Clearance Of Levofloxacin Research Articles

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

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. 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. 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. 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.

Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis.

This study aimed to explore the population pharmacokinetic modeling (PopPK) of levofloxacin (LFX) and moxifloxacin (MXF), as well as the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24 h and the in vitro minimum inhibitory concentration (AUC0-24/MIC) in Ethiopian multidrug resistant tuberculosis (MDR-TB) patients. Steady state-plasma concentration of the drugs in MDR-TB patients were determined using optimized liquid chromatography-tandem mass spectrometry. PopPK and simulations were run at various doses, and pharmacokinetic parameters were estimated. The effect of covariates on the PK parameters and PTA for maximum mycobacterial kill and resistance prevention was also investigated. LFX and MXF both fit in a one-compartment model with adjustments. Serum-creatinine (Cr) influenced (p = 0.01) the clearance of LFX, whereas body mass index (BMI) influenced (p = 0.01) the apparent volume of distribution (V) of MXF. The PTA for LFX maximal mycobacterial kill at the critical MIC of 0.5 mg/L with the simulated 750 mg, 1000 mg, and 1500 mg doses were 29%, 62%, and 95%, respectively, whereas the PTA for resistance prevention at 1500 mg was only 4.8%, with none of the lower doses achieving this target. At the critical MIC of 0.25 mg/L, there was no change in the PTA for maximum bacterial kill when the MXF dose was increased (600 mg, 800 mg, and 1000 mg), but the PTA for resistance prevention was improved. The standard doses of LFX and MXF may not provide adequate drug exposure. PopPK of LFX is more predictable for maximum mycobacterial kill, whereas MXF's resistance prevention target increases with dose. Cr and BMI are likely important covariates for dose optimization in Ethiopian patients.

Oral levofloxacin: population pharmacokinetics model and pharmacodynamics study in bone and joint infections.

This study aimed at characterizing the pharmacokinetics (PK) of oral levofloxacin in adult patients in order to optimize dosing scheme and explore the PK/pharmacodynamics (PD) of levofloxacin in bone and joint infections (BJIs). From November 2015 to December 2019, all patients hospitalized in Cochin Hospital, treated with levofloxacin and who had at least one dosage for therapeutic drug monitoring were included. PK was described using non-linear mixed-effect modelling. In a subgroup of patients with BJIs, the association between PK, MIC for the isolated pathogen and clinical outcome was investigated. Monte Carlo simulations investigated dosing regimens to achieve the PK/PD target (AUC/MIC ratio >100). One hundred and two patients were included (199 measurements), including 32 treated for BJI. A one-compartment model with first-order absorption and elimination best described the data. Effects of estimated creatinine clearance (eCLCR) and age were significant on levofloxacin clearance. In BJI patients, no significant association was found between levofloxacin PK/microbiological parameters and either clinical outcome or adverse events. Based on our model, we proposed optimized oral levofloxacin dosing regimens according to renal function, to reach the PK/PD target AUC/MIC ratio >100 for three frequent causative pathogens (Staphylococcus aureus, Enterobacterales and Pseudomonas aeruginosa). Our results reinforce the need of determining the MIC and using therapeutic drug monitoring in complex infections caused by P. aeruginosa.

Obesity is not strongly associated with increased risk for febrile neutropenia during levofloxacin prophylaxis in patients with hematological malignancies receiving intermediate-risk myelosuppressive chemotherapy.

Levofloxacin given at a standard dose of 500 mg daily is recommended for antibacterial prophylaxis in patients receiving myelosuppressive chemotherapy. Obese patients have been shown to exhibit enhanced clearance of levofloxacin and may be at risk for prophylactic failure. This single center, retrospective cohort study from June 2014 to May 2017 evaluated adult patients with estimated creatinine clearance ≥50 mL/min receiving their first cycle of a National Comprehensive Cancer Network defined intermediate-risk regimen. Primary endpoint was incidence of febrile neutropenia. Secondary endpoints included 30-day mortality and the correlation between estimated levofloxacin area under the concentration-time curve and rates of febrile neutropenia. Febrile neutropenia occurred in 26 patients: 12 (35.3%) obese and 14 (21.9%) non-obese (P = 0.16). Six (23.1%) of these patients required intensive care, but there were no deaths within 30 days of a febrile neutropenia event. Estimated creatinine clearance was similar between obese and non-obese patients (median 97.5 vs. 91.8 mL/min, P = 0.39), as was estimated levofloxacin area under the concentration-time curve (median 85.6 vs. 90.8 mg×h/L, P = 0.39). There were no significant associations between body weight-related variables - total body weight (median 83.4 vs. 80.6 kg, P = 0.51), body mass index (mean 29.6 vs. 26.8 kg/m2, P = 0.35), or body surface area (1.98 vs. 1.99 m2, P = 0.68) - and febrile neutropenia in this cohort of patients with similar renal function. Obesity should not be a justification for more aggressive levofloxacin dosing schemes when used for febrile neutropenia prophylaxis.

