Modeling the economic impact of linezolid versus vancomycin in confirmed nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus

Introduction

We compared the economic impacts of linezolid and vancomycin for the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA)–confirmed nosocomial pneumonia.

Methods

We used a 4-week decision tree model incorporating published data and expert opinion on clinical parameters, resource use and costs (in 2012 US dollars), such as efficacy, mortality, serious adverse events, treatment duration and length of hospital stay. The results presented are from a US payer perspective. The base case first-line treatment duration for patients with MRSA-confirmed nosocomial pneumonia was 10 days. Clinical treatment success (used for the cost-effectiveness ratio) and failure due to lack of efficacy, serious adverse events or mortality were possible clinical outcomes that could impact costs. Cost of treatment and incremental cost-effectiveness per successfully treated patient were calculated for linezolid versus vancomycin. Univariate (one-way) and probabilistic sensitivity analyses were conducted.

Results

The model allowed us to calculate the total base case inpatient costs as $46,168 (linezolid) and $46,992 (vancomycin). The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with lower costs ($824 less) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA nosocomial pneumonia). Approximately 80% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). The results of our probabilistic sensitivity analysis indicated that linezolid is the cost-effective alternative under varying willingness to pay thresholds.

Conclusion

These model results show that linezolid has a favorable incremental cost-effectiveness ratio compared to vancomycin for MRSA-confirmed nosocomial pneumonia, largely attributable to the higher clinical trial response rate of patients treated with linezolid. The higher drug acquisition cost of linezolid was offset by lower treatment failure–related costs and fewer days of hospitalization.     

Higher clinical success in patients with ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study

Introduction

Controversy exists regarding optimal treatment for ventilator-associated pneumonia (VAP) due to methicillin-resistant Staphylococcus aureus (MRSA). The primary objective of this study was to compare clinical success of linezolid versus vancomycin for the treatment of patients with MRSA VAP.

Methods

This was a multicenter, retrospective, observational study of patients with VAP (defined according to Centers for Disease Control and Prevention criteria) due to MRSA who were treated with linezolid or vancomycin. MRSA VAP was considered when MRSA was isolated from a tracheal aspirate or bronchoalveolar lavage. Clinical success was evaluated by assessing improvement or resolution of signs and symptoms of VAP by day 14. After matching on confounding factors, logistic regression models were used to determine if an association existed between treatment arm and clinical success.

Results

A total of 188 patients were evaluated (101 treated with linezolid and 87 with vancomycin). The mean ± standard deviation Acute Physiology and Chronic Health Evaluation (APACHE) II score was 21 ± 11 for linezolid- and 19 ± 9 for vancomycin-treated patients (P = 0.041). Clinical success occurred in 85% of linezolid-treated patients compared with 69% of vancomycin-treated patients (P = 0.009). After adjusting for confounding factors, linezolid-treated patients were 24% more likely to experience clinical success than vancomycin-treated patients (P = 0.018).

Conclusions

This study adds to the evidence indicating that patients with MRSA VAP who are treated with linezolid are more likely to respond favorably compared with patients treated with vancomycin.     

Impact of Weight on Treatment Efficacy and Safety in Complicated Skin and Skin Structure Infections and Nosocomial Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Background

There are few data on dose optimization and clinical outcomes of antimicrobial agents based on patients’ weight, despite the rising prevalence of obesity. Because there are physiologic, pharmacologic, and dosing differences related to weight, it is important to evaluate the impact of weight on antimicrobial agents to optimize clinical outcomes.

Objectives

This study compared effects of weight on efficacy and safety in patients treated with linezolid or vancomycin for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA).

Methods

We analyzed data from 2 clinical trials of patients randomized to receive a fixed dose of linezolid or weight-based dosing of vancomycin for the treatment of cSSSIs or NP caused by MRSA. For each study, patients were stratified into quartiles (Q1–4 [lowest to highest weight, respectively]). Clinical success, microbiologic success, and adverse events (AEs) were evaluated.

