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Antimicrob Agents Chemother. Aug 2000; 44(8): 2222–2224.
PMCID: PMC90047
Note

In Vitro Activities of MK-826 (L-749,345) against 363 Strains of Anaerobic Bacteria

Abstract

The activity of MK-826 was compared to the activities of cefoxitin, ceftriaxone, imipenem, and meropenem against 363 gram-negative and gram-positive anaerobes by using NCCLS procedures. At least 98% of the strains were susceptible to the carbapenems. All strains of Clostridium perfringens, Fusobacterium nucleatum, Peptostreptococcus, and Sutterella wadsworthensis were susceptible to all agents tested.

Antimicrobial resistance in anaerobes has been found for virtually all classes of antimicrobial agents. Resistance to beta-lactams is generally due to the production of beta-lactamases; resistance to beta-lactam–beta-lactamase combinations, clindamycin, macrolides, tetracyclines, and 5-nitroimidazoles has also been seen (9). Imipenem resistance is generally due to metallo-beta-lactamase enzymes, which hydrolyze the antimicrobial agent (1, 3). MK-826 (ertapenem; formerly L-749,345) is a potent 1-beta-methyl carbapenem with a long half-life and a broad spectrum of activity (5). MK-826, like other carbapenems, exerts its activity by binding to penicillin-binding proteins and inhibiting cell wall synthesis; MK-826 showed high-affinity binding to the essential penicillin-binding proteins of Escherichia coli (7). MK-826 was shown to be very potent against extended-spectrum and broad-spectrum beta-lactamase-producing gram-negative pathogens (7). MK-826 has been evaluated against many aerobes (4, 5, 6), but its anti-anaerobic spectrum has not been evaluated. This study was designed to evaluate the efficacy of MK-826 and four comparative agents against anaerobic bacteria.

The bacteria included in this study were recent clinical isolates from the Greater Los Angeles Veterans Administration Healthcare Center. Bacteria were identified according to established procedures (10). MICs were determined by the NCCLS-approved Wadsworth agar dilution technique, using 105 CFU of inoculum per spot and brucella base–laked-blood agar (8). Plates were incubated in an anaerobic chamber (Anaerobe Systems, San Jose, Calif.) for 48 h at 37°C. MICs were defined as the lowest concentration of antimicrobial resulting in a marked change in the appearance of growth as compared to the control plate, as described in the NCCLS protocol. Reference strains of Bacteroides fragilis (ATCC 25285) and Bacteroides thetaiotaomicron (ATCC 29741) were used as controls in each test. Antimicrobial agents were obtained as powders from the following companies: cefoxitin, imipenem, and MK-826 (Merck, Rahway, N.J.), ceftriaxone (Sigma, St. Louis, Mo.), and meropenem (AstraZeneca, Wilmington, Del.).

For analysis, the bacteria tested were placed into species or genus groups with more than five isolates, and MIC ranges and the MICs at which 50 or 90% of the isolates were inhibited (MIC50 and MIC90) were determined (Table (Table1).1).

TABLE 1
Activity of MK-826 against anaerobic bacteria

B. fragilis strains were inhibited by all the carbapenems at ≤4 μg/ml. Cefoxitin inhibited 96% of strains at 16 μg/ml and 98% of strains at 32 μg/ml. Ceftriaxone was less active against these strains, inhibiting 42% at 16 μg/ml and 70% at 32 μg/ml. A similar pattern was seen with other B. fragilis group species: all strains were inhibited by the carbapenems at ≤8 μg/ml, and cefoxitin and ceftriaxone inhibited 97 and 44%, respectively, at 32 μg/ml. For the B. fragilis group species other than B. fragilis, MK-826 tended to have higher MICs for B. thetaiotaomicron (60% of MICs were ≥1 μg/ml) than for the other species (16% of MICs were ≥1 μg/ml).

Bilophila wadsworthia, a recently described gram-negative anaerobe, was the third most common anaerobe isolated from cases of perforated or gangrenous appendicitis (2). All the agents tested inhibited all strains of Bilophila wadsworthia; the carbapenems had MIC90s of 0.12 μg/ml or less. Prevotella and Porphyromonas species were also very susceptible to the carbapenem agents, with MIC90s ranging from 0.062 to 0.25 μg/ml. There was very little difference in carbapenem MICs between different species of Porphyromonas and Prevotella. Prevotella bivia and Prevotella buccae were more resistant to ceftriaxone than the other Prevotella species tested. Ceftriaxone had MICs of 64 μg/ml for one strain each of Prevotella buccae and Prevotella bivia; the MICs of cefoxitin for these strains were 2 and 1 μg/ml, respectively. Ceftriaxone had MICs of 32 μg/ml for an additional three strains of these two species and an MIC of 256 μg/ml for one strain of Porphyromonas gingivalis (the cefoxitin MIC was 4 μg/ml). Campylobacter gracilis was inhibited by the carbapenems at ≤0.5 μg/ml and by cefoxitin at ≤16 μg/ml. One strain of Campylobacter gracilis was resistant to ceftriaxone. Sutterella wadsworthensis, a gram-negative anaerobic rod described in 1996 (11), is found in more than 10% of intraabdominal specimens. S. wadsworthensis, Fusobacterium nucleatum, and other Fusobacterium species were all susceptible to all of the agents tested (other than Fusobacterium mortiferum and ceftriaxone). MICs of the carbapenems did not vary significantly among the different species of Fusobacterium tested. Five strains of F. mortiferum were resistant to ≥128 μg of ceftriaxone/ml; additionally, cefoxitin MICs tended to be two twofold dilutions lower for F. necrophorum than for the F. mortiferum/varium group.

Clostridium difficile was inhibited by all of the carbapenems at ≤8 μg/ml. At 4 μg/ml, 100, 94, and 53% of strains, respectively, were susceptible to meropenem, imipenem, and MK-826. The variation among the agents may be significant, or it may be a function of the MICs clustering at breakpoint concentrations (since all strains were susceptible at 8 μg/ml). Neither cefoxitin nor ceftriaxone was very active against C. difficile. All strains of Clostridium perfringens were inhibited by all agents at ≤1 μg/ml, except for three strains of C. perfringens for which ceftriaxone had MICs of 2, 4, and 8 μg/ml. One strain of Clostridium ramosum was resistant to ceftriaxone; all strains were susceptible to the carbapenems at ≤2 μg/ml.

All of the gram-positive cocci tested were susceptible to all of the agents at ≤4 μg/ml. Among the gram-positive non-spore-forming rods, two strains were resistant to ceftriaxone; all other strains were susceptible to the agents tested (to the carbapenems at ≤2 μg/ml and to cefoxitin at ≤16 μg/ml).

Carbapenems are generally stable to most beta-lactamases, although imipenem resistance has been observed in a number of B. fragilis isolates in Japan (up to 6%) and is usually attributed to imipenem-hydrolyzing metallo-beta-lactamases (1) (coded for by the cfiA gene [12]). The resistance is most often attributed to degradation by this enzyme, but there may be other mechanisms which are also important (3).

The carbapenem MK-826 appears to have excellent activity against anaerobic bacteria (with the possible exception of C. difficile), as do the other carbapenem agents. Clinical studies are needed to assess the clinical utility of this agent in infections involving anaerobes.

Acknowledgments

This study was funded in part by Greater Los Angeles Veterans Administration Medical Center research funds and in part by Merck Sharp and Dohme (Rahway, N.J.).

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