Kinetically guided therapy with gentamicin in critically ill septic preterm newborns in the first week of life. An open – label prospective study (part I)


Authors: P. Pokorná 1;  J. Záhora 3;  J. Chládek 2;  V. Vobruba 1;  I. Selke-Krulichová 3;  Š. Studená 2;  J. Chládková 4;  J. Martinková 2
Authors‘ workplace: Jednotka intenzivní a resuscitační péče, Klinika dětského a dorostového lékařství UK 1. LF a VFN, Praha přednosta prof. MUDr. J. Zeman, DrSc. 1;  Ústav farmakologie, Lékařská fakulta Univerzity Karlovy, Hradec Králové přednosta doc. MUDr. S. Mičuda, Ph. D. 2;  Ústav lékařské biofyziky, Lékařská fakulta Univerzity Karlovy, Hradec Králové přednosta doc. Ing. J. Hanuš, Ph. D. 3;  Dětská klinika Fakultní nemocnice, Hradec Králové přednosta prof. MUDr. M. Bayer, CSc. 4
Published in: Čes-slov Pediat 2013; 68 (4): 219-233.
Category: Original Papers

Overview

Objective:
The aim of the study was to predict dosing with gentamicin (Ge) of which the effect is dependent on plasma concentrations (Cpl) more than on dosage, to achieve the target range of steady state through Cpl: Ctrough,3 (0.5–2.0 mg/l) and peak Cpeak,4 (5.0–10.0 mg/l), i.e. 0.5 h before the fourth and one h after the start of the fourth dose. Cpeak,4 determines bactericidal effect, Ctrough,3 predicts neurotoxicity and nephrotoxicity.

Methods:
The analysis was performed by Ge fluorescence polarization immunoassay; Abbott Laboratories, Abbott Park Illinois). Fitting the parameters in a two-compartment model with four Cpl Ge were estimated: volume of distribution (Vd1) and clearance (Cl1) by the MW-Pharm 3.15 (Mediware, Groningen, NL). If the simulation of Cpl with standard dosing (4 mg/kg/24–48 h according to GV and birth weight) did not achieve the target Cpl, the standard dosing after the second dose was changed according to the estimated kinetic parameters, Ctrough,3 and Cpeak,4, and verified by ongoing analysis.

Results:
In 54 newborns (32 very low preterm, gestational age below 34 weeks and 22 low preterm GA <38 weeks) Cpeak,1 (after the first infusion) reached the target range in 80% Ctrough,1 <2 mg/l in all newborns. The standard dosing was adjusted in 85% of them, mainly by decreasing the rate of infusion or do you mean number of dosages per 24 hours (65%). The target Cpeak,4 was reached in 69% of very low preterm and 68% of low preterm newborns, Cpeak,4 <5 mg/l was reached in 31% of very low preterm and 32% of low preterm newborns. The target Ctrough,3 was obtained in all except one subject. The difference of the predicted and verified Cpeak,4 was caused by retention of fluids between the first and the fourth infusion of Ge. In case of persistent ductus arteriosus it reached up to +374.0 (45.1) ml/kg.

Conclusion:
Kinetically guided therapy with Ge in septic newborns in the first week of life based on the Cpl after the first infusion is recommended in very low preterm newborns especially. In order to reach bactericidal Cpeak,4 the decision should be based on retention of fluids, accompanying the critical condition.

Key words:
newborn, sepsis, gentamicin, kinetically guided therapy, persistent ductus arteriosus G.


Sources

1. Avent ML, Kinney JS, Istre GR, Whitfield JM. Gentamicin and tobramycin in neonates: comparison of a new extended dosing interval regimen with a traditional multiple daily dosing regimen. Am J Perinatol 2002; 19 (8): 413–420.

2. Stolk LM, Degraeuwe PL, Norman FH, de Wolf MC, de Boer A. Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates. Ther Drug Monit 2002; 24 (4): 527–531.

3. Měchurová A, Vlk R, Unzeitig V, Macko J, Zach J. Doporučené postupy v perinatologii a neonatologii. Čes Gynek 2010; 75 (Suppl 1).

4. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 2004; 114 (1): e111–e118.

