Comparative In Vitro Activities of Ertapenem (MK-0826) - Antimicrobial ...

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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.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2000, p. 2389–2394 0066-4804/00/$04.00⫹0 Copyright © 2000, American Society for Microbiology. All Rights Reserved.

Vol. 44, No. 9

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 AND KERIN L. TYRRELL1 R. M. Alden Research Laboratory, Santa Monica-University of California at Los Angeles Medical Center, Santa Monica, California 90404,1 and School of Medicine, University of California at Los Angeles, Los Angeles, California 900242 Received 18 February 2000/Returned for modification 14 May 2000/Accepted 12 June 2000

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. 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.

Ertapenem (MK-0826; L749,345; 1-␤-methyl carbapenem (4R,5S,6S,8R,21S,41S)-3-[2-[[(3-carboxyphenyl)amino]carbonyl]pyrrolidin-4-yl]-4-methyl-6-(1-hydroxyethyl)-7-oxo-1azabicyclo[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

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. For the in vitro susceptibility studies, isolates were taken from frozen stocks

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 Belgium Brazil Canada Chile Colombia France Germany Guatemala Italy Mexico Peru Russia South Africa Spain Switzerland Venezuela

1 1 1 3 1 2 1 1 1 3 1 1 1 3 4 3 1

8 8 44 49 22 24 6 3 46 15 11 21 42 68 32 26 2

100.0 100.0 90.9 93.9 77.3 87.5 100.0 100.0 95.7 86.7 72.7 95.2 92.9 92.6 96.9 100.0 100.0

0.0 12.5 4.5 10.2 0.0 8.3 0.0 0.0 4.3 6.7 18.2 9.5 0.0 1.5 0.0 7.7 0.0

62.5 12.5 22.7 28.6 22.7 33.3 16.7 0.0 4.3 20.0 0.0 9.5 19.0 36.8 40.6 11.5 100.0

0.4 2.4 3.2 2.0 2.8 1.3 2.5 2.0 4.1 2.2 3.5 3.4 2.6 2.3 1.9 2.8 0.0

1.9 3.5 2.8 2.2 3.1 2.9 4.5 2.7 4.0 2.6 2.8 2.8 3.4 3.2 2.8 3.3 2.0

0–1 0–4 0–8 0–8 0–6 0–6 0–6 1–3 0–11 0–6 0–7 0–8 0–8 0–13 0–8 0–6 0–0

1–3 0–5 0–7 0–6 0–6 0–6 3–7 2–3 0–7 0–6 0–7 0–6 0–7 0–9 0–7 0–9 1–3

26–62 (32) 2–6 (3) 2–6 (3) 1–7 (2) 2–7 (3) 2–8 (3) 2–5 (3) 2–3 (3) 2–8 (4) 4–10 (7) 2–11 (5) 1–8 (3) 3–37 (8) 3–15 (7) 2–7 (5) 2–15 (5) 7–34

a b

With any growth. From date of collection to date of processing.

* Corresponding author. Mailing address: 2021 Santa Monica Blvd., Suite 640E, Santa Monica, CA 90404. Phone: (310) 315-1511. Fax: (310) 315-3662. E-mail: [email protected]. 2389

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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)

Anaerobic streptococcus spp. (15)a MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

MIC (␮g/ml) Range

ⱕ0.015–0.25 ⱕ0.015–0.06 ⱕ0.06–1 ⱕ0.06–2 ⱕ0.06–0.25 0.125–8 ⱕ0.06–16 1–8 ⱕ0.06–0.25 ⱕ0.06–⬎32 0.125–1

50%

0.03 ⱕ0.015 ⱕ0.06 ⱕ0.06 ⱕ0.06 1 ⱕ0.06 2 ⱕ0.06 32 0.6

90%

Range

0.25 0.06 0.5 1 0.25 8 2 4 0.125 ⬎32 1

Bacteroides stercoris-Bacteroides merdae group (16)b MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.03–1 0.06–0.5 ⱕ0.06–16 ⱕ0.06–16 0.25–16 0.5–64 0.125–⬎128 0.5–8 ⱕ0.06–⬎3 0.5–4