1591. Infectious Outcomes of Levofloxacin Prophylaxis in Obese vs. Non-obese Patients with Hematologic Malignancies

BackgroundLevofloxacin given at a standard dose of 500 mg daily is recommended for antibacterial prophylaxis in patients receiving myelosuppressive chemotherapy. Obese patients have been shown to exhibit enhanced clearance of levofloxacin and may be at risk for prophylactic failure.MethodsThis was a single-center, retrospective cohort study evaluating the infectious outcomes of obese (BMI >30 kg/m2) and non-obese (BMI ≤ 30 kg/m2) adult patients who received standard dose levofloxacin as primary prophylaxis after chemotherapy. Patients were included if they were treated at our institution from June 1, 2014 through May 31, 2017 and had National Comprehensive Cancer Network (NCCN) defined intermediate infection risk. Patients were excluded if they were lost to follow-up, treated at another institution for febrile neutropenia (FN), or had renal impairment (estimated creatinine clearance (CrCL) less than 50 mL/minute). The primary endpoint was incidence of FN as defined by NCCN guidelines. Secondary endpoints included 30-day mortality and the correlation between estimated levofloxacin AUC and rates of FN. Levofloxacin AUC was estimated from CrCL using the method of Pai et al.ResultsA total of 98 patients met the inclusion criteria (34 obese and 64 non-obese). Estimated CrCL was similar between obese and non-obese patients (mean 84.5 vs. 81.6 mL/minute, P = 0.61), as was estimated levofloxacin AUC (mean 115.1 mg hour/L vs. 107.8 mg hour/L, P = 0.25). FN occurred in 26 patients: 12 (35.3%) obese and 14 (21.9%) non-obese (P = 0.16). Bivariate comparisons between patients who did and did not experience FN found no significant associations with the weight-related variables total body weight (mean 84.7 vs. 82.0 kg, P = 0.56), BMI (mean 28.8 vs. 28.0 kg/m2, P = 0.51), or body surface area (1.99 vs. 1.96 m2, P = 0.62). Multivariate analysis identified presence of mucositis and diagnosis of multiple myeloma as variables independently associated with FN. No patients died within 30 days of the FN event.ConclusionThere were no significant associations between body weight-related variables and FN in this cohort of patients with similar renal function. Obesity should not be a justification for more aggressive levofloxacin dosing schemes when used for FN prophylaxis.Disclosures All authors: No reported disclosures.

Levofloxacin Dosing Regimen in Severely Morbidly Obese Patients (BMI ≥40 kg/m2) Should Be Guided by Creatinine Clearance Estimates Based on Ideal Body Weight and Optimized by Therapeutic Drug Monitoring

Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24h (AUC24). A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18years of age with a body mass index ≥40kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24. A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p<0.05) related to height but not weight. As a result, levofloxacin CL was best related (R (2)=0.57) to creatinine CL (CLcr) estimated by the Cockcroft-Gault (CG) equation and ideal body weight (IBW) because IBW is a height transformation. An empiric four-category daily-dose regimen (500, 750, 1,000, 1,250mg) stratified by CLcr (CG-IBW) is expected to have >90% probability of achieving an AUC24 of 50-150mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen. The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese.

