Antibiotic Dosing in Pediatric Critically Ill Patients

  • Pieter A. J. G. De Cock
  • Karel Allegaert
  • Matthew W. Linakis
  • Catherine M. T. Sherwin
Chapter
First Online:

Abstract

Despite being some of the most frequently utilized drugs in children, caregivers still commonly prescribe antibiotics in neonates and children based on dosing regimens linearly extrapolated from adults. Although this practice is not limited to antibiotics, specific concerns related to dosing inaccuracy for antibiotics are treatment failure, antimicrobial resistance, and maturational toxicity.

In this chapter, we first discuss the simultaneous impact of maturation and critical illness on pediatric pharmacokinetics (PK), including the specific impact of major burns and extracorporeal equipment. Both aspects (maturation and critical illness) will play a significant role in the final, phenotypic PK in a given child. Second, a section on pharmacodynamics (PD) focuses on the developmental safety of antibiotics. Developmental PD aspects may result in differences in risk rate, or altogether different risks compared to adult observations. Third, some compound-specific PK/PD observations (aminoglycosides, vancomycin, meropenem) in neonates and children are discussed to further illustrate the complex interaction between physiology and pathophysiology, including the limitations of the currently available guidance. In the final part of the chapter, the contribution of PK modeling and simulation and advanced therapeutic drug monitoring is explored as a tool towards tailored pharmacotherapy in pediatric critically ill patients.

Keywords

Pharmacokinetics Pharmacodynamics Antibiotics Pediatric intensive care Neonatal intensive care 

