Cannabinoid enhanced silver antifungals

Abstract

Pharmaceutical formulations and treatments are provided that make combined use of selected antimycotic cannabinoids with silver-containing medicaments. Therapeutically effective regimens are provided that facilitate positive drug-drug interactions between the cannabinoid and the silver-containing medicament.

Description

CANNABINOID ENHANCED SILVER ANTIFUNGALSFIELD OF THE INVENTION

[0001] The invention is in the field of antifungal medicinal preparations and treatments involving the combined use of silver-containing medicaments and specific phenolic cannabinoids.BACKGROUND OF THE INVENTION

[0002] A very wide range of physiological activities have been ascribed to compounds derived from flowering plants in the genus Cannabis, particularly phytocannabinoid compounds (see Cunha et al., 1980; Moraleset al., 2017; US Patent No 6,630,507). There are more than 80 cannabinoids found in cannabis plant extracts (Russo, 2011), including: cannabidiol (CBD), its acid form cannabidiolic acid (CBDA), cannabichromene (CBC), its acid form cannabichromenic acid (CBCA), cannabigerol (CBG), its acidic form cannabigerolic acid (CBGA), tetrahydrocannabinol (THC), and its acidic form, tetrahydrocannabinolic acid (THCA). Studies have suggested that Cannabis extracts, or compounds derived from the Cannabis plant, have a very wide range of, often ill defined, anti-microbial activities (Van Klingeren & Ten Ham, 1976; Abdelaziz, 1982; Appendino et al., 2011; Appendino et al., 2008; Eisohly et al., 1982; Eisohly et al., 1982; Appendino et al., 2008; Turner & Eisohly, 1981; Mechoulam & Gaoni, 1965; WO2012 / 012498; WO2018 / 011813).

[0003] Silver in a variety of chemical forms has an ancient history as an antiseptic, with antimicrobial medicinal properties of silver for example being described by Hippocrates. More recently, with the invention of potent antimycotics in the 20thcentury, beginning with sulfa drugs and penicillin, the use of silveras an antimicrobial has assumed less clinical significance. Antimicrobial uses of silver compounds nevertheless remain important, and a variety of silver nanoparticles have relatively recently been added to the catalogue of silver antimicrobials, a catalogue which includes metallic silver, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate and silver sulfadiazine (Rai et al., 2009; Khundkar et al., 2010; Barnea et al., 2010; Franci et al, 2015). Colloidal silver is a term used for a category of commercial products, frequently characterized as suspensions of silver-containing particles between 1 and 1000 nm in size, in formulations that may also contain a number ofother forms of silver such as silver ions, nanoscale silver oxide, silver chloride, silver sulfide, or metallic silver (along with stabilizers and additives). Silver nanoparticles, for purposes of the present application, are particles of silver between about 1 nm and 100 nm in size, comprised principally of metallic silver and / or silver oxide. Clinical evidence indicates a lack of efficacy of currently used silver-containing products in preventing catheter-associated urinary tract infections (Lam et al. 2014), treating infected wounds (Vermeulen et al. 2007), preventing infection in burns and other wounds (Storm-Versloot et al. 2010) and treating diabetic ulcers (Bergin et al. 2006).

[0004] Fungal infection (mycosis) is a significant cause of human and veterinary morbidity and death, a public health issue made worse by the emergence of resistance to the limited number of existing effective treatments (Mussin & Giusiano, 2022; Gorka & Kubinski, 2024). One aspect of this involves the role of fungal pathogens, such as C. albicans, in forming biofilms on the surface of implantable medical devices or organs (Kumamoto, 2002).BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1 includes checkerboard data for three-compound combinations consisting of silver sulfate (Ag2SO4) combined with CBC and CBG against A. fumigatus (ATCC 96918) A: at 1:1 CBC+CBG and B: at 2:1 CBC+CBG: Figure 1-A, A. fumigatus ATCC 96918 (FICI 0.88); Figure 1-B, A. fumigatus ATCC 96918 (FICI 0.56);

[0006] Figure 2 includes checkerboard data presentation of three-compound combinations consisting of silver sulfate (Ag2SO4) combined with CBC and CBG against C. albicans (MYA-1023) A: at 1:2 CBC+CBG, B: at 1:1 CBC+CBG and C: at 2:1 CBC+CBG: Figure 2-A, C. albicans MYA-1023 (FICI 0.44); Figure 2-B, C. albicans MYA-1023 (FICI 0.13); Figure 2-C, C. albicans MYA-1023 (FICI 0.63).

[0007] Figure 3 includes checkerboard data presentation of three-compound combinations consisting of CBC and CBG combined with silver sulfate (Ag2SO4) at fixed silver concentrations against C. albicans (MYA-1023). A: Silver at 5.0 pg / mL, B: Silver at 2.5 pg / mL, C: Silver at 1.25 pg / mL, D: Silver at 0.625 pg / mL (elemental silverconcentration is reported): Figure 3-A, C. albicans MYA-1023; Figure 3-B, C. albicans MYA-1023; Figure 3-C, C. albicans MYA-1023; Figure 3-D, C. albicans MYA-1023.

[0008] Figure 4 includes checkerboard data presentation of three-compound combinations consisting of silver nanoparticles (NP) paired with CBC and CBG against A. fumigatus (ATCC 96918) A: at 1:2 CBC+CBG, B: at 1:1 CBC+CBG and C: at 2:1 CBC+CBG: Figure 4-A, A. fumigatus ATCC 96918 (FICI 0.88); Figure 4-B, A. fumigatus ATCC 96918 (FICI 0.50); Figure 4-C, A. fumigatus ATCC 96918 (FICI 0.13).

[0009] Figure 5 includes checkerboard data presentation of three-compound combinations consisting of silver NP combined with CBC and CBG against C. albicans (MYA-1023) A: at 1:2 CBC+CBG, B: at 1:1 CBC+CBG and C: at 2:1 CBC+CBG:Figure 5-A, C. albicans MYA-1023 (FICI 0.63); Figure 5-B, C. albicans MYA-1023 (FICI 0.75); Figure 5-C, C. albicans MYA-1023 (FICI 0.41).

[0010] Figure 6A-B: includes time kill curves relative to the initial inoculum following treatment with CBC (A) or CBG (B) at 14, 14 and 1 x MIC against A. fumigatus ATCC 96918: Figure 6-A, A. fumigatus ATCC 96918; Figure 6-B, A. fumigatus ATCC 96918.

[0011] Figures 7A-I: includes time kill-curves relative to the initial inoculum and synergistic ratios of silver sulfate at 14, 14 and 1 x MIC combined with cannabinoids CBC + CBG at 14, 14 and 1 x MIC against A. fumigatus ATCC 96918:A: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. B: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. C: 14 MIC silver sulfate alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 1 x MIC CBC+CBG. D: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. E: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. F: 14 MIC silver sulfate alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 1 x MIC CBC+CBG.G: 1 x MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver sulfate with 14 MIC CBC+CBG. H: 1 x MIC silver sulfate alone, the double combination of t MIC CBC+CBG, and the triple combination of 1 x MIC silver sulfate with t MIC CBC+CBG. I: 1 x MIC silver sulfate alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 1 MIC silver sulfate with 1 x MIC CBC+CBG.

[0012] Figures 8 A-l: includes time kill-curves relative to the initial inoculum and synergistic ratios of silver nanoparticles (NP) at 14, 14 and 1 x MIC combined with cannabinoids CBC + CBG at 14, 14 and 1 x MIC against A. fumigatus ATCC 96918.A: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.B: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.C: 14 MIC silver NP alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 1 x MIC CBC+CBG.D: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.E: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.F: 14 MIC silver NP alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 1 x MIC CBC+CBG.G: 1 x MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver NP with 14 MIC CBC+CBG.H: 1 x MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver NP with 14 MIC CBC+CBG.I: 1 x MIC silver NP alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 1 MIC silver NP with 1 x MIC CBC+CBG.

[0013] Figure 9A-B: includes time kill curves relative to the initial inoculum following treatment with CBC (A) or CBG (B) at 14, 14 and 1 MIC against C. albicans MYA-1023: Figure 9-A, C. albicans MYA-1023; Figure 9-B, C. albicans MYA-1023.

[0014] Figure 10A-I: includes time kill-curves relative to the initial inoculum and synergistic ratios of silver sulfate at 14, 14 and 1 x MIC combined with cannabinoids CBC + CBG at 14, 14 and 1 x MIC against C. albicans MYA-1023.A: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. B: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. C: 14 MIC silver sulfate alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 1 x MIC CBC+CBG. D: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. E: 14 MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 14 MIC CBC+CBG. F: 14 MIC silver sulfate alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver sulfate with 1 x MIC CBC+CBG. G: 1 x MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver sulfate with 14 MIC CBC+CBG. H: 1 x MIC silver sulfate alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver sulfate with 14 MIC CBC+CBG. I: 1 x MIC silver sulfate alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 1 MIC silver sulfate with 1 x MIC CBC+CBG.

[0015] Figures 11 A-l: includes time kill-curves relative to the initial inoculum and synergistic ratios of silver nanoparticles (NP) at 14, 14 and 1 x MIC combined with cannabinoids CBC + CBG at 14, 14 and 1 x MIC against C. albicans MYA-1023.A: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.B: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.C: 14 MIC silver NP alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 1 x MIC CBC+CBG.D: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.E: 14 MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 14 MIC CBC+CBG.F: 14 MIC silver NP alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 14 MIC silver NP with 1 x MIC CBC+CBG.G: 1 x MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver NP with 14 MIC CBC+CBG.H: 1 x MIC silver NP alone, the double combination of 14 MIC CBC+CBG, and the triple combination of 1 x MIC silver NP with 14 MIC CBC+CBG.I: 1 x MIC silver NP alone, the double combination of 1 x MIC CBC+CBG, and the triple combination of 1 MIC silver NP with 1 x MIC CBC+CBG.

[0016] Figures 12A-C: illustrates 72 hour kill rate of silver (0.2, 0.25, or 0.3% w / w) alone and in triple combination with 1.8% CBC + 0.9% CBG, 2.0% CBC +1.0 % CBG, 2.2% CBC +1.1% CBG, 1.8% CBC + 1.8% CBG, 2.0% CBC + 1.8% CBG, 2.2% CBC + 1.6% CBG, or 2.5% CBC + 1.2% CBG in polyurethane wound dressings against A. fumigatus ATCC 96918 (A) and C. albicans MYA-1023 (B and C).

[0017] Figure 13 includes checkerboard data presentation of two-compound combinations consisting of CBC combined with CBG against C. albicans MYA-1023 FICI 0.40).SUMMARY

[0018] One general aspect of the innovations disclosed herein includes methods of treating or preventing a fungal infection in a subject in need thereof. The method of treating or preventing involves the administration of cannabigerol (CBG), cannabichromene (CBC) and a silver-containing medicament. The cannabinoids and the silver-containing medicament may each be administered in a regimen, and the combination of the regimens adapted to provide a positive drug-drug interaction between the cannabinoids and the silver-containing medicament in the subject.

[0019] Implementations may include one or more of the following features. The method where the positive drug-drug interaction between the cannabinoids and the silver-containing medicament is a positive antimycotic drug-drug interaction that enhances the antimycotic effect of the cannabinoids and / or the silver-containingmedicament in the subject. The positive drug-drug antimycotic interaction may for example include a synergistically effective combined antimycotic activity. The fungal infection may superficial, subcutaneous, and systemic. The fungal infection may be an infection by an antimycotic resistant fungi. The fungal infection may for example be eumycetoma, chromoblastomycosis, cryptococcosis, histoplasmosis, pneumocystis pneumonia, aspergillosis or mucormycosis.

[0020] The cannabinoids may be administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the silver-containing medicament. The cannabinoids may for example reduce the MIC of the silver-containing medicament when the cannabinoids are present in an amount that is less than the MIC of the cannabinoids. The silver-containing medicament may be administered in a regimen that reduces the MIC of the cannabinoids. The silver-containing medicament may reduce the MIC of the cannabinoids when the silver-containing medicament is present in an amount that is less than the MIC of the silver-containing medicament.

[0021] The cannabinoids may be administered, used or applied in a relative amount that provides at least a 2 to 128 fold decrease in the MIC of the silver-containing medicament, for example so as to reduce the MIC of the silver-containing medicament to below a value that corresponds to 0.3% by weight of the formulation or material in which the silver-containing medicament is provided (0.3% by weight being a threshold for some silver-containing products beyond which silver staining may occur in use of the product). The silver-containing medicament may be administered in a relative amount that provides at least a 2 to 128 fold decrease in the MIC of the cannabinoids. The cannabinoids may for example be derived from a plant, such as cannabis sativa or cannabis indica, or may be synthetically produced.

[0022] In select embodiments, no antimycotic other than the cannabinoids and the silver-containing medicament is administered to the subject. The method may include administering to the subject the effective amounts of the cannabinoids and the silver-containing medicament, with no other medicaments, or no other antimycotics, or where no phytocannabinoid other than the cannabinoids is administered to the subject. The silver-containing medicament may be one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, acolloidal silver, a silver zeolite, or silver sulfadiazine. The subject may be a mammal, such as a human patient.

[0023] The therapeutically effective regimen of the cannabinoids may include administration of from 0.001 to 5,000 mg per day of the cannabinoids. The therapeutically effective regimen of the silver-containing medicament may include administration of from 0.001 to 10,000 mg per day elemental silver of the silver-containing medicament. The cannabinoids and the silver-containing medicament may be co-administered. The cannabinoids and the silver-containing medicament may be administered sequentially, in any order, for example Ag then Ci then C2, orCi then Ag then C2, or Ci then C2 then Ag (where “Ci” and “C2” are any two cannabinoids and “Ag” is the silver-containing medicament). Similarly, any two active ingredients may be co-administered, sequentially before or after a third active ingredient.

[0024] One general aspect includes an antimycotic formulation that includes cannabigerol (CBG), cannabichromene (CBC) and a silver-containing medicament. In the antimycotic formulation, the cannabinoids and the silver-containing medicament may each be present in an amount, and the combination of the amounts provides a positive drug-drug interaction between the cannabinoids and the silver-containing medicament, for example in a subject when the formulation is administered to the subject or when present in or on a substrate, such as a medical device, textile, fabric, surface coating, plastic or other material.

[0025] Implementations may include one or more of the features summarized above, in the discussion of the therapeutic regimen, or as follows. In the antimycotic formulation, the cannabinoids may for example be present at 0.01 – 5% w / w. The silver-containing medicament may for example be present in the formulation at an elemental silver concentration of 0.01 - 5% w / w, 0.01 - 4%, 0.01 - 3%, 0.01 - 2.5%, 0.01 - 2%, 0.01 - 1.25%, 0.01 - 1 %, 0.01 - 0.9%, 0.01 - 0.8%, 0.01 - 0.7%, 0.01 - 0.6%, 0.01 - 0.5%, 0.01 - 0.4%, 0.01 - 0.3%; 0.01 - 0.2%, or up to a maximum elemental silver concentration of 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%. The cannabinoids and / or the silver-containing medicament may be dissolved, dispersed, mixed or suspended in the formulation with a pharmaceutically acceptable carrier.

[0026] The positive drug-drug interaction between the cannabinoids and the silver-containing medicament may be a positive antimycotic drug-drug interaction that enhances the antimycotic effect of the cannabinoids and / or the silver-containingmedicament, for example in the subject or when present in or on a substrate, such as a medical device, textile, fabric, surface coating, plastic or other material. The positive drug-drug antimycotic interaction may include a synergistically effective combined antimycotic activity. The cannabinoids may be synthetic or may be derived from a plant, such has a Cannabis sativa or Cannabis indica plant.

[0027] In some embodiments, no antimycotic other than the cannabinoids and the silver-containing medicament is present in the formulation. The formulation may be made up essentially of the cannabinoids and the silver-containing medicament as active ingredients, i.e. including no other active medicament ingredients. The formulation may for example include no phytocannabinoid other than the cannabinoids. The silver-containing medicament may be one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

[0028] The antimycotic formulation may be for use in formulating a medicament for treating or preventing a fungal infection, for example in a subject in need thereof, or when present in or on a substrate, such as a medical device, textile, fabric, surface coating, plastic or other material, as summarized above.

