Ceftazidime dosage recommendations in burn patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations.

BACKGROUND: Ceftazidime dosage regimen recommendations based on pharmacokinetic/pharmacodynamic approaches are not available for burn patients. OBJECTIVE: The goal of this study was to propose a continuous dosage regimen of ceftazidime in burn patients, taking into account different MICs and pharmacokinetic covariates. METHODS: The population pharmacokinetic analysis was conducted by using software dedicated to the analysis of nonlinear mixed effects models. The population pharmacokinetic model was first developed and validated in 70 adult burn patients. Taking into account various MICs of pathogens, 3 Monte Carlo simulation trials were conducted by using target concentration intervals (10-100, 20-100, and 40-100 mg/L). The recommended dosages were defined as the minimum dose leading to the highest percentage of patients whose ceftazidime concentrations were included in the target interval. RESULTS: Serum creatinine and age were identified as covariates of ceftazidime clearance. Age was also involved in volume of distribution. The simulations showed that a dose of 6 g/d did not allow achievement of the target interval in most patients. Regardless of dosage regimen, age, and serum creatinine, the mean percentage of patients reaching the 10- to 100-mg/L and the 20- to 100-mg/L target intervals were 99.4% (0.3%) and 96.1% (0.8%), respectively. For the 40- to 100-mg/L target interval, this percentage was only 76.4% (2.1%) (range, 65%-80%). CONCLUSIONS: Age and serum creatinine level can be used at the bedside to determine the initial doses of ceftazidime. These Monte Carlo simulations highlight the need of a reappraisal of ceftazidime's use in burn patients. Doses between 3 and 16 g/d are proposed, taking into account the pathogens' MICs. However, for sepsis caused by a pathogen with an MIC ≥ 8 mg/L, an insufficient percentage of burn patients will reach the therapeutic target with the recommended dosages.

Use of multiple sources and capture-recapture method to estimate the frequency of hospitalizations related to drug abuse.

PURPOSE: Addictive behaviours are often associated with hidden characteristics that are difficult to detect by usual approaches. This study aimed to estimate the incidence of serious drug-related complications by using the capture-recapture method in defined geographical area. METHODS: Hospitalizations with mention of disorders related to drug of abuse were considered serious drug-related complications. We searched these cases in and crossed three sources of data: spontaneous reports of drug of abuse-related disorders called NotS ('Notification Spontanee') collected by the regional addictovigilance centre, computerised hospital database Programme de Medicalisation des Systemes d'Information (PMSI) and toxicological analyses (TA) carried out for hospitalized patients. RESULTS: In 2007 and 2008, 1509 distinct cases were captured. After data modelling, the estimated number of psychoactive drug-related hospitalizations was 4744 (95%CI = 4060-5429). Most frequent products were opioids (34%), cannabis (19%) and cocaine (13%). 'Multiple drugs' were observed in 26% of cases. The incidence of serious drug-related complications in the area covered should be estimated at 5.7 (95%CI = 5.5-5.9) per thousand 15- to 64-year-old inhabitants. The exhaustiveness of sources were 0.4% (95%CI = 0.2-0.6) for NotS, 11.6% (95%CI = 10.7-12.5) for TA and 22.6% (95%CI = 21.4-23.8) for PMSI. CONCLUSIONS: The 'real' number of cases far exceeds that of cases that can be identified through simple counts. In particular, it confirms the underreporting and even quantifies its magnitude. These results confirm that drug users are frequently hospitalised and require heavy medical management. Moreover, these results show the real although limited advantage of hospitalization database in detecting drug associated disorders in epidemiological studies. Copyright © 2012 John Wiley & Sons, Ltd.

