Compositions and methods of their use

Abstract

Provided are compositions for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA). Uses of the compositions, alone or in combination with certain other agents, are also disclosed.

Description

[0001]Docket 2217701P2WO-O 1 Compositions and Methods of Their Use Background Bacterial resistance to antibiotics is an increasingly pervasive problem. Methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic resistant (AR) bacteria pose threats to human health in hospitals and elsewhere. S. aureus is a gram-positive cocci-shaped bacterium that commonly colonizes human epithelia. While S. aureus is not naturally pathogenic on epithelial surfaces, infections can occur in these areas and range from pimples and impetigo to pneumonia and meningitis (Yarwood JM et al., “Quorum sensing in Staphylococcus infections”, J. Clin. Invest. 112:1620-1625 (2003)). Pathogenicity can develop through the infection of S. aureus in the bloodstream, and these infections are of great medical relevance due to their prevalence and virulence. Infections caused by antibiotic-resistant strains of S. aureus have reached epidemic proportions globally (Grundmann et al., “Emergence and resurgence of methicillin-resistant Staphylococcus aureus as a public-health threat”, Lancet, Sep 2; 368(9538):874-85 (2006)). All implanted medical devices are susceptible to colonization by staphylococci, and staphylococcal biofilm-associated infections have been associated with devices ranging from implanted catheters to prosthetic heart valves, cardiac pacemakers, contact lenses, cerebrospinal fluid shunts, joint replacements and intravascular lines (Donlan et al., “Biofilms: survival mechanisms of clinically relevant microorganisms”, Clin. Microbiol. Rev.15:167–193 (2002)). Damaged host tissue is also a risk factor for developing biofilm-associated infection. S. epidermidis and S. aureus, which are part of the normal skin flora, are opportunistic pathogens that can cause deep-seated skin infections, for example in burn or post-operative wounds (Hammond et al., “An in vitro biofilm model to examine the effect of antibiotic ointments on biofilms produced by burn wound bacterial isolates”, Burns 37:312–321 (2011)). They are also known to form biofilms on damaged heart valves, leading to the development of life-threatening infective endocarditis (Claret et al., “The flagellar sigma factor FliA regulates adhesion and invasion of Crohn disease-associated Escherichia coli via a cyclic dimeric GMP-dependent pathway”, J. Biol. Chem.282:33275–33283 (2007)). Brief Description There is provided, in accordance with an embodiment of the invention, a composition comprising a mixture of (a) deTHC mix (discussed below), (b) CBDA, (c) erythromycin, and (d) at least one of BCP and CBC, which combination is substantially free of THC, wherein the concentration of CBD in the deTHC mix is not more than 1 wt.%, and wherein the only CBD and the only CBG in the composition comes from the deTHC mix. In some embodiments, the concentration of CBG in the composition is less than 0.25 wt.%. In some embodiments, the concentration of CBD in the composition is less than 0.25 wt.%. In some embodiments, the total concentration of cannibinoids other than CBDA and CBC in the composition is less than 30 wt.%. In some embodiments, the composition comprises a mixture of deTHC mix, CBDA, erythromycin, and BCP. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is not more than 10:1. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is in the range of 1:3 to 3:1. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is in the range of 1.1:1 to 1:1.1. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the Docket 2217701P2WO-O 2 others of deTHC mix, CBDA, erythromycin, and BCP is 1:1. In some embodiments, the also comprises CBC. In some embodiments, the total concentration of deTHC mix, CBDA, erythromycin, and BCP taken together in the composition is at least 2.5 microgram / ml composition. In some embodiments, the total concentration of deTHC mix, CBDA, erythromycin, and BCP taken together in the composition is at least 2.5 microgram / g composition. In some embodiments, the composition comprises a mixture of deTHC mix, CBDA, erythromycin, and CBC. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is not more than 10:1. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is in the range of 1:3 to 3:1. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is in the range of 1.1:1 to 1:1.1. In some embodiments, the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is 1:1. In some embodiments, the composition also comprises BCP. In some embodiments, the total concentration of deTHC mix, CBDA, erythromycin, and CBC taken together in the composition is at least 2.5 microgram / ml composition. In some embodiments, the total concentration of deTHC mix, CBDA, erythromycin, and CBC taken together in the composition is at least 2.5 microgram / g composition. In some embodiments, the composition is free of compounds that activate both the CB1receptor and the CB2 receptor, viz. the composition is not psychotropic. In some embodiments, the composition also comprises at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition is in the form of a tablet or caplet. In some embodiments, the composition is in the form of a powder. In some embodiments, the composition is in the form of a liquid. In some embodiments, the composition is in the form of a paste. In some embodiments, the composition is in the form of a lozenge. In some embodiments, the composition is in the form of a gelcap. In some embodiments, the composition is contained in a capsule. In some embodiments, the liquid is formulated as an oral rinse. In some embodiments, the liquid is formulated for aerosolization or nebulization for use for oral or nasal inhalation. In some embodiments, the composition is the form of a suppository. There is also provided, in accordance with an embodiment of the invention, a method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA), comprising contacting MRSA with a composition as described herein, in an amount and for a time efficacious to control such growth. In some embodiments, the MRSA is in a biofilm. In some embodiments, the MRSA is not in a biofilm. There is also provided, in accordance with an embodiment of the invention, a method of reducing the likelihood of infection by Staphylococcus aureus (MRSA) in a patient, or of reducing the severity of an MRSA infection in a patient, comprising administering to the patient a pharmaceutical composition as described herein. There is also provided, in accordance with an embodiment of the invention, a method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA) in a medium, comprising contacting said medium with a composition as described herein in an amount and for a time efficacious to control such growth. There is also provided, in accordance with an embodiment of the invention, a method for inhibiting the formation of a biofilm containing methicillin-resistant Staphylococcus aureus (MRSA) Docket 2217701P2WO-O 3 on a surface, comprising contacting said surface or a fluid which contacts said surface with a composition as described herein in an amount and for a time efficacious to inhibit such growth. There is also provided, in accordance with an embodiment of the invention, a composition as described herein for use as a control agent for controlling the growth of MRSA. There is also provided, in accordance with an embodiment of the invention, a composition as described herein for use as a medicine for controlling MRSA growth in a patient. Definitions: BCP: (-)-beta-caryophyllene, CAS registry number 118-65-0 CBD: (-)-trans-Cannabidiol, CAS registry number 13956-29-1 CBDA: cannabidiolic acid, CAS registry number 1244-58-2 CBG: Cannabigerol, CAS registry number 25654-31-3 CBGA: Cannabigerolic acid, CAS registry number 25555-57-1 CBC: Cannabichromene, CAS registry number 20675-51-8 CBCA: Cannabichromenic acid, CAS registry number 185505-15-1 CBN: cannabinol, CAS registry number 521-35-7 CBNA: cannabinolic acid, CAS registry number 2808-39-1 THC: (−)-trans-Δ9-Tetrahydrocannabinol, CAS registry number 1972-08-3 THCA: Tetrahydrocannabinolic acid (with the -COOH group at either the 2- or the 4-position, viz. ortho or para to the hydroxy group), CAS registry number 23978-85-0 or 23978-84-9 THCV: Tetrahydrocannabivarin, CAS registry number 31262-37-0 THCVA: Tetrahydrocannabivarinic acid, CAS registry number 39986-26-0 CBDV: Cannabidivarin, CAS registry number 24274-48-4 CBDVA: Cannabidivarinic acid, CAS registry number 31932-13-5 deTHC mix: a mixture of cannibinoids prepared as described below, which contains principally CBDVA, CBDV, CBDA, CBGA, CBG, CBD, THCV, THCVA, THCA, CBN, CBNA, CBC, CBCA and is free of THC CB1 receptor: cannabinoid receptor type 1 CB2receptor: cannabinoid receptor type 2 Pharmaceutical Compositions Compositions in accordance with embodiments of the invention include pharmaceutical compositions, which can be administered to a patient to reduce the likelihood of infection