Study Design

We retrospectively reviewed electronic medical records and clinical microbiology records of patients with positive blood cultures for Corynebacterium spp. in Kameda Medical Center (Chiba, Japan) during January 2014–May 2020. This facility is an 865-bed, tertiary-care general medical center that provides a wide variety of services including general medicine, surgery, oncology, cardiothoracic surgery, hematopoietic stem cell transplantation, and renal transplantation to ≈310,000 persons each year. All patients with blood cultures positive for any organism are automatically referred to the infectious diseases department for consultation. Board-certified infectious disease physicians evaluate the patients and document the consultation report in medical records. The study protocol was reviewed and approved by the Kameda Medical Center Institutional Review Board (reference no. 20-046). The need for written informed consent was waived. The study complied with the principles of the Declaration of Helsinki.

Study Population

We included all patients at the hospital who had blood cultures positive for Corynebacterium spp. during the study period. We collected data about age, sex, underlying conditions, clinical diagnosis, 90-day mortality rates, species of Corynebacterium, and antimicrobial susceptibility. If the same patient had multiple episodes of Corynebacterium bacteremia during the study period, we included only the first episode.

Definitions

We defined a case as true bacteremia when 2 sets of blood cultures from a patient with signs of infection were positive for Corynebacterium spp. or when 1 set of blood cultures and a clinically relevant specimen from another site (e.g., urine or sputum) where the infection was thought to exist (on the basis of signs/symptoms and examination findings) were both positive for the same species of Corynebacterium. For patients with only 1 set of blood cultures in which Corynebacterium spp. were detected and for whom bacteremia was clinically suspected, new blood cultures were performed, and reevaluated as necessary, before antimicrobial agents were initiated. These patients were carefully followed by our infectious disease physicians to ensure the absence of infection. This definition was based on a previous study (9).

Catheter-related bloodstream infection (CRBSI) was considered definite for patients who met 1 of the following 3 criteria: 1) >1 set of blood cultures and semiquantitative cultures of a catheter segment (>15 CFUs/plate) were both positive for the same Corynebacterium species; 2) peripheral blood cultures and blood cultures from a catheter lumen were both positive for the same species of Corynebacterium, and its differential time to positivity was >2 hours (10); or 3) 2 sets of blood cultures were positive for Corynebacterium species, and signs of inflammation or purulence were present at the catheter insertion site (11). Diagnosis of other focal infections were based on the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria (12).

We classified a case as no focus when physical examination by infectious disease physicians revealed no localized signs of infection, urinalysis was negative for pyuria or bacteriuria, chest images (radiographs or computed tomography scans) showed no infiltrates or masses, and the case still satisfied the criteria for true bacteremia. Chronic kidney disease was defined as being present when serum creatinine level was >2.0 mg/dL. Liver disease was defined as presence of liver cirrhosis or chronic hepatitis B or C.

Laboratory Methods

We used RapID CB Plus (Kyokuto Pharmaceutical Industrial Co. Ltd., https://www.kyokutoseiyaku.co.jp) for bacterial identification during January 2014–May 2015. This kit correctly identifies 95% of Corynebacterium isolates to the species level (13). Starting in June 2015, we identified strains by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and a Bruker MALDI Biotyper (Bruker Daltonics GmbH, https://www.bruker.com). We used score cutoff values according to recommendations proposed by the manufacturer (>2.0). For some cases in which no identification or ambiguous identification was achieved by these methods, we confirmed identification by using 16S rRNA gene sequence analysis. We performed antimicrobial susceptibility tests by broth microdilution, using Clinical and Laboratory Standards Institute (CLSI, https://clsi.org) M45 A2:2ED 2010 during January 2014–December 2016 and CLSI M45 3rd edition from January 2017 on.

Statistical Analyses

We used Fisher exact or Pearson χ² tests to compare categorical variables. For continuous variables, we used Mann–Whitney U or paired t-tests, and for estimating survival probabilities we used Kaplan-Meier curves. We estimated and compared the cumulative incidence of mortality by using the log-rank test and compared differences in antimicrobial susceptibility between Corynebacteria species by using Fisher exact or Pearson χ² tests. We considered p<0.05 to indicate statistical significance. We performed all statistical analyses by using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation, https://www.r-project.org) (14).

Proportion of True Bacteremia Cases

Of 115 patients in this study, C. striatum was detected in 67 (58%), C. jeikeium in 14 (12%), and other Corynebacteria species in 34 (30%) patients. The category of other consisted of 15 species (Table 1). In total, there were 60 cases of true bacteremia and 55 cases of contamination, resulting in 52% of patients having true bacteremia. Of the 60 patients with true bacteremia, 55 had >2 sets of positive blood cultures with Corynebacterium spp.; 5 had 1 set of positive blood cultures but met the definition of true bacteremia in our study. Of 115 patients, >2 genera of bacteria were detected in blood culture from only 1 patient; this patient had diverticulitis and bacteremia caused by Corynebacterium spp. and Escherichia coli. The patient recovered after receiving treatment for E. coli bacteremia alone; Corynebacterium spp. were considered to be contaminants. The percentages of true bacteremia cases caused by C. striatum (70%) and C. jeikeium (71%) were significantly higher than those for other species (9%; p<0.001 for each) (Table 2).

Clinical Diagnosis and Underlying Diseases

Hematologic malignancy was the most common underlying disease (33%), especially in 64% of patients with C. jeikeium bacteremia, followed by solid tumors (24%) and diabetes mellitus (23%) (Table 2). C. striatum and C. jeikeium were more frequently detected than other species in patients with hematologic malignancy (p = 0.036 and p<0.001, respectively) and neutropenia (p<0.01 and p<0.001, respectively). Of the 60 patients with true bacteremia, 25 (42%) had infection at an unknown site; 17 (28%) had CRBSI; and 18 (30%) had infection at other foci, including SSTI, pyelonephritis, pneumonia, empyema, infective endocarditis, vertebral osteomyelitis, central venous port infection, and spontaneous bacterial peritonitis.

Mortality Rates

Mortality rates among patients with true bacteremia were 34% among those with bacteremia caused by C. striatum, 30% by C. jeikeium, and 0 by other species of Corynebacterium. (Figure). We observed no significant differences in survival rates between these groups (C. striatum p = 0.25 and C. jeikeium p = 0.32). Six patients experienced a fulminant course of illness that resulted in death within 7 days; for all 6 patients, the causative organism was C. striatum.

Antimicrobial Susceptibility

All tested strains of Corynebacterium, regardless of species, were susceptible to vancomycin, linezolid, and minocycline (Table 3). C. striatum and C. jeikeium were less susceptible than other species to penicillin (p<0.001 for each), ceftriaxone (p<0.001 for each), meropenem (p<0.001 for each), erythromycin (p<0.01 for each), and ciprofloxacin (p<0.001 for C. striatum and p = 0.02 for C. jeikeium).