Literature Commentary by Dr. John G. Bartlett: Clostridium difficile, January 2008

John G. Bartlett, MD


January 08, 2008

Hubert B, Loo VG, Bourgault AM, et al. A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec. Clin Infect Dis. 2007;44:238-344.
The study investigators provide an analysis of the epidemic of Clostridium difficile in Quebec.

Background: Several studies in Quebec and more recently in the United States have called attention to increasing rates of C difficile that have been attributed to the NAP1, ribotype 027 and group B1 strain.[1,2,3] This strain was found to produce large quantities of toxins A and B to possibly account for increased virulence, and was highly resistant to fluoroquinolones, which may contribute to the increased rate of infections.[4] The present study was designed to address some of the issues associated with the epidemiology of the NAP1 strain, antibiotic-sensitivity test results, virulence factors, and outcome.

Methods: In February 2005, 88 acute-care hospitals in Quebec contributed 15 consecutive stool samples from patients with nosocomial C difficile diarrhea as proven with a positive toxin assay. For each isolate, there was accompanying clinical data relevant to the case. The strains were tested for in-vitro activity by various antibiotics. Pulsed-field gel electrophoresis (PFGE) was done to characterize the strains, and they were analyzed for binary toxin and deletions in the tcdC gene, which modulates toxin production in C difficile.

Results: PFGE typing was performed on 478 clinical isolates. The predominant strain was a lineage I, which consists of 16 pulsovars that showed 67% relatedness. The predominant pulsovar was A, which accounted for 274 isolates or 56% of the total strains collected. This strain corresponds to the NAP1 strain that has been found in other epidemics and which is resistant to gatifloxacin, is sensitive to clindamycin, and has the tcdC deletion. The second most common strain was from lineage III, which includes 5 pulsovars with 81% relatedness. The predominant pulsovars were B and B1; these correspond to the NAP2 strain, which is resistant to clindamycin and gatifloxacin and does not have the tcdC deletion. These results are summarized in Table 1 .

In terms of incidence, Table 2 provides an analysis of clonal type correlated with various hospitals, number of cases, and case rates. This shows the predominance of pulsovar A, which was found in 24 of 29 hospitals in the Montreal area. Pulsovar B/B1 was found in 7 of 8 hospitals in the area of Quebec City. It is noted that the incidence of disease expressed per 10,000 person-days was significantly increased with clone A and clone B, but was greater with clone A. In regard to the tcdC deletion, there was 100% correlation with binary toxin, and this was correlated with mortality with a relative risk (RR) of 1.7 when it was present and a RR of 2.1 for severe disease. These data are summarized in Table 2 .

Conclusions: The study investigators concluded that the presence of binary toxin genes was closely associated with tcdC deletions and that this factor makes it complicated to ascribe virulence to either to the exclusion of the other. They noted the "plasticity" of the C difficile genome with mutations in the tcdA and tcdB genes, and also call attention to the severity of disease that is found with the NAP1 strain. An additional conclusion is that stools should be cultured for C difficile because this permits typing to determine clonal dominance and antibiotic susceptibility and analysis of virulence factors. Finally, their study showed widespread dissemination of the NAP1 strain in Quebec in 2005, which involved multiple hospitals and was associated with a substantial incidence and severe disease.

Comment: This is quite an extraordinary review. It required participation of 88 hospitals in Quebec and showed a regional outbreak of C difficile in which the predominant strain was NAP1, characterized by the presence of the binary toxin of unknown importance and tcdA and tcdB deletions, which may account for increased toxin production because these downregulate that process. The authors plead for stool culture for C difficile, but it should be noted that this is rarely done by laboratories in the United States and would substantially increase the cost of C difficile evaluation. In fact, in the absence of epidemic disease, it is not certain that the increased cost is merited because the management of individual cases would not be affected on the basis of strain type. Also, the antibiotic history is perhaps most useful in terms of determining the inducing agent that may require better control of antibiotic usage.


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