Effect of dosing interval on the efficacy of topical ophthalmic gatifloxacin against Enterococcus faecalis in an in vitro pharmacokinetic model simulating the local eye compartment.
Improved dosing regimens have been proposed for various antimicrobial agents by application of pharmacokinetic/pharmacodynamic (PK/PD) principles. However, for topical ophthalmic use there are several limitations to changing the dosing regimen, such as drug formulation and bioavailability. In this study, we investigated the relationship between dosing interval and antibacterial efficacy in an in vitro PK model mimicking post-operative endophthalmitis. The in vitro PK model simulated the aqueous humour concentration following topical application of 0.3% gatifloxacin ophthalmic solution to rabbit eyes. A clinical isolate of Enterococcus faecalis was exposed to gatifloxacin three times repeatedly at various intervals from 0 h to 8 h. The area between the control growth curve and the bacterial killing and re-growth curve for 24 h (ABBC) was used to evaluate efficacy. The ABBC showed bell-shaped dependence on the dosing interval with a peak at 3h. Under limited condition of total exposure amount, i.e. area under the concentration-time curve, the antimicrobial efficacy appears to be associated with the cumulative time of a 24-h period such that the concentration exceeds the minimum inhibitory concentration (T>MIC) rather than the peak concentration:MIC ratio. The length of intermission of T>MIC during repeated dosing appears to be proportional to the decrease in efficacy of gatifloxacin against E. faecalis. A longer dosing interval, as long as T>MIC is continuous, would likely be more efficient at preventing post-operative enterococcal endophthalmitis. However, further investigation is necessary to explore whether this model is applicable to a variety of pathogens and drugs.
Preclinical Laboratories, Senju Pharmaceutical Co Ltd, Kobe, Hyogo, Japan. s-kozai@senju.co.jp
Seiko
S
Kozai
Tomoyuki
T
Wada
Tetsuo
T
Kida
Tetsuya
T
Tajika
Hideyuki
H
Sakaki
Akira
A
Ohtori
D000287:Administration, Topical; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015169:Colony Count, Microbial; D013293:Enterococcus faecalis / Q000187:drug effects*; D005123:Eye / Q000382:microbiology*; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077734:Gatifloxacin; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D008962:Models, Theoretical; D013997:Time Factors
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077734:Gatifloxacin