Ratiometric Fluorescence Detection of Levofloxacin Based on a Cube-like Zn(II)-Eu(III) Nanocluster: Functionalized Sodium Alginate Film for the Detection in Serum and Medicine.

A cube-like Zn(II)-Eu(III) nanocluster 1 (molecular sizes: 1.8 × 2.0 × 2.0 nm) was constructed by the use of a new long-chain Schiff base ligand. It shows a ratiometric fluorescence response to levofloxacin (LFX) with high sensitivity and selectivity, which can be expressed as I615 nm/I550 nm = A*[LFX]2 + B*[LFX] + C. It is used to quantitatively detect the LFX concentrations in fetal calf serum (FCS) and tablets sold in pharmacy. Filter paper strips bearing 1 can be used to qualitatively detect LFX by a color change to red under a UV lamp. 1 and its hybrid with sodium alginate (SA), 1@SA, display potential applications in the qualitative detection of LFX in FCS and the medicine. The limit of detection of 1 to LFX is as low as 2.1 × 10-2 nM.

Population pharmacokinetics and dose optimization of levofloxacin in elderly patients with pneumonia.

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.

Population pharmacokinetics of oral levofloxacin in healthy volunteers and dosing optimization for multidrug-resistant tuberculosis therapy.

Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32 L h-1 (22.6%), apparent central volume of distribution 35.8 L (45.2%), apparent peripheral volume of distribution 39.7 L, intercompartmental clearance 40.6 L h-1 (43.8%), absorption rate constant 7.45 h-1 (150%), mean absorption transit time 0.355 h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000 mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5 mg L-1 , while a dose of 1500 mg was required for strains with an MIC of 1 mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.

Facile Synthesis of Ag/AgVO3/N-rGO Hybrid Nanocomposites for Electrochemical Detection of Levofloxacin for Complex Biological Samples Using Screen-Printed Carbon Paste Electrodes.

Silver vanadate nanorods (ß-AgVO3) with silver nanoparticles (Ag-NPs) decorated on the surface of the rods were synthesized by using simple hydrothermal technique and later anchored onto nitrogen-doped reduced graphene oxide (N-rGO) to make a novel nanocomposite. Experimental analyses were carried out to identify the electronic configuration by X-ray diffraction analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy analysis, which revealed monoclinic patterns of the C12/m1 space group with Wulff construction forming beta silver vanadate (ß-AgVO3) crystals with optical density and phase transformations. Ag nucleation showed consistent results with metallic formation and electronic changes occurring in [AgO5] and [AgO3] clusters. Transmission electron microscopy and field-emission scanning electron microscopy with elemental mapping and EDX analysis of the morphology reveals the nanorod structure for ß-AgVO3 with AgNPs on the surface and sheets for N-rGO. Additionally, a novel electrochemical sensor is constructed by using Ag/AgVO3/N-rGO on screen-printed carbon paste electrodes for the detection of antiviral drug levofloxacin (LEV) which is used as a primary antibiotic in controlling COVID-19. Using differential pulse voltammetry, LEV is determined with a low detection limit of 0.00792 nm for a linear range of 0.09-671 µM with an ultrahigh sensitivity of 152.19 µA µM-1 cm-2. Furthermore, modified electrode performance is tested by real-time monitoring using biological and river samples.

Which Analysis Approach Is Adequate to Leverage Clinical Microdialysis Data? A Quantitative Comparison to Investigate Exposure and Reponse Exemplified by Levofloxacin.

