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Linezolid

A Review of its Use in the Management of Serious Gram-Positive Infections

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Summary

Abstract

Linezolid is the first of a new class of antibacterial drugs, the oxazolidinones. It has inhibitory activity against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant enterococci (VRE) and penicillinresistant Streptococcus pneumoniae. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp. and Bacteroides fragilis.

In controlled phase III studies, linezolid was as effective as vancomycin in the treatment of patients with infections caused by methicillin-resistant staphylococci and also demonstrated efficacy against infections caused by VRE. Further phase III studies have demonstrated that linezolid is an effective treatment for patients with nosocomial pneumonia, for hospitalised patients with communityacquired pneumonia, and for patients with complicated skin or soft tissue infections (SSTIs). In these studies, linezolid was as effective as established treatments, including third-generation cephalosporins in patients with pneumonia, and oxacillin in patients with complicated SSTIs. Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia.

Linezolid is a generally well tolerated drug. The most frequently reported adverse events in linezolid recipients were diarrhoea, headache, nausea and vomiting. Thrombocytopenia was also documented in a small proportion (about 2%) of patients treated with the drug.

Conclusions: Linezolid has good activity against Gram-positive bacteria, particularly multidrug resistant strains of S. aureus (including GISA), Enterococcus faecium and E. faecalis (including VRE). In controlled clinical trials, linezolid was as effective as vancomycin in eradicating infections caused by methicillinresistant Staphylococcus spp. and has demonstrated efficacy against infections caused by VRE. As the level of resistance to vancomycin increases among S. aureus and enterococci, linezolid is poised to play an important role in the management of serious Gram-positive infections.

Antibacterial Activity

Although their precise mechanism of action has not been determined, oxazolidinones are known to act via inhibition of the initiation phase of bacterial protein synthesis. It has been proposed that agents of this class disrupt the interaction of fMet-tRNA with the 50S subunit during formation of the preinitiation complex.

Linezolid has good activity against staphylococci, including strains resistant to methicillin, glycopeptides and other antibacterial agents. A recent trial that tested the in vitro activity of linezolid against 1707 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated between 1997 and 1999 reported 100% susceptibility to the drug [minimal inhibitory concentration (MIC) for 90% of strains (MIC90) 4 mg/L]. The drug also shows good activity against glycopeptideintermediate S. aureus (GISA) [MIC range 0.5 to 2 mg/L; n = 9], although data are limited at present.

In addition, linezolid is active against enterococci, including vancomycinresistant strains. In a study that evaluated the activity of the drug against recent (1997 to 1999) isolates, the MIC90 of linezolid was 4 mg/L for both Enterococcus faecalis (n = 3092) and E. faecium (n = 1503). All isolates of E. faecalis and 99.7% of E. faecium were susceptible to the drug.

Linezolid also shows good activity against penicillin-susceptible Streptococcus pneumoniae (mean weighted MIC90 1 mg/L) and against strains of S. pneumoniae with intermediate susceptibility or resistance to penicillin (mean weighted MIC901.6 mg/L), and S. pyogenes. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile and Peptostreptococcus spp., Bacteroides fragilis, Fusobacterium nucleatum and F. meningosepticum.

Linezolid shows only moderate in vitro inhibitory activity against Haemophilus influenzae (MIC908 mg/L) and Moraxella catarrhalis (MIC904 to 8 mg/L). Enterobacteriaceae and Pseudomonas aeruginosa are not susceptible to linezolid.

In vitro resistance to linezolid was not easily induced in Gram-positive bacteria, including S. aureus and S. epidermidis.

Pharmacokinetic Properties

Linezolid is rapidly and completely absorbed after oral administration, with a mean absolute bioavailability of about 100%. Peak plasma concentrations of linezolid are achieved in 1 to 2 hours. In volunteers, steady-state peak plasma concentrations were ≈12 and 18 mg/L after twice-daily administration of 375 and 625mg oral doses, respectively. Intravenous (IV) infusion of linezolid 500 or 625mg twice daily for 7.5 days produced respective steady-state Cmin values of 3.5 and 3.8 mg/L. The drug has a steady-state volume of distribution (Vss) of about 40 to 50L and is moderately (31%) bound to plasma proteins.

Linezolid appears to be primarily metabolised by oxidation of the morpholine ring, resulting in the formation of 2 inactive metabolites; the cytochrome P450 enzyme system does not appear to be involved in the metabolism of the drug. In volunteers, unchanged linezolid accounted for 90% of the circulating dose with the major metabolite accounting for <6%. 80 to 85% of a single 500mg oral dose was recovered in urine, and 7 to 12% in faeces, over a 7-day period following administration.

Total clearance (CL) and renal clearance (CLr) of linezolid were 7.2 and 3 L/h (120 and 50 ml/min), respectively, after oral or IV administration. The elimination half-life (t½) was 4.5 to 5.5 hours at steady-state or after a single dose.

Patient age did not influence the pharmacokinetic properties of an oral 600mg dose of linezolid in young versus older adult volunteers. The pharmacokinetic properties of linezolid were generally similar in children and adolescents (when various age groups were compared). Compared with adults, CL was elevated and t½ shorter (3 to 3.7h) in paediatric patients receiving similar dosages on a mg/kg basis.

Results of a study in volunteers with varying degrees of renal impairment indicate that the dosage of linezolid need not be adjusted in individuals with mild to moderately impaired renal function [creatinine clearance (CLcr) 10 to 39 ml/min and 40 to 79 ml/min]. In patients undergoing haemodialysis, the dialyser extraction ratio (mean value 38%) was constant throughout the dialysis session.

