BAL 9141, a new broad-spectrum pyrrolidinone cephalosporin: activity against clinically significant anaerobes in comparison with 10 other antimicrobials

M. Wootton, K. E. Bowker, H. A. Holt and A. P. MacGowan,*

Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust and University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
The in vitro potency of BAL 9141, a new pyrrolidinone cephalosporin, was tested against non-duplicate strains of anaerobic bacteria. The MIC50 was 1 mg/L against Actinomyces species, Clostridium species, Gram-positive anaerobic cocci, Porphyromonas species, Fusobacterium species, Lactobacillus species, Prevotella species and Veillonella species. The MIC50 was 16 mg/L for Bacteroides fragilis and other Bacteroides species. BAL 9141 was not active against cefoxitin-resistant Bacteroides fragilis.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
BAL 9141 is a new broad-spectrum pyrrolidinone-3-ylidene-methyl cephalosporin active against methicillin-resistant Staphylococcus aureus. The MIC90 for methicillin-resistant S. aureus (MRSA) is 4 mg/L and BAL 9141 is bactericidal against MRSA in a time-dependent manner. BAL 9141 is more potent than cefotaxime against strains of Streptococcus pneumoniae with reduced susceptibility to penicillin and has equivalent activity to ceftazidime against Pseudomonas aeruginosa. It is not active against all strains of Escherichia coli or Klebsiella pneumoniae that produce extended-spectrum ß-lactamases or Proteus vulgaris.1 Animal studies of MRSA experimental endocarditis have indicated that BAL 9141 is more effective than either co-amoxiclav or vancomycin.2 Little is known about its activity against anaerobic bacteria, which remain important human pathogens, being associated with intra-abdominal, pulmonary, head, neck, soft tissue, intracerebral and bloodstream infection. In many areas of the world, ß-lactams such as piperacillin/tazobactam, co-amoxiclav, cefoxitin, cefotetan and meropenem or imipenem are used in therapy or prophylaxis of mixed aerobic and anaerobic infection. Hence, it is important to establish the potential activity of new ß-lactams such as BAL 9141 against this pathogen group.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
Three hundred and forty-four anaerobe isolates were tested. These were clinical isolates from this Centre or from the PHLS Anaerobic Reference Laboratory, Cardiff, UK. The following control strains were used: Bacteroides fragilis ATCC 25285, Clostridium perfringens NCTC 1229, Peptostreptococcus magnus ATCC 14956, S. aureus ATCC 9144 and E. coli ATCC 10536. The antibiotics used were obtained from the following manufacturers: piperacillin/ tazobactam (Wyeth, Maidenhead, UK); co-amoxiclav and ticarcillin/clavulanate (GlaxoSmithKline, Uxbridge, UK); cefoxitin (MSD, Hoddesdon, UK), cefotetan and meropenem (AstraZeneca, Luton, UK); ceftazidime (GlaxoSmithKline); metronidazole (PMU Healthcare, Exeter, UK) and BAL 9141, cefoperazone/sulbactam, ceftriaxone (F. Hoffmann-La Roche, Basel, Switzerland). Susceptibilities were determined by the standard agar incorporation method recommended by the BSAC.3 Agar dilution MICs were performed on Wilkins–Chalgren agar (CM 619; Unipath, Basingstoke, UK) supplemented with 5% lysed horse blood. The antibiotics were incorporated into the media in a log 2 series from 0.008–128 mg/L. ß-Lactamase inhibitors were used at a fixed concentration of 4 mg/L. The inocula were prepared by dilution in a saline suspension equivalent to McFarland 0.5 standard, 1 in 10, which resulted in 104 cfu/spot when applied by a Denley multipoint inoculator. The plates were incubated at 37°C for 40 h in a Wise anaerobic workstation (Don Whitley Scientific, Shipley, UK) in an atmosphere of 80% N2, 10% H2 and 10% CO2, and were read by eye in comparison with an antibiotic-free control plate. The MIC was defined as the lowest concentration of drug to inhibit macroscopically visible colonies. MICs of ß-lactam–ß-lactamase inhibitor combinations were expressed as the concentration of the ß-lactam in the combination.