Results

The analysis included 632 patients with cSSSIs (linezolid, n = 316; vancomycin, n = 316) and 447 patients with NP (linezolid, n = 224; vancomycin, n = 223). Among patients with cSSSIs, clinical success rates at the study end with fixed-dose linezolid were similar across all weight quartiles and similar to weight-based dosing of vancomycin for Q1–3. Among Q4 (the highest weight quartile [97–295 kg]), clinical success with vancomycin was significantly lower compared with linezolid (69.5% vs 86.2%; P = 0.03). Among patients with NP, no significant differences in success rates between fixed-dose linezolid and weight-based dosing of vancomycin were observed across all quartiles. Frequencies of AEs were consistent across the quartiles for both indications and by treatment.

Conclusions

Except for Q4 within the vancomycin-treated patients for MRSA cSSSI, the efficacy of fixed-dosed linezolid and weight-based dosing of vancomycin was maintained across all weight quartiles and MRSA infection types. The AEs were consistent with the known safety profiles of each drug regardless of weight quartile. ClinicalTrials.gov identifiers: NCT00087490 and NCT00084266.     

Early Response Assessment to Guide Management of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections With Vancomycin Therapy

Background

A subset of vancomycin-treated patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) developed persistent positive blood cultures. Treatment eventually failed.

Methods

A retrospective study was conducted to determine whether early response on day 3 after initiation of vancomycin therapy for MRSA BSI was associated with reduced rates of persistent bacteremia, end-of-treatment failure, and infection-related mortality. Patients’ medical charts were reviewed. Susceptibility testing and molecular characterization of bacterial isolates were performed.

Results

In this elderly cohort (n = 111; median age 70 years, interquartile range: 57–80 years), early response was observed in 62% of patients and was significantly (P < 0.0001) associated with lower rates of end-of-treatment failure (19% vs 57%) and infection-related death (1% vs 29%), but not with persistent bacteremia (17% vs 29%, P = 0.23). Nearly half (46%; 46 of 100 patients) remained on vancomycin therapy for the entire treatment course; those who continued despite lack of early response had a trend toward a higher risk of death than those who were switched to alternative therapy (38% vs 10%, P = NS). Most (68%) isolates had vancomycin MIC of >1 µg/mL, whereas 10% showed heterogeneous glycopeptide-intermediate Staph aureus (hGISA) phenotype. Nearly half (47%) were typed with staphylococcal cassette chromosome mec IV or V. In a multivariate logistic regression model, lack of response at day 3 was the strongest predictor for end-of-treatment failure, after adjustment for confounders such as age, Acute Physiology And Chronic Health Evaluation II score, intensive care unit admission, vancomycin MIC >1 µg/mL, unbound trough concentration <4 to 5× MIC, and continued vancomycin therapy without change.

Conclusions

Early response assessment after initiation of vancomycin therapy appeared to be useful for considering further diagnostic workup or a switch to alternative therapy to affect a positive outcome in patients with MRSA BSI.     

A comparison of costs and hospital length of stay associated with intravenous/oral linezolid or intravenous vancomycin treatment of complicated skin and soft-tissue infections caused by suspected or confirmed methicillin-resistant Staphylococcus aureus in elderly US patients

OBJECTIVES: This study compared the costs and hospital length of stay (LOS) and duration of intravenous therapy associated with intravenous/oral linezolid or intravenous vancomycin treatment of complicated skin and soft-tissue infections (cSSTIs) caused by suspected or confirmed methicillin-resistant Staphylococcus aureus (MRSA) in elderly US patients. METHODS: Data were obtained from elderly (>or=65 years) US patients participating in a multinational randomized trial of hospitalized cSSTI patients treated with linezolid or vancomycin. Costs (hospital and total) from the provider perspective were estimated for intent-to-treat (ITT) patients (ie, all those receiving >or=1 dose) using national 2003 costs (ward, medication, intravenous administration). LOS for inpatient care, duration of intravenous linezolid and vancomycin therapy (ITT and MRSA groups), and cure rates were evaluated. RESULTS: Of 717 enrolled subjects, 163 (23%) were elderly (87 linezolid, 76 vancomycin), with no significant differences in demographic characteristics between the linezolid and vancomycin groups. Mean hospitalization and total costs were lower with linezolid compared with vancomycin (hospitalization: US $4510 vs US $6478, P<0.001; total: US $6009 vs US $7329, P=0.03). Linezolid was associated with a 3.5-day reduction in LOS and a 9.5-day reduction in the duration of intravenous therapy compared with vancomycin in the ITT group (both, P<0.001). Cure rates were comparable between linezolid and vancomycin in both the ITT group (88.7% vs 81.4%, respectively) and the MRSA group (80.0% vs 71.4%). In multivariate analyses of the ITT group, linezolid patients were 57% less likely than vancomycin patients to have a LOS >7 days (odds ratio = 0.43; 95% CI, 0.21-0.87). Chronic renal failure, malnutrition, and a diagnosis of infected ulcer predicted an LOS >7 days. CONCLUSIONS: In this analysis of data from elderly patients with cSSTI caused by suspected or confirmed MRSA, linezolid treatment was associated with reductions in the costs of care, LOS, and duration of intravenous treatment without affecting the clinical outcomes. Although the use of a subset of patients from a larger trial that did not focus on the elderly can be seen as a study limitation, the elderly represent an important population when evaluating health care resource use and costs.     

