title: Amikacin-fosfomycin at a five-to-two ratio: characterization of mutation rates in microbial strains causing ventilator-associated pneumonia and interactions with commonly used antibiotics.
abstract: The amikacin-fosfomycin inhalation system (AFIS), a combination of antibiotics administered with an in-line nebulizer delivery system, is being developed for adjunctive treatment of ventilator-associated pneumonia (VAP). The in vitro characterization of amikacin-fosfomycin (at a 5:2 ratio) described here included determining resistance selection rates for pathogens that are representative of those commonly associated with VAP (including multidrug-resistant strains) and evaluating interactions with antibiotics commonly used intravenously to treat VAP. Spontaneous resistance to amikacin-fosfomycin (5:2) was not observed for most strains tested (n, 10/14). Four strains had spontaneously resistant colonies (frequencies, 4.25 × 10(-8) to 3.47 × 10(-10)), for which amikacin-fosfomycin (5:2) MICs were 2- to 8-fold higher than those for the original strains. After 7 days of serial passage, resistance (>4-fold increase over the baseline MIC) occurred in fewer strains (n, 4/14) passaged in the presence of amikacin-fosfomycin (5:2) than with either amikacin (n, 7/14) or fosfomycin (n, 12/14) alone. Interactions between amikacin-fosfomycin (5:2) and 10 comparator antibiotics in checkerboard testing against 30 different Gram-positive or Gram-negative bacterial strains were synergistic (fractional inhibitory concentration [FIC] index, ≤ 0.5) for 6.7% (n, 10/150) of combinations tested. No antagonism was observed. Synergy was confirmed by time-kill methodology for amikacin-fosfomycin (5:2) plus cefepime (against Escherichia coli), aztreonam (against Pseudomonas aeruginosa), daptomycin (against Enterococcus faecalis), and azithromycin (against Staphylococcus aureus). Amikacin-fosfomycin (5:2) was bactericidal at 4-fold the MIC for 7 strains tested. The reduced incidence of development of resistance to amikacin-fosfomycin (5:2) compared with that for amikacin or fosfomycin alone, and the lack of negative interactions with commonly used intravenous antibiotics, further supports the development of AFIS for the treatment of VAP.
authors.affiliation: Cardeas Pharma, Seattle, Washington, USA Bruce.Montgomery@CardeasPharma.com.
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Montgomery
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Rhomberg
authors.affiliation: Cardeas Pharma, Seattle, Washington, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Abuan
authors.affiliation: Cardeas Pharma, Seattle, Washington, USA.
authors.forename: Kathie-Anne
authors.initials: KA
authors.lastname: Walters
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Flamm
mesh_terms: D000583:Amikacin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004338:Drug Combinations; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004357:Drug Synergism; D005578:Fosfomycin / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics / Q000502:physiology; D053717:Pneumonia, Ventilator-Associated / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D005578:Fosfomycin; D000583:Amikacin
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