Vancomycin Toxicity in Neonates: A Review of the Evidence

Jodi M. Lestner; Louise F. Hill; Paul T. Heath; Mike Sharland

Disclosures

Curr Opin Infect Dis. 2016;29(3):237-247. 

In This Article

Abstract and Introduction

Abstract

Purpose of review Vancomycin is a first-line agent in the treatment of serious Gram-positive infections in the neonatal population. The published evidence on vancomycin toxicity in neonates is limited. This review summarizes preclinical studies and clinical trials describing vancomycin toxicity. We discuss proposed pathophysiology and summarize evidence supporting dose–response relationships, genetic and environmental determinants, and consider future research required to further define vancomycin toxicity.

Recent findings Current dosing regimens for vancomycin result in subtherapeutic levels in a large proportion of patients. Higher daily doses have been proposed, which have led to concerns regarding increased toxicity. Nephrotoxicity occurs in 1–9% of neonates receiving currently recommended doses. The incidence is highest in those receiving concomitant nephrotoxic drugs. Vancomycin-associated ototoxicity is rare in patients of all ages. Exposure–toxicity relationships in relation to nephrotoxicity and ototoxicity have not been clearly defined in neonates receiving vancomycin.

Summary Current evidence supports the favourable safety profile of vancomycin in neonates. Further studies that address safety concerns relating to high-dose intermittent dosing regimens are needed. Such studies must include robust and standardized definitions of renal and hearing impairment, and include follow-up of sufficient length to establish the long-term implications of experimental findings.

Introduction

Vancomycin is a glycopeptide bactericidal antibiotic that disrupts cell wall synthesis in Gram-positive bacteria.[1] Impurities from early fermentation processes were associated with significant toxicity when the drug was first introduced in the early 1950s. The drug's poor safety profile, along with its thick brown appearance, led to the disparaging nickname 'Mississippi mud'. Refined purification methods improved the safety profile of vancomycin, and Food and Drug Administration approval was granted in 1958. Despite this, safety concerns lingered, leading to the drug's limited use. In recent decades, clinical use has increased, however, owing to the rising incidence of infections caused by methicillin-resistant Staphylococcus aureus and other resistant Gram-positive pathogens that are susceptible to vancomycin.[2]

Vancomycin dosing strategies vary greatly and are generally based on a combination of postmenstrual age, postnatal age, weight and/or renal function (see Table 1). Therapeutic drug monitoring is widely advocated. Currently, clinical guidelines recommend target trough concentrations of 10–15 μg/ml.[3,4] However, recent studies suggest the need for target trough levels less than 15 μg/ml, based on the concern that lower trough concentrations may be selective for hetero-resistance.[5–7] In adults, higher daily doses of vancomycin (15 mg/kg 6 hourly) have yet to receive regulatory approval but have been proposed in recent consensus documents published by the Infectious Diseases Society of America, the American Society of Health-System Pharmacists and the Society of Infectious Diseases Pharmacists.[8–10] The use of higher vancomycin doses has raised concerns regarding the potentially increased risk of toxicity. The significance of these concerns in paediatric populations is unclear. Here, we summarize the current evidence relating to vancomycin toxicity including proposed pathophysiology, dose–toxicity relationships, genetic and environmental factors and future research needs. Studies pertaining to vancomycin-induced toxicity between March 1950 and March 2015 were identified from PubMed, Embase, Cochrane Controlled Trial Registry and Medline databases. The following search terms were used 'vancomycin', 'toxicity', 'adverse effects', 'nephrotoxicity', 'kidney disease', 'renal impairment', 'ototoxicity', 'hearing loss', 'neonate', 'infant', 'child' and 'paediatrics'.

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