Population pharmacokinetics of gentamicin among neonates admitted at Mwananyamala Regional Referral Hospital, Dar es Salaam Tanzania

Abstract

Background: Gentamicin is an important drug in the class of aminoglycosides, most commonly used to treat resistant gram-negative organisms. Due to its rapid bactericidal activity, gentamicin is widely used in empirical antimicrobial regimens to treat neonatal infections caused by both gram-negative and gram-positive bacteria. Although highly effective, reservations concerning potential otovestibular toxicity and nephrotoxicity have often limited the use of this agent. The recommended use of gentamicin by the World health organization (WHO) requires therapeutic drug monitoring. However, because of limited resources, therapeutic drug monitoring is not commonly done in our country. By not monitoring the serum levels of gentamicin there is a possibility that a considerable number of neonates may be suffering from acute kidney injury after high gentamicin exposure and may later develop chronic kidney disease and or permanent hearing loss. Objectives: The objectives of this study were to determine the peak and trough serum levels of gentamicin achieved by the neonates following once daily dosing of intravenous gentamicin. We also determined the population gentamicin clearance, volume of distribution and discerned whether there was a significant increase in serum creatinine levels after gentamicin therapy for more than 48 hours. Materials and methods: This was a population pharmacokinetic study (popPK) in which term neonates admitted and prescribed to receive gentamicin for more than 48 hours were included in the study. The study excluded very sick term neonates in decompensate state and requiring resuscitation, term neonates who had severe congenital malformation and term neonates who were on gentamicin therapy in the past 72 hours before the study. Sparse sampling was employed where 2 to 3 participants contributed serum samples for gentamicin concentration at each time point after the initial intravenous gentamicin dose, using a predetermined sampling schedule. However, serum samples for peak gentamicin concentration were obtained from 12 participants 30minutes after the first dose and steady state trough gentamicin concentration were obtained from each participant 20hours after the second dose. Serum gentamicin concentration was determined using chemiluminescent microparticle immunoassay (CMIA) technology (Abbott architect ci4100 analyzer, Abbott diagnostics in Illinois, United States).In addition, serum creatinine levels before and seven days after start of gentamicin treatment were determined for each participant using Erba XL-100 analyzer (Erba Mannheim Diagnostics Company, India). Data analysis: The serum gentamicin concentrations-time profile was fitted using stata version 14.2 software (StataCorp LLC in California, United states) with the assumption of one compartment model where popPK parameters (elimination rate constant, elimination half-life and area under the curve) were directly estimated and clearance together with volume of distribution were calculated from these estimates. Categorical data were presented as proportions and compared using McNemar test; continuous data were expressed as mean ± S.D (standard deviation) and were compared using one sample t-test and paired samples t-test. The results were considered statistically significant at P values <0.05. Results: In this population, peak and steady state trough gentamicin concentration was higher than the recommended upper limit of normal peak and trough serum levels for the typical term neonate (M=16.669, SD ± 0.646, P< 0.001) and (M=3.283, SD ± 0.707, P< 0.001) for peak and trough concentration respectively. By contrast, gentamicin clearance (0.40 mLmin-1kg-1) and volume of distribution (0.31Lkg-1) estimated from PK data in our study were lower than the lower limit of the reported reference range. Overall, there was a significant increase in serum creatinine level after gentamicin treatment, suggesting occurrence of renal injury, in most of the study participants. Conclusions: Neonates achieved high peak and trough serum gentamicin levels which could be explained by the population pharmacokinetics estimates (lower clearance and volume of distribution). Also, high gentamicin concentration may have caused significant renal injury leading to a significant increase in serum creatinine in the majority of study participants. Recommendations: It is important that the Ministry of Health, Community Development, Gender, Elderly and Children considers therapeutic drug monitoring practice in our health facilities as an important tool in maximizing therapeutic outcomes and minimizing the potential toxic effects associated with higher serum levels when neonates are on gentamicin treatment. Also, kidney function test before, during and after treatment with gentamicin, should be made a routine practice in our health facilities to ensure that doses are given according to the patient’s renal function in order to attain serum gentamicin levels which are within the recommended ranges thereby preventing toxicity (nephrotoxicity and ototoxicity).