Journal of Antimicrobial Chemotherapy (1999) 43, 703-706
© 1999 The British Society for Antimicrobial Chemotherapy
Brief report |
In-vitro antimicrobial activity of a carbapenem, MK-0826 (L-749,345) and provisional interpretive criteria for disc tests
The Clinical Microbiology Institute, 9725 SW Commerce Circle, Suite A-1, Wilsonville, OR 97070, USA
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResults and discussionReferences |
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The in-vitro activity of MK-0826, a new oral carbapenem, was compared with that of imipenem by broth microdilution susceptibility tests against 545 bacterial isolates. MK-0826 had significantly greater activity against Enterobacteriaceae and poorer activity against Pseudomonas aeruginosa and many Gram-positive species. MK-0826 disc diffusion tests were also performed according to the NCCLS procedure and tentative interpretive criteria were determined for possible susceptible MIC breakpoints of
4.0 and 2.0 mg/L. |
Introduction |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Carbapenems are a class of ß-lactam antibiotics structurally characterized by having a trans-hydroxyethyl side chain in position 6 of the ß-lactam molecule, and they lack sulphur or oxygen in the bicyclic nucleus. They exert a broad range of antibacterial activity against both Gram-positive and Gram-negative bacteria, and are stable to most ß-lactamases. 1,2,3,4 These features make them useful in the empirical treatment of many serious infections.
MK-0826 (L-749,345) is a new oral carbapenem with broad spectrum antimicrobial activity. The present study was designed to: (i) define the in-vitro antibacterial activity of MK-0826, in comparison with imipenem, against a broad variety of common species of aerobic and facultatively anaerobic bacteria, and (ii) determine tentative interpretive criteria for disc diffusion tests using commercially prepared 10 µg MK-0826 discs.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Micro-organisms
A collection of 545 bacterial isolates representing 34 species was selected from our stock culture collection of clinical isolates. The individual species and the number of isolates of each species are listed in the Table. Two or more of the following quality control (QC) isolates were tested on each test day: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213 (dilution tests only), S. aureus ATCC 25923 (disc tests only), Enterococcus faecalis ATCC 29212 (dilution tests only) and Streptococcus pneumoniae ATCC 49619. All 30 disc diffusion and all 59 broth microdilution susceptibility tests of imipenem were within published QC ranges. 5,6
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Antimicrobial agents
The study drugs, MK-0826 and imipenem, were provided as standardized powder by Merck, Sharp and Dohme (Rahway, NJ, USA). For the disc diffusion studies, commercially prepared 10 µg MK-0826 discs (BBL 508649) and 10 µg imipenem discs (BBL 501629) were used.
Test procedures
Disc diffusion and broth microdilution susceptibility tests were those outlined by the National Committee for Clinical Laboratory Standards (NCCLS). 5,6 When testing streptococci, the cation adjusted Mueller–Hinton broth was supplemented with 2–3% lysed horse blood to support growth and the agar contained 5% sheep blood.
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Results and discussion |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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The Table summarizes the MICs of MK-0826 and imipenem for all 545 bacterial isolates tested. The activity of MK-0826 differed significantly from that of imipenem against different organism groups (Table). Against members of the family Enterobacteriaceae, MK-0826 was considerably more active than imipenem. This varied from as little as three times greater activity against Citrobacter diversus to 12–90 times greater activity against members of the tribe Proteeae. In contrast, imipenem was 3–10 times more active against different Pseudomonas spp. and Acinetobacterspp. MK-0826 was nearly twice as active as imipenem against Stenotrophomonas maltophilia, and the two drugs were comparable in activity against Burkholderia cepacia. With the exception of Corynebacterium jeikeium, Gram-positive bacteria were inhibited by lower concentrations of imipenem than MK-0826. The differences were minimal for some streptococcal species, but were three- to-six-fold for different staphylococcal species.
The Figure displays a scattergram comparing MK-0826 MICs and disc
diffusion zone diameters.
The zone diameter breakpoints were determined for possible MIC breakpoints of 2.0 or
4.0 mg/L for susceptible and 
8.0 or 16 mg/L for resistant. The MIC breakpoint
ultimately selected will depend on continuing pharmacokinetic studies and clinical data. With
the 4.0 mg/L susceptible MIC breakpoint, the zone diameter breakpoints would be 16
mm for susceptible and 12 mm for resistant. With those breakpoints interpretive discrepancy
rates were very low, i.e. no very major discrepancies, 0.2% major discrepancies, and
4.4% minor
discrepancies. With a susceptible MIC breakpoint of 2.0 mg/L, the zone diameter
breakpoints would be 3 mm larger, with no major discrepancies, 0.8% very major
discrepancies
and 2.9% minor discrepancies. The corresponding discrepancy rates for imipenem disc
tests were
1.2%, 0 and 0.8%, respectively.
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0.92.MK-0826 is an interesting carbapenem with excellent activity against most Enterobacteriaceae. Against other species, MK-0826 is active but imipenem is more potent. Disc diffusion susceptibility tests with 10 mg MK-0826 discs perform reliably: provisional interpretive criteria were selected for use during continuing clinical trials. Those provisional criteria will be reassessed once data are available from the clinical trials.
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Acknowledgments |
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This study was made possible by a grant from Merck & Co., Inc., Merck, Sharp and Dohme, Rahway, NJ., USA.
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Notes |
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* Corresponding author. Tel: +1-503-682-3232; Fax: +1-503-682-2065
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References |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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1 . Hoban, D. J., Jones, R. N., Yamane, N., Frei, R., Trilla, A. & Pignatari, A. C. (1993). In-vitro activity of three carbapenem antibiotics: comparative studies with biapenem (L-627), imipenem, and meropenem against aerobic pathogens isolated worldwide. Diagnostic Microbiology and Infectious Disease 17, 299–305.[Web of Science][Medline]
2 . Kropp, H. L., Gerckens, L., Sundelof, J. G. & Kahan, F. M. (1985). Antibacterial activity of imipenem: the first thienamycin antibiotic. Review of Infectious Diseases 7 , Suppl. 3, S389–410.
3
.
Malanoski, G. J., Collins, L., Wennersten, C., Moellering, R. C. & Eliopoulos, G. M. (1993).
In-vitro activity of biapenem against clinical isolates of Gram-positive and Gram-negative
bacteria. Antimicrobial Agents and Chemotherapy37 , 2009–16.
4
.
Neu, H. C. & Labthavikul, P. (1982). Comparative in-vitro activity of
N-formimidoyl
thienamycin against Gram-positive and Gram-negative aerobic and anaerobic species and its
ß -lactamase stability. Antimicrobial Agents and Chemotherapy21 , 180–7.
5 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically— Fourth Edition: Approved Standard M7-A4. NCCLS, Wayne, PA.
6 . National Committee for Clinical Laboratory Standards. (1997). Performance Standards for Antimicrobial Disk Susceptibility Tests— Sixth Edition: Approved Standard M2-A6 . NCCLS, Wayne, PA.
Received 16 September 1998; returned 11 November 1998; revised 7 December 1998; accepted 6 January 1999
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