Abstract
This study compared the in vitro activities of the new long-half-life carbapenem ertapenem (also known as MK-0826 and L-749,345) with those of imipenem, amoxicillin-clavulanate, and ciprofloxacin against 5,558 recent clinical isolates from 11 North American medical centers. We confirmed the greater activity of ertapenem than of imipenem against the Enterobacteriaceae and the greater activity of imipenem against pseudomonads and gram-positive bacteria.
Ertapenem (also known as MK-0826 and L-749,345) is a new long-half-life carbapenem with a broad spectrum of antimicrobial activity against both gram-positive and gram-negative bacteria (1–4, 7). Preliminary pharmacokinetic studies indicate that ertapenem has a prolonged half-life (half-life at β phase of 4.9 ± 0.7 h) sufficient to permit once-a-day dosing (2, 8). This long half-life is largely due to its high protein binding of >95% (8). Ertapenem MICs found in the presence of serum were no more than eightfold higher than in standard tests (I. Pelak, S. Gerckens, P. M. Scott, C. Gill, C. Pacholok, L. Lynch, K. Dorso, J. Kohler, D. Shungu, and H. Kropp, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F119, p. 120, 1996). In animal studies the high protein binding had no apparent deleterious effect on ertapenem's in vivo efficacy (2). Peak levels in plasma of human volunteers following a 1.0-g intravenous dose were >100 μg/ml (8). The drug is currently undergoing clinical trials. The present study was designed to assess the in vitro activity of ertapenem in comparison with those of imipenem, amoxicillin-clavulanate, and ciprofloxacin against clinical isolates from 11 North American medical centers.
For these studies, 5,558 bacterial isolates were obtained from the 11 North American medical centers listed at the end of this paper. These isolates included 2,019 nonfastidious gram-negative bacteria, 540 fastidious gram-negative bacteria, 2,789 gram-positive isolates, and 210 anaerobes. Each center was requested to collect consecutive isolates that were deemed clinically significant during late winter to early spring of 1999. For each species, collection continued until a predefined target number of isolates was obtained or until the collection period ended. Multiple isolates from one patient were not included so that the consecutive isolates truly represent bacterial pathogens being encountered at that time. All isolates submitted for testing were identified by each contributing laboratory using their own standard methods. All susceptibility tests were performed at the Clinical Microbiology Institute, Wilsonville, Oreg. The species and numbers of each species tested are listed in Table 1.
