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. 2000 Sep;44(9):2389–2394. doi: 10.1128/aac.44.9.2389-2394.2000

Comparative In Vitro Activities of Ertapenem (MK-0826) against 1,001 Anaerobes Isolated from Human Intra-Abdominal Infections

Ellie J C Goldstein 1,2,*, Diane M Citron 1, C Vreni Merriam 1, Yumi Warren 1, Kerin L Tyrrell 1
PMCID: PMC90074  PMID: 10952584

Abstract

By using an agar dilution method, the comparative in vitro activities of ertapenem (MK-0826) were studied against 1,001 anaerobes isolated from human intra-abdominal infections in 17 countries worldwide. MK-0826 was uniformly active against all isolates, including all Bacteroides fragilis group species isolates, with the exception of 12 of 61 (20%) strains of Bilophila wadsworthia, 3 strains of lactobacilli, and 1 isolate of Acidaminococcus fermentans. Geographical variation in activity was not observed.

Ertapenem (MK-0826; L749,345; 1-β-methyl carbapenem (4R,5S,6S,8R,21S,41S)-3-[2-[[(3-carboxyphenyl)amino]carbonyl]pyrrolidin-4-yl]- 4-methyl-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monosodium salt) is a new parenteral carbapenem that is highly resistant to inactivation by a wide variety of beta-lactamases and has a broad spectrum of antimicrobial activity (4, 5, 8, 9, 14). It binds preferentially to penicillin-binding proteins 1b, 2, and 3. It is more resistant than imipenem to renal dehydropeptidase 1 inactivation and therefore does not require the addition of cilastatin. MK-0826 has a half-life of ∼4.5 h, ∼30 to 40% of a dose is excreted as intact drug in the urine, and its pharmacokinetic profile allows single daily dosing (5, 14). While the in vitro activity of MK-0826 against many aerobes has been reported (4, 5, 8, 9, 13), few data regarding its activity against anaerobes have been reported (M. D. Appleman, D. M. Citron, P. N. R. Heseltine, H. Belzberg, A. E. Yellin, J. Murray, and T. V. Berne, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-43, p. 244, 1998). In order to evaluate MK-0826's activity against anaerobes and to assess its potential utility in mixed infections, we studied its in vitro activity against 1,001 clinical isolates from human intra-abdominal infections.

MATERIALS AND METHODS

The 1,001 anaerobic strains studied were recently isolated (1998 to 1999) from human clinical infections as part of an international, multicenter clinical trial. Aspirated specimens of abdominal pus were obtained intraoperatively and were placed in anaerobic transport tubes (Anaerobe Systems, Morgan Hill, Calif.) and sent via express delivery services from the study site to the R. M. Alden Research Laboratory in Santa Monica, Calif. Twenty-nine study centers located in 17 countries worldwide contributed various numbers of specimens (see Table 1). Upon receipt, the specimens were placed in an anaerobe chamber and plated onto anaerobic media including supplemented brucella, phenylethyl alcohol blood, Bacteroides bile esculin, and kanamycin-vancomycin laked blood agars (Anaerobe Systems) and were incubated anaerobically at 37°C for 5 days. Trypticase soy blood agar, Rose agar, and MacConkey agar (Hardy Diagnostics, Santa Maria, Calif.) were used to recover aerobic organisms. Isolates were identified by standard criteria (7, 13) and were stored in skim milk at −70°C.

TABLE 1.

Microbiological characteristics of intra-abdominal specimens, by country

Country No. of sites No. of specimens % Growth % Anaerobes only % Aerobes only Avg no. of anaerobes/ specimen Avg no. of aerobes/ specimen Range of no. of anaerobes/ specimena Range of no. of aerobes/ specimena Range (median) no. of days in transportb
Argentina 1 8 100.0 0.0 62.5 0.4 1.9 0–1 1–3 26–62 (32)
Belgium 1 8 100.0 12.5 12.5 2.4 3.5 0–4 0–5 2–6 (3)
Brazil 1 44 90.9 4.5 22.7 3.2 2.8 0–8 0–7 2–6 (3)
Canada 3 49 93.9 10.2 28.6 2.0 2.2 0–8 0–6 1–7 (2)
Chile 1 22 77.3 0.0 22.7 2.8 3.1 0–6 0–6 2–7 (3)
Colombia 2 24 87.5 8.3 33.3 1.3 2.9 0–6 0–6 2–8 (3)
France 1 6 100.0 0.0 16.7 2.5 4.5 0–6 3–7 2–5 (3)
Germany 1 3 100.0 0.0 0.0 2.0 2.7 1–3 2–3 2–3 (3)
Guatemala 1 46 95.7 4.3 4.3 4.1 4.0 0–11 0–7 2–8 (4)
Italy 3 15 86.7 6.7 20.0 2.2 2.6 0–6 0–6 4–10 (7)
Mexico 1 11 72.7 18.2 0.0 3.5 2.8 0–7 0–7 2–11 (5)
Peru 1 21 95.2 9.5 9.5 3.4 2.8 0–8 0–6 1–8 (3)
Russia 1 42 92.9 0.0 19.0 2.6 3.4 0–8 0–7 3–37 (8)
South Africa 3 68 92.6 1.5 36.8 2.3 3.2 0–13 0–9 3–15 (7)
Spain 4 32 96.9 0.0 40.6 1.9 2.8 0–8 0–7 2–7 (5)
Switzerland 3 26 100.0 7.7 11.5 2.8 3.3 0–6 0–9 2–15 (5)
Venezuela 1 2 100.0 0.0 100.0 0.0 2.0 0–0 1–3 7–34
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a

With any growth. 

b

From date of collection to date of processing. 

