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Antimicrobial Agents and Chemotherapy, November 2004, p . 4430-4434, Vol . 48, No . 11
Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species
Kim L . Credito and
Peter C . Appelbaum*
Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania
Received 16 June 2004/
Returned for modification 22 July 2004/
Accepted 26 July 2004
Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes . OPT-80 was active against gram-positive strains only, especially Clostridium spp . (85 strains tested, including 21 strains of C . difficile), with MICs ranging between
 0.016 and 0.25 µg/ml .
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 .
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FIG . 1 . Structure of OPT-80.
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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 –70°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 ranging between
0.016 and 0.25 µg/ml . For the 21 C . difficile strains, 12 required MICs of
0.016 µg/ml, 1 required an MIC of 0.03 µg/ml, 4 required MICs of 0.06 µg/ml, 3 required MICs of 0.125 µg/ml, and 1 required an MIC of 0.25 µg/ml . Against gram-positive non-spore-forming rods and peptostreptococci, OPT-80 MICs were higher, ranging between
0.016 and 16.0 µg/ml . Gram-positive anaerobes for which OPT-80 MICs were
 4.0 µg/ml comprised the Propionibacterium acnes species as well as lactobacilli; lactobacilli also required higher linezolid, vancomycin, teicoplanin, and quinupristin/dalfopristin MICs . Linezolid, vancomycin, teicoplanin, and quinupristin/dalfopristin were (with the exception of the latter) active mainly against gram-positive anaerobes, while amoxicillin/clavulanate and imipenem were active against both groups . Some Bacteroides fragilis group strains and clostridia (notably C . difficile) were clindamycin resistant, while all strains except gram-positive non-spore-forming rods were susceptible to metronidazole . Results with other agents reflect previously published findings (5) .
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TABLE 1 . MICs (µg/ml) of agents
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OPT-80 (tiacumicin B) is a member of a novel group of 18-membered macrocyclic antibiotics with in vitro activity against pathogenic gram-positive bacteria and selected anaerobes, notably C . difficile (1, 14, 15) . Previous studies testing tiacumicin B and C have demonstrated MICs against C . difficile of between 0.125 and 0.25 µg/ml . The resistance frequency was <2.9 x 10–8 at four and eight times the MIC, and both compounds at oral doses of 0.2, 1, or 5 mg per kg of body weight protected 100% of clindamycin-treated hamsters exposed to C . difficile (14) . In the present study, MICs of OPT-80 against C . difficile were lower than those reported by Swanson and colleagues (14) . In a recent study (1), Ackermann and colleagues reported MICs a few dilutions lower than ours against 207 strains of C . difficile and a more limited number of other gram-positive and gram-negative anaerobic species . The MIC differences in the these three studies may be due to methodology (agar dilution MICs in Wilkins Chalgren agar in the work of Swanson et al . [14], microdilution MICs in Wilkins-Chalgren medium in the work of Ackermann et al . [1], and agar dilution using enriched Brucella blood agar medium in our work) . Additionally, Ackermann et al . (1) tested dilutions lower than was the case in our study . Although the MIC distribution for C . difficile differs somewhat in these three studies, all MICs were <0.5 µg/ml . We have no explanation for the species-related MIC differences of OPT-80 among anaerobic gram-positive cocci .
Results of this study suggest a potential place for OPT-80 in oral treatment of clostridial infections, especially pseudomembranous colitis caused by C . difficile toxin . Pharmacokinetic-pharmacodynamic and additional experimental animal studies are necessary to further delineate the clinical role of these compounds in treatment of anaerobic infections .
This study was supported by a grant from Optimer Pharmaceuticals, Inc., San Diego, Calif .
* Corresponding author . Mailing address: Department of Pathology, Hershey Medical Center, P.O . Box 850, Hershey, PA 17033 . Phone: (717) 531-5113 . Fax: (717) 531-7953 . E-mail: pappelbaum{at}psu.edu .
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