Early lactic acidosis associated with linezolid therapy in paediatric patients

https://doi.org/10.1016/j.ijantimicag.2014.06.017Get rights and content

Highlights

  • Lactic acidaemia or acidosis occurred in 32% of a series of 50 children treated with linezolid, but did not require adjustment or discontinuation of treatment.

  • The onset of lactic acidaemia (median 1.5 days; range 1–72 days) and lactic acidosis (median 2 days; range 1–13 days) was much earlier than is usually reported in adults.

  • Being an ICU patient and requiring mechanical ventilation were strong risk factors for development of lactic acidosis and acidaemia.

  • Linezolid use in children appears to be as safe and effective as in adults.

Abstract

Linezolid, an oxazolidinone class antibiotic, is used to treat Gram-positive infections, including those due to meticillin-resistant staphylococci and vancomycin-resistant enterococci. In paediatric clinical trials, the frequency of possible linezolid-related adverse events ranged from 18.8% to 25.6%. The most commonly reported side effects are gastrointestinal disturbances, headache, rash and liver function alterations. Lactic acidosis has been reported as a side effect of linezolid treatment, and limited data suggest it may be more common in children. We report on our experience of treating 50 children aged 1 month to years with linezolid. Eight patients (16%) developed lactic acidosis and another eight (16%) had lactic acidaemia without acidosis. Onset of lactic acidaemia (median 1.5 days; range 1–72 days) and lactic acidosis (median 2 days; range 1–13 days) tended to be early. Being an ICU patient and requiring mechanical ventilation significantly increased the risk of lactic acidaemia or acidosis (OR = 22.75, 95% CI 4.24–122.09; OR = 32.67, 95% CI 5.83–183.19, respectively; P < 0.001). All 16 patients were able to continue linezolid treatment. Linezolid therapy was effective (microbiologic and/or clinical cure) in 39 patients (78%). Nine patients died whilst receiving linezolid treatment; the deaths were not considered to be a result of linezolid treatment failure. Two patients who did not respond clinically to linezolid recovered after their treatment was changed to vancomycin. Linezolid use in children appears to be as safe and effective as in adults. However, lactic acidosis appears to be more common, and occur earlier, in children.

Introduction

Linezolid is an oxazolidinone class antibiotic that inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit [1], preventing the formation of a functional 70S initiation complex that is necessary for bacterial protein synthesis. Linezolid exhibits a broad spectrum of activity against Gram-positive bacteria, including meticillin-resistant staphylococci, vancomycin-resistant enterococci (VRE), penicillin-resistant Streptococcus pneumoniae and Nocardia spp. [2], [3]. Based on evidence from prospective studies, case reports and case series, the US Food and Drug Administration (FDA) has approved linezolid for use in infants and children of all ages [1], [4], [5], [6], [7]. The aim of this study was to analyse the safety of linezolid in a large cohort of children, with particular emphasis on the occurrence of lactic acidosis.

Section snippets

Materials and methods

Patients aged ≤18 years who received ≥3 days of linezolid therapy between February 2007 and July 2012 at Ankara Hematology and Oncology Research Hospital (Ankara, Turkey) were included in the study. Data collected for each patient included: age; sex; diagnosis; day of therapy on which lactic acidaemia, and lactic acidosis if present, started; accompanying antimicrobial therapy if applicable; therapy modification if needed; outcome; and mortality. The normal range for serum lactate

Results

In total, 50 paediatric patients (20 female and 30 male) aged between 1 month and 17 years (median 3.5 years; mean 6.1 years) received ≥3 days of linezolid therapy; 22 were in the intensive care unit (ICU), of whom 20 were being mechanically ventilated. Indications for linezolid therapy are summarised in Table 1. Of the 50 patients, 31 (62%) had unresolved staphylococcal infections and the remainder had infections with VRE. In all patients, linezolid was administered at a dosage of 10 mg/kg

Discussion

Use of linezolid in children has been evaluated in several clinical studies and reviews [5], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Lactic acidosis is considered a rare adverse event that was first reported in 2003 by Apodaca and Rakita [17], who described the case of a 52-year-old woman developing lactic acidosis after 11 weeks of oral linezolid therapy. Since then, several additional cases have been published [18], [19], [20], [21], [22], [23], mostly in older patients [24].

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