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.

Assessment of the impact of clinical recommendations on antibiotic use for CAP and HCAP: results from an implementation program in an Academic Hospital.

BACKGROUND: Local guidelines and recommendations to treat common infectious diseases are a cornerstone of most Antimicrobial Stewardship programs. The evaluation of the adherence to guidelines is an effective quality measure of the programs themselves; the proposed evaluation model aimed at examining antibiotic treatment for pneumonia. STUDY DESIGN: A retrospective pre-post intervention study was conducted in a North-Eastern Italian Academic Hospital. METHODS: 231 patients with Community-Acquired Pneumonia and 95 with Healthcare-Associated Pneumonia were divided into pre- and post-intervention groups (188 and 138, respectively). A course and a pocket summary of Pneumonia Regional Recommendations were the stewardship activities adopted. The compliance degree of prescriptions with Regional Recommendations was tested for drug(s), dosage and duration of treatment in both groups for Community-Acquired and Healthcare-Associated Pneumonia and a comparison with International guidelines was performed. RESULTS: A significant improvement in the compliance with Regional Recommendations for the variable drug emerged for Community-Acquired (38.8% vs 52.2%), but not for Healthcare-Associated Pneumonia; no significant variation in compliance was registered for dosage and duration of treatment. The significant decrease in consumption of levofloxacin showed the positive impact of the Regional Antimicrobial Stewardship programs. A high level of adherence to International Guidelines for the variable drug for Community-Acquired Pneumonia was found in both groups (75.5% and 77.2%, respectively). CONCLUSIONS: Our study highlighted that room for improvement in antibiotic prescription in Community-Acquired and Healthcare-Associated Pneumonia currently remains. New strategies for a better use of the adopted tools and definition of new antimicrobial stewardship initiatives are needed to improve compliance to Regional Recommendations.

Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis: 5-year results of the APPAC randomized clinical trial.

BACKGROUND: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years. METHODS AND FINDINGS: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p<0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p<0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy. CONCLUSIONS: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up.

Fluoroquinolone Antibiotic Prophylaxis to Prevent Post-Traumatic Bacterial Infectious Endophthalmitis: Using Monte Carlo Simulation to Evaluate the Probability of Success.

Purpose: Patients with open globe injuries routinely receive fluoroquinolone (FQ) prophylaxis to prevent bacterial infectious endophthalmitis. Owing to the rarity of this infection, there is an absence of clinical trials evaluating optimal prophylactic FQ dosing. To address this knowledge gap, we conducted a Monte Carlo simulation (MCS)-based study to identify the FQ dosing option(s) that optimize pharmacokinetic-pharmacodynamic FQ target attainment against common bacterial pathogens implicated in post-traumatic bacterial infectious endophthalmitis (PTBIE). Methods: Weighted mean pharmacokinetic parameters and standard deviations for ciprofloxacin, levofloxacin, and moxifloxacin were calculated from published studies in healthy volunteers. The incidence and FQ susceptibility profiles for the most common bacteria causing PTBIE were extracted from the literature. MCS was used to determine the cumulative fraction of response (CFR) for 5 FQ dosing options to determine the probability of attaining pathogen-specific target 24-hour area under the curve to minimum inhibitory concentration ratios in the vitreous humor of the eye against the 4 most common causative bacteria seen in PTBIE. Results: Moxifloxacin 400 mg po daily (M400) achieved the highest CFR (72%). Levofloxacin dosing options achieved CFRs between 54% and 63%. Ciprofloxacin dosing options achieved CFRs between 28% and 35%. Conclusion: M400 optimized the likelihood of prophylactic success in the prevention of PTBIE, and based on the study findings, M400 is predicted to optimize the probability of success compared with ciprofloxacin and levofloxacin dosing options currently endorsed by expert opinion.

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.

Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP).

BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. METHODS: The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15-20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18-24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. DISCUSSION: If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis.

