AU2007231679B2

AU2007231679B2 - Antimicrobial medical devices

Info

Publication number: AU2007231679B2
Application number: AU2007231679A
Authority: AU
Inventors: Shanta M. Modak; Lester A. Sampath
Original assignee: Columbia University in the City of New York
Current assignee: Columbia University in the City of New York
Priority date: 2000-12-22
Filing date: 2007-10-26
Publication date: 2011-10-06
Anticipated expiration: 2021-12-21
Also published as: AU2007231679A1

Abstract

P OPER\MKRSPECIh:R22 IO69 -d,, doc-6/I/m The present disclosure invention relates to medical devices treated with a solution comprising one or more solvents and a combination of chlorhexidine free base and a 5 water-soluble chlorhexidine salt in a molar ratio of between about 1:1 to about 1:5, preferably about 1:1.

Description

Australian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: The Trustees of Columbia University in the City of New York Actual Inventors: Sampath, Lester, A Modak, Shanta, M Address for Service: DAVIES COLLISON CAVE, Patent & Trademark Attorneys, of 1 Nicholson Street, Melbourne, 3000, Victoria, Australia Ph: 03 9254 2777 Fax: 03 9254 2770 Attorney Code: DM Invention Title: "Antimicrobial medical devices" The following statement is a full description of this invention, including the best method of performing it known to us: nAD1rA.Ak'R\C.FNFRA1 30392540-div doc P OPRVK SL l.'M23(h., doc .:I,;1' )7 ANTIMICROBIAL MEDICAL DEVICES This is a divisional of Australian patent application No. 2002231069, the entire contents of which are incorporated herein by reference. 5 1.0 INTRODUCTION The present invention relates to medical devices treated with a solution comprising a combination of chlorhexidine free base and a water-soluble chlorhexidine salt, in a ratio that facilitates chlorhexidine uptake by the devices and hence improves 10 antimicrobial effectiveness. 2.0 BACKGROUND OF THE INVENTION Whenever a medical device comes in contact with a patient, a risk of infection is created. Thus, a contaminated examination glove, tongue depressor, or stethoscope could transmit infection. The risk of infection dramatically increases for 15 invasive medical devices, such as intravenous catheters, arterial grafts, intrathecal or intracerebral shunts and prosthetic devices, which not only are, themselves, in intimate contact with body tissues and fluids, but also create a portal of entry for pathogens. Catheter related infections, especially blood stream infections, are associated with increased morbidity (10 to 20 percent), prolonged hospitalization (by a 20 period having a mean of seven days), and increased medical costs (approximately $6,000 per hospitalization). According to a survey of intensive care units from 1986 through 1990 by the National Nosocomial Infection Surveillance System, the rate of catheter-related blood stream infections ranged from 2.1 to 30.2 per 1,000 catheter-days. Infections associated with central venous catheters have been reported to result from the 25 transcutaneous migration of the pathogens from the insertion site with the eventual colonization of the catheter tip. In addition, intraluminal colonization has been suggested to result from contaminated hubs and infusates that contribute to catheter related blood stream infections. The longer the duration of catheterization, the greater the susceptibility to either luminal or outer surface colonization of catheters. Even for short term use of 30 catheters, infections have been reported due to contamination of the insertion sites.

A number of methods for reducing the risk of infection have been developed which incorporate anti-infective agents into medical devices. Such devices desirably provide effective levels of anti-infective agent during the period that the device is being used. Sustained release may be problematic to achieve, in that a 5 mechanism for dispensing anti-infective agent over a prolonged period of time may be required, and the incorporation of sufficient amounts of anti-infective agent may adversely affect the surface characteristics of the device. The difficulties encountered in providing effective antimicrobial protection increase with the development of drug resistant pathogens. 10 One potential solution to these problems is the use of a synergistic combination of anti-infective agents that requires relatively low concentrations of individual anti-infective agents which may have differing patterns of bioavailability. For example, WO 97/250S5 relates to medical devices comprising synergistic combinations of chlorhexidine and triclosan. United States Patent Nos. 5,616,33S and 15 5,019,096 relate to infection resistant medical devices comprising synergistic combinations of a silver salt, a biguanide (such as chlorhexidine) and a polymeric component that forms a matrix to provide a sustained release of the silver salt and biguanide. United States Patent Nos. 5,165,952 and 5,451,424 relate to medical 20 articles with chlorhexidine both coated on and bulk distributed throughout the medical articles. When chlorhexidine is bulk distributed it adversely affects certain characteristics of the device such as tensile strength, and the high temperatures needed for extension of plastics such as polyurethane may damage the chlorhexidine. United States Patent No. 5,089,205 relates to incorporation of 25 chlorhexidine free base or one of its salts in a medical device such as a glove by both a distribution.or dipping process. Chlorhexidine is a broad spectrum antimicrobial agent and has been used as an antiseptic for several decades with minimal risk of developing resistant microbes. When relatively soluble chlorhexidine salts, such as chlorhexidine acetate, 30 were used to impregnate catheters, the release was undesirably rapid. The duration of the antimicrobial efficacy of medical devices impregnated with chlorhexidine salts, 2 such as chlorhexidine acetate, is short lived. Chliorhexidine fl-ee base is not soluble in water or alcohol and cannot be impregnated in sufficient amounts because of low solubility in a solvent system. In contrast to the present invention, none of the above-cited references 5 teach medical articles treated with a solution comprising a combination of chlorhexidine fiee base and a water-soluble chlorhexidine salt, at particular ratios, which provide improved antimicrobial effectiveness through an increased uptake of chlorhexidine into the medical device, increased retention of chlorhexidine in the medical device and prolonged release of chlorhexidine from the medical device, while 10 utilizing relatively low levels of chlorhexidine. 3.0 SUMMARY OF THE INVENTION The present invention relates to medical devices treated with a solution comprising one or more solvents and a combination of chlorhexidine free base and a water-soluble chlorhexidine salt, in a weight/weight ratio of between about 1:1 to 15 about 1:5 (inclusive), preferably about 1:1 of chlorhexidine free base to chlorhexidine salt. The invention further relates to methods of preparing medical devices by exposing them, in whole or in part, to a solution comprising one or more solvents and the above-recited combinations of chlorhexidine free base and chlorhexidine salt. This invention is based, at least in part, on the discovery that devices 20 treated with combinations of chlorhexidine free base and a water-soluble chlorhexidine salt exhibit improved antimicrobial effectiveness due to increased uptake of chlorhexidine into the medical device, increased retention of chlorhexidine in the medical device, and prolonged release of chlorhexidine while utilizing relatively low levels of chlorhexidine, and, in certain non-limiting embodiments, in 25 the absence of agents other than chlorhexidine. In particular, while it had been previously found that triclosan can be particularly useful when used in conjunction with chlorhexidine free base, it has been further discovered that medical articles having suitable antimicrobial properties may be prepared, according to the present invention, without the use of triclosan. Therefore, in particular embodiments, medical 30 articles according to the present invention offer the advantage of preventing or 3 -4 inhibiting infection while avoiding undesirable adverse reactions to antimicrobial agents other than chlorhexidine by allergic individuals. In one embodiment, the present invention provides an antimicrobial medical artcile prepared by a method comprising treating a surface of a polymeric articles, for an effective 5 period of time, with a solution consisting essentially of one or more solvents and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 and 1:5, and wherein the combined concentration of chlorhexidine free base and a water-soluble salt of chlorhexidine is about 2.00 percent 10 (w/v) or greater. In another embodiment, the present invention provides an antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution consisting essentially of one or more solvents and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, 15 wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v). In another embodiment, the present invention provides an antimicrobial medical article prepared by a method comprising treating a surface of polymeric medical article, for an effective period of time, with a solution consisting essentially of a mixture of 20 chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 and 1:5, and comprising a solvent comprising methanol. In another embodiment, the present invention provides an antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, 25 for an effective period of time, with a solution comprising one or more solvent, a silver compound, and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 and 1:5. In another embodiment, the present invention provides an antimicrobial medical 30 article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution consisting essentially of one or more -4A solvents and a mixture of chlorhexidine free base and the water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is greater than 1:1. In another embodiment, the present invention provides an antimicrobial medical 5 article prepared by a method comprising treating a surface of a polymeric article, for an effective period of time, with a solution consisting essentially of one or more solvents and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 and 1:5, wherein the article is a hydrophobic polymeric medical 10 article, optionally comprising expanded polytetrafluoroethylene. In another embodiment, the present invention an antimicrobial medical article prepared by a method comprising treating a surface of polymeric medical article, for an effective period of time, with a solution consisting essentially of (1) one or more solvents; 15 (2) a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt; and (3) one or more of (i) an organic acid, at a concentration of between 0.1 and 5 percent; (ii) an anti-inflammatory agent, at a concentration of between 0.1 and 5 percent; or (iii) a hydrogel at a concentration of between 0.5 to 10 percent, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble 20 chlorhexidine salt in the solution is between 1:1 to 1:5. In another embodiment, the present invention provides a method of preparing a medical article comprising the steps of (i) placing the medical article in a solution consisting essentially of (a) a solvent comprising methanol; and 25 (b) a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5; (ii) soaking the medical article in the solution for an effective period of time to allow the medical article to swell; 30 (iii) removing the medical article from the solution; and (iv) drying the medical article.

