Therapeutic Monitoring of Vancomycin for Serious Methicillin-resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840.

Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.

Vancomycin remains the mainstay treatment for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) despite increased treatment failures. Daptomycin has been shown to improve clinical outcomes in patients with BSIs caused by MRSA isolates with vancomycin MICs of >1 mg/liter, but these studies relied on automated testing systems. We evaluated the outcomes of BSIs caused by MRSA isolates for which vancomycin MICs were determined by standard broth microdilution (BMD). A retrospective, matched cohort of patients with MRSA BSIs treated with vancomycin or daptomycin from January 2010 to March 2015 was completed. Patients were matched using propensity-adjusted logistic regression, which included age, Pitt bacteremia score, primary BSI source, and hospital of care. The primary endpoint was clinical failure, which was a composite endpoint of the following metrics: 30-day mortality, bacteremia with a duration of ≥7 days, or a change in anti-MRSA therapy due to persistent or worsening signs or symptoms. Secondary endpoints included MRSA-attributable mortality and the number of days of MRSA bacteremia. Independent predictors of failure were determined through conditional backwards-stepwise logistic regression with vancomycin BMD MIC forced into the model. A total of 262 patients were matched. Clinical failure was significantly higher in the vancomycin cohort than in the daptomycin cohort (45.0% versus 29.0%; P = 0.007). All-cause 30-day mortality was significantly higher in the vancomycin cohort (15.3% versus 6.1%; P = 0.024). These outcomes remained significant when stratified by vancomycin BMD MIC. There was no significant difference in the length of MRSA bacteremia. Variables independently associated with treatment failure included vancomycin therapy (adjusted odds ratio [aOR] = 2.16, 95% confidence interval [CI] = 1.24 to 3.76), intensive care unit admission (aOR = 2.46, 95% CI = 1.34 to 4.54), and infective endocarditis as the primary source (aOR = 2.33, 95% CI = 1.16 to 4.68). Treatment of MRSA BSIs with daptomycin was associated with reduced clinical failure and 30-day mortality; these findings were independent of vancomycin BMD MIC.

Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis.

Given the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC0-24) and the minimum concentration at 24 h (Cmin 24) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC0-24/MIC as determined by BMD of ≤600 relative to those with AUC0-24/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively, P = 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37; P = 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC0-24/MIC as determined by BMD of ≤600 present an increased risk of failure.

Evaluation of vancomycin population susceptibility analysis profile as a predictor of outcomes for patients with infective endocarditis due to methicillin-resistant Staphylococcus aureus.

Infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA IE) is associated with high morbidity and mortality. Vancomycin continues to be the primary treatment for this disease. The emergence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), defined as a modified population analysis profile (PAP) of ≥ 0.9, may affect patient outcomes. The objective of this study was to evaluate the relationship of vancomycin subpopulation susceptibility and the clinical outcomes of MRSA IE. We conducted a retrospective cohort study of patients treated with vancomycin for MRSA IE from 2002 to 2013 at the Detroit Medical Center. A modified PAP was used to measure the vancomycin PAP MIC and the PAP-to-area under the curve (AUC) ratio. Treatment failure was defined as bacteremia for ≥ 7 days or death attributed to MRSA. Classification and regression tree (CART) analysis was used to select a failure breakpoint between the PAP-AUC ratios and the PAP MIC. A total of 202 patients were included in the study. Twenty-seven percent of the patients had left-sided IE, 19% of the strains were hVISA, and 70% of the strains were staphylococcal cassette chromosome mec element (SCCmec) type IV. Overall treatment failure was observed in 64%; 59% had persistent bacteremia, and the 30-day attributable mortality rate was 21%. The CART breakpoint between failure and success in terms of the PAP-AUC ratio was 0.9035. On logistic regression analysis, intensive care unit (ICU) admission (adjusted odds ratio [aOR], 2.8; 95% confidence interval [CI], 1.5 to 5.2) and a PAP MIC of ≥ 4 mg/liter (aOR, 3.2; 95% CI, 1.3 to 8.4) were associated with failure (P = 0.001 and 0.015, respectively). A PAP MIC of ≥ 4 mg/liter and ICU admission were significant for treatment failure for patients with MRSA IE. The PAP-AUC ratio of ≥ 0.9035 predicted failure consistent with the hVISA definition. The role of population MIC analysis in predicting outcome with MRSA infections warrants further investigation.