0.5 0.5 1 0.5 1 8 16 4 1 2

1 0.5 8 4 4 32 ⬎128 8 ⬎32 2

Bacteroides thetaiotaomicron (90) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.03–2 0.06–0.5 ⱕ0.06–32 ⱕ0.06–16 0.5–16 1–128 4–⬎128 2–16 ⱕ0.06–⬎32 0.25–4

1 0.25 16 1 1 32 64 8 4 1

1 0.25 16 4 4 32 ⬎128 8 ⬎32 4

Bacteroides uniformis (50) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.03–2 0.125–16 ⱕ0.06–⬎128 0.125–⬎128 ⱕ0.06–⬎32 1–64 4–⬎128 2–8 ⱕ0.06–⬎32 ⱕ0.06–4

0.25 0.125 2 0.5 1 8 32 8 1 2

1 0.5 8 2 4 32 ⬎128 8 ⬎32 2

Bacteroides vulgatus (33) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.015–1 0.125 0.03–1 0.125 ⱕ0.06–16 2 ⱕ0.06–4 0.125 0.25–16 1 1–16 4 0.5–⬎128 3 0.5–8 4 ⱕ0.06–⬎32 ⱕ0.06 0.25–2 1

0.5 0.5 8 2 8 16 128 4 ⬎32 2

Bilophila wadsworthia (51) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.015–⬎32 0.06–⬎32 ⱕ0.06–⬎128 ⱕ0.06–⬎128 0.25–⬎32 0.125–⬎128 ⱕ0.06–⬎128 0.5–8 ⱕ0.06–4 ⱕ0.06–0.25

0.06 0.25 16 0.25 2 16 1 4 0.5 0.125

⬎32 ⬎32 ⬎128 ⬎128 16 ⬎128 ⬎128 8 1 0.25

0.06–4 0.125–4 ⱕ0.06–128 1–128 0.25–16 2–16 0.5–128 1–8 ⱕ0.06–4 ⱕ0.06–2 0.5–1

1 1 8 16 1 4 4 2 1 0.125 0.5

4 2 128 32 16 16 64 4 2 0.25 1

Bacteroides caccae (27) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.125–8 0.03–32 ⱕ0.06–⬎128 ⱕ0.06–⬎128 0.5–⬎32 4–64 1–⬎128 4–8 ⱕ0.06–⬎32 0.25–8

0.5 0.125 2 1 2 16 32 8 2 1

4 0.25 16 8 8 64 ⬎128 8 ⬎32 4

Bacteroides distasonis (50) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.125–4 0.03–4 0.125–⬎128 0.125–⬎128 0.5–⬎32 8–⬎128 0.5–⬎128 4–8 ⱕ0.06–⬎32 0.25–4

0.5 0.5 4 4 4 16 32 8 2 1

2 2 16 32 16 64 ⬎128 8 ⬎32 2

Bacteroides fragilis (134) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.06–8 ⱕ0.5–2 ⱕ0.06–16 ⱕ0.06–64 0.25–16 4–32 0.5–⬎128 2–16 ⱕ0.06–⬎32 0.125–8

0.125 0.06 0.25 0.25 1 8 16 4 0.5 1

Bacteroides ovatus (46) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.25–4 0.125–4 0.25–32 0.25–16 0.5–16 4–128 32–⬎128 4–8 ⱕ0.06–⬎32 ⱕ0.06–4

0.5 0.125 4 1 1 32 64 8 2 1

Bacteroides splanchnicus (9) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

0.03–0.06 ⱕ0.015–0.06 ⱕ0.06–0.5 ⱕ0.06–0.5 0.5 0.5–2 1–8 2–16 ⱕ0.06–⬎32 ⱕ0.06–0.5

0.03 0.03 ⱕ0.06 ⱕ0.06 0.5 1 4 4 ⱕ0.06 0.25

MIC (␮g/ml)

Organism and agent (no. of isolates)

1 0.25 1 2 8 16 64 8 ⬎32 4 1 0.5 16 2 4 32 ⬎128 8 ⬎32 2

Clostridium clostridioforme (53) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

50%

90%

Continued on following page

VOL. 44, 2000

COMPARATIVE ACTIVITIES OF MK-0826 AGAINST ANAEROBES

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TABLE 2—Continued Organism and agent (no. of isolates)

