Meropenem Population Pharmacokinetics and Simulations in Plasma, Cerebrospinal Fluid, and Brain Tissue.

Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis of a previously published prospective study of patients admitted to the neurointesive care unit between 2016 and 2019 who received 2 g of meropenem intravenously every 8 h. Meropenem concentration was determined in blood, cerebrospinal fluid (CSF), and brain microdialysate. Meropenem was described by a six-compartment model: two compartments in the blood, two in the CSF, and two in the brain tissue. Creatinine clearance and brain glucose were included as covariates. The median elimination rate constant was 1.26 h-1, the central plasma volume was 5.38 L, and the transfer rate constants from the blood to the CSF and from the blood to the brain were 0.001 h-1 and 0.02 h-1, respectively. In the first 24 h, meropenem 2 g, administered every 8 h via intermittent and extended infusions achieved good target attainment in the CSF and brain, but continuous infusion (CI) was better at steady-state. Administering a 3 g loading dose (LD) followed by 8 g CI was beneficial for early target attainment. In conclusion, a meropenem PK model was developed using blood, CSF, and brain microdialysate samples. An 8 g CI may be needed for good target attainment in the CSF and brain. Giving a LD prior to the CI improved the probability of early target attainment.

Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study.

BACKGROUND: The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED). METHODS: Prospective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa. RESULTS: A two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC ≤ 2 mg/L) was > 95% for a dose of 0.5 g 8-hourly. In patients with a residual diuresis of 300 mL/d 1 g 12-hourly and 2 g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2 g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis. CONCLUSIONS: We found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing. TRIAL REGISTRATION: Clincialtrials.gov, NCT02287493 .

Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300 mg I.V. q12h, q8h, and q6h, and 600 mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5 h) and an EI (1 h, 2 h, 3 h, and 4 h). For a target of 40%fT>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug-resistant P. aeruginosa (MDR-PA) and even non-MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600 mg q12h over 2-4 h EI regimens could achieve CFR>90% with 20%fT>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions.

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.

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae.

We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations (Css) of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T>1×MIC, 100% T>2×MIC, 100% T>3×MIC, and 100% T>4×MIC, where "T>MIC" represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n = 169). Ninety-seven meropenem Css were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T>1×MIC against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

Pharmacokinetic/Pharmacodynamic Analysis of Meropenem for the Treatment of Nosocomial Pneumonia in Intracerebral Hemorrhage Patients by Monte Carlo Simulation.

BACKGROUND: Nosocomial pneumonia (NP) is a frequent complication among patients with intracerebral hemorrhage (ICH). However, there are currently no pharmacokinetic (PK) and pharmacodynamic (PD) data to guide meropenem dosing in these patients. OBJECTIVE: To investigate the PK/PD properties of meropenem in these patients and whether the usual dosing regimens of meropenem (2-hour infusion, 1 g, every 8 hours) was suitable. METHODS: A total of 11 patients with a diagnosis of ICH complicated with NP were selected in the emergency internal medicine and treated with a 1-g/2-hours extended infusion model. The plasma concentrations of meropenem were determined by high-performance liquid chromatography. PK parameters were estimated by plasma concentration versus time profile using WinNonlin software. The probability of target attainments (PTAs) of meropenem at different minimum inhibitory concentrations (MICs) based on percentage time that concentrations were above the minimum inhibitory concentration (%T>MIC) value were performed by Monte Carlo simulation. RESULTS: The volume of distribution and total body clearance of meropenem were 55.55 L/kg and 22.89 L/h, respectively. Using 40%T>MIC, PTA was >90% at MICs ≤4 µg/mL. Using 80% or 100%T>MIC, PTA was >90% only at MICs ≤1 µg/mL. CONCLUSIONS: The PK/PD profile of dosing regimens tested will assist in selecting the appropriate meropenem regimens for these patients. At a target of 40%T>MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤4 µg/mL. However, when a higher target (80% or 100%) is desired for difficult-to-treat infections, larger doses, prolonged infusions, shorter intervals, and/or combination therapy may be required.

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT>5×MIC = 56 and 69%, fCmin/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT>5×MIC ≥ 82%, fCmin/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function.

