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Although they poorly accumulate in eukaryotic cells, \u03b2-lactams show activity against intracellular methicillin (meticillin)-susceptible<jats:italic>S. aureus<\/jats:italic>(MSSA) if the exposure times and the drug concentrations are sufficient. Intraphagocytic methicillin-resistant<jats:italic>S. aureus<\/jats:italic>(MRSA) strains are susceptible to penicillins and carbapenems because the acidic pH favors the acylation of PBP 2a by these \u03b2-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 (<jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>), relative potency (the concentration causing a reduction of the inoculum halfway between<jats:italic>E<\/jats:italic><jats:sub>0<\/jats:sub>and<jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>[EC<jats:sub>50<\/jats:sub>]), and static concentration (<jats:italic>C<jats:sub>s<\/jats:sub><\/jats:italic>)} were measured. All strains showed sigmoidal dose-responses, with<jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>being about a 1 log<jats:sub>10<\/jats:sub>CFU decrease from the postphagocytosis inoculum, and EC<jats:sub>50<\/jats:sub>and<jats:italic>C<jats:sub>s<\/jats:sub><\/jats:italic>being 0.2 to 0.3\u00d7 and 0.6 to 0.9\u00d7 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.<\/jats:p>","DOI":"10.1128\/aac.01135-08","type":"journal-article","created":{"date-parts":[[2009,3,17]],"date-time":"2009-03-17T00:54:09Z","timestamp":1237251249000},"page":"2289-2297","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":39,"title":["Activities of Ceftobiprole and Other Cephalosporins against Extracellular and Intracellular (THP-1 Macrophages and Keratinocytes) Forms of Methicillin-Susceptible and Methicillin-Resistant<i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"53","author":[{"given":"Sandrine","family":"Lemaire","sequence":"first","affiliation":[{"name":"Unite\u0301 de Pharmacologie Cellulaire et Mole\u0301culaire, Louvain Drug Research Institute, Universite\u0301 Catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youri","family":"Glupczynski","sequence":"additional","affiliation":[{"name":"Laboratoire de Microbiologie, Cliniques Universitaires UCL de Mont-Godinne, Yvoir, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vale\u0301rie","family":"Duval","sequence":"additional","affiliation":[{"name":"Centre d'Inge\u0301nierie des Prote\u0301ines, Universite\u0301 de Lie\u0300ge, Sart-Tilman, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Joris","sequence":"additional","affiliation":[{"name":"Centre d'Inge\u0301nierie des Prote\u0301ines, Universite\u0301 de Lie\u0300ge, Sart-Tilman, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Tulkens","sequence":"additional","affiliation":[{"name":"Unite\u0301 de Pharmacologie Cellulaire et Mole\u0301culaire, Louvain Drug Research Institute, Universite\u0301 Catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franc\u0327oise","family":"Van Bambeke","sequence":"additional","affiliation":[{"name":"Unite\u0301 de Pharmacologie Cellulaire et Mole\u0301culaire, Louvain Drug Research Institute, Universite\u0301 Catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002530100703"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00336-08"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1L016"},{"key":"e_1_3_2_5_2","first-page":"1","year":"1998","unstructured":"Angehrn, P., P. 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