Dataset Information

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

ABSTRACT:

Background

Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ?4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined.

Methods

Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a ?-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs.

Results

Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L.

Conclusions

For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ?1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

SUBMITTER: Avery LM

PROVIDER: S-EPMC6938208 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

Avery Lindsay M LM Kuti Joseph L JL Weisser Maja M Egli Adrian A Rybak Michael J MJ Zasowski Evan J EJ Arias Cesar A CA Contreras German A GA Chong Pearlie P PP Aitken Samuel L SL DiPippo Adam J AJ Wang Jann-Tay JT Britt Nicholas S NS Nicolau David P DP

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190501 10

<h4>Background</h4>Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined.<h4>Methods</h4>Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who re ...[more]

PMID: 30188976

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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.

Project description:IntroductionEvolution of antibacterial resistance in pathogenic enterococcal strains poses a growing therapeutic challenge. Daptomycin, a cyclic lipopeptide, exhibits broad antibiotic activity against Gram-positive bacteria.MethodsThe European Cubicin(®) Outcomes Registry and Experience, a multicenter, retrospective, non-interventional study, recorded clinical outcomes following daptomycin treatment.ResultsOverall, 472 patients (predominantly elderly Caucasian males) were treated for enterococcal infections. Of those, 72.7% received antibiotics prior to daptomycin treatment, whereas 77.1% received other antibiotics concomitantly. Failure of previous therapy, resistant or non-susceptible pathogen, and narrowing of antibiotic therapy were the main reasons for switching to daptomycin treatment. Nosocomial infections comprised 55.8% of the cohort. Bacteremia (29.9%), complicated skin and soft tissue infection (29.2%) and endocarditis (12.3%) were the most common primary infections. Clinical success was achieved in 77.1% of patients, with similar success rates across all primary infection categories. The overall clinical success rate was marginally higher (82.5% vs 74.6%, p = 0.09) with daptomycin use as first-line versus second-line therapy. Patients receiving higher doses of daptomycin exhibited the highest clinical success rates (85.7% for ≥8 mg/kg/day vs 75.8% for <8 mg/kg/day, p = 0.08). While 81 (17.2%) patients reported at least one adverse event (AE), only 11 (2.3%) and 3 (0.6%) had treatment-related AEs and serious AEs, respectively. Separate microbiologic findings from Leipzig University Hospital demonstrate small proportions of Enterococcus faecium isolates with daptomycin minimum inhibitory concentrations = 4 mg/L (4%) or ≥8 mg/L (0.8%), which are regarded as non-susceptible.ConclusionFor enterococcal infections, daptomycin appears to be an effective and well-tolerated treatment option, exhibiting highest clinical success rates at higher doses.

Dataset Information

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

Background

Methods

Results

Conclusions

Publications

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

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