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.     

Linezolid: an oxazolidinone antimicrobial agent

BACKGROUND: Linezolid is the first oxazolidinone anti-infective agent marketed in the United States. It is indicated for the treatment of nosocomial pneumonia, complicated skin and skin-structure infections caused by methicillin-sensitive or methicillin-resistant Staphylococcus aureus and other susceptible organisms, and vancomycin-resistant Enterococcus faecium infections. It also is indicated for the treatment of uncomplicated skin and skin-structure infections caused by methicillin-sensitive S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by penicillin-sensitive Streptococcus pneumoniae. OBJECTIVE: This article reviews the pharmacologic properties and clinical usefulness of linezolid. METHODS: Using the terms linezolid, PNU-100766, and oxazolidinone, we performed a literature search of the following databases: MEDLINE (1966 to September 2000), HealthSTAR (1993 to September 2000), Iowa Drug Information Service (1966 to September 2000), International Pharmaceutical Abstracts (1970 to September 2000), PharmaProjects (January 2000 version), and meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996 to 2000). RESULTS: Linezolid has a unique structure and mechanism of action, which targets protein synthesis at an exceedingly early stage. Consequently, cross-resistance with other commercially available antimicrobial agents is unlikely. It is primarily effective against gram-positive bacteria. To date, resistance to linezolid has been reported in patients infected with enterococci. The pharmacokinetic parameters of linezolid in adults are not altered by hepatic or renal function, age, or sex to an extent requiring dose adjustment. Linezolid is metabolized via morpholine ring oxidation, which is independent of the cytochrome P450 (CYP450) enzyme system; as a result, linezolid is unlikely to interact with medications that stimulate or inhibit CYP450 enzymes. Compassionate-use trials and other clinical studies involving mainly adult hospitalized patients with gram-positive infections have shown that linezolid administered intravenously or orally is effective in a variety of nosocomial and community-acquired infections, including those caused by resistant gram-positive organisms. Reported adverse effects include thrombocytopenia. diarrhea, headache, nausea, vomiting, insomnia, constipation, rash, and dizziness. Preliminary pharmacoeconomic data indicate that a significantly higher percentage of patients receiving linezolid therapy versus comparator could be discharged from the hospital by day 7 (P = 0.005). CONCLUSIONS: Linezolid appears to be effective while maintaining an acceptable tolerability profile. Due to the risk of bacterial resistance, linezolid should be reserved for the treatment of documented serious vancomycin-resistant enterococcal infections.     

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.     

Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies

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.     

Linezolid-associated peripheral neuropathy

Linezolid is the first drug in a new class of synthetic antimicrobials, the oxazolidinones, to be approved by the Food and Drug Administration. Linezolid is active against methicillin- and vancomycin-resistant gram-positive microorganisms. We describe 2 patients who developed peripheral neuropathy after prolonged treatment with linezolid. Linezolid-associated peripheral neuropathy has not been well documented. Most reported cases of linezolid-associated peripheral neuropathy have occurred in patients who took linezolid for a period longer than the recommended 28 or fewer days. Health care providers must be alert to the potential for serious adverse effects associated with linezolid use, including peripheral neuropathy.     

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.     

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.     

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.     

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.     

Activities of the oxazolidinones linezolid and eperezolid in experimental intra-abdominal abscess due to Enterococcus faecalis or vancomycin-resistant Enterococcus faecium

The in vivo effectiveness of oxazolidinones eperezolid (U-100592) and linezolid (U-100766) against one strain each of Enterococcus faecalis and vancomycin-resistant Enterococcus faecium was examined in a rat model of intra-abdominal abscess. MICs of both drugs were 2 microg/ml for each strain. At doses of 25 mg/kg of body weight twice daily intravenously or orally, linezolid produced small but statistically significant reductions in abscess bacterial density for E. faecalis. The reduction in viable cells observed would not likely be clinically relevant. Eperezolid was ineffective at this dose. At a dosage of 100 mg/kg/day, linezolid treatment led to an approximately 100-fold reduction in viable cells per gram of abscess. Against E. faecium infections, intravenous eperezolid and oral linezolid were effective, reducing densities approximately 2 log(10) CFU/g. Both oxazolidinones demonstrated activity against enterococci in this model. However, results were modest with the dosing regimens employed.     

