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Review

A Current Perspective on Daptomycin for the Clinical Microbiologist

Romney M. Humphries, Simon Pollett, George Sakoulas
Romney M. Humphries
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California, USAa
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  • For correspondence: rhumphries@mednet.ucla.edu
Simon Pollett
Sydney Institute of Emerging Infections and Biosecurity, University of Sydney, Sydney, New South Wales, Australiab
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George Sakoulas
Division of Pediatric Pharmacology and Drug Discovery, University of California San Diego School of Medicine, La Jolla, California, USAc
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DOI: 10.1128/CMR.00030-13
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    Fig 1

    Daptomycin structure (A) and interaction with the cytoplasmic membrane (B).

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    Fig 2

    MIC distributions for Gram-positive clinical isolates collected in Europe, North America, and South America in 2002, before the introduction of daptomycin for clinical use. (Based on data from reference 56.)

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    Fig 3

    Percent probability of pharmacokinetic-pharmacodynamic target attainment for area under the curve targets of 180 for S. aureus (A) and 48 for E. faecalis (B). Data were generated from Monte Carlo analysis by applying a total drug AUC/MIC criterion of 180 or 48 for efficacy, based on murine thigh and thigh and renal models for S. aureus and E. faecalis, respectively. A 4-mg/kg q24h dose of daptomycin with an AUC of 494 ± 75 μg · h/ml was used in this simulation.

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    Fig 4

    Mutations in MprF identified in daptomycin-NS S. aureus. MprF consists of an N-terminal flippase domain and a C-terminal phosphatidylglycerol lysylination domain. Mutations have been identified in both domains, as outlined in the following references: a, reference 96; b, reference 101; c, reference 88; d, reference 98; e, reference 103; f, reference 115; g, reference 90; h, reference 201; i, reference 94.

Tables

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  • Table 1

    Daptomycin MIC breakpoints established by the CLSI, FDA, and EUCAST

    OrganismMIC breakpoint (μg/ml) established by a :
    CLSI FDA EUCAST
    SRSRSR
    Staphylococcus ≤1 ≤1 ≤1>1
    Enterococcus ≤4 ≤4 b
    Beta-hemolytic Streptococcus ≤1 ≤1 ≤1>1
    Viridans group Streptococcus, excluding S. pneumoniae ≤1
    Corynebacterium ≤1
    Lactobacillus ≤4
    • ↵a S, susceptible; R, resistant; CLSI, Clinical and Laboratory Standards Institute; FDA, Food and Drug Administration; EUCAST, European Committee on Antimicrobial Susceptibility Testing.

    • ↵b Due to the lack of clinical data, the FDA clinical breakpoint is approved for vancomycin-susceptible E. faecalis alone.

  • Table 2

    Daptomycin cure rate of MRSA infections by daptomycin MIC a

    Daptomycin MIC, μg/ml b Cure, n c Total, n d Cure rate, % (95% CI) e References
    ≤137643486.6 (83.4–89.8) 11, 12, 73, 202 – 217
    2153148.4 (30.8–66.0) 12, 98, 202, 216 – 222
    431421.4 (0.0–42.9) 12, 216, 217 223, 224
    ≥8020 76, 77
    • ↵a MRSA, methicillin-resistant Staphylococcus aureus.

    • ↵b MIC by broth microdilution, Etest, or automated method. The isolate with the highest MIC was included. Etest results were rounded up to the nearest dilutional integer for comparison.

    • ↵c Microbiological or clinical cure. Where both were presented in a relevant study, the lower cure rate was chosen for a more conservative estimate.

    • ↵d Data pooled from multiple studies and case reports, with additional data clarification by the study authors where possible. See Table S1 in the supplemental material for further details.

    • ↵e 95% CI, 95% confidence interval.

  • Table 3

    Daptomycin cure rate of VRE infections by daptomycin MIC a

    Daptomycin MIC, μg/ml b Cure, n c Total, n d Cure rate, % (95% CI) e References
    ≤16785.7 (60.6–100) 79, 225 – 227
    2121963.2 (37.5–88.9) 79, 225, 228 – 231
    4334475.0 (52.3–97.7) 79, 225, 230 – 233
    ≥8050.0 75, 160, 183, 234, 235
    • ↵a VRE, vancomycin-resistant Enterococcus, including E. faecalis, E. faecium, E. raffinosus, and E. gallinarum.

