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Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance

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Abstract

Background

Critically ill children frequently display observed alterations of pharmacokinetic (PK) parameters, leading to a reduction in β-lactam concentrations. This study aimed to develop a PK population model for piperacillin in order to optimize individual dosing regimens.

Methods

All children aged ≤ 18 years, weighing more than 2.5 kg, and receiving piperacillin infusions were included in this study. Piperacillin was quantified by high-performance liquid chromatography, and PK were described using the non-linear mixed-effect modeling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimens in order to attain two PK targets: 50% fT>MIC and 100% fT>MIC.

Results

We included 50 children with a median (range) postnatal age of 2.3 years (0.1–18), body weight (BW) of 11.9 kg (2.7–50), Pediatric Logistic Organ Dysfunction-2 (PELOD-2) severity score of 4 (0–16), and estimated glomerular filtration rate (eGFR) of 142 mL.min−1.1.73 m−2 (29–675). A one-compartment model with first-order elimination adequately described the data. Median (range) values for piperacillin clearance (CL) and volume of distribution were 3 L.h−1 (0.71–10) and 0.33 L.kg−1 (0.21–0.86), respectively. BW was integrated with the allometric relationship. eGFR and PELOD-2 severity score were the covariates explaining between-subject variability in CL and volume, respectively. According to the simulations, extended and continuous infusion provided the highest probability of reaching the target of 50% fT>MIC and 100% fT>MIC for normal and augmented renal clearance, respectively.

Conclusions

Unlike standard intermittent piperacillin dosing regimens, extended and continuous infusion allows the PK targets to be reached, for children with normal or augmented renal clearance.

Trial Registration Number

Registered at http://www.clinicaltrials.gov (NCT02539407).

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References

  1. Amadeo B, Zarb P, Muller A, Drapier N, Vankerckhoven V, Rogues A-M, et al. European Surveillance of Antibiotic Consumption (ESAC) point prevalence survey 2008: paediatric antimicrobial prescribing in 32 hospitals of 21 European countries. J Antimicrob Chemother. 2010;65:2247–52.

    Article  CAS  Google Scholar 

  2. Blinova E, Lau E, Bitnun A, Cox P, Schwartz S, Atenafu E, et al. Point prevalence survey of antimicrobial utilization in the cardiac and pediatric critical care unit. Pediatr Crit Care Med. 2013;14:e280–8.

    Article  Google Scholar 

  3. Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H. The worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016;71:1106–17.

    Article  CAS  Google Scholar 

  4. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of “bug and drug”. Nat Rev Microbiol. 2004;2:289–300.

    Article  CAS  Google Scholar 

  5. Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015;70:3178–83.

    CAS  PubMed  Google Scholar 

  6. Mouton JW, Vinks AA. Continuous infusion of beta-lactams. Curr Opin Crit Care. 2007;13:598–606.

    Article  Google Scholar 

  7. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58:1072–83.

    Article  CAS  Google Scholar 

  8. Chen Y, Lu J, Dong M, Wu D, Zhu Y, Li Q, et al. Target attainment analysis and optimal sampling designs for population pharmacokinetic study on piperacillin/tazobactam in neonates and young infants. Eur J Clin Pharmacol. 2016;72:1479–88.

    Article  CAS  Google Scholar 

  9. Lau WK, Mercer D, Itani KM, Nicolau DP, Kuti JL, Mansfield D, et al. Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2006;50:3556–61.

    Article  CAS  Google Scholar 

  10. Aardema H, Nannan Panday P, Wessels M, van Hateren K, Dieperink W, Kosterink JGW, et al. Target attainment with continuous dosing of piperacillin/tazobactam in critical illness: a prospective observational study. Int J Antimicrob Agents. 2017;50:68–73.

    Article  CAS  Google Scholar 

  11. Thakkar N, Salerno S, Hornik CP, Gonzalez D. Clinical pharmacology studies in critically ill children. Pharm Res. 2017;34:7–24.

    Article  CAS  Google Scholar 

  12. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient: concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014;77:3–11.

    Article  CAS  Google Scholar 

  13. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37:840–51.

    Article  CAS  Google Scholar 

  14. De Cock PAJG, van Dijkman SC, de Jaeger A, Willems J, Carlier M, Verstraete AG, et al. Dose optimization of piperacillin/tazobactam in critically ill children. J Antimicrob Chemother. 2017;72:2002–11.

    Article  Google Scholar 

  15. Nichols K, Chung EK, Knoderer CA, Buenger LE, Healy DP, Dees J, et al. Population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin and tazobactam in critically ill children. Antimicrob Agents Chemother. 2016;60:522–31.

    Article  CAS  Google Scholar 

  16. Cies JJ, Shankar V, Schlichting C, Kuti JL. Population pharmacokinetics of piperacillin/tazobactam in critically ill young children. Pediatr Infect Dis J. 2014;33:168–73.

