WO2016134363A1 - Compositions comprising benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent - Google Patents

Abstract

The invention relates to compositions and kits comprising benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent, which may be used, for example, to reduce Propionibacterium Acnes (P. Acnes) in mammalian skin (e.g., human skin) during the perioperative period of an invasive procedure; methods comprising administering to the mammal (e.g., a human) in need thereof compositions comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent; and methods of reducing bacteria, such as, for example, P. Acnes, in mammalian skin (e.g., human skin) during the perioperative period of an invasive procedure comprising administering to a mammal (e.g., a human) in need thereof a First Composition comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and administering to the mammal a Second Composition comprising, consisting of, or consisting essentially of at least one antiseptic skin preparation agent.

Description

International PCT Patent Application For:

COMPOSITIONS COMPRISING BENZOYL PEROXIDE OR A DERIVATIVE THEREOF AND AT LEAST ONE ANTISEPTIC SKIN PREPARATION AGENT

By Inventor:

Paul M. Sethi

COMPOSITIONS COMPRISING BENZOYL PEROXIDE OR A DERIVATIVE THEREOF AND AT

LEAST ONE ANTISEPTIC SKIN PREPARATION AGENT

By Inventor: Paul M. Sethi

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. Provisional Patent Application No. 62/118,762, filed February 20, 2015, and U.S. Provisional Patent Application No. 62/183,883, filed June 24, 2015, which are each incorporated herein by reference in their entirety.

BACKGROUND

[0002] Despite the implementation of pre-operative preventive measures, which include skin cleansing with antiseptic skin preparation agents, such as aqueous-based (e.g., povidone-iodine) or alcohol-based (e.g., chlorhexidine-isopropanol) agents, surgical-site infection occurs in 300,000 to 500,000 patients who undergo surgery in the United States each year.¹ For example, Propionibacterium Acnes (P. Acnes) infection is a significant problem following shoulder surgery. Immediately after surgical skin preparation, residual P. Acnes is found on the skin up to 29% of the time, and in 70% of dermal biopsy. These residual bacteria may be a source for infection. Identifying more ideal antiseptic skin preparation agents may help reduce the risk of infection for patients undergoing surgery, including, for example, shoulder surgery, elbow surgery, spinal surgery, and neurosurgery.

[0003] The most common antiseptic skin preparation agents used today include aqueous- or alcohol-based products containing iodophors or chlorhexidine gluconate, such as, for example, aqueous-iodophor (e.g., Betadine®, Scrub Care®), aqueous-chlorhexidine gluconate (e.g., Hibiclens®), alcohol -iodophor (e.g., DuraPrep®, Prevail-FX®), and alcohol-chlorhexidine gluconate (ChloraPrep®).² Aqueous-based iodophors, such as povidone-iodine, contain iodine complexed with a solubilizing agent that allows for the release of free iodine when in solution.² Iodine acts in an antiseptic fashion by destroying microbial proteins and DNA.² Iodophor- containing products enjoy widespread use because of their broad-spectrum antimicrobial properties, efficacy, and safety on nearly all skin surfaces in patients regardless of age.² A second product, aqueous-based chlorhexidine gluconate, works by disrupting bacterial cell membranes.² Chlorhexidine gluconate has more sustained antimicrobial activity and is more resistant to neutralization by blood products than the iodophors.²

[0004] Ethanol and isopropanol are two of the most effective antiseptic skin preparation agents available.² When used alone, alcohol is fast and short acting, has broad-spectrum antimicrobial activity, and is relatively inexpensive.² Alcohol-based solutions that contain chlorhexidine gluconate or iodophors have sustained and durable antimicrobial activity that lasts long after alcohol evaporation.² Studies suggest that these products may have greater efficacy, easier application, improved durability, and a superior cost profile when compared with traditional aqueous-based solutions.² However, there is a need for improved antiseptic skin preparation agents to help reduce the risk of infection for patients undergoing surgery, including, for example, shoulder and upper extremity surgery, elbow surgery, spinal surgery, neck surgery, insertion of a central venous catheter (a central line), pacemaker surgery, and neurosurgery, from infection, including infection by bacteria, such as, for example, P. Acnes. This invention addresses this need.

SUMMARY OF THE INVENTION

[0005] Surprisingly, it was found that the use of benzoyl peroxide (BPO) or a derivative thereof, in addition to at least one antiseptic skin preparation agent, such as, for example, an aqueous- based antiseptic skin preparation agent {e.g., aqueous-iodophor, aqueous-chlorhexidine gluconate) and/or an alcohol -based antiseptic skin preparation agent (e.g., alcohol -iodophor, alcohol-chlorhexidine gluconate), eliminates residual bacteria from the skin, for example, the presence of P. Acnes on the skin during the perioperative period of an invasive procedure, including, for example, shoulder and upper extremity surgery, elbow surgery, spinal surgery, neck surgery, insertion of a central venous catheter (a central line), pacemaker surgery, and neurosurgery, to a greater extent than antiseptic skin preparation agents alone.

[0006] For example, adding BPO to an alcohol-chlorhexidine gluconate antiseptic skin preparation agent reduced the number of positive P. Acnes cultures identified during the perioperative period of surgery. Specifically, fifty patients, undergoing 1^st time primary arthroscopic shoulder surgery, were treated with topical 5% benzoyl peroxide cream starting 48 hours prior to surgery. After standardized skin preparation, which included the application of an alcohol-chlorhexidine gluconate antiseptic skin preparation agent, 13 samples per subject were obtained throughout the surgery. 650 total cultures were obtained. Cultures were held for 14 days. The skin was positive at the initiation of surgery in 6% of cases. Tissue samples were positive in 6% of samples. The skin was positive in 10% of cases at the end of surgery. None of these rates of positive culture were different than the 4% rate observed with a control swab. Thus, it was determined that application of BPO and at least one antiseptic skin preparation agent is an effective way to reduce bacteria, including P. Acnes, found on, within, and/or beneath mammalian skin (e.g., human epidermis, dermis, and/or hypodermis) during the perioperative period of a surgical procedure. This may result in a lower risk for postoperative infection.

[0007] The invention thus relates to compositions and kits comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent, which may be used, for example, to reduce bacteria, such as, for example, P. Acnes on, within, and/or beneath mammalian skin (e.g., human epidermis, dermis, and/or hypodermis) during the perioperative period of an invasive procedure. These compositions and kits may be, for example, antiseptic, cosmetic, dermatological, or pharmaceutical compositions. The invention further relates to methods of reducing bacteria, such as, for example, P. Acnes, on, within, and/or beneath mammalian skin (e.g., human epidermis, dermis, and/or hypodermis) during the perioperative period of an invasive procedure comprising administering to a mammal (e.g., a human) in need thereof compositions comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent. The invention also relates to methods of reducing bacteria, such as P. Acnes, on, within, and/or beneath mammalian skin (e.g., human epidermis, dermis, and/or hypodermis) during the perioperative period of an invasive procedure comprising administering to a mammal (e.g., a human) in need thereof a First Composition comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and administering to said mammal a Second

Composition comprising, consisting of, or consisting essentially of at least one antiseptic skin preparation agent.

