RESUMO
Among the viridans group streptococci, S. mitis-oralis strains are frequently resistant to multiple ß-lactams and tolerant to vancomycin (VAN). This scenario has led to the proposed clinical use of newer agents, like daptomycin (DAP) for such S. mitis-oralis strains. However, recent recognition of the rapid and durable emergence of high-level DAP-resistance (DAP-R; DAP MICs > 256 µg/ml) induced by DAP exposures in vitro and in vivo has dampened enthusiasm for such approaches. In this study, we evaluated a broad range of DAP combination regimens in vitro for their capacity to prevent emergence of high-level DAP-R in a prototype S. mitis-oralis strain (351) during serial passage experiments, including DAP + either gentamicin (GEN), rifampin (RIF), trimethoprim-sulfamethoxazole (TMP-SMX), imipenem (IMP), ceftaroline (CPT), tedizolid (TDZ), or linezolid (LDZ). In addition, we assessed selected DAP combination regimens for their ability to exert either an early bactericidal impact and/or synergistically kill the S. mitis-oralis study strain. During serial passage, three of the eight antibiotic combinations (DAP + GEN, CPT, or TMP- SMX) exhibited significantly reduced DAP MICs (≈ by 8-40 fold) vs serial exposure in DAP alone (DAP MICs > 256 µg/ml). In addition, combinations of DAP + GEN and DAP + CPT were both bactericidal and synergistic in early time-kill curve interactions.
Assuntos
Antibacterianos/farmacologia , Daptomicina/farmacologia , Streptococcus mitis/efeitos dos fármacos , Streptococcus oralis/efeitos dos fármacos , Cefalosporinas/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana , Gentamicinas/farmacologia , Humanos , Imipenem/farmacologia , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Organofosfatos/farmacologia , Oxazóis/farmacologia , Rifampina/farmacologia , Combinação Trimetoprima e Sulfametoxazol/farmacologia , CeftarolinaRESUMO
The defining hallmark of the newly described species, Staphylococcus argenteus, in comparison to its sister species, S. aureus and S. schweitzeri, is the absence of production of the carotenoid pigment, staphyloxanthin. Staphylococcus argenteus lacks the responsible genetic locus crtOPQMN. We examined the impact of carotenoid synthesis in two non-pigmented S. argenteus strains, MSHR1132 and SCC1165. Following complementation with a plasmid containing the carotenoid operon (pTX-crtOPQMN), compared to wild type, both complemented strains showed substantial carotenoid production, with a resultant increase in cell membrane rigidity. Surprisingly, both crtOPQMN-complemented strains exhibited increased susceptibility to the host defense peptides, LL-37 and hNP-1 in vitro, and reduced virulence in an experimental rabbit endocarditis model.
Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Endocardite/imunologia , Interações Hospedeiro-Patógeno , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/metabolismo , Xantofilas/metabolismo , alfa-Defensinas/metabolismo , Animais , Vias Biossintéticas/genética , Modelos Animais de Doenças , Endocardite/microbiologia , Endocardite/patologia , Teste de Complementação Genética , Óperon , Plasmídeos , Coelhos , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Virulência , CatelicidinasRESUMO
High-dose daptomycin (DAP) therapy failed in a neutropenic patient with bloodstream infection caused by a DAP-susceptible Enterococcus faecium (minimum inhibitory concentration, 3 µg/mL) harboring genetic changes associated with DAP resistance, with persistent bacteremia and selection of additional resistances. Daptomycin monotherapy should be used cautiously against DAP-susceptible E. faecium strains with minimum inhibitory concentrations >2 µg/mL.
