Green method by National Environmental Methods Index and Eco-Scale Assessment for evaluation of gatifloxacin-based product by HPLC.

The literature reveals gaps in the availability of green analytical methods for assessing products containing gatifloxacin (GFX), a fluoroquinolone. Presently, method development is supported by tools such as the National Environmental Methods Index (NEMI) and Eco-Scale Assessment (ESA), which offer objective insights into the environmental friendliness of analytical procedures. The objective of this work was to develop and validate a green method by the NEMI and ESA to quantify GFX in eye drops using HPLC. The method utilized a C8 column (4.6 × 150 mm, 5 µm), with a mobile phase of purified water containing 2% acetic acid and ethanol (70:30, v/v). The injection volume was 10 µL and the flow rate was 0.7 mL/min in isocratic mode at 25°C, with detection performed at 292 nm. The method demonstrated linearity in the range of 2-20 µg/mL, and precision at intra-day (relative standard deviation [RSD] 1.44%), inter-day (RSD 3.45%), and inter-analyst (RSD 2.04%) levels. It was selective regarding the adjuvants of the final product (eye drops) and under forced degradation conditions. The method was accurate (recovery 101.07%) and robust. The retention time for GFX was approximately 3.5 min. The greenness of the method, as evaluated by the NEMI, showed four green quadrants, and by ESA, it achieved a score of 88.

Gatifloxacin Pharmacokinetics/Pharmacodynamics-based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis.

Background: Gatifloxacin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The optimal dose is unknown. Methods: We performed a 28-day gatifloxacin hollow-fiber system model of tuberculosis (HFS-TB) study in order to identify the target exposures associated with optimal kill rates and resistance suppression. Monte Carlo experiments (MCE) were used to identify the dose that would achieve the target exposure in 10000 adult patients with meningeal or pulmonary MDR-TB. The optimal doses identified were validated using probit analyses of clinical data from 2 prospective clinical trials of patients with pulmonary and meningeal tuberculosis. Classification and regression-tree (CART) analyses were used to identify the gatifloxacin minimum inhibitory concentration (MIC) below which patients failed or relapsed on combination therapy. Results: The target exposure associated with optimal microbial kill rates and resistance suppression in the HFS-TB was a 0-24 hour area under the concentration-time curve-to-MIC of 184. MCE identified an optimal gatifloxacin dose of 800 mg/day for pulmonary and 1200 mg/day for meningeal MDR-TB, and a clinical susceptibility breakpoint of MIC ≤ 0.5 mg/L. In clinical trials, CART identified that 79% patients failed therapy if MIC was >2 mg/L, but 98% were cured if MIC was ≤0.5 mg/L. Probit analysis of clinical data demonstrated a >90% probability of a cure in patients if treated with 800 mg/day for pulmonary tuberculosis and 1200 mg/day for meningeal tuberculosis. Doses ≤400 mg/day were suboptimal. Conclusions: Gatifloxacin doses of 800 mg/day and 1200 mg/day are recommended for pulmonary and meningeal MDR-TB treatment, respectively. Gatifloxacin has a susceptible dose-dependent zone at MICs 0.5-2 mg/L.

Notes on testing noninferiority in ordinal data under the parallel groups design.

When testing the noninferiority of an experimental treatment to a standard (or control) treatment in a randomized clinical trial (RCT), we may come across the outcomes of patient response on an ordinal scale. We focus our discussion on testing noninferiority in ordinal data for an RCT under the parallel groups design. We develop simple test procedures based on the generalized odds ratio (GOR). We note that these test procedures not only can account for the information on the order of ordinal responses without assuming any specific parametric structural model, but also can be independent of any arbitrarily subjective scoring system. We further develop sample size determination based on the test procedure using the GOR. We apply Monte Carlo simulation to evaluate the performance of these test procedures and the accuracy of sample size calculation formula proposed here in a variety of situations. Finally, we employ the data taken from a trial comparing once-daily gatifloxican with three-times-daily co-amoxiclav in the treatment of community-acquired pneumonia to illustrate the use of these test procedures and sample size calculation formula.

Evaluation of initial and steady-state gatifloxacin pharmacokinetics and dose in pulmonary tuberculosis patients by using monte carlo simulations.

