WO2012094009A2

WO2012094009A2 - Methods of reducing surgical site infection

Info

Publication number: WO2012094009A2
Application number: PCT/US2011/020391
Authority: WO
Inventors: Rabih O. Darouiche
Original assignee: CareFusion, Inc.
Priority date: 2011-01-06
Filing date: 2011-01-06
Publication date: 2012-07-12

Description

METHODS OF REDUCING SURGICAL SITE INFECTION

BACKGROUND OF THE INVENTION

[0001] Antisepsis is the destruction or inhibition of microorganisms that exist on living tissue. Antiseptics kill or prevent the growth of the microorganisms. Commonly used antiseptics include iodine, boric acid, and alcohol. Pre-operative preventive measures with use of antiseptics have been used to reduce the number of infections post-surgery. However, despite the implementation of preoperative preventive measures, which include skin cleansing with povidone -iodine as well as other antiseptics, surgical-site infections (also known as "SSIs") still occur at a frequency of about half million patients who undergo surgery in the United States every year and are the second most common cause of nosocomial, i.e., hospital-acquired, infections. See, e.g., J. P. Burke, "Infection Control-A Problem for Patient Safety", N. Engl. J. Med., 2003, 348, pp. 651-656.

SUMMARY OF THE INVENTION

[0002] Described herein are methods of reducing post-operative surgical site infection in a patient having surgery. In one aspect, the methods comprise pre-operatively applying a formulation comprising of less than 4% w/v chlorhexidine or a salt thereof in an alcohol solution to a patient's skin at a surgical site; scrubbing the skin with the formulation to completely wet the area at the surgical site for at least 30 seconds; and air drying the skin for at least 30 seconds; wherein the infection reduction is greater than or equal to about 40% than an administration of a povidone-iodine formulation.

[0003] In some embodiments, the surgical site is a site for clean-contaminated surgery. In certain instances, the clean-contaminated surgery is colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic or urologic surgery.

[0004] In some embodiments, the formulation comprises about 3.5% w/v chlorhexadine. In other embodiments, the formulation comprises about 3.0%> w/v chlorhexadine. In yet other embodiments, the formulation comprises about 2.5% w/v chlorhexadine. In further embodiments, the formulation comprises about 2.0%> w/v chlorhexadine.

[0005] In certain embodiments, the chlorhexidine is a chlorhexidine salt. In some instances the chlorhexidine salt is selected from a group of salts consisting of gluconate, acetate, chloride, bromide, nitrate, sulfate, carbonate and phosphanilate. In certain instances, the chlorhexidine salt is chlorhexidine gluconate.

[0006] Provided in some of the embodiments, the formulation further comprises a dye. In certain instances, the dye is selected from a group consisting of Food, Drug and Cosmetic (FD&C) Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, FD&C Red No. 3, FD&C Red No. 40, FD&C Yellow No. 5, FD&C Yellow No. 6 and combinations thereof. [0007] Also provided in some of the embodiments, the alcohol is further selected from the group consisting of methanol, ethanol, propanol and isopropanol. In some instances, the alcohol is isopropanol. In certain instances, the alcohol is about 50-95% v/v of the formulation. In further instances, the alcohol is about 70% v/v of the formulation.

[0008] In some embodiments of the described methods, the application and/or scrubbing of the formulation is by an applicator. In other embodiments, the application and/or scrubbing of the formulation is by a sponge.

[0009] In certain embodiments of the described methods, the infection is a superficial incisional infection. In other embodiments, the infection is deep incisional infection. In yet other

embodiments, the infection is sepsis. In further embodiments, the infection is infection by a Streptococcus bacteria.

[0010] In further embodiments of the described methods, the patient undergoes preoperative shower prior to application of the formulation. In yet further embodiments of the described methods, antibiotics are administered to the patient pre-operatively or post-operatively.

[0011] Described also herein are methods of reducing Streptococcus bacteria in post-operative surgical site infection in a patient having surgery. In one aspect, the methods comprise pre- operatively applying a formulation comprising of less than 4% w/v chlorhexidine or a salt thereof in an alcohol solution to a patient's skin at a surgical site; scrubbing the skin with the formulation to completely wet the area at the surgical site for at least 30 seconds; and air drying the skin for at least 30 seconds; wherein the Streptococcus bacteria reduction is greater than or equal to about 40% than an administration of a povidone -iodine formulation.

