Chapter 25 : Plasmid-Mediated Quinolone Resistance

Abstract:

Plasmid-mediated quinolone resistance (PMQR) was late in being discovered. Nalidixic acid, the first quinolone to be used clinically, was introduced in 1967 for urinary tract infections. Resistance was soon observed and could also be readily selected in the laboratory. It was produced by amino acid substitutions in the cellular targets of quinolone action: DNA gyrase and topoisomerase IV ( 1 – 3 ). Later, decreased quinolone accumulation due to pump activation and porin loss was added as an additional resistance mechanism. The search for transferable nalidixic acid resistance in over 500 Gram-negative strains in the 1970s was unrevealing ( 4 ). In the 1980s fluoroquinolones became available that were more potent and broader in spectrum. Quinolone usage increased, with subsequent parallel increases in quinolone resistance ( 5 , 6 ). In 1987 PMQR was reported to be present in a nalidixic acid-resistant isolate of Shigella dysenteriae from Bangladesh ( 7 ), but this claim was later withdrawn ( 8 ). True PMQR was reported in 1998 in a multiresistant urinary Klebsiella pneumoniae isolate at the University of Alabama that could transfer low-level resistance to nalidixic acid, ciprofloxacin, and other quinolones to a variety of Gram-negative recipients ( 9 ). The responsible gene was termed qnr, later amended to qnrA as additional qnr alleles were discovered. Investigation of a qnrA plasmid from Shanghai that provided more than the expected level of ciprofloxacin resistance led to the discovery in 2006 of a second mechanism for PMQR: modification of certain quinolones by a particular aminoglycoside acetyltransferase, AAC(6′)-Ib-cr ( 10 ). A third mechanism for PMQR was added in 2007 with the discovery of plasmid-mediated quinolone efflux pumps QepA ( 11 , 12 ) and OqxAB ( 13 ). A multiplex PCR assay for eight PMQR genes (lacking only qnrVC) has recently been perfected ( 14 ). In the past decade these genes have been found in bacterial isolates from around the world. They reduce the susceptibility of bacteria to quinolones, usually not to the level of nonsusceptibility but facilitating the selection of more quinolone-resistant mutants and treatment failure. PMQR has been frequently reviewed ( 15 – 20 ).