C:\NRPVotbWCCSXD\383335I DOC-302M/0 I -4B In another embodiment, the present invention provides a method for preparing a catheter having a lumen comprising the steps of (i) exposing the lumen of the catheter to a solution consisting essentially of (a) a solvent comprising methanol; and 5 (b) mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and water-soluble chlorhexidine salt in the solution is between 1:1 and 1:5; (ii) filling the lumen of the catheter with the solution for an effective period of time to allow the lumen of the catheter to swell; 10 (iii) removing the solution from the lumen of the catheter; and (iv) drying the catheter. In another embodiment of the invention there is provided an antimicrobial catheter prepared by treating a polymeric catheter, for an effective period of time, with a solution 15 comprising a solvent and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the molar ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5. In a further embodiment of the invention there is provided an antimicrobial catheter prepared by treating a polymeric catheter, for an effective period of time, with a solution 20 comprising methanol and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight to weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5. In another embodiment of the invention there is provided an antimicrobial catheter 25 prepared by treating a polymeric catheter, for an effective period of time, with a solution comprising (1) a solvent; (2) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt; and (3) a substance selected from the group consisting of (i) an organic acid, at a concentration of between 0.1 and 5 percent; (ii) an anti-inflammatory agent, at a concentration of between 0.1 to 5 percent; and C:\NRPortb\DCCSXDU3333 I DOC-30MSN/II - 4C (iii) a hydrogel at a concentration of between 0.5 to 10 percent, wherein the molar ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5. In another embodiment of the invention there is provided a method of preparing a 5 catheter having a lumen comprising (i) contacting the lumen with a solution comprising (a) a solvent selected from the group consisting of water, alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof; and (b) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble 10 chlorhexidine salt, wherein the molar ratio of chlorhexidine free base and water soluble chlorhexidine salt in the solution is between 1:1 and 1:5; (ii) contacting the lumen with a solution for an effective period of time to allow the lumen to swell; (iii) removing the solution from the lumen; and 15 (iv) drying the catheter. In another embodiment of the invention there is provided a catheter prepared by treating a polymeric catheter for about thirty minutes to about one hour with a solution comprising a solvent and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water soluble chlorhexidine salt, 20 wherein the weight/weight ratio of the chlorhexidine free base and the water soluble chlorhexidine salt in the solution is between 1:1 and 1:5 and wherein the treated catheter exhibits sustained antimicrobial activity for at least about six days. 25 4.0 DETAILED DESCRIPTION OF THE INVENTION The present invention provides for medical articles treated with a solution comprising one or more solvents and a combination of chlorhexidine free base ("CHX") and a water-soluble chlorhexidine salt, and further provides for methods of preparing medical devices by exposing the device, in whole or in part, to said solution.

