I Portillo-Calderón1,2, M Ortiz-Padilla1,2, B de Gregorio-Iaria1, V Merino-Bohorquez3, J Blázquez4, J Rodríguez-Baño1,2,5, J M Rodríguez-Martínez2,6, A Pascual1,2,6, F Docobo-Pérez2,6. 1. Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain. 2. Instituto de Biomedicina de Sevilla IBIS, Hospital Universitario Virgen Macarena/CSIC/Universidad de Sevilla, Seville, Spain. 3. Unidad de Gestión de Farmacia Hospitalaria, Hospital Universitario Virgen Macarena, Seville, Spain. 4. Centro Nacional de Biotecnología (CNB) Madrid, Spain. 5. Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain. 6. Departamento de Microbiología, Universidad de Sevilla, Sevilla, Spain.
Abstract
Objectives: To evaluate human-like intravenous doses of fosfomycin (8g/Q8h) and amikacin (15mg/kg/Q24h) efficacy in monotherapy and in combination against six fosfomycin-heteroresistant Escherichia coli isolates using a hollow-fiber infection model (HFIM).Materials and methods:Six fosfomycin-heteroresistant E. coli isolates (4 with strong mutator phenotype) and the control strain E. coli ATCC 25922 were used. Mutant frequencies for rifampin (100mg/L), fosfomycin (50 and 200mg/L) and amikacin (32mg/L) were determined. Fosfomycin and amikacin MICs were assessed by agar dilution (AD), gradient strip (GSA) and broth microdilution (BMD) assays. Fosfomycin and amikacin synergies were studied by checkerboard and time-kill assays at different concentrations. Fosfomycin (8g/Q8h) and amikacin (15mg/kg/Q24h) efficacy alone and in combination were assessed using a HFIM. Results: Five isolates were resistant to fosfomycin by AD and BMD, but all susceptible by GSA. All isolates were considered susceptible to amikacin. Antibiotic combinations were synergistic in two isolates and no antagonism was detected. In time-kill assays, all isolates survived under fosfomycin at 64mg/L, although, at 307mg/L, only the normomutators and two hypermutators survived. Four isolates survived under 16mg/L amikacin and none at 45mg/L. No growth was detected under combination conditions. In HFIM, fosfomycin and amikacin monotherapies failed to sterilise bacterial cultures, however, fosfomycin and amikacin combination showed a rapid eradication.Conclusions.There may be a risk of treatment failure of fosfomycin-heteroresistant E. coli isolates using either amikacin or fosfomycin in monotherapy. These results support that the combination amikacin-fosfomycin can rapidly decrease bacterial burden and prevent the emergence of resistant subpopulations against fosfomycin-heteroresistant strains.
Objectives: To evaluate human-like intravenous doses of fosfomycin (8g/Q8h) and amikacin (15mg/kg/Q24h) efficacy in monotherapy and in combination against six fosfomycin-heteroresistant Escherichia coli isolates using a hollow-fiber infection model (HFIM).Materials and methods:Six fosfomycin-heteroresistant E. coli isolates (4 with strong mutator phenotype) and the control strain E. coli ATCC 25922 were used. Mutant frequencies for rifampin (100mg/L), fosfomycin (50 and 200mg/L) and amikacin (32mg/L) were determined. Fosfomycin and amikacin MICs were assessed by agar dilution (AD), gradient strip (GSA) and broth microdilution (BMD) assays. Fosfomycin and amikacin synergies were studied by checkerboard and time-kill assays at different concentrations. Fosfomycin (8g/Q8h) and amikacin (15mg/kg/Q24h) efficacy alone and in combination were assessed using a HFIM. Results: Five isolates were resistant to fosfomycin by AD and BMD, but all susceptible by GSA. All isolates were considered susceptible to amikacin. Antibiotic combinations were synergistic in two isolates and no antagonism was detected. In time-kill assays, all isolates survived under fosfomycin at 64mg/L, although, at 307mg/L, only the normomutators and two hypermutators survived. Four isolates survived under 16mg/L amikacin and none at 45mg/L. No growth was detected under combination conditions. In HFIM, fosfomycin and amikacin monotherapies failed to sterilise bacterial cultures, however, fosfomycin and amikacin combination showed a rapid eradication.Conclusions.There may be a risk of treatment failure of fosfomycin-heteroresistant E. coli isolates using either amikacin or fosfomycin in monotherapy. These results support that the combination amikacin-fosfomycin can rapidly decrease bacterial burden and prevent the emergence of resistant subpopulations against fosfomycin-heteroresistant strains.
Authors: María-Rosario Baquero; Annika I Nilsson; María del Carmen Turrientes; Dorthe Sandvang; Juan Carlos Galán; Jose Luís Martínez; Niels Frimodt-Møller; Fernando Baquero; Dan I Andersson Journal: J Bacteriol Date: 2004-08 Impact factor: 3.490
Authors: Miao Zhao; Zackery P Bulman; Justin R Lenhard; Michael J Satlin; Barry N Kreiswirth; Thomas J Walsh; Amanda Marrocco; Phillip J Bergen; Roger L Nation; Jian Li; Jing Zhang; Brian T Tsuji Journal: J Antimicrob Chemother Date: 2017-07-01 Impact factor: 5.790
Authors: Abi Jenkins; Alison H Thomson; Nicholas M Brown; Yvonne Semple; Christine Sluman; Alasdair MacGowan; Andrew M Lovering; Phil J Wiffen Journal: J Antimicrob Chemother Date: 2016-07-11 Impact factor: 5.790