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2004 OMIG, Abstract 7

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Combination of Pharamacokinetics and Susceptibility Data as Predictive Indicator of Bacterial Keratitis
DW Stroman1, JJ Dajcs1, R Vidal2, Mridvika2, C Martinez2, BA Thibodeaux3, RJ O'Callaghan3, BA Schlech1. 1Alcon Research, Ltd, Fort Worth, Texas, 2Icon Cusi, Barcelona, Spain, 3LSU Health Sciences Center, New Orleans, Louisiana

Purpose: To determine whether the ocular pharmacokinetics (PK) of moxifloxacin and levofloxacin combined with the in vitro susceptibility of Staphylococcus aureus correlates with the prevention of experimental keratitis in rabbits.
Method: PK studies were performed by applying one topical drop of 1.5% moxifloxacin (M), 0.5% moxifloxacin (V,VIGAMOX®), or 1.5% levofloxacin (L) to rabbit eyes and measuring concentrations in the aqueous humor (AH) from 15 minutes to 4 hours. Susceptibility to the fluoroquinolones was defined by broth dilution end-point MICs. A quinolone-susceptible S. aureus (8325-4) strain and a quinolone-resistant S. aureus (30155) strain were employed to measure the efficacy of the fluoroquinolones in a rabbit keratitis model. One drop of each antibiotic formulation (50 ul) was applied to eyes at various times prior to corneal intrastromal injection of approximately 500 colony forming units of S. aureus. Rabbits were sacrificed at 5 hours post-inoculation and corneas were removed and cultured to quantify viable bacteria.
Results: AH fluoroquinolone concentrations measured at 60 minutes were 4.0, 1.3, 2.2 ug/ml for M, V, and L, respectively. By 2 hours, AH concentrations of M, V, and L declined to approximately 1.0, 0.5, 1.0 ug/ml, respectively. At 4 hours, M had the highest fluoroquinolone concentration of 0.34 ug/ml, V and L were 0.25 ug/ml or less. The quinolone-susceptible S. aureus were killed when one drop of M or V was administered 3 hours prior to inoculation. The quinolone-resistant S. aureus was not able to establish infection when one drop of M or V was administered 30 minutes prior to inoculation. In contrast, one drop of L had no effect on the growth of the quinolone-resistant S. aureus.
Conclusions: AH concentrations of moxifloxacin were increased proportionally to the concentration in the two formulations applied to eye. 1.5% moxifloxacin produced the highest AH peak concentration. While the 1.5% levofloxacin formulation produced AH concentrations approximately 50% higher than those generated by 0.5% moxifloxacin, levofloxacin had no effect on growth of the resistant strain whereas moxifloxacin prevented the infection. By combining the pharmacokinetic data of AH fluoroquinolone concentration over time with the fluoroquinolone susceptibility data for a specific strain, it is possible to predict the amount of protection provided to the cornea in these experimental keratitis studies.

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