{"paper_id":"138ea76e-d435-4595-a984-bfe63911d562","body_text":"We retrospectively reviewed electronic medical records and clinical microbiology records in Kurashiki Central Hospital (Okayama, Japan), a 1,166-bed, tertiary-care hospital that provides care to ≈300,000 persons annually. Clinical specimens submitted to the microbiology laboratory included blood, sputum, urine, bile, ascites, feces, placenta, tissue, and pus. Information about identified bacteria and antimicrobial susceptibility were kept as microbiology laboratory records for each specimen. We considered bacteremia to exist when >1 set of blood cultures was positive. We identified all cultures growing  E. tarda  from clinical specimens submitted during January 2005–December 2016.\nWe processed blood culture samples using the BacT/Alert system (Sysmex bioMérieux Co. Ltd.,  https://www.biomerieux.com ) and conducted microbial culture using KBM Chocolate HB Agar (Kohjin Bio Co. Ltd.,  http://www.kohjin-bio.jp/english ), KBM Sheep Blood Agar (Kohjin Bio Co. Ltd.), and BTB agar (Kyokuto Pharmaceutical Co. Ltd.,  https://ssl.kyokutoseiyaku.co.jp/english/index.html ). We used different bacterial identification and antimicrobial susceptibility testing methods in our hospital throughout the study period. We used ID test EB-20 Nissui (Nissui Pharmaceutical Co. Ltd.,  https://www.nissui-pharm.co.jp/english ) for bacterial identification and Kirby–Bauer disk (Eiken Chemical Co. Ltd.,  http://www.eiken.co.jp ) for antimicrobial susceptibility testing from January 2005 through June 2007. EB-20 is a system to identify glucose-fermenting gram-negative rods by 20 patterns of biochemical properties, using hydrogen sulfide, indole, lysine, ONPG (2-nitrophenyl-β-D-galactopyranoside), adunit, inositol, rhamnose, mannit, esculin, Voges-Proskauer, arginine, urea, inositol, sorbitol, arabinose, phenylpyruvic acid, citric acid, ornithine, malonic acid, raffinose, and sugar. Thereafter, automatic systems were introduced at our hospital: DPS192 (Eiken Chemical Co. Ltd,  http://www.eiken.co.jp ) during July 2007–February 2013 and MicroScan WalkAway (Beckman Coulter, Inc,  https://www.beckmancoulter.com/en ) during March 2013–March 2014. Since April 2014, we have used MALDI Biotyper (Bruker Daltonics GmbH,  https://www.bruker.com ), using the manufacturer-provided database, for bacterial identification. We judged the drug susceptibility of a microorganism based on clinical breakpoints set by the Clinical and Laboratory Standards Institute; in particular, we used the document M100-S22 ( 2 ) during June 1, 2013–December 31, 2016.\nWe collected all clinical information of patients with positive  E. tarda  bacteremia results from electronic medical records, including age, sex, underlying diseases, source of infection, antimicrobial drug administered, treatment period, and outcome. We defined chronic kidney disease as a serum creatinine level of  > 2.0 mg/dL (reference range 0.65–1.07 mg/dL) and chronic liver disease as liver cirrhosis or chronic hepatitis B or C infection. We defined nosocomial bloodstream infection, healthcare-associated bloodstream infection, community-acquired bloodstream infection, and febrile neutropenia according to the previous study and guideline ( 3 , 4 ). We defined 30-day mortality as patient death within 30 days after the onset of  E. tarda  bacteremia and 90-day mortality as patient death within 90 days after onset. We also collected information of patients with  E. tarda  nonbacteremic infections.\nWe described the clinical characteristics and 30-day mortality of patients with  E. tarda  bacteremia, along with the source of infection and antimicrobial susceptibility. We then compared the characteristics of patients with  E. tarda  bacteremia by 30-day mortality. We also compared the characteristics of patients with bacteremic and nonbacteremic  E. tarda  infections. We also conducted an exploratory multivariable logistic regression analysis to investigate the risk for  E. tarda  bacteremia incidence among all  E. tarda  infections.