Cefdinir: an expanded-spectrum oral cephalosporin

OBJECTIVE: To review the antimicrobial activity, pharmacokinetics, clinical efficacy, and tolerability of cefdinir, an expanded-spectrum oral cephalosporin. DATA SOURCES: Literature was identified by a MEDLINE search (January 1983-November 1999) of the medical literature, review of English-language literature and bibliographies of these articles, and product information. STUDY SELECTION: Clinical efficacy data were selected from all published trials mentioning cefdinir. Additional information concerning in vitro susceptibility, safety, chemistry, and pharmacokinetic profile of cefdinir was also reviewed. DATA SYNTHESIS: Cefdinir, an oral expanded-spectrum cephalosporin, has a broad spectrum of activity against many gram-negative and -positive aerobic organisms, including Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefdinir is stable to hydrolysis by many common beta-lactamases. Cefdinir is rapidly absorbed from the gastrointestinal tract and is primarily eliminated via renal clearance of unchanged drug. The terminal disposition half-life of cefdinir is approximately 1.5 hours. Efficacy has been demonstrated in a number of clinical trials in adults and children with upper and lower respiratory tract infections (e.g., pharyngitis, sinusitis, acute otitis media, acute bronchitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia) and skin and skin-structure infections. The adverse event profile is similar to that of comparator agents. CONCLUSIONS: Cefdinir is a second-line alternative to first-line antimicrobial agents, with convenient once- or twice-daily dosing in the treatment of upper and lower respiratory tract infections and skin and skin-structure infections. Similar to other oral expanded-spectrum cephalosporins, cefdinir has activity against common pathogens of the respiratory tract and skin and is stable in the presence of many beta-lactamases. The clinical choice of an oral expanded-spectrum cephalosporin will be based on patient acceptance, frequency of administration, and cost.     

利奈唑胺的体外抗菌作用研究

目的评价抗菌新药利奈唑胺的体外抗菌作用。方法采用琼脂对倍稀释法测定利奈唑胺对579株临床分离菌的体外抗菌活性，并与有关抗菌药进行比较；测定利奈唑胺的杀菌浓度和杀菌曲线；培养条件对利奈唑胺抗菌活性的影响。结果利奈唑胺对葡萄球菌属、肺炎链球菌等链球菌属、肠球菌属临床分离菌均具高度抗菌活性，包括对其中的甲氧西林耐药葡萄球菌、青霉素中介肺炎链球菌亦具良好的抗菌作用。对流感嗜血杆菌、淋病奈瑟菌的抗菌活性较低。对脆弱拟杆菌等厌氧菌具较高抗菌活性。利奈唑胺对耐药的革兰阳性球菌的抗菌作用与万古霉素和替考拉宁相仿或略强。最低杀菌浓度（MBC）测定及杀菌曲线试验结果显示利奈唑胺对肺炎链球菌、溶血性链球菌具有很强的杀菌作用，对大部分葡萄球菌属具杀菌作用，对肠球菌仅具抑菌作用。培养基pH值的改变、细菌接种量的改变对利奈唑胺抗菌活性有一定影响，人血清含量改变对该药抗菌活性无明显影响。结论利奈唑胺对需氧革兰阳性球菌，包括多重耐药菌具有高度抗菌活性，且与其他抗菌药问无交叉耐药。提示利奈唑胺对革兰阳性球菌，尤其是多重耐药株所致感染的控制将具有重要作用。     

Dalbavancin: a new option for the treatment of gram-positive infections

OBJECTIVE: To review the pharmacology, microbiology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of dalbavancin, a new semisynthetic lipoglycopeptide. DATA SOURCES: A MEDLINE search, restricted to the English language, was conducted from 1966 through January 2006. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, and the Infectious Diseases Society of America from 2000 to 2005 and information available from the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: In vitro and preclinical studies, as well as Phase I, II, and III clinical trials, were evaluated to summarize the microbiology, pharmacology, clinical efficacy, and safety of dalbavancin. All published trials and abstracts citing dalbavancin were selected. DATA SYNTHESIS: Dalbavancin, a novel lipoglycopeptide, has a mechanism of action similar to that of other glycopeptides. It has in vitro activity against a variety of gram-positive organisms, but no activity against gram-negative or vancomycin-resistant enterococci that possess VanA gene. Due to its prolonged half-life (6-10 days), dalbavancin can be administered intravenously once weekly. In Phase II and III clinical trials, dalbavancin was effective and well tolerated for the treatment of skin and soft-tissue infections, catheter-related bloodstream infections, and skin and skin-structure infections. To date, adverse events are mild and limited; the most common include pyrexia, headache, nausea, oral candidiasis, diarrhea, and constipation. CONCLUSIONS: Dalbavancin appears to be a promising antimicrobial agent for the treatment of gram-positive infections. A new drug application was filed with the Food and Drug Administration (FDA) in December 2004. The FDA issued an approvable letter in 2005 for dalbavancin. If approved, dalbavancin is expected to be launched in the first quarter of 2006.     

