Use of linezolid in children: an overview of recent advances

Linezolid is the first member of a new generation of antibiotics, the synthetic oxazolidinones, to become available, with a broad spectrum of in vitro activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant E. faecium. Linezolid is showing great promise currently for the treatment of multiresistant gram-positive bacterial infections, especially complicated skin infections, catheter-induced bacteremia or nosocomial pneumonia both in the community and in a hospital setting, in children and in adults. Although most recent reports are favorable and anticipatory of a more extensive use of linezolid in appropriately selected pediatric population groups in the near future, following treatment failure of conventional antimicrobial agents, more clinical trials are, however, required to investigate the safety profile and tolerability of this new antibiotic in the pediatric population.     

A review of linezolid: the first oxazolidinone antibiotic

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox^®, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin^®, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.     

A review of linezolid: the first oxazolidinone antibiotic

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.     

Efficacy of linezolid versus comparator therapies in Gram-positive infections

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.     

A simplified three-times weekly daptomycin dosing regimen for chronic hemodialysis patients

Evaluation of: Salama NN, Segal JH, Churchwell MD et al. Intradialytic administration of daptomycin in end stage renal disease patients on hemodialysis. Clin. J. Am. Soc. Nephrol. 4, 1190–1194 (2009).

Approximately 2.3 million patients worldwide are undergoing chronic renal replacement therapy. In that population, acute infections substantially contribute to the excessive morbidity and mortality. The risk for invasive methicillin-resistant Staphylococcus aureus infections in this population is approximately 100-fold higher than in the general population, therefore dialysis patients currently account for up to approximately 15% of all invasive methicillin-resistant Staphylococcus aureus infections. A simplified three-times weekly dosing regimen for hemodialysis patients now allows for practical, hassle-free and effective treatment with daptomycin, which is licensed for the treatment of complicated skin and soft tissue infections, including resistant strains of Staphylococcus aureus and life-threatening Gram-positive infections, vancomycin-resistant enterococcal infections and right-sided endocarditis.     

Role of linezolid in the treatment of orthopedic infections

Gram-positive organisms, particularly staphylococci and streptococci, are responsible for the majority of bone and joint infections. The rising incidence of antimicrobial resistance among Staphylococcus aureus, coagulase-negative staphylococci and enterococci means that novel antibiotics with unique mechanisms of antimicrobial activity are needed, especially in orthopedic infections. Linezolid is the first of the oxazolidinones, a new class of antibacterial agents particularly effective against Gram-positive infections including methicillin- and vancomycin-resistant strains. With an excellent oral bioavailability and acceptable safety profile, linezolid offers a valuable alternative to more traditional therapies, such as glycopeptides. No large randomized trials have been published on its use in patients with orthopedic infections, but early results are encouraging. Reported adverse events, especially bone marrow suppression and optic neuropathy seen with prolonged administration, mean that treatment of such patients must be undertaken with careful follow-up of laboratory tests. Until now, little resistance has been reported.     

Linezolid

Multiple antibiotic resistance is increasing worldwide in Gram-positive bacteria, especially in hospitals. Problem organisms include multiply resistant strains of pneumococci, Staphylococcus aureus and enterococci; for many of these the glycopeptide vancomycin has become the treatment of last resort. This situation has been made worse by the emergence of vancomycin-resistant enterococci and vancomycin-intermediate S. aureus. Fortunately, several compounds active against resistant Gram-positive bacteria are in active development. One of these is linezolid, the first of the oxazolidinones, a new class of antibacterial. Linezolid is a synthetic agent which is active against all the clinically important Gram-positive bacteria, including multiply resistant strains. It has good pharmacokinetics, with equal bioavailability by both oral and intravenous routes and no need for dose adjustment in patients with renal impairment. The drug has a good safety profile and clinical trials have given excellent results in a variety of skin and soft tissue, respiratory and bloodstream infections. Linezolid is a promising drug, which, together with prudent antibiotic use and the prevention and control of hospital infection, will help in the battle against multiply antibiotic resistant Gram-positive bacteria.     

