Method of forming device for insertion into hub on proximal end of transdermal catheter, and device for sealing lumen of transdermal catheter

Abstract

To provide systems, methods and devices for providing an antimicrobial composition to proximal elements of a transdermal catheter and into a lumen of the transdermal catheter.SOLUTION: The device includes a cap 220 configured to be removably secured to the hub, the cap comprising: a ring member comprising first threads for engaging second threads on the hub of the transdermal catheter, the ring member having an opening through its interior; and an insert member secured into the opening of the ring member; where the insert member comprises an antimicrobial composition and where the ring and insert members do not readily rotate with regard to one another.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] This application relates to a catheter cap, and more particularly to a cap having a central insert and a retaining ring.

Background Art

[0002] This application is filed as an applicant for designations in all countries by Pursuit Vascular, Inc., a domestic company in the United States, and as an inventor for designations in all countries by Robert J. Ziebol, a citizen of the United States, as a PCT international patent application on November 21, 2019, claiming the priority of US Provisional Application No. 62 / 770,552 filed on November 21, 2018, the content of which is incorporated herein by reference in its entirety.

[0003] With a hemodialysis catheter, patients with kidney disease can remove toxins from their bloodstream. Without the use of a catheter, many of these patients would not be able to survive. However, long-term hemodialysis catheters have a significant drawback in that a significant percentage of catheters become non-functional due to infection, resulting in high mortality rates and high annual medical costs associated with treatment. Furthermore, bloodstream infections are a major cause of death in the United States, and many of those infections are attributable to vascular access devices such as hemodialysis catheters. The mortality rates associated with such infections are substantial. Therefore, there is a need for a method that can reduce infections associated with long-term hemodialysis catheters.

Summary of the Invention

Means for Solving the Problems

[0004] This application is in part directed to an apparatus for delivering an antimicrobial composition to the proximal end of a percutaneous catheter, the apparatus comprising a cap configured to be disposed on the proximal end of the catheter and an antimicrobial composition positioned at least in part within the cap.

[0005] The present disclosure is, in part, directed to an apparatus for insertion onto a hub at a proximal end of a percutaneous catheter, the apparatus comprising a cap configured to be removably secured to the hub, the cap comprising a ring member having a first thread for engaging a second thread on the hub of the percutaneous catheter, the ring member having an opening therethrough, and an insert member secured within the opening of the ring member. The ring member and the insert member are held together such that the ring member and the insert member, which are not readily rotatable and do not move relative to each other, and the insert member comprises an antimicrobial composition. An apparatus having a secure connection where the ring and insert are joined without readily recognizable movement therebetween allows for a better "feel" for smoother placement and removal on a female connector. Also, this design without readily recognizable movement provides a secure connection that does not easily loosen a structure involving movement between the ring and the insert. Further, this design provides a single release when removed from the connector, rather than a continuous release.

[0006] The present application is, in part, directed to an apparatus for insertion onto a hub at a proximal end of a percutaneous catheter, the apparatus comprising a cap configured to be removably secured to the hub, the cap comprising: i) a ring member having a first thread for engaging a second thread on the hub of the percutaneous catheter, the ring member having an opening therethrough; and ii) an insert member secured within the opening of the ring member, the insert member comprising an antimicrobial composition.

[0007] In one embodiment, the threaded ring member and the insert member are joined by an interference fit. In an exemplary embodiment, the threaded ring member and the insert member do not rotate relative to each other. In some embodiments, the threaded ring member and the insert member are prevented from rotating by an interference fit between the threaded ring member and the insert member. For example, the fit between the ring member and the insert member can be such that the threaded ring member and the insert member do not substantially rotate relative to each other when subjected to a torque of 0.0565 - 0.362 N-m (0.5 - 3.2 lb.-in).

[0008] Optionally, the threaded ring member and the insert member also do not move axially relative to each other. The threaded ring member and the insert member can be prevented from axial movement by an interference fit between the threaded ring member and the insert member. In some embodiments, the insert member has one or more fins protruding from the insert member. Optionally, the ring member and the insert member each comprise one or more fins, and the fins of the ring member and the insert member are in contact with each other along the interference fit. The fins enable the insert member to be fixed to the ring without any easily detectable movement or play between the parts. Thus, the insert and the ring feel as if they are integral and there is no easily detectable movement between them. A number of benefits can be identified in this regard. First, unlike conventional structures where the insert and the ring are at least slightly rotatable relative to each other, the improvement by interference fit prevents their rotation relative to each other. By preventing that rotation, it prevents the "retreat" of the ring from the insert that could occur otherwise. Second, the handling of the cap is improved because the cap feels like a single integral part.

[0009] In some embodiments, the ring member comprises an antibacterial substance on at least a portion of the first thread. In an exemplary embodiment, the insert member further comprises an elongate member configured to be inserted into the hub of the percutaneous catheter.

[0010] This application also relates to a method of forming an apparatus for insertion into a hub on a proximal end portion of a percutaneous catheter, the method comprising providing a ring member having a first thread for engaging a second thread on the hub of the percutaneous catheter, the ring member having an opening therethrough; providing an insert member configured to be inserted through the opening in the ring member; applying an antibacterial composition to at least a portion of the ring member; and securing the insert member to the ring member such that the ring member is fixed within the opening.

[0011] The method optionally further comprises applying the antibacterial composition to at least a portion of the ring member prior to securing the insert member to the threaded ring member, and the threaded ring member and the insert member are joined by an interference fit. The threaded ring member and the insert member preferably do not rotate relative to each other. Optionally, rotation between the threaded ring member and the insert member is prevented by an interference fit between the threaded ring member and the insert member.

[0012] This application further relates to an apparatus for sealing the lumen of a percutaneous catheter, the apparatus comprising a cap configured to removably seal the lumen at the hub at the proximal end of the percutaneous catheter. The cap comprises: i) a ring member having a first thread for engaging a second thread on the hub, the ring member having an opening therethrough, the opening having one or more first fins; and ii) an insert member having a tapered outer surface for engaging the tapered inner surface of the hub to seal fluid within the lumen, the insert member further comprising one or more second fins. The insert member is fixed within the opening of the ring member, and the second fins are configured to engage the first fins to prevent rotation of the insert member within the ring member. Optionally, the first thread contains an antibacterial composition such as a coating.

[0013] This application further relates to an apparatus for sealing the lumen of a percutaneous catheter, the apparatus comprising a cap configured to removably seal the lumen at the hub at the proximal end of the percutaneous catheter, the cap comprising: i) a ring member having a first thread for engaging a second thread on the hub, the ring member having an opening therethrough, the opening having one or more first fins; and ii) an insert member having a tapered outer surface for engaging the tapered inner surface of the hub to seal fluid within the lumen, the insert member further comprising one or more second fins. The insert member is fixed within the opening of the ring member, and the second fins are configured to engage the first fins by means of an interference fit or the like to prevent relative rotation between the ring member and the insert member.

[0014] This summary is not intended to limit the invention. The invention is further described in the following detailed description and claims. The invention can be understood in more detail in connection with the following drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

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DETAILED DESCRIPTION OF THE INVENTION

[0016] In some cross-sectional views, it will be noticed that the explanatory diagrams are simplified, such as removing the threads behind the cap to make various aspects of the present invention clearer. For example, refer to FIG. 11A where the threads behind are removed, as compared with FIG. 3B where the threads behind are shown.

[0017] The present invention relates to devices, systems, and methods for controlling, arresting, and removing infectious organisms within medical devices such as catheters and drainage tubes, and preventing the organisms from entering the bloodstream. The devices, systems, and methods deliver an antibacterial composition near the lumen and the inlet region of the catheter and the drainage tube. In particular, the present application is directed to a device for delivering an antibacterial composition to the proximal end of a percutaneous catheter, the device comprising a cap configured to be disposed on the proximal end of the catheter, and an antibacterial composition positioned on the cap to be delivered to the proximal end of the catheter such that the antibacterial composition is retained at the proximal end of the catheter and / or released to the outer portion of the proximal end of the catheter.

[0018] Over the past 20 years, research and development for preventing catheter-related bloodstream infections (CRBSIs) has focused on methods for killing bacteria along the inner and outer lengths of catheters. This research has been successful in reducing the incidence of CRBSIs in some catheter types. For example, commercially successful antimicrobial-coated catheters have reduced the incidence of infections in applications using short-term (non-implanted) catheters.

[0019] However, these coatings are washed away by use and are therefore not effective for long-term use. The use of long-term (implanted, cuffed) hemodialysis catheters results in approximately 2.3 bloodstream infections per 1000 days of catheter use. Stated another way, patients undergoing dialysis with hemodialysis catheters can be expected to develop a bloodstream infection on average every 14 months.

[0020] The present invention can prevent, reduce, and even remove infectious organisms in the inlet region of a catheter or tube, and on the inner lumen surface of a catheter or other similar medical device, by providing means for the long-term presence of an antimicrobial composition and / or by providing means for periodically scrubbing the inlet region and / or lumen of a catheter or other medical device to remove infectious organisms and biofilms in which infectious organisms grow.

[0021] The present invention includes methods and devices for killing organisms and preventing organism growth and biofilm formation in a catheter so that the organisms cannot exit the catheter and enter the patient's bloodstream. The articles of the present invention prevent organisms from reaching the bloodstream or reduce the number of organisms reaching the bloodstream by employing some or all of the following exemplary prevention methods: 1) physical prevention of organism movement outside the catheter; 2) killing of organisms along the threads, end faces, and luer connectors (inside and outside of the connectors) at the proximal end of the catheter (outside the body) using an antibacterial composition; and / or 3) killing of organisms in a limited area of the catheter using an antibacterial composition and / or a physical barrier within the catheter lumen. A fourth mode of action, scrubbing of the catheter wall (for physically removing organisms adhering to the inner wall when the cap is removed from the catheter), may also be used in conjunction with other methods and devices.

[0022] The antibacterial composition can be delivered as a coating eluting from a coated elongate member, which is coated on or impregnated in the elongate member (such as a layer of about 2 μm thickness of 250 μg of chlorhexidine acetate along an elongate member / rod of 17 mm in length × 1.9 mm in diameter). The elongate member has the additional advantage of moving fluid from within the catheter when the elongate member is inserted and delivering the solution to the outer base region (end face and threads) of the catheter connector.

[0023] The antimicrobial composition from the cap dissolves in the displaced fluid, thereby disinfecting the proximal end portion of the connector. Further still, when the fluid dries, it forms a coating of chlorhexidine acetate or other suitable antimicrobial composition on the connector as described above. As an alternative to the use of the elongate member, chlorhexidine acetate or other antimicrobial composition may be delivered by a coating on the luer tip (such as 250 μg of chlorhexidine acetate in a layer about 20 μm thick). The luer portion is also coated with an antimicrobial composition in some embodiments (such as 50 μg of chlorhexidine acetate in a layer about 0.4 μm thick). It is also possible to deliver the antimicrobial composition through the connector tip cavity (a dry-soluble amount applicable to citrate or others that require a large amount of antimicrobial composition).

[0024] In one exemplary embodiment, the present invention is directed to a method of delivering an antimicrobial composition to the proximal end of a percutaneous catheter, the method comprising: a) providing a percutaneous catheter to be implanted in a patient, the percutaneous catheter having a proximal end disposed outside the patient and a distal end at least partially disposed within a blood vessel of the patient, the catheter comprising: i) a hub disposed at the proximal end of the catheter; ii) external threads on the proximal end of the hub; and iii) an internal channel of the hub that communicates from an opening at the proximal end of the catheter to the lumen of the catheter, at least a portion of the internal channel having a tapered inner surface; b) providing an antimicrobial composition delivery device for insertion into the base opening of the catheter, the antimicrobial composition delivery device comprising: i) a tapered member configured for insertion into the catheter hub, the tapered member being configured to substantially seal the proximal end of the catheter; ii) an elongate member extending from the tapered member, the elongate member being configured for insertion into the catheter hub; iii) an antimicrobial composition positioned on the elongate member; and iv) a retaining ring having threads configured to engage the external threads on the catheter hub; c) injecting a liquid lock solution into the percutaneous catheter such that at least the proximal end of the percutaneous catheter is substantially filled with the lock solution; d) applying a clamp to the proximal end of the catheter, the clamp substantially preventing fluid flow across the clamped portion of the catheter; and e) after applying the clamp, inserting the elongate member and the tapered member of the antimicrobial substance delivery device into the hub disposed at the proximal end of the catheter. The elongate member is substantially retained within the hub of the percutaneous catheter, the tapered member of the antimicrobial substance delivery device sealingly engages the tapered member of the catheter hub, and the antimicrobial composition elutes into the lock solution on the proximal end of the clamp.

[0025] In one embodiment, upon insertion of the elongate member into the catheter hub, the antimicrobial composition does not enter the distal end of the catheter or the patient. In certain embodiments, when inserting the elongate member and the tapered member into the hub, at least a portion of the locking solution flows backward from the hub so as to moisten the threads on the retaining ring and the threads on the hub.

[0026] In certain embodiments, when inserting the elongate member and the tapered member of the antimicrobial delivery device into the hub, the interior of the hub defines a first volume of locking solution, a second volume of locking solution, and a third volume of locking solution. The first and third volumes of locking solution are separated by the second volume of locking solution, and the second volume of locking solution has a constriction such that it has a smaller cross-sectional area than the first volume of locking solution or the third volume of locking solution.

[0027] In certain embodiments, when inserting the elongate member and the tapered member of the antimicrobial delivery device into the hub, the interior of the catheter defines a first volume of locking solution, a second volume of locking solution, and a third volume of locking solution. The first volume of locking solution has an average diameter larger than the average diameter of the second volume, the second volume of locking solution has an average cross-sectional area smaller than the average cross-sectional area of the first and third volumes, and the third volume of locking solution has a cross-sectional area approximately equal to the average luminal cross-sectional area of the catheter on the proximal side with respect to the clamp. In certain embodiments, the first volume of locking solution comprises locking solution disposed in a portion of the inner channel of the hub between the end of the tapered member and the end of the tapered inner surface of the inner channel, the second volume of locking solution is disposed between the end of the tapered inner surface of the inner channel and the end of the elongate member, and the third volume of locking solution comprises locking solution disposed within the catheter between the end of the elongate member and the clamp. Optionally, the second volume is smaller than the first volume and the first volume is smaller than the third volume. In certain embodiments, when inserting the elongate member and the tapered member into the hub, the antimicrobial concentration in the first volume is initially higher than the antimicrobial concentration in the third volume. In certain embodiments, the antimicrobial concentration in the first volume after 48 hours is at least 10 times higher than the antimicrobial concentration in the third volume. In certain embodiments, the amount of antimicrobial in the first and second volumes after 48 hours is at least 3 times more than the amount of antimicrobial in the third volume.

