Amikacin or Vancomycin Exposure Alters the Postnatal Serum Creatinine Dynamics in Extreme Low Birth Weight Neonates

Abstract

Background: Disentangling renal adverse drug reactions from confounders remains a major challenge to assess causality and severity in neonates, with additional limitations related to the available tools (modified Kidney Disease Improving Global Outcome, or Division of Microbiology and Infectious Diseases pediatric toxicity table). Vancomycin and amikacin are nephrotoxic while still often prescribed in neonates. We selected these compounds to assess their impact on creatinine dynamics as a sensitive tool to detect a renal impairment signal. Methods: A recently developed dynamical model that characterized serum creatinine concentrations of 217 extremely low birth weight (<1000 g, ELBW) neonates (4036 observations) was enhanced with data on vancomycin and/or amikacin exposure to identify a potential effect of antibiotic exposure by nonlinear mixed-effects modelling. Results: Seventy-seven percent of ELBW patients were exposed to either vancomycin or amikacin. Antibiotic exposure resulted in a modest increase in serum creatinine and a transient decrease in creatinine clearance. The serum creatinine increase was dependent on gestational age, illustrated by a decrease with 56% in difference in serum creatinine between a 24 or 32-week old neonate, when exposed in the 3rd week after birth. Conclusions: A previously described model was used to explore and quantify the impact of amikacin or vancomycin exposure on creatinine dynamics. Such tools serve to explore minor changes, or compare minor differences between treatment modalities.

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

“…In addition, this model can quantify drug impact on kidney function after beginning well-known nephrotoxic therapies, such as amikacin and vancomycin. 3 …”

“…In addition, this model can quantify drug impact on kidney function after beginning well-known nephrotoxic therapies, such as amikacin and vancomycin. 3 In addition to the maturation of liver and kidney function, body composition also changes with age. For example, the body of a preterm neonate consists of 80% total body water, whereas a term neonate has 70%, decreasing to 60% by the toddler age.…”

Plasma concentration and eGFR in preterm and term neonates receiving gentamicin or successive amikacin therapy

“…The lack of improvement of renal function with increasing neonatal chronological age observed in amikacin neonates could be due to the successive exposure of the newborns to the two aminoglycosides which resulted in nephrotoxicity. The impact of prolonged exposure to amikacin on postnatal serum creatinine dynamics in ELBW neonates has been reported [ 22 ]. However, it worth noting that in 89.6% of neonates receiving amikacin, piperacillin/tazobactam was also administered as a comedication.…”

Pharmacovigilance of nephrotoxic drugs in neonates: the Pottel method for renal signal detection in ELBW neonates

“…A previously reported dataset, initially used to de ne Scr trends and drug-toxicity signals in ELBW neonates admitted to the NICU of the University Hospitals Leuven in the two periods of July 2007 to August 2011 and June 2015 to March 2017, was re-used for this analysis [13,16,17]. This dataset contains retrospectively collected data on demographics, relevant clinical data (e.g.…”

“…In previous work on Scr patterns in ELBW neonates, a modest decrease of creatinine clearance and a shift of Scr of about 1 standard deviation (SD) in ibuprofen-exposed neonates was documented, as well as a minor increase of Scr when treated with amikacin and/or vancomycin [14,16,17]. In the present study, we investigated whether the Pottel method also enables detection of a drug-related nephrotoxic signal in the same dataset, as this approach would make detection more feasible bedside, as e.g.…”