[0008] As used herein, "a," "an," "the," "at least one," and "one or more" are used

interchangeably. The term "and/or" means one or all of the listed elements (e.g., an antiseptic skin preparation agent means one or more antiseptic skin preparation agents).

[0009] Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 - 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0010] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

DETAILED DESCRIPTION OF THE INVENTION

[0006] P. Acnes, a gram-positive anaerobic bacillus, resides nonpathogenically in the sebaceous glands associated with hair follicles, but is a significant pathogen in patients undergoing surgical procedures, such as shoulder surgery, elbow surgery, spinal surgery, and neurosurgery.⁵' ⁶' ⁷ Infection following surgical procedures, such as shoulder surgery, has serious impact on patient outcome, costs, and value associated with care. When it is unrecognized or untreated in the case of shoulder surgery, indolent infection with P. Acnes may result in persistent shoulder pain and glenohumeral arthrosis, sometimes many years after the index procedure.²⁵ The diagnosis of P. Acnes infection is challenging, given the slow growth rate and a lack of consensus about how to identify a true infection.²⁵ Numerous methods for reducing surgical site infection (SSI) have been studied, with a particular interest in povidone-iodine and chlorhexidine gluconate as the most ideal skin preparations.⁴' ^u' ¹⁴' ¹⁸' ²³' ²⁴

[0007] Chlorhexidine gluconate combined with isopropyl alcohol (ChloraPrep®) has been suggested to be the most effective surgical skin preparation for shoulder surgery, but this effect is not specific for P. Acnes.¹⁴' ²³' ²⁴ P. Acnes may persist on the skin from 7 to 29% of the time immediately following skin preparation.^{12, 19}' ²⁴ This may increase to 41 to 63% chance of finding this bacteria at the end of the surgical procedure.²⁵ Furthermore, P. Acnes was identified in 70%) of subjects undergoing a dermal biopsy after skin preparation with ChloraPrep®.¹⁴ These residual bacteria may be present because current skin preparations appear to not sufficiently penetrate the dermal layer of skin, where P. Acnes resides in the sebaceous glands.¹⁸ Alternately, P. Acnes may reside in the normal shoulder, or may even be a precursor pathologic organism to developing arthritis.¹⁵

[0008] The high rate of residual bacteria left on the epidermis and dermis both may be the source of infection in susceptible patients, particularly those having procedures with a surgical implant.¹⁸ A more ideal surgical skin preparation to address the residual bacteria and potentially reduce the risk for SSI is, therefore, needed.

[0009] Dermatologically, benzoyl peroxide (BPO) has been an important component of topical therapy for acne vulgaris for more than five decades due to its ability to markedly reduce P. Acnes.³' ⁸' ⁹' ¹⁶' ¹⁷ In one embodiment, the invention disclosed herein used dermatologic principles of reducing P. Acnes as part of the surgical skin preparation.

[0010] The effect that benzoyl peroxide, when used in addition to at least one antiseptic skin preparation agent {e.g., an aqueous- and/or alcohol -based antiseptic skin preparation agent), would have on the presence of P. Acnes cultured at the time of shoulder surgery was evaluated. It was surprisingly discovered that treatment with BPO in conjunction with ChloraPrep® reduced the percent of subjects with positive P. Acnes cultures to a superior extent than treatment with ChloraPrep® alone.

[0011] In one embodiment, the invention provides compositions comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent, which may be used, for example, to reduce bacteria, such as, for example, P. Acnes, in mammalian skin {e.g., human skin) during the perioperative period of an invasive procedure.

[0012] In one embodiment of the composition of the invention, the benzoyl peroxide or a derivative thereof may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the composition. Derivatives of benzoyl peroxide include, but are not limited to, compounds of Formula (I) being independently substituted by one to five substitutions on at least one of the benzene rings, with a substituent selected from Ci-C₆ alkyl, C2-C6 alkenyl, Ci-C₆ alkynyl, and Ci-C₆ cycloalkyl.

[0013] In one embodiment of the composition of the invention, the at least one antiseptic skin preparation agent may be selected from, for example, an aqueous-based antiseptic skin preparation agent, an alcohol-based antiseptic skin preparation agent, or mixtures thereof.

[0014] In another embodiment of the composition of the invention, the aqueous-based antiseptic skin preparation agent may be selected from, for example, an aqueous-iodophor antiseptic skin preparation agent and an aqueous-chlorhexidine antiseptic skin preparation agent. As used herein, "iodophor" means a composition comprising iodine complexes with a solubilizing agent, such as, for example, a surfactant or povidone. The iodophor in the aqueous-iodophor antiseptic skin preparation may be selected from, for example, povidone-iodine. The iodine in the aqueous-iodophor antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%), and most preferably about 0.75 - 5 wt.%>, in each case based on the total weight of the composition. The aqueous-iodophor antiseptic skin preparation agent may be, for example, Betadine® or Scrub Care®. [0015] In one embodiment of the composition of the invention, the chlorhexidine in the aqueous- chlorhexidine antiseptic skin preparation agent may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate. The chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.%, in each case based on the total weight of the composition. The aqueous-chlorhexidine antiseptic skin preparation agent may be, for example, Hibiclens®.

[0016] In another embodiment of the composition of the invention, the alcohol-based antiseptic skin preparation agent may be selected from, for example, an alcohol -iodophor antiseptic skin preparation agent and an alcohol-chlorhexidine antiseptic skin preparation agent. The iodophor in the alcohol -iodophor antiseptic skin preparation may be selected from, for example, povidone- iodine. The iodine in the alcohol-iodophor antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 0.7 - 0.8 wt.%, in each case based on the total weight of the composition. The alcohol-iodophor antiseptic skin preparation agent may be, for example, DuraPrep® or Prevail-FX®.

[0017] In another embodiment of the composition of the invention, the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate. The chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.%, in each case based on the total weight of the composition. The alcohol-chlorhexidine antiseptic skin preparation agent may be, for example, ChloraPrep®.

[0018] In another embodiment of the composition of the invention, the alcohol in the alcohol- iodophor and alcohol-chlorhexidine antiseptic skin preparation agents may be selected from, for example, at least one monohydric alcohol, such as, for example, methanol, ethanol, isopropanol, butanol, and pentanol, at least one polyhydric alcohol, such as, for example, ethylene glycol, propylene glycol, glycerol, erythritol, and xylitol, or mixtures thereof. The alcohol is preferably an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n- butanol, isobutanol, t-butanol, or glycerol, most preferably isopropanol. The alcohol in the alcohol -iodophor and the alcohol-chlorhexidine antiseptic skin preparation agents may be present in the composition of the invention in an amount ranging from, for example, about 50 - 90 wt.%, more preferably about 60 - 80 wt.%, and most preferably about 70 - 75 wt.%, in each case based on the total weight of the composition.

[0019] In another embodiment, the composition of the invention may also include at least one additional active ingredient, such as, for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, and mixtures thereof. Preferably, the at least one additional active ingredient may be selected from an antibiotic, including, without limitation, erythromycin, clindamycin, tetracycline, and cefazoline, preferably clindamycin. The at least one additional active ingredient may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the composition.

