Journal of Antimicrobial Chemotherapy (2002) 50, 101-105
© 2002 The British Society for Antimicrobial Chemotherapy
Anti-anaerobic activity of AZD2563, a new oxazolidinone, compared with eight other agents
1 Department of Pathology, Hershey Medical Center, 500 University Drive, Hershey, PA 17033; 2 Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
Received 2 January 2002; returned 13 March 2002; revised 26 March 2002; accepted 13 April 2002
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Abstract |
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The anti-anaerobic activity of AZD2563, a new oxazolidinone, was compared with that of eight other agents against 201 Gram-positive and 99 Gram-negative anaerobes. MIC50 and MIC90 values (mg/L) for the 201 Gram-positive organisms were as follows: AZD2563, 1.0/4.0; linezolid, 1.0/4.0; quinupristin/dalfopristin, 0.5/1.0; amoxicillin, 0.25/1.0; clindamycin, 0.25/8.0; metronidazole, 0.5/>16.0; vancomycin, 0.5/2.0; teicoplanin, 0.125/0.25; and meropenem, 0.06/1.0. AZD2563, linezolid, vancomycin, teicoplanin and quinupristin/dalfopristin were mainly active against Gram-positive anaerobes, with no useful activity against Gram-negative anaerobes.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Anaerobes are frequent causes of human infections, especially in immunocompromised and otherwise debilitated hosts, e.g. intra-abdominal infections. ß-Lactamase production is found in most of the Bacteroides fragilis group, and has increasingly been found in Prevotella, Porphyromonas and Fusobacterium spp. Clindamycin resistance is found in the B. fragilis group and some Clostridium strains, and metronidazole resistance, common among anaerobic Gram-positive non-spore-forming bacilli, has also been found in the B. fragilis group.1–4
The oxazolidinones are a new class of synthetic antimicrobial agent active mainly against Gram-positive organisms, including Gram-positive anaerobes such as Clostridium spp., Peptostreptococcus spp. and Propionibacterium acnes. Linezolid, the oxazolidinone for which most data are currently available, is active against staphylococci, streptococci, enterococci, aerobic Gram-positive non-spore-forming bacilli as well as some anaerobes. Activity against Gram-negative organisms is less marked.5–8
The current study examines the in vitro activity of AZD2563, a new oxazolidinone targeted at Gram-positive infections,7 compared with that of linezolid, quinupristin/dalfopristin, amoxicillin, clindamycin, metronidazole, vancomycin, teicoplanin and meropenem against 300 Gram-positive and Gram-negative anaerobes. AZD2563 has a similar structure to linezolid, differing only at positions 3 and 4 of the aryl ring and on the C-5 side chain.7
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Strains were all clinical isolates, most of which were isolated during the past 3 years and identified by conventional methodology.9 Before testing, organisms were stored in double-strength skimmed milk (Difco Laboratories, Detroit, MI, USA) at –70°C. Purity throughout the study was checked by Gram’s stain and colonial morphology. AZD2563 was obtained from AstraZeneca Laboratories (Macclesfield, Cheshire, UK) and other drugs from their respective manufacturers. Amoxicillin powder was obtained from Sigma Chemical Co., Inc. (St Louis, MO, USA). ß-Lactamase production was tested by the cefinase disc method (BBL Microbiology Systems, Cockeysville, MD, USA).1 Agar dilution MICs were determined according to NCCLS methodology using Brucella laked blood agar plates and inocula of 1 x 105 cfu/mL.10 Plates were incubated for 48 h in anaerobic jars (BBL Microbiology Systems). Standard quality control strains were included in each run.10
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Results |
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MICs are presented in Table 1. Against Gram-positive strains, AZD2563, linezolid, quinupristin/dalfopristin, teicoplanin and vancomycin were generally active. MICs of AZD2563 and linezolid were similar. With the exception of one Peptostreptococcus, two lactobacilli and three clostridia (MICs 2.0–4.0 mg/L), quinupristin/dalfopristin MICs were all
1.0 mg/L for Gram-positive strains. Three lactobacilli with vancomycin and teicoplanin MICs of >16.0 mg/L were glycopeptide resistant. Vancomycin MICs for one strain each of Clostridium innocuum and Clostridium spp. were 16.0 mg/L; however, teicoplanin MICs for both strains were 0.5 and 0.25 mg/L, respectively.