Background: Ethionamide is used to treat multidrug-resistant tuberculosis (MDR-TB). The antimicrobial pharmacokinetics/pharmacodynamics, the contribution of ethionamide to the multidrug regimen, and events that lead to acquired drug resistance (ADR) are unclear. Methods: We performed a multidose hollow fiber system model of tuberculosis (HFS-TB) study to identify the 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios that achieved maximal kill and ADR suppression, defined as target exposures. Ethionamide-resistant isolates underwent whole-genome and targeted Sanger sequencing. We utilized Monte Carlo experiments (MCEs) to identify ethionamide doses that would achieve the target exposures in 10000 patients with pulmonary tuberculosis. We also identified predictors of time-to-sputum conversion in Tanzanian patients on ethionamide- and levofloxacin-based regimens using multivariate adaptive regression splines (MARS). Results: An AUC0-24/MIC >56.2 was identified as the target exposure in the HFS-TB. Early efflux pump induction to ethionamide monotherapy led to simultaneous ethambutol and isoniazid ADR, which abrogated microbial kill of an isoniazid-ethambutol-ethionamide regimen. Genome sequencing of isolates that arose during ethionamide monotherapy revealed mutations in both ethA and embA. In MCEs, 20 mg/kg/day achieved the AUC0-24/MIC >56.2 in >95% of patients, provided the Sensititre assay MIC was <2.5 mg/L. In the clinic, MARS revealed that ethionamide Sensititre MIC had linear negative relationships with time-to-sputum conversion until an MIC of 2.5 mg/L, above which patients with MDR-TB failed combination therapy. Conclusions: Ethionamide is an important contributor to MDR-TB treatment regimens, at Sensititre MIC <2.5 mg/L. Suboptimal ethionamide exposures led to efflux pump-mediated ADR.

Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis.

Background: Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however the optimal dose is unknown. Methods: We used the hollow fiber system model of tuberculosis (HFS-TB) to identify 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs) were used to identify doses best able to achieve the HFS-TB-derived target exposures in cavitary tuberculosis and tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI) algorithms to identify the most important predictors of sputum conversion, ADR, and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis treated with a levofloxacin-containing regimen. We also performed probit regression to identify optimal levofloxacin doses in Vietnamese tuberculous meningitis patients. Results: In the HFS-TB, the AUC0-24/MIC associated with maximal Mtb kill was 146, while that associated with suppression of resistance was 360. The most common gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms identified an AUC0-24/MIC of 160 as predictive of microbiologic cure, followed by levofloxacin 2-hour peak concentration and body weight. Probit regression identified an optimal dose of 25 mg/kg as associated with >90% favorable response in adults with pulmonary tuberculosis. Conclusions: The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for replacement of high-dose moxifloxacin in treatment of multidrug-resistant tuberculosis.

Population Pharmacokinetics and Pharmacodynamics Modeling of Oral Levofloxacin.

Background: Levofloxacin, a fluoroquinolone, is an isomer of ofloxacin with an extensive spectrum of antimicrobial efficacy. In common with other fluoroquinolones, the main pharmacokinetic/pharmacodynamic (PK/PD) index that correlates with its therapeutic efficacy is the area under the plasma time-concentration curve (AUC)/the minimum inhibitory concentration (MIC) ratios. Objective: To evaluate the population PK and determine the efficacy of various dosage regimens in achieving the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of oral levofloxacin when prescribed as the switching therapy after intravenous levofloxacin treatment. Material and Method: The PK studies were conducted in 45 healthy volunteers who received one 500 mg tablet of levofloxacin and PTAs were determined by using a Monte Carlo simulation. The dosage regimens were predicted to achieve CFR greater than or equal to 90% by referral to the MIC distributions database of the European Committee on Antimicrobial Susceptibility Testing. Results: The population PKs of levofloxacin were; the volume of distribution (V) = 101.71±1.41 L, total clearance (CL) = 8.51±1.43 L/hour and the area under the plasma time-concentration curve from 0 to 24 hours (AUC0-24 ) = 66.19±1.30 mg*hour/L. The predicted CFRs for a target AUC0-24 /MIC ratio of 30 for S. aureus and S. pneumoniae were 83.12% and 92.63%, respectively for 500 mg levofloxacin, and 84.96% and 98.17%, respectively for 750 mg levofloxacin. The predicted CFRs for a target AUC0-24 /MIC ratio of 125 for E. coli and Klebsiella spp. were 84.25% and 88.81%, respectively for 500 mg levofloxacin and 86.00% and 91.34%, respectively for 750 mg levofloxacin. Conclusion: The population PKs of levofloxacin in the present study were similar to the values obtained from the previous study. Both 500 mg qd and 750 mg qd of oral levofloxacin dosage regimens had a high probability of achieving optimal impact against S. pneumoniae, but only the 750 mg qd dosage regimen achieved optimal exposure against Klebsiella spp.

