Definitions

Underlying conditions were stratified on the basis of the McCabe and Jackson score (11) and the comorbidity score of Charlson et al. (12). Severity of illness was evaluated on the first day of bacteremia onset by means of the Acute Physiology and Chronic Health Evaluation II Score (13), Simplified Acute Physiology Score II (14), and the Pittsburgh bacteremia score (15). The physiologic response to bacteremia was categorized as severe sepsis if the patient met the criteria for severe sepsis specified by the American College of Chest Physicians/Society for Critical Care Medicine Consensus Conference Committee (16). Immunosuppressive therapy was defined as the receipt of corticosteroid treatment (10 mg/day or an equivalent dosage) for >2 weeks of antineoplastic chemotherapy or antirejection medication within 30 days before admission. Sepsis-related death was defined as the death of a patient with a clinical course that suggested persistently active infection if the patient had no other obvious explanation for the death.

Bacteremia was defined as the presence of an organism in a blood culture specimen. Clinically significant bacteremia was defined as >1 positive blood culture and clinical features compatible with fever and sepsis syndrome; patients with noteworthy bacteremia were included in this study. An episode of bacteremia was considered to be hospital acquired if a bacteremic episode was noted at >48 hours after hospitalization; healthcare associated if it occurred within 48 hours of hospitalization in patients with extensive contact with the healthcare system (such as nursing home residence, organ transplantation, hemodialysis dependence, presence of an indwelling intravascular catheter, or surgery within the previous 30 days), or the patients had been transferred from another hospital or long-term care facility; or community acquired if it occurred <48 hours of admission in patients without extensive healthcare contact. In the case of secondary bacteremia, a primary focus of infection was defined according to the criteria of the Centers for Disease Control and Prevention (17).

Antimicrobial drug therapy in the preceding 30 days was documented through a review of medical records. Previous antimicrobial drug therapy was defined as the receipt of an oral or parenteral antimicrobial agent for >72 hours within the preceding 2 months.

Identification of Isolates and Clonality

Bacteria colonies suspected of being C. difficile on the basis of characteristic odor, typical morphologic features, and Gram staining results were phenotypically identified by using standard methods (18) and the API 32A system (bioMérieux, Las Halles, France). These organisms were further confirmed to the species level by using partial 16S rRNA gene sequence analysis. Two primers were used: PS13 5′-GGAGGCAGCAGTGGGGAATA-3′ and PS14 5′-TGACGGGCGGTGTGTACAAG-3′, as described (19). The partial sequences obtained (529 bp) were compared with published sequences in the GenBank database by using the BLASTN algorithm (www.ncbi.nlm.nih.gov/blast). Molecular typing of these isolates by pulsed-field gel electrophoresis (PFGE) using SmaI (New England Biolabs, Beverly, MA, USA)–digested DNA and repetitive-element PCR typing (DiversiLab Kits for C. difficile; bioMérieux) were performed to identify the clonality of the isolates (20,21). For PFGE, gels were run for 22 h at 13°C by using a CHEF DR-III system (Bio-Rad Laboratories, Hercules, CA, USA) at 5.5 V/cm with initial and final pulse times of 5 s and 60 s, respectively (20). The production of C. difficile toxin A or B was detected by a qualitative enzyme immunoassay (Premier toxin A&B; Meridian Bioscience, Inc., Cincinnati, OH, USA).

Antimicrobial Drug Susceptibility Testing

MICs of 14 antimicrobial drugs (penicillin, piperacillin/tazobactam, ampicillin/sulbactam, cefmetazole, meropenem, imipenem, doripenem, ertapenem, metronidazole, vancomycin, teicoplanin, fusidic acid, clindamycin, and daptomycin) were determined by the agar dilution method described by the Clinical and Laboratory Standards Institute (22). MICs of tigecycline were measured by the broth microdilution method. The antimicrobial agents used for susceptibility testing were obtained from their corresponding manufacturers. The MIC breakpoints followed those recommended by the Clinical and Laboratory Standards Institute (22) or the European Committee on Antimicrobial Susceptibility Testing (www.eucast.org).

Statistical Analysis

The results were analyzed with SPSS software for Windows, version 13.0 (SPSS, Chicago, IL, USA). Continuous variables were expressed as mean ± SD, and categorical variables were expressed as percentages of total number of specific patients analyzed. Categorical variables were compared by the Fisher exact test or χ² test, as appropriate. Continuous variables were compared by the Mann–Whitney U or Student t test. All tests for statistical significance were 2-tailed, and p values <0.05 were considered significant.