Predictors of Clinical Success Among a National Veterans Affairs Cohort With Methicillin-Resistant Staphylococcus aureus Pneumonia

Background

The treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is exceedingly complicated, which is concerning because of the high mortality rate associated with the infection. Identification of independent predictors of clinical success can optimize patient care by assisting clinicians in treatment decisions.

Objectives

Our goal was to identify independent predictors of clinical success in a national Veterans Affairs (VA) cohort of patients with MRSA pneumonia.

Methods

A nested case-control study was conducted among a cohort of VA patients with MRSA pneumonia receiving linezolid or vancomycin between January 2002 and September 2010. Cases included those demonstrating clinical success, defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Control subjects represented nonsuccess, defined as therapy change, intubation, intensive care unit admission, readmission, or death between treatment initiation and day 14. The potential predictors assessed included treatment, patient demographic and admission characteristics, previous health care and medication exposures, comorbidities, and medical history. Odds ratios (ORs) and 95% CIs were calculated from logistic regression.

Results

Our study included 2442 cases of clinical success and 1290 control subjects. Demographic characteristics varied between the clinical success and nonsuccess groups, including age, race, and region of facility. A current diagnosis of chronic respiratory disease (46% vs 42%) and diagnosis of pneumonia in the year before the MRSA pneumonia admission (37% vs 32%) were both more common in the clinical success group. Despite these significant differences, only 2 predictors of clinical success were identified in our study: previous complication of an implant or graft, including mechanical complications and infections, in the year before the MRSA pneumonia admission (adjusted OR, 1.55 [95% CI, 1.17–2.06]) and treatment with linezolid (adjusted OR, 1.53 [95% CI, 1.12–2.10]). Predictors of nonsuccess (adjusted OR [95% CI) included diagnosis of concomitant urinary tract infection (0.82 [0.70–0.96]), intravenous line (0.76 [0.66–0.89]), previous coagulopathy (0.74 [0.56–0.96]), previous amputation procedure (0.72 [0.53–0.98]), current coagulopathy diagnosis (0.71 [0.53–0.96]), dialysis (0.54 [0.38–0.76]), multiple inpatient procedures (0.53 [0.45–0.62]), inpatient surgery (0.48 [0.41–0.57]), and previous endocarditis (0.24 [0.07–0.81]).

Conclusions

MRSA pneumonia tends to affect patients with complex care, and identification of the predictors of clinical success is useful when considering different therapeutic approaches. In this national cohort of VA patients with MRSA pneumonia, treatment was the only modifiable variable predicting clinical success.     

Cost-effectiveness analysis of linezolid compared with vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus

OBJECTIVE: This study compared the cost-effectiveness of linezolid and vancomycin in the treatment of patients with nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: A retrospective decision-analytic model was applied to pooled data from 2 prospective, randomized, controlled, double-blind studies, and claims data from a large health plan (3.3 million members) located in the Mid-Atlantic region. Using hospital claims for patients in the health plan with suspected NP, we then determined their daily billed (submitted) hospital charges for 4 mutually exclusive potential health outcomes of linezolid or vancomycin treatment: survival with bacteremia, survival without bacteremia, nonsurvival with bacteremia, and nonsurvival without bacteremia. To generate the expected total daily billed hospital charge for each drug-treatment group, we weighted the determined daily billed hospital charges by the probabilities of each outcome developing in each treatment arm, as derived from the clinical-trial data. Drug acquisition costs were then incorporated, and the difference in expected total costs relative to the difference in rates of survival between the linezolid and vancomycin arms was used to calculate the incremental cost-effectiveness ratio (ICER) for linezolid. RESULTS: Costs were higher for nonsurviving patients compared with surviving patients. Estimated median daily billed treatment charges were $2888 for linezolid and $2993 for vancomycin. Based on Monte Carlo simulations, the respective 95% CIs were $2671 to $3106 and $2615 to $3372. Using mean treatment durations of 11.3 and 10.7 days, respectively, we obtained expected total hospitalization charges of $32,636 for linezolid treatment (95% CI, $30,182-$35,098), compared with $32,024 for vancomycin treatment (95% CI, $27,978-$36,078). The ICER for linezolid per life saved was $3600. CONCLUSIONS: The higher acquisition cost of linezolid was almost completely offset by improved survival and a reduction in health care costs associated with improved survival. As a result, linezolid was almost cost-neutral compared with vancomycin in the treatment of NP caused by MRSA.     

Daily practice and prognostic factors for pneumonia caused by methicillin-resistant Staphylococcus aureus in Japan: A multicenter prospective observational cohort study

Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia.This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed.In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31–14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35–7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26–9.92) were risk factors for mortality.In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.     

Linezolid for treatment of ventilator-associated pneumonia: a cost-effective alternative to vancomycin

OBJECTIVES: To determine the incremental cost-effectiveness of linezolid compared with vancomycin for treatment of ventilator-associated pneumonia due to Staphylococcus aureus. DESIGN: Decision model analysis of the cost and efficacy of linezolid vs. vancomycin for treatment of ventilator-associated pneumonia. The primary outcome was the incremental cost-effectiveness of linezolid in terms of cost per added quality-adjusted life-year gained. Other outcomes were the marginal costs per hospital survivor and per year of life saved generated by using linezolid. Model estimates were derived from prospective trials of linezolid for ventilator-associated pneumonia and from other studies describing the costs and outcomes for ventilator-associated pneumonia. SETTING AND PATIENTS: Hypothetical cohort of 1,000 patients diagnosed with ventilator-associated pneumonia. INTERVENTIONS: In the model, patients received either linezolid or vancomycin. MEASUREMENTS AND MAIN RESULTS: The incremental cost-effectiveness of linezolid was calculated as the additional quality-adjusted life-years resulting from therapy with linezolid divided by the sum of the incremental costs arising because of use of linezolid (e.g., higher direct costs for linezolid, costs per in-hospital care of survivors, and posthospitalization costs). Despite its higher cost, linezolid was cost-effective for treatment of ventilator-associated pneumonia. The cost per quality-adjusted life-year equals approximately 30,000 dollars. The model was moderately sensitive to the estimated efficacy of linezolid over vancomycin. Nonetheless, even with all inputs simultaneously skewed against, linezolid remains a cost-effective option (cost per quality-adjusted life-year approximately 100,000 dollars). Based on Monte Carlo simulation, the results of our analysis are robust across a range of model inputs and assumptions (95% confidence interval for cost per quality-adjusted life-year ranges from 23,637 dollars to 42,785 dollars). CONCLUSIONS: Linezolid is a cost-effective alternative to vancomycin for the treatment of ventilator-associated pneumonia.     

Linezolid versus vancomycin for nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus in the elderly: A retrospective cohort analysis: Effectiveness of linezolid in the elderly

Objectives

Several reports have compared the efficacy of linezolid (LZD) in Methicillin-resistant Staphylococcus aureus (MRSA) infections with that of vancomycin (VCM); however, these two antibiotics for the treatment of nosocomial MRSA pneumonia in elderly patients has not been well evaluated. The purpose of this study is to evaluate the efficacy and safety of LZD compared with VCM for the treatment of elderly patients with nosocomial MRSA pneumonia in a retrospective chart review of a cohort.