Efficacy and safety of linezolid for Gram-positive orthopedic infections: a prospective case series

Linezolid is an attractive alternative for orthopedic infections because of oral bioavailability and activity against methicillin-resistant staphylococci and vancomycin-resistant enterococci. To determine efficacy and safety, we prospectively monitored 51 consecutive adults who were not vancomycin candidates and who received linezolid for 53 Gram-positive orthopedic infections, usually chronic osteomyelitis (n = 25) or prosthetic joint infection (n = 23). Pathogens were usually Staphylococcus aureus (n = 27) or coagulase-negative staphylococci (n = 19); 38 were methicillin resistant. After remission, 17 infections required long-term suppression, usually because of retained hardware. Clinical and microbiologic failure occurred in only one patient. The most common adverse events were thrombocytopenia (n = 5) and anemia (n = 5), necessitating treatment discontinuation in 3 patients. One patient developed reversible optic and irreversible peripheral neuropathy after 24 months of linezolid. Linezolid, with surgery, may be a reasonable alternative for Gram-positive orthopedic infections. We recommend weekly hematologic monitoring, and, if therapy lasts >2 months, periodic ophthalmologic monitoring.     

Faropenem: review of a new oral penem

Faropenem medoxomil is a new orally administered penem antibiotic. Its chiral tetrahydrofuran substituent at position C2 is responsible for its improved chemical stability and reduced CNS effects, compared with imipenem. Faropenem demonstrates broad-spectrum in vitro antimicrobial activity against many Gram-positive and -negative aerobes and anaerobes, and is resistant to hydrolysis by nearly all β-lactamases, including extended-spectrum β-lactamases and AmpC β-lactamases. However, faropenem is not active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, Pseudomonas aeruginosa or Stenotrophomonas maltophilia. Prospective, multicenter, randomized, double-blind, comparative (not vs placebo) clinical trials of acute bacterial sinusitis (ABS), acute exacerbations of chronic bronchitis (AECB), community-acquired pneumonia (CAP) and uncomplicated skin and skin structure infections (uSSSIs) have demonstrated that faropenem medoxomil has equivalent efficacy and safety compared with cefuroxime, clarithromycin, azithromycin, amoxicillin, cefpodoxime and amoxicillin–clavulanate. The evidence supports faropenem medoxomil as a promising new oral β-lactam with proven efficacy and safety for the treatment of a variety of community-acquired infections. However, the US FDA recently rejected faropenem for all four indications stating that the clinical trials in ABS and AECB should have been performed versus a placebo. In the CAP studies, the FDA stated that they could not be certain of the validity of the study population actually having the disease and for uSSSI, the FDA stated that only a single trial was not adequate evidence of efficacy for this indication.     

In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci.

The emergence of resistance in gram-positive bacteria has necessitated a search for new antimicrobial agents. Linezolid is an oxazolidinone, a new class of antibacterial agents with enhanced activity against pathogens. We compared the activity of linezolid to those of other antimicrobial agents against 3,945 clinical isolates. Linezolid demonstrated potent activity against all isolates tested. For all vancomycin-susceptible enterococci, staphylococci, and streptococci, the activity of linezolid was comparable to that of vancomycin. Against oxacillin-resistant staphylococci and vancomycin-resistant enterococci, linezolid was the most active agent tested. In summary, linezolid appears to be a promising new antimicrobial agent for the treatment of gram-positive infections.     

