Assessment of Tedizolid In Vitro Activity and Resistance Mechanisms against a Collection of Enterococcus spp. Causing Invasive Infections, Including Isolates Requiring an Optimized Dosing Strategy for Daptomycin from U.S. and European Medical Centers, 2016 to 2018.

High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4% to 40.3% of E. faecium isolates exhibited these phenotypes. Tedizolid inhibited 98.9% to 100.0% of enterococci causing serious invasive infections, including resistant subsets. Oxazolidinone resistance was mainly driven by G2576T; however, optrA and poxtA genes were also detected, including poxtA in the United States and Turkey.

Pharmacokinetic/pharmacodynamic research on three different infusion time regimens of linezolid in healthy Chinese volunteers.

OBJECTIVE: To evaluate the pharmacokinetic and pharmacodynamic (PK/PD) results of three different infusion time regimens of single doses of 600 mg linezolid in healthy Han Chinese volunteers. METHODS: We conducted a clinical trial involving 6 male and 6 female healthy Chinese volunteers. They were randomized to receive intravenous linezolid infusion (600 mg/0.5 hours, 600 mg/2 hours, or 600 mg/4 hours) in three periods with washout periods of 7 days between each dosage. Serum linezolid concentration was measured in each subject at pre-dose (at 0 hours) until 24 hours after each dose. The ratio of the area under the serum concentration-time curve (AUC) to the minimum inhibitory concentration (MIC), AUC/MIC, was adopted as the major relevant parameter. Monte Carlo simulation was used to evaluate the probability of target attainment (PTA) of these three linezolid regimens. RESULTS: One subject in 600 mg/0.5 hours regimen complained of mild pain at the injection site. No significant difference was found in pharmacokinetic parameters among the three different infusion regimens. When AUC/MIC was applied as parameter, PTA of 4 hours infusion regimen was much lower than that of the 0.5 hours and 2 hours infusion regimens (55.65% vs. 74.91% and 72.03%, respectively). Especially at higher MIC (2 µg/mL), the PTAs of the 0.5 hours and 2 hours infusion regimens decreased to 57.2% and 50.1%, respectively, while that of the 4 hours infusion regimen dropped sharply to only 25.95%. When T>MIC was applied as a parameter, PTA of the 0.5 hours regimen was higher than 90%, while the 2 hours and 4 hours regimens remained 100%. CONCLUSION: Our findings suggest that 2 hours infusion of linezolid at a fixed dose (600 mg) regimen is appropriate to achieve the safety and efficacy against MRSA-caused infections in Chinese adults.

Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function.

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 µM versus 6.4 ± 1.2 µM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.

Developments in the pharmacokinetic/pharmacodynamic index of linezolid: a step toward dose optimization using Monte Carlo simulation in critically ill patients.

OBJECTIVES: This study evaluated the efficacy of the pharmacokinetic/pharmacodynamic (PK/PD) index for increasing the success rate of linezolid treatment based on Monte Carlo simulation, and compared differences between the calculated PK/PD breakpoints and those defined by committee for critically ill patients with linezolid treatment. METHODS: A Monte Carlo simulation involving 10000 subjects was used to analyze the pharmacokinetic parameters and microbiological data of linezolid for an effectiveness evaluation at the corresponding AUC24/MIC values (area under the serum concentration-time curve over 24h/minimum inhibitory concentration). RESULTS: As the PK/PD index of linezolid increased from 80 to 120, the corresponding probability of target attainment (PTA) decreased from 99.91% to 18.97%, with a MIC of 2mg/l. Furthermore, the cumulative fraction of response (CFR) reached <90% for several pathogens at an AUC24/MIC of 100-120, revealing a relatively lower efficacy with recommended linezolid dosing. CONCLUSIONS: These findings reveal that the target AUC24/MIC value of 80-120 requires further classification for more accurate assessment of the linezolid dose regimen. At a MIC of ≥2mg/l, the clinical outcome varies greatly for different AUC24/MIC values when applying the same dose of linezolid. In such cases, we suggest optimized adjustment of the linezolid dosage regimen.

Monte Carlo simulation analysis of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit-isolated methicillin-resistant Staphylococcus aureus.