    Article  Google Scholar 

  17. Alobaid AS, Wallis SC, Jarrett P, Starr T, Stuart J, Lassig-Smith M, et al. Population pharmacokinetics of piperacillin in nonobese, obese, and morbidly obese critically ill patients. Antimicrob Agents Chemother. 2017;61:e01276.

    Article  CAS  Google Scholar 

  18. Tsai D, Stewart P, Goud R, Gourley S, Hewagama S, Krishnaswamy S, et al. Pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. Antimicrob Agents Chemother. 2016;60:7402–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, et al. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother. 2007;59:285–91.

    Article  CAS  Google Scholar 

  20. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8.

    Article  Google Scholar 

  21. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F. PELOD-2: an update of the PEdiatric Logistic Organ Dysfunction Score. Crit Care Med. 2013;41:1761–73.

    Article  Google Scholar 

  22. Schwartz G, Brion L, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin N Am. 1987;34:571–90.

    Article  CAS  Google Scholar 

  23. European Committee on Antimicrobial Susceptibility Testing (EUCAST). Antimicrobial wild type distributions of microorganisms, piperacillin-tazobactam. https://mic.eucast.org/Eucast2/SearchController/search.jsp?action=performSearch&BeginIndex=0&Micdif=mic&NumberIndex=50&Antib=251&Specium=-1. Accessed 1 Apr 2018.

  24. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry, Bioanalytical method validation. https://www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdf. Accessed 1 Apr 2018.

  25. Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.

    Article  CAS  Google Scholar 

  26. Drug Bank. FDA Professional Drug Information. Piperacillin. https://www.drugs.com/pro/piperacillin-and-tazobactam.html. Accessed 1 Apr 2018.

  27. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP) assessment report pursuant to Article 30 of Directive 2001/83/EC, as amended for Tazocin and associated names (INN: piperacillin-tazobactam). http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Tazocin_30/WC500154789.pdf. Accessed 1 Apr 2018.

  28. Tornøe CW, Tworzyanski JJ, Imoisili MA, Alexander JJ, Korth-Bradley JM, Gobburu JVS. Optimising piperacillin/tazobactam dosing in paediatrics. Int J Antimicrob Agents. 2007;30:320–4.

    Article  Google Scholar 

  29. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24:67–76.

    Article  Google Scholar 

  30. Padgett D, Ostrenga A, Lepard L. Comparison of methods of estimating creatinine clearance in pediatric patients. Am J Health Syst Pharm. 2017;74:826–30.

    Article  Google Scholar 

  31. Filler G, Yasin A, Medeiros M. Methods of assessing renal function. Pediatr Nephrol. 2014;29:183–92.

    Article  Google Scholar 

  32. Nakhjavan-Shahraki B, Yousefifard M, Ataei N, Baikpour M, Ataei F, Bazargani B, et al. Accuracy of cystatin C in prediction of acute kidney injury in children; serum or urine levels: which one works better? A systematic review and meta-analysis. BMC Nephrol. 2017;17:120.

    Article  Google Scholar 

  33. Mian AN, Schwartz GJ. Measurement and estimation of glomerular filtration rate in children. Adv Chron Kidney Dis. 2017;24:348–56.

    Article  Google Scholar 

  34. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49:1–16.

    Article  CAS  Google Scholar 

  35. Avedissian SN, Bradley E, Zhang D, Bradley JS, Nazer LH, Tran TM, et al. Augmented renal clearance using population-based pharmacokinetic modeling in critically ill pediatric patients. Pediatr Crit Care Med. 2017;18:e388–94.

    Article  Google Scholar 

  36. Udy AA, Putt MT, Boots RJ, Lipman J. ARC—augmented renal clearance. Curr Pharm Biotechnol. 2011;12:2020–9.

    Article  CAS  Google Scholar 

  37. De Cock PAJG, Standing JF, Barker CIS, de Jaeger A, Dhont E, Carlier M, et al. Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children. Antimicrob Agents Chemother. 2015;59:7027–35.

    Article  Google Scholar 

  38. Lee B, Kim J, Park JD, Kang HM, Cho YS, Kim KS. Predicting augmented renal clearance using estimated glomerular filtration rate in critically-ill children. Clin Nephrol. 2017;88:148–55.

    Article  CAS  Google Scholar 

  39. Carlier M, Carrette S, Roberts JA, Stove V, Verstraete A, Hoste E, et al. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit Care. 2013;17:R84.

    Article  Google Scholar 

  40. Delvallée M, Mazingue F, Abouchahla W, Delebarre M, Wallet F, Courcol R, et al. Optimization of continuous infusion of piperacillin-tazobactam in children with fever and neutropenia. Pediatr Infect Dis J. 2013;32:962–4.

    Article  Google Scholar 

  41. Blondiaux N, Wallet F, Favory R, Onimus T, Nseir S, Courcol RJ, et al. Daily serum piperacillin monitoring is advisable in critically ill patients. Int J Antimicrob Agents. 2010;35:500–3.

    Article  CAS  Google Scholar 

  42. Conil J-M, Georges B, Mimoz O, Dieye E, Ruiz S, Cougot P, et al. Influence of renal function on trough serum concentrations of piperacillin in intensive care unit patients. Intensive Care Med. 2006;32:2063–6.

    Article  CAS  Google Scholar 

  43. Yang H, Cui X, Ma Z, Liu L. Evaluation outcomes associated with alternative dosing strategies for piperacillin/tazobactam: a systematic review and meta-analysis. J Pharm Sci. 2016;19:274–89.

    Google Scholar 

  44. Goldstein EJC, Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56:272–82.

    Article  Google Scholar 

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Acknowledgements

The authors thank the PICU team (physicians and nurses) that selected the children and collected the samples, making this work possible. They also thank the pharmacology laboratory of the Cochin Teaching Hospital, which analyzed the samples. Agathe Béranger received a grant from the Agence Régionale de Santé Ile-de-France for a 1-year research fellowship in the EA7323.

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Authors and Affiliations

  1. Unité de Recherche Clinique-Centre d’Investigation Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Agathe Béranger, Saïk Urien & Jean-Marc Tréluyer

  2. EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Université Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France

    Agathe Béranger, Sihem Benaboud, Saïk Urien, Déborah Hirt, Jean-Marc Tréluyer & Mehdi Oualha

  3. Service de pharmacologie clinique, Hôpital Cochin, Université Paris Descartes, Sorbonne-Paris Cité, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France

    Sihem Benaboud, Yi Zheng, Inès Gana, Déborah Hirt & Jean-Marc Tréluyer

  4. Service de réanimation et surveillance continue médico-chirurgicales, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Florence Moulin, Fabrice Lesage, Mathieu Genuini, Sylvain Renolleau & Mehdi Oualha

  5. Laboratoire de microbiologie, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Emmanuelle Bille

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  1. Agathe Béranger
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Corresponding author

Correspondence to Agathe Béranger.

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Conflict of interest

Agathe Béranger, Sihem Benaboud, Saïk Urien, Florence Moulin, Emmanuelle Bille, Fabrice Lesage, Yi Zheng, Mathieu Genuini, Inès Gana, Sylvain Renolleau, Déborah Hirt, Jean-Marc Tréluyer, and Mehdi Oualha declare no conflicts of interest.

Funding

The research study did not receive funds or support from any source.

Informed Consent

Informed consent was obtained from all parents of the children included in the study.

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40262_2018_682_MOESM1_ESM.tif

Probability of target attainment (100% fT>MIC in blue and 50% fT>MIC in green) according to our dosing regimen (DR), European (EMA) and American (FDA) assessments. (TIFF 1783 kb)

40262_2018_682_MOESM2_ESM.tiff

Probability of target attainment obtained from 1200 simulations for each body weight, for continuous infusion and a target defined as 100% fT>MIC. Four groups were defined according to renal function (a and c for augmented, and b and d for normal) and PELOD-2 severity score (a and b if < 5, and c and d if ≥ 5). Daily dosing regimens were defined according to renal function: 400 mg.kg−1.day−1 for augmented, 300 mg.kg−1.day−1 for normal. (TIFF 1341 kb)

40262_2018_682_MOESM3_ESM.tiff

Concentrations versus time courses for augmented renal clearance (eGFR > 130 mL.min−1.1.73 m−2), for PELOD-2 score < 5, depending on the different simulated administrations, for a daily dosing regimen of 400 mg.kg−1.day−1. The thick line depicts the median, the dashed lines are the 25th and 75th interquartile, and the dotted lines are the 95th confidence interval. The grey horizontal lines are the inferior (16 mg.L−1) and superior (150 mg.L−1) concentration targets, respectively. (TIFF 1565 kb)

40262_2018_682_MOESM4_ESM.tiff

Concentrations versus time courses for normal renal function (eGFR 40-130 mL.min−1.1.73 m−2), for PELOD-2 score < 5, depending on the different simulated administrations, for a daily dosing regimen of 300 mg.kg−1.day−1. The thick line depicts the median, the dashed lines are the 25th and 75th interquartile, and the dotted lines are the 95th confidence interval. The grey horizontal lines are the inferior (16 mg.L−1) and superior (150 mg.L−1) concentrations target, respectively. (TIFF 1565 kb)

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Béranger, A., Benaboud, S., Urien, S. et al. Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance. Clin Pharmacokinet 58, 223–233 (2019). https://doi.org/10.1007/s40262-018-0682-1

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