[0012] In some embodiments, the Streptococcus bacteria reduction is greater than or equal to 60%. In other embodiments, the Streptococcus bacteria reduction is greater than or equal to 70%. In further embodiments, the Streptococcus bacteria reduction is greater than or equal to 80%. INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0014] Provided herein, are methods of reducing post-operative surgical site infections in a patient having surgery with an antiseptic formulation described herein, wherein the infection reduction is greater than an administration of a povidone -iodine formulation. Also provided herein, are methods of reducing Streptococcus bacteria in post-operative surgical site infections in a patient having surgery with an antiseptic formulation described herein, wherein the Streptococcus bacteria reduction is greater than an administration of a povidone -iodine formulation. The methods described herein comprise pre-operatively applying an antiseptic formulation to a patient's skin at a surgical site, scrubbing the skin with the formulation to completely wet the area at the surgical site and air drying the skin.

[0015] Patients having surgery in the methods described herein include patients undergoing a wide range of surgical and invasive procedures. Non-limiting examples of surgical procedures include: colorectal surgery, small intestinal surgery, gastroesophageal surgery, thoracic surgery, gynecologic or urologic surgery, cardiothoracic surgery, vascular surgery, colon surgery, hip or knee

arthroplasty, biliary surgery, abdominal hysterectomy, percutaneous gastronomy, repair of long bone fractures, ear, nose or throat surgery, Cesarean section, and the like. Non-limiting examples of invasive medical procedures include: bladder catheter insertions, insertion of nasal cannulas, biopsies, dermatological procedures, hair transplants, removal of a foreign object from the skin, eye, nasal, ear, or other body cavities and the like.

[0016] In certain embodiments, the surgery is a clean-contaminated surgery. Clean-contaminated surgery includes, but is not limited, to procedures such as colorectal, small intestinal,

gastroesophageal, biliary, thoracic, gynecologic or urologic surgery. Clean-contaminated surgery also includes appendix surgery. Other types of clean-contaminated surgery are defined by wound class or type involved. Generally, clean-contaminated surgery involves Class II-operative wounds (CDC, 1999).

[0017] The methods described herein reduce any post-operative surgical site infection resulting from the surgical or invasive procedure. Non-limiting examples of surgical site infections include skin infections, abdominal infections, urinary tract infections, bacteremia, septicemia, endocarditis, incisional infections including superficial and deep, infections associated with an atrio-ventricular shunt, vascular access infections, meningitis, peritoneal infections, bone infections, deep sternal wound infections, joint infections, infection associated with a catherization, infections associated with placement of a stent, infections associated with placement of a prosthetic device, Gram- negative bacterial infections, Staphylococcus aureus infections, including those caused by methicillin-resistant Staphylococcus aureus bacteria, Streptococcus bacteria infections, enterococcal infections, including those caused by vancomycin-resistant enterococci, Bacteriodes infections, other aneaerobic bacterial organism caused infections, and linezolid-resistant infections. In certain instances, the infection reduced is a superficial incisional infection. In other instances, the infection reduced is a deep incisional infection. In further instances, the infection reduced is a Streptococcus bacteria infection.

[0018] In some embodiments of the methods described herein, post-operative surgical site infections are reduced more than an administration of a a povidone -iodine formulation. In some instances of the methods described herein, the infection reduction is greater than or equal to 40% than an administration of a povidone-iodine formulation. In certain instances, the infection reduction is greater than or equal to 45%, greater than or equal to 50%, greater than or equal to 55%, greater than or equal to 60% or greater than or equal to 65% than an administration of a povidone -iodine formulation.

[0019] In further embodiments, levels of Streptococcus bacteria are reduced in post-operative surgical site infections by the methods provided herein. In some instances, the Streptococcus bacteria reduction is greater than or equal to 40% than an administration of a povidone-iodine formulation. In certain instances, the Streptococcus bacteria reduction is greater than or equal to 40%), greater than or equal to 50%, greater than or equal to 60%>, greater than or equal to 70%, greater than or equal to 80%> or greater than or equal to 85% than an administration of a povidone- iodine formulation.

[0020] Povidone-iodine formulations refer to standard administration of a povidone-iodine formulation that is used in surgical and/or invasive procedures. Povidone-iodine formulations include about 5% to about 10% povidone-iodine formulations that are administered by known methods including scrubbing and/or painting. Povidone-iodine formulations can be left on the surgical site or washed off.

[0021] Preoperative application of the antiseptic formulation is at an appropriate time prior to the patient undergoing the surgical or invasive medical procedure. The appropriate time for application includes factors such as the pharmacokinetic profile of the antiseptic formulation, delivery and device used in the application, time required for completing application, patient characteristics, type of surgery or invasive medical procedure, area of the surgical site, desired clinical outcome, etc. In certain embodiments, the application of the antiseptic formulation is about 6 hours prior up to immediately before the surgical or invasive medical procedure. In other embodiments, the application of the antiseptic formulation is about 6 hours, about 5 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 40 minutes, about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes or about 2 minutes before the surgical or invasive medical procedure.