The aim of the present study was to compare the potential of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) targets against methicillin-resistant Staphylococcus aureus isolates collected from intensive care unit (ICU) settings. Monte Carlo simulations were carried out to simulate the PK/PD indices of the investigated antimicrobials. The probability of target attainment (PTA) was estimated at minimum inhibitory concentration values ranging from 0.03 to 32 µg/mL to define the PK/PD susceptibility breakpoints. The cumulative fraction of response (CFR) was computed using minimum inhibitory concentration data from the Canadian National Intensive Care Unit study. Analysis of the simulation results suggested the breakpoints of 4 µg/mL for ceftobiprole (500 mg/2 h t.i.d.), 0.25 µg/mL for dalbavancin (1000 mg), 0.12 µg/mL for daptomycin (4 mg/kg q.d. and 6 mg/kg q.d.) and tigecycline (50 mg b.i.d.), and 2 µg/mL for linezolid (600 mg b.i.d.) and vancomycin (1 g b.i.d. and 1.5 g b.i.d.). The estimated CFR were 100, 100, 70.6, 88.8, 96.5, 82.4, 89.4, and 98.3% for ceftobiprole, dalbavancin, daptomycin (4 mg/kg/day), daptomycin (6 mg/kg/day), linezolid, tigecycline, vancomycin (1 g b.i.d.) and vancomycin (1.5 g b.i.d.), respectively. In conclusion, ceftobiprole and dalbavancin have the highest probability of achieving their requisite PK/PD targets against methicillin-resistant Staphylococcus aureus isolated from ICU settings. The susceptibility predictions suggested a reduction of the vancomycin breakpoint to 1 µg/mL.

Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia.

Alpha-toxin (AT) is a major virulence factor in the disease pathogenesis of Staphylococcus aureus. We previously identified a monoclonal antibody (MAb) against AT that reduced disease severity in a mouse dermonecrosis model. Here, we evaluate the activity of an affinity-optimized variant, LC10, in a mouse model of S. aureus pneumonia. Passive immunization with LC10 increased survival and reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverse S. aureus clinical isolates. The lungs of S. aureus-infected mice exhibited bacterial pneumonia, including widespread inflammation, whereas the lungs of mice that received LC10 exhibited minimal inflammation and retained healthy architecture. Consistent with reduced immune cell infiltration, LC10-treated animals had significantly lower (P < 0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid than did those of the control animals. This reduction in inflammation and damage to the LC10-treated animals resulted in reduced vascular protein leakage and CO2 levels in the blood. LC10 was also assessed for its therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (P < 0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, the lungs of animals treated with antibiotic plus LC10 exhibited less inflammatory tissue damage than those that received monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy against S. aureus pneumonia.

Pharmacophore assessment through 3-D QSAR: evaluation of the predictive ability on new derivatives by the application on a series of antitubercular agents.

Pharmacophoric mapping is a useful procedure to frame, especially when crystallographic receptor structures are unavailable as in ligand-based studies, the hypothetical site of interaction. In this study, 71 pyrrole derivatives active against M. tuberculosis were used to derive through a recent new 3-D QSAR protocol, 3-D QSAutogrid/R, several predictive 3-D QSAR models on compounds aligned by a previously reported pharmacophoric application. A final multiprobe (MP) 3-D QSAR model was then obtained configuring itself as a tool to derive pharmacophoric quantitative models. To stress the applicability of the described models, an external test set of unrelated and newly synthesized series of R-4-amino-3-isoxazolidinone derivatives found to be active at micromolar level against M. tuberculosis was used, and the predicted bioactivities were in good agreement with the experimental values. The 3-D QSAutogrid/R procedure proved to be able to correlate by a single multi-informative scenario the different activity molecular profiles thus confirming its usefulness in the rational drug design approach.

Front-loaded linezolid regimens result in increased killing and suppression of the accessory gene regulator system of Staphylococcus aureus.

Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 10(6) CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log(10) CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of -6.15 and -6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27× increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.

Low fitness cost of the multidrug resistance gene cfr.

The recently described rRNA methyltransferase Cfr that methylates the conserved 23S rRNA residue A2503, located in a functionally critical region of the ribosome, confers resistance to an array of ribosomal antibiotics, including linezolid. A number of reports of linezolid-resistant cfr-positive clinical strains indicate the possible rapid spread of this resistance mechanism. Since the rate of dissemination and the efficiency of maintenance of a resistance gene depend on the fitness cost associated with its acquisition, we investigated the fitness cost of cfr expression in a laboratory Staphylococcus aureus strain. We found that acquisition of the cfr gene does not produce any appreciable reduction in the cell growth rate. Only in a cogrowth competition experiment was some loss of fitness observed because Cfr-expressing cells slowly lose to the cfr-negative control strain. Interestingly, cells expressing wild-type and catalytically inactive Cfr had very similar growth characteristics, indicating that the slight fitness cost associated with cfr acquisition stems from expression of the Cfr polypeptide rather than from the modification of the conserved rRNA residue. In some clinical isolates, cfr is coexpressed with the erm gene, which encodes a methyltransferase targeting another 23S rRNA residue, A2058. Dimethylation of A2058 by Erm notably increases the fitness cost associated with the Cfr-mediated methylation of A2503. The generally low fitness cost of cfr acquisition observed in our experiments with the laboratory S. aureus strain offers a microbiological explanation for the apparent spread of the cfr gene among pathogens.