Ceftazidime dosage regimen in intensive care unit patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The large variability in drug pharmacokinetic disposition has already been described in ICU patients leading to important variations in drugs concentrations. The usual recommended dosage of ceftazidime is not adapted for all ICU situations and ceftazidime should be monitored closely. New recommendations have to be given for some specific cases. WHAT THIS STUDY ADDS: Our results propose individual therapeutic drug monitoring taking into account: For the patient: the reason of admission in the ICU, the mechanical ventilation status and the creatinine clearance calculated by the modified diet in renal disease (MDRD). • For the antibiotics: the lung distribution, the minimal inhibitory concentration (MIC) of the strain to eradicate and the potential toxicity. AIM To predict the ceftazidime dosage regimen as a function of the glomerular filtration rate expressed by the modification of the diet in renal disease (MDRD), reason for admission and mechanical ventilation in intensive care unit (ICU) patients to treat Pseudomonas aeruginosa pneumonia. METHOD: A published and qualified population pharmacokinetic model was used to perform Monte Carlo simulations of ceftazidime concentrations. The serum target of 40-100 mg l(-1) was defined based on the minimal inhibitory concentration (MIC), the European break point (EBP), the pulmonary drug diffusion and toxicity. The recommended dosage regimens were based on the maximum percentile of the patients with simulated steady state concentrations reaching the target. RESULTS: Steady-state was reached at 72 h whatever the MDRD. The simulations of serum concentrations generated higher percentiles of the population reaching the target after continuous administration. We recommend a 4 g continuous dose after the usual 2 g loading dose for patients with MDRD from 10 to 30 ml min(-1) , 6 g for MDRD between 40 and 80 ml min(-1) , 8 g for MDRD from 90 to 110 ml min(-1) , 10 g for MDRD from 120 to 190 ml min(-1) and 12 g day(-1) for patients with MDRD higher than 200 ml min(-1) . CONCLUSION: Our study demonstrated that in ICU patients for a given MDRD, steady-state takes longer to reach in polytrauma patients than in patients with medical or post surgery reasons for admission. Continuous infusion ensures that a higher percentage of patients reaches the target than the same dose given by discontinuous administration and this only depends on MDRD.

Optimizing ciprofloxacin dosing in intensive care unit patients through the use of population pharmacokinetic-pharmacodynamic analysis and Monte Carlo simulations.

OBJECTIVES: To explore different ciprofloxacin dosage regimens for the treatment of intensive care unit (ICU) patients with respect to clinical outcome and the development of bacterial resistance for the major Gram-negative pathogens. METHODS: A population pharmacokinetic model was first developed on ciprofloxacin serum concentrations obtained in 102 ICU patients. Then, based on this model, pharmacokinetic-pharmacodynamic Monte Carlo simulations (MCSs) were carried out to explore the appropriateness of different ciprofloxacin dosage regimens in ICU patients. The defined targets were free AUC(24)/MIC ≥90 h (as a predictor of clinical outcome) and T(MSW) ≤20% (as a predictor of selecting resistance), where T(MSW) is the time spent within the mutant selection window over 24 h. Two simulation trials were conducted: Trial 1 took into account the whole MIC distribution for each causative pathogen in line with empirical antibiotherapy; Trial 2 used MIC breakpoints given by the Antibiogram Committee of the French Microbiology Society in order to treat the 'worst-case' scenario. RESULTS: Trial 1 showed that for Pseudomonas aeruginosa and Acinetobacter baumannii, the common dosage regimens of 400 mg twice or three times a day did not achieve the desired target attainment rates (TARs) with respect to T(MSW), while suboptimal TARs were found for AUC(24)/MIC. Trial 2 showed that ≤ 18% of patients reached the target of T(MSW) ≤ 20% for MIC breakpoints of 0.5 and 1 mg/L, regardless of the administered dose. CONCLUSIONS: Based on the mutant selection window concept, our simulations truly question the use of ciprofloxacin for the treatment of P. aeruginosa and A. baumannii infections in ICU patients due to the potential for developing resistance.

Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study.

INTRODUCTION: The aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT). METHODS: This was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR . RESULTS: Among the 106 patients with a CLCR above 120 mL minute(-1) 1.73 m(-2), 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute(-1) 1.73 m(-2) with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute(-1). 1.73 m(-2) were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute(-1). 1.73 m(-2). Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR. CONCLUSIONS: In ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination.

Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations.

