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Background: Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen., Methods: Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses., Results: HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets., Conclusions: Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: We investigated physical and chemical stability of daptomycin and vancomycin in heparin or sodium citrate lock solutions. The aim of this study was to find the optimal combination of antimicrobials and additives for lock solutions, which maximized patient safety., Methods: Vancomycin and daptomycin were diluted with heparin or sodium citrate to achieve final concentrations of vancomycin-heparin 2.5 mg/mL-833.33 U/mL, vancomycin-citrate 2.5-33.3 mg/mL, daptomycin-heparin 5 mg/mL-800 U/mL, and daptomycin-citrate 5-32 mg/mL and they were stored at room temperature (+25°C), 4°C, -20°C, and 37°C. Physical and chemical stability were analyzed for each antibiotic-anticoagulant combination in all conditions immediately after preparation, at 24, 48, 72 h and at different time points until unstable concentrations were obtained. Daptomycin-sodium citrate microbiological activity was also studied by evaluating two Staphylococcus aureus cultures in a calcium enriched medium with a daptomycin E test, with and without sodium citrate., Results: After incubation at 37°C vancomycin and daptomycin combined with heparin retained at least 90% of the initial concentration over 48 h. Vancomycin-sodium citrate solution stored at 37°C reduced more than 10% of the initial concentration at 24 h. On the other hand, daptomycin-sodium citrate preparation was stable at 37°C for 72 h but the microbiological activity of daptomycin was lower in the presence of sodium citrate., Conclusions: The purpose is to prepare vancomycin and daptomycin lock solutions combined with heparin. They should be changed at 48 h and its stability is over 3 days at 25°C and 7 days at 4°C, which allow Hospital Pharmacy Services to manage their stocks. Daptomycin-sodium citrate combination is more stable for extended periods but its bioactivity has not been demonstrated., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The emergence of vancomycin resistant Enterococci (VRE) is shortening the choices for clinical anti-infective therapy. The aim of this study was to investigate the mechanism of vancomycin resistance and evaluate the effect of fosfomycin (FM), rifampin (RIF), vancomycin (VAN), linezolid (LNZ), daptomycin (DAP) alone or in combination against VRE., Methods: Eight VRE isolates were collected. A total of 18 antibiotics susceptibility tests were further done for VRE. Whole genome sequencing and bioinformatics analysis were performed. The effect of FM, RIF, VNA, LNZ, DAP alone or in combination was determined using anti-biofilm testing and the time-kill assay., Results: All isolates were susceptible to LNZ and DPA. The high-level resistance determinant of VAN in these strains was due to VanA-type cassette. MLST revealed two different STs for vancomycin-resistant Enterococcus faecium (VREm) and four different STs for vancomycin-resistant E. faecalis (VREs). Virulence genes in VREs were more than VREm, especially for 4942 isolated from blood. Gene acm and uppS were only identified in VREm, while virulence genes related to cytolysin were only found in E. faecalis. Further in vitro studies indicated FM (83 mg/L) combined with DAP (20.6 mg/L) and DAP monotherapy (47.1 mg/L) had bactericidal effect against VRE isolates at 24h., Conclusion: High-level resistance determinant of VAN in tested isolates was due to VanA-type cassette. FM combined with DAP is a potential therapeutic option for VRE infections., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Tong et al.)

Objectives: Dalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5-16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials such as vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA., Methods: We simulated average, post-distributional exposures of single-dose (1500 mg) dalbavancin (fCmax 9.9 μg/mL, β-elimination t 1/2 204 h) in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for 28 days (672 h) against five MRSA strains and one methicillin-susceptible strain (MSSA). Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole-genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and six β-lactams with varying penicillin-binding protein (PBP) affinities., Results: Dalbavancin was bactericidal against most strains for days 1-4 before regrowth of less susceptible subpopulations occurred. Isolates with eight-fold increases in dalbavancin MIC were detected as early as day 4 but increased 64-128-fold in all models by day 28. Vancomycin and daptomycin MICs increased 4-16-fold, exceeding the susceptibly breakpoints for both antibiotics; β-lactam MICs generally decreased by two-to eight-fold, suggesting a dalbavancin-β-lactam seesaw effect, but increased by eight-fold or more in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR, apt, stp1, and atl., Conclusions: In our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to β-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear, but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin intermediate susceptibility and daptomycin non-susceptibility, most commonly walKR-associated genes., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Data supporting oral step-down therapy in methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are sparse; linezolid offers potential in this setting. This study aimed to determine the effectiveness and safety of oral step-down linezolid compared with standard parenteral therapy (SPT) in MRSA-BSI. This was a retrospective cohort performed in adults receiving step-down/outpatient linezolid or SPT (vancomycin, daptomycin) for MRSA-BSI from 2011-2019. Primary outcome was 90-day infection-related re-admission (IRR) from clinical worsening/relapse or infection recurrence. 215 patients included (54 linezolid, 161 SPT). Infection sources were skin (34%), bone/joint (15%), endocarditis (13%), other (32%), multiple (6%). Patients receiving SPT more commonly had complicated bacteraemia (72% vs. 41%; P < 0.0001) and metastatic foci (45% vs. 20%; P = 0.001). 90-day IRR occurred in 17% and 26% of linezolid and SPT groups, respectively (P = 0.159). When accounting for disease severity, linezolid use was not independently associated with 90-day IRR (adjOR, 1.0, 95% CI 0.24-4.3; P = 0.986). There were no differences in all-cause 90-day mortality (4% vs. 6%, P = 0.487) or overall incidence of drug-related adverse events (AEs) (17% vs. 16%; P = 0.843) between the groups. More patients in the SPT group developed an AE requiring re-hospitalisation (12% vs. 2%; P = 0.024), most commonly line-related complications. Oral step-down linezolid demonstrated similar clinical and safety outcomes compared with SPT for MRSA-BSI, except linezolid was associated with fewer AEs requiring re-hospitalisation. Additional research is needed exploring step-down linezolid in MRSA-BSI, particularly in patients requiring shorter durations of outpatient therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

What Is Known and Objective: Our previous report indicated that teicoplanin (TEIC) caused fewer adverse effects than vancomycin (VCM) in patients with febrile neutropenia (FN) receiving haematopoietic stem cell transplantation (HSCT). However, we observed breakthrough methicillin-resistant-Staphylococcus haemolyticus (MR-S haemolyticus) infection during TEIC therapy in these patients. In this study, we sought to compare the incidence of breakthrough Gram-positive cocci (GPC) infection during VCM and TEIC therapy in this population., Methods: A single-centre, retrospective cohort study was conducted. Patients who had received HSCT and were administered VCM (n = 19) or TEIC (n = 38) for FN from 1 September 2011 to 31 August 2019 were enrolled. We compared the incidence of breakthrough GPC infection between the VCM and TEIC groups., Results: Breakthrough GPC infection during glycopeptide therapy in febrile neutropenic patients received HSCT was observed in three patients (7.9%) in the TEIC group but in none of patients (0%) in the VCM group. MR-S haemolyticus with low glycopeptide susceptibility (TEIC MIC = 2-8 μg/mL, VCM MIC = 2-4 μg/mL) was isolated from blood cultures in all patients with breakthrough GPC infections. All breakthrough infections were cured by changing from TEIC to daptomycin (DAP)., What Is New and Conclusion: The incidence of breakthrough GPC infection during glycopeptide therapy in febrile neutropenic HSCT patients was higher in the TEIC group than in the VCM group. MR-S haemolyticus with low glycopeptide susceptibility was isolated from all patients with breakthrough GPC infection and successfully treated with DAP., (© 2020 John Wiley & Sons Ltd.)