[0022] The methods described herein also include, in some embodiments, additional applications of the antiseptic formulation prior to, during, or after the surgical or invasive medical procedure.

Examples where an applications of the antiseptic formulation may be required can include where the commencement of the surgical or invasive medical procedure is delayed relative to the initial application of the antiseptic formulation, or where the surgical or invasive medical procedure takes longer to complete than originally anticipated, or where it is found from monitoring of blood or tissues or other appropriate analyses of the patient or subject that further application of the antiseptic formulation is warranted.

[0023] Application of the antiseptic formulation is via any known method or device and includes application by sponges, wipes, scrubs, cloths, swabs and the like as well as specialized applicators such as those described in US Pat. No. 6,729,786; 6,991,393 and 5,772,346, which are incorporated herein for the description of applicators. Applicators and other devices are further described in subsequent sections.

[0024] Surgical sites for applying the antiseptic include any skin area on a patient's body. Surgical sites include sites that are "dry" such as the abdomen, arm or leg as well as sites that are considered "moist", e.g., underarms, inguinal folds and the like.

[0025] In some of the embodiments of the methods described herein, the patient's skin is further scrubbed with the formulation to completely wet the area at the surgical site. "Completely wet the area" in certain embodiments refers to scrubbing the treatment area until the antiseptic formulation is visible on the skin. Various scrubbing methods are within the scope of the embodiments herein and include scrubbing methods such as back-and-forth stroking, circular motions, and other contemplated regimens. Additionally, in some embodiments, scrubbing is achieved by any known method or device. In certain instances, scrubbing the skin is via the same device or method that was previously employed in applying the antiseptic formulation onto the skin. In other instances, scrubbing the skin is via a different device that was previously employed in applying the antiseptic formulation onto the skin. In some embodiments, scrubbing is via sponges, wipes, scrubs, cloths, swabs and the like as well as other specialized applicators that can also be used for scrubbing such as those described in US Pat. No. 6,729,786; 6,991,393 and 5,772,346, which are incorporated herein for the description of applicators.

[0026] Scrubbing the antiseptic formulation onto the patient's skin to wet the area is at an appropriate time duration. The appropriate duration for scrubbing includes factors such as the pharmacokinetic profile of the antiseptic formulation, delivery and device used in the application, time required for wetting the area, patient characteristics, type of surgery or invasive medical procedure, area and type of the surgical site, desired clinical outcome, etc. In certain embodiments, scrubbing the antiseptic formulation onto the patient's skin to wet the area ranges from at least 10 minutes to at least 30 seconds. In other embodiments, the scrubbing of the antiseptic formulation onto the patient's skin to wet the area is at least 10 minutes, at least 8 minutes, at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, at least 2 minutes, at least 1 minute or at least 30 seconds. In certain instances, the scrubbing duration is at least 2 minutes. In other instances, the scrubbing duration is at least 30 seconds. In further instances, the scrubbing duration is according to the surgical site type. For example, a moist surgical site is typically scrubbed for a longer duration (e.g., at least 2 to at least 5 minutes) than a dry surgical site (e.g., at least 30 seconds to at least 1 minute).

[0027] In some embodiments the methods described herein, the patient's skin is further dried after scrubbing. Drying the skin is performed via any known method and includes drying methods such as by air, heat, fan, vacuum, blotting by a sterile cloth or wipe, and the like. In certain instances, the patient's skin is air dried.

[0028] Additionally, drying the patient's skin is at an appropriate dryness. The appropriate dryness for scrubbing includes factors such as the volativity of the antiseptic formulation, amount of antiseptic applied, time required for wetting the area, drying method, type of surgery or invasive medical procedure, area and type of the surgical site, desired clinical outcome, etc. In certain embodiments, the patient's skin is dried to complete dryness. In certain embodiments, the patient's skin is dried to partial or incomplete dryness. In further embodiments, the patient's skin is dried for a set duration dependent on the drying method. For example, in air drying embodiments, the patient's skin is air dried for at least 10 minutes to at least 30 seconds. In other embodiments, the patient's skin is air dried at least 10 minutes, at least 8 minutes, at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, at least 2 minutes, at least 1 minute or at least 30 seconds. In certain instances, the patient's skin is air dried at least 2 minutes. In other instances, the patient's skin is air dried at least 1 minute. In further instances, the patient's skin is air dried at least 30 seconds. In further instances, the scrubbing duration is according to the surgical site type. For example, a moist surgical site is typically dried for a longer duration (e.g., at least 2 to at least 5 minutes) than a dry surgical site (e.g., at least 30 seconds to at least 1 minute).