UNLABELLED: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? It is well known that tobramycin given as an once daily dose according to the usual recommendations needs therapeutic drug monitoring by measurement of peak and trough concentrations. In the literature, there are only few published studies on the population pharmacokinetics of once daily tobramycin in critically ill patients. Glomerular filtration rate and bodyweight were identified as covariates contributing to the inter-individual variability in the disposition of aminoglycosides. The study, by Peris-Marti et al. [24], only evaluated the pharmacodynamic effectiveness of a 4 mg kg(-1) dose of tobramycin given once daily in critically ill patients. The authors concluded with a simulation showing that for a theoretical MIC of 1 or 2 mg l(-1) , a 7 mg kg(-1) dose was required. WHAT THIS STUDY ADDS: Our results confirm the high variability of tobramycin disposition in intensive care patients and consequently the possible lack of effectiveness. By using a population pharmacokinetic approach, two explicative covariates (height and Cockcroft creatinine clearance) added to a two-compartment model with proportional error, explained much of the inter-individual variability of tobramycin disposition in the critically ill patient population. In a median ICU patient, simulations were performed at various dosage regimens and peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Drug monitoring is required to manage efficacy and toxicity. AIM: The aim of this study was to evaluate the disposition of tobramycin (TOB) in critically ill patients (ICU) by a population pharmacokinetic approach, to determine the covariates involved, and to simulate tobramycin dosage regimens. METHODS: Forty-nine adult ICU patients received TOB (5 mg kg(-1) ) once daily. NonMem modelling was performed on 32 patients. The 17 other patients were used for the qualification process by normalized prediction distribution error. Then Monte Carlo simulations (MCS) were performed. RESULTS: A two-compartment model with a proportional error best fitted the data. TOB total clearance (CL(TOB) ) was significantly correlated with Cockcroft creatinine clearance (COCK) and height. TOB clearance was 4.8 ± 1.9 l h(-1) (range 1.22-8.95), the volume of distribution of the central compartment was 24.7 ± 3.7 l (range 17.34-32.83) and that of the peripheral compartment and the inter-compartmental clearance were 30.6 l and 4.74 l h(-1) , respectively. Only 29% of the patients presented a target AUC between 80 and 125 mg l(-1) h and 61% were lower than 80 mg l(-1) h. After considering COCK and height, MCS showed that only 50% of the population could achieve the target AUC for the 375 and 400 mg dosages. CONCLUSION: Even after taking into account COCK and height, for strains with an MIC ≤ 1 mg l(-1) , MCS doses evidenced that peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Combination therapy in addition to drug monitoring are required to manage efficacy and toxicity.

Cost-effectiveness analysis of individualized mycophenolate mofetil dosing in kidney transplant patients in the APOMYGRE trial.

BACKGROUND: In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization. METHOD: The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective. RESULTS: The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost. CONCLUSION: In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

Population pharmacokinetics of ceftazidime in intensive care unit patients: influence of glomerular filtration rate, mechanical ventilation, and reason for admission.

The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.

Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches.

The objective of this study was to evaluate the properties of ciprofloxacin in intensive care patients using a population approach. Seventy patients received ciprofloxacin. On Day 1, three to eight blood samples were taken over a 12-h period. Peak drug concentration (Cmax) and 24-h area under the concentration-time curve (AUC) were compared with the French breakpoint defining antibiotic susceptibility. A population pharmacokinetic modelling approach was then carried out. A two-compartment open model with a proportional error model best fitted the data. A relationship between the elimination constant rate and the Cockcroft creatinine clearance was found. Ciprofloxacin clearance was 13.6+/-5.8L/h, the volume of distribution was 62.0+/-10.7 L and the ciprofloxacin half-life was 3.7+/-1.8h. When the minimum inhibitory concentration (MIC) was equal to 1mg/L the inhibitory ratio (IR) was > or = 8 in only 10.8% of cases, and the AUC/MIC ratio (AUIC) was 42.0+/-36. In conclusion, this study highlights that the Cockcroft clearance significantly influences ciprofloxacin elimination. Target plasma concentrations for ciprofloxacin, the IR and AUIC were rarely reached with a standard dosing regimen. In critically ill patients, the observed pharmacokinetic variability is mainly responsible for the overly frequent low concentrations of ciprofloxacin, emphasising the need for therapeutic monitoring.

