Abstract
Doripenem was evaluated against 527 recent clinical isolates, i.e., 404 Bacteroides fragilis isolates and 123 gram-positive anaerobe isolates. Against B. fragilis, doripenem was as active as imipenem, meropenem, and piperacillin-tazobactam and more active than ertapenem or ampicillin-sulbactam. Doripenem was active against isolates resistant to ertapenem, ampicillin-sulbactam, cefoxitin, clindamycin, and moxifloxacin. All of the gram-positive isolates tested were susceptible to doripenem.
The carbapenems currently in clinical use (imipenem, meropenem, ertapenem, and most recently doripenem) are the most active in vitro agents against members of the Bacteroides fragilis group (2, 11-13). Doripenem is a new carbapenem resistant to hydrolysis by dehydropeptidase 1 that shows a broad spectrum of activity against bacterial pathogens (1, 3, 5, 7-9, 14). The new carbapenem has been approved for clinical use in the treatment of complicated intraabdominal and urinary tract infections (Doribax package insert; Johnson & Johnson). Previous reports of its in vitro activity indicate that the new agent has good activity against members of the B. fragilis group and other anaerobic bacteria. However, none of these publications represents a large collection of B. fragilis group isolates illustrating the national susceptibility trends among the species of the B. fragilis group (3, 5, 7, 11-14). We evaluated the in vitro activity of doripenem against a large number of recent clinical anaerobic isolates and compared its activity with that of other agents by using CLSI (Clinical and Laboratory Standards Institute [formerly the National Committee for Clinical Laboratory Standards])-recommended procedures (10).
Included in this evaluation were 404 B. fragilis group and 123 gram-positive anaerobic bacterial isolates. The B. fragilis group isolates are part of a collection referred by medical centers in the United States (11-13). We tested 16 isolates of B. caccae, 15 isolates of B. distasonis, 198 isolates of B. fragilis, 35 isolates of B. ovatus, 78 isolates of B. thetaiotaomicron, 21 isolates of B. uniformis, and 31 isolates of B. vulgatus, as well as 5 isolates of B. eggerthii, 1 isolate of B. merdae, 1 isolate of B. nordii, and 3 isolates of other species pending identification. Multidrug-resistant strains were included in the testing. The gram-positive anaerobic isolates were referred by the clinical laboratory at New England Medical Center and included 41 Clostridium, 51 gram-positive coccus, and 31 Propionibacterium isolates. Some strains resistant to vancomycin and/or other antibiotics were included.
Confirmation of the identification of the isolates was done by following the manufacturer's instructions for rapid methodology (API 20A). When identification was not conclusive, the methods outlined in the Wadsworth Anaerobic Bacteriology Manual and/or in the Anaerobic Laboratory Manual of Virginia Polytechnic Institute were used (4, 6).
The antimicrobials tested against the B. fragilis group isolates were doripenem, ertapenem, imipenem, meropenem, ampicillin-sulbactam, piperacillin-tazobactam, cefoxitin, clindamycin, moxifloxacin, and metronidazole. The susceptibilities of the gram-positive isolates were tested against the agents listed above plus linezolid and vancomycin. The following standard powders were provided by their respective manufacturers: doripenem, Johnson & Johnson, Raritan, NJ; ertapenem, imipenem, and cefoxitin, Merck & Company, West Point, PA; meropenem, Astra-Zeneca Pharmaceuticals, Wilmington, DE; piperacillin and tazobactam, Wyeth-Ayerst Research, Pearl River, NY; ampicillin, sulbactam, and linezolid, Pfizer, Inc., New York, NY; moxifloxacin, Bayer Pharmaceuticals, West Haven, CT. Metronidazole and clindamycin were purchased from the Sigma Chemical Co., St. Louis, MO. The powders were solubilized by following the manufacturers' specifications. Frozen aliquots were stored at −70°C until the day of use.
