DOSE-EXPOSURE SIMULATION FOR PIPERACILLIN-TAZOBACTAM DOSING STRATEGIES IN INFANTS AND YOUNG CHILDREN
Main Article Content
Keywords
modeling and simulation, pharmacokinetics, pharmacodynamics, piperacillin-tazobactam, children
Abstract
Background: Extended piperacillin-tazobactam (TZP) infusions have been associated with favorable outcomes. There are currently no pediatric dosing recommendations.
Objective: To determine appropriate TZP dosing strategies in children 2 months – 6 years according to age and different minimal inhibitory concentrations (MICs).
Methods: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 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: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ? 90% at MICs ? 16 mg/L. Standard 0.5h infusions reached PTAs ? 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ? 90% for MICs ? 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m.
Conclusion: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ? 90%.
References
1. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis. Pediatr Crit Care Med 2013;14(7):6 86–93.
2. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. American journal of respiratory and critical care medicine. 2003;167(5):69 5–701.
3. Ruth A, McCracken CE, Fortenberry JD, et al. Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatr Crit Care Med 2014;15(9):8 28–38.
4. Ames SG, Workman JK, Olson JA, et al. Infectious etiologies and patient outcomes in pediatric septic shock. J Pediatr Infect Dis Soc 2017 Mar 1;6(1):80–86. doi: 10.1093/jpids/p iv108.
5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Int Care Med 2013;39(2):16 5–228.
6. Fusco NM, Parbuoni KA, Morgan JA. Time to first antimicrobial administration after onset of sepsis in critically ill children. The journal of pediatric pharmacology and therapeutics: JPPT 2015;20(1): 37–44.
7. Wolf MF, Simon A. The use of piperacillin-tazobactam in neonatal and paediatric patients. Exp Opin Drug Metab Toxicol 2009;5(1): 57–69.
8. Vogelman B, Gudmundsson S, Leggett J, et al. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988;158(4):8 31–47.
9. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nature Rev Microbiol 2004;2(4):28 9–300.
10. Logan LK, Braykov NP, Weinstein RA, Laxminarayan R. Extended-spectrum beta-lactamase-producing and third-generation cephalosporin-resistant enterobacteriaceae in children: Trends in the United States, 1999-2011. J Pediatr Infect Dis Soc 2014;3(4): 320–8.
11. McDonald LC. Trends in antimicrobial resistance in health care-associated pathogens and effect on treatment. Clin Infect Diseases 2006;42 Suppl 2:S 65–71.
12. Felton TW, Hope WW, Lomaestro BM, et al. Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections. Antimicrob Agents Chemother 2012;56(8):40 87–94.
13. Kim A, Sutherland CA, Kuti JL, Nicolau DP. Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy 2007;27(11):1 490–7.
14. Shea KM, Cheatham SC, Smith DW, et al. Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients. Ann Pharmacother 2009;43(11):17 47–54.
15. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Diseases 2014;58(8):10 72–83.
16. Abdul-Aziz MH, Lipman J, Akova M, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 2016;71(1):19 6–207.
17. Bao H, Lv Y, Wang D, Xue J, Yan Z. Clinical outcomes of extended versus intermittent administration of piperacillin/tazobactam for the treatment of hospital-acquired pneumonia: a randomized controlled trial. Eur J Clin Microbiol Infect Dis 2017;36(3):4 59–66.
18. Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent beta-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Medicine 2016;194(6):6 81–91.
19. 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 Diseas 2013;56(2):2 72–82.
20. Chant C, Leung A, Friedrich JO. Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis. Crit Care (London, England). 2013;17(6): R279.
21. Patel GW, Patel N, Lat A, et al. Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections. Diagnost Microbiol Infect Disease 2009;64(2):2 36–40.
22. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. BetaLactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intens Care Med 2016;42(10):1535–45.
23. Cutro SR, Holzman R, Dubrovskaya Y, et al. Extended infusion versus standard-infusion piperacillin-tazobactam for sepsis syndromes at a tertiary medical center. Antimicrob Agents Chemother 2014;58(8):4 470–5.
24. Cies JJ, Jain J, Kuti JL. Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia. Pediatr Blood Cancer 2015;62(3):4 77–82.
25. Cies JJ, Shankar V, Schlichting C, Kuti JL. Population pharmacokinetics of piperacillin/tazobactam in critically ill young children. Pediatr Infect Dis Journal 2014;33(2):1 68–73.
26. Cohen-Wolkowiez M, Watt KM, Zhou C, et al. Developmental pharmacokinetics of piperacillin and tazobactam using plasma and dried blood spots from infants. Antimicrob Agents Chemother 2014;58(5):28 56–65.
