Association of Relapse of Clostridium difficile Disease with BI/NAP1/027

Abstract

bRecurrent Clostridium difficile infection (CDI) occurs in up to 35% of patients. Recurrences can be due to either relapse with the same strain or reinfection with another strain. In this study, multilocus variable-number tandem-repeat analysis (MLVA) was performed on C. difficile isolates from patients with recurrent CDI to distinguish relapse from reinfection. In addition, univariate and multivariate analyses were performed to identify risk factors associated with relapse. Among patients with a single recurrence, relapse due to the original infecting strain was more prevalent than reinfection and the interval between episodes was shorter than among patients who had reinfections. Among patients with >1 recurrence, equal distributions of relapse and reinfection or a combination of the two episode types were observed. Initial infection with the BI/NAP1/027 epidemic clone was found to be a significant risk factor for relapse. This finding may have important implications for patient therapy. Classification of recurrent CDI episodes by MLVA can be utilized to make informed patient care decisions and to accurately define new CDI cases for infection control and reimbursement purposes. One of the most problematic aspects of Clostridium difficile infections (CDI) is the propensity of recurrence in 15% to 35% of patients who initially respond to antimicrobial therapy. In addition, recurrent CDI is difficult to treat and contributes to significant morbidity and mortality and increased health care expenditures (10,11,27).The molecular epidemiology of CDI has changed since 2000 with the global spread of an epidemic clone, designated BI/NAP1/ 027 by restriction endonuclease analysis (REA), pulsed-field gel electrophoresis, and PCR ribotyping. However, recent studies have raised doubts regarding the role of BI/NAP1/027 in increased CDI incidence, severity, and recurrence rates (4, 21).Recurrent CDI can caused by either relapse due to the original infecting strain or reinfection with a new strain. Previous studies have demonstrated that continued non-CDI antibiotic treatment and a failed immune response to C. difficile toxins A and B are risk factors for recurrent CDI (15,20,25). Most recently, lower cure rates and higher rates of recurrence due to BI/NAP1/027 infection were reported in phase 3 clinical trials of fidaxomicin (26). Recent estimates suggest that 65% to 88% of recurrent CDI is attributable to relapse with the original infecting strain (2, 3, 12). However, some of the molecular typing methods used in these studies such as PCR-ribotyping and random amplification of polymorphic DNAs (RAPD) lack sufficient discriminatory power and may have misclassified reinfections as relapses. In a study using restriction endonuclease analysis (REA), 83.3% of recurrences were due to relapse (8). In this study, multilocus variable-number tandemrepeat analysis (MLVA), a highly discriminatory C. difficile genotyping method, was used to define relapse in patients with recurrent CDI and to identify risk factors associated with relapse. ...

Practical Guidance for Clinical Microbiology Laboratories: Diagnosis of Bacterial Gastroenteritis

“…At the time, this change in severity of CDI was attributed to the "hypervirulent" nature of the NAP1/027/B1 strain. NAP1/027/B1 has since become the predominant strain in many locations, and it continues to be associated with high mortality and relapse rates (77). Early studies pointed to heightened toxin expression (78), more efficient sporulation (79,80), expression of the binary toxin, and fluoroquinolone resistance (75) as reasons for the epidemiological success of this strain.…”

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

“…This correlates with hospital-specific reports dating back to 2000, where many of the outbreaks were found to have been caused by a NAP1/BI/027 strain and an unexpectedly high mortality rate alerted clinicians to a possible change in CDI epidemiology. In addition, a recent study at the University of Pittsburgh found that patients initially infected by NAP1/BI/027 strains were more likely to relapse than patients infected with other strains of C. difficile (172). Thus, the clinical and surveillance evidence from the past decade shows that an increased frequency of 027 ribotypes correlates with increased mortality.…”

Hypervirulent Clostridium difficile ribotypes are CpG depleted

“…This includes all available full-length sequences from the hypervirulent ribotypes 027 and 078 (n = 15) and all available full-length sequences from the non-hypervirulent ribotype 012 (n = 6). Differences in transmission rates, ability to cause epidemics, toxin production, sporulation and antimicrobial resistance has been documented across C.difficile ribotypes [10,11]; nonetheless, only ribotypes 027 and 078 have been designated as “hypervirulent” based on several factors including increased morbidity and mortality associated with CDI by these ribotypes [1,12,13]. In addition, most studies investigating the mechanisms underlying hypervirulence use ribotype 012 as the reference, representing non-hypervirulent or “typical” strains.…”