Population Pharmacokinetics and Penetration into Prostatic, Seminal, and Vaginal Fluid for Ciprofloxacin, Levofloxacin, and Their Combination

Background: Our objectives were to assess the pharmacokinetic interaction and body fluid penetration of ciprofloxacin and levofloxacin. Methods: This study was a single-dose open randomized three-way crossover in 15 healthy volunteers receiving 500 mg oral levofloxacin, 500 mg oral ciprofloxacin, or 250 mg levofloxacin and 250 mg ciprofloxacin co-administered. Serum, urine, and body fluid concentrations were determined by high-performance liquid chromatography and analyzed via population pharmacokinetic modeling. Results: Modeling indicated that ciprofloxacin inhibited the renal reabsorption of levofloxacin. Ciprofloxacin increased the net renal clearance of levofloxacin by 13%, as its estimated affinity for a putative tubular reabsorption transporter was 12-fold higher (Km: 568 µM) compared to levofloxacin (Km: 6,830 µM). Levofloxacin increased the bioavailability of ciprofloxacin by 12% and achieved significantly (p < 0.05) higher concentrations at 3 h in ejaculate, prostatic, seminal, and vaginal fluid compared to ciprofloxacin. Conclusion: Modeling suggested that ciprofloxacin inhibited the tubular reabsorption of levofloxacin due to a 12-fold higher affinity for a putative tubular reabsorption transporter compared to levofloxacin. This pharmacokinetic interaction was not clinically relevant.

Pharmacometrics-Based Dose Selection of Levofloxacin as a Treatment for Postexposure Inhalational Anthrax in Children

Levofloxacin was recently (May 2008) approved by the U.S. Food and Drug Administration as a treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess the efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg of body weight levofloxacin and two studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and the volume of distribution. Consistently with developmental physiology, clearance also was found to be reduced in pediatric patients under 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (area under the concentration-time curve from 0 to 24 h at steady state, maximum concentration of drug in serum at steady state, and minimum concentration of drug in serum at steady state) following the approved adult dose of 500 mg once a day. The recommended dose of 8 mg/kg twice a day was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve efficacy comparable to that of adults.

Clearance of Levofloxacin by an in Vitro Model of Continuous Venovenous Hemodialysis (CVVHD)

Information about the elimination and the adequate dosing of levofloxacin during renal replacement therapy is scarce. The aim of this study was to characterize in vitro the elimination of levofloxacin during continuous venovenous hemodialysis (CVVHD) and to investigate whether the CVVHD clearances of creatinine and urea are correlated with the levofloxacin clearance in order to facilitate dosage adjustments. An in vitro model of CVVHD was established using five dialyzer membranes at varying dialysate flow rates applied in the clinical setting (8, 16, 25, 33 and 41 ml/min). Plasma and dialysate samples were drawn for determination of levofloxacin, creatinine and urea concentrations to evaluate clearances by CVVHD. During CVVHD, the clearance of levofloxacin varied between 9.02 and 33.30 ml/min, depending on the chosen setup. Positive correlations (p<0.001) were received for: dialysate flow rate (QD) and creatinine/ urea clearances (R(2)>0.93); QD and levofloxacin clearance (R(2) 0.59-0.71); levofloxacin and creatinine clearance (R(2) 0.69-0.75); and levofloxacin and urea clearance (R(2) 0.56-0.75) as well. When dosing critically ill patients, therefore, extracorporeal as well as total clearance of levofloxacin should be considered.

Pharmacokinetic Analysis of Transcellular Transport of Levofloxacin across LLC-PK1 and Caco-2 Cell Monolayers

To characterize the membrane transport responsible for the renal excretion and intestinal absorption of levofloxacin, we performed pharmacokinetic analysis of transcellular transport across LLC-PK(1) and Caco-2 cell monolayers. Transcellular transport of levofloxacin in LLC-PK(1) cells was greater in the basolateral-to-apical direction than in the opposite direction. Pharmacokinetic analysis indicated that basolateral uptake was the direction-determining step for the transcellular transport of levofloxacin in LLC-PK(1) cells. The apical efflux clearance of levofloxacin in LLC-PK(1) cells was increased at the medium pH 6 as compared with at pH 8, suggesting that membrane transport characteristics of levofloxacin are apparently similar to those of a prototypical organic cation, tetraethylammonium. On the other hand, transcellular transport of levofloxacin in Caco-2 cells was only slightly greater in the basolateral-to-apical direction than in the opposite direction. The apical efflux clearance of levofloxacin in Caco-2 cells was greater than basolateral efflux clearance, and apical influx clearance was greater than any other membrane transport clearance. In addition, the apical uptake of levofloxacin as well as quinidine in Caco-2 cells was inhibited significantly by nicotine and imipramine. The findings indicated that some transporters are responsible not only for the efflux but also for the influx of levofloxacin at the apical membrane of Caco-2 cells.

