Optimizing Therapy for Vancomycin-resistant Enterococcal Bacteremia in Children

Pranita D. Tamma; Alice J. Hsu

Disclosures

Curr Opin Infect Dis. 2014;27(6):517-527. 

In This Article

Linezolid

Linezolid, the first agent of the oxazolidinones, quickly replaced quinupristin-dalfopristin for the treatment of invasive VRE infections because of a more favorable side-effect profile, oral bioavailability, and coverage against E. faecalis.[29] Linezolid inhibits bacterial protein synthesis, specifically the initiation step, by binding to the 23S ribosomal RNA component of the 50S ribosomal subunit.[30] Notably, its site of action is different from that of other inhibitors of bacterial protein synthesis (e.g., chloramphenicol, aminoglycosides, macrolides), which interfere with the elongation process.[30] Therefore, cross-resistance between linezolid and other protein synthesis inhibitors is unlikely.[31]

Pharmacokinetic Data

Linezolid's oral bioavailability approaches 100%, allowing for early conversion from i.v. to oral therapy.[32] Furthermore, it achieves therapeutic levels in most tissues including bone, muscle, fat, lung, and cerebral fluid[33–39]The high degree of tissue penetration is at least partially caused by the low plasma protein binding (31%) of linezolid.[40]

Linezolid is primarily metabolized in the liver with approximately 30% being eliminated unchanged by the kidney.[31,41] Dosage modification is not required in patients with altered kidney or liver function. However, serum levels of linezolid can decrease to subtherapeutic levels after renal replacement therapy.[42]

Pharmacokinetic data are limited for infants under 1 year of age and considerable interindividual variability in plasma concentrations has been observed.[37,43–45] Because of lower systemic clearance values in preterm infants less than 7 days old, a dosing regimen of 10 mg/kg/dose every 12 h is suggested[46] with adjustment to 10 mg/kg/dose every 8 h for preterm neonates by the 7th day of life[45,46] (Table 1). For infants ≥34 weeks gestational age, 10 mg/kg/dose of linezolid every 8 h is recommended regardless of day of life.

Beyond day of life 7, infants have clearance values approximately three-fold greater than those of adolescents and adults.[43,47] Doses as high as 15 mg/kg/dose every 8 h have been used to treat VRE endocarditis in infants.[48]

Similarly, children under 12 years demonstrate faster linezolid clearance than older adolescents and adults.[31,41,47] Adolescents at least 12 years of age should receive the same dosage regimen as adults for most indications, including VRE bacteremia.[47]

Clinical Outcomes Data

Given the primarily bacteriostatic activity of linezolid against enterococci, it has had surprising success with treating infections even involving cardiac valves[49,50] or cerebrospinal fluid.[34,51,52] In a noncomparative, compassionate use programme of mostly adult patients, 251 treatment courses for VRE bacteremia demonstrated approximately 80% clinical cure.[50]

Evaluating 40 cancer patients with VRE infection randomized to receive linezolid 600 mg every 12 h or quinupristin-dalfopristin 7.5 mg/kg/dose every 8 h,[23] there were no differences in clinical responses, mortality, or relapse rates between the groups. Similarly, a retrospective study of 91 patients with VRE bacteremia found no difference in mortality between patients receiving these agents.[53] Although 30-day mortality was no different in another observational study including 113 patients, the development of resistance in blood isolates [defined as at least a four-fold increase in minimum inhibitory concentration (MIC)] was more frequently observed in the quinupristin-dalfopristin group than in the linezolid group at 11 vs. 0%, respectively.[54] Studies comparing linezolid and daptomycin are described in subsequent sections of this review.