Abbreviations

ADME

Absorption, distribution, metabolism, elimination

AKI

Acute kidney injury

ARC

Augmented renal clearance

AUC

Area under the concentration time curve

Cmax

Maximal concentration, peak concentration

CPB

Cardiopulmonary bypass

CRRT

Continuous renal replacement therapy

ECMO

Extracorporeal membrane oxygenation

eGFR

Estimated glomerular filtration rate

F

Bioavailability

GA

Gestational age

GFR

Glomerular filtration rate

ICU

Intensive care unit

MIC

Minimal inhibitory concentration

NICU

Neonatal intensive care unit

PD

Pharmacodynamics

PICU

Pediatric intensive care unit

PK

Pharmacokinetics

PNA

Postnatal age

TDM

Therapeutic drug monitoring

Vd

Distribution volume

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References

  1. 1.
    Hsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin DK Jr, Smith PB (2014) Medication use in the neonatal intensive care unit. Am J Perinatol 31(9):811–821. doi: 10.1055/s-0033-1361933 PubMedCrossRefGoogle Scholar
  2. 2.
    Metsvaht T, Nellis G, Varendi H, Nunn AJ, Graham S, Rieutord A, Storme T, McElnay J, Mulla H, Turner MA, Lutsar I (2015) High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination. BMC Pediatr 15:41. doi: 10.1186/s12887-015-0359-y PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Johnson JK, Laughon MM (2016) Antimicrobial agent dosing in infants. Clin Ther 38(9):1948–1960. doi: 10.1016/j.clinthera.2016.06.017 PubMedCrossRefGoogle Scholar
  4. 4.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 349(12):1157–1167. doi: 10.1056/NEJMra035092 PubMedCrossRefGoogle Scholar
  5. 5.
    Manolis E, Pons G (2009) Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br J Clin Pharmacol 68(4):493–501. doi: 10.1111/j.1365-2125.2009.03484.x PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Coppini R, Simons SH, Mugelli A, Allegaert K (2016) Clinical research in neonates and infants: challenges and perspectives. Pharmacol Res 108:80–87. doi: 10.1016/j.phrs.2016.04.025 PubMedCrossRefGoogle Scholar
  7. 7.
    Thakkar N, Salerno S, Hornik CP, Gonzalez D (2017) Clinical pharmacology studies in critically ill children. Pharm Res 34(1):7–24. doi: 10.1007/s11095-016-2033-y PubMedCrossRefGoogle Scholar
  8. 8.
    Smits A, Kulo A, de Hoon JN, Allegaert K (2012) Pharmacokinetics of drugs in neonates: pattern recognition beyond compound specific observations. Curr Pharm Des 18(21):3119–3146PubMedCrossRefGoogle Scholar
  9. 9.
    Lopez-Herce J, Sanchez C, Carrillo A, Mencia S, Santiago MJ, Bustinza A, Vigil D (2006) Transpyloric enteral nutrition in the critically ill child with renal failure. Intensive Care Med 32(10):1599–1605. doi: 10.1007/s00134-006-0271-x PubMedCrossRefGoogle Scholar
  10. 10.
    Lopez-Herce J, Santiago MJ, Sanchez C, Mencia S, Carrillo A, Vigil D (2008) Risk factors for gastrointestinal complications in critically ill children with transpyloric enteral nutrition. Eur J Clin Nutr 62(3):395–400. doi: 10.1038/sj.ejcn.1602710 PubMedCrossRefGoogle Scholar
  11. 11.
    Rowland Yeo K, Aarabi M, Jamei M, Rostami-Hodjegan A (2011) Modeling and predicting drug pharmacokinetics in patients with renal impairment. Expert Rev Clin Pharmacol 4(2):261–274. doi: 10.1586/ecp.10.143 PubMedCrossRefGoogle Scholar
  12. 12.
    van Boekel GA, Aarnoutse RE, van der Heijden JJ, Hoogtanders KE, Hilbrands LB (2012) Effect of mild diarrhea on tacrolimus exposure. Transplantation 94(7):763–767. doi: 10.1097/TP.0b013e3182629e13 PubMedCrossRefGoogle Scholar
  13. 13.
    Mooij MG, de Koning BA, Huijsman ML, de Wildt SN (2012) Ontogeny of oral drug absorption processes in children. Expert Opin Drug Metab Toxicol 8(10):1293–1303. doi: 10.1517/17425255.2012.698261 PubMedCrossRefGoogle Scholar
