1: J Antimicrob Chemother. 2007 Sep 25; (2007) 60, 965–97

Selection of quinolone resistance in Streptococcus pneumoniae exposed in vitro to
subinhibitory drug concentrations.

Avrain L, Garvey M, Mesaros N, Glupczynski Y, Mingeot-Leclercq MP, Piddock LJ,
Tulkens PM, Vanhoof R, Van Bambeke F.

Université Catholique de Louvain, Unité de Pharmacologie Cellulaire et
Moléculaire, Brussels, Belgium.

Objectives Does exposure to subinhibitory concentrations of quinolones favour
overexpression of efflux pumps or selection of target site mutations? Methods
ATCC 49619 (fully susceptible) and SP32 (clinical isolate with PmrA-mediated
efflux and mutation in ParE) were exposed for 24 h in broth to ciprofloxacin,
levofloxacin, moxifloxacin or garenoxacin at concentrations of 0.5x the MIC, with
daily re-adjustments for up to 13 days. Efflux was detected phenotypically
(decrease in MIC in the presence of reserpine), and expression of pmrA and
patA/patB was measured by real-time PCR and comparative RT-PCR, respectively.
Target site mutations were detected by sequencing of the quinolone resistance
determining regions in parC, parE and gyrA. The clonal identity of isolates was
checked by PFGE of genomic DNA. Results Ciprofloxacin selected for stable mutants
with 2.5-5-fold MIC increases for ciprofloxacin, 2-3-fold for levofloxacin and
1.3-2-fold for garenoxacin and moxifloxacin [partial reversion with reserpine for
ciprofloxacin, gemifloxacin and levofloxacin (SP32 strain only), but not for
garenoxacin and moxifloxacin]. Increased MICs were associated with overexpression
of patA/B but not pmrA. In contrast, exposure to levofloxacin, moxifloxacin or
garenoxacin selected target site mutations (gyrA, parC, parE) in both strains.
Increases in MIC caused by efflux were similar to those caused by target site
mutations. Conclusions Exposure of Streptococcus pneumoniae to subinhibitory MICs
of ciprofloxacin, a substrate for efflux pumps, results in patA/B-mediated efflux
whatever the initial level of expression of pmrA of the strain. Quinolones that
are poorly (levofloxacin) or not affected (moxifloxacin, garenoxacin) in their
activity by efflux transporters preferentially select for target site mutants.

PMID: 17693451 [PubMed - as supplied by publisher]

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