Hybrid Ofloxacin/eugenol co-loaded solid lipid nanoparticles with enhanced and targetable antimicrobial properties.

In the global context of an imminent emergence of multidrug-resistant microorganisms, the present work combined the use of nanotechnology and the therapeutic benefits of natural compounds as a strategy to potentiate antimicrobial action of the wide-spectrum antibiotic Ofloxacin (Ofx). Hybrid solid lipid nanoparticles (SLN) were synthesized by incorporation of chitosan (Chi, a cationic biopolymer with antimicrobial activity) and eugenol (Eu, a phenolic compound that interferes with bacterial quorum sensing) into a lipid matrix by hot homogenization/ultrasonication method. The developed SLN/Chi/Eu sustainably released the encapsulated Ofx for 24 h. Characterization by DLS, TEM, DSC, TGA and XRD revealed the presence of positively charged spherical nanoparticles with diameters around 300 nm and Ofx entrapped in amorphous state. The SLN exhibited an enhanced bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus. The minimum inhibitory concentration (MIC) for free and nanoencapsulated Ofx formulations was below 1.0 µg/ml. The MIC values decreased by 6.1- to 16.1-fold when Ofx was encapsulated in SLN/Chi/Eu. Fluorescent-labeled nanoparticles had the ability to interact with the bacterial cell membrane. Selective toxicity of SLN/Chi/Eu-Ofx was tested in the range of 0.3-30.0 µg/ml and showed no toxicity up to 3.0 µg/ml Ofx in human cell models (A549 and Wi-38) at 24 h and 48 h exposure. It was proved that the administration of hybrid SLN to mice by dry powder inhalation reached therapeutic Ofx levels in lungs.

Penetration of 0.3% ciprofloxacin, 0.3% ofloxacin, and 0.5% moxifloxacin into the cornea and aqueous humor of enucleated human eyes.

We aimed to quantify the penetration of ciprofloxacin, ofloxacin, and moxifloxacin into the cornea and aqueous humor of cadaver eyes. A total of 60 enucleated eyes, not eligible for corneal transplantation, were divided into three groups and immersed in commercial solutions of 0.3% ciprofloxacin, 0.3% ofloxacin, or 0.5% moxifloxacin for 10 min. Whole corneas and samples of aqueous humor were then harvested and frozen, and drug concentrations analyzed by liquid chromatography tandem mass spectrometry. The mean corneal concentration of moxifloxacin was twice as high as ofloxacin, and the latter was twice as high as ciprofloxacin. The mean concentration of moxifloxacin in the aqueous humor was four times higher than the other antibiotics, and the mean concentrations of ciprofloxacin and ofloxacin were statistically similar. The amount of drug that penetrated the anterior chamber after a 10-min immersion was far below the safe limit of endothelial toxicity of each preparation. Moxifloxacin demonstrated far superior penetration into the cornea and anterior chamber of cadaver eyes compared to ciprofloxacin and ofloxacin. One should not expect endothelial toxicity with the commercial eye drops of ciprofloxacin, ofloxacin, and moxifloxacin that reach the anterior chamber through the cornea.

Penetration of 0. 3% ciprofloxacin, 0. 3% ofloxacin, and 0. 5% moxifloxacin into the cornea and aqueous humor of enucleated human eyes

We aimed to quantify the penetration of ciprofloxacin, ofloxacin, and moxifloxacin into the cornea and aqueous humor of cadaver eyes. A total of 60 enucleated eyes, not eligible for corneal transplantation, were divided into three groups and immersed in commercial solutions of 0.3% ciprofloxacin, 0.3% ofloxacin, or 0.5% moxifloxacin for 10 min. Whole corneas and samples of aqueous humor were then harvested and frozen, and drug concentrations analyzed by liquid chromatography tandem mass spectrometry. The mean corneal concentration of moxifloxacin was twice as high as ofloxacin, and the latter was twice as high as ciprofloxacin. The mean concentration of moxifloxacin in the aqueous humor was four times higher than the other antibiotics, and the mean concentrations of ciprofloxacin and ofloxacin were statistically similar. The amount of drug that penetrated the anterior chamber after a 10-min immersion was far below the safe limit of endothelial toxicity of each preparation. Moxifloxacin demonstrated far superior penetration into the cornea and anterior chamber of cadaver eyes compared to ciprofloxacin and ofloxacin. One should not expect endothelial toxicity with the commercial eye drops of ciprofloxacin, ofloxacin, and moxifloxacin that reach the anterior chamber through the cornea.