OBJECTIVES: The aim of this study was to evaluate different dosage regimens of meropenem in elderly patients in relation with renal function using a population pharmacokinetic (popPK) model. METHODS: The data of 178 elderly patients treated with meropenem was collected from different sources. A popPK model was developed by using NONMEM® and the influence of different covariates on meropenem CL and V1 was observed. Monte Carlo dosing simulations were performed at steady state to observe the % T > MIC for targets of 40, 60 and 80% of dosage intervals at different levels of creatinine clearance (CLCR). RESULTS: The data was described by a two-compartment model and the values of parameter estimates for CL, V1, Q and V2 were 5.27 L/h, 17.2 L, 9.92 L/h and 10.6 L, respectively. The CLCR, body weight and centre had a significant influence on meropenem CL while no direct influence of age was observed. Extended infusions had pharmacokinetic and pharmacodynamic (PK/PD) breakpoint one dilution greater than corresponding short infusion regimens for each target of % T > MIC. CONCLUSION: Meropenem CL was significantly lower in the elderly compared to CL reported in younger patients due to the reduced renal function. An extended infusion of 1000 mg q8h can be considered for empirical treatment of infections in elderly patients when CLCR is ≤ 50 mL/min. A continuous infusion of 3000 mg daily dose is preferred if CLCR > 50 mL/min. However, a higher daily dose of meropenem would be required for resistant strains (MIC >8 mg/L) of bacteria if CLCR is >100 mL/min.

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients.

The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients-11 nonobese (body mass index [BMI] < 30 kg/m2 ), 9 obese (30 kg/m2 ≤ BMI < 40 kg/m2 ), and 20 morbidly obese (BMI ≥ 40 kg/m2 )-received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000-patient Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2-compartment linear-elimination model best described the serum concentration-time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.

Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis.

Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine samples as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration-time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CLCr) and patient weight, respectively. Patient ethnicity was not supported as a covariate in the final model. Significant differences were observed for meropenem clearance between the Indigenous and Caucasian groups [median 11.0 (range 3.0-14.1) L/h vs. 17.4 (4.3-30.3) L/h, respectively; P <0.01]. Standard dosing regimens (1 g intravenous every 8 h as a 30-min infusion) consistently achieved target exposures at the minimum inhibitory concentration breakpoint in the absence of augmented renal clearance. No significant interethnic differences in meropenem pharmacokinetics between the Indigenous and Caucasian groups were detected and CLCr was found to be the strongest determinant of appropriate dosing regimens.

Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery.

Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.).

A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients.

BACKGROUND: Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population. METHODS: This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem. RESULTS: A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat. CONCLUSIONS: This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.

Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections.

In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16µg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32µg/mL only infusion achieved adequate PTA. For a MEM MIC of 4µg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.

Optimal dosing regimen of biapenem in Chinese patients with lower respiratory tract infections based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation.

In this study, a population pharmacokinetic (PPK) model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs) was developed and optimal dosage regimens based on Monte Carlo simulation were proposed. A total of 297 plasma samples from 124 Chinese patients were assayed chromatographically in a prospective, single-centre, open-label study, and pharmacokinetic parameters were analysed using NONMEN. Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance. The final PPK model was: CL (L/h)=9.89+(CLCr-66.56)×0.049; Vc (L)=13; Q (L/h)=8.74; and Vp (L)=4.09. Monte Carlo simulation indicated that for a target of ≥40% T>MIC (duration that the plasma level exceeds the causative pathogen's MIC), the biapenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was 4µg/mL for doses of 0.3g every 6h (3-h infusion) and 1.2g (24-h continuous infusion). For a target of ≥80% T>MIC, the PK/PD breakpoint was 4µg/mL for a dose of 1.2g (24-h continuous infusion). The probability of target attainment (PTA) could not achieve ≥90% at the usual biapenem dosage regimen (0.3g every 12h, 0.5-h infusion) when the MIC of the pathogenic bacteria was 4µg/mL, which most likely resulted in unsatisfactory clinical outcomes in Chinese patients with LRTIs. Higher doses and longer infusion time would be appropriate for empirical therapy. When the patient's symptoms indicated a strong suspicion of Pseudomonas aeruginosa or Acinetobacter baumannii infection, it may be more appropriate for combination therapy with other antibacterial agents.

Meropenem dosing requirements against Enterobacteriaceae in critically ill patients: influence of renal function, geographical area and presence of extended-spectrum ß-lactamases.

The aim of this study was the evaluation of the influence of the susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates, specifically the presence of extended-spectrum ß-lactamases and the geographical area (Europe and USA), on the meropenem dosing requirements in critically ill patients with different degrees of renal function by estimation of the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Additionally, estimation of the PK/PD breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach was also an objective. Six dosing regimens were evaluated: 0.5 g, 1 g and 2 g every 8 h given as 0.5-h or 3-h infusions. Pharmacokinetic data were obtained from the literature, and susceptibility data to meropenem for E. coli and K. pneumoniae were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) surveillance study. For the same dose level, the 3-h infusion provided a probability of target attainment (PTA) ≥90 % for minimum inhibitory concentration (MIC) values up to two-fold dilution higher than those obtained with the 0.5-h infusion. For E. coli, the cumulative fraction of response (CFR) was 100 % in most cases, and neither the dose nor the infusion length nor the geographical area significantly affected the probability to reach the target. With regards to K. pneumoniae, the CFR increased when increasing the dose and decreasing the creatinine clearance (CLCR). The CFR for Spanish and USA strains was higher than that calculated for European strains. Meropenem PK/PD breakpoints are dependent on the dose, infusion length and CLCR, ranging from 2 to 32 mg/L. Based on our results, meropenem administered as a extended infusion is the best option to treat infections due to E. coli and K. pneumoniae.

