Tailored gatifloxacin Pluronic® F-68-loaded contact lens: Addressing the issue of transmittance and swelling.

Loading of gatifloxacin in contact lenses affects critical lens properties (optical and swelling) owing to drug precipitation in the contact lens matrix. The presence of Pluronic® F-68 in the packaging solution creates in-situ micelles in the contact lens to dissolve gatifloxacin precipitates and provide sustained drug release. The micelles further improved the drug uptake from the drug-packaging solution to create an equilibrium of drug between the lens matrix and the packaging solution. In this study, we optimized gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and gatifloxacin loading capacity as well as sustained drug delivery. Optimization of gatifloxacin-pluronic-loaded contact lens was carried out using a 32 factorial design by tailoring the concentration of Pluronic® F-68 in the packaging solution (X1) and the amount of gatifloxacin in the monomer solution (X2) to achieve the desired lens properties. The optimized batch (X1 = 0.3%w/v and X2 = 0.3%w/v) showed an optical transmittance of 92.84%, swelling of 92.36% and gatifloxacin loading capacity of 92.56 µg. The in vitro flux data of the optimized batch (GT-Pl-CL) showed sustained release up to 72 h, whereas soaked contact lenses (SM-CL) and direct gatifloxacin-loaded contact lenses (DL-CL) showed a sustained release up to 48 h. The in vivo gatifloxacin release data for rabbit tear fluid showed sustained release with a high gatifloxacin level for the GT-Pl-CL lens in comparison to the SM-CL and the eye drop solution. This study demonstrates the application of the 32 full factorial design to optimize gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and drug loading capacity.

Ultrasound-assisted gatifloxacin delivery in mouse cornea, in vivo.

Gatifloxacin is a 4th generation fluoroquinolone antibiotic used in the clinic to treat ocular infection. One limitation of gatifloxacin is its relatively poor corneal penetration, and the increase of its trans-corneal delivery would be beneficial to reduce the amount or frequency of daily dose. In this study, ultrasound treatment was applied to enhance the trans-corneal delivery of gatifloxacin without damage. Experiments were conducted on mouse eyes in ex vivo and in vivo conditions. Ultrasound waves with 1 MHz in frequency, 1.3 W/cm2 in intensity were applied onto the mouse cornea for 5 minutes, and then gatifloxacin ophthalmic solution was instilled and left there for 10 minutes. 3D gatifloxacin distribution in the cornea was measured by two-photon microscopy (TPM) imaging based on its intrinsic fluorescence. Longitudinal TPM imaging of ultrasound treated mouse corneas showed the increase of initial gatifloxacin intensities on the corneal surface compared to untreated mouse corneas by 67%, and then the increased gatifloxacin delivery into the cornea from the surface at later time. The delivered gatifloxacin in the corneal epithelium stayed longer in the ultrasound treated corneas than in the untreated corneas. The enhanced trans-corneal delivery and extended stay of gatifloxacin in the mouse cornea by ultrasound treatment could be beneficial for therapeutic effects. This study demonstrated the detail process of enhanced trans-corneal gatifloxacin delivery by ultrasound treatment.

Artificial intelligence-derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.

Background: In the experimental arm of the OFLOTUB trial, gatifloxacin replaced ethambutol in the standard 4-month regimen for drug-susceptible pulmonary tuberculosis. The study included a nested pharmacokinetic (PK) study. We sought to determine if PK variability played a role in patient outcomes. Methods: Patients recruited in the trial were followed for 24 months, and relapse ascertained using spoligotyping. Blood was drawn for drug concentrations on 2 separate days during the first 2 months of therapy, and compartmental PK analyses was performed. Failure to attain sustained sputum culture conversion at the end of treatment, relapse, or death during follow-up defined therapy failure. In addition to standard statistical analyses, we utilized an ensemble of machine-learning methods to identify patterns and predictors of therapy failure from among 27 clinical and laboratory features. Results: Of 126 patients, 95 (75%) had favorable outcomes and 19 (15%) failed therapy, relapsed, or died. Pyrazinamide and rifampicin peak concentrations and area under the concentration-time curves (AUCs) were ranked higher (more important) than gatifloxacin AUCs. The distribution of individual drug concentrations and their ranking varied significantly between South African and West African trial sites; however, drug concentrations still accounted for 31% and 75% of variance of outcomes, respectively. We identified a 3-way antagonistic interaction of pyrazinamide, gatifloxacin, and rifampicin concentrations. These negative interactions disappeared if rifampicin peak concentration was above 7 mg/L. Conclusions: Concentration-dependent antagonism contributed to death, relapse, and therapy failure but was abrogated by high rifampicin concentrations. Therefore, increasing both rifampin and gatifloxacin doses could improve outcomes. Clinical Trials Registration: NCT00216385.

Gatifloxacin Pharmacokinetics/Pharmacodynamics-based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis.

Background: Gatifloxacin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The optimal dose is unknown. Methods: We performed a 28-day gatifloxacin hollow-fiber system model of tuberculosis (HFS-TB) study in order to identify the target exposures associated with optimal kill rates and resistance suppression. Monte Carlo experiments (MCE) were used to identify the dose that would achieve the target exposure in 10000 adult patients with meningeal or pulmonary MDR-TB. The optimal doses identified were validated using probit analyses of clinical data from 2 prospective clinical trials of patients with pulmonary and meningeal tuberculosis. Classification and regression-tree (CART) analyses were used to identify the gatifloxacin minimum inhibitory concentration (MIC) below which patients failed or relapsed on combination therapy. Results: The target exposure associated with optimal microbial kill rates and resistance suppression in the HFS-TB was a 0-24 hour area under the concentration-time curve-to-MIC of 184. MCE identified an optimal gatifloxacin dose of 800 mg/day for pulmonary and 1200 mg/day for meningeal MDR-TB, and a clinical susceptibility breakpoint of MIC ≤ 0.5 mg/L. In clinical trials, CART identified that 79% patients failed therapy if MIC was >2 mg/L, but 98% were cured if MIC was ≤0.5 mg/L. Probit analysis of clinical data demonstrated a >90% probability of a cure in patients if treated with 800 mg/day for pulmonary tuberculosis and 1200 mg/day for meningeal tuberculosis. Doses ≤400 mg/day were suboptimal. Conclusions: Gatifloxacin doses of 800 mg/day and 1200 mg/day are recommended for pulmonary and meningeal MDR-TB treatment, respectively. Gatifloxacin has a susceptible dose-dependent zone at MICs 0.5-2 mg/L.