The disposition of linezolid does not appear to be affected by the presence of mild to moderate hepatic impairment and dosage adjustment does not seem to be warranted in this patient group.

Therapeutic Use

Linezolid demonstrated good efficacy in a compassionate use programme that evaluated the efficacy of the drug in patients with significant Gram-positive infections with no apparent alternative treatment option. Several patients who participated in the linezolid compassionate use programme were infected with E. faecium that developed resistance to linezolid during treatment.

In addition, linezolid showed good efficacy in controlled phase III studies that evaluated its use in the treatment of patients with infections caused by methicillinresistant staphylococci or vancomycin-resistant enterococci (VRE).

In the larger of the 2 trials, which was conducted in patients with mainly pneumonia, skin and soft tissue infections (SSTIs) or urinary tract infections (UTIs) caused by methicillin-resistant Staphylococcus spp. (MRSS), IV/oral linezolid 600mg every 12 hours was compared with IV vancomycin 1g every 12 hours. 94.2% of linezolid versus 87.3% vancomycin recipients achieved clinical success at the TOC assessment (clinically evaluable population). Respective microbiological eradication rates at the same time-point were 71.9 and 72.6%.

Linezolid was also effective in patients with infections (mainly pneumonia, SSTIs or UTIs) caused by VRE, producing clinical success rates of 81.3% at a dosage of 600mg every 12 hours, and 78.4% at a dosage of 400mg every 12 hours in clinically evaluable patients. Microbiological eradication was achieved in 30 of 35 (85.7%) microbiologically evaluable patients receiving the higher dose of linezolid and in 17 of 29 (58.6%) recipients of the lower dose (p = 0.015). Rates of study withdrawal were high in both of these phase III studies; however, withdrawal was seldom attributed to drug treatment.

Further phase III studies have demonstrated that linezolid is an effective treatment for pneumonia, including nosocomial pneumonia and community-acquired pneumonia requiring hospitalisation, and complicated SSTIs. In these studies, linezolid was as effective as established treatments including third-generation cephalosporins in patients with pneumonia, and oxacillin or flucloxacillin in patients with complicated SSTIs.

Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia.

Tolerability

Linezolid is a generally well tolerated drug. A total of 2046 patients received linezolid in 7 phase III studies and a further 2001 patients were treated with comparator drugs, including vancomycin, cefpodoxime proxetil, ceftriaxone, clarithromycin, dicloxacillin and oxacillin. The most frequently reported adverse events in recipients of linezolid were diarrhoea (incidence 8.3%), headache (6.5%), nausea (6.2%) and vomiting (3.7%).

Thrombocytopenia (platelet count <75% of the lower limit of normal and/or baseline values) occurred at a rate of 2.4% (range 0.3 to 10%) in patients treated with linezolid <600mg twice daily for <28 days in phase III trials. Thrombocytopenia in patients treated with linezolid appears to be dependent on the duration of therapy and, in most patients, platelet counts returned to the normal range/baseline during the follow-up period of the study.

Dosage and Administration

In patients with infection caused by VRE or MRSA, the recommended dosage of linezolid is 600mg every 12 hours. The drug may be given via IV infusion or orally. Dosage adjustment is not necessary when switching from IV to oral administration of linezolid. The recommended duration of treatment for VRE infections is 14 to 28 days. In patients with MRSA treated with linezolid in clinical trials, the duration of treatment, as defined by the study protocol, ranged from 7 to 28 days. The duration of treatment was determined by the treating physician based on the site and severity of infection, and on the clinical response of the patient.

The recommended dosage of linezolid for the treatment of patients with nosocomial or community-acquired pneumonia, or complicated SSTIs is 600mg every 12 hours for 10 to 14 days. In patients with uncomplicated SSTIs, the recommended dosage of linezolid is 400mg every 12 hours for 10 to 14 days.

Linezolid is a weak monoamine oxidase inhibitor and therefore has the potential to interact with adrenergic and serotonergic agents, although clinical effects were not observed during clinical studies.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Caroline M. Perry & Blair Jarvis

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  1. Caroline M. Perry
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  2. Blair Jarvis
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Correspondence to Caroline M. Perry.

Additional information

Various sections of the manuscript reviewed by: E. Bergogne-Bérézin, University Bichat-Claude Bernard, Paris, France; M.C. Birmingham, Kenmore, New York, USA; D.J. Diekema, Division of Infectious Diseases, Division of Medical Microbiology, University of Iowa College of Medicine, Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, USA; A.P. Johnson, Antibiotic Resistance Monitoring and Reference Laboratory, Central Public Health Laboratory, Colindale, London, England; R. Leclercq, Service de Microbiologie, CHU Côte de Nacre, Caen, France; E. Rubinstein, Infectious Diseases Unit, Chaim Sheba Medical Center, Sackler School of Medicine, Tel-Hashomer, Israel; A.P. Wilson, Department of Clinical Microbiology, University College Hospital, London, England; R. Wise, Department of Medical Microbiology, City Hospital NHS Trust, Birmingham, England; M. Wood, Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, England.

Data Selection

Sources: Medical literature published in any language since 1980 on linezolid, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘linezolid’ or ‘U 100766’. EMBASE search terms were ‘linezolid’ or ‘U 100766’. AdisBase search terms were ‘linezolid’ or ‘PNU-100766’ or ‘U-100766’. Searches were last updated 26th February 2001.

Selection: Studies in patients with various infections who received linezolid. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Linezolid, infection, pharmacodynamics, pharmacokinetics, therapeutic use.

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Perry, C.M., Jarvis, B. Linezolid. Drugs 61, 525–551 (2001). https://doi.org/10.2165/00003495-200161040-00008

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