TABLE 1.
Susceptibilities of 5,558 clinical isolates to ertapenem and three comparator drugs
| Microorganism(s) (no. of isolates) and antimicrobial agentb | MIC (μg/ml)
|
||
|---|---|---|---|
| Range | 50% | 90% | |
| Acinetobacter spp.a (86) | |||
| Ertapenem | 0.06–>16 | 4.0 | 16 |
| Imipenem | ≤0.008–>16 | 0.25 | 2.0 |
| Amox-clav | 0.06–>32 | 16 | >32 |
| Ciprofloxacin | ≤0.008–>16 | 1.0 | >16 |
| Aeromonas spp.c (21) | |||
| Ertapenem | 0.03–1.0 | 0.06 | 0.25 |
| Imipenem | 0.25–4.0 | 0.5 | 2.0 |
| Amox-clav | 16–>32 | 32 | >32 |
| Ciprofloxacin | ≤0.008–1.0 | 0.016 | 0.12 |
| Burkholderia cepacia (13) | |||
| Ertapenem | 4.0–>16 | 8.0 | >16 |
| Imipenem | 8.0–>16 | 16 | >16 |
| Amox-clav | 32–32 | >32 | >32 |
| Ciprofloxacin | 1.0–>16 | 4.0 | >16 |
| Citrobacter spp.d (216) | |||
| Ertapenem | ≤0.008–4.0 | ≤0.008 | 0.25 |
| Imipenem | 0.06–2.0 | 0.5 | 1.0 |
| Amox-clav | 2.0–>32 | 16 | >32 |
| Ciprofloxacin | ≤0.008–>16 | 0.03 | 1.0 |
| Enterobacter spp.e (239) | |||
| Ertapenem | ≤0.008–>16 | 0.03 | 0.5 |
| Imipenem | 0.12–>16 | 1.0 | 2.0 |
| Amox-clav | 1.0–>32 | >32 | >32 |
| Ciprofloxacin | ≤0.008–>16 | 0.03 | 1.0 |
| Escherichia coli (254) | |||
| Ertapenem | ≤0.008–0.5 | ≤0.008 | 0.016 |
| Imipenem | 0.06–2.0 | 0.12 | 0.25 |
| Amox-clav | 1.0–>32 | 8.0 | 32 |
| Ciprofloxacin | ≤0.008–>16 | 0.03 | 0.06 |
| Klebsiella spp.f (359) | |||
| Ertapenem | ≤0.008–>16 | ≤0.008 | 0.03 |
| Imipenem | 0.06–>16 | 0.25 | 0.5 |
| Amox-clav | 1.0–>32 | 4.0 | 16 |
| Ciprofloxacin | ≤0.008–>16 | 0.06 | 1.0 |
| Pasteurella multocida (22) | |||
| Ertapenem | ≤0.008–0.03 | 0.016 | 0.03 |
| Imipenem | 0.03–0.5 | 0.25 | 0.5 |
| Amox-clav | 0.06–0.5 | 0.25 | 0.5 |
| Ciprofloxacin | ≤0.008–0.06 | ≤0.008 | 0.016 |
| Proteeaeg (284) | |||
| Ertapenem | ≤0.008–4.0 | 0.016 | 0.03 |
| Imipenem | 0.016–16 | 4.0 | 4.0 |
| Amox-clav | 0.5–>32 | 16 | >32 |
| Ciprofloxacin | ≤0.008–>16 | 0.06 | >16 |
| Pseudomonas aeruginosa (161) | |||
| Ertapenem | 0.12–>16 | 8.0 | >16 |
| Imipenem | 0.25–>16 | 2.0 | 8.0 |
| Amox-clav | 32–>32 | >32 | >32 |
| Ciprofloxacin | 0.03–>16 | 0.5 | >16 |
| Pseudomonas spp.h (29) | |||
| Ertapenem | ≤0.008–>16 | 8.0 | >16 |
| Imipenem | 0.12–>16 | 1.0 | >16 |
| Amox-clav | 1.0–>32 | >32 | >32 |
| Ciprofloxacin | ≤0.008–>16 | 0.25 | 1.0 |
| Salmonella spp.i (112) | |||
| Ertapenem | ≤0.008–0.06 | ≤0.008 | ≤0.008 |
| Imipenem | 0.12–1.0 | 0.25 | 0.5 |
| Amox-clav | 1.0–>32 | 1.0 | 16 |
