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In vivo development of daptomycin resistance in vancomycin-susceptible methicillin-resistant Staphylococcus aureus severe infections previously treated with glycopeptides

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Abstract

Our aim was to describe the clinical and microbiological features of four cases of severe vancomycin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) infections in which the vancomycin non-susceptibility development and daptomycin resistance occurred under therapy with teicoplanin (three cases) and daptomycin switched to vancomycin (one case). Clinical data were retrospectively reviewed. On nine clinical epidemiologically unrelated daptomycin-susceptible (DAP-S) and daptomycin-resistant (DAP-R) MRSA, we performed: (i) DAP-VAN-TEC-CFX-RIF minimum inhibitory concentrations (MICs); (ii) glycopeptide resistance detection (GRD) by δ-hemolysis; (iii) glycopeptide population analysis; (iv) molecular characterization by PFGE-MLST-SCCmec-agr-typing; (v) rpoB and mprF single nucleotide polymorphisms (SNPs); (vi) dltA-mprF-atl-sceD expression by real-time quantitative polymerase chain reaction (qPCR). Three out of the four patients did not survive despite salvage treatment; two died with active MRSA infection and one died because of Stenotrophomonas maltophilia sepsis. The fourth patient, in which a reversion to a DAP-S phenotype occurred, survived with daptomycin plus trimethoprim/sulfamethoxazole and oxacillin treatment, and endovascular device removal. Daptomycin resistance development was preceded by a stable heterogeneous vancomycin-intermediate S. aureus (hVISA) or VISA phenotype acquisition, while in one case, daptomycin resistance was preceded by an unstable daptomycin heteroresistance (hDAP) behavior reverting to DAP-S during vancomycin plus rifampin therapy followed by high doses of daptomycin. All DAP-R strains showed hVISA or DAP-R traits, including mutations and/or up-regulation of genes involved in cell wall turnover and cell membrane perturbation. In our study, daptomycin resistance arose during glycopeptide therapy. The emergence of DAP-R isolates was preceded by a stable VISA or hVISA phenotype or by instability reverting to a DAP-S heteroresistant phenotype. Daptomycin, as first-line therapy for the treatment of severe MRSA infections, should be used at optimal dosage combined with other agents such as beta-lactams, to prevent daptomycin resistance occurrence.

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Acknowledgments

This work was partially supported by the grant DIAMOND HV PO-FESR 2007–2013 from MIUR Italy. We wish to thank the Scientific Bureau of the University of Catania for the language support.

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    Authors and Affiliations

    1. National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy

      A. Capone & N. Petrosillo

    2. Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy

      V. Cafiso, F. Campanile & S. Stefani

    3. Department of Microbiology, San Camillo-Forlanini Hospital, Rome, Italy

      G. Parisi & B. Mariani

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    1. A. Capone
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    2. V. Cafiso
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    Correspondence to V. Cafiso.

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    A. Capone and V. Cafiso contributed equally to this work.

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    Capone, A., Cafiso, V., Campanile, F. et al. In vivo development of daptomycin resistance in vancomycin-susceptible methicillin-resistant Staphylococcus aureus severe infections previously treated with glycopeptides. Eur J Clin Microbiol Infect Dis 35, 625–631 (2016). https://doi.org/10.1007/s10096-016-2581-4

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    • DOI: https://doi.org/10.1007/s10096-016-2581-4

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