Multicenter study of high-dose daptomycin for treatment of enterococcal infections.

Enterococci are among the leading pathogens isolated in hospital-acquired infections. Current antimicrobial options for vancomycin-resistant enterococci (VRE) are limited. Prior data suggest that daptomycin at >6 mg/kg of body weight/day may be used to treat enterococcal infections. We retrospectively evaluated the effectiveness and safety of high-dose daptomycin (HD-daptomycin) therapy (>6 mg/kg) in a multicenter cohort of adult patients with enterococcal infections to describe the characteristics and outcomes. Two hundred forty-five patients were evaluated. Enterococcus faecium was identified in 175 (71%), followed by Enterococcus faecalis in 49 (20%) and Enterococcus spp. in 21 (9%); overall, 204 (83%) isolates were VRE. Enterococcal infections included bacteremia (173, 71%) and intra-abdominal (35, 14%) and bone and joint (25, 10%) infections. The median dosage and duration of HD-daptomycin were 8.2 mg/kg/day (interquartile range [IQR], 7.7 to 9.7) and 10 days (IQR, 6 to 15), respectively. The overall clinical success rate was 89% (193/218), and microbiological eradication was observed in 93% (177/191) of patients. The median time to clearance of blood cultures on HD-daptomycin was 3 days (IQR, 2 to 5). The 30-day all-cause mortality rate was 27%, and 5 (2%) patients developed daptomycin-nonsusceptible enterococcal strains while on HD-daptomycin. Seven patients (3%) had creatine phosphokinase (CPK) elevation, yet no HD-daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic. Overall, there was a high frequency of clinical success and microbiological eradication in patients treated with HD-daptomycin for enterococcal infections, even in patients with complicated and difficult-to-treat infections. No adverse event-related discontinuation of HD-daptomycin was noted. HD-daptomycin may be an option for the treatment of enterococcal infections.

A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis.

OBJECTIVES: Despite significant medical advances, infective endocarditis (IE) remains an infection associated with high morbidity and mortality. The objective was to assess the safety and efficacy of high-dose daptomycin, defined as ≥ 8 mg/kg/day, in patients with confirmed or suspected staphylococcal and/or enterococcal IE. METHODS: This was a multicentre, retrospective observational study (2005-11). Adult patients, not undergoing haemodialysis, with blood cultures positive for staphylococci or enterococci and a definitive or possible diagnosis of IE, who received daptomycin ≥ 8 mg/kg/day (based on total body weight) for ≥ 72 h were included. RESULTS: Seventy patients met the inclusion criteria and comprised 33 (47.1%) with right-sided IE (RIE), 35 (50%) with left-sided IE (LIE) and 2 with both RIE and LIE. Several patients had concomitant sites of infection, with bone/joint infection being most prevalent (12.9%). Sixty-five patients received daptomycin as salvage therapy. Pathogens were isolated from 64 patients, with methicillin-resistant Staphylococcus aureus as the most common organism (84.4%), followed by vancomycin-resistant Enterococcus faecium (7.8%). The median (IQR) daptomycin dose was 9.8 mg/kg/day (8.2-10.0 mg/kg/day), and was similar in RIE and LIE patients (9.8 and 9.3 mg/kg/day, respectively). A total of 24 (34.3%) received combination therapy. For those patients with pathogens isolated (n = 64), the organism was eradicated in 57 (89.1%) patients. Among 64 clinically evaluable patients, 55 (85.9%) achieved clinical success. No patients required discontinuation of high-dose daptomycin due to creatine phosphokinase elevations. CONCLUSIONS: Patients with both RIE and LIE had successful outcomes with high-dose daptomycin therapy. Additional clinical trials evaluating high daptomycin dosages in patients with IE are warranted.

Role of the pharmacist in preventing distribution of counterfeit medications.

