title: Daptomycin-oxacillin combinations in treatment of experimental endocarditis caused by daptomycin-nonsusceptible strains of methicillin-resistant Staphylococcus aureus with evolving oxacillin susceptibility (the "seesaw effect").
abstract: In vivo development of daptomycin resistance (DAPr) among Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA) strains, in conjunction with clinical treatment failures, has emerged as a major problem. This has raised the question of DAP-based combination regimens to enhance efficacy against such strains. We studied five recent DAP-susceptible (DAPs)/DAPr clinical MRSA strain pairs obtained from patients who failed DAP monotherapy regimens, as well as one DAPs/DAPr MRSA strain pair in which the resistant strain was generated by in vitro passage in DAP. Of note, we identified a DAP-oxacillin (OX) "seesaw" phenomenon in vitro in which development of DAPr was accompanied by a concomitant fall in OX resistance, as demonstrated by 3- to 4-fold decreases in the OX MIC, a susceptibility shift by population analyses, and enhanced early killing by OX in time-kill assays. In addition, the combination of DAP and OX exerted modest improvement in in vitro bactericidal effects. Using an experimental model of infective endocarditis and two DAPs/DAPr strain pairs, we demonstrated that (i) OX monotherapy was ineffective at clearing DAPr strains from any target tissue in this model (heart valve, kidneys, or spleen) and (ii) DAP-OX combination therapy was highly effective in DAPr strain clearances from these organs. The mechanism(s) of the seesaw effect remains to be defined but does not appear to involve excision of the staphylococcal cassette chromosome mec (SCCmec) that carries mecA.
authors.affiliation: LA Biomedical Research Institute at Harbor-UCLA, 1124 West Carson Street, RB-2, Rm. 230, Torrance, CA 90502, USA. sjyang@labiomed.org
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Yang
authors.forename: Yan Q
authors.initials: YQ
authors.lastname: Xiong
authors.forename: Susan
authors.initials: S
authors.lastname: Boyle-Vavra
authors.forename: Robert
authors.initials: R
authors.lastname: Daum
authors.forename: Tiffanny
authors.initials: T
authors.lastname: Jones
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D017576:Daptomycin / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin; D010068:Oxacillin