title: In vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing Enterobacteriaceae strains.
abstract: Carbapenemase-producing Enterobacteriaceae (CPE) cause serious infections and are associated with high mortality in part due to limited treatment options. The in vitro activities of the new aminoglycoside plazomicin and comparators were evaluated against a collection of 164 CPE (VIM-1, n=125; KPC-2, n=34; OXA-48, n=4; and IMP-22, n=1). MIC90 values of gentamicin, tobramycin and amikacin were 256, 64 and 16 mg/L, respectively. Plazomicin exhibited an MIC range of 0.12-4 mg/L with MIC50 and MIC90 values of 0.25 and 1 mg/L. The MICs of plazomicin did not correlate with the other aminoglycoside MICs, with the resistance phenotype or with the carbapenemase harboured. Chequerboard experiments against 10 carbapenemase-producing Klebsiella pneumoniae isolates showed that combinations of plazomicin with colistin yielded synergy against 60% of the strains. Synergy of plazomicin with meropenem or fosfomycin was detected against 20% and 25% of the isolates, respectively. Using time-kill methodology, the interactions of plazomicin at 2×, 1× and 0.5× MIC with meropenem, colistin, fosfomycin or tigecycline at steady-state concentrations against two K. pneumoniae carrying the VIM-1 enzyme were investigated. Bactericidal activity was evident for both isolates at 2× MIC of plazomicin. Synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin against both isolates, whilst the combination with tigecycline resulted in indifference. Antagonism was not observed for any of the combinations tested. The results of this study suggest that plazomicin may address the need for new therapeutic options for the treatment of infections due to CPE.
authors.affiliation: Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Plaza de Cristo Rey s/n, 28040 Madrid, Spain. Electronic address: iciaravial@hotmail.com.
authors.forename: Iciar
authors.initials: I
authors.lastname: Rodríguez-Avial
authors.affiliation: Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Plaza de Cristo Rey s/n, 28040 Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Pena
authors.affiliation: Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Plaza de Cristo Rey s/n, 28040 Madrid, Spain; Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Picazo
authors.affiliation: Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodríguez-Avial
authors.affiliation: Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Plaza de Cristo Rey s/n, 28040 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Culebras
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D003091:Colistin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004754:Enterobacter / Q000187:drug effects / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000188:drug therapy*; D005578:Fosfomycin / Q000494:pharmacology*; D006801:Humans; D041121:Klebsiella oxytoca / Q000187:drug effects / Q000302:isolation & purification; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D012706:Serratia marcescens / Q000187:drug effects / Q000302:isolation & purification; D012853:Sisomicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013845:Thienamycins / Q000494:pharmacology*; D000078304:Tigecycline; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013845:Thienamycins; D005578:Fosfomycin; D000078304:Tigecycline; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem; D008911:Minocycline; C550938:plazomicin; D012853:Sisomicin; D003091:Colistin
keywords: Chequerboard; Combination therapy; Time–kill