CAMPION J, MCNAMARA PJ, EVANS ME; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. A-1324.
University of Kentucky, Lexington, KY.
BACKGROUND: Fluoroquinolones (FQ) are often ineffective in treatment of MRSA infections because they select grlA mutants from wild-type populations. We developed a PD model that describes the selection of grlA mutants in mixed cultures containing wild-type and grlA mutants of MRSA that were exposed to multiple GNX, GAT, and CIP pharmacokinetic (PK) profiles in a hollow-fiber in vitro system (IVS). METHODS: Two FQ-susceptible MRSA strains (8043 and 8282 MICs: GNX 0.03, GAT 0.13, CIP 0.5 microg/ml) and their grlA mutant derivatives (8043C0-1 S80Y, MICs: GNX 0.13, GAT 1, CIP 4 microg/ml; 8282C0-1 A116P MICs: GNX 0.06, GAT 0.5, CIP 0.5 microg/ml) were used. Log-phase cultures of each strain alone (5 log CFU/ml) and in combination (5 log CFU/ml wild-type + 2 log CFU/ml grlA mutant) were exposed to a series of clinical (GNX 400mg q24h, GAT 400mg q24h, CIP 400mg q8h) and experimental PK profiles for 96 h. An E[max] PD model with growth (g) and killing (k) rate constants for wild-type (S) and grlA mutant (R) populations was developed. Nonlinear regression was used to simultaneously fit PD model equations to viable count-time profiles for each parent strain and corresponding grlA mutant. RESULTS: Mean (SE) PD parameters: [table: see text]. Selection of grlA mutants occurred when the mixed cultures were exposed to clinically relevant CIP concentration profiles but not with GNX or GAT. CONCLUSIONS: For GNX and GAT, unlike CIP, the C[50R] values of the MRSA grlA mutants are sufficiently low in relation to clincally achievable concentrations to produce a faster rate of killing, thereby preventing selection of resistance.
Publication Types:
Keywords:
- Ciprofloxacin
- Fluoroquinolones
- GAT
- In Vitro
- Microbial Sensitivity Tests
- Peptides
- Staphylococcal Infections
- Staphylococcus aureus
- gatifloxacin
Other ID:
UI: 102265987
From Meeting Abstracts