    Results and discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
The TableGo shows the in vitro activity of these agents against the various anaerobic genera summarized in terms of MIC range, MIC50 and MIC90 (mg/L). BAL 9141 had the lowest or equal lowest MIC50 of the cephalosporins tested against Actinomyces species, Gram-positive anaerobic cocci, Porphyromonas species, Fusobacterium species, Lactobacillus species and Prevotella species. Cefoxitin was the most active cephalosporin against B. fragilis and other Bacteroides species (MIC50 8 mg/L). In general, the penicillins (co-amoxiclav, piperacillin/tazobactam and ticarcillin/ clavulanate) had lower MIC50s against all the genera than the cephalosporins and meropenem was the most potent ß-lactam tested. Metronidazole was an active agent in all groups except Actinomyces species and Lactobacillus species.


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Table. Activity of BAL 9141 and comparators against anaerobe strains
 
The susceptibility of the Bacteroides species were analysed further based on cefoxitin MICs (FigureGo). The MIC50s of BAL 9141, cefotetan, piperacillin/tazobactam, co-amoxiclav and meropenem all increased as the cefoxitin MIC increased.



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Figure. Susceptibility of B. fragilis group to BAL 9141 and comparators on cefoxitin MIC. Key: {blacksquare}, BAL 9141; {blacktriangleup}, cefotetan; {square}, piperacillin/tazobactam; {circ}, co-amoxiclav; x, meropenem.

 
No study has reported the in vitro activity of BAL 9141 against human anaerobic pathogens. In terms of MIC50s, BAL 9141 was similar to that of cefoxitin; activity was superior to cefotetan and cefperazone/sulbactam against most species, and was almost always superior to ceftazidime and ceftriaxone. However, the activity of BAL 9141 was notably poorer than cefoxitin against Bacteroides spp., and MIC50s were higher for BAL 9141 against B. fragilis than cefoxitin and cefotetan. In terms of MIC90s, BAL 9141 had clearly inferior activity to cefoxitin against most genera and was not more active against members of the B. fragilis group that had reduced cefoxitin susceptibility.

However, antimicrobial clinical efficacy does not depend exclusively on in vitro potency. Owing to insufficient solubility, in man BAL 9141 will be administered as a prodrug that is rapidly cleared in the blood to BAL 9141, which has a human protein binding of 38%.1 Early pharmacokinetic studies in a range of animals indicate a volume of distribution (Vd) at steady state of 0.25–0.36 L/kg, and have suggested that the half-life in man will be in the range 2–3 h, with urinary excretion likely.4 Once human pharmacokinetic studies and pharmacodynamic modelling data become available, it will be easier to predict the possible role for BAL 9141 in the management of human anaerobic infection. Such speculation can only be confirmed by well conducted clinical trials.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
We wish to thank Peter Hohl for his advice and help during the course of the study and preparation of the manuscript. This study was supported by a grant from F. HoffmannLa Roche, A.G., Basel, Switzerland. Part of this work was presented at the Thirty-eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998 (abstract F-20).


    Notes
 
* Corresponding author. Tel: +44-117-959-5652; Fax: +44-117-959-3154; E-mail: macgowan_a{at}southmead.swest.nhs.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
1 . Hebeisen, P., Heinze-Krauss, I., Angehrn, P., Hohl, P., Page, M. G. & Then, R. L. (2001). In vitro and in vitro properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Antimicrobial Agents and Chemotherapy 45, 825–36.[Abstract/Free Full Text]

2 . Entenza, J. M., Hohl, P., Heinze-Krauss, I., Vouillamoz, J., Glaser, M. P. & Moreillon, P. (1998). Ro 63-9141, a novel broad spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus in the treatment of experimental endocarditis. In Program and Abstracts of the Thirty-eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract F-14, p. 236. American Society for Microbiology, Washington, DC.

3 . Working Party on Antibiotic Sensitivity Testing of the British Society for Antimicrobial Chemotherapy. (1991). A guide to sensitivity testing. Journal of Antimicrobial Chemotherapy 27, Suppl. D, 1–50.[ISI][Medline]

4 . Theil, F. P., Schonlein, K., Schenk, P. & Scmitt-Hoffmann, A. (1998). Pharmacokinetics of the cephalosporin Ro 63-9141 in five animal species-extrapolation to man. In Program and Abstracts of the Thirty-eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract F-25, p. 239. American Society for Microbiology, Washington, DC.

Received 25 July 2001; returned 26 September 2001; revised 12 November 2001; accepted 26 November 2001





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