FIRSOV A, VOSTROV S, LUBENKO I, DRLICA K, PORTNOY Y, ZINNER S; 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-1148.

Gause Inst. of New Antibiotics, Moscow, Russian Federation.

Objective. Threshold ratios of the 24-h area under the curve (AUC) to the MIC that prevent the selection of resistant Staphylococcus aureus have been estimated at 200-240 h in our previous study with four quinolones. These AUC/MICs correspond to levels above the mutant prevention concentrations (MPCs), i.e., the upper border of the mutant selection window (MSW). Can this selection be prevented using the smaller AUC/MICs seen with antibiotic combinations? To test this hypothesis, changes in the susceptibility of S. aureus exposed to moxifloxacin (M; threshold AUC/MIC of 220 h), alone and in combination with doxycycline (D) were examined in an in vitro dynamic model. Methods. Once-daily administration of M and D were simulated for 5 consecutive days. The AUC/MIC ratios of M and D were designed to provide the summed AUC/MICs at which significant (60 h), moderate (90 h) and negligible (230 h) increases in MIC were expected. MICs of M and D for bacterial cultures sampled from the model were determined daily for 6 days. Results. Significant losses in susceptibility were observed with monotherapy where M or D concentrations fall into the MSW for most of the dosing interval (AUC/MIC 60 h). Less pronounced changes in MIC occurred when the ratios of summed concentrations of M (AUC/MIC 60 h) + D (30 h) or M (30 h) + D (60 h) to their MICs were lower than MPC/MIC for 55% of the dosing interval. No losses in susceptibility were associated with summed MIC-related concentrations of M (AUC/MIC 60 h) + D (170 h) or M (170 h) + D (60 h) when MPC/MIC was exceeded for the entire dosing interval. Conclusions. These data suggest that the total AUC/MIC of 230 h might protect against S. aureus resistance. As this value is close to that predicted with M monotherapy (220 h), an additive protective effect of M+D on the selection of resistant S. aureus is proposed.

Publication Types:

• Meeting Abstracts

Keywords:

• Anti-Bacterial Agents
• Area Under Curve
• Aza Compounds
• Doxycycline
• In Vitro
• Microbial Sensitivity Tests
• Models, Biological
• Quinolines
• Quinolones
• Selection (Genetics)
• Staphylococcus aureus
• genetics
• moxifloxacin

Other ID:

• GWAIDS0025764

UI: 102265388

From Meeting Abstracts