MICs were determined by the agar dilution method by following CLSI recommendations (10). The organisms were grown to logarithmic phase, and their turbidity was adjusted to a 0.5 McFarland standard (∼108 CFU/ml). The antibiotic-containing plates were prepared on the day of the test. The medium used was enriched brucella agar (brucella agar supplemented with 5% [vol/vol] lysed, defibrinated sheep red blood cells and 1 μg/ml vitamin K1). A Steers replicator was used to deliver ∼105 CFU/spot to the surface of the agar. The plates were incubated in an anaerobic chamber at 37°C for 48 h. The MICs were read as the lowest concentration of drug that resulted in a marked change in growth compared to the control plate (10). B. fragilis ATCC 25285 and B. thetaiotaomicron ATCC 29741 were used as controls when testing the B. fragilis group isolates. Eubacterium lentum ATCC 43055 was the control versus the gram-positive isolates. Tests were repeated when the MICs for the control(s) were outside the CLSI-specified range. The rates of resistance of the antimicrobial agents were determined by using CLSI-recommended breakpoints for anaerobes (10).
Table 1 summarizes the results of the evaluation of doripenem and comparative agents versus 404 isolates of the B. fragilis group. Among the carbapenems, doripenem was as active as imipenem and meropenem and more active (two- to fourfold) than ertapenem. Only three isolates of B. fragilis were nonsusceptible to doripenem (MIC = 16 μg/ml) (see footnotes b to Tables 1 and 2). Two of these isolates were resistant to all β-lactams, clindamycin, and moxifloxacin. Doripenem showed activity similar to that of piperacillin-tazobactam but was more active than ampicillin-sulbactam. The new agent was also considerably more active than cefoxitin, clindamycin, and moxifloxacin. All B. fragilis group isolates were susceptible to metronidazole at concentrations of ≤2 μg/ml (data not shown).
TABLE 1.
Activities of doripenem and comparative agents versus 404 B. fragilis group isolatesf
| Species (no. of isolates), % of total, and antibiotic(s) | MIC range | MIC50d | MIC90e | % Resistanta,b |
|---|---|---|---|---|
| B. caccae (16), 4.0 | ||||
| Doripenem | 0.25-4 | 0.5 | 2 | 0 |
| Ertapenem | 0.25-8 | 0.5 | 2 | 0 |
| Imipenem | 0.125-4 | 0.5 | 2 | 0 |
| Meropenem | 0.125-4 | 0.25 | 2 | 0 |
| Ampicillin-sulbactam | 2-16 | 4 | 16 | 0 |
| Piperacillin-tazobactam | 0.5-8 | 1 | 8 | 0 |
| Cefoxitin | 4-128 | 16 | 32 | 6.3 |
| Clindamycin | 0.5-128 | 1 | 128 | 31.3 |
| Moxifloxacin | 0.5-32 | 4 | 16 | 50.0 |
| B. distasonis (15), 3.7 | ||||
| Doripenem | 0.125-2 | 0.5 | 2 | 0 |
| Ertapenem | 0.25-8 | 1 | 4 | 0 |
| Imipenem | 0.125-8 | 0.25 | 2 | 0 |
| Meropenem | 0.25-8 | 1 | 2 | 0 |
| Ampicillin-sulbactam | 0.5-32 | 8 | 16 | 6.7 |
| Piperacillin-tazobactam | 0.25-16 | 4 | 16 | 0 |
