Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species

Abstract

Clostridium difficile is a leading cause of antibiotic-associated diarrhea, especially in hospitals and long-term facilities (8,11,12). The organism accounts for about 20% of hospitalized patients who develop diarrhea after treatment with anti-infectives (and occasionally cytotoxic chemotherapeutic agents) and the majority of cases of antibiotic-associated colitis (3,7,10,17). The rising incidence of C. difficile-associated diarrhea has been attributed to the increasingly common prescription of broad-spectrum antibiotics (16). It is also important to note that the etiology of pseudomembranous colitis appears to be multifactorial and not dependent only on the in vitro activity of an agent against C. difficile (17).Initial treatment involves discontinuation of the offending medication, as well as supportive therapy, but antimicrobial therapy is necessary if these measures fail to alleviate the symptoms (7, 10). The two most commonly used antimicrobial therapies are vancomycin and metronidazole, and while both are effective in treating the infection, both have shortcomings, including high (approximately 20%) relapse rates (6). In addition, metronidazole may have significant side effects, including nausea, neuropathy, leukopenia, and seizures (6, 18), while widespread use of vancomycin may lead to increased vancomycin resistance in enterococci and staphylococci (2, 4). The above-described shortcomings have necessitated a search for new therapeutic options for this disease.OPT-80 (Fig. 1) is a novel macrocycle which is inactive against gram-negative organisms with moderate activity against gram-positive organisms, such as staphylococci and enterococci, but excellent activity against clostridia. This study compares the in vitro activity of OPT-80 to those of linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/ clavulanate, imipenem, clindamycin, and metronidazole against 350 anaerobes.All anaerobes were clinical strains identified by standard procedures (9) and kept frozen in double-strength skim milk (dehydrated skim milk: Difco Laboratories, Detroit, Mich.) at Ϫ70°C until use. All organisms, including the 21 C. difficile strains, were separate isolates and not clonally related. Prior to testing, strains were subcultured twice onto enriched Brucella agar plates (13). OPT-80 was obtained from Optimer Pharmaceuticals, Inc., San Diego, Calif., and other drugs were obtained from respective manufacturers. Agar dilution susceptibility testing was carried out according to the latest method recommended by the NCCLS (13), using Brucella agar with 5% sterile defibrinated laked sheep blood. Clavulanate was combined with amoxicillin in a 1:2 ratio. All quality-control gram-negative and -positive strains recommended by NCCLS (13) were included with each run: in every case, results (where available) were in range.Results of MIC testing are presented in Table 1. As can be seen, OPT-80 was active only against gram-positive anaerobes, especially against Clostridium species (including C. difficile), with MICs ra...

Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile

“…The narrow antimicrobial spectrum of activity of fidaxomicin has been well established by several studies; however, there are no data on the killing kinetics of the compound and its major metabolite (Ackermann et al, 2004;Credito & Appelbaum, 2004;Finegold et al, 2004). This study investigated the killing rate of both fidaxomicin and OP-1118 in comparison with vancomycin in wild-type hypervirulent strains, as well as in laboratory-derived strains with reduced susceptibility to fidaxomicin.…”

“…Fidaxomicin (formerly OPT-80 and PAR-101) is a novel, narrow-spectrum antibiotic in development for the treatment of C. difficile infection (Ackermann et al, 2004;Credito & Appelbaum, 2004;Finegold et al, 2004). The putative target for fidaxomicin is the RNA polymerase (Talpaert et al, 1975).…”

Novel Riboswitch-Binding Flavin Analog That Protects Mice against Clostridium difficile Infection without Inhibiting Cecal Flora

“…The broad-spectrum antibacterial activities of metronidazole and vancomycin are thought to contribute to recurrence by preventing the regrowth of healthy intestinal flora (29)(30)(31)(32)(33). A newer treatment, fidaxomicin, has a narrower spectrum of activity than vancomycin or metronidazole (34)(35)(36) and causes less alteration to the intestinal flora of CDI patients (32,33). Consistent with this narrower spectrum of activity, multiple clinical trials have demonstrated a lower rate of CDI recurrence after treatment with fidaxomicin than after vancomycin or metronidazole treatment (37,38).…”

Safety and efficacy of fidaxomicin in the treatment of Clostridium difficile-associated diarrhea

“…The molecular structure of fidaxomicin is shown in Figure 1. In vitro, fidaxomicin is bacteriocidal against many species of Clostridia and all types of C. difficile compared with vancomycin, which is bacteriostatic [Ackermann et al 2004;Credito and Appelbaum, 2004;Finegold et al 2004;Karlowsky et al 2008;Hecht et al 2007]. In vitro, fidaxomicin kills organisms more rapidly with a prolonged postantibiotic effect (5.5-10 h) compared with vancomycin (0-1.5 h) Biedenbach et al 2010].…”

“…[Louie et al 2011]. The Minimum Inhibitory Concentration required to inhibit the growth of 90% of organisms (MIC 90 ) of fidaxomicin against C. difficile ranges between 0.0078 and 0.25 µg/ml [Ackermann et al 2004;Credito and Appelbaum, 2004;Finegold et al 2004]. Fidaxomicin is poorly active against gramnegative organisms, Bacteroides spp.…”