Do intensive care patients need an individualized dosing regimen for levofloxacin?

In general, the pharmacokinetics (PK) of antibiotics in intensive care unit (ICU) patients are known to differ from healthy subjects. These differences can pose challenges in developing appropriate dosing guidelines. The primary objective of this report was to characterize the disposition of levofloxacin in critically ill patients and to assess any relationships between patient covariates and the PK parameters. 20 patients in the ICU were given levofloxacin, 500 mg, as an i.v. infusion for a half hour. Plasma samples were taken until 24 hours and assayed using HPLC. The concentration-time data were analyzed using population analysis with NONMEM. The data were described using a 2-compartment model. Creatinine clearance was determined to be a statistically significant predictor of variability in total levofloxacin clearance. For patients with higher levofloxacin clearance, the resulting efficacy for different strains of bacteria (expressed as free AUC/MIC ratios) suggested that for less sensitive pathogens, a dosage adjustment may be needed. A model describing the pharmacokinetics of levofloxacin in critically ill patients was developed. It was determined that creatinine clearance has a significant role in the disposition of levofloxacin. This may have significant implications in the clinical setting for identifying optimal dosage regimens for ICU patients.

Pharmacodynamic target attainment analysis against Streptococcus pneumoniae using levofloxacin 500 mg, 750 mg and 1000 mg once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia (CAP)

The pharmacokinetics and pharmacodynamics of levofloxacin in patients with respiratory infections such as community-acquired pneumonia (CAP) are poorly documented. This work aimed at assessing the pharmacodynamic target attainment against Streptococcus pneumoniae using levofloxacin 500 mg, 750 mg and 1000 mg administered once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia. The pharmacokinetics of levofloxacin in elderly (≥65 years) compared with younger patients (<65 years) hospitalized with CAP were simulated. Susceptibility data with S. pneumoniae from our ongoing national surveillance study ( Canadian Respiratory Organism Susceptibility Study—CROSS) were then used to produce pharmacodynamic indices of AUC 0–24/MIC all. Monte Carlo simulations were then used to analyse target attainment of levofloxacin using doses of 500 mg, 750 mg and 1000 mg once daily to achieve free drug AUC 0–24/MIC all ≥ 30–100 versus S. pneumoniae in patients with CAP. Pharmacokinetics of levofloxacin simulated after 500 mg, 750 mg and 1000 mg once daily dosing resulted in levofloxacin volume of distribution: elderly patients = younger patients, while levofloxacin clearance was: elderly patients < younger patients. Levofloxacin t 1/2 values were longer in elderly patients (9.8 ± 2.5 h) than younger patients with CAP (7.4 ± 2.5 h). Free levofloxacin AUC 0–24 as well as AUC 0–24/MIC all for S. pneumoniae were higher in elderly patients than younger patients. Monte Carlo simulation using levofloxacin 500 mg yielded probabilities of achieving free-drug AUC 0–24/MIC all of 30 in P and ELF (95.7% and 98.1%) in elderly and younger patients (72.7% and 80.6%) respectively. Levofloxacin 750 mg and 1000 mg once daily had probability of achieving free-drug AUC 0–24/MIC all of 30 in P/ELF of 98.1%/98.6% and 99.2%/99.0%, respectively, in elderly patients compared with 89.9%/94.1% and 95.2%/96.5%, respectively, for younger patients. Probability of achieving of AUC 0–24/MIC all of 100 in P or ELF was very low in both patient populations at different doses except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg once daily P/ELF of 78.5%/87.0%. We conclude that levofloxacin pharmacokinetics in elderly patients with CAP are markedly different from those of younger patients. Levofloxacin 750 mg OD provides high probabilities of achieving free-drug AUC 0–24/MIC all of 30 in both plasma and epithelial lining fluid in patients with CAP including younger patients. Levofloxacin 500 mg OD provides high probabilities of achieving free-drug AUC 0–24/MIC all of 30 in elderly patients with CAP, although we favour the 750 mg dosing in these patients as well. Levofloxacin 750 mg OD results in high probability of pharmacodynamic target attainment and improved bacteriological outcome against S. pneumoniae in patients with CAP.

