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Serious infection with vancomycin-resistant enterococci (VRE) usually occurs in patients with significantly compromised host defences and serious co-morbidities, and this magnifies the importance of effective antimicrobial treatment. Assessments of antibacterial efficacy against VRE have been hampered by the lack of a comparator treatment arm(s), complex treatment requirements including surgery, and advanced illness-severity associated with a high crude mortality. Treatment options include available agents which don't have a specific VRE approval (chloramphenicol, doxycycline, high-dose ampicillin or ampicillin/sulbactam), and nitrofurantoin (for lower urinary tract infection). The role of antimicrobial combinations that have shown in vitro or animal-model in vivo efficacy has yet to be established. Two novel antimicrobial agents (quinupristin/ dalfopristin and linezolid) have emerged as approved therapeutic options for vancomycin-resistant Enterococcus faecium on the basis of in vitro susceptibility and clinical efficacy from multicentre, pharmaceutical company-sponsored clinical trials. Quinupristin/dalfopristin is a streptogramin, which impairs bacterial protein synthesis at both early peptide chain elongation and late peptide chain extrusion steps. It has bacteriostatic activity against vancomycin-resistant E. faecium [minimum concentration to inhibit growth of 90% of isolates (MIC(90)) = 2 microg/ml] but is not active against Enterococcus faecalis (MIC(90 )= 16 microg/ml). In a noncomparative, nonblind, emergency-use programme in patients who were infected with Gram-positive isolates resistant or refractory to conventional therapy or who were intolerant of conventional therapy, quinupristin/dalfopristin was administered at 7.5 mg/kg every 8 hours. The clinical response rate in the bacteriologically evaluable subset was 70.5%, and a 65.8% overall response (favourable clinical and bacteriological outcome) was observed. Resistance to quinupristin/dalfopristin on therapy was observed in 6/338 (1.8%) of VRE strains. Myalgia/arthralgia was the most frequent treatment-limiting adverse effect. In vitro studies which combine quinupristin/dalfopristin with ampicillin or doxycyline have shown enhanced killing effects against VRE; however, the clinical use of combined therapy remains unestablished. Linezolid, an oxazolidinone compound that acts by inhibiting the bacterial pre-translational initiation complex formation, has bacteriostatic activity against both vancomycin resistant E. faecium (MIC(90) = 2 to 4 microg/ml) and E. faecalis (MIC(90) = 2 to 4 microg/ml). This agent was studied in a similar emergency use protocol for multi-resistant Gram-positive infections. 55 of 133 evaluable patients were infected with VRE. Cure rates for the most common sites were complicated skin and soft tissue 87.5% (7/8), primary bacteraemia 90.9% (10/11), peritonitis 91.7% (11/12), other abdominal/pelvic infections 91.7% (11/12), and catheter-related bacteraemia 100% (9/9). There was an all-site response rate of 92.6% (50/54). In a separate blinded, randomised, multicentre trial for VRE infection at a variety of sites, intravenous low dose linezolid (200mg every 12 hours) was compared to high dose therapy (600 mg every 12 hours) with optional conversion to oral administration. A positive dose response (although statistically nonsignificant) was seen with a 67% (39/58) and 52% (24/46) cure rate in the high- and low-dose groups, respectively. Adverse effects of linezolid therapy have been predominantly gastrointestinal (nausea, vomiting, diarrhoea), headache and taste alteration. Reports of thrombocytopenia appear to be limited to patients receiving somewhat longer courses of treatment (>14 to 21 days). Linezolid resistance (MIC > or = 8 microg/ml) has been reported in a small number of E. faecium strains which appears to be secondary to a base-pair mutation in the genome encoding for the bacterial 23S ribosome binding site. At present a comparative study between the two approved agents for VRE (quinupristin/dalfopristin and linezolid) has not been performed. Several investigational agents are currently in phase II or III trials for VRE infection. This category includes daptomycin (an acidic lipopeptide), oritavancin (LY-333328; a glycopeptide), and tigilcycline (GAR-936; a novel analogue of minocycline). Finally, strategies to suppress or eradicate the VRE intestinal reservoir have been reported for the combination of oral doxycyline plus bacitracin and oral ramoplanin (a novel glycolipodepsipeptide). If successful, a likely application of such an approach is the reduction of VRE infection during high risk periods in high risk patient groups such as the post-chemotherapy neutropenic nadir or early post-solid abdominal organ transplantation.
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PMID:Treatment options for vancomycin-resistant enterococcal infections. 1182 58