Comparative in vivo efficacies of epithelial lining fluid exposures of tedizolid, linezolid, and vancomycin for methicillin-resistant Staphylococcus aureus in a mouse pneumonia model

The antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistant Staphylococcus aureus (MRSA) were compared in an in vivo mouse pneumonia model. Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA and subsequently administered 20 mg/kg TZD every 24 hours (q24h), 120 mg/kg linezolid q12h, or 25 mg/kg vancomycin q12h over 24 h. These regimens produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg TZD q24h, 600 mg linezolid q12h, and 1 g vancomycin q12h. The differences in CFU after 24 h of treatment were compared between control and treatment groups. Vehicle-dosed control groups increased in bacterial density an average of 1.1 logs. All treatments reduced the bacterial density at 24 h with an average of 1.2, 1.6, and 0.1 logs for TZD, linezolid, and vancomycin, respectively. The efficacy of TZD versus linezolid regimens against the three MRSA isolates was not statistically different (P > 0.05), although both treatments were significantly different from controls. In contrast, the vancomycin regimen was significantly different from TZD against one MRSA isolate and from linezolid against all isolates. The vancomycin regimen was less protective than either the TZD or linezolid regimens, with overall survival of 61.1% versus 94.7% or 89.5%, respectively. At human simulated exposures to epithelial lining fluid, vancomycin resulted in minimal reductions in bacterial counts and higher mortality compared to those of either TZD or linezolid. TZD and linezolid showed similar efficacies in this MRSA pneumonia model.     

Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia

Purpose  

The objective of this study is to assess the distribution of vancomycin minimum inhibitory concentrations (MICs) in methicillin-resistant Staphylococcus aureus (MRSA) isolates and evaluate the efficacy of vancomycin relative to vancomycin MICs in adult patients with MRSA nosocomial pneumonia.     

A comparison of linezolid with glycopeptides in severe MRSA pneumonia

Evaluation of: Luna CM, Bruno DA, García-Morato J et al. Effect of linezolid compared with glycopeptides in methicillin-resistant Staphylococcus aureus severe pneumonia in piglets. Chest 135(6), 1564–1571 (2009).

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major pathogen in nosocomial infections and accounts for a large proportion of nosocomial pneumonia. However, there are limited antibiotics available for the treatment of this serious and potentially lethal infection. Until recently, the only effective antibiotic was vancomycin, but the oxazolidinones, such as linezolid, have been shown to be a valuable addition to the arsenal of antimicrobial agents that can be used for MRSA pneumonia. Clinical trials have been conducted to compare vancomycin and linezolid head-to-head in pneumonia and, in post hoc subgroup analyses, showed that linezolid use was associated with improved survival. The ensuing debate over these results was dominated by two opinions; there were those who speculated on the mechanism by which linezolid achieved this benefit, namely attributing it to pharmacodynamics and pharmacokinetics, and others who criticized the methodology of the studies and questioned the validity of the results altogether. This study by Luna and colleagues was designed with several goals in mind. The first was to attempt to generate an animal model of MRSA pneumonia in piglets by duplicating techniques used in animal models of Gram-negative pneumonia. Then they studied the effect of three antibiotics (vancomycin, linezolid and teicoplanin) on outcomes in the same model, while simultaneously measuring antibiotic levels in the serum, bronchoalveolar lavage fluid and lung tissue, in an attempt to attribute differences in survival to pharmacological properties of the drugs used. Their results showed a survival benefit only for linezolid, despite the fact that all three antibiotics had levels above MIC in all the compartments sampled, leading them to speculate that linezolid may have improved outcomes by mechanisms not directly related to its antimicrobial actions.     

Vancomycin and Piperacillin-Tazobactam Against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Intermediate Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Purpose

Synergy between β-lactams and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA) has been observed in vitro and in vivo. However, studies investigating piperacillin-tazobactam with vancomycin against MRSA and VISA are limited despite broad clinical use of these antibiotics in combination. This study evaluated vancomycin and piperacillin-tazobactam against MRSA and VISA by using an in vitro pharmacokinetic/pharmacodynamic model.

Methods

Two clinical MRSA strains (M3425 and M494) and one VISA strain (Mu50) were tested in duplicate by using a 72-hour, 1-compartment pharmacokinetic/pharmacodynamic model with the following exposures: growth control, vancomycin only, piperacillin-tazobactam only, and vancomycin with piperacillin-tazobactam. Vancomycin 1 g every 12 hours (free trough concentration, 8.75 mg/L; C_min, 17.5 mg/L) and piperacillin-tazobactam 13.5 g per 24 hours’ continuous infusion (free steady-state concentration, 27 mg/L) were simulated. Time–kill curves were constructed, and reductions in log₁₀ CFU/mL at all time points were compared between regimens tested.