[0029] In some embodiments of the methods described herein also comprise additional steps such as, prior to application of the antiseptic formulation, the patient undergoes preoperative showering. Preoperative showering can be showering generally with soap and water or with an anti-microbial skin cleanser (e.g., Hibiclens®). Other preoperative washing methods are included in the methods described herein. Additional steps in the methods described herein also include shaving or cutting the hair of the skin area prior to application of the antiseptic formulation.

[0030] In some embodiments of the methods described herein further comprises administering to the patient antibiotics to aid in the reduction of surgical site infections. In certain embodiments, the antibiotics are administered either pre-operatively or post-operatively. The antibiotics can be administered by any routes of aministration including oral and i.v. or s.c. injection. Antibiotics include, but are not limited to, penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacllin, penicillin, piperacillin, temocillin, ticarcillin), floxins (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin,

lomefloxacin, moxifloxacin, nalidixic acid, orfloxacin, olfoxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine, sulfacetamide, sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim), cyclines (tetracycline, doxycycline, minocycline, oxytetracycline, democlocycline), macrolides (e.g., clarithromycin, dirthromycin, azithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin), aminoglycosides (gentamycin, neomycin, kanamycin, tobramycin, paromomycin, amikacin), cephalpsporins (first through five generation types), and the like.

Antiseptic Formulations

[0031] Antiseptic formulations suitable for the methods described herein include antiseptics such as chlorhexidine, olanexidine, alexidine and octenidine and salts thereof. In some embodiments of the methods described herein, the antiseptic is chlorhexidine. In other embodiments, the antiseptic is a salt of chlorhexidine. Examples of such suitable chlorhexidine salts include gluconate, acetate, chloride, bromide, nitrate, sulphate, carbonate, and phosphanilate. In some instances, antiseptic is chlorhexidine is gluconate (CHG). In certain instances, a mixture of antiseptics is employed in the methods described herein. For example, the antiseptics may include alexidine dihydrochloride, octenidine dihydrochloride, octenidine digluconate and octenidine mesylate, and olanexidine hydrochloride.

[0032] The concentration of chlorhexidine or a chlorhexidine salt in an antiseptic formulation may vary within various embodiments. However, in some embodiments, the concentration of chlorhexidine or a chlorhexidine salt is about 0.1% w/v to less than 4.0% w/v. In certain instances, the concentration of chlorhexidine or a chlorhexidine salt is less than 4.0%> w/v. In other instances, the concentration of chlorhexidine or a chlorhexidine salt is about 3.5% w/v, about 3.0%> w/v, about 2.5% w/v, about 2.0% w/v, about 1.5% w/v, about 1.0% w/v, about 0.5% w/v, or about 0.1% w/v. In further instances, the concentration of chlorhexidine or a chlorhexidine salt is about 2.0%> w/v. In yet further instances, the concentration of chlorhexidine or a chlorhexidine salt is about 2.5% w/v. In yet further instances, the concentration of chlorhexidine or a chlorhexidine salt is about 3.0%> w/v.

[0033] The antiseptic formulations for the methods described herein include suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additional agents such as suspending, stabilizing and/or dispersing agents. Antiseptic formulations also include aqueous solutions of the antiseptic in water-soluble form. An aqueous solution is any solution in which water is a dissolving medium or solvent. Other forms of the antiseptic formulations include a variety of topically administrable formulations, such as lotions, gels, pastes, medicated sticks, balms, creams or ointments.

[0034] In other embodiments, the antiseptic formulations for the methods described herein comprise alcohol. Alcohols include those that aid in solubilizing the antiseptic, provide stability and/or increase the antiseptic properties of formulation. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol alcohol, n-butanol, isobutanol, sec-butanol, tert-butanol, benzyl alcohol, phenol and the like. In certain embodiments, antiseptic formulations comprise ethanol. In other embodiments, antiseptic formulations comprise isopropanol alcohol. In some embodiments, the concentration of alcohol in an antiseptic formulation range from about 10%> v/v to about 95%) v/v. In other embodiments, the concentration of alcohol in an antiseptic formulation is about 95% v/v, about 90% v/v, about 85% v/v, about 80% v/v, about 75% v/v, about 70% v/v, about 65% v/v, about 60% v/v, about 55% v/v, about 50% v/v, about 45% v/v, about 40% v/v, about 35%) v/v, about 30% v/v, about 25% v/v, about 20% v/v, about 15% v/v or about 10% v/v. In certain instances, the concentration of alcohol is about 50% v/v to about 95% v/v. In certain instances, the concentration of alcohol is about 70% v/v. In other instances, the concentration of alcohol is 95% v/v. In further instances, the concentration of alcohol is 50% v/v.

