Comparative study of the susceptibility of major epidemic clones of MRSA to oxacillin and to the new broad spectrum cephalosporin ceftobiprole

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Comparative study of the susceptibility of major epidemic clones of MRSA to oxacillin andto the new broad spectrum cephalosporin ceftobiprole

Marilyn Chung, Aude Antignac, Choonkeun Kim and Alexander Tomasz*Laboratory of Microbiology, The Rockefeller University, New York, NY, USA

*

Corresponding author: Alexander Tomasz, The Rockefeller University, 1230 York Avenue,New York, NY 10065, USA. Phone: (212) 327 8277; fax: (212) 327 8688e-mail: tomasz@rockefeller.edu

Copyright © 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.00266-08AAC Accepts, published online ahead of print on 27 May 2008

a t U ni v er s i t y of P i t t s b ur gh H S L S on J ul y 3 ,2 0 0 8 a a c . a s m. or gD ownl o a d e d f r om

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ABSTRACT

1Multidrug resistant strains of

Staphylococcus

aureus

continue to increase in frequency2worldwide – both in hospitals and in the community – raising serious problems for the3chemotherapy of staphylococcal disease. Ceftobiprole (BAL9141) – renamed BPR – the active4constituent of the prodrug ceftobiprole medocaril (BAL5788) is a new cephalosporin which was5already shown to have powerful activity against a number of bacterial pathogens including

S.

6

aureus

. In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we7examined the susceptibility of the relatively few pandemic MRSA clones that are responsible for8the great majority of staphylococcal disease worldwide. We also included in the tests the highly9oxacillin resistant subpopulations that are present with low frequencies in the cultures of these10clones. Such subpopulations may represent a natural reservoir from which MRSA strains with11decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR12against MRSA with reduced susceptibility to vancomycin and against MRSA carrying the13enterococcal vancomycin resistant gene complex. BPR was shown to be uniformly effective14against all these resistant MRSA strains and the mechanism of superb antimicrobial activity15correlated with the strikingly increased affinity of the cephalosporin against penicillin binding16protein 2A (PBP2A) – the protein product of the antibiotic resistance determinant

mecA

.17

a t U ni v er s i t y of P i t t s b ur gh H S L S on J ul y 3 ,2 0 0 8 a a c . a s m. or gD ownl o a d e d f r om

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INTRODUCTION

1Since the introduction of antibiotics in the 1940s,

Staphylococcus aureus

, a frequent2cause of potentially life-threatening hospital-borne infections, has become increasingly resistant3to most chemotherapeutic agents. In 1960 the first methicillin-resistant clinical isolates of 4

Staphylococcus aureus

(MRSA) appeared in the clinical environment and multidrug resistant5derivatives of MRSA clones began to spread worldwide – initially in the hospital environment6but more recently in the community as well (11, 22). To treat MRSA infections, new antibiotics7were developed and beginning with the mid-1990’s the glycopeptide antibiotic vancomycin8became the therapy of first choice against MRSA infections (3). Recently, MRSA isolates with9reduced susceptibility to vancomycin (VISA) began to appear in several countries (4, 20, 25, 27)10and MRSA strains that had acquired the enterococcal

vanA

gene complex (VRSA) were also11recovered from clinical specimen. These VRSA strains also carried the

β

-lactam resistance gene12

mecA

and were therefore resistant to both glycopeptide and

β

-lactam antibiotics (4, 24).13Ceftobiprole (BPR), the active component of the water-soluble prodrug ceftobiprole14medocaril (BAL5788) (19), is a new cephalosporin that was shown to have powerful15antimicrobial activity against many gram-positive pathogens (2, 15).16The primary purpose of this study was to determine the potency of this novel drug against17highly oxacillin resistant MRSA strains that exist with low frequencies in cultures of the most18widely spread pandemic clones of MRSA (10). Under selective pressure such subpopulations of 19highly

β

-lactam resistant cells could become the source of lineages with increased MIC values20against BPR. We also included in this study two MRSA strains that carried the enterococcal21vancomycin resistance gene (VRSA) and two MRSA strains with reduced susceptibility (VISA)22to vancomycin.23