Amikacin Treatment With or Without Aminophylline in Neonates with Suspected Sepsis at Korle-Bu Teaching Hospital: A Pharmacokinetic and Pharmacodynamic Study

Abstract

Background: Sepsis is a major cause of death among neonates. In neonates, symptoms of sepsis are often non-specific and diagnosis requires a high index of suspicion. Thus, the role of additional diagnostic markers is important. Amikacin is used as first-line treatment of neonatal sepsis and it is usually co-administered with aminophylline in preterm neonates in Ghana. Amikacin dosing is well established, however, optimal effect requires specific dose titration and maintenance therapy should be individualized. Aim: To describe the PK and evaluate selected aspects of the PD of amikacin in neonates with suspected sepsis. Methods: Neonates with suspected sepsis (n=322) and requiring amikacin or amikacin with aminophylline treatment were recruited at the Neonatal Intensive Care Unit, Korle-Bu Teaching Hospital, Ghana. Admission clinical and demographic information was collected, using case record forms. Blood culture and sensitivity, selected hematological (FBC), and biochemical [urea, creatinine, total bilirubin, C-reactive protein (CRP) and procalcitonin (PCT)] parameters were measured before treatment. A standard dose of amikacin was administered as per local guidelines. Brainstem auditory evoked potential was done before treatment commencement and seven days later in a randomly selected group of neonates. Serum amikacin concentration was measured at specified times after treatment initiation and amikacin concentration data was analyzed, using population PK modeling. Results: A total of 163 (50.6%) of admitted neonates were born preterm, of which 14 (4.3%) were extreme preterm. A total of 79 (24.5%) had signs/symptoms consistent with birth asphyxia. There was 13.6% (41/302) culture positivity. Among neonates categorized as having ―highly probable‖, ―probable‖ or ―less probable‖ sepsis, mean PCT was significantly different (P<0.001). The sensitivity, PPV, NPV and AUC was higher compared with CRP. The proportion of neonates with elevated PCT on admission was significantly higher in the ―highly probable‖ group compared with the ―probable group‖ [91% (20/22 versus 31.6% (6/19), p<0.001]. Overall mortality was 12%, with case fatality being highest among extreme preterms or those with birth weight less than 1 kg, or with elevated PCT. A total of 419 plasma concentration profile data was available for 247 neonates for population pharmacokinetic modeling. A one-compartment model best fitted amikacin disposition. The mean peak amikacin serum concentration was 20.56+8.7 μg/mL, and trough 6.68+3.86 μg/mL. Neonates administered amikacin with or without aminophylline showed varying CL and V, but with a high BSV, suggesting possible lack of effect of aminophylline co-administration on amikacin disposition. The population clearance (CL), and volume of distribution (V) of amikacin were related as: CL = 0.153 (birth weight/2.5)1.31, V = 2.94 (birth weight/2.5)1.18, with 58.9 and 50.7% between-subject variability in clearance and volume, respectively. Mean half-life (t1/2) of amikacin was 13.6 hours. There was no difference in the baseline and follow-up BAEP of neonates who received amikacin and those who did not. Conclusion: Birth weight was an important predictor of amikacin CL and V. Co-administration of aminophylline with amikacin did not influence the pharmacokinetics of amikacin. There was a relatively large V and long t1/2 of amikacin in recruited neonates. No difference existed in baseline and follow-up BAEP results of neonates treated with amikacin, although one subject showed a high BAEP threshold post-amikacin dose. PCT was a more sensitive marker than CRP in the diagnosis of early onset neonatal sepsis.