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC0-∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC0-∞ of 41.2 µg · h/ml decreased on average by 14.3% (90% confidence interval [CI], -90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of ≥125 only when the MIC was <0.125 µg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.).

[Cost-effectiveness of the treatment of acute and chronic rhinosinusitis at the IMSS]. / Costo-efectividad del tratamiento de rinosinusitis aguda y crónica en el IMSS.

INTRODUCTION: Rhinosinusitis is one of the more common diseases encountered in outpatient visits to health care. The objective of this study was to determine the most cost-effective antibiotic treatment for patients with acute (RSA) and chronic rhinosinusitis (RSC) that is available at the Mexican Institute of Social Security (IMSS). METHODS: Cost-effectiveness analysis of RSA and RSC treatment from an institutional perspective. Effectiveness outcome was defined as the percentage of cure. A decision tree with a Bayesian approach included the following therapeutic alternatives: ciprofloxacin, gatifloxacin, trimetoprim/sulfametoxazol (TMP/SMX), amoxicilin/clavulanic acid (AAC) and clindamicin. RESULTS: Treatment for RSA with AAC showed a mean cost per cured patient of $ 878 pesos. The remaining antibiotics had a higher cost per unit of success, and therefore the results showed that AAC was the best alternative considering this criterion. The therapy that showed a larger percentage of cured patients in RSC was clindamicin; however, the therapeutic alternative with the lowest cost per successful unit was the one based on ciprofloxacin, which dominates gatifloxacin and AAC. CONCLUSIONS: The most cost-effective alternative in the antibiotic treatment of patients with RSA was ACC while for RSC it was ciprofloxacin; sensitivity analysis showed the strength of the base study results.

Pharmacokinetics-pharmacodynamics of gatifloxacin in a lethal murine Bacillus anthracis inhalation infection model.

We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC of the drug for the organism (AUC(0-24)/MIC ratio) was the PK-PD measure most predictive of survival (R(2) = 0.96). The 50% effective dose (ED(50)) and the ED(90) and ED(99) corresponded to AUC(0-24)/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED(99)). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

Topical ophthalmic fourth-generation fluoroquinolones: Appropriate use and cost considerations.

PURPOSE: The utilization and refill rates of topical ophthalmic fourth-generation fluoroquinolones among physicians, as well as the associated costs, were studied. METHODS: A large data set of retrospective pharmacy prescription claims was obtained from multiple plans, including commercial managed care organizations, Medicaid, and Medicare. The data included the number and cost of all new and refill prescriptions for six months for gatifloxacin 0.3% and moxifloxacin 0.5% by physician specialty. New prescription and refill data were also analyzed from a state Medicaid plan to determine if similar trends existed. RESULTS: Primary care physicians wrote approximately 7,000 (7.7%) gatifloxacin and 84,000 (92.3%) moxifloxacin prescriptions, with pediatricians accounting for 4,000 (5.1%) gatifloxacin and 75,000 (94.9%) moxifloxacin prescriptions. Eye care physicians accounted for a similar amount of prescriptions for each antibiotic during the same period. The total cost of prescriptions for all primary care practitioners was approximately $170,000 for gatifloxacin and $2.5 million for moxifloxacin; prescriptions written by pediatricians accounted for $110,000 for gatifloxacin and $2.2 million for moxifloxacin. CONCLUSION: Prescription drug claims from payers using pharmacy benefit management companies during a six-month period indicated that the numbers of prescriptions written for gatifloxacin and moxifloxacin were similar among eye care physicians, but primary care physicians wrote a greater number of prescriptions for moxifloxacin. Analysis of claims to a Medicaid database revealed an increase in the prescriptions written by primary care physicians for moxifloxacin after its addition to the drug formulary.

Population pharmacokinetic model for gatifloxacin in pediatric patients.