\nBecause a previous literature review suggested seasonal variation in the occurrence of  E. tarda  bacteremia ( 5 ), we thus examined whether such variation or trend existed in the cases in our study by using Cochran-Armitage test. We tested dichotomous variables with Fisher exact test and and continuous variables by Wilcoxon signed-rank test. Statistical analysis was performed using Stata version 15.1 (StataCorp,  http://www.stata.com ). We considered p<0.05 to be statistically significant.\nThe Ethics Committee of Kurashiki Central Hospital approved this study (no. 2,527). Only persons with appropriate authorization had access to participants’ records, and patient confidentiality was maintained. Given the nature of a retrospective chart review, written consent from the patients was waived.\n\nWe obtained 182,668 sets of blood cultures during the study period, of which 19,234 sets were positive for some organisms and 40 sets from 26 patients were  E. tarda –positive.  E. tarda  bacteremia was diagnosed in 26 patients (13 men and 13 women); their median age was 75 years (range 45–101 years) ( Table 1 ).\n*IQR, interquartile range; NE, not evaluated.\nSome patients had  > 1 underlying disease: solid tumors (12 patients), cardiovascular diseases (4 patients), diabetes mellitus (3 patients), gallstone disease (3 patients), chronic liver disease (2 patients), cerebrovascular disease (2 patients), and hematologic malignancy (1 patient) (Table 1). Four patients had no underlying disease. Sites of solid tumors included pancreas (3 patients), gallbladder/bile duct (3 patients), colon (2 patients), and esophagus, gastric, liver, and thyroid (1 patient each). Of the 12 patients with solid tumors, 4 were receiving chemotherapy for their cancer when  E. tarda  bacteremia occurred.\nClinical diagnoses by the site of infection were cholangitis (9 patients); liver abscess (6 patients); enterocolitis (4 patients); cholecystitis (3 patients); and spontaneous bacterial peritonitis, mycotic aneurysm, necrotizing fasciitis, empyema, osteomyelitis, and secondary peritonitis (1 patient each) ( Table 2 ). Seventeen patients had community-acquired bloodstream infections. The source of infection was not identified in 5 patients, including 1 with febrile neutropenia; 3 patients had nosocomial bloodstream infections, and 6 had healthcare-associated bloodstream infections.\n*AMP, ampicillin;  B. fragilis ,  Bacteroides fragilis ; CFP/SUL, cefoperazon–sulbactam;  C. freundii ,  Citrobacter freundii ; CFZ, cefazolin; CLI, clindamycin; CMZ, cefmetazole; CRO, ceftriaxone; CZO, cefozopran;  E. faecalis ,  Enterococcus faecalis ;  E. faecium ,  Enterococcus faecium ;  E. coli ,  Escherichia coli ; FEP, cefepime;  F. nucleatum ,  Fusobacterium nucleatum ; GEN, gentamycin; IPM/CIL, imipenem–cilastatin;  K. pneumoniae ,  Klebsiella pneumoniae ; LEX, cephalexin; LVX, levofloxacin; MEM, meropenem; MIN, minocycline; PNP, panipenem; PIP, piperacillin; PZX, pazufloxacin, SAM, ampicillin sulbactam;  S. anginosus ,  Streptococcus anginosus ;  S. gallolyticus ,  Streptococcus gallolyticus ; Tx, treatment; TZP, piperacillin tazobactam. Arrows indicate the order of antimicrobial drugs used. Blank cells indicate no other concurrent organisms.\nPatients with  E. tarda  bacteremia were older and more likely to have solid tumors than were patients with  E. tarda  nonbacteremic infections ( Table 3 ). In addition, we observed hepatobiliary infection, such as cholangitis and liver abscess, more frequently in patients with bacteremia.\n*IQR, interquartile range.\nBecause the cohort included 26  E. tarda  bacteremia patients, we conducted a multivariable logistic regression analysis adjusted with 2 explanatory variables. We hypothesized that underlying liver disease and old age could be associated with the incidence of  E. tarda  bacteremia and selected these 2 variables as the covariates. Our analysis suggested that age  > 65 years was significantly associated with an increased risk for  E. tarda  bacteremia incidence (odds ratio 2.70; 95% CI 1.11–6.55; p = 0.028). However, underlying chronic liver disease was not the risk factor for  E. tarda  bacteremia (odds ratio 2.48; 95% CI 0.41–14.99; p = 0.32).\nAll  E. tarda  strains isolated from blood cultures were susceptible to all tested antimicrobial drugs.  E. tarda  bacteremia patients were treated with a variety of antimicrobial drugs according to the treating physicians’ discretion ( Table 3 ). The median duration of treatment was 12 days (range 1–77 days). Overall 30-day mortality for  E. tarda  bacteremia was 12% (3/26) and overall 90-day mortality 27% (7/26).