| Ciprofloxacin | ≤0.008–0.12 | 0.016 | 0.03 |
| Serratia marcescens (110) | |||
| Ertapenem | ≤0.008–>16 | 0.03 | 0.12 |
| Imipenem | 0.12–>16 | 1.0 | 2.0 |
| Amox-clav | 4.0–>32 | >32 | >32 |
| Ciprofloxacin | ≤0.008–>16 | 0.25 | 4.0 |
| Shigella spp.j (37) | |||
| Ertapenem | ≤0.008 | ≤0.008 | ≤0.008 |
| Imipenem | 0.06–0.5 | 0.25 | 0.25 |
| Amox-clav | 4.0–32 | 16 | 32 |
| Ciprofloxacin | ≤0.008–0.25 | ≤0.008 | 0.06 |
| Stenotrophomonas maltophilia (54) | |||
| Ertapenem | 1.0–>16 | >16 | >16 |
| Imipenem | 8.0–>16 | >16 | >16 |
| Amox-clav | 4.0–>32 | >32 | >32 |
| Ciprofloxacin | 1.0–>16 | 8.0 | >16 |
| Miscellaneous gram-negative bacteriak (22) | |||
| Ertapenem | ≤0.008–>16 | 0.03 | 4.0 |
| Imipenem | 0.06–>16 | 1.0 | 4.0 |
| Amox-clav | 0.12–>32 | 8.0 | 32 |
| Ciprofloxacin | ≤0.008–>16 | 0.5 | 4.0 |
| Haemophilus spp.l (332) | |||
| Ertapenem | ≤0.008–0.5 | 0.03 | 0.06 |
| Imipenem | ≤0.008–2.0 | 0.5 | 1.0 |
| Ampicillin | 0.12–>4.0 | 0.5 | >4.0 |
| Ciprofloxacin | ≤0.008–16 | 0.016 | 0.03 |
| Moraxella catarrhalis (181) | |||
| Ertapenem | ≤0.008–0.25 | ≤0.008 | 0.016 |
| Imipenem | ≤0.008–1.0 | 0.12 | 0.25 |
| Ampicillin | ≤0.03–1.0 | 0.25 | 0.5 |
| Ciprofloxacin | ≤0.008–0.5 | 0.016 | 0.03 |
| Neisseria meningitidis (27) | |||
| Ertapenem | ≤0.008–0.03 | ≤0.008 | 0.016 |
| Imipenem | 0.03–1.0 | 0.25 | 0.5 |
| Ampicillin | 0.12–0.5 | 0.12 | 0.25 |
| Ciprofloxacin | ≤0.008 | ≤0.008 | ≤0.008 |
| Corynebacterium spp.m (29) | |||
| Ertapenem | ≤0.008–>16 | 0.5 | >16 |
| Imipenem | ≤0.008–>16 | 1.0 | >16 |
| Amox-clav | ≤0.03–>32 | 0.5 | >32 |
| Ciprofloxacin | 0.5–>16 | >16 | >16 |
| Enterococcus faecalisn (387) | |||
| Ertapenem | 0.06–>16 | 8.0 | >16 |
| Imipenem | 0.03–>16 | 2.0 | 16 |
| Amox-clav | 0.06–>32 | 0.5 | 1.0 |
| Ciprofloxacin | 0.25–>16 | 1.0 | >16 |
| Enterococcus faeciumo (140) | |||
| Ertapenem | 0.12–>16 | >16 | >16 |
| Imipenem | 0.25–>16 | >16 | >16 |
| Amox-clav | 0.06–>32 | >32 | >32 |
| Ciprofloxacin | 0.25–>16 | >16 | >16 |
| Enterococcus spp.p (other) (23) | |||
| Ertapenem | 0.5–>16 | 8.0 | >16 |
| Imipenem | 0.03–>16 | 4.0 | >16 |
| Amox-clav | 0.12–>32 | 1.0 | 32 |
| Ciprofloxacin | 0.06–>16 | 2.0 | >16 |
| Staphylococcus aureus | |||
| Oxacillin susceptible (375) | |||
| Ertapenem | 0.03–>16 | 0.12 | 0.25 |
| Imipenem | 0.016–>16 | 0.016 | 0.03 |
| Amox-clav | 0.06–8.0 | 1.0 | 1.0 |
| Ciprofloxacin | 0.03–>16 | 0.25 | 0.5 |
| Oxacillin resistant (172) | |||
| Ertapenem | 0.12–>16 | >16 | >16 |
| Imipenem | 0.03–>16 | 16 | >16 |
| Amox-clav | 0.12–>32 | >32 | >32 |
| Ciprofloxacin | 0.12–>16 | >16 | >16 |
