Reassessment of Clostridium difficile Susceptibility to Metronidazole and Vancomycin

Abstract

Clostridium difficile is the most frequently identified enteric pathogen in patients with nosocomially acquired, antibiotic-associated diarrhea. The drugs most commonly used to treat diseases associated with C. difficile are metronidazole and vancomycin. Most clinical laboratories assume that all C. difficile isolates are susceptible to metronidazole and vancomycin. We report on the antimicrobial susceptibilities of 415 C. difficile isolates to metronidazole and vancomycin over an 8-year period (1993 to 2000). The overall rate of resistance to metronidazole at the critical breakpoint (16 g/ml) was 6.3%. Although full resistance to vancomycin was not observed, the overall rate of intermediate resistance was 3.1%. One isolate had a combination of resistance to metronidazole and intermediate resistance to vancomycin. Rates of resistance to metronidazole and vancomycin were higher among isolates from human immunodeficiency virus-infected patients. Molecular typing methods proved the absence of clonality among the isolates with decreased susceptibilities to the antimicrobials tested.Clostridium difficile-associated diarrhea (CDAD) is the most common nosocomial diarrhea in adults, occurring mainly in patients with prior antimicrobial therapy. The disease has variable incidences and severities in different hospital populations (2,6,22,25,27,38) The most serious cases of CDAD require antimicrobial therapy with agents which are active against C. difficile. Metronidazole is the drug of choice due to its in vitro activity, its efficacy by either the oral or the intravenous route of administration, its presumed lower potential for selection of vancomycin-resistant Enterococcus (VRE), and the low cost of treatment with the drug. Nowadays, vancomycin is considered a second-line drug, mainly due to the potential for the selection of VRE and its high cost. Both drugs are considered equivalent in efficacy, but infection recurrence rates of 15 to 35% have been reported for both drugs (3, 7).In vitro determination of the susceptibility of C. difficile to these antibiotics is not routinely performed, as it is broadly accepted that C. difficile is regularly and predictably susceptible to metronidazole and vancomycin. The assay method is timeconsuming, and the use of susceptibility breakpoints is based on the therapeutic levels of drugs in serum and not on the levels in the intraluminal area, where higher drug concentrations can be achieved (1,19). At present, metronidazole resistance in C. difficile is considered anecdotal and vancomycin resistance has been, to the best of our knowledge, reported only once (16), although on that occasion the method used was not the present standard.In 1994, we sounded the alarm when we reported on the first series of metronidazole-resistant C. difficile isolates (T. Peláez, R. Sánchez, R. Blázquez, P. Catalán, P. Muñoz, and E. Bouza, Abstr. 34th. Intersci. Conf. Antimicrob. Agents Chemother., abstr. E-34, p. 50, 1994). The aim of the present study is to report on the decrease in the rates of suscept...

Laboratory diagnosis of Clostridium difficile-associated diarrhoea: a plea for culture

“…Both are of crucial interest in the clinical management of individual cases and hospital outbreaks. Typing allows clonal strains to be traced and recognition of specific virulent groups (Brazier, 2001), whereas susceptibility testing might become mandatory in the future since the observation of the emergence of strains with a decreased susceptibility to vancomycin or metronidazole (Pelaez et al, 2002;Barbut et al, 1999). …”

Alternative treatments for Clostridium difficile disease: what really works?

“…A study from Spain documented metronidazole resistance in 6 . 3 % of C. difficile strains over an 8-year period (Pelaez et al, 2002). Intolerance is also a problem as some patients cannot take metronidazole due to side effects including metallic taste, nausea, an antabuse effect and rare cases of neurotoxic complications (Beloosesky et al, 2000).…”

“…In addition, such regimes may aid restoration of the normal microflora. One concern, particularly for pulsed dosing, is that such treatment may encourage antibiotic-resistant strains of C. difficile to develop (Sanchez et al, 1999;Pelaez et al, 2002).…”

In Vitro Activity of OPT-80 against Clostridium difficile

“…First-line antimicrobials for the treatment of CDAD are metronidazole and vancomycin. Meanwhile, diminished susceptibility was observed for both substances (1,4,8,12); however, this was not directly linked to treatment failures. On the other hand, as many as 20% of patients had at least one recurrence of CDAD after the initial therapy was discontinued (3).…”