\nPatient 4 had end-stage hepatocellular carcinoma and liver failure. On day 2 after admission,  E. tarda  bacteremia developed; the source of infection was unidentified. He was treated with cefepime and promptly became afebrile.  E. tarda  bacteremia was considered controlled by cefepime; however, the patient died of hepatic failure on day 11.\nIn patient 20, necrotizing fasciitis was diagnosed, and  E. tarda  was detected from wound and blood cultures. Although meropenem and clindamycin were administered, he died on day 2.\nPatient 26, who had end-stage alcoholic liver cirrhosis, was admitted for massive pleural effusion and ascites.  E. tarda  was detected from pleural effusion but not from ascites. Empyema and spontaneous bacterial peritonitis caused by  E. tarda  were diagnosed. Although these fluids were drained and antimicrobial drugs were given, she died on day 5.\nPatient 5 was admitted for evaluation of fever and back pain. Blood cultures drawn on admission day revealed  E. tarda , and he was treated with imipenem–cilastatin. However, his fever persisted. Computed tomography scan of the chest and abdomen revealed mycotic thoracic aneurysm, liver abscess, and vertebral osteomyelitis. He was treated with multiple antimicrobial drugs but died of a ruptured mycotic aneurysm on day 39.\nIn patients 6, 9, and 21,  E. tarda  bacteremia developed and improved with antimicrobial therapy. However, these patients died of underlying diseases.\nThe incidence of  E. tarda  infection did not vary by season ( Figure ). We found no trend of  E. tarda  bacteremia incidence among all  E. tarda  infections when we examined them by month (p = 0.46) or by season, defined as a set of 3 months (p = 0.53).\nSeasonal variation in the incidence of  Edwardsiella tarda  infection, Kurashiki Central Hospital, Okayama, Japan, 2005–2016. Black bars, blood culture; gray bars, all specimens (including blood cultures).\n\nE. tarda  is associated with freshwater and marine life, including fish, reptiles, and amphibians ( 1 ). The organism resembles  Salmonella  biochemically and clinically ( 1 ).  Salmonella  usually ferments D-mannitol, urease, oxidase, and D-sorbitol, whereas  E. tarda  produces hydrogen sulfide and indole ( 6 ).\nE. tarda  is a rare human pathogen and is primarily associated with gastrointestinal diseases, including the asymptomatic carrier state ( 1 ). Approximately 80% of infections are intestinal.  E. tarda  causes a  Salmonella -like gastrointestinal infection, usually self-limited enteritis, with intermittent watery diarrhea and low-grade fever ( 1 , 7 ).\nThe pathogenesis of  E. tarda  and its disease-causing mechanism remain unclear. Twelve classes of bacterial protein secretion systems are known; these systems transport virulence proteins into the cell and, in some cases, directly into the cytoplasm of a target cell ( 8 ). The bacterial type III and type VI secretion systems (T3SS and T6SS) are believed to play an essential role in  E. tarda  survival, replication, and virulence inside the host. In particular, T6SS is proposed to enable  E. tarda  to establish inside the host, cause severe systemic infection, and eventually kill the host.\nWe reviewed 26 cases of  E. tarda  bacteremia. Clinical diagnoses included 15 (58%) biliary tract infections (cholangitis, cholecystitis, and liver abscess). Eight of these patients had hepatobiliary diseases including cholangiocarcinoma, gallbladder cancer, pancreatic cancer, gallstone disease. Therefore, hepatobiliary diseases may be a predisposing factor of  E. tarda  biliary tract infections. However, our multivariable logistic regression found that only age  > 65 years was associated with the incidence of  E. tarda  bacteremia. We acknowledge that the sample size of our study and the number of  E. tarda  bacteremia incidence were still small, and thus the finding from our multivariable analysis might be only exploratory.\nPrevious studies reported high rates of death for  E. tarda  bacteremia, ranging from 22.7% to 44.6% ( 1 , 5 , 9 ). In contrast, the death rate for patients with  E. tarda  bacteremia in the cohort reported here was low at 12%. However, 2 of these 3 patients had end-stage liver disease; only 1 death among these patients was attributed to  E. tarda  bacteremia.