    • ↵b MIC by broth microdilution, Etest, or automated method. The isolate with the highest MIC was included. Etest results were rounded up to nearest dilutional integer for comparison.

    • ↵c Microbiological or clinical cure. Where both were presented in a relevant study, the lower cure rate was chosen for a more conservative estimate.

    • ↵d Data pooled from multiple studies and case reports, with additional data clarification by study authors where possible. See Table S2 in the supplemental material for further details.

    • ↵e 95% CI, 95% confidence interval.

  • Table 4

    Daptomycin susceptibilities of S. aureus strains with various vancomycin susceptibility phenotypes

    S. aureus phenotype a No. of isolates tested% Daptomycin susceptibilityReference(s)
    hVISA2785 133
    88100 60
    VISA7017 b 129
    3330 134
    1753 60
    1362 133
    VRSA13100 129, 134
    • ↵a hVISA, vancomycin-heteroresistant S. aureus; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

    • ↵b Includes isolates with vancomycin MICs of 16 μg/ml.

  • Table 5

    Mutations in the cardiolipin synthetase gene, cls, identified among daptomycin-nonsusceptible Enterococcus strains

    Species and mutationPredicted Cls domainDaptomycin MIC (μg/ml)Reference
    Enterococcus faecium
        H215RProximal to the PLD1 active site (within 10 Å)48 a 164
        H270RSpacer regions between PLD1 and PLD232 157
        K60TLinker region32 160
        MPL insertion at 110Linker region24 a 164
        N13IN-terminal transmembrane helix32 a 164
        N13SN-terminal transmembrane helix192 157
        N13TN-terminal transmembrane helix>256 160
        R218QHKD of PLD132 a 164
        R218QHKD of PLD148 a 164
        R218QHKD of PLD116 162
    Enterococcus faecalis
        Deletion of K61Linker region12 164
        R218QHKD of PLD1256 163
        N77-Q79 delLinker region256 163
        R218QHKD of PLD1512 163
    • ↵a MIC measured by Etest.

  • Table 6

    Essential agreement and error rates for automated antimicrobial test systems versus the CLSI reference broth microdilution method a

    Automated systemOrganism(s)n (no. NS)% EA% CA% ME% VMEReference
    BD Phoenix E. faecalis 39 (4)828714.20 236
    E. faecium 46 (22)9810000 236
    S. aureus 63 (26)9810000 236
    CoNS26 (1)10010000 236
    MicroScan E. faecalis 1311 (0)NR99.60.4 237
    E. faecium 362 (0)NR91.28.8 237
    Enterococcus 128 (17)91–94 b 88NRNR 238
    S. aureus 161 (0)97.51000 191
    Vitek 2 Enterococcus faecium 30 (3)NR100 0 239
    CoNS100 (0)98991 196
    S. aureus 270 (20)80.795.45.410.7 196
    S. aureus and S. agalactiae 751 (19)97.296.83.03.3 240
    Staphylococcus 184 (0)98.2100 241
    • ↵a NS, nonsusceptible; EA, essential agreement; CA, categorical agreement; ME, major error; VME, very major error; NR, not reported; CoNS, coagulase-negative Staphylococcus.

    • ↵b Dependent on Prompt or turbidity methods of inoculum preparation.

Additional Files

  • Figures
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  • Supplemental material

    Files in this Data Supplement:

    • Supplemental file 1 -

      Correlations of MRSA daptomycin MIC (Table S1) and VRE daptomycin MIC (Table S2) with clinical outcomes in comparative studies.

      PDF, 420K

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A Current Perspective on Daptomycin for the Clinical Microbiologist
Romney M. Humphries, Simon Pollett, George Sakoulas
Clinical Microbiology Reviews Oct 2013, 26 (4) 759-780; DOI: 10.1128/CMR.00030-13

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A Current Perspective on Daptomycin for the Clinical Microbiologist
Romney M. Humphries, Simon Pollett, George Sakoulas
Clinical Microbiology Reviews Oct 2013, 26 (4) 759-780; DOI: 10.1128/CMR.00030-13
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  • Top
  • Article
    • SUMMARY
    • INTRODUCTION
    • DAPTOMYCIN MECHANISM OF ACTION AND SPECTRUM OF ACTIVITY
    • DAPTOMYCIN BREAKPOINTS
    • DAPTOMYCIN NONSUSCEPTIBILITY
    • SUSCEPTIBILITY TESTING
    • CONCLUSION
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
    • Author Bios
  • Figures & Data
  • Info & Metrics
  • PDF

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