Population Pharmacokinetics of Piperacillin/Tazobactam in Critically Ill Young Children

Cies, Jeffrey J.; Shankar, Venkat; Schlichting, Christine; Kuti, Joseph L.

doi:10.1097/inf.0b013e3182a743c7

Cited by 66 publications

(107 citation statements)

References 32 publications

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“…43 Despite increasing appreciation of this phenomenon, scarce data are available in children receiving β-lactam antibiotics. 14,40,44 In our study population clearance values higher than expected were observed in some patients with observed individual piperacillin clearances up to 0.35 L/h/kg. We hypothesize that such an apparent variation in clearance results from an increase in renal blood flow, leading to hyperfiltration in those patients with sepsis.…”

Section: Discussionmentioning

confidence: 90%

“…14 These findings of underdosing are consistent with previously reported exposure data in critically ill children of the same age. 14,15 For the treatment of Pseudomonas infections, no clear-cut fT>CT target values are available for tazobactam, in combination with piperacillin. Therefore, we performed a PTA analysis appraising different targets (20-60-80% fT>CT) (Figure S1, S2).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, while the relationship between markers of renal function is plausible and expected, variations in drug clearances in this group of patients were captured primarily by body weight and the maturation function, which is in agreement with findings from previous studies in critically ill children. 14,15 Cystatin C is a low molecular weight protein which is completely filtered through the glomeruli, rendering it a promising biomarker for measuring Glomerular Filtration Rate (GFR) in children. Recently, it was found to predict elimination of the renally cleared amoxicillin/clavulanic acid with a similar covariate model as ours, in a comparable population PK study in critically ill children (n=50 patients).…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] To date, the pharmacokinetics of piperacillin/tazobactam have been described in (pre)term neonates and non-ICU children, but only in a small number of children admitted to the paediatric ICU (n=13 and n=12 patients), between 1 and 9 years of age. 7,[11][12][13][14][15] Any effort to define the dose rationale in infants and young children needs to account for the effect of developmental processes, which are known to affect drug exposure and potentially treatment response. 16 Moreover, the impact of pathophysiological changes on pharmacokinetics has been widely demonstrated in critically ill adults.…”

Section: Introductionmentioning

confidence: 99%

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Dose optimization of piperacillin/tazobactam in critically ill children

Cock¹,

Dijkman

Jaeger

et al. 2017

Journal of Antimicrobial Chemotherapy

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Running title: Paediatric piperacillin/tazobactam dose rationale SynopsisObjectives. The aim of this study was to characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.Patients and Methods. This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg q6h based on piperacillin). Piperacillin/tazobactam concentrations were measured by a liquid chromatography-tandem mass spectrometry method. Pharmacokinetic data was analysed using nonlinear mixed effects modelling.Results. Piperacillin and tazobactam blood samples were collected from 47 patients (median age: 2.83 years; range: 2 months -15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model which included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 L/h and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) q4h over 2 hours, 100 mg/kg q4h given over 1 hour or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24h were minimally required to achieve the therapeutic targets for piperacillin (60 % fT>MIC>16 mg/L). Conclusion. Standard intermittent dosing regimens do not ensure optimalpiperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dose optimization of piperacillin/tazobactam in critically ill children

Cock¹,

Dijkman

Jaeger

et al. 2017

Journal of Antimicrobial Chemotherapy

View full text Add to dashboard Cite

show abstract

“…A complete review of experience with these dosing strategies in adults is beyond the scope of this report. While adoption of these dosing strategies has become increasingly common in the adult population, there remain limited data in children regarding efficacy, safety, and prevalence [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Optimized Antimicrobial Dosing Strategies: A Survey of Pediatric Hospitals

2014

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Abstract:Background Extended-interval aminoglycoside (EIAG) and extended-and continuous-infusion β-lactam (EIBL and CIBL) dosing strategies are increasingly used in adults, but pediatric literature is limited. ObjectiveThe objective of this study was to describe the use of EIAG, EIBL, and CIBL dosing in pediatric hospitals in the USA. Study Design, Setting, and ParticipantsA national survey of children's hospitals was conducted. A single practitioner from each target hospital was identified through the Children's Hospital Association. Practice-based survey questions identified whether hospitals utilize EIAG, EIBL, and CIBL dosing. Main Outcome MeasureThe main outcome measure was the percentage utilization of the dosing strategies, with secondary outcomes being the reasons for not using these dosing strategies. ResultsSeventy-seven of 215 identified practitioners (36 %) participated in the survey. EIAG, EIBL, and CIBL dosing were utilized in 63 %, 24 %, and 13 % of responding hospitals, respectively. The most common reasons for not using EIAG were concern regarding lack of efficacy data (56 %) and concern regarding the duration of the drug-free period (41 %). Respondents who did not utilize EIBL cited concern due to lack of pediatric EIBL efficacy data (54 %), the need for more intravenous access (54 %), intravenous medication compatibility issues (39 %), and the time during which the patient is attached to an intravenous infusion (31 %). ConclusionThis survey of children's hospitals indicates that EIAG is used in over 50 % of hospitals, but there is some lag in adoption of EIBL and CIBL dosing, both of which are used in fewer than 25 % of hospitals.Additional studies may provide much-needed evidence to increase the utilization of these strategies.2

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Continuous infusion of piperacillin‐tazobactam significantly improves target attainment in children with cancer and fever

et al. 2021

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Background Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β‐lactam concentrations. Aims This study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin‐tazobactam, in order to optimize the dosing regimen. Methods This prospective PK study included children with cancer, aged 1–17 years, who were treated with piperacillin‐tazobactam for suspected or verified infection. A piperacillin‐tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high‐performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% f T > MIC) and 50% f T > 4xMIC. Results We included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1–54.0). A three‐compartment model adequately described the concentration‐time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% f T > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% f T > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses. Conclusion Unlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% f T > MIC to be reached for children with febrile neutropenia.

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Population Pharmacokinetics of Piperacillin/Tazobactam in Critically Ill Young Children

Cited by 66 publications

References 32 publications

Dose optimization of piperacillin/tazobactam in critically ill children

Dose optimization of piperacillin/tazobactam in critically ill children

Optimized Antimicrobial Dosing Strategies: A Survey of Pediatric Hospitals

Continuous infusion of piperacillin‐tazobactam significantly improves target attainment in children with cancer and fever

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