Quadruple, sequential, and concomitant first-line therapies for H. pylori eradication: a prospective, randomized study.

BACKGROUND: Current Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country. AIM: To perform a 'head-to-head' comparison among these three therapies as first-line treatment for H. pylori eradication in clinical practice. METHODS: This was a prospective, open-label randomized study enrolling consecutive patients diagnosed with H. pylori infection never previously treated. Patients were randomized to receive one of the following 10-day therapies: (a) Bismuth-based therapy: esomeprazole 20mg b.i.d and Pylera 3 tablets q.i.d; (b) Concomitant therapy: esomeprazole 20mg plus amoxicyllin 1,000mg, clarithromycin 500mg and tinidazole 500mg (all b.i.d.), and (c) Sequential therapy: esomeprazole 20mg plus amoxicyllin 1,000mg for 5days followed by esomeprazole 20mg plus clarithromycin 500mg and tinidazole 500mg for 5days (all b.i.d). H. pylori eradication was assessed by using UBT 4-6 weeks after the end of therapy. RESULTS: Overall, 187 patients were enrolled. The eradication rates achieved with Pylera, concomitant and sequential were 85.2%, 95.2%, and 93.6%, respectively, at intention to treat, and 94.5%, 96.7%, and 95.1% at per protocol analyses, without a statistically significant difference. The incidence of severe side-effects was higher with the bismuth-based therapy than with the two bismuth-free regimens (9.8% vs 1.6%; p=0.046). CONCLUSIONS: Bismuth-based and bismuth-free therapies are equally effective for first-line H. pylori eradication. However, bismuth therapy was more frequently interrupted for side-effects than bismuth-free therapies.

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.

Cost-effectiveness analysis of oral versus intravenous drip infusion of levofloxacin in the treatment of acute lower respiratory tract infection in Chinese elderly patients.

AIM: Pharmacoeconomic cost-effectiveness analysis of two different dosage regimens of levofloxacin in the treatment of acute lower respiratory tract infection in elderly patients. METHODS: A total of 108 elderly patients with acute lower respiratory tract infection who visited by our hospital between September 2013 and September 2014 were randomly divided into Group A and Group B, with 54 patients in each group. In Group A, levofloxacin injection was given for continuous intravenous infusion treatment, whereas in Group B, levofloxacin injection and levofloxacin capsule were given as sequential therapy (ST). The period of treatment for both the groups was 10 days, and minimum cost analysis was used to analyze the treatment. RESULTS: Groups A and B had cure rates of 61.1% and 59.3% (P>0.05), effective rates of 88.9% and 83.3% (P>0.05), bacterial clearance rates of 96.3% and 92.6% (P>0.05), and incidence rates of adverse reactions of 7.4% and 3.7% (P>0.05), respectively. Treatment costs of Groups A and B were 1,588 RMB and 1,150 RMB, respectively, whereas the cost-effectiveness of the two groups was at 17.86 and 13.81, respectively (P<0.05). CONCLUSION: Levofloxacin ST had relatively higher cost-effectiveness ratio for the treatment of acute lower respiratory tract infection in elderly patients, especially Chinese.

Pharmacodynamically Guided Levofloxacin Dosing for Pediatric Community-Acquired Pneumonia.

BACKGROUND.: Oral levofloxacin is recommended as a preferred treatment for infection with Streptococcus pneumoniae with a penicillin minimum inhibitory concentration (MIC) of ≥4 µg/mL and as an alternative for infection with S pneumoniae with a penicillin MIC of ≤2 µg/mL. To investigate the current dosing recommendations and create a pharmacodynamically guided regimen, a Monte Carlo simulation was performed. METHODS.: The simulation included a previously published 1-compartment model, and incorporated a formula that takes into account age-appropriate weights for hospitalized patients. Three different dosing regimens, including community-acquired pneumonia guideline dosing, inhalational anthrax dosing, and a pharmacodynamically guided regimen, were assessed. The probability of target attainment was described as the proportion of patients who achieve an unbound-drug area under the concentration-time curve over 24 hours divided by the MIC above 33.7 µg/mL per hour. Microbiologic data from 2 stand-alone pediatric tertiary care centers were included. RESULTS.: Guideline-recommended doses of levofloxacin seem to produce suboptimal exposure in patients aged 5-14 years for pneumococci with an MIC of 1 µg/mL. Anthrax dosing was suboptimal in patients aged <5 years and in those aged >15 years. The pharmacodynamically guided regimen maintained a probability of target attainment of >90% for all age groups without producing peak concentrations higher than those previously described. None of the regimens attained the pharmacodynamic targets for a levofloxacin MIC of 2 µg/mL. CONCLUSIONS.: Current dosing recommendations were found to be suboptimal for specific age groups. A pharmacodynamically guided levofloxacin dosing regimen was determined, but it will need to be studied clinically for safety and tolerability.

Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

Comparison of the effectiveness and antibiotic cost among ceftriaxone, ertapenem, and levofloxacin in treatment of community-acquired complicated urinary tract infections.

PURPOSE: To study characteristics of patients with community-acquired complicated urinary tract infections (cUTIs) and to compare effectiveness and antibiotic cost of treatment with ceftriaxone (CRO), levofloxacin (LVX), and ertapenem (ETP). METHODS: This retrospective study enrolled patients who had community-acquired cUTIs admitted to Division of Infectious Diseases in a single medical center from January 2011 to March 2013. Effectiveness, antibiotic cost, and clinical characteristics were compared among patients treated with CRO, LVX, and ETP. RESULTS: There were 358 eligible cases, including 139 who received CRO, 128 treated with ETP, and 91 with LVX. The most common pathogen was Escherichia coli. The susceptibilities of these three agents were higher and more superior than first-line antibiotics. Treatment with ETP was associated with a significantly shorter time to defervescence since admission (CRO: 39 hours, ETP: 30 hours, and LVX: 38 h; p = 0.031) and shorter hospitalization stay (CRO: 4 days, ETP: 3 days, and LVX: 4 days; p < 0.001). However, the average antibiotic costs in the CRO group were significantly lower than that in the other two groups [CRO: 62.4 United States dollars (USD), ETP: 185.33 USD, and LVX: 204.85 USD; p < 0.001]. CONCLUSION: The resistance of cUTIs isolates to first-line antibiotic is high. Using ETP, CRO, and LVX in the treatment of cUTIs for good clinical response should be suggested. Among the three agents, ETP had better susceptibility than CRO and LVX, reached defervescence sooner, and was associated with shorter hospital stays. However, using CRO in cUTIs was less expensive than the other two agents.

Does Critical Illness Change Levofloxacin Pharmacokinetics?

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.

Levofloxacin dosing regimen in severely morbidly obese patients (BMI ≥40 kg/m(2)) should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring.

BACKGROUND: 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. OBJECTIVE: 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 24 h (AUC24). METHODS: A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18 years of age with a body mass index ≥40 kg/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. RESULTS: A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg 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, 1,250 mg) stratified by CLcr (CG-IBW) is expected to have >90 % probability of achieving an AUC24 of 50-150 mg·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. CONCLUSIONS: The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese.

Economic evaluation of adjustments of levofloxacin dosage by dispensing pharmacists for patients with renal dysfunction.

Since April 2011, a dosage adjustment program has been implemented at Gifu Municipal Hospital. In this program, upon receiving a prescription for renally eliminated drugs, pharmacists verify patients' serum creatinine concentrations by using a computerized medical record system to evaluate the patient's kidney function and suggest the appropriate dosage to doctors, if necessary. In our study, we used questionnaires that were administered to pharmacists and doctors at the hospital to investigate their respective working times and the cost of the program, in order to comprehensively analyze the clinical resource costs of the hospital and evaluate the economic burden of the program for levofloxacin. In addition, we studied the pharmacists' and doctors' attitudes toward the program and the circumstances of prescriptions for patients with renal dysfunction. The questionnaire comprised items such as time required for the program; attitude toward the program, including satisfaction; and attitude toward the circumstances of prescriptions for patients with renal dysfunction. The pharmacists' and doctors' working times and cost of the program were obtained from the questionnaire responses. For cost estimation, we used data from this study as well as those of our previous study that suggested that the levofloxacin program was economically beneficial. Furthermore, their attitudes toward the program and circumstances of prescriptions for patients with renal dysfunction were clarified. Regarding the pharmacists' tasks and interventions, we need to not only investigate attitudes toward them but also perform a cost analysis by the method of the economic evaluation of the medical techniques used in our study.