For the in vitro susceptibility studies, isolates were taken from frozen stocks and were subcultured twice on brucella agar supplemented with hemin, vitamin K1, and 5% sheep blood. Susceptibility testing was performed by the reference agar dilution method according to the standards of the National Committee for Clinical Laboratory Standards (11). Brucella agar supplemented with hemin, vitamin K1, and 5% laked sheep blood was the basal medium. The antimicrobial agents were reconstituted according to the manufacturers' instructions. Serial twofold dilutions of various concentrations of antimicrobial agents were prepared on the day of the test and added to the agar medium. Ampicillin-sulbactam was fixed in a ratio of 2:1; ticarcillin was diluted with clavulanate and was tested at a constant concentration of 2 μg/ml, and piperacillin was diluted with tazobactam and was tested at a constant concentration of 4 μg/ml.

The agar plates were inoculated with a Steers replicator (Craft Machine Inc., Chester, Pa.) with an inoculum of 105 CFU per spot. The plates were incubated in an anaerobic chamber for 44 h at 37°C prior to examination. The MIC was defined as the lowest concentration of an agent that yielded no growth or a marked change in the appearance of growth compared to the growth on a control plate. Control strains Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741 were included for each drug tested. The numbers and species of isolates tested are given in Table 2.

TABLE 2.

In vitro activities of MK-0826 (L-749,345) and 10 other antimicrobial agents against human intra-abdominal anaerobic pathogens

