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Objectives To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population. Methods A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration–time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients. Results For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants. Conclusions Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.

Background Standard dosing regimens of meropenem and piperacillin-tazobactam frequently fail to achieve targeted plasma concentrations in critically ill patients. Extended or continuous regimens are often used to improve target attainment. Although prompt antibiotic initiation is a major determinant of survival, few studies have reported systemic concentrations early after treatment initiation. No prior study has reported concentrations immediately after the loading dose and first extended infusion. This study aimed to evaluate plasma target attainment during the first dosing interval with an extended infusion regimen in a general intensive care unit (ICU). Methods Adult ICU patients were prospectively included in conjunction with the first administration of meropenem or piperacillin-tazobactam. Treatment was initiated with a 0.5 h loading dose immediately followed by a 3 h extended infusion; typically 4 + 4 g piperacillin or 1(− 2)g + 1(− 2)g meropenem, in line with the local ICU protocol. Patients requiring renal replacement therapy were excluded. Plasma concentrations were measured post-loading dose (C max ), near the end of the first extended infusion, and at the end of the first dosing interval (C min ). Samples were analyzed using validated tandem mass spectrometry (UHPLC-MS/MS) methods. The primary endpoint was the proportion of patients achieving 100% time above minimum inhibitory concentrations ( f T > MIC) during the first dosing interval. This was evaluated using observed C min above 2 mg/L (meropenem) and 20 mg/L (piperacillin). Additionally, published pharmacokinetic models were applied to the observed data for %fT > MIC estimation, using an a posteriori Bayesian approach. Results We included 65 meropenem and 142 piperacillin measurements from 22 and 48 patients, respectively. Many patients (45% meropenem, 38% piperacillin) failed to reach 100% f T > MIC with the standard regimens used. Target non-attainment was associated with high estimated glomerular filtration rates (eGFR) and suspected augmented renal clearance (ARC). All meropenem patients that failed to reach target had eGFR > 90 mL/min/1.73 m 2 , as did 76% of corresponding piperacillin patients. Patients with suspected ARC frequently exhibited a tenfold or greater peak-to-trough decline (C min /C max  < 0.1). Conclusions Despite aggressive dosing, plasma concentrations often fail to reach 100% f T > MIC during the first dosing interval. Alternative regimens and early plasma concentration measurements followed by adaptive dose adjustments should be considered to improve target attainment.

Background: The antibacterial effect of piperacillin/sulbactam depends on the time of drug concentration above the minimal inhibitory concentration (MIC). Therefore, continuous infusion (CI) may be a more rational approach than standard intermittent short-term infusion (SI). The study investigated whether CI achieves effective drug concentrations comparable with SI. Methods: Seven intensive care unit patients received either piperacillin/sulbactam as 4/1 g intravenous infusion over 15–20 min every 8 h or as 4/1 g intravenous loading dose (15–20 min) followed by 8/2 g intravenous CI per 24 h. After 2 days, regimes were crossed over. Results: Pharmacokinetic parameters (mean ± SD) for SI piperacillin/sulbactam were: (1) peak serum concentration: piperacillin 231 ± 66 mg/l, sulbactam 53.1 ± 15.0 mg/l; (2) minimum serum concentration: piperacillin 11.5 ± 14.8 mg/l, sulbactam 4.2 ± 3.5 mg/l; (3) clearance: piperacillin 197 ± 72 ml/min (CI 269 ± 123 ml/min), sulbactam 167 ± 61 ml/min (CI 212 ± 109 ml/min); (4) half-life: piperacillin 2.4 ± 1.2 h, sulbactam 3.1 ± 1.6 h. Steady-state concentrations during CI were 25.5 ± 14.5 mg/l for piperacillin and 8.0 ± 3.7 mg/l for sulbactam. Average serum concentrations were comparable in both regimens. Conclusion: A large German survey demonstrated that approximately 89% of Pseudomonas aerugionsa have an MIC ≤16 mg/l and approximately 82% have an MIC ≤8 mg/l. According to this threshold, appropriate anti-bacterial concentrations of piperacillin/sulbactam were achievable with CI. CI dosing has the additional advantage that less drug is necessary. Further prospective studies are warranted to compare the clinical efficacy of CI and SI regimens in bacterial infections.