C :NRPonbr\DCOSXD\383335-II.DOC.30/20I I -4D While not being bound or limited by any particular theory, it is believed that the combination of CHX and water-soluble chlorhexidine salt forms a soluble complex. This would explain the increased uptake of chlorhexidine into the medical device, increased retention of chlorhexidine in the medical device, and increased sustained release of 5 chlorhexidine in the medical device while utilizing relatively low levels of chlorhexidine in the absence of agents other than chlorhexidine. The following are definitions of terms used herein unless otherwise indicated: Water soluble chlorhexidine salts have a solubility of at least about 2.0 grams per 100 ml in water at 20*C. Examples of water soluble chlorhexidine salts include 10 chlorhexidine diacetate (also referred to herein as chlorhexidine acetate, or "CHA") and chlorhexidine digluconate (or "CHG") with CHA being preferred. The terms "medical article" and "medical device" are used interchangeably herein. Medical articles that may be treated according to the invention are either fabricated from and/or coated or treated with biomedical polymer (and hence may be referred to as 15 "polymeric medical articles") and include, but are not limited to, catheters including urinary catheters and vascular catheters (e.g., peripheral and central vascular catheters), wound drainage tubes, arterial grafts, soft tissue patches (such as polytetrafluoroethylene (PTFE) soft tissue patches), gloves, condoms, shunts, stents, tracheal catheters, wound dressings, sutures, guide wires and prosthetic devices (e.g., heart valves and LVADs). 20 Medical articles that may be treated according to the invention include soft tissue patches made of expanded PTFE ("e-PTFE"), which is commercially available from W.L. Gore under the trade name Gore-Tex. Polymeric medical articles that may be treated according to the invention also include biodegradable polymers (such as polylactic acid (PLA), polyglycolic acid 5 (PGA) and polycaprolactone (PCL)) with PCL being preferred. Vascular catheters which may be prepared according to the present invention include, but are not limited to, single and multiple lumen central venous catheters, peripherally inserted central venous catheters, emergency infusion catheters, percutaneous sheath introducer systems and thennodilution catheters, including the hubs and ports of such vascular 10 catheters. The present invention may be further applied to medical articles that have been prepared according to United States Patent Nos. 5,616,338 and 5,019,096 by Fox, Jr. et al. and United States Patent No. 5,772,640 by Modak et al. The term "hydrophilic polymeric medical article" is a medical article fabricated from a hydrophilic polymer. As used herein, "hydrophilic polymer" refers 15 to polymers that have a water absorption greater than 0.6 percent by weight (and, in preferred embodiments, less than 2 percent by weight; as measured by a 24 hour immersion in distilled water, as described in ASTM Designation D570-81) including, but not limited to biomedical polyurethanes (e.g., ether-based polyurethanes and ester based polyurethanes, as set forth in Baker, 1987, in Controlled Release of Biologically 20 Active Agents, John Wiley and Sons, pp. 175-177 and Lelah and Cooper, 1986, Polyurethanes in Medicine, CRC Press, Inc., Fla. pp. 57-67; polyurethanes comprising substantially aliphatic backbones such as TecoflexTM 93A; polyurethanes comprising substantially aromatic backbones such as TecothaneTM; and PellethaneT"), polylactic acid, polyglycolic acid, natural rubber latex, and gauze or water-absorbent 25 fabric, including cotton gauze and silk suture material. The term "hydrophobic polymeric medical article" is a medical article fabricated from a hydrophobic polymer. As used herein, "hydrophobic polymer" refers to a polymer that has a water absorption of less than 0.6% (w/w) and includes, but is not limited to, silicone polymers such as biomedical silicones (e.g., Silastic 30 Type A) or elastomers (e.g., as set forth in Baker, 1987, in Controlled Release of Biologically Active Agents, John Wiley and Sons, pp. 156-162), Dacron, PTFE (also 5 "Teflon"), expanded PTFE, polyvinyl chloride (PVC), cellulose acetate, polycarbonate, and copolymers such as silicone-polyurethane copolymers (e.g., PTUE 203 and PTUE 205 polyurethane-silicone interpenetrating polymer). The terms "treat", "treated", "treating", etc., as used herein, refer to 5 coating, impregnating, or coating and impregnating a medical article with anti infective agent. Medical articles are "treated" by exposing them, for an effective period of time, to a treatment solution, where an "effective period of time" is that period of time sufficient to introduce anti-infective qualities of the anti-infective agent to the articles. Medical articles may be dipped, soaked, or otherwise have a surface 10 coated. The term "dipped" suggests briefer exposure to the treatment solution relative to "soaking," and preferably is for a period of time less than fifteen minutes. Percentages recited herein refer to weight/volume (w/v), except as indicated otherwise (e.g., volume/volume or "v/v"). The term "CFU" means colony forming unit. 15 The term "about" indicates a variation within 20 percent. The present invention provides for medical articles treated with a solution comprising one or more solvents and a combination of CHX and a water soluble chlorhexidine salt, in a weight/weight ratio of between about 1:1 and 1:5, preferably about 1:1. Such medical articles include hydrophilic polymeric medical 20 articles as well as hydrophobic polymeric medical articles fabricated from and/or coated or treated with such a biomedical polymer. In addition, the present invention may be applied to medical articles that have been prepared according to United States Patent Nos. 5,616,338 and 5,019,096 by Fox, Jr. et al. and United States Patent No. 5,772,640 by Modak et al. Such one or more solvents may be selected from the group 25 consisting of water, reagent alcohol, ammonium hydroxide, methyl alcohol, tetrahydrofuran ("THF"), dimethylsulfoxide, dimethylformamide, N-methyl-2 pyrrolidone, and mixtures thereof. In a specific non-limiting embodiment, the treatment solution comprises CHX-CHA in a weight/weight ratio between about 1:1 and about 1:5, 30 preferably about 1:1 of CHX to CHA. 6 The present invention further provides, in a non-limiting embodiment, for methods of preparing medical devices by treating the device, in whole or in part, with a solution comprising one or more solvents and a complex formed by synergistic combinations of chlorhexidine free base and chlorhexidine acetate. 5 In non-limiting embodiments, medical articles may be treated with a solution comprising the steps of (i) placing the medical article in a solution comprising (a) a solvent selected from the group consisting of water, reagent alcohol, ammonium hydroxide, methyl alcohol, THF, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof and (b) a mixture of CHX and a water 10 soluble chlorhexidine salt, preferably CHA, preferably in a weight/weight ratio of between about 1:1 and about 1:5; (ii) soaking the medical article in the solution for an effective period of time to allow the medical article to swell and to incorporate the anti-infective agents; (iii) removing the medical article from the solution; and (iv) drying the medical article. 