Organism and agent (no. of isolates) MIC (μg/ml)
Range 50% 90%
Anaerobic streptococcus spp. (15)a
 MK-0826 ≤0.015–0.25 0.03 0.25
 Imipenem ≤0.015–0.06 ≤0.015 0.06
 Piperacillin-tazobactam ≤0.06–1 ≤0.06 0.5
 Ticarcillin-clavulanate ≤0.06–2 ≤0.06 1
 Ampicillin-sulbactam ≤0.06–0.25 ≤0.06 0.25
 Cefoxitin 0.125–8 1 8
 Ceftriaxone ≤0.06–16 ≤0.06 2
 Chloramphenicol 1–8 2 4
 Clindamycin ≤0.06–0.25 ≤0.06 0.125
 Metronidazole ≤0.06–>32 32 >32
 Vancomycin 0.125–1 0.6 1
Bacteroides caccae (27)
 MK-0826 0.125–8 0.5 4
 Imipenem 0.03–32 0.125 0.25
 Piperacillin-tazobactam ≤0.06–>128 2 16
 Ticarcillin-clavulanate ≤0.06–>128 1 8
 Ampicillin-sulbactam 0.5–>32 2 8
 Cefoxitin 4–64 16 64
 Ceftriaxone 1–>128 32 >128
 Chloramphenicol 4–8 8 8
 Clindamycin ≤0.06–>32 2 >32
 Metronidazole 0.25–8 1 4
Bacteroides distasonis (50)
 MK-0826 0.125–4 0.5 2
 Imipenem 0.03–4 0.5 2
 Piperacillin-tazobactam 0.125–>128 4 16
 Ticarcillin-clavulanate 0.125–>128 4 32
 Ampicillin-sulbactam 0.5–>32 4 16
 Cefoxitin 8–>128 16 64
 Ceftriaxone 0.5–>128 32 >128
 Chloramphenicol 4–8 8 8
 Clindamycin ≤0.06–>32 2 >32
 Metronidazole 0.25–4 1 2
Bacteroides fragilis (134)
 MK-0826 ≤0.06–8 0.125 1
 Imipenem ≤0.5–2 0.06 0.25
 Piperacillin-tazobactam ≤0.06–16 0.25 1
 Ticarcillin-clavulanate ≤0.06–64 0.25 2
 Ampicillin-sulbactam 0.25–16 1 8
 Cefoxitin 4–32 8 16
 Ceftriaxone 0.5–>128 16 64
 Chloramphenicol 2–16 4 8
 Clindamycin ≤0.06–>32 0.5 >32
 Metronidazole 0.125–8 1 4
Bacteroides ovatus (46)
 MK-0826 0.25–4 0.5 1
 Imipenem 0.125–4 0.125 0.5
 Piperacillin-tazobactam 0.25–32 4 16
 Ticarcillin-clavulanate 0.25–16 1 2
 Ampicillin-sulbactam 0.5–16 1 4
 Cefoxitin 4–128 32 32
 Ceftriaxone 32–>128 64 >128
 Chloramphenicol 4–8 8 8
 Clindamycin ≤0.06–>32 2 >32
 Metronidazole ≤0.06–4 1 2
Bacteroides splanchnicus (9)
 MK-0826 0.03–0.06 0.03
 Imipenem ≤0.015–0.06 0.03
 Piperacillin-tazobactam ≤0.06–0.5 ≤0.06
 Ticarcillin-clavulanate ≤0.06–0.5 ≤0.06
 Ampicillin-sulbactam 0.5 0.5
 Cefoxitin 0.5–2 1
 Ceftriaxone 1–8 4
 Chloramphenicol 2–16 4
 Clindamycin ≤0.06–>32 ≤0.06
 Metronidazole ≤0.06–0.5 0.25
Bacteroides stercoris-Bacteroides merdae group (16)b
 MK-0826 0.03–1 0.5 1
 Imipenem 0.06–0.5 0.5 0.5
 Piperacillin-tazobactam ≤0.06–16 1 8
 Ticarcillin-clavulanate ≤0.06–16 0.5 4
 Ampicillin-sulbactam 0.25–16 1 4
 Cefoxitin 0.5–64 8 32
 Ceftriaxone 0.125–>128 16 >128
 Chloramphenicol 0.5–8 4 8
 Clindamycin ≤0.06–>3 1 >32
 Metronidazole 0.5–4 2 2
Bacteroides thetaiotaomicron (90)
 MK-0826 0.03–2 1 1
 Imipenem 0.06–0.5 0.25 0.25
 Piperacillin-tazobactam ≤0.06–32 16 16
 Ticarcillin-clavulanate ≤0.06–16 1 4
 Ampicillin-sulbactam 0.5–16 1 4
 Cefoxitin 1–128 32 32
 Ceftriaxone 4–>128 64 >128
 Chloramphenicol 2–16 8 8
 Clindamycin ≤0.06–>32 4 >32
 Metronidazole 0.25–4 1 4
Bacteroides uniformis (50)
 MK-0826 0.03–2 0.25 1
 Imipenem 0.125–16 0.125 0.5
 Piperacillin-tazobactam ≤0.06–>128 2 8
 Ticarcillin-clavulanate 0.125–>128 0.5 2
 Ampicillin-sulbactam ≤0.06–>32 1 4
 Cefoxitin 1–64 8 32
 Ceftriaxone 4–>128 32 >128
 Chloramphenicol 2–8 8 8
 Clindamycin ≤0.06–>32 1 >32
 Metronidazole ≤0.06–4 2 2
Bacteroides vulgatus (33)
 MK-0826 ≤0.015–1 0.125 0.5
 Imipenem 0.03–1 0.125 0.5
 Piperacillin-tazobactam ≤0.06–16 2 8
 Ticarcillin-clavulanate ≤0.06–4 0.125 2
 Ampicillin-sulbactam 0.25–16 1 8
 Cefoxitin 1–16 4 16
 Ceftriaxone 0.5–>128 3 128
 Chloramphenicol 0.5–8 4 4
