Antimicrob Agents Chemother. 2007; 51:1627–1632 
[Epub ahead of print: Feb 16, 2007

Intraphagocytic Methicillin-Resistant Staphylococcus aureus are susceptible to
Meropenem and Cloxacillin: role of acid pH.


Lemaire S, Van Bambeke F, Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM.

Unite de Pharmacologie cellulaire et moleculaire, Universite catholique de
Louvain, Brussels; Laboratoire de Microbiologie, Cliniques universitaires de
Mont-Godinne, Yvoir; Belgium.


Early studies showed that methicillin-resistant S. aureus (MRSA) are susceptible
to beta-lactams when exposed to pH </= 5.5 in broth. Because S. aureus survives
in phagolysosomes of macrophages where pH may be acidic, we have examined the
susceptibility of MRSA ATCC 33591 phagocytized by human THP-1 macrophages to
meropenem (MEM) and cloxacillin (CLX). Using a pharmacodynamic model assessing
key pharmacological (EC50, Emax) and microbiological (static concentration)
descriptors of antibiotic activity, we show that intraphagocytic MRSA are as
sensitive to MEM and CLX as methicillin susceptible S. aureus (MSSA ATCC 25923).
This observation was replicated in broth if pH was brought to 5.5, and was
confirmed with clinical strains. Electron microscopy showed that both MRSA and
MSSA localized and multiplied in membrane-bounded structures (phagolysosomes) in
the absence of beta-lactams. Incubation of the infected macrophages with
ammonium chloride (to raise the phagolysosomal pH) made MRSA insensitive to MEM
and CLX. No difference was seen in mec, mecA, mecI, mecR1, femA, and femB
expression (reversed-transcription PCR), and in PB2a content (immunodetection)
in MRSA grown in broth at pH 5.5 vs. 7.4. [(14)C]-benzyl-penicillin binding to
cell walls prepared from a non beta-lactamase producing MRSA (clinical isolate)
was 2 times lower than for MSSA ATCC 25923 at pH 7.4, but increased to similar
values for both strains at pH 5.5. These data suggests that the restoration of
susceptibility of intraphagocytic of MRSA to MEM and CLX is due to the acid pH
prevailing in phagolysosomes, and is mediated by an enhanced binding to PBP's.

PMID: 17307986 [PubMed - as supplied by publisher]

Related Link

Combined effect of pH and concentration on the activities of gentamicin and
oxacillin against Staphylococcus aureus in pharmacodynamic models of
extracellular and intracellular infections. [J Antimicrob Chemother. 2007]
PMID:17220162