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INFECTIOUS DISEASES

Fluoroquinolone AUIC Break Points and the Link to Bacterial Killing Rates

Part 1: In Vitro and Animal Models

CPL Associates, LLC; Professor of Pharmaceutical Sciences and Pharmacy, School of Pharmacy, University at Buffalo, Buffalo, NY

Alison K Meagher, PharmD

Director, Anti-Infective and Sepsis Research, CPL Associates, LLC

Alan Forrest, PharmD

Director, Pharmacometric and Biostatistical Analysis, CPL Associates, LLC; Research Professor of Pharmacy Practice, School of Pharmacy, University at Buffalo; Adjunct Professor of Pharmaceutics, School of Pharmacy, University at Buffalo

Reprints: Jerome J Schentag PharmD, School of Pharmacy, University at Buffalo, 543 Hochstetter Hall, Buffalo, NY 14260-1200, FAX 716/838-0756, schentag{at}buffalo.edu

OBJECTIVE: To review in vitro and animal model studies with fluoroquinolones and the pharmacokinetic and pharmacodynamic relationships that are predictive of clinical and microbiologic outcomes and resistance. Data on fluoroquinolones are summarized and examine the premise that a single area under the inhibitory concentrationñtime curve (AUIC) target >125 may be used for all fluoroquinolones with concentration-dependent killing actions and against all target organisms.

DATA SOURCES: Primary articles were identified by MEDLINE search (1966ñFebruary 2002) and through secondary sources.

STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included.

DATA SYNTHESIS: The fluoroquinolones exhibit concentration-dependent killing. This effect clearly depends on concentrations achieved, and outcomes depend on endpoints established by individual investigators. With AUIC values <60, the actions of fluoroquinolones are essentially bacteriostatic; any observed bacterial killing is the combined effect of low concentrations in relation to minimum inhibitory concentration and the action of host factors such as neutrophils and macrophages. AUIC values >100 but <250 yield bacterial killing at a slow rate, but usually by day 7 of treatment. AUICs >250 produce rapid killing, and bacterial eradication occurs within 24 hours. Disagreements regarding target endpoints are the expected consequences of comparing microbial and clinical outcomes across animal models, in vitro experiments, and humans when the endpoints are clearly not equivalent. Careful attention to time-related events, such as speed of bacterial killing, versus global endpoints, such as bacteriologic cure, allows optimal break points to be defined.

CONCLUSIONS: Evidence from in vitro and animal models favors the use of AUIC values >250 for rapid bactericidal action, regardless of whether the organism is gram-negative or gram-positive.

Key Words: animal models, fluoroquinolones, in vitro models, pharmacodynamics

Published Online, July 10, 2003. www.theannals.com, DOI 10.1345/aph.1C199

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