| Staphylococcus spp., coagulase negative Oxacillin susceptible (182) | |||
| Ertapenem | 0.03–4.0 | 0.12 | 0.5 |
| Imipenem | ≤0.008–1.0 | 0.016 | 0.06 |
| Amox-clav | ≤0.03–32 | 0.25 | 4.0 |
| Ciprofloxacin | 0.03–2.0 | 0.25 | 0.5 |
| Oxacillin resistant (346) | |||
| Ertapenem | 0.06–>16 | 8.0 | >16 |
| Imipenem | ≤0.008–>16 | 1.0 | >16 |
| Amox-clav | 0.12–>32 | 32 | >32 |
| Ciprofloxacin | 0.06–>16 | 8.0 | >16 |
| Streptococcus agalactiae (206) | |||
| Ertapenem | 0.016–0.25 | 0.06 | 0.06 |
| Imipenem | ≤0.008–0.06 | 0.016 | 0.03 |
| Amox-clav | ≤0.03–0.12 | 0.06 | 0.12 |
| Ciprofloxacin | 0.5–4.0 | 1.0 | 1.0 |
| Streptococcus pneumoniae | |||
| Penicillin susceptible (373) | |||
| Ertapenem | ≤0.008–0.06 | 0.016 | 0.03 |
| Imipenem | ≤0.008–0.03 | ≤0.008 | 0.016 |
| Amox-clav | 0.06–0.25 | 0.06 | 0.06 |
| Ciprofloxacin | 0.5–16 | 1.0 | 2.0 |
| Penicillin intermediate (93) | |||
| Ertapenem | ≤0.008–1.0 | 0.25 | 0.5 |
| Imipenem | ≤0.008–0.5 | 0.12 | 0.25 |
| Amox-clav | ≤0.03–2.0 | 0.5 | 1.0 |
| Ciprofloxacin | 0.5–16 | 1.0 | 2.0 |
| Penicillin resistant (110) | |||
| Ertapenem | 0.12–4.0 | 1.0 | 2.0 |
| Imipenem | 0.12–2.0 | 0.25 | 1.0 |
| Amox-clav | 0.12–8.0 | 1.0 | 8.0 |
| Ciprofloxacin | 0.5–8.0 | 1.0 | 2.0 |
| Streptococcus pyogenes (238) | |||
| Ertapenem | ≤0.008–0.25 | ≤0.008 | 0.016 |
| Imipenem | ≤0.008–0.06 | ≤0.008 | ≤0.008 |
| Amox-clav | ≤0.03–0.12 | ≤0.03 | ≤0.03 |
| Ciprofloxacin | 0.12–2.0 | 0.5 | 1.0 |
| Streptococcus spp.q (other) (77) | |||
| Ertapenem | ≤0.008–4.0 | 0.12 | 0.5 |
| Imipenem | ≤0.008–2.0 | 0.016 | 0.12 |
| Amox-clav | ≤0.03–8.0 | ≤0.03 | 0.25 |
| Ciprofloxacin | 0.016–16 | 0.5 | 8.0 |
| Miscellaneous gram-positive bacteriar (38) | |||
| Ertapenem | ≤0.008–>16 | 0.25 | 2.0 |
| Imipenem | ≤0.008–4.0 | 0.03 | 0.12 |
| Amox-clav | 0.03–>32 | 0.12 | 0.5 |
| Ciprofloxacin | 0.03–>16 | 1.0 | 4.0 |
| Bacteroides fragilis (56) | |||
| Ertapenem | 0.016–4.0 | 0.25 | 1.0 |
| Imipenem | ≤0.008–2.0 | 0.12 | 0.5 |
| Bacteroides spp.s (64) | |||
| Ertapenem | 0.03–8.0 | 0.5 | 2.0 |
| Imipenem | 0.03–4.0 | 0.25 | 1.0 |
| Clostridium perfringens (21) | |||
| Ertapenem | ≤0.008–0.12 | 0.06 | 0.06 |
| Imipenem | 0.03–0.5 | 0.06 | 0.12 |
| Proprionibacterium acnes (21) | |||
| Ertapenem | 0.03–4.0 | 0.06 | 0.25 |
| Imipenem | ≤0.008–1.0 | ≤0.008 | 0.03 |
| Miscellaneous anaerobest (48) | |||
| Ertapenem | ≤0.008–4.0 | 0.12 | 0.5 |
| Imipenem | ≤0.008–2.0 | 0.06 | 0.25 |
Species (no. of isolates): A. anitratus (12), A. baumannii (59), A. haemolyticus (8), and A. lwoffii (7).
Amox-clav, amoxicillin-clavulanate.