 Clindamycin ≤0.06–>32 ≤0.06 >32
 Metronidazole 0.25–2 1 2
Bilophila wadsworthia (51)
 MK-0826 ≤0.015–>32 0.06 >32
 Imipenem 0.06–>32 0.25 >32
 Piperacillin-tazobactam ≤0.06–>128 16 >128
 Ticarcillin-clavulanate ≤0.06–>128 0.25 >128
 Ampicillin-sulbactam 0.25–>32 2 16
 Cefoxitin 0.125–>128 16 >128
 Ceftriaxone ≤0.06–>128 1 >128
 Chloramphenicol 0.5–8 4 8
 Clindamycin ≤0.06–4 0.5 1
 Metronidazole ≤0.06–0.25 0.125 0.25
Clostridium clostridioforme (53)
 MK-0826 0.06–4 1 4
 Imipenem 0.125–4 1 2
 Piperacillin-tazobactam ≤0.06–128 8 128
 Ticarcillin-clavulanate 1–128 16 32
 Ampicillin-sulbactam 0.25–16 1 16
 Cefoxitin 2–16 4 16
 Ceftriaxone 0.5–128 4 64
 Chloramphenicol 1–8 2 4
 Clindamycin ≤0.06–4 1 2
 Metronidazole ≤0.06–2 0.125 0.25
 Vancomycin 0.5–1 0.5 1
Clostridium innocuum (40)
 MK-0826 0.5–4 2 2
 Imipenem 0.5–4 1 2
 Piperacillin-tazobactam 0.5–2 1 1
 Ticarcillin-clavulanate 4–16 16 16
 Ampicillin-sulbactam ≤0.06–0.5 0.25 0.25
 Cefoxitin 16–>128 64 128
 Ceftriaxone 2–16 8 8
 Chloramphenicol 8–16 8 16
 Clindamycin 0.125–>32 0.5 >32
 Metronidazole 0.25–2 1 2
 Vancomycin 8–16 8 16
Clostridium perfringens (29)
 MK-0826 ≤0.015–0.125 ≤0.015 0.06
 Imipenem ≤0.015–0.125 0.06 0.125
 Piperacillin-tazobactam ≤0.06–0.5 ≤0.06 0.125
 Ticarcillin-clavulanate ≤0.06–0.5 0.25 0.5
 Ampicillin-sulbactam ≤0.06–0.125 ≤0.06 0.125
 Cefoxitin 0.25–2 0.5 1
 Ceftriaxone ≤0.06–2 ≤0.06 2
 Chloramphenicol 1–4 4 4
 Clindamycin ≤0.06–4 0.25 2
 Metronidazole 0.125–8 1 4
 Vancomycin 0.25–0.5 0.5 0.5
Clostridium ramosum (20)
 MK-0826 0.25–1 0.5 1
 Imipenem 0.125–0.25 0.125 0.25
 Piperacillin-tazobactam ≤0.06–0.5 ≤0.06 0.5
 Ticarcillin-clavulanate 0.5–8 1 4
 Ampicillin-sulbactam ≤0.06–0.25 ≤0.06 0.125
 Cefoxitin 2–64 8 64
 Ceftriaxone 0.125–0.25 0.25 0.25
 Chloramphenicol 2–32 4 8
 Clindamycin 2–>32 4 >32
 Metronidazole 0.5–2 1 2
 Vancomycin 4 4 4
Clostridium spp. (36)c
 MK-0826 ≤0.015–4 0.126 2
 Imipenem ≤0.015–4 0.125 1
 Piperacillin-tazobactam ≤0.06–32 0.25 8
 Ticarcillin-clavulanate ≤0.06–64 2 32
 Ampicillin-sulbactam ≤0.06–4 0.25 2
 Cefoxitin 0.125–128 4 64
 Ceftriaxone ≤0.06–128 2 32
 Chloramphenicol 0.125–>32 2 4
 Clindamycin ≤0.06–>32 0.25 8
 Metronidazole ≤0.06–8 0.25 2
 Vancomycin 0.125–8 1 2
Eubacterium lentum (41)
 MK-0826 0.03–1 0.5 1
 Imipenem ≤0.015–0.5 0.25 0.5
 Piperacillin-tazobactam ≤0.06–32 16 32
 Ticarcillin-clavulanate ≤0.06–64 16 32
 Ampicillin-sulbactam ≤0.06–2 1 2
 Cefoxitin 0.5–128 8 16
 Ceftriaxone ≤0.06–>128 64 >128
 Chloramphenicol 2–8 4 8
 Clindamycin ≤0.06–>32 0.25 2
 Metronidazole 0.125–>32 0.5 1
 Vancomycin 0.25–16 1 2
Eubacterium spp. (54)d
 MK-0826 ≤0.015–1 0.06 1
 Imipenem ≤0.015–1 0.03 0.25
 Piperacillin-tazobactam ≤0.06–64 0.126 16
 Ticarcillin-clavulanate ≤0.06–32 1 32
 Ampicillin-sulbactam ≤0.06–2 0.125 1
 Cefoxitin ≤0.06–2 ≤0.06 2
 Ceftrixone ≤0.06–1 0.125 1
 Chloramphenicol 0.25–8 2 8
 Clindamycin ≤0.06–>32 ≤0.06 0.5
 Metronidazole ≤0.06–>32 0.25 4
 Vancomycin ≤0.06–2 0.5 2
Fusobacterium mortiferum- Fusobacterium varium (9)e
 MK-0826 ≤0.015–0.25 0.125
 Imipenem 0.125–1 0.5
 Piperacillin-tazobactam ≤0.06–4 0.25
 Ticarcillin-clavulanate 1–4 2
 Ampicillin-sulbactam 0.5–8 1
 Cefoxitin 2–8 4
 Ceftriaxone ≤0.06–>128 64
 Chloramphenicol 0.25–2 0.5
 Clindamycin ≤0.06–4 ≤0.06
 Metronidazole 0.25–1 0.5
Fusobacterium spp. (17)f
 MK-0826 ≤0.015–0.25 ≤0.015 0.03
 Imipenem ≤0.015–0.125 ≤0.015 0.125
 Piperacillin-tazobactam ≤0.06–32 ≤0.06 ≤0.06
 Ampicillin-sulbactam ≤0.06–0.25 ≤0.06 0.125
 Cefoxitin ≤0.06–2 ≤0.06 2
 Ceftriaxone ≤0.06–1 0.125 1
 Chloramphenicol 0.5–2 1 2
 Clindamycin ≤0.06 ≤0.06 ≤0.06
 Metronidazole ≤0.06–0.5 0.125 0.25
Lactobacillus spp. (18)g
 MK-0826 0.03–>32 0.25 >32
 Imipenem ≤0.015–8 0.125 8
 Piperacillin-tazobactam ≤0.06–4 0.5 4
 Ticarcillin-clavulanate ≤0.06–64 4 64
 Ampicillin-sulbactam ≤0.06–4 0.25 4
 Cefoxitin 0.25–>128 128 >128
 Ceftriaxone ≤0.06–>128 0.5 >128
 Chloramphenicol 1–>32 4 16
 Clindamycin ≤0.06–4 0.125 4
 Metronidazole 0.5–>32 >32 >32
 Vancomycin 0.25–>32 8 >32
Peptostreptococcus micros (23)
 MK-0826 0.03–0.125 0.06 0.06
 Imipenem ≤0.015–0.06 ≤0.015 0.06
 Piperacillin-tazobactam ≤0.06 ≤0.06 ≤0.06
 Ticarcillin-clavulanate ≤0.06–0.25 ≤0.06 ≤0.06
 Ampicillin-sulbactam ≤0.06–0.5 ≤0.06 0.125
 Cefoxitin 0.25–2 0.5 1
 Ceftriaxone 0.125–1 0.25 0.5
 Chloramphenicol 1–2 2 2
 Clindamycin ≤0.06–0.25 0.125 0.25
 Metronidazole 0.125–0.5 0.25 0.5
 Vancomycin 0.5 0.5 0.5
Peptostreptococcus spp. (25)h
 MK-0826 ≤0.015–2 0.06 0.5
 Imipenem ≤0.015–0.5 0.03 0.5
 Piperacillin-tazobactam ≤0.06–32 0.25 2
 Ticarcillin-clavulanate ≤0.06–128 0.5 16
 Ampicillin-sulbactam ≤0.06–8 ≤0.06 0.5
 Cefoxitin ≤0.06–8 1 8
 Ceftriaxone ≤0.06–8 1 8
 Chloramphenicol 1–8 2 4
 Clindamycin ≤0.06–16 ≤0.06 2
 Metronidazole ≤0.06–>32 0.5 2
 Vancomycin ≤0.06–1 0.25 1
Porphyromonas spp. (20)i
 MK-0826 ≤0.015–0.06 ≤0.015 ≤0.015
 Imipenem ≤0.015–0.25 ≤0.015 0.03
 Piperacillin-tazobactam ≤0.06–2 ≤0.06 ≤0.06
 Ticarcillin-clavulanate ≤0.06–0.25 ≤0.06 ≤0.06
 Ampicillin-sulbactam ≤0.06–0.5 ≤0.06 ≤0.06
 Cefoxitin ≤0.06–4 0.25 0.25
 Ceftriaxone ≤0.06–0.5 ≤0.06 0.125
 Chloramphenicol 1–2 1 2
 Clindamycin ≤0.06–32 ≤0.06 ≤0.06
 Metronidazole ≤0.06–0.25 0.125 0.25
Prevotella intermedia (13)
 MK-0826 ≤0.015–0.06 0.03 0.06
 Imipenem ≤0.015–0.06 ≤0.015 0.03
 Piperacillin-tazobactam ≤0.06 ≤0.06 ≤0.06
 Ticarcillin-clavulanate ≤0.06 ≤0.06 ≤0.06
 Ampicillin-sulbactam ≤0.06–0.25 ≤0.06 0.25
 Cefoxitin ≤0.06–2 0.25 0.5
 Ceftriaxone ≤0.06–2 ≤0.06 2
 Chloramphenicol 0.5–2 1 2
 Clindamycin ≤0.06 ≤0.06 ≤0.06
 Metronidazole ≤0.06–2 1 2
Prevotella spp. (28)j
 MK-0826 ≤0.015–0.5 0.06 0.5
 Imipenem ≤0.015–0.25 0.03 0.25
 Piperacillin-tazobactam ≤0.06–4 ≤0.06 1
 Ticarcillin-clavulanate ≤0.06–1 ≤0.06 0.5
 Ampicillin-sulbactam ≤0.06–8 0.125 2
 Cefoxitin ≤0.06–16 1 16
 Ceftriaxone ≤0.06–>128 0.5 16
 Chloramphenicol 1–8 2 4
 Clindamycin ≤0.06–>32 ≤0.06 4
 Metronidazole ≤0.06–2 0.5 2
Miscellaneous gram-negative Bacillus spp. (32)k
 MK-0826 ≤0.015–>32 0.125 0.5
 Imipenem ≤0.015–16 0.125 0.5
 Piperacillin-tazobactam ≤0.06–>128 0.25 >128
 Ticarcillin-clavulanate ≤0.06–>128 0.25 4
 Ampicillin-sulbactam ≤0.06–>32 0.5 4
 Cefoxitin 0.25–>128 2 32
 Ceftriaxone ≤0.06–>128 4 32
 Chloramphenicol 0.25–32 2 8
 Clindamycin ≤0.06–>32 0.25 >32
 Metronidazole ≤0.06–>32 0.25 4
Miscellaneous gram-positive spp. (12)l
 MK-0826 0.06–0.5 0.125 0.5
 Imipenem ≤0.015–0.125 ≤0.015 0.125
 Piperacillin-tazobactam ≤0.06–2 0.125 1
 Ticarcillin-clavulanate ≤0.06–4 ≤0.06 2
 Ampicillin-sulbactam ≤0.06–1 0.125 0.5
 Cefoxitin 0.125–32 0.5 2
 Ceftriaxone ≤0.06–0.5 0.25 0.5
 Chloramphenicol 0.5–8 1 2
 Clindamycin ≤0.06–4 0.125 4
 Metronidazole 4–>32 >32 >32
 Vancomycin 0.125–4 0.5 2
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a

