Tolerability and Outcomes of Kinetically Guided Therapy With Gentamicin in Critically Ill Neonates During the First Week of Life: An Open-Label, Prospective Study

• Published in: Clinical therapeutics 2010-12, Vol.32 (14), p.2400-2414
• Main Authors: Martínková, Jirina, MD, PhD, Pokorná, Pavla, MD, Záhora, Jiri, PhD, Chládek, Jaroslav, PhD, Vobruba, Václav, MD, Selke-Krulichová, Iva, PhD, Chládková, Jirina, MD
• Format: Article
• Language: English
• Subjects: aminoglycosides; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - therapeutic use; Biological and medical sciences; Birth Weight; Critical Illness; Drug Administration Schedule; gentamicin; Gentamicins - administration & dosage; Gentamicins - adverse effects; Gentamicins - blood; Gentamicins - therapeutic use; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Intensive Care, Neonatal - methods; Internal Medicine; Male; Medical Education; Medical sciences; neonates; Pharmacology. Drug treatments; Prospective Studies; sepsis; Sepsis - blood; Sepsis - drug therapy; Time Factors; tolerability; Treatment Outcome
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2011.01.013

Background Aminoglycosides are bactericidal antibiotics used worldwide for the treatment of serious infections in critically ill patients, including neonates. Critically ill neonates constitute a unique challenge in dosing owing to the pathologic alterations that accompany severe illness and the rapidly changing conditions of these patients. Objectives The main objective of this study was to analyze the kinetically guided dosage adjustment of gentamicin in neonates critically ill during the first week of life based on plasma concentrations after the first dose and to identify the impact of covariates (eg, fluid intake, body fluid retention) with respect to gestational age (GA). Tolerability of therapy was also assessed. Methods This 10-day, open-label, prospective study included neonates critically ill during the first week of life admitted to the neonatal intensive care unit of a children's hospital between January 2006 and July 2009. Hearing and renal assessments were conducted over a 24-month follow-up period. The patients were treated with gentamicin for suspected sepsis, proven sepsis, or pneumonia as an early sign of sepsis. The first and second doses of gentamicin 4 mg/kg were adjusted according to birth weight and GA: group 1 (GA < 34 weeks), 48-hour interdose intervals; group 2 (GA 34–38 weeks), 36 hours; and group 3 (GA > 38 weeks), 24 or 48 hours. Individual pharmacokinetic parameters were estimated after the first dose (given in 30-minute intravenous infusions) using 4 concentrations. Individual pharmacokinetic parameters were estimated by fitting the parameters of a 2-compartment model into 4 concentrations. The last 2 blood samples were taken 30 minutes before the fourth infusion (Ctrough,3 ) and 1 hour after its start (Cmax,4 ). Dosing was individualized to reach target ranges for the Ctrough,3 (0.5–2.0 mg/L) and Cmax,4 (6–10 mg/L) values. If needed, initial dosing was changed after the second dose by adjusting (reducing or increasing) the third and subsequent doses, or by adjusting (prolonging or shortening) the interdose intervals. Ctrough,3 and Cmax,4 were assessed to determine differences between predicted and assayed values. Fluid retention was registered as the difference between fluid intake and urine output at different intervals related to the first dose per kilogram of birth weight, and from the start of the first infusion (0 hour) to the day of the fourth infusion. The Cmax /minimum inhibitory concentration (MIC) ratio was determi