| Cefoxitin | 4-256 | 16 | 32 | 6.7 |
| Clindamycin | 0.5-128 | 1 | 128 | 13.3 |
| Moxifloxacin | 0.5-16 | 8 | 16 | 53.3 |
| B. fragilis (198), 49.0 | ||||
| Doripenem | 0.125-16 | 0.5 | 1 | 1.5 |
| Ertapenem | 0.25-16 | 0.5 | 2 | 2 |
| Imipenem | 0.125-16 | 0.5 | 1 | 1 |
| Meropenem | 0.125-16 | 0.25 | 1 | 1.5 |
| Ampicillin-sulbactam | 0.25-128 | 4 | 16 | 4.5 |
| Piperacillin-tazobactam | 0.25-512 | 1 | 2 | 1 |
| Cefoxitin | 2-128 | 16 | 32 | 3 |
| Clindamycin | 0.5-128 | 0.5 | 128 | 29.3 |
| Moxifloxacin | 0.25-64 | 1 | 8 | 29.3 |
| B. ovatus (35), 8.7 | ||||
| Doripenem | 0.25-4 | 0.5 | 2 | 0 |
| Ertapenem | 0.25-16 | 1 | 4 | 2.9 |
| Imipenem | 0.125-4 | 0.5 | 2 | 0 |
| Meropenem | 0.125-4 | 0.5 | 2 | 0 |
| Ampicillin-sulbactam | 1-64 | 4 | 32 | 11.4 |
| Piperacillin-tazobactam | 0.5-32 | 4 | 8 | 0 |
| Cefoxitin | 8-64 | 16 | 64 | 14.3 |
| Clindamycin | 0.5-128 | 2 | 128 | 42.9 |
| Moxifloxacin | 1-32 | 2 | 32 | 40.0 |
| B. thetaiotaomicron (78), 19.3 | ||||
| Doripenem | 0.125-8 | 0.5 | 1 | 0 |
| Ertapenem | 0.125-8 | 2 | 4 | 0 |
| Imipenem | 0.125-8 | 1 | 2 | 0 |
| Meropenem | 0.125-8 | 0.5 | 2 | 0 |
| Ampicillin-sulbactam | 1-64 | 4 | 16 | 3.8 |
| Piperacillin-tazobactam | 0.5-512 | 8 | 32 | 1.3 |
| Cefoxitin | 4-128 | 32 | 64 | 10.3 |
| Clindamycin | 0.5-128 | 2 | 128 | 34.6 |
| Moxifloxacin | 0.5-64 | 4 | 32 | 30.8 |
| B. uniformis (21), 5.2 | ||||
| Doripenem | 0.125-1 | 0.5 | 1 | 0 |
| Ertapenem | 0.125-2 | 0.5 | 2 | 0 |
| Imipenem | 0.25-1 | 1 | 1 | 0 |
| Meropenem | 0.125-2 | 0.25 | 0.5 | 0 |
| Ampicillin-sulbactam | 1-16 | 4 | 16 | 0 |
| Piperacillin-tazobactam | 0.5-16 | 2 | 8 | 0 |
| Cefoxitin | 4-64 | 16 | 64 | 9.5 |
| Clindamycin | 0.5-128 | 2 | 128 | 3.8 |
| Moxifloxacin | 1-64 | 4 | 64 | 14.3 |
| B. vulgatus (31), 7.7 | ||||
| Doripenem | 0.125-2 | 0.5 | 2 | 0 |
| Ertapenem | 0.125-4 | 0.5 | 2 | 0 |
| Imipenem | 0.25-2 | 1 | 2 | 0 |
| Meropenem | 0.25-4 | 0.5 | 2 | 0 |
| Ampicillin-sulbactam | 2-32 | 8 | 16 | 0 |
| Piperacillin-tazobactam | 0.5-16 | 2 | 16 | 0 |
| Cefoxitin | 2-64 | 8 | 32 | 3.2 |
| Clindamycin | 0.5-128 | 0.5 | 128 | 32.3 |
| Moxifloxacin | 0.25-128 | 8 | 64 | 48.4 |
| Other speciesc (10), 2.30 | ||||
| Doripenem | 0.25-1 | 0.5 | 1 | 0 |
| Ertapenem | 0.5-4 | 1 | 2 | 0 |
| Imipenem | 0.25-2 | 0.5 | 1 | 0 |
| Meropenem | 0.125-4 | 0.25 | 1 | 0 |
| Ampicillin-sulbactam | 2-16 | 4 | 16 | 0 |
| Piperacillin-tazobactam | 0.5-16 | 4 | 8 | 0 |
| Cefoxitin | 8-32 | 16 | 32 | 0 |
| Clindamycin | 0.5-128 | 1 | 8 | 20.0 |
| Moxifloxacin | 0.5-32 | 2 | 16 | 40.0 |
The breakpoints for resistance are those recommended by CLSI and are as follows: for ertapenem, imipenem, and meropenem, 16 μg/ml; piperacillin-tazobactam, 128 μg/ml; ampicillin-sulbactam, 32 μg/ml; cefoxitin, 64 μg/ml; clindamycin and moxifloxacin, 8 μg/ml.