[0020] In another embodiment, the compositions of the invention may be formulated together with at least one pharmaceutically acceptable excipient, filler, extender, binder, humectant, disintegrating agent, solution retarder, absorption accelerator, wetting agent, adsorbent, lubricant, buffering agent, carrier, diluent, adjuvant, emollient, emulsifier, wax, solubilizer, electrolyte, hydroxyacid, stabilizer, cationic polymer, film former, thickener, gelling agent, superfattening agent, refattening agent, antimicrobial active compound, biogenic active compound, astringent, deodorizing compound, antioxidant, moisturizer, solvent, colorant, pearlizing agent, fragrance, opacifier, silicone, or mixtures thereof. The compositions of the invention may be prepared by methods known in the pharmaceutical formulation art, for example, see Remington's

Pharmaceutical Sciences, 18^th Ed. (Mack Publishing Company, Easton, PA., 1990), which is incorporated herein by reference. In one embodiment of the invention, the compositions of the invention are present in the form of fluids, gels, foams, sprays, lotions, or creams. In one embodiment, the compositions are formulated on an aqueous or aqueous-alcoholic basis or are present as solutions, emulsions, or dispersions.

[0021] In a preferred embodiment, a composition of the invention comprises, consists of, or consists essentially of benzoyl peroxide, chlorhexidine gluconate, and isopropanol.

[0022] In other embodiments, the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent of the invention may be separately administered, simultaneously or sequentially, for example, during the perioperative period of an invasive procedure. [0023] The term "administered sequentially" refers to ordered and successive administration of a composition of the invention or their components comprised in separate containers. For example, a topical composition of the invention may be applied once, twice, three times a day, or more. The order of addition of the components of the composition may be optional.

[0024] Thus, the invention further provides a kit comprising at least one container comprising, consisting of, or consisting essentially of at least one component of the invention; and instructions for administration of said containers. For example, in one embodiment, the invention provides a kit comprising: a first container comprising, consisting of, or consisting essentially of at least one component of the invention; a second container comprising, consisting of, or consisting essentially of at least one component of the invention; and instructions for administration of said containers. In another embodiment, the invention provides a kit comprising at least one container comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent of the invention. For example, a first container of the kit may comprise, consist of, or consist essentially of benzoyl peroxide or a derivative thereof, and a second container of the kit may comprise, consist of, or consist essentially of at least one antiseptic skin preparation agent of the invention. In a preferred embodiment, a kit of the invention comprises a first container comprising, consisting of, or consisting essentially of benzoyl peroxide and a second container comprising, consisting of, or consisting essentially of chlorhexidine gluconate and isopropanol.

[0025] In another embodiment, a kit of the invention comprises a first container comprising, consisting of, or consisting essentially of benzoyl peroxide and a second container comprising, consisting of, or consisting essentially of an antiseptic where the benzoyl peroxide and antiseptic are formulated as a fluid, gel, foam, spray, lotion, or cream or present on brushes, rollers, swabs, foams (e.g., polyethylene foam) packed fibers, wipes, towel ettes, or as an aerosol and the like. In a further embodiment the antiseptic may be chlorhexidine, chlorhexidine gluconate, or chlorhexidine gluconate, and isopropanol. The benzoyl peroxide and the antiseptic, such as chlorhexidine gluconate, may be used in a kit in accordance with USFDA monographs regarding OTC topical acne products and OTC topical antiseptic drug products.

[0026] As used herein, the term "instructions" when used in the context of a kit includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the kit for its designated use. For example, instructions may indicate administration of a first container on non-consecutive days and for administration of a second container daily. The instructions can, for example, be affixed to or included within a container for the kit.

[0027] In some embodiments, the components of a composition of the invention in the first and second container are the same. In other embodiments, the components of a composition of the invention in the first and second container are different. In a further embodiment, the

components of a composition of the invention may be comprised in multiple, i.e., more than two, containers.

[0028] For ease of storage and administration, compatible components of a composition of the invention may be placed in one container, separated from other components of said composition.

[0029] According to some embodiments, each component of a composition of the invention is contained in a separate container. In another embodiment, all components for administration on a particular day are combined and stored in one container for ease of use and storage. If necessary for stability purposes, the container may be stored frozen and thawed before administration, e.g., by placing in a refrigerator one or two days before administration. [0030] The term "container" as used herein refers to any receptacle or applicator means capable of holding, storing, and/or applying at least one component of a composition of the invention. Such a container may be in any container configuration known to a person skilled in the art, such as, but not limited to, a swab, a pouch, a syringe, an ampoule, a bottle, a jar, a vial, or a box. The containers may be made of any material suitable for the components contained therein and additionally suitable for short and/or long term storage under any kind of temperature. Such material s include, by way of example, inorganic material s, such as Type I glass (including amber colored glass), ceramics, metals (e.g., aluminum, tin, and tin coated tubes), etc., and organic materials such as inert polymers including po!yo!efms (e.g., high density polyethylene), fluorinated polyolefins, and the like. Suitable containers include those that maintain the sterility and integrity of their contents, for example, by providing a barrier to moisture. The preferred container is also one which is compatible with any chosen method of sterilization, including, for example, irradiation. The suitable containers may have an appropriate applicator means, surface, or tip to dispense the compositions of the invention from the container and apply onto mammalian skin, such as, for example, brushes, rollers, swabs, foams (e.g., polyethylene foam) packed fibers, wipes, towelettes, or as an aerosol, and the like. In one embodiment, the containers may be sealed as separate articles or are combined into a single article of manufacture having a barrier between the containers. This barrier can either be removed or destroyed allowing mixing of the components of the composition of the invention in each of the containers at the appropriate time. Such barriers include frangible or crushable barriers or envelopes.

[0031] In some embodiments, the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent are contained in at least two containers in a kit of the invention. In other embodiments, a kit of the invention is composed of a dual chamber container wherein the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent are contained in each one of the chambers. In other embodiments, a kit of the invention is for use in reducing bacteria, such as, for example, P. Acnes, in mammalian skin during the perioperative period of an invasive procedure.

[0032] The kit may also contain in one or more containers any of the additional components described herein, including, for example, at least one additional active ingredient, such as, for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, or mixtures thereof, and/or at least one

pharmaceutically acceptable excipient, filler, extender, binder, humectant, disintegrating agent, solution retarder, absorption accelerator, wetting agent, adsorbent, lubricant, buffering agent, carrier, diluent, adjuvant, emollient, emulsifier, wax, solubilizer, electrolyte, hydroxyacid, stabilizer, cationic polymer, film former, thickener, gelling agent, superfattening agent, refattening agent, antimicrobial active compound, biogenic active compound, astringent, deodorizing compound, antioxidant, moisturizer, solvent, colorant, pearlizing agent, fragrance, opacifier, silicone, or mixtures thereof. These additional components may be in the same or different containers as the one or more containers comprising the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent.

[0033] In another embodiment, the invention provides methods of reducing bacteria, such as, for example, P. Acnes, in mammalian skin {e.g., human skin) during the perioperative period of an invasive procedure comprising administering to a mammal {e.g., a human) in need thereof compositions of the invention described herein. The invasive procedure may be a surgical procedure, such as an arthroscopic surgical procedure or an endoscopic surgical procedure.

Preferably, the invasive procedure is shoulder and upper extremity surgery, elbow surgery, spinal surgery, neck surgery, insertion of a central venous catheter (a central line), pacemaker surgery, and neurosurgery, most preferably shoulder surgery. The compositions of the invention may be administered to the mammal in need thereof before, during, and/or after the invasive procedure.