[0035] In other embodiments, the antiseptic formulations for the methods described herein are "Alcohol-free". "Alcohol-free" typically means that the formulation contains less than about 10% alcohol by weight. In certain instances, alcohol-free means that the formulation contains less than about 5%), about 2%, or about 1% alcohol by volume. In other instances,, alcohol-free means that the formulation contains less than about 0.5% alcohol by volume. In further instances, alcohol-free means that the formulation contains no alcohol.

[0036] Antiseptic formulations for the methods described herein employ, in some embodiments, additional components. For example, in some embodiments, an antiseptic formulation in the form of an aqueous solution employs a surfactant. Examples of such suitable surfactants include, but are not limited to, polyvinyl pyrrolidone (PVP) (average molecular weight 10,000) and PVP (average molecular weight 1,300,000). In some embodiments, the concentration of surfactant in an aqueous antiseptic solution range from about 0.5% w/v to about 5% w/v. In certain embodiments, PVP (average molecular weight 10,000) is added as a surfactant in a concentration of about 1% w/v.

[0037] Additionally, in some embodiments, antiseptic formulations employ a solubilization aid. Examples of such suitable solubilization aids include, but are not limited to, polyethylene glycol (PEG) (average molecular weight 200), PEG (average molecular weight 400), and glycerol. In some embodiments, the concentration of a solubilization aid in an aqueous antiseptic solution of embodiments range from about 1% v/v to about 49% v/v. In certain embodiments, PEG (average molecular weight 200) is added as a solubilization aid in a concentration of about 1% v/v to about 49% v/v.

[0038] Colorants and dyes are also included in the antiseptic formulations in some embodiments. The colorants and dyes may include, but are not limited to, anionic FD&C dyes, such as, for example, FD&C Blue No. 1 (Brilliant Blue FCF), FD&C Blue No. 2 (Indigo Carmine), FD&C Green No. 3 (Fast Green FCF), FD&C Red No. 3 (Erythrosine), FD&C Red No. 40 (Allura Red), FD&C Yellow No. 5 (Tartrazine), and FD&C Yellow No. 6 (Sunset Yellow FCF) and cationic dyes such as crystal violet, acriflavine, Bismarck brown, malachite green, methyl green, Victoria pure blue BO, and azure. Other compatible colorants and dyes can be used with the antiseptic formulations. Colorants and dyes are used in some embodiments at concentrations to provide a tint or color for aesthetic purposes. In other embodiments, colorants and dyes are used at concentrations in an amount sufficient to stain or color a patient's skin. In further embodiments, colorants and dyes are used at concentrations that do not reduce the efficacy of the antiseptic or salt thereof. The staining or coloring of a patient's skin provides substantial benefit by allowing users to readily identify where the antiseptic solutions have been applied to a patient.

[0039] Additional additives are employed within antiseptic formulations of further embodiments described herein including buffers, viscosity enhancers, fragrances and the like. Such additives are employed by any known methods.

Applicators and other devices for Antiseptic Formulations

[0040] In some embodiments, an antiseptic formulation is provided in conjunction with a liquid applicator. For example, a liquid applicator may be provided that comprises a hollow body defining an internal chamber to receive at least one ampoule formed of a frangible material. In some embodiments, the ampoule(s) contain an aqueous antiseptic solution having a dye therein as described hereinabove. The ampoule(s) may be fractured, and the antiseptic formulation may be applied to the desired surface. In other embodiments, the ampoule(s) contain an untinted antiseptic formulation, and the liquid applicator includes a porous element with a compatible dye therein. The porous element is positioned such that upon fracturing the ampoule(s), the untinted antiseptic formulation is passed through the porous element and dye is transferred to the solution, which may then be applied to the desired surface. Examples of such liquid applicators are further described in: U.S. Pat. Nos. 6,729,786; 6,991,393, and U.S. patent application Ser. No. 11/254,318, filed Oct. 20, 2005; each of which is herein incorporated by reference in its entirety.

[0041] The body of a liquid applicator may take many forms. In some embodiments, the body has an internal chamber that is adapted to receive at least one ampoule. In other embodiments, the body is shaped to hold multiple ampoules. In one form, the body is shaped to generally conform to the ampoule(s) contained within the body. In further embodiments, body of a liquid applicator has an internal reservoir containing an antiseptic formulation.