Includes metronidazole-resistant strains that did not grow aerobically or in 10% CO2. 

b

B. merdae (n = 4) and B. stercoris (n = 12). 

c

C. bifermentans (n = 4), C. butyricum (n = 5), C. cadaveris (n = 2), C. cochlearium (n = 1), C. difficile (n = 3), C. leptum (n = 1), C. sordellii (n = 3), C. sphenoides (n = 1), C. sporogenes (n = 1), C. symbiosum (n = 7), C. tertium (n = 2), and no good fit (n = 6). 

d

E. aerofaciens (n = 2), E. contortum (n = 1), E. limosum (n = 2), no good fit (n = 49). 

e

F. mortiferum (n = 6), and F. varium (n = 3). 

f

F. gonidiaformans (n = 1), F. necrophorum (n = 8), and F. nucleatum (n = 8). 

g

L. acidophilus (n = 1), L. casei (n = 4), L. catenaforme (n = 2), L. confusus (n = 1), L. delbrueckii (n = 1), L. fermentum (n = 1), L. plantarum (n = 3), and no good fit (n = 5). 

h

P. anaerobius (n = 4), P. asaccharolyticus (n = 3), P. heliotinreducens (n = 1), P. magnus (n = 6), P. prevotii (n = 5), P. productus (n = 1), P. tetraadius (n = 1) and no good fit (n = 4). 

i

P. asaccharolytica (n = 15), P. gingivalis (n = 2), and no good fit (n = 3). 

j

P. bivia (n = 1), P. buccae (n = 7), P. corporis (n = 1), P. melaninogenica (n = 8), P. oris (n = 2), and no good fit (n = 9). 

k

Miscellaneous gram-negative bacillus species include Acidaminococcus fermentans (n = 2), Bacteroides capillosus (n = 2), Bacteroides fragilis group, no good fit (n = 4), Bacteroides putredinis (n = 6), Bacteroides ureolyticus (n = 1), Bacteroides species, no good fit (n = 3), Campylobacter gracilis (n = 3), Desulfomonas pigra (n = 1), Desulfomonas species (n = 1), Dialister pneumosintes (n = 2), Sutterella wadsworthensis (n = 1), Tissierella praecuta (n = 1), Veillonella species (n = 2), unusual gram-negative rods, no good fit (n = 3). 

l

Miscellaneous gram-positive organisms include Actinomyces odontolyticus (n = 2), Actinomyces species (n = 1), Bifidobacterium breve (n = 1), Propionibacterium acnes (n = 5), Propionibacterium avidum (n = 1), Propionibacterium species (n = 1), unusual gram-positive bacilli, no good fit (n = 1). 