[0034] In another embodiment, the invention provides methods of reducing bacteria, such as, for example, P. Acnes, in mammalian skin {e.g., human skin) during the perioperative period of an invasive procedure comprising administering to a mammal {e.g., a human) in need thereof a First Composition comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof, and administering to the mammal a Second Composition comprising, consisting of, or consisting essentially of at least one antiseptic skin preparation agent. In one embodiment, the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal before, at the same time, and/or after the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal. In a preferred embodiment, the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof is administered to the mammal before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal. The First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal, for example, at least about 12 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60 hours, and/or at least about 72 hours before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal. Preferably, the First

Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal on at least one or more separate occasions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 separate times) before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal. In one embodiment, the invasive procedure may be a surgical procedure, such as an arthroscopic surgical procedure or an endoscopic surgical procedure.

Preferably, the invasive procedure is shoulder and upper extremity surgery, elbow surgery, spinal surgery, neck surgery, insertion of a central venous catheter (a central line), pacemaker surgery, and neurosurgery, most preferably shoulder surgery.

[0035] In one embodiment, the benzoyl peroxide or a derivative thereof may be present in the First Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the First Composition.

[0036] In one embodiment, the at least one antiseptic skin preparation agent in the Second Composition may be selected from, for example, an aqueous-based antiseptic skin preparation agent, an alcohol-based antiseptic skin preparation agent, or mixtures thereof.

[0037] In another embodiment, the aqueous-based antiseptic skin preparation agent in the Second Composition may be selected from, for example, an aqueous-iodophor antiseptic skin preparation agent and an aqueous-chlorhexidine antiseptic skin preparation agent. In one embodiment, the iodine in the aqueous-iodophor antiseptic skin preparation agent may be present in the Second Composition an amount ranging from, for example, about 0.05% - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 0.75 - 5 wt.%, in each case based on the total weight of the Second Composition. The aqueous-iodophor antiseptic skin preparation agent in the Second Composition may be, for example, Betadine® or Scrub Care®. [0038] In one embodiment, the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent in the Second Composition may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate. The chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent may be present in the Second

Composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.%, in each case based on the total weight of the Second Composition. The aqueous-chlorhexidine antiseptic skin preparation agent in the Second Composition may be, for example, Hibiclens®

[0039] In another embodiment, the at least one alcohol-based antiseptic skin preparation agent in the Second Composition may be selected from, for example, an alcohol -iodophor antiseptic skin preparation agent and an alcohol-chlorhexidine antiseptic skin preparation agent. The iodine in the alcohol -iodophor antiseptic skin preparation agent may be present in the Second Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%), and most preferably about 0.7 - 0.8 wt.%, in each case based on the total weight of the Second Composition. The alcohol -iodophor antiseptic skin preparation agent in the Second Composition may be, for example, DuraPrep® or Prevail-FX®.

[0040] In one embodiment, the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent in the Second Composition may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate. The chlorhexidine may be present in the alcohol-chlorhexidine antiseptic skin preparation agent in the Second Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.% , in each case based on the total weight of the Second Composition. The alcohol-chlorhexidine antiseptic skin preparation agent in the Second Composition may be, for example, ChloraPrep®.

[0041] In one embodiment, the alcohol in the alcohol-iodophor and alcohol-chlorhexidine antiseptic skin preparation agents in the Second Composition may be selected from, for example, at least one monohydric alcohol, such as, for example, methanol, ethanol, isopropanol, butanol, and pentanol, at least one polyhydric alcohol, such as, for example, ethylene glycol, propylene glycol, glycerol, erythntol, and xylitol, or mixtures thereof. The alcohol is preferably an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-butanol, or glycerol, most preferably isopropanol. The alcohol in the alcohol- iodophor and the alcohol-chlorhexidine antiseptic skin preparation agents in the Second

Composition may be present in an amount ranging from, for example, about 50 - 90 wt.%, more preferably about 60 - 80 wt.%, and most preferably about 70 - 75 wt.% , in each case based on the total weight of the Second Composition.

[0042] In another embodiment, the First and/or Second Composition may further comprise at least one additional active ingredient, such as for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, and mixtures thereof. The at least one additional active ingredient may also be optionally administered to said mammal before, during, and/or after the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof and/or the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent are administered to said mammal. Preferably, the at least one additional active ingredient may be selected from an antibiotic, including, without limitation, erythromycin, clindamycin, tetracycline, and cefazoline, preferably clindamycin. The at least one additional active ingredient may be present in the First and/or Second Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the First and/or Second Composition.

[0043] In another embodiment, the present invention further provides a kit comprising one or more containers comprising the Fist Composition of the invention; the Second Composition of the invention; and instructions for administration of said one or more containers.

[0044] In another embodiment, the invention provides methods of treating and/or preventing a dermatological condition, such as, for example, acne, comprising administering to a mammal (e.g., a human) in need thereof (e.g., suffering from, susceptible to, and/or displaying symptoms of a dermatological condition) compositions of the invention described herein. In some embodiments, the compositions of the invention are administered locally to an affected site (e.g., face, neck, back, arms, chest, etc.).

[0045] In another embodiment, the compositions of the invention and methods of treatment of the inventions described herein may be administered to the mammal in need thereof by any route accepted as appropriate by the medical community, and is not limited to any particular route. For example, the invention contemplates routes of delivering or administering that include, but are not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, intradermal, rectal, vaginal,

intraperitoneal, intragastric, topical and/or transdermal (e.g., by lotions, creams, liniments, ointments, powders, gels, drops, deodorants, antiperspirants, sunscreens, foams, balms, waxes, salves, solutions, suspensions, dispersions, water in oil or oil in water emulsions,

microemulsions, pastes, oils, lozenges, boluses, and sprays, and the like), mucosal, intranasal, buccal, enteral, vitreal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; as an oral spray, nasal spray, and/or aerosol, and/or through a portal vein catheter; and/or combinations thereof.

[0046] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.

EXPERIMENTAL

[0047] In the following examples, efforts have been made to ensure accuracy with respect to numbers used, but some experimental error and deviation should be accounted for. The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

[0048] Fifty -two (52) patients indicated for first time arthroscopic shoulder surgery were identified. Inclusion criterion was patients indicated for primary arthroscopic shoulder surgery to participate. Subjects were excluded if they had previous shoulder surgery or if they had taken any antibiotics 2 months prior to surgery.

[0049] All patients consented to participation. Patients were asked to apply the provided 5% BPO gel starting two mornings prior to their surgery. After a wash, rinse, and dry of the area, patients were asked to apply a half dollar size dollop of BPO to the entire shoulder and armpit area. This application would then be repeated at night, the following morning and night, and the morning of surgery for a total of five applications. Patients were asked to record the times and dates of application on a provided data sheet.

[0050] A total of twelve samples were obtained from each subject: eight sterile skin swabs, an aspirated joint fluid, and three tissue samples were collected from fifty (50) patients undergoing shoulder arthroscopy without any previous shoulder surgery. A thirteenth control swab was waived in the air and sent for culture for each subject. Demographic data, VAS pain scale, medical comorbidities, history of cortisone injection, antibiotics used during surgery, and the duration of the surgery were also collected.