[0028] In some embodiments, the antimicrobial composition forms a precipitate having antimicrobial properties. The precipitate deposits inside the hub. In some embodiments, the antimicrobial composition is coated on a elongate member. In some embodiments, the elongate member is entirely proximal to the clamp. In some embodiments, the elongate member is entirely contained within the hub. Optionally, the elongate member has a cross-sectional area of at least 25 percent of the cross-sectional area at the narrowest point in the channel of the hub.

[0029] The elongate member may have a cross-sectional area of at least 50 percent of the cross-sectional area at the narrowest point in the channel of the hub, at least 75 percent of the cross-sectional area at the narrowest point in the channel of the hub, or less than 90 percent of the cross-sectional area at the narrowest point in the channel of the hub (e.g.).

[0030] In some embodiments, the percutaneous catheter is a hemodialysis catheter having two hubs, and the two antimicrobial devices are mounted on the two hubs. Typically, the elongate member has a length longer than the length of the tapered member. The elongate member may have a cross-sectional area less than 50 percent of the average cross-sectional area of the tapered member. Optionally, the elongate member has a cross-sectional area less than 50 percent of the maximum cross-sectional area of the tapered member. In some embodiments, the elongate member has a cross-sectional area less than 50 percent of the minimum cross-sectional area of the tapered member. The elongate member may have a volume of at least 50 percent of the volume of the tapered member. In one embodiment, the elongate member displaces at least 0.03 mL of volume from the hub. The tapered member and the elongate member can be rigidly attached to each other and cannot be separable.

[0031] The present invention also relates to a method of coating an antibacterial composition on the proximal end portion of a percutaneous catheter, the method comprising: a) providing a percutaneous catheter to be implanted in a patient, the percutaneous catheter having a proximal end portion disposed outside the patient and a distal end portion at least partially disposed within a blood vessel of the patient, the catheter comprising: i) a hub disposed at the proximal end portion of the catheter; ii) external threads on the proximal end of the hub; and iii) an internal channel extending from an opening at the proximal end of the catheter to the lumen of the catheter, at least a portion of the internal channel having a tapered inner surface; b) providing an antibacterial substance delivery device for insertion into the base opening of the catheter, the device comprising: i) a tapered member configured for insertion into the catheter hub and configured to substantially seal the proximal end of the catheter; ii) an elongate member extending from the tapered member and configured for insertion into the catheter hub; iii) an antibacterial composition positioned on the antibacterial substance delivery device; and iv) a retaining ring having threads configured to engage external threads on the catheter hub; c) injecting a liquid lock solution into the percutaneous catheter such that at least the proximal end portion of the percutaneous catheter is substantially filled with the lock solution; d) applying a clamp to the proximal end of the catheter, the clamp substantially preventing fluid flow across the clamped portion of the catheter; and e) after applying the clamp, inserting the elongate member and the tapered member of the antibacterial substance delivery device into the hub disposed at the proximal end of the catheter, wherein upon insertion of the elongate member, the antibacterial composition forms an antibacterial precipitate within the lock solution, and the antibacterial precipitate coats the internal channel of the hub of the catheter. Optionally, when the antibacterial precipitate coats the internal channel of the hub, the antibacterial agent and the antibacterial precipitate are not delivered to the catheter lumen on the distal side of the clamp or to the patient. Further, the antibacterial substance can be formed through a chemical reaction involving chlorhexidine ions and chlorine ions.

[0032] The following detailed description shows an explanation of certain embodiments that assist in understanding the claims. However, the invention may be practiced in many different embodiments defined and encompassed by the claims.

[0033] In one aspect, the present invention includes a biological barrier at the outer end of a catheter, also referred to herein as the proximal end of the catheter. This barrier provides a seal that prevents organisms from reaching the end face and luer portion of the connector on the catheter. This can be achieved in a first embodiment by disposing an elastomeric flap or gasket (i.e., silicone, neoprene, polyurethane, etc.) at the end of the connector of the cap or, alternatively, along the inner wall of the locking ring of the cap. The flap preferably creates a fluid-tight seal against the outer wall of the catheter connector, thereby reducing the potential for microbial invasion and preventing microbial growth. As another method, the barrier may preferably be formed by disposing a foam of closed or open cells, which preferably contains an antibacterial composition, along the inner wall of the retaining ring of the cap and / or at the lowermost position of the cap such that the foam abuts and seals the proximal end of the catheter connector surface (also referred to as the end face).

[0034] Embodiments that use an antibacterial composition along the threaded region of the cap but do not include a biological barrier can also be used to reduce the number of organisms that may enter the catheter. This reduction in the number of organisms that may enter the catheter can be achieved by killing the organisms within the threaded and end face regions.

[0035] The cap is optionally designed to transfer an antimicrobial composition from the cap to the catheter threads. This is achieved, for example, by moving fluid from the catheter to the threaded region of the connector. In certain embodiments, the elongate member and the luer, when entering the catheter, move the catheter fluid and cause the fluid to flow out into the threaded region between the connector and the cap. The antimicrobial composition is dissolved in the fluid and saturates the fluid with the antimicrobial composition. The antimicrobial fluid creates an effective disinfection zone and kills organisms on the connector. Additionally, when the fluid dries, the antimicrobial substance precipitates out of the fluid and deposits on the catheter threads and end faces. This process is repeated each time a new cap is placed on the catheter, thus replenishing the antimicrobial composition on the base region of the catheter with each new cap.

[0036] In a further aspect, the invention is directed to adding an antimicrobial composition along the luer connector. This can be achieved, for example, by coating the male luer connector with various antimicrobial compositions.

[0037] In an additional aspect, the invention is directed to delivering an antimicrobial composition inside the catheter. The antimicrobial substance can be delivered as a coating that elutes from a coated elongate member (or an elongate member impregnated with the antimicrobial substance) coated on the elongate member. The elongate member has the further advantage of moving fluid from within the catheter when the elongate member is inserted, thereby transferring the fluid to the outer base region (end face and threads) of the catheter connector. The antimicrobial composition from the cap dissolves in the moved fluid, thereby disinfecting the proximal end of the connector.

[0038] Furthermore, when the fluid dries, it forms a coating of chlorhexidine acetate or other suitable antimicrobial composition on the connector as described above. As an alternative to the use of the elongate member, chlorhexidine acetate or other antimicrobial composition may be delivered by a coating on the luer tip (such as 250 μg of chlorhexidine acetate in a layer about 20 μm thick). The minimum of 10 μg of chlorhexidine acetate on the elongate member is effective against many organisms in some embodiments. Values exceeding the desirable minimum of 100 μg are effective against most organisms, and a further desirable minimum of 250 μg is highly effective against all of the major target organisms.

[0039] The types of antimicrobial compositions can include, but are not limited to, chlorhexidine base, chlorhexidine acetate, chlorhexidine gluconate, EDTA, iodine, silver sulfadiazine, or taurolidine, or combinations thereof. Other antimicrobial compositions may also be used.

[0040] Typically, these methods are also used in conjunction with confining an antimicrobial substance to a catheter, for example, by relying on a catheter clamp that confines the antimicrobial composition to a portion of the proximal end of the catheter (the portion of the catheter outside the patient, particularly the portion closest to the catheter connector where fluid enters and exits the catheter). Extension tube clamps are typically part of each hemodialysis catheter and are currently used to confine the lock solution that is used to help ensure catheter patency. Using existing clamping methods, the risk of air embolism and lock solution entering the patient is very small and is consistent with the state of the art for performing hemodialysis procedures. For other medical devices such as catheters that do not have a catheter clamp, a swellable cap tip or other confining techniques as described in U.S. Patent Application Publication No. 2010 / 0106103 may be used.

[0041] Mechanical removal of organisms can also be utilized. In this regard, a portion of the elongate member can, for example, have ribs incorporated into the elongate member such that the catheter wall can be discarded during removal. In some embodiments, after the elongate member is inserted into the catheter, anisotropic swelling moves the rib (or other protrusion) against the inner wall of the catheter, thereby providing a tight fit against the wall after swelling and further facilitating mechanical removal of organisms when the elongate member is removed from the catheter along with the remainder of the sealing cap. Also, in some embodiments, the tip (or other portion such as a swelling rib) of the elongate member swells, or swelling occurs along the length of the elongate member. Generally, when the elongate member is inserted, the unswollen diameter of the elongate member is smaller than the catheter lumen but swells to conform to the inner shape (or larger shape) of the catheter lumen, enhancing mechanical removal of organisms during removal. Various polyurethanes or other materials may be used to provide suitable anisotropic swelling and mechanical stability. More specifically, Lubrizol 1065D is suitable for non-swelling elongate members, and TG-500 is suitable for anisotropic swelling (or isotropic swelling) tips that may be adhered to each other using thermal adhesion or other suitable methods.

[0042] As used herein, embodiments of the invention referred to as "caps" prevent movement of infectious organisms into the body by providing an antimicrobial substance and / or a physical barrier that prevents movement of infectious organisms into the catheter and further prevents propagation of infectious organisms within the proximal end of the catheter.

[0043] The cap optionally includes an elongate member that can be inserted into a medical device such as a catheter or drainage tube. For simplicity, the term "catheter" is used for all medical devices into which the present invention can be inserted and which can be used for the control, prevention, and removal of infectious organisms. The cap may be removed from the catheter to enable the catheter to be used in a dialysis procedure or other procedure. After the procedure is completed, a new cap may be used to seal and protect the catheter. The removal of one cap and replacement with a new cap may be repeated an indefinite number of times. Each new cap restores the antimicrobial composition on the inside and outside of the catheter. In another aspect, the antimicrobial composition is transferred from the cap to the catheter each time it is used.

[0044] When the cap is used with a dialysis catheter, the present invention is generally designed to be replaced regularly, generally after each dialysis session, about three times per week. This replenishes the antimicrobial composition with each replacement, resulting in a stable, high concentration of the antimicrobial composition being present within and on the catheter, continuously reducing the risk of infection. However, the containment method, such as a clamp, used with the present invention prevents a significant amount of the antimicrobial composition from leaking regularly into the bloodstream, thereby maintaining a higher concentration of the antimicrobial composition at the proximal end of the catheter where there is a significant risk of microbial ingress.

[0045] Furthermore, since the non-antibiotic antibacterial substance is used by separating the antibacterial composition from the blood, as a result, the infection rate can be made lower, the side effects can be made fewer, and the risk of producing resistant bacteria can be made smaller. In certain embodiments, the present invention creates a physical barrier between the blood and the antibacterial composition. The barrier significantly reduces the exchange of the antibacterial composition with the blood circulating in the body, and as a result, there are fewer side effects from the antibacterial composition. Thereby, along the length of the catheter adjacent to the cap, the antibacterial composition can be at a more stable level. Further, the barrier reduces the amount of the antibacterial composition entering the bloodstream, and thus, the risk of side effects to the composition or the risk of producing organisms resistant to the antibacterial composition is reduced.

[0046] In comparison, as is well known, liquid lock compositions can move into the bloodstream and typically do so, and the blood can move into the catheter, thus reducing the effectiveness of the antibacterial composition, increasing the likelihood of bacteria entering the bloodstream, and accelerating the rate of thrombus formation in the catheter. By the act of flushing the catheter lumen with a fluid composition into the lumen, as a result, blood is removed from the lumen, and thus, the risk of thrombus formation is reduced. If the liquid composition is an antithrombotic lock such as heparinized saline or saline containing 4% sodium citrate, the risk of thrombus formation is further reduced. By using a confinement means such as a swellable elongate member tip, a swellable elongate member, or a catheter clamp as described in the present invention, blood is prevented from re-entering the lumen, and as a result, the risk of thrombus formation in the lumen is lower.

[0047] A further aspect of the present invention relates to protecting the cap from contamination during use and handling to maintain the sterility of the elongate member and the luer before insertion into the catheter. A package covering the elongate member and the luer may be used. A standard package protecting one luer and one elongate member is suitable for maintaining the sterility of one elongate member and one luer. A novel package that improves handleability while maintaining sterility protection and facilitates low-cost injection molding is described below.

[0048] The packaging container holds two caps, the two caps are axially offset and held in opposite directions by 180 degrees, usually at least a part of the two elongated members axially overlap each other, and there is a physical barrier between the two caps. The packaging container functions as a shield that protects the caps, maintains the sterilization of the caps, and further prevents the reduction of the antibacterial composition disposed on the portion of the cap inserted into the catheter.

[0049] The packaging container may have a thread to provide means for removably attaching the cap to the package. With this configuration, the user can hold not two but one part, so that handling becomes easier and the risk of dropping the cap is reduced. The barrier between the two caps ensures that when one cap is removed from the packaging container, the other cap remains sterilized. The cap fixed inside the package may be included in a pouch using a suitable material such as a metal film made of a polymer laminate that facilitates heat sealing. The metal layer is useful for minimizing the adverse effects of humidity. The device inside the pouch may be sterilized using gamma rays or other suitable sterilization methods. Gamma rays have the advantage of effectively sterilizing the product while keeping the product in a moisture-proof package.

[0050] Referring now to the drawings, an exemplary embodiment of the present invention is shown. FIG. 1A shows an exploded view of a packaging container system 210 including an arterial cap 220, a venous cap 320, and a packaging container 250. The packaging container system 210 includes two caps within the same packaging container 250. The colors of the caps are usually selected as red for the arterial cap 220 and blue for the venous cap 320 so as to conform to the standard colors used in hemodialysis. Usually, the arterial cap 220 and the venous cap 320 are the same except for the color.

[0051] Since the packaging container 250 has relatively few parts to handle and hold, the handling and storage of the caps 220 and 320 are easier. The packaging container system 210 is optionally transported and stored in a heat-sealed foil pouch (not shown) and is gamma-sterilized, although other packaging and sterilization techniques can be used. The foil pouch is generally opened at the clinic immediately before use of the cap. The cap thread 141 removably engages the packaging container thread 159, enabling easy removal of the caps 220, 320 from the packaging container 250. The cap 220 also shows a central projection 131 with an additional elongate member 133 extending beyond the central projection 131. The flat side 157 of the packaging container 250 provides a convenient feature for gripping the packaging container 250 when removing the caps 220, 320. Further, the flat side 157 of the packaging container 250 disrupts the rotational symmetry of the packaging container 250, so that the packaging container system 210 is less likely to roll on the floor or less likely to fall to the floor.

