Patent Application
20170136210
The invention is generally directed to catheters that release ionic silver, preferably in response to the application of electric current to the catheter.
The indwelling urinary catheter was introduced by F. E. B. Foley in 1927 (Foley, J Urol, 21:289-306 (1929)). Since its inception, the indwelling catheter has been associated with complications, some of which are severe. Today, indwelling urinary catheters are a leading cause of healthcare-associated urinary tract infections (UTIs) (van den Broek, P. J., et. al., (2011)). Symptoms of a UTI may include: fever, chills, headache, burning of the urethra or genital area, leaking of urine out of the catheter, blood in the urine, foul smelling urine, low back pain and achiness. Additional complications associated with urinary catheters include, but are not limited to allergic reaction to the material used in the catheter, such as latex, bladder stones, injury to the urethra, kidney damage (with long-term indwelling catheters), and infection of the urinary tract, kidney, or blood (septicemia). Urinary catheter associated bloodstream infection is a serious complication that can result in death (Bursle, E. C., J Infect., pii: S0163-4453 (2015)).
Other types of catheters can also be sources of infection. These catheters include vascular catheters such as central venous catheters (CVCs), peripherally inserted catheters and (PICCs), and endotracheal catheters. Regardless of the type of catheter, the catheter serves as an entry point for microbial infection.
A typical catheter-related urinary tract infection can occur, for example, when a urethral catheter inoculates organisms into the bladder and thereby promotes colonization by providing a surface for bacterial adhesion and causing mucosal irritation. (Vergidis, P, and Patel, R. Infect Dis Clin North Am, 26(1):173-86 (2012)). The presence of a urinary catheter is the most important risk factor for bacteriuria.
Once a catheter is placed, the daily incidence of bacteriuria is 3-10%. Between 10% and 30% of patients who undergo short-term catheterization (i.e., 2-4 days) develop bacteriuria and are asymptomatic. Between 90% and 100% of patients who undergo long-term catheterization develop bacteriuria. About 80% of nosocomial UTIs are related to urethral catheterization; only 5-10% are related to genitourinary manipulation. (John L Brusch, Medscape, 2013).
Exemplary pathogens include Escherichia coli, Pseudomonas species, Enterococcus species, Staphylococcus aureus, coagulase-negative staphylococci, Enterobacter species, and yeast. Proteus and Pseudomonas species are the organisms most commonly associated with biofilm growth on catheters. More recently, anti-biotic resistant strains of bacteria are becoming problematic.
Thus, there is a need for antimicrobial catheters that reduce or inhibit microbial infections in a subject.
It is an object of the present invention to provide methods and catheters to reduce, inhibit, or prevent catheter-related microbial infections.
It is another object of the invention to provide a non-fouling, antimicrobial catheter.
It is another object to provide an antimicrobial catheter that releases an effective amount of an antimicrobial metal to inhibit, reduce or prevent biofilm formation on the catheter.
The disclosed non-fouling, antimicrobial catheters release a therapeutically effective amount of silver ions in response to an electrical current to prevent, inhibit, or reduce bacteria or fungi from passing through the catheter into the body of a subject, for example passing through the urethra and into the bladder via the gap between the external surface of the catheter and the urethral wall. The release of silver ions in response to the electrical current also inhibits, reduces, or prevents microbes from passing through the catheter into the subject via the internal features of the catheter. The release of silver ions also reduces, inhibits or prevents microbes from colonizing and developing a fibrous matrix on the exterior surface of the catheter (also known as biofilm). Microbes on the catheter, in the urine, or in the tissue of a subject in contact with the catheter are killed by the ionic silver.
The catheter can be a Foley catheter (indwelling catheter), venous catheter (CVCs), peripherally inserted catheter (PICCs), or an endotracheal catheter. It has been discovered that changing the polarity of the current as well as modulating the amount of current enables the disclosed catheters to release therapeutically effective amounts of the silver ions over prolonged periods of time. For example, some embodiment provides catheters that alternated current from 0.0 μAmps to 100 μAmps, preferably between 20 μAmps and 60 μAmps. In one embodiment, the current is alternated from −150 μAmps to +150, preferably about −60 μAmps to +60 μAmps, or even −20 μAmps to +20 μAmps. In one embodiment, the catheter releases a therapeutic amount of silver ions for at least 7 days without complications including infections.
In one embodiment, the disclosed catheters are urinary catheters used for draining the bladder.
