title: Potentiation effects of amikacin and fosfomycin against selected amikacin-nonsusceptible Gram-negative respiratory tract pathogens.
abstract: The amikacin-fosfomycin inhalation system (AFIS) is a combination of 2 antibiotics and an in-line nebulizer delivery system that is being developed for adjunctive treatment of pneumonia caused by Gram-negative organisms in patients on mechanical ventilation. AFIS consists of a combination of amikacin and fosfomycin solutions at a 5:2 ratio (amikacin, 3 ml at 100 mg/ml; fosfomycin, 3 ml at 40 mg/ml) and the PARI Investigational eFlow Inline System. In this antibiotic potentiation study, the antimicrobial activities of amikacin and fosfomycin, alone and in a 5:2 combination, were assessed against 62 Gram-negative pathogens from a worldwide antimicrobial surveillance collection (SENTRY). The amikacin MICs for 62 isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were ≥32 μg/ml (intermediate or resistant according to the Clinical and Laboratory Standards Institute [CLSI]; resistant according to the European Committee on Antimicrobial Susceptibility Testing [EUCAST]). Each isolate was tested against amikacin (0.25 to 1,024 μg/ml), fosfomycin (0.1 to 409.6 μg/ml), and amikacin-fosfomycin (at a 5:2 ratio) using CLSI reference agar dilution methods. The median MIC values for amikacin and fosfomycin against the 62 isolates each decreased 2-fold with the amikacin-fosfomycin (5:2) combination from that with either antibiotic alone. Interactions between amikacin and fosfomycin differed by isolate and ranged from no detectable interaction to high potentiation. The amikacin-fosfomycin (5:2) combination reduced the amikacin concentration required to inhibit all 62 isolates from >1,024 to ≤ 256 μg/ml and reduced the required fosfomycin concentration from 204.8 to 102.4 μg/ml. These results support continued development of the amikacin-fosfomycin combination for aerosolized administration, where high drug levels can be achieved.
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: D040981:Acinetobacter baumannii / Q000187:drug effects; D000583:Amikacin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D005578:Fosfomycin / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012141:Respiratory Tract Infections / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D000583:Amikacin
references.citation: Chest. 2005 Oct;128(4):2778-87
references.pmid: 16236955
references.citation: Rev Infect Dis. 1981 Jan-Feb;3(1):67-73
references.pmid: 7013001
references.citation: Clin Infect Dis. 2012 Aug;55(4):551-61
references.pmid: 22677711
references.citation: J Trauma. 2008 Oct;65(4):871-6; discussion 876-8
references.pmid: 18849805
references.citation: Chest. 1997 Mar;111(3):676-85
references.pmid: 9118708
references.citation: Clin Microbiol Rev. 2006 Oct;19(4):637-57
references.pmid: 17041138
references.citation: Pharmacotherapy. 2002 Aug;22(8):972-82
references.pmid: 12173800
references.citation: Antimicrob Agents Chemother. 2014 Jul;58(7):3708-13
references.pmid: 24752276
references.citation: Am J Respir Crit Care Med. 2011 Jul 1;184(1):106-15
references.pmid: 21474643
references.citation: Antimicrob Agents Chemother. 2012 Mar;56(3):1529-38
references.pmid: 22232284
references.citation: J Crit Care. 2008 Mar;23(1):74-81
references.pmid: 18359424
references.citation: J Antimicrob Chemother. 1996 Dec;38(6):1107-8
references.pmid: 9023661
references.citation: Antimicrob Agents Chemother. 2005 Nov;49(11):4448-54
references.pmid: 16251282
references.citation: Chest. 1995 Dec;108(6):1655-62
references.pmid: 7497777
references.citation: Eur J Clin Microbiol Infect Dis. 2008 Jun;27(6):439-43
references.pmid: 18214558
references.citation: J Aerosol Med Pulm Drug Deliv. 2014 Dec;27(6):441-8
references.pmid: 24383962
references.citation: Pediatr Pulmonol. 1989;7(4):265-71
references.pmid: 2515523
references.citation: Pediatr Pulmonol. 2008 Jan;43(1):47-58
references.pmid: 18041081
references.citation: Am Rev Respir Dis. 1985 Oct;132(4):761-5
references.pmid: 3931522
references.citation: J Antimicrob Chemother. 2009 Sep;64(3):563-6
references.pmid: 19561148
references.citation: Intensive Care Med. 2012 Feb;38(2):263-71
references.pmid: 22147112
references.citation: J Antimicrob Chemother. 2009 Oct;64(4):829-36
references.pmid: 19679597
references.citation: Crit Care Med. 2008 Jul;36(7):2008-13
references.pmid: 18552684