[0052] Figure 1B shows a cross-section of the packaging container system 210 having an arterial cap 220 and a venous cap 320, with each cap inserted into the same packaging container 250 as the packaging container system 210, although both the cap 220 and the cap 320 are mounted on the packaging container 250. The packaging container 250 is designed to continue axially offset the caps 220, 320 as indicated by the arterial cap axis 154 and the venous cap axis 254. The offset axes are advantageous over a coaxial design as they reduce the length of the packaging container system 210, can be housed in a shorter pouch, and are easier to handle. Further, the caps 220, 320 are 180 degrees opposite each other, so that the retaining rings 240, 340 are physically separated from each other. This physically prevents the arterial retaining ring 240 from bringing a finger close to the venous retaining ring 340 and vice versa, making it easier to grip the retaining rings 240, 340.

[0053] The packaging container 250 provides protection to the caps 220, 320 and further promotes sterilization before use because each of the caps 220, 320 is separated by a wall 256. In one exemplary embodiment, the lowermost base 231 of the central protrusion 131 on the cap 220 contacts the receiving edge 158 of the packaging container 250. The central protrusion 131 functions as a protrusion for later engaging the proximal end of the catheter and seals the proximal end of the catheter. In the embodiment shown in FIG. 1B, the central protrusion 131 includes a further elongate member 133 extending beyond the central protrusion 131. In an exemplary embodiment, most of the central protrusion 131 does not contact the wall 256, thereby minimizing the risk that the antimicrobial coating on the central protrusion 131 will be removed. Typically, the elongate member 133 also does not contact the wall 256 so as to minimize the risk that the antimicrobial coating will be removed when the elongate member 133 is coated with an antimicrobial composition.

[0054] FIG. 2A shows a perspective view of a single packaging container system 110 having a cap 120 and a packaging container 150. The packaging container 150 enables holding one cap within the housing of the packaging container 150. The single packaging container system 110 can be packaged in a heat-sealed foil pouch (not shown) and gamma sterilized. The foil pouch is typically opened at the clinic immediately prior to use of the cap 120. The cap thread 141 removably engages the packaging container thread 159, enabling easy removal of the cap 120 from the single packaging container 150.

[0055] FIG. 2B shows a cross-sectional view of the single packaging container system 110 of FIG. 2A, with the cap 120 inserted into the single packaging container 150. The cap 120 is inserted into the single packaging container 150. The single packaging container 150 provides protection to the cap 120 and further ensures that sterility is maintained prior to use. This is achieved by surrounding the cap 120 with the wall 156. In one exemplary embodiment, the lowermost base 231 of the central protrusion 131 contacts the receiving edge 158 of the single packaging container 150. In this exemplary embodiment, the remainder of the central protrusion 131 does not contact the wall 156, thereby minimizing the risk of removal of the antibacterial coating on the central protrusion 131. The elongate member 133 also preferably does not contact the wall 156 in order to minimize the risk of removal of the antibacterial coating.

[0056] FIG. 3A shows the cap 120 made in accordance with an exemplary embodiment of the present invention. The cap 120 can be injection molded as a single unit from a thermoplastic polymer resin in one exemplary embodiment, enabling mass production at low manufacturing costs. The cap 120 includes a central protrusion 131 formed as a male luer connector configured to engage a female luer connection at the proximal end of a transdermal catheter. The central protrusion 131 formed as a male luer connector in the illustrated embodiment also includes an elongate member 133. The elongate member 133 optionally functions to deliver an antibacterial composition inside the proximal end of the transdermal catheter.

[0057] Furthermore, the elongate member 133 provides a volume that aids in the movement of fluid into the proximal end of the percutaneous catheter, such as delivering an antimicrobial composition to the proximal end of the percutaneous catheter (e.g., the end of the catheter hub and the threads on the catheter hub where fluid exits the proximal end of the percutaneous catheter). This movement of fluid combined with the delivery of the antimicrobial composition to the catheter results in a flow of the antimicrobial composition that includes the fluid flowing out through the proximal end of the percutaneous catheter. Alternatively, or further, the movement of fluid from the proximal end of the percutaneous catheter can wet the antimicrobial composition coated on the central projection 131 formed as a male luer connector, as well as on the cap threads 141 and inside the cap 120. This wetting of the antimicrobial composition can bring the antimicrobial composition into solution, thereby killing microorganisms near the proximal end of the catheter (both inside the catheter and outside the catheter in certain embodiments).

[0058] In this way, the antimicrobial composition is delivered to positions along the exit path for the fluid being moved, i.e., positions along the luer connection, the position of the end of the percutaneous catheter, and the threads of both the external threads on the cap 120 and on the proximal end of the catheter. Thus, multiple processes can be combined to reduce the population of microorganisms at the proximal end of the catheter, thereby preventing or limiting the migration of microorganisms into the interior of the catheter from locations where the microorganisms could otherwise later migrate into the patient's bloodstream.

[0059] The elongate member 133 is generally formed from a polymeric material that can be bent without breaking. A polymer having a minimum elongation at break of 100% is preferred. Further, the polymer allows the solvent (used in the antimicrobial composition coating process) to evenly wet the surface until the solvent evaporates, and the antimicrobial composition typically adheres well to the surface of the elongate member 133 so that the coating does not flake off or fall off during handling. Various polymeric materials such as polyester, nylon, polyetherimide, polypropylene, polyvinyl chloride, or other similar materials that meet these requirements may be used. Alternatively, the elongate member 133 may be manufactured using a soluble material impregnated with the antimicrobial composition, such that when the elongate member 133 dissolves, the antimicrobial substance is released into the solution.

[0060] A portion of the cap 120 is typically coated and / or impregnated with the antimicrobial composition. In one embodiment, the antimicrobial composition is applied as a coating, and optionally, different amounts are applied to the elongate member 133, the central protrusion 131, and the cap thread 141. The antimicrobial composition can also be incorporated into the bulk polymeric material, but surface coating is generally preferred because it can release into solution faster than the bulk agent. Further, the surface coating tends to require less antimicrobial composition overall because the antimicrobial composition on the surface is more easily dissolved. In some embodiments, a combination of surface coating and incorporation into the bulk polymeric material is used.

[0061] Suitable methods for coating the cap 120 are spraying and dipping, with spray coating being desirable because it can be more easily adjusted without affecting the amount of antimicrobial composition applied to each region (the elongate member 133, the central protrusion 131, and the cap thread 141) compared to the amount applied to other regions.

[0062] Silicone, fluoropolymers, or other lubricious coatings may also be applied to the central projection 131 to reduce the amount of torque necessary to remove the cap from the catheter hub.

[0063] FIG. 3B shows a cross-section of a cap 120 made in accordance with an embodiment of the present invention. The length and diameter of the elongate member 133 are dimensioned to fit into the proximal end of the catheter, particularly the hub of the catheter. In the embodiments described herein, the catheter is a hemodialysis catheter. The central projection 131 and the cap thread 141 can be manufactured in accordance with International Organization for Standardization standard ISO 594-2:1998(E) so as to be compatible with all hemodialysis catheters made in accordance with the standard. In certain embodiments, the cap thread 141 is coated with an antibacterial composition.

[0064] FIG. 4A shows an exemplary hemodialysis catheter 170 for use with an embodiment of the invention, shown together with an arterial cap 220 within an arterial hub 272 and a venous cap 320 within a venous hub 372. When used by a hemodialysis patient, the two-lumen tube 187 is passed under the patient's skin from the upper chest to the jugular vein. The two-lumen tube 187 enters the jugular vein and extends until the catheter tip 189 is in the region of the right atrium of the heart. The arterial lumen 188 extends inside the catheter 170 from the arterial hub 272 until it exits the catheter tip 189. The venous lumen 288 similarly extends inside the catheter 170 until it exits near the catheter tip 189. If bacteria or fungi are present in one or both of the lumens 188, 288, the organisms causing these infections can enter the bloodstream and cause a bloodstream infection, and thus it is important to prevent the entry and growth of microorganisms into the catheter 170.

[0065] The catheter includes a branch portion 186 where the extension tube 180 transitions from two tubes having two lumens to one tube having two lumens. The two lumens 188, 288 extend from the hubs 272, 372 to the catheter tip 189 without fluid connection to the other lumen. The arterial hub 272 is attached to the proximal end of one extension tube 180, and the venous hub 372 is attached to the proximal end of the other extension tube 180. In the illustrated embodiment, the clamps 184 are positioned on each of the extension tubes 180 and are capable of blocking or releasing the flow within the lumen. In practice, the clamps 184 are closed except during a dialysis session or other transfer of fluid within the catheter 170. To minimize the risk of damaging the extension tube 180 by multiple clamps at the same location, the clamps 184 are typically moved each time they are opened. The clamps 184 are generally closed prior to the insertion of either cap 220, 320. Thus, the caps 220, 320 do not have a portion that protrudes deeply into the catheter. Instead, in one exemplary embodiment, the design is such that the cap mainly protrudes into the hubs 272, 372 by the elongate member 133 (see, e.g., FIG. 3B), often just encompassing the proximal end of the catheter within the hub, such that, for example, the cap can be inserted while the clamp is closed. This design also provides for expelling fluid from the end of the catheter at the proximal end of the catheter when the elongate member is inserted into the catheter hub. Thus, the design actually shown promotes the flow of fluid from the proximal end of the hub rather than a deeper flow within the catheter.

[0066] Referring to FIG. 4B, a cross-section of the proximal end of the catheter and the sealing cap is shown. Clamp 184 is shown disposed proximate to hub 172. When closed, clamp 184 creates a pinch point 185 that impedes fluid flow within the lumen. Preferably, elongate member 133 is only short enough to ensure that clamp 184 does not clamp over elongate member 133. Thus, the elongate member typically does not extend beyond hub 172. Elongate member 133 must preferably be only stiff enough to allow insertion into hub 172 without the need for a sheath, tube, or other insertion aid.

[0067] Furthermore, elongate member 133 must have a diameter small enough to ensure that it can physically fit within hub lumen 179. In embodiments where elongate member 133 is long enough to enter extension tube 180 that extends from hub 172, the diameter of extension tube 180 must also correspond to that of the elongate member.

[0068] The surface area of elongate member 133 must be large enough to enable coating of a desired amount of the antimicrobial composition onto the surface using spraying and dipping operations (or other application methods including direct incorporation onto the elongate member). The surface area is generally sized to provide an acceptable elution rate such that the antimicrobial composition enters the lock solution at an acceptable rate and dosage. It is desirable for the antimicrobial composition to reach effective levels within the time that cap 120 is inserted into catheter 170.

[0069] When the elongate member reaches the pinch point 185 of the clamp 184, it may sometimes cause damage or leakage of the locking solution present within the catheter. Thus, the length of the elongate member 133 must be short enough only to ensure that the elongate member 133 does not reach the pinch point 185 of the clamp 184. Suitable diameters of the elongate member 133 include from 1.0 mm to 2.0 mm, and from 1.7 mm to 1.9 mm. Suitable lengths of the elongate member 133 include less than 20 mm, or less than 10 mm, less than 30 mm, or less than 40 mm. A particularly desirable length is from 17 mm to 19 mm, but it can be varied for use with various catheters. Usually, the elongate member 133 is longer than the central projection 131. For example, the elongate member can be from 1 to 10 times the length of the central projection 131. In some embodiments, the elongate member can be from 1 to 5 times the length of the central projection 131. In one embodiment, the elongate member is from 1 to 2.5 times the length of the central projection 131. It is also possible to make the elongate member 133 shorter than the central projection 131. Generally, the elongate member 133 is considerably thinner than the central projection 131, for example, having a diameter less than half the maximum diameter of the central projection 131.

[0070] Referring now to FIG. 4C, an embodiment is shown showing an end cross-sectional view A-A as shown in FIG. 4B. The cap 120 is shown fully inserted into the catheter hub 172. When fully inserted, the central projection 131 formed as a male luer contacts the female luer 175 to create a fluid-tight seal. The threads 141 of the cap 120 engage the catheter threads 178 to hold the cap 120 on the hub 172. However, even after the cap 120 is fully inserted into the hub 172, there is often a gap 194 between the retaining ring 140 on the cap 120 and the hub 172. This gap 194 can be a path for pathogens to move, and thus it becomes possible to contaminate the hub surface with pathogens in the region between the retaining ring 140 and the hub 172. To reduce the occurrence of catheter-related bloodstream infections, it is desirable to reduce the number of pathogens in this region or to remove the pathogens.

[0071] Referring now to FIGS. 5A - 5C, various stages of the attachment of the cap 120 are shown, where inserting the cap (along with the elongate member) causes liquid containing an antimicrobial agent to flow from the end of the catheter hub and kill microorganisms that might otherwise enter the hub and then the catheter lumen. In FIG. 5A, the cap 120 is shown immediately prior to insertion into the hub 172 of the catheter 170. Inside the hub lumen 179 is a lock solution 190, which is normally a liquid, and its most proximal base forms a meniscus 192. The lock solution for a hemodialysis catheter is often heparinized saline (heparin at 100 IU / ml - 5000 IU / ml), a sodium citrate solution (usually 4% sodium citrate), or saline. Patient care technicians and nurses are trained to maintain the meniscus 192 at the proximal end 174 of the hub 172. However, it is not uncommon for the meniscus to drop several millimeters within the hub lumen 179. The antimicrobial composition must provide a desirable effect in any standard lock solution. In practice, the clamp 184 remains closed (creating a pinch point 185) unless fluid is being transferred through the catheter 170.

[0072] Referring to FIG. 5B, the elongate member 133 is shown partially inserted into the hub lumen 179. The elongate member 133 moves the lock solution 190, whereby the meniscus 192 is pushed out of the hub lumen 179 onto the end face 176 of the hub 172 of the catheter 170 (see FIG. 5A). Eventually, as the cap 120 continues to be inserted, the meniscus 192 (and the lock solution 190) moves over the catheter threads 178, delivering the antimicrobial agent to those threads.