Although a number of studies have been conducted evaluating the safety and efficacy of linezolid in children, most included few to no children with VRE bacteremia.[55–61] Linezolid has been successfully used to treat infections in infants and children with VRE ventriculitis, brain abscesses, endocarditis, necrotizing enterocolitis, and osteoarticular infections.[38,39,44,48,62–71]

Adverse Events

Notable adverse effects associated with linezolid use include thrombocytopenia, anemia, lactic acidosis, peripheral or optic neuropathy, and serotonin syndrome. After linezolid became commercially available, postmarketing surveillance included reports of myelosuppression, notably anemia and thrombocytopenia, prompting recommendations for complete blood cell count monitoring for patients expected to be receiving this agent for at least 2 weeks.[46] Thrombocytopenia has been described in up to 30% of both children and adults receiving linezolid[31,50,56,72–74] and typically resolves after discontinuation of the drug.[75] End-stage renal disease has been described as an independent risk factor for the development of thrombocytopenia during linezolid therapy.[75–80] Linezolid therapy has also been associated with transient and reversible anemia in patients of all ages with an incidence of 6 to 32%.[56,72,81,82]

Lactic acidosis associated with linezolid treatment has since been reported in a number of case reports in both children and adults.[83–86] Physiologic similarities between the bacterial 23S rRNA and the mammalian mitochondrial 16S rRNA supports the mechanism of linezolid-induced lactic acidosis as being related to structural homology between bacterial and mammalian mitochondrial rRNA.[83] Lactic acidosis generally manifests as nausea, emesis, and abdominal discomfort after several days to weeks of linezolid therapy and is reversible after discontinuation of the drug.

Peripheral and optic neuropathies are uncommon but important side effects of linezolid that have been described in the setting of prolonged linezolid administration[87–92] in 0.4 to 9% of patients treated with linezolid[50,93] and are occasionally irreversible.[88,89,92,93] Monitoring visual function is recommended for all patients receiving linezolid for extended periods. The adverse events of peripheral neuropathy and optic neuropathy are well described in the adult literature; however, limited information is available in pediatrics.[94–96] Eight cases of neuropathy in children, attributable to linezolid use, were identified in the FDA Adverse Events Reporting System from 2000 to 2009. Linezolid treatment duration ranged from 4 weeks to 1 year. Resolution of symptoms generally occurred between 2 weeks and 6 months after discontinuation of the agent.[97]

Serotonin syndrome is a progressive syndrome consisting of a clinical triad of behavioral changes, autonomic instability, and neuromuscular abnormalities from an excess of serotonin in the CNS.[98] Monoamine oxidase inhibitors are preferentially responsible for the metabolism of serotonin, along with epinephrine and norepinephrine.[99] Linezolid exhibits weak monoamine oxidase inhibition.[100] A review of FDA postmarketing adverse event reports identified 29 cases of serotonin syndrome exacerbated by linezolid use.[100] The majority of patients had an onset of serotonin toxicity within 7 days (range, 1–21 days) of initiating linezolid. Of the 16 patients for whom outcomes were reported, three patients died and six required interventions to prevent permanent impairment.

Controversy exists regarding whether linezolid and selective serotonin reuptake inhibitors (SSRIs) can be given concomitantly. A retrospective study including 52 patients who received concomitant linezolid and an SSRI and 20 patients who did not receive these agents concomitantly but within a 14-day period sought to answer this question.[101] Although the outcome was rare (3%) limiting the ability to draw meaningful conclusions, the investigators suggested that if a clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with these agents, without a 14-day washout period.[101] The package insert has a similar recommendation;[46] however, Micromedex[102] strongly cautions against concurrent use of linezolid and SSRIs and recommends waiting at least 14 days after discontinuing SSRIs before initiating linezolid. We believe that concomitant administration of these agents is appropriate on a case by case basis so long as patients and their caretakers are aware of concerning signs and symptoms suggestive of serotonin syndrome.

Resistance

The widespread clinical success of linezolid was quickly tempered by descriptions of linezolid-resistant VRE cases with subsequent reports of nosocomial transmission of linezolid-resistant VRE in hospitals.[2,70,103,104] Fortunately, enterococci resistant to linezolid remain relatively rare although with increased usage, ongoing surveillance is necessary. In large studies, cumulatively involving over 45 000 isolates from the US and Europe, linezolid resistance in VRE has been described in less than 2% of isolates.[50,105–107] As linezolid is a synthetic agent, there is a low probability of naturally occurring resistance mechanisms.[29] Nonsusceptible organisms usually demonstrate alterations in the 23S rRNA target, which remains the main resistance mechanism observed in enterococci.[105]

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