The vast majority of community-acquired skin and soft tissue infections (SSTIs) are caused by gram-positive cocci or are polymicrobial in nature. Hospital-acquired SSTIs are caused by gram-positive cocci in more than 50% of patients. Multidrug-resistant gram-positive cocci are rarely associated with community-acquired SSTIs but are frequently found in hospital-acquired SSTIs. Linezolid is the first member of a new class of antibiotics, the oxazolidinones. These antimicrobial agents have a unique mechanism of action and exhibit excellent activity against a variety of gram-positive organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Linezolid is 100% orally absorbed, allowing for easy intravenous-to-oral continuation therapy. There is considerable clinical experience with the use of linezolid in SSTIs in phase II and III clinical trials. In comparative trials, linezolid was as effective as oxacillin-dicloxacillin or flucloxacillin in patients with complicated SSTIs caused by gram-positive organisms. Linezolid was also associated with significantly earlier hospital discharge than comparator agents among patients with SSTIs. It was equally effective as vancomycin in patients with SSTIs caused by methicillin-resistant Staphylococcus aureus and has also demonstrated efficacy in patients with SSTIs caused by vancomycin-resistant enterococci. Linezolid is well tolerated: the most common adverse events (gastrointestinal effects, headache) are reported in frequencies similar to those reported for comparator agents. Myelosuppression has been reported after prolonged administration but is reversible after discontinuation of the drug. Overall, linezolid has favorable efficacy and safety profiles and will be an increasingly useful option for the treatment of SSTIs, particularly those due to multidrug-resistant, gram-positive organisms.
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PMID:Efficacy and safety of linezolid in the treatment of skin and soft tissue infections. 1262 92

The pharmacology, antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effects of linezolid are reviewed. Linezolid, the only oxazolidinone antimicrobial approved for use in the United States, has significant activity against gram-positive bacteria, including penicillin-, cephalosporin-, and vancomycin-resistant species. Linezolid inhibits bacterial protein synthesis via binding to the 50S ribosomal subunit to prevent translation. The drug lacks cross-resistance with other antimicrobials. Linezolid is primarily excreted renally as unchanged drug. The measured plasma half-life of four to five hours permits twice-daily administration for all indicated infections. Virtually complete oral bioavailability allows for 1:1 conversion between the intravenous and oral dosage forms. Controlled comparative clinical trials demonstrate that linezolid is effective in the treatment of vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus (MRSA) infections, nosocomial and community-acquired pneumonia, and skin and skin-structure infections due to susceptible organisms. The recommended dosage is 600 mg i.v. or p.o. twice daily for all indications except uncomplicated skin and skin-structure infections (400 mg twice daily); adjustments for mild to moderate renal or hepatic impairment are not necessary. Clinically important interactions with monoamine oxidase inhibitors have not been observed. Reversible myelosuppression has been observed in a few patients. Linezolid has gram-positive activity comparable to that of vancomycin, is effective in a variety of infections, and is well tolerated, with diarrhea, headache, and nausea being the most frequently reported adverse effects. Linezolid provides a reasonable therapeutic alternative for patients with vancomycin-resistant E. faecium infections and patients infected with MRSA who cannot tolerate vancomycin.
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PMID:Linezolid: an oxazolidinone antimicrobial agent. 1250 40

Clinical trials have shown that linezolid (600 mg twice daily in adults) is safe and generally well tolerated for up to 28 days. Drug-related adverse events, which are typically mild to moderate in intensity and of limited duration, include diarrhoea, nausea and headache in adults, and diarrhoea, loose stools and vomiting in children. Clostridium difficile-related complications with linezolid are uncommon. Linezolid is a weak, reversible monoamine oxidase inhibitor: foods containing high concentrations of tyramine should be avoided, and linezolid should be used with caution in patients taking adrenergic or serotonergic agents or in those with uncontrolled hypertension. In the majority of patients, linezolid has minimal adverse effects on blood chemistry or haematology. There have been case reports of reversible thrombocytopenia, anaemia and neutropenia associated with linezolid therapy. In Phase III studies, 2.4% of patients treated with linezolid and 1.5% of patients treated with comparator drugs developed reversible thrombocytopenia (P = 0.066), but there was no evidence of an increased risk of agranulocytosis, aplastic anaemia or other irreversible blood dyscrasias. Reduced platelet counts were associated with linezolid treatment for >/=2 weeks; complete blood counts should be monitored weekly in patients receiving linezolid for more than 14 days and treatment should be discontinued if there is evidence of myelosuppression.
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PMID:Safety and tolerability of linezolid. 1273 Jan 42

