Development of Poly Lactide-Co-Glycolide Nanodispersions for Enhanced Ocular Delivery of Moxifloxacin
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To determine the effectiveness of moxifloxacin and besifloxacin prophylactic therapy for experimental Staphylococcus aureus infections originating in the rabbit anterior chamber.Microbiology Department, University of Mississippi Medical Center, Jackson, Mississippi, USA.Experimental study.Minimum inhibitory concentrations (MICs) of moxifloxacin 0.5% and besifloxacin 0.6% for methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) strains were determined. Eyes were treated with moxifloxacin, a moxifloxacin alternative formulation 0.5%, or besifloxacin (45 μL) 30 minutes or 60 minutes before anterior chamber infection (10(6) colony-forming units [CFUs]). Aqueous humor was removed 30 minutes after infection for quantification of antibiotic and bacteria.The MIC for both organisms was 0.06 μg/mL for moxifloxacin and 0.03 μg/mL for besifloxacin. In MSSA infections, the untreated eyes contained 5.18 log CFU/mL, which was similar to besifloxacin-treated eyes with either treatment (P≥.1091). Eyes treated with moxifloxacin or moxifloxacin alternative formulation contained significantly fewer CFUs than untreated controls or besifloxacin-treated eyes with either treatment (P≤.0020). The aqueous humor in eyes treated with moxifloxacin or moxifloxacin alternative formulation contained significantly more drug than besifloxacin-treated eyes at both prophylactic time points (P≤.0012). In MRSA infections, the untreated eyes contained 4.91 log CFU/mL, which was similar to besifloxacin-treated eyes with either treatment (P≥.5830). Eyes treated with moxifloxacin or moxifloxacin alternative formulation contained significantly fewer CFUs than untreated controls or besifloxacin-treated eyes at both prophylactic time points (P≤.0008).Moxifloxacin had greater in vivo effectiveness against MSSA and MRSA than besifloxacin. The aqueous antibiotic concentrations suggest limited penetration by besifloxacin, accounting for its lack of effectiveness.
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Moxifloxacin 400 mg is a widely used positive control in thorough QT (TQT) studies, but its QT-prolonging effects in Korean subjects have not been studied. The present study was conducted to collect pilot data in Korean subjects after moxifloxacin administration to evaluate the adequacy of moxifloxacin as a positive control.
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To the Editor: Gillespie et al. (Oct. 23 issue)1 report that two moxifloxacin-containing regimens for the treatment of tuberculosis were not effective with a shortened treatment period of 4 months. The authors used a moxifloxacin dose of 400 mg per day, which may have contributed to the unfavorable results. Rifampin decreases the average exposure to moxifloxacin (assessed according to the area under the curve [AUC]) by approximately 30%,2 which can be compensated for by an increase in the dose of moxifloxacin.3 In addition, preclinical data combined with pharmacokinetic and pharmacodynamic modeling showed that a higher moxifloxacin dose, of 800 mg per day, is likely to achieve better Mycobacterium tuberculosis microbial killing and suppression of drug resistance.4 Limited data have shown that moxifloxacin at a dose of 800 mg can be given safely.3,5 The inclusion of moxifloxacin drug exposure as a covariate would have been of additional value, considering that the ratio of the AUC to the minimum inhibitory concentration is the driver of moxifloxacin efficacy and that the AUC for moxifloxacin can vary among patients by a factor of 7.6 Such a pharmacokinetic and pharmacodynamic analysis could have shown whether the results of this trial could have been explained by a drug exposure to moxifloxacin that was too low.