MIC (␮g/ml) Range

50%

90%

Clostridium innocuum (40) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

0.5–4 0.5–4 0.5–2 4–16 ⱕ0.06–0.5 16–⬎128 2–16 8–16 0.125–⬎32 0.25–2 8–16

2 1 1 16 0.25 64 8 8 0.5 1 8

Clostridium perfringens (29) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

ⱕ0.015–0.125 ⱕ0.015–0.125 ⱕ0.06–0.5 ⱕ0.06–0.5 ⱕ0.06–0.125 0.25–2 ⱕ0.06–2 1–4 ⱕ0.06–4 0.125–8 0.25–0.5

ⱕ0.015 0.06 ⱕ0.06 0.25 ⱕ0.06 0.5 ⱕ0.06 4 0.25 1 0.5

0.06 0.125 0.125 0.5 0.125 1 2 4 2 4 0.5

Clostridium ramosum (20) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

0.25–1 0.125–0.25 ⱕ0.06–0.5 0.5–8 ⱕ0.06–0.25 2–64 0.125–0.25 2–32 2–⬎32 0.5–2 4

0.5 0.125 ⱕ0.06 1 ⱕ0.06 8 0.25 4 4 1 4

1 0.25 0.5 4 0.125 64 0.25 8 ⬎32 2 4

Clostridium spp. (36)c MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

ⱕ0.015–4 ⱕ0.015–4 ⱕ0.06–32 ⱕ0.06–64 ⱕ0.06–4 0.125–128 ⱕ0.06–128 0.125–⬎32 ⱕ0.06–⬎32 ⱕ0.06–8 0.125–8

0.126 0.125 0.25 2 0.25 4 2 2 0.25 0.25 1

Eubacterium lentum (41) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

0.03–1 ⱕ0.015–0.5 ⱕ0.06–32 ⱕ0.06–64 ⱕ0.06–2 0.5–128 ⱕ0.06–⬎128 2–8 ⱕ0.06–⬎32 0.125–⬎32 0.25–16

Eubacterium spp. (54)d MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftrixone

ⱕ0.015–1 ⱕ0.015–1 ⱕ0.06–64 ⱕ0.06–32 ⱕ0.06–2 ⱕ0.06–2 ⱕ0.06–1

0.5 0.25 16 16 1 8 64 4 0.25 0.5 1 0.06 0.03 0.126 1 0.125 ⱕ0.06 0.125

2 2 1 16 0.25 128 8 16 ⬎32 2 16

2 1 8 32 2 64 32 4 8 2 2 1 0.5 32 32 2 16 ⬎128 8 2 1 2 1 0.25 16 32 1 2 1

Organism and agent (no. of isolates)

MIC (␮g/ml) Range

50%

0.25–8 ⱕ0.06–⬎32

2 ⱕ0.06

Fusobacterium mortiferumFusobacterium varium (9)e MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.015–0.25 0.125–1 ⱕ0.06–4 1–4 0.5–8 2–8 ⱕ0.06–⬎128 0.25–2 ⱕ0.06–4 0.25–1

0.125 0.5 0.25 2 1 4 64 0.5 ⱕ0.06 0.5

Fusobacterium spp. (17)f MK-0826 Imipenem Piperacillin-tazobactam Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.015–0.25 ⱕ0.015–0.125 ⱕ0.06–32 ⱕ0.06–0.25 ⱕ0.06–2 ⱕ0.06–1 0.5–2 ⱕ0.06 ⱕ0.06–0.5

ⱕ0.015 ⱕ0.015 ⱕ0.06 ⱕ0.06 ⱕ0.06 0.125 1 ⱕ0.06 0.125

Lactobacillus spp. (18)g MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

0.03–⬎32 ⱕ0.015–8 ⱕ0.06–4 ⱕ0.06–64 ⱕ0.06–4 0.25–⬎128 ⱕ0.06–⬎128 1–⬎32 ⱕ0.06–4 0.5–⬎32 0.25–⬎32

0.25 0.125 0.5 4 0.25 128 0.5 4 0.125 ⬎32 8

Peptostreptococcus micros (23) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

0.03–0.125 ⱕ0.015–0.06 ⱕ0.06 ⱕ0.06–0.25 ⱕ0.06–0.5 0.25–2 0.125–1 1–2 ⱕ0.06–0.25 0.125–0.5 0.5