[0051] At the time of surgery, patients were given pre-operative antibiotics. Preoperatively two grams of Cefazolin were routinely given, or 900 mg of Clindamycin if cephalosporin allergy was present. At this time, four skin swabs were taken: the anterior deltoid of the surgical arm, the axilla of the surgical arm, the anterior deltoid of the non-surgical arm, and the axilla of the nonsurgical arm. Following this, patients were draped and sanitized by scrubbing the arm, shoulder, and axilla with a scrub brush 3.3% Chloroxylenol Cleansing Solution. The skin was then patted dry with a sterile towel. The surgical site was prepared with three applications of 2%

chlorhexidine gluconate (ChloraPrep®; CareFusion, San Diego, California, USA). This is generally routine for all patients undergoing shoulder surgery. After preparations and draping, the skin of the anterior deltoid and axilla were each swabbed with a skin swab. A cotton swab of the air was taken at this time as a control. Each swab was placed into individual charcoal mediums. [0052] After incision for trochar placement, the glenohumeral joint was aspirated. If no fluid was available, the glenohumeral joint was flushed with five cc's of saline and then collected in a sterile specimen container. Three samples of debrided tissue were collected through a cannula. The first tissue sample was collected from the middle glenohumeral ligament (MGHL). If the patient was having a rotator cuff repair, the second tissue sample came from the rotator interval and the third from the bursa. For a patient undergoing a labrum repair, the second tissue sample was collected from the high rotator interval and the third from the low rotator interval. Each sample was placed into individual specimen containers.

[0053] Prior to skin closure, two final skin swabs of the anterior deltoid and axilla were taken and placed into a charcoal medium. The skin swabs were placed into individual charcoal mediums.

[0054] All samples for each patient were placed into individual transport bags and delivered to the Microbiology Lab within one hour, where they were placed in a fume hood that had been sterilized with 1.4% hydrogen peroxide spray for one minute. Medical technicians following sterile procedure processed all samples. Each sample was plated on a blood agar plate (BAP) to facilitate the growth of any organism, a MacConkey agar plate to select for gram negative rods (MAC), a Colistin and Nalidixic acid plate (CNA) to identify gram positive organisms, and a CDC blood agar plate kept in anaerobic conditions with a gentamicin disk (ANA CDC) to select for anaerobic organisms.

[0055] Each control and skin swabs were removed from their transport bag and streaked across a microscope slide to check immediately for contaminating organisms with a Gram stain. The swabs were next streaked across the first quadrant of each agar plate. The swabs were then placed in a test tube of thioglycollate broth to encourage the growth of any organisms present. Individual, disposable sterile loops were used to streak the remaining quadrants of each plate.

[0056] One drop of the aspirate joint fluid sample was transferred to each agar plate as well as a microscope slide for immediate analysis. Four to five drops of joint fluid were transferred to thioglycollate broth test tubes. Each drop of joint fluid was streaked across the agar plates with individual, disposable sterile loops.

[0057] Each tissue sample was added with 1 mL of thioglycollate broth to a sterile tissue grinder (Precision® Disposable Tissue Grinder; Covidien, Dublin, Ireland) and ground for one minute or until homogenized. One drop of the dissolved tissue sample was transferred to each agar plate and to a microscope slide. Individual, disposable sterile loops were used to streak the agar plates. Four to five drops of the tissue sample were then placed into a test tube of thioglycollate broth.

[0058] The BAP, MAC, and CNA plates were incubated aerobically at 37 °C. for forty-eight (48) hours and then checked for growth to rule out contamination. The ANA CDC plates with gentamicin disks were kept in sterile bags with a carbon dioxide (CO2) pouch system to maintain anaerobic conditions. Each sterile bag included an oxygen-indicator to ensure anaerobic conditions were met. The ANA CDC plates were incubated at 37 °C. for seven days and then analyzed for P. Acnes. Thioglycollate broth test tubes were sealed with parafilm to protect against contamination. These samples were incubated at 37 °C. for thirty (30) days or until a positive P. Acnes diagnosis could be made. All cultures were checked daily for bacterial growth.

[0059] Bacterial colonies suspected of being P. Acnes were smeared onto microscope slides and Gram stained. Isolated P. Acnes were tested for biotype with a Microscan Rapid Anaerobe ID (MicroScan®; Siemens, Erlangen, Germany). Isolated P. Acnes were then streaked on brucella agar/ ANA CDC agar to measure hemolysis. Hemolysis was defined as when there was at least 2 mm of hemolysis around bacterial colonies.¹⁰ Each biotype isolated from a patient was also tested for antimicrobial sensitivities with Epsilometer tests.

[0060] A positive culture was defined by growth on the anaerobic plate within seven days and/or if the thioylcollate broth became turbid, and subtyped as P. Acnes within fourteen days.

[0061] A priori power analysis was carried out. In order to detect a 50% reduction in the risk of positive culture, based on a previous 58% chance of having positive culture for ⁵. Acnes, with Alpha set at 0.05, Power set at 0.8, forty-seven (47) subjects were required.

[0062] Bivariate tests of statistical significance were conducted with a statistical significance level set to P < 0.05. Related sample comparisons for skin swab cultures were made by the McNemar; (Binomial and Chiquare); a X², t-test, binomial test, or a Wilcoxen Test was used to test all independent bivariate associations. Statistical analysis was performed with SPSS Statistics for Windows, version 21.0 (IBM Corps., Armonk, NY, USA).

RESULTS AND DISCUSSION

[0063] Fifty-two (52) subjects were enrolled. Two patients each missed one application of BPO and were excluded, leaving fifty (50) subjects {i.e., 96% of patients were able to comply). Two patients reported mild skin rash that resolved without treatment and did not alter the timing surgery.

[0064] There were twenty-three (23) men (46%) and twenty-seven (27) women (54%). The mean age of patients was 52.3 (range, 17-87 years). Medical comorbidities included five patients with osteoarthritis of joints other than the shoulder, one had a history of smoking, three had type 2 diabetes mellitus, and fourteen were obese. Sixty -percent of subjects had not had a cortisone injection on the surgical shoulder before surgery, and 40% had either one or more cortisone injections on the operative shoulder. Patients underwent arthroscopic shoulder surgery for subacromial depression and/or debridement (6.0%), subacromial decompression and bicep tenodesis (16.0%), rotator cuff repair (68.0%), or labrum or instability repair (10.0%). The average duration of surgery was 56 minutes (range 28-115). Thirty -two percent of patients had surgery on the left shoulder and 68% of patients had surgery on the right shoulder. The average VAS pain score recorded by a patient was a 4.38, and a minimum recorded was 0.

[0065] A total of 650 cultures were obtained and studied. Fifty control cultures (one per patient) with cotton swabs waived in the air were collected. Four percent (2/50) of the controls were positive for P. Acnes.

[0066] 200 cultures were obtained prior to skin preparation. Sixteen percent (8/50) of cultures from the anterior deltoid of the BPO treated arm were positive, compared to thirty two percent (16/50) of the skin on the anterior deltoid of the untreated arm (P = 0.001). Samples of the nonsurgical (untreated) side of the anterior deltoid before skin preparation also demonstrated a significant difference between men (47.8%) and women (18.5%) (P = 0.036). Similarly, the axilla of the BPO treated arm was positive in 8% (4/50) and in 28% (14/50) of the untreated arm (P = 0.013).

