This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Firsov, A. A. Articles by Zinner, S. H. Search for Related Content PubMed PubMed Citation Articles by Firsov, A. A. Articles by Zinner, S. H.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2005, p. 2642-2647, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2642-2647.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

Alexander A. Firsov,^1* Irene Y. Lubenko,^1,2 Sergey N. Vostrov,¹ Yury A. Portnoy,¹ and Stephen H. Zinner³

Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics,¹ Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia,² Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts³

Received 30 March 2004/ Returned for modification 11 October 2004/ Accepted 28 March 2005

Prediction of the relative efficacies of different fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC₅₀ or the MIC₉₀ and with the assumption of antibiotic-independent patterns of the AUC/MIC-response relationships. To ascertain whether this assumption is correct, the pharmacodynamics of seven pharmacokinetically different quinolones against two clinical isolates of Staphylococcus aureus were studied by using an in vitro model. Two differentially susceptible clinical isolates of S. aureus were exposed to two 12-h doses of ciprofloxacin (CIP) and one dose of gatifloxacin (GAT), gemifloxacin (GEM), grepafloxacin (GRX), levofloxacin (LVX), moxifloxacin (MXF), and trovafloxacin (TVA) over similar AUC/MIC ranges from 58 to 932 h. A specific bacterial strain-independent AUC/MIC relationship with the antimicrobial effect (I_E) was associated with each quinolone. Based on the I_E-log AUC/MIC relationships, breakpoints (BPs) that are equivalent to a CIP AUC/MIC ratio of 125 h were predicted for GRX, MXF, and TVA (75 to 78 h), GAT and GEM (95 to 103 h) and LVX (115 h). With GRX and LVX, the predicted BPs were close to those established in clinical settings (no clinical data on other quinolones are available in the literature). To determine if the predicted AUC/MIC BPs are achievable at clinical doses, i.e., at the therapeutic AUCs (AUC_thers), the AUC_ther/MIC₅₀ ratios were studied. These ratios exceeded the BPs for GAT, GEM, GRX, MXF, TVA, and LVX (750 mg) but not for CIP and LVX (500 mg). AUC/MIC ratios above the BPs can be considered of therapeutic potential for the quinolones. The highest ratios of AUC_ther/MIC₅₀ to BP were achieved with TVA, MXF, and GEM (2.5 to 3.0); intermediate ratios (1.5 to 1.6) were achieved with GAT and GRX; and minimal ratios (0.3 to 1.2) were achieved with CIP and LVX.

---

* Corresponding author. Mailing address: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya St., Moscow 119021, Russia. Phone: 7(095) 708-3341. Fax: 7(095) 245-0295. E-mail: firsov{at}dol.ru.

---

Antimicrobial Agents and Chemotherapy, July 2005, p. 2642-2647, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2642-2647.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Murillo, O., Pachon, M. E., Euba, G., Verdaguer, R., Tubau, F., Cabellos, C., Cabo, J., Gudiol, F., Ariza, J. (2008). Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection. Antimicrob. Agents Chemother. 52: 3681-3686 [Abstract] [Full Text]  
• Lim, W S (2007). Pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic. Thorax 62: 1-46 [Full Text]  
• Murillo, O., Domenech, A., Garcia, A., Tubau, F., Cabellos, C., Gudiol, F., Ariza, J. (2006). Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus. Antimicrob. Agents Chemother. 50: 4011-4017 [Abstract] [Full Text]