  14. 14.
    Huang NN, High RH (1953) Comparison of serum levels following the administration of oral and parenteral preparations of penicillin to infants and children of various age groups. J Pediatr 42(6):657–658PubMedCrossRefGoogle Scholar
  15. 15.
    van den Anker JN, Schwab M, Kearns GL (2011) Developmental pharmacokinetics. Handb Exp Pharmacol 205:51–75. doi: 10.1007/978-3-642-20195-0_2 PubMedCrossRefGoogle Scholar
  16. 16.
    Woolsey CA, Coopersmith CM (2006) Vasoactive drugs and the gut: is there anything new? Curr Opin Crit Care 12(2):155–159. doi: 10.1097/01.ccx.0000216584.72427.e4 PubMedCrossRefGoogle Scholar
  17. 17.
    King W, Petrillo T, Pettignano R (2004) Enteral nutrition and cardiovascular medications in the pediatric intensive care unit. JPEN J Parenter Enteral Nutr 28(5):334–338PubMedCrossRefGoogle Scholar
  18. 18.
    Lopez-Herce J, Mencia S, Sanchez C, Santiago MJ, Bustinza A, Vigil D (2008) Postpyloric enteral nutrition in the critically ill child with shock: a prospective observational study. Nutr J 7:6. doi: 10.1186/1475-2891-7-6 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Dewez JE, Chellani HK, Halim A, van den Broek N (2015) Simplified antibiotic regimens for neonatal sepsis—AFRINEST. Lancet 386(10001):1337–1338. doi: 10.1016/s0140-6736(15)00330-x PubMedCrossRefGoogle Scholar
  20. 20.
    Lingvall M, Reith D, Broadbent R (2005) The effect of sepsis upon gentamicin pharmacokinetics in neonates. Br J Clin Pharmacol 59(1):54–61. doi: 10.1111/j.1365-2125.2005.02260.x PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, Eichler HG, Muller M (2001) Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 29(2):385–391PubMedCrossRefGoogle Scholar
  22. 22.
    Durward A, Mayer A, Skellett S, Taylor D, Hanna S, Tibby SM, Murdoch IA (2003) Hypoalbuminaemia in critically ill children: incidence, prognosis, and influence on the anion gap. Arch Dis Child 88(5):419–422PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Horowitz IN, Tai K (2007) Hypoalbuminemia in critically ill children. Arch Pediatr Adolesc Med 161(11):1048–1052. doi: 10.1001/archpedi.161.11.1048 PubMedCrossRefGoogle Scholar
  24. 24.
    Smits A, Kulo A, Verbesselt R, Naulaers G, de Hoon J, Vermeersch P, Allegaert K (2012) Cefazolin plasma protein binding and its covariates in neonates. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical. Microbiology 31(12):3359–3365. doi: 10.1007/s10096-012-1703-x Google Scholar
  25. 25.
    Martin E, Fanconi S, Kalin P, Zwingelstein C, Crevoisier C, Ruch W, Brodersen R (1993) Ceftriaxone—bilirubin-albumin interactions in the neonate: an in vivo study. Eur J Pediatr 152(6):530–534PubMedCrossRefGoogle Scholar
  26. 26.
    Brodersen R, Robertson A (1989) Ceftriaxone binding to human serum albumin: competition with bilirubin. Mol Pharmacol 36(3):478–483PubMedGoogle Scholar
  27. 27.
    de Wildt SN, Tibboel D, Leeder JS (2014) Drug metabolism for the paediatrician. Arch Dis Child 99(12):1137–1142. doi: 10.1136/archdischild-2013-305212 PubMedCrossRefGoogle Scholar
  28. 28.
    Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL (2014) Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14(6):498–509. doi: 10.1016/s1473-3099(14)70036-2 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vet NJ, de Hoog M, Tibboel D, de Wildt SN (2011) The effect of inflammation on drug metabolism: a focus on pediatrics. Drug Discov Today 16(9–10):435–442. doi: 10.1016/j.drudis.2011.02.014 PubMedCrossRefGoogle Scholar
  30. 30.