Assessment of linezolid resistance mechanisms among Staphylococcus epidermidis causing bacteraemia in Rome, Italy.

OBJECTIVES: To characterize linezolid resistance among blood cultured Staphylococcus epidermidis from patients at the Polyclinic Agostino Gemelli (2006-08). Isolates also showed elevated MICs of macrolide, lincosamide and streptogramin (MLS) compounds, which were investigated. METHODS: Ten S. epidermidis exhibiting linezolid MICs ≥ 4 mg/L were included. Isolates were screened for cfr mutations in 23S rRNA, L3, L4 and L22, and MLS genes by PCR/sequencing. Ribosomal proteins were compared with those from a linezolid-susceptible (MIC, 1 mg/L) clinical strain and ATCC 12228. cfr location was determined by Southern blot/hybridization. The cfr strain was submitted to plasmid curing. Epidemiology was assessed by PFGE and multilocus sequence typing (MLST). RESULTS: S. epidermidis displayed linezolid MICs of 4 or 8 mg/L, except for strain 4303A (MIC, 64 mg/L). These organisms and a linezolid-susceptible strain exhibited L3 Leu101Val compared with ATCC 12228. Isolates also showed L3 Phe147Leu and Ala157Arg, and L4 Asn158Ser. Strain 12375A possessed L4 Lys68Arg. Isolates were wild-type for 23S rRNA and L22. cfr was plasmid located in strain 4303A and the plasmid-cured strain exhibited a linezolid MIC (4 mg/L) similar to that for cfr-negative strains (4-8 mg/L). All organisms harboured erm(A) and msr(A), while vga(A) was detected in several isolates. All isolates were clonally related and ST-23. CONCLUSIONS: L3 Phe147Leu and/or Ala157Arg appeared responsible for the elevated linezolid MIC, since adjacent alterations have been associated with resistance. L4 Asn158Ser has been reported in a linezolid-susceptible isolate and Lys68Arg detected here did not seem to provide an additive effect. Acquisition of cfr markedly increased (8- to 16-fold) the linezolid MICs. vga(A) was associated with higher MICs of quinupristin/dalfopristin and retapamulin.

Methicillin-resistant Staphylococcus aureus: the superbug.

Over the last decade, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as serious pathogens in the nosocomial and community setting. Hospitalization costs associated with MRSA infections are substantially greater than those associated with methicillin-sensitive S. aureus (MSSA) infections, and MRSA has wider economic effects that involve indirect costs to the patient and to society. In addition, there is some evidence suggesting that MRSA infections increase morbidity and the risk of mortality. Glycopeptides are the backbone antibiotics for the treatment of MRSA infections. However, several recent reports have highlighted the limitations of vancomycin, and its role in the management of serious infections is now being reconsidered. Several new antimicrobials demonstrate in vitro activity against MRSA and other Gram-positive bacteria. Data from large surveys indicate that linezolid, daptomycin, and tigecycline are almost universally active against MRSA. This review will briefly discuss the epidemiology, costs, outcome, and therapeutic options for the management of MRSA infections.

Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Linezolid for the treatment of drug-resistant infections.

Multidrug-resistant pathogens have become increasingly common in contemporary healthcare. Specific to Gram-positive pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is of particular concern, as it has been associated with increased hospital length of stay, higher healthcare expenditures and poorer outcomes. To date, linezolid is the first and only oxazolidinone approved by the US FDA for the treatment of infections caused by Gram-positive pathogens, including MRSA. This article will serve as a comprehensive review of linezolid, including an overview of the current market and its in vitro activity, with an in-depth review of its pharmacokinetic and pharmacodynamic profile. Emphasis will be placed on clinical data for the drug, both on- and off-label. The article will conclude with a brief overview of linezolid's pharmacoeconomic implications and safety profile, followed by a commentary and 5-year prospective analysis remarking on the future of the antimicrobial field as it relates to MRSA.

Benefit-risk assessment of linezolid for serious gram-positive bacterial infections.

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.

Use of an in vitro pharmacodynamic model to derive a linezolid regimen that optimizes bacterial kill and prevents emergence of resistance in Bacillus anthracis.

Simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for > or =700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthracis without resistance selection. Linezolid at < or =600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at > or =500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthracis was predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (C(max))/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg x h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg x h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracis and prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.

Linezolid resistance in Staphylococcus aureus: gene dosage effect, stability, fitness costs, and cross-resistances.

Linezolid resistance in Staphylococcus aureus is typically associated with mutations in the 23S rRNA gene. Here we show that the accumulation of a single point mutation, G2576T, in the different copies of this gene causes stepwise increases in resistance, impairment of the biological fitness, and cross-resistance to quinupristin-dalfopristin and chloramphenicol.

Pharmacodynamic comparison of linezolid, teicoplanin and vancomycin against clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci collected from hospitals in Brazil.

Pharmacodynamic exposures, measured as the ratio of steady-state total drug area under the curve to MIC (AUC/MIC), were modelled using a 5000-patient Monte-Carlo simulation against 119 non-duplicate clinical isolates of Staphylococcus aureus and 82 coagulase-negative staphylococci (CNS) collected from hospitals in Brazil between 2003 and 2005. Pharmacodynamic targets included an AUC/MIC >82.9 for linezolid and >345 for teicoplanin and vancomycin, as well as a free drug AUC/MIC >180 for vancomycin. The cumulative fractions of response (CFRs) against all S. aureus isolates were 96.0%, 30.1%, 71.6%, 48.0% and 65.1% for linezolid 600 mg every 12 h, teicoplanin 400 mg every 24 h and 800 mg every 24 h, and vancomycin 1000 mg every 12 h and every 8 h, respectively. Using a free drug target for vancomycin improved the CFR to 94.6% for the high-dose regimen, but did not substantially alter results for the lower dose. CFRs against all CNS isolates were 97.8%, 13.4%, 34.6%, 10.9% and 31.3%, respectively, for the same antibiotic regimens. The CFR was reduced for all compounds among the methicillin-resistant isolates, except for linezolid against methicillin-resistant CNS. Sensitivity analyses did not alter the final order of pharmacodynamic potency against these isolates. Although higher doses of vancomycin and teicoplanin increased the CFR, the likelihood of achieving bactericidal targets was still lower than with linezolid. The results for the high-dose vancomycin regimen were highly dependent on the pharmacodynamic target utilised. These data suggest that linezolid has a greater probability of attaining its requisite pharmacodynamic target than teicoplanin and vancomycin against these staphylococci.

Linezolid for the treatment of Nocardia spp. infections.

OBJECTIVE: To review the available evidence regarding the use of linezolid for the treatment of Nocardia spp. infections. DATA SOURCES: Data were identified through a search of MEDLINE (1966-May 2007), American Search Premier (1975-May 2007), International Pharmaceutical Abstracts (1960-2007), Science Citation Index Expanded (1996-2007), and Cochrane Databases (publications archived until May 2007) using the terms linezolid and Nocardia. STUDY SELECTION AND DATA EXTRACTION: Prospective and retrospective studies, case reports, case series, and in vitro studies were eligible for inclusion if they used linezolid for nocardiosis regardless of site of infection and outcome. DATA SYNTHESIS: We identified 11 published cases of linezolid use for Nocardia spp. infections. The predominant species isolated were N. asteroides (n = 4; 36%) and N. farcinica (n = 3; 27%). Nocardiosis with central nervous system involvement (n = 7; 64%) or disseminated disease (n = 4; 36%) were most common. The main reason for discontinuation of previous antimicrobials was most often related to adverse effects (n = 5; 45%), followed by clinical failure (n = 3; 27%). Linezolid was associated with cure or improvement in all cases (n = 11; 100%). However, the majority of patients developed serious complications that may have led to premature discontinuation of therapy with linezolid, including myelosuppression (n = 5; 45%) or possible/confirmed peripheral neuropathy (n = 2; 18%). CONCLUSIONS: The limited published data suggest that linezolid appears to be an effective alternative to trimethoprim/sulfamethoxazole for the treatment of nocardiosis. Unfortunately, the high cost and potentially serious long-term toxicities of linezolid appear to limit its use and relegate it to salvage therapy alone or in combination with other antimicrobials.

In vitro and in vivo assessment of linezolid combined with ertapenem: a highly synergistic combination against methicillin-resistant Staphylococcus aureus.

Linezolid in combination with ertapenem showed in vitro synergy against methicillin-resistant Staphylococcus aureus strains. We confirmed this interaction in vivo by using a rabbit endocarditis experimental model and simulation of the human pharmacokinetics in animals for both antibiotics. Linezolid plus ertapenem exhibited highly synergistic activity in vivo after 4 days of treatment.