The combination of vancomycin or daptomycin plus ceftaroline has showed synergistic results in vitro. This study aimed to investigate in vitro synergy of vancomycin or daptomycin plus ceftaroline for seven patients with daptomycin non-susceptible Staphylococcus aureus (SA) bacteremia Thirteen isolates from seven patients were evaluated: two methicillin-susceptible and five methicillin-resistant SA infections. All patients were treated with daptomycin and became non-susceptible (minimum inhibitory concentration (MIC) >1 μg/mL) with therapy or had resistant strains initially. Time kill experiments were completed with 0.25 × MIC, 0.5 × MIC, and 0.75 × MIC concentrations. No synergy was seen at 0.25 × MIC. Synergy was observed for 4 isolates with vancomycin plus ceftaroline and with daptomycin plus ceftaroline for 2 isolates at 0.5 × MIC. These results are in accordance with literature that supports synergistic combinations of daptomycin or vancomycin with ceftaroline for SA bacteremia. Daptomycin non-susceptible SA bacteremia presents a treatment challenge., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Observational and randomized controlled trials of the combination of vancomycin or daptomycin with a beta-lactam (BL) in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia have shown conflicting results on patient outcomes., Objectives: The primary purpose of this meta-analysis was to compare clinical failure with the combination of vancomycin or daptomycin with a BL versus vancomycin or daptomycin monotherapy in MRSA bacteremia or endocarditis., Methods: A systematic literature search of PubMed, Embase, CINAHL, and meeting proceedings was conducted from inception through February 11, 2020, to identify relevant studies. The primary outcome was clinical failure and secondary outcomes were mortality, nephrotoxicity, and bacteremia. The meta-analysis was performed using Comprehensive Meta Analysis (version 3.0) with a random effects model. Outcomes were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs)., Results: Nine studies of 1636 patients receiving vancomycin or daptomycin monotherapy versus the combination of vancomycin or daptomycin plus BL for MRSA bacteremia were included. Results showed combination therapy was associated with significantly lower clinical failure rates (OR 0.56, 95% CI 0.39-0.79, I 2  = 26.22%, p=0.001). Improvement in clinical failure was driven by lower rates of bacteremia relapse and persistence. However, no difference was seen with mortality., Conclusions: Combination therapy with vancomycin or daptomycin plus BL for MRSA bacteremia showed lower clinical failure rates, however, no significant difference was seen in mortality., (© 2020 Pharmacotherapy Publications, Inc.)

Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram-positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.02-20.51); p = 0.04], female sex (OR, 3.28; 95%CI, 1.41-7.67; P < .01), and longer hospitalization (OR, 1.06; 95%CI, 1.01-1.11; P = .02] independently predicted moderate-to-severe AKI. In the vancomycin group, trough concentrations increased after discharge, and were higher in female compared to male patients, and in those who developed moderate-to-severe AKI compared to those who did not. Female sex (OR, 8.37; 95%CI, 2.35-29.82; P < .01) and higher concentrations (OR, 1.12; 95%CI, 1.05-1.19; P < .01) predicted moderate-to-severe AKI in patients receiving vancomycin. In conclusion, premature antibiotic discontinuations and nephrotoxicity are more frequent in patients treated at home with vancomycin compared to daptomycin. Among patients receiving vancomycin, plasma concentrations increased after hospital discharge and predicted moderate-to-severe AKI. Women had higher vancomycin concentrations and higher risk for AKI., (© 2019, The American College of Clinical Pharmacology.)

Background: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC., Methods: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI., Results: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively., Conclusions: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

New antimicrobial agents are being designed to treat infections of multidrug-resistant pathogens and have been introduced in the past few years, but there has been a worldwide increase in the incidence of vancomycin-resistant enterococci (VRE) infections, and treatment options are still limited. In this study, it was aimed to investigate the in vitro activity of vancomycin combined with daptomycin against 30 VRE strains. The minimum inhibitory concentration (MIC) values of antibiotics were determined using broth microdilution assay as described by the Clinical and Laboratory Standards Institute (CLSI). The activities of antibiotics in combination were assessed using a broth microcheckerboard method. In addition, 4 of the 30 strains were randomly selected to determine the time-kill curves at 1 × MIC concentrations and 2 of 4 strains at ½ × MIC concentrations. Viable counts were determined at 0-, 4-, 8-, 12-, 24-, 48-, and 72-hr intervals. This was accomplished by subculturing 0.1 mL from repetitive serial dilutions in Eppendorf tubes, followed by subculturing 0.1 mL from tubes onto Tryptic Soy Agar plates. All plates were incubated at 35°C for 24 hr. The synergistic effect was found 100% using the broth microcheckerboard method, and in strains tested using the time-kill method at both 1 × MIC and ½ × MIC concentrations. The results of this study suggest that this combination could be effective in the treatment of the VRE-associated infection.

Background: Gram-positive organisms are a leading cause of infection in cardiovascular surgery. Furthermore, these patients have a high risk of developing postoperative renal failure in intensive care unit (ICU). Some antibiotic drugs are known to impair renal function. The aim of the study was to evaluate whether patients treated for Gram-positive cardiovascular infection with daptomycin (DAP) experienced a lower incidence of acute kidney injury (AKI) when compared to patients treated with vancomycin (VAN), with comparable efficacy., Methods: ICU patients who received either DAP or VAN, prior to or after cardiovascular surgery or mechanical circulatory support, from January 2010 to December 2012, were included in this observational retrospective cohort study. We excluded patients with end stage renal disease and antibiotic prophylaxis. The primary endpoint was the incidence of AKI within the first week of treatment. Secondary endpoints were the incidence of AKI within the first 14 days of treatment, the severity of AKI including renal replacement therapy (RRT), the rates of clinical failure (unsuccessful infection treatment) and of premature discontinuation and mortality. To minimize selection bias, we used a propensity score to compare the 2 groups. Univariate and multivariate analysis were performed to determine factors associated with AKI., Results: Seventy two patients, treated for infective endocarditis, cardiovascular foreign body infection, or surgical site infection were included (DAP, n = 28 and VAN, n = 44). AKI at day 7 was observed in 28 (64%) versus 6 (21%) of the VAN and DAP patients, respectively (p = 0.001). In the multivariate analysis adjusted to the propensity score, vancomycin treatment was the only factor associated with AKI (Odds Ratio 4.42; 95% CI: 1.39-15.34; p = 0.014). RRT was required for 2 (7%) DAP patients and 13 (30%) VAN patients, p = 0.035. Premature discontinuation and clinical failure occurred more frequently in VAN group than in DAP group (25% versus 4%, p = 0.022 and 42% versus 12%, respectively, p = 0.027)., Conclusions: Daptomycin appears to be safer than vancomycin in terms of AKI risk in ICU patients treated for cardiovascular procedure-related infection. Daptomycin could be considered as a first line treatment to prevent AKI in high-risk patients.

