Antibiotic combination therapies
Inventors
Trebosc, Vincent • Kemmer, Christian • Dale, Glenn E. • Lociuro, Sergio • Gitzinger, Marc
Assignees
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Publication Number
US-11766425-B2
Publication Date
2023-09-26
Expiration Date
Abstract
The invention provides antibiotic combination therapies for treating an A. baumannii infection in a subject. The combination therapies include rifabutin and a second antibiotic, such as colistin and cefiderocol.
Core Innovation
The invention provides rifabutin-based combination therapies for treating an Acinetobacter baumannii infection in a subject by administering rifabutin together with a second antibiotic selected from a group consisting of polymyxin and cefiderocol. The combination therapy includes rifabutin and the second antibiotic in a therapeutically effective amount. The subject is infected with A. baumannii, including infections associated with resistance to rifabutin and/or to the selected second antibiotic.
A core feature of the invention is the selection of polymyxin, including specific polymyxins described in the document, and cefiderocol as the second antibiotic component used together with rifabutin. The document further constrains the target infection by including A. baumannii having an rpoB mutation in some embodiments. The combinations are evaluated using checkerboard assay criteria based on fractional inhibitory concentration index (FICI) thresholds, including synergy defined by a FICI value of ≤0.5.
The document states that rifabutin plus cefiderocol shows synergistic growth inhibition meeting the defined FICI criteria across tested strain panels, including unexpectedly effective activity against strains resistant to both antibiotics individually and including isolates with rpoB mutations. For rifabutin plus colistin, the document likewise states synergy across tested strains and includes major MIC shifts in rpoB-mutant isolates, with discussion of partial reduction when using a colistin derivative, while indicating the need for colistin’s intrinsic antibacterial activity.
Claims Coverage
The document includes two independent claims directed to a treatment method and a combination therapy. Across these independent claims, the inventive coverage centers on providing rifabutin with a second antibiotic selected from polymyxin and cefiderocol, with therapeutically effective amounts, and it allows dependent refinements that add pathogen resistance/genotype and formulation/administration specifics. Overall, the independent-claim structure identifies two primary inventive aspects: the combination pairing and its use for treating A. baumannii infection in a subject.
Rifabutin plus polymyxin or cefiderocol for treating Acinetobacter baumannii
Providing, to a subject infected with Acinetobacter baumannii, rifabutin and a second antibiotic selected from the group consisting of a polymyxin and cefiderocol.
Therapeutically effective rifabutin and second antibiotic combination
A combination therapy comprising rifabutin and a second antibiotic selected from the group consisting of a polymyxin and cefiderocol, wherein the combination therapy comprises rifabutin and the second antibiotic in a therapeutically effective amount to treat an Acinetobacter baumannii infection in a subject.
The claims coverage is anchored on co-administering or combining rifabutin with a second antibiotic selected from polymyxin and cefiderocol in therapeutically effective amounts for treating A. baumannii infection in a subject. Dependent claims further narrow the second antibiotic to cefiderocol and specify polymyxin variants, as well as adding constraints related to resistance and/or an rpoB mutation and specifying pharmaceutical/administration form.
Stated Advantages
Synergistic growth inhibition based on checkerboard assay and FICI synergy criteria (FICI ≤ 0.5).
Unexpectedly effective activity against strains resistant to both rifabutin and the second antibiotic individually.
Effective activity against isolates including strains with rpoB mutations.
Documented Applications
Treating an Acinetobacter baumannii infection in a subject using rifabutin in combination with a second antibiotic selected from polymyxin and cefiderocol.
Using the combination therapy against infections associated with A. baumannii that include rpoB mutations.
Using rifabutin plus cefiderocol and rifabutin plus colistin combinations in contexts evaluated by checkerboard assay and FICI criteria across tested strain panels.
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