3--hydroxy-5--(4-isobutylpiperazinyl)benzoxazinorifamycin and Enterocolitis--Pseudomembranous

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 (MIC(50)) and MIC(90) values of 0.0075 and 0.015 microg/ml, 0.0075 and 0.03 microg/ml, 0.06 and 0.125 microg/ml, 0.06 and 0.125 microg/ml, 0.125 and 0.125 microg/ml, respectively. However, for three isolates the rifalazil and rifaximin MICs were very high (MIC of >256 microg/ml). Ramoplanin, vancomycin, doripenem, and meropenem were also very active in vitro with narrow MIC(50) and MIC(90) 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.

Topics: Anti-Bacterial Agents; Bacterial Toxins; Clostridioides difficile; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Humans; Microbial Sensitivity Tests; United States

Although vancomycin and metronidazole effectively treat Clostridium difficile-associated diarrhea and colitis (CDAD), their use is associated with a high incidence of relapsing C. difficile infection. Rifalazil is a new benzoxazinorifamycin that possesses activity against Mycobacterium tuberculosis and gram-positive bacteria. Here we compared rifalazil and vancomycin for effectiveness in preventing or treating clindamycin-induced cecitis in a hamster model of CDAD. Golden Syrian hamsters were injected subcutaneously with clindamycin phosphate (10 mg/kg), followed 24 h later by C. difficile gavage. Hamsters received by gavage for 5 days vehicle, vancomycin (50 mg/kg), or rifalazil (20 mg/kg) either simultaneously with (prophylactic protocol) or 24 h after C. difficile administration (treatment protocol). While all vehicle-administered animals became moribund within 48 h of C. difficile administration, no rifalazil- or vancomycin-treated animals in either protocol showed signs of morbidity after 7 days. Ceca of rifalazil-treated animals showed absence of epithelial cell damage, significantly reduced congestion and edema, and less, but not statistically significantly less, neutrophil infiltration compared to those of vehicle-treated animals. In contrast, vancomycin-treated animals demonstrated severe epithelial cell damage and mildly reduced congestion and edema. Moreover, hamsters relapsed and tested C. difficile toxin positive (by enzyme-linked immunosorbent assay) 10 to 15 days after discontinuation of vancomycin treatment. None of the rifalazil-treated hamsters showed signs of disease or presence of toxins in their feces 30 days after discontinuation of treatment. Our results indicate that once daily rifalazil may be superior to vancomycin for curative treatment of CDAD.

Topics: Animals; Anti-Bacterial Agents; Cecum; Clostridioides difficile; Cricetinae; Diarrhea; Enterocolitis, Pseudomembranous; Enzyme-Linked Immunosorbent Assay; Mesocricetus; Microbial Sensitivity Tests; Rifamycins; Secondary Prevention; Survival Analysis; Vancomycin; Weight Loss