PURPOSE: Systematic comparison of analysis methods of clinical microdialysis data for impact on target-site drug exposure and response. METHODS: 39 individuals received a 500 mg levofloxacin short-term infusion followed by 24-h dense sampling in plasma and microdialysate collection in interstitial space fluid (ISF). ISF concentrations were leveraged using non-compartmental (NCA) and compartmental analysis (CA) via (ii) relative recovery correction at midpoint of the collection interval (midpoint-NCA, midpoint-CA) and (ii) dialysate-based integrals of time (integral-CA). Exposure and adequacy of community-acquired pneumonia (CAP) therapy via pharmacokinetic/pharmacodynamic target-attainment (PTA) analysis were compared between approaches. RESULTS: Individual AUCISF estimates strongly varied for midpoint-NCA and midpoint-CA (≥52.3%CV) versus integral-CA (≤32.9%CV) owing to separation of variability in PK parameters (midpoint-CA = 46.5%-143%CVPK, integral-CA = 26.4%-72.6%CVPK) from recovery-related variability only in integral-CA (41.0%-50.3%CVrecovery). This also led to increased variability of AUCplasma for midpoint-CA (56.0%CV) versus midpoint-NCA and integral-CA (≤33.0%CV), and inaccuracy of predictive model performance of midpoint-CA in plasma (visual predictive check). PTA analysis translated into 33% of evaluated patient cases being at risk of incorrectly rejecting recommended dosing regimens at CAP-related epidemiological cut-off values. CONCLUSIONS: Integral-CA proved most appropriate to characterise clinical pharmacokinetics- and microdialysis-related variability. Employing this knowledge will improve the understanding of drug target-site PK for therapeutic decision-making.

Simultaneous quantification of plasma levels of 12 antimicrobial agents including carbapenem, anti-methicillin-resistant Staphylococcus aureus agent, quinolone and azole used in intensive care unit using UHPLC-MS/MS method.

OBJECTIVES: Critically ill patients in intensive care unit (ICU) are susceptible to infectious diseases, thus empirical therapy is recommended. However, the therapeutic effect in ICU patients is difficult to predict due to fluctuation in pharmacokinetics because of various factors. This problem can be solved by developing personalized medicine through therapeutic drug monitoring. However, when different measurement systems are used for various drugs, measurements are complicated and time consuming in clinical practice. In this study, we aimed to develop an assay using ultra-high performance liquid chromatography coupled with tandem mass spectrometry for simultaneous quantification of 12 antimicrobial agents commonly used in ICU: doripenem, meropenem, linezolid, tedizolid, daptomycin, ciprofloxacin, levofloxacin, pazufloxacin, fluconazole, voriconazole, voriconazole N-oxide which is a major metabolite of voriconazole, and posaconazole. DESIGN & METHODS: Plasma protein was precipitated by adding acetonitrile and 50% MeOH containing standard and labeled IS. The analytes were separated with an ACQUITY UHPLC CSH C18 column, under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method fulfilled the criteria of US Food and Drug Administration for assay validation. The recovery rate was more than 84.8%. Matrix effect ranged from 79.1% to 119.3%. All the calibration curves showed good linearity (back calculation of calibrators: relative error ≤ 15%) over wide concentration ranges, which allowed determination of Cmax and Ctrough. Clinical applicability of the novel method was confirmed. CONCLUSIONS: We have developed an assay for simultaneous quantification of 12 antimicrobial agents using a small sample volume of 50 µL with a short assay time of 7 min. Our novel method may contribute to simultaneous calculation of pharmacokinetic and pharmacodynamic parameters.

Development and validation of a UPLC-MS/MS method for simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin in human plasma: Application to the therapeutic drug monitoring in osteoarticular infections.

BACKGROUND: Fluoroquinolones and rifampicin are antibiotics frequently used for the treatment of osteoarticular infections, and their therapeutic drug monitoring is recommended. The aim of this study was to develop and validate a rapid and selective method of simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin with short pretreatment and run times in order to be easily used in clinical practice. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-performance liquid chromatography system coupled with mass tandem spectrometry in a positive ionization mode. The mobile phase consisted of a gradient elution of water-formic acid (100:0.1, v/v)-ammonium acetate 2 mM (A) and methanol-formic acid (100:0.1, v/v)-ammonium acetate 2 mM (B) at a flow rate at 0.3 mL/min. RESULTS: Analysis time was 5 min per run, and all analytes and internal standards eluted within 0.85-1.69 minutes. The calibration curves were linear over the range from 0.5-30 µg/mL for levofloxacin, ciprofloxacin, moxifloxacin and rifampicin with linear regression coefficients above 0.995 for all analytes. The intra-day and inter-day coefficients of variation were below 10 % for lower and higher concentration. This method was successfully applied to drug monitoring in patients with an osteoarticular infection. CONCLUSION: A simple, rapid, and selective liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin in human plasma.

