Combination therapy for treatment of resistant bacterial infections
Inventors
DeJonge, Boudewijn Lodewijk Maria • Durand-Reville, Thomas Francois • Verheijen, Jeroen Cunera • Tommasi, Ruben • Mueller, John
Assignees
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Publication Number
US-9968593-B2
Publication Date
2018-05-15
Expiration Date
Abstract
The present invention is directed to combinations of a β-lactamase inhibitor with sulbactam and, optionally, imipenem/cilastatin. The combinations are useful for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant pathogens. More particularly, the invention relates to a combination of β-lactamase inhibitor compound 1: or a pharmaceutically acceptable salt thereof, with sulbactam, or a pharmaceutically acceptable salt thereof, and, optionally, imipenem/cilastatin, or a pharmaceutically acceptable salt thereof.
Core Innovation
The disclosed subject matter relates to treatment of resistant-bacterial infections using a combination that includes the β-lactamase inhibitor compound 1 together with sulbactam. The disclosure states that sulbactam alone has limited coverage against many β-lactamases, and therefore potentiation is targeted by combining sulbactam with compound 1 as a β-lactamase inhibitor.
The disclosure further describes a resistant-bacterial infection treatment that can additionally include imipenem and cilastatin, forming a broader double versus quad combination approach. The specification identifies targeted pathogens including Acinetobacter spp., Pseudomonas aeruginosa, Enterobacteriaceae, and Burkholderia spp., including multidrug-resistant strains, and it emphasizes that β-lactamase classes such as Class A, B, C, and D, including ESBLs, and specific enzymes such as TEM-1 and KPC are relevant to the resistant infections addressed.
The disclosure includes support language describing formulation and administration contexts for the combinations, including salts and separate versus concurrent dosing. It also summarizes in vitro and in vivo potentiation and synergy data showing restored MIC activity and improved efficacy when compound 1 is combined with sulbactam, with further enhancement when combined with imipenem/cilastatin across multidrug-resistant clinical isolate panels and models.
Claims Coverage
The partial claims provided identify two independent claims that each recite a β-lactamase inhibitor with sulbactam, and further include imipenem and cilastatin in the combination composition claim and in the administration of the method claim. Across the independent claims, the main inventive features are the defined multi-component drug combination and the method of treating bacterial infection in a subject by administering an effective amount of those components, each optionally in pharmaceutically acceptable salt forms.
β-Lactamase inhibitor, sulbactam, imipenem, and cilastatin combination
A combination comprising the β-lactamase inhibitor or a pharmaceutically acceptable salt thereof, sulbactam or a pharmaceutically acceptable salt thereof, imipenem or a pharmaceutically acceptable salt thereof, and cilastatin or a pharmaceutically acceptable salt thereof.
Administering β-lactamase inhibitor, sulbactam, imipenem, and cilastatin to treat bacterial infection
A method of treating bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of the β-lactamase inhibitor or a pharmaceutically acceptable salt thereof, an effective amount of sulbactam or a pharmaceutically acceptable salt thereof, an effective amount of imipenem or a pharmaceutically acceptable salt thereof, and an effective amount of cilastatin or a pharmaceutically acceptable salt thereof.
Across the two independent claims, the inventive core is the use of a multi-component regimen containing a β-lactamase inhibitor together with sulbactam, with imipenem and cilastatin as additional components in a combination, used either as a composition or via administration to treat bacterial infection in a subject.
Stated Advantages
Restored MIC activity with compound 1 plus sulbactam.
Improved efficacy with compound 1 plus sulbactam.
Further enhancement of efficacy when compound 1 and sulbactam are combined with imipenem/cilastatin against multidrug-resistant clinical isolate panels and models.
Documented Applications
Treatment of resistant-bacterial infections in a subject, including infections caused by Acinetobacter spp., Pseudomonas aeruginosa, Enterobacteriaceae, and Burkholderia spp., including MDR strains.
Treatment context discussed in resistant-infection models, including neutropenic thigh and lung mouse models, and melioidosis associated with B. pseudomallei K96243.
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