Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin

Abstract

Objective: To review the current literature describing pharmacology, pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and safety of linezolid and daptomycin for the treatment of central nervous system (CNS) infections caused by vancomycin-resistant Enterococcus (VRE) faecium. Data Sources: A literature search of PubMed/MEDLINE databases was conducted (from 1950 to April 2020) utilizing the following key terms: vancomycin-resistant Enterococcus, VRE, meningitis, ventriculitis, CNS infection, daptomycin, and linezolid. Study Selection and Data Extraction: All relevant studies and case reports describing the treatment of VRE faecium from the CNS with linezolid or daptomycin were included. Data Synthesis: A total of 17 reports describing 22 cases were identified. There were 15 of 19 cases involving linezolid that reported clinical cure, of which 53.3% were monotherapy. Only 5 of 9 cases involving intravenous (IV) daptomycin resulted in cure; all 4 cases reporting daptomycin administration via the intrathecal or intraventricular route achieved clearance from the cerebrospinal fluid (CSF). Relevance to Patient Care and Clinical Practice: The preferred treatment option for VRE faecium infections involving the CNS remains unclear. Supporting evidence through observational case reports have described varying outcomes with linezolid and daptomycin. This review compares reported outcomes between the 2 agents and provides a thorough discussion on drug- and patient-specific variables to consider. Conclusions: Linezolid monotherapy appears to be safe and effective for the treatment of susceptible-VRE faecium CNS infections, with consideration of therapeutic drug monitoring in special populations and with prolonged treatment duration. Daptomycin is an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. The role of IV daptomycin remains inconclusive.

Clinical Pharmacokinetics of Daptomycin

“…After IV infusion of daptomycin 10 mg/kg to patients with meningitis, daptomycin has a minimal penetration into central nervous system (<1% which was corrected to 11.5% after accounting for protein binding). [52,61] By contrast, daptomycin can be an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. [52] Distribution into peritoneal fluid.…”

“…[52,61] By contrast, daptomycin can be an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. [52] Distribution into peritoneal fluid. After IV administration, Gika et al reported good daptomycin distribution within peritoneal fluid, although the ratio between area under the curve (AUC) was not indicated.…”

Inadequate Cerebrospinal Fluid Concentrations of Available Salvage Agents Further Impedes the Optimal Treatment of Multidrug-Resistant Enterococcus faecium Meningitis and Bacteremia

“…This is further illustrated by the lack of VREf infection found on autopsy, suggesting that antimicrobial therapy may have been effective at eradicating the pathogen from extravascular tissue where drug concentrations were likely sufficiently high, but not in the CSF. Importantly, to our knowledge this is the first study to report CSF concentrations of oritavancin and tedizolid in humans and one of exceedingly few to measure CSF concentrations of any anti-VREf agent in a patient without an indwelling device such as an extraventricular drain or ventriculoperitoneal shunt [ 5 , 6 , 33 ]. Our work also adds to the currently limited data regarding the in vitro susceptibility of new agents against resistant strains of VREf, specifically eravacycline, omadacycline, and lefamulin [ 34 , 35 , 36 , 37 , 38 ].…”

“…These difficulties are further augmented when attempting to treat VREf in less pervious body sites, such as the central nervous system (CNS) [ 5 ]. Enterococci are responsible for just 0.3–4% of reported bacterial meningitis cases, with VREf representing exceptionally few of these infections [ 6 ].…”

Vancomycin-Resistant Enterococci (VRE) in Nigeria: The First Systematic Review and Meta-Analysis

“…Genetic elements known as van genes confer resistance to Enterococcus of which vanA and vanB present mostly in E. faecium occur the most and are well-distributed, especially among hospital isolates [ 13 ]. There is a disturbing trend following several reports on the resistance of enterococcus to linezolid and daptomycin, two potent antibiotics used against VRE infection [ 14 , 15 ] while Melese et al [ 16 ] stated that the persistent increase in nosocomial infection caused by VRE is being reported by several studies.…”