Levofloxacin pharmacokinetics in ESRD and removal by the cellulose acetate high performance-210 hemodialyzer

Background:No published data are available describing the pharmacokinetics of intravenous levofloxacin in patients with end-stage renal disease (ESRD). Objectives of this study are to determine the pharmacokinetics and dialytic clearance of levofloxacin and develop dosing strategies in these patients. Methods:Eight noninfected subjects receiving long-term thrice-weekly hemodialysis, with no measurable residual renal function, were administered intravenous levofloxacin, 250 mg, over 1 hour after a scheduled hemodialysis session. Blood samples were collected serially during the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum concentrations of levofloxacin were determined by high-performance liquid chromatography. Differential equations describing a 2-compartment open-infusion pharmacokinetic model were fit to each individual subject's serum concentration-time data by iterative nonlinear weighted least-squares regression analysis using Adapt II (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). Ratios of maximum serum concentration (Cmax) to minimum inhibitory concentration (MIC) were calculated for common respiratory pathogens by using MIC for 90% of isolates (MIC90) data from published studies. Results:All subjects completed the study, and no adverse events were reported. Median systemic clearance, volume of distribution at steady state, elimination half-life, and Cmax were 37.0 mL/min (range, 12.8 to 42.7 mL/min), 103.3 L (range, 39.8 to 139.3 L), 34.4 hours (range, 28.4 to 39.3 hours), and 5.2 μg/mL (range, 4.1 to 11.3 μg/mL), respectively. Median dialytic clearance and levofloxacin reduction ratios were 84.4 mL/min (range, 61.8 to 107.6 mL/min) and 0.244 (range, 0.181 to 0.412), respectively. Median Cmax-MIC90 ratios were 10 or greater for Haemophilus influenzae, Moraxella catarrhalis, Enterobacter cloacae, and Klebsiella pneumoniae, approximately 5 for Streptococcus pneumoniae, and less than 1 for Pseudomonas aeruginosa. Conclusion:The administration of levofloxacin to patients with ESRD as 500 mg initially, followed by 250 mg every 48 hours, will provide adequate Cmax-MIC ratios after the first and subsequent doses for most patients with respiratory tract infections caused by organisms with levofloxacin MICs of 1 μg/mL or less.

Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin in Patients with Early-Onset Ventilator-Associated Pneumonia

To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily. Prospective non-blinded pharmacokinetic-pharmacodynamic study. Ten critically ill adult patients with normal renal function. Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed. Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases. The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.

Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with lower respiratory tract infections.

Levofloxacin is considered an effective antibiotic in the treatment of community-acquired lower respiratory tract infections (LRTIs). A study was carried out on 17 in-patients to assess the pharmacokinetics of a 500 mg once-daily switch intravenous (i.v.)/oral regimen of levofloxacin in the treatment of LRTI patients. Blood samples were collected under steady-state conditions at appropriate intervals. Levofloxacin plasma concentrations were analysed by means of HPLC and pharmacokinetic parameters were estimated using the WinNonlin pharmacokinetic software package. A lower clearance of levofloxacin (<2 mL/min/kg), conditioning both a longer elimination half-life (approximately 9 h) and a larger AUC(0-tau) (approximately 80 mg/L x h), was observed for both routes in our patients than in healthy volunteers. These differences may be explained considering that levofloxacin is excreted mainly as unchanged drug by the renal route, and most of our patients (71%) were very elderly subjects whose renal function physiologically declines with age. The almost complete (> or =99%) absolute oral bioavailability suggests that a comparable exposure to the iv regimen may be achieved after oral administration. The overall clinical success rate was 94.1%.

Elimination of levofloxacin in critically ill patients with renal failure: influence of continuous veno-venous hemofiltration.

