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INFECTIOUS DISEASES

Fluoroquinolone AUIC Break Points and the Link to Bacterial Killing Rates Part 2: Human Trials

CEO, CPL Associates, LLC; Professor, School of Pharmacy, University at Buffalo, Buffalo, NY

Alison K Meagher, PharmD

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

Alan Forrest, PharmD

Director, Pharmacometrics 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 clinical trials with fluoroquinolones and the pharmacokinetic and pharmacodynamic parameters predictive of clinical and microbiologic outcomes and resistance. Data on fluoroquinolones are summarized and the premise that a single AUIC target >125 may be used for all fluoroquinolones against all target organisms is examined.

DATA SOURCES: Primary articles were identified by a MEDLINE search (1966–February 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 upon concentrations achieved and outcomes depend upon 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 (Part 1), 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 human trials favors the use of AUIC values >250 for rapid bactericidal action, regardless of whether the organism is gram-negative or gram-positive.

Key Words: fluoroquinolones, human infections, in vitro models, pharmacodynamics

Published Online, August 29, 2003. www.theannals.com, DOI 10.1345/aph.1C419

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