[0067] 400 samples were obtained after comprehensive skin preparation as described in the methods. 6.25 percent (25/100) grew P. Acnes. This was not different when compared to the 4% rate for control (P = 1.0). The rate of positive culture increased to 10% at the end of the procedure, prior to removing the drapes. This was not different when compared to the control rate (P = 0.375), or the rate observed at the initiation of surgery (P = 0.625). There were no significant differences in the rate of positive cultures between any of the specimens obtained after skin preparation and the control swab. See Table 3. In contrast to the pre-skin preparation, there were no significant difference rates of male subjects with positive cultures (4.0%) and female subjects (2.25%) (P = 0.06).

[0068] There was no association with positive culture for age and history of cortisone injection. Duration of surgery, type of surgery, or medical comorbidity (osteoarthritis, diabetes mellitus, smoking) also had no significant bearing on culture results among patients with a single positive culture. Age when evaluated above and below 55 years, and duration of surgery when evaluated as longer or shorter than 60 minutes were not significant. See Table 1.

[0069] There was a statistically significant difference in the mean BMI for samples taken in the anterior deltoid (P = 0.045) and the axilla (P = 0.043) surgical side before skin preparation and in the axilla surgical side at the end of surgery but not for the remaining samples (P= 0.022). See Table 2.

[0070] All patients had serial examination at 2-month interval. None of the patients had unusual pain, delayed wound healing, erythema, or fever that would suggest clinical infection. None of the patients had poor clinical outcome or required additional surgery. The mean follow-up for patients in this study was 9 months.

[0071] When topical benzoyl peroxide (BPO) cream is used starting forty eight hours prior to shoulder surgery, there was no significant detectable difference in the rate of positive cultures between a control air swab and surgically obtained samples. This is a pertinent negative finding in an appropriately powered study. 6.1% of tissue and skin cultures obtained after skin preparation were positive for P. Acnes, compared to 4.0%> for the control swab (P = 0.40). These findings are important as recent studies have demonstrated a 36%> - 70% increased risk above controls for having a positive P. Acnes cultures.¹²' ¹⁴' ¹⁸ Adding 5% topical BPO cream to current skin preparation can reduce the rate at which residual P. Acnes is identified. This may extrapolate to a lower risk of clinical infection with P. Acnes.

[0072] Current skin preparations do not eliminate P. Acnes from cleansed skin up to 29% of the time at the onset of surgery.¹²' ¹⁸' ²⁵ This rate may be as high 63% when measuring males subjects skin at the end of the surgical procedure.²⁵ Dermal biopsy of surgically cleansed skin was positive in 70% of patients in whom ChloraPrep® was used.¹⁴ This is likely a consequence of imperfect skin preparation which does not reach the dermis. Furthermore, there is subsequent bacterial leakage from sebaceous glands released into the wounds after skin incision.¹⁸ This residual bacterial exposure may be the source of infection in those patients who develop infection. It is for these reasons that current skin cleansing methods need to be improved.

Although it is possible that P. Acnes resides in the normal joint, and that it may be a pathologic precursor to shoulder arthritis¹⁵' ¹⁸, it is more likely contamination from the dermis. The experiments described herein support the dermis as the primary source of P. Acnes, as adding an agent that crosses the dermis and is toxic to the local bacteria substantially reduced the bacteria that was identified both in the joint and on the skin.

[0073] The ability of 5% BPO to suppress P. Acnes is well established in the dermatologic literature. Leyden described a 90% reduction in P. Acnes after 48 hours of topical treatment and a 99%) reduction after 72 hours treatment.^{16, 17} Leyden' s described 48-hour skin treatment protocol for this study, five (5) skin applications over two and one half days, was used. In contrast to antibiotics, which alter bacterial structure, BPO is a powerful antimicrobial agent which is directly toxic to both surface and ductal bacteria. Its lipophilic properties permit penetration of the pilosebaceous duct. Once applied to the skin, BPO decomposes to release free oxygen radicals, which have potent bactericidal activity in the sebaceous follicles.⁸' ¹⁰ Given its efficacy, relatively low cost, and low risk of adverse events, BPO was chosen to be used in surgical skin preparation, which has not yet been done.

[0074] A similar study obtaining skin and tissue specimens in patients undergoing shoulder surgery with skin preparation using ChloraPrep® alone had been previously performed.²⁴ There, 56% of 50 subjects had at least one culture positive for P. Acnes. In contrast, after using topical BPO in the invention described herein, only 6.5% of all subjects had at least one specimen obtained after skin preparation test positive for ⁵. Acnes. In the experiments described herein, the overall rate of 6.5% positive culture was not different than control rate of 4.0% (P = 0.40), suggesting the combined skin preparation reduced the risk of having a positive culture equal to that of the control air swab. While it is not appropriate to perform statistical analysis between the two distinct studies, the reduction rate of P. Acnes after using BPO from 56% to 6.5% is substantial and may be clinically relevant. See Table 3.

[0075] In the experiments described herein and the previous study we obtained cultures at the beginning and at the end of the surgical procedure. This assesses how well the skin preparation functions while the epidermis and dermis are manipulated, sweat, and react to surgery. In the previous study, this went from a 15.8% chance of positive culture at the beginning of the procedure to 41% at the end of the procedure. The rate of positive culture went up to 63 % positive when examining males at the end of the surgical procedure. In the previous study, all these values were statistically different from one another.²⁵ See Table 3. The experiments described herein had a 6.0% risk of positive culture at the beginning of surgery, and a 10% rate of positive culture at the end of the procedure and was no different than control (P = 1.0, P = 0.375). The addition of BPO eliminated any statistical differences between the control swab, skin swabs after skin preparation, tissue culture, and skin at the end of the surgical procedure. See Table 3. There was also no difference in gender and rate of positive culture at the end of this procedure. Significantly, these findings demonstrate that a lower bacterial burden to contaminate and potentially infect the wound at the end of surgery can be obtained using the invention in comparison to skin preparation using ChloraPrep® alone.

[0076] BPO alone, prior to ChloraPrep®, had a significant effect in reducing P. Acnes. The untreated arm had a significantly higher rate of P. Acnes compared to the BPO treated arm before skin preparation (P = 0.039). The anterior deltoid and axilla of the untreated arm was positive 32% and 28% of the time, respectively. This is a lower incidence of P. Acnes than we would have expected as compared to the general population. The lower rate of culture observed may have a few explanations. These patients were all treated with topical BPO on the contralateral arm and may have had some systematic absorption. These patients also had all bathed the morning of surgery, had not been active, and received IV antibiotics. The sample was taken before surgical preparation and draping without opportunity to sweat, and certainly no disruption of the dermis occurred. Our initial studies had a 70% incidence in active males, suggesting our microbiological methodology is not flawed. The experiments described herein also are consistent with Hudek et al.'s suggesting that the axilla is not the richest source of P. Acnes.¹¹

[0077] Males have a higher chance of having P. Acnes present on their skin before preparation, after preparation, and at the end of the procedure.¹³' ¹⁴' ¹⁸' ²⁰' ²¹ The experiments described herein are consistent with previous publications, as male subjects had a higher rate of P. Acnes found on their skin. This effect was significant only in untreated arm (P = 0.036) and in the treated arm prior to skin preparation (P = 0.017). Once the skin has been surgically cleansed, however, there was no significant difference between males and females in any of the subsequent specimens. See Table 1. This suggests that the combination of BPO and ChloraPrep®is equally effective in males and females, and actually may equalize the risk of residual bacteria in male and female.