The term “therapeutic amounts of ionic silver” refers to amounts of ionic silver that inhibit, reduce, or prevent microbial infections resulting from bacteria or fungi including antibiotic resistant microorganisms. The term “therapeutic amounts of ionic silver” refers to more than antimicrobial activity of a few microorganisms. As used herein the term refers to the amount of ionic silver needed to prevent or inhibit the geometric growth of the microorganisms and/or the amount of ionic silver necessary to inhibit or prevent the formation of biofilm. Typically, the amount of ionic silver is expressed as a concentration of ionic silver that is maintained over a period of time. For example, a therapeutic amount of ionic silver includes, but is not limited to greater than 5 μg/ml to 100 μg/ml of ionic silver for at least 2 hours, preferably for 1 to 7 days.
The term “Foley catheter” refers to an indwelling catheter, typically an indwelling urinary catheter.
The term “antibiotic resistant microorganisms” refers to and includes but is not limited to Clostridium difficile (CDIFF carbapenem-resistant Enterobacteriaceae (CRE), drug resistant Neisseria gonorrhoeae, multidrug-resistant Acinetobacter, drug-resistant Campylobacter, fluconazole-resistant Candida, Extended Spectrum Enterobacteriaceae (ESBL), vancomycin-resistant Enterococcus (VRE), multidrug-resistant Pseudomonas aeruginosa, drug-resistant non-typhoidal Salmonella, drug-resistant Salmonella Serotype Typhi, drug-resistant Shigella collapsed, methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Streptococcus pneumoniae, drug-resistant tuberculosis, vancomycin-resistant Staphylococcus aureus, erythromycin-resistant Group A Streptococcus, and clindamycin-resistant Group B Streptococcus. The disclosed catheters preferably release amounts of ionic silver to inhibit, reduce, or prevent infection from at least one antibiotic resistant microorganism, preferably at least two antibiotic resistant microorganisms, and most preferably at least three antibiotic resistant microorganisms.
The term “biofilm” refers to an assemblage of surface-associated microbial cells that is enclosed in an extracellular polymeric substance matrix. (R. Donlan, Emerging Infectious Diseases, 8(9):881-890 (2002)). Microorganisms commonly associated with biofilms on indwelling medical devices include, but are not limited to Candida albicans, Coagulase-negative staphylococci, Enterococcus spp., Klebsiella pneumonia, Pseudomonas aeruginosa, and Staphylococcus aureus.
The term “non-fouling” refers to a surface or instrument that resists or inhibits the formation of a biofilm.
The disclosed catheters share core components with conventional catheters. A conventional catheter is typically a flexible tube that is inserted in the body. Urinary catheters are flexible tubes that go through the urethra and into the bladder to drain urine out of the bladder. A typical urinary catheter has two separated channels, or lumens, running down its length. One lumen is open at both ends, and allows urine to drain out into a collection bag and typically has a funnel connector. The other lumen has a valve on the outside end and connects to a balloon at the tip. The balloon is inflated with sterile water when inside the bladder to prevent it from accidently slipping out of the bladder. The balloon lumen can have a one-way luer activated valve for syringes.
The balloon component can withstand external pressure in bladder without deforming to a point of allowing sliding back through urethra. Additionally, the balloon component can withstand internal pressures to allow safe inflation with saline. The tubing can be made of materials such as silicone or polyurethane, latex, or polyvinyl chloride (PVC). The diameter of the tubing range from 6 to 30 F, with pediatrics approx. 6-12 F. The relative size of a catheter is described using French units (F) . . . 1 F is equivalent to 0.33 mm=0.013″= 1/77″ of diameter. 14-16-18 F appear to be the most common. Typical Foley catheter shaft lengths are approximately 32-35 cm (13-14 inch). Intermittent urinary catheters have male (16″ OAL) and female (6″ OAL) specific offerings and therefore have shorter length versions. Exemplary catheters have a size of 16 F (approximately 0.210″ shaft diameter) and length 33 CM.
The electrodes are preferably silver or a silver alloy capable of releasing silver ions in response to electric current. In certain embodiments, the electrodes are contain enough silver metal to release therapeutic amounts of silver in response to current passed through the electrodes. In other embodiments, the electrodes are in contact with silver metal on the electrode so that when electricity is passed through the electrodes, the silver metal releases a therapeutic amount of ionic silver.
In one embodiment the electrode is placed on the exterior surface of the catheter and is constructed to provide an electrically active field in a strategically placed zone that maximizes the desired antimicrobial effect. One embodiment provides the electrodes inside the bladder outlet (conical section of bladder), therefore in the location just proximal to the balloon, or approx. 5-7 cm from the distal tip of the catheter.
Another embodiment has the electrodes placed inside the urethra, close to the urethral opening: approx. 9-12 cm from the distal tip for an average adult female, 24-27 cm for average male.