Linezolid resistance since 2001: SENTRY Antimicrobial Surveillance Program

BACKGROUND: The oxazolidinone class of antimicrobials has demonstrated remarkable activity against gram-positive cocci. Linezolid has proven to be a first-line therapeutic option for vancomycin-resistant strains. Linezolid clinical trial results and subsequent published case reports cite rare resistance emerging in patients receiving prolonged therapy. OBJECTIVE: To report the initial linezolid-resistant organisms from cases obtained through the SENTRY Antimicrobial Surveillance Program, after screening >40,000 gram-positive cocci without resistance between 1998 and 2000. METHODS: During 2001-2002, 8 resistant strains (from 8 different patients) located in 6 states from 7 different participating SENTRY institutions in the US were identified among bloodstream, respiratory, skin and soft tissue, and urinary tract infection isolates of Enterococcus faecalis, Enterococcus faecium, Staphylococcus epidermidis, and Streptococcus oralis. Resistance was detected by reference broth microdilution methods and confirmed by identical results using Etest (AB BIODISK, Solna, Sweden) and the standardized disk diffusion method. RESULTS: Minimum inhibitory concentration (MIC) and disk diffusion tests showed elevated MICs (> or =8 microg/mL) and small inhibitory zone diameters (< or =15 mm) for all strains to both linezolid and the investigational oxazolidinone AZD2563. Vancomycin resistance was detected in 2 of the 8 linezolid-resistant strains. All enterococci and the viridans-group streptococcus (S. oralis) strain showed resistance to erythromycin. E. faecium strains were resistant to penicillins, but susceptible to quinupristin/dalfopristin. Only 3 of the patients had previously received the drug. CONCLUSIONS: Linezolid resistance remains rare, with only 8 isolates among 9833 (0.08%) monitored isolates identified between January 1, 2001, and June 30, 2002. Resistance, however, was no longer limited to enterococci. Clinical laboratories should test linezolid more widely to detect emerging resistance, especially for patients receiving oxazolidinone therapy. Longitudinal surveillance programs are warranted to detect a trend in the development of resistance, determine the molecular mechanism of resistance, and recommend alternative therapies or epidemiologic interventions.     

Pharmacokinetics of linezolid in subjects with renal dysfunction

Linezolid is a member of a new, unique class of synthetic antibacterial agents called oxazolidinones that are effective against gram-positive bacteria, including vancomycin-resistant organisms. We tested the hypothesis that the linezolid clearance would not be altered in subjects with renal dysfunction. Twenty-four subjects with renal function that ranged from normal to severe chronic impairment were enrolled, including patients with end-stage renal disease who were maintained on hemodialysis. Hemodialysis subjects were studied while they were both on and off dialysis. Linezolid was administered as a single oral 600-mg dose, and plasma and urine samples were assayed for linezolid and metabolites for 48 h for all subjects and for up to 96 h for those subjects with impaired renal function not on dialysis. The total apparent oral clearance of linezolid did not change with renal function and ranged from 92.5 to 109.6 ml/min for subjects not requiring dialysis. For subjects on dialysis, the total apparent oral clearance increased from 76.6 ml/min on their off-dialysis day to 130.0 ml/min on their on-dialysis day. Approximately one-third of the dose was removed by dialysis. However, those subjects with severe renal insufficiency (creatinine clearance, <40 ml/min) and those with end-stage renal disease maintained on hemodialysis had higher concentrations of both metabolites. We conclude that no adjustment of the linezolid dosage is needed in subjects with renal dysfunction or subjects on hemodialysis.     

Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 microg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 microg/mL), Bacteroides fragilis (MIC 2.0 microg/mL), and Peptostreptococcus magnus (MIC 1.0 microg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 microg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 microg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (> or =6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 microg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC > or =4.0 microg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.     

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.