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis.

The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2-93.8) to 82.5 hour·mg/L (range 8.7-161.0) in plasma and from 3.5 hour·mg/L (range 1.2-9.6) to 6.0 hour·mg/L (range 0.7-15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

Eu3+-Functionalized Covalent Organic Framework Hybrid Material as a Sensitive Turn-On Fluorescent Switch for Levofloxacin Monitoring in Serum and Urine.

The research on luminescent lanthanide-functionalized covalent organic framework (COF)-based hybrid materials has not been reported so far. When a straightforward functionalized modification strategy is employed, a chemical stable Eu3+-modified COF hybrid material, Eu@TpPa-1, is first developed. The functional process does not affect the size and shape of TpPa-1, but after the introduction of Eu3+, Eu@TpPa-1 as a fluorescence sensor exhibits a turn-on response toward levofloxacin. Eu3+ plays a bridge role in the whole detection system, and TpPa-1 serves as a host matrix to provide protection for the introduced Eu3+. This reusable sensor shows strong pink-white and yellow emissions toward the high and low concentration ranges of levofloxacin, respectively. It displays excellent sensitivity and fast response to levofloxacin within 1 min, while refraining from the interference of other coexisting species in serum and urine. The good selectivity and high antidisturbance lead Eu@TpPa-1 to be successfully applied in serum and urine systems for sensing levofloxacin.

Evaluation of Saliva as a Potential Alternative Sampling Matrix for Therapeutic Drug Monitoring of Levofloxacin in Patients with Multidrug-Resistant Tuberculosis.

Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multidrug-resistant tuberculosis (MDR-TB) patients. The objectives of this study were (i) to evaluate the correlation between plasma and salivary levofloxacin (Lfx) concentrations in MDR-TB patients and (ii) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in areas where TB is endemic. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (750- to 1,000-mg once-daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental kinetics. Lfx drug exposures were evaluated in 23 MDR-TB patients. During the first month, the median (interquartile range [IQR]) areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 67.09 (53.93 to 98.37) mg ⋅ h/liter in saliva and 99.91 (76.80 to 129.70) mg ⋅ h/liter in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53 to 0.99). Similarly, during the second month, the median (IQR) AUC0-24 were 75.63 (61.45 to 125.5) mg ⋅ h/liter in saliva and 102.7 (84.46 to 131.9) mg ⋅ h/liter in plasma, with an S/P ratio of 0.73 (0.66 to 1.18). Furthermore, large inter- and intraindividual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semiquantitatively predicting Lfx plasma levels. (This study has been registered at ClinicalTrials.gov under identifier NCT03000517.).

Pharmacokinetics of levofloxacin after single intravenous, oral and subcutaneous administration to dogs.

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg-1  hr-1 and a T½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half-life and Tmax were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p Ë‚ 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC24 hr /MIC and Cmax /MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram-negative bacteria with MIC values of 0.1 µg/ml. For Gram-positive bacteria with MIC values of 0.5 µg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC-based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 µg/ml and E. coli strains with MIC values ≤0.125 µg/ml.

Voltammetric determination of levofloxacin using silver nanoparticles deposited on a thin nickel oxide porous film.

The authors describe a simplified chemical precipitation method and silver mirror reaction to synthesize a nanocomposite consiting of silver nanoparticles on a thin and porous nickel oxide film. Placed on a glassy carbon electrode (GCE), it allows for the determination of levofloxacin (LEV) via square wave voltammetry (SWV). Under optimal detection conditions, the voltammetric signal (typically measured at around 0.96 V vs. SCE) increases linearly in the 0.25-100 µM LEV concentration range. And the detection limit was calculated as 27 nM (at S/N = 3). The sensor is highly selective, stable and repeatable. It was applied to the determination of LEV in spiked human serum samples, and the satisfactory results confirm the applicability of this sensor to practical analyses. Graphical abstract Schematic of a two-step method to synthesize a nanocomposite consisting of nickel oxide porous thin-film supported silver nanoparticles. The composite was used for improved voltammetric determination of levofloxacin.

Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients.

Levofloxacin is an antituberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate the area under the concentration curve for the 24-h dosing interval (AUC0-24) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach. The popPK model and Bayesian LSS were developed using data from 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum time span, 8 h; minimum interval, 1 h; 1 to 3 samples) were tested. Performance criteria were root-mean-square error (RMSE) of <15%, mean prediction error (MPE) of <5%, and r2 value of >0.95. A one-compartment model with lag time best described the data while only slightly underestimating the AUC0-24 (mean, -7.9%; standard error [SE], 1.7%). The Bayesian LSS using 0- and 5-h postdose samples (RMSE, 8.8%; MPE, 0.42%; r2 = 0.957) adequately estimated the AUC0-24, with a mean underestimation of -4.4% (SE, 2.7%). The multiple linear regression LSS using 0- and 4-h postdose samples (RMSE, 7.0%; MPE, 5.5%; r2 = 0.977) was internally validated, with a mean underestimation of -0.46% (SE, 2.0%). In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis.

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Population Pharmacokinetics of Levofloxacin in Plasma and Bone of Patients Undergoing Hip or Knee Surgery.

Patients undergoing hip or knee replacement therapy are routinely pretreated with antibiotics before they enter the operation theater. This treatment intends to reduce the incidence of peri- or postsurgical infections. Here, we calculated the uptake kinetics of levofloxacin into bone to see whether levofloxacin could be obtained from the trabecular and cortical bone and at what time concentrations are sufficiently high to inhibit the usual hospital infections. Patients (n = 42) undergoing routine surgery were treated with 500 mg levofloxacin intravenously immediately prior to the operation. Plasma samples were taken before and at 3 points after termination of drug infusion. After replacement of the bones, extracts were obtained from them. Levofloxacin was quantified using high-performance liquid chromatography. The kinetics of levofloxacin and its distribution into bone were analyzed using a population approach (ADAPT5). Clearance was 14.0 L/h, and distribution volume was 77 L. Bone uptake t½ was calculated as 4.2 and 5.4 hours for cortical bone and trabecular bone, respectively. In knee samples (but not in hip samples), we noted that the cortical bone contained higher levels of levofloxacin than the trabecular bone. From our data, we can conclude that levofloxacin might be useful for prophylactic use in bone surgery.

Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study.

PURPOSE: To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection. METHODS: Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used. RESULTS: Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points. CONCLUSION: The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

High-performance liquid chromatography with time-programmed fluorescence detection for the quantification of Levofloxacin in human plasma and cerebrospinal fluid in adults with tuberculous meningitis.

An accurate and reliable high-performance liquid chromatography with time-programmed fluorescence detection was developed and validated to measure levofloxacin in human plasma and cerebrospinal fluid (CSF). After solid phase extraction process using Evolute® ABN 96 fixed well plate; levofloxacin and internal standard-enoxacin were separated using a mobile phase consisting of phosphate buffer 10mM with 0.025% triethylamine pH 3.0 - acetonitrile (88:12, v/v) on a Purosphere RP-8e column (5µm, 125×4.0mm) at a flow rate of 1.2mL/min at 35°C. The excitation/emission wavelengths were set to 269/400nm and 294/500nm, for enoxacin and levofloxacin, respectively. The method was linear over the concentration range of 0.02 to 20.0µg/mL with a limit of detection of 0.01µg/mL. The relative standard deviation of intra-assay and inter-assay precision for levofloxacin at four quality controls concentrations (0.02, 0.06, 3.0 and 15.0µg/mL) were less than 7% and the accuracies ranged from 96.75% to 101.9% in plasma, and from 93.00% to 98.67% in CSF. The validated method was successfully applied to quantify levofloxacin in a considerable quantity of plasma (826) and CSF (477) samples collected from 232 tuberculous meningitis patients, and the preliminary intensive pharmacokinetics analysis from 14 tuberculous meningitis patients in Vietnam is described in this paper.