Combined effects of the siderophore monosulfactam BAL30072 and carbapenems on multidrug-resistant Gram-negative bacilli.
OBJECTIVE
Carbapenem resistance in Gram-negative bacteria, mediated by restricted net influx and carbapenem-hydrolysing β-lactamases, is a growing problem. The monosulfactam antibiotic BAL30072 is stable to most carbapenemases, suggesting that it could be complementary to carbapenems. We have investigated the antimicrobial activity of BAL30072 combined with imipenem, meropenem and doripenem.


METHODS
The in vitro activities of the combinations were evaluated using broth microdilution susceptibility and agar disc diffusion tests, broth dilution chequerboard titration and time-kill studies, using strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter with carbapenem MICs ≥ 2 mg/L.


RESULTS
The combinations were effective against 70%-80% of the isolates tested in the presence of 1 mg/L of each antibiotic, whereas the carbapenems were ineffective and BAL30072 alone was effective against 20%-40% of the strains. Synergistic effects were observed with many Enterobacteriaceae and P. aeruginosa, but were less common among the Acinetobacter, although additive effects, where the activity of one partner compensated for lack of activity of the other, were common. None of the combinations exhibited an antagonistic effect in all tests, in contrast to other β-lactams where negative interactions were frequently observed. Animal models of septicaemia demonstrated that the synergy observed in vitro with BAL30072 and meropenem can translate into greater in vivo efficacy.


CONCLUSIONS
BAL30072/carbapenem combinations were effective against a broader range of multidrug-resistant Gram-negative bacteria than either of the single agents. Additive and synergistic effects were observed in Enterobacteriaceae and P. aeruginosa, and this enhanced activity was frequently associated with suppression of resistance development. The in vitro activity translated into improved in vivo efficacy.
Basilea Pharmaceutica International Ltd, Grenzacherstrasse 487, CH-4058 Basel, Switzerland.
Beatrice
B
Hofer
Clothilde
C
Dantier
Klaus
K
Gebhardt
Eric
E
Desarbre
Anne
A
Schmitt-Hoffmann
Malcolm G P
MG
Page
D000150:Acinetobacter / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D000077726:Doripenem; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects*; D015378:Imipenem / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008997:Monobactams / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology
D000900:Anti-Bacterial Agents; C552042:BAL 30072; D015780:Carbapenems; D008997:Monobactams; D013844:Thiazoles; D013845:Thienamycins; D015378:Imipenem; D000077726:Doripenem; D000077731:Meropenem