The broad spectrum of antimicrobial activity, oral bioavailability, extensive tissue distribution, and once-daily intravenous or oral dosing of gatifloxacin, an expanded-spectrum 8-methoxy fluoroquinolone, make it a potentially useful agent for the treatment of pediatric infections. A population pharmacokinetic model was developed to describe the pharmacokinetics of gatifloxacin in children. Data for analysis were obtained from a single-dose safety/pharmacokinetic study utilizing intensive blood sampling in patients aged 6 months to 16 years. Each subject received a single oral dose of gatifloxacin as a suspension, at doses of 5, 10, or 15 mg/kg of body weight. A total of 845 samples were obtained from 82 patients. A one-compartment model with first-order absorption and elimination was the most appropriate to describe the gatifloxacin concentrations. Covariate analysis using forward selection and backward elimination found that apparent clearance was related to body surface area, and apparent volume of distribution was related to body weight. No effect of age on drug clearance could be identified once clearance was corrected for body surface area. Based on pharmacokinetic simulations, the 10-mg/kg (maximum, 400 mg) once-daily dose of gatifloxacin is expected to provide drug exposure similar to that in healthy adults. The population pharmacokinetic model described herein will be used for Bayesian analyses of sparse pharmacokinetic sampling in phase II/III clinical trials and for Monte Carlo simulation experiments. The success of this strategy provides a model for future pediatric drug development programs.

[The proper use of quinolones to the elderly patient with community-acquired pneumonia examined by Monte Carlo simulation].

Recently, proper use of antimicrobial agents for treatment of infections based on pharmacokinetics (PK)/ pharmacodynamics (PD) theory has been recommended to many clinical doctors. To consider the optimized administration method based on PK/PD theory for the elderly patients of gatifloxacin (GFLX), which was one of the oral respiratory quinolone antibacterial, Monte Carlo Simulation was conducted with community-acquired pneumonia and susceptibility data for Streptococcus pneumoniae (345 strains) collected by the second gatifloxacin surveillance study. From this results, the probabilities of achieving AUC/MIC 30 against pneumococcus for the elderly patients was 96.3% at twice-daily dosing of GFLX 100 mg, 97.2% at twice-daily dosing of GFLX 200 mg, therefore, it was suggested that the clinical effectiveness of the regimen of GFLX 100 mg was as well as the regimen of GFLX 200 mg.

Confocal assessment of the effects of fourth-generation fluoroquinolones on the cornea.

PURPOSE: To evaluate the toxicity of fourth-generation fluoroquinolone antibiotic solutions on the rabbit corneal epithelium. METHODS: In vivo confocal microscopy was used to assess epithelial structure in 18 rabbits, and tight junction integrity of superficial epithelial cells was evaluated with ZO-1 labeling in 10 rabbits. Eyes were bathed with commercial solutions of moxifloxacin (Vigamox) or gatifloxacin (Zymar) solution for 3 minutes, rinsed with balanced salt solution, and immediately examined. Balanced salt solution rinsing alone served as the control. RESULTS: A decrease in epithelial cell size was observed after treatment with Zymar (P < 0.05, two-way repeated-measures analysis of variance), but not with Vigamox or the control. Normal ZO-1 organization was observed in controls and eyes treated with Vigamox. ZO-1 staining in eyes treated with Zymar was disrupted, patchy, and generally weaker than that in control eyes. CONCLUSIONS: After short-term, intensive exposure to Vigamox, corneal epithelial integrity and tight junction organization are maintained. Zymar induces a loss of superficial epithelial cells and breakdown of tight junctions under similar conditions.

Pharmacodynamic assessment of the activity of high-dose (750 mg) levofloxacin, ciprofloxacin, and gatifloxacin against clinical strains of Pseudomonas aeruginosa.

The objective of this study was to comparatively evaluate specific bacterial killing ability of high-dose (750 mg) levofloxacin, ciprofloxacin, and gatifloxacin against 2 clinical isolates of Pseudomonas aeruginosa (PA-21 and PA-2105). An in vitro pharmacodynamic modeling apparatus was used to expose the P. aeruginosa isolates to total peak concentrations and elimination characteristics associated with each quinolone. All experiments were conducted over 24 h, and a subsequent dose of ciprofloxacin was given at 12 h to emulate twice-daily dosing. Respective 3-log reductions in PA-24 occurred after 0.6, 1.0, and 2.6 h for levofloxacin, ciprofloxacin, and gatifloxacin; regrowth was seen with all 3 agents, but was greatest with gatifloxacin. PA-2105 had 2- to 4-fold higher minimal inhibitory concentrations (MICs) than PA-24. Gatifloxacin failed to achieve a 3-log reduction. Levofloxacin and ciprofloxacin took roughly 3.5 h to decrease initial inoculum by 3 logs, but regrowth of PA-2105 followed. Simulated doses of levofloxacin and ciprofloxacin showed comparable activity against each study isolate; less activity was observed with gatifloxacin. Levofloxacin versus PA-24 was the only regimen that approached the desired AUC/MIC(0-24) ratio of greater than 100-125 and achieved the targeted peak/MIC ratio of > or =8. Although quinolones are typically used in combination with other antibiotics for P. aeruginosa, differences in activity favor the use of levofloxacin or ciprofloxacin for the study isolates. Use of gatifloxacin may contribute to the increased rate of quinolone-resistant P. aeruginosa.