Introduction: This study aimed to characterize Staphylococcus aureus isolates from bloodstream infections in patients attending a teaching hospital, between 2011 and 2015., Methods: The minimum inhibitory concentration for daptomycin, linezolid, oxacillin, teicoplanin, vancomycin, and trimethoprim/sulfamethoxazole was accessed by broth microdilution. SCCmec type and clonal profile were determined by molecular tests. Vancomycin heteroresistance was evaluated using screening tests and by population analysis profile/area under the curve., Results: Among 200 S. aureus isolates, 55 (27.5%) were MRSA, carrying SCCmec II (45.5%) or IV (54.5%). The most frequent MRSA lineages were USA100 (ST5-II) (45.5%) and USA800 (ST5-IV) (30.9%). Six isolates were confirmed as vancomycin heteroresistant, showing area under the curve ratio 1.1, 1.2 or 1.3 (four USA100, one USA800 and one USA1100 isolates)., Conclusions: Daptomycin and vancomycin non-susceptible MRSA clonal lineages were found in bloodstream infections over five years, highlighting the importance of continuous surveillance of multiresistant bacteria in hospitals., (Copyright © 2019 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: The aim of this study was to determine the persistence of the adverse prognostic effect of elevated vancomycin minimum inhibitory concentration (MIC) in methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in a setting with low vancomycin use., Methods: A retrospective study focusing on episodes of bacteraemia due to MRSA diagnosed from January 2010 through December 2015 was designed. The main outcome measures were 30-day mortality and treatment failure. Multivariate logistic regression analysis was used to identify variables associated with patient mortality and treatment outcome., Results: In total, 79 MRSA bacteraemia episodes were included. The vancomycin MIC was >1.0μg/mL in 53 episodes (67.1%). The presence of high vancomycin MIC was not associated with a higher mortality rate or treatment success. A daptomycin MIC≥0.5μg/mL was present in 16 (26.2%) of 61 episodes for which the daptomycin MIC was obtained and was associated with 30-day mortality in the multivariate analysis (odds ratio=4.72, 95% confidence interval 1.19-18.71). None of the antimicrobials used were associated with a lower risk of treatment failure or mortality., Conclusions: The pernicious effect of high vancomycin MIC disappears in the absence of a predominant use of this antibiotic. However, a high daptomycin MIC in MRSA bacteraemia is associated with higher mortality in patients with bacteraemia, irrespective of antimicrobial treatment choice., (Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Background: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations., Methods: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60., Results: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3-5 days in the vancomycin arm and 3-7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in both arms. There was one case of musculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection., Conclusion: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success., Trial Registration: ClinicalTrials.gov, NCT01975662 . Registered on 5 November 2013.

Whole-genome sequencing was used to examine a persistent Enterococcus faecium bacteremia that acquired heteroresistance to three antibiotics in response to prolonged multidrug therapy. A comparison of the complete genomes before and after each change revealed the emergence of known resistance determinants for vancomycin and linezolid and suggested that a novel mutation in fabF , encoding a fatty acid synthase, was responsible for daptomycin nonsusceptibility. Plasmid recombination contributed to the progressive loss of vancomycin resistance after withdrawal of the drug., (Copyright © 2018 Chacko et al.)

The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model., (Copyright © 2017 American Society for Microbiology.)

The use of vancomycin minimum inhibitory concentration (MIC) as an outcome predictor in patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia has become an important topic for debate in the last few years. Given these previous results, we decided to investigate whether MICs to vancomycin or daptomycin had any effect on the evolution of patients with ventilator-associated pneumonia (VAP) due to MSSA. An observational, retrospective, multicenter study was conducted among patients with MSSA VAP. We analyzed the relationship between vancomycin and daptomycin MICs and early clinical response (72 h), 30-day mortality, intensive care unit (ICU) length of stay (LOS), and duration on mechanical ventilation. Univariate and multivariate analyses were performed. Sixty-six patients from 12 centers were included. Twenty-six patients (39%) had an infection due to MSSA strains with a vancomycin MIC ≥1.5 μg/mL. Daptomycin MIC was determined in 58 patients, of whom 17 (29%) had an MIC ≥1.0 μg/mL. Ten patients (15%) did not respond to first-line treatment. Only daptomycin MIC ≥1.0 μg/mL had a significant association [odds ratio (OR): 30.00; 95% confidence interval (CI): 2.91-60.41] with early treatment failure. The 30-day mortality was 12% (n = 8). Any variable was associated with mortality in the multivariate analysis. None of the variables studied were associated with ICU LOS or duration on mechanical ventilation. In patients with MSSA VAP, vancomycin MIC does not influence the response to antibiotic treatment or the 30-day mortality. Daptomycin MIC was directly related to early treatment failure.

Enterococci have become increasingly important pathogens for nosocomial infection (e.g. bacteremia, intra-abdominal infection, endocarditis, etc.), related to their intrinsic resistance to many antibiotics. Although the in vitro susceptibility of daptomycin (DAP) against Enterococci is well established, the Food and Drug Administration has only approved its use for complicated skin and skin structure infections induced by Enterococcus faecalis. In this study we evaluated the potential therapeutic application of DAP in a murine model of enterococcal experimental peritonitis. Mice were injected intraperitoneally with 4 × 10 10 colony-forming units of Enterococcus faecium. DAP alone, DAP combined with ampicillin, vancomycin, or linezolid were administered 2 h after enterococcal inoculation and examined the survival, viable bacteria counts, the level of KC/CXCL1 in the peritoneal fluid. The viable bacteria counts in the peritoneal fluid of the DAP- or DAP plus ampicillin-treated groups were decreased significantly compared to those of the vancomycin- and linezolid-treated groups (P < 0.05) at 6 and 12 h after the inoculation of Enterococcus. The level of neutrophil chemoattractants KC in the peritoneal fluid at 12 h after enterococcal inoculation was significantly decreased in the DAP plus ampicillin-treated group (P < 0.05). In addition DAP showed the inhibitory effect of enterococcal biofilm formation dose-dependently by a microtiter biofilm assay. These results indicate that DAP, particularly with β-lactams, is a possible alternative agent to treat severe enterococcal infection such as peritonitis., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti-VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed., (© 2017 Pharmacotherapy Publications, Inc.)

