opt-80 and Enterocolitis--Pseudomembranous

Clostridium difficile-associated diarrhoea has become a major problem over the last years. Increasing incidence and more severe clinical cases initiated the search for new treatment options.. OPT-80, also known as tiacumicin B, lipiarmycin or PAR-101, is a macrocyclic antimicrobial with little or no systemic absorption after oral administration and narrow activity spectrum against Gram-positive aerobic and anaerobic bacteria.. Data on OPT-80 available from published studies, presentations at conferences and the manufacturer were collected and reviewed.. The in vitro studies of OPT-80 and clinical C. difficile strains showed high activity at low concentrations. Safety and efficacy of the drug were found to be favourable. More Phase II and III clinical trials are to be completed.

Topics: Animals; Anti-Infective Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Glycosides; Humans; Microbial Sensitivity Tests; Molecular Structure; Treatment Outcome

Optimer Pharmaceuticals Inc, in collaboration with Par Pharmaceutical Companies Inc, is developing OPT-80, a narrow-spectrum macrocyclic antibiotic secreted by the actinomycete Dactylosporangium aurantiacum, for the potential treatment of Clostridium difficile-associated diarrhea (CDAD) and vancomycin-resistant Enterococcus infection. A phase IIb/III clinical trial of OPT-80 in patients with CDAD is underway.

Topics: Animals; Anti-Bacterial Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Clostridioides difficile; Diarrhea; Drug Evaluation, Preclinical; Enterocolitis, Pseudomembranous; Glycosides; Humans

Clostridium difficile infection (CDI) has been increasing in incidence and severity in recent years, coincident with the spread of a "hypervirulent" strain, REA type BI (ribotype 027, PFGE NAP 1). Exacerbating the problem has been the observation that metronidazole may be showing decreased effectiveness, particularly in the more severe cases. Fidaxomicin is an 18-membered macrocycle currently in phase 3 trials for the treatment of C. difficile infection (CDI). An open-label, phase II study in CDI patients has been completed and the clinical results published. C. difficile organisms were isolated from patient stool specimens and typed by restriction endonuclease analysis (REA) in order to determine the frequency and susceptibility of the C. difficile isolates and their response to treatment.. Fecal samples were plated on CCFA agar for isolation of C. difficile. These isolates were tested for susceptibility to fidaxomicin, vancomycin, and metronidazole using CLSI agar dilution methods and were typed by REA.. C. difficile was isolated from 38 of 49 subjects and 16 (42%) were the epidemic C. difficile BI group. The BI strain was distributed approximately equally in the three dosing groups. Overall antibiotic susceptibilities were consistent with the previously reported MIC(90) values for the three antibiotics tested, but the MIC(90) of BI strains was two dilutions higher than non-BI strains for metronidazole and vancomycin (for both antibiotics, MIC(90) was 2 microg/mL vs. 0.5 microg/mL, P<0.01 for metronidazole, P=NS for vancomycin). Clinical cure for BI isolates (11/14, 79%) was not significantly different from non-BI isolates (21/22, 95%).. These results underscore the high prevalence of the BI epidemic strain and demonstrate that mild to moderate CDI infection as well as severe disease can be caused by these strains. Fidaxomicin cure rates for subjects with BI and with non-BI strains are similar, although the small numbers of subjects preclude a robust statistical comparison.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; Clostridioides difficile; DNA Restriction Enzymes; Dose-Response Relationship, Drug; Enterocolitis, Pseudomembranous; Feces; Glycosides; Humans; Microbial Sensitivity Tests; Prohibitins; Ribotyping; Treatment Outcome

Current therapies for Clostridium difficile infection (CDI) are encumbered by treatment failures and recurrences. Due to its high in vitro activity against C. difficile but low activity against the typical intestinal flora, minimal absorption, and durable cure in the hamster model of C. difficile infection, OPT-80 was considered for clinical development as a therapy for CDI. This trial consisted of two phases. Four single oral doses of OPT-80 (100, 200, 300, and 450 mg) were administered in a crossover manner to 16 healthy volunteers in a double-blind, placebo-controlled phase 1A study; a 1- to 2-week washout interval separated the treatments. In the double-blind phase 1B study, 24 healthy subjects were randomized to receive OPT-80 (150, 300, or 450 mg) or placebo for 10 days. In both studies, OPT-80's safety and tolerability were evaluated and the concentrations of OPT-80 and its primary metabolite (OP-1118) in plasma and feces were determined. OPT-80 levels in the urine were also analyzed for the phase 1A study. In both the single-dose and the multiple-dose studies, OPT-80 was well tolerated by all subjects in all dose groups. Maximal plasma concentrations were near or below the limit of quantification (5 ng/ml) across the dose range; urine concentrations were below the detection limit. The fecal total recovery of OPT-80 plus its major metabolite, OP-1118, approximated 100%. The tolerability, high fecal concentration, and low systemic exposure data from these studies support the further clinical development of OPT-80 as an oral therapy for CDI.

Topics: Anti-Infective Agents; Clostridioides difficile; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enterocolitis, Pseudomembranous; Feces; Glycosides; Healthy Volunteers; Humans; Treatment Outcome

The effects of the inoculum, pH, cation concentrations, and different lots of commercial media on the in vitro susceptibility of Clostridium difficile to fidaxomicin were examined. Of the factors evaluated, only pH alterations influenced the activity of fidaxomicin against C. difficile, noticeably reducing its activity at higher pH (> or =7.9).

Topics: Agar; Aminoglycosides; Anti-Bacterial Agents; Cations; Clostridioides difficile; Colony Count, Microbial; Culture Media; Enterocolitis, Pseudomembranous; Fidaxomicin; Glycosides; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Microbial Sensitivity Tests

Agar dilution antimicrobial susceptibility testing (CLSI, M11-A7, 2007) performed for 208 toxin-producing clinical isolates of Clostridium difficile resulted in OPT-80 MICs ranging from 0.06 to 1 microg/ml, with 90% of the isolates inhibited by a concentration of 0.5 microg/ml. The in vitro activity of OPT-80 was independent of the susceptibilities of isolates to nine other antimicrobial agents.

Topics: Anti-Bacterial Agents; Bacterial Toxins; Clostridioides difficile; Cross Infection; Enterocolitis, Pseudomembranous; Glycosides; Humans; In Vitro Techniques; Microbial Sensitivity Tests