0.06 ⱕ0.015 ⱕ0.06 ⱕ0.06 ⱕ0.06 0.5 0.25 2 0.125 0.25 0.5

Peptostreptococcus spp. (25)h MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

ⱕ0.015–2 ⱕ0.015–0.5 ⱕ0.06–32 ⱕ0.06–128 ⱕ0.06–8 ⱕ0.06–8 ⱕ0.06–8 1–8 ⱕ0.06–16 ⱕ0.06–⬎32 ⱕ0.06–1

0.06 0.03 0.25 0.5 ⱕ0.06 1 1 2 ⱕ0.06 0.5 0.25

Porphyromonas spp. (20)i MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate

ⱕ0.015–0.06 ⱕ0.015–0.25 ⱕ0.06–2 ⱕ0.06–0.25

ⱕ0.015 ⱕ0.015 ⱕ0.06 ⱕ0.06

Chloramphenicol Clindamycin Metronidazole Vancomycin

ⱕ0.06–⬎32 ⱕ0.06–2

0.25 0.5

90%

8 0.5 4 2

0.03 0.125 ⱕ0.06 0.125 2 1 2 ⱕ0.06 0.25 ⬎32 8 4 64 4 ⬎128 ⬎128 16 4 ⬎32 ⬎32 0.06 0.06 ⱕ0.06 ⱕ0.06 0.125 1 0.5 2 0.25 0.5 0.5 0.5 0.5 2 16 0.5 8 8 4 2 2 1 ⱕ0.015 0.03 ⱕ0.06 ⱕ0.06

Continued on following page

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ANTIMICROB. AGENTS CHEMOTHER. TABLE 2—Continued

Organism and agent (no. of isolates)

MIC (␮g/ml) Range

50%

90%

Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.06–0.5 ⱕ0.06–4 ⱕ0.06–0.5 1–2 ⱕ0.06–32 ⱕ0.06–0.25

ⱕ0.06 0.25 ⱕ0.06 1 ⱕ0.06 0.125

ⱕ0.06 0.25 0.125 2 ⱕ0.06 0.25

Prevotella intermedia (13) MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.015–0.06 ⱕ0.015–0.06 ⱕ0.06 ⱕ0.06 ⱕ0.06–0.25 ⱕ0.06–2 ⱕ0.06–2 0.5–2 ⱕ0.06 ⱕ0.06–2

0.03 ⱕ0.015 ⱕ0.06 ⱕ0.06 ⱕ0.06 0.25 ⱕ0.06 1 ⱕ0.06 1

0.06 0.03 ⱕ0.06 ⱕ0.06 0.25 0.5 2 2 ⱕ0.06 2

Prevotella spp. (28)j MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol

ⱕ0.015–0.5 ⱕ0.015–0.25 ⱕ0.06–4 ⱕ0.06–1 ⱕ0.06–8 ⱕ0.06–16 ⱕ0.06–⬎128 1–8

0.06 0.03 ⱕ0.06 ⱕ0.06 0.125 1 0.5 2

0.5 0.25 1 0.5 2 16 16 4

Organism and agent (no. of isolates)

Clindamycin Metronidazole

MIC (␮g/ml) Range

50%

90%

ⱕ0.06–⬎32 ⱕ0.06–2

ⱕ0.06 0.5

4 2

Miscellaneous gram-negative Bacillus spp. (32)k MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole

ⱕ0.015–⬎32 ⱕ0.015–16 ⱕ0.06–⬎128 ⱕ0.06–⬎128 ⱕ0.06–⬎32 0.25–⬎128 ⱕ0.06–⬎128 0.25–32 ⱕ0.06–⬎32 ⱕ0.06–⬎32

0.125 0.125 0.25 0.25 0.5 2 4 2 0.25 0.25

Miscellaneous gram-positive spp. (12) l MK-0826 Imipenem Piperacillin-tazobactam Ticarcillin-clavulanate Ampicillin-sulbactam Cefoxitin Ceftriaxone Chloramphenicol Clindamycin Metronidazole Vancomycin

0.06–0.5 ⱕ0.015–0.125 ⱕ0.06–2 ⱕ0.06–4 ⱕ0.06–1 0.125–32 ⱕ0.06–0.5 0.5–8 ⱕ0.06–4 4–⬎32 0.125–4

0.125 ⱕ0.015 0.125 ⱕ0.06 0.125 0.5 0.25 1 0.125 ⬎32 0.5

0.5 0.5 ⬎128 4 4 32 32 8 ⬎32 4

0.5 0.125 1 2 0.5 2 0.5 2 4 ⬎32 2

a

Includes metronidazole-resistant strains that did not grow aerobically or in 10% CO2. B. merdae (n ⫽ 4) and B. stercoris (n ⫽ 12). 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). b c

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 ␮g/ml, and piperacillin was diluted with tazobactam and was tested at a constant concentration of 4 ␮g/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. 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.