[0029] The antimycotic formulation may be provided in or coating a supporting matrix, such as a gel, a hydrogel, a film, a polymer, a foam or a ceramic. The antimycotic formulation may be a hydrogel formulation that is a dried film. The dried film may be in the form of, or is for use as, a wound dressing. The hydrogel material may for example be a polyvinyl alcohol (PVA). The antimycotic formulation may for example coat a catheter, such as a urethral catheter or a vascular catheter. The supporting matrix may be in the form of a wound dressing, a biomedical implant, an endotracheal tube, a surgical mask, cotton fibers, synthetic fibers, synthetic polymers, a component of an invasive medical device, a catheter or a catheter coating. The matrix may include more than one silver-containing medicament and the releasability of the different silver-containing medicaments from the matrix may be different. For example, a first silver-containing medicament may be formulated in the matrix for sustained release, and a second silver-containing medicament formulated in the matrix for quick release. The matrix may include one or more additional medicaments, and the releasability from the matrix of the additional medicament(s) may be differentfrom the releasability of the silver-containing medicament. The additional medicament may for example be an additional antimycotic.

[0030] Fungal species amenable to inhibition with alternative formulations and products may for example include A. fumigatus and C. albicans or other Trichocomaceae spp. or Saccharomycetaceae spp., such as Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei,DETAILED DESCRIPTION OF THE INVENTION

[0031] In one aspect, pharmaceutical formulations and treatments are provided that make combined use of selected antimycotic cannabinoids with silver-containing medicaments. In particular, formulations may include cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), cannabichromene (CBC), delta-9-tetrahydrocannabinol or delta-8 tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabiphorol (THCP), hexahydrocannabinol (HHC), cannabidiphorol (CBDP), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin carboxylic acid (THCVA), cannabinol (CBN), cannabitriol (CBT), cannabigerovarin (CBGV), cannabigerovarin carboxylic acid (CBGVA), cannabidivarin (CBDV), cannabidivarin carboxylic acid (CBDV A), cannabichromevarin (CBCV).

[0032] In alternative aspects, formulations may include one or more cannabinoids that are: D9-THCAA; cannabinodiol (CBND); cannabicyclol (CBL); Cannabicyclolic acid (CBLA); Cannabicyclovarin (CBLV); tetrahydrocannabiorcol (D9-THCO or D9-THC1); the monomethyl ether of CBGAA (CBGAM); the monomethyl ether of (E)-CBG (CBGM); cannabidiol monomethylether (CBDM);Cannabidiorcol (CBD-C); cannabidihexol (CBDH); Cannabitwinol, (CBDD); cannabielsoin (CBE); cannabielsoin acid A (CBEAA); CBNM; cannabifuran (CBF); 8-hydroxy-isohexahydrocannabivirin (OH-iso-HHCV); dehydrocannabifuran (DCBF); 10-oxo-D6a(10a)-tetrahydrocannabinol (OTHC); cannabicoumaronone (CBCON); cannabiripsol (CBR); cannabitetrol (CBTT); cannabichromanone (CBCN); D7-cis-isotetrahydrocannabivarin-C3 (cis-iso-D7-THCV); (-)-D7-trans- (1 R,3R,6R)-isotetrahydrocannabinol-C5 (trans-iso-D7-THC); (-)-D7-trans-(1 R,3R,6R)-isotetrahydrocannabi- varin-C3 (trans-iso-D7-THCV);dehydrocannabifuran (DCBF); Cannabitracin (CBT); Cannabimovone (CBM);Cannabioxepane (CBX).

[0033] Therapeutically effective regimens are provided that facilitate positive drug-drug interactions between the cannabinoids and the silver-containing medicament, for example in a subject, or when present in or on a substrate, such as a medical device, textile, fabric, surface coating, plastic or other material. In select embodiments, these positive drug-drug interactions may provide antimycotic synergy.

[0034] The antimycotically effective ingredients may for example be provided in synergistically effective relative amounts. For example, the cannabinoids and the silver-containing medicament may be provided at relative concentrations that are antimycotically active in synergistic combination. In synergistic combination, the inhibitory concentrations of the cannabinoids and / or the silver-containing medicament may for example decrease, for example by two or more fold, for example from 2-16 fold. The components may accordingly be present in relative amounts that approximate the ratio of the respective MICs for the components in synergistic combination. For example, this may occur when the weight ratio of elemental silver from the silver-containing medicament to cannabinoids is from about 10:1 to 1:25, or 9:1 to 1:24, or 8:1 to 1:23, or 7:1 to 1:22, or6.4:1 to 1:21.3, or6:1 to 1:21, or 6.4:1 to 1:4.8, 1:6.2 to 1:10.7, and 1:12.3 to 1:21.3, or6.4:1 to 1:4.3, 1:6.2 to 1:10.7, and 1:12 to 1:21.3, or 6.4:1, 3.6:1 to 1:4.8, 1:6.2 to 1:10.7, and 1:12 to 1:18.5 and 1:21.3 (reflecting the MIC ratios of the components in synergistic combination) or about 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:13, 1:12, 1:11 and 1:10. This may occur when the weight ratio of CBC to CBG is from about 20:1 to 1:20, or 19:1 to 1:19, or 18:1 to 1:18, or 17:1 to 1:17, or 5:1 to 1:8, or 3:1 to 1:5, or 1.5:1, or 2:1 or 1:1 or 1:2 or 1:1.5.

[0035] Alternatively, this may occur when the molar ratio of elemental silver from the silver-containing medicament:cannabinoids is from 12:1 to 1:7 (reflecting the MIC ratios of the components in synergistic combination).

[0036] Anti-microbial formulations may be used to prophylactically or therapeutically treat microbial infections, or otherwise inhibit microbial growth or multiplication. An antimycotic or antifungal is an antimicrobial that is active against fungi, and in this context includes naturally-occurring, semi-synthetic and syntheticsubstances that kill or inhibit the growth or multiplication of fungi by any mechanism, including antiseptic or disinfectant modalities.

[0037] Fungal species amenable to inhibition may for example include with alternative formulations and products may for example include A. fumigatus and C. albicans or other Trichocomaceae spp. or Saccharomycetaceae spp., such as Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei. Alternative species amenable to inhibition may for example include: Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp., Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and Paracoccidioides spp.

[0038] Subjects amenable to treatment include mammalian subjects, such as human patients, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs, horses, fowl), or household pets (e.g., dogs, cats, rodents, birds), for example belonging to the taxonomic groups of primates, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, Aves or lagomorphs. Human patients to be treated may for example be male orfemale, or at a specific stage of development: neonate, infant, juvenile, adolescent, adult and geriatric. Specific veterinary indications amenable to treatment may for example include aspergillosis, candidiasis (such as oropharyngeal or thrush candidiasis), coccidioidomycosis (valley fever), cryptococcosis, geotrichosis, histoplasmosis, mycetomas, blastomycosis, hyalohyphomycosis, oomycosis (pythiosis and lagenidiosis), phaeohyphomycosis, rhinosporidiosis, and sporotrichosis.

[0039] The cannabinoids may for example be obtained from a plant extract, such as an extract of Cannabis sativa or Cannabis indica. A wide variety of methods may be used to prepare these plant extracts, including, but not limited to, supercritical or subcritical extraction with CO2, extraction with hot gas, and extraction with solvents. Biosynthetic approaches to the production of cannabinoids are also available, as are a variety of synthetic approaches (based for example on approaches used to synthesize THC / dronabinol, see US Patent No. 7,323,576 and Trost and Dogra, 2007). Alternative approaches involve expressing cannabinoid biosynthetic genes in recombinant hosts, such as recombinant yeast (see Luo et al., 2019). The cannabinoidcomponents of the formulation may accordingly be from a culture, such as a culture of a recombinant host, such as a recombinant yeast expressing the components. Formulations may also specifically exclude additional cannabinoids, terpenoids or terpenes, including plant-derived phytocannabinoids, terpenoids or terpenes, such as astaxanthin or other sesquiterpenes, tetraterpenes, triterpenes, diterpenes or monoterpenes. Alternatively, one or more additional compounds may be included, or specifically excluded, in alternative formulations, including for example: terpenes, terpenoid, sterols, triglycerides, alkanes, squalene, tocopherol, carotenoids, chlorophyll, flavonoid glycosides, or alkaloids.

[0040] A titratable dosage may for example be adapted to allow a patient to take the medication in doses smaller than the unit dose, wherein a "unit dose" is defined as the maximum dose of medication that can be taken at any one time or within a specific dosage period. Titration of doses will allow different patients to incrementally increase the dose until they feel that the medication is efficacious, as not all patients will require the same dose to achieve the same benefits. A person with a larger build or faster metabolism may require larger doses to achieve the same effect as another with a smaller build or slower metabolism. Therefore, a titratable dosage has advantages over a standard dosage form.

[0041] In select embodiments, formulations may be adapted to be delivered in such a way as to target one or more of the following: dermal, cutaneous, subcutaneous, dental, sublingual, buccal, oral, rectal, nasal, vaginal, parenteral and via the pulmonary system. Formulations may for example be in one or more of the following forms: cream, gel, gel spray, tablet, liquid, capsule, by injection, or for vaporization.

[0042] Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the formulations to subjects. Routes of administration may for example include, parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, otic, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, inhalational, aerosol, topical, dermal, cutaneous, sublingual or oral administration. Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets, capsules, liquid solutions or suspensions; for topical or dermal administration may bein the form of cream, lotion, paste, ointment, emulsion or gel; for intranasal formulations, in the form of powders, nasal drops, or aerosols; and for sublingual formulations, in the form of drops, aerosols or tablets. Formulations may be presented inside or as coatings on devices such as (but not restricted to) bone cement, dental cement, dental implants, wound dressings, catheter lines, injectable pastes or microimplants. In certain embodiments wound dressings may be manufactured from polymers such as polyurethane, poly vinyl alcohol or from numerous hydrogel forming materials such as (but not limited to) alginate / calcium, hyaluronic acid, cellulose derivatives, poloxamers and carbomers, pegylated polymers, chitosan or combinations of these or from materials well known to pharmaceutical scientists and outlined by Kamoun E et al (2017 ) in either a solvent cast or electrospun membrane form. Materials may be used as described or further modified chemically to improve performance. Alternatively, existing, commercially available, wound dressings may be simply soaked in any of the formulations. Implants may be simply coated with the drug formulations directly or provided in a coating material that both anchors the drugs to the implants whilst potentially providing controlled release of the drugs. Implant coating materials may be polymeric, ceramic, ionic, metals, paint-like materials or hydrogels.

[0043] Methods well known in the art for making formulations are found in, for example, “Remington: The Science and Practice of Pharmacy” (21st edition), ed. David Troy, 2006, Lippincott Williams & Wilkins. Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Numerous polymeric systems may be used to encapsulate the drugs to provide both a suitable means of drug administration and / or a controlled release aspect. Systems may be presented as monolithic units such as films or seeds or as microspheres, pastes, gels, nanoparticles. These systems may be manufactured from numerous degradable or non degradable polymers which are well described by Leichty W et al 2017. Other potentially useful parenteral delivery systems include osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether,glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0044] Pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient may take the form of one or more dosage units, where for example, a tablet, capsule or cachet may be a single dosage unit, and a container of the compound in aerosol form may hold a plurality of dosage units.

[0045] Materials used in preparing the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The inventive compositions may include one or more compounds (active ingredients) known for a particularly desirable effect. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed.

[0046] In general, the pharmaceutical composition includes a formulation of the present invention as described herein, in admixture with one or more carriers. The carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.

[0047] When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

[0048] As a solid formulation for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, cachet, chewing gum, wafer, lozenges, or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as syrups, acacia, sorbitol,polyvinylpyrrolidone, carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate orSterotex; fillers such as lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent. When the composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0049] The formulation may be in the form of a liquid, e.g., an elixir, syrup, solution, aqueous or oily emulsion or suspension, or even dry powders which may be reconstituted with water and / or other liquid media prior to use. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to the present compounds, one or more of a sweetening agent, thickening agent, preservative (e.g., alkyl p-hydoxybenzoate), dye / colorant and flavor enhancer (flavorant). In a composition intended to be administered by injection, one or more of a surfactant, preservative (e.g., alkyl p-hydroxybenzoate), wetting agent, dispersing agent, suspending agent (e.g., sorbitol, glucose, or other sugar syrups), buffer, stabilizer and isotonic agent may be included. The emulsifying agent may be selected from lecithin or sorbitol monooleate.

[0050] The liquid pharmaceutical formulations of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antifungal agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; bufferssuch as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0051] The pharmaceutical formulation may be intended for topical or dermal administration to intact skin, broken skin, catheter insertion and / or wounds sites, in which case the carrier may suitably comprise a solution, emulsion, ointment, cream, lotion hydrogel, film, or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

[0052] The formulation may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. Low-melting waxes are preferred for the preparation of a suppository, where mixtures of fatty acid glycerides and / or cocoa butter are suitable waxes. The waxes may be melted, and the aminocyclohexyl ether compound is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0053] The formulation may include various materials which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule or cachet.

[0054] The pharmaceutical formulation may consist of gaseous dosage units, e.g., it may be in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, ortri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit.

[0055] Some biologically active compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt such as the hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art. The appropriate salt would be chosen to enhance bioavailability or stability of the compound for the appropriate mode of employment (e.g., oral or parenteral routes of administration).

[0056] The present invention also provides kits that contain a pharmaceutical formulation, together with instructions for the use of the formulation. Preferably, a commercial package will contain one or more unit doses of the formulation. Formulations which are light and / or air sensitive may require special packaging and / or formulation. For example, packaging may be used which is opaque to light, and / or sealed from contact with ambient air, and / or formulated with suitable coatings or excipients.

[0057] The formulations of the invention can be provided alone or in combination with other compounds (for example, small molecules, nucleic acid molecules, peptides, or peptide analogues), in the presence of a carrier or any pharmaceutically or biologically acceptable carrier. As used herein “pharmaceutically acceptable carrier” or “excipient” includes any and all solvents, dispersion media, coatings, antifungal and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for any appropriate form of administration. Pharmaceutically acceptable carriers generally include sterile aqueous solutions or dispersions and sterile powders. Supplementary active compounds can also be incorporated into the formulations.

[0058] An “effective amount” of a formulation according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a formulation may vary according to factors such as the diseasestate, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the formulation or active compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. For any particular subject, the timing and dose of treatments may be adjusted overtime (e.g., timing may be daily, every other day, weekly, monthly) according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0059] The final concentrations of active components in antimycotic formulations may be in excess of the individual compounds’ MIC values, for a given indication. The concentrations of active components in the present formulations may accordingly be adapted based on clinical efficacy, pharmacokinetic and pharmacodynamic parameters, time over AUC, maximum concentration over MIC, AUC over MIC, stability, solubility, desired skin penetration properties, release characteristics from the formulation. Although the final formulation concentration may be an excess of the MIC value for the active components, an aspect of select embodiments of the present formulations is the preservation of the ratio of multiple active components within the synergistic range(s).

[0060] A drug interaction is a therapeutic circumstance in which a substance affects the activity of a drug, i.e. the biological effects of the drug are increased or decreased, or the substance and the drug together produce a new effect that neither produces on its own. In the context of an interaction between active pharmaceutical ingredients, this is known as a drug-drug interaction. Drug interactions occur on pharmacodynamic and pharmacokinetic levels, and may be positive or negative. Pharmacodynamic interactions are generally understood to be those in which drugs influence each other’s effects directly. Pharmacokinetic interactions involve the reciprocal influences of disparate active ingredients on the absorption, distribution, metabolization, and / or elimination of each active ingredient. One category of positive drug interactions involves degrees of synergy between disparate active ingredients. Other positive drug interactions may include any therapeutically beneficial pharmacodynamic and / or pharmacokinetic interaction inwhich the therapeutic benefit of the combined use of the active ingredients, for example in a particular dosage regimen, is improved compared to the individual use of the active ingredients, for example in a comparable dosage regimen.

