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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References
van Hal SJ, Lodise TP, Paterson DL (2012) The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 54:755–771
Yoon YK, Kim JY, Park DW et al (2010) Predictors of persistent methicillin-resistant Staphylococcus aureus bacteraemia in patients treated with vancomycin. J Antimicrob Chemother 65:1015–1018
Lodise TP, Drusano GL, Lazariu V et al (2014) Quantifying the matrix of relationships between reduced vancomycin susceptibility phenotypes and outcomes among patients with MRSA bloodstream infections treated with vancomycin. J Antimicrob Chemother 69:2547–2545
Mishra NN, Bayer AS, Weidenmaier C et al (2014) Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. PLoS One 16, e107426
Schweizer ML, Furuno JP, Sakoulas G et al (2011) Increased mortality with accessory gene regulator (agr) dysfunction in Staphylococcus aureus among bacteremic patients. Antimicrob Agents Chemother 55:1082–1087
Harigaya Y, Ngo D, Lesse AJ et al (2011) Characterization of heterogeneous vancomycin-intermediate resistance, MIC and accessory gene regulator (agr) dysfunction among clinical bloodstream isolates of Staphyloccocus aureus. BMC Infect Dis 11:287
Cafiso V, Bertuccio T, Spina D et al (2012) A novel δ-hemolysis screening method for detecting heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate S. aureus. J Clin Microbiol 50:1742–1744
Chang SC, Liu TP, Chen CJ et al (2015) Detection of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates using a combination of δ-hemolysis assay and Etest. Diagn Microbiol Infect Dis 81:246–250
Stefani S, Campanile F, Santagati M et al (2015) Insights and clinical perspectives of daptomycin resistance in Staphylococcus aureus: a review of the available evidence. Int J Antimicrob Agents 46:278–289. doi:10.1016/j.ijantimicag.2015.05.008
Bayer AS, Schneider T, Sahl HG et al (2013) Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall. Ann N Y Acad Sci 1277:139–158
Cafiso V, Bertuccio T, Purrello S et al (2014) dltA overexpression: a strain-independent keystone of daptomycin resistance in methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 43:26–31
Mishra NN, Bayer AS, Weidenmaier C et al (2014) Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. PLoS One 9, e107426
Kelley PG, Gao W, Ward PB et al (2011) Daptomycin non-susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure. J Antimicrob Chemother 66:1057–1060
Cafiso V, Bertuccio T, Spina D et al (2012) Modulating activity of vancomycin and daptomycin on the expression of autolysis cell-wall turnover and membrane charge genes in hVISA and VISA strains. PLoS One 7, e29573
Campanile F, Bongiorno D, Borbone S et al (2009) Hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) in Italy. Ann Clin Microbiol Antimicrob 8:22
Stefani S, Bongiorno D, Cafiso V et al (2009) Pathotype and susceptibility profile of a community-acquired methicillin-resistant Staphylococcus aureus strain responsible for a case of severe pneumonia. Diagn Microbiol Infect Dis 63:100–104
Cafiso V, Bertuccio T, Santagati M et al (2007) agr-Genotyping and transcriptional analysis of biofilm-producing Staphylococcus aureus. FEMS Immunol Med Microbiol 51:220–227
Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30, e36
Matsuo M, Hishinuma T, Katayama Y et al (2011) Mutation of RNA polymerase beta subunit (rpoB) promotes hVISA-to-VISA phenotypic conversion of strain Mu3. Antimicrob Agents Chemother 55:4188–4195
Cui L, Isii T, Fukuda M et al (2010) An RpoB mutation confers dual heteroresistance to daptomycin and vancomycin in Staphylococcus aureus. Antimicrob Agents Chemother 54:5222–5233
Moise PA, North D, Steenbergen JN et al (2009) Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions. Lancet Infect Dis 9:617–624
Bassetti M, Villa G, Ansaldi F et al (2015) Risk factors associated with the onset of daptomycin non-susceptibility in Staphylococcus aureus infections in critically ill patients. Intensive Care Med 41:366–368
Wichelhaus T, Schäfer V, Brade V et al (2001) Differential effect of rpoB mutations on antibacterial activities of rifampicin and KRM-1648 against Staphylococcus aureus. J Antimicrob Chemother 47:153–156
Smirnova MV, Vostrov SN, Strukova EV et al (2009) The impact of duration of antibiotic exposure on bacterial resistance predictions using in vitro dynamic models. J Antimicrob Chemother 64:815–820
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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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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