Standard laboratory powders were supplied as follows: MK-0826, imipenem, and cefoxitin, Merck & Co., West Point, Pa.; ticarcillin and clavulanate, SmithKline Beecham, Philadelphia, Pa.; piperacillin and tazobactam, Wyeth-Ayerst, Philadelphia, Pa.; ampicillin and sulbactam, Pfizer Inc., New York, N.Y.; clindamycin, Pharmacia Upjohn Co., Kalamazoo, Mich.; metronidazole, Searle Research & Development, Skokie, Ill.; penicillin G and chloramphenicol, Sigma Chemical Co., St. Louis, Mo.; ceftriaxone, Roche, Nutley, N.J.; and vancomycin, Eli Lilly & Co., Indianapolis, Ind.

RESULTS AND DISCUSSION

Table 1 analyzes the demographics of the specimens received. Four hundred twenty-seven individual specimens were received from the 29 study sites in 17 countries. Bacterial growth was obtained for 72.7 to 100% of specimens (mean, 93%; median, 95.2%), usually as mixed growth, and yielded an average of 3 aerobes (range, 0 to 9) and 2.3 anaerobes (range, 0 to 13) per specimen. This particularly attests to the quality of the transport system used, since the median time from collection of specimens to processing was 4 days (range, 2 to 62 days). While specimens from Canada and certain European countries generally arrived within 36 to 72 h, the sometimes erratic policies of other international airlines and couriers meant that specimens from Mexico or South Africa, for example, often sat in transit up to 1 week from the day of collection; in the case of Russia, one specimen was “lost” for 6 weeks, yet it still yielded eight anaerobes.

Baron et al. (2) looked at the effect of long-distance transport on 10 specimens from diverse locations in the United States on isolate survival and found that it “did not compromise recovery of clinically relevant microbes.” They also noted no difference due to the weather conditions at the source location on recovery. A study by Bennion et al. (3) on the bacteriology of samples obtained from 30 patients with gangrene and perforated appendicitis noted the recovery of 2.7 aerobes and 7.4 anaerobes per specimen. They used local transportation (mean time, 15.7 h) and had optimal conditions of collection, transport, and culture. A survey of all relevant literature prior to that time noted an overall mean of 1.2 aerobes and 0.9 anaerobes per patient (3).

The comparative activities of MK-0826 and the other agents tested are presented in Table 2. Determination of susceptibility to MK-0826 was based on the published preliminary breakpoints for susceptibility (≤4 μg/ml), intermediate (8 μg/ml), and resistance (≥16 μg/ml) (4). In general, MK-0826 was active at ≤8 μg/ml against all anaerobes tested, including B. fragilis group species, with the exception of 12 of 61 (20%) Bilophila wadsworthia isolates, 3 isolates of Lactobacillus spp. (1 L. acidophilus isolate and 2 L. casei isolates), and 1 isolate of Acidaminococcus fermentans, for which the MICs were ≥16 μg/ml. MK-0826 was generally 1 to 2 dilutions less active than imipenem except against B. wadsworthia. Appleman et al. (38th ICAAC) also studied the comparative activities of MK-0826 against 88 anaerobic isolates obtained from 60 patients with serious intra-abdominal infections and found that MK-0826 had “excellent activity” against the 41 B. fragilis group strains (MICs at which 90% of isolates are inhibited [MIC90s], ≤4 μg/ml). Using the same agar dilution method that we used, they found that 99% of their isolates were susceptible to both MK-0826 and imipenem (MICs, ≤4 μg/ml).

The gene for metalloenzymes, both constitutive and plasmid mediated, has been reported to occur in ∼1 to 3% of Bacteroides spp. (1, 12, 15). Expression requires the presence of zinc and a single-step conversion with insertion of an insertion sequence element into a promoter to cause carbapenem resistance. While this has been reported in clinical isolates, especially from Japan (1), only three strains of B. fragilis species showed some degree of carbapenem resistance in our study. For one strain of B. fragilis the MK-0826 MIC was 8 μg/ml (intermediate), for one strain of Bacteroides caccae the imipenem MIC was 32 μg/ml and the MK-0826 MIC was 8 μg/ml, and for one strain of Bacteroides uniformis the imipenem MIC was 16 μg/ml.

As expected with a “static” agent, the chloramphenicol MICs covered a wide range, with the chloramphenicol MICs for many isolates clustered at 4 to 8 μg/ml (the MIC for intermediate susceptibility is 16 μg/ml). While occasional metronidazole resistance has been noted (10, 15), including one report in which it was also associated with imipenem resistance, all of our 455 B. fragilis group species isolates were susceptible. Of note were our MIC90s of metronidazole for B. fragilis, B. thetaiotaomicron, and B. caccae, 4 μg/ml, which is slightly higher than the values usually obtained. This was due to a “statistical” occurrence since the MIC89 for each species was 2 μg/ml and was more usual. We retained the “accurate” but somewhat misleading value in Table 2. Overall, our data suggest that the frequency of metronidazole resistance remains low worldwide. Ceftriaxone had uniformly poor activity against B. fragilis group species. There appeared to be increasing levels of resistance of B. fragilis group species to ampicillin-sulbactam and cefoxitin compared to those in our prior survey (6).