27. Courter JD, Kuti JL, Girotto JE, Nicolau DP. Optimizing bactericidal exposure for beta-lactams using prolonged and continuous infusions in the pediatric population. Pediatr Blood Cancer. 2009;53(3):3 79–85.
28. Nichols K, Chung EK, Knoderer CA, et al. Population Pharmacokinetics and pharmacodynamics of extended-infusion piperacillin and tazobactam in critically ill children. Antimicrob Agents Chemother 2015;60(1):5 22–31.
29. World Health Organization, Dietitians of Canada, Canadian Paediatric Society, The College of Family Physicians of Canada, Community Health Nurses of Canada. WHO Growth Charts for Canada. 2014.
30. Reed MD, Goldfarb J, Yamashita TS, Lemon E, Blumer JL. Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children. Antimicrob Agents Chemother 1994;38(12):28 17–26.
31. Taketomo C, Hodding J, Kraus D. Pediatric & Neonatal Dosage Handbook. 23rd ed. Hudson, OH Lexi-Comp, Inc.; 2016.
32. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26(1):1–10; quiz 1–2.
33. Inc S. Piperacillin and tazobactam (piperacillin sodium and tazobactam sodium) injection, powder, for solution. Bethesda, MD: National Library of Medicine; 2014.
34. Clinical Laboratory Standards Institute. Performance standard for antimicrobial susceptibility testing (CLSI M100-S26) 26th edition. Clinical Laboratory Standards Institute; 2016.
35. Gilbert DN, Chambers HF, Eliopoulos GM, Saag MS, Pavia AT. The Sanford Guide to Antimicrobial Therapy 2016: Antimicrobial Therapy; 2016.
36. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. LK P, CJ B, DW K, SS L, editors. Elk Grove Village, IL: Author; 2012.
37. Zhanel GG, Adam HJ, Baxter MR, et al. Antimicrobial susceptibility of 22746 pathogens from Canadian hospitals: results of the CANWARD 2007-11 study. J Antimicrob Chemother 2013;68 Suppl 1: i7–22.
38. Kliegman R SB, St.Geme J, Schor N, Behrman R. Nel-son Textbook of Pediatrics, 19th Edition Philadelphia, PA: Elsevier; 2011.
39. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013;56(2):2 36–44.
40. Taccone FS, Laterre PF, Dugernier T, et al. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care (London, England) 2010;14(4) : R126.
41. Udy AA, Roberts JA, Boots RJ, et al Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 2010;49(1):1–16.
2. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. American journal of respiratory and critical care medicine. 2003;167(5):69 5–701.
3. Ruth A, McCracken CE, Fortenberry JD, et al. Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatr Crit Care Med 2014;15(9):8 28–38.
4. Ames SG, Workman JK, Olson JA, et al. Infectious etiologies and patient outcomes in pediatric septic shock. J Pediatr Infect Dis Soc 2017 Mar 1;6(1):80–86. doi: 10.1093/jpids/p iv108.
5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Int Care Med 2013;39(2):16 5–228.
6. Fusco NM, Parbuoni KA, Morgan JA. Time to first antimicrobial administration after onset of sepsis in critically ill children. The journal of pediatric pharmacology and therapeutics: JPPT 2015;20(1): 37–44.
7. Wolf MF, Simon A. The use of piperacillin-tazobactam in neonatal and paediatric patients. Exp Opin Drug Metab Toxicol 2009;5(1): 57–69.
8. Vogelman B, Gudmundsson S, Leggett J, et al. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988;158(4):8 31–47.
9. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nature Rev Microbiol 2004;2(4):28 9–300.
10. Logan LK, Braykov NP, Weinstein RA, Laxminarayan R. Extended-spectrum beta-lactamase-producing and third-generation cephalosporin-resistant enterobacteriaceae in children: Trends in the United States, 1999-2011. J Pediatr Infect Dis Soc 2014;3(4): 320–8.
11. McDonald LC. Trends in antimicrobial resistance in health care-associated pathogens and effect on treatment. Clin Infect Diseases 2006;42 Suppl 2:S 65–71.
12. Felton TW, Hope WW, Lomaestro BM, et al. Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections. Antimicrob Agents Chemother 2012;56(8):40 87–94.
13. Kim A, Sutherland CA, Kuti JL, Nicolau DP. Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy 2007;27(11):1 490–7.
14. Shea KM, Cheatham SC, Smith DW, et al. Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients. Ann Pharmacother 2009;43(11):17 47–54.
15. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Diseases 2014;58(8):10 72–83.