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.

OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ±â€Š0.23 L/h/kg and 0.30 ±â€Š0.17 L/kg, respectively. Half-life was 1.11 ±â€Š0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.

Efficacy and safety of biapenem against lower respiratory tract infections in elderly Chinese patients and optimal dosing regimen based on pharmacokinetic/pharmacodynamic analysis.

The present study evaluated the efficacy and safety of biapenem in elderly Chinese patients with lower respiratory tract infections (LRTIs) and proposed optimal dosage regimen on the basis of pharmacokinetic/pharmacodynamic (PK/PD) analysis. The clinical efficacy, bacterial eradication and comprehensive therapeutic effect rates of biapenem were 70.3 (78/111), 68.5 (37/54) and 61.1% (33/54), respectively. Drug-related adverse reactions were seen in 12.6% of patients (14/111). The total protein level, Acute Physiology and Chronic Health Evaluation (APACHE) II score, %fT>MIC, fAUC24/MIC and fCmax/MIC values of patients had significant impacts (P < 0.05) on clinical and bacteriological efficacy. However, logistic regression analysis showed that only %fT>MIC independently influenced comprehensive therapeutic effect (P < 0.01, odds ratio = 1.064). The cut-off value for predicting comprehensive therapeutic effect using %fT>MIC was 75.0%; the sensitivity and specificity were 87.9 and 85.7%, respectively. Monte Carlo simulations revealed that the usual dosage regimen (300 mg every 12 hours, 0.5 hour infusion) was considered to be insufficient to obtain satisfactory therapeutic outcomes against low susceptible pathogens for elderly Chinese patients with LRTIs (CLcr = 70 ml/min).

Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications.

VIM-producing Klebsiella pneumoniae isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The in vitro antibacterial activity of meropenem against one WT and three VIM-producing K. pneumoniae clinical isolates (median MICs 0.031, 8, 16 and 128 mg l- 1) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The in vitro PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The in vitro model was correlated with the in vivo data, with log10CFU/ml reduction of < 1 for the VIM-producing (MIC 16 mg l- 1) and >2 for the WT (MIC 0.031 mg l- 1) isolates, with %f T >MIC 25 and 100%, respectively. The in vitro bactericidal activity for all isolates was associated with 40 % f T>MIC and attained in >90% of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l- 1. For isolates with MICs of 2-8 mg l- 1, prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3-6 g) are required. For isolates with a MIC of 16 mg l- 1 the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing K. pneumoniae isolates.

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.

Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m(2)). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.).

Evaluation of a pharmacokineticpharmacodynamic approach using software to optimize the carbapenem antibiotic regimen.

OBJECTIVE: Meropenem (MEPM) and doripenem (DRPM), whose antipseudomonal activity is more potent than that of other carbapenem antimicrobials, were used in the study. Monte Carlo simulation of drug concentrations was performed to develop an administration plan for MEPM and DRPM that takes into account the pharmacokinetics (PK)-pharmacodynamics (PD) of MEPM and DRPM and the renal function of each patient. Drug administration plans were proactively applied to patients with pneumonia to determine the usefulness of the method by assessing treatment efficacy and safety. METHODS: Patients with healthcareassociated pneumonia and an indication for MEPM or DRPM chemotherapy underwent drug administration in accordance with the MEPM and DRPM treatment plan developed by the PK-PD software applications. The primary efficacy endpoints were the clinical and bacteriological efficacy of the drugs agains pneumonia. The safety of the antimicrobials was assessed based on abnormal laboratory findings and the seizure disorders in accordance with the criteria for safety evaluation of antimicrobial agents. RESULTS: This study examined 12 and 11 patients in the MEPM and DRPM group, respectively; however, 3 DRPM patients were excluded due to the administration of anti-methicillin-resistant Staphylococcus aureus drugs after the initiation of DRPM treatment. MEPM and DRPM drug administration was determined to be safe and effective in all patients. CONCLUSIONS: The present results suggest that the Monte Carlo simulation-based PK-PD software is an effective tool for planning individualized antimicrobial chemotherapy with carbapenem in accordance with the PK-PD theory of antimicrobials. It is also possible to propose safe and effective drug administration plans for patients with healthcare-associated pneumonia.