Species (no. of isolates): C. amalonaticus (8), C. brackii (1), C. diversus (18), C. farmeri (3), C. freundii (119), C. koseri (66), and Citrobacter spp. NOS (1).
Species (no. of isolates): E. aerogenes (111), E. agglomerans (9), E. asburiae (1), E. cancerogenus (1), E. cloacae (112), E. intermedius (2), E. sakasaki (1), and Enterobacter spp. NOS (2).
Species (no. of isolates): K. ornitholytica (1), K. oxytoca (103), and K. pneumoniae (255).
Species (no. of isolates): M. morganii (94), P. mirabilis (113), P. vulgaris (25), P. rettgeri (18), and P. stuartii (34).
Species (no. of isolates): P. fluorescens/putida group (22), P. paucimobilis (1), P. stutzeri (2), P. vesiculare (1), and Pseudomonas spp. NOS (3).
Species (no. of isolates): S. enterica serovar Tyhi (3) and non-serovar Typhi salmonellae (109).
Species (no. of isolates): S. bovdii (1), S. flexneri (7), S. sonnei (27), and Shigella spp. NOS (2).
Species (no. of isolates): Alcaligenes faecalis (5), Bordetella bronchiseptica (1), Brevundimonas vesicularis (1), Commamonas spp. (1), Flavobacterium breve (1), F. mengosepticum (1), Hafnia alvei (2), Pasteurella spp. NOS (2), Serratia liquefaciens (1), S. rubidaea (1), Shawanella putrefaciens (1), and Yersinia enterocolitica (5).
Species (no. of isolates): H. aegypticus (1), H. aphrophilus (3), H. haemolyticus (4), H. influenzae (233; 86 β-lactamase-positive), H. parahaemolyticus (1), and H. parainfluenzae (30).
Species (no. of isolates): C. afermentans (1), C. amycolatum (1), C. jeikeium (7; resistant to all drugs), C. pseudodiphtheriticum (1), C. striatum (3), C. ureolyticum (3; resistant to all drugs), and Corynebacterium spp. NOS (13).
Includes 10 vancomycin-resistant strains.
Includes 90 vancomycin-resistant strains.
Species (no. of isolates): E. avium (9), E. casseliflavus (3), E. durans (1), E. gallinarum (8), E. raffinosus (1), and Enterococcus spp. NOS (1).
Species (no. of isolates): group C (5), group F (6), group G (21), S. bovis (6), S. milleri (13), S. mitis (2), S. mutans (2), S. salivarius (3), S. sanguis (4), and S. viridans NOS (15).
Species (no. of isolates): Aerococcus spp. NOS (2), A. urinae (4), Bacillus spp. NOS (8), Lactobacillus spp. NOS (10), Micrococcus spp. NOS (13), and L. monocytogenes (1).
Species (no. of isolates): B. fragilis group, NOS (9), B. ovatus (9), B. thetaiotaomicron (19), B. uniformis (11), B. vulgatus (5), and Bacteroides spp. NOS (11).
Ertapenem and imipenem were provided as standardized powders by Merck Research Laboratories, Rahway, N.J. Ciprofloxacin, amoxicillin-clavulanate, and ampicillin were obtained from their respective U.S. manufacturers or other commercial source. All aerobic bacteria were evaluated by broth microdilution methods as outlined by the NCCLS (5). Microdilution panels were prepared by PML Microbiologicals, Wilsonville, Oreg., and stored at −70°C until used. The cation-adjusted Mueller-Hinton broth was supplemented with ca. 3% lysed horse blood when necessary for growth (e.g., streptococci). Haemophilus test medium was used for testing Haemophilus species. Concentrations of drugs tested were serial twofold dilutions ranging from 16 to 0.008 μg/ml for ertapenem, imipenem, and ciprofloxacin; 32 to 0.03 μg/ml for amoxicillin-clavulanate; and 4.0 to 0.03 for ampicillin (fastidious gram-negative isolates only). Anaerobic bacteria were tested by the agar dilution method recommended by the NCCLS (6), using Brucella blood agar supplemented with vitamin K1 (1.0 μg/ml) and hemin (5 μg/ml) and using an inoculum of ca. 105 CFU per spot.