[0073] Next, referring to FIG. 5C, the cap 120 is shown fully inserted into the catheter 170. In this embodiment, the meniscus 192 moves across the void 194 and completely fills the void 194 with the locking solution. The locking solution dissolves the antibacterial composition and transfers the antibacterial composition from one or more of the coated portions (the elongate member 133, the central projection (male luer) 131, and the cap thread 141) to the solution. Further, insertion of the elongate member into the locking solution further transfers the antibacterial composition to uncoated portions such as the wall defining the hub lumen 179 and the extension lumen 182, the female luer 175, the end face 176, and the catheter thread 178. Within a few hours, the solution in the void 194 may dry, but the coating of the antibacterial composition remains.

[0074] In this way, the coating of the antibacterial composition is transferred to the catheter thread 178 and the end face 176, enhancing the ability to kill any organisms on the catheter thread 178 and the end face 176 even if the surface is contaminated by organisms after the solution has dried. In practice, the void is often infiltrated with sweat containing organisms. In this scenario, the dried antibacterial composition is hydrated by the sweat and kills organisms that may be present in the sweat. Furthermore, the catheter thread 178 and the end face 176 are replenished with additional antibacterial composition each time a new cap 120 is inserted. In current practice, new caps are used for each dialysis session. The ability of the cap 120 to replenish the antibacterial composition on the catheter 170 to the high-risk target sites that act as sources of microorganisms overcomes the significant drawback of an antibacterial-coated catheter where the antibacterial composition is depleted with use or applied only inside the catheter. The desired amount of the antibacterial composition on the catheter thread 178 and the cap thread 141 is 20 μg to 2 mg, or 200 μg to 1.5 mg, preferably 500 μg to 1.2 mg of chlorhexidine acetate. However, it will be understood that different levels can be achieved successfully.

[0075] Typically, the central projection 131 contacts the female luer 175 to create a fluid-tight seal. These components are typically manufactured in accordance with the International Organization for Standardization standard ISO 594-2:1998(E) to ensure proper sealing and fit. However, the bifurcation between the male luer forming the central projection 131 and the female luer 175 is not fluid-tight along the entire length of the interface. Some manufacturers of medical device hubs intentionally manufacture their female luers such that the male luer contacts the female luer near the end face of the male luer. This is done to reduce the risk of cracking the hub. However, as an unintended result, the proximal end of the luer interface allows for potential ingress of organisms.

[0076] In conventional practice, once organisms are present, when a cap (or other device) is subsequently inserted, those organisms may be further pushed into the hub lumen 179 by the most recent cap (or other device). Once organisms are present within the hub lumen (distal to the male luer), they can proliferate, becoming planktonic and sessile organisms and ultimately a biofilm. This problem can be addressed by disposing an antimicrobial composition along the central projection 131. The antimicrobial composition kills organisms that are present along or may come to be present along the female luer 175 before they are pushed into the hub lumen 179, i.e., before they have the opportunity to further proliferate. Even with these protective measures in place, there still exists the possibility that organisms can proliferate beyond the female luer 175. To overcome this potential shortcoming, the antimicrobial composition may also be present in the elongate member 133, which dissolves or elutes into the lock solution 190 to kill organisms within the hub lumen.

[0077] The minimum amount of the antimicrobial composition on the elongate member 133 is the amount necessary to obtain an acceptable reduction (also referred to as killing) of the organisms that cause infection. It is important to understand that the volume of the solution in which the antimicrobial composition dissolves can dilute the antimicrobial composition more as there is more solution present. The limited volume of the lock solution 190 within the lumen is defined by the position of the meniscus 192, the geometric shape of the hub lumen 179, the geometric shape of the extension lumen 182, and the position of the pinch point 185. Since each of these items can be varied, the possible range of the limited fluid volume is quite broad. After considering the design variations of existing hemodialysis catheters, it is apparent that the exemplary embodiments need to produce a therapeutic concentration of the antimicrobial composition within a 0.7 ml volume. In one embodiment, the amount of chlorhexidine acetate on the elongate member 133 is from 10 μg to 5 mg. In an alternative embodiment, the amount of chlorhexidine acetate is from 100 μg to 2 g. In yet another embodiment, the elongate member comprises from 250 μg to 550 μg of chlorhexidine acetate.

[0078] The desired maximum amount of the antimicrobial composition disposed on each of the surfaces of the cap was considered by first examining what level of antimicrobial is safe for the patient and then comparing how much of the antimicrobial composition the patient could potentially be exposed to by each of the surfaces of the cap 120 that contain the antimicrobial composition (the elongate member 133, the central projection 131, and the cap threads 141). The amount of antimicrobial that is safe for the patient was determined by examining published information regarding levels that are generally considered safe for the patient (particularly, blood stream levels).

[0079] Tests were conducted to determine how much of the antimicrobial composition a patient could potentially be exposed to from the cap 120. The tests were designed to determine the transfer efficiency of the antimicrobial composition from each applicable component (elongate member 133, central projection 131, and cap threads 141) into the bloodstream. Potential patient exposures that could occur under various conditions, including unusual use or misuse (e.g., injection of the lock solution into the patient's bloodstream instead of aspiration of the solution), were considered to determine potential blood levels. Potential patient exposures were determined for each component individually and for the cap 120.

[0080] These embodiments can effect broad-spectrum killing of target organisms and, further, result in an administration amount of chlorhexidine acetate that is low enough such that blood levels remain at safe levels even if all of the lock solution containing chlorhexidine acetate is directly injected into the bloodstream. Thus, the present invention is characterized by a relatively high concentration of the antimicrobial composition within a relatively small fluid volume, although the actual amount of antimicrobial agent used is relatively small. Also, generally, addition of the antimicrobial agent to the patient's bloodstream can be prevented because the antimicrobial agent is generally contained in the proximal (outside the body) portion of the catheter and, further, a relatively small amount of antimicrobial material is used.

[0081] Furthermore, in typical embodiments, it will be appreciated that a certain percentage of the antimicrobial agent is not even delivered and retained within the catheter, but rather is delivered to the external proximal portion of the catheter, such as the end of the hub and the threads outside the hub. This positioning of the antimicrobial agent at these locations can potentially more strongly exclude microorganisms while at the same time avoiding addition of the antimicrobial composition to the patient's bloodstream. In some exemplary embodiments, up to 50 percent of the antimicrobial agent is delivered to the outer surface of the proximal end of the catheter. In other embodiments, up to 25 percent of the antimicrobial composition is delivered to the outer surface of the proximal end of the catheter. In yet other embodiments, up to 10 percent of the antimicrobial composition is delivered to the outer surface of the proximal end of the catheter.

[0082] In certain embodiments of the present invention, the antimicrobial composition is selected for its ability to form antimicrobial microparticles within the lock solution through a chemical reaction known as precipitation. Preferred antimicrobial compositions form precipitates within the most common lock solutions such as heparin and saline. Preferred antimicrobial compositions create a precipitate that deposits on the catheter wall at the proximal end of the catheter, resulting in an effective antimicrobial-coated catheter. A preferred antimicrobial composition is chlorhexidine acetate. Other antimicrobial compositions may be selected, for example, for their ability to precipitate other chlorhexidine salts.

[0083] In such embodiments, a significant amount of the chlorhexidine precipitate remains on the catheter wall even after flushing the catheter with the lock solution and further rinsing with saline flush, thereby demonstrating that the present invention provides antimicrobial properties to the catheter even after the antimicrobial delivery device has been removed. Further, in certain embodiments, the amount of the antimicrobial composition on the catheter wall increases with repeated use of the present invention. Laboratory experiments have demonstrated that the amount of the antimicrobial composition on one or more of the surfaces that are the catheter surface, the extension lumen 182, the hub lumen 179, the female luer 175, the proximal end 174, and the catheter thread 178 increases with multiple uses of the embodiment with the cap 141. The present invention may be used to create an antimicrobial coating on the catheter hub threads, the catheter end face, the catheter luer taper, the internal channels of the hub, or combinations thereof.

[0084] Referring now to FIG. 6A, a side cross-sectional view of a cap 120 made in accordance with an embodiment of the present invention is shown, with the cap 120 prior to insertion into a catheter. The cap 120 includes a cap thread 141 and an elongate member 133 configured to be inserted into the proximal end of the catheter. The elongate member 133 moves the locking solution 190 such that the meniscus 192 is extruded from the catheter onto the end face 176 of the catheter 170. Eventually, as the cap 120 continues to be worn, the meniscus 192 (and the locking solution) moves up the cap thread 141. This transfer of fluid up the thread 141 can assist in delivering an antimicrobial composition to the threads of the catheter hub either by transfer of the antimicrobial from the thread 141 to the catheter hub or by conveyance of the antimicrobial from the elongate member 133 (and / or central projection) to the outside of the catheter hub including the space between the threads on the catheter hub and the threads on the cap 120. FIG. 6B shows an end cross-sectional view of the hub 172 of FIG. 6A taken along line A-A'.

[0085] Referring now to FIG. 7A, a side cross-sectional view of a cap made in accordance with an embodiment of the present invention is shown, with the cap 120 shown partially inserted into a catheter. When the cap 120 is inserted into the catheter, the elongate member 133 moves the locking solution 190, for example, moving the meniscus 192 proximally as the locking solution 190 moves out of the hub 172. After a clamp is placed on the catheter to clamp the closed catheter, the cap 120 can be inserted. This prevents the moving locking solution from flowing distally from the catheter, and as a result, the moving locking solution and the meniscus 192 move proximally. FIG. 7B shows an end cross-sectional view of the cap partially inserted into the catheter of FIG. 7A taken along line A-A', with the elongate member 133 partially inserted into the female luer 175.

[0086] Referring to the side cross-sectional view of the cap 120 made according to an embodiment of the present invention in FIG. 8A, the cap 120 is partially inserted into the catheter. As the cap 120 further advances within the catheter, more locking solution 190 is extruded, and the meniscus 192 may increase in size from the further displaced locking solution. The cap thread 141 contacts the meniscus 192 of the locking solution 190 in the illustrated embodiment, thereby receiving an antibacterial composition from the locking solution and / or adding a further antibacterial composition to the locking solution.

[0087] Next, FIG. 8B shows a cross-sectional view of the catheter and hub taken along line A-A' of FIG. 8A. When the cap 120 is inserted into the catheter, a gap 196 can be defined, for example, between a central projection 131 (formed as a male luer) and a female luer 175. The gap 196 is at least partially occupied by the locking solution 190, and for example, the locking solution 190 can be passed from the catheter to the cap thread 141.

[0088] FIG. 9A is a side cross-sectional view of the cap 120 made according to an embodiment of the present invention, with the cap 120 almost completely inserted into the catheter. As the cap 120 advances within the catheter, air bubbles 193 can form within the cap, and further, the locking solution 190 and the meniscus 192 continue to advance to further cover the cap thread 141. Further, FIG. 9B is a detail of the side cross-sectional view taken along line A-A' of FIG. 9A. The gap 196 can be at least partially defined between the central projection 131 and the female luer 175, and for example, allows the locking solution 291 to pass from the catheter to the cap 120.

[0089] Referring to the side cross-sectional view of the cap 120 made in accordance with an embodiment of the present invention in FIG. 10A, the cap 120 is fully inserted into the catheter hub. The high-concentration antibacterial composition in the lock solution 190 can be disposed in the hub 172. The lock solution can be trapped in the gap 196. The lock solution can no longer pass through the gap 196, and the lock solution is disposed on the cap thread 141. In certain embodiments of the present invention, the elongate member 133 is fully proximal to the clamp. Thus, the cap 120 can be removed from the catheter while the catheter is still clamped and closed. Referring to FIG. 10B, an end cross-sectional view of the cap 120 of FIG. 10A taken along line A-A' of FIG. 10A is shown. The gap 196 can be made narrow enough to prevent further flow of the lock solution 190 from the catheter to the cap 120.

[0090] Referring to FIG. 11A, a side cross-sectional view of the cap 120 made in accordance with an embodiment of the present invention is shown. The cap 120 does not include an elongate member in this embodiment. The meniscus 192 can be formed where the male luer defining the central protrusion 131 enters the catheter. Further, FIG. 11B shows an end cross-sectional view of the catheter hub of FIG. 11A. The female luer 175 is at least partially filled with the lock solution 190. The lock solution can form the meniscus 192 where the central protrusion 131 enters the female luer 175, as shown in FIG. 11A.

[0091] Referring now to FIG. 12A, a side cross-sectional view of the cap 120 made according to the embodiment of FIG. 11A is shown, and the cap 120 is partially inserted into the catheter. When the central protrusion 131 (formed as a male luer) is further inserted into the female luer 175, more locking solution 190 moves from the catheter, and when the volume of the locking solution outside the catheter increases, the meniscus 192 moves towards the proximal end. The locking solution 190 can pass from the female luer, through the gap 196, to the meniscus 192 and the cap 120. The gap 196 can be a passage between the central protrusion 131 (male luer) and the female luer 175. FIG. 12B shows an end cross-sectional view of the cap of FIG. 12A. The gap 196 can be ring-shaped and can allow the locking solution 190 to pass between the female luer 175 and the central protrusion 131.

[0092] Referring to the side cross-sectional view of the cap 120 made according to the embodiment of the present invention in FIG. 13, the cap 120 is almost completely inserted into the catheter hub. When the central protrusion 131 is inserted into the catheter hub, the locking solution 190 moves from the female luer 175, such as through the gap 196. The meniscus 192 can further advance along the cap thread 141 when the locking solution 290 exits the catheter. The volume of the locking solution 290 is disposed between the cap thread 141 and the catheter, and the surface is defined by the meniscus 192.

[0093] Furthermore, referring to the side cross-sectional view of the cap 120 made according to the embodiment of the present invention in FIG. 14, the cap 120 is completely inserted into the catheter. The central protrusion 131 can contact the female luer 175, for example, to stop the flow of the locking solution 190. Thus, the volume of the locking solution 190 can be disposed between the catheter and the cap 120.