by MRSA, or to reduce the severity of an MRSA infection. Such pharmaceutical compositions will thus Docket 2217701P2WO-O 4 comprise, in addition to deTHC mix, CBDA, erythromycin, and at least one of BCP and CBC, one or more pharmaceutically acceptable carriers or excipients. The carrier(s) or excipients must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations are discussed more extensively, inter alia, in Remington: The Science and Practice of Pharmacy, 23rdEdition, Academic Press an imprint of Elsevier, 2021, and pages 359-380, 381-393, and 633-643 therein are incorporated herein by reference. Pharmaceutical compositions in accordance with embodiments of the invention may also be formulated as suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association with deTHC mix, CBDA, erythromycin, and at least one of BCP and CBC (“active ingredients”) the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredients may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi- dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or Docket 2217701P2WO-O 5 tragacanth, and pastilles comprising the active ingredients in a basis such as gelatin and glycerin or sucrose and acacia. Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Liquid formulations for use as a mouthwash may also contain, for example, other anti-bacterial agents (such as cetyl pyridinium chloride, chlorhexidine, saline, menthol, thymol, clove, eucalyptus oil, cinnamon oil, methyl salicylate), humectants (such as glycerin, sorbitol, and polyethylene glycols), surfactants (such as sodium lauryl sulphate), fluoride, alcohol, coloring agents, and / or sweetening agents. Non-Pharmaceutical Formulations Compositions in accordance with embodiments of the invention may be formulated for application to surfaces that may be infected with or come into contact with MRSA, including biotic and abiotic surfaces such as human epithelium, endothelium, skin, teeth, and implanted medical devices. In cases in which the compositions are to be used in a human or animal body, they should be formulated so as to be compatible for such use, e.g. as pharmaceutical formulations. In situations in which the compositions will not be used in a human or animal body or introduced thereto, they may be formulated to contain ingredients that are not compatible with the body. Experimental The mixture referred to herein as “deTHC mix” was prepared by HPLC, by fractionation of a partially purified sample of Cannabis sativa inflorescence macerated in methanol for 48 hours, filtered and evaporated to dryness. A Dionex Ultimate 3000 HPLC system and a Phenomenex C-18 (4.6 x 250) Luna column were used for the fractionation. The sample was dissolved in methanol and injected at a flow rate of 1 ml / min. The final conditions used for analytic HPLC were as follow: Time Solvent A Solvent B 0.1% formic acid in water 0.1% formic acid in acetonitrile 0 50% 50% 1 min 50% 50% 10 min 20% 80% 20 min 5% 95% 30 min 5% 95% The temperature of the column was 50°C, and detection was carried out at 210 nm. Fractions containing cannabinoids were collected and pooled, except that a reference standard was used to determine the retention time for THC, so that no THC was collected in these fractions. The principal cannabinoids obtained were thus CBDVA, CBDV, CBDA, CBGA, CBG, CBD, THCV, THCVA, THCA, CBN, CBNA, CBC, and CBCA, none of which bind the CB1 or CB2 receptors, which are the receptors to which THC binds and give THC its psychotropic properties. Docket 2217701P2WO-O 6 The efficacy of the compositions disclosed herein against growth of methicillin-resistant Staphylococcus aureus (MRSA) and biofilm formation by MRSA were demonstrated as follows. Materials Erythromycin was purchased from a commercial supplier. CBC, CBDA, and BCP were either purchased from commercial suppliers or obtained via HPLC from alcoholic extracts from the inflorescences of Cannabis sativa. The material referred to as deTHC was also obtained via HPLC from alcoholic extracts from the leaves of Cannabis sativa, in which the fractions containing THC were discarded or kept separate from the fractions containing cannabinoids, as described above. Those remaining cannabinoid fractions were then combined, and concentrated by removal of solvent until dryness. Methods Inhibition of bacterial growth: Dilutions of compounds in TSB (tryptic soy broth) were prepared in a polystyrene flat bottomed 96-well microplate. Wells with no compounds and with bacteria served as positive controls. Wells with no bacteria and with compounds served as blanks. An equal volume (100 μl) of the bacterial suspension at optical density (OD)600= 0.01 was added to each well. After a 24-h incubation at 37°C under aerobic conditions, growth was monitored by recording the OD at 600 nm using a Tecan plate reader Spectrophotometer. Each assay was performed in triplicate. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of compound(s) that resulted in at least 90% (MIC90) inhibition of the bacterial growth compared with that in the untreated controls. Inhibition of biofilm formation: each assay was performed as described above for inhibition of bacterial growth, except that the bacterial medium, TSB, was supplemented with glucose 1%. After incubation for 24 h, spent media and free-floating bacteria were removed by aspiration and the wells were washed carefully three times with doubly distilled water (DDW), prior to quantification of biofilm by crystal violet staining. The minimum biofilm inhibition concentration (MBIC) was defined as the lowest concentration of compound(s) that resulted in at least 90% (MBIC90) inhibition of the formation of biofilms compared with that in the untreated controls. Agents tested individually were the cannabinoids CTC (a mixture of CBG, THCA and CBDVA), deTHC mix (see below), CBDA, CBC, the terpenoid BCP, and the antibiotics erythromycin, gentamicin and vancomycin. Different combinations of agents were also tested on MRSA growth and biofilm formation as described above. In the combinations, each agent was present in the same concentration by weight, either 5 micrograms / ml each or 2.5 micrograms / ml each, for a total concentration of the four components of either 20 micrograms / ml or 10 micrograms / ml, except that for CTC the amount was 3 micrograms of CBG, THCA and CBDVA. Crystal violet test: 0.02% crystal violet was added to wells and left in each well for 45 min, which then was washed twice with DDW to remove unbound dye. After adding 200 μl of 30% acetic acid into each well, the plate was shaken for 10 min to release the dye, and the biofilm was quantified by measuring the absorbance at 595 nm using a Tecan plate reader Spectrophotometer. Each assay was performed in triplicate. Docket 2217701P2WO-O 7 Results Table 1 shows the results expressed in micrograms / ml (μl / ml) for inhibition of bacterial growth (MIC90) for deTHC mix, CBC, CBDV, BCP, and erythromycin individually, as well as for each of the following combinations: (a) deTHC mix + BCP + CBC + erythromycin; (b) deTHC mix + BCP + CBDA + erythromycin; (c) deTHC mix + CBDA + CBC + erythromycin. Table 2 shows the results expressed in μl / ml for inhibition of biofilm growth (MBIC90) for these same individual materials and combinations. It will be noted that in these combinations, no cannabinoids or terpenoids (e.g. sesquiterpenes, diterpenes, triterpenes) were present, apart from those listed or that were present in deTHC mix. TABLE 1 AGENT MIC90AGENT MIC90AGENT MIC90deTHC mix 6.25 deTHC mix 6.25 deTHC mix 6.25 BCP >100 BCP >100 -- CBC 25 -- CBC 25 -- CBDA 6.25 CBDA 6.25 erythromycin >100 Erythromycin >100 Erythromycin >100 Combination: conc. 1.25, Combination: 0.625, Combination: 0.625, of each of deTHC 1.25, conc. of each of 0.625, conc. of each of 0.625, mix, BCP, CBC, 1.25, deTHC mix, BCP, 0.625, deTHC mix, CBC, 0.625, erythromycin (total 1.25 CBDA, 0.625 CBDA 0.625 conc.) (5) erythromycin (2.5) erythromycin (2.5) (total conc.) (total conc.) TABLE 2 AGENT MBIC90AGENT MBIC90AGENT MBIC90deTHC mix 6.25 deTHC mix 6.25 deTHC mix 6.25 BCP 100 BCP 100 -- CBC 25 -- CBC 25 -- CBDA 6.25 CBDA 6.25 erythromycin 100 Erythromycin 100 Erythromycin 100 Combination: conc. 1.25, Combination: 0.625, Combination: 0.625, of each of deTHC 1.25, conc. of each of 0.625, conc. of each of 0.625, mix, BCP, CBC, 1.25, deTHC mix, BCP, 0.625, deTHC mix, CBC, 0.625, erythromycin (total 1.25 CBDA, 0.625 CBDA 0.625 conc.) (5) erythromycin (2.5) erythromycin (2.5) (total conc.) (total conc.) The combinations of deTHC mix + CBDA + erythromycin + BCP and deTHC mix + CBDA + erythromycin + CBC thus show significant synergistic effects on both bacterial growth and biofilm formation. Without wishing to be bound by theory, it appears that since inhibitory growth activity was similar to anti-biofilm effect, these combinations of compounds prevent biofilm formation due to their bacteriostatic effect. The combinations may thus be suitable for controlling MRSA growth and associated infections, with reduced risk of adverse effects as well as lower cost as compared to use of each agent alone.

