Pharmacodynamic characterization of efflux and topoisomerase IV-mediated fluoroquinolone resistance in Streptococcus pneumoniae.
OBJECTIVE
Most in vitro investigations of fluoroquinolone resistance involving Streptococcus pneumoniae have described genotypic changes in quinolone resistance-determining regions (QRDRs) that occur as the result of exposure to fluoroquinolones obtained with static antimicrobial concentrations. The objectives of this study were to determine whether differences exist between moxifloxacin, sparfloxacin and levofloxacin antimicrobial effect (AME) and their ability to select out stepwise mutations with wild-type, efflux-expressing and parC-mediated fluoroquinolone resistance while simulating the in vivo dosing and pharmacokinetics of the respective agents.


METHODS
A one-compartment pharmacodynamic model simulated fluoroquinolone dosing regimens. Duplicate 24 h experiments were carried out in Mueller-Hinton broth with 3% horse blood at 1 x 10(8) cfu/mL. Reserpine (10 mg/L) was added to select experiments conducted with efflux-expressing strains. AME was expressed as the area under the time-concentration kill curve (AUEC24). Strains expressing increased MIC post-time-concentration kill curve (TCKC) were evaluated for changes in QRDR.


RESULTS
Moxifloxacin exhibited a greater AME against all isolates. Efflux was generally associated with partial loss of AME for all fluoroquinolones, and levofloxacin retained no AME against parC-expressing S. pneumoniae. Increased fluoroquinolone MIC post-TCKC was more common with efflux expression. The addition of reserpine was associated with enhanced AME for levofloxacin and moxifloxacin, but was not associated with altered resistance selection. Isolates recovered post-TCKC from experiments involving efflux- or parC mutation-containing isolates generally exhibited a more than four-fold increase in MIC, which was associated with commonly reported substitutions in both parC and gyrA.


CONCLUSIONS
The results of this study generally indicate that resistance selection under pharmacodynamic conditions is similar to results reported with static fluoroquinolone concentrations. While moxifloxacin AME was greater than levofloxacin and sparfloxacin, the overall selection of resistant isolates did not differ.
Madaras-Kelly
Karl J
KJ
Veterans Affairs Medical Center, 500 W. Fort Street, Boise, ID 83702, USA. kmk@otc.isu.edu
Daniels
Christopher
C
Hegbloom
Marissa
M
Thompson
Michelle
M
D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000502:physiology*; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology* / Q000302:isolation & purification
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D024841:Fluoroquinolones; D027101:DNA Topoisomerase IV