[0094] Referring now to FIG. 15, there is shown a side cross-sectional view of a cap 120 made in accordance with an embodiment of the present invention, showing the relative dimensions and volumes of the cap 120 components within the hub lumen 179. When the hub lumen 179 is filled with a fluid, such as a locking solution 190, up to the end face 176, the volume of fluid displaced is equal to the volume of the central projection 131 plus the volume of the elongate member 133. Four cross-sectional planes A-A', B-B', C-C', and D-D' are shown in FIG. 15. Each of these pairs of planes defines a volume within the catheter. Thus, there is a volume within the catheter hub between planes A-A' and B-B'. This volume is occupied in FIG. 15 by the central projection 131. The next volume is from B-B' to C-C'. This volume extends from the end of the central projection 131 to the end of the point where the elongate member 133 enters the constriction within the hub lumen. The third volume is located between C-C' and D-D', and this volume in the illustrated embodiment has a particularly small cross-sectional area because this volume includes the relatively narrow portion of the lumen along with the elongate member 133 extending within the lumen, such that the volume is only the space between the elongate member and the wall of the hub lumen. The fourth volume, only partially shown in FIG. 15, is in the form of the volume up to a clamp positioned closer to the patient (not shown) at D-D'.

[0095] When the cap is inserted into the proximal end of the percutaneous catheter, the antimicrobial composition elutes into the lock solution 190. However, the volume configuration as shown in FIG. 15 is such that a large amount of the antimicrobial composition is initially contained within the volume between B-B' and C-C'. A portion of this antimicrobial composition ultimately spreads from the volume between B-B' and C-C' through the narrow portion between C-C' and D-D' and ultimately reaches the larger volume on the distal side with respect to D-D'. However, the geometry is such that the concentration in the volume B-B' to C-C' has a relatively high level for a long period (in typical embodiments). This high concentration often results in the precipitation of a portion of the antimicrobial composition onto the walls of the hub lumen between B-B' and C-C' and between C-C' and D-D'. This precipitated antimicrobial composition can extend the antimicrobial action and even provide protection without exposing the patient's blood supply to a high concentration of the antimicrobial composition during changes to the cap 120.

[0096] Thus, in one embodiment, upon insertion of the elongate member and the tapered member of the antimicrobial delivery device into the hub, the interior of the catheter defines a first volume (such as B-B’ to C-C’) of the lock solution, a second volume (such as C-C’ to D-D’) of the lock solution, and a third volume (such as D-D’ to the catheter clamp) of the lock solution. The first volume of the lock solution has an average diameter greater than the average diameter of the second volume, the second volume of the lock solution has an average cross-sectional area smaller than the average cross-sectional areas of the first and third volumes, and the third volume of the lock solution has a cross-sectional area substantially equal to the average lumen cross-sectional area of the catheter on the proximal side with respect to the clamp. In one embodiment, the first volume of the lock solution comprises the lock solution disposed in a portion of the inner channel of the hub between the end of the tapered member and the end of the tapered inner surface of the inner channel, the second volume is the lock solution disposed between the end of the tapered inner surface of the inner lumen and the end of the elongate member, and the third volume of the lock solution comprises the lock solution disposed within the catheter between the end of the elongate member and the clamp. Optionally, the second volume is smaller than the first volume, and the first volume is smaller than the third volume. In one embodiment, upon insertion of the elongate member and the tapered member into the hub, the antimicrobial concentration in the first volume is initially higher than the antimicrobial concentration in the third volume. In one embodiment, the antimicrobial concentration in the first volume after 48 hours is at least 10 times higher than the antimicrobial concentration in the third volume. In one embodiment, the amount of antimicrobial in the first and second volumes after 48 hours is at least 3 times more than the amount of antimicrobial in the third volume.

[0097] In one embodiment, the syringe can be used to fill the hub lumen 179, and when the syringe is removed without injecting additional fluid when removed, the hub volume becomes insufficiently filled by the syringe protrusion. In that case, the volume being displaced is equal to the volume of the central protrusion 131 plus the volume of the elongate member 133 minus the volume of the syringe protrusion. In one embodiment, the volume of the syringe protrusion is 0.070 mL. In one embodiment, the volume of the central protrusion is 0.074 mL. In one embodiment, the volume of the elongate member is 0.053 mL. In one embodiment, the volume of the threaded region of the cap 120 is 0.034 mL. It is desirable to wet the threads of the retaining ring and the hub with the displaced lock solution. To ensure thread wetting in this embodiment, the elongate member has a volume equal to or greater than 0.030 mL.

[0098] FIG. 16A is a side cross-sectional view of a cap made in accordance with an embodiment of the present invention, showing a gap 197 between the end face 176 of the catheter hub and the cap 120. FIG. 16B is a side cross-sectional view of a cap made in accordance with an embodiment of the present invention, further having the gap 197 and the cap 120 at the end face 176 of the catheter.

[0099] Referring now to FIG. 17, an enlarged side cross-sectional view of the cap 120 is shown. The cap 120 is made in accordance with an embodiment of the present invention and shows fluid on the threads of the proximal end of the catheter. When the cap 120 is inserted onto the catheter 170, a meniscus 192 of the lock solution 191 can be formed. The lock solution 191 containing the antimicrobial composition can be disposed between the cap threads 141 and the catheter threads 178.

[0100] Referring to FIG. 18, a side cross-sectional view of a cap made in accordance with an embodiment of the present invention is shown, showing at least a portion of the fluid of FIG. 17 that has evaporated leaving an antimicrobial residue. Over time, the lock solution 191 evaporates, leaving an antimicrobial residue 291 on and between the cap threads 141 and the catheter threads 178. FIG. 19 is a side cross-sectional view of a cap made in accordance with an embodiment of the present invention, showing rehydration of a portion of the antimicrobial residue of FIG. 18. As shown in FIG. 19, FIG. 20 is a side cross-sectional view of a cap made in accordance with an embodiment of the present invention, showing at least a portion of the fluid of FIG. 19 that has evaporated leaving an antimicrobial residue. As shown in FIG. 20, the antimicrobial residue 291 is retained on both the cap threads and the catheter threads.

[0101] Referring to FIG. 21, cap 120 is shown fully inserted onto catheter 170. The present embodiment includes an end seal 147. The end seal 147 prevents organisms from entering the tip opening 144, thereby providing an additional benefit by preventing organisms from traveling through the void 194 where the organisms could potentially contaminate the end face 176 and female luer 175 next. By reducing the number of organisms that can enter the tip opening 144, the occurrence of CRBSI can be further reduced. The end seal 147 can be made of an elastic material such that the end seal 147 is stretchable over the catheter thread 178 while the cap 120 is inserted, and the end seal 147 must also conform to the shape of the hub 172 such that the end seal 147 creates an effective biobarrier seal. The end seal 147 is preferably made of a durable material so as not to break or tear. The end seal 147 generally must be thin and flexible so as to be easily insertable. The end seal 147 allows fluid to escape when the cap 120 is inserted onto the catheter 170 and further acts as a barrier to substantially retain the lock solution pushed into the void 194 during insertion. In a preferred embodiment, this is achieved by maintaining a thin, flexible wall that is only thick enough to allow increased pressure to escape from where the end seal 147 contacts the hub 172. In one exemplary embodiment, the end seal 147 is overmolded onto the retaining ring 140. Thermoplastic elastomers such as Exxon Mobile's Santoprene can be used. However, other materials such as silicone may be suitable. In one embodiment, the end seal 147 is between 0.127 mm (0.005 inches) and 2.54 mm (0.100 inches) thick. In another embodiment, the end seal 147 is between 0.254 mm (0.010 inches) and 1.02 mm (0.040 inches) thick.

[0102] The lock solution in the void 194 also serves as a barrier against biological ingress. The lock solution includes an antimicrobial composition dissolved from the surface of the cap 120 (along with the elongate member 133, the central projection 131, and the catheter threads 178). In a preferred embodiment, the antimicrobial level results in an antimicrobial substance concentration that is highly effective in the killing of a broad spectrum of organisms.

[0103] Referring to FIG. 22, the cap 120 is shown inserted completely into the catheter 170 in cross-section. This embodiment can include a threaded seal 148 impregnated with the same amount (and instead) of the antimicrobial composition as the amount on the cap threads 141 of FIG. 5C. The threaded seal 148 provides an additional benefit by preventing organisms from entering the tip opening 144, where the void 194 is occupied by the threaded seal 148, thus preventing organisms from proceeding through the occupied void 194 to contaminate the end face 176 and the female luer 175 if they were not so prevented. By reducing the number of organisms that can enter the tip opening 144, the occurrence of CRBSI can be further reduced.

[0104] The thread seal 148 is preferably made of an elastomeric foam material that can follow around the catheter thread 178 while the cap 120 is inserted. The thread seal 148 must also conform to the shape of the hub 172 such that the thread seal 148 makes an effective biobarrier seal. The leading edge of the thread seal 148 often has a thin layer of closed-cell polyurethane that aids in reducing evaporation of the solution. The thread seal 148 is preferably made of a durable material so that it does not break or tear. In one aspect of the thread seal 148, the thread seal 148 allows fluid to cover the thread seal 148 when the cap 120 is inserted into the catheter 170 and further acts as a barrier to substantially retain the locking solution pushed into the occupied void 194 during insertion. In a preferred embodiment, this is achieved by manufacturing the thread seal 148 from an open-cell hydrophilic medical polyurethane foam and having a thin layer of solid polyurethane at the leading edge of the thread seal 148. The thread seal 148 and the antimicrobial composition incorporated therein also act as a barrier against biological ingress. The thread seal 148 contains an antimicrobial composition dissolved from the surface of the cap 120 (e.g., one or more of the elongate member 133, the central projection 131, and the thread seal 148).

[0105] FIG. 23A depicts an alternative embodiment of the cap 120 that holds the tip 234, which has a diameter smaller than the diameter of the hub lumen 179 when the tip 234 is inserted into the catheter 170, but then expands in size. This embodiment is particularly advantageous when used with a catheter 170 that does not have a clamp for confining the solution, or when it is desirable to further limit the amount of antimicrobial composition required (less volume of solution is confined, so less amount is needed). The tip 234, in its unswollen state, is shown in FIG. 23A during insertion to allow for easy insertion of the elongate member and to minimize the possibility of pushing organisms towards the tip side with respect to the tip 234 by the pushing action. The elongate member of the preferred embodiment remains sufficiently rigid while being inserted into the catheter 170 and does not require additional parts or aids for insertion.

[0106] FIG. 23B represents an alternative embodiment of the cap 120 described with reference to FIG. 23A, except that the chip 334 is shown in its swollen state. In the embodiment shown, the diameter of the chip 334, in its swollen state, is equal to the diameter of the hub lumen 179. The chip 334 preferably conforms to the surface of the hub lumen 179 when swollen. The swollen chip 334 is advantageous for containing a solution or when it is desirable to further limit the amount of the antibacterial composition required (less volume of the solution is contained, so less amount is required). The chip 334 is removable from the hub lumen 179 when an appropriate removal force is applied to the cap 120. This is achieved by selecting the material and size of the chip 334 such that the vertical force exerted by the chip 334 on the wall of the hub lumen 179 is small enough to allow an acceptable removal force when the chip 334 is in the swollen state. In one exemplary embodiment, the diameter of the unswollen chip 234 (see FIG. 23A) is 1.52 mm (0.060 inches), the diameter of the contained swollen chip 334 is 2.49 mm (0.098 inches) (the same diameter as the hub lumen 179), and the diameter of the unconfined swollen chip is 2.79 mm (0.110 inches) when placed in normal saline solution. However, these diameters vary to fit the diameter of the device in which the cap is used. The preferred (defined as the diameter at which the chip expands when not confined by the lumen wall) unconfined swollen diameter is slightly larger than the diameter of the hub lumen 179. An additional advantageous effect on the swollen chip is that the swollen chip creates a scrubbing effect on the catheter wall that physically removes organisms attached to the inner wall section when removing the cap from the catheter.

[0107] In one embodiment, the chip is manufactured to produce anisotropic swelling, whereby the diameter increases but the length does not substantially increase. In another embodiment, the entire elongate member is made of an anisotropic swelling material such that the diameter increases but the length does not substantially increase.

[0108] In one embodiment, the material of the chip 334 is made of a swellable polyurethane such as Lubrizol TG-500 heat-sealed onto an elongate member 133 made of a non-swellable polyurethane such as Lubrizol 1065D. These materials provide acceptable swelling, durability, strength, and flexibility. The elongate member is coated with an antibacterial composition in an amount sufficient to obtain an appropriate antibacterial effect and yet small enough to remain safe for the patient.

[0109] Referring to FIG. 24, this alternative embodiment of the present invention is useful in applications where the inner diameter of the catheter is so small that the elongate member does not fit within the catheter, such as by means of a peripherally inserted central catheter (PICC). In this embodiment, the cap 120 does not include an elongate member as in the previous embodiments. Instead, the cap has a flat or slightly concave end face 138, which is coated with an antibacterial layer 139. The preferred types and amounts of antibacterial substances in the antibacterial layer 139 are the same as those of the elongate member (see description of FIG. 5C). Similarly, the central projection 131 and the catheter thread 178 preferably include the same types and amounts of antibacterial composition as in the other embodiments. The antibacterial composition is preferably applied to the end face as 15% chlorhexidine acetate in methanol solution using an accurate metering pump. Other solvents, ratios, and coating methods may be used.

[0110] Referring to FIG. 25A, an alternative embodiment of the present invention is shown in which the cap 420 is made from two components, a retaining ring 440 and an insert 130. It is desirable to have a very controlled and repeatable amount of the antimicrobial composition disposed on the desired regions of the cap 420. It is also preferred to have different amounts of the antimicrobial substance on different regions. Coating each region of the cap 420 is made easier if the retaining ring 440 does not interfere with access to the central projection 131 (and vice versa). This is achieved by manufacturing the cap 420 as two separate parts, the retaining ring 440 and the insert 130. The preferred amount of the antimicrobial composition within each region remains the same as above (see reference 5C).

[0111] Referring to FIG. 25B, the insert 130 is coated with chlorhexidine acetate along the elongate member 133 and the central projection 131. The plate 132, the cap shoulder 136, and the retaining flange 137 do not require coating. The two parts to be coated are the central projection 131 and the elongate member 133, and they contain the same amount of the antimicrobial substance as that referred to above.

[0112] Referring to FIG. 25C, the plate 132 at the proximal end of the insert 130 has a hole 135. The purpose of this hole 135 is to improve manufacturing. For example, the hole 135 provides a convenient feature that can be used for holding and rotating the insert 130 and allows rotation of the part when the insert 130 is being coated. The hole 135 also reduces shrinkage of the insert 130, which is typically injection molded, by creating a more uniform wall thickness.