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients’ outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml −1 ) from only 1 µl of serum. The system’s applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

In critical burn patients, the pharmacokinetic parameters (absorption, distribution, metabolism, and excretion) of many classes of drugs, including antibiotics, are altered. The aim of this study was to compare 2 groups of burn patients undergoing treatment for health care–associated infections with and without therapeutic drug monitoring. A retrospective analysis of a clinical intervention (ie, a before/after study) was conducted with patients with health care–associated pneumonia, burn infection, bloodstream infection, and urinary tract infection in the burn intensive care unit of a tertiary care hospital. The patients were divided into 2 groups: (1) those admitted from May 2005 to October 2008 who received conventional antimicrobial dose regimens; and (2) those admitted from November 2008 to June 2011 who received antibiotics (imipenem, meropenem, piperacillin, and vancomycin) with doses adjusted according to plasma monitoring and pharmacokinetic modeling. General characteristics of the groups were analyzed, as were clinical outcomes and 14-day and in-hospital mortality. Sixty-three patients formed the conventional treatment group, and 77 comprised the monitored treatment group. The groups were homogeneous, median age was 31 years (range: 1–90) and 66% were male. Improvement occurred in 60% of the patients under monitored treatment (vs 52% with conventional treatment); 14-day mortality was 16% vs 14%; and the in-hospital mortality was similar between groups (39% vs 36%). In the final multivariate models, variables significantly associated with in-hospital mortality were total burn surface area ≥30%, older age, and male sex. Treatment group did not affect the prognosis. Therapeutic drug monitoring of antimicrobial treatment did not alter the prognosis of these burn patients. More trials are needed to support the use of therapeutic drug monitoring to optimize treatment in burn patients.

The purpose of this study is to review the rationale of prolonged (ie, extended or continuous) infusion of piperacillin/tazobactam (PIP/TAZ) in critically ill patients and to perform a systematic review that compare the effectiveness of prolonged infusion with intermittent bolus of PIP/TAZ. A search of Medline, Web of Science, Embase, and Cochrane databases was conducted up to April 2014. For systematic review, studies comparing the effectiveness of prolonged and bolus administration of PIP/TAZ were included. The level of evidence is determined using best-evidence synthesis, which consisted of 5 possible levels of evidence: strong, moderate, limited, conflicting, or no evidence. The pharmacokinetic/pharmacodynamic studies that account for an eventual benefit of prolonged PIP/TAZ infusion were reviewed. In the systematic review, 1 randomized controlled trial was identified that showed higher “cure” in the prolonged than in the intermittent infusion group, yet the chosen clinical outcome in this study, decline in mean Acute Physiology and Chronic Health Evaluation II score is controversial. Of 6 retrospective cohort studies, 4 showed either less mortality, a higher clinical cure rate, or shorter length of hospital stay with prolonged PIP/TAZ treatment. The level of evidence supporting a better clinical outcome with prolonged infusion of PIP/TAZ is moderate. Pharmacokinetic/pharmacodynamic studies provide a robust rationale to prefer prolonged above intermittent infusion of PIP/TAZ. However, although some studies suggest a better outcome in critically ill patients receiving prolonged infusion, the level of evidence is moderate.

ObjectiveTo evaluate the predictive performance of population pharmacokinetic models for piperacillin (PIP) available in the software MwPharm, TDMx and ID-ODs for initial dosing selection and therapeutic drug monitoring (TDM) purposes.MethodsThis is a prospective observational study in adult patients with severe infections receiving PIP treatment. Plasma concentrations were quantified by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The differences between predicted and observed PIP concentrations were evaluated with Bland-Altman plots; additionally, the relative and absolute bias and precision of the models were determined.ResultsA total of 145 PIP plasma concentrations from 42 patients were analysed. For population prediction, MwPharm showed the best predictive performance with a mean relative difference of 34.68% (95% CI −197% to 266%) and a root mean square error (RMSE) of 60.42 µg/mL; meanwhile TDMx and ID-ODs under-predicted PIP concentrations. For individual prediction, the TDMx model was found to be the most precise with a mean relative difference of 7.61% (95% CI −57.63 to 72.86%), and RMSE of 17.86 µg/mL.ConclusionCurrent software for TDM is a valuable tool, but it may also include different population pharmacokinetic models in patients with severe infections, and should be evaluated before performing a model-based TDM in clinical practice. Considering the heterogeneous characteristics of patients with severe infections, this study demonstrates the need for therapy personalisation for PIP to improve pharmacokinetic/pharmacodynamic target attainment.

Therapeutic drug monitoring is a cornerstone of antibacterial therapy, especially in an era of increasing antibacterial resistance in individualizing antimicrobial therapy. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay was used for the simultaneous measurement of piperacillin, tazobactam, meropenem, ceftazidime, and linezolid in 50 μl plasma samples over a wide range. The overall turnaround time for the assay was 20 minutes. Intra-assay precision and accuracy for quality control samples ranged within 1·8-8·5 and 91·4-106·7%, respectively. Inter-assay precision and accuracy ranged within 1·3-14·4 and 95·8-104·6%, respectively. The lower limit of quantification was below 1·5 μg/ml for all the five antibiotics. No ion suppression due to matrix effects was found. A simple and rapid LC-MS/MS method which provides high specificity, precision and accuracy for the simultaneous quantification of piperacillin, tazobactam, meropenem, ceftazidime, and linezolid in human plasma has been developed and validated. The present method is suitable for therapeutic drug monitoring in paediatrics.