JAC Advance Access originally published online on October 8, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 735-741
© 2002 The British Society for Antimicrobial Chemotherapy
Comparative in vitro activities of ertapenem against bacterial pathogens from patients with acute pelvic infection
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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This study compared the in vitro activities of ertapenem, ceftriaxone, co-amoxiclav, ciprofloxacin and piperacillin–tazobactam against 314 aerobic bacteria and of ertapenem, piperacillin–tazobactam, cefoxitin, ceftriaxone, chloramphenicol, ticarcillin–clavulanate, ampicillin–sulbactam, clindamycin and metronidazole against 500 anaerobic bacteria from 212 patients with acute pelvic infection. Antimicrobial susceptibilities were determined by broth microdilution (aerobes) or agar dilution (anaerobes), following NCCLS guidelines. The most common isolates were Enterobacteriaceae and Peptostreptococcus spp. Ertapenem was the most active drug tested against Enterobacteriaceae (100% susceptible) and anaerobes (99.8% susceptible); the least active agents were co-amoxiclav (79% of Enterobacteriaceae susceptible) and ceftriaxone (85.9% of anaerobes susceptible). All agents tested had excellent activity against ß-haemolytic streptococci and methicillin-susceptible Staphylococcus aureus.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Ertapenem (formerly MK-0826, Merck & Co.) is a once-a-day parenteral ß-lactam antimicrobial agent licensed in the USA in November 2001 and in Europe in May 2002. This structurally unique carbapenem has a focused spectrum of activity in that it is highly active against many Gram-positive and Gram-negative aerobic, facultative and anaerobic bacteria that are generally associated with community-acquired infections but has minimal activity against Pseudomonas aeruginosa, Acinetobacter spp. and enterococci,1,2 which are more often associated with nosocomial infection. Given this spectrum of activity, a large double-blind clinical trial was conducted to assess the efficacy of ertapenem in the treatment of moderate to severe acute pelvic infection.3 These infections typically contain a mixture of aerobic and anaerobic bacteria against which ertapenem is highly active in vitro.
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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Aerobic and anaerobic bacteria isolated from a specimen from the site of pelvic infection collected at surgery or with a protected sampling device or from the bloodstream of patients with acute pelvic infection were identified using standard procedures.4,5 Isolates of aerobic bacteria were shipped to Merck Research Laboratories (Rahway, NJ, USA) on trypticase soy or chocolate agar slants at room temperature or were frozen at –70°C and shipped on dry ice. For anaerobic culture, specimens of pus or tissue were placed in anaerobic transport tubes (Anaerobe Systems, Morgan Hill, CA, USA) and sent via express delivery services to the R. M. Alden Research Laboratory (Santa Monica, CA, USA), where they were processed in an anaerobic chamber, plated on selective and non-selective anaerobic agar media and incubated at 35°C in the anaerobic chamber for at least 5 days before examination. After identification, aerobes were stored in 15% skimmed milk or in 2x concentrated trypticase soy broth with 15% glycerol/50% horse serum, and anaerobes were stored in skimmed milk, both at –70°C. Before antimicrobial susceptibility testing, cultures were thawed and subcultured twice on sheep blood or chocolate agar plates (aerobes) or brucella agar supplemented with haemin, vitamin K and 5% sheep blood (anaerobes).
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 Sorensen’s 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. Ampicillin–sulbactam 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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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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After excluding duplicate isolates, 814 bacteria [314 (38.6%) aerobes, 500 (61.4%) anaerobes] from 212 patients enrolled at centres in the USA, Latin America, Europe, Russia and South Africa were included in this study. Enterobacteriaceae comprised 48.1% (151/314) of the aerobic bacteria (18.6% of all isolates). The most common single aerobe was Escherichia coli, which accounted for 28.7% of the aerobic bacteria (59.6% of the Enterobacteriaceae). Non-fermentative Gram-negative bacilli were encountered infrequently (3.8% of the aerobes, 1.5% of all isolates). Of the anaerobes, although 280 (56.0%) were Gram-negative organisms, the genus isolated most often was Peptostreptococcus (169 isolates, 33.8% of all anaerobes). Bacteroides spp. comprised 17.4% of all anaerobes (87 isolates). Peptostreptococcus anaerobius, Prevotella bivia and Peptostreptococcus asaccharolyticus were the most commonly encountered species of anaerobes.
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 piperacillin–tazobactam 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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Ertapenem, piperacillin–tazobactam, chloramphenicol and ampicillin–sulbactam were most active against anaerobes: respectively, 99.8%, 99.6%, 99.4% and 98.8% of all anaerobes were susceptible to these agents. Based on MIC50 and MIC90 values, ertapenem had the most potent activity against the Bacteroides fragilis group. No anaerobe was resistant to ertapenem or piperacillin–tazobactam, although one (Bacteroides caccae) was intermediate to ertapenem and two (Bacteroides distasonis and Fusobacterium gonidiaformans) were intermediate to piperacillin–tazobactam. One isolate (Peptostreptococcus magnus) was resistant and two were intermediate to chloramphenicol; two (B. distasonis and Bacteroides ovatus) were resistant and four were intermediate to ampicillin–sulbactam. Ticarcillin–clavulanate, cefoxitin and metronidazole also had good activity: respectively, 97.6%, 96.8% and 95.8% of all isolates were susceptible to these drugs; 93.2% were susceptible to clindamycin; and 85.9% to ceftriaxone. Resistance to the latter two agents was seen primarily in the B. fragilis group.
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.8–10 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 piperacillin–tazobactam, ceftriaxone, ciprofloxacin and co-amoxiclav against Enterobacteriaceae and more active than piperacillin–tazobactam, ceftriaxone, ticarcillin–clavulanate, ampicillin–sulbactam, metronidazole, cefoxitin, clindamycin and chloramphenicol against anaerobes, which were the most frequent pathogens.
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Acknowledgements |
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This study was supported by Merck & Co., Inc.
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Footnotes |
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* Corresponding author. Tel: +1-484-344-2481; Fax: +1-484-344-3404; E-mail: gail_woods{at}merck.com
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References |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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1 . Fuchs, P. C., Barry, A. L. & Brown, S. D. (2001). In vitro activities of ertapenem (MK-0826) against clinical bacterial isolates from 11 North American medical centers. Antimicrobial Agents and Chemotherapy 45, 1915–8.
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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, 1860–7.
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.
5 . Murray, P. R., Baron, E. J., Pfaller, M. A., Tenover, F. C. & Yolken, R. H. (1999). Manual of Clinical Microbiology, 7th edn. American Society for Microbiology, Washington, DC, USA.
6 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fifth Edition: NCCLS Document M7-A5. NCCLS, Wayne, PA, USA.
7 . National Committee for Clinical Laboratory Standards. (2001). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Fifth 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, 507–12.[Medline]
9 . Apuzzio, J. J., Stankiewicz, R., Ganesh, V., Jain, S., Kaminski, Z. & Louria, D. (1989). Comparison of parenteral ciprofloxacin with clindamycin-gentamicin in the treatment of pelvic infection. American Journal of Medicine 87, Suppl. 5A, 148S–51S.[Medline]
10 . Sweet, R. L., Roy, S., Faro, S., O’Brien, W. F., Sanfilippo, J. S., Seidlin, M. et al. (1994). Piperacillin and tazobactam versus clindamycin and gentamicin in the treatment of hospitalized women with pelvic infection. Obstetrics and Gynecology 83, 280–6.[Medline]
11 . Gall, S. (1990). Therapeutic dilemmas in the treatment of pelvic infections. Journal of Reproductive Medicine 35, Suppl. 11, 1091–4.[Medline]
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