[0113] Referring to FIG. 25D, the retaining ring 440 is a commercially available product from Value Plastics, Inc., except that the cap thread 141 is coated with the antimicrobial composition. The antimicrobial composition in the preferred embodiment is the same preferred amount of chlorhexidine acetate as the above disclosure. The retaining ring 440 is easily coated using a spraying technique in which the retaining ring 440 rotates along its axis, and the antimicrobial substance is sprayed directly onto the cap thread. As an alternative coating method, the cap thread 141 is coated by filling the inner portion of the ring 440 with a 7% chlorhexidine methanol solution, and then the solution is drained to allow the part to dry. This results in approximately 1.2 mg of chlorhexidine acetate on the cap thread 141. The dosage of the antimicrobial substance may be adjusted by adjusting the solution concentration.

[0114] Referring to FIG. 25E, when the insert is inserted inside the retaining ring 440, the shoulder 146 contacts the insert (not shown). The base opening 143 is first used to receive the insert 130 during assembly (see FIG. 10F). The retaining fingers 145 are designed to hold the retaining ring 440 on the insert as described in the following reference. The ring shoulder 146 aids in securing the insert.

[0115] Referring to FIG. 25F, a preferred embodiment of a two-piece cap 420 is shown. The insert 130 is shown fully inserted into the retaining ring 440. The chip 134 is pushed through the base opening until the retaining ring 440 bottoms out on the plate 132. The retaining fingers 145 engage the retaining flange 137 to secure the retaining ring 440 on the insert 130. It is desirable that the retaining ring 440 does not rotate freely on the insert 130. Instead, the torque is preferably greater than 0 Newton - meter (N - m) (0 pound - inch (lb. - in)) but less than 0.226 N - m (2.0 lb. - in). In one exemplary embodiment, the torque is from 0.0113 N - m (0.1 lb. - in) to 0.141 N - m (1.25 lb. - in). In another embodiment, the torque is from 0.0226 N - m (0.2 lb. - in) to 0.0565 N - m (0.5 lb. - in). In some examples, the torque is from 0.0113 N - m (0.1 lb. - in) to 0.339 N - m (3 lb. - in). In other embodiments, the torque is greater than 0.0113 N - m (0.1 lb. - in), and in other embodiments, the torque is greater than 0.0226 N - m (0.2 lb. - in). By controlling the diameter of the shoulder 136 such that the shoulder 136 interferes with the ring shoulder 146, the torque can be controlled as shown in the graph shown in FIG. 26. In some embodiments, to maintain the rotational torque within an acceptable range, it is desirable to maintain the interference between the ring shoulder 146 and the insert shoulder 136 in the range of 0.0508 mm (0.002 inch) to 0.229 mm (0.009 inch).

[0116] FIGS. 26 - 31 show the results from experiments using an apparatus having a cap and an insert containing an antibacterial substance, and the experimental data is discussed below. Referring now to FIGS. 32A - 32E, an example of a two - part cap construction is shown that has an insert with ribs or fins to prevent rotation relative to the retaining ring. Referring to FIG. 32A, an embodiment is shown in which cap 1420 is manufactured from two components, a retaining ring 1440 and an insert 1130. It is desirable to have a very controlled and repeatable amount of the antimicrobial composition disposed on the desired regions of cap 1420. It is also preferred to have different amounts of the antimicrobial substance on different regions. If the retaining ring 1440 does not interfere with access to the central projection 1131 having the chip 1134 (and vice versa), it is easier to coat each region of cap 1420. This is achieved by manufacturing cap 1420 as two separate parts, the retaining ring 1440 and the insert 1130.

[0117] Referring to FIG. 32B, insert 1130 is coated with an antimicrobial substance such as chlorhexidine acetate along the elongate member 1133 and optionally along the central projection 1131. In most embodiments, the plate 1132, the cap shoulder 1136, and the retaining flange 1137 typically do not require coating. Further, in this configuration, insert 1130 includes one or more fins 1138 (usually at least two) disposed around insert 1130 near the plate 1132. These fins 1138 are constructed, for example, preferably by an interference fit that avoids relative movement between the seal ring and the insert, to provide a tight fit into the ring 1440 (shown in FIGS. 32A and 32C). Thus, the fins 1138 of insert 1130 engage the recesses of the retaining ring 1440, prevent rotation of the two components relative to each other, and provide a fit tight enough to avoid easily recognizable movement between insert 1130 and retaining ring 1440, typically when attaching and removing cap 1420 to / from the end of the catheter (different from prior art caps that provide only a relatively loose fit that allows play in the connection between the insert and the retaining ring).

[0118] Figure 32C shows a perspective view of the retaining ring 1440, which includes a cap thread 1141 inside the retaining ring 1440. Referring to FIG. 32D, which is a cross-section of the retaining ring 1440 taken through plane A-A', the cap thread 1141 of the retaining ring 1440 is shown in further detail. The cap thread 1141 is optionally coated with an antibacterial composition. The antibacterial composition in an exemplary embodiment is the same amount of chlorhexidine acetate as described above. FIG. 32D also shows a retaining shoulder 1146, a base opening 1143 into which the insert 1130 is inserted during manufacture, and retaining fingers 1145.

[0119] Referring to FIG. 32E, when the insert 1130 is inserted inside the retaining ring 1440, the retaining shoulder 1146 contacts the insert shoulder 1136. The base opening 1143 is, during assembly, the first to receive the insert 1130. The ring shoulder 1146 aids in securing the insert. The retaining fingers 1145 include a gap therebetween, which is referred to herein as a recess, and the retaining fingers 1145 are designed to engage the fins 1138 of the insert 1130 (see FIG. 32B) to secure the retaining ring 1440 onto the insert 1130 and further prevent rotation of the insert 1130 within the ring 1440. The insert 1130 is shown fully inserted into the retaining ring 1440. The chip 1134 is passing through the base opening. The retaining fingers 1145 engage the retaining flange 1137 to secure the retaining ring 1440 onto the insert 1130, and fins (not shown) engage the recess between the retaining fingers 1145 to prevent rotation. The insert 1130 and the ring 1440 are typically made from injection molded polymer materials. Although various materials can be used, in one exemplary embodiment, the ring 1440 is formed from nylon, while the insert 1130 is formed from polypropylene.

[0120] It is desirable that the retaining ring 1440 does not rotate freely on the insert 1130. The cap 1420 described herein is typically formed from a plastic material, and it will be appreciated that a sufficiently high torque force will necessarily move the retaining ring 1440 and the insert 1130 relative to each other (e.g., a sufficiently high torque may break the fin 1138). It is preferred that the torque is greater than 0.362 N-m (3.2 lb.-in) and there is no perceptible rotation between the retaining ring and the insert. In one exemplary embodiment, a torque of 0.141 N-m (1.25 lb.-in) does not generate a perceptible rotation. Alternatively, a torque of 0.0566 N-m (0.5 lb.-in) does not generate a perceptible rotation. Further, in addition to preventing rotation of the retaining ring 1440 and the insert 1130 relative to each other, it is desirable to eliminate play between the two components, such as slight axial relative movement between the components when the physician handles the cap 1420. However, the design of the cap 1420 described herein reduces relative movement under vertical forces due to handling, attachment, and removal of the cap 1420 within the range where the two components can be handled as if they were integral, without an easily recognizable movement between the retaining ring 1440 and the insert 1130 that is perceptible to a typical user during typical handling, attachment, and removal operations.

[0121] FIG. 33 is a cross-sectional view of a retaining ring 1440 made in accordance with an exemplary embodiment of the present invention, showing the retaining ring 1440 having a plurality of recesses 1442. In the embodiment shown, these recesses 1442 are disposed between adjacent retaining fingers 1145. FIG. 34 is an enlarged partial cross-sectional view of the retaining ring 1440, showing an example of the recess 1442. In the embodiment shown, there are a total of twelve recesses 1442 and twelve retaining fingers 1445. In alternative configurations, it will be appreciated that the number of recesses 1442 can be more or less than twelve. In some embodiments, the number of recesses is 2, 4, 6, 8, 10, 12, 14, or 16. Alternatively, the number of recesses can be 1, 3, 5, 7, 9, 11, 13, or 15. Generally, the number of recesses 1442 is between 4 and 10. In general, the recesses are disposed at symmetric positions around the interior of the ring 1440, the recesses 1442 are equally spaced, allowing for easy placement of the insert 1130.

[0122] Referring now to FIGS. 35 and 36, a cross-sectional view of the insert 1130 made in accordance with an exemplary embodiment (FIG. 35) is shown together with an enlarged cross-sectional view of the insert 1130 having fins 1138 (FIG. 36). This insert 1130 includes a plurality of fins 1138. In the illustrated embodiment, the insert 1130 has two fins 1138 disposed on both sides of the insert 1130. In some embodiments, it is possible to use only one fin, or more than two fins such as 3, 4, 5, 6, or more fins. The number of fins of the insert 1130 is optionally significantly less than the number of recesses of the retaining ring 1440. By reducing the number of fins relative to the number of recesses, the insert 1130 and the retaining ring 1440 can be assembled more easily because the fins 1138 have a plurality of recesses 1442 into which the fins 1138 can fit. However, when the fins 1138 are pushed into the recesses 1442 and locked in place, the insert 1130 and the retaining ring 1440 are not easily removable from each other, and the fins 1138 and the recesses 1442 form an interference fit along at least one or more surfaces to prevent significant movement between the insert 1130 and the retaining ring 1440.

[0123] FIGS. 33 and 35 show the outer radius R of the insert 1130 including the fins 1138 f , and the inner radius R of the retail ring 1440 that occupies the recess 1442 r . Measurements of these two radius measurements R f and R r are measured from the center of each component (the insert 1130 and the retaining ring 1440 respectively) to the outer edge of the fins 1138 and the recesses 1442. The measurements are taken in the same plane perpendicular to the central axis of the cap 1420 when measured before the insert 1130 and the retaining ring 1440 are joined. FIGS. 37A and 37B show these dimensions as arcuate dimensions A r and A fis further shown. FIG. 37A is an enlarged partial cross-sectional view of a retaining ring 1440 made in accordance with an exemplary embodiment of the present invention, showing the aspect of a recess 1442 within the retaining ring 1440. The recess 1442 shows a radial dimension R r along with an arcuate distance from two outer edges of A r . FIG. 37B is an enlarged cross-sectional view of an insert 1130 made in accordance with an exemplary embodiment of the present invention, showing the aspect of fins 1138 on the insert 1130. The fins 1138 include a radius R F measured at the center of the insert 1130 and an arcuate distance A f measured along the base of the fins 1138. Preferably, the fins 1138 on the insert 1130 fit tightly into the recess 1442 to prevent rotation of the insert 1130 relative to the ring 1440. Thus, the dimensions of the elements are configured such that the fins 1138 and the recess 1442 have an interference fit. To achieve such an interference fit, desirably, R f ≥ R r , or R f ≥ 0.99R r , or R f ≥ 0.98R r . In this way, an interference fit, or something close to an interference fit, can be achieved between the fins 1138 and the recess 1442 to prevent rotation of the insert 1130 relative to the ring 1440. The interference fit used to assemble the cap 1420 typically results in plastic deformation, residual stress, and permanent deformation in the retaining ring 1440 and the insert 1130.

[0124] FIG. 38 shows an exemplary configuration in which an insert 1130 having fins 1138 is disposed within a ring 1440 having a recess 1442. In the configuration shown, three common regions, I1, I2, and I3, are shown between the fins 1138 and the recess 1442 (not shown). In a typical structure, the common regions provide an interference fit between the fins 1138 and the recess 1442. In certain embodiments, there is no gap between the fins 1138 and the recess 1442 at positions I1, I2, and I3. However, in some embodiments, it will be understood that the interference fit at positions I1, I2, and I3 is not perfect over all surfaces, but nonetheless a rotation-preventing interference fit is obtained. Thus, in some embodiments, I1, I2, and I3 provide a complete interference fit with no significant gap between the fins 1138 and the recess 1442. On the other hand, in other embodiments, I1, I2, and I3 have some gap, but nonetheless provide a proper connection to the recess 1442 such that the insert 1130 and the ring 1440 do not easily rotate (or exhibit a "play" between components that is easily recognizable to a gloved operator, i.e., even a discernible freedom of movement). For example, there may be a gap at I1, but the interference fit at I2 and I3 may be sufficient to prevent rotation between the insert 1130 and the ring 1440. Also, there may be an interference fit only at a portion of I2 and I3 that will nonetheless prevent rotation. As the amount of interference at I1, I2, and I3 increases, the force required to combine the insert 1130 with the ring 1440 increases, and equipment may be used to facilitate assembly of the insert 1130 and retention of the ring 1440.

[0125] FIG. 39A is an enlarged partial cross-sectional view of a retention ring made in accordance with another exemplary embodiment of the present invention, showing the configuration of a recess 1442' within the retention ring 1440'. On the other hand, FIG. 39B is an enlarged cross-sectional view of an insert 1130' made in accordance with an exemplary embodiment of the present invention, showing the configuration of fins 1138' on the insert 1130'. In this embodiment, the fin 1138' has a dimension R f greater than dimension R rAs will be appreciated, it is shown to be considerably shorter than the recess 1442'. However, even so, when the side portion of the fin 1138' engages the side portion, the recess 1442', such a structure can still provide an interference fit between the ring 1440' and the insert 1130'.

[0126] Figures 40A - 40B show an alternative structure of an insert 1130'' having fins 1132'' and a retaining ring 1440'' having recesses 1442'', made according to an exemplary embodiment. In these exemplary structures, alternative shapes for the recesses 1442'' and fins 1138'', particularly those having a curved cross - sectional profile. Further, the shape of the recess 1142 may be selected to cut into the fin 1138 to form an interference fit. Selecting a high material hardness and yield strength for the retaining ring 1440, and a sharp tip (facing the recess 1442 (not shown)) together with a lower yield strength for the fins 1138 of the insert 1130 will result in skiving the tip and deforming or cutting into the fins to provide an interference fit. In this example, the retaining ring 1440 may be nylon and the insert 1130 may be polypropylene. Alternatively, the retaining ring may have a sharp edge on one or more proximal edges of the fingers 1145 for deforming the surface of the shoulder 1136.

[0127] Although Figures 32A - 40B have described the cap, it will be understood that a connector (providing flow within a catheter) may also be made using the principles of the invention described herein.