[0061] In therapeutic applications, synergy between active ingredients occurs when an observed combined therapeutic effect is greater than the sum of therapeutic effects of individual active ingredients, or a new therapeutic effect is produced that the active ingredients could not produce alone. Accordingly, when components of a formulation are present in synergistically effective amounts, the formulation yields a therapeutic effect that is greater than would be achieved by the individual active ingredients administered alone at comparable dosages. In this context, the enhancement of therapeutic effect may take the form of increased efficacy or potency and / or decreased adverse effects. The synergistic effect may be mediated in whole or in part by the pharmacokinetics and / or pharmacodynamics of the active ingredients in a subject, so that the amount and proportion of the ingredients in the formulation may be synergistic in vivo. This in vivo synergy may be effected with a formulation that includes the active ingredients in amounts and proportions that are also synergistic in in vitro assays of efficacy. As used herein, the term “synergistically effective amounts” accordingly refers to amounts that are synergistic in vivo and / or in vitro. A numeric quantification of synergy is often expressed as a fractional inhibitory concentration index (FICI), which represents the sum of the fractional inhibitory concentrations (FICs) of each drug tested, where the FIC is determined for each drug by dividing the minimum inhibitory concentration (MIC, the lowest concentration of the drug which prevents visible growth of the fungi in a standard in vitro assay - standard colorometric assay based on resazurin) of each drug when used in combination by the MIC of each drug when used alone. In very general terms, a FICI lower or higher than 1 indicates positively correlated activity (at least additive or potentiation) or an absence of positive interactions, respectively. More definitively, synergy of two compounds may be conservatively defined as a FICI of ≤0.5 (see Odds, 2003); partial synergy or potentiation corresponding to a FICI of >0.5 to ≤0.75; no interaction (indifference) corresponding to a FICI of >1 to ≤4; and antagonism corresponding to a FICI of »4. (as described and used by Joung DK et al. and Rakoliya K et al.). With respect to combinations of three compounds, FICI of <1 has been considered synergistic (asdescribed and used by Berenbaum (1978) J. Infect. Dis. 137:122; Yoon et al. (2004) Antimicrob. Agents Chemother. 48:753; Yu et al. (1980) J. Infect. Dis. 142:602).EXAMPLES

[0062] To illustrate the positive antifungal interaction between silver and cannabinoids, The antifungal MICs of silver sulfate, silver nanoparticles, and the cannabinoids CBD, CBC, CBG, CBDA, CBCA and CBGA were determined against test isolates of Aspergillus fumigatus (ATCC 96918) and Candida albicans (MYA-1023).

[0063] In the context of the present disclosure, synergism occurs when two or more compounds interact in ways that mutually enhance, amplify or potentiate each other’s effect more significantly than the simple sum of the effects of the compounds when used separately. Synergism accordingly contrasts with antagonism, in which a combination of compounds is antagonistic if their joint effect is weaker than the sum of effects of the individual agents or weaker than the effect of either individual agent. An additive interaction is the effect where the combined action is equivalent to the sum of the activities of each drug when used alone. An indifferent interaction between treatments occurs if their joint effect is equal to the effect of either of the individual agents, alone.General Methods:Fungal strains and growth:

[0064] The inoculum suspensions of Aspergillus fumigatus (ATCC 96918) were prepared in compliance with the protocols outlined in the NCCLS M38-P document. The source cultures, aged between 5 and 7 days, were cultivated on Sabouraud Dextrose Agar (SDA) slants at a temperature of 35°C. Following incubation, the conidial suspensions were adjusted to optical densities ranging from 0.85 to 0.3 at 530 nm, which corresponds to transmittance values of 85% to 60%. These suspensions predominantly comprised conidia. The final concentrations of the inoculum suspensions were determined to be between 1.0 x 10A6 and 2.0 x 1OA6 CFU / ml, as verified by quantitative colony counts on SDA plates. For the purposes of subsequentexperiments, Aspergillus fumigatus (ATCC 96918) was cultured in RPMI 1640 medium, with the pH adjusted to 7.0 using MOPS.

[0065] Candida albicans (ATCC MYA-1023), was prepared by first culturing the organism on Sabouraud Dextrose Agar (SDA) plates overnight. Colonies were then harvested and diluted with sterile 0.9% NaCI to create the inoculum suspension. The cell density was adjusted spectrophotometrically with sterile saline to obtain the required starting inoculum concentration. Candida albicans (ATCC MYA-1023) was cultured in RPMI 1640 medium buffered to a pH of 7.0 with MOPS.Checkerboard assays:

[0066] Cannabinoids and silver compounds (concentrations expressed as elemental silver concentration, excluding salts) were serially diluted in a 2-fold or 1.5-fold manner across a 96-well microplate (COSTAR® 96-Well Flat-Bottom Microplate, catalog no. 3370). To each well, 100 pL of fungal cultures, with an optical density (OD600) of 0.0025, were added. The concentration ranges for cannabinoids for the serial 2-fold dilutions were from 32 pg / mL to 0.25 pg / mL, while the ranges for the 1.5-fold dilutions were from 8 pg / mL to 0.47 pg / mL or from 5.33 pg / mL to 0.31 pg / mL. Silver nanoparticles having a mean diameter of 10 nm and silver sulfate were tested at concentrations ranging from 80 pg / mLto 0.08 pg / mL. Checkerboard microplates contained the compounds in combination while control microplates run in parallel contained each compound alone in triplicate per dilution to determine the minimum inhibitory concentration (MIC) of each compound alone. The microplates were sealed with aluminum foil and incubated at 37°C for 24 hours (C. albicans) or 46 to 50 hours (A. fumigatus).

[0067] Post-incubation, the turbidity of the wells was evaluated using a TECAN™ (M100 PRO) microplate reader. Inhibition of fungal growth was taken as a turbidity reading of less than 10% of the untreated control. Outlier wells with turbidity reading that differ significantly from their surrounding wells or expected results were removed from the FICI analysis and corresponding wells were blacked out in the checkerboard figures.FICl computation:

[0068] Fractional Inhibitory Concentration Index (FICl) was calculated in a checkerboard assay based on the turbidity of the wells. Fractional Inhibitory Concentration (FIC) of each agent was determined as the ratio of the minimal inhibitory concentration (MIC) of one agent in the presence of the other agent(s) to the MIC of that agent alone. FICl was consequently computed as the sum of each agent’s FIC. Note: FIC indices (FICl) were interpreted as follows for two-compound combinations: <0.5, synergy (Odds 2003, Mukherjee, Sheehan et al. 2005, Joung, Kang et al. 2016), while a FICl value of > 0.5-4.0 can be interpreted as no interaction or indifference and FICl > 4, antagonism (Odds 2003, Mukherjee, Sheehan et al. 2005). FICl were interpreted as follows for three-compound combinations: <1, synergy; and >1, additivity or no interaction, as described by (Berenbaum 1978), (Yoon, Urban et al.2004), and (Yu, Felegie et al. 1980).

[0069] Synergistic silvercannabinoid weight ratio for the triple combination of silver, CBC and CBG was calculated as follows by taking the respective compound concentrations present in the checkerboard microplate well giving a synergistic FICl of <1 (and these respective compound concentrations correspond to the MICs in triple combination):

[0070] If the concentration of silver < the combined concentration of CBC + CBG, both the concentration of silver and the combined concentration of CBC + CBG are divided by the concentration of silver. For example, if a synergistic triple combination of silver nanoparticles, CBC and CBG had respective MICs of 0.5 pg / mL, 2 pg / mL and 2 pg / mL, the concentration of silver (0.5 pg / mL) is divided by itself (0.5 pg / mL), giving a value of 1. The combined concentration of CBC + CBG (4 pg / mL) is also divided by the concentration of silver (0.5 pg / mL), giving a value of 8. The synergistic silver: cannabinoid ratio would therefore be 1:8.

[0071] If the concentration of silver > the combined concentration of CBC + CBG, both the concentration of silver and the combined concentration of CBC + CBG are divided by the combined concentration of CBC + CBG. For example, if a synergistic triple combination of silver nanoparticles, CBC and CBG had respective MICs of 8 pg / mL, 2 pg / mL and 2 pg / mL, the concentration of silver nanoparticles (8 pg / mL) is divided by the combined concentration of CBC + CBG (4 ug / mL), giving a value of 2. The combined concentration of CBC + CBG (4 pg / mL) is divided by itself(4 |jg / m L), giving a value of 1. The synergistic silver: cannabinoid ratio would therefore be 2:1.

[0072] In all cases, elemental silver concentrations are reported and accordingly, all ratios are stated in terms of elemental silver.Kill-curve test:

[0073] The silver compound (concentrations expressed as elemental silver concentration, excluding salts), either as a single agent or in combination with CBC and CBG was added to the fungal growth media inoculated with approximately 106CFU / mL, at concentrations to allow for assessment of synergy. All concentrations expressed in pg / mL. An untreated growth control was included in all tests. All samples were incubated at 35°C. At designated time points, 100 pL of each sample was serially diluted in 1 mL of phosphate-buffered saline (PBS), and 100 pL of each dilution was plated onto SDA plates for colony counting (cfu / mL) after 24 hours. Time-kill curves were generated by plotting logw (cfu / mL) change from the initial inoculum against time. The limit of detection (LOD) was 2-log10 (cfu / mL). Fungistatic and fungicidal activity were defined as <3-logw and >3-logw reduction in cfu / mL, respectively, relative to the initial inoculums (Klepser, Ernst et al. 1998). Furthermore, a >2 logw in killing as measured by viable cfu / mL between the combination and the most active constituent was defined as synergy, and a <2 but >1 logw killing was defined as additive, while an increase in cfu / mL of no more than 2 logw cfu / mL from the least active agent was defined as indifference, whereas an increase of >2 logw cfu / mL was defined as antagonism (Eliopoulos 1996, Klepser, Ernst et al. 1998, Pfaller, Sheehan etal. 2004).

[0074] Synergistic ratio was calculated as follows, taking each compound’s respective concentration when the kill curve test indicated synergy of the triple combination:

[0075] If the concentration of silver < the combined concentration of CBC + CBG, both the concentration of silver and the combined concentration of CBC + CBG are divided by the concentration of silver. For example, if a synergistic triple combination of silver nanoparticles, CBC and CBG had respective compound concentrations of 0.5 pg / mL, 2 pg / mL and 2 pg / mL, the concentration of silver (0.5 pg / mL) is divided by itself (0.5 pg / mL), giving a value of 1. The combined concentrationof CBC + CBG (4 pg / rriL) is also divided by the concentration of silver (0.5 pg / mL), giving a value of 8. The synergistic silver: cannabinoid ratio would therefore be 1:8.

[0076] If the concentration of silver > the combined concentration of CBC + CBG, both the concentration of silver and the combined concentration of CBC + CBG are divided by the combined concentration of CBC + CBG. For example, if a synergistic triple combination of silver nanoparticles, CBC and CBG had respective MICs of 8 pg / mL, 2 pg / mL and 2 pg / mL, the concentration of silver nanoparticles (8 pg / mL) is divided by the combined concentration of CBC + CBG (4 ug / mL), giving a value of 2. The combined concentration of CBC + CBG (4 pg / mL) is divided by itself (4 pg / mL), giving a value of 1. The synergistic silver: cannabinoid ratio would therefore be 2:1.CFU Reduction in Wound Dressings

[0077] Absorbent polyurethane wound dressings having a thickness of approximately 4 mm were prepared containing no antimicrobial (vehicle control), silver sulfate (silver control), or the triple combination of silver sulfate, CBC and CBG in varying concentrations. In all cases, silver sulfate and cannabinoid content present in the polyurethane wound dressing is expressed as % w / w. Log-reductions were determined following the FDA protocol for solid wound dressings containing antimicrobial (FDA 2016). One mL of simulated wound fluid (Biochemazone, Chemazone Inc, Canada) containing a fungal inoculum of between 1 x 106to 1 x 107colony forming units (CFU) was added to a 2.5 cm x 2.5 cm sample of each dressing weighing approximately 0.5 grams in borosilicate glass vials. Actual inoculum sizes administered were determined by CFU enumeration on SDA plates. Vials containing the inoculated dressings were stored in an incubator at 35°C for the following time periods: 0.5 hours (vehicle control only), 24, 48 and 72 hours (all groups). At the specified time points, fungi were extracted by the addition of growth media followed by 100 pL aliquot sampling for CFU analysis. Aliquots underwent serial 10-fold dilutions and 100 pL of each dilution was spread onto SDA or PDA plates and incubated at 35°C to quantify CFU per mL. Colony counts of <20 per plate were considered too few to count (TFTC). The detection limit was 2-logw CFU / mL. Change in Log CFU / mL at 24, 48 and 72h is reported relative to the 0.5h vehicle control.Example 1: MICs and checkerboard analysis of cannabinoids and silver against pathogenic fungi.

[0078] The antifungal MICs of silver sulfate, silver nanoparticles, and the cannabinoids CBD, CBC. CBG, CBDA, CBCA and CBGA were determined against the test isolates Aspergillus fumigatus (ATCC 96918) and Candida albicans (MYA-1023) and are presented in Table 1. Neither the cannabinoids nor the silver compounds showed strong anti-fungal activity (i.e., MICs were all > 10 pg / mL). The MICs of all six cannabinoids were 1-fold dilution from each other, either 16 or 32 pg / mL, against both fungal species. The MICs of the silver sulfate and silver nanoparticles were within one dilution of each other; 10 pg / mL and 20 pg / mL, respectively against both fungal species.Table 1: Minimum Inhibitory Concentration (MIC) of individual cannabinoid and silver compounds against A. fumigatus (ATCC 96918) and C. albicans (MYA-1023).Elemental silver concentration is reported.Compound MIC (pg / mL)A. fumigatus C. albicans(ATCC 96918) (MYA-1023)CBD 32 16CBC 32 16CBG 16 16CBDA 32 32CBCA 32 32CBGA 32 32Silver (from silver 10 10sulfate)Silver nanoparticles 20 20

[0079] Pairwise silver-cannabinoid combinations were screened against Aspergillus fumigatus (ATCC 96918) and none of the combinations showed synergistic enhancement of anti-fungal activity (Table 2). Fractional Inhibitory ConcentrationIndex (FICI) scores for each combination were above 0.50, showing that silver combined with any one of the cannabinoids CBD, CBC, CBG, CBDA, CBCA or CBGA is not synergistic (Table 2).Table 2: Fractional Inhibitory Concentration Index (FICI) of two-compound combinations consisting of silver sulfate (Ag2SO4) paired with CBD, CBC, CBG, CBDA, CBCA or CBGA against A. fumigatus (ATCC 96918). Elemental silver concentration is reported.CB1Paired FIC Silver FIC CB1FICI2Conclusionwith SilverSulfateCBD 0.25 0.50 0.75 no synergyCBC 0.50 0.13 0.63 no synergyCBG 0.50 0.03 0.53 no synergyCBDA 0.50 0.25 0.75 no synergyCBCA 0.50 0.25 0.75 no synergyCBGA 0.25 0.50 0.75 no synergy1CB: Cannabinoid (CBD, CBC, CBG, CBDA, CBCA or CBGA)2FICI of a 2 compound combination > 0.5 indicates no synergyExample 2: Checkerboard analysis of CBC and CBG in 1:1 and augmented relative ratios as a three-compound combination with silver against A. fumigatus and C. albicans.