Pharmacodynamic analysis of ceftriaxone, gatifloxacin,and levofloxacin against Streptococcus pneumoniae with the use of Monte Carlo simulation.

STUDY OBJECTIVE: To evaluate the pharmacodynamics of four intravenous antimicrobial regimens-ceftriaxone 1 g, gatifloxacin 400 mg, levofloxacin 500 mg, and levofloxacin 750 mg, each every 24 hours-against recent Streptococcus pneumoniae isolates. DESIGN: Pharmacodynamic analysis using Monte Carlo simulation. DATA SOURCE: The Surveillance Network (TSN) 2002 database. MEASUREMENTS AND MAIN RESULTS: Streptococcus pneumoniae isolates (7866 isolates) were stratified according to penicillin susceptibilities as follows: susceptible (4593), intermediate (1986), and resistant (1287). Risk analysis software was used to simulate 10,000 patients by integrating published pharmacokinetic parameters, their variability, and minimum inhibitory concentration (MIC) distributions from the TSN database. Probability of target attainment was determined for percentage of time above the MIC (%T > MIC) from 0-100% for ceftriaxone and area under the concentration-time curve (AUC):MIC ratio from 0-150 for the fluoroquinolones. For ceftriaxone, probability of target attainment remained 90% or greater against the three isolate groups until a %T > MIC of 70% or greater, and it remained 90% or greater against susceptible and intermediate isolates over the entire interval (%T > MIC 0-100%). For levofloxacin 500 mg, probability of target attainment was 90% at an AUC:MIC < or = 30, but the curve declined sharply with further increases in pharmacodynamic target. Levofloxacin 750 mg achieved a probability of target attainment of 99% at an AUC:MIC ratio < or = 30; the probability remained approximately 90% until a target of 70 or greater, when it declined steeply. Gatifloxacin demonstrated a high probability (99%) of target attainment at an AUC:MIC ratio < or = 30, and it remained above 90% until a target of 70. CONCLUSION: Ceftriaxone maintained high probability of target attainment over a broad range of pharmacodynamic targets regardless of penicillin susceptibility (%T > MIC 0-60%). Levofloxacin 500 mg maintained high probability of target attainment for AUC:MIC ratios 0-30; whereas, levofloxacin 750 mg and gatifloxacin maintained high probability of target attainment for AUC:MIC ratios 0-60. Rate of decline in the pharmacodynamic curve was most pronounced for the two levofloxacin regimens and more gradual for gatifloxacin and ceftriaxone.

Comparison of gatifloxacin and levofloxacin administered at various dosing regimens to hospitalised patients with community-acquired pneumonia: pharmacodynamic target attainment study using North American surveillance data for Streptococcus pneumoniae.

This work aimed at determining the target attainment potential of gatifloxacin and levofloxacin in specific age-related patient populations such as elderly (> or =65 years) versus younger (<65 years) hospitalised patients with community-acquired pneumonia (CAP). Previously described population pharmacokinetic models of gatifloxacin and levofloxacin administration in patients with serious CAP were utilised to simulate gatifloxacin and levofloxacin pharmacokinetics. Pharmacokinetic simulations and susceptibility data for Streptococcus pneumoniae from the ongoing national surveillance study, Canadian Respiratory Organism Susceptibility Study (CROSS), were then used to produce pharmacodynamic indices of free-drug area under the curve over 24h relative to the minimum inhibitory concentration (free-drug AUC(0-24)/MIC(all)). Monte Carlo simulations were then used to analyse target attainment both of gatifloxacin and levofloxacin to achieve free-drug AUC(0-24)/MIC(all)> or =30 against S. pneumoniae in patients with CAP. Dosing regimens for gatifloxacin were 400 mg once daily (qd) administered to younger patients (<65 years) and gatifloxacin 200 mg qd to elderly patients (> or =65 years). Dosing regimens for levofloxacin were simulated as 500 mg, 750 mg and 1000 mg qd administered to elderly patients as well as younger patients. Monte Carlo simulations using gatifloxacin 400mg against S. pneumoniae yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 96.6% for all patients, 92.3% for younger patients and 97.7% for elderly patients. When administered to elderly patients, a reduced dose of gatifloxacin 200mg qd could achieve a target attainment potential of 91.4%. Monte Carlo simulation using levofloxacin 500 mg qd yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 92.3% for all patients, 95.7% for elderly patients compared with 72.7% for younger patients. Using levofloxacin 750 mg and 1000 mg qd had probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 97.0% and 98.3%, 98.1% and 99.2%, and 90.1% and 95.2% for all patients, elderly patients and younger patients, respectively. The probability of achieving free-drug AUC(0-24)/MIC(all) of 100 was low both with gatifloxacin and levofloxacin, except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg qd (78.5%). We conclude that gatifloxacin and levofloxacin pharmacokinetics in elderly patients with CAP are markedly different from those of younger patients. Higher gatifloxacin/levofloxacin AUC and longer half-life (t(1/2)) values in elderly patients with CAP compared with younger patients provide better pharmacodynamic parameters (free-drug AUC(0-24)/MIC) leading to a higher probability of pharmacodynamic target attainment and improved bacteriological outcome against S. pneumoniae. Gatifloxacin 400mg qd results in a high probability of target attainment and improved bacteriological outcome against S. pneumoniae both in young and elderly CAP patients. However, gatifloxacin administered at a lowered dose of 200 mg qd in elderly patients could still be successful in producing a favourable antibacterial effect. Levofloxacin administered at a dose of 750 mg qd results in a high probability of target attainment and improved bacteriological outcome against S. pneumoniae in all patients with CAP.

Designing fluoroquinolone breakpoints for Streptococcus pneumoniae by using genetics instead of pharmacokinetics-pharmacodynamics.

We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.

In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome.

The proarrhythmic effects of fluoroquinolone antibacterial agents, sitafloxacin, gatifloxacin and moxifloxacin, were compared using three in vivo models. In the halothane-anesthetized dogs (n=5), intravenous 10-min infusion of gatifloxacin and moxifloxacin (1-3 mg/kg) prolonged the ventricular effective refractory period and the repolarization period to a similar extent, whereas sitafloxacin (1-3 mg/kg) prolonged the former only. No significant change was detected in other cardiovascular parameters. In the chronic complete atrioventricular block dogs (n=4), oral administration of 100 mg/kg of gatifloxacin (2 of 4) and moxifloxacin (3 of 4) induced torsades de pointes, which was not observed by sitafloxacin. In the alpha-chloralose-anesthetized rabbits (n=5), intravenous 20-min infusion of 60 mg/kg of gatifloxacin induced torsades de pointes (1 of 5) in the presence of methoxamine infusion, which was not observed by sitafloxacin or moxifloxacin. Thus, the halothane-anesthetized model is suitable for assessing QT prolongation, whereas the chronic complete atrioventricular block model is sensitive for detecting torsadogenic action of drugs. The alpha-chloralose-anesthetized model is the simplest and least expensive method, but its sensitivity to detect proarrhythmic action may be less great.

Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases.

