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BackgroundSevere bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application.MethodsA prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T>MIC, 50%T>4×MIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment.ResultsLarge inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T>MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T>4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment).ConclusionsThe investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.Trial registrationClinicaltrials.gov, NCT01793012. Registered on 24 January 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1829-4) contains supplementary material, which is available to authorized users.

Objectives: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. Methods: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600e1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices.Results: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0e44.9%). Both factors caused lower area under the concentrationetime curve in typical obese patients in plasma (e20.4%, 95% CI e22.0% to e15.9%) and at target-site (e37.7%, 95% CI e47.1% to e24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900-and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) 2 mg/L (probability of target attainment 62.5e100%) but could not be reached for MIC ¼ 4 mg/L (probability of target attainment 82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. Discussion: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC 2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Background Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. Methods We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m 2 for obese or between 18.5 and 30 kg/m 2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0–8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC 0-8 ) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. Discussion Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. Trial registration EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776);

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used f AUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m 2 ) and 15 non-obese (23.9 ± 2.1 kg/m 2 ) patients were analyzed. AUC 0-8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.