Blood concentrations of hydroxychloroquine and its desethyl derivative correlate negatively with the percentage of CD45RO+ cells among CD4+ lymphocytes in hydroxychloroquine-treated lupus patients.

The objective of the study was to investigate the influence of the blood concentrations of hydroxychloroquine ([HCQ]) and its derivative desethylhydroxychloroquine ([DHCQ]) on lymphocyte activation or differentiation in HCQ-treated lupus patients. We studied the correlations between [HCQ], [DHCQ], and the frequency of various lymphocyte subsets in 58 HCQ-treated lupus patients (mean HCQ dose: 4.93 +/- 1.58 mg/kg/day; mean duration of the disease: 122 +/- 64 months). [HCQ] and [DHCQ] were determined by high-performance liquid chromatography (HPLC). Lymphocyte markers were studied by flow cytometry using monoclonal anti-CD3, -CD4, -CD8, -CD25, -DR, -CD45RA, -CD45RO, -CD19, -CD38, and -CD86 antibodies. sIL2-R serum concentrations were measured by enzyme-linked immunosorbent assay (ELISA). [HCQ] and [DHCQ] were 599.9 ng/mL (median: 529.5; range: 55-1935) and 353.43 (median: 286 ng/mL; range: 118-1090). In a multiple regression analysis, [HCQ] and [DHCQ] were associated with the HCQ prescribed dose in mg/kg/day (P = 0.0002 and P = 0.03) and with compliance to the treatment (P = 0.004 and P = 0.03). We found a negative correlation between [HCQ], [DHCQ], and the CD45RO+ cell frequency among CD3+CD4+ cells (P = 0.03 and P = 0.007, respectively). Other lymphocyte subset markers (LSMs) and sIL2-R concentrations were not significantly associated with [HCQ] or [DHCQ]. In the multiple regression analysis, CD45RO+ expression was negatively influenced by [HCQ] (P = 0.005), and positively influenced by smoking habits (P = 0.005) and age (P = 0.005). Similar results were found in the multivariate model including [DHCQ]. Disease activity and taking more than 10 mg/day of corticosteroids or an immunosuppressive drug did not influence CD45RO+ expression. Lupus patients had less CD3+CD4+CD45RO+ cells than controls (P = 0.03). In lupus patients, HCQ and DHCQ may alter the generation or the blood circulation of CD4+CD45RO+ lymphocytes in a concentration-dependent pattern.

[Prenatal exposure to psychoactive substances: results of NENUPHAR study]. / Exposition in utero à des substances psychoactives: résultats de l'étude "NENUPHAR" .

The aim of this study is to describe the impact of maternal psychotropic use or abuse on late pregnancy in newborns, using data from hospital laboratory (positive assay for psychoactive drugs). Fifty three newborns were included between 1998 and 2002. Most of cases have been exposed to benzodiazepines, opioids and cannabis. Ninety two and a half per cent had a neonatal disease. Neonatal withdrawal, respiratory disease, hypotonia and hypotrophy were the most frequent neonatal pathologies. Many cases were exposed to cannabis which might increase neonatal disease risk. These results underline the impact of psychotropic use or abuse during pregnancy on neonatal outcomes.

A population pharmacokinetic approach to ceftazidime use in burn patients: influence of glomerular filtration, gender and mechanical ventilation.

