Dataset Information

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ?-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

ABSTRACT: Importance:Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ?-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective:To determine whether combining an antistaphylococcal ?-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants:Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions:Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ?-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n?=?174) or standard therapy alone (n?=?178). Total duration of therapy was determined by treating clinicians and the ?-lactam was administered for 7 days. Main Outcomes and Measures:The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results:The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance:Among patients with MRSA bacteremia, addition of an antistaphylococcal ?-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration:ClinicalTrials.gov Identifier: NCT02365493.

SUBMITTER: Tong SYC

PROVIDER: S-EPMC7042887 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Tong Steven Y C SYC Lye David C DC Yahav Dafna D Sud Archana A Robinson J Owen JO Nelson Jane J Archuleta Sophia S Roberts Matthew A MA Cass Alan A Paterson David L DL Foo Hong H Paul Mical M Guy Stephen D SD Tramontana Adrian R AR Walls Genevieve B GB McBride Stephen S Bak Narin N Ghosh Niladri N Rogers Benjamin A BA Ralph Anna P AP Davies Jane J Ferguson Patricia E PE Dotel Ravindra R McKew Genevieve L GL Gray Timothy J TJ Holmes Natasha E NE Smith Simon S Warner Morgyn S MS Kalimuddin Shirin S Young Barnaby E BE Runnegar Naomi N Andresen David N DN Anagnostou Nicholas A NA Johnson Sandra A SA Chatfield Mark D MD Cheng Allen C AC Fowler Vance G VG Howden Benjamin P BP Meagher Niamh N Price David J DJ van Hal Sebastiaan J SJ O'Sullivan Matthew V N MVN Davis Joshua S JS

JAMA 20200201 6

<h4>Importance</h4>Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted.<h4>Objective</h4>To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bact ...[more]

PMID: 32044943

Similar Datasets

Project description:IntroductionA one-time vancomycin loading dose of 25-30 mg/kg is recommended in the current iteration of the vancomycin consensus guidelines in order to more rapidly achieve target serum concentrations and hasten clinical improvement. However, there are few clinical data to support this practice, and the extents of its benefits are largely unknown.MethodsA multicenter, retrospective, cohort study was performed to assess the impact of a vancomycin loading dose (≥ 20 mg/kg) on clinical outcomes and rates of nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. The study matched patients in a 1:1 fashion based on age, Pitt bacteremia score, and bacteremia source. The primary outcome was composite treatment failure (30-day mortality, bacteremia duration ≥ 7 days after vancomycin initiation, persistent signs and symptoms of infection ≥ 7 days after vancomycin initiation, or switch to an alternative antimicrobial agent). Secondary outcomes included duration of bacteremia, length of stay post-bacteremia onset, and nephrotoxicity.ResultsA total of 316 patients with MRSA bacteremia were included. Median first doses in the loading dose and non-loading dose groups were 23.0 mg/kg and 14.3 mg/kg, respectively (P < 0.001). No difference was found in composite failure rates between the non-loading dose and loading dose groups (40.5% vs. 36.7%; P = 0.488) or in the incidence of nephrotoxicity (12.7% vs. 16.5%; P = 0.347). While multivariable regression modeling showed receipt of a vancomycin loading dose on a mg/kg basis was not significantly associated with composite failure [aOR 0.612, 95% CI (0.368-1.019)]; post hoc analyses demonstrated that initial doses ≥ 1750 mg were independently protective against failure [aOR 0.506, 95% CI (0.284-0.902)] without increasing the risk for nephrotoxicity [aOR 0.909, 95% CI (0.432-1.911)].ConclusionThese findings suggest that initial vancomycin doses above a certain threshold may decrease clinical failures without increasing toxicity and that weight-based dosing might not be the optimal strategy.