[0042] The ampoule(s) may be numerous different shapes and sizes depending on the amount of liquid needed to be applied. For example, a liquid applicator may include long cylindrical ampoule(s) or may contain vial-type ampoule(s). Furthermore, more than one ampoule may be received by the body. Preferably, the ampoule(s) are formed of glass, although other materials are entirely within the scope of the present invention. The wall of the ampoules is of a thickness sufficient to contain the desired liquid during transport and storage, yet allow the ampoule to be fractured upon the application of localized pressure.

[0043] The ampoule(s) contained within the body of the applicator may be broken by any method known to those skilled in the art. These include, but are not limited to, squeezing the walls of the body inwardly to break the ampoule(s), using a lever or other mechanism to break the ampoule(s), or utilizing projecting wings with tappets. [0044] The porous element of an exemplary liquid applicator also may take many forms. In some embodiments, the porous element is a porous plug and/or a porous pad. In further embodiments, a porous plug is located within the body of the applicator between the ampoule and an open end of the body. Additionally or alternatively, a porous pad is located at an open end of the body in some embodiments. In some embodiments, a compatible dye (e.g., a cationic dye or an anionic dye/cationic excipient composition) may be provided in and/or on the porous element. The porous element is positioned such that when the ampoule(s) is fractured, the untinted antiseptic formulation flows through the porous element and dye is transferred to the solution to be applied. The porous element may be made of any porous material that allows liquid to flow through the material. The porous element may be, but is not limited to, a fabric, foam or a felt material. Dye may be saturated throughout the porous element or may be placed only on part of the element.

[0045] In further embodiments, an antiseptic formulation is poured over or sprayed onto a porous element and packaged as a wetted product such as a wetted swab or sponge. Porous elements may be made of any porous material that allows liquid to flow through the material. The porous element may be hydrophobic or hydrophilic foam or a felt material, such as polyurethane foam or felt. In one embodiment, the porous element is a hydrophilic ester polyurethane foam. The hydrophilic ester polyurethane foam has pore sizes in the ranges of from 70 to 130 per linear inch or 70 to 90 pores per linear inch. The hydrophilic ester polyurethane foam may also have a double cell or sea spongelike structure. The double cell structure has a distribution of larger and medium sized cells scattered across a background of finer cells. The larger cells may range from 0.06 to 0.09 inches in diameter. Definitions

[0046] The term "patient" or "subject", as used herein, means the human or animal (in the case of an animal, more typically a mammal) subject that would be subjected to a surgical or invasive medical procedure. Such patient or subject could be considered to be in need of the methods of reducing the risk of or preventing the infection due to a surgical procedure or an invasive medical procedure.

[0047] The term "reducing post-operative surgical site infections", as used herein, refers to the lowering of the likelihood or probability of an infection occurring due to a surgical or invasive medical procedure, for example when the patient or subject is predisposed to an infection or at risk of contracting an infection.

[0048] The term "clean-contaminated surgery", as used herein, refers to procedures in which a hollow viscus is opened in planned surgery and has a higher infection risk than clean surgery. Non- limited examples of clean-contaminated surgical procedures include colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic or urologic surgery. In clean-contaminated surgical cases, prophylactic antibiotics are advised in most situations. EXAMPLES

Example 1 : Chlorhexidine Gluconate Formulations

Example la: Isopropanol Formulations

[0049] Example lb: Alcohol-free Formulation

[0050] 1 gram of polyvinyl pyrrolidone (average molecular weight 10,000) is dissolved in 30 ml of distilled water. Then, 5 ml of PEG (average molecular weight 200) is added. Additionally, 10.6 grams of 20% w/v aqueous chlorhexidine gluconate solution is provided and dissolved water is added until the 100-ml mark was reached. A small amount of alcohol (less than 5%) may be added to the aqueous chlorhexidine gluconate solution.

[0051] The above formulations in Examples la and lb are further added to a glass ampoule, which was then sealed and placed inside the hollow body of the liquid applicator.

Example 2: Efficacy Study of Antiseptic Preoperative Scrubs in Prevention of Postoperative Wound Infections

[0052] This clinical trial compared the impact of disinfecting the skin with a 2% chlorhexidine and 70%o isopropyl alcohol antiseptic formulation vs. 10%> povidone-iodine formulation on the rates of infection of clean-contaminated surgical wounds.

[0053] Study Design: A prospective, multicenter, randomized clinical trial was conducted at six hospitals in the United States. The institutional review board at each hospital approved the study protocol, and written informed consent was obtained from all patients before enrollment.

[0054] Objective: The primary objective of this trial was to compare the impact of disinfecting the skin with a 2% chlorhexidine and 70% isopropyl alcohol antiseptic formulation vs. 10% povidone- iodine formulation on the rates of infection of clean-contaminated surgical wounds. The primary end point of the study was the occurrence of any surgical-site infection within 30 days after surgery.

