pathol. 1926;2:357-80.7. 10. Kimura M, Tanikawa T, Suzuki M, et al. Detection of Streptobacillus spp. in feral rats by specific polymerase chain reaction. Microbiol Immunol. 2008;52:9-15.

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