[0080] Surprisingly, pairing of the CBC and CBG cannabinoids and their combination with either silver sulfate or silver nanoparticles as a triple combination gave rise to synergistic anti-fungal activity, as demonstrated by checkerboard analysis (see Table 3Tables 11 and Figures 1-5). Furthermore, augmenting the relative concentrations of the CBC and CBG cannabinoids in triple combination with silverresulted in additional synergistic anti-fungal interactions (Table 3Tables 11 and Figures 1-5).Table 3: Fractional Inhibitory Concentration Index (FICI) of the Silver Sulfate, CBC and CBG three-compound combinations against A. fumigatus (ATCC 96918) at varying CBC: CBG weight ratios. Elemental silver concentration is reported.CBC: CBG FIC FIC CBC FIC CBG FICI1ConclusionRatio Silver1:1 0.50 0.13 0.25 0.88 FICI < 1: Synergy2:1 0.06 0.25 0.25 0.56 FICI < 1: Synergy1FICI of a 3 compound combination < 1 indicates synergy and > 1, no interactionTable 4A -B: Synergistic concentrations and SilverCannabinoid Weight Ratios of the Silver Sulfate, CBC and CBG Triple Combinations Demonstrating Synergy (FICI <1) against A. fumigatus (ATCC 96918) in Checkerboard assay. Elemental silver concentration is reported.A.Compound MIC (pg / mL) Fold FICI SilverCannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple1:1) in MICCombinationCBC 32 4 8 0.88 1:1.6CBG 16 4 4 (FICI <1,Silver (from 10 5 2 Synergy)silversulfate)B.Compound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple2:1) in MICCombinationCBC 32 8 4 0.56 1:19.2CBG 16 4 4 (FICI <1,Silver (from 10 0.625 16 Synergy)silversulfate)

[0081] The silver sulfate, CBC and CBG triple combination was definitively synergistic against A. fumigatus and C. albicans at a range of compound ratios, as shown by triple combination checkerboard experiments (see Table 3Tables 7 and Figures 1-3).

[0082] Against A. fumigatus, the 1:1 and 2:1 CBC: CBG weight ratios were synergistic in triple combination with silver sulfate with FICIs < 1, 0.88 and 0.56, respectively (Table 3). The 1:1 and 2:1 CBC: CBG weight ratios combined with silver sulfate demonstrated far greater antifungal activity than the individual compounds with reduction of MICs ranging from 2 to 16-fold (Table 4A-B). Raw data from the triple combination checkerboard experiments in A. fumigatus (Figure 1A-B) shows the respective concentrations of each compound which resulted in fungal growth (shaded cells), fungal killing (colorless cells), and the FICI minimum point (bold bordered cell). For each checkerboard point corresponding to synergy (FICI <1), the respective synergistic concentration of the compounds (i.e., MIC in triple combination) and their relative weight ratio (in terms of elemental silver: cannabinoid) is presented (Table 4A-B). With CBC and CBG present in equal amounts, synergy of silver, CBC and CBG occurred at 5, 4 and 4 pg / mL, respectively, corresponding to a silvercannabinoid weight ratio of 1:1.6 (Table 4A). With CBC present at twice the concentration of CBG, synergy of silver, CBC and CBG occurred at 0.625, 8 and 4 pg / mL, respectively, corresponding to a silver: cannabinoid weight ratio of 1:19.2 (Table 4B).Table 5: Fractional Inhibitory Concentration Index (FICI) of the Silver Sulfate, CBC and CBG three-compound combination against C. albicans (MYA-1023) at varying CBC: CBG weight ratios. Elemental silver concentration is reported.CBC: CBG FIC FIC FIC FICI1ConclusionRatio Silver CBC CBG1:2 0.25 0.06 0.13 0.44 FICI < 1: Synergy1:1 0.06 0.03 0.03 0.12 FICI < 1: Synergy2:1 0.25 0.25 0.13 0.63 FICI < 1: Synergy1FICI of a 3 compound combination < 1 indicates synergy and > 1, no interactionTable 6A-C: Synergistic concentrations and SilverCannabinoid Weight Ratios of the Silver Sulfate, CBC and CBG Triple Combinations Demonstrating Synergy (FICI <1) against C. albicans (MYA-1023) in Checkerboard assay. Elemental silver concentration is reported.A.Compound MIC (pg / mL) Fold FICI SilverCannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple1:2) in MICCombinationCBC 16 1 16 0.44 1:1.2CBG 16 2 8 (FICI <1,Silver (from 10 2.5 4 Synergy)silversulfate)Compound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple1:1) in MICCombinationCBC 16 0.5 32 0.13 1:1.6CBG 16 0.5 32 (FICI <1,Silver (from 10 0.625 16 Synergy)silversulfate)c.Compound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple2:1) in MICCombinationCBC 16 4 4 0.63 1:2.4CBG 16 2 8 (FICI <1,Silver (from 10 2.5 4 Synergy)silversulfate)

[0083] Against C. albicans, the 1:2, 1:1 and 2:1 CBC: CBG weight ratios were synergistic in triple combination with silver sulfate with FICIs < 1, 0.44, 0.12 and 0.63 respectively (Table 5). The 1:2, 1:1 and 2:1 CBC: CBG weight ratios combined with silver sulfate demonstrated far greater antifungal activity than the individual compounds with reduction of MICs ranging from 4 to 16-fold (Table 6A-C). Raw data from the triple combination checkerboard experiments in C. albicans (Figure 2A-C) shows the respective concentrations of each compound which resulted in fungal growth (shaded cells), fungal killing (colorless cells), and the FICI minimum point (bold bordered cell). For each checkerboard point corresponding to synergy (FICI <1), the respective synergistic concentration of the compounds (i.e., MIC in triple combination) and their relative weight ratio in terms of elemental silvercannabinoid is presented (Table 6A-C). With CBG present in twice the amount of CBC, synergy of silver, CBCand CBG occurred at 2.5, 1 and 2 pg / mL, respectively, corresponding to a silver: cannabinoid weight ratio of 1:1.2 (Table 6A). With CBC and CBG present in equal amounts, synergy of silver, CBC and CBG occurred at 0.625, 0.5 and 0.5 pg / mL, respectively, corresponding to a silvercannabinoid weight ratio of 1:1.6 (Table 6B). With CBC present in twice the amount of CBG, synergy of silver, CBC and CBG occurred at 2.5, 4 and 2 pg / mL, respectively, corresponding to a silvercannabinoid weight ratio of 1:2.4 (Table 6C).Tables 7A-D: Fractional Inhibitory Concentration Index (FICI), synergistic concentrations and silver: cannabinoid weight ratios of the Silver Sulfate, CBC and CBG three-compound combinations demonstrating synergy (FICI <1) against C. albicans (MYA-1023) at fixed silver concentrations. Elemental silver concentration is reported.A. Silver at 5 pg / mLMIC in Triple Fold Reduction in MIC FICI Silver: Cannabinoid Combination Synergistic Ratio (pg / mL)CBC CBG CBC CBG Silver0.31 5.33 51.60 3.00 2.00 0.85 1:1.1 5.33 0.31 3.00 51.60 2.00 0.85 1:1.1 0.47 5.33 34.00 3.00 2.00 0.86 1:1.2 0.70 5.33 22.90 3.00 2.00 0.88 1:1.2 2.37 3.55 6.80 4.50 2.00 0.87 1:1.2 3.55 2.37 4.50 6.80 2.00 0.87 1:1.2 5.33 0.70 3.00 22.90 2.00 0.88 1:1.2 5.33 0.47 3.00 34.00 2.00 0.86 1:1.21.05 5.33 15.20 3.00 2.00 0.90 1:1.3 5.33 1.05 3.00 15.20 2.00 0.90 1:1.31.58 5.33 10.10 3.00 2.00 0.93 1:1.4 3.55 3.55 4.50 4.50 2.00 0.94 1:1.40.47 1.05 34.00 15.20 2.00 0.60 3.3:1 0.70 0.70 22.90 22.90 2.00 0.59 3.6:1 0.47 0.31 34.00 51.60 2.00 0.55 6.4:1B. Silver at 2.5 pg / mLMIC in Triple Fold Reduction in MIC FICI Silver: Cannabinoid Combination Synergistic Ratio (pg / mL)CBC CBG CBC CBG Silver0.47 2.37 34.04 6.75 4.00 0.43 1:1.1 1.05 1.58 15.24 10.13 4.00 0.41 1:1.1 1.58 1.05 10.13 15.24 4.00 0.41 1:1.1 0.70 2.37 22.86 6.75 4.00 0.44 1:1.2 2.37 0.70 6.75 22.86 4.00 0.44 1:1.2 1.58 1.58 10.13 10.13 4.00 0.45 1:1.3 1.05 2.37 15.24 6.75 4.00 0.46 1:1.4 2.37 1.05 6.75 15.24 4.00 0.46 1:1.4 1.58 2.37 10.13 6.75 4.00 0.50 1:1.6 2.37 1.58 6.75 10.13 4.00 0.50 1:1.6 3.56 0.47 4.49 34.04 4.00 0.50 1:1.6 0.70 3.56 22.86 4.49 4.00 0.52 1:1.7 3.56 0.70 4.49 22.86 4.00 0.52 1:1.7 1.05 3.56 15.24 4.49 4.00 0.54 1:1.8 3.56 1.05 4.49 15.24 4.00 0.54 1:1.8 2.37 2.37 6.75 6.75 4.00 0.55 1:1.9 1.58 3.56 10.13 4.49 4.00 0.57 1:2.1 3.56 1.58 4.49 10.13 4.00 0.57 1:2.1 0.47 5.33 34.04 3.00 4.00 0.61 1:2.3 5.33 0.47 3.00 34.04 4.00 0.61 1:2.3MIC in Triple Fold Reduction in MIC FICI Silver: Cannabinoid Combination Synergistic Ratio (pg / mL)CBC CBG CBC CBG Silver0.70 5.33 22.86 3.00 4.00 0.63 1:2.4 2.37 3.56 6.75 4.49 4.00 0.62 1:2.4 3.56 2.37 4.49 6.75 4.00 0.62 1:2.4 5.33 0.70 3.00 22.86 4.00 0.63 1:2.4 1.05 5.33 15.24 3.00 4.00 0.65 1:2.6 5.33 1.05 3.00 15.24 4.00 0.65 1:2.6 5.33 1.58 3.00 10.13 4.00 0.68 1:2.8 2.37 5.33 6.75 3.00 4.00 0.73 1:3.1 5.33 2.37 3.00 6.75 4.00 0.73 1:3.1 0.47 8.00 34.04 2.00 4.00 0.78 1:3.4 8.00 0.47 2.00 34.04 4.00 0.78 1:3.4 0.70 8.00 22.86 2.00 4.00 0.79 1:3.5 8.00 0.70 2.00 22.86 4.00 0.79 1:3.5 1.05 8.00 15.24 2.00 4.00 0.82 1:3.6 3.56 5.33 4.49 3.00 4.00 0.81 1:3.6 5.33 3.56 3.00 4.49 4.00 0.81 1:3.6 1.58 8.00 10.13 2.00 4.00 0.85 1:3.8 8.00 1.58 2.00 10.13 4.00 0.85 1:3.8 2.37 8.00 6.75 2.00 4.00 0.90 1:4.1 8.00 2.37 2.00 6.75 4.00 0.90 1:4.1 5.33 5.33 3.00 3.00 4.00 0.92 1:4.3 0.70 1.58 22.86 10.13 4.00 0.39 1.1:1 0.47 1.58 34.04 10.13 4.00 0.38 1.2:1 1.05 1.05 15.24 15.24 4.00 0.38 1.2:1C. Silver at 1.25 pg / mLMIC in Triple Fold Reduction in MIC FICI Silver: Cannabinoid Combination Synergistic Ratio (pg / mL)CBC CBG CBC CBG Silver8.00 1.58 2.00 10.13 8.00 0.72 1:7.7 8.00 2.37 2.00 6.75 8.00 0.77 1:8.3 8.00 3.56 2.00 4.49 8.00 0.85 1:9.3 5.33 2.37 3.00 6.75 8.00 0.61 1:6.2 5.33 3.56 3.00 4.49 8.00 0.68 1:7.1 5.33 5.33 3.00 3.00 8.00 0.79 1:8.5 5.33 8.00 3.00 2.00 8.00 0.96 1:10.7 3.56 5.33 4.49 3.00 8.00 0.68 1:7.1 3.56 8.00 4.49 2.00 8.00 0.85 1:9.3 2.37 8.00 6.75 2.00 8.00 0.77 1:8.3 1.58 8.00 10.13 2.00 8.00 0.72 1:7.7 1.05 8.00 15.24 2.00 8.00 0.69 1:7.2D. Silver at 0.625 pg / mLMIC in Triple Fold Reduction in MIC FICI Silver: Cannabinoid Combination Synergistic Ratio (pg / mL)CBC CBG CBC CBG Silver8.00 2.37 2.00 6.75 16.00 0.71 1:16.6 8.00 3.56 2.00 4.49 16.00 0.79 1:18.5 8.00 5.33 2.00 3.00 16.00 0.90 1:21.3 5.33 2.37 3.00 6.75 16.00 0.54 1:12.3 5.33 3.56 3.00 4.49 16.00 0.62 1:14.2 5.33 5.33 3.00 3.00 16.00 0.73 1:17.1 5.33 8.00 3.00 2.00 16.00 0.90 1:21.3 3.56 5.33 4.49 3.00 16.00 0.62 1:14.23.56 8.00 4.49 2.00 16.00 0.79 1:18.5 2.37 8.00 6.75 2.00 16.00 0.71 1:16.6 1.58 8.00 10.13 2.00 16.00 0.66 1:15.3

[0084] The initial checkerboard experiments with the triple combination of silver, CBC and CBG indicated that synergistic interactions were occurring at several different silver: cannabinoid weight ratios. Additional checkerboard experiments with a modified layout were conducted, having further augmented CBC and CBG relative amounts outside of 2:1 to 1:2, and covering a finer differential in concentration gradient. These experiments demonstrate the synergy (FICI <1) of the triple combination to be occurring broadly within the silvercannabinoid weight ratio ranges of 6.4:1 to 1:21.3, or 6.4:1 to 1:4.3, or 1:6.2 to 1:10.7, or 1:12.3 to 1:21.3 (Figure 3A-D and Tables 7A-D). These experiments were conducted with C. albicans MYA-1023 and utilized 1.5-fold dilutions of CBG and CBG, which were combined at concentrations ranging from either 8 pg / mLto 0.47 pg / mLor5.33 pg / mLto 0.31 pg / mL in a 8 x 8 checkerboard with fixed concentrations of silver sulfate (either 0.625, 1.25, 2.5 or 5 pg / mL elemental silver) added to each well to produce the triple combination (Figure 3A-D and Tables 7A-D). Raw data from the triple combination 1.5-fold dilution checkerboard experiments (Figure 3A-D) shows the respective concentrations of each compound which resulted in fungal growth (shaded cells), inhibition of fungal growth (colorless cells), and the synergistic points resulting in FICI <1 (bold bordered cells).

[0085] With the concentration of silver fixed at 5 pg / mL, 44 of the triple combinations were synergistic (FICI <1 ), with Fl Cl s ranging from 0.55 to 0.94 (Tables 7A). The synergistic concentrations of CBC and CBG both ranged from 0.31 to 5.33 pg / mL, including relative CBC: CBG amounts ranging from 17:1 to 1:17, comprising 44 synergistic silver: cannabinoid ratios ranging from 6.4:1 to 1:1.4 (Table 7A)

[0086] With the concentration of silver fixed at 2.5 pg / mL, 44 of the triple combinations were synergistic (FICI <1), with FICIs ranging from 0.38 to 0.92 (Table 7B). The synergistic concentrations of CBC and CBG both ranged from 0.47 to 8.00pg / mL, including relative CBC: CBG amounts ranging from 17:1 to 1:17, comprising 44 synergistic silvercannabinoid ratios ranging from 1.2:1 to 1:4.3 (Table 7B).

[0087] With the concentration of silver fixed at 1.25 pg / mL, 12 of the triple combinations were synergistic (FICI <1), with FICIs ranging from 0.38 to 0.92 (Table 7C). The synergistic concentrations of CBC and CBG both ranged from 1.05 to 8.00 pg / mL, including relative CBC: CBG amounts ranging from 5:1 to 1:8, comprising 12 synergistic silvercannabinoid ratios ranging from 1:6.2 to 1:10.7 (Table 7C).