BACKGROUND: Bacteria that produce extended-spectrum beta-lactamases (ESBLs) are resistant to penicillins,cephalosporins, and monobactams. The results of clinical studies suggest that the carbapenems imipenem and meropenem may be effective against bacteria that produce ESBLs, although it is not known whether the new once-daily carbapenem ertapenem or the fluoroquinolones are useful against infections caused by ESBL-producing bacteria. OBJECTIVE: The present study compared the simulated pharmacodynamics of the carbapenems imipenem,meropenem, and ertapenem; the simulated pharmacodynamics of the fluoroquinolones levofloxacin, gatifloxacin, and ciprofloxacin with those of the carbapenems; and the simulated pharmacodynamics of levofloxacin 750 mg with those of levofloxacin 500 mg, all against gram-negative isolates that did and did not produce ESBLs METHODS: Pharmacokinetic data were obtained from studies in healthy humans. Minimum inhibitory concentrationsMICs) for bacteria that did and did not produce ESBLs were determined in triplicate using broth-microdilution techniques as recommended by National Committee for Clinical Laboratory Standards guidelines. Monte Carlo simulation was used to construct pharmacodynamic models for imipenem, meropenem, ertapenem, levofloxacin, gatifloxacin, and ciprofloxacin. Pharmacodynamic measures of interest were the probability of the free concentration remaining above the MIC >-40% of the time (T>MIC > or =40%) for carbapenems and the likelihood of achieving a free AUC:MIC ratio > or =125 for fluoroquinolones. RESULTS: MICs were determined for 39 isolates that produced ESBLs and 45 isolates that did not Bacteria that did not produce ESBLs were > or =93% susceptible to all carbapenems and fluoroquinolones tested. Among bacteria that produced ESBLs, rates of susceptibility to the specific agents were as follows: imipenem, 100%; meropenem, 97%; ertapenem, 87%; levofloxacin, 54%; gatifloxacin, 44%; and ciprofloxacin, 36%. In the pharmacodynamic models, imipenem and meropenem had an equal likelihood of achieving a free T>MIC > or =40% against bacteria that produced ESBLs (> or =97%) and bacteria that did not produce ESBLs (> or =98%). In contrast, the likelihood of ertapenem achieving a free T>MIC > or =40% was lower against bacteria that produced ESBLs (78%) than against bacteria that did not produce ESBLs (94%). Similarly, the fluoroquinolones were less likely to achieve a free AUC:MIC ratio > or =125 against bacteria that produced ESBLs (2%-13%) than against bacteria that did not produce ESBLs (85%-91%). CONCLUSIONS: Carbapenems had superior in vitro activity against bacteria that produced ESBLs compared with fluoroquinolones. Pharmacodynamic modeling based on local ESBL-producing isolates and pharmacokinetic data from healthy humans indicated that imipenem and meropenem may have a greater likelihood of achieving pharmacodynamic targets against bacteria that produce ESBLs than ertapenem or fluoroquinolones.

Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction.

OBJECTIVES: Recently, anecdotal reports via the FDA's MedWatch reporting system have documented rare but serious hyperglycaemia in elderly patients receiving gatifloxacin. One possible factor contributing to these events may be gatifloxacin overexposure, resulting from age-related decreases in renal function in elderly patients predisposed to glycaemic alterations. These analyses examine gatifloxacin exposure in 10 patients with severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic (PK-PD) rationale for a potential age-related dose reduction to avoid high exposures, and evaluate the likely impact of such a dose reduction on clinical efficacy in this specific patient population. METHODS: First, a previously derived population pharmacokinetic model, with patient demographics, was used to estimate gatifloxacin AUC0-24 following a dosage regimen of 400 mg/24 h in 10 index patients with severe hyperglycaemia. Second, the population pharmacokinetic model and patient demographic data from 2696 patients aged > or =65 years from two New Drug Application (NDA) databases were used to estimate AUC0-24 following dosage regimens for gatifloxacin of 200 and 400 mg/24 h. Finally, Monte Carlo simulation was utilized to assess the probability of achieving PK-PD target exposures against Streptococcus pneumoniae in elderly patients using these regimens. RESULTS: The mean estimated AUC0-24 among severe hyperglycaemia cases was 74 mg.h/L (range 57-100). Gatifloxacin AUC0-24 exposures for the 400 mg regimen were predicted to be higher in patients aged > or =65 years and similar to the severe hyperglycaemia cases. The probability of AUC0-24 > or =60 and > or =70 in patients aged > or =65 years for the 200 mg regimen was 0.03 and <0.01, respectively, versus 0.51 and 0.35 for the 400 mg regimen, respectively. The probability of achieving PK-PD target exposures against S. pneumoniae in patients aged > or =65 years receiving the 200 mg regimen was 0.99. CONCLUSIONS: The probability of a patient aged > or =65 years having an AUC0-24 > or =60-70 mg.h/L is markedly lower following a 200 mg regimen relative to a 400 mg regimen, suggesting a decreased risk of severe hyperglycaemia in a predisposed patient. Moreover, a dose reduction does not appear to significantly modify the likelihood of achieving the PK-PD target of gatifloxacin against S. pneumoniae.