Findings

Vancomycin and piperacillin-tazobactam MICs for M494, M3425, and Mu50 were 1, 1, and 4 and 1.5, 32, and >256 mg/L, respectively. All isolates had an oxacillin MIC ≥4 mg/L. Against all 3 isolates, vancomycin with piperacillin-tazobactam achieved a significant reduction in inoculum at 72 hours compared with vancomycin alone (all, P ≤ 0.015). The superiority of vancomycin with piperacillin-tazobactam compared with vancomycin alone became detectable at 8 hours for M3425 (P < 0.001) and at 24 hours for M494 and Mu50 (both, P ≤ 0.008). Although vancomycin with piperacillin-tazobactam achieved enhanced antibacterial activity at 72 hours against M3425 compared with vancomycin alone, bacterial regrowth occurred. Reduced susceptibility to vancomycin at 72 hours for M3425 was confirmed by using population analysis profile/AUC analysis. At 72 hours, M3425 had a PAP/AUC ratio of 0.77 compared to 0.51 at baseline.

Implications

Vancomycin with piperacillin-tazobactam demonstrated enhanced antimicrobial activity against MRSA and VISA compared with vancomycin alone. These results further enhance existing data that support using vancomycin in combination with a β-lactam for invasive MRSA infections. Combination therapy with vancomycin and a β-lactam against MRSA warrants clinical consideration.     

Traitement des infections sévères à staphylocoques dorés résistants à la méticilline : vancomycine ou nouvelles molécules ? Données récentes

Whether vancomycin is still themainstay of therapy for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) is currently a matter for debate. Vancomycin resistance among MRSA strains remains extremely rare. However, because of minimum inhibitory concentration (MIC) creep and of the link between vancomycin failure and higher MICs, clinicians should consider using alternative agents either empirically or when vancomycin MIC is > 1 mg/L. Despite intense researches in anti-Gram positive development over the past decade, only few agents have been licensed. Randomized controlled trials and metaanalyses suggest that linezolid is not inferior than glycopeptides for the treatment of hospital-acquired pneumonia and may be even superior in the subset of patients with MRSA infection. Daptomycin, a lipopeptide antibiotic, is extremely bactericidal and is active against biofilm-producing staphylococci. This molecule is an attractive agent for the treatment of bacteremia and endocarditis caused by MRSA. Telavancin, a lipoglycopeptide agent was shown to be non-inferior to vancomycin in the treatment of hospital-acquired pneumonia. Finally, ceftarolin is a broad-spectrum cephalosporin with in vitro activity against methicillin-resistant staphylococci.     

In Vivo Efficacy of Ceftaroline Fosamil in a Methicillin-Resistant Panton-Valentine Leukocidin-Producing Staphylococcus aureus Rabbit Pneumonia Model

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.     

Clinical Efficacy of Oral Linezolid Compared With Intravenous Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus-Complicated Skin and Soft Tissue Infections: A Retrospective, Propensity Score-Matched, Case-Control Analysis

BackgroundLinezolid is 100% bioavailable in oral and intravenous formulations. In a recent prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial in adults with complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), linezolid achieved clinical and microbiologic success comparable to appropriately dosed intravenous vancomycin. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy using oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication.ObjectiveThe objective of this study was to assess the efficacy and tolerability of linezolid when administered orally in adults with cSSTI caused by MRSA. In this retrospective analysis, we examined data collected from the aforementioned trial to compare outcomes in patients who received either oral linezolid or intravenous vancomycin therapy.MethodsThis study analyzed outcomes in patients who received treatment for 7 to 14 days with either oral linezolid (600 mg q12h; n = 95) or intravenous vancomycin (15 mg/kg q12h, adjusted for creatinine clearance and trough concentration; n = 210). By design, these groups were not randomized. Propensity score matching on baseline variables was used to balance these groups by identifying a comparable group of patients who received vancomycin therapy and comparing them with patients who received oral linezolid therapy. Clinical and microbiologic success rates at the end of treatment and the end of the study (EOS) were then directly compared between the groups using matched-pair logistic regression. The tolerability of the 2 treatments (within this matched group) was also described.ResultsNinety-two patients with well-matched baseline characteristics were included in each treatment group. At EOS, the odds ratio for clinical success of oral linezolid therapy vs intravenous vancomycin therapy was 4.0 (95% CI, 1.3–12.0; P = 0.01), and the odds ratio for microbiologic success at EOS was 2.7 (95% CI, 1.2–5.7; P = 0.01). Overall rates of adverse events in each group were consistent with reported safety profiles for each drug.ConclusionA favorable clinical cure rate was achieved with oral linezolid therapy when compared with intravenous vancomycin therapy in propensity score–matched patients with cSSTI proved to be caused by MRSA. ClinicalTrials.gov Identifier: NCT00087490.     

Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies

OBJECTIVES: To compare outcomes in patients with Staphylococcus aureus bacteraemia treated with linezolid with those of vancomycin-treated patients. METHODS: We pooled and analysed five randomized studies comparing linezolid with vancomycin, focusing on the 144 adults with S. aureus bacteraemia, which was secondary in >70% of patients. Efficacy variables were clinical cure of primary infection, microbiological success (eradication of S. aureus from blood or presumed eradication based on clinical cure of primary infection), survival, and outcome predictors identified by multivariate logistic regression. RESULTS: Of 99 clinically evaluable patients, primary infection was cured in 28 (55%) of 51 linezolid recipients and 25 (52%) of 48 vancomycin recipients [odds ratio (OR) for cure with linezolid versus vancomycin, 1.12; 95% confidence interval (CI), 0.51-2.47]. There were no between-group differences in the meta-analysis (OR, 1.16; 95% CI, 0.5-2.65). Of 53 evaluable patients with methicillin-resistant S. aureus (MRSA) bacteraemia, clinical cure occurred in 14 (56%) of 25 linezolid recipients and 13 (46%) of 28 vancomycin recipients (OR, 1.47; 95% CI, 0.50-4.34). Microbiological success occurred in 41 (69%) of 59 linezolid recipients and 41 (73%) of 56 vancomycin recipients (OR, 0.83; 95% CI, 0.37-1.87). Fifty-five (74%) of 74 linezolid recipients survived versus 52 (74%) of 70 vancomycin recipients (OR, 1.00; 95% CI, 0.47-2.12). In the multivariate analysis, treatment group was not a significant predictor of clinical cure or survival. CONCLUSIONS: Linezolid was associated with outcomes that were not inferior to those of vancomycin in patients with secondary S. aureus bacteraemia.     

Clinical and Epidemiologic Characteristics as Predictors of Treatment Failures in Uncomplicated Skin Abscesses Within Seven Days After Incision and Drainage

Background

Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is now the leading cause of superficial abscesses seen in the Emergency Department.

Study Objectives

Our primary aim was to determine if an association exists between three predictor variables (abscess size, cellulitis size, and MRSA culture) and treatment failure within 7 days after incision and drainage in adults. Our secondary aim was to determine if an association exists between two clinical features (abscess size and size of surrounding cellulitis) and eventual MRSA diagnosis by culture.

Methods

Logistic regression models were used to examine clinical variables as predictors of treatment failure within 7 days after incision and drainage and MRSA by wound culture.

Results

Of 212 study participants, 190 patients were analyzed and 22 were lost to follow-up. Patients who grew MRSA, compared to those who did not, were more likely to fail treatment (31% to 10%, respectively; 95% confidence interval [CI] 8–31%). The failure rates for abscesses ≥ 5 cm and < 5 cm were 26% and 22%, respectively (95% CI −11–26%). The failure rates for cellulitis ≥ 5 cm and < 5 cm were 27% and 16%, respectively (95% CI −2–22%). Larger abscesses were no more likely to grow MRSA than smaller abscesses (55% vs. 53%, respectively; 95% CI −22–23%). The patients with larger-diameter cellulitis demonstrated a slightly higher rate of MRSA-positive culture results compared to patients with smaller-diameter cellulitis (61% vs. 46%, respectively; 95% CI −0.3–30%), but the difference was not statistically significant.

Conclusion

Cellulitis and abscess size do not predict treatment failures within 7 days, nor do they predict which patients will have MRSA. MRSA-positive patients are more likely to fail treatment within 7 days of incision and drainage.