Update on linezolid: the first oxazolidinone antibiotic
October 2005, Vol. 6, No. 13, Pages 2315-2326
Mark H Wilcox
Old Medical School, Department of Microbiology, Leeds General Infirmary, Leeds LS1 3EX, UK. Mark.Wilcox@Leedsth.nhs.uk
Linezolid is the first of an entirely new class of antibiotics, the oxazolidinones, in decades. It has a spectrum of activity against virtually all important Gram-positive pathogens. The unique mechanism of action of linezolid makes cross-resistance with other antimicrobial agents unlikely. Linezolid has both intravenous and oral formulations and the latter is 100% bioavailable. Since its first approval and marketing in March 2000 in the US, linezolid has gained approval for use in many other countries for the treatment of community-acquired and nosocomial pneumonia, complicated and uncomplicated skin and soft-tissue infections, and infections caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, including cases with concurrent bacteraemia. Several earlier comprehensive reviews summarised the chemistry, mechanism of action, pharmacokinetics, clinical efficacy and safety profile of linezolid. The present review provides an update on the latest data regarding the antimicrobial activity of linezolid versus other commonly used agents, the clinical and health-economic outcomes of linezolid versus vancomycin and teicoplanin, and safety issues.
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Linezolid: A new antibioticXiong, Y.-Q., et al.
The U.S. Food and Drug Administration recently approved linezolid for the treatment of patients with methicillin-resistant staphylococcal and vancomycin-resistant enterococcal infections. This oxazolidinone antibacterial agent represents the first approved antibiotic of a new structural class in 35 years. Linezolid is a synthetic compound that acts by inhibiting the initiation complex formation in bacterial protein synthesis, a mechanism of action distinct from other commercially available antibiotics. Thus, cross-resistance between linezolid and other current antimicrobial agents has not been demonstrated to date. Linezolid has a wide spectrum of in vitro activity against Gram-positive organisms, including methicillin-resistant staphylococci, penicillin-resistant pneumococci and vancomycin-resistant enterococci. Some anaerobes, such as Clostridium spp., Peptostreptococcus spp. and Prevotella spp. are also susceptible to linezolid. In addition, linezolid has exhibited good efficacy in experimental animal models of acute otitis media, endocarditis and meningitis due to many common aerobic Gram-positive bacteria. In clinical trials involving hospitalized patients with skin/soft tissue infections, community-acquired pneumonia and serious Gram-positive bacterial infections, linezolid appeared to be an effective treatment option, comparable in efficacy to vancomycin.
Journals on the Web
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Linezolid--a review of the first oxazolidinone.
The Swedish Institute for Infectious Disease Control, SE17182 Solna, Sweden. Ragnar.Norrby@smi.ki.se
Linezolid is the first of a truly new class of antibiotics, the oxazolidinones. It acts as an inhibitor of bacterial protein synthesis by blocking the formation of the 70S ribosomal initiation complex. Its activity is bacteriostatic against some species (e.g., enterococci) and bactericidal against others (e.g., pneumococci). The antibacterial spectrum of linezolid includes Gram-positive pathogens and some Gram-negative anaerobic species but not Gram-negative aerobes.
Importantly, multi-drug resistant organisms such as methicillin-resistant staphylococci, staphylococci with reduced susceptibility to vancomycin, penicillin- and macrolide-resistant pneumococci and vancomycin-resistant enterococci are fully susceptible to linezolid. Linezolid has almost 100% bioavailability and the area under the plasma concentration curve is identical after oral and iv. administration. This enables initial oral administration of linezolid in those patients who can absorb the drug normally and also an early step-down therapy from iv. to oral. Controlled, randomised clinical studies have documented efficacy and safety of linezolid in hospital- and community-acquired pneumonia, uncomplicated and complicated skin and soft tissue infections and infections caused by vancomycin-resistant enterococci. The safety and tolerability of linezolid are advantageous.
Linezolid is a weak and reversible monoamine oxidase (MAO) inhibitor and although no increased frequency of adrenergic or serotonergic adverse events has been reported, it is recommended that linezolid is used with caution in patients treated with other MAO inhibitors.