Background: Use of alternative antimicrobials to vancomycin is a potential strategy to reduce acute kidney injury (AKI) in high-risk patients, but current data do not support widespread adoption of this practice., Objective: To determine the efficacy of early switch to a nonnephrotoxic alternative for prevention of AKI in high-risk patients who receive vancomycin., Methods: This was an IRB-approved, prospective randomized controlled trial in a single, tertiary care academic medical center. Patients initially prescribed vancomycin between October 2011 to April 2013 with at least 2 risk factors for AKI were included. Treatment randomization was stratified by indication for therapy. Patients were randomized to continuation of dose-optimized vancomycin or early switch to an alternative antimicrobial agent. The primary end point was nephrotoxicity by consensus guideline definition adjudicated by blinded review; the secondary end point was AKI network-defined AKI., Results: A total of 103 patients were randomized; 100 were included in the modified intent-to-treat population, 51 in the vancomycin group and 49 in the alternative group. The incidence of nephrotoxicity was 6.1% in the alternative therapy arm and 9.8% in the vancomycin group ( P = 0.72). The incidence of AKI was 32.7% in the alternative therapy group and 31.4% in the vancomycin group ( P = 0.89)., Conclusions: No significant difference in nephrotoxicity or AKI was detected among patients treated with alternative antimicrobials compared with vancomycin. The use of alternative antimicrobial therapy instead of vancomycin solely for the purpose of preventing AKI in high-risk patients does not appear to be warranted.

Purpose: Case reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated., Methods: We performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest., Findings: Forty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio = 1.79, 95% CI, 0.52-6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3-4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3-4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant (P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all-cause 30-day mortality approached statistical significance (P = 0.06)., Implications: Duration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30-day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Bacteria may hide in a hydrated polysaccharide matrix known as a biofilm. The structure of the bacterial biofilm renders phagocytosis difficult and increases antibiotic resistance. We hypothesized that repeated doses of antibiotics have an effect on bacteria within the biofilm and that it could inhibit or eradicate biofilm formation. Two clinical biofilm-positive coagulase-negative staphylococcus isolates were evaluated. The effects of antibiotics on preformed and nascent biofilm and on bacterial eradication within the biofilm were determined using different doses of vancomycin, daptomycin, and tigecycline for different durations in an in vitro biofilm model. Vancomycin neither penetrated the biofilm nor had any microbicidal effect on bacteria within the biofilm. Daptomycin had a microbicidal effect on bacteria within the biofilm but had no effect on biofilm inhibition and eradication (independent from dose and treatment time). Tigecycline inhibited and eradicated biofilm formation and had a microbicidal effect on bacteria within the biofilm. In conclusion, (i) biofilm formation appeared to be a major barrier to vancomycin activity, (ii) daptomycin had an antimicrobial effect on the bacteria within the biofilm but not on the biofilm burden, and (iii) tigecycline had effects both on bacteria within the biofilm and on biofilm burden. Thus, both tigecycline and daptomycin might be promising candidates for the treatment of biofilm infections.

We investigated the prognostic role of high MICs for antistaphylococcal agents in patients with methicillin-sensitive Staphylococcus aureus catheter-related bloodstream infection (MSSA CRBSI). We prospectively reviewed 83 episodes from 5 centers in Spain during April 2011-June 2014 that had optimized clinical management and analyzed the relationship between E-test MICs for vancomycin, daptomycin, oxacillin, and linezolid and development of complicated bacteremia by using multivariate analysis. Complicated MSSA CRBSI occurred in 26 (31.3%) patients; MICs for vancomycin and daptomycin were higher in these patients (optimal cutoff values for predictive accuracy = 1.5 μg/mL and 0.5 μg/mL). High MICs for vancomycin (hazard ratio 2.4, 95% CI 1.2-5.5) and daptomycin (hazard ratio 2.4, 95% CI 1.1-5.9) were independent risk factors for development of complicated MSSA CRBSI. Our data suggest that patients with MSSA CRBSI caused by strains that have high MICs for vancomycin or daptomycin are at increased risk for complications.

Complex infection with methicillin-resistant Staphylococcus aureus (MRSA) is associated with high healthcare and societal costs; thus, evaluation of the costs and health benefits of interventions is an important consideration in a modern healthcare system. This study estimated the cost consequences of the use of daptomycin compared with vancomycin for the first-line treatment of patients with proven MRSA-induced bacteraemia-infective endocarditis (SAB-IE) with a vancomycin minimum inhibitory concentration (MIC) >1mg/L in the UK. A decision model was developed to assess total healthcare costs of treatment, including inpatient, outpatient and drug costs. Data were sourced from the literature (treatment efficacy and safety), a physician survey (resource use) and publicly available databases (unit costs). Assuming the same length of stay for daptomycin and vancomycin, the total healthcare costs per patient were £17917 for daptomycin and £17165 for vancomycin. However, extrapolating from published studies and supported by a physician survey, daptomycin was found to require fewer therapeutic switches and a shorter length of stay. When the length of stay was reduced from 42 days to 28 days, daptomycin saved £4037 per person compared with vancomycin. In conclusion, daptomycin is an effective and efficient alternative antibiotic for the treatment of SAB-IE. However, the level of cost saving depends on the extent to which local clinical practice allows early discharge of patients before the end of their antibiotic course when responding to treatment., (Copyright © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Purpose: To compare bactericidal activities of daptomycin (DAP) and vancomycin (VAN) in an experimental rabbit model of Enterococcus faecalis endophthalmitis., Materials and Methods: The right vitreous cavities of 24 New Zealand rabbits were inoculated with 100 colony-forming units of E. faecalis; and after 24 h, rabbits were randomly divided into three groups. DAP group (n = 8, 0.2 mg/0.05 ml intravitreally), VAN group (n = 8, 1 mg/0.05 ml intravitreally) and balanced salt solution group (BSS, n = 8, 0.05 ml intravitreally). Clinical examination scores were recorded, and vitreous aspirates were obtained for microbiological analysis on days 0, 1, 2, 3 and 4. Rabbits were sacrificed, and the eyes were enucleated for histopathological assessment., Results: There was no difference between the DAP, VAN and BSS groups in terms of the clinical grading of endophthalmitis 24 h after the inoculation. The bacterial counts were similar between the VAN and DAP groups except on day 1, where it was significantly lower than those in the VAN group (p = 0.003). On day 4, 62% of the eyes treated with DAP, and 50% of the eyes treated with VAN were sterilized. All of the eyes from the BSS group showed increasing bacterial growth from day 0 to day 4. There was no difference between the DAP and VAN groups in terms of the histopathological and clinical examination scores, while they were significantly lower than those in the BSS group., Conclusions: This study demonstrates evidence of the effectiveness of DAP for the treatment of experimental E. faecalis endophthalmitis.