[0088] With the concentration of silver fixed at 0.625 pg / mL, 11 triple combinations were synergistic (FICI <1), with FICIs ranging from 0.54 to 0.90 (Table 7D). The synergistic concentrations of CBC and CBG both ranged from 1.58 to 8.00 pg / mL, including relative CBC: CBG amounts ranging from 3:1 to 1:5, comprising 11 synergistic silvercannabinoid ratios ranging from 1:12.3 to 1:21.3 (Table 7D).Table 8: Fractional Inhibitory Concentration Index (FICI) of the Silver Nanoparticle (NP), CBC and CBG three-compound combination against A. fumigatus (ATCC 96918) at varying CBC: CBG weight ratios.CBC: CBG FIC FIC FIC FICI1ConclusionRatio Silver CBC CBGNP1:2 0.25 0.13 0.50 0.88 FICI < 1: Synergy1:1 0.125 0.125 0.25 0.50 FICI < 1: Synergy2:1 0.63 0.31 0.31 0.13 FICI < 1: Synergy1FICI of a 3 compound combination < 1 indicates synergy and > 1, no interactionTables 9A -C: Synergistic Concentrations and SilverCannabinoid Weight Ratios of the Silver Nanoparticle (NP), CBC and CBG Triple Combinations Demonstrating Synergy (FICI <1) against A. fumigatus (ATCC 96918). Elemental silver concentration is reported.A.Compound MIC (pg / mL) FICI(CBC: CBG Alone In Triple Fold1:2) Combination Reducti Silver: Cannabinoid on in Synergistic Ratio MIC CBC 32 4 8 0.88 1:2.4CBG 16 8 2 (FICI <1,Silver NP 20 5 4 Synergy)B.Compound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reductio Synergistic Ratio Alone In Triple1:1) n in MICCombinationCBC 32 4 8 0.50 1:3.2CBG 16 4 4 (FICI <1,Silver NP 20 2.5 8 Synergy)Compound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple2:1) in MICCombinationCBC 32 1 32 0.13 1:1.2CBG 16 0.5 32 (FICI <1,Silver NP 20 1.25 16 Synergy)

[0089] The triple combination of silver nanoparticles, CBC and CBG was definitively synergistic against A. fumigatus and C. albicans at a range of compound ratios, as shown by triple combination checkerboard experiments (Table 8Tables 11 and Figures 4-5).

[0090] Against A. fumigatus, the 1:2, 1:1 and 2:1 CBC: CBG weight ratios were synergistic in triple combination with silver nanoparticles with Fl Cl s < 1, 0.88, 0.50 and0.13, respectively (Table 8). The 1:2, 1:1 and 2:1 CBC: CBG weight ratios combined with silver nanoparticles demonstrated far greater antifungal efficacy than the individual compounds with reduction of MICs ranging from 2 to 32-fold (Tables 9A-C). Raw data from the triple combination checkerboard experiments in A. fumigatus (Figure 4A-C) shows the respective concentrations of each compound which resulted in fungal growth (shaded cells), fungal killing (colorless cells), and the FICI minimum point (bold bordered cell). For each checkerboard point corresponding to synergy (FICI <1), the respective synergistic concentration of the compounds (i.e., MIC in triple combination) and their relative weight ratio in terms of elemental silver: cannabinoid is presented (Table 9A-C). With CBG present in twice the amount of CBC, synergy of silver, CBC and CBG occurred at 5, 4 and 8 pg / mL, respectively, corresponding to a silvercannabinoid weight ratio of 1:2.4 (Tables 9A). With CBC and CBG present in equal amounts, synergy of silver, CBC and CBG occurred at 2.5, 4 and 4 pg / mL, respectively, corresponding to a silvercannabinoid weight ratio of 1:3.2 (Tables 9B). With CBC present in twice the amount of CBG, synergy of silver, CBC and CBG occurred at 1.25, 1 and 0.5 pg / mL, respectively, corresponding to a silvercannabinoid weight ratio of 1:1.2 (Tables 9C).Table 10: Fractional Inhibitory Concentration Index (FICI) of the Silver Nanoparticle (NP), CBC and CBG three-compound combination against C. albicans (MYA-1023) at varying CBC: CBG weight ratios.CBC: CBG FIC FIC FIC FICI1ConclusionRatio Silver CBC CBGNP1:2 0.63 0.63 0.50 0.63 FICI < 1: Synergy1:1 0.25 0.25 0.25 0.75 FICI < 1: Synergy2:1 0.03 0.25 0.13 0.41 FICI < 1: Synergy1FICI of a 3 compound combination < 1 indicates synergy and > 1, no interactionTables 11 A -C: Synergistic Concentrations and SilverCannabinoid Weight Ratios of the Silver Nanoparticle (NP), CBC and CBG Triple Combinations DemonstratingSynergy (FICI <1) against C. albicans (MYA 1023). Elemental silver concentration is reported.A.Compound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple1:2) in MICCombinationCBC 16 4 4 0.63 1:9.6CBG 16 8 2 (FICI <1,Silver 20 1.25 16 Synergy)NanoparticlesCompound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple1:1) in MICCombinationCBC 16 4 4 0.75 1:1.6CBG 16 4 4 (FICI <1,Silver 20 5 4 Synergy)NanoparticlesCompound MIC (pg / mL) Fold FICI Silver: Cannabinoid (CBC: CBG Reduction Synergistic Ratio Alone In Triple2:1) in MICCombinationCBC 16 4 4 0.41 1:9.6CBG 16 2 6 (FICI <1,Silver 20 0.625 32 Synergy)Nanoparticles

[0091] Against C. albicans, the 1:2, 1:1 and 2:1 CBC: CBG weight ratios were synergistic in triple combination with silver nanoparticles with Fl Cl s < 1, 0.63, 0.75 and0.41, respectively (Table 10). The 1:2, 1:1 and 2:1 CBC: CBG weight ratios combined with silver nanoparticles demonstrated far greater antifungal efficacy than the individual compounds with reduction of MICs ranging from 4 to 32 fold (Tables 11A-C). Raw data from the triple combination checkerboard experiments in C. albicans (Figure 5A-C) shows the respective concentrations of each compound which resulted in fungal growth (shaded cells), fungal killing (colorless cells), and the FICI minimum point (bold bordered cell). For each checkerboard point corresponding to synergy (FICI <1), the respective synergistic concentration of the compounds (i.e., MIC in triple combination) and their relative weight ratio in terms of elemental silvercannabinoid is presented (Table 11 A-C). With CBG present in twice the amount of CBC, synergy of silver, CBC and CBG occurred at 1.25, 4 and 8 pg / mL, respectively, corresponding to a silver: cannabinoid weight ratio of 1:9.6 (Tables 11 A). With CBC and CBG present in equal amounts, synergy of silver, CBC and CBG occurred at 5, 4 and 4 pg / mL, respectively, corresponding to a silver: cannabinoid weight ratio of 1:1.6 (Tables 11 B). With CBC present in twice the amount of CBG, synergy of silver, CBC and CBG occurred at 0.625, 4 and 2 pg / mL, respectively, corresponding to a silver: cannabinoid weight ratio of 1:9.6 (T able 11 C).Example 3: Time kill curves of silver, CBC and CBG against A. fumigatus and C. albicans.

[0092] Time-kill methods can be used to determine the dynamic effect of a double and triple drug combination when compared to the compounds alone or in double combination, respectively. The time kill figures show the effect of the different silver / cannabinoid treatments on the growth of the pathogenic fungi relative to the initial inoculum at 2, 4, 6 and 24 hrs post-treatment. The possible results indicate synergistic, additive, indifferent or antagonistic effects. The assay also allows the determination on whether a treatment has fungistatic or fungicidal activity against the pathogenic fungi.

[0093] The silver sulfate, silver nanoparticle, CBC and CBG compounds as single, double or triple treatments were administered at ¼, ½, or 1 x MIC against A. fumigatus ATCC 96918 or C. albicans MYA-1023 fungi. Each of the compounds administered alone at MIC showed weak fungistatic activity with a net increase in fungal growth at 24 hours (Figures 6-11). Double combinations of CBC with CBG werealso fungistatic, but more active than silver sulfate or silver NP at ¼, ½, or 1 x-MIC (Figures 7-8 and 10-11). A ≥2 log10CFU / mL reduction with the CBC+CBG in double combination compared to the most active cannabinoid alone after 24 hours was defined as synergy. Furthermore, a ≥2 log10CFU / mL reduction with the triple combination compared to the double CBC+CBG combination was defined as synergy. The horizontal dashed line in Figures 7-8 and 10-11 indicates the synergistic zone for the corresponding triple silver, CBC and CBG combinations.

[0094] The double CBC and CBG combinations at 14, 14, or 1 x MIC were synergistic against A. fumigatus ATCC 96918 (Figures 6-8) with log10CFU / mL reductions from the most active of the 2 cannabinoids, of 3.1, 2.0 and 2.5, respectively.

[0095] Surprisingly, pairing of the CBC and CBG cannabinoids and their combination with silver as a triple combination gave rise to a synergistic anti-fungal kill kinetic with conversion from fungistatic to fungicidal activity against both A. fumigatus and C. albicans (Figures 7-8 and 10-11).

[0096] Kill-curves in Figures 6-A and 6-B show that the cannabinoids CBC and CBG administered individually at ¼, ½, or 1 x MIC have little impact on A. fumigatus ATCC 96918 growth overtime. Silver sulfate (Ag2SO4) administered individually also had little impact on A. fumigatus ATCC 96918 growth overtime (Figure 7A-I).

[0097] The triple combinations of silver from silver sulfate at 2.5, 5.0 and 10.0 pg / mL, with the CBC and CBG cannabinoids at ¼, ½ and 1 x MIC were not only fungicidal by killing >3 log10CFU / ml at 24 hours, but also synergistic (Figure 7A-I). The silver: cannabinoid weight to weight synergistic ratios of the 2.5 pg / mL silver from silver sulfate combined with CBC and CBG at ¼, ½ and 1 x MIC were 1:4.8, 1:9.6 and 1:19.2, respectively (Figures 7A-C and Table 12). The silver: cannabinoid weight to weight synergistic ratios of the 5.0 pg / mL silver from silver sulfate combined with CBC and CBG at ¼, ½ and 1 x MIC were 1:2.4, 1:4.8 and 1:9.6, respectively (Figures 7D-F and Table 12). The silver: cannabinoid weight to weight synergistic ratios of the 10 pg / mL silver from silver sulfate combined with CBC and CBG at ¼, ½ and 1 x MIC were 1:1.2, 1:2.4 and 1:4.8, respectively (Figures 7G-I and Table 12).

[0098] Similarly to silver sulfate, silver nanoparticles (AgNP) at ¼, ½, or 1 x MIC had little impact on A. fumigatus ATCC 96918 growth overtime (Figure 8A-I). The triple combinations of AgNP at ¼ or ½ MIC with CBC and CBG showed fungistatic activity (Figures 8A-F), and similarly, the triple combination of AgNP at 1 x MIC with CBC andCBG each at 14 MIC showed fungistatic activity (Figure 8G). The triple combination of ½ MIC AgNP with CBC and CBG each at ½ MIC was synergistic (Figure 8E). Furthermore, the triple combinations of AgNP at 20 pg / mL (1 x MIC), with the CBC and CBG cannabinoids at ½ MIC was not only synergistic, but also fungicidal by killing >3 log10CFU / ml at 24 hours (Figure 8H). The same result was observed with the triple combination of AgNP, CBC and CBG with each compound at 1x MIC (Figure 8I). The silver:cannabinoid weight to weight synergistic ratio of the 10 pg / mL AgNP (½ MIC) combined with CBC and CBG at ½ MIC was 1:2.4 (Figure 8E and Table 13). The silver: cannabinoid weight to weight synergistic ratios of the 20 pg / mL AgNP combined with CBC and CBG at ½ and 1 x MIC were 1:1.2 and 1:2.4, respectively (Figures 8H-I and Table 13).

[0099] Kill-curves in Figures 9A and 9B show that CBC and CBG administered individually at ¼, ½, or 1 x MIC have little impact on C. albicans MYA-1023 growth overtime. Silver sulfate (Ag2SO4) administered individually also had little impact on C. albicans MYA-1023 growth overtime (Figure 10A-I).

[0100] The triple combinations of silver from silver sulfate at 2.5, 5.0 and 10.0 pg / mL, with the CBC and CBG cannabinoids at ¼, ½ and 1 x MIC was not only fungicidal by killing >3 log10CFU / ml at 24 hours, but also synergistic (Figure 10C-I). The silver: cannabinoid weight to weight synergistic ratios of the 2.5 pg / mL silver from silver sulfate combined with CBC and CBG at 1 x MIC was 1:12.8 (Figure 10C and Table 14), the ¼ and ½ fold MICs were not synergistic (Figures 10A-B). The silver: cannabinoid weight to weight synergistic ratios of the 5.0 pg / mL silver from silver sulfate combined with CBC and CBG at ¼, ½ and 1 x MIC were 1:1.6, 1:3.2 and 1:6.4, respectively (Figures 10D-F and Table 14). The silvercannabinoid weight to weight synergistic ratios of the 10 pg / mL silver from silver sulfate combined with CBC and CBG at ¼, ½ and 1 x MIC were 1.25:1, 1:1.6 and 1:3.2, respectively (Figures 10G-I and Table 14).

[0101] Similarly to silver sulfate, silver nanoparticles (AgNP) at ¼, ½, or 1 x MIC had little impact on C. albicans MYA-1023 growth overtime (Figure 11A-I). The triple combinations of AgNP at ¼ MIC with CBC and CBG showed fungistatic activity (Figures 11A-C), and similarly, the triple combination of AgNP at 1 x MIC with CBC and CBG each at ½ MIC showed fungistatic activity (Figure 11E). The triple combinations of ½ MIC AgNP with CBC and CBG each at ¼ MIC, as well as ½ MICAgNP with CBC and CBG each at 1 x MIC were synergistic (Figure 11 D and F). Furthermore, the triple combinations of AgNP at 20 pg / mL (1 x MIC), with the CBC and CBG cannabinoids at ¼, ½ or 1 x MIC were not only synergistic, but also fungicidal by killing >3 log10CFU / ml at 24 hours (Figures 11G-I). The silver: cannabinoid weight to weight synergistic ratio of the 10 pg / mL AgNP (14 MIC) combined with CBC and CBG at 14 and 1 x MIC were 1.25:1 and 1:3.2, respectively (Figures 11 D and F and Table 15). The silvercannabinoid weight to weight synergistic ratios of the 20 pg / mL AgNP combined with CBC and CBG at ¼, ½ and 1 x MIC were 2.5:1, 1.25:1 and 1:1.6, respectively (Figures 11-I and Table 15).Table 12: Kill Curve Synergistic Concentrations and SilverCannabinoid Ratios of Silver Sulfate, CBC and CBG in triple combinations against A. fumigatus (ATCC 96918). Elemental silver concentration is reported.Kill-curve Silver CBC CBG Log10Silver:Cannabinoid figure (µg / mL; (µg / mL) (µg / mL) reduction1Synergistic Ratio2from silver sulfate) 6A 2.5 8 4 2.8 1:4.8 6B 2.5 16 8 4.5 1:9.6 6C 2.5 32 16 3.3 1:19.2 6D 5 8 4 4.3 1:2.4 6E 5 16 8 4.5 1:4.8 6F 5 32 16 3.3 1:9.6 6G 10 8 4 4.3 1:1.2 6H 10 16 8 4.5 1:2.4 6I 10 32 16 3.3 1:4.81Log10CFU / mL reduction from the CBC+CBG double combination.2Synergy: ≥2 log10CFU / mL reduction from the CBC+CBG double combination.Table 13: Kill Curve Synergistic Concentrations and SilverCannabinoid Ratios of Silver NP, CBC and CBG in triple combinations against A. fumigatus (ATCC 96918).Kill Silver NP CBC CBG Log10Silver:Cannabinoid curve (µg / mL) (µg / mL) (µg / mL) reduction1Synergistic Ratio2figure7E 10 16 8 2.0 1:2.47H 20 16 8 3.8 1:1.27I 20 32 16 2.5 1:2.41Log10CFU / mL reduction from the CBC+CBG double combination.2Synergy: ≥2 log10CFU / mL reduction from the CBC+CBG double combination.Table 14: Kill Curve Synergistic Concentrations and SilverCannabinoid Ratios of Silver Sulfate, CBC and CBG in triple combinations against C. albicans (MYA-1023). Elemental silver concentration is reported.Kill-curve Silver CBC CBG Log10Silver:Cannabinoid figure (µg / mL; (µg / mL) (µg / mL) reduction1Synergistic Ratio2from silver sulfate)9C 2.5 16 16 3.5 1:12.89D 5 4 4 3.6 1:1.69E 5 8 8 3.6 1:3.29F 5 16 16 3.0 1:6.49G 10 4 4 4.4 1.25:19H 10 8 8 4.5 1:1.69I 10 16 16 3.5 1:3.21Log10CFU / mL reduction from the CBC+CBG double combination.2Synergy: ≥2 log10CFU / mL reduction from the CBC+CBG double combination.Table 15: Kill Curve Synergistic Concentrations and Silver:Cannabinoid Ratios of Silver NP, CBC and CBG in triple combinations against C. albicans (MYA-1023). Kill-curve Silver NP CBC CBG Log10Silver:Cannabinoid figure (µg / mL) (µg / mL) (µg / mL) reduction1Synergistic Ratio210D 10 4 4 2.1 1.25:110F 10 16 16 2.5 1:3.210G 20 4 4 3.9 2.5:110H 20 8 8 3.1 1.25:1101 20 16 16 3.0 1:1.61Log10CFU / mL reduction from the CBC+CBG double combination.2Synergy: ≥2 log10CFU / mL reduction from the CBC+CBG double combination.Example 4: Efficacy of CBC + CBG combined with silver sulfate in wound dressing formulations in reducing Logio CFU / mL of A. fumigatus (ATCC 96918) and C. albicans (MYA-1023) over 72 hours

