In Vitro Activities of 15 Antimicrobial Agents against 110 Toxigenic Clostridium difficile Clinical Isolates Collected from 1983 to 2004

Abstract

The incidence and severity of Clostridium difficile-associated disease (CDAD) is increasing, and standard treatment is not always effective. Therefore, more-effective antimicrobial agents and treatment strategies are needed. We used the agar dilution method to determine the in vitro susceptibility of the following antimicrobials against 110 toxigenic clinical isolates of C. difficile from 1983 to 2004, primarily from the United States: doripenem, meropenem, gatifloxacin, levofloxacin, moxifloxacin, OPT-80, ramoplanin, rifalazil, rifaximin, nitazoxanide, tizoxanide, tigecycline, vancomycin, tinidazole, and metronidazole. Included among the isolates tested were six strains of the toxinotype III, NAP1/BI/027 group implicated in recent U.S., Canadian, and European outbreaks. The most active agents in vitro were rifaximin, rifalazil, tizoxanide, nitazoxanide, and OPT-80 with MICs at which 50% of the isolates are inhibited (MIC50) and MIC90 values of 0.0075 and 0.015 μg/ml, 0.0075 and 0.03 μg/ml, 0.06 and 0.125 μg/ml, 0.06 and 0.125 μg/ml, 0.125 and 0.125 μg/ml, respectively. However, for three isolates the rifalazil and rifaximin MICs were very high (MIC of >256 μg/ml). Ramoplanin, vancomycin, doripenem, and meropenem were also very active in vitro with narrow MIC50 and MIC90 ranges. None of the isolates were resistant to metronidazole, the only agent for which there are breakpoints, with tinidazole showing nearly identical results. These in vitro susceptibility results are encouraging and support continued evaluation of selected antimicrobials in clinical trials of treatment for CDAD.

Clinical update for the diagnosis and treatment ofClostridium difficileinfection

“…Testing of rifalazil against 110 isolates of C. difficile collected from 1983-2004 revealed excellent activity with an MIC 90 of 0.03 μg/mL, with only one isolate from the United States found to be resistant [82] . In a study of C. difficile in the hamster model, all animals treated with rifalazil or vancomycin were protected from disease.…”

“…Aspevall et al [81] studied 238 isolates of C. difficile collected from 2000 to 2001 and found no evidence of resistance to metronidazole or vancomycin. Hecht et al [82] studied 110 strains collected between 1983 and 2004. All strains were sensitive to metronidazole at less than or equal to 0.5 μg/mL.…”

“…In such a situation, the authors propose the use of Ringer's Lactate, which contains a lower concentration of chloride [71] . Tigecycline is a broad-spectrum glycylcycline antibiotic with reportedly low MIC values against C. difficile, along with evidence that it does not promote growth or toxin production in both a mouse and human model [82,129,130] . To date no clinical trials have been performed on the use of tigecycline; however, several case reports have reported the successful use of Ⅳ tigecycline in severe or severe complicated CDI in which patients failed prior treatment with metronidazole and vancomycin [131] .…”

A Review of Doripenem for the Treatment of Serious Bacterial Infections

“…44,47,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] The MIC 90 for species of interest are usually #1 µg/mL ( 75,76 Likewise, in 69 P. aeruginosa isolates from South Wales, doripenem activity was similar to meropenem and superior to imipenem. 77 As part of the 2006 to 2008 Tracking Resistance in the United States Today (TRUST) surveillance study, among 7 antimicrobials tested, doripenem and meropenem showed the lowest MIC 50/90 values against 3111 P. aeruginosa isolates from either intensive care unit infections or hospitaltreated lower respiratory infections.…”

“…84 Doripenem shares the broad antibacterial potency against aerobic and anaerobic Gram-positive and Gram-negative bacteria that is seen for the carbapenem class, yet there are differences among the carbapenems. 44,47,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] A key difference is that doripenem generally exhibits 2-to 4-fold greater activity vs. Pseudomonas isolates than imipenem and meropenem, including strains isolated from patients with cystic fibrosis.…”