Purpose: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation., Methods: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance., Findings: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035)., Implications: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Background: Incidence of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in complicated skin and skin structure infection (cSSSI) presenting to emergency departments (EDs). Treatment is heterogeneous and can require inpatient admission to an observation unit (OU). Vancomycin is commonly used in the OU for treatment, but increasing MRSA resistance to vancomycin suggests the need for alternatives. Daptomycin is an alternative but it is not known how it compares with vancomycin., Objective: This study tested the hypothesis that daptomycin is noninferior to vancomycin for the treatment of cSSSI in an OU, using a relative risk (RR) of 1.3 as the noninferiority limit., Methods: Subjects admitted to an ED-based OU with a diagnosis of cSSSI were eligible. Consenting subjects were randomized 1:1 to intravenous (i.v.) vancomycin at 15 mg/kg dosing every 12 h or i.v. daptomycin at 4 mg/kg once. Subjects were followed until they met objective criteria for discharge home or hospital admission. Discharged patients were prescribed 10-14 days of oral cephalexin and trimethoprim-sulfamethoxazole, or clindamycin if allergic to either of these medications. The primary endpoint was meeting objective discharge criteria with no change in antibiotic therapy or return to the ED for the same cellulitis within 30 days of OU discharge., Results: There were 100 patients enrolled. RR for satisfying the endpoint was 1.07 (95% confidence interval 0.58-1.98) for daptomycin compared with vancomycin. Hospital admission rates were 36% and 32% for daptomycin and vancomycin treatment, respectively., Conclusion: Daptomycin was not inferior to vancomycin in the treatment of cSSSI in an OU., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The association between varying durations of previous vancomycin therapy and subsequent daptomycin success rates was evaluated in a subset of patients with methicillin-resistant Staphylococcus aureus bacteremia from the Cubicin® Outcomes Registry and Experience 2005-2009 (n=159). Previous vancomycin exposure did not adversely affect daptomycin outcomes; success rates were 81% in patients treated with first-line daptomycin and 89%, 83%, and 88%, respectively, in patients with 1-3days, 4-6days, and ≥7days of previous vancomycin exposure (P=0.5)., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: In light of recent evidence suggesting enhancement of daptomycin activity against vancomycin-resistant Enterococcus (VRE) by ampicillin and other β-lactam antibiotics, we evaluated the safety profile and clinical efficacy of daptomycin with and without concomitant β-lactam antimicrobials in the treatment of VRE (faecium or faecalis) bacteremia from multiple centers across the United States., Methods: Data were collected retrospectively as part of a larger multicenter registry (The Cubicin Outcomes Registry and Experience). Efficacy and clinical outcomes in patients with VRE bacteremia who received at least 3 days of daptomycin with or without concomitant β-lactams were analyzed. Although all the cases involved daptomycin-susceptible VRE, additional analysis was performed to examine whether the adjunctive β-lactam would play a more pivotal role in cases where the daptomycin MIC was in the upper limit of the susceptibility range, indicating that daptomycin monotherapy efficacy may be relatively compromised compared with cases with lower daptomycin MICs., Findings: Two hundred sixty-two patients from 33 hospitals were evaluated. Most patients had at least one significant comorbidity, such as solid-organ or bone marrow transplantation (16%), neutropenia (36%), dialysis dependency (20%), or critical illness (36%) requiring care in an intensive care unit. Overall treatment success was 86% (n = 225/262), and treatment success for patients taking concomitant β-lactams was 86% (n = 105/122). Logistic regression identified treatment failure to be associated with sepsis (odds ratio = 3.42; P = 0.009) and an elevated daptomycin MIC (3-4 µg/mL) (odds ratio = 3.23, P = 0.013). No significant increase in clinical failure was seen among patients with elevated daptomycin MIC who received concomitant β-lactam therapy (clinical success, 88% vs 79% for MIC ≤2 vs 3-4 µg/mL, respectively; P = 0.417). Of 262 patients, 33 (13%) experienced ≥1 adverse event possibly related to daptomycin (increased creatine kinase in 8 patients)., Implications: Overall, daptomycin was effective and well tolerated for VRE bacteremia, with lower effectiveness noted with daptomycin MIC of 3 to 4 µg/mL. Concomitant β-lactam therapy with daptomycin may improve clinical outcomes in this setting. Further studies are needed to characterize the potential benefit of concomitant β-lactams with daptomycin., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Vancomycin has been considered the standard of care for treatment of Gram-positive skin and soft-tissue infections (SSTIs). Its value has been questioned over the last decade owing to well acknowledged limitations in efficacy and tolerability and the emergence of newer meticillin-resistant Staphylococcus aureus (MRSA)-active antibacterial agents. However, no single agent has shown better results versus vancomycin in SSTI trials. The aim of this review was to identify and summarise data from meta-analyses (MAs) for the treatment of Gram-positive and MRSA SSTIs. A systematic search identified 21 published MAs examining the use of newer antibiotics and vancomycin in SSTIs. In terms of clinical and microbiological efficacy, linezolid (in Gram-positive and MRSA SSTIs) and telavancin (in MRSA SSTIs) were shown to be more effective than vancomycin. The safety of newer antimicrobials in general was comparable with vancomycin, except for telavancin, which was associated with more severe adverse events (AEs), and tigecycline owing to an all-cause mortality imbalance observed in all infections but not confirmed in SSTIs. Specific AEs were related to the use of newer agents, such as nephrotoxicity for telavancin, creatine phosphokinase elevations for daptomycin, and thrombocytopenia with linezolid. Some evidence suggests that daptomycin could be associated with reduced treatment duration, and linezolid with reduced length of intravenous treatment and hospital length of stay compared with vancomycin. Considering the limitations of this type of research and the comparative efficacy results demonstrated in head-to-head randomised controlled trials, data are still not sufficient to support the widespread use of new agents over vancomycin., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Enterococcal infections are relatively common among hospitalized patients, likely because these organisms are commensals of human gastrointestinal and genitourinary tracts. With widespread usage of glycopeptides in both humans and livestock, vancomycin-resistant enterococci (VRE) quickly emerged. Bloodstream infections caused by these isolates are of significant concern with limited bactericidal options for treatment. Presently, daptomycin and linezolid serve as the mainstays of therapy, although resistance to both agents has been documented. Newer antimicrobials, specifically lipoglycopeptides and oxazolidinones, have been developed with in vitro activity against these organisms. However, no clinical data are available with their usage for VRE infections, let alone those in the bloodstream. This review focuses on the epidemiology, current and potential future therapeutic options for the treatment of VRE bacteremia.

Objective: To review the literature on the pharmacotherapy of bloodstream infections (BSI) caused by vancomycin-resistant enterococci (VRE)., Data Sources: A MEDLINE literature search was performed for the period 1946 to May 2014 using the search terms Enterococcus, enterococci, vancomycin-resistant, VRE, bacteremia, and bloodstream infection. References were also identified from selected review articles., Study Selection and Data Extraction: English-language case series, cohort studies, and meta-analyses assessing the options in the pharmacotherapy of VRE BSIs in adult patients were evaluated., Data Synthesis: Studies were identified that utilized linezolid, quinupristin/dalfopristin (Q/D), and daptomycin. In all, 8 comparative retrospective cohort studies, 2 meta-analyses of daptomycin and linezolid, and 3 retrospective comparisons of linezolid and Q/D were included for review. Mortality associated with VRE BSIs was high across studies, and the ability to determine differences in outcomes between agents was confounded by the complex nature of the patients included. Two meta-analyses comparing daptomycin with linezolid for VRE BSIs found modest advantages for linezolid, but these conclusions may be hampered by heterogeneity within the included studies., Conclusions: VRE BSIs remain a difficult-to-treat clinical situation. Differences in toxicity between the agents used to treat it are clear, but therapeutic differences are more difficult to discern. Meta-analyses suggest that a moderate advantage for linezolid over daptomycin may exist, but problems with the nature of studies that they included make definitive conclusions difficult., (© The Author(s) 2014.)

Objectives: Staphylococcus aureus is a notorious bacterial pathogen and antibiotic-resistant isolates complicate current treatment strategies. We characterized S. aureus VC40, a laboratory mutant that shows full resistance to glycopeptides (vancomycin and teicoplanin MICs ≥32 mg/L) and daptomycin (MIC = 4 mg/L), to gain deeper insights into the underlying resistance mechanisms., Methods: Genomics and transcriptomics were performed to characterize changes that might contribute to development of resistance. The mutations in vraS were reconstituted into a closely related parental background. In addition, antimicrobial susceptibility testing, growth analyses, transmission electron microscopy, lysostaphin-induced lysis and autolysis assays were performed to characterize the phenotype of resistant strains., Results: Genome sequencing of strain VC40 revealed 79 mutations in 75 gene loci including genes encoding the histidine kinases VraS and WalK that control cell envelope-related processes. Transcriptomics indicated the increased expression of their respective regulons. Although not reaching the measured MIC for VC40, reconstitution of the L114S and D242G exchanges in VraS(VC40) into the susceptible parental background (S. aureus NCTC 8325) resulted in increased resistance to glycopeptides and daptomycin. The expression of VraS(VC40) led to increased transcription of the cell wall stress stimulon, a thickened cell wall, a decreased growth rate, reduced autolytic activity and increased resistance to lysostaphin-induced lysis in the generated mutant., Conclusions: We show that a double mutation of a single gene locus, namely vraS, is sufficient to convert the vancomycin-susceptible strain S. aureus NCTC 8325 into a vancomycin-intermediate S. aureus., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Guidelines for the treatment of MRSA infection, recently published by the IDSA and JSC, recommend daptomycin for sepsis and skin and soft tissue infections comparably to or more strongly than vancomycin. Meanwhile MIC creeping with an increased isolation frequency of MRSA isolates with vancomycin MIC of 2 μg/mL has become a problem. In the present study, the MIC creeping rate of MRSA strains in the Tohoku district, Japan in 2012 was 13%, a significantly higher value than 3.3% in 2008 (P < 0.01). Of these isolates, the MIC and mutant prevention concentration (MPC) values of daptomycin and vancomycin were determined for 30 clinical isolates of MRSA in 2012. The MIC50/MIC80 values of daptomycin and vancomycin were 0.125/0.5 μg/mL and 0.125/1 μg/mL, respectively. The MPC50/MPC80 values of daptomycin and vancomycin were both 32/64 μg/mL. In the present study, the mutant selection window (MSW) of daptomycin and vancomycin was ≥64 MIC. Of strains that selected in the MSW, daptomycin non-susceptible isolates accounted for 70.0%, while MRSA with vancomycin MIC of 2 μg/mL accounted for 26.7%. On the other hand, 50% of the strains that selected in the vancomycin MSW were daptomycin non-susceptible strain. The detection rate of MRSA with vancomycin MIC of 2 μg/mL that selected in the daptomycin MSW was 36.7%. These results showed that MRSA with vancomycin MIC of 2 μg/mL and daptomycin non-susceptible isolates were selected by exposure to both antibiotics. Therefore, though vancomycin is frequently used for treatment of MRSA infection, both antibiotics should be selected as a first-line drug appropriately., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

It is not clear if patients with heterogeneous intermediate resistance to vancomycin (hVISA) infectious endocarditis (IE) differ from methicillin-resistant S. aureus (MRSA) IE patients. All cases of hVISA and MRSA IE diagnosed at the Sheba Medical Centre from 2003 to 2010 were included. Isolates were screened prospectively for hVISA. Medical records were reviewed. The t-test, chi-square test, Fisher exact test and Kaplan Meier analysis were used. Fourteen hVISA IE and 32 MRSA IE were identified. The mean age was 76 years, mean Charlson score was 4.5 and 24% of patients had prosthetic valves. Pacemakers and implantable cardioverter-defibrillators (P/ICDs) were more common in the hVISA group (50% vs. 22%, p 0.05). P/ICDs IE occurred in 29% of hVISA patients vs. 6.3% of MRSA patients (p 0.06). hVISA patients had more positive blood cultures (eight vs. five, p 0.007) and a trend toward longer bacteraemia (15 vs. 7.5 days, p 0.08). Vancomycin minimal inhibitory concentrations (MICs) were similar in the two groups (1.5 μg/mL vs. 1.1 μg/mL, p 0.11). The MIC to daptomycin was higher in hVISA (0.75 μg/mL vs. 0.32 μg/mL, p 0.049). MRSA patients received vancomycin. hVISA patients were switched to other antibiotics. Cardiac surgery and/or P/ICD extraction was performed more commonly in hVISA patients (50% vs. 16%, p 0.027). Mortality was high in both groups (57-66%). The median time to death was 39 days in the hVISA group and 19 days in the MRSA group (p 0.3). hVISA IE is associated with P/ICDs. Both hVISA and MRSA are associated with high mortality. Low rates of surgical intervention and P/ICD extraction reflect the high co-morbidity of patients. Caution should be employed in the empirical use of daptomycin in hVISA patients., (© 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.)