Table 3 reports the comparative susceptibilities of the various agents studied by country when there were more than five isolates per genus or species. No differences were noted in the overall geographic susceptibilities of the anaerobes studied to MK-0826 or imipenem. B. wadsworthia isolates from the five countries from which such isolates were obtained had similar susceptibilities to all the agents studied. Appleman et al. (38th ICAAC) also noted that for 9 of the 10 strains of B. wadsworthia that they tested the MIC90 of MK-0826 was ≤2 μg/ml and that one strain was highly resistant. Clindamycin susceptibility varied the most by geographical origin. For B. fragilis, the isolates from Canada and Mexico were relatively more susceptible than those from other locations, although the number of strains studied is relatively small. Clostridium innocuum isolates from Canada and South Africa were generally more susceptible to clindamycin than were those isolated from Brazil and Guatemala, perhaps reflecting local antibiotic usage patterns.

TABLE 3.

Comparative susceptibilities to selected antimicrobial agents, by country

Isolate Country No. of isolates MIC (μg/ml)
MK-0826
Imipenem
Cefoxitin
Ampicillin-sulbactam
Piperacillin-tazobactam2
Clindamycin
Range 50%/90% Range 50%/90% Range 50%/90% Range 50%/90% Range 50%/90% Range 50%/90%
B. distasonis Brazil 7 0.125–1 0.5/−a 0.03–1 0.25/− 8–32 16/− 0.5–4 2/− 0.5–8 4/− 0.125–4 1/−
Guatemala 10 0.25–1 0.5/1 0.125–2 0.5/1 8–32 16/32 1–16 4/8 1–6 8/16 1–>32 4/>32
Switzerland 6 0.25–1 0.5/− 0.125–0.5 0.5/− 8–64 16/− 0.5–8 4/− 1–8 4/− 0.125–>32 2/−
B. fragilis Brazil 19 0.125–4 0.125/1 0.03–1 0.06/0.25 4–32 8/16 0.5–8 1/8 0.125–1 0.25/1 0.125–>32 0.5/>32
Canada 16 0.125–4 0.125/1 ≤0.015–1 0.06/0.5 4–32 8/16 0.25–8 1/4 ≤0.06–2 0.25/1 ≤0.06–1 0.5/1
Guatemala 22 0.125–8 0.125/4 0.03–1 0.06/0.25 4–32 8/16 0.5–16 1/8 0.125–4 0.5/2 0.125–>32 0.5/2
Mexico 5 0.125–0.5 0.125/− 0.03–0.125 0.06/− 8–16 8/− 0.5–4 1/− 0.125–0.5 0.25/− 0.25–1 0.5/−
Peru 13 0.125–8 0.25/4 0.06–2 0.06/1 8–32 16/32 1–8 1/8 0.125–4 1/2 ≤0.06–>32 1/2
Russia 12 0.125–1 0.125/0.25 0.06–0.5 0.125/0.25 4–32 8/16 0.5–8 1/4 0.125–16 0.25/0.5 0.25–>32 0.5/>32
South Africa 15 0.06–8 0.125/1 0.03–2 0.06/0.25 4–32 8/16 1–16 1/8 0.125–1 0.25/1 0.125–>32 0.5/1
Spain 11 0.125–4 0.125/1 ≤0.015–2 0.06/0.25 4–32 8/16 0.5–8 1/4 ≤0.06–16 1/1 ≤0.06–>32 2/>32
Switzerland 10 0.125–0.5 0.125/0.25 0.03–1 0.06/0.125 4–32 8/16 0.5–4 1/1 0.25–2 1/1 0.25–>32 0.5/32
B. ovatus Canada 7 0.5–1 0.5/− 0.125–0.5 0.25/− 16–32 32/− 1–2 1/− 2–32 8/− 0.25–>32 2/−
Guatemala 9 0.5–2 1/− 0.125–0.25 0.125/− 16–64 32/− 1–4 1/− 2–16 4/− ≤0.06–>32 2/−
Peru 5 0.25–4 0.5/− 0.125–1 0.125/− 16–128 16/− 1–8 1/− 2–8 2/− 0.25–>32 1/−
Switzerland 5 0.5–1 0.5/− 0.125–0.5 0.125/− 16–32 16/− 1–2 1/− 2–32 8/− 0.5–4 1/−
B. thetaiotaomicron Brazil 12 0.25–2 1/1 0.125–0.5 0.25/0.25 16–32 32/32 1–8 2/4 4–16 16/16 0.5–>32 8/>32
Canada 6 0.5–1 1/− 0.125–0.25 0.25/− 16–32 32/− 0.5–2 1/− 4–16 8/− 0.25–>32 2/−
Chile 5 0.5–1 0.5/− 0.125–0.25 0.125/− 16–32 32/− 1–1 1/− 4–16 8/− ≤0.06–>32 2/−
Colombia 5 1–2 1/− 0.125–0.5 0.5/− 32–128 32/− 1–16 8/− 16–16 16/− 4–>32 >32/−
Guatemala 18 0.5–1 1/1 0.06–0.25 0.125/0.25 16–64 32/32 1–2 1/2 8–32 16/32 1–>32 4/>32
Russia 10 0.125–2 1/1 0.125–0.25 0.25/0.25 8–64 32/32 1–8 2/8 0.25–16 8/16 0.25–>32 4/>32
South Africa 10 0.125–1 0.5/1 0.125–0.5 0.125/0.25 2–32 32/32 1–4 2/2 0.25–16 16/16 0.25–>32 4/4
Spain 7 0.25–1 0.5/− 0.125–0.5 0.125/− 8–32 32/− 1–4 2/− ≤0.06–16 8/− 0.5–>32 >32/−
Switzerland 9 0.5–2 1/− 0.125–0.5 0.25/− 8–32 32/− 1–4 2/− 0.125–16 16/− 0.5–8 2/−
B. uniformis Brazil 6 0.06–2 0.125/− 0.125–1 0.125/− 1–32 2/− 1–8 1/− 0.25–2 0.25/− 0.25–>32 >32/−
Russia 7 0.125–0.5 0.25/− 0.125–0.25 0.125/− 2–32 8/− 1–4 1/− ≤0.06–2 2/− ≤0.06–>32 1/−
South Africa 10 0.125–2 0.25/0.5 0.125–0.5 0.125/0.25 2–64 8/32 1–8 1/2 1–4 2/4 ≤0.06–>32 1/2
Switzerland 6 0.03–0.5 0.25/− 0.125–0.5 0.25/− 4–8 4/− ≤0.06–8 2/− ≤0.06–2 1/− ≤0.06–>32 1/−
B. vulgatus Brazil 8 0.03–0.25 0.125/− 0.03–0.5 0.06/− 2–4 4/− 0.25–4 1/− 1–4 2/− ≤0.06–>32 ≤0.06/−
Russia 5 0.125–0.5 0.125/− 0.03–0.125 0.03/− 4–16 4/− 0.25–2 1/− 1–2 1/− ≤0.06–>32 0.125/−
South Africa 5 0.06–0.125 0.125/− 0.06–0.25 0.06/− 2–8 2/− 0.5–1 0.5/− ≤0.06–2 2/− ≤0.06–>32 ≤0.06/−
B. wadsworthia Brazil 7 0.03–8 0.5/− 0.125–>32 0.25/− 2–32 16/− 1–8 2/− ≤0.06–128 16/− 0.25–1 0.5/−
Chile 5 ≤0.015–0.5 0.03/− 0.125–>32 0.25/− 4–32 16/− 1–4 2/− ≤0.06–64 16/− 0.25–0.5 0.5/−
Guatemala 14 ≤0.015–>32 0.125/>32 0.125–>32 0.125/>3 0.125–>128 4/>128 0.25–>32 2/>32 0.25–>128 16/>128 ≤0.06–2 0.5/0.5
Peru 5 ≤0.015–16 0.25/− 0.125–>32 0.25/− 2–128 4/− 1–32 2/− 1–>128 8/− 0.25–1 0.5/−
S. Africa 10 ≤0.015–>32 0.06/0.5 0.125–>32 0.125/0.25 0.125–32 16/16 0.25–>32 1/4 ≤0.06–128 8/32 <=0.06–0.5 0.5/0.5
C. clostridioforme Brazil 9 0.5–4 1/− 0.5–2 2/− 2–16 4/− 0.5–16 1/− 4–128 4/− 0.125–2 1/−
Guatemala 9 0.125–4 2/− 0.25–2 2/− 4–16 4/− 0.5–16 1/− ≤0.06–128 8/− 0.125–2 0.25/−
Peru 7 0.5–4 2/− 0.25–4 1/− 2–16 4/− 0.25–16 1/− 4–128 8/− ≤0.06–1 1/−
Russia 6 0.06–2 1/− 0.5–2 1/− 4–16 8/− 0.5–8 4/− 4–32 8/− ≤0.06–4 4/−
South Africa 7 0.125–4 0.5/− 0.5–4 1/− 2–16 4/− 0.5–8 1/− 0.5–64 4/− 0.125–4 0.5/−
Spain 5 0.5–4 2/− 1–4 1/− 4–16 16/− 0.5–16 1/− 0.25–64 8/− ≤0.06–1 0.125/−
C. innocuum Brazil 9 1–4 2/− 1–2 2/− 32–>128 64/− 0.125–0.5 0.25/− 0.5–1 1/− 0.5–>32 0.5/−
Canada 5 0.5–2 2/− 0.5–2 1/− 16–128 64/− ≤0.06–0.25 0.25/− 0.5–1 1/− 0.125–0.5 0.5/−
Guatemala 6 2–2 2/− 1–4 2/− 64–128 64/− 0.25–0.25 0.25/− 1–2 1/− 0.125–>32 1/−
S. Africa 6 1–2 2/− 1–1 1/− 32–64 64/− 0.125–0.5 0.25/− 0.5–1 1/− 0.25–0.5 0.5/−
C. perfringens Guatemala 10 ≤0.015–0.125 ≤0.015/0.03 ≤0.015–0.125 0.06/0.06 0.25–1 0.5/1 ≤0.06–0.125 ≤0.06/≤0.06 ≤0.06–0.5 ≤0.06/≤0.0 ≤0.06–4 1/2
South Africa 6 ≤0.015–0.06 0.03/− 0.03–0.125 0.06/− 0.5–2 1/− ≤0.06–≤0.06 ≤0.06/− ≤0.06–≤0.0 ≤0.06/− ≤0.06–2 0.5/−
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a

−, no data. 

This study demonstrates the potent anaerobic activity of MK-0826 against a wide range of clinical anaerobic isolates from diverse locations worldwide. Clinical trials to correlate these findings are in progress.

ACKNOWLEDGMENTS

We thank Judee H. Knight and Alice E. Goldstein for various forms of assistance.

This study was funded, in part, by an educational grant from Merck & Co., West Point, Pa.

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