5. García B, Barcia E, Pérez F, Molina IT. Population pharmacokinetics of gentamicin in premature newborns. J Antimicrob Chemother 2006; 58 (2): 372–379.

6. de Hoog M, Mouton JW, Schoemaker RC, Verduin CM, van den Anker JN. Extended-interval dosing of tobramycin in neonates: implications for therapeutic drug monitoring. Clin Pharmacol Ther 2002; 71 (5): 349–358.

7. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis 1984; 149 (3): 443–448.

8. Pons G, d‘Athis P, Rey E, de Lauture D, Richard MO, et al. Gentamicin monitoring in neonates. Ther Drug Monit 1988; 10 (4): 421–427.

9. Schentag JJ, Jusko WJ. Renal clearance and tissue accumulation of gentamicin. Clin Pharmacol Ther 1977; 22 (3): 364–370.

10. Rocha MJ, Almeina AM, Alfonso E, Martins V, Santos J, et al. The kinetic profile of gentamicin in premature neonates. J Pharm Pharmacol 2000; 52 (9): 1091–1097.

11. Triginer C, Izquierdo I, Fernández R, Rello J, Torrent J, et al. Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med 1990; 16 (5): 303–306.

12. Glover ML, Shaffer CL, Rubino CM, Cuthrell C, Schoening S, et al. A multicenter evaluation of gentamicin therapy in the neonatal intensive care unit. Pharmacotherapy 2001; 21 (1): 7–10.

13. De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet 2002; 41 (14): 1135–1151.

14. Martínková J, Pokorná P, Záhora J, Chládek J, Vobruba V, et al. Tolerability and outcomes of kinetically guided therapy with gentamicin in critically ill neonates during the first week of life: An open-label, prospective study. Clin Ther 2010; 32 (14): 2400–2414.

15. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11 (2): R31.

16. Mathur VS, Swan SK, Lambrecht LJ, Anjum S, Fellmann J, et al. The effects of fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects. Crit Care Med 1999; 27 (9): 1832–1837.

17. Gerberdig JL, Fleming DW. Centres for Diseases Control and Prevention Guidelines for the prevention of intravascular catheter – related infections, 2002.MMWR August 9, 2002; 51 (RR-10): 1–29.

18. de Brito CS, de Brito DV, Abdallah VO, Gontijo Filho PP. Occurrence of bloodstream infection with different types of central vascular catheter in critically neonates. J Infect 2010; 60 (2): 128–132.

19. Young TE. A Manual of Drugs Used in Neonatal Care. 19th ed. Raleigh, North Carolina: Acorn Publishing USA, NeoFax, 2006.

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 (1): 2–8.

21. Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL. 3–5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006; 69 (1): 184–189.

22. Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol 2009; 24 (2): 265–274.

23. Isemann BT,Kotagal UR, Mashni SM. Optimal gentamicin therapy in preterm neonates includes loading doses and early monitoring. Ther Drug Monit 1996; 18: 549–555.

24. Lingvall M, Reith D, Broadbent R. The effect of sepsis upon gentamicin pharmacokinetics in neonates. Br J Clin Pharmacol 2005; 59 (1): 54–61.

25. Yaffe SJ, Aranda JV. Pediatric pharmacology. In: Assael B, Rusconi F (eds). Aminoglycoside Antibiotics. 2nd ed. Philadelphia: Philadelphia Saunders, 1992: 244–251.

26. van den Anker JN. Pharmacokinetics and renal function in preterm infants. Acta Paediatr 1996; 85 (12): 1393–1399.

27. Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet 2009; 48 (2): 71–88.

28. Allegaert K, Anderson BJ, van den Anker JN. Renal drug clearance in preterm neonates: Relation to prenatal growth. Ther Drug Monit 2007; 29: 284–291.

29. Buijk SE, Mouton JW, Gyssens IC. Experience with a once-daily dosing program of a aminoglykosides in critically ill patiens. Intensive Care Med 2002; 28: 936–942.

30. van Dalen R, Vree TB. Pharmacokinetics of antibiotics in critically ill patients. Intensive Care Med 1990; 16 (3): S235–S238.

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