Determination of the correlation between amikacin serum concentrations and ototocity in neonates using otoacoustic emissions : a multidiciplinary approach at Dr George Mukhari Academic Hospital, Gauteng Province

Abstract

Neonates, particularly when premature, are prone to more infections due to being immunocompromised. Sixty percent of preterm neonates receive at least one antibiotic and 43% of the antibiotics administered to these neonates are aminoglycosides (AGs). This class of antibiotics is concentration dependent thus achieving a therapeutic maximum concentration of amikacin in plasma is associated with a significant decrease in the rate of mortality due to infection in critical ill patients. Amikacin has a very narrow therapeutic range and can cause side effects such as nephrotoxicity and ototoxicity. Neonates are a high risk population and the internal and external risk factors necessitate close monitoring in this population. The main aim of the study was to determine a possible correlation between amikacin serum concentrations and ototoxicity in neonates by using otoacoustic emissions (OAEs). The study was done at the Neonatal Intensive Care Unit of Dr George Mukhari Hospital (DGMH), a public sector academic hospital in Ga-Rankuwa, west of Pretoria in the Gauteng Province. A descriptive quantitative study with a correlation research design was used for the study. The correlation design was between the amikacin peak and trough levels and otoacoustic emission amplitudes measured at four different frequencies. Although the clinical therapeutic range for amikacin trough level is less than 10 mcg/mL, for the purpose of the study trough levels higher than 2 mcg/mL were used as a referral end point for OAEs. Over the period of five months, 83 neonates receiving amikacin therapy were recruited. Data were obtained from 55 (66%) of these recruited neonates. Kinetic-only data were obtained from 33 neonates and kinetic-and-audiology data from 22 neonates. The total population group had a mean gestational age (GA) of approximately 33 weeks with a mean weight of 1.91kg. This group received a mean maintenance dose of 19.59 mg/kg per day. Their glomerular filtration rate (GFR) was within limits and the mean was 19.58 mL/min per 1.73m2. Pharmacokinetic (PK) calculations revealed Determination of the correlation between amikacin serum concentrations and ototoxicity in neonates using otoacoustic emissions: A multidisciplinary approach at Dr George Mukhari Academic Hospital: Gauteng Province xix a mean true peak value of 47.45 mcg/mL which was higher than the recommended range of 30 to 40 mcg/mL. The reference half-life is between 4 and 8 hours, but was much longer at 10.93 hours. With regards to the volume of distribution (Vd), it was towards the upper limit, calculated at 0.665 L/kg. The interquartile range (IQR) for the whole population (n = 55) showed that 50% of the true trough levels ranged between 2.07 and 6.15 mcg/mL with true peak levels between 36.14 and 53.43 mcg/mL. The kinetics-only group had a mean GA of 33 weeks with a mean weight of 1.84 kg. This group received a mean maintenance dose of 19.84 mg/kg and had a GFR of 19.51 mL/min per 1.73m2. A mean peak of 45.67 mcg/mL and a mean trough of 7.07 mcg/L, both much higher than desired. The mean half-life was much higher than the reference range at 12.88 hours and the volume of distribution within range but towards the upper limit. The kinetic-and-audiology group had a mean GA of 33 weeks with a mean weight of 2 kg. This group received a mean maintenance dose of 20.12 mg/kg and had a GFR of 139.71 mL/min per 1.73m2. A mean peak of 50.13 mcg/mL and a mean trough of 5 mcg/L, both much higher than desired. The half-life was toward the upper limit and the volume of distribution within range. During the ototoxic monitoring, a DPOAE assessment was completed at baseline for the sub-population of 22 patients. These baselines were determined within 24 hours from when the patient was identified and consent obtained. A follow-up DPOAE was performed on the day of the third MD and therapeutic drug monitoring (TDM). Distortion product otoacoustic emissions (DPOAEs) were obtained at four different frequencies for each ear, namely at 2, 4, 6 and 8 kHz. Trough levels above 2 mcg/mL, but below the accepted therapeutic level of 10 mcg/mL, affected seven neonates ears (left and/or right), thus 32% of the sub-population. Three neonates (n = 22; 14%) had trough levels above 10 mcg/mL and reflected a change in outer hair cell function at some to all the frequency levels. Peak levels above 50 mcg/mL affected eight neonates’ ears (left and/or right), accounting for 36% of the sub- Determination of the correlation between amikacin serum concentrations and ototoxicity in neonates using otoacoustic emissions: A multidisciplinary approach at Dr George Mukhari Academic Hospital: Gauteng Province xx population. A total of six patients had both ears affected with peak and trough levels, thus 27.3% of the sub-population. This study indicated that outer hair cell (OHC) function is affected from baseline to follow-up audiology in neonatal patients treated with amikacin. A multidisciplinary approach between pharmacists, audiologists and doctors is imperative to reduce the morbidity in vulnerable population groups. Diagnostic OAE and PKs for ototoxic medications should be further investigated in a larger study population. Keywords: neonates, aminoglycoside, amikacin, ototoxicity, outer hair cell, otoacoustic emission