Pharmacodynamics
Rifapentine
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Moxifloxacin has been the most commonly used positive control in "thorough" QTc (TQT) studies. In a TQT study, the assay sensitivity is often considered to be established if the baseline corrected mean difference in QTc between moxifloxacin and placebo is greater than 5 ms in common practice at one or more prespecified time points and the observed moxifloxacin induced QTc effect over time follows the proper pharmacokinetics profile. To better understand the statistical characteristics of moxifloxacin-induced QTc prolongation and to provide guidance for future studies, 20 TQT studies that involved moxifloxacin have been evaluated. We study the QTc profile of the baseline adjusted mean difference in QTc between moxifloxacin and placebo over time. Zhang (2008) proposed that the moxifloxacin induced QTc effect can be evaluated between 1 and 4 h after a single dose (400 mg) administration near the time (T(max)) of peak concentration instead of all time points (typically 9-12 time points) at which QT was measured for the study drug evaluation. After evaluating 20 TQT studies, we confirm that the maximum moxifloxacin effect occurs in the time window between 1 and 4 h post dose. We also investigate the variability of the data as well as correlations between time points and between regimens. These findings and results can be used as a reference for future studies.
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Previously we reported a 2-month clinical trial of moxifloxacin therapy in eight patients with MB leprosy (7 LL and 1 BL), finding both rapid killing of M. leprae and clinical improvement, without serious side effects or toxicities. Here we report the outcomes in two patients treated with moxifloxacin.Two previously untreated LL patients were treated with a single 400 mg dose of moxifloxacin, no therapy for 7 days and then daily 400 mg moxifloxacin for 48 days. Clinical response, viability of M. leprae in the skin, and side effects/toxicities were carefully monitored.In both patients a single dose of moxifloxacin resulted in significant killing of M. leprae (P < 0.001%). In both patients no viable M. leprae were found after 15 doses of moxifloxacin. Improvement in skin lesions occurred again remarkably rapidly and no untoward effects were noted.Loss of viable M. leprae was quite rapid, similar to that found previously only for rifampicin, patients improved rapidly, and moxifloxacin was well tolerated.
Mycobacterium leprae
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Objective:To establish a method for quantitative determination of moxifloxacin.Methods:Al3+ can enhance the UV characteristic of moxifloxacin.Based on this reaction,moxifloxacin was determined by UV spectrophotometry.Results:The reaction conditions were investigated in detail.In Al3+-MXFX system,the linear range was 1.82～15.68 μg/ml and regression equation was A=0.02573+0.1060C(μg/ml)(r=0.9991).The average recovery of Levofloxacin was 97.70% with RSD of 2.68%.Conclusion:This method is simple,accurate,rapid and can be used to determine moxifloxacin in tablet.
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Бұл зерттеужұмысындaКaно моделітурaлы жәнеоғaн қaтыстытолықмәліметберілгенжәнеуниверситетстуденттерінебaғыттaлғaн қолдaнбaлы (кейстік)зерттеужүргізілген.АхметЯссaуи университетініңстуденттеріүшін Кaно моделіқолдaнылғaн, олaрдың жоғaры білімберусaпaсынa қоятынмaңыздытaлaптaры, яғнисaпaлық қaжеттіліктері,олaрдың мaңыздылығытурaлы жәнесaпaлық қaжеттіліктерінеқaтыстыөз университетінқaлaй бaғaлaйтындығытурaлы сұрaқтaр қойылғaн. Осы зерттеудіңмaқсaты АхметЯсaуи университетіндетуризмменеджментіжәнеқaржы бaкaлaвриaт бaғдaрлaмaлaрыныңсaпaсынa қaтыстыстуденттердіңқaжеттіліктерінaнықтaу, студенттердіңқaнaғaттaну, қaнaғaттaнбaу дәрежелерінбелгілеу,білімберусaпaсын aнықтaу мен жетілдіружолдaрын тaлдaу болыптaбылaды. Осы мaқсaтқaжетуүшін, ең aлдыменКaно сaуaлнaмaсы түзіліп,116 студенткеқолдaнылдыжәнебілімберугежәнеоның сaпaсынa қaтыстыстуденттердіңтaлaптaры мен қaжеттіліктерітоптықжұмыстaрaрқылыaнықтaлды. Екіншіден,бұл aнықтaлғaн тaлaптaр мен қaжеттіліктерКaно бaғaлaу кестесіменжіктелді.Осылaйшa, сaпa тaлaптaры төрт сaнaтқa бөлінді:болуытиіс, бір өлшемді,тaртымдыжәнебейтaрaп.Соңындa,қaнaғaттaну мен қaнaғaттaнбaудың мәндеріесептелдіжәнестуденттердіңқaнaғaттaну мен қaнaғaттaнбaу деңгейлерінжоғaрылaту мен төмендетудеосытaлaптaр мен қaжеттіліктердіңрөліaйқын aнықтaлды.Түйінсөздер:сaпa, сaпaлық қaжеттіліктер,білімберусaпaсы, Кaно моделі.