    Brouwer KL, Aleksunes LM, Brandys B, Giacoia GP, Knipp G, Lukacova V, Meibohm B, Nigam SK, Rieder M, de Wildt SN (2015) Human ontogeny of drug transporters: review and recommendations of the pediatric transporter working group. Clin Pharmacol Ther 98(3):266–287. doi: 10.1002/cpt.176 PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gupta S, Sengar GS, Meti PK, Lahoti A, Beniwal M, Kumawat M (2016) Acute kidney injury in Pediatric Intensive Care Unit: incidence, risk factors, and outcome. Indian J Crit Care Med 20(9):526–529. doi: 10.4103/0972-5229.190368 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Momtaz HE, Sabzehei MK, Rasuli B, Torabian S (2014) The main etiologies of acute kidney injury in the newborns hospitalized in the neonatal intensive care unit. J Clin Neonatol 3(2):99–102. doi: 10.4103/2249-4847.134691 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Vieux R, Fresson J, Guillemin F, Hascoet JM (2011) Perinatal drug exposure and renal function in very preterm infants. Arch Dis Child Fetal Neonatal Ed 96(4):F290–F295. doi: 10.1136/adc.2009.197699 PubMedCrossRefGoogle Scholar
  34. 34.
    Soler YA, Nieves-Plaza M, Prieto M, Garcia-De Jesus R, Suarez-Rivera M (2013) Pediatric risk, injury, failure, loss, end-stage renal disease score identifies acute kidney injury and predicts mortality in critically ill children: a prospective study. Pediatr Crit Care Med 14(4):e189–e195. doi: 10.1097/PCC.0b013e3182745675 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hobbs AL, Shea KM, Roberts KM, Daley MJ (2015) Implications of augmented renal clearance on drug dosing in critically ill patients: a focus on antibiotics. Pharmacotherapy 35(11):1063–1075. doi: 10.1002/phar.1653 PubMedCrossRefGoogle Scholar
  36. 36.
    De Cock PA, Standing JF, Barker CI, de Jaeger A, Dhont E, Carlier M, Verstraete AG, Delanghe JR, Robays H, De Paepe P (2015) Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children. Antimicrob Agents Chemother 59(11):7027–7035. doi: 10.1128/aac.01368-15 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hirai K, Ishii H, Shimoshikiryo T, Shimomura T, Tsuji D, Inoue K, Kadoiri T, Itoh K (2016) Augmented renal clearance in patients with febrile neutropenia is associated with increased risk for subtherapeutic concentrations of vancomycin. Ther Drug Monit 38(6):706–710. doi: 10.1097/ftd.0000000000000346 PubMedCrossRefGoogle Scholar
  38. 38.
    Gomez DS, Campos EV, de Azevedo RP, Silva-Jr JM, Ferreira MC, Sanches-Giraud C, Silva-Jr CV, Santos SR (2013) Individualised vancomycin doses for paediatric burn patients to achieve PK/PD targets. Burns 39(3):445–450. doi: 10.1016/j.burns.2012.07.005 PubMedCrossRefGoogle Scholar
  39. 39.
    Yu T, Stockmann C, Healy DP, Olson J, Wead S, Neely AN, Kagan RJ, Spigarelli MG, Sherwin CM (2015) Determination of optimal amikacin dosing regimens for pediatric patients with burn wound sepsis. J Burn Care Res 36(4):e244–e252. doi: 10.1097/BCR.0000000000000159 PubMedCrossRefGoogle Scholar
  40. 40.
    Yang RH, Rong XZ, Hua R, Zhang T (2009) Pharmacokinectics of vancomycin and amikacin in the subeschar tissue fluid in patients with severe burn. Burns 35(1):75–79. doi: 10.1016/j.burns.2008.05.016 PubMedCrossRefGoogle Scholar
  41. 41.
    Steer JA, Papini RP, Wilson AP, Dhillon S, Hichens MF, McGrouther DA, Frame JD, Parkhouse N (1996) Pharmacokinetics of a single dose of teicoplanin in burn patients. J Antimicrob Chemother 37(3):545–553PubMedCrossRefGoogle Scholar
  42. 42.
    Wildschut ED, Ahsman MJ, Houmes RJ, Pokorna P, de Wildt SN, Mathot RA, Tibboel D (2012) Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO). Curr Drug Metab 13(6):767–777PubMedCrossRefGoogle Scholar
  43. 43.
    Sherwin CM, Zobell JT, Stockmann C, McCrory BE, Wisdom M, Young DC, Olson J, Ampofo K, Spigarelli MG (2014) Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis. J Pharmacokinet Pharmacodyn 41(1):71–79. doi: 10.1007/s10928-013-9348-7 PubMedCrossRefGoogle Scholar