CLSI does not have susceptibility breakpoints for doripenem. The FDA recommends a susceptibility breakpoint only of <1 μg/ml. Therefore, the listed percentage for doripenem represents only those isolates with MICs of >16 μg/ml.
Includes five isolates of B. eggerthii, one isolate of B. merdae, one isolate of B. nordii, and three isolates of species not identified.
MIC50, MIC for 50% of the strains tested.
MIC90, MIC for 90% of the strains tested.
All MIC values are in micrograms per milliliter.
TABLE 2.
Activities of doripenem and comparative agents versus 123 gram-positive anaerobic bacteriag
| Species (no. of isolates) and antibiotic(s) | MIC range | MIC50e | MIC90f | % Resistanta,b |
|---|---|---|---|---|
| C. difficile (9) | ||||
| Doripenem | 1-2 | |||
| Ertapenem | 2-8 | |||
| Imipenem | 2-32 | |||
| Meropenem | 1-2 | |||
| Ampicillin-sulbactam | 4-16 | |||
| Piperacillin-tazobactam | 2-16 | |||
| Cefoxitin | 8->128 | |||
| Clindamycin | 1-32 | |||
| Moxifloxacin | 2-64 | |||
| Vancomycin | 1-4 | |||
| Linezolid | 1-2 | |||
| Metronidazole | 0.5-2 | |||
| C. perfringens (13) | ||||
| Doripenem | 0.06-0.125 | 0.06 | 0.125 | 0 |
| Ertapenem | 0.06-0.25 | 0.06 | 0.25 | 0 |
| Imipenem | 0.25-4 | 0.5 | 0.5 | 0 |
| Meropenem | 0.06-0.125 | 0.06 | 0.125 | 0 |
| Ampicillin-sulbactam | 0.25-4 | 1 | 2 | 0 |
| Piperacillin-tazobactam | 0.5-4 | 0.5 | 4 | 0 |
| Cefoxitin | 1-8 | 1 | 4 | 0 |
| Clindamycin | 0.125-4 | 0.25 | 2 | 0 |
| Moxifloxacin | 0.5-1 | 0.5 | 1 | 0 |
| Vancomycin | 1-16 | 1 | 2 | 0 |
| Linezolid | 2-4 | 2 | 4 | 0 |
| Metronidazole | 0.5-32 | 2 | 4 | 7.8 |
| Clostridium sp.c (19) | ||||
| Doripenem | 0.06-8 | 1 | 2 | 0 |
| Ertapenem | 0.06-8 | 4 | 8 | 0 |
| Imipenem | 0.06-16 | 2 | 2 | 16.7 |
| Meropenem | 0.06-8 | 2 | 2 | 0 |
| Ampicillin-sulbactam | 0.25->128 | 0.5 | 8 | 5.6 |
| Piperacillin-tazobactam | 0.5->256 | 2 | 16 | 5.6 |
| Cefoxitin | 1->128 | 64 | >128 | 55.6 |
| Clindamycin | 0.125-32 | 2 | 32 | 22.2 |
| Moxifloxacin | 0.5-4 | 1 | 2 | 0 |
| Vancomycin | 1-16 | 8 | 16 | 0 |
| Linezolid | 1-8 | 4 | 8 | 11.0 |
| Metronidazole | 0.5-32 | 2 | 2 | 5.6 |
| Finegoldia magna (10) | ||||
| Doripenem | 0.06-0.125 | 0.125 | 0.125 | 0 |
| Ertapenem | 0.06-0.125 | 0.125 | 0.125 | 0 |
| Imipenem | 0.125-0.25 | 0.25 | 0.25 | 0 |
| Meropenem | 0.06-0.25 | 0.125 | 0.125 | 0 |
| Ampicillin-sulbactam | 0.5-8 | 2 | 2 | 0 |
| Piperacillin-tazobactam | 0.5-0.5 | 0.5 | 0.5 | 0 |
| Cefoxitin | 1-1 | 1 | 1 | 0 |
| Clindamycin | 0.25-32 | 0.5 | 32 | 20.0 |
| Moxifloxacin | 0.25-64 | 4 | 32 | 40.0 |
| Vancomycin | 0.5-1 | 1 | 1 | 0 |
| Linezolid | 2-2 | 2 | 2 | 0 |
| Metronidazole | 0.5-0.5 | 0.5 | 0.5 | 0 |
| Anaerobic gram-positive coccid (41) | ||||
| Doripenem | 0.06-2 | 0.06 | 0.5 | 0 |
| Ertapenem | 0.06-4 | 0.125 | 0.5 | 0 |
| Imipenem | 0.06-1 | 0.125 | 0.5 | 0 |
| Meropenem | 0.06-4 | 0.125 | 0.5 | 0 |
| Ampicillin-sulbactam | 0.25-8 | 0.5 | 2 | 0 |
| Piperacillin-tazobactam | 0.5-32 | 0.5 | 0.5 | 0 |
| Cefoxitin | 1-8 | 1 | 4 | 0 |
| Clindamycin | 0.125-32 | 0.25 | 32 | 12.2 |
| Moxifloxacin | 0.06-32 | 0.5 | 16 | 14.8 |
| Vancomycin | 0.25-64 | 1 | 2 | 2.4 |
| Linezolid | 0.25-4 | 1 | 2 | 0 |
| Metronidazole | 0.5-32 | 1 | 32 | 34.1 |
| Propionibacterium acnes (18) | ||||
| Doripenem | 0.06-0.06 | 0.06 | 0.06 | 0 |
| Ertapenem | 0.06-0.06 | 0.06 | 0.06 | 0 |
| Imipenem | 0.06-0.125 | 0.06 | 0.06 | 0 |
| Meropenem | 0.06-0.06 | 0.06 | 0.06 | 0 |
| Ampicillin-sulbactam | 0.25-0.5 | 0.25 | 0.5 | 0 |
| Piperacillin-tazobactam | 0.25-0.5 | 0.25 | 0.5 | 0 |
| Cefoxitin | 1-1 | 1 | 1 | 0 |
| Clindamycin | 0.25-32 | 0.25 | 0.5 | 5.6 |
| Moxifloxacin | 0.125-4 | 0.25 | 0.5 | 0 |
| Vancomycin | 1-2 | 1 | 1 | 0 |
| Linezolid | 0.5-2 | 0.5 | 1 | 0 |
| Metronidazole | 16-32 | 32 | 32 | 94.4 |
| Propionibacterium sp. (13) | ||||
| Doripenem | 0.06-0.06 | 0.06 | 0.06 | 0 |
| Ertapenem | 0.06-0.25 | 0.06 | 0.25 | 0 |
| Imipenem | 0.06-0.25 | 0.06 | 0.25 | 0 |
| Meropenem | 0.06-0.25 | 0.06 | 0.25 | 0 |
| Ampicillin-sulbactam | 0.06-0.25 | 0.25 | 0.5 | 0 |
| Piperacillin-tazobactam | 0.25-1 | 0.25 | 0.5 | 0 |
| Cefoxitin | 1-1 | 1 | 1 | 0 |
| Clindamycin | 0.25-32 | 0.25 | 2 | 7.7 |
| Moxifloxacin | 0.25-4 | 0.25 | 0.5 | 0 |
| Vancomycin | 1-1 | 1 | 1 | 0 |
| Linezolid | 0.5-1 | 0.5 | 0.5 | 0 |
| Metronidazole | 8-32 | 32 | 32 | 92.3 |
The breakpoints used are those recommended by CLSI and are as follows: for ertapenem, imipenem, and meropenem, 16 μg/ml; ampicillin-sulbactam, 32 μg/ml; piperacillin-tazobactam, 128 μg/ml; cefoxitin, 64 μg/ml; clindamycin and moxifloxacin, 8 μg/ml.
CLSI does not have susceptibility breakpoints for doripenem. The FDA recommends a susceptibility breakpoint only of <1 μg/ml. Therefore, the listed percentage for doripenem represents only those isolates with MICs of >16 μg/ml. The resistance breakpoints for vancomycin (>32 μg/ml) and linezolid (>8 μg/ml) are CLSI recommendations for aerobic gram-positive bacteria.
Includes four isolates of C. innocuum, one isolate of C. paraputrificum, one isolate of C. subterminale, and one isolate of C. tertium.
Includes 3 isolates of Peptoniphilus asaccharolyticus, 5 isolates of Micromonas micros, 1 isolate of Anaerococcus prevotii, and 32 isolates of Peptostreptococcus sp.
MIC50, MIC for 50% of the strains tested.
MIC90, MIC for 90% of the strains tested.
All MIC values are in micrograms per milliliter.
Table 2 illustrates the activity of doripenem versus gram-positive anaerobic isolates. Doripenem and meropenem were the most active carbapenems against Clostridium difficile (MIC range, 1 to 2 μg/ml). Ampicillin-sulbactam, piperacillin-tazobactam, vancomycin, linezolid, and metronidazole showed good activity versus C. difficile. As expected, most of the C. difficile isolates were resistant to cefoxitin and more than half of the isolates were also resistant to imipenem. Doripenem, ertapenem, and meropenem were very active against C. perfringens, with MICs of ≤0.125 μg/ml. A multiresistant Clostridium sp. isolate showed an elevated MIC of 8 μg/ml versus doripenem, imipenem, ertapenem, and meropenem. With the exception of moxifloxacin, this isolate was resistant to all of the other agents included in the evaluation.
Doripenem and the other carbapenems were active versus all 41 gram-positive anaerobic cocci (MIC, 0.5 μg/ml), including strains that were resistant to metronidazole, vancomycin, moxifloxacin, and clindamycin. All 10 Finegoldia magna (previously Peptostreptococcus magnus) isolates were susceptible to doripenem and to all of the other comparative agents, excepting 4 isolates that were resistant to moxifloxacin and 2 isolates that were resistant to clindamycin.
All Propionibacterium sp. isolates, including 18 P. acnes isolates, were susceptible to doripenem and the comparative agents, with the exception of metronidazole.
Our results agree with those of Wexler et al. (14), who evaluated the activity of doripenem versus 150 isolates of the B. fragilis group. Conversely, Goldstein et al. (3) reported lower MICs when testing 25 isolates of this group. This difference could be explained by epidemiologic factors (center and/or body site), as well as the number of isolates tested.
Given the increasing resistance of B. fragilis to routinely used antibiotics and the frequent isolation of anaerobic gram-positive pathogens, our results indicate that doripenem, with its broad spectrum of activity against aerobic and anaerobic bacteria, could be a good therapeutic choice for the treatment of mixed infections.
Acknowledgments
This study was funded in part by a grant from Johnson & Johnson Research and Development Institute.
Footnotes
Published ahead of print on 6 October 2008.
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