15 Medical articles prepared according to the invention may be treated on an external surface, internal surface, or both. For example, and not by way of limitation, where the medical article is a catheter having a lumen, the internal (i.e., luminal) surface and/or external surface of the catheter may be treated together or separately according to the invention. An open-ended catheter may be placed in a 20 treatment solution such that the internal and external surfaces are exposed to the treatment solution. Alternatively, the ends of the catheter may be sealed before being placed in the treatment solution so that only the external surface is exposed to the treatment solution. Alternatively, only the internal surface may be exposed to the treatment solution if the solution is pushed, pulled or allowed to pass through and/or 25 fill the lumen without immersing the catheter in the treatment solution. In specific non-limiting embodiments, a catheter having a lumen may be treated with a solution comprising the steps of (i) exposing the lumen of the catheter to a solution comprising (a) a solvent selected from the group consisting of water, alcohol, ammonium hydroxide, methyl alcohol, THF, dimethylsulfoxide, 30 dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof and (b) a mixture of CHX and a water-soluble chlorhexidine salt, preferably CHA, preferably in a molar 7 ratio of between about 1:1 and about 1:5; (ii) filling the lumen of the catheter with the solution by pushing, pulling, or allowing passage of the solution into the lumen for an effective period of time to allow the material surrounding the lumen of the catheter to swell and to incorporate the chlorhexidine; (iii) removing the solution from the lumen 5 of the catheter; and (iv) drying the catheter. In the foregoing methods, the duration of exposure of the medical article or portion thereof to the treatment solution may preferably, but not by limitation, be ten seconds to one hour. The duration of exposure of the lumen of a catheter may preferably, but not by limitation, be ten seconds to two minutes. Longer 10 periods of exposure may be used provided that undesirable deterioration of the medical article does not occur. The treatment solutions may optionally further comprise (i) an organic acid, at a concentration of between about 0.1 and about 5 percent, preferably between about 0.1 and about 2 percent; (ii) an anti-inflammatory agent, at a concentration of 15 between about 0.1 and about 5 percent, preferably between about 0.1 and about I percent; (iii) a hydrogel at a concentration of between about 0.5 to about 10 percent, preferably between about I and about 5 percent; and/or a polymer at a concentration of between about 0.1 and about 6 percent, preferably between about 0.1 and about 4 percent. 20 5.0 WORKING EXAMPLES The following methods were used in performing experiments discussed in the following examples, unless indicated otherwise: Method of Treatment of a Medical Article with Solution. The medical article was treated by exposing the entire medical article, or a portion thereof, to a 25 solution containing CHA alone, CHX alone or the CHX-CHA combination in various amounts in a solvent system. The medical article, or a portion thereof, was exposed by soaking the article in the solution for 100 seconds before removing the article from the solution. For articles, such as catheters, having an internal lumen, the solution was pushed into the lumen and allowed to remain for 100 seconds before removal. 8 Method-ofDeteriining Drug Uptake. The amount of drug uptake into the treated polymeric medical articles was determined using a spectrophotometric method after extraction in alcohol. Method of Determining Long Term Antimicrobial Efficacy in Catheter 5 Lumen. In order to determine the duration of antimicrobial efficacy in catheter lumens exposed to treatment solutions, catheters were perfused for 7 days using the following continuous perfusion model. The distal lumens of catheters were connected to a peristaltic pump in a closed loop, wherein 1.5 L of 10% (v/v) trypticase soy broth in saline was constantly perfused by recycling it through each catheter lumen at a rate of 10 83 ml/hr for 7 days. On the eighth day the catheters were disconnected and used for evaluation of bacterial adherence. Method of Evaluating Microbial Adherence to a Catheter Luinen. After perfusion of catheters for 7 days as set forth above, the distal lumens of each catheter were filled with a 108 CFU/ml culture of bacteria or yeast. In the case of 15 exposure to E. aerogenes, P. aeruginosa and C. albicans, cultures containing 106 CFU/ml were used. The ends of the catheters were heat sealed and the catheters were incubated for 24 hours in an orbital shaker at 37*C. After 24 hours, the lock cultures were collected from the lumen and subcultured after serial dilution using agent inactivating media. The outer surface of the whole catheter was sterilized by wiping 20 the outer surface with an alcohol swab. Thereafter, the lumens were flushed with 20 ml trypticase soy broth to remove non-adherent bacteria. The body of the catheters were subdivided into 2 cm segments, which were further cut into 2 mm subsegments. The subsegments were placed in 4.0 ml agent inactivating media and sonicated in a 4*C water bath using an Astrasan Sonicator (Model 9T) at 60 KHertz. Thereafter, 0.5 25 ml of the extract was then subcultured on a trypticase soy agar plate and incubated at 37'C for 24 hours. Colony counts were then determined. Method of Evaluating Bacterial Adherence to PTFE Soft Tissue Patch Disks. Polytetrafluoroethylene (PTFE) disks were soaked and agitated in 3.0 ml of media containing 50% (v/v) bovine adult serum and 50% (v/v) trypticase soy broth. 30 The media was changed on days 1, 2 and 4. On the fourth day, 10' CFU/ml of bacteria was added to the media. On the fifth day, the disks were removed, rinsed and 9 rolled on drug inactivating agar. The plates were then incubated for 24 hours at 37 0 C. Colony counts were determined thereafter. Method of Determining Zones of Inhibition. Zones of inhibition were measured by seeding a specified amount of bacteria onto a trypticase soy agar plate. 5 Then, three units of a specified amount of medical article were placed on the plate. The plates were incubated at 37*C for 24 hours. The zones of inhibition were then measured for Day 1. To measure the zones of inhibition on Day 2 and subsequent days, the units of medical article were transferred onto a fiesh plate of similarly prepared agar, incubated at 37*C for 24 hours and colony-free zones were measured. 10 5.1 EXAMPLE: POLYURETHANE CENTRAL VENOUS CATHETERS Polyurethane central venous catheters, which are hydrophilic polymeric medical articles, were separated into three otherwise identical groups of catheters and separately treated with a solution that either (i) contained no antimicrobial agents; (ii) contained CHA alone, or (iii) contained a combination of CHX and CHA ("CHX 1 5 CHA") in accordance with the present invention. In particular, the luminal surfaces of the catheters were separately treated with one of the following solutions: (1) a solvent system of 80% (v/v) reagent alcohol and 20% (v/v) THF with no antimicrobial agents; (2) 2.4% CHA in a solvent system of 80% (v/v) reagent alcohol and 20 20% (v/v) THF; and(3) 1.2% CHX and 1.2% CHA in a solvent system of 80% (v/v) reagent alcohol and 20% (v/v) THF. The solution was exposed to the luminal surface of the catheter by pushing the solution into the lumen and allowing the solution to remain in the lumen for 100 seconds. Thereafter, the solution was removed, and the distal lumens of the 25 catheters were connected to a peristaltic pump in a closed loop, wherein 1.5 L of 10% trypticase soy broth in saline was constantly perfused by recycling it through each catheter lumen at a rate of 83 ml/hr for 7 days, according to the continuous perfusion method discussed above. On the eighth day the catheters were disconnected and the ability of bacteria to adhere to the lumens was tested as follows. 