1 Merck Research Laboratories, Rahway, NJ; 2 R. M. Alden Research Laboratory, Santa Monica, CA; 3 Merck Research Laboratories, BL 3-4, PO Box 4, West Point, PA 19846-0004, USA
Received 14 March 2002; returned 11 July 2002; revised 6 August 2002; accepted 12 August 2002
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Abstract |
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Introduction |
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The objectives of this study were to assess the in vitro activity of ertapenem against aerobic and anaerobic bacterial pathogens isolated from patients with acute pelvic infection enrolled in the clinical trial and to compare the activity of ertapenem with agents that may be used to treat acute pelvic infection as single-agent or combination therapy.
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Materials and methods |
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Antimicrobial agents were obtained from their respective US manufacturers: ertapenem and cefoxitin from Merck; amoxicillin, ticarcillin and clavulanate from SmithKline Beecham; ceftriaxone from Hoffman-LaRoche; piperacillin and tazobactam from Lederle/Wyeth-Ayerst; ciprofloxacin from Bayer Pharmaceuticals; oxacillin from Bristol-Myers Squibb; ampicillin and sulbactam from Pfizer; clindamycin from Pharmacia Upjohn; metronidazole from Searle Research & Development; and penicillin G and chloramphenicol from Sigma Chemical. For testing aerobic bacteria, stock solutions of ertapenem were prepared in 10 mM 3-(N-morpholino)propanesulphonic acid (MOPS) buffer, pH 7. The remaining agents were solubilized in M/15 Sorensens phosphate buffer, pH 7, at 1.0 mg base/mL. Stock solutions were filter-sterilized and diluted in the appropriate medium. For testing anaerobes, antimicrobial agents were reconstituted according to the manufacturers directions. Serial two-fold dilutions of various concentrations of the drugs were prepared on the day of testing and added to supplemented (as above) brucella agar. Ampicillinsulbactam was in a fixed ratio of 2:1; ticarcillin was serially diluted and combined with clavulanate, tested at a constant concentration of 2 mg/L; and piperacillin was serially diluted and combined with tazobactam, which was tested at a constant concentration of 4 mg/L.
Antimicrobial susceptibility of aerobic bacteria was evaluated by broth microdilution, using microtitre trays prepared in-house, according to NCCLS guidelines.6 Trays were inoculated using a Dynatech MIC-2000 Inoculator (Dynex Technologies, Chantilly, VA, USA). To ensure an appropriate inoculum density, bacterial concentrations in the growth control wells of randomly selected isolates were assayed. Anaerobes were tested by agar dilution according to NCCLS guidelines.7 Supplemented brucella agar plates were prepared with dilutions of each of the test antimicrobial agents and inoculated with 105 colony forming units per spot, using a Steers replicator (Craft Machine, Chester, PA, USA), and incubated in an anaerobic chamber at 37°C for 44 h. The MIC was defined as the lowest concentration of an agent that yielded no growth or a marked reduction in growth compared with the growth control. When testing aerobic and anaerobic bacteria, standard quality control strains were included with each test run.
Interpretive MIC breakpoints (in mg/L) for ertapenem are 2 for susceptible, 4 for intermediate and
8 for resistant for Enterobacteriaceae and staphylococci; and
4 for susceptible, 8 for intermediate and
16 for resistant for anaerobes. For ß-haemolytic streptococci, the breakpoint for susceptible is
1 mg/L. There are no proposed breakpoints for ertapenem against enterococci, as there are none defined for other carbapenems, or non-fermentative Gram-negative bacilli, because the drug is not indicated for treatment of infections caused by these organisms.
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Results and discussion |
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The antimicrobial activities of ertapenem and comparator agents against the aerobic and anaerobic bacteria tested are summarized in Tables 1 and 2, respectively. Ertapenem was the most active agent against Enterobacteriaceae and had the most potent activity, based on values for inhibition of 50% (MIC50) and 90% (MIC90) of the isolates. All isolates of Enterobacteriaceae were susceptible to ertapenem, compared with 99% for ciprofloxacin and ceftriaxone, 87% for piperacillintazobactam and 79% for co-amoxiclav. All antimicrobials had excellent activity against streptococci and methicillin-susceptible Staphylococcus aureus (MSSA). Ertapenem had the most potent activity against MSSA on a per-weight basis. As expected, ertapenem, ceftriaxone and co-amoxiclav had minimal activity against P. aeruginosa, as did ertapenem and ceftriaxone against enterococci.
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The acute pelvic infections in this clinical trial were usually polymicrobial, with causal pathogens representing the normal vaginal flora: Streptococcus agalactiae, E. coli, peptostreptococci, Prevotella spp. and Bacteroides spp., as has been reported by others.810 In this in vitro study, ertapenem was the most active of the agents evaluated against the broad array of pathogens isolated. As anticipated, ertapenem had minimal activity against the unusual isolates of non-fermentative Gram-negative bacilli and the more frequently encountered enterococci. However, although commonly isolated in polymicrobial acute pelvic infections, enterococci are generally considered of low pathogenicity compared with other pyogenic organisms in mixed infections.11 In the present clinical trial, all patients with acute pelvic infection whose cultures grew enterococci and who were treated with ertapenem were cured, thus substantiating the lack of virulence of enterococci in these infections.3
In summary, ertapenem was highly active in vitro against many aerobic and anaerobic bacterial pathogens recovered from patients with acute pelvic infection. Ertapenem was more active than piperacillintazobactam, ceftriaxone, ciprofloxacin and co-amoxiclav against Enterobacteriaceae and more active than piperacillintazobactam, ceftriaxone, ticarcillinclavulanate, ampicillinsulbactam, metronidazole, cefoxitin, clindamycin and chloramphenicol against anaerobes, which were the most frequent pathogens.
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Acknowledgements |
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Footnotes |
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References |
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2
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Livermore, D. M., Carter, M. W., Bagel, S., Wiedemann, B., Baquero, F., Loza, E. et al. (2001). In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia. Antimicrobial Agents and Chemotherapy 45, 18607.
3 . Roy, S., Higareda, I., Angel-Muller, E., Ismail, M., Deyi, B., Hague, C. et al. (2001). Results of a phase III randomized, double-blind study of ertapenem vs piperacillin-tazobactam for acute pelvic infection in women. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract L-888, p. 456. American Society for Microbiology, Washington, DC, USA.
4 . Summanen, P., Baron, E. J., Citron, D. M., Strong, C. A., Wexler, H. M. & Finegold, S. M. (1993). Wadsworth Anaerobic Bacteriology Manual, 5th edn. Star Publishing, Belmont, CA, USA.
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6 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: NCCLS Document M7-A5. NCCLS, Wayne, PA, USA.
7 . National Committee for Clinical Laboratory Standards. (2001). Methods for Antimicrobial Susceptibility Testing of Anaerobic BacteriaFifth Edition: Approved Standard M11-A5. NCCLS, Wayne, PA, USA.
8 . Crombleholme, W. R., Ohm-Smith, M., Robbie, M. O., DeKay, V. & Sweet, R. L. (1987). Ampicillin/sulbactam versus metronidazole-gentamicin in the treatment of soft tissue pelvic infections. American Journal of Obstetrics and Gynecology 156, 50712.[ISI][Medline]
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