Development and evaluation of bilayer tablets of combination of antibiotics for the treatment of sexually transmitted disease

ABSTRACT The present research work was envisaged to develop bilayer tablets to improve therapeutic efficacy of antibiotic combination for the treatment of sexually transmitted diseases. The combination of two antibiotics i.e. cefixime trihydrate and ofloxacin were used for the preparation of bilayer tablets which act against genito-urinary infections. The formulations comprise of cefixime trihydrate as immediate release layer formulated using different superdisintegrants and ofloxacin as extended release layer containing HPMC K100M. Evaluation of bilayer tablets were performed for the immediate release cefixime layer and sustain release ofloxacin layer with optimization of excipients. The immediate release layer of cefixime showed complete release within 30 min and ofloxacin release was extended up to 24 hours. The similarity factor value of ofloxacin sustained release layer was found to be 87.01 for initial and 80.35 after 3 months stability when compared with marketed reference product. The present study revealed that cefixime trihydrate and ofloxacin bilayer tablets were successfully developed for the use against sexually transmitted infections.

Determination of ofloxacin in tear by HPLC-ESI-MS/MS method: comparison of ophthalmic drug release between a new mucoadhesive chitosan films and a conventional eye drop formulation in rabbit model.

Ofloxacin, second-generation fluoroquinolone derivative, is one of the most commonly used to treat and prevent superficial ocular infection in animals and human beings. However, poor bioavailability, rapid elimination, and non compliance by patients are several problems associated with ocular route. Ophthalmic controlled drug delivery offers the potential to enhance the efficacy of treatment for pathological conditions, while reducing the side effects and the toxicity associated with frequent applications. Specific analytical methods to determine drugs in eye are needed to analyze and compare the new controlled release ocular devices with those conventional eye drops. The topical eye administration of ophthalmic drugs induces lachrymation, and the tear promotes a drug wash out. Quantify drugs in tear is a good tool to study their kinetic comportment in the eye. A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method for quantitation of ofloxacin in rabbits' tears was developed and validated. The tear was collected with tear strips, extracted by a liquid extraction procedure and then separated on an ACE C(18) column with a mobile phase composed of 0.15% aqueous formic acid and methanol (60:40, v/v). Calibration curve was constructed over the range of 10-5000 ng/mL for ofloxacin. The mean R.S.D. values for the intra-run and inter-run precision were 5.15% and 4.35%, respectively. The mean accuracy value was 100.16%. The validated method was successfully applied to determine the ofloxacin concentration in tears of rabbits treated with a mucoadhesive chitosan films and a conventional eye drop formulation.

Pharmacokinetic/pharmacodynamic modelling of the bactericidal activity of free lung concentrations of levofloxacin and gatifloxacin against Streptococcus pneumoniae.

The aim of this work was to compare the pharmacological properties of levofloxacin and gatifloxacin against Streptococcus pneumoniae by pharmacokinetic/pharmacodynamic (PK/PD) modelling of the time-kill curves employing an E(max) model. An in vitro infection model was used to simulate free pulmonary fluctuating concentrations expected after multiple dosing regimens of both drugs in humans or constant multiples of the minimum inhibitory concentration. PK/PD parameters and PK/PD indices of the simulated dosing regimens were compared. The levofloxacin EC(50) (concentration producing 50% of the maximum effect) (mean ± standard deviation 3.57±2.16 mg/L) was higher than that for gatifloxacin (0.95±0.56 mg/L) when simulating multiple dosing regimens as well as constant concentrations (EC(50,levofloxacin)=2.75±0.45 mg/L; EC(50,gatifloxacin)=1.03±0.52 mg/L). The maximum killing rate constant (k(max)) was not statistically different for both drugs independent of fluctuating (k(max,levofloxacin)=0.40±0.19 h(-1); k(max,gatifloxacin)=0.48±0.15 h(-1)) or constant concentrations (k(max,levofloxacin)=0.34±0.06 h(-1); k(max,gatifloxacin)=0.39±0.23 h(-1)). The PK/PD model was able to describe the effect of levofloxacin and gatifloxacin against S. pneumoniae in vitro for all the simulations investigated. Gatifloxacin was more potent than levofloxacin, but both presented equivalent efficacy. The model can be used for simulating alternative regimens and optimising therapy to treat streptococcal infextions.

Biowaiver monographs for immediate release solid oral dosage forms: levofloxacin.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levofloxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the current Biopharmaceutics Classification System, levofloxacin can be assigned to Class I. No problems with BE of IR levofloxacin formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. In addition, levofloxacin has a wide therapeutic index. On the basis of this evidence, a biowaiver is recommended for IR solid oral dosage forms containing levofloxacin as the single API provided that (a) the test product contains only excipients present in IR levofloxacin drug products that have been approved in International Conference on Harmonization (ICH) or associated countries and which have the same dosage form; (b) both the test and comparator dosage form are "very rapidly dissolving" or "rapidly dissolving" with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8; and (c) if the test product contains polysorbates, it should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content.