[0102] Combining CBC, CBG and silver sulfate together in relative amounts that fell within the range of synergistic silvercannabinoid ratios identified in Examples 2 and 3 and formulating the constituents within polyurethane wound dressings, the antifungal effects of the dressings were determined against the test isolates Aspergillus fumigatus (ATCC 96918) and Candida albicans (MYA-1023) (Figure 12A-C). Wound dressings containing no drug (vehicle control) and silver sulfate alone were used as experimental controls. Vehicle control dressings showed considerable fungal growth with 3.4 – 4.2 Log10CFU / mL increases at 72 hours (Figure 12A-C). Dressings containing silver sulfate alone at 0.2, 0.25, or 0.3% w / w didn’t have fungicidal activity but did slow the growth of A. fumigatus (ATCC 96918) and C. albicans (MYA-1023) at 24, 48 and 72 hours (Figure 12A-C). However, all silver control dressings had net fungal growth over 72 hours, with Log10CFU / mL increases ranging from 1.8 – 2.3 (Figure 12A-C).

[0103] The wound dressing formulations with the triple combinations 0.2% Ag2SO4+ 0.9% CBG + 1.8% CBC and 0.25% Ag2SO4+ 0.9% CBG + 1.8% CBC showed fungal killing activity with CFU / mL reductions up to 1.2 log10over the 72 hours incubation period against A. fumigatus (ATCC 96918) (Figure 12A). The wound dressing formulation 0.2% Ag2SO4+ 1.1% CBG + 2.2% CBC had a maximal killing effect of 4.1 log10at 24 and 48 hours, bringing the CFU / mL count below the level of detection but an approximately 1 log 10 regrowth was detected at 72 hours. The 2 most active wound dressing formulations against A. fumigatus were 0.2% Ag2SO4+ 1.1% CBG + 2.2% CBC and 0.25% Ag2SO4+ 1.0% CBG + 2.0% CBC with a maximal fungicidal effect of 4.1 log10reduction at 24, 48 and 72 hours (Figure 12A). These formulations are considered fungicidal against A. fumigatus (ATCC 96918) since they induce a reduction of ≥ 3 log10CFU / mL compared to the initial inoculum (Figure 12A).

[0104] Against C. albicans (MYA-1023), five wound dressing formulations containing varying amounts of Ag2SO4+ CBG + CBC in triple combination were all fungicidal at 24 hours, having a maximal killing effect of 4.2 log10, bringing the CFU / mL count below the level of detection (Figure 12B). Of these five dressings containing thetriple combination, the % (w / w) Ag2SO4 content ranged from 0.2% to 0.25%, the CBG content ranged from 0.9% - 1.1%, and the CBC content ranged from 1.8% - 2.2%. After 24 hours, fungal regrowth was observed with approximately -0.7 to -1.2 log10CFU / mL detected at 48 hours and -2 to -3.2 log10CFU / mL at 72 hours (Figure 12B). The 0.2% Ag2SO4+ 1.1% CBG + 2.2% CBC formulation can be considered fungicidal against C. albicans (MYA-1023) since it induced a reduction of ≥ 3 log10CFU / mL compared to the initial inoculum (Figure 12B). Furthermore, wound dressings with increased concentrations of Ag2SO4+ CBG + CBC were fungicidal and also effective in preventing regrowth of C. albicans, resulting in CFU / mL counts below the limit of detection at 72 hours (Figure 12C). These included the 0.3% Ag2SO4+ 2.0% CBC + 1.81% CBG formulation (5.3 Log10CFU / mL reduction at 72 hours), and the 0.3% Ag2SO4+ 2.46% CBC + 1.22% CBG formulation (4.8 Log10CFU / mL reduction at 72 hours; Figure 12C).

[0105] The data indicates that wound dressing formulations with >3.0% w / w of CBC + CBG and >0.2% Ag2SO4will be fungicidal against A. fumigatus (MYA-1023). A higher w / w concentration of the constituents is required in wound dressing formulations for C. albicans since the data indicates that wound formulations with >3.3% w / w of CBC + CBG and >0.2% Ag2SO4can be fungicidal against C. albicans (MYA-1023), with higher concentrations required to prevent fungal regrowth over 72 hours (i.e., >3.7% w / w of CBC + CBG and >0.3% w / w Ag2SO4).Example 5: Checkerboard and kill curve analysis of CBC and CBG in double combination against A. fumigatus and C. albicans.

[0106] The double combination of CBC and CBG gave rise to synergistic antifungal activity against C. albicans MYA-1023, as demonstrated by checkerboard analysis (Table 16 and Figure 13) and kill-kinetic against A. fumigatus ATCC 96918 (Figures 6-7) as described in Example 3.

[0107] FICIs of 2 compound combinations < 0.5 are considered synergistic. Against C. albicans, CBC and CBG were synergistic in double combination with FICIs of 0.40, 0.43, 0.44 and 0.48 (Table 16). The synergistic concentrations of CBC and CBG which gave synergy in the checkerboard analysis (Figure 13) are listed in Table16 as the MIC in Double Combination. The corresponding synergistic weight ratios of CBC: CBG range from 1:1 to 1:5.08 (Table 16).

[0108] As recited in Example 3, CBC and CBG combined at ¼, ½ and 1 x MIC against A. fumigatus were synergistic, resulting in ≥2 Log10CFU / mL reductions from the most active constituent alone (Figures 6-7). The combination of 8 µg / mL CBC and 4 µg / mL CBG (compounds combined at ¼ x MIC) resulted in a 3.1 Log10CFU / mL reduction from CBC alone at 8 µg / mL (Figures 6 and 7-A). This corresponds to a synergistic CBC: CBG weight ratio of 2:1. Additionally, the combination of 16 pg / mL CBC and 8 pg / mL CBG (compounds combined at 14 x MIC) resulted in a 2.0 Log10CFU / mL reduction from CBG alone at 8 µg / mL (Figures 6 and 7-B). This also corresponds to a synergistic CBC: CBG weight ratio of 2:1. Additionally, the combination of 32 pg / mL CBC and 16 pg / mL CBG (compounds combined at 1 x MIC) resulted in a 2.5 Log10CFU / mL reduction from CBC alone at 32 µg / mL (Figures 6 and 7-C). This also corresponds to a synergistic CBC: CBG weight ratio of 2:1.Table 16: Concentrations and Synergistic Ratios of CBC and CBG Double Combinations Demonstrating Synergy (FICI < 0.5) against C. albicans (MYA-1023).MIC in Double Fold Reduction FICI CBC: CBG Combination in MIC Cannabinoid (pg / mL) Synergistic Ratio CBC CBG CBC CBG1.05 5.33 15.2 3.0 0.40 1:5.081.58 5.33 10.1 3.0 0.43 1:3.372.37 5.33 6.8 3.0 0.48 1:2.253.56 3.56 4.5 4.5 0.44 1:1DEFINITIONS AND REFERENCES

[0109] Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of theinvention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing.

[0110] Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference. All documents cited or referenced in herein cited documents, together with any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings. In some embodiments, the invention excludes steps that involve medical or surgical treatment.

[0111] References:

[0001] Abdelaziz, A., (1982) Studies on the antimicrobial activity of cannabinoids. MS thesis, Ohio State University.

[0002] Andre, C. M.; Hausman, J.-F.; Guerriero, G. (2016). " Cannabis sativa:The Plant of the Thousand and One Molecules". Frontiers in Plant Science. 7: 19.

[0003] Appendino, G., G. Chianese & 0. Taglialatela-Scafati, (2011) Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem 18: 1085-4099.

[0004] Appendino, G., Gibbons, S., Giana, A., Pagani, A., Grassi, G., Stavri, M., Smith, E., and Rahman, M. M., 2008, “Antifungal Cannabinoids from Cannabis Sativa: A Structure-Activity Study,” J. Nat. Prod., 71(8), pp. 1427-1430.

[0005] Appendino, G., S. Gibbons, A. Giana, A. Pagani, G. Grassi, M. Stavri, E. Smith & M. M. Rahman, (2008) Antifungal cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod 71: 1427-1430.

[0006] Arias, C. A. & B. E. Murray, (2012) The rise of the Enterococcus: beyond vancomycin resistance. Nat Rev Microbiol 10: 266-278.

[0007] Arias, C. A., D. Panesso, D. M. McGrath, X. Qin, M. F. Mojica, C. Miller, L.Diaz, T. T. Tran, S. Rincon, E. M.

[0008] Arthur, M. & P. Courvalin, (1993) Genetics and mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother 37: 1563-1571.

[0009] Ashurst, P. R., Bohlmann, F., Farkas, L., Gaoni, Y., KLING, H., Mechoulam, R., Morrison, G. A., Pallos, L., Romo, J., Romo De Vivar, A., Sutherland, J. K., and Waldschmidt-Leitz, E., 1967, Progress in the Chemistry of Organic Natural Products, Springer Science & Business Media.

[0010] Baltz RH (December 2006). " Molecular engineering approaches to peptide, polyketide and other antimycotics". Nature Biotechnology. 24 (12): 1533-40.

[0011] Barbu, J. Reyes, J. H. Roh, E. Lobos, E. Sodergren, R. Pasqualini, W.Arap, J. P. Quinn, Y. Shamoo, B. E. Murray & G. M. Weinstock, (2011) Genetic basis for in vivo daptomycin resistance in enterococci. N Engl.' Med 365: 892- 900.

[0012] Barnea, Y., Weiss, J., and Gur, E., 2010, “A Review of the Applications of the Hydrofiber Dressing with Silver (Aquacel Ag®) in Wound Care,” Then Clin. Risk Manag., 6(1), pp. 21-27.

[0013] Bell, A., 2005, “Antimalarial Drug Synergism and Antagonism:Mechanistic and Clinical Significance,” FEMS Microbiol. Lett., 253(2), pp. 171 — 184.

[0014] Berenbaum, M. C. (1978). " A method for testing for synergy with any number of agents." J Infect Dis 137(2): 122-130.

[0015] Berenbaum, M. C. 1978. A method for testing for synergy with any number of agents. J. Infect. Dis. 137:122-130.

[0016] Bergin, S., and Wraight, P., 2006, “Silver based wound dressings and topical agents for treating diabetic foot ulcers,” Cochrane Database of Systematic Reviews, (1).

[0017] Chakraborty, S., Afaq, N., Singh, N., and Majumdar, S., 2018, “Antimicrobial Activity of Cannabis Sativa, Thuja Orientalis and Psidium Guajava Leaf Extracts against Methicillin-Resistant Staphylococcus Aureus,” J. Integr. Med., 16(5), pp. 350-357.

[0018] Chopra, I., 2007, “The increased use of silver-based products as antimicrobial agents: a useful development or a cause for concern?” Journal of Antimicrobial Chemotherapy, 59, pp. 587-590.

[0019] Consroe, P., J. Laguna, J. Allender, S. Snider, L. Stern, R. Sandyk, K.Kennedy & K. Schram, (1991) Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacol Biochem Behav 40: 701-708.

[0020] Cunha, J. M., E. A. Carlini, A. E. Pereira, O. L. Ramos, C. Pimentel, R.Gagliardi, W. L. Sanvito, N. Lander & R. Mechoulam, (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21: 175-185.

[0021] Eisohly, H. N., C. E. Turner, A. M. Clark & M. A. Eisohly, (1982) Synthesis and antimicrobial activities of certain cannabichromene and cannabigerol related compounds. J Pharm Sci 71: 1319-1323.

[0022] Eliopoulos, G. M., and R. C. Moellering, Jr. (1996). Antimicrobial combinations. Antibiotics in Laboratory Medecine. V. Lohan. Baltimore, Md., The Williams & Wilkins Co.: 330-396.

[0023] Fang, L., Li, X., Li, L., Li, S., Liao, X., Sun, J. and Liu, Y., 2016, “Cospread of metal and antimycotic resistance within ST3-lncHI2 plasmids from E. coli isolates of food-producing animals,” Scientific reports, 6(1), pp.1-8.

[0024] Farha, M. A., El-Halfawy, O. M., Gale, R. T., Macnair, C. R., Carfrae, L.A., Zhang, X., Jentsch, N. G., Magolan, J., and Brown, E. D., 2020, “Uncovering the Hidden Antimycotic Potential of Cannabis,” ACS Infect. Dis., 6(3), pp. 338- 346.

[0025] FDA. (2016). " Classification of Wound Dressings Combined with Drugs." Retrieved September 24th 2024, from https: / / www.fda.gov / media / 100442 / download.

[0026] Finley, P. J., Norton, R., Austin, C., Mitchell, A., Zank, S., Durham, P., 2015, “Unprecedented silver resistance in clinically isolated Enterofungiceae: major implications for burn and wound management,” Antimicrob Agents Chemother, 59(8), pp. 4734-4741.

[0027] Franci, G., Falanga, A., Galdiero, S., Palomba, L., Rai, M., Morelli, G., and Galdiero, M., 2015, “Silver Nanoparticles as Potential Antifungal Agents,” Molecules, 20(5), pp. 8856-8874.

[0028] Galloway-Pena, J. R., S. R. Nallapareddy, C. A. Arias, G. M. Eliopoulos & B. E. Murray, (2009) Analysis of clonality and antimycotic resistance among early clinical isolates of Enterococcus faecium in the United States. J Infect Dis 200: 1566-1573.

[0029] Gemmell, C. G., Edwards, D. I., Fraise, A. P., Gould, F. K., Ridgway, G. L., and Warren, R. E., 2006, “Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK,” Journal of Antimicrobial Chemotherapy, 57(4), pp. 589-608.

[0030] Gorka, K., & Kubinski, K. (2024). Antifungal Activity against Human and Plant Mycopathogens, and Green Synthesis of Silver Nanoparticles Exhibiting Such Activity. Applied Sciences, 14(1), 115.

[0031] Gupta, A., Matsui, K., Lo, J. F. and Silver, S., 1999, “Molecular basis for resistance to silver cations in Salmonella,” Nature medicine, 5(2), pp.183-188.

[0032] Hanczvikkel, A., Fiizi, M., Ungvari, E. and Toth, A., 2018, “Transmissible silver resistance readily evolves in high-risk clone isolates of Klebsiella pneumoniae,” Acta microbiologica et immunologica Hungarica, 65(3), pp.387- 403.

[0033] Hidron, A. I., J. R. Edwards, J. Patel, T. C. Horan, D. M. Sievert, D. A.Pollock, S. K. Fridkin, T. National Healthcare Safety Network & F. Participating National Healthcare Safety Network, (2008) NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 29: 996-1011.