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Purpose: Compare the efficacy of treatment of pneumococcal keratitis with cholesterol, moxifloxacin, or a mixture of the two (moxifloxacin/cholesterol).Materials and Methods: New Zealand white rabbits were injected intrastromally with 106 colony-forming units (CFU) of a clinical keratitis strain of Streptococcus pneumoniae. Eyes were examined before and after treatment of topical drops every 2 hr from 25 to 47 hr post-infection (PI). Corneas were harvested to quantitate bacterial CFU, and myeloperoxidase (MPO) activity was measured at 48 hr PI. Eyes were extracted for histology. Minimal inhibitory concentrations (MICs) were determined for each compound.Results: Eyes treated with moxifloxacin/cholesterol had a significantly lower mean slit lamp examination (SLE) score than eyes treated with phosphate-buffered saline (PBS), moxifloxacin alone, or cholesterol alone (P ≤ 0.02). A significantly lower log10 CFU was recovered from corneas treated with moxifloxacin/cholesterol and moxifloxacin alone as compared to corneas of eyes treated with PBS or cholesterol alone (P < 0.01). At 48 hr PI, significantly lower MPO activity was quantitated from eyes treated with moxifloxacin/cholesterol as compared to eyes treated with cholesterol or moxifloxacin alone (P ≤ 0.046). Eyes treated with moxifloxacin/cholesterol had fewer immune cells and less corneal destruction than eyes from all other treatment groups. The MIC for moxifloxacin alone was 0.125 μg/mL, and cholesterol alone was unable to inhibit growth at any of the concentrations tested. The MIC for moxifloxacin when combined with 1% cholesterol was 0.0625 μg/mL.Conclusions: Treatment with a mixture of moxifloxacin and cholesterol significantly lowers the severity of infection caused by pneumococcal keratitis as compared to treatment with moxifloxacin alone, cholesterol alone, or PBS. This treatment mixture eradicates the bacteria in the cornea, unlike treatment with PBS or cholesterol alone. Using cholesterol with moxifloxacin as a treatment for bacterial keratitis could help lower the clinical severity of the infection.
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BackgroundLowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effect of an activated charcoal-based adsorbent, DAV131A, on fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced C. difficile infection.Methods215 hamsters receiving moxifloxacin subcutaneously (D1-D5) were orally infected at D3 with C. difficile spores. They received various doses (0-1800mg/kg/day) and schedules (BID, TID) of DAV131A (D1-D8). Moxifloxacin concentration and C. difficile counts were determined at D3, and mortality at D12. We compared mortality, moxifloxacin concentration and C. difficile counts according to DAV131A regimens, and modelled the link between DAV131A regimen, moxifloxacin concentration and mortality. ResultsAll hamsters that received no DAV131A died, but none of those that received 1800mg/kg/day. A significant dose-dependent relationship between DAV131A dose and (i) mortality rates, (ii) moxifloxacin concentration and (iii) C. difficile counts was evidenced. Mathematical modeling suggested that (i) lowering moxifloxacin concentration at D3, which was 58$\mu$g/g (95%CI=50-66) without DAV131A, to 17$\mu$g/g (14-21) would reduce mortality by 90% and (ii) this would be achieved with a daily DAV131A dose of 703mg/kg (596-809).ConclusionsIn this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing fecal free moxifloxacin concentration.
Pseudomembranous colitis
Regimen
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