[0055] Inclusion Criteria: Adult patients who were scheduled for a clean-contaminated surgical procedure of the alimentary or respiratory tract (i.e., colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic, or urologic operations performed under controlled conditions without substantial spillage or unusual contamination) were eligible for participation. A clean-contaminated wound is one that was entered under controlled conditions without unusual contamination.

[0056] Exclusion Criteria: Patients were excluded form the study if: they were unable or unwilling to give informed consent; the patient was less than 18 years of age; there as evidence of pre-existing infection at or adjacent to the operative site; a break in sterile technique occurred; the patient had a history of allergy to chlorhexidine, alcohol or iodophores; and the perceived inability to follow the patient's course for 30 days after surgery.

[0057] Intervention Arms: Enrolled patients were randomly assigned in a 1 : 1 ratio to have the skin at the surgical site either preoperatively scrubbed with an applicator that contained 2% chlorhexidine gluconate and 70% isopropyl alcohol (ChloraPrep, Cardinal Health) or preoperatively scrubbed and then painted with an aqueous solution of 10% povidone-iodine (Scrub Care Skin Prep Tray, Cardinal Health). More than one chlorhexidine-alcohol applicator was used if the coverage area exceeded 33 by 33 cm. To help match the two groups and address potential interhospital differences, randomization was stratified by hospital with the use of computer-generated randomization numbers without blocking.

[0058] Efficacy Outcomes: The primary end point of the study was the occurrence of any surgical- site infection within 30 days after surgery. The operating surgeon was aware of which intervention had been assigned only after the patient was brought to the operating room. Both the patients and the site investigators who diagnosed surgical-site infection on the basis of criteria developed by the Center for Disease Control remained unaware of the group assignments. Secondary end points included the occurrence of individual types of surgical-site infections. These were classified as superficial incisional infection (which involved only skin and subcutaneous tissue and excluded stitch-related abscesses), deep incisional infection (which involved fascia and muscle), organ-space infection (which involved any organ or space other than the incised layer of body wall that was opened or manipulated during the operation), or sepsis from surgical-site infection.

[0059] Clinical Assessment: Preoperative evaluation included obtaining the patient's medical history and a physical examination, as well as routine hematologic and blood chemical laboratory tests. The surgical site and the patient's vital signs were assessed at least once a day during hospitalization, on discharge, at the time of follow-up evaluation, and whenever surgical-site infection occurred. After discharge, the investigators called the patients once a week during the 30- day follow-up period and arranged for prompt clinical evaluation if infection was suspected. Whenever surgical-site infection was suspected or diagnosed, clinically relevant microbiologic samples were cultured. Investigators who were unaware of the patients' group assignments assessed the seriousness of all adverse events and determined whether they were related to the study.

[0060] Statistical Analysis: Approximately 430 patients in each study group were evaluated in order for the study to have 90% power to detect a significant difference in the rates of surgical-site infection between the two groups, at a two-tailed significance level of 0.05 or less.

[0061] The significance of differences between the two study groups in terms of patient characteristics was determined with the use of the Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables. For efficacy outcomes, the proportions of patients in the two study groups who could be evaluated and who had any type of surgical-site infection were compared, using Fisher's exact test and calculating the relative risk of infection and 95% confidence intervals. The consistency of the effects of the study intervention on infections across different types of surgery was examined with the use of an interaction test. To determine whether the results were consistent across the six participating hospitals, a prespecified Breslow-Day test for homogeneity was performed. To compare the proportions of patients in the two study groups who were free of surgical-site infection as a function of the length of time since surgery, log-rank tests on Kaplan- Meier estimates based on analyses were performed in which data for patients who did not have infections were censored 30 days after surgery. Both the frequency of isolating certain organisms and categories of organisms and the incidence of adverse and serious adverse events were compared between the study groups with the use of Fisher's exact test. All reported P values are based on two- tailed tests of significance and were not adjusted for multiple testing.

[0062] Univariate and multivariate analyses were conducted to assess whether risk factors contributed to the occurrence of surgical-site infection. The univariate analysis for categorical factors was performed with the use of Fisher's exact test. For continuous factors, we used a single- variable logistic-regression model that involved generalized estimating equations (GEE) to account for hospital site as a random effect. A multivariate logistic -regression analysis that also adjusted for the hospital site as a random effect (by means of GEE) was performed to assess factors deemed significant (P<0.10) by univariate analysis or considered clinically important. The assessed risk factors were prespecified in the protocol, and the statistical methods were preplanned except for the inclusion of hospital site as a random effect. Since some types of surgery did not result in infection in either study group, a dichotomous variable— "abdominal" surgery (including colorectal, biliary, small intestinal, and gastroesophageal operations) versus "nonabdominal" surgery (including thoracic, gynecologic, and urologic operations)— was created for the GEE logistic-regression model.