10 The distal lumens of each of the three groups of catheters were separately filled with 8 x 108 CFU/ml culture of S. epidermidis. The ends of the catheters were heat sealed and the catheters were incubated for 24 hours in an orbital shaker at 3 7'C. After 24 hours, the lock cultures were collected from the lumen and 5 subcultured after serial dilution using agent inactivating media. The outer surface of the whole catheter was sterilized by wiping the outer surface with an alcohol swab. Thereafter, the lumens were flushed with 20 ml trypticase soy broth to remove non adherent bacteria. The bodies of the catheters were subdivided into 2 cm segments, which were further cut into 2 mm subsegments. The subsegments were placed in 4.0 10 ml agent inactivating media and sonicated in a 4*C water bath using an Astrasan Sonicator (Model 9T) at 60 KHertz. Thereafter, 0.5 ml of the extract was then subcultured on a trypticase soy agar plate and incubated at 37*C for 24 hours. Colony counts were then detennined and are shown below in Table 1. TABLE 1 Solution Bacterial Adherence of S. epidermidis (CFU/cm) 80% (v/v) reagent alcohol + 2.2 x10 20% (v/v) THF 2.4% CHA in 3 x 102 80% (v/v) reagent alcohol + 20% (v/v) THF 1.2% CHX + 2 1.2% CHA in SO% (v/v) reagent alcohol + 20% (v/v) THF 15 The luminal surfaces of catheters were also tested according to the above described techniques to evaluate the adherence of a wide variety of organisms. The luminal surfaces of catheters were separately treated with the following solutions: (1) a solvent system of 80% (v/v) reagent alcohol and 20% (v/v) THF 20 with no antimicrobial agents; and 11 (2) 1.2% CHX and 1.2% CHA in a solvent system of SO% (v/v) reagent alcohol and 20% (v/v) THE. The luminal surfaces were exposed to the respective solutions for 100 seconds. Thereafter, the solutions were removed, and the lumens were perfused 5 according to the continuous perfusion method discussed above. On the eighth day, the catheters were disconnected and susceptibility to microbial adherence was evaluated. The distal lumens of each group of catheters were separately filled with the following amounts of bacteria (S. aureus, P. aeruginosa, and Enterobacter) or yeast (C. albicans): 10 (1) S x 108 CFU/ml culture of S. aureus; (2) 8 x 106 CFU/ml culture of P. aeruginosa; (3) 8 x 108 CFU/ml culture of Enterobacter; and (4) S x 106 CFU/ml culture of C. albicans. The four subgroups of lumens were prepared for evaluating microbial adherence to the 15 catheter lumens as described above. The ends of the catheters were heat sealed, incubated, subcultured, externally sterilized, flushed, subdivided, placed in inactivating media and sonicated according to the techniques set forth supra. Thereafter, 0.5 ml of the extract was subcultured, incubated and examined to determine the colony counts. The results are shown below in Table 2. 12 TABLE 2 Solution Adherence of Adherence Adherence of Adherence of o f Enterobacter C. albicans S. aureus P. aeruginosa (CFU/cm) (CFU/cm) (CFU/cm) (CFU/cm) So% (v/v) 1.3 x 10 4 >101 >10s 1.7 x 10 4 reagent alcohol + 20% (v/v) THIF 1.2% CHX + 3 9 2 26 1.2% CHA in 80% (v/,) reagent alcohol + 20% (v/v) THF The results shown in Table 1 demonstrate the synergistic antimicrobial 5 effect of treating a polyurethane central venous catheter lumen with a solution comprising the mixture of CHX and CHA. Table 2 shows that articles treated with CHX and CHA exhibit an increased effectiveness across a wide variety of organisms by decreasing luminal adherence substantially more than articles treated with no antimicrobial agents. 10 In a further study, the luminal surface of three groups of otherwise identical polyurethane central venous catheters were separately treated with one of the following three solutions: (1) 2% CHA in a solvent system of 80% (v/v) ethanol and 20% (v/v) THfF; 15 (2) 0.625% CHX and 1.375% CHA in a solvent system of 80% (v/v) ethanol plus 20% (v/v) THF; and (3) 1% CHX and 1% CHA in a solvent system of 80% (v/v) ethanol plus 20% (v/v) THF. The solution was pushed into the lumen and allowed to remain for 100 seconds. 13 The amount of uptake of chlorhexidine in the catheters was determined using a spectrophotometric method after extraction with alcohol. In order to determine the amount of drug retention and antimicrobial efficacy, the catheters were perfused for 6 days with 1.500 L of saline per day. The 5 treated catheters were then studied on Day 1 and Day 6 after perfusion to determine the amount of drug retention. The chlorhexidine in the catheter after perfusion was determined using a spectrophotometric method after extraction with alcohol. The antibacterial activity was measured on Day 6 after perfusion by counting the CFU/cm of S. epidermidis. Table 3 shows results of the uptake, drug retention and 10 antibacterial activity of the treated catheters. TABLE3 Solution Uptake Retention of Drug Antibacterial (pg/cm) (pg/cm) Activity (CFU/cm) Day 1 Day 6 S. epidernidis Day 6 2% CHA in 44 34 8 102 80% (v/v) Ethanol 20% (v/v) THF 0.625% CHX + 70 43 22 0 1.375% CHA in 80% (v/v) Ethanol 20% (v/v) THF I% CHX + 80 45 26 0 1% CHA in 80% (v/v) Ethanol 20% (v/v) THF These results demonstrate the synergistic antimicrobial effect of 15 treating a polyurethane central venous catheter lumen with a solution comprising a mixture of CHX and CHA. 14 5.2 EXAMPLE: ULNARY CATHETERS Hydrophilic urinary catheters were separated into two otherwise identical groups, and the whole catheters (i.e., external and luminal surfaces of the catheter) were treated with a solution containing either: 5 (1) 4% CHA in a solvent system of 85% (v/v) THF and 15% (v/v) methanol; or (2) 2% CHX plus 2% CHA in a solvent system of 85% (v/v) THF and 15% (v/v) methanol. The catheters of each group were soaked in the respective solution for 10 30 minutes to one hour. Thereafter, the catheters were removed from the solution. The amount of uptake of chlorhexidine was determined using a spectrophotometric method after extraction with alcohol, which results are shown below in Table 4. The two groups of catheters were separately exposed to cultures of 15 P. aeruginosa and C. albicans in order to study the antimicrobial efficacy of the medical article. Trypticase soy agar plates were seeded with 0.3 ml of 108 CFU/ml of P. aeruginosa and C. albicans, respectively. Thereafter, a 0.5 cm length of urinary catheter was placed on each plate with three units per plate. The plates were then incubated for 24 hours at 37*C. After 24 hours, the zones of inhibition were measured 20 for Day 1. To measure the zones of inhibition for Day 2 to Day 6, the process was repeated upon transferring the units to fresh agar plates similarly prepared. The results are shown in Table 4. 15 TABLE4 Solution Uptake Antimicrobial Efficacy Antimicrobial Efficacy (gg/cm) (Zone of Ihibition (Zone of Inhibition (mm)) (mm)) P. aeruginosa C. albicans Day Day 1 2 3 4 5 6 1 2 3 4 5 6 4%CHAin 123 15 11 10 9 0 0 11 9 0 0 0 0 85% (v/v) THF + 15% (v/v) Methanol 2% CHX + 380 16 13 11 10 10 10 12 11 11 10 9 6 2% CHA in 85% (v/v) THF + 15% (v/v) Methanol These results demonstrate the synergistic antimicrobial effect of 5 treating the urinary catheters with a solution comprising a mixture of CHX and CHA. 5.3 EXAMPLE: PTFE SOFT TISSUE PATCHES Disks cut from PTFE soft tissue patches, which are hydrophobic polymeric medical articles, were treated with a solution that contained CHA alone and a solution that contained a CHX-CHA complex in accordance with the present 10 invention. Groups of disks having a I nun thickness were treated for one hour with one of the following solutions: (1) 0.4% CHA in a solvent system of 70% (v/v) THF and 30% (v/v) methanol; or (2) 0.2% CHX and 0.2% CHA in a solvent system of 70% (v/v) THF 15 and 30% (v/v) methanol. The amount of uptake of chlorhexidine in the PTFE disks was determined using a spectrophotometric method after extraction with alcohol, and the results are shown below in Table 5. 16 The two groups of disks were separately exposed to cultures of P. aeruginosa and S. epidermidis in order to study their antimicrobial efficacy. Trypticase soy agar plates were seeded with 0.3 ml of 108 CFU/ml of P. aeruginosa and C. albicans, respectively. Thereafter, 0.5 cm diameter disks were placed on each 5 plate with three units per plate. The plates were then incubated for 24 hours at 37*C. After 24 hours, the zones of inhibition were measured for Day 1. The process was repeated upon transferring the disks to fresh agar plates similarly prepared for Day 2 to Day 6. The zones of inhibition are shown in Table 5. 