Background: At this time, several antibiotics have been investigated as possibilities for aerosol administration, but local therapy has been found to be more efficient in several diseases., Materials and Methods: The drugs linezolid (Zyvox), vancomycin (Voncon), and daptomycin (Cubicin) were tested with three jet nebulizers with seven different residual cups and different loadings. Moreover, three ultrasound nebulizers were again tested with these drugs, with different loadings and mouthpiece attachments., Results: When drugs are combined with particular cup designs, they significantly lower the droplet size to 1.60 and 1.80 μm, which represents the best combination of Zyvox and cup G and Cubicin and cup D, respectively. Cup design D is suggested as the most effective cup for lowering the droplet size (2.30 μm) when considering a higher loading level (8 mL)., Conclusion: Modification of current drugs from dry powder to solution is possible, and the residual cup design plays the most important role in droplet size production when the nebulization systems have the same properties.

Background: Concerns regarding the efficacy of daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections in patients with impaired renal function are reflected in a recent package insert change by the Food and Drug Administration (FDA). However, this decision was based on a small subgroup analysis and it is unclear if this is a true association., Methods: We conducted a retrospective cohort study of patients with MRSA bacteremia treated at a tertiary hospital from 2001 to 2011 and who received either vancomycin or daptomycin. We used propensity score and multivariable logistic regression to assess the outcome of treatment failure, via blinded adjudication, in daptomycin- vs vancomycin-treated subjects and the interaction with renal function., Results: One hundred fifty patients were analyzed, 100 in the vancomycin arm and 50 in the daptomycin arm. The average age was 61 years, and 60% were men. Of patients treated with daptomycin or vancomycin, 29 (58%) and 51 (51%), respectively, had an estimated glomerular filtration rate (GFR) <50 mL/minute/1.73 m(2). Compared with vancomycin, the usage of daptomycin in patients was not significantly associated with treatment failure in patients with a GFR >50 mL/minute/1.73 m(2) (odds ratio [OR], 0.45; 95% confidence interval [CI], .11 -1.79), nor in patients with a GFR of <50 mL/minute/1.73 m(2) (OR, 0.46; 95% CI, .11 -1.94). There was no significant interaction between them (P = .54)., Conclusions: In patients with MRSA bacteremia, daptomycin efficacy was not affected by GFR level and was similar to vancomycin's efficacy. Although our sample size was small, it was larger than than the one used by the FDA. However, smaller differences may be significant with a larger sample size.

Objective: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL., Data Sources: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013)., Study Selection and Data Extraction: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included., Data Synthesis: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d)., Conclusions: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area.

Antibiotic-resistant bacterial infection is one of the most serious clinical problems worldwide. Vancomycin, teicoplanin, daptomycin, and colistin are glycopeptide and lipopeptide antibiotics that are frequently used to treat multidrug-resistant bacterial infections. Therapeutic drug monitoring is recommended to ensure both safety and efficacy and to improve clinical outcomes. This study developed a fast, simple, and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of the concentrations of these four drugs in human plasma. The sample preparation process includes a simple protein denaturation step using acetonitrile, followed by an 11-fold dilution with 0.1% formic acid. Eight target peaks for the four drugs can be analyzed within 3 min using a Kinetex™ 2.6 μm C18 column. The mass spectrometry parameters were optimized, and two transitions for each target peak were used for multiple reaction monitoring, which provided high sensitivity and specificity. The UHPLC-MS/MS method was validated over clinical concentration ranges. The intra-day and inter-day precisions for the ratio of the peak area of each analyte to the peak area of the internal standard were all below 12.7 and 14.7% relative standard deviations, respectively. The accuracy at low, medium, and high concentrations of the eight target peaks was between 89.3 and 110.7%. The standard curves for the analytes were linear and had coefficients of determination higher than 0.997. The limits of detection were all below 70 ng mL(-1). The use of this method to analyze patient plasma samples confirmed that it is effective for the therapeutic drug monitoring of these four drugs and can be used to improve the therapeutic efficacy and safety of treatment with antibiotics., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Recent reports have described decreased effectiveness with vancomycin treatment for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) when the vancomycin minimum inhibitory concentration (MIC) is >1 µg/mL., Methods: This matched, retrospective cohort study compared the clinical effectiveness of daptomycin with that of vancomycin for the treatment of MRSAB with vancomycin MICs >1 µg/mL. The primary outcome was clinical failure, defined as a composite of 30-day mortality or bacteremia persisting for ≥7 days., Results: One hundred seventy patients were matched 1:1 with respect to the antimicrobial administered. In the daptomycin group, all patients received <72 hours of vancomycin (median, 1.7 days [interquartile range, 1.1-2.3 days]) prior to switching to daptomycin. The rate of clinical failure at 30 days was significantly lower in the daptomycin arm compared to the vancomycin arm (20.0% vs 48.2%; P < 0.001). Both 30-day mortality and persistent bacteremia were significantly lower in the daptomycin group compared to the vancomycin group (3.5% vs 12.9% [P = .047] and 18.8% vs 42.4% [P = .001], respectively). Logistic regression confirmed the association between vancomycin treatment and increased risk of clinical failure (adjusted odds ratio, 4.5; 95% confidence interval, 2.1-9.8)., Conclusions: This is the first matched study comparing early daptomycin versus vancomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL. Treatment with daptomycin resulted in significantly improved outcomes, including decreased 30-day mortality and persistent bacteremia. These results support the practice of switching early from vancomycin to daptomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL.

We compared the in vitro activity of daptomycin, a new lipopeptide antibiotic, with that of vancomycin and other selected agents against 95 coagulase negative staphylococci (CNS) isolates causing septicemia or foreign-body infections in immunocompromised patients. These strains were classified as follows: 51 methicillin-susceptible CNS (23 slime producers); 44 methicillin-resistant CNS (23 slime producers). We also investigated the activity of daptomycin against 50 Enterococcus faecalis isolates. Minimal inhibitory concentrations (MICs) were determined by the broth microdilution method. Daptomycin at a concentration of 2 mg/L was inhibitory for all the evaluated strains. Vancomycin and ciprofloxacin showed good activity: 90% of the strains were inhibited by these agents at 8 mg/L. The activity of netilmicin, rifampin and trimethoprim-sulfamethoxazole was instead limited. Resistance to the antimicrobial agents tested was seen with increased frequency among slime producing strains. Daptomycin and teicoplanin were the most active agents tested against E. faecalis (MIC90 0.25 mg/L and 0.12 mg/L).