[0063] Results: The overall rate of surgical-site infection was greater than 40% lower in the chlorhexidine-alcohol group than in the povidone-iodine group (9.5% vs. 16.1%; P=0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine-alcohol was significantly more protective than povidone-iodine against both superficial incisional infections by more than 50% (4.2% vs. 8.6%), P=0.008) and deep incisional infections (1% vs. 3%>, P=0.05) but not against organ- space infections (4.4% vs. 4.5%). Sepsis was also observed lower in the Chlorhexidine-alcohol treated group also by about 40% (2.7% vs. 4.3%).

[0064] Microbial Follow-up Studies: The surgical site of 60 infected patients were cultured and yield a growth of 107 different isolates. Gram-positive aerobic bacteria outnumbered gram-negative aerobic bacteria by a factor of about 2.5, and 38% of cultures were polymicrobial. There were no significant differences in the frequency of isolates with the exception of Streptococci, which were about 85%) less in the chlorhexidine-alcohol group as compared with the povidone-iodine group.

[0065] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of reducing post-operative surgical site infection in a patient having surgery comprising:

pre-operatively applying a formulation comprising of less than 4% w/v chlorhexidine or a salt thereof in an alcohol solution to a patient's skin at a surgical site;

scrubbing the skin with the formulation to completely wet the area at the surgical site for at least 30 seconds; and

air drying the skin for at least 30 seconds;

wherein the infection reduction is greater than or equal to about 40% than an administration of a povidone -iodine formulation.

2. The method of claim 1, wherein the surgical site is a site for clean-contaminated surgery.

3. The method of claim 2, wherein the clean-contaminated surgery is colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic or urologic surgery.

4. The method of claim 1, wherein the formulation comprises about 3.5%> w/v chlorhexadine.

5. The method of claim 1, wherein the formulation comprises about 3%> w/v chlorhexadine.

6. The method of claim 1, wherein the formulation comprises about 2.5%> w/v chlorhexadine.

7. The method of claim 1, wherein the formulation comprises about 2%> w/v chlorhexadine.

8. The method of claim 1, wherein the chlorhexidine is a chlorhexidine salt.

9. The method of claim 8, the chlorhexidine salt is selected from a group of salts consisting of gluconate, acetate, chloride, bromide, nitrate, sulfate, carbonate and phosphanilate.

10. The method of claim 8, the chlorhexidine salt is chlorhexidine gluconate.

11. The method of claim 1 , wherein the formulation further comprises a dye.

12. The method of claim 1, wherein the dye is selected from a group consisting of Food, Drug and Cosmetic (FD&C) Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, FD&C Red No. 3,

FD&C Red No. 40, FD&C Yellow No. 5, FD&C Yellow No. 6 and combinations thereof.

13. The method of claim 1, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol and isopropanol.

14. The method of claim 1, wherein the alcohol is isopropanol.

15. The method of claim 1, wherein the alcohol is about 50-95%) v/v.

16. The method of claim 1, wherein the alcohol is about 70%> v/v.

17. The method of claim 1 , wherein

is by an applicator.

18. The method of claim 1 , wherein

is by a sponge.

19. The method of claim 1 , wherein

20. The method of claim 1 , wherein

21. The method of claim 1 , wherein

22. The method of claim 1 , wherein

bacteria.

23. The method of claim 1, wherein prior to application of the formulation, the patient undergoes preoperative shower.

24. The method of claim 1, wherein the method further comprises administering to the patient antibiotics pre-operatively or post-operatively.

25. The method of claim 1, wherein the infection reduction is greater than or equal to 50%.

26. The method of claim 1, wherein the infection reduction is greater than or equal to

60%.

27. The method of claim 1, wherein the infection reduction is greater than or equal to

65%.

28. A method of reducing Streptococcus bacteria in post-operative surgical site infection in a patient having surgery comprising:

air drying the skin for at least 30 seconds;

wherein the Streptococcus bacteria reduction is greater than or equal to 40% than an administration of a povidone-iodine formulation.

29. The method of claim 1, wherein the Streptococcus bacteria reduction is greater than or equal to 60%.

30. The method of claim 1, wherein the Streptococcus bacteria reduction is greater than or equal to 70%.

31. The method of claim 1 , wherein the Streptococcus bacteria reduction is greater than or equal to 80%.