We thank Manabe and colleagues [1] for their careful examination of the diagnostic aspects of C. difficile diarrhea. Although the case definition required a positive toxin assay result, the sensitivity of a single cytotoxin assay was only 79%. Using different case criteria, other investigators have found the sensitivity of cytotoxin assay to range from 67% to 74% [2].

Manabe and coworkers report that diagnostic sensitivity may be increased by obtaining two to three serial stool specimens for cytotoxin assay. However, Aronsson and colleagues [3] reported that additional specimens increase the rate of detection by only 10%. We suggest the combination of cytotoxin assay and toxigenic culture of the initial specimen as a useful alternative solution to this problem [2] that prevents the need for submitting multiple specimens. If the result of the direct cytotoxin assay is negative and C. difficile is identified on selective medium, the isolate should be tested for elaboration of cytotoxin in vitro. Confirmation of toxigenicity is important because nontoxigenic C. difficile strains are not pathogenic. The addition of culture improves the sensitivity of laboratory diagnosis to as high as 96% [2] and permits strain typing of individual isolates. The latter facilitates recognition of outbreaks of nosocomial infection [4].

We have found this combined diagnostic approach to be convenient, efficient, cost-effective, and reasonably rapid (cytotoxin assays may be completed in 24 hours; toxigenic cultures, in 4 to 5 days). At the University of Colorado, 41 of 120 culture-confirmed cases of C. difficile diarrhea were cytotoxin negative during a 12-month period. Similarly, at Northwestern University's Memorial Hospital, 61 of 160 cases detected during a 6-month period were cytotoxin negative. Because we and others [5] have seen patients who have this disorder but no positive result on direct-stool cytotoxin assay progress to pancolitis or even death, clinicians must recognize the limited sensitivity of cytotoxin assays and the potential utility of culture for the diagnosis of C. difficile diarrhea.