\nE. tarda  is susceptible to most antimicrobial drugs, including tetracyclines, aminoglycosides, quinolones, antifolates, chloramphenicol, nitrofurantoin, fosfomycin, and most β-lactams ( 10 ), and is naturally resistant to benzylpenicillin, colistin, and polymyxin B ( 1 , 11 ). In our study,  E. tarda  was susceptible to most commonly used antimicrobial drugs.  E. tarda  susceptibilities to colistin and polymyxin B are unknown because susceptibility testing is not routinely performed for these drugs in our institution. Previous studies have shown that all strains of  E. tarda  were positive for β-lactamase production examined with nitrocefin β-lactamase disks, but an ampicillin-resistant  E. tarda  strain has not been reported ( 10 , 11 ). Whether  E. tarda  isolates detected in our institution produced β-lactamase is not clear because we did not perform the β-lactamase test, but 5 cases were successfully treated with ampicillin.\nHirai et al. suggested that  E. tarda  bacteremia is likely to develop during summer and autumn months in the Northern Hemisphere ( 8 ). The authors conducted a literature review of 77  E. tarda  bacteremia cases reported from diverse areas and suggested seasonal variation in incidence for 22 cases. Our study of 26  E. tarda  bacteremia cases suggests no such seasonal distribution. Several possible reasons might account for this discrepancy. First,  E. tarda  can colonize. In our study, hepatobiliary infection (such as cholangitis, cholecystitis, and liver abscess) was diagnosed in 58% (15/26) patients, and patients colonizing  E. tarda  developed  E. tarda  bacteremia. Second, diversity might exist in the patients’ dietary patterns.  E. tarda  frequently infects fish. Hirai et al. included patients from many parts of the world, so the intake of fish might have differed according to the season or geographic area across reports. In contrast, our study included only people in a single area of Japan who habitually ate raw seafood, such as sashimi, throughout the year; this tendency might have led to no seasonal variation of  E. tarda  bacteremia incidence. Third, our study had no missing clinical data for any patients, whereas Hirai et al. examined 22 of all 77 eligible patients, which might have rendered their analysis vulnerable to information bias.\nOur study had some strengths. First, we elucidated that no seasonal variation existed in  E. tarda  bacteremia in this population. Second, we described the characteristics of each patient with  E. tarda  bacteremia and provided risk factors for  E. tarda  bacteremia incidence among all  E. tarda  infections.\nOur study also had some limitations. First, the number of blood cultures submitted increased in recent years in our hospital. The number of blood cultures submitted in 2016 nearly doubled that for 2005. This increase might have resulted in the underestimation of  E. tarda  bacteremia in the earlier years of our study period. Second, ours was a retrospective and single-center study. However, our study had no missing data regarding clinical information. Furthermore, we successfully presented a particularly large case series of  E. tarda  bacteremia.\nIn conclusion,  E. tarda  bacteremia is a rare disease that is not associated with high rates of death.  E. tarda  bacteremia patients in our cohort in Japan had more severe underlying diseases, such as hepatobiliary disease and solid tumors, than did patients in previous studies. Hepatobiliary infections, such as cholangitis, cholecystitis, and liver abscess, are the most common clinical manifestations in patients with  E. tarda  bacteremia. The major underlying diseases in this study were hepatobiliary diseases and malignancy. Furthermore,  E. tarda  strains we isolated were susceptible to most antimicrobial drugs, including β-lactams, aminoglycoside, tetracycline, fosfomycin, fluoroquinolone, and trimethoprim/sulfamethoxazole, and  E. tarda  bacteremia was successfully treated with ampicillin. Finally, we observed no seasonal distribution of  E. tarda  bacteremia. Risk factors for  E. tarda  bacteremia–related death remain to be investigated.","source_license":"CC-BY-4.0","license_restricted":false}