Pharmacokinetic data on levofloxacin in critically ill patients are sparse and conflicting. Aim of the study was to assess the clearance of levofloxacin in critically ill patients treated with continuous veno-venous hemofiltration (CVVH). Pharmacokinetics of levofloxacin were studied in 11 critically ill patients. Four patients were treated with CVVH because of renal failure, 4 patients had moderately impaired renal function but were not on hemofiltration, and 3 patients had approximately normal renal function. Patients received 0.5 g levofloxacin infused over 0.5 hours. Plasma levels of levofloxacin were determined by HPLC and pharmacokinetic parameters were calculated using a non-compartmental model. Levofloxacin clearance in critically ill patients with approximately normal renal function was similar to that in healthy subjects. In critically ill patients with impaired renal function not on CVVH, mean half-life was prolonged by a factor of about 3 (20-25 hours). The mean residence time and the volume of distribution were also increased. In renal failure treated with CVVH, a wide variability in pharmacokinetics was seen. The half-life was about 30 hours and the mean levofloxacin clearance was raised by a factor of 2. The area under the concentration-time curve was reduced by hemofiltration, while the volume of distribution was increased. There was a positive correlation between blood flow through the hemofilter and levofloxacin clearance. Variable amounts of the drug were recovered from the hemofilter. Most plasma levels, however, were in the therapeutic range and drug accumulation to toxic plasma concentrations was not observed in renal failure patients undergoing CVVH and receiving single daily administration of 0.5 g of levofloxacin i.v. During CVVH using polysulfone membrane hemofilters, plasma concentrations of levofloxacin are not easily predictable. Levofloxacin clearance may be affected by binding to secondary membranes formed in hemofilters during CVVH and blood flow rates have a significant impact on the pharmacokinetics of levofloxacin.

Pharmacokinetics of levofloxacin and ciprofloxacin during continuous renal replacement therapy in critically ill patients.

The pharmacokinetics of intravenously administered levofloxacin and ciprofloxacin were studied in intensive care unit patients during continuous venovenous hemofiltration (CVVH; four patients received levofloxacin, and five received ciprofloxacin) or hemodiafiltration (CVVHDF; six patients received levofloxacin, and five received ciprofloxacin). Levofloxacin clearance was substantially increased during both CVVH and CVVHDF, while ciprofloxacin clearance was affected less. The results of this study suggest that doses of levofloxacin of 250 mg/day and ciprofloxacin of 400 mg/day are sufficient to maintain effective drug concentrations in the plasma of patients undergoing CVVH or CVVHDF.

Pharmacokinetics of levofloxacin during continuous veno-venous hemofiltration.

To study the effect of continuous veno-venous hemofiltration (CVVHF) on the pharmacokinetics of levofloxacin in critically ill patients with acute renal failure. Open-label study. Anesthesiology ICU, University Hospital of Regensburg. Six critically ill patients treated with CVVHF because of acute renal failure needing antimicrobial therapy. Levofloxacin i.v. 250 mg qd with a starting dose of 500 mg. CVVHF with the following characteristics: hemofilter AN69 hollow fibers of 0.90 m2 area, blood flow 150 ml/min, ultrafiltrate flow 1.3 l/h, filtrate substitution in post-dilution mode. The plasma pharmacokinetics and clearance of levofloxacin by hemofiltration were established on day 1 and day 4-6 of treatment. Levofloxacin was determined by high-performance liquid chromatography (HPLC). Mean (range) peak plasma concentrations after levofloxacin 500 mg single dose (s.d.) and 250 mg multiple dose (m.d.) were 6.4 (2.7-9.4) and 8.2 (4.7-10.3) mg/l, trough levels 2.7 (1.4-5.0) and 2.9 (1.7-3.9) mg/l, half-life 28 (19-38) and 22 (17-31) h, volume of distribution 1.2 (0.72-1.6) l/kg and 0.91 (0.52-2.0) l/kg, respectively. The mean sieving coefficient was 0.96 (0.79-1.09), mean total clearance 47 (20-89) ml/min, and mean clearance by hemofiltration 21 (13-27) ml/min, respectively. A dosage schedule of levofloxacin 250 mg qd with a 500 mg loading dose seems appropriate for anuric patients during CVVHF. Sufficiently high steady-state concentrations of levofloxacin were achieved after the first dose. Undesired accumulation of levofloxacin was not observed.

Peritoneal Clearance and Optimum Dosage Regimen of Levofloxacin in Patients under Continuous Ambulatory Peritoneal Dialysis.