[0034] Hosny, A. E. D. M. S., Rasmy, S. A., Aboul-Magd, D. S., Kashef, M. T., El- Bazza, Z. E., 2019, “The increasing threat of silver-resistance in clinical isolates from wounds and burns,” Infect. Drug Resist., 12, pp. 1985-2001.

[0035] Hwang, I. sok, Hwang, J. H., Choi, H., Kim, K. J., and Lee, D. G., 2012, “Synergistic Effects between Silver Nanoparticles and Antimycotics and the Mechanisms Involved,” J. Med. Microbiol., 61(PART12), pp. 1719-1726.

[0036] Iseppi, R., Brighenti, V., Licata, M., Lambertini, A., Sabia, C., Messi, P., Pellati, F., and Benvenuti, S., 2019, “Chemical Characterization and Evaluation of the Antifungal Activity of Essential Oils from Fibre-Type Cannabis Sativa L. (Hemp),” Molecules, 24(12), pp. 7-12.

[0037] Joung, D. K., Kang, O. H., Seo, Y. S., Zhou, T., Lee, Y. S., Han, S. H., Mun, S. H., Kong, R., Song, H. J., Shin, D. W., and Kwon, D. Y., 2016, “Luteolin Potentiates the Effects of Aminoglycoside and p-Lactam Antimycotics against Methicillin-Resistant Staphylococcus Aureus in Vitro,” Exp. Ther. Med., 11(6), pp. 2597-2601.

[0038] Joung, D. K., O. H. Kang, Y. S. Seo, T. Zhou, Y. S. Lee, S. H. Han, S.H. Mun, R. Kong, H. J. Song, D. W. Shin and D. Y. Kwon (2016). " Luteolin potentiates the effects of aminoglycoside and beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus in vitro." Exp Ther Med 11(6):2597-2601.

[0039] Khundkar, R., Malic, C., and Burge, T., 2010, “Use of Acticoat™ Dressings in Burns: What Is the Evidence?,” Burns, 36(6), pp. 751-758.

[0040] Klepser, M. E., E. J. Ernst, R. E. Lewis, M. E. Ernst and M. A. Pfaller (1998). " Influence of test conditions on antifungal time-kill curve results: proposal for standardized methods." Antimicrob Agents Chemother 42(5):1207-1212.

[0041] Kosgodage, U. S., Matewele, P., Awamaria, B., Kraev, I., Warde, P., Mastroianni, G., Nunn, A. V., Guy, G. W., Bell, J. D., Inal, J. M., and Lange, S., 2019, “Cannabidiol Is a Novel Modulator of Fungal Membrane Vesicles,” Front. Cell. Infect. Microbiol., 9(September), pp. 1-13.

[0042] Kumamoto CA (December 2002). " Candida biofilms". Current Opinion in Microbiology. 5 (6): 608-611.

[0043] Lam, T. B. L., Omar, M. I., Fisher, E., Gillies, K., MacLennan, S., 2014, “Types of indwelling urethral catheters for short-term catheterisation in hospitalised adults,” Cochrane Database of Systematic Reviews, (9).

[0044] Lok, C. N., Ho, C. M., Chen, R., Tam, P. K. H., Chiu, J. F., Che, C. M., 2008, “Proteomic identification of the Cus system as a major determinant of constitutive Escherichia coli silver resistance of chromosomal origin,” Journal of proteome research, 7(6), pp. 2351-2356.

[0045] Luo X, Reiter MA, d’Espaux L, Wong J, Denby CM, Lechner A, Zhang Y, Grzybowski AT, Harth S, Lin W, Lee H, Yu C, Shin J, Deng K, Benites VT, Wang G, Baidoo EEK, Chen Y, Dev I, Petzold CJ, Keasling JD. 2019. Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. Nature 567:123-126

[0046] Massani, M. B., Klumpp, J., Widmer, M., Speck, C., Nisple, M., Lehmann, R. and Schuppler, M., 2018, “Chromosomal Sil system contributes to silver resistance in E. coli ATCC 8739,” Biometals, 31(6), pp.1101-1114.

[0047] McHugh, G. L., Moellering, R. C., Hopkins, C. C., Swartz, M. N., 1975, “Salmonella typhimurium resistant to silver nitrate, chloramphenicol, and ampicillin,” Lancet, 305(7901), pp. 235-240.

[0048] Mechoulam, R. & Y. Gaoni, (1965) Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21: 1223-1229.

[0049] Miao V, Coeffet-Le Gal MF, Nguyen K, Brian P, Penn J, Whiting A, Steele J, Kau D, Martin S, Ford R, Gibson T, Bouchard M, Wrigley SK, Baltz RH (March 2006). " Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antimycotics". Chemistry & Biology. 13 (3): 269-76.

[0050] Morales, P., D. P. Hurst & P. H. Reggio, (2017) Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod 103: 103- 131.

[0051] Mukherjee, P. K., D. J. Sheehan, C. A. Hitchcock and M. A. Ghannoum (2005). " Combination treatment of invasive fungal infections." Clin Microbiol Rev 18(1): 163-194.

[0052] Murdoch, D. R., G. R. Corey, B. Hoen, J. M. Miro, V. G. Fowler, Jr., A. S.Bayer, A. W. Karchmer, L. Olaison, P. A. Pappas, P. Moreillon, S. T. Chambers,V. H. Chu, V. Falco, D. J. Holland, P. Jones, J. L. Klein, N. J. Raymond, K. M. Read, M. F. Tripodi, R. Utili, A. Wang, C. W. Woods, C. H. Cabell & I. International Collaboration on Endocarditis-Prospective Cohort Study, (2009) Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med 169: 463-473.

[0053] Mussin Javier, Giusiano Gustavo, 2022, Biogenic silver nanoparticles as antifungal agents, Frontiers in Chemistry, v.10.

[0054] Najafi K, Ganbarov K, Gholizadeh P, Tanomand A, Rezaee MA, Mahmood SS, Asgharzadeh M, Kafil HS. 2019. Oral cavity infection by Enterococcus faecalis: virulence factors and pathogenesis. Reviews in Medical Microbiology 29: OOO Publish Ahead of Print.

[0055] Navarro, G., Varani, K., Reyes-Resina, I., de Medina, V. S., Rivas- Santisteban, R., Callado, C. S. C., Vincenzi, F., Casano, S., Ferreiro-Vera, C., Canela, E. I., Borea, P. A., Nadal, X., and Franco, R., 2018, “Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1-CB2 Heteroreceptor Complexes,” Front. Pharmacol., 9, pp. 1-14.

[0056] Nguyen KT, Kau D, Gu JQ, Brian P, Wrigley SK, Baltz RH, Miao V (September 2006). " A glutamic acid 3-methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus". Molecular Microbiology. 61 (5): 1294-307.

[0057] Nguyen, K. T., He, X., Alexander, D. C., Li, C., Gu, J. Q., Mascio, C., Van Praagh, A., Mortin, L., Chu, M., Silverman, J. A., Brian, P., & Baltz, R. H. (2010). Genetically engineered lipopeptide antimycotics related to A54145 and daptomycin with improved properties. Antimicrobial agents and chemotherapy, 54(4), 1404-1413.

[0058] Odds, F. C. (2003). " Synergy, antagonism, and what the chequerboard puts between them." J Antimicrob Chemother 52(1 ): 1.

[0059] Odds, F. C., Synergy, antagonism, and what the chequerboard puts between them, Journal of Antimicrobial Chemotherapy, (2003) 52, 1.

[0060] PACHER, P., BA'TKAI, S., and KUNOS, G., 2006, “The Endocannabinoid System as an Emerging Target of Pharmacotherapy,” Pharmacol. Rev., 58(1), pp. 389-462.

[0061] Paganelli, Fernanda L et al. “Enterococcus faecium biofilm formation: identification of major autolysin AtlAEfm, associated Acm surface localization, and AtlAEfm-independent extracellular DNA Release.” mBio vol. 4,2 e00154.16 Apr. 2013, doi:10.1128 / mBio.00154-13.

[0062] Pertwee, R. G., 2008, “The Diverse CB 1 and CB 2 Receptor Pharmacology of Three Plant Cannabinoids: A 9-Tetrahydrocannabinol, Cannabidiol and A 9-Tetrahydrocannabivarin,” Br. J. Pharmacol., 153(2), pp.199-215.

[0063] Pfaller, M. A., D. J. Sheehan and J. H. Rex (2004). " Determination of fungicidal activities against yeasts and molds: lessons learned from bactericidal testing and the need for standardization." Clin Microbiol Rev 17(2): 268-280.

[0064] Pinzi, L., Lherbet, C., Baltas, M., Pellati, F., and Rastelli, G., 2019, “In Silico Repositioning of Cannabigerol as a Novel Inhibitor of the Enoyl Acyl Carrier Protein (ACP) Reductase (INHA),” Molecules, 24(14).

[0065] Prematunge, C., C. MacDougall, J. Johnstone, K. Adomako, F. Lam, J.Robertson & G. Garber, (2016) VRE and VSE Bacteremia Outcomes in the Era of Effective VRE Therapy: A Systematic Review and Meta-analysis. Infect Control Hosp Epidemiol 37: 26-35.

[0066] Rai, M., Yadav, A., and Gade, A., 2009, “Silver Nanoparticles as a New Generation of Antimicrobials,” Biotechnol. Adv., 27(1), pp. 76-83.

[0067] Rakholiya, K. D., Kaneria, M. J., and Chanda, S. V., 2013, “Medicinal Plants as Alternative Sources of Therapeutics against Multidrug-Resistant Pathogenic Microorganisms Based on Their Antimicrobial Potential and Synergistic Properties,” Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components, Academic Press, pp. 165-179.

[0068] Ruben Morones-Ramirez, J., Winkler, J. A., Spina, C. S., and Collins, J.J., 2013, “Silver Enhances Antimycotic Activity against Gram-Negative Fungi,” Sci. Transl. Med., 5(190), pp. 1-12.

[0069] Russo, E. B., (2011) Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J Pharmacol 163: 1344- 1364.

[0070] Staehlin, B. M., Gibbons, J. G., Rokas, A., O’Halloran, T. V. and Slot, J. C., 2016, “Evolution of a heavy metal homeostasis / resistance island reflectsincreasing copper stress in enterofungi,” Genome biology and evolution, 8(3), pp. 811-826.

[0071] Stahl, V., and Vasudevan, K., 2020, “Comparison of Efficacy of Cannabinoids versus Commercial Oral Care Products in Reducing Fungal Content from Dental Plaque: A Preliminary Observation,” Cureus, 12(1), pp. 1- 12.

[0072] Storm -Versloot, M. N., Vos, C. G., Ubbink, D. T. and Vermeulen, H., 2010, “Topical silver for preventing wound infection,” Cochrane Database of Systematic Reviews, (3).

[0073] Sutterlin, S., Edquist, P., Sandegren, L., Adler, M., Tangden, T., Drobni, M., Olsen, B. and Melhus, A., 2014, “Silver resistance genes are overrepresented among Escherichia coli isolates with CTX-M production,” Appl. Environ. Microbiol., 80(22), pp.6863-6869.

[0074] T rost and Dogra, (2007) Synthesis of (-)-A9-trans-T etrahydrocannabinol - Stereocontrol via Mo-catalyzed Asymmetric Allylic Alkylation Reaction. Org Lett. 2007 March 1; 9(5): 861-863.

[0075] Turner, C. E. & M. A. Elsohly, (1981) Biological activity of cannabichromene, its homologs and isomers. J Clin Pharmacol 21: 2835-2915.

[0076] Udoh, M., Santiago, M., Devenish, S., McGregor, I. S., and Connor, M., 2019, “Cannabichromene Is a Cannabinoid CB2 Receptor Agonist,” Br. J. Pharmacol., 176(23), pp. 4537-4547.

[0077] Van Klingeren, B. & M. Ten Ham, (1976) Antifungal activity of delta9- tetrahydrocannabinol and cannabidiol. Antonie Van Leeuwenhoek 42: 9-12.

[0078] Vermeulen, H., van Hattem, J. M., Storm -Versloot, M. N., Ubbink, D. T.and Westerbos, S. J., 2007, “Topical silver for treating infected wounds,” Cochrane Database of Systematic Reviews, (1).

[0079] Yoon, J., C. Urban, C. Terzian, N. Mariano and J. J. Rahal (2004). " In vitro double and triple synergistic activities of Polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii." Antimicrob Agents Chemother 48(3): 753-757.

[0080] Yoon, J., Urban, C., et al., (2004) In Vitro Double and Triple Synergistic Activities of Polymyxin B, Imipenem, and Rifampin against Multidrug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother., 48(3), pp. 753-757.

[0081] Yu, V. L., T. P. Felegie, R. B. Yee, A. W. Pasculle and F. H. Taylor (1980). " Synergistic interaction in vitro with use of three antibiotics simultaneously against Pseudomonas maltophilia." J Infect Dis 142(4): 602- 607.

[0082] Yu, V. L., Felegie, T. P., et al., (1980) Synergistic Interaction in Vitro with Use of Three Antimycotics Simultaneously against Pseudomonas maltophilia. J Infect. Dis., 142(4), pp 602-607.

[0083] Zhong et al., (2017) Comparative genomic analysis of the genus Enterococcus. Microbiological Research, Volume 196, March 2017, Pages 95- 105.

Claims

CLAIMS:

1. A medical device, comprising all three of:a cannabigerol (CBG) cannabinoid present in a CBG-amount, a cannabichromene (CBC) cannabinoid present in a CBC-amount, and, a silver-containing substance present in an Ag-amount;wherein the presence in or on the medical device of the CBG in the CBG- amount, the CBC in the CBC-amount and the silver-containing substance in the Ag-amount together provides a positive antimycotic drug-drug interaction between the cannabinoids and the silver-containing substance that inhibits a fungal colonization of the medical device.

2. The medical device of claim 1, wherein the weight ratio of CBC to CBG is from 20:1 to 1:20.

3. The medical device of claim 1, wherein the weight ratio of CBC to CBG is 1:1, 2:1, 1:2, 1:1.5 or 1.5:1, or from 19:1 to 1:19, or 18:1 to 1:18, or 17:1 to 1:17, or 5:1 to 1:8, or 3:1 to 1:5.

4. The medical device of any one of claims 1-3, wherein the weight ratio of combined cannabinoids CBC and CBG to silver-containing substance is from 25:1 to 1:10.

5. The medical device of any one of claims 1-3, wherein the weight ratio of combined cannabinoids CBC and CBG to silver-containing substance is from 6.4:1 to 1:21.3, or6.4:1 to 1:4.8, or 1:6.2 to 1:10.7, or 1:12.3 to 1:21.

36. The medical device of any one of claims 1 -5, wherein the combined weight ratio of cannabinoids CBC and CBG to silver-containing substance is 6.4:1, or from 3.6:1 to 1:4.8, or 1:6.2 to 1:10.

77. The medical device of any one of claims 1-6, wherein the cannabinoids are each present in a formulation in or on the medical device at 0.01 – 5% w / w.

8. The medical device of any one of claims 1-7, wherein the silver-containingsubstance is present in a formulation in or on the medical device at 0.01 – 5% w / w.

9. The medical device of any one of claims 1-8, wherein the cannabinoids and / or the silver-containing substance are dissolved, dispersed, mixed or suspended in or on the medical device.

10. The medical device of any one of claims 1-9, wherein the positive drug-drug interaction between relative amounts of the cannabinoids and the silver- containing substance provides a fractional inhibitory concentration index (FICI) of <1 in an in vitro assay against a test fungal species.

11. The medical device of any one of claims 1-10, wherein the positive drug-drug antimycotic interaction comprises a synergistically effective combined antimycotic activity in an in vitro assay against a test fungal species.

12. The medical device of any one of claims 10 or 11, wherein the test fungal species is: A. fumigatus, C. albicans, Trichocomaceae spp., Saccharomycetaceae spp., Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei, Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp., Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and / or Paracoccidioides spp.

