title: In vivo development of daptomycin resistance in vancomycin-susceptible methicillin-resistant Staphylococcus aureus severe infections previously treated with glycopeptides.
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.
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Capone
authors.affiliation: Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy. v.cafiso@unict.it.
authors.forename: V
authors.initials: V
authors.lastname: Cafiso
authors.affiliation: Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Campanile
authors.affiliation: Department of Microbiology, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Parisi
authors.affiliation: Department of Microbiology, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Mariani
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Petrosillo
authors.affiliation: Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Stefani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000032:analysis / Q000235:genetics; D017576:Daptomycin / Q000494:pharmacology* / Q000627:therapeutic use; D024881:Drug Resistance, Bacterial; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D020869:Gene Expression Profiling; D006461:Hemolysis; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D013203:Staphylococcal Infections / Q000382:microbiology*; D017334:Teicoplanin / Q000627:therapeutic use; D016896:Treatment Outcome; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017334:Teicoplanin; D014640:Vancomycin; D017576:Daptomycin
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