Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia

Lindsay M. Avery, Joseph L. Kuti, Maja Weisser, Adrian Egli, Michael J. Rybak, Evan J. Zasowski, Cesar A. Arias, German A. Contreras, Pearlie P. Chong, Samuel L. Aitken, Adam J. DiPippo, Jann Tay Wang, Nicholas S. Britt, David P. Nicolau

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration–time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold. Data were pooled from seven published trials assessing outcomes in daptomycin-treated enterococcal bacteraemia, including patients receiving daptomycin (≥72 h) and any β-lactam, intravenous aminoglycoside, linezolid, tigecycline and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding and daptomycin Etest MIC. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following pooling of data, 240 adults were included; 137 (57.1%) were alive at 30 days. A majority of patients were immunosuppressed (65.8%) and received a β-lactam (94.6%). Examining the threshold in low-acuity patients (n = 135) to control for co-morbidities, these patients were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% vs. 20.0%; P = 0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (P = 0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤ 2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteraemia.

Original languageEnglish (US)
Pages (from-to)346-350
Number of pages5
JournalInternational Journal of Antimicrobial Agents
Volume54
Issue number3
DOIs
StatePublished - Sep 2019

Keywords

  • Bacteraemia
  • Combination therapy
  • Daptomycin
  • Enterococcus
  • Pharmacodynamics

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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  • Cite this

    Avery, L. M., Kuti, J. L., Weisser, M., Egli, A., Rybak, M. J., Zasowski, E. J., Arias, C. A., Contreras, G. A., Chong, P. P., Aitken, S. L., DiPippo, A. J., Wang, J. T., Britt, N. S., & Nicolau, D. P. (2019). Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia. International Journal of Antimicrobial Agents, 54(3), 346-350. https://doi.org/10.1016/j.ijantimicag.2019.07.002