16. Abdul-Aziz MH, Lipman J, Akova M, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 2016;71(1):19 6–207.
17. Bao H, Lv Y, Wang D, Xue J, Yan Z. Clinical outcomes of extended versus intermittent administration of piperacillin/tazobactam for the treatment of hospital-acquired pneumonia: a randomized controlled trial. Eur J Clin Microbiol Infect Dis 2017;36(3):4 59–66.
18. Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent beta-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Medicine 2016;194(6):6 81–91.
19. 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 Diseas 2013;56(2):2 72–82.
20. Chant C, Leung A, Friedrich JO. Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis. Crit Care (London, England). 2013;17(6): R279.
21. Patel GW, Patel N, Lat A, et al. Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections. Diagnost Microbiol Infect Disease 2009;64(2):2 36–40.
22. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. BetaLactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intens Care Med 2016;42(10):1535–45.
23. Cutro SR, Holzman R, Dubrovskaya Y, et al. Extended infusion versus standard-infusion piperacillin-tazobactam for sepsis syndromes at a tertiary medical center. Antimicrob Agents Chemother 2014;58(8):4 470–5.
24. Cies JJ, Jain J, Kuti JL. Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia. Pediatr Blood Cancer 2015;62(3):4 77–82.
25. Cies JJ, Shankar V, Schlichting C, Kuti JL. Population pharmacokinetics of piperacillin/tazobactam in critically ill young children. Pediatr Infect Dis Journal 2014;33(2):1 68–73.
26. Cohen-Wolkowiez M, Watt KM, Zhou C, et al. Developmental pharmacokinetics of piperacillin and tazobactam using plasma and dried blood spots from infants. Antimicrob Agents Chemother 2014;58(5):28 56–65.
27. Courter JD, Kuti JL, Girotto JE, Nicolau DP. Optimizing bactericidal exposure for beta-lactams using prolonged and continuous infusions in the pediatric population. Pediatr Blood Cancer. 2009;53(3):3 79–85.
28. Nichols K, Chung EK, Knoderer CA, et al. Population Pharmacokinetics and pharmacodynamics of extended-infusion piperacillin and tazobactam in critically ill children. Antimicrob Agents Chemother 2015;60(1):5 22–31.
29. World Health Organization, Dietitians of Canada, Canadian Paediatric Society, The College of Family Physicians of Canada, Community Health Nurses of Canada. WHO Growth Charts for Canada. 2014.
30. Reed MD, Goldfarb J, Yamashita TS, Lemon E, Blumer JL. Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children. Antimicrob Agents Chemother 1994;38(12):28 17–26.
31. Taketomo C, Hodding J, Kraus D. Pediatric & Neonatal Dosage Handbook. 23rd ed. Hudson, OH Lexi-Comp, Inc.; 2016.
32. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26(1):1–10; quiz 1–2.
33. Inc S. Piperacillin and tazobactam (piperacillin sodium and tazobactam sodium) injection, powder, for solution. Bethesda, MD: National Library of Medicine; 2014.
34. Clinical Laboratory Standards Institute. Performance standard for antimicrobial susceptibility testing (CLSI M100-S26) 26th edition. Clinical Laboratory Standards Institute; 2016.
35. Gilbert DN, Chambers HF, Eliopoulos GM, Saag MS, Pavia AT. The Sanford Guide to Antimicrobial Therapy 2016: Antimicrobial Therapy; 2016.
36. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. LK P, CJ B, DW K, SS L, editors. Elk Grove Village, IL: Author; 2012.
37. Zhanel GG, Adam HJ, Baxter MR, et al. Antimicrobial susceptibility of 22746 pathogens from Canadian hospitals: results of the CANWARD 2007-11 study. J Antimicrob Chemother 2013;68 Suppl 1: i7–22.
38. Kliegman R SB, St.Geme J, Schor N, Behrman R. Nel-son Textbook of Pediatrics, 19th Edition Philadelphia, PA: Elsevier; 2011.
39. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013;56(2):2 36–44.
40. Taccone FS, Laterre PF, Dugernier T, et al. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care (London, England) 2010;14(4) : R126.
41. Udy AA, Roberts JA, Boots RJ, et al Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 2010;49(1):1–16.
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Aug 31, 2017
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Thibault, C., Kassir, N., Théorêt, Y., Varin, F., Litalien, C., & Autmizguine, J. (2017). DOSE-EXPOSURE SIMULATION FOR PIPERACILLIN-TAZOBACTAM DOSING STRATEGIES IN INFANTS AND YOUNG CHILDREN. Journal of Population Therapeutics and Clinical Pharmacology, 24(3), e33-e44. https://doi.org/10.15586/jptcp.v24i3.17
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