2393 COMPARATIVE ACTIVITIES OF MK-0826 AGAINST ANAEROBES VOL. 44, 2000

TABLE 3. Comparative susceptibilities to selected antimicrobial agents, by country

Range

0.25/⫺ 0.5/1 0.5/⫺

50%/90%

8–32 8–32 8–64

Range

8/16 8/16 8/16 8/⫺ 16/32 8/16 8/16 8/16 8/16

16/⫺ 16/32 16/⫺

50%/90%

1–2 1–4 1–8 1–2

0.5–8 0.25–8 0.5–16 0.5–4 1–8 0.5–8 1–16 0.5–8 0.5–4

0.5–4 1–16 0.5–8

Range

1/⫺ 1/⫺ 1/⫺ 1/⫺

1/8 1/4 1/8 1/⫺ 1/8 1/4 1/8 1/4 1/1

2/⫺ 4/8 4/⫺

50%/90%

4–16 4–16 4–16 16–16 8–32 0.25–16 0.25–16 ⱕ0.06–16 0.125–16

2–32 2–16 2–8 2–32

0.125–1 ⱕ0.06–2 0.125–4 0.125–0.5 0.125–4 0.125–16 0.125–1 ⱕ0.06–16 0.25–2

0.5–8 1–6 1–8

Range

16/16 8/⫺ 8/⫺ 16/⫺ 16/32 8/16 16/16 8/⫺ 16/⫺

8/⫺ 4/⫺ 2/⫺ 8/⫺

0.25/1 0.25/1 0.5/2 0.25/⫺ 1/2 0.25/0.5 0.25/1 1/1 1/1

4/⫺ 8/16 4/⫺

50%/90%

0.5–⬎32 0.25–⬎32 ⱕ0.06–⬎32 4–⬎32 1–⬎32 0.25–⬎32 0.25–⬎32 0.5–⬎32 0.5–8

0.25–⬎32 ⱕ0.06–⬎32 0.25–⬎32 0.5–4

0.125–⬎32 ⱕ0.06–1 0.125–⬎32 0.25–1 ⱕ0.06–⬎32 0.25–⬎32 0.125–⬎32 ⱕ0.06–⬎32 0.25–⬎32

0.125–4 1–⬎32 0.125–⬎32

⬎32/⫺ 1/⫺ 1/2 1/⫺

8/⬎32 2/⫺ 2/⫺ ⬎32/⫺ 4/⬎32 4/⬎32 4/4 ⬎32/⫺ 2/⫺

2/⫺ 2/⫺ 1/⫺ 1/⫺

0.5/⬎32 0.5/1 0.5/2 0.5/⫺ 1/2 0.5/⬎32 0.5/1 2/⬎32 0.5/32

1/⫺ 4/⬎32 2/⫺

MIC (␮g/ml)

50%/90%

0.03–1 0.125–2 0.125–0.5 4–32 4–32 4–32 8–16 8–32 4–32 4–32 4–32 4–32 32/⫺ 32/⫺ 16/⫺ 16/⫺

2/4 1/⫺ 1/⫺ 8/⫺ 1/2 2/8 2/2 2/⫺ 2/⫺

0.25–⬎32 ⱕ0.06–⬎32 ⱕ0.06–⬎32 ⱕ0.06–⬎32

0.25–1 0.25–0.5 ⱕ0.06–2 0.25–1 ⬍⫽0.06–0.5

50%/90%

16/⫺ 16/⫺ 16/⬎128 8/⫺ 8/32

0.125–2 0.125–2 ⱕ0.06–1 ⱕ0.06–4 0.125–4 ⱕ0.06–1

0.5/⫺ 0.5/⫺ 1/⫺ 0.5/⫺

Range

Clindamycin

Range

0.5/⫺a 0.5/1 0.5/⫺ 0.06/0.25 0.06/0.5 0.06/0.25 0.06/⫺ 0.06/1 0.125/0.25 0.06/0.25 0.06/0.25 0.06/0.125 16–32 16–64 16–128 16–32

