Antibiotic cannabinoid-terpene formulations

Abstract

Pharmaceutical formulations are provided that include at least two antibiotically active ingredients: a cannabinoid that is one or more of cannabichromene (CBC), cannabidiol (CBD) and/or cannabigerol (CBG); a sesquiterpene that is one or both of α-humulene and/or β-caryophyllene; and a lipopeptide antibiotic that is daptomycin or an analogue thereof. The antibiotically active ingredients may be provided in relative amounts that amplify their individual activities, including amounts that are synergistically effective in an assay to inhibit growth and/or reproduction of an Enterococcus faecium or an Enterococcus faecalis. Therapies are provided that utilize these formulations as anti-microbials, and provide for the combined use of two or more of the antibiotically active compounds.

Description

FIELD OF THE INVENTION[0001]The invention is in the field of medicinal preparations comprising a mixture of two or more organic antibiotically active ingredients, optionally including specific phenolic cannabinoids in optional combination with specific sesquiterpenes in optional combination with a lipopeptide antibiotic such as daptomycin. The therapeutic use of cannabinoid and / or sesquiterpene formulations is also disclosed, for synergistic treatment of enterococcal infections, including combined uses with lipopeptide antibiotics such as daptomycin.BACKGROUND OF THE INVENTION[0002]Enterococcus faecium and Enterococcus faecalis are bacterial species that asymptomatically colonize the gastrointestinal (GI) tract in humans, but can also be pathogenic in certain circumstances (in the relevant literature, Enterococcus faecium was previously classified as Streptococcus faecium, see Schleifer & Kilpperbalz, 1984). In particular, these organisms are known to be a leading cause of dangerous...

AI Technical Summary

Benefits of technology

[0016]In an alternative aspect, methods are provided for treating a bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of: a cannabinoid that is one or more of cannabichromene (CBC), cannabidiol (CBD) and / or cannabigerol (CBG); and, a lipopeptide antibiotic that is daptomycin or an analogue thereof; wherein the cannabinoid and the lipopeptide antibiotic are administered in an antibiotically effective weight ratio of from 16:1 to 1:16; and, wherein: if the cannabinoid is CBD, then the lipopeptide antibiotic is administered in an effective amount that is less than 4 mg / kg; and / or, if the cannabinoid is CBD, then the bacterial infection comprises infection by an infectious organism having a daptomycin MIC of 4 μg / mL or greater; and / or, if the cannabinoid is CBD, then the bacterial infection comprises infection by an infectious organism for which results from an assay of bacterial growth indicate that daptomycin produces an inhibitory and / or bactericidal effect at concentrations of less than 4 μg / mL when administered with CBD in an amount that is less than the MIC of CBD. The infection may for example include an infection by an Enterococcus faecium or an Enterococcus faecalis. These treatments may further include administering to the subject an effective amount of a sesquiterpene that is one or both of α-humulene and / or β-caryophyllene.

Problems solved by technology

In particular, these organisms are known to be a leading cause of dangerous infections in hospital patients being treated with antibiotics.

The intestinal colonization by enterococci, particularly in hospital patients, may facilitate continual person-to-person spread by environmental contamination from fecal droplets, leading to opportunistic infection.

Therapy for enterococcal infections is made more difficult by the frequency of antibiotic resistance.

However, the emergence of resistance, particularly mediated by a mutation in a penicillin binding protein (pbp5) in E. faecium, has severely limited the utility of this traditional strategy (Galloway-Pena et al., 2009, Arias & Murray, 2012).

From a public health perspective, the spread of VRE as a nosocomial infection has been particularly problematic since it reportedly causes 1.8 fold higher mortality and results in an average of 5 days longer hospital stay according to a meta-analysis (Prematunge et al., 2016).

However, although linezolid resistance has been reported to be rare, daptomycin resistance appears to emerge frequently de novo during daptomycin treatment (Arias et al., 2011); in such strains, linezolid becomes the only effective antibiotic available.

Linezolid as sole available therapy is problematic due to a litany of negative side effects, such as hepatic toxicity, myelosuppression, and serotonin syndrome (if used with other serotonergic drugs).

Given the limited options for treatment of enterococcal infections and the adverse effects associated with existing treatments, new treatments are urgently needed.

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