13. The medical device of any one of claims 1-12, wherein the cannabinoid is derived from a plant.

14. The medical device of claim 13, wherein the plant is a Cannabis sativa or Cannabis indica plant.

15. The medical device of any one of claims 1-14, wherein no antimycotic otherthan the cannabinoids and the silver-containing substance is present in or on the device.

16. The medical device of any one of claims 1-15, wherein the device comprises no phytocannabinoid other than the cannabinoids CBG and CBC.

17. The medical device of any one of claims 1-16, wherein the silver-containing substance is one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

18. The medical device of any one of claims 1-17, wherein the fungal colonization comprises a colonization by one or more of: A. fumigatus, C. albicans, Trichocomaceae spp., Saccharomycetaceae spp., Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei, Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp., Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and / or Paracoccidioides spp.

19. The medical device of any one of claims 1-17, wherein the fungal colonization comprises a Candida spp. colonization.

20. The medical device of claim 19, wherein the fungal colonization comprises a Candida albicans colonization.

21. The medical device of any one of claims 1-20, wherein the fungal colonization comprises an Aspergillus spp. colonization.

22. The medical device of claim 21, wherein the fungal colonization comprises anAspergillus fumigatus colonization.

23. The medical device of any one of claims 1-22, wherein the fungal colonization comprises colonization by a plurality of fungi.

24. The medical device of any one of claims 1-23, wherein the fungal colonization comprises colonization by an antimycotic resistant fungi.

25. The medical device of any one of claims 1-24, wherein the cannabinoids are present in amounts that reduce the minimum inhibitory concentration (MIC) of the silver-containing substance.

26. The medical device of any one of claims 1-25, wherein the silver-containing substance is present in an Ag-amount that reduces the minimum inhibitory concentration (MIC) of the cannabinoids.

27. The medical device of any one of claims 1-26, wherein the cannabinoids are present in relative amounts that provide at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the silver-containing substance.

28. The medical device of any one of claims 1 to 27, wherein the silver-containing substance is present in a relative Ag-amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of one or both of the cannabinoids.

29. The medical device of any one of claims 1 to 28, wherein the formulation comprises more than one silver-containing substance.

30. The medical device of any one of claims 1-29, wherein the medical device is a wound dressing.

31. The medical device of claim 30, wherein the wound dressing is an absorbentsolid wound dressing.

32. The medical device of claim 31, wherein the absorbent solid wound dressing is an absorbent solid foam wound dressing.

33. The medical device of any one of claims 1 to 29, wherein the medical device is provided in or coating a supporting matrix.

34. The medical device of claim 33, wherein the supporting matrix comprises a gel, a hydrogel, a cream, an ointment, a liquid wound wash, a soap, a lotion, a paste, a film, a polymer or a ceramic.

35. The medical device of claim 33 or 34, wherein the supporting matrix is in the form of a wound dressing, a biomedical implant, a periodontal or endodontal device, an endotracheal tube, a surgical mask, cotton fibers, synthetic fibers, a component of an invasive medical device, a catheter or a catheter coating.

36. The medical device of any one of claims 33 to 35, wherein the medical device comprises a hydrogel formulation that is a dried film.

37. The medical device of claim 36, wherein the dried film is in the form of, or is for use as, a wound dressing.

38. The medical device of claim 36 or 37, wherein the hydrogel material is poly vinyl alcohol.

39. The medical device of ay one of claims 36 to 38, wherein the hydrogel formulation coats a catheter.

40. The medical device of claim 39, where the catheter is a urethral catheter.

41. The medical device of any one of claims 33 to 40, wherein the matrix comprises more than one silver-containing substance and the releasability of the differentsilver-containing substances from the matrix is different.

42. The medical device of claim 41, wherein a first silver-containing substance is formulated in the matrix for sustained release, and a second silver-containing substance is formulated in the matrix for quick release.

43. The medical device of any one of claims 33 to 40, wherein the matrix comprises an additional substance, and the releasability from the matrix of the additional substance is different from the releasability of the silver-containing substance.

44. The medical device of claim 43, wherein the additional substance is an additional antimycotic.

45. Use of the medical device of any one of claims 1 to 44, for prophylactically treating or preventing a fungal infection in a subject in need thereof.

46. A method of inhibiting fungal infection of a wound, comprising applying to the wound the medical device of any one of claims 1 to 44.

47. A method of treating or preventing a fungal infection in a subject in need thereof, comprising administering to the subject an effective amount of a formulation comprising:a cannabigerol (CBG) cannabinoid in a CBG-amount,a cannabichromene (CBC) cannabinoid in a CBC-amount, and, a silver-containing medicament in an Ag-amount;wherein the treatment with the CBG in the CBG-amount, the CBC in the CBC-amount and the silver-containing medicament in the Ag-amount together provides a positive antimycotic drug-drug interaction between the cannabinoids and the silver-containing medicament that inhibits fungal growth.

48. The method of claim 47, wherein the weight ratio of CBC to CBG is from 20:1 to 1:20.

49. The method of claim 47, wherein the weight ratio of CBC to CBG is 1:1, 2:1,1:2, 1:1.5 or 1.5:1, or from 19:1 to 1:19, or 18:1 to 1:18, or 17:1 to 1:17, or 5:1 to 1:8, or 3:1 to 1:5.

50. The method of any one of claims 47-49, wherein the weight ratio of combined cannabinoids CBC and CBG to silver-containing substance is from 25:1 to 1:10.

51. The medical device of any one of claims 47-49, wherein the weight ratio of combined cannabinoids CBC and CBG to silver-containing substance is from 6.4:1 to 1:21.3, or6.4:1 to 1:4.8, or 1:6.2 to 1:10.7, or 1:12.3 to 1:21.

352. The method of any one of claims 47-51, wherein the positive drug-drug interaction between the cannabinoids and the silver-containing medicament provides a fractional inhibitory concentration index of the formulation of <1 in an in vitro assay against a test fungal species.

53. The method of any one of claims 47-51, wherein the positive drug-drug antimycotic interaction comprises a synergistically effective combined antimycotic activity in an in vitro assay against a test fungal species.

54. The method of claim 52 or 53, wherein the test fungal species is: A. fumigatus, C. albicans, Trichocomaceae spp., Saccharomycetaceae spp., Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei, Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp., Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and / or Paracoccidioides spp.

55. The method of any one of claims 47 to 54, wherein the fungal infection comprises infection by one or more of: A. fumigatus, C. albicans, Trichocomaceae spp., Saccharomycetaceae spp., Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei, Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp.,Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and / or Paracoccidioides spp.

56. The method of any one of claims 47 to 54, wherein the fungal infection comprises infection by a Candida spp., optionally by a Candida albicans.

57. The method of any one of claims 47 to 56, wherein the fungal infection comprises infection by a Aspergillus spp., optionally an Aspergillus fumigatus.

58. The method of any one of claims 47 to 57, wherein the fungal infection comprises a biofilm.

59. The method of any one of claims 47 to 58, wherein the treatment is a topical treatment.

60. The method of any one of claims 47 to 59, wherein the fungal infection comprises infection by an antimycotic resistant fungi.

61. The method of any one of claims 47 to 60, wherein the cannabinoids are administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the silver-containing medicament.

62. The method of any one of claims 47 to 61, wherein the silver-containing medicament is administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the cannabinoids.

63. The method of any one of claims 47 to 62, wherein the cannabinoids are administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the silver-containing medicament, and / or decrease the MIC of the silver-containing medicament to below a valuethat corresponds 0.3% by weight of the formulation.

64. The method of any one of claims 47 to 63, wherein the silver-containing medicament is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the cannabinoids.

65. The method of any one of claims 47 to 64, wherein the cannabinoid is derived from a plant.

66. The method of claim 65, wherein the plant is a Cannabis sativa or Cannabis indica plant.

67. The method of any one of claims 47 to 66, wherein no antimycotic other than the cannabinoids and the silver-containing medicament is administered to the subject.

68. The method of any one of claims 47 to 67, wherein the method consists essentially of administering to the subject the effective amounts of the cannabinoids and the silver-containing medicament.

69. The method of any one of claims 47 to 68, wherein no phytocannabinoid other than the cannabinoids are administered to the subject.

70. The method of any one of claims 47 to 69, wherein the silver-containing medicament is one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, asilver zeolite, or silver sulfadiazine.

71. The method of any one of claims 47 to 70, wherein the subject is a mammal.

72. The method of claim 71, wherein the subject is a human patient.

73. The method of any one of claims 47 to 72, wherein the therapeutically effective regimen of the cannabinoids comprises administration of from 0.001 to 5,000 mg per day of the cannabinoids.

74. The method of any one of claims 47 to 73, wherein the therapeutically effective regimen of the silver-containing medicament comprises administration of from 0.001 to 10,000 mg per day elemental silver of the silver-containing medicament.

75. The method of any one of claims 47 to 74, wherein the cannabinoids and the silver-containing medicament are co-administered.

76. The method of any one of claims 47 to 75, wherein the cannabinoids and the silver-containing medicament are administered sequentially, in any order.

77. An antimycotic formulation, comprising:cannabigerol (CBG),cannabichromene (CBC); and,a silver-containing medicament;wherein the cannabinoids and the silver-containing medicament are each present in an amount, and the combination of the amounts provides a positive drug-drug interaction between the cannabinoids and the silver- containing medicament against a fungal species.

78. The antimycotic formulation of claim 77, wherein the weight ratio of CBC to CBG is from 20:1 to 1:20.

79. The antimycotic formulation of claim 77, wherein the weight ratio of CBC to CBG is 1:1, 2:1, 1:2, 1:1.5 or 1.5:1, or from 19:1 to 1:19, or 18:1 to 1:18, or 17:1 to 1:17, or 5:1 to 1:8, or 3:1 to 1:5.

80. The antimycotic formulation of any one of claims 77-79, wherein the weight ratio of combined cannabinoids CBC and CBG to silver-containing substance is from 25:1 to 1:10.

81. The antimycotic formulation of any one of claims 77-79, wherein the weight ratio of combined cannabinoids CBC and CBG to silver-containing substance is from 6.4:1 to 1:21.3, or 6.4:1 to 1:4.8, or 1:6.2 to 1:10.7, or 1:12.3 to 1:21.

382. The antimycotic formulation of any one of claims 77-81, wherein the combined weight ratio of cannabinoids CBC and CBG to silver-containing substance is 6.4:1, or from 3.6:1 to 1:4.8, or 1:6.2 to 1:10.

783. The antimycotic formulation of any one of claims 77-82, wherein the cannabinoids are present in the formulation at 0.01 – 5% w / w.

84. The antimycotic formulation of any one of claims 77-83, wherein the silver- containing medicament is present in the formulation at 0.01 – 5% w / w.

85. The antimycotic formulation of any one of claims 77 to 84, wherein the cannabinoids and / or the silver-containing medicament are dissolved, dispersed, mixed or suspended in the formulation with a pharmaceutically acceptable carrier.

86. The antimycotic formulation of any one of claims 77 to 85, wherein the positive drug-drug interaction between the cannabinoids and the silver-containing medicament is a positive antimycotic drug-drug interaction that enhances the antimycotic effect of the cannabinoid and / or the silver-containing medicamentin an in vitro assay against a test fungal species.

87. The antimycotic formulation of any one of claims 77 to 86, wherein the positive drug-drug antimycotic interaction comprises a synergistically effective combined antimycotic activity in an in vitro assay against a test fungal species.

88. The antimycotic formulation of claim 86 or 87, wherein the test fungal species is: A. fumigatus, C. albicans, Trichocomaceae spp., Saccharomycetaceae spp., Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei, Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp., Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and / or Paracoccidioides spp.

89. The antimycotic formulation of any one of claims 77 to 88, wherein the cannabinoids are derived from a plant.

90. The antimycotic formulation of claim 89, wherein the plant is a Cannabis sativa or Cannabis indica plant.

91. The antimycotic formulation of any one of claims 77 to 90, wherein no antimycotic other than the cannabinoids and the silver-containing medicament is present in the formulation.

92. The antimycotic formulation of any one of claims 77 to 91, wherein the formulation consists essentially of the cannabinoids and the silver-containing medicament as active ingredients.

93. The antimycotic formulation of any one of claims 77 to 92, wherein the formulation comprises no phytocannabinoid other than the cannabinoids.

94. The antimycotic formulation of any one of claims 77 to 93, wherein the silvercontaining medicament is one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

95. The antimycotic formulation of any one of claims 77 to 94, wherein the fungal infection comprises infection by one or more of: A. fumigatus, C. albicans, Trichocomaceae spp., Saccharomycetaceae spp., Candida glabrata (Nakaseomyces glabrata), Candida tropicalis, Candida parapsilosis, Candida auris and Candida krusei, Cryptococcus neoformans, Candida auris, Histoplasma spp., Eumycetoma causative agents, Mucorales, Fusarium spp., Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and / or Paracoccidioides spp.

96. The antimycotic formulation of any one of claims 77 to 95, wherein the fungal infection comprises infection by a Aspergillus spp. or a Candida spp.

97. The antimycotic formulation of any one of claims 77 to 96, wherein the fungal infection comprises a biofilm.

98. The antimycotic formulation of any one of claims 77 to 97, wherein the fungal infection comprises infection by a Candida albicans.

99. The antimycotic formulation of any one of claims 77 to 98, wherein the fungal infection comprises infection by an Aspergillus fumigatus.

100. The antimycotic formulation of any one of claims 77 to 99, wherein the fungal infection comprises infection by an antimycotic resistant fungi.

101. The antimycotic formulation of any one of claims 77 to 100, wherein the cannabinoids are administered in a regimen that reduces the minimuminhibitory concentration (MIC) of the silver-containing medicament.

102. The antimycotic formulation of any one of claims 77 to 101, wherein the silver- containing medicament is administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the cannabinoids.

103. The antimycotic formulation of any one of claims 77 to 102, wherein the cannabinoids are present in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the silver-containing medicament, and / or decreases the MIC of the silver-containing substance to below a value that corresponds to 0.3% by weight of the formulation.

104. The antimycotic formulation of any one of claims 77 to 103, wherein the silver- containing medicament is present in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the cannabinoids.

105. The antimycotic formulation of any one of claims 77 to 104, wherein the formulation comprises more than one silver-containing medicament.

106. The antimycotic formulation of any one of claims 77 to 105, wherein the antimycotic formulation is provided in or coating a supporting matrix.

107. The antimycotic formulation of claim 106, wherein the supporting matrix comprises a gel, a hydrogel, a cream, an ointment, a liquid wound wash, a soap, a lotion, a paste, a film, a polymer or a ceramic.

108. The antimycotic formulation of claim 106 or 107, wherein the supporting matrix is in the form of a wound dressing, a biomedical implant, a periodontal or endodontal device, an endotracheal tube, a surgical mask, cotton fibers, synthetic fibers, a component of an invasive medical device, a catheter or acatheter coating.

109. The antimycotic formulation of any one of claims 106-108, wherein the antimycotic formulation comprises a hydrogel formulation that is a dried film.

110. The antimycotic formulation of claim 109, wherein the dried film is in the form of, or is for use as, a wound dressing.

111. The antimycotic formulation of claim 109 or 110, wherein the hydrogel material is poly vinyl alcohol.

112. The antimycotic formulation of any one of claims 109 to 111, wherein the hydrogel formulation coats a catheter.

113. The antimycotic formulation of claim 112, where the catheter is a urethral catheter.

114. The antimycotic formulation of any one of claims 106 to 113, wherein the matrix comprises more than one silver-containing medicament and the releasability of the different silver-containing medicaments from the matrix is different.

115. The antimycotic formulation of claim 114, wherein a first silver-containing medicament is formulated in the matrix for sustained release, and a second silver-containing medicament is formulated in the matrix for quick release.

116. The antimycotic formulation of any one of claims 106 to 113, wherein the matrix comprises an additional medicament, and the releasability from the matrix of the additional medicament is different from the releasability of the silver- containing medicament.

117. The antimycotic formulation of claim 116, wherein the additional medicament isan additional antimycotic.

118. Use of the antimycotic formulation of any one of claims 77 to 117, for treating or preventing a fungal infection in a subject in need thereof.

Images