Claims

Docket 2217701P2WO-O 8 CLAIMS 1. A composition comprising a mixture of (a) deTHC mix, (b) CBDA, (c) erythromycin, and (d) at least one of BCP and CBC, which combination is substantially free of THC, wherein the concentration of CBD in the deTHC mix is not more than 1 wt.%, and wherein the only CBD and the only CBG in the composition comes from the deTHC mix.

2. The composition of claim 1, wherein the concentration of CBG in the composition is less than 0.25 wt.%.

3. The combination of claim 1 or claim 2, wherein the concentration of CBD in the composition is less than 0.25 wt.%.

4. The composition of any one of claims 1 to 3, wherein the total concentration of cannibinoids other than CBDA and CBC in the composition is less than 30 wt.%.

5. The composition of any one of claims 1 to 4, wherein the composition comprises a mixture of deTHC mix, CBDA, erythromycin, and BCP.

6. The composition of claim 5, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is not more than 10:

1.

7. The composition of claim 6, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is in the range of 1:3 to 3:

1.

8. The composition of claim 7, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is in the range of 1.1:1 to 1:1.

1.

9. The composition of claim 8, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and BCP to the others of deTHC mix, CBDA, erythromycin, and BCP is 1:

1.

10. The composition of any one of claims 5-9, which also comprises CBC.

11. The composition of any one of claims 5-10, wherein the total concentration of deTHC mix, CBDA, erythromycin, and BCP taken together in the composition is at least 2.5 microgram / ml composition.

12. The composition of any one of claims 5-10, wherein the total concentration of deTHC mix, CBDA, erythromycin, and BCP taken together in the composition is at least 2.5 microgram / g composition.

13. The composition of any one of claims 1 to 4, wherein the composition comprises a mixture of deTHC mix, CBDA, erythromycin, and CBC.

14. The composition of claim 13, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is not more than 10:

1.

15. The composition of claim 14, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is in the range of 1:3 to 3:1.Docket 2217701P2WO-O 9 16. The composition of claim 15, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is in the range of 1.1:1 to 1:1.

1.

17. The composition of claim 16, wherein the ratio by weight of each one of deTHC mix, CBDA, erythromycin, and CBC to the others of deTHC mix, CBDA, erythromycin, and CBC is 1:

1.

18. The composition of any one of claims 13-17, which also comprises BCP.

19. The composition of any one of claims 13-18, wherein the total concentration of deTHC mix, CBDA, erythromycin, and CBC taken together in the composition is at least 2.5 microgram / ml composition.

20. The composition of any one of claims 13-18, wherein the total concentration of deTHC mix, CBDA, erythromycin, and CBC taken together in the composition is at least 2.5 microgram / g composition.

21. The composition of any one of claims 1 to 20, wherein the composition does not contain a compound that activates both the CB1 receptor and the CB2 receptor.

22. The composition of any one of claims 1-21, which also comprises at least one pharmaceutically acceptable carrier or excipient.

23. The composition of claim 22 which is in the form of a tablet or caplet.

24. The composition of claim 22 which is in the form of a powder.

25. The composition of claim 22 which is in the form of a liquid.

26. The composition of claim 22 which is in the form of a paste.

27. The composition of claim 22 which is in the form of a lozenge.

28. The composition of claim 22 which is in the form of a gelcap.

29. The composition of claim 22 which is contained in a capsule.

30. The composition of claim 25, wherein the liquid is formulated as an oral rinse.

31. The composition of claim 25, wherein the liquid is formulated for aerosolization or nebulization for use for oral or nasal inhalation.

32. The composition of claim 22 which is the form of a suppository.

33. A method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA), comprising contacting MRSA with a composition according to any one of claims 1-21 in an amount and for a time efficacious to control such growth.

34. The method of claim 33, wherein the MRSA is in a biofilm.

35. The method of claim 33, wherein the MRSA is not in a biofilm.

36. A method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA) in a medium, comprising contacting said medium with a composition according to any one of claims 1-21 in an amount and for a time efficacious to control such growth.Docket 2217701P2WO-O 10 37. A method for inhibiting the formation of a biofilm containing methicillin-resistant Staphylococcus aureus (MRSA) on a surface, comprising contacting said surface or a fluid which contacts said surface with a composition according to any one of claims 1-21 in an amount and for a time efficacious to inhibit such growth.

38. A method of reducing the likelihood of infection by Staphylococcus aureus (MRSA) in a patient, or of reducing the severity of an MRSA infection in a patient, comprising administering to the patient a composition according to any one of claims 22 to 32 39. A composition according to any one of claims 1 to 21 for use as a control agent for controlling the growth of MRSA.

40. A composition according to any one of claims 22 to 32 for use as a medicine for controlling MRSA growth in a patient.