Linezolid, an oxazolidinone antibiotic, has 100% oral bioavailability and favorable activities against gram-positive pathogens including multidrug-resistant staphylococci, enterococci, and pneumococci. Safety assessments were conducted for 2,046 linezolid-treated patients and 2,001 comparator drug-treated patients from seven controlled clinical trials comparing the activities of linezolid and comparator drugs against nosocomial and community-acquired pneumonia, skin and skin structure infections, and methicillin-resistant staphylococcal infections. Drug-related adverse events were primarily transient. The most frequent (> or = 2%) adverse events caused by linezolid and the comparator drugs were diarrhea (4.3 and 3.2%, respectively; P = 0.074), nausea (3.4 and 2.3%, respectively; P = 0.036), and headache (2.2 and 1.3%, respectively; P = 0.047). Treatment discontinuations due to drug-related events (2.4 and 1.9%, respectively), serious adverse events (11.4 and 10.6%, respectively), and deaths (4.8 and 4.9%, respectively) were similar. No clinically significant drug-related hematologic events were reported, and laboratory safety data were comparable. In the first 6 months of postmarketing surveillance, hematologic abnormalities were reported in 0.1% of linezolid-treated patients, but no irreversible blood dyscrasias were documented. The risk for transient, reversible hematologic effects from treatment with linezolid should be considered together with the clinical benefits associated with its use.
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PMID:Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies. 1276 Aug 54

Linezolid is an oxazolidinone antibacterial agent that has inhibitory activity against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. The systemic clearance and, therefore, the area under the plasma concentration-time curve and elimination half-life of linezolid change with increasing age in pediatric patients. With the exception of pre-term neonates aged <1 week, systemic clearance is more rapid in pediatric patients aged 0-11 years than in adolescents. The pharmacokinetic profile of linezolid is similar in adolescents and adults. Linezolid was as effective as vancomycin in the treatment of pediatric patients with Gram-positive infections (clinical cure rate 89.3% vs 84.5%), and as effective as cefadroxil in the treatment of children and adolescents with Gram-positive uncomplicated skin and skin structure infections (91.0% vs 90.0%) in the clinically evaluable population of two randomized, comparator-controlled trials. The clinical cure rate with linezolid was 92.4% in a noncomparative trial in hospitalized pediatric patients with community-acquired pneumonia. All patients with proven pneumococcal pneumonia were considered cured. Linezolid is generally well tolerated. The most common drug-related adverse events in the comparator-controlled trials were diarrhea, nausea, and headache; most events were mild to moderate in severity.
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PMID:Linezolid: in infants and children with severe Gram-positive infections. 1276 93

A splenectomized patient with systemic lupus erythematosus, who had previously been treated with high doses of corticosteroids, presented with headaches and symptoms of a respiratory tract infection. A magnetic resonance imaging scan of the brain revealed a ring-enhancing lesion, and Nocardia asteroides was isolated from a stereotactic biopsy specimen. After adverse reactions to a number of antibiotics, infection control was finally achieved by the new oxazolidinone drug, linezolid. Nocardiosis should be considered as a differential diagnosis in all immunocompromised patients who develop an obscure infection; delay in diagnosis and subsequent initiation of appropriate treatment often results in a fatal outcome. Linezolid is a new option for the treatment of nocardiosis and is effective when given orally.
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PMID:Systemic nocardiosis in a splenectomized patient with systemic lupus erythematosus: successful treatment using linezolid. 1704 23