OBJECTIVE: To provide an overview of the counterfeit medication problem and recommendations of a joint American Pharmacists Association (APhA) Academy of Pharmaceutical Research and Science and APhA Academy of Pharmacy Practice and Management taskforce. DATE SOURCES: SciFinder and PubMed were searched from 1980 to March 2011 using the following keywords: counterfeit drug product, counterfeit medications, drug product authentication, drug product verification, and track-and-trace. Publications, presentations, and websites of organizations that research the counterfeit medication problem in the United States and other countries were reviewed. A representative from the security division of a pharmaceutical manufacturer and a representative from a supplier of anticounterfeiting technologies gave presentations to the taskforce. SUMMARY: The taskforce recommends that pharmacists (1) purchase medications from known, reliable sources; (2) warn patients of the dangers of purchasing medications over the Internet; (3) confirm with distributors that products were purchased from manufacturers or other reliable sources; (4) monitor counterfeit product alerts; (5) examine products for suspicious appearance; (6) work with the pharmaceutical industry, distributors, and the Food and Drug Administration (FDA) to close gaps in the supply chain, especially for drugs in short supply; (7) use scanning technology in the pharmacy as part of a prescription verification process; (8) educate themselves, coworkers, and patients about the risks of counterfeit medications; and (9) report suspicious medications to FDA, the distributor, and the manufacturer. CONCLUSION: The consequence of a patient receiving a counterfeit medication in the United States could be catastrophic, and pharmacists must play an active role in preventing such an event from occurring.

Multicenter Cohort Study of Ceftaroline Versus Daptomycin for Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infection.

BACKGROUND: Observational data suggest ceftaroline may be effective for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI), but comparative data with standard of care are limited. This analysis compares the outcomes of MRSA BSI treated with ceftaroline or daptomycin. METHODS: Multicenter, retrospective, observational cohort study of adult patients with MRSA BSI from 2010 to 2017. Patients treated with ≥72 hours of ceftaroline or daptomycin were included. Those clearing BSI before study drug and those with a pneumonia source were excluded. The primary outcome was composite treatment failure, defined as 30-day mortality, BSI duration ≥7 days on study drug, and 60-day MRSA BSI recurrence. Inverse probability of treatment weighted risk difference in composite failure between daptomycin and ceftaroline groups was computed and 15% noninferiority margin applied. RESULTS: Two hundred seventy patients were included; 83 ceftaroline and 187 daptomycin. Ceftaroline was noninferior to daptomycin with respect to composite failure (39% daptomycin, 32.5% ceftaroline; weighted risk difference, 7.0% [95% confidence interval, -5.0% to 19.0%]). No differences between treatment groups was observed for 30-day mortality or other secondary efficacy outcomes. Creatine phosphokinase elevation was significantly more common among daptomycin patients (5.3% vs 0%, P = .034). Rash was significantly more common among ceftaroline patients (10.8 vs 1.1%, P = .001). CONCLUSIONS: No difference in treatment failure or mortality was observed between MRSA BSI treated with ceftaroline or daptomycin. These data support future study of ceftaroline as a primary MRSA BSI treatment and current use of ceftaroline when an alternative to vancomycin and daptomycin is required.

Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets.

BACKGROUND: High rates of vancomycin failure in methicillin-resistant Staphylococcus aureus (MRSA) infections have been increasingly reported over time. The primary objective of our study was to determine the impact of vancomycin exposure and outcomes in patients with MRSA bacteremia initially treated with vancomycin. METHODS: This was a single-center retrospective analysis of 320 patients with documented MRSA bacteremia initially treated with vancomycin from January 2005 through April 2010. Two methods of susceptibility, Etest and broth microdilution, were performed for all isolates to determine the correlation of susceptibility testing to patient outcomes. RESULTS: Among a cohort of 320 patients, more than half (52.5%) experienced vancomycin failure. Independent predictors of vancomycin failure in logistic regression included infective endocarditis (adjusted odds ratio [AOR], 4.55; 95% confidence interval [CI], 2.26-9.15), nosocomial-acquired infection (AOR, 2.19; 95% CI, 1.21-3.97), initial vancomycin trough <15 mg/L (AOR, 2.00; 95% CI, 1.25-3.22), and vancomycin minimum inhibitory concentration (MIC) >1 mg/L by Etest (AOR, 1.52; 95% CI, 1.09-2.49). With use of Classification and Regression Tree (CART) analysis, patients with vancomycin area under the curve at 24 h (AUC(24h)) to MIC ratios <421 were found to have significantly higher rates of failure, compared with patients with AUC(24h) to MIC ratios >421 (61.2% vs 48.6%; P = .038). CONCLUSIONS: In light of the high failure rates associated with this antimicrobial, optimizing the pharmacokinetic/pharmacodynamic properties of vancomycin by targeting higher trough values of 15-20 mg/L and AUC(24h)/MIC ratios ≥400 in selected patients should be considered.

Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.

Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections (SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility to vancomycin, and vancomycin treatment failures.

Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary.

Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections (SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility to vancomycin, and vancomycin treatment failures.

Daptomycin compared to standard therapy for the treatment of native valve endocarditis.

INTRODUCTION: In a recent randomized trial of Staphylococcus aureus bacteremia and native valve endocarditis, daptomycin was found not inferior to standard therapy. We summarized findings in the subgroup of patients with endocarditis according to the Duke criteria. METHODS: Patients were randomly assigned to receive daptomycin 6 mg/kg/day or standard therapy (vancomycin 1g every 12h or antistaphylococcal penicillin 2g every 4h, both with gentamicin 1mg/kg every 8h for the first 4 days). The primary end point was success in the modified intent-to-treat population 6 weeks after the end of therapy. RESULTS: Fifty-three patients were included: 35 with right-sided endocarditis (RIE) and 18 with left-sided endocarditis (LIE). The success rates in patients with RIE were similar between daptomycin and the comparator (42% vs 44%). Patients with RIE with septic pulmonary infarcts responded similarly to treatment with daptomycin and standard therapy (60% vs 67%). In the LIE population, treatment success rates were poor in both arms (11% vs 22%). CONCLUSION: Daptomycin is an efficacious and well-tolerated alternative to standard therapy in the treatment of RIE. Patients with LIE had a poor outcome regardless of the treatment received. Daptomycin is also effective in treating endocarditis with septic pulmonary infarcts.

Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

BACKGROUND: Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring. METHODS AND RESULTS: This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. CONCLUSIONS: The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.

Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic.

BACKGROUND: The safety of adding initial low-dose gentamicin to antistaphylococcal penicillins or vancomycin for treatment of suspected Staphylococcus aureus native valve endocarditis is unknown. This study evaluated the association between this practice and nephrotoxicity. METHODS: We performed a prospective cohort study of safety data from a randomized, controlled trial of therapy for S. aureus bacteremia and native valve infective endocarditis involving 236 patients from 44 hospitals in 4 countries. Patients either received standard therapy (antistaphylococcal penicillin or vancomycin) plus initial low-dose gentamicin (n=116) or received daptomycin monotherapy (n = 120). We measured renal adverse events and clinically significant decreased creatinine clearance in patients (1) in the original randomized study arms and (2) who received any initial low-dose gentamicin either, as a study medication or or=65 years and receipt of any initial low-dose gentamicin. CONCLUSIONS: Initial low-dose gentamicin as part of therapy for S. aureus bacteremia and native valve infective endocarditis is nephrotoxic and should not be used routinely, given the minimal existing data supporting its benefit.

Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists.

Practice guidelines for therapeutic monitoring of vancomycin treatment for Staphylococcus aureus infection in adult patients were reviewed by an expert panel of the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. A literature review of existing evidence regarding vancomycin dosing and monitoring of serum concentrations, in addition to patient outcomes combined with expert opinion regarding the drug's pharmacokinetic, pharmacodynamic, and safety record, resulted in new recommendations for targeting and adjustment of vancomycin therapy.

Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.

BACKGROUND: Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed. METHODS: We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy. RESULTS: Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and methicillin-resistant S. aureus. Daptomycin therapy was associated with a higher rate of microbiologic failure than was standard therapy (19 vs. 11 patients, P=0.17). In 6 of the 19 patients with microbiologic failure in the daptomycin group, isolates with reduced susceptibility to daptomycin emerged; similarly, a reduced susceptibility to vancomycin was noted in isolates from patients treated with vancomycin. As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P=0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P=0.004). CONCLUSIONS: Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).

