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Antimicrobial Agents and Chemotherapy, June 2009, p. 2289-2297, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01135-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Activities of Ceftobiprole and Other Cephalosporins against Extracellular and Intracellular (THP-1 Macrophages and Keratinocytes) Forms of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus
,
Sandrine Lemaire,1
Youri Glupczynski,2
Valérie Duval,3
Bernard Joris,3
Paul M. Tulkens,1* and
Françoise Van Bambeke1
Unité de Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium,1 Laboratoire de Microbiologie, Cliniques Universitaires UCL de Mont-Godinne, Yvoir, Belgium,2 Centre d'Ingénierie des Protéines, Université de Liège, Sart-Tilman, Belgium3
Received 24 August 2008/ Returned for modification 19 January 2009/ Accepted 7 March 2009
Staphylococcus aureus is an opportunistic intracellular organism. Although they poorly accumulate in eukaryotic cells, β-lactams show activity against intracellular methicillin (meticillin)-susceptible S. aureus (MSSA) if the exposure times and the drug concentrations are sufficient. Intraphagocytic methicillin-resistant S. aureus (MRSA) strains are susceptible to penicillins and carbapenems because the acidic pH favors the acylation of PBP 2a by these β-lactams through pH-induced conformational changes. The intracellular activity (THP-1 macrophages and keratinocytes) of ceftobiprole, which shows almost similar in vitro activities against MRSA and MSSA in broth, was examined against a panel of hospital-acquired and community-acquired MRSA strains (MICs, 0.5 to 2.0 mg/liter at pH 7.4 and 0.25 to 1.0 mg/liter at pH 5.5) and was compared with its activity against MSSA isolates. The key pharmacological descriptors {relative maximal efficacy (Emax), relative potency (the concentration causing a reduction of the inoculum halfway between E0 and Emax [EC50]), and static concentration (Cs)} were measured. All strains showed sigmoidal dose-responses, with Emax being about a 1 log10 CFU decrease from the postphagocytosis inoculum, and EC50 and Cs being 0.2 to 0.3x and 0.6 to 0.9x the MIC, respectively. Ceftobiprole effectively competed with Bocillin FL (a fluorescent derivative of penicillin V) for binding to PBP 2a at both pH 5.5 and pH 7.4. In contrast, cephalexin, cefuroxime, cefoxitin, or ceftriaxone (i) were less potent in PBP 2a competitive binding assays, (ii) showed only partial restoration of the activity against MRSA in broth at acidic pH, and (iii) were collectively less effective against MRSA in THP-1 macrophages and were ineffective in keratinocytes. The improved activity of ceftobiprole toward intracellular MRSA compared with the activities of conventional cephalosporins can be explained, at least in part, by its greater ability to bind to PBP 2a not only at neutral but also at acidic pH.
* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70 Avenue E. Mounier 73, Brussels B-1200, Belgium. Phone: 32-2-7622136. Fax: 32-2-7647373. E-mail: tulkens{at}facm.ucl.ac.be
Published ahead of print on 16 March 2009.
Supplemental material for this article may be found at http://aac.asm.org/.
Antimicrobial Agents and Chemotherapy, June 2009, p. 2289-2297, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01135-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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