1: J Antimicrob Chemother. 2007 Nov;60(5):965-72. Epub 2007 Aug 10. 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 - in process] Related Links Mutant prevention concentrations for single-step fluoroquinolone-resistant mutants of wild-type, efflux-positive, or ParC or GyrA mutation-containing Streptococcus pneumoniae isolates. [Antimicrob Agents Chemother. 2004] PMID:15388458 Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin and moxifloxacin in Streptococcus pneumoniae. [J Antimicrob Chemother. 2001] PMID:11533001 Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. [J Antimicrob Chemother. 2002] PMID:12003975 Antipneumococcal activity of DK-507k, a new quinolone, compared with the activities of 10 other agents. [Antimicrob Agents Chemother. 2003] PMID:14638489 In vitro activities of garenoxacin (BMS-284756) against Streptococcus pneumoniae, viridans group streptococci, and Enterococcus faecalis compared to those of six other quinolones. [Antimicrob Agents Chemother. 2003] PMID:14576115