Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK
Keywords: C. difficile , infections , treatment
Sir,
Treatment of Clostridium difficile infection (CDI) has changed little since the recognition of the disease in the late 1970s. Currently accepted treatment options are essentially limited to oral metronidazole or vancomycin, ideally following withdrawal of the precipitating antimicrobial. Metronidazole is currently preferred due to its perceived clinical equivalence to vancomycin, in terms of overall response and rates of symptomatic recurrences, and lower cost.1 However, recent reports of poor clinical outcome following metronidazole therapy for CDI2,3 have prompted closer scrutiny of the treatment options and raised the issue of potential for emergence of resistance in C. difficile to metronidazole and vancomycin.
We compared the activity of metronidazole and vancomycin against selected C. difficile isolates from symptomatic patients (n = 74) and their environment (n = 71) over a 6 year period (19952001) at the Leeds General Infirmary. Isolates were fingerprinted by RAPD and RS-PCR as described previously.4 We examined 37 UK epidemic clonal isolates (PCR ribotype 00Iconfirmed by J. S. Brazier, Anaerobe Reference Unit) from the period 199596 (20 from patients and 17 from the hospital environment) and 28 isolates from the period 200001 (19 from patients and 9 from the hospital environment). Isolates were selected on the basis of date (at least one patient and one environmental isolate per calendar month were available). All (n = 49) non-epidemic C. difficile isolates recovered from patients (n = 4) or the hospital environment (n = 45) between 1995 and 2001 were examined (16 RAPD types). We also examined the antibiotic susceptibility of 31 UK epidemic clonal C. difficile isolates (PCR ribotype I) recovered sequentially from 13 patients with CDI; two isolates from each of nine patients, three isolates from each of three patients and four isolates from one patient. MICs were determined by agar incorporation. Briefly, following culture in pre-reduced Schaedlers anaerobic broth (Oxoid, UK) at 37°C for 48 h, strains were multipoint inoculated (104 cfu per spot) onto Wilkins-Chalgren agar (Oxoid, UK) and then cultured anaerobically for 48 h. Bacteroides fragilis NCTC 9343 and Staphylococcus aureus NCTC 6571 were used as control organisms.
MICs of metronidazole and vancomycin for UK epidemic clonal (199596 and 200001), non-epidemic and sequential epidemic clonal C. difficile isolates are shown in Table 1. There was little variation in the MICs of either metronidazole or vancomycin, and with one exception all strains were susceptible. The MICs of metronidazole and vancomycin for the UK epidemic strain from both 199596 and 200001 were 0.251 mg/L and 0.51 mg/L, respectively. The solitary, non-toxigenic C. difficile strain showing reduced susceptibility to metronidazole (MIC; 8 mg/L) was isolated from an environmental swab collected towards the beginning of this study period (April 1996).5 This strain was never isolated again, either from patients or the hospital environment, and thus is of doubtful clinical significance. The MICs of metronidazole and vancomycin for isolates recovered from recurrent CDI episodes had MICs essentially the same (within one doubling dilution) as for those from initial symptomatic episodes. Thus, symptomatic recurrences were not associated with reduced susceptibility of C. difficile to either metronidazole or vancomycin. Although we tested limited numbers of patients and isolates associated with treatment failure, we believe this represents the largest number of strains examined from such cases. Sanchez et al. had similar conclusions based on testing isolates from patients in whom metronidazole treatment failed (14 patients out of 632 CDI episodes).6 The MIC (mean ± SD) of metronidazole failure-associated C. difficile isolates (n = 10) was very similar to the MIC of isolates from metronidazole success cases (0.23 ± 0.21 versus 0.29 ± 0.19 mg/L; P = 0.4).
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Our results suggest that resistance to metronidazole or vancomycin remains very uncommon, whether in primary or recurrent CDI settings. Decreased susceptibility of the organism to either agent is unlikely to be the cause of symptomatic recurrence or treatment failure in CDI. Therapeutic failures may occur as a result of other factors, such as poor faecal concentrations of metronidazole, suboptimal host immune response or possibly spore recrudescence.10 However, particularly as the treatment options for CDI are limited, continued vigilance for the emergence of resistance to metronidazole or vancomycin is warranted.
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