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Against Gram-negative bacilli, activity of both oxazolidinones, glycopeptides and quinupristin/dalfopristin was poor, especially against members of the B. fragilis group; oxazolidinone MICs were lower for Prevotella, Porphyromonas and Fusobacterium spp.
Although most strains were susceptible to clindamycin, resistance was encountered in some Gram-negative and Gram-positive strains, particularly Clostridium difficile. With the exception of anaerobic Gram-positive non-spore-forming bacilli, all anaerobes were susceptible to metronidazole. Meropenem was very active against all strains tested with the exception of two strains of lactobacilli (both also glycopeptide resistant), for which meropenem MICs were 
8.0 mg/L.
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Discussion |
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Goldstein and co-workers5 have documented that the MIC of linezolid, the currently approved oxazolidinone, was
2.0 mg/L for fusobacteria, Prevotella spp., Porphyromonas spp. and peptostreptococci. Because only bite wound organisms were tested, no strains of the B. fragilis group were tested. Wise and co-workers6 have reported linezolid MICs of 4.0 mg/L for B. fragilis, <2.0 mg/L for Clostridium perfringens and 8.0 mg/L for C. difficile. MICs of AZD2563 for anaerobes in the current study were similar to those described above for linezolid, with lower MICs for Gram-positive compared with Gram-negative organisms and also low MICs for fusobacteria. Our results for linezolid are also similar to those of other workers cited above.5,6 Teicoplanin, like vancomycin, was active only against Gram-positive organisms.5 MICs of other compounds tested in the current study were similar to those reported by other workers,1–3,5–7 with meropenem having the greatest overall activity against all groups of bacteria.1–3 In summary, both AZD2563 and linezolid were active against most Gram-positive anaerobes. These results provide a basis for testing the clinical performance of AZD2563 in skin and soft tissue infections caused by aerobic and anaerobic Gram-positive organisms.
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Acknowledgements |
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This study was supported by a grant from AstraZeneca Pharmaceuticals, Cheshire, UK.
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Footnotes |
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* Corresponding author. Tel: +1-717-531-5113; Fax: +1-717-531-7953; E-mail: pappelbaum{at}psu.edu
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References |
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1 . Appelbaum, P. C., Spangler, S. K. & Jacobs, M. R. (1990). ß-Lactamase production and susceptibilities to amoxicillin, amoxicillin–clavulanate, ticarcillin, ticarcillin–clavulanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis Bacteroides isolates and 129 fusobacteria from 28 US centers. Antimicrobial Agents and Chemotherapy 34, 1546–50.
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Appelbaum, P. C., Spangler, S. K. & Jacobs, M. R. (1991). Susceptibilities of 394 Bacteroides fragilis, non-B. fragilis group Bacteroides species, and Fusobacterium species to newer antimicrobial agents. Antimicrobial Agents and Chemotherapy 35, 1214–8.
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Appelbaum, P. C., Spangler, S. K. & Jacobs, M. R. (1993). Susceptibility of 539 Gram-positive and -negative anaerobes to new agents, including RP 59500, biapenem, trospectomycin and piperacillin/tazobactam. Journal of Antimicrobial Chemotherapy 32, 223–31.
4 . Haggoud, A., Reysset, G. & Sebald, M. (1992). Cloning of a Bacteroides fragilis chromosomal determinant coding for 5-nitroimidazole resistance. FEMS Microbiology Letters 95, 1–6.
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Goldstein, E. J. C., Citron, D. M. & Merriam, C. V. (1999). Linezolid activity compared to those of selected macrolides and other agents against aerobic and anaerobic pathogens isolated from soft tissue bite infections in humans. Antimicrobial Agents and Chemotherapy 43, 1469–74.
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Wise, R., Andrews, J. M., Boswell, F. J. & Ashby, J. P. (1998). The in-vitro activity of linezolid (U-100766) and tentative breakpoints. Journal of Antimicrobial Chemotherapy 42, 721–8.
7 . Jones, R. N., Biedenbach, D. J. & Anderegg, T. R. (2002). In vitro evaluation of AZD2563, a new oxazolidinone, tested against unusual Gram-positive species. Diagnostic Microbiology and Infectious Disease 42, 119–22.[Web of Science][Medline]
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Livermore, D. M. (2000). Quinupristin/dalfopristin and linezolid: where, when, which and whether to use? Journal of Antimicrobial Chemotherapy 46, 347–50.
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10 . National Committee for Clinical Laboratory Standards. (1997). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Fourth edition: Approved standard M11-A4. NCCLS, Wayne, PA.
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