10 Table 5 Solution Uptake Antimicrobial Efficacy Antimicrobial (pg/cm) (Zone of Inhibition Efficacy (Zone of (mm)) Inhibition (mm)) P. ae-uginosa S. epidermidis Day Day 1 2 3 4 1 2 3 4 0.4% CHA in 450 8 5 0 0 12 10 9 9 70% (v/v) THF + 30% (v/v) Methanol 0.2% CHX + 840 12 8 S 7 15 13 12 11 0.2% CHA in 70% (v/v) THF + 30% (v/v) Methanol These results demonstrate the synergistic effect of treating PTFE soft tissue patches with a solution comprising a mixture of CHX and CHA. Bacterial adherence on PTFE soft tissue patch disks treated with CHA 15 alone, CHX alone, or a mixture of CHA and CHX were studied. 2 mm thick disks were separated into four groups and separately treated with one of the following solutions: (1) a solvent system of 70% (v/v) THF and 30% (v/v) methanol with no antimicrobial; 20 (2) 0.4% CHA in a solvent system of 70% (v/v) THF and 30% (v/v) methanol; 17 (3) 0.4% CHX in a solvent system of 70% (v/v) THF and 30% (v/v) methanol; and (4) 0.2% CHX and 0.2% CHA in a solvent system of 70% (v/v) THF and 30% (v/v) methanol. 5 In order to determine the bacterial adherence to the PTFE, three disks of 1 cm diameter from patches in each treatment group were soaked and agitated in 3.0 ml of media containing 50% (v/v) bovine adult serum and 50% (v/v) trypticase soy broth. The media was changed on days 1, 2 and 4. On the fourth day, 10 5 CFU/ml of S. aureus was added to the media. On the fifth day after agitation in 10 media, the disks were removed, rinsed and rolled on to plates of drug inactivation agar. The plates were then incubated for 24 hours at 37*C. Thereafter, the colony counts were determined, and the amount of antimicrobial present in the disks was detennined by extracting the antimicrobial from the disk with alcohol, followed by spectrophotometric measurement. The results are shown in Table 6. 15 TABLE 6 Solution Drug levels Bacterial Adherence of ([tg/disk) S. aureus (CFU/cm) Day 5 70%(v/v) THF + 0 >10 5 30% (v/v) methanol 0.4% CHA in 264 8x 102 70% (v/v) THF + 30% (v/v) methanol 0.4% CHX in 361 1 x 10 2 70% (v/v) THF + 30% (v/v) methanol 0.2% CHA + 360 60 0.2% CHX in 70% (v/v) THF + 30% (v/v) methanol These results demonstrate the synergistic effect of treating PTFE soft tissue patches with a solution comprising a mixture of CHX and CHA. 18 5.4 EXAMPLE. POLYURETH ANE CENTRAL VENOUS CATHETERS In a further study of the drug retention properties of polyurethane central venous catheters treated with a solution containing a combination of CHX and 5 CHA ("CHX-CHA") in accordance with the present invention, the outer surfaces of otherwise identical catheters were treated with (i) CHA and silver sulfadiazine ("AgSD"), and (ii) CHX-CHA and AgSD. In particular, the ends of the catheters were sealed and the outer surfaces of the catheters were impregnated by dipping the closed catheters for 5 seconds in one of the following solutions: 10 (1) 3.5% CHA + 0.75% AgSD + 3% 93A + 1% 60D; (2)2% CHA + 1.5% CHX + 0.75% AgSD + 3% 93A + 1% 60D; and (3) 2% CHA + 1.5% CHX + 0.75% AgSD + 2.5% 93A + 2% 60D. The treated catheters were then tested for drug retention at various times using an in vitro agar tract model (method A) or an in vivo rat subcutaneous 15 model (method B). Method A: The bodies of the treated catheters were subdivided into 4 cm segments and implanted into 12.5 ml culture medium of 0.5 agar + 0.03 trypticase soy broth ("TSB") + 20% bovine adult serum ("BAS") + 0.5% Parmalat in a 15 ml culture tube. The catheter segments were transferred fo fresh medium on day 8, 26, 20 33, and 40 to simulate in vivo drug clearance. The drug levels were determined at day 8, 14, 22 and 50. Method B: The bodies of the treated catheters were subdivided into 4 cm segments and implanted under the skin of the test rats. The catheter segments were removed at day 8, 14 and 22 for determination of drug level. 25 In order to determine the drug level, 1 cm segments of the catheters were extracted with 2 ml dichloromethane. Thereafter, 4 ml of 50% reagent alcohol were added to remove the chlorhexidine from the dichloromethane layer. The results were read spectrophotometrically at 251 nm to determine the concentrations. The drug levels in, measured in jig/cm, were determined over time and are shown for those 30 catheters tested under method A in Table 7 below and for those catheters tested under method B in Table 8 below. 19 TABLE 7 SOLUTION CHLORHEXIDINE RETENTION (ig/cm) Method A (in vitio) Day 0 Day 7 Day 14 Day 22 Day 50 3.5 % CHA + 431 173 123 96 89 0.75 % AgSD + 3% 93A + 1% 60D 2% CHA + 1.5% CHX + 426 256 214 161 113 0.75% AgSD + 3% 93A + 1% 60D 2% CHA + 1.5% CHX + 444 328 257 236 158 0.75% AgSD + 2.5% 93A + 2% 60D , 5 TABLE 8 SOLUTION CHLORHEXIDINE RETENTION ( ig/cm) Method B (in vivo) Day 0 Day 7 Day 14 Day 22 3.5 % CHA + 431 145 144 103 0.75% AgSD + 3% 93A + 1% 60D 2%CHA + 1.5% CHX + 426 301 259 195 0.75% AgSD + 3% 93A + 1% 60D 2% CHA + 1.5% CHX + 444 345 308 263 0.75% AgSD + 2.5% 93A + 2% 60D |_ , These results demonstrate that the drug levels of catheters treated with 10 CHX-CHA and AgSD have a significantly higher drug retention under either testing method than catheters treated with similar drug levels of CHA alone with AgSD. Further, it is observed that changing the polymer component of the treatment solution containing CHX-CHA from 3% 93A + 1% 60D to 2.5% 93A + 2% 60D enhanced the effectiveness of the drug retention. 20 Catheters were prepared for evaluating bacterial adherence to the outer surfaces of each of the three groups of catheters described above. Catheters from each of the three groups were separately implanted according to either the agar tract model (method A) or the rat subcutaneous model (method B) described above and infected 5 with Staphylococcus aureus at various time intervals. Bacterial adherence was determined 7 days after infection. Under method A, the medium was changed at day 8, 26, 33 and 40, as stated previously, and infected at day 14, 29 and 44 with 20 pl of a 1 x 107 cfu/ml of S. aureus suspension. Under method B, each catheter segment was infected with a 25 pl of a 1 x 108 cfu/ml of S. aureus suspension on day 21. The body 10 of the catheters were subdivided into 1 cm subsegments , placed in a 4.0 ml drug inactivating media, and sonicated in a 4'C water bath using an Astrasan Sonicator (Model 9T) at 60 KI ertz. Thereafter, 0.5 ml of the extract was then subcultured on a trypticase soy agar plate and incubated at 37'C for 24 hours. Colony counts were then determined. The results of the colony counts under methods A and B are shown in 15 Table 9 by day of infection. TABLE 9 SOLUTION BACTERIAL ADHERENCE (cfu/cm) (S. aureus) Method A (in vitro) Method B (in vivo) Day 14 Day 21 Day 44 Day 14 Day 21 3.5 % CHA + 3 11 390 0 10 0.75% AgSD + 3% 93A + 1% 60D 2% CHA + 1.5% CHX + 0 6 59 0 6 0.75% AgSD + 3% 93A + 1% 60D 2% CHA +1.5% CHX + 0 7 59 0 9 0.75% AgSD + 2.5% 93A + 2% 60D 20 These results demonstrate that under methods A and B all of the groups of catheters were effective up to the 21st day post implantation. However, at 44 days post infection the catheters treated with CHA-CHX and AgSD in accordance with the 21 present invention had significantly lower colonization than the catheters with similar drug levels of CHA and AgSD without combination with CHX. Further, it is observed that changing the polymer component of the treatment solution containing CHX-CHA from 2.5% 93A + 2% 60D to 3% 93A + 1% 60D resulted in even lower 5 colonization. 5.5 EXAMPLE: EXPANDED PTFE SOFT TISSUE PATCHES In a further study of the drug retention properties and bacterial adherence of soft tissue patches, disks cut from expanded PTFE soft tissue patches were separately treated with one of the following solutions containing the specified 10 amounts of CHA, CHX-CHA complex in accordance with the present invention, silver carbonate ("Ag 2 CO3"), triclosan ("TC") and/or polycaprolactone ("PCL") in a solvent system containing ammonium hydroxide