Linezolid for the treatment of resistant gram-positive cocci

OBJECTIVE: To provide a comprehensive review of linezolid, the first of a new class of antibiotics, the oxazolidinones. Therapeutic issues regarding the emergence of multidrug-resistant bacteria and a brief history of the oxazolidinones are also discussed. DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Unpublished clinical data, adverse effects, and dosing information were abstracted from product labeling. STUDY SELECTION: Clinical efficacy data were extracted from clinical trials, case reports, and abstracts that mentioned linezolid. Additional information concerning antibiotic resistance, the oxazolidinones, in vitro susceptibility and the pharmacokinetic profile of linezolid also was reviewed. DATA SYNTHESIS: Linezolid exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Linezolid inhibits bacterial protein synthesis at an early step in translation and is rapidly and completely absorbed from the gastrointestinal tract following oral administration. Efficacy has been demonstrated in a number of unpublished clinical trials in adults with pneumonia, skin and skin structure infections, and vancomycin-resistant E. faecium infections. The adverse effect profile is similar to that of comparator agents (beta-lactams, clarithrornycin, vancomycin). CONCLUSIONS: Linezolid is the first oral antimicrobial agent approved for the treatment of vancomycin-resistant enterococci. Since the oxazoildinones have a unique mechanism of action and expanded spectrum of activity against virulent and highly resistant gram positive pathogens, linezolid is a valuable alternative to currently available treatment options. Clinical trials evaluating linezolid and other oxazolidinones for antibiotic-resistant gram-positive infections, as well as comparator studies comparing linezolid with other candidate drugs, such as quinupristin/dalfopristin and choramphenicol, will further define the role of linezolid.     

Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent

Ramoplanin, a novel antibiotic with activity against aerobic and anaerobic Gram-positive bacteria, acts to prevent cell wall peptidoglycan formation by binding to a key intermediate moiety, lipid II. It has been fast-tracked by the US FDA for the prevention of enterococcal infections and the treatment of Clostridium difficile. The minimum inhibitory concentration_90s have been ≤1.0 µg/ml against Gram-positive organisms examined. In carriers of vancomycin-resistant enterococci, a double-blind, placebo-controlled Phase II trial of two doses of ramoplanin versus placebo showed proof of concept. A second Phase II trial also demonstrated the equivalence of ramoplanin compared with vancomycin for the treatment of C. difficile colitis. The clinical value and place in therapy of ramoplanin is dependent upon the results of Phase III trials addressing its utility in suppressing carriage of target organisms in the gastrointestinal tract or in the nares.     

In vitro activity of linezolid against vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae.

We report the activity of the new oxazolidinone antimicrobial agent linezolid against 37 clinical isolates of vancomycin-resistant enterococci (including organisms carrying the vanA, vanB, vanC-1, and vanC-2/3 genes), 26 clinical isolates of methicillin-resistant S. aureus and 20 clinical isolates of high-level penicillin-resistant S. pneumoniae. All isolates of vancomycin-resistant enterococci were inhibited by < or = 4 ug/ml of linezolid. All isolates of methicillin-resistant S. aureus were inhibited by < or = 8 ug/ml of linezolid. All isolates of penicillin-resistant S. pneumoniae were inhibited by < or = 2 ug/ml of linezolid. Linezolid inhibits strains of multidrug resistant Gram-positive cocci in vitro at concentrations < or = 8 ug/ml.     

Ceftobiprole: a new cephalosporin for the treatment of skin and skin structure infections

Ceftobiprole is among the first of a new generation of cephalosporins with activity against aerobic Gram-negative bacilli, which extends to cefepime-sensitive Pseudomonas aeruginosa, and activity against Gram-positive organisms, which includes methicillin-resistant Staphylococcus aureus. Ceftobiprole is currently undergoing evaluation by the US FDA for the treatment of complicated skin and skin structure infections, with a decision pending further evaluation of study site monitoring. It is also being evaluated for the treatment of community-acquired and healthcare-associated pneumonia. Two Phase III multicenter trials have demonstrated noninferiority in complicated skin and skin structure infections when tested against vancomycin in primarily Gram-positive bacterial infections, and when tested against vancomycin plus ceftazidime in Gram-positive and Gram-negative bacterial infections. It is well tolerated, with the most common side effects being nausea and dysgeusia. Ceftobiprole is likely to prove useful as an empiric as well as directed monotherapy in patients with complicated skin and skin structure infections, in which both Gram-positive pathogens including methicillin-resistant S. aureus and Gram-negative pathogens including cefepime-sensitive P. aeruginosa may be involved.     