AIMS: The aim of this study was to evaluate the disposition of ceftazidime in burn patients using a population pharmacokinetic approach, and to identify the clinical and biological parameters influencing its pharmacokinetics. METHODS: The development of the pharmacokinetic model was based on 237 serum ceftazidime concentrations from 50 burn patients. The determination of the pharmacokinetic parameters and the selection of covariates were performed using a nonlinear mixed-effect modelling method. RESULTS: A two-compartment model with first order elimination incorporating a proportional error model best fitted the data. Ceftazidime clearance (CL, l h(-1)) was significantly correlated with creatinine clearance (CL(CR)), and the distribution volume of the peripheral compartment (V2, l) was correlated with gender, mechanical ventilation and the CL(CR). The final model was defined by the following equations: Ceftazidime clearance was 6.1 and 5.7 l h(-1) for mechanically ventilated males and females, respectively, and 7.2 and 6.6 l h(-1) for nonventilated patients. The total volume of distribution was 31.6 and 49.4 l for mechanically ventilated males and females, respectively, and 22.8 and 28.1 l h (-1)for nonventilated patients. CONCLUSIONS: We have shown that gender, mechanical ventilation and CL(CR) significantly influence the disposition of ceftazidime in burn patients. Interindividual variability in the pharmacokinetics of ceftazidime was significant and emphasizes the need for therapeutic monitoring.

Influence of renal function on trough serum concentrations of piperacillin in intensive care unit patients.

OBJECTIVE: To explore the effects of renal function estimated by measured creatinine clearance (Cl(CR)) on trough serum concentration (C(min)) of piperacillin given to critically ill patients. DESIGN: Prospective observational study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Seventy critically ill patients, including 22 with severe trauma. INTERVENTIONS: All subjects received an intravenous infusion of piperacillin 4 g three times (n = 61) or four times (n = 9) per day. Piperacillin C(min) values were determined 24 h after treatment started and compared to the French breakpoint defining antibiotic susceptibility against Enterobacteriaceae (8 mg/l) or Pseudomonas sp. (16 mg/l). RESULTS: Median (range) piperacillin C(min) was 11.9 (< 1-156.3) mg/l, with a great variability among patients. Although the median value was close to the breakpoints, sub-therapeutic plasma levels were frequently observed. Piperacillin C(min) was lower than the breakpoint for Enterobacteriaceae in 37% of patients, and lower than the breakpoint for P. aeruginosa in 67% of them. A strong relationship was observed between piperacillin C(min) and Cl(CR): the higher the Cl(CR,) the lower the piperacillin C(min )in serum. For patients with a Cl(CR) < 50 ml/min, enough piperacillin C(min) was achieved in most patients with 12 g piperacillin per day. For patients with higher Cl(CR) values, a piperacillin daily dose of 16 g or more may be warranted. CONCLUSIONS: In critically ill patients, therapeutic monitoring must be part of the routine, and knowledge of Cl(CR) value may be useful for the choice of adequate initial piperacillin dosing.

Influence of simulated weightlessness on the intramuscular and oral pharmacokinetics of promethazine in 12 human volunteers.

The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (C(max)), time to C(max) (t(max)), and area under plasma concentration versus time curve from 0 to infinity (AUC(inf)) were determined, and the bioequivalence was tested between bed-rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed-rest and ambulatory position. Simulated weightlessness did not influence the ratio AUC(bed rest)/AUC(ambulatory) after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3-fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.

Risk of emergence of Pseudomonas aeruginosa resistance to beta-lactam antibiotics in intensive care units.

OBJECTIVE: The emergence of Pseudomonas aeruginosa resistance to antimicrobial drugs is frequent in intensive care units and may be correlated with the use of some specific drugs. The purpose of our study was to identify a relationship between the use of various beta-lactam antibiotics and the emergence of resistance and to characterize the mechanism of resistance involved. DESIGN: We conducted an open prospective study over a 3-yr period by including all patients in whom P. aeruginosa had been isolated from one or more specimens: bronchial aspiration, blood cultures, catheters, and urinary cultures. SETTING: General intensive care unit. PATIENTS: One hundred and thirty-two intensive care unit patients. INTERVENTIONS: The antibiotics studied were amoxiclav, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepim, and imipenem. The mechanisms of resistance studied were production of penicillinase or cephalosporinase, nonenzymatic mechanisms, and loss of porin OprD2. Analysis was performed using Cox proportional-hazard regression with time-dependant variables. MEASUREMENTS AND MAIN RESULTS: Forty-two strains became resistant, 30 to one antibiotic, nine to two, and three to three, leading to the study of 57 resistant strains. Imipenem (hazard ratio 7.8; 95% confidence interval, 3.4-18.1), piperacillin-tazobactam (hazard ratio 3.9; 95% confidence interval, 1.3-11.9), and cefotaxim (hazard ratio 9.3; 95% confidence interval, 2.9-30.2) were strongly linked to the emergence of resistance. The use of imipenem (p<.0001) was associated with the loss of porin OprD2. Thirty-six strains from nine patients, assayed by pulsed-field gel electrophoresis, showed that for any one patient, all the strains were genetically related. CONCLUSIONS: Our results show that there is a high risk of the emergence of drug resistance during treatment with cefotaxime, imipenem, and piperacillin-tazobactam. This has to be taken into account in the therapeutic choice and in the patient's surveillance.