Introduction: We investigated the clinical significance of the peritoneal clearance of levofloxacin, which is used to treat exit-site infections caused by Pseudomonas aeruginosa in patients under continuous ambulatory peritoneal dialysis (CAPD), and proposed an optimum dose and dosage interval for treating these patients.Methods: We measured the concentrations of levofloxacin in the plasma, the drainage from peritoneal dialysis and the plasma ultrafiltrate by HPLC in 6 patients receiving CAPD, and determined the plasma unbound fraction (fuB). We also estimated the total clearance (CLtot/F), distribution volume (Vd/F) and peritoneal clearance (CLpd) in each patient.Results: The mean (S. D.) CLtot/F, Vd/F, CLpd, and fuB were 22.6 (7.34) ml/min, 76.3 (21.9) L, 3.42 (0.831) ml/min, and 69.7 (13.76) %, respectively. We examined the possible factors affecting the peritoneal clearance of levofloxacin, but did not find any definite trends.Discussion: The average CLpd was about 17% of the CLtot, but in some patients it was above 20%. It seems that the peritoneal clearance values should not be ignored in clinical practice. The minimum plasma concentration of levofloxacin in the steady state in patients under CAPD given 100mg of levofloxacin every 24h was 2.7±0.72μg/ml, which exceeded the MIC50 of the drug for P. aeruginosa. Administration of the drug at a dose of 100 mg every 48 h, a common clinical practice, may not be adequate to maintain a blood concentration high enough to attain an appropriate antibacterial effect.

Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection.

Population pharmacokinetic modeling is a useful approach to obtaining estimates of both population and individual pharmacokinetic parameter values. The potential for relating pharmacokinetic parameters to pharmacodynamic outcome variables, such as efficacy and toxicity, exists. A logistic regression relationship between the probability of a successful clinical and microbiological outcome and the peak concentration-to-MIC ratio (and also the area under the plasma concentration-time curve [AUC]/MIC ratio) has previously been developed for levofloxacin; however, levofloxacin assays for determination of the concentration in plasma are not readily available. We attempted to derive and validate demographic variable models to allow prediction of the peak concentration in plasma and clearance (CL) from plasma for levofloxacin. Two hundred seventy-two patients received levofloxacin intravenously for the treatment of community-acquired infection of the respiratory tract, skin or soft tissue, or urinary tract, and concentrations in plasma, guided by optimal sampling theory, were obtained. Patient data were analyzed by the Non-Parametric Expectation Maximization approach. Maximum a posteriori probability Bayesian estimation was used to generate individual parameter values, including CL. Peak concentrations were simulated from these estimates. The first 172 patients were used to produce demographic models for the prediction of CL and the peak concentration. The remaining 100 patients served as the validation group for the model. A median bias and median precision were calculated. A two-compartment model was used for the population pharmacokinetic analysis. The mean CL and the mean volume of distribution of the central compartment (V1) were 9.27 liters/h and 0.836 liter/kg, respectively. The mean values for the intercompartmental rate constants, the rate constant from the central compartment to the peripheral compartment (Kcp) and the rate constant from the peripheral compartment to the central compartment (Kpc), were 0.487 and 0.647 h(-1), respectively. The mean peak concentration and the mean AUC values normalized to a dosage of 500 mg every 24 h were 8.67 microg/ml and 72.53 microg x h/ml, respectively. The variables included in the final model for the prediction of CL were creatinine clearance (CLCR), race, and age. The median bias and median precision were 0.5 and 18.3%, respectively. Peak concentrations were predicted by using the demographic model-predicted parameters of CL, V1, Kcp and Kpc, in the simulation. The median bias and the median precision were 3.3 and 21.8%, respectively. A population model of the disposition of levofloxacin has been developed. Population demographic models for the prediction of peak concentration and CL from plasma have also been successfully developed. However, the performance of the model for the prediction of peak concentration was likely insufficient to be of adequate clinical utility. The model for the prediction of CL was relatively robust, with acceptable bias and precision, and explained a reasonable amount of the variance in the CL of levofloxacin from plasma in the population (r2 = 0.396). Estimated CLCR, age, and race were the final model covariates, with CLCR explaining most of the population variance in the CL of levofloxacin from plasma. This model can potentially optimize the benefit derived from the pharmacodynamic relationships previously developed for levofloxacin.