Clinical trials with daptomycin were halted in December 1990 because of treatment failures including two resistant Staphylococcus aureus strains. High protein binding of daptomycin (> 90%) and the lower-than-expected concentrations in serum with the dosage regimen of 3 mg/kg of body weight every 12 h may have contributed to these failures. To evaluate the effect that higher concentrations would have on bactericidal activity measured by time-kill curves, peak and trough concentrations were estimated for dosage regimens of 3, 5, and 10 mg/kg every 12 h. MICs, MBCs, and killing curves for daptomycin and vancomycin were performed by using the estimated concentrations with four S. aureus strains obtained from patients who failed daptomycin therapy for endocarditis. MICs and MBCs of daptomycin demonstrated a greater inoculum effect than those of vancomycin; MICs and MBCs of daptomycin increased three- to fourfold, but those of vancomycin increased only one- to twofold when the inoculum was increased from 5 x 10(5) to 5 x 10(7) CFU/ml. No pH-dependent effect on MICs or MBCs was seen. Strenuous experimental conditions were chosen: high inoculums (5 x 10(7) CFU/ml), extremes of pH (6.4, 7.4, and 8), and stationary and exponentially growing organisms; and all experiments completed in the presence of pooled human serum. Daptomycin exhibited concentration-dependent killing and statistically faster kill rates than vancomycin against stationary- or exponential-growth-phase organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. The results indicate that the use of higher dosage regimens with compounds similar to daptomycin may be capable of overcoming the effects of pH, high inoculum, and protein binding.

Infections with enterococci that are resistant to multiple antibiotics are an emerging clinical problem. We evaluated the antibiotic treatment of experimental enterococcal endocarditis caused by two strains with different mechanisms of penicillin resistance. Enterococcus faecalis HH-22 is resistant to aminoglycosides and penicillin on the basis of plasmid-mediated modifying enzymes; Enterococcus raffinosus SF-195 is susceptible to aminoglycosides but is resistant to penicillin on the basis of low-affinity penicillin-binding proteins. Animals infected with strain HH-22 received 5 days of treatment with the following: no treatment; daptomycin (20 mg/kg of body weight twice daily [b.i.d.], intramuscularly [i.m.]), vancomycin (20 mg/kg b.i.d., intravenously), or ampicillin (100 mg/kg three times daily, i.m.) plus gentamicin (2.5 mg/kg b.i.d. i.m.). Although vancomycin was superior to ampicillin-gentamicin (P less than 0.01), daptomycin was significantly better than all other treatment regimens (P less than 0.01) in reducing intravegetation enterococcal densities, although no vegetations were rendered culture negative by this agent. Animals infected with strain SF-195 received 5 days of no therapy, ampicillin, ampicillin-gentamicin, vancomycin, or daptomycin (all at the dosage regimens described above). Daptomycin, vancomycin, and ampicillin-gentamicin each lowered intravegetation enterococcal densities significantly better than did ampicillin monotherapy or no treatment (P less than 0.01); moreover, these three treatment regimens rendered significantly more vegetations culture negative than did ampicillin monotherapy or no treatment (P less than 0.05). Serum daptomycin levels remained above the MICs and MBCs for both enterococcal strains throughout the 12-h dosing interval used in the study. Daptomycin and vancomycin were both active in vivo in these models of experimental enterococcal endocarditis caused by penicillin-resistant strains, irrespective of the mechanism of resistance. This activity correlated with the unique cell wall sites of action of these agents (binding to lipoteichoic acid and pentapeptide precursor, respectively) compared with the sites of action of beta-lactams (penicillin-binding proteins). Beta-Lactamase production by strain HH-22 precluded in vivo efficacy with ampicillin-gentamicin combinations. In contrast, this combination was active in vivo against strain SF-195, which exhibited intermediate-level penicillin resistance (MIC, 32 micrograms/ml), likely reflecting the ability of high-dose ampicillin to achieve enough binding to low-affinity penicillin-binding proteins to cause augmented aminoglycoside uptake.

The in vitro activities of teicoplanin, daptomycin, ramoplanin, and PD127,391, a new quinolone, were compared with that of vancomycin. Teicoplanin showed the lowest MICs against Enterococcus faecalis. Ramoplanin was slightly more active than the other peptide antibiotics against oxacillin-resistant Staphylococcus aureus. The MICs of the four peptide antibiotics were similar for the oxacillin-susceptible S. aureus. Daptomycin had good activity against staphylococci but was the least active agent against E. faecalis. The MICs of vancomycin against all isolates were in general higher than those of the new antibiotics, with the exceptions of the MICs of daptomycin against E. faecalis and teicoplanin against oxacillin-resistant Staphylococcus epidermidis. PD127,391 was the most active agent against all staphylococcal isolates.

Gram-positive organisms such as Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, Enterococcus spp., and Streptococcus spp. have in recent years emerged as significant pathogens in hospitals and are now being isolated more frequently than gram-negative bacilli. These organisms are often multidrug resistant. Therefore, alternative agents with potent activity against gram-positive organisms are of considerable interest. In addition to the glycopeptide antibiotic vancomycin and the aminoglycoside antibiotic arbekacin, which can be used in MRSA infections, teicoplanin, RP 59500 and daptomycin are now under basic research in Japan. These antimicrobial agents are very active against gram-positive organisms, including MRSA and appear to be potent agents against infections due to gram-positive cocci, particularly MRSA.

The pharmacokinetics and bactericidal killing rates (BR) of daptomycin (D) and vancomycin (V) in 12 intravenous drug abusers (6 treated with daptomycin and 6 treated with vancomycin) were evaluated. Pharmacokinetic parameters were determined from multiple serum samples drawn at steady state over a 12-h dosing interval after intravenous infusions of 3 mg of D per kg of body weight and 1,000 mg of V. The BRs were determined from the 1- and 6-h serum samples by using four isolates of Staphylococcus aureus (three methicillin susceptible and one methicillin resistant) obtained from the patients enrolled in the study. Peak serum daptomycin concentrations were lower and volumes of distribution were higher than reported in healthy volunteers. Although not statistically different, D clearance was 22% higher than reported in healthy volunteers. V pharmacokinetics were similar to those reported in previous studies. Daptomycin's BRs, although comparable to those of V in patients' serum, were significantly decreased compared with those found in broth. This may be related to the high degree of protein binding of D (93% versus 50% for V). Conversely, the BRs of V in serum were significantly greater than those in broth. The BRs of D and V in broth were greater when killing curves were performed with test strains in logarithmic versus stationary-phase growth. The ability to kill organisms in stationary phase may be an important factor in determining the performance of an antibiotic in deep-seated infections such as endocarditis.3+

The in-vitro activity of four peptide antibiotics against 43 penicillin-resistant Streptococcus pneumoniae isolated from cerebrospinal fluid (CSF) was evaluated. The activity of SKF104662 was slightly greater to that of vancomycin, teicoplanin and daptomycin (MICs for 90% of the isolates tested 0.06, 0.25, 0.12 and 0.25 mg/L, respectively) and superior to the other 15 drugs tested. The serotype of these penicillin-resistant strains was also determined. The strains that belonged to the predominant serotype 9 were resistant only to penicillin. All six erythromycin- and clindamycin-resistant strains belonged to serotype 6 and three of them were also resistant to chloramphenicol and tetracycline (plus penicillin).