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Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

ABSTRACT: BACKGROUND:Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. METHODS:To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to ? (AUCss,0-?) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-? and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-? and Cmaxss were reported. RESULTS:We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median (interquartile range) piperacillin dose was 225?mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUCss,0-? and Cmaxss) and clinical and laboratory AEs. CONCLUSIONS:We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.

SUBMITTER: Salerno S

PROVIDER: S-EPMC5555808 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

Salerno Sara S Hornik Christoph P CP Cohen-Wolkowiez Michael M Smith P Brian PB Ku Lawrence C LC Kelly Matthew S MS Clark Reese R Gonzalez Daniel D

The Pediatric infectious disease journal 20170901 9

<h4>Background</h4>Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking.<h4>Methods</h4>To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed ...[more]

PMID: 28410277

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Project description:Background and objectivesCurrent recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions.Design, setting, participants, & measurementsA multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters.ResultsForty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h(-1), intraquartile range=0.052 h(-1)) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered.ConclusionsThere is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.

Project description:We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using anin vitroinfection model and the same isogenic CTX-M-15-producingEscherichia colitriplet set genetically engineered to transcribe different levels ofblaCTX-M-15, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different ?-lactam agent, or differentblaCTX-M-15transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 ?g/ml for the low-, moderate-, and high-level CTX-M-15-producingE. colistrains, respectively. The MIC value for piperacillin in the presence of 4 ?g/ml of tazobactam was 2 ?g/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of ?-lactamase transcription (r(2)= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 ?g/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2)= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log10-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a ?-lactam-?-lactamase inhibitor combination is dependent on the amount of ?-lactamase produced. These data provide important information for the development of ?-lactam-?-lactamase inhibitor combination agents.

Project description:Infection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of ?-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT.We conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 ?g/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate.Sixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ?45% target attainment, whereas 12 g/d was associated with ?95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion.Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

Dataset Information

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

Publications

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

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