In vivo and in vitro activity of the siderophore monosulfactam BAL30072 against Acinetobacter baumannii

• Published in: Journal of antimicrobial chemotherapy Vol. 66; no. 4; pp. 867 - 873
• Main Authors: RUSSO, Thomas A, PAGE, Malcolm G. P, BEANAN, Janet M, OLSON, Ruth, HUJER, Andrea M, HUJER, Kristine M, JACOBS, Michael, BAJAKSOUZIAN, Saralee, ENDIMIANI, Andrea, BONOMO, Robert A
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-2011; Oxford Publishing Limited (England)
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter Infections - drug therapy; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacology; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Disease Models, Animal; Drug Interactions; Drug resistance; Genotype & phenotype; Gram-negative bacteria; Medical sciences; Medical treatment; Microbial Sensitivity Tests; Monobactams - administration & dosage; Monobactams - pharmacology; Original Research; Pharmacology. Drug treatments; Rats; Rodent Diseases - drug therapy; Siderophores - administration & dosage; Siderophores - pharmacology; Thiazoles - administration & dosage; Thiazoles - pharmacology; Thienamycins - administration & dosage; Thienamycins - pharmacology; Tissues; Treatment Outcome; time-kill assays; Drug susceptibility test; Neisseriaceae; MICs; drug susceptibility testing; Medical screening; In vitro; Biological activity; In vivo; Acinetobacter baumannii; Siderophore; Multiple resistance; Minimum inhibitory concentration; Bacteria; Micrococcales; multidrug resistant
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkr013

New antibiotics that are active against multidrug-resistant (MDR) Acinetobacter baumannii are urgently needed. BAL30072, a siderophore monosulfactam antibiotic that rapidly penetrates the outer membrane of A. baumannii and has potent activity against most isolates, including those harbouring AmpC β-lactamases and metallo- (class B) or OXA- (class D) carbapenemases, is being developed to meet that need.
We assessed the in vitro activity of BAL30072, meropenem and the combination of BAL30072 and meropenem (2:1 and 1:1 ratios) by MIC and time-kill studies. Proof-of-principle in vivo efficacy was determined using a rat soft-tissue infection model. Five diverse strains with defined phenotypic and genetic profiles were tested (AB307-0294, AB8407, AB1697, AB3340 and AB0057).
In microdilution assays, combining BAL30072 with meropenem lowered meropenem MICs 2-8-fold. In time-kill studies, the BAL30072 and meropenem combinations resulted in bactericidal concentrations 2-8-fold lower than those of meropenem or BAL30072 alone. In the rat model, BAL30072 was active against four of five strains (AB307-0294, AB8407, AB1697 and AB3340), including meropenem-susceptible and -non-susceptible strains. AB0057 was the only strain resistant to BAL30072 in vivo and in vitro (MIC >64 mg/L). Meropenem was active in vivo against two of the five strains tested (AB307-0294 and AB3340). Both BAL30072 and BAL30072 with meropenem were equally effective in vivo.
These data support the continued evaluation of BAL30072 for use in the treatment of infections caused by MDR A. baumannii.