  44. 44.
    Wildschut ED, Ahsman MJ, Allegaert K, Mathot RA, Tibboel D (2010) Determinants of drug absorption in different ECMO circuits. Intensive Care Med 36(12):2109–2116. doi: 10.1007/s00134-010-2041-z PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Sherwin J, Heath T, Watt K (2016) Pharmacokinetics and dosing of anti-infective drugs in patients on extracorporeal membrane oxygenation: a review of the current literature. Clin Ther 38(9):1976–1994. doi: 10.1016/j.clinthera.2016.07.169 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Cies JJ, Moore WS II, Dickerman MJ, Small C, Carella D, Chopra A, Parker J (2014) Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support. Pharmacotherapy 34(10):e175–e179. doi: 10.1002/phar.1476 PubMedCrossRefGoogle Scholar
  47. 47.
    Cies JJ, Moore WS II, Conley SB, Dickerman MJ, Small C, Carella D, Shea P, Parker J, Chopra A (2016) Pharmacokinetics of continuous infusion meropenem with concurrent extracorporeal life support and continuous renal replacement therapy: a case report. J Pediatr Pharmacol Ther 21(1):92–97. doi: 10.5863/1551-6776-21.1.92 PubMedPubMedCentralGoogle Scholar
  48. 48.
    Knoderer CA, Saft SA, Walker SG, Rodefeld MD, Turrentine MW, Brown JW, Healy DP, Sowinski KM (2011) Cefuroxime pharmacokinetics in pediatric cardiovascular surgery patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 25(3):425–430. doi: 10.1053/j.jvca.2010.07.022 PubMedCrossRefGoogle Scholar
  49. 49.
    Hatzopoulos FK, Stile-Calligaro IL, Rodvold KA, Sullivan-Bolyai J, Del Nido P, Levitsky S (1993) Pharmacokinetics of intravenous vancomycin in pediatric cardiopulmonary bypass surgery. Pediatr Infect Dis J 12(4):300–304PubMedCrossRefGoogle Scholar
  50. 50.
    Adrianzen Vargas MR, Danton MH, Javaid SM, Gray J, Tobin C, Brawn WJ, Barron DJ (2004) Pharmacokinetics of intravenous flucloxacillin and amoxicillin in neonatal and infant cardiopulmonary bypass surgery. Eur J Cardiothorac Surg 25(2):256–260PubMedCrossRefGoogle Scholar
  51. 51.
    Himebauch AS, Nicolson SC, Sisko M, Moorthy G, Fuller S, Gaynor JW, Zuppa AF, Fox E, Kilbaugh TJ (2014) Skeletal muscle and plasma concentrations of cefazolin during cardiac surgery in infants. J Thorac Cardiovasc Surg 148(6):2634–2641. doi: 10.1016/j.jtcvs.2014.06.064 PubMedCrossRefGoogle Scholar
  52. 52.
    Sargel C, Karsies T, Lutmer J (2013) Pediatric drug dosing during renal replacement therapy: searching for help. Pediatr Crit Care Med 14(9):904–906. doi: 10.1097/PCC.0b013e3182a1262a PubMedCrossRefGoogle Scholar
  53. 53.
    Rizkalla NA, Feudtner C, Dai D, Zuppa AF (2013) Patterns of medication exposures in hospitalized pediatric patients with acute renal failure requiring intermittent or continuous hemodialysis. Pediatr Crit Care Med 14(9):e394–e403. doi: 10.1097/PCC.0b013e31829f5bc8 PubMedCrossRefGoogle Scholar
  54. 54.
    Lee J, Geer J, Swartz S, Srivaths P (2016) Cefazolin in 4 children on chronic hemodialysis: a proposed dosing regimen. Ann Pharmacother. doi: 10.1177/1060028016667381
  55. 55.
    Stidham T, Reiter PD, Ford DM, Lum GM, Albietz J (2011) Successful utilization of high-flux hemodialysis for treatment of vancomycin toxicity in a child. Case Rep Pediatr 2011:678724. doi: 10.1155/2011/678724 PubMedGoogle Scholar
  56. 56.
    Schoumacher R, Chevalier RL, Gomez RA, Rogol AD, Cummings R, Spyker DA (1989) Enhanced clearance of vancomycin by hemodialysis in a child. Pediatr Nephrol 3(1):83–85PubMedCrossRefGoogle Scholar
  57. 57.
    Cohen-Wolkowiez M, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Randolph DA, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Rich W, Brozanski BS, van den Anker J, Blumer J, Laughon M, Watt KM, Kearns GL, Capparelli EV, Martz K, Berezny K, Benjamin DK Jr, Smith PB (2012) Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections. Clin Infect Dis 55(11):1495–1502. doi: 10.1093/cid/cis758 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Smith PB, Cohen-Wolkowiez M, Castro LM, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Bhatt-Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Brozanski BS, Sanchez P, van den Anker J, Blumer J, Kearns GL, Capparelli EV, Anand R, Benjamin DK Jr (2011) Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections. Pediatr Infect Dis J 30(10):844–849. doi: 10.1097/INF.0b013e31822e8b0b PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hornik CP, Herring AH, Benjamin DK Jr, Capparelli EV, Kearns GL, van den Anker J, Cohen-Wolkowiez M, Clark RH, Smith PB (2013) Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants. Pediatr Infect Dis J 32(7):748–753. doi: 10.1097/INF.0b013e31828be70b PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kent A, Turner MA, Sharland M, Heath PT (2014) Aminoglycoside toxicity in neonates: something to worry about? Expert Rev Anti-Infect Ther 12(3):319–331. doi: 10.1586/14787210.2014.878648 PubMedCrossRefGoogle Scholar
  61. 61.
    Rao SC, Srinivasjois R, Hagan R, Ahmed M (2011) One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev (11):Cd005091. doi: 10.1002/14651858.CD005091.pub3
  62. 62.
    Nestaas E, Bangstad HJ, Sandvik L, Wathne KO (2005) Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. Arch Dis Child Fetal Neonatal Ed 90(4):F294–F300. doi: 10.1136/adc.2004.056317 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lestner JM, Hill LF, Heath PT, Sharland M (2016) Vancomycin toxicity in neonates: a review of the evidence. Curr Opin Infect Dis 29(3):237–247. doi: 10.1097/qco.0000000000000263 PubMedCrossRefGoogle Scholar
  64. 64.
    Ragab AR, Al-Mazroua MK, Al-Harony MA (2013) Incidence and predisposing factors of vancomycin-induced nephrotoxicity in children. Infect Dis Ther 2(1):37–46. doi: 10.1007/s40121-013-0004-8 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Cotten CM (2016) Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr 28(2):141–149. doi: 10.1097/mop.0000000000000338 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Turta O, Rautava S (2016) Antibiotics, obesity and the link to microbes—what are we doing to our children? BMC Med 14:57. doi: 10.1186/s12916-016-0605-7 PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Monte SV, Prescott WA, Johnson KK, Kuhman L, Paladino JA (2008) Safety of ceftriaxone sodium at extremes of age. Expert Opin Drug Saf 7(5):515–523. doi: 10.1517/14740338.7.5.515 PubMedCrossRefGoogle Scholar
  68. 68.
    Roberts JK, Stockmann C, Constance JE, Stiers J, Spigarelli MG, Ward RM, Sherwin CM (2014) Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clin Pharmacokinet 53(7):581–610. doi: 10.1007/s40262-014-0147-0 PubMedCrossRefGoogle Scholar
  69. 69.
    Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP (2004) Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 114(1):e111–e118PubMedCrossRefGoogle Scholar
  70. 70.
    Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH (2009) Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 24(1):67–76. doi: 10.1007/s00467-008-0997-5 PubMedCrossRefGoogle Scholar
  71. 71.
    Allegaert K, Cossey V, Langhendries JP, Naulaers G, Vanhole C, Devlieger H, Van Overmeire B (2004) Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life. Biol Neonate 86(3):207–211. doi: 10.1159/000079618 PubMedCrossRefGoogle Scholar
  72. 72.
    De Cock RF, Allegaert K, Schreuder MF, Sherwin CM, de Hoog M, van den Anker JN, Danhof M, Knibbe CA (2012) Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. Clin Pharmacokinet 51(2):105–117. doi: 10.2165/11595640-000000000-00000 PubMedCrossRefGoogle Scholar
  73. 73.
    Smits A, Kulo A, van den Anker J, Allegaert K (2016) The amikacin research program: a stepwise approach to validate dosing regimens in neonates. Expert Opin Drug Metab Toxicol 13(2):157–166. doi: 10.1080/17425255.2017.1234606 PubMedCrossRefGoogle Scholar
  74. 74.
    Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ (2004) Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 43(13):925–942PubMedCrossRefGoogle Scholar
  75. 75.
    De Cock RF, Allegaert K, Brussee JM, Sherwin CM, Mulla H, de Hoog M, van den Anker JN, Danhof M, Knibbe CA (2014) Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res 31(10):2643–2654. doi: 10.1007/s11095-014-1361-z PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Giachetto GA, Telechea HM, Speranza N, Oyarzun M, Nanni L, Menchaca A (2011) Vancomycin pharmacokinetic-pharmacodynamic parameters to optimize dosage administration in critically ill children. Pediatr Crit Care Med 12(6):e250–e254. doi: 10.1097/PCC.0b013e3181fe4047 PubMedCrossRefGoogle Scholar
  77. 77.
    Oyaert M, Spriet I, Allegaert K, Smits A, Vanstraelen K, Peersman N, Wauters J, Verhaegen J, Vermeersch P, Pauwels S (2015) Factors impacting unbound vancomycin concentrations in different patient populations. Antimicrob Agents Chemother 59(11):7073–7079. doi: 10.1128/aac.01185-15 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Hospira I (2016) Vancomycin hydrochloride for injection, USP. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/062911s035lbl.pdf. Accessed 26 Oct 2016
  79. 79.
    Pharmaceuticals A (2016) MERREM® I.V. (meropenem for injection). http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050706s022lbl.pdf. Accessed 26 Oct 2016
  80. 80.
    Jacqz-Aigrain E, Leroux S, Zhao W, van den Anker JN, Sharland M (2015) How to use vancomycin optimally in neonates: remaining questions. Expert Rev Clin Pharmacol 8(5):635–648. doi: 10.1586/17512433.2015.1060124 PubMedCrossRefGoogle Scholar
  81. 81.
    Goldstein SL, Murry DJ, May S, Aleksic A, Sowinski KM, Blaney S (2001) Meropenem pharmacokinetics in children and adolescents receiving hemodialysis. Pediatr Nephrol 16(12):1015–1018. doi: 10.1007/s004670100015 PubMedCrossRefGoogle Scholar
  82. 82.
    Nehus EJ, Mizuno T, Cox S, Goldstein SL, Vinks AA (2016) Pharmacokinetics of meropenem in children receiving continuous renal replacement therapy: validation of clinical trial simulations. J Clin Pharmacol 56(3):291–297. doi: 10.1002/jcph.601 PubMedCrossRefGoogle Scholar
  83. 83.
    Depre M, van Hecken A, Verbesselt R, Tjandra-Maga TB, Gerin M, de Schepper PJ (1992) Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use. Fundam Clin Pharmacol 6(6):259–262PubMedCrossRefGoogle Scholar
  84. 84.
    Jenner P, Konen-Bergmann M, Schepers C, Haertter S (2009) Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies. Clin Ther 31(11):2698–2711. doi: 10.1016/j.clinthera.2009.10.018 PubMedCrossRefGoogle Scholar
  85. 85.
    Rashid A, Ahmad M, Minhas MU, Hassan IJ, Malik MZ (2014) Pharmacokinetic studies of metformin and glibenclamide in normal human volunteers. Pak J Pharm Sci 27(1):153–159PubMedGoogle Scholar
  86. 86.
    Mould DR, Upton RN (2013) Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol 2:e38. doi: 10.1038/psp.2013.14 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Administration USFaD (1999) FDA guidance for industry-population pharmacokinetics. Tech. rep., Food and Drug AdministrationGoogle Scholar
  88. 88.