Bioavailability of two oral formulations of a single dose of levofloxacin 500 mg: an open-label, randomized, two-period crossover comparison in healthy Mexican volunteers.

BACKGROUND: Levofloxacin is a synthetic fluoroquinolone with a broad spectrum of antibacterial activity. It is indicated for the treatment of respiratory, sinus, skin, and urinary tract infections. Although generic formulations of oral levofloxacin are marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations; these data would be relevant to secure marketing of a test formulation in Mexico. OBJECTIVE: The aim of this study was to compare the bioavailability and determine the bioequivalence of a test formulation (an oral tablet containing levofloxacin 500 mg) with its corresponding listed reference-drug formulation in Mexico (a list issued by Mexican Health Authorities). METHODS: A single-dose, open-label, randomized-sequence, 2-period crossover design was used in this study. Eligible participants were healthy Mexican adults of either sex, randomly assigned to receive the test formulation followed by the corresponding reference formulation, or vice versa, with a 1-week washout period between doses. After a 10-hour overnight fast, the participants received the assigned formulation. Plasma concentrations of levofloxacin were determined using high-performance thin-layer chromatography, and densitometric analysis was performed at 300 nm. For the analysis of pharmacokinetic parameters, including C(max), AUC0(-24), and AUC(0-infinity)), blood samples were drawn at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. The test formulation was considered to meet the criteria for bioequivalence if the geometric mean ratios (test/reference) were with- in the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, vital signs, laboratory analysis, and interviews with participants about adverse events. RESULTS: A total of 26 participants were enrolled, including 14 men and 12 women with a mean (SD) age of 24 (4) years (range, 18-34 years), weight of 62.2 (10.0) kg (range, 45.5-80.0 kg), height of 163 (9) cm (range, 148-176 cm), and body mass index of 23.3 (2.4) kg/m(2) (range, 19.2-27.1 kg/m(2)). The 90% CIs for log-transformed C(max), AUC(0-24), and AUC(0-infinity) were 94.48% to 106.22%, 90.01% to 116.44%, and 85.11% to 114.00%, respectively. Eleven participants reported a total of 20 adverse events during the study. None of the adverse events were considered serious. CONCLUSIONS: In this small study in healthy, fasting Mexican adults, a single 500-mg dose of the test formulation of orally administered levofloxacin met the regulatory requirements to assume bioequivalence based on the rate and extent of absorption. Both formulations were well tolerated.

Comparative bioavailability of two oral formulations of levofloxacin in healthy Mexican volunteers.

OBJECTIVE: To assess the bioequivalence of two levofloxacin 500 mg tablets marketed in Mexico. MATERIAL AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-part, two-treatment, two-period crossover study, in 27 healthy male volunteers. 1 tablet of each formulation was administered with 200 ml of water after 10 h overnight fast. After dosing, serial blood samples were collected for a period of 24 h. Plasma concentrations were determined by a validated high-performance liquid chromatographic method and pharmacokinetic parameters were obtained by non-compartmental approach. Analysis of variance (ANOVA) was carried out using log-transformed AUClast, AUC yen and Cmax and untransformed tmax, and 90% confidence intervals for AUClast, AUC yen and Cmax were calculated. If the 90% confidence intervals (CI) for AUClast, AUC yen and Cmax fell fully within the interval 80 - 125%, the bioequivalence of the two formulations was established. RESULTS: The means (test and reference) for AUClast were 58.869 and 56.297 microg x h/ml, for AUC yen were 63.456 and 60.748 microg x h/ml and for Cmax were 8.691 and 8.445 microg/ml. The geometric mean ratios of the test formulation to reference formulation for AUClast, AUC yen and Cmax (CI) were 104.53% (102.73 - 106.36%), 104.37% (102.04 - 106.75%) and 103.45% (95.57 - 111.97%), respectively. All 90% CI for AUClast, AUC yen and Cmax fell within the Mexican Federal Commission for Prevention of Sanitary Risks (COFEPRIS) accepted bioequivalence range of 80 - 125%. CONCLUSIONS: Based on the results, the formulations tested are bioequivalent.

Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis.

The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 microg/ml; gatifloxacin, 4.75 microg/ml; moxifloxacin, 6.13 microg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used.

Pharmacokinetics of levofloxacin after single intravenous and repeat oral administration to cats.

