Jean Lavigne (1), Nastya Kassir (1), Céline Thibault (2,3,4,6), Catherine Litalien (2,3,4), Julie Autmizguine (2,3,4,5)
(1) Certara Strategic Consulting, Canada, (2) Department of Pediatrics, CHU Sainte-Justine, Montreal, Canada, (3) Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Canada, (4) Research Center, CHU Sainte-Justine, Montreal, Canada, (5) Department of Pharmacology and Physiology, Université of Montréal, Montreal, Canada, (6) Research Institute, Children's Hospital of Philadelphia, Philadelphia, USA
Introduction: Sepsis is one of the leading cause of morbidity and mortality in infants and children.[1,2] Sepsis treatment depends on early, effective antibiotic therapy,[3,4] but therapeutic efficacy is increasingly challenged by antibiotic resistance.[5] Piperacillin-tazobactam efficacy depends on achieving appropriate drug concentrations in the body. Similar to other β-lactam antibiotics, piperacillin exerts bactericidal activity in a time-dependent manner.[6] Consequently, piperacillin is most effective when the free (unbound to plasma protein) drug concentration exceeds the pathogen’s minimal inhibitory concentration (MIC) for at least 50% of dosing interval (50% fT > MIC).[6] Time over MIC is therefore the pharmacodynamic (PD) parameter serving as a surrogate target for efficacy.[6]
Objectives: The objectives of the current analysis were 1) to describe the population pharmacokinetics (PK) of piperacillin-tazobactam, 2) to establish extended-infusion piperacillin-tazobactam dosing recommendations in infants and young children 2 months to 6 years of age with normal renal function for the treatment of sepsis caused by bacteria with decreased susceptibility to piperacillin-tazobactam, and 3) to provide dosing recommendations according to different levels of antibiotic susceptibility.
Methods: Piperacillin-tazobactam is a combination with a fixed ratio of 8:1. This was a single-center prospective pharmacokinetic study. Piperacillin-tazobactam was administrated intravenously (IV) with a dose of 80 mg/kg of piperacillin every 6 hours infused over 2 hours for infants 2 to 5 months old, and 90 mg/kg of piperacillin every 8 hours infused over 4 hours for children 6 months to 6 years of age. A total of 79 children with 165 and 163 samples of piperacillin and tazobactam, respectively, were included in the analysis. Population PK analysis was performed using nonlinear mixed effect[7] and sources of variability (body weight, sex, age, race, ethnicity, markers of liver/kidney function, concomitant medication, hospital unit) were explored using a stepwise covariate analysis[8]. Simulations were performed to support dosing of piperacillin-tazobactam in children. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 32 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal.
Results: Both piperacillin and tazobactam were best described with a 2 compartment PK model with linear elimination. Weight (WT), albumin (ALB) and concomitant furosemide use were significant covariates in the piperacillin PK model. Typical clearance (CL), distribution clearance (CLd), central volume of distribution (Vc) and peripheral volume of distribution (Vp) were 4.53 L/h, 133 L/h, 2.19 L, and 2.00 L, respectively [for child with WT of 11.4 kg, ALB of 29 g/L and not taking furosemide as concomitant medication]. Typical CL, CLd, Vc, and Vp of tazobactam were 2.88 L/h, 1.04 L, 8.10 L/h and 1.66 L, respectively [for child with WT of 11.4 kg, and ALB of 29 g/L]. Piperacillin and tazobactam elimination half-life were 0.646 and 0.744 h, respectively. Simulations were done using MICs of 4, 8, 16 and 32 mg/L in 3 age groups: 2-11 months, 12-23 months, and 2-6 years. PTAs increased as age increased. Among the tested dosing regimens, 100 mg/kg/dose every 4h infused over 2h reached the optimal PD target at MICs of 4 mg/L and 8 mg/L in all age groups and PTAs at MICs of 16 mg/L and 32 mg/L were 85% and 60-69%, respectively.
Conclusions: Both piperacillin and tazobactam exposure were affected by weight. Concomitant furosemide use increased piperacillin exposure possibly due to competition of tubular secretion. The recommended piperacillin dosing is 100 mg/kg IV over 2 h at every 4 h.
References:
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[2] Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. American journal of respiratory and critical care medicine. Mar 1 2003; 167(5):695-701.
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[6] Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nature reviews. Microbiology. Apr 2004;2(4):289-300.
[7] Beal SL et al. 1989-2013. NONMEM Users Guides. Icon Development Solutions, Hanover, Maryland, USA.
[8] Jonsson EN and Karlsson MO. Automated Covariate Model Building Within NONMEM.
Pharm Res 1998 15(9): 1463-8.
Reference: PAGE 28 (2019) Abstr 9190 [www.page-meeting.org/?abstract=9190]
Poster: Drug/Disease Modelling - Paediatrics