[0128] Antibacterial composition The antibacterial composition can be incorporated into the elongate member material of the present invention and / or on the surface of the elongate member. In a preferred embodiment, the antibacterial composition is chlorhexidine acetate. Approximately 250 μg of chlorhexidine acetate is coated onto a rod-shaped elongate member having a length of 17 mm and a diameter of 1.9 mm, forming a chlorhexidine acetate layer with a thickness of approximately 2 μm along the elongate member. The luer portion is coated with 50 μg of chlorhexidine acetate, forming a layer with a thickness of approximately 0.4 μm. It is also possible to inject the antibacterial composition into the catheter using a syringe or to deliver the antibacterial composition through the connector tip cavity (a dry-soluble amount applicable to citrate or others that require a large amount of antibacterial composition).

[0129] The elongate member has the further advantage of moving fluid from within the catheter when the elongate member is inserted, transferring the solution to the outer base region (end face and threads) of the catheter connector. The antibacterial composition from the cap dissolves in the transferred fluid, thereby disinfecting the proximal end portion of the connector. Furthermore, when the fluid dries, it forms a coating of chlorhexidine acetate or other suitable antibacterial substance on the connector as described above. When it is an alternative to the use of the elongate member, chlorhexidine acetate or other antibacterial composition may be delivered by a coating on the luer tip (such as 250 μg of chlorhexidine acetate in a layer with a thickness of approximately 20 μm).

[0130] The antimicrobial composition is disposed on the outer surfaces of the elongate member, male luer connector, and retention ring. The antimicrobial composition elutes from the elongate member after insertion of the elongate member / rod into the catheter. When the system is inserted into the catheter, the antimicrobial composition dissolves in the fluid contained within the catheter, and thus contacts the connector surface and the lumen wall of the catheter, or infectious organisms that may be present within the solution. Further, the antimicrobial composition and any infectious organisms are trapped together in small spaces along the inside of the catheter. Another advantage is that the constricting action of the clamp traps any infectious microorganisms within the catheter, preventing the infectious microorganisms from spreading to other areas of the catheter or to the body and preventing systemic infections.

[0131] The antimicrobial composition must kill Gram-positive bacteria, Gram-negative bacteria, and fungi and / or must result in the arrest of Gram-positive bacteria, Gram-negative bacteria, and fungi. The agent may also be effective in killing organisms within established biofilms and / or degrading the extracellular matrix of the film. However, since the present invention is designed to kill organisms before they have the opportunity to form biofilms, this is not necessary for the present invention to be advantageous. A preferred antimicrobial composition is chlorhexidine diacetate, also known as chlorhexidine acetate. Other compounds containing chlorhexidine may be used (e.g., chlorhexidine free base, chlorhexidine gluconate, and chlorhexidine containing dyes). Chlorhexidine acetate has an advantage over chlorhexidine gluconate in that it can minimize the risks associated with parachloroaniline. Other suitable antimicrobial compositions may also be used. Generally, preferred antimicrobial substances are water-soluble, have a history of clinical use with a demonstrated safety profile, are antibiotic-free, can be applied to medical devices, and can then be dissolved in a composition having an effective concentration to inhibit the growth of bacterial and fungal organisms. Suitable materials include chlorhexidine, chlorhexidine salts (e.g., chlorhexidine acetate or chlorhexidine gluconate), tetra-sodium ethylenediaminetetraacetate (tetra-sodium EDTA), sodium citrate (resulting in a concentration of 30% or more), iodine, taurultamide, disodium EDTA, silver compounds (including silver nanoparticles and ions), silver sulfadiazine, and triclosan.

[0132] One particular drug or antimicrobial composition can suppress a variety of challenging organisms that can potentially lead to catheter-related bloodstream infections, but two or more agents may be used to enhance the effect against a wide range of infectious organisms (bacteria and fungi).

[0133] In particular, catheter-related infections arise from three broad classes of organisms: fungi, gram-negative bacteria, and gram-positive bacteria. If an antibacterial composition can be identified that weakens one or two of these types of organisms, this is certainly advantageous but leaves the patient vulnerable to the remaining types. By pairing drugs with different modes of action, infections due to an increasing spectrum of organisms can be prevented. This synergistic effect can lead to a further reduction in catheter-related morbidity and mortality and reduce the impact of the implanted catheter on the patient's quality of life. Preferred combinations of antibacterial compositions are chlorhexidine acetate and EDTA, silver sulfadiazine and sodium dodecyl sulfate, and silver sulfadiazine and methylene blue.

[0134] The primary use of the cap is to treat, prevent, and eliminate infectious organisms to prevent infection, but secondary benefits including the incorporation of additional agents can also be envisioned. Antithrombotic drugs eluting from the elongate member can be used to improve the action of heparin currently used in the lock solution. Enzymes or agents that promote the degradation of the extracellular matrix of biofilms (generally composed of polysaccharides) may enable the use of the cap for treatment as well as prevention.

[0135] In principle, antibiotics (such as rifampin, minocycline) can be incorporated into the cap or similar device and may be as effective as non-antibiotic antibacterial substances. However, continuous exposure to one antibiotic can lead to antibiotic-resistant strains, such as methicillin resistant S. aureus (MRSA). Accordingly, preferred embodiments use antibacterial compositions selected from a subset of substances that are not antibiotics. If for some reason an antibiotic is used, the risk of increasing bacterial antibiotic-resistant strains may be mitigated by preparing a second complementary cap containing a different antibiotic. By using two caps alternately in successive hemodialysis, infectious organisms resistant to one antibiotic may be killed by the other.

[0136] When the elongate member is inserted into the hub, the elongate member creates a constriction within the internal channel of the hub that aids in reducing the diffusion of the antimicrobial composition and organisms from the hub to the more distal portions of the catheter. Since most of the organisms are seen to enter the catheter at the hub, it is important to kill the organisms in this area before they have the opportunity to spread through the catheter. The restriction created by the elongate member within the hub is effective in creating a containment within the hub region. For example, the present invention was manufactured using injection molding such that the tapered luer member and the elongate member are firmly attached to each other as an integral structure of the polymer. The diameter of the elongate member was 1.98 mm (0.078 inches) and the diameter of the narrowest section of the hub channel was 2.54 mm (0.100 inches). In this embodiment, insertion of the elongate member into the hub reduced the cross-sectional area of the channel by more than 60%, substantially reducing diffusion even further.

[0137] After injection molding, the tapered member and the elongate member were then each coated with 60 μg and 225 μg of chlorhexidine acetate, respectively. The length of the elongate member was 17.78 mm (0.700 inches). When the device was fully inserted into the catheter, the elongate member extended along the internal channel of the hub and the elongate member terminated near the end of the hub. Since the elongate member remained substantially within the hub, the elongate member was easily inserted into the catheter even when the catheter clamp was placed at its most proximal position.

[0138] A series of tests were conducted using the above-described embodiments. In one experiment, the catheter was filled with a locking solution and the device was inserted. The catheter and device were left for 48 hours. After 48 hours, the device was removed from the catheter and the amount of chlorhexidine in the hub region and the remaining regions of the catheter region, as measured for each catheter, was determined. The results demonstrated that the present invention is highly effective in maintaining chlorhexidine in the hub region. On average, more than 80% of the chlorhexidine remained in the hub region after 48 hours. Twenty percent was in the tip region of the catheter. The experiments were repeated with various antimicrobial dosages in heparin and saline locking solutions. A total of 50 devices were tested and similar results were obtained. In another experiment, the above-described embodiment was placed on a catheter filled with a locking solution containing Pseudomonas aeruginosa, a microorganism that is difficult to kill, at approximately 200,000 colony-forming units per catheter. After 48 hours, the device was removed from the catheter. The catheter was then examined for the presence of microorganisms. All microorganisms were killed in all catheters, further demonstrating the effectiveness of the present invention.

[0139] Experiments were conducted to examine the performance of an exemplary embodiment of the present invention, referred to as "Pursuit Vascular's ClearGuard HD" or "ClearGuard HD". These experiments demonstrate that ClearGuard HD is effective in substantially reducing organisms among the catheters for which it is intended. Two of the experiments are highlighted below.

[0140] In experiments conducted with Pursuit Vascular, the coated cap was effective in stably delivering more than 50 μg of chlorhexidine acetate (also known as chlorhexidine diacetate) onto the threads of the catheter by a single connection. Such delivery provides the catheter with a means to further reduce organisms that cause infections which are replenished with each use of the present invention. Chlorhexidine above 10 μg is effective in reducing bacteria and other organisms that cause infections at the threads and further prevents the entry of organisms into the catheter connector end face, luer, and lumen. When used outside the catheter where there is little risk of chlorhexidine acetate entering the bloodstream, chlorhexidine acetate has a broad safety profile. The preferred range of chlorhexidine on the cap threads is 100 μg to 2500 μg. More preferably, it is 500 μg to 1200 μg.

[0141] For example, when using a chlorhexidine-based antimicrobial, in some embodiments, about 50 μg of chlorhexidine acetate may be effective. This was demonstrated in experiments conducted with Pursuit Vascular where 50 μg of chlorhexidine was coated on the luer portion of the cap. The cap containing the coated luer killed all Candida albicans inoculated within the catheter luer region. During the same experiment, when an uncoated cap was used, Candida albicans remained viable. Chlorhexidine acetate above 5 μg on the luer region is effective. Preferably, it is 10 μg to 300 μg, and most preferably, it is 30 μg to 80 μg.

[0142] Laboratory tests conducted for Pursuit Vascular demonstrated that 250 μg of chlorhexidine acetate on the elongate member results in a greater than 10,000-fold reduction in the number of organisms causing infection when the cap is used with a standard hemodialysis catheter containing physiological saline, heparinized saline, or saline containing 4% sodium citrate. The safety profile of the present invention can be enhanced by limiting the amount of chlorhexidine acetate available for introduction into the bloodstream, with a preferred maximum amount of chlorhexidine acetate on the elongate member being 2000 μg, more preferably 1000 μg, and most preferably 350 μg.

Example

[0143] Experiment 1 The purpose of this experiment was to evaluate the antibacterial effect of the Pursuit Vascular ClearGuard HD device in the most challenging clinically relevant model. Since the ClearGuard HD is placed at the catheter hub and is not intended to extend into the extension tubing, the catheter model was selected to be a female luer connector, extension tubing, and clamp. The total length of the female luer connector and extension tubing was manufactured to maximize the lengths and volumes expected to be encountered clinically. Candida albicans (fungus) was selected as the challenge microorganism because in previous tests it had been shown to be the most challenging microorganism for ClearGuard HD to eradicate. Candida albicans was added to three different lock solutions: heparinized serum, saline serum, and SDB broth. These solutions represent the most relevant (and challenging) solutions expected clinically. The catheter was filled with the lock solution and Candida albicans, then a cap (ClearGuard HD or standard cap) was secured, and subsequently the catheter was incubated for approximately 46 hours to simulate the time between dialysis sessions. After incubation, the cap was removed and the lock solution was examined for the presence of organisms.

[0144] Results of Experiment 1. The organism counts are shown in Figure 27 for ClearGuard HD caps and standard caps (designated as "with CGHD" and "without CGHD", respectively).

[0145] [Table 1]

[0146] The antibacterial effect of ClearGuard HD was evaluated against Candida albicans, a microorganism that was most difficult to eradicate when tested in a clinically relevant catheter model containing the most challenging clinically relevant fluids.

[0147] All test samples using ClearGuard HD completely killed Candida albicans. In comparison, all control samples demonstrated growth of CA. Since Candida albicans did not survive during the ClearGuard HD part of the test, the actual reduction of Candida albicans can be considerably higher (better) than the sensitivity of this test. The minimum reduction of Candida albicans was shown to be as follows when using ClearGuard HD instead of the standard cap.

[0148] a. 3.6×10 6 CFU / ml (heparin containing 25% serum) b. 3.8×10 3 CFU / ml (physiological saline containing 25% serum) c. 7.7×10 8 CFU / ml (SDB broth) This test demonstrates that ClearGuard HD brings about a significant reduction of Candida albicans within a clinically relevant catheter with a clinical solution. Candida albicans was previously shown to be the organism with the most difficult reduction among other clinically relevant microorganisms tested, and thus it is concluded that ClearGuard HD brings about a broad-spectrum reduction in clinically relevant microorganisms.

[0149] Experiment 2 The purpose of this experiment was to evaluate the relative rates of microbial contamination of hemodialysis catheter lumens when using ClearGuard HD versus standard caps in a simulated clinical environment. This experiment was intended to investigate the effectiveness of ClearGuard HD compared to standard caps in a simulated clinical environment when preventing microbial contamination of hemodialysis catheter lumens (both proximal and distal to the extension tube clamp). Instead of a standard lock solution, a growth medium was used within the catheter to provide a highly sensitive means of detecting whether any microorganisms had entered the interior of the catheter.

[0150] During clinical use, hemodialysis catheter hubs are typically exposed to microorganisms since the catheter and hub are placed on the patient's skin. All commercially available catheter caps are primarily designed to maintain fluid within the catheter lumen but are not appropriately designed to prevent the access and colonization of microorganisms into the catheter lumen.

[0151] To compare whether the rate of microbial colonization was affected by cap type (ClearGuard HD versus standard caps), 20 identical catheters were attached to clothing to maintain the contact of the catheter with human skin as occurs during clinical use. The catheters remained in contact with the skin for up to 26 days. When the catheter lumen was determined to be in a contaminated state, the catheter was removable from the study. The study consisted of two arms: 1) the ClearGuard HD arm, and 2) the standard cap arm. The two arms were identical in all other ways except for the cap type used (i.e., same catheters, solutions, handling, etc.).

[0152] The investigation was designed to mimic hemodialysis clinical practice as closely as possible. When present, the entire volume of the lock solution containing the solution on the tip side of the clamp was included in the microbiological test to ensure with a high probability that the microorganisms were present anywhere within the catheter where they were detected. Standard microbiological techniques were used to test for the presence of organisms.

[0153] The number of catheters remaining free of microbial contamination over time is shown in Figure 28. Within 14 days, all catheters using standard caps were contaminated, while catheters using ClearGuard HD remained uncontaminated throughout the entire 26-day experiment.