The influence of weightlessness on pharmacokinetics.

The primary hostile factor during a spaceflight is the lack of gravity, which can induce space motion sickness and act on bones, muscles and the cardiovascular system. These physiological effects may modify the pharmacokinetics of the drugs administered during the flight producing reduced pharmacological activity or appearance of adverse effects. Given the small number of spaceflights and the difficulties of conducting experiments during missions, pharmacokinetic data obtained in flight are insufficient to determine if drug monitoring is necessary for the drugs present in the onboard medical kit. Therefore, validated earthbound models like tail-suspension performed with animals and long-term bedrest performed with human volunteers are used to simulate weightlessness and to study the pharmacokinetic variations of either absorption, distribution, or elimination of drugs. As a result of these studies, it is possible to make some dosing recommendations but more information is necessary to predict with precision all of the pharmacokinetic variations occurring in spaceflight. To collect more pharmacokinetic information, head-down bedrest studies are still the best solution and as saliva is an appropriate substitution for plasma for some drugs, salivary sampling can be planned during flights.

Plasma kinetics and efficacy of oral megazol treatment in Trypanosoma brucei brucei-infected sheep.

Experimentally infected sheep have been previously developed as an animal model of trypanosomosis. We used this model to test the efficacy of megazol on eleven Trypanosoma brucei brucei-infected sheep. When parasites were found in blood on day 11 post-infection, megazol was orally administered at a single dose of 40 or 80mg/kg. After a transient aparasitaemic period, all animals except two relapsed starting at day 2 post-treatment, which were considerated as cured on day 150 post-treatment and showed no relapse after a follow-up period of 270 days. In order to understand the high failure of megazol treatment to cure animals, a kinetic study was carried out. Plasma concentrations of megazol determined, by reverse-phase high-performance liquid chromatography at 8h post-treatment in these animals, were lowered, suggesting slow megazol absorption, except in cured animals. However, megazol plasma profiles in uninfected sheep after a single oral dose of megazol showed a fast megazol lowered absorption associated with a short plasma half-life of drug. Inter-individual variation of megazol pharmacokinetic properties was also observed. These findings suggested that the high failure rates of megazol treatment were related to poor drug availability after oral administration in sheep. In conclusion, megazol could cure sheep with T. b. brucei infection but oral administration was not an effective route.

Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat.

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible 'stress effect' caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.

Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a gastric emptying probe in man: a plasma and a saliva study.

This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and -6 degrees head-down bed rest to simulate zero gravity. Eighteen volunteers were given 1 g of acetaminophen orally before the bed rest and at days 1, 18, and 80. Cmax, tmax, AUC0- infinity, AUC0-t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 microg/mL [day 1] to 14.74 microg/mL [day 80]), while tmax significantly decreased (1.41 h [day 1] to 0.91 h [day 80]). Similar results were obtained with saliva, and there were significant increases in the AUCs. The good correlation between the plasma and saliva data suggests that saliva sampling can be valid for acetaminophen pharmacokinetics. The changes in Cmax and tmax indicated more rapid drug absorption, which could have been as a result of faster gastric emptying or an increased blood flow to the intestine.