Project description:IntroductionVancomycin (VAN) failures associated with the treatment of complicated methicillin-resistant Staphylococcus aureus (MRSA) infections have been well described. The reported "seesaw effect" demonstrates improved β-lactam activity when VAN and/or daptomycin (DAP) susceptibility decreases. However, there are minimal data comparing ceftaroline (CPT) susceptibility with these agents or teicoplanin (TEI). Therefore, to further explore the seesaw effect, we evaluated the relationship between CPT and VAN, TEI, and DAP susceptibilities.MethodsOne hundred and fifty clinical MRSA isolates from the Anti-Infective Research Laboratory (Detroit, MI, USA) from 2008 to 2012 were analyzed. VAN, TEI, DAP and CPT minimum inhibitory concentrations (MIC) were determined via Etest methodology. MIC50 and MIC90 were calculated for each antibiotic. Additionally, four isogenic strain pairs were randomly selected for evaluation by time-kill methodology for the potential of enhanced killing by CPT as MICs increased to VAN, TEI, and DAP.ResultsCPT MICs were inversely correlated with VAN, DAP, and TEI MICs with correlation coefficients of -0.535, -0.483, and -0.386, respectively (P ≤ 0.05). Comparison of the MIC relationship for glycopeptides and lipopeptides resulted in a positive correlation for all agent combinations. In time-kill evaluations, CPT demonstrated greater reductions in log10 colony-forming unit (CFU)/mL against mutant strains (3.73 ± 0.67) versus parents (2.79 ± 0.75) despite no change in CPT MIC (P = 0.112).ConclusionThis study demonstrated a marked "seesaw effect" whereby CPT displayed increased susceptibility as the VAN, DAP, and TEI MICs increased. Additionally, we observed a positive linear correlation between VAN, DAP, and TEI MICs for all agent combinations. Enhanced activity was noted with CPT in mutant strains versus the parent strains despite no change in MIC. Based upon the enhanced CPT activity observed against strains with decreased susceptibility to VAN, DAP and TEI, CPT may provide an option for infections with reduced susceptibility to glycopeptides or lipopeptides. Further evaluation is warranted to investigate the clinical implications of the seesaw effect.

Project description:BackgroundLinezolid, which has bacteriostatic activity, is approved for the treatment of vancomycin-resistant enterococci (VRE) infections. Meanwhile, daptomycin exerts bactericidal activity against VRE, but is not approved for the treatment of VRE bacteremia. Only a few studies with small sample sizes have compared the effectiveness of these drugs for treatment of VRE bacteremia.MethodsPubMed, EMBASE, and the Cochrane Library were searched for studies of VRE bacteremia treatment published before January 1, 2014. All studies reporting daptomycin and linezolid treatment outcomes simultaneously were included. The endpoints were mortality and microbiological cure. The adjusted odds ratios (aORs) of mortality in daptomycin- and linezolid-treated patients were extracted if available. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for all outcomes using a random-effects model.ResultsThirteen studies (532 patients receiving daptomycin, 656 patients receiving linezolid) met the selection criteria. All studies had retrospective cohort designs and relatively small sample sizes. Eight studies compared the aORs of mortality in daptomycin- and linezolid-treated patients. Four studies were published as conference papers and there was significant heterogeneity among these studies (I2 = 63%, p = 0.04). Daptomycin use was not associated with better microbiological cure (daptomycin vs. linezolid, OR: 0.67, 95% CI: 0.42-1.06, p = 0.09). However, mortality was higher in patients receiving daptomycin (OR: 1.43, 95% CI: 1.09-1.86, p = 0.009). Subgroup analysis of studies that reported aORs indicated that daptomycin was associated with higher mortality (OR: 1.59, 95% CI: 1.02-2.50, p = 0.04). There was no evidence of publication bias, but all enrolled studies were retrospective, had small sample sizes, and had substantial limitations.ConclusionsAlthough limited data is available, the current meta-analysis shows that linezolid treatment for VRE bacteremia was associated with a lower mortality than daptomycin treatment. However, the results should be interpreted cautiously because of limitations inherent to retrospective studies and the high heterogeneity among studies. A large randomized trial is needed to confirm the present results.

Dataset Information

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ?-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Publications

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets