Association between Nephrotoxic Drug Combinations and Acute Kidney Injury in the Neonatal Intensive Care Unit

Salerno, Sara; Liao, Yuting; Jackson, Wesley M.; Greenberg, Rachel G.; McKinzie, Cameron J.; McCallister, Ashley; Benjamin, Daniel K.; Laughon, Matthew M.; Sanderson, Keia; Clark, Reese H.; González, Daniel

doi:10.1016/j.jpeds.2020.08.035

Cited by 34 publications

(22 citation statements)

References 33 publications

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“…This effect did not significantly differ (27%) when assessing the combination therapy or improved the model fit. Interestingly, Salerno et al very recently reported on the association between nephrotoxic drugs (including aminoglycosides, i.e., gentamicin or tobramycin, and vancomycin) and AKI, using the modified KDIGO criteria in a larger cohort of preterm (22–36 weeks) cases [ 31 ]. Seventeen percent of cases in this dataset were classified with at least stage 1 AKI ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Seventeen percent of cases in this dataset were classified with at least stage 1 AKI ( Table 1 ). However, based on Odd ratios with the combined exposure to gentamicin + indomethacin as reference, duration of therapy (days) and sepsis, but not combined exposure to aminoglycosides + vancomycin, it was associated with an increased odd of AKI [ 31 ]. Related to this analysis, we would like to repeat that the need for inotropic agents (as surrogate marker for sepsis) was not an independent covariate in our model.…”

Section: Discussionmentioning

confidence: 99%

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

Donge

Smits

Anker

et al. 2021

IJERPH

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Donge

Smits

Anker

et al. 2021

IJERPH

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“…The UK Medicines for Neonates research program described the feasibility of developing routinely recorded operational clinical data from electronic patient records as a reliable resource to improve health care 46 . The earlier mentioned Salerno et al analysis on the association of drug combinations and their duration of administration with AKI incidence serves as an illustration on the potential of such an approach 24 . As another illustration, the association between caffeine exposure and sleep‐wake behavior patterns in preterm neonates has been described.…”

Section: Discussionmentioning

confidence: 99%

“…When combined in a cohort of preterm neonates with an AKI incidence of 17%, and compared to gentamicin + indomethacin as reference, vancomycin + piperacillin‐tazobactam, and furosemide + tobramycin were associated with a proportionally lower risk of developing AKI. However, the main driver to develop AKI was a longer duration (total dose, exposure) of a combination of nephrotoxic therapies 24 . In another study, the Baby NINJA (Nephrotoxic Injury Negated by Just‐in‐Time Action) study documented that a reduction of exposure of nephrotoxic drugs (duration of treatment) resulted in a decrease in AKI incidence and severity 25 .…”

Section: Signal Detectionmentioning

confidence: 99%

Dose‐Related Adverse Drug Events in Neonates: Recognition and Assessment

Allegaert

Anker

2021

The Journal of Clinical Pharma

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The efficacy and safety of a drug is dose or exposure related, and both are used to assess the benefit‐risk balance of a given drug and ultimately to decide on the specific drug license, including its dose and indication(s). Unfortunately, both efficacy and safety are much more difficult to establish in neonates, resulting in very few drugs licensed for use in this vulnerable population. This review will focus on dose‐related adverse events in neonates. Besides the regulatory classification on seriousness, adverse event assessment includes aspects related to signal detection, causality, and severity. Disentangling confounders from truly dose‐related adverse drug events remains a major challenge, as illustrated for drug‐induced renal impairment, drug‐induced liver injury, and neurodevelopmental outcome. Causality assessment, using either routine tools (Naranjo algorithm, World Health Organization's Uppsala Monitoring Center causality tool) or a Naranjo algorithm tailored to neonates, still does not sufficiently and reliably document causality in neonates. Finally, very recently, a first neonatal severity‐grading tool for neonates has been developed. Following the development of advanced pharmacokinetic approaches and techniques to predict and assess drug exposure, additional efforts are needed to truly and fully assess dose adverse drug events. To further operationalize the recently developed tools on causality and severity, reference databases on a palette of biomarkers and outcome variables and their covariates are an obvious next step. These databases should subsequently be integrated in modeling efforts to truly explore safety outcome, including aspects associated with or caused by drug dose or exposure.

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“…The U.S. FDA experience with drug development in neonates is minimal; of 301 pediatric drug development programs reviewed in 2015, only 26 included neonatal labeling, and only 8 drugs had studies that contained sufficient neonate data to support population PK (POPPK) analysis in this age group 4 . In 2021, clinical trial networks like the Pediatric Trials Network continue to make progress in informing pediatric labeling for the understudied neonatal populations 5–11 …”

mentioning

confidence: 99%