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

Abstract

OBJECTIVES:

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.

METHODS:

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).

RESULTS:

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.

CONCLUSIONS:

These data support the continued evaluation of BAL30072 for use in the treatment of infections caused by MDR A. baumannii.

• Authors: Thomas A Russo, Malcolm G P Page, Janet M Beanan, Ruth Olson, Andrea M Hujer, Kristine M Hujer, Michael Jacobs, Saralee Bajaksouzian, Andrea Endimiani, Robert A Bonomo
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 66 Issue 4 Pg. 867-73 (Apr 2011) ISSN: 1460-2091 [Electronic] England
• PMID: 21393224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• BAL 30072
• Monobactams
• Siderophores
• Thiazoles
• Thienamycins
• Meropenem

Topics

• Acinetobacter Infections (drug therapy)
• Acinetobacter baumannii (drug effects)
• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacology)
• Disease Models, Animal
• Drug Interactions
• Meropenem
• Microbial Sensitivity Tests
• Monobactams (administration & dosage, pharmacology)
• Rats
• Rodent Diseases (drug therapy)
• Siderophores (administration & dosage, pharmacology)
• Thiazoles (administration & dosage, pharmacology)
• Thienamycins (administration & dosage, pharmacology)
• Treatment Outcome