("NH

4 0H"), methyl alcohol ("MetOH"), and tetrahydrofuran ("THF"): (1) 0.4 % CHA + 0.2 % Ag 2

CO

3 in 20 % (v/v) NH40H + 10% (v/v) 15 MetOH + 70% (v/v) THF; (2) 0.4% CHA + 0.1% Ag 2 CO3 + 1% PCL (w/v) in 10% (v/v) NH40H + 10% (v/v) MetOH + 80% (v/v) THF; (3) 0.2 % CHA + 0.2% CHX + 0.2% Ag 2

CO

3 in 10% (v/v) N-1 4 0H + 10% (v/v) MetOH + 80% (v/v) THF; 20 (4) 0.2 % CHA + 0.2% CHX + 0.1% Ag 2

CO

3 +1% (w/v) PCL in 10% (v/v) NH 4 0H + 10% (v/v) MetOH + 80% (v/v) THF; (5) 0.2% CHA + 0.2% TC + 0.2% Ag 2

CO

3 in 20% (v/v) NH 4 OH + 10% (v/v) MetOH + 70% (v/v) THF; (6) 0.1% CHA + 0.1% CHX + 0.2% TC +0.2% Ag 2 CO3 in 20% (v/v) 25 NH 4 0H + 10% (v/v) MetOH + 70% (v/v) THF; (7) 0.1% CHA + 0.1% CHX + 0.2% TC +0.1% Ag 2 CO3 in 20% (v/v) NH40H + 10% (v/v) MetOH + 70% (v/v) THF; (8) 0.1% CHA + 0.1% CHX + 0.2% TC +0.1% Ag 2 CO3 + 1% (w/v) PCL in 10% (v/v) NH40H + 10% (v/v) MetOH + 80% (v/v) THF; 22 (9) 0.4% CHA + 0.2% TC in 20% (v/v) NH 4 0H + 10% (v/v) MetOH + 70% (v/v) THF; or (10) 0.2% CHA + 0.2% CHX + 0.2% TC in 20% (v/v) NH 4 0H + 10% (v/v) MetOH + 70% (v/v) THF. 5 Groups of disks having a 1 mm thickness were treated for one hour with one of the above solutions. The amount of drug uptake was determined using a spectrophotometric method after extraction with alcohol. The results are shown below in Table 10. In order to determine the bacterial adherence to the expanded PTFE 10 soft tissue patches, six 1 cm 2 pieces 1 mm thick expanded PTFE soft tissue repair material from each treatment group were soaked in media containing 50% (v/v) BAS and 50% (v/v) TSB, incubated at 37'C and agitated on a shaker at 50 RPM. At each 7 day interval, the patches were removed, rinsed and placed in fresh media consisting of 50% (v/v) BAS and 50% (v/v) TSB infected with 105 cfu of Staphylococcus aureus , 1 5 which is available from the American Type Culture Collection, ATCC # 10390. After each 24 hour period of incubation at 37'C and shaking at 50 RPM, the patches were removed, blotted, rinsed twice and pushed across the surface of D/E drug inactivating agar to semi quantitatively determine the number of adherent organisms. Patches with greater than 100 cfu/cm 2 were considered colonized. The results are shown in Table 20 10 below. TABLE 10 SOLUTION 9g Mi tp Total Duration of chlorhexidine/cn 2 TC/cm2 Drug/cm Activity days) Control 0 0 0 0 (1) 0.4 % CHA + 226 226 <7 0.2 % Ag 2