The pharmacokinetic properties of the fluoroquinolone levofloxacin, were investigated in five cats after single intravenous and repeat oral administration at a daily dose of 10 mg/kg. Levofloxacin serum concentration was analyzed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as test microorganism. Serum levofloxacin disposition after intravenous and oral dosing was best fitted to a bicompartmental and a monocompartmental open models with first-order elimination, respectively. After intravenous administration, distribution was rapid (t(1/2(d)) 0.26 +/- 0.18 h) and wide as reflected by the steady-state volume of distribution of 1.75 +/- 0.42 L/kg. Drug elimination was slow with a total body clearance of 0.14 +/- 0.04 L/h.kg and a t(1/2) for this process of 9.31 +/- 1.63 h. The mean residence time was of 12.99 +/- 2.12 h. After repeat oral administration, absorption half-life was of 0.18 +/- 0.12 h and Tmax of 1.62 +/- 0.84 h. The bioavailability was high (86.27 +/- 43.73%) with a peak plasma concentration at the steady state of 4.70 +/- 0.91 microg/mL. Drug accumulation was not significant after four oral administrations. Estimated efficacy predictors for levofloxacin after either intravenous or oral administration indicate a good profile against bacteria with a MIC value below of 0.5 microg/mL. However, for microorganisms with MIC values of 1 microg/mL it would be efficacious only when administered intravenously.

Oral levofloxacin in the treatment of community-acquired pneumonia

We evalueted the efficacy of oral levofloxacin (500mg/day for 7-21 days) in the treatment of adults patients with community-acquired pneumonia (CAP) requiring hospitalization in an open prospective stydy. The microbiological cause of the pneumonia was identified in 14/20 patients using lower respiractory tract secretions obtained by bronhoscopy (12) and/or blood culture (2). Eight patients has S.pneumoniae, 2 P.aeruginosa, 1 H.influenzae, 1 S.aureus, 1 mixed S.aureus and K.pneumoniae, and 1 E.coli and Grp.D Streptococcus. All of the patients evaluated were judged to be improved or cured. Levofloxacin is an additional option as monotherapy for the treatment of CAP.

Infecciones respiratorias adquiridas en la comunidad: relación con agentes etiológicos y antibióticos con especial atención a levofloxacino / Community acquired respiratory infections: relationship to causal agents and antibiotics with special focus on levofloxacine

Los microorganismos involucrados en infecciones del tracto respiratorio alto y bajo, incluyen tanto bacterias "típicas" tales como Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes y Moraxella catarrhalis, y bacterias "atípicas", como Mycoplasma pneumoniae, Chlamydia pneumoniae y Legionella pneumophila. El primer grupo ha adquirido resistencia, tanto a nivel mundial como nacional, a los antimicrobianos de uso habitual en el tratamiento de estas infecciones, como son penicilina, ampicilina, cotrimoxazol, cefuroxima y cefotaxima, entre otros. Debido a lo anterior, se han desarrollado nuevas moléculas siendo una de ellas levofloxacino, una nueva quinolona, levoisómero de D-L racemato de ofloxacino. Este compuesto posee un amplio espectro "in vitro" contra bacteria Gram positivas, incluyendo S. pneumoniae resistente a penicilina, bacterias Gram negativas, bacterias atípicas y algunas bacterias anaerobias. Su biodisponibilidad en forma oral es de 100 por ciento. Es metabolizada en el hígado y su excreción a nivel renal es de 80 por ciento. En estudios clínicos levofloxacino ha demostrado eficacia y seguridad incluso con erradicación microbiológica demostrada en infecciones respiratorias adquiridas en la comunidad, lo que la convierte en una alternativa real de tratamiento

Estudo comparativo entre lomefloxacina e ofloxacina no tratamento da prostatite bacteriana crônica / Clinical trial comparing lomefloxacin and ofloxacin in the treatment of chronic bacterial prostatitis

Foram tratados 33 pacientes com prostatite bacteriana crônica, sintomáticos, diagnosticados pelo método de Meares-Stamey, com lomefloxacina 400 mg, uma vez ao dia, ou ofloxacina 200 mg, duas vezes ao dia, num estudo randomizado, por um período de 42 dias. Todos os microorganismos eram sensíveis a ambas as drogas. Os pacientes foram seguidos por seis meses com exames bacteriológicos de urina e líquido prostático pelo método descrito. Após seis meses a taxa de cura foi de 66,6 por cento para lomefloxacina e 60 por cento para ofloxacina. Nenhum paciente com infecçäo causada por P. aeruginosa foi curado e sem computar estes pacientes a taxa de cura seria 70,5 por cento e 64 por cento, respectivamente. Os efeitos colaterais observados foram em pequeno número e de pequena intensidade, em nenhuma ocasiäo obrigando à suspensäo do tratamento. Ambas as fluoroquinolonas se mostraram eficientes no tratamento desta difícil infecçäo bacteriana. A lomefloxacina, que pode ser administrada em dose única, provavelmente é mais prática para o paciente e resulta em melhor aderência a este longo tratamento