[0078] P. Acnes is a significant pathogen with a specific predilection for SSI in shoulder surgery. Current skin preparation with antiseptic skin preparation agents, such as for example, aqueous- iodophor, aqueous-chlorhexidine gluconate, alcohol -iodophor, and alcohol-chlorhexidine gluconate are imperfect; residual bacteria are identified on the skin up to 29% of the time at the beginning of the surgical procedure, 63% of the time at the conclusion of surgery in individuals undergoing first time shoulder surgery, and in 70% of dermal biopsy. The high rate of residual bacteria left on the epidermis and dermis both may be the source of infection in susceptible patients, particularly those having procedures with a surgical implant. The addition of 5% topical benzoyl peroxide cream to current skin preparation substantially reduces the rate at which P. Acnes is identified to 6%, which is no different when compared to control samples. Thus, the addition and/or co-administration of benzoyl peroxide to current antiseptic skin preparation agents substantially reduces the rate at which bacteria, such as, for example, P. Acnes, is identified during the perioperative period of an invasive procedure when compared to current antiseptic skin preparation agents used alone.

REFERENCES

1. Darouiche et al., N Engl J Med 362(1): 18-26 (2010).

2. Hemani et al., Rev Urol. 11(4): 190-195 (2009).

3. Amin et al., J Drugs Dermatol 6(9):873-80 (2007).

4. Bayston et al., J Biomed Mater Res A 81(3):705-9 (2007).

5. Butler-Wu et al., J Clin Microbiol 49(7):2490-5 (2011). 6. Cheung et al., J Shoulder Elbow Surg 17(3):371-5 (2008).

7. Dramis et al., Int Orthop 33 (3): 829-33 (2009).

8. Fulton et al., J Cutan Pathol 1 : 191-200 (1974).

9. Gollnick et al., J Am Acad Dermatol 49:S 1-S37 (2003).

10. Haider et al., JAMA 292:726-735 (2004).

11. Hasan et al., J Shoulder Elbow Surg 11(5):431-41 (2002).

12. Hudek et al., J Shoulder Elbow Surg. 23(12): 1763-71 (2014).

13. Kelly et al., Clin Orthop Relat Res 467(9):2343-8 (2009).

14. Lee et al., J Bone Joint Surg Am. 96(17): 1447-50 (2014).

15. Levy et al., J Shoulder Elbow Surg 22(4):505-l l (2013).

16. Leyden, Cutis. 69:475-480 (2002).

17. Leyden et al., Cutis. 79(6 Suppl):9-25 (2007).

18. Matsen et al., J Bone Joint Surg Am 95(23):el81 1-7 (2013).

19. McLorinan et al., Clin Orthop Relat Res (437):67-73 (2005).

20. Patel et al., J Shoulder Elbow Surg 18(6):897-902 (2009).

21. Pottinger et al., J Bone Joint Surg Am 94(22):2075-83 (2012).

22. Richards et al., Spine (Phila Pa 1976) 26(18): 1990-6 (2001).

23. Saltzman et al., J Am Acad Orthop Surg 19(4):208-18 (2011).

24. Saltzman et al., J Bone Joint Surg Am 91(8): 1949-53 (2009).

25. Sethi et al., J Shoulder Elbow Surg S1058-2746(14)00541-2 (2014). Table 1 Discrete Factors Associated with Having a Risk of a Single Culture Positive for ⁵. Acnes

MGHL (middle glenohumeral ligament); BPO (Benzoyl Peroxide)

This chart depicts bivariate analysis of risk factors associated with subjects with a positive P. Acnes culture within 14 days. There was no significant difference associated with positive culture for age above and below 55 years and history of cortisone injection.

Duration of surgery longer or shorter than 60 minutes, type of surgery, or medical comorbidity (osteoarthritis, diabetes mellitus, smoking) also had no significant bearing on culture results among patients with a single positive culture. There was a significant difference associated positive culture amongst males and females in the untreated skin anterior deltoid (P = 0.036) and in the treated skin anterior deltoid prior to skin preparation (P = 0.017). There was no significant difference between males and females in any of the subsequent samples.

* Statistically significant (P< 05), independent t test.

† Pre-incision skin sample taken after patient was surgically prepped and draped and before incision.

% Skin sample at closure taken at the completion of the procedure with surgical draping still in place.

Table 2 Continuous Factors Associated with Having a Single Culture Positive for P. Acnes

SD (standard deviation); BMI (body mass index); MGHL (middle glenohumeral ligament); BPO (Benzoyl Peroxide)

This chart depicts bivariate analysis of risk factors associated with subjects with a positive P. Acnes culture within 14 days. There was no difference in mean age and duration of surgery for subjects with a positive vs. negative culture. There was a statistically significant difference in the mean BMI for samples taken in the skin anterior deltoid (P = 0.045) and skin axilla surgical side (P = 0.043) before skin preparation as well as in the skin axilla surgical side (P = 0.022) at the end of surgery but not for the remaining samples.

* Statistically significant (P< 05), independent t test.

† Pre-incision skin sample taken after patient was surgically prepped and draped and before incision.

% Skin sample at closure taken at the completion of the procedure with surgical draping still in place.

Table 3 Rate of Positive P. Acnes Culture by Individual Specimen Location

MGHL (middle glenohumeral ligament); BPO (Benzoyl Peroxide)

This table depicts the rate of positive cultures obtained by location of specimen obtained. The top half of the chart depicts rate of positive culture prior to ChloraPrep® skin preparation. Samples 3 and 4, the non-surgical arm that did not have topical BPO, were significantly greater than the control swab. Sample 3, the untreated anterior deltoid skin, was also significantly greater than sample 1, the BPO treated anterior deltoid skin (P = 0.03). Similarly sample 4, the untreated axilla skin, was significantly greater than sample 1, the BPO treated axilla skin.

None of the samples obtained after skin preparation with ChloraPrep® and BPO were significantly different than control.

* Statistically significant (P≤.05).

† Pre-incision skin sample taken after patient was surgically prepped and draped and before incision.

% Skin sample at closure taken at the completion of the procedure with surgical draping still in place.

Claims

The claimed invention is:

1. A composition, comprising benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent.

2. The composition of claim 1, wherein the at least one antiseptic skin preparation agent is selected from an aqueous-based antiseptic skin preparation agent, an alcohol-based antiseptic skin preparation agent, or mixtures thereof.

3. The composition of claim 2, wherein the aqueous-based antiseptic skin preparation agent is selected from an aqueous-iodophor antiseptic skin preparation agent and an aqueous- chlorhexidine antiseptic skin preparation agent.

4. The composition of claim 3, wherein the iodophor in the aqueous-iodophor antiseptic skin preparation agent is povidone-iodine.