[0154] When the catheters were filled with growth medium and worn to simulate actual patient end-use, following the standard dialysis fluid exchange schedule, this experiment showed that catheters using standard caps were contaminated with microorganisms with an average failure life of 8.9 days, and all of these catheters (10 out of 10) were contaminated by 14 days. In comparison, none of the catheters using ClearGuard HD were contaminated (0 out of 10) throughout the 26-day test. ClearGuard HD functions considerably better than standard caps (current standard of care) with respect to reducing microbial contamination within catheters in a simulated clinical environment.

[0155] Experiment 3 The purpose of this experiment was to confirm whether an appropriate amount of the antimicrobial composition elutes from the cap into the catheter within an acceptable time. Each catheter was filled with one of three lock solutions: sodium heparin, sodium citrate, and sodium chloride (physiological saline). Next, the cap was placed on the catheter hub for the following periods: less than 10 seconds, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. Five tests were repeated for each time point and each lock solution. At the end of the time period, ClearGuard HD was removed from the catheter, and the chlorhexidine eluted into each of the catheters was measured.

[0156] The average elution within 6 hours after the ClearGuard HD cap was inserted into the catheter exceeded 20 μg for all lock solutions (corresponding to an amount greater than 10% of the antimicrobial substance present in the elongate member). The amount of the eluted antimicrobial composition increased with time and, on average, exceeded 30 μg for all lock solutions at 72 hours (an amount greater than 15% of the antimicrobial substance present in the elongate member).

[0157] In this test, it was confirmed that the cap was able to deliver an appropriate amount of the antimicrobial agent to the catheter within 6 hours of insertion. Experiment 4 The purpose of this experiment was to confirm whether the cap was able to deliver more of the antimicrobial composition to the catheter hub than to other areas of the catheter. The experiment was performed to quantify the distribution of chlorhexidine along the length of the catheter resulting from the ClearGuard HD cap inserted into the catheter. The following test results demonstrated that the cap was able to preferentially deliver more of the antimicrobial agent to the catheter hub than to the rest of the catheter, and that this preferential distribution was sufficient even after the cap had been in place for 48 hours.

[0158] In this experiment, the catheter was filled with a heparinized saline lock solution and the catheter was clamped at 96 millimeters from the proximal end face of the hub. Next, a cap was inserted into the catheter and the cap was allowed to stand for 48 hours, which generally represents the time for staying in place in a clinical situation. After 48 hours elapsed, the catheter was separated into multiple regions using hemostatic forceps to enable measurement of the amount of chlorhexidine in each region. The total amount of chlorhexidine present in each region was measured using HPLC and was performed using 10 replicate tests.

[0159] Figure 29 shows the positions of the separated regions. There were four regions consisting of a hub region and three extension tube regions (referred to as segments 1, 2, and 3) on the proximal side with respect to the catheter clamp. The length of each of these regions was 24 mm. The final region was on the distal side with respect to the clamp. After 48 hours, the cap was removed and measurements were taken. 10 replicate tests were performed and the average amount of the antimicrobial substance in each region is shown in Figure 30.

[0160] As shown in Figure 30, on average, approximately 28 μg of chlorhexidine eluted into the heparinized saline lock solution, and 20 μg (72% of the eluted amount) was contained in the hub region, which was more than the total of all other regions combined. The hub contained 0.084 mL of the lock solution, and thus, the hub contained more than 235 μg / mL of chlorhexidine. In comparison, each of segments 1, 2, and 3 contained approximately 0.180 mL of the lock solution, and had average chlorhexidine concentrations of 29, 11, and 3 μg / mL in segments 1, 2, and 3, respectively. Initially, an average of 214 μg of chlorhexidine acetate was present in the elongate member. Thus, approximately 13% of the antimicrobial substance originally present in the elongate member eluted into the lock solution.

[0161] This test was repeated using sodium citrate and saline lock solutions. In all cases, the average amount of chlorhexidine in the hub exceeded 200 μg / mL, and the maximum amount of the antimicrobial agent was present in the hub and was hardly contained in the tip-side region relative to the hub. In all cases, the amount of the antimicrobial agent was substantially greater in the hub due to deposits adhering to the catheter wall and the entrapment / flow restriction effect of the elongate member within the hub. When heparinized saline was used as the lock solution, more than 50% of the amount of the antimicrobial composition eluting into the lock solution precipitated on the inner wall of the catheter.

[0162] Prior to the change in the movement of organisms to the tip region of the catheter, it is desirable to have a high concentration of the antimicrobial composition in the hub region, particularly along the wall of the hub. It is also advantageous to have no measurable antimicrobial composition on the tip side relative to the clamp to substantially reduce the possibility of the antimicrobial agent entering the patient's bloodstream.

[0163] Experiment 5 The purpose of this experiment was to demonstrate that a particular embodiment of the cap of the present invention is capable of depositing an antimicrobial composition on the inner and outer surfaces of the catheter. One of the greatest drawbacks of today's antimicrobial-treated catheters is that the antimicrobial agent rapidly disappears over time. In the case of commercially available antimicrobial catheters, more than 50% of the amount of the antimicrobial agent may be flushed out after two days of use.

[0164] In this experiment, initially, catheters without an antimicrobial composition were used with ClearGuard HD caps, intended to simulate hemodialysis use over multiple hemodialysis sessions. Each catheter was filled (locked) with saline, clamped, and a new cap inserted. Each cap remained on the catheter for 2 - 3 days, which is standard practice in dialysis. After the 2 - 3 day period, the cap was removed and the catheter aspirated and flushed according to the clinical protocol. At this point, the catheter was examined (removed from further simulated dialysis) to quantify the amount of antimicrobial substance on the surface, or received another use including simulated dialysis (saline flowing through the catheter at 350 mL / hr), following which a new cap was inserted for 2 - 3 days until the cap was removed and the catheter aspirated and flushed. Successive runs were continued until all data at the desired time points were collected. Four lots of 3 - 5 catheters were used. One lot was used at each of the 1 - use, 3 - use, 5 - use, and 9 - use time points. New caps were inserted with each use of the catheter, for a total of 90 caps used.

[0165] The amount of antimicrobial substance on the inner and outer surfaces of the catheter was measured at specific time points, and the results of this experiment are shown in Figure 31. Log fitting was performed on the data, showing that the cap adds the antimicrobial composition to the catheter and that the amount of antimicrobial composition on both the inner and outer surfaces of the catheter increases with multiple uses but approaches an upper limit with multiple uses. On the inner surface, most of the antimicrobial substance is contained within the hub. On the outer surface, the antimicrobial substance is contained on the hub base end face and the thread hills. Protection by the residue on the catheter surface alone is sufficient to provide substantial protection against infectious organisms. The same test was performed using a heparin - saline lock solution instead of the saline lock solution. This test also demonstrated that the cap adds the antimicrobial composition to the catheter.

[0166] Experiment 6 The purpose of this experiment was to confirm that the cap of a particular embodiment of the present invention was capable of killing a broad spectrum of microorganisms in a clinically relevant test model. The test was designed to evaluate the effect of killing organisms at the catheter hub. The test was designed to simulate a scenario where the hemodialysis hub becomes challenging to microorganisms at the end of the dialysis session, and the cap was employed to reduce or eliminate the contaminating organisms.

[0167] In addition to the test device, a control device was used to enable comparison of the effect of the present invention (test device) with an uncoated cap (control device). Each catheter was inoculated with organisms from one of the multiple strains of organisms being tested. After inoculation of the catheters, a cap was inserted onto each of the inoculated catheters. For each strain of organism, three replicate tests were performed in both the test arm and the control arm. Two days after incubation (representing the time between dialysis sessions), the caps were removed and microbiological tests were performed to quantify the number of remaining organisms within each catheter. The results showed that the cap of the present invention reduced the number of organisms at the catheter hub by 4 log (10,000-fold) or more for each of the following organisms.

[0168] Staphylococcus aureus Staphylococcus aureus (MRSA) Staphylococcus epidermidis (MRSE) Enterococcus faecium (VRE) Pseudomonas aeruginosa Acinetobacter baumannii Escherichia coli Candida albicans Candida paratropicalis The organisms on the above list account for approximately 70% of all catheter-related bloodstream infections, and they include gram-negative bacteria, gram-positive bacteria, and fungi. Thus, the cap of the present invention is effective in killing a wide range of clinically relevant organisms of catheters.

[0169] Although the present invention has been described particularly with reference to its embodiments, it will be understood by those skilled in the art that the foregoing as well as other changes in form and detail may be made therein without departing from the spirit and scope of the invention.

Claims

1. 1. An apparatus for inserting a hub on a proximal end of a percutaneous catheter, said apparatus comprising: A cap configured to be removably secured to the hub The cap comprises: i) a ring member having a first thread for engaging a second thread on the hub of the percutaneous catheter, the ring member having an opening therethrough; ii) an insert member secured within the opening of the ring member; and Equipped with the ring member and the insert member are held together such that it is not easy for the ring member and the insert member to rotate relative to one another; the insert member comprises an antimicrobial composition; Device.

2. The ring member and the insert member are joined by an interference fit.

13. Apparatus according to any one of claims 1 or 3 to 12.

3. the ring member and the insert member do not rotate relative to each other; 13. Apparatus according to any one of claims 1 to 2 or 4 to 12.

4. the ring member and the insert member are prevented from rotating by an interference fit between the ring member and the insert member; An apparatus according to any one of claims 1 to 3 or 5 to 12.

5. the ring member and the insert member are configured to be substantially non-rotatable relative to one another when subjected to a torque of 0.362 N-m (3.2 lb.-in); 13. Apparatus according to any one of claims 1 to 4 or 6 to 12.

6. The ring member and the insert member are configured to not move axially relative to each other.

13. Apparatus according to any one of claims 1 to 5 or 7 to 12.

7. the ring member and the insert member are prevented from axial movement by an interference fit between the ring member and the insert member; 13. Apparatus according to any one of claims 1 to 6 or 8 to 12.

8. the ring member includes one or more fingers projecting into the opening through the interior of the ring; 13. Apparatus according to any one of claims 1 to 7 or 9 to 12.

9. the insert member secured within the ring member has one or more fins protruding from the insert member; 13. Apparatus according to any one of claims 1 to 8 or 10 to 12.

10. the ring member comprises one or more fingers; the insert member comprises one or more fins; the fingers of the ring member and the fins of the insert member contact one another along an interference fit; An apparatus according to any one of claims 1 to 9 or 11 to 12.

11. the ring member comprising an antimicrobial substance on at least a portion of the first thread; Apparatus according to any one of claims 1 to 10 or 12.

12. The insert member further comprises an elongated member; the elongate member is configured for insertion into the hub of the percutaneous catheter. An apparatus according to any one of claims 1 to 11.

13. 1. A method of forming a device for insertion into a hub on a proximal end of a percutaneous catheter, the method comprising: providing a ring member having a first thread for engaging a second thread on the hub of the percutaneous catheter, the ring member having an opening therethrough; providing an insert member configured for insertion into the opening through the interior of the ring member; applying an antimicrobial composition to at least a portion of the ring or insert member; fixing the insert member to the ring member such that the ring member is fixed within the opening of the ring member, whereby the insert member and the ring member do not readily rotate relative to one another; Including, method.

14. The insert member and the ring member do not easily rotate relative to each other when attached to or detached from the hub of the percutaneous catheter.

23. The method according to any one of claims 13 or 15 to 22.

15. the insert member and the ring member do not easily rotate by more than 5 degrees relative to each other when attached to or detached from the hub of the percutaneous catheter; 23. The method according to any one of claims 13 to 14 or 16 to 22.

16. the insert member and the ring member do not easily rotate by more than 10 degrees relative to each other when attached to or detached from the hub of the percutaneous catheter; 23. The method according to any one of claims 13 to 15 or 17 to 22.

17. applying the antimicrobial composition to at least a portion of the ring member prior to securing the insert member to the ring member. Further comprising:

23. The method according to any one of claims 13 to 16 or 18 to 22.

18. the ring member and the insert member are joined by an interference fit; 23. The method according to any one of claims 13 to 17 or 19 to 22.

19. the ring member and the insert member are prevented from rotating by an interference fit between the ring member and the insert member; 23. The method according to any one of claims 13 to 18 or 20 to 22.

20. the ring member and the insert member do not substantially rotate relative to one another when subjected to a torque of 0.362 N-m (3.2 lb.-in); 23. The method according to any one of claims 13 to 19 or 21 to 22.

21. the ring member comprising an antimicrobial substance on at least a portion of the internally disposed threads of the ring member; 23. The method according to any one of claims 13 to 20 or 22.

22. The insert member further comprises an elongated member; the elongate member is configured for insertion into the hub of the percutaneous catheter. The method according to any one of claims 13 to 21.

23. 1. An apparatus for sealing a lumen of a percutaneous catheter, said apparatus comprising: a cap configured to seal the lumen at a hub at the proximal end of the percutaneous catheter; The cap comprises: i) a ring member having a first thread for engaging a second thread on the hub, said ring member having an opening therethrough, said opening having one or more first fingers; ii) an insert member having a tapered outer surface for engaging a tapered inner surface of the hub to seal fluid inside the lumen, the insert member further comprising one or more fins; and Equipped with the insert member is secured within the opening in the ring member; the fins are configured to engage the fingers to prevent significant rotational movement of the insert member relative to the ring member during normal operation. Device.

24. the walls of the fins are configured to engage the walls of the fingers with an interference fit; 28. Apparatus according to any one of claims 23 or 25 to 27.

25. an outer surface of the fin configured to engage an inner surface on the ring member; the outer surface of the fin has a larger diameter than the mating inner surface on the ring member; 28. Apparatus according to any one of claims 23-24 or 26-27.

26. the insert member is configured to create an axial interference fit with the ring member; 28. Apparatus according to any one of claims 23 to 25 or 27.

27. the insert member is secured within the opening in the ring member by a push-on latch mechanism; Apparatus according to any one of claims 23 to 26.

28. 1. An apparatus for sealing a lumen of a percutaneous catheter, said apparatus comprising: a cap configured to removably seal the lumen at a hub at the proximal end of the percutaneous catheter; The cap comprises: i) a ring member having a first thread for engaging a second thread on said hub, said ring member having an opening therethrough, said opening having one or more fingers; ii) an insert member having a tapered outer surface for engaging a tapered inner surface of the hub to seal fluid inside the lumen, the insert member further comprising one or more fins; and Equipped with the insert member is secured within the opening in the ring member; the fingers are configured to engage the fins with an interference fit; Device.

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