Twelve patients, 7 from National Taiwan University Hospital and 5 from National Cheng Kung University Hospital, with CDB during the period of the study were identified. Most (11) patients were identified after 2000. The partial 16S rRNA gene sequence analysis of 10 available isolates identified by conventional methods showed that they most closely matched C. difficile isolates (accession number FN545816.1; maximal identity: 100% [529/529]). Only 10 isolates were available, and the earliest isolate was obtained in 2005. Their genotyping patterns determined by the repetitive-element PCR and PFGE were different, indicating that no intrahospital or interhospital spread of C. difficile isolates occurred in the 2 hospitals.

The epidemiologic and clinical data of the 12 patients with C. difficile bacteremia are shown in Tables 1 and 2. Their mean ± SD age was 59.9 ± 22.1 years (range 12–87 years). Women (7 cases) outnumbered men. All patients had chronic medical illnesses, particularly diabetes mellitus (4) and cirrhosis of the liver (6). Eleven patients had no underlying or rapidly fatal diseases, according to the McCabe and Bearman classification, and the mean comorbidity score of Charlson et al. was 5.2 (SD 2.2). At the time of bacteremia onset, the mean Acute Physiology And Chronic Health Evaluation II Score or Simplified Acute Physiology Score II score was 25.4 (SD 0.9) or 50.0 (SD 25.2), respectively. Seven patients had critical illness defined as having at least 4 points of the Pittsburgh bacteremia score (15). Five patients were considered to have community-onset CDB, but all had a history of recent hospitalization or referral from a chronic care facility and thus all of their infections can be classified as healthcare associated. . The average length of hospital stay before CDB was 16.4 days. Primary bacteremia noted in 7 patients was the most common infection noted, followed by intraabdominal infections (4, 33%), bone and joint infections (1, 8.3%), and skin and soft-tissue infections (1, 8.3%).

When patients were first seen, their signs and symptoms included fever (9, 75%), abdominal pain (6, 50%), and leukocytosis, which was defined as a leukocyte count >12,000 cells/μL (7, 58.3%). Of note, 5 (41.7%) patients had gastrointestinal disorders or conditions at the time of bacteremia onset. Four (33.3%) had a documented episode of diarrhea before CDB, and 2 patients with diarrhea had endoscopically documented pseudomembranous colitis. Five (41.7%) patients had recent exposure to antimicrobial drugs. Six patients had concurrent bacteremia caused by pathogens other than C. difficile (Table 2).

Five (50%) of 10 available isolates showed a positive result for the C. difficile toxin assay. All isolates were susceptible to metronidazole and vancomycin (Table 3). Other antimicrobial agents demonstrated variable in vitro antibacterial activity against C. difficile isolates. In contrast to imipenem, ertapenem, and doripenem, meropenem showed excellent in vitro activity with a narrow MIC range (0.12 μg/mL–2 μg/mL). Of these isolates, 90% of 10 isolates were resistant to penicillin, and 30% were resistant to clindamycin. Tigecycline and daptomycin, 2 newly marketed drugs for which a recommended breakpoint for C. difficile has not yet been determined, show favorable antibacterial activity with low 90% MIC values, 0.06 μg/mL and 2 μg/mL, respectively.

Before microbiologic information was available, 6 patients received antimicrobial therapy, metronidazole (3 patients), vancomycin (2), or cefmetazole (1). Overall, only 1 of 8 patients definitively treated with metronidazole or vancomycin died; in contrast, all 4 patients treated by drugs other than metronidazole or vancomycin died (p = 0.01). Of 5 patients who died, 3 died directly of CDB. Seven patients survived and were discharged, and 1 patient was treated surgically for septic prosthetic hip arthritis. The survivors remained in the hospital for a mean of 28 days (range 12–47 days) after diagnosis of CDB.

Literature Review

Twenty reports of patients with CDB have been published in English in the literature since 1962 (3,5–10,23–30). The epidemiologic and clinical data are summarized in Table 2. Most (14) patients had polymicrobial bacteremia; concomitant gastrointestinal diseases or conditions of varying severity were noted in 15 patients. Excluding a patient with unknown outcome, 10 of 19 patients died in the hospital. The results of stool toxin assay were available for 12 patients, and clostridial toxin A or B could be detected in 8 patients. Drug information was available for 16 patients. Seven patients (3 of whom died) were treated with metronidazole, and 7 were treated with vancomycin (3 of these patients died). The crude death rate for these published cases was similar to that in the present study (10/19, 52.6% vs. 5/12, 41.7%; p = 0.72).