On each day of testing, colony counts were performed on the bacterial suspension in the growth control wells of two randomly selected microdilution trays to ensure an inoculum density of approximately 5 × 105 CFU/ml. Standard control strains that were included with each test run were those that were appropriate for the species of clinical isolates being tested.
Table 1 summarizes the antimicrobial activities of ertapenem and three comparison agents against 5,558 strains of clinical bacterial isolates. Ertapenem was more active against all species of Enterobacteriaceae than imipenem. Ertapenem MICs were generally 10 to 20 times lower than those of imipenem for most species and were over 100 times lower for some species of the tribe Proteeae. Against Pseudomonas aeruginosa and related species, both drugs were less active than against the Enterobacteriaceae, but imipenem was more active than ertapenem. Amoxicillin-clavulanate was the least active of the four drugs tested against nonfastidious gram-negative bacteria. Ciprofloxacin MICs were generally slightly higher than those of ertapenem and lower than those of imipenem for Enterobacteriaceae, and for most species of non-Enterobacteriaceae they were lower than those of the other drugs tested.
Ertapenem was active against gram-positive bacteria other than enterococci and oxacillin-resistant staphylococci (Table 1). Imipenem was more potent than ertapenem against nearly all gram-positive species. The MICs of ertapenem and imipenem were higher for penicillin-resistant pneumococci (MICs at which 90% of the isolates tested were inhibited [MIC90], 2.0 and 1.0 μg/ml) than against penicillin-susceptible pneumococci (MIC90, 0.03 and 0.016 μg/ml). The geometric mean MICs of both carbapenems were 40-fold higher for penicillin-resistant pneumococci than for penicillin-susceptible strains. A similar difference in MICs was observed with amoxicillin-clavulanate, but ciprofloxacin MICs were unaffected by penicillin susceptibility of pneumococci.
Fastidious gram-negative bacteria, except for ampicillin resistance of β-lactamase-producing Haemophilus spp., were highly susceptible to all four test drugs (Table 1). For Haemophilus spp., the MICs of ertapenem were 2- to 10-fold lower than those of imipenem. β-Lactamase production by H. influenzae had no perceptible effect on the MICs of either carbapenem or ciprofloxacin.
Virtually all anaerobic isolates tested were susceptible to ≤4.0 μg of both carbapenems per ml (Table 1). Against Clostridium perfringens, ertapenem was twice as active as imipenem, but against the other anaerobic bacteria, imipenem was more potent.
In summary, ertapenem was superior to the other study drugs in its potency against the Enterobacteriaceae but it had relatively little activity against Pseudomonas spp. Although ertapenem was active against most gram-positive cocci, imipenem was somewhat more potent. Both carbapenems had little activity against the enterococci, especially vancomycin-resistant strains. Anaerobic bacteria were also susceptible to both carbapenems even though imipenem was more potent than ertapenem. Because ertapenem may be given once a day and because of its potency against the Enterobacteriaceae, ertapenem might be useful in treating a variety of infections in humans.
Acknowledgments
We gratefully acknowledge the following for providing the clinical isolates for this study: M. Bauman, Providence St. Vincent Medical Center, Portland, Oreg; T. Cleary, University of Miami, Miami, Fla.; M. J. Ferraro, Massachusetts General Hospital, Boston; D. Hardy, University of Rochester Medical Center, Rochester, N.Y.; J. Hindler, UCLA Medical Center, Los Angeles, Calif.; S. Jenkins, Carolinas Medical Center, Charlotte, N.C.; G. Overturf, University of New Mexico Medical Center, Albuquerque; R. Rennie, University of Alberta Hospital, Edmonton, Alberta, Canada; K. Waites, University of Alabama at Birmingham, Birmingham; G. Procop, The Cleveland Clinic Foundation, Cleveland, Ohio; and P. Murray, Washington University School of Medicine, St. Louis, Mo.
This study was supported by a financial grant from Merck Research Laboratories, Rahway, N.J.
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