1: Antimicrob Agents Chemother. 2009 Jun;53(6):2289-97. Epub 2009 Mar 16.

Activities of ceftobiprole and other cephalosporins against extracellular and
intracellular (THP-1 macrophages and keratinocytes) forms of
methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

Lemaire S, Glupczynski Y, Duval V, Joris B, Tulkens PM, Van Bambeke F.

Unité de Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research
Institute, Université Catholique de Louvain, UCL 73.70 Avenue E. Mounier 73,
Brussels B-1200, Belgium.

Staphylococcus aureus is an opportunistic intracellular organism. Although they
poorly accumulate in eukaryotic cells, beta-lactams show activity against
intracellular methicillin (methicillin)-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
beta-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 (E(max)), relative potency (the
concentration causing a reduction of the inoculum halfway between E(0) and E(max)
[EC(50)]), and static concentration (C(s))} were measured. All strains showed
sigmoidal dose-responses, with E(max) being about a 1 log(10) CFU decrease from
the postphagocytosis inoculum, and EC(50) and C(s) 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.

PMID: 19289525 [PubMed - in process]

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