Current Microbiology

, Volume 75, Issue 8, pp 1062–1067 | Cite as

Prevention of High-Level Daptomycin-Resistance Emergence In Vitro in Streptococcus mitis-oralis by Using Combination Antimicrobial Strategies

  • Brianne Zapata
  • Danya N. Alvarez
  • Sabrina Farah
  • Cristina Garcia-de-la-Maria
  • Jose M. Miro
  • George Sakoulas
  • Arnold S. Bayer
  • Nagendra N. Mishra


Among the viridans group streptococci, S. mitis-oralis strains are frequently resistant to multiple β-lactams and tolerant to vancomycin (VAN). This scenario has led to the proposed clinical use of newer agents, like daptomycin (DAP) for such S. mitis-oralis strains. However, recent recognition of the rapid and durable emergence of high-level DAP-resistance (DAP-R; DAP MICs > 256 µg/ml) induced by DAP exposures in vitro and in vivo has dampened enthusiasm for such approaches. In this study, we evaluated a broad range of DAP combination regimens in vitro for their capacity to prevent emergence of high-level DAP-R in a prototype S. mitis-oralis strain (351) during serial passage experiments, including DAP + either gentamicin (GEN), rifampin (RIF), trimethoprim–sulfamethoxazole (TMP–SMX), imipenem (IMP), ceftaroline (CPT), tedizolid (TDZ), or linezolid (LDZ). In addition, we assessed selected DAP combination regimens for their ability to exert either an early bactericidal impact and/or synergistically kill the S. mitis-oralis study strain. During serial passage, three of the eight antibiotic combinations (DAP + GEN, CPT, or TMP- SMX) exhibited significantly reduced DAP MICs (≈ by 8–40 fold) vs serial exposure in DAP alone (DAP MICs > 256 µg/ml). In addition, combinations of DAP + GEN and DAP + CPT were both bactericidal and synergistic in early time-kill curve interactions.



This study was supported by a research grant to NNM from Merck Laboratories. ASB and NNM were also supported in part by a research grant from NIH-NIAID (1RO1AI130056-01). JMM received a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. BZ received a research grant from NIH (NIH-NIGMS 5R25GM07592). These data were presented as part of Master’s Thesis in Biology by B. Zapata at California State University-Dominguez Hills Carson, CA.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Brianne Zapata
    • 1
  • Danya N. Alvarez
    • 1
    • 5
  • Sabrina Farah
    • 1
  • Cristina Garcia-de-la-Maria
    • 2
  • Jose M. Miro
    • 2
  • George Sakoulas
    • 3
  • Arnold S. Bayer
    • 1
    • 4
  • Nagendra N. Mishra
    • 1
    • 4
    • 6
  1. 1.Divison of Infectious DiseasesLos Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterTorranceUSA
  2. 2.Hospital Clinic-IDIBAPSUniversity of BarcelonaBarcelonaSpain
  3. 3.Division of Host-Microbe Systems & TherapeuticsUniversity of California San Diego, School of MedicineLa JollaUSA
  4. 4.David Geffen School of Medicine at University of CaliforniaLos AngelesUSA
  5. 5.Center for Infectious DiseasesCalifornia State Department of Public HealthRichmondUSA
  6. 6.Division of Infectious DiseasesLos Angeles Biomedical Research Institute at Harbor – UCLA Medical CenterTorranceUSA

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