Clinical Biochemistry xxx (2014) xxx–xxx

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Clinical Biochemistry

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Short Communication

The impact of therapeutic drug monitoring in neonatalclinical pharmacology

Johannes N. van den Anker ⁎Division of Pediatric Clinical Pharmacology, Children's National Health System, Washington, DC, USAIntensive Care, Erasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsDepartment of Paediatric Pharmacology, University Children's Hospital Basel, Switzerland

Introduction

Optimal administration of aminoglycosides (both used in early andlate onset sepsis) and vancomycin (primarily used in late onsetinfections) in neonatal intensive care units (NICUs) will profit fromthe appropriate use of therapeutic drug monitoring (TDM). All healthcare providers involved in care for neonates need to understand theprinciples of TDM. Therefore a close working relationship between spe-cialists in neonatal medicine, nurse practitioners, physician-assistants,pharmacists and pediatric pharmacologists is necessary. Irrespective ofthe antibacterial agents that are being used for the treatment of diverseinfectious diseases it is important to focus at the pharmacokinetic/pharmacodynamic (PK/PD) relationship of these agents. This presenta-tion will aim solely at aminoglycosides and vancomycin. Aminoglyco-sides are still one of the most commonly used antibiotics in NICUsacross the world despite the fact that they belong to one of the oldestclasses of antimicrobial agents and have been in use since the mid-1940. There are various factors that have contributed to their successsuch as a low rate of resistance and a low cost. Vancomycin becamethe drug of choice for staphylococcal infections in the 1950s, whenstaphylococcal strains developed resistance to penicillin. It was replacedbymethicillin in the 1960s, butwhen the incidence of late onset neonatalsepsis due to coagulase negative staphylococci and methicillin-resistantstaphylococci increased, vancomycin use increased too and vancomycinis currently the drug of choice for the treatment of resistant neonatalstaphylococcal infections.

Administration of antibacterial agents in the NICU

The intravenous administration of drugs is the preferred route inneonates. In very small and premature infants the total body watercompartmentmay be 85% of the total bodyweightwith a very high pro-portion being extracellular fluid. This high proportion of extracellularfluid is a very important parameter that explains that the volume ofdistribution of hydrophilic drugs is very high in neonates.

⁎ Children's National Health System, Integrative Systems Biology, Pharmacology &Physiology, The George Washington University, School of Medicine and Health Sciences,111 Michigan Avenue, NW, Washington, DC 20010, USA. Fax: +1 202 476 3425.

E-mail address: jvandena@childrensnational.org.

http://dx.doi.org/10.1016/j.clinbiochem.2014.05.0180009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rig

Please cite this article as: den Anker JN, The impact of therapeutic drughttp://dx.doi.org/10.1016/j.clinbiochem.2014.05.018

As an example, the volume of distribution of aminoglycosides ismuch larger than that in older children and adults. The fact that amino-glycosides are dependent on high concentrations to be able to kill thebacteria for which they are administered warrants the use of higherdose per gift in neonates than in older children. In recent years thedose of tobramycin and gentamicin has been increased from 2.5 mg/kgto 4–5 mg/kg per dose [1]. This change has resulted in peak/MIC ratiosthat are sufficient to kill bacteria causing neonatal infections. Clearly,after increasing the total amount of drug administered to the neonatethat is dependent on glomerular filtration rate for its clearance, it isimportant to realize that the neonatal kidney has a reduced capacity toexcrete antibacterial agents such as aminoglycosides [3]. As a conse-quence, neonates need more time to clear their immature bodies fromthe administered antimicrobial agents. Therefore we have seen a largechange in the dosing interval of gentamicin and tobramycin from every8–12 h to every 24–48 h in neonates with varying gestational ages.

Vancomycin, one of themost studied drugs in neonates using popu-lation pharmacokinetic approaches to characterize its pharmacokineticparameters, has also shown a large interindividual variability in neo-nates but it has become clear that age, renal function and body weightare all important in fine-tuning the dosing regimens for neonates withdifferent gestational and postnatal ages [2]. The ratio of the 24 h areaunder the concentration vs. time curve and MIC is the best predictorof vancomycin effectiveness. The best outcomes are noted if this ratioreaches a value of more than 400 in case of invasive MRSA infection inadults. However, the recent increase in vancomycin MIC values fromless than 1 mg/L to over 1 mg/L has indicated that reaching a ratio ofmore than 400 is virtually impossible with the current dosing recom-mendations in both children and adults. As a consequence continuousinfusion of vancomycin is being considered as a viable alternative wayto reach a sufficient ratio to kill the increasingly resistant bacteria. Todate no studies have been conducted in neonates addressing thisemerging issue, but it is clear that to achieve the adequate AUC/MIC tar-get, the neonatal dose of vancomycin needs to be increased if bacterialMIC continues to increase.

Conclusion

Safe and effective use of antibacterial agents in neonateswill dependon several important issues such as application of modeling and

hts reserved.

monitoring in neonatal clinical pharmacology, Clin Biochem (2014),

2 J.N. den Anker / Clinical Biochemistry xxx (2014) xxx–xxx

simulation techniques to optimize dosing regimens of antimicrobialagents for use in the newborn population, consensus on what doseand dosing regimen to use in NICUs and a continuous electronic updateon new insights in this important area, and finally reporting of newdataon short- and long-term side effects of the use of these important anti-bacterial agents to assure an optimal use of these drugs.

References

[1] Fjalstad JW, Laukli E, van den Anker J, Klingenberg C. High dose gentamicin in new-born infants: is it safe? Eur J Pediatr Nov 14 2013 [Epub ahead of print].

Please cite this article as: den Anker JN, The impact of therapeutic drughttp://dx.doi.org/10.1016/j.clinbiochem.2014.05.018

[2] ZhaoW, Kaguelidou F, Biran V, Zhang D, Allegaert K, Capparelli E, Holford N, Kimura T,Lo Y-L, Peris J-E, Thomson A, van den Anker J, Fakhoury M, Jacqz-Aigrain E. Externalvalidation of population pharmacokinetic models of vancomycin in neonates: thetransferability of published models to different clinical settings. Br J Clin Pharmacol2013;75(4):1068–80.

[3] De Cock R, Allegaert K, Schreuder M, Sherwin C, de Hoog M, van den Anker J, DanhofM, Knibbe C. Maturation of glomerular filtration rate in neonates as reflected byamikacin clearance. Clin Pharmacokinet 2012;51(2):105-17.

monitoring in neonatal clinical pharmacology, Clin Biochem (2014),