Challenges in assessing microbial susceptibility and predicting clinical response to newer-generation fluoroquinolones.

PURPOSE: To determine the most appropriate methods for assessing the potential effectiveness of the newer topical fluoroquinolones gatifloxacin, moxifloxacin, and besifloxacin.
METHODS: This article is based on a literature search for published articles about the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of and measure of bacterial susceptibility to topical ophthalmic fluoroquinolones. Search terms included fluoroquinolones, susceptibility, resistance, minimal/minimum inhibitory concentration (MIC), PDs, PKs, and ocular, ophthalmic, or topical antibiotics.
RESULTS: Topical fluoroquinolones, particularly besifloxacin, gatifloxacin, and moxifloxacin, have become important treatment options for common ocular bacterial infections due to their broad-spectrum bactericidal activity and low toxicity. An important challenge in ophthalmology is identifying the most accurate in vivo and in vitro methods for evaluating the efficacy of these topical fluoroquinolones. The MIC is the most commonly used measure of in vitro susceptibility. In systemic therapy, this measure is combined with PK data of antibiotics to generate PD indices PK/PD whose breakpoints differentiate clinically susceptible from nonsusceptible bacterial pathogen populations. PD breakpoints are further tested in prospective studies for their ability to predict clinical efficacy. However, it is not known whether systemically derived breakpoints apply to the assessment of clinical susceptibility to ocular agents. Topical ocular antibiotics likely achieve higher concentrations at the target site than do systemically administered antibiotics, but these higher concentrations can be quickly reduced by reflex tearing and blinking induced by instillation. Hence, studies have been conducted in animals and humans to determine the PK concentrations of topically administered antibiotics in ocular compartments. When combined with MIC values for topical pathogens, the results have the potential to predict clinical efficacy after identification of the appropriate PK/PD target. Ocular studies incorporating PK/PD assessments have recently begun to be reported with newer fluoroquinolones, including besifloxacin, gatifloxacin, and moxifloxacin, whose prolonged contact time and potent bactericidal activity have translated into some of the most favorable PK/PD target values. However, the clinical relevance of these studies has yet to be determined.
CONCLUSION: There is still a clear need for predictive models to extend our understanding of the clinical susceptibility of ocular pathogens.