CO

3 in 20 % NH 4 0H + 10% MetOH + 70% THF (2) 0.4% CHA + 373 373 <7 0.1% Ag 2

CO

3 + 1% PCL in 20% NH40H + 10% MetOH + 70% THF 23 0.2 % CHA + 0.2% CHX+ 307 307 >7<14 0.2% Ag 2

CO

3 in 20% NH 4 0H + 10% MetOH + 70% THF _ ) 0.2 % CHA + 0.2% CHX + 400 400 >7 <14 0.1% Ag 2 CO3 + 1% PCL in 20% NH40H + 10% MetOH + 70% TI-F ) 0.2% CHA + 74 168 242 >7 <14 0.2% TC + 0.2% Ag 2

CO

3 in 20% NH 4 0H + 10% MetOH + 70% THF ) 0.1% CHA + 0.1% CHX + 118 155 273 <7 0.2% TC + 0.2% Ag 2 CO3 in 20% NTH 4 0H + 10% MetOH + 70%/'o THF 7) 0.1% CH A+ 0.1% CHX + 209 244 453 >7 <14 0.2% TC + 0.1% Ag 2

CO

3 in 20% NH40H + 10% MetOH + 70% THF 8) 0.1% CHA + 0.1% CHX + 128 140 268 >21 0.2% TC + 0.1% Ag 2

CO

3 + 1% PCL in 20% NH40H + 10% MetOH + 70% THF (9) 0.4% CHA + 433 158 591 <7 0.2% TC + in 20% NH40H + 10% MetOH + 70% THF (10) 0.2% CHA + 0.2% CHX + 515 215 730 >7 <14 0.2% TC + in 20% NH 4 0H + 10% MetOH + 70% THF These results demonstrate the synergistic effect of treating expanded PTFE soft tissue patches with a mixture of CHX and CHA, particularly when comparing the significant improvement in chlorhexidine retention and increased 9)4 P IPE R\SM F( R ISP 2E 3 H -das doc-26110/07 -25 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or 5 steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general 10 knowledge in the field of endeavour to which this specification relates.

Claims

1. An antimicrobial catheter prepared by treating a polymeric catheter, for an effective period of time, with a solution comprising a solvent and an antimicrobial mixture 5 consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the molar ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5.

2. The antimicrobial catheter of claim 1, wherein the ratio is 1:1. 10

3. The antimicrobial catheter of claim 1, wherein the solvent is selected from the group consisting of water, alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof. 15

4. The antimicrobial catheter of claim 1, wherein the solvent is methanol.

5. The antimicrobial catheter of claim 3, wherein the solvent is a mixture of between 10 and 30 percent (volume/volume) tetrahydrofuran and 70 and 90 percent (volume/volume) ethanol. 20

6. The antimicrobial catheter of claim 3, wherein the solvent is a mixture of 20 percent (volume/volume) tetrahydrofuran and 80 percent (volume/volume) ethanol.

7. The antimicrobial catheter of claim 3, wherein the solvent is a mixture of between 25 75 and 95 percent (volume/volume) tetrahydrofuran and 5 and 25 percent (volume/volume) methanol.

8. The antimicrobial catheter of claim 3, wherein the solvent is a mixture of about 85 percent (volume/volume) tetrahydrofuran and 15 percent (volume/volume) methanol. 30 C:\NRPortb CC\SXD\3833351-I.DOC-30)082H -27

9. The antimicrobial catheter of claim 1, wherein the catheter has a lumen that is treated for an effective period of time with a solution comprising a solvent and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the molar ratio of chlorhexidine free base and the water-soluble 5 chlorhexidine salt in the solution is between 1:1 to 1:5.

10. An antimicrobial catheter prepared by treating a polymeric catheter, for an effective period of time, with a solution comprising methanol and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, 10 wherein the weight to weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5.

11. The antimicrobial catheter of claim 1 or claim 10, wherein the catheter is a hydrophilic polymeric catheter. 15

12. The antimicrobial catheter of claim 1 or claim 10, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

13. An antimicrobial catheter prepared by treating a polymeric catheter, for an effective 20 period of time, with a solution comprising (1) a solvent; (2) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt; and (3) a substance selected from the group consisting of (i) an organic acid, at a concentration of between 0.1 and 5 percent; (ii) an anti-inflammatory agent, at a concentration of between 0.1 to 5 percent; and (iii) a hydrogel at a concentration of 25 between 0.5 to 10 percent, wherein the molar ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:1 to 1:5.

14. The antimicrobial catheter of claim 13, wherein the concentration of organic acid in the solution is between 0.1 and 2 percent. 30 C:\NRPortb\DCC\SXD\833351_1.DOC.30/05/2011 -28

15. The antimicrobial catheter of claim 13, wherein the concentration of anti inflammatory agent is between 0.1 and 1 percent.

16. The antimicrobial catheter of claim 13, wherein the concentration of hydrogel in 5 the solution is between 1 and 5 percent.

17. A method of preparing a catheter comprising (i) contacting the catheter with a solution comprising (a) a solvent selected from the group consisting of water, alcohol, tetrahydrofuran, dimethylsulfoxide, 10 dimethylformamide, N-methyl-2-pyrrolidone, and a mixture thereof; and (b) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the molar ratio of chlorhexidine free base and water soluble chlorhexidine salt in the solution is between 1:1 and 1:5; (ii) allowing the catheter to stay in contact with the solution for an effective 15 period of time to allow the catheter to swell; (iii) removing the catheter from the solution; and (iv) drying the catheter.

18. A method of preparing a catheter having a lumen comprising 20 (i) contacting the lumen with a solution comprising (a) a solvent selected from the group consisting of water, alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof; and (b) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the molar ratio of chlorhexidine free base and water soluble 25 chlorhexidine salt in the solution is between 1:1 and 1:5; (ii) contacting the lumen with a solution for an effective period of time to allow the lumen to swell; (iii) removing the solution from the lumen; and (iv) drying the catheter. 30 C:\NRonbDCC\SXD\383335_1J DOC-30AW2011 - 29

19. A catheter prepared by treating a polymeric catheter for about thirty minutes to about one hour with a solution comprising a solvent and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water soluble chlorhexidine salt, wherein the weight/weight ratio of the chlorhexidine free base and the water 5 soluble chlorhexidine salt in the solution is between 1:1 and 1:5 and wherein the treated catheter exhibits sustained antimicrobial activity for at least about six days.

20. The catheter of any of claims 17, 18 or 19, wherein the solvent comprises between 10 75 and 95 percent (volume/volume) tetrahydrofuran and 5 and 25 percent (volume/volume) methanol.