Linezolid is an oxazolidinone, a new class of antibacterial with a unique mechanism of action, namely inhibition of the formation of a functional 70S initiation complex in the 50S bacterial ribosomal subunit. Linezolid is highly active against multidrug-resistant Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate and vancomycin-resistant S. aureus, and vancomycin-resistant enterococci; its spectrum of activity also includes some anaerobic bacteria. Linezolid has been studied in several randomized controlled trials for the treatment of patients with community-acquired and nosocomial pneumonia, skin and soft tissue infections (SSTIs), urinary tract infections and bacteraemia. The available evidence suggests that linezolid is at least as effective as vancomycin for patients with nosocomial pneumonia, and there are some retrospective analyses supporting its superiority in comparison with vancomycin for MRSA nosocomial pneumonia, including ventilator-associated pneumonia. Linezolid is more effective than glycopeptides, macrolides and beta-lactams for SSTIs. The limited available data for the treatment of patients with bacteraemia suggest that it may be a better treatment option than vancomycin and beta-lactams for these patients, but questions have arisen regarding patients with catheter-related bacteraemias. Compared with other antibacterials, linezolid is associated with a greater frequency of adverse events, mainly nausea, vomiting, diarrhoea and headaches. Thrombocytopenia also occurs more frequently in patients taking linezolid but there is no increased frequency of anaemia. Other adverse events potentially related to linezolid therapy include fungal infections (moniliasis), hypertension and serotonin-like syndrome, tongue discolouration and taste alterations, dizziness, insomnia, rash and Clostridium difficile-related diarrhoea. The majority of adverse events develop after prolonged administration (i.e. >2 weeks) and subside shortly after discontinuation of linezolid. Peripheral or optic neuropathy, another possible adverse effect, is associated with an even longer duration of treatment (3-6 months). In conclusion, linezolid is an important treatment option for the treatment of patients with multidrug-resistant, Gram-positive bacterial infections. However, in order to reduce the possibility of development of resistance and preserve its activity, the use of linezolid should be restricted to treatment of patients with infections associated with high morbidity and mortality, particularly those caused by multidrug-resistant bacteria.
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PMID:Benefit-risk assessment of linezolid for serious gram-positive bacterial infections. 1870 90

Limited therapeutic options are available for vancomycin intermediate-resistant Staphylococcus Epidermidis (VISE) infections and no optimum therapy has been established. We report a case of VISE skull osteomyelitis that was successfully treated with linezolid. The patient was a 53-year-old man who presented with headache, nausea and dysphasia. Brain computerized tomography (CT) demonstrated a subdural hematoma in the left hemisphere. Craniotomy and hematoma evacuation was performed and he showed good recovery despite a scalp wound infection caused by methicillin-resistant Staphylococcus aureus (MRSA). The organism isolated from the scalp wound was sensitive to vancomycin. The patient was treated with intravenous vancomycin for 44 days. However, he showed a high fever, persistent positive methicillin-resistant Staphylococcus Epidermidis (MRSE) blood cultures, and a deteriorating clinical status. He underwent infected skull bone flap removal and linezolid treatment for 35 days. During one year of follow up, he has not had any further episodes of osteomyelitis or fever. Linezolid has shown to be effective agent to eradiate osteomyelitis caused by VISE.
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PMID:Linezolid Treatment for Osteomyelitis due to Staphylococcus Epidermidis with Reduced Vancomycin Susceptibility. 1909 38

In this case report, we describe the course of a chronic hemodialysis patient who has been treated for 7 days with linezolid for pneumonia caused by a methicillin-resistant staphylococcus aureus and who developed severe thrombocytopenia which was reversible after having stopped the treatment. Since there is an increasing evidence that linezolid induces severe thrombocytopenia, especially in patients requiring hemodialysis, indication for treatment with linezolid should be made with caution and monitoring of blood count in short-term intervals should be performed in critically ill patients. Linezolid is a representative of a new antibiotic class, i.e. an oxazolidinone, which inhibits the bacterial protein synthesis at the ribosom. Such agents do not have any relation to common anti-infectives and act nearly exclusively against Gram-positive bacteria and mycobacteria. In clinical practice, linezolid is most widely used for treatment of Gram-positive infections, mainly caused by methicillin-resistant Staphylococcus aureus (MRSA). The major adverse effects of linezolid are diarrhoea, nausea, and headache. Furthermore, abnormalities in blood count, i.e. leukocytopenia, thrombocytopenia and anaemia, have been reported.
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PMID:[Case report: severe thrombocytopenia]. 1936 27


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