Full Text Article
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Efficacy of linezolid versus comparator therapies in Gram-positive infections.
Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK. firstname.lastname@example.org
Treatment of Gram-positive bacterial infections is currently a therapeutic challenge because many of these pathogens are now resistant to standard antimicrobial agents. The emergence of multidrug-resistant, Gram-positive pathogens emphasizes the need for new antimicrobial therapy. Linezolid is an oxazolidinone antibiotic with a novel mechanism of action that works by inhibiting bacterial protein synthesis by blocking formation of the initiation complex. It is active against Gram-positive organisms resistant to other antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci (VRE). Results are encouraging from several large-scale, randomized, Phase III trials comparing the efficacy and safety of linezolid with standard comparator agents for the treatment of nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and infections due to MRSA and VRE. Intravenous/oral linezolid is a promising antimicrobial agent and provides the clinician with an additional treatment option, particularly among the limited therapies for resistant Gram-positive bacterial infections.
Full text Article
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Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.
Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.Kaplan SL, Deville JG, Yogev R, Morfin MR, Wu E, Adler S, Edge-Padbury B, Naberhuis-Stehouwer S, Bruss JB; Linezolid Pediatric Study Group.Baylor College of Medicine and Texas Children's Hospital, 6621 Fannin Street, MC3-2371, Feigin Center No. 1150, Houston, TX 77030, USA. Skaplan@bcm.tmc.edu
BACKGROUND: Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci.
OBJECTIVE: To assess clinical efficacy and safety of linezolid vs.vancomycin in antibiotic-resistant Gram-positive infections in children.DESIGN Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days.
RESULTS: There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs.74% (P = 0.36) and 89% vs.85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs.94%; P = 0.82), methicillin-resistant S. aureus (88% vs.90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs.83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 +/- 4.8; 10.9 +/- 5.8 days, respectively; P < p =" 0.003).">
CONCLUSIONS: Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 12913766 [PubMed - indexed for MEDLINE]
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Linezolid - Indian Pediatrics
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Linezolid: a pharmacoeconomic review of its use in serious Gram-positive infections.
Plosker GL, Figgitt DP.Adis International Limited, Auckland, New Zealand. email@example.com
Linezolid (Zyvox), the first available oxazolidinone antibacterial agent, has good activity against Gram-positive pathogens, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Randomised multicentre trials in patients with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. In some subgroup analyses, which must be interpreted with a degree of caution, clinical advantages were noted for linezolid (e.g. versus vancomycin in confirmed MRSA nosocomial pneumonia and MRSA-complicated skin and soft tissue infections). Although generally well tolerated, gastrointestinal adverse effects are relatively common with linezolid and it has been associated with thrombocytopenia and myelosuppression. The oral bioavailability of linezolid is approximately 100%, thus allowing sequential intravenous-to-oral administration without changing the drug or dosage regimen. Healthcare resource use data from various countries indicate that this practical advantage translates into at least a trend towards reduced length of hospital stay compared with vancomycin, which may offset its several-fold higher acquisition cost. Modelled analyses from the US, despite some limitations, indicate that, compared with vancomycin, linezolid is associated with lower total hospitalisation costs for the treatment of patients with cellulitis and has a favourable incremental cost-effectiveness ratio of approximately US30,000 dollars per QALY gained (2001 value) for patients with ventilator-associated pneumonia. Broadly similar results have also been reported in modelled analyses from other countries. In conclusion, for patients with serious Gram-positive infections, including those caused by suspected or proven multidrug-resistant pathogens such as MRSA, linezolid is an effective and generally well tolerated therapeutic option. Linezolid is currently the only antibacterial agent with good activity against MRSA that can be administered orally (as well as intravenously). It may be particularly useful as an alternative to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Healthcare resource use studies and pharmacoeconomic analyses generally support the use of linezolid in some subgroups of patients, although results should be interpreted with due consideration of the study limitations.
PMID: 16153136 [PubMed - indexed for MEDLINE]