Mechanisms of vancomycin resistance in Staphylococcus aureus

Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive bacterial infections. Traditionally, it has been used as a drug of last resort; however, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) strains with decreased susceptibility to vancomycin (vancomycin intermediate-resistant S. aureus [VISA]) and more recently with high-level vancomycin resistance (vancomycin-resistant S. aureus [VRSA]) have been described in the clinical literature. The rare VRSA strains carry transposon Tn1546, acquired from vancomycin-resistant Enterococcus faecalis, which is known to alter cell wall structure and metabolism, but the resistance mechanisms in VISA isolates are less well defined. Herein, we review selected mechanistic aspects of resistance in VISA and summarize biochemical studies on cell wall synthesis in a VRSA strain. Finally, we recapitulate a model that integrates common mechanistic features of VRSA and VISA strains and is consistent with the mode of action of vancomycin.     

Varying linezolid susceptibility of vancomycin-resistant Enterococcus faecium isolates during therapy: a case report

OBJECTIVES: Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by vancomycin-resistant enterococci. Resistance to linezolid has been associated with a G2576U mutation in domain V of the 23S rRNA. Patient and methods: We present clinical details and susceptibility data from multiple Enterococcus faecium strains isolated from a liver transplant patient over 13 months. MICs of linezolid, vancomycin and quinupristin/dalfopristin were determined using Etest. Molecular typing was performed by pulsed-field gel electrophoresis. Domain V of the 23S rRNA gene in the vancomycin-resistant Enterococcus faecium was amplified. Linezolid concentrations were analysed by HPLC. RESULTS: We report the emergence of resistance to linezolid in a vancomycin-resistant Enterococcus faecium during linezolid treatment. After discontinuation of the linezolid therapy, the isolate reverted to susceptibility. However, after re-administration of linezolid the vancomycin-resistant Enterococcus faecium became resistant to linezolid again. The isolates that were resistant to linezolid had a G2576T mutation in their 23S rDNA. CONCLUSION: We describe a clinical case that shows the shift of a vancomycin-resistant Enterococcus faecium from linezolid resistance to susceptibility and then back to resistance again related to linezolid therapy.     

Safety and efficacy of linezolid in 16 infants and children in Japan

Linezolid, an oxazolidinone antibiotic, exhibits a broad spectrum of activity against Gram-positive bacteria. It has been licensed for adult use in Japan since 2006 for MRSA infections, and has also been used off-label for pediatric patients. At our university hospital, a total of 16 infants and children (including one non-Japanese Asian) were administered linezolid owing to infection with multidrug-resistant Gram-positive bacteria, after consent had been provided. All patients had severe underlying diseases or indications for surgery. Eighty-eight percent of the causal microorganisms were methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase-negative Staphylococcus and all were sensitive to linezolid. Linezolid was administered because the antecedent anti-MRSA medications were ineffective or contraindicated, or intravenous-to-oral switch therapy was requested owing to cardiac or orthopedic surgical-site infections. The median duration of administration was 13 days (range 3-31 days). The overall efficacy was 91 % (10/11) in those for whom efficacy could be evaluated. Only two patients (both teen-aged) encountered linezolid-related adverse effects (13 %, 2/16). One patient showed elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), requiring that administration be withdrawn, but enzyme levels returned to normal after the patient had been switched to vancomycin. The other patient showed transiently decreased platelet counts. Linezolid is considered generally safe and effective for children in Japan, especially for those who cannot use other anti-MRSA medications or those who require oral antibiotics for infections with multidrug-resistant Gram-positive bacteria.     

Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study

OBJECTIVES: Linezolid, the only commercially available oxazolidinone, is indicated for the treatment of Gram-positive infections, although little has been published specifically on its use in the critically ill. A randomized, prospective study was therefore performed to compare linezolid with the glycopeptide antibiotic, teicoplanin, for the treatment of suspected or proven Gram-positive infections in an intensive care population. METHODS: Using a double-blind, double-dummy, prospective design, patients were randomized to (i) intravenous linezolid (600 mg/12 h) plus teicoplanin dummy [one dose/12 h for three doses then every 24 h intravenously (iv)] or (ii) teicoplanin (400 mg/12 h for three doses then 400 mg/24 h iv) plus linezolid dummy (one dose/12 h iv). Other antibiotics were used in combination with the trial agents in empirical treatment. Clinical and microbiological assessments were made daily in the first week, and at 8 and 21 days after treatment. RESULTS: One hundred patients received linezolid plus placebo-teicoplanin, whereas 102 received teicoplanin plus placebo-linezolid. Population baseline characteristics were similar in both groups. At end of treatment, clinical success [71 (78.9%) linezolid versus 67 (72.8%) teicoplanin] and microbiological success [49 (70.0%) versus 45 (66.2%)] rates were similar, as were adverse effects, intensive care unit mortality, and success rates at short- and long-term follow-up. Linezolid was superior at initial clearance of methicillin-resistant Staphylococcus aureus (MRSA) colonization (end of treatment, 51.1% versus 18.6%, P = 0.002). Two MRSA isolates showed reduced susceptibility to teicoplanin. CONCLUSIONS: Linezolid has similar safety and efficacy to teicoplanin in treating Gram-positive infections in the critically ill. Short-term MRSA clearance achieved with linezolid suggests better skin and mucosal penetration.     

Nouvelles molécules anti-infectieuses. Quelle place en médecine intensive réanimation pour le tédizolide,la ceftaroline et le ceftobiprole ?

Although decreasing in the past years, severe infections caused by Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci, remain a matter of concern. Indeed, there is a need for new antibiotics given the issues raised by the use of glycopeptides. Accordingly, in addition to possible loss of efficiency against MRSA and safety concerns, vancomycin-resistant enterococci are regularly responsible for significant outbreaks among hospitalized patients. In this context, the Oxazolidinone family has grown since tedizolid, the spectrum of which includes the above-mentioned resistant pathogens, has been successfully developed. Current data suggest that tedizolid could be more efficient and less toxic than linezolid, thus allowing longer durations of treatment. Indeed, although the drug is licensed only for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), several clinical trials are currently ongoing. New cephalosporins owing antibacterial activity against MRSA have also appeared recently. In addition to a strong bactericidal activity and a favourable safety profile, these drugs have proven efficient for the treatment of infections involving Gram-positive agents, that is, community-acquired pneumonia (ceftaroline), health care-associated pneumonia (ceftobiprole), as well as ABSSSIs. In spite of a broad spectrum of activity covering Gram-negative bacteria including Pseudomonas aeruginosa (ceftobiprole only), clinical data are mandatory before expanding their use to the critically ill patients with pneumonia, given pharmacokinetic issues in this setting. Administration of these drugs should actually be optimized in order to make use of their whole efficiency.     

Daptomycin: first in a new class of antibiotics for complicated skin and soft-tissue infections

With increasing antibiotic resistance reported worldwide, there is an urgent need for novel treatments for infections caused by Gram-positive bacteria. Daptomycin is the first in a new class of antibiotic, the cyclic lipopeptides, with activity against a range of Gram-positive pathogens. US approval of daptomycin for the treatment of complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria was gained in 2003, with European approval granted in January 2006. Most Gram-positive clinical isolates tested have proved susceptible to daptomycin, including methicillin- and vancomycin-resistant strains. Daptomycin has a novel mode of action, is rapidly bactericidal in vitro and has a low potential for the development of resistance. Two pivotal phase III studies, in a total of 1092 patients with cSSTIs, demonstrated non-inferiority to currently used antibiotics and a comparable tolerability profile. The unique mode of action of daptomycin is described alongside studies demonstrating its potential in the treatment of cSSTIs and other infections caused by Gram-positive bacteria.