    European Medicines Agency (2007) Guideline on reporting the results of population pharmacokinetic analyses. EMA, LondonGoogle Scholar
  89. 89.
    Ward RM, Sherwin CM (2016) Newborns still lack drug data to guide therapy. Br J Clin Pharmacol 82(6):1410–1411. doi: 10.1111/bcp.13074 PubMedCrossRefGoogle Scholar
  90. 90.
    Samara E, Granneman R (1997) Role of population pharmacokinetics in drug development. A pharmaceutical industry perspective. Clin Pharmacokinet 32(4):294–312. doi: 10.2165/00003088-199732040-00003 PubMedCrossRefGoogle Scholar
  91. 91.
    Wahlby U, Jonsson EN, Karlsson MO (2002) Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci 4(4):E27. doi: 10.1208/ps040427 PubMedCrossRefGoogle Scholar
  92. 92.
    MacDonald A, Scarola J, Burke JT, Zimmerman JJ (2000) Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther 22(Suppl B):B101–B121PubMedCrossRefGoogle Scholar
  93. 93.
    Smith J, Andes D (2008) Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Ther Drug Monit 30(2):167–172. doi: 10.1097/FTD.0b013e318167d0e0 PubMedCrossRefGoogle Scholar
  94. 94.
    Dansirikul C, Morris RG, Tett SE, Duffull SB (2006) A Bayesian approach for population pharmacokinetic modelling of sirolimus. Br J Clin Pharmacol 62(4):420–434. doi: 10.1111/j.1365-2125.2005.02533.x PubMedCrossRefGoogle Scholar
  95. 94.
    Dorofaeff T, Bandini RM, Lipman J, Ballot DE, Roberts JA, Parker SL (2016) Uncertainty in antibiotic dosing in critically Ill neonate and pediatric patients: can microsampling provide the answers? Clin Ther 38(9):1961–1975. doi:  10.1016/j.clinthera.2016.07.093. Epub 2016 Aug 17
  96. 95.
    Germovsek E, Kent A, Metsvaht T, Lutsar I, Klein N, Turner MA, Sharland M, Nielsen EI, Heath PT, Standing JF (2016) Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants. Antimicrob Agents Chemother 60(8):4869–4877. doi: 10.1128/aac.00577-16 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 96.
    Marik PE, Lipman J, Kobilski S, Scribante J (1991) A prospective randomized study comparing once-versus twice-daily amikacin dosing in critically ill adult and paediatric patients. J Antimicrob Chemother 28(5):753–764PubMedCrossRefGoogle Scholar
  98. 97.
    Munckhof WJ, Grayson ML, Turnidge JD (1996) A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 37(4):645–663PubMedCrossRefGoogle Scholar
  99. 98.
    Sherwin CM, Wead S, Stockmann C, Healy D, Spigarelli MG, Neely A, Kagan R (2014) Amikacin population pharmacokinetics among paediatric burn patients. Burns 40(2):311–318. doi: 10.1016/j.burns.2013.06.015 PubMedCrossRefGoogle Scholar
  100. 99.
    Kuepfer L, Niederalt C, Wendl T, Schlender JF, Willmann S, Lippert J, Block M, Eissing T, Teutonico D (2016) Applied concepts in PBPK modeling: how to build a PBPK/PD model. CPT Pharmacometrics Syst Pharmacol 5(10):516–531. doi: 10.1002/psp4.12134 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Pieter A. J. G. De Cock
    • 1
    • 2
    • 3
  • Karel Allegaert
    • 4
    • 5
  • Matthew W. Linakis
    • 6
  • Catherine M. T. Sherwin
    • 6
    • 7
  1. 1.Department of PharmacyGhent University HospitalGhentBelgium
  2. 2.Heymans Institute of PharmacologyGhent UniversityGhentBelgium
  3. 3.Department of Paediatric Intensive CareGhent University HospitalGhentBelgium
  4. 4.Intensive Care and Department of SurgeryErasmus MC Sophia Children’s HospitalRotterdamthe Netherlands
  5. 5.Department of Development and RegenerationKU LeuvenLeuvenBelgium
  6. 6.Division of Clinical Pharmacology, Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  7. 7.Department of Pharmacology and ToxicologyCollege of Pharmacy, University of UtahSalt Lake CityUSA

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