2004
DOI: 10.1093/jac/dkh393
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In vivo pharmacodynamic efficacy of gatifloxacin against Streptococcus pneumoniae in an experimental model of pneumonia: impact of the low levels of fluoroquinolone resistance on the enrichment of resistant mutants

Abstract: This study shows that the acquisition of a low level of fluoroquinolone resistance (especially a parC mutation and to a lesser extent an efflux mechanism) is associated with a clearly lower potential for preventing resistance development. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the mutant selection window and suggest that in vivo dynamic models have to be used to predict the relative abilities of quinolones to prevent mutant sele… Show more

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Cited by 48 publications
(42 citation statements)
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“…From a practical perspective, to maintain drug levels above MPC is often more stringent than necessary and increases risk of toxicity. However, the MPC‐based PK/PD measurement, AUC 24 /MPC, has been tested to be more accurate than AUC 24 /MIC in predicting resistance occurrence (Firsov et al, 2006; Olofsson et al, 2006; Drlica and Zhao, 2007), and in vivo experiments also prove the usefulness to control the frequency of resistant mutant development by maintaining drug levels above MPC for certain time of period (Croisier et al, 2004; Etienne et al, 2004). Given the high plasma drug exposure potential and wide safety margin of CD101, and the fact that CD101 and MCF have the same MPC value suggests a possible advantage of CD101 in preventing resistance to currently approved echinocandin drugs.…”
Section: Discussionmentioning
confidence: 99%
“…From a practical perspective, to maintain drug levels above MPC is often more stringent than necessary and increases risk of toxicity. However, the MPC‐based PK/PD measurement, AUC 24 /MPC, has been tested to be more accurate than AUC 24 /MIC in predicting resistance occurrence (Firsov et al, 2006; Olofsson et al, 2006; Drlica and Zhao, 2007), and in vivo experiments also prove the usefulness to control the frequency of resistant mutant development by maintaining drug levels above MPC for certain time of period (Croisier et al, 2004; Etienne et al, 2004). Given the high plasma drug exposure potential and wide safety margin of CD101, and the fact that CD101 and MCF have the same MPC value suggests a possible advantage of CD101 in preventing resistance to currently approved echinocandin drugs.…”
Section: Discussionmentioning
confidence: 99%
“…The second animal experiment focused on pneumococcal pneumonia in rabbits. When treated with moxifloxacin, the recovery of mutants was suppressed when serum drug concentrations exceeded the MPC for slightly less than one-half of the duration of the dosing period [41,42]. Quantitative comparisons with other systems are difficult, because pharmacokinetics were not measured at the infection site.…”
Section: The Selection Window In Animal Modelsmentioning
confidence: 99%
“…MICs were determined by an agar dilution method on Difco Balanced Sensitivity Test medium (see above) following the method described in (32). For each strain, 10 4 CFU were applied per spot using a multipoint inoculator (Mast Laboratories Ltd., Liverpool, United Kingdom). Plates were incubated at 36°C Ϯ 1°C and checked for visible growth after 20 and 44 h incubation in the dark under ambient atmosphere.…”
Section: Fq Drugs Evaluatedmentioning
confidence: 99%
“…Hence, at least static activity is exerted on even the most refractory variants present. Growth of such clones would require the concurrent presence of a second target mutation conferring FQ resistance, which may be contained in a much larger population of about 10 14 CFU (14). As a consequence, clonal expansion of variants is inhibited at drug concentrations ՆMPC.…”
mentioning
confidence: 99%
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