Volume 16, Number 8—August 2010
CME ACTIVITY - Synopsis
Clostridium difficile Bacteremia, Taiwan1
To determine clinical characteristics and outcome of patients with Clostridium difficile bacteremia (CDB), we identified 12 patients with CDB in 2 medical centers in Taiwan; all had underlying systemic diseases. Five had gastrointestinal diseases or conditions, including pseudomembranous colitis (2 patients); 4 recalled diarrhea, but only 5 had recent exposure to antimicrobial drugs. Ten available isolates were susceptible to metronidazole and vancomycin. Five isolates had C. difficile toxin A or B. Of 5 patients who died, 3 died of CDB. Of 8 patients treated with metronidazole or vancomycin, only 1 died, and all 4 patients treated with other drugs died (12.5% vs. 100%; p = 0.01). C. difficile bacteremia, although uncommon, is thus associated with substaintial illness and death rates.
Clostridium difficile Bacteremia, Taiwan
Clostridium difficile is well recognized as the etiologic agent of pseudomembranous colitis and has been implicated as the cause of 10%–25% of cases of antimicrobial drug–associated diarrhea (1). The pathogen has been responsible for numerous recent hospital-based epidemics and is also emerging in the community (2). The clinical features, disease spectrum and pathogenesis, and optimal treatments of C. difficile–associated diarrhea have been well studied. In contrast, reports of the isolation of C. difficile in body sites other than the intestines, or extraintestinal infections, have been anecdotal (3,4). Extracolonic manifestations of C. difficile infections reported were variable, including bacteremia, osteomyelitis, visceral abscess, empyema, reactive arthritis, pyelonephritis, prosthetic joint infection, and skin and soft tissue infection (3–10). Most cases of extracolonic C. difficile infections have been preceded by gastrointestinal events, either C. difficile colitis or surgical and anatomic disruption of the colon (4).
Recently, Libby and Bearman reviewed the literature on bacteremia caused by C. difficile (6). Most cases were identified from individual case reports. However, as the incidence of C. difficile infection increases, an increase in cases of C. difficile bacteremia (CDB) is likely (10). Knowledge of the clinical signs and symptoms of these extracolonic manifestations of bloodstream infections will be useful in patient care and could improve clinical outcomes (4). To outline the spectrum and clinical significance of CDB, we report 12 cases of CDB over a recent 10-year period at 2 medical centers in Taiwan and review the literature published in English.
Patients with blood cultures positive for C. difficile at 2 teaching hospitals (National Cheng Kung University Hospital, a 1,100-bed tertiary care hospital in southern Taiwan and National Taiwan University Hospital, a 2,800-bed tertiary care hospital in northern Taiwan) during January 1989 through February 2009, were retrospectively identified from laboratory records, and their medical records were reviewed. If a patient experienced >1 episode of CDB, only information about the first episode was included. Information about age, sex, underlying diseases, clinical course, antimicrobial drug therapy, and clinical outcome was recorded in a case-record form.
We conducted a literature review to find relevant articles published between January 1, 1962, and August 31, 2009, by querying the PubMed database using the keywords “Clostridium difficile,” “bacteremia,” “sepsis,” and “bloodstream infection.” The references of available articles were surveyed for additional cases.
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).
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.
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).
A clear clinical picture of C. difficile bacteremia has been highlighted in this study: a rare extracolonic C. difficile infection with severe illness and high death rates in persons with chronic medical illness. However, the case-patients with CDB had several remarkable clinical characteristics, compared with those of patients with C. difficile–associated diarrhea. First, only 64% of 22 bacteremic C. difficile isolates had toxin A or B, the virulence factors of C. difficile–associated diarrhea. Second, bacteremic patients did not commonly have diarrhea before or at admission to the hospital, and in patients with CDB, a history of recent antimicrobial drug exposure (a common predisposing factor of C. difficile–associated diarrhea) was rarely recognized.
Because Clostridium species are inhabitants of the gastrointestinal tract, they compromise the integrity of the gastrointestinal tract and may lead to translocation with bacteremia. This translocation is supported by the fact that 75% of 32 patients had certain gastrointestinal symptoms or disorders, which may predispose to CDB either by direct extension through perforation or by promoting translocation of the organism across the intestinal wall (10). These findings are consistent with the literature, in which C. difficile bacteremia is typically associated with underlying gastrointestinal pathology and frequently occurs as a mixed infection with other gut flora (6,31,32).
Clostridium species have been shown to enhance the pathogenicity of other bacteria in mixed infections (10), and even monomicrobial Clostridium bacteremia has been associated with a high death rate in 2 previous series (10,33). Half of the patients in the current series had polymicrobial bacteremia. The portal of entry of Clostridium species in cirrhotic cases is usually obscure, and the gastrointestinal tract is the most likely source (34,35). Translocation of intestinal bacteria is the major mechanism for the production of bloodstream infection (34). In our study, all patients had >1 preexisting illness, and most (75%) experienced gastrointestinal diseases or conditions. Substantial damage to normal mucosal barriers may provide a portal for anaerobes (32,35), which suggests that patients with gastrointestinal disorders, such as gastrointestinal bleeding and perforation or advanced liver failure, would be susceptible to C. difficile bacteremia. Primary bacteremia accounted for more than half (17, 53.1%) of the 32 cases of CDB. The likelihood of undiagnosed C. difficile colitis in these patients seems to be minimal given the absence of diarrhea and radiographic manifestation of colitis shown on computed tomographic scan. Subsequently, the resultant monomicrobial bacteremia was likely secondary to bacterial translocation in the setting of immunologic deficiency from an overwhelming preexisting illness (2,6,31,36).
Antimicrobial drug therapy for bacteremia and other extracolonic C. difficile infections varies greatly in the literature (3,4) because most infections have been polymicrobial in nature, and antimicrobial therapy has been directed at all organisms (4,6). Thus, optimal therapy for monomicrobial C. difficile bacteremia remains undefined. Intravenous vancomycin or metronidazole was frequently used in cases of bacteremia with well-described treatment regimens. Inappropriate antibacterial therapy for anaerobes, in general, appears to have serious consequences for patients (32,35,37). Based on in vitro antimicrobial drug susceptibility data, metronidazole may be the drug of choice for C. difficile bacteremia, although vancomycin was also effective in our patients. Clinical experiences in treating severe C. difficile infections were limited and mainly focused on C. difficile–associated diarrhea (1,2,38).
CDB, although uncommon, can be observed in persons with chronic underlying illness or coexisting gastrointestinal illnesses and is associated with high death rates. In the present study, a major finding was that the survival rate among patients who received appropriate antimicrobial therapy (either metronidazole or vancomycin) was higher than that among patients who received inappropriate antimicrobial drug therapy. Although multiple factorial conditions contributed to the high death rates among patients with CDB, insufficient therapeutic coverage for C. difficile may have contributed to the deaths of the patients. Early treatment of CDB with metronidazole or vancomycin may be helpful.
Dr Lee is an infectious disease physician at National Cheng Kung University Hospital, Tainan, Taiwan. His research interests include antimicrobial drug resistance in clinical bacterial pathogens and the epidemiology and treatment of bloodstream infections.
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