Still another embodiment provides the electrodes inside the bladder, therefore located on the most distal 1-2 cm of the catheter shaft.
One embodiment has a distinct electrode pairs running axially for approximately 20-40 mm and 180 degrees from each other around the catheter shaft.
Another embodiment has continuous electrode “stripes” with length approximately 40 mm and spaced 180 deg from each other. The number of electrode stripes can vary. For example, the electrode can have four anode and for cathode stripes. The electrode stripes can be produced using “silver ink” or can be solid wires. One type of conductive ink that may be used is a silver-based epoxy ink. Conductive ink of this type may be obtained from Creative Metals Incorporated as product number CMI 119-21 and referred to as Printable Solvent Resistant Electrically Inductive Ink.
Another embodiment provides a continuous electrode helix, with length approximately 40 mm of the catheter shaft.
Another embodiment provides electrode rings around the shaft (360 degree), for example a pair of rings spaced axially a distance 40 mm from each other.
Yet another embodiment provides a catheter with electrode rings sharing a common cathode, for example two anodes with the common cathode.
The disclosed catheters include electronics for controlling the amount of current passing through the electrodes as well as for alternating the polarity of the electric current. The electronics are attached to the catheter in such a way that it does not encumber the end user. The location of electronics can be integrated with a juncture/manifold hub. See
The electronics can be primarily contained in a small envelop or housing. In
The electronic board shall include a power source, i.e., a battery (or batteries), capable of being programmed to deliver a range of constant currents. Likely current range is between 20 and 150 μA for at least one, two, three, four or as many as 20 weeks of continuous operation. An exemplary battery is SR66, a commercially available super silver oxide 1.5V battery.
In one embodiment, the electronics is capable of delivering a range of current density from approximately 1-5 A/m2, which is dependent upon the programmed current and electrodes' configuration.
The electronics preferably to self-adjust power consumption to be of a constant current type. Additionally, the electronics is capable of alternating and cycling the current from positive to negative and back to positive (i.e., swapping poles)
In one embodiment the electronics can be programmed to deliver a predefined duty cycle that includes at least 2 current magnitudes, directions, and durations, preferably 4 and can have 1-8 cycle periods. For example, a typical cycle can be:
5. Back to step 1
The activation of the power can be “automatic” in that current will flow when the circuit is completed via body fluids. Alternatively, fluids could be provided on the catheter to activate the electrodes. This could be of the form of a saline wash running through micro channels of the catheter, or otherwise an aqueous sublayer
Additional optional features that should be considered include an ON/OFF switch, visual alarm when current is active (e.g., LED), visual alarm when ON, but not active (i.e., on but no current flow), and visual low battery alarm. Additional features include diagnostics such as communications external to the device, for collecting and storing current and/or voltage data, etc.
As noted above, the disclosed catheters can be any form of catheter.
Preferably, the disclosed catheters are indwelling catheters such as urinary catheters.
In one embodiment the catheter has a third lumen that is dedicated to the electrical wires. There is a possibility that “the wires” are external such as the completely printed version (not shown) or the wires are completely embedded in the wall of the shaft and not down a lumen.
One embodiment provides a catheter having a body made of a biocompatible material and comprising silver-containing electrodes and a power source having a first terminal and a second terminal with one of the terminals being in electrical communication with the silver-containing electrodes. The catheter also has an impedance device placed in a current path between the first terminal of the power source and the second terminal of the power source reducing or inhibiting current flowing from the first terminal from reaching the second terminal. Impedance devices are known in the art and include but are not limited to resistors. The impedance device can inhibit the current by 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99%. The catheter also includes a current generator connected to the power source that creates a flow of antimicrobial ions from the silver-containing electrode when current passes through the silver-containing electrode. The silver ions kill microbes in the environment of the catheter.
The catheter can also have electronics connected to the current generator to alternate cycling of the current from positive to negative and back to positive. In one embodiment, the current passes through along the silver-containing electrodes and the body tissue.
Another embodiment provides a method for inhibiting microbial infection associated with an indwelling catheter by providing a catheter as described herein. The method also includes delivering a current to the silver-containing electrodes when the catheter is located in a human body at a site of potential infection, and wherein the delivery of current to the silver-containing electrodes causes release of an effective amount of silver metal ions to inhibit the microbial infection. The infection can contain a Gram positive bacterium a Gram negative bacterium, a fungus or a combination thereof. In a preferred embodiment, the bacteria are resistant to antibiotics.