Open-Label Randomized Trial of Early Clinical Outcomes of Ceftaroline Fosamil Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections at Risk of Methicillin-Resistant Staphylococcus aureus.

INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSSIs) remain among the most common infectious processes seen in the clinical setting. For patients with complicated ABSSSIs deemed to require intravenous antibiotics, vancomycin remains the mainstay therapy. Ceftaroline has been shown to be non-inferior to vancomycin and may result in faster resolution of signs of infection. METHODS: Multicenter, prospective, open-label, randomized trial of ceftaroline versus vancomycin for the treatment of adult patients admitted for management of ABSSSIs from April 2012 to May 2016; 166 patients in the clinically evaluable (CE) group were needed to determine a 20% difference in primary outcome of clinical response at day 2 or 3 of antibiotics. Clinical response was defined as cessation of spread of lesion and improvement in systemic signs/symptoms of infection. A secondary outcome was a ≥ 20% reduction in lesion size at day 2 or 3 of antibiotics. RESULTS: One hundred seventy-four patients were enrolled in the intention-to-treat (ITT) group and 108 were CE. Among CE patients, 54 were randomized to ceftaroline and 54 to vancomycin. Baseline characteristics were similar except patients in the ceftaroline arm were older and had a non-significantly higher degree of comorbidities (median Charlson score 2 vs. 4, respectively). Cellulitis was the most common type of ABSSSI (85.2% vs. 79.6%, respectively). Rapid diagnostic testing of available cultures (n = 55) demonstrated high agreement with clinical microbiology for identification of Staphylococcus aureus (100%) and MRSA (100%). There was no significant difference in primary outcome of day 2 or 3 clinical response (50.0% vs. 51.9%). CONCLUSION: Early clinical response between vancomycin- and ceftaroline-treated ABSSSIs was similar. Patients with ABSSSIs rarely remained hospitalized for > 2-3 days, thus limiting our ability to critically assess clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02582203. FUNDING: Allergan plc.

Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis.

BACKGROUND: Coagulase-negative staphylococci (CoNS) are an infrequent cause of native valve endocarditis (NVE), and our understanding of NVE caused by CoNS is incomplete. METHOD: The International Collaboration on Endocarditis-Prospective Cohort Study includes patients with endocarditis from 61 centers in 28 countries. Patients with definite cases of NVE caused by CoNS who were enrolled during the period June 2000-August 2006 were compared with patients with definite cases of NVE caused by Staphylococcus aureus and patients with NVE caused by viridans group streptococci. Multivariable logistic regression was used to determine factors associated with death in patients with NVE caused by CoNS. RESULTS: Of 1635 patients with definite NVE and no history of injection drug use, 128 (7.8%) had NVE due to CoNS. Health care-associated infection occurred in 63 patients (49%) with NVE caused by CoNS. Comorbidities, long-term intravascular catheter use, and history of recent invasive procedures were similar among patients with NVE caused by CoNS and among patients with NVE caused by S. aureus. Surgical treatment for endocarditis occurred more frequently in patients with NVE due to CoNS (76 patients [60%]) than in patients with NVE due to S. aureus (150 [33%]; P=.01) or in patients with NVE due to viridans group streptococci (149 [44%]; P=.01). Despite the high rate of surgical procedures among patients with NVE due to CoNS, the mortality rates among patients with NVE due to CoNS and among patients with NVE due to S. aureus were similar (32 patients [25%] and 124 patients [27%], respectively; P=.44); the mortality rate among patients with NVE due to CoNS was higher than that among patients with NVE due to viridans group streptococci (24 [7.0%]; P=.01). Persistent bacteremia (odds ratio, 2.65; 95% confidence interval, 1.08-6.51), congestive heart failure (odds ratio, 3.35; 95% confidence interval, 1.57-7.12), and chronic illness (odds ratio, 2.86; 95% confidence interval, 1.34-6.06) were independently associated with death in patients with NVE due to CoNS (c index, 0.73). CONCLUSIONS: CoNS have emerged as an important cause of NVE in both community and health care settings. Despite high rates of surgical therapy, NVE caused by CoNS is associated with poor outcomes.