1–8 0.5–2 1–1 1–16 1–2 1–8 1–4 1–4 1–4

0.25/⫺ 2/⫺ 2/4 1/⫺

ⱕ0.06–128 ⱕ0.06–64 0.25–⬎128 1–⬎128 ⱕ0.06–128

4/⫺ 8/⫺ 8/⫺ 8/⫺ 4/⫺ 8/⫺

0.5–⬎32 0.125–0.5 0.125–⬎32 0.25–0.5

1/2 0.5/⫺

1/⫺ 0.25/⫺ 1/⫺ 4/⫺ 0.5/⫺ 0.125/⫺

0.5/⫺ 0.5/⫺ 0.5/0.5 0.5/⫺ 0.5/0.5 4–128 ⱕ0.06–128 4–128 4–32 0.5–64 0.25–64

1/⫺ 1/⫺ 1/⫺ 1/⫺

ⱕ0.06–4 ⱕ0.06–2

Piperacillin-tazobactam2

No. of isolates

0.125–1 0.25–1 0.25–1 0.03–1 ⱕ0.015–1 0.03–1 0.03–0.125 0.06–2 0.06–0.5 0.03–2 ⱕ0.015–2 0.03–1 0.25/⫺ 0.125/⫺ 0.125/⫺ 0.125/⫺

32/32 32/⫺ 32/⫺ 32/⫺ 32/32 32/32 32/32 32/⫺ 32/⫺

0.25–2 ⱕ0.06–2 1–4 ⱕ0.06–2

Ampicillin-sulbactam

Country

7 10 6 0.125/1 0.125/1 0.125/4 0.125/⫺ 0.25/4 0.125/0.25 0.125/1 0.125/1 0.125/0.25 0.125–0.5 0.125–0.25 0.125–1 0.125–0.5

16–32 16–32 16–32 32–128 16–64 8–64 2–32 8–32 8–32

1/⫺ 1/⫺ 1/2 2/⫺

ⱕ0.06/⫺ 0.125/⫺ ⱕ0.06/⫺

Cefoxitin

Brazil Guatemala Switzerland 0.125–4 0.125–4 0.125–8 0.125–0.5 0.125–8 0.125–1 0.06–8 0.125–4 0.125–0.5 0.5/⫺ 1/⫺ 0.5/⫺ 0.5/⫺ 0.25/0.25 0.25/⫺ 0.125/⫺ 0.5/⫺ 0.125/0.25 0.25/0.25 0.125/0.25 0.125/⫺ 0.25/⫺

1–8 1–4 1–8 ⱕ0.06–8

ⱕ0.06–⬎32 ⱕ0.06–⬎32 ⱕ0.06–⬎32

Imipenem

B. distasonis

19 16 22 5 13 12 15 11 10 0.5–1 0.5–2 0.25–4 0.5–1 0.125–0.5 0.125–0.25 0.125–0.25 0.125–0.5 0.06–0.25 0.125–0.25 0.125–0.5 0.125–0.5 0.125–0.5

2/⫺ 8/⫺ 8/32 4/⫺

2/⫺ 1/⫺ 2/⫺

MK-0826

B. fragilis Brazil Canada Guatemala Mexico Peru Russia South Africa Spain Switzerland 7 9 5 5 1/1 1/⫺ 0.5/⫺ 1/⫺ 1/1 1/1 0.5/1 0.5/⫺ 1/⫺

1–32 2–32 2–64 4–8

1–4 1–2 ⱕ0.06–2

Isolate

B. ovatus Canada Guatemala Peru Switzerland 0.25–2 0.5–1 0.5–1 1–2 0.5–1 0.125–2 0.125–1 0.25–1 0.5–2

0.125/⫺ 0.125/⫺ 0.125/0.25 0.25/⫺

1/⫺ 1/⫺ 0.5/⫺

B. thetaiotaomicron 12 6 5 5 18 10 10 7 9 0.125–1 0.125–0.25 0.125–0.5 0.125–0.5

0.25–4 0.25–2 0.5–1

Brazil Canada Chile Colombia Guatemala Russia South Africa Spain Switzerland 0.125/⫺ 0.25/⫺ 0.25/0.5 0.25/⫺