5. The composition of claim 3, wherein the iodine in the aqueous-iodophor antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

6. The composition of claim 3, wherein the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent is selected from a chlorhexidine salt.

7. The composition of claim 6, wherein the chlorhexidine salt is chlorhexidine gluconate.

8. The composition of claim 3, wherein the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

9. The composition of claim 2, wherein the alcohol-based antiseptic skin preparation agent is selected from an alcohol -iodophor antiseptic skin preparation agent and an alcohol- chlorhexidine antiseptic skin preparation agent.

10. The composition of claim 9, wherein the iodophor in the alcohol -iodophor is povidone- iodine.

11. The composition of claim 9, wherein the iodine in the alcohol-iodophor antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

12. The composition of claim 9, wherein the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent is selected from a chlorhexidine salt.

13. The composition of claim 12, wherein the chlorhexidine salt is chlorhexidine gluconate.

14. The composition of claim 9, wherein the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent is present in an amount ranging from about 0.1 - 15 wt.%.

15. The composition of claim 9, wherein the alcohol in the alcohol-iodophor antiseptic skin preparation agent or the alcohol-chlorhexidine antiseptic skin preparation agent is selected from at least one monohydric alcohol, at least one polyhydric alcohol, or mixtures thereof.

16. The composition of claim 9, wherein the alcohol in the alcohol-iodophor antiseptic skin preparation agent or the alcohol-chlorhexidine antiseptic skin preparation agent is selected from methanol, ethanol, and isopropanol.

17. The composition of claim 9, wherein the alcohol in the alcohol-iodophor antiseptic skin preparation agent or the alcohol-chlorhexidine antiseptic skin preparation agent is present in an amount ranging from about 50 - 90 wt.%.

18. The composition of claim 1, further comprising at least one antibiotic.

19. The composition of claim 18, wherein the at least one antibiotic is selected from clindamycin and cefazoline.

20. The composition of claim 1, wherein the benzoyl peroxide or a derivative thereof is present in an amount ranging from about 0.05 - 15 wt.%.

21. A method of reducing bacteria in mammalian skin during the perioperative period of an invasive procedure, comprising administering to a mammal in need thereof the composition of claim 1.

22. The method of claim 21, wherein the invasive procedure is a surgical procedure.

23. The method of claim 22, wherein the surgical procedure is an arthroscopic surgical procedure.

24. The method of claim 22, wherein the surgical procedure is an endoscopic surgical procedure.

25. The method of claim 22, wherein the surgical procedure is selected from shoulder surgery, elbow surgery, spinal surgery, and neurosurgery.

26. The method of claim 21, wherein the composition is administered to the mammal in need thereof before, during, and/or after the invasive procedure.

27. The method of claim 21, wherein the bacteria is Propionibacterium Acnes.

28. A method of reducing bacteria in mammalian skin during the perioperative period of an invasive procedure, comprising:

administering to a mammal in need thereof a first composition comprising benzoyl peroxide or a derivative thereof; and

administering to said mammal a second composition comprising at least one antiseptic skin preparation agent.

29. The method of claim 28, wherein the at least one antiseptic skin preparation agent is selected from an aqueous-based antiseptic skin preparation agent, an alcohol-based antiseptic skin preparation agent, or mixtures thereof.

30. The method of claim 29, wherein the aqueous-based antiseptic skin preparation agent is selected from an aqueous-iodophor antiseptic skin preparation agent and an aqueous- chlorhexidine antiseptic skin preparation agent.

31. The method of claim 30, wherein the iodophor in the aqueous-iodophor antiseptic skin preparation agent is povidone-iodine.

32. The method of claim 30, wherein the iodine in the aqueous-iodophor antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

33. The method of claim 30, wherein the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent is selected from a chlorhexidine salt.

34. The method of claim 33, wherein the chlorhexidine salt is chlorhexidine gluconate.

35. The method of claim 30, wherein the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

36. The method of claim 29, wherein the alcohol-based antiseptic skin preparation agent is selected from an alcohol -iodophor antiseptic skin preparation agent and an alcohol-chlorhexidine antiseptic skin preparation agent.

37. The method of claim 36, wherein the iodophor in the alcohol -iodophor is povidone- iodine.

38. The method of claim 36, wherein the iodine in the alcohol -iodophor antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

39. The method of claim 36, wherein the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent is selected from a chlorhexidine salt.

40. The method of claim 39, wherein the chlorhexidine salt is chlorhexidine gluconate.

41. The method of claim 36, wherein the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent is present in an amount ranging from about 0.05 - 15 wt.%.

42. The method of claim 36, wherein the alcohol in the alcohol-iodophor antiseptic skin preparation agent or the alcohol-chlorhexidine antiseptic skin preparation agent is selected from at least one monohydric alcohol, at least one polyhydric alcohol, or mixtures thereof.

43. The method of claim 36, wherein the alcohol in the alcohol-iodophor antiseptic skin preparation agent or the alcohol-chlorhexidine antiseptic skin preparation agent is selected from methanol, ethanol, and isopropanol.

44. The method of claim 36, wherein the alcohol in the alcohol-iodophor antiseptic skin preparation agent or the alcohol-chlorhexidine antiseptic skin preparation agent is present in an amount ranging from about 50 - 90 wt.%.

45. The method of claim 28, further comprising administering to said mammal at least one antibiotic.

46. The method of claim 45, wherein the at least one antibiotic is selected from clindamycin and cefazoline.

47. The method of claim 28, wherein said first composition and/or said second composition further comprises at least one antibiotic.

48. The method of claim 28, wherein the benzoyl peroxide or a derivative thereof is present in an amount ranging from about 0.05 - 15 wt.%.

49. The method of claim 28, wherein the bacteria is Propionibacterium Acnes.

50. The method of claim 28, wherein the benzoyl peroxide or a derivative thereof is administered before the at least one antiseptic skin preparation agent is administered.

51. The method of claim 28, wherein the invasive procedure is a surgical procedure.

52. The method of claim 51, wherein the surgical procedure is an arthroscopic surgical procedure.

53. The method of claim 51, wherein the surgical procedure is an endoscopic surgical procedure.

54. The method of claim 51, wherein the surgical procedure is selected from shoulder surgery, elbow surgery, spinal surgery, and neurosurgery.

55. A kit comprising at least one container comprising benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent.

56. The kit according to claim 55, wherein said benzoyl peroxide or a derivative thereof are contained in a first container and said at least one antiseptic skin preparation agent is contained a second container.

57. The kit according to claim 55, composed of a dual chamber container wherein said benzoyl peroxide or a derivative thereof and said at least one antiseptic skin preparation agent are contained in each one of the chambers.

58. The kit according to claim 55, further comprising an applicator means on the at least one container for applying the benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent onto mammalian skin.

59. The kit according to claim 58, wherein said at least one container and applicator means are combined into a single article.

60. The kit according to claim 58, wherein said at least one container and applicator means are separate articles.

61. The kit according to claim 56, wherein said first container comprises benzoyl peroxide and said second container comprises said at least one antiseptic skin preparation agent is chlorhexidine gluconate and isopropanol.

62. The kit according to claim 55, for reducing bacteria in mammalian skin during the perioperative period of an invasive procedure.

63. The kit according to claim 62, wherein said bacteria is Propionibacterium Acnes.