RESUMO
This study evaluated the activity of colistin, rifampicin, imipenem and sulbactam/ampicillin alone or in combination against nine epidemic multidrug-resistant Acinetobacter baumannii isolates producing OXA-58 carbapenemase in Naples, Italy. The isolates were susceptible to colistin but differed in their resistance to imipenem and rifampicin. Time-kill studies showed a bactericidal effect for colistin but not for imipenem, rifampicin or sulbactam/ampicillin used as single agents. Synergism was observed with combinations of rifampicin+imipenem or sulbactam/ampicillin for all isolates and with colistin+rifampicin for isolates showing higher minimum inhibitory concentrations for rifampicin. Combined use of the antimicrobials tested may provide good therapeutic options for OXA-58 carbapenemase-producing A. baumannii infections.
Assuntos
Infecções por Acinetobacter/epidemiologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Proteínas de Bactérias/biossíntese , Surtos de Doenças , Farmacorresistência Bacteriana Múltipla , beta-Lactamases/biossíntese , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/enzimologia , Acinetobacter baumannii/genética , Acinetobacter baumannii/isolamento & purificação , Ampicilina/farmacologia , Carbapenêmicos/farmacologia , Colistina/farmacologia , Sinergismo Farmacológico , Eletroforese em Gel de Campo Pulsado , Humanos , Imipenem/farmacologia , Itália/epidemiologia , Testes de Sensibilidade Microbiana , Rifampina/farmacologia , SulbactamRESUMO
OBJECTIVES: We evaluated the genetic and molecular basis of high-level resistance to gentamicin and amikacin in 91 clinical isolates of Enterococcus faecalis and Enterococcus faecium in a university hospital in southern Italy from 1987 to 2003. METHODS: Antibiotic susceptibility was evaluated by disc diffusion and microdilution methods. Genotyping was performed by PFGE and dendrogram analysis. Aminoglycoside resistance genes were analysed by multiplex PCR. Aminoglycoside resistance gene transfer was performed by filter mating. RESULTS: In our strain collection, 44% of E. faecalis and 52% of E. faecium were high-level-resistant to gentamicin. Fifty-two PFGE profiles were identified for E. faecalis and 15 for E. faecium. Although the majority of PFGE patterns were single isolates, four patterns (two for E. faecalis and two for E. faecium) were isolated each in 8 and 4, and 6 and 4 different patients, respectively. The aac(6')-Ie-aph(2'')-Ia gene was responsible for high-level resistance to gentamicin and amikacin in E. faecalis and E. faecium; the aph(2'')-Id gene responsible for resistance to gentamicin was also isolated in E. faecium; the aph(3')-IIIa and ant(4')-Ia genes responsible for resistance to amikacin were also isolated in E. faecalis and E. faecium. High-level resistance to gentamicin, along with the aac(6')-Ie-aph(2'')-Ia gene, was transferred at a frequency of about 10(-5) to 10(-8) per recipient cell in 14 of 17 E. faecalis and 3 of 4 E. faecium different genotypes. CONCLUSIONS: The spread of the aac(6')-Ie-aph(2'')-Ia gene was responsible for high-level resistance to gentamicin and amikacin among enterococci isolated from patients in our geographical area.
Assuntos
Aminoglicosídeos/farmacologia , Farmacorresistência Bacteriana/genética , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Acetiltransferases/genética , Amicacina/farmacologia , Antibacterianos/farmacologia , Cromossomos Bacterianos/genética , Cromossomos Bacterianos/metabolismo , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Eletroforese em Gel de Campo Pulsado , Enterococcus faecalis/classificação , Enterococcus faecalis/genética , Enterococcus faecalis/isolamento & purificação , Enterococcus faecium/classificação , Enterococcus faecium/genética , Enterococcus faecium/isolamento & purificação , Técnicas de Transferência de Genes , Transferência Genética Horizontal , Genes Bacterianos , Genótipo , Gentamicinas/farmacologia , Hospitais Universitários , Humanos , Itália , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
Our previous studies indicated that millimolar doses of aspirin induced growth arrest and resistance to anticancer drug treatment in Caco-2 cells. The present study was designed to better elucidate at the molecular level the effect of aspirin treatment on pathways that regulate cell death during serum withdrawal. Caco-2 cells were cultured under serum deprivation in the presence or absence of aspirin. Effects on cell cycle, phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein (MAP) kinase pathways were investigated. We found that aspirin, but not the selective cyclooxygenase-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398); prevented apoptosis and G2/M transition after prolonged Caco-2 cells serum deprivation. Aspirin-dependent inhibition of apoptosis and G2/M transition was prevented by treatment with the PI3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), but not with the MAP kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059). The effects of aspirin were mediated at molecular levels, through activation of PI3-kinase/AKT pathway and increase in the p21Cip/WAF1 level. The ability of aspirin to activate AKT protein was observed also in presence of etoposide cotreatment. Our data indicate a new intracellular target of aspirin with potential clinical impact for treatment schedules involving both anticancer agents and aspirin in malignancies.