4/⫺ 4/⫺ 2/⫺

B. uniformis 0.06–2 0.125–0.5 0.125–2 0.03–0.5

2–4 4–16 2–8

B. wadsworthia

6 7 10 6

0.06/⫺ 0.03/⫺ 0.06/⫺

2/⫺ 2/⫺ 2/⬎32 2/⫺ 1/4

Brazil Russia South Africa Switzerland

0.03–0.5 0.03–0.125 0.06–0.25

1–8 1–4 0.25–⬎32 1–32 0.25–⬎32

B. vulgatus

0.125/⫺ 0.125/⫺ 0.125/⫺

16/⫺ 16/⫺ 4/⬎128 4/⫺ 16/16

Brazil Chile Guatemala Peru S. Africa

0.03–0.25 0.125–0.5 0.06–0.125

2–32 4–32 0.125–⬎128 2–128 0.125–32

C. clostridioforme

8 5 5

0.25/⫺ 0.25/⫺ 0.125/⬎3 0.25/⫺ 0.125/0.25

1/⫺ 1/⫺ 1/⫺ 4/⫺ 1/⫺ 1/⫺

9 9 7 6 7 5

Brazil Russia South Africa

0.125–⬎32 0.125–⬎32 0.125–⬎32 0.125–⬎32 0.125–⬎32

0.5–16 0.5–16 0.25–16 0.5–8 0.5–8 0.5–16

Brazil Guatemala Peru Russia South Africa Spain

0.5/⫺ 0.03/⫺ 0.125/⬎32 0.25/⫺ 0.06/0.5

4/⫺ 4/⫺ 4/⫺ 8/⫺ 4/⫺ 16/⫺

C. innocuum

0.03–8 ⱕ0.015–0.5 ⱕ0.015–⬎32 ⱕ0.015–16 ⱕ0.015–⬎32

2–16 4–16 2–16 4–16 2–16 4–16

0.5–1 0.5–1 1–2 0.5–1

7 5 14 5 10

2/⫺ 2/⫺ 1/⫺ 1/⫺ 1/⫺ 1/⫺

0.25/⫺ 0.25/⫺ 0.25/⫺ 0.25/⫺

1–4 0.5–2 2–2 1–2

0.5–2 0.25–2 0.25–4 0.5–2 0.5–4 1–4

0.125–0.5 ⱕ0.06–0.25 0.25–0.25 0.125–0.5

9 5 6 6

1/⫺ 2/⫺ 2/⫺ 1/⫺ 0.5/⫺ 2/⫺

64/⫺ 64/⫺ 64/⫺ 64/⫺

Brazil Canada Guatemala S. Africa

0.5–4 0.125–4 0.5–4 0.06–2 0.125–4 0.5–4

32–⬎128 16–128 64–128 32–64

ⱕ0.06/ⱕ0.0 ⱕ0.06/⫺

2/⫺ 1/⫺ 2/⫺ 1/⫺

ⱕ0.06–0.5 ⱕ0.06–ⱕ0.0

1–2 0.5–2 1–4 1–1

ⱕ0.06/ⱕ0.06 ⱕ0.06/⫺

2/⫺ 2/⫺ 2/⫺ 2/⫺

ⱕ0.06–0.125 ⱕ0.06–ⱕ0.06

ⱕ0.015/0.03 0.03/⫺

0.25–1 0.5–2

0.5/1 1/⫺

ⱕ0.015–0.125 ⱕ0.015–0.06

0.06/0.06 0.06/⫺

10 6

ⱕ0.015–0.125 0.03–0.125 Guatemala South Africa ⫺, no data.

C. perfringens a

2394

GOLDSTEIN ET AL.

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 (ⱕ4 ␮g/ml), intermediate (8 ␮g/ml), and resistance (ⱖ16 ␮g/ml) (4). In general, MK-0826 was active at ⱕ8 ␮g/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 ⱖ16 ␮g/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], ⱕ4 ␮g/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, ⱕ4 ␮g/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 ␮g/ml (intermediate), for one strain of Bacteroides caccae the imipenem MIC was 32 ␮g/ml and the MK-0826 MIC was 8 ␮g/ml, and for one strain of Bacteroides uniformis the imipenem MIC was 16 ␮g/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 ␮g/ml (the MIC for intermediate susceptibility is 16 ␮g/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 ␮g/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 ␮g/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

ANTIMICROB. AGENTS CHEMOTHER.

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 ⱕ2 ␮g/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. 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. REFERENCES 1. Bandoh, K., K. Ueno, K. Watanabe, and N. Kato. 1993. Susceptibility patterns and resistance to imipenem in the Bacteroides fragilis group species in Japan: a four-year study. Clin. Infect. Dis. 16(Suppl. 4):S382–S386. 2. Baron, E. J., C. A. Strong, M. McTeague, M. L. Vaisamen, and S. M. Finegold. 1995. Survival of anaerobes in original specimens transported by overnight mail services. Clin. Infect. Dis. 20(Suppl. 2):174–177. 3. Bennion, R. S., E. J. Baron, J. E. Thompson, J. Downes, P. Summanen, D. A. Talan, and S. M. Finegold. 1990. The bacteriology of gangrenous and perforated appendicitis—revisited. Ann. Surg. 211:155–171. 4. Fuchs, P. C., A. L. Barry, and S. D. Brown. 1999. In vitro antimicrobial activity of a carbapenem, MK-0826 (L-749,345) and provisional interpretive criteria for disc tests. J. Antimicrob. Chemother. 43:703–706. 5. Gill, C. J., J. J. Jackson, L. S. Gerckens, B. A. Pelak, R. K. Thompson, J. G. Sundelof, H. Kropp, and H. Rosen. 1998. In vitro activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L748,345). Antimicrob. Agents Chemother. 42:1996–2001. 6. Goldstein, E. J. C., and D. M. Citron. 1988. Bacteroides fragilis group: annual incidence, epidemiology, and comparative in vitro susceptibility to cefoxitin, cefotetan, cefmetazole, and ceftizoxime against recent community acquired isolates. J. Clin. Microbiol. 26:2361–2366. 7. Holdeman, L. V., and W. E. C. Moore. 1977. Anaerobic laboratory manual, 4th ed. Virginia Polytechnic Institute and State University, Blacksburg. 8. Jacoby, G., P. Han, and J. Tran. 1997. Comparative in vitro activities of carbapenem L-749,345 and other antimicrobials against multiresistant gramnegative clinical pathogens. Antimicrob. Agents Chemother. 41:1830–1831. 9. Koehler, J., K. L. Dorso, K. Young, G. G. Hammond, H. Rosen, H. Kropp, and L. L. Silver. 1999. In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum ␤-lactamase- and extended-spectrum ␤-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates. Antimicrob. Agents Chemother. 43:1170–1176. 10. Nariklawa, S., T. Suzuki, M. Yamamoto, and N. Nakamura. 1991. Lactate dehydrogenase activity as a cause of metronidazole resistance. J. Antimicrob. Chemother. 28:47–53. 11. National Committee for Clinical Laboratory Standards. 1997. Methods for antimicrobial susceptibility testing of anaerobic bacteria, 4th ed. Approved standard. NCCLS publication no. M11-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa. 12. Rasmussen, B. A., K. Bush, and F. P. Tally. 1993. Antimicrobial resistance in Bacteroides. Clin. Infect. Dis. 16(Suppl. 4):S390–S400. 13. Summanen, P., E. J. Baron, D. M. Citron, C. A. Strong, H. M. Wexler, and S. M. Finegold. 1993. Wadsworth anaerobic bacteriology manual, 5th ed. Star Publishing Co., Belmont, Calif. 14. Sundelof, J. G., R. Hajdu, C. J. Gill, R. Thompson, H. Rosen, and H. Kropp. 1997. Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates. Antimicrob. Agents Chemother. 41:1743–1748. 15. Turner, P., R. Edwards, V. Weston, A. Gazis, P. Ispahani, and D. Greenwood. 1995. Simultaneous resistance to metronidazole, co-amoxiclav, and imipenem in clincal isolates of Bacteroides fragilis. Lancet 345:1275–1277.