The current can be applied in a duty cycle that includes at least two current magnitudes, at least two current directions, and at least two current durations. For example, the current can be applied in a duty cycle that includes at least four current magnitudes, at least two current directions, and at least four current durations. In one embodiment, the current is applied in 1-8 cycle periods. In another embodiment, the cycle is:
To record the current across electrode catheters when the catheter's electrodes are submerged in 0.9% NaCl solution (NS) or 0.09% solution over a specified time period. This report contains a series of studies at various setup conditions, which are summarized in the Table 1.
Materials and Methods
Sample Preparation and Testing Procedure
Normal saline was prepared by weighing 4.5 g NaCl per 500 ml de-ionized water. Approx 30 ml or 10 ml of NS was placed in a vial which in turn was placed in a 37° C. water bath. The catheter was introduced through the lid of the vial at T=0 at which time the data logger was started. The catheter was plugged into its power box seconds later. The initial current was verified to be approx 19 μA for the 20 μA power box and approximately 61 μA for the 60 μA power box, confirming “normal” expected operation.
Results
Detailed graphical results of Test No. 1 are attached. The catheter was designed with book end rings as shown in
Cleaning of the electrodes from Test No. 1 and 2 with 70/30 isopropyl alcohol (“IPA”) sprayed onto a paper-towel resulted in the apparent removal of the residue and also smoothing of the electrode surface. Water bath was approximately 19° C. during test.
A second cleaning of the electrodes from Test No. 3 with IPA was less visually pleasing. There was obvious residual brown streaks that were not removable with normal cleaning. A lint-free cloth was used to clean the electrodes prior to the use of a paper towel.
A third cleaning of the electrodes from Test No. 4 with IPA along with more aggressive cleaning with 400 grit sand paper was performed. The electrode was refreshed in 0.9% saline. Although most of the oxidation appeared to be removed (or mixed in the surface), results were highly variable.
Electrodes were cleaned with IPA (4×) and the catheter was tested in the same saline vial (×2).
See attachment 6B.
A new catheter with book end ring electrodes was tested in fresh 0.9% saline.
A new catheter having book end ring electrodes with alternate electrode epoxy was tested in fresh 0.9% saline. Note that the graph's X axis is in hours. Much better results in terms of longevity of current were obtained. Oxidation could only be removed with a sharp object (scalpel).
A new catheter with axial stripe electrodes (
The same catheter was cleaned with IPA which caused the removal of both the oxidation and the electrode material. The catheter was tested in attempt to use the proximal “good” section of the electrodes in approximately 45 ml of tryptic soy broth (“TSB”).
A new axial stripe electrode catheter was tested in TBS for 40 hour test.
A silver wire wrapped electrode was tested in TBS. The electrode was switched to 0.9% NaCl after approximate 3.5 days. The test ran for about 4.6 days.
A printed axial striped catheter was tested. One time impression (i.e., “thinnest” silver thickness) and with 60 μA. The test ran for about 3.5 before erratic behavior, with spikes and valleys averaging around 20 μA. The current recovery to 60 μA observed in the graph after 8 hrs. is the copper anode exposure. The silver based top coat deteriorated over time to the point where the electrical connectivity was made with the underlying copper wire, rebounding the current.
A printed axial striped catheter with 6× printed impressions (i.e., “thickest” silver thickness) was tested with 60 μA. The test ran for about 8 hrs before erratic behavior started. These catheters had 6 of 8 legs electrically active (2 were missing due to printing difficulty) and the poles were reversed to avoid a copper anode (underlying wire) connection. Contrasting the results with test Nr 13, areas of discontinuity can be seen visually on the parts, but with the darker corrosion starting proximal to distal, and a more “gradient” and less “abrupt” transitions to lighter corrosion. Some electrical conductivity occurred at the lid-line.
A marketed silicone catheter was modified with a 99.9% Ag ø.008″ wire and ø.020 Cu wire, and with 2 zones of exposure, totaling approx. 8 mm in length for each electrode.
Several hanging wire test samples were constructed with the intent of exposing progressively more anode surface area to saline to develop a baseline current versus surface area profile. Anode exposure to saline were 2, 3, 4, 5, 6, 7, 8, 9, 10 mm length of ø.008″ Ag wire. A ø.020″ Cu cathode was also used.
Approximate areas and volumes of the electrode are as follows:
All current profiles were observed to have a similar pattern of a period of steady decline followed by a steep drop in current. Other notables are an increase in wire diameter after the test and what appears to be “coring” on the inside of the wire.
Test 17 shows a prototype construction whereby the anode electrode was created by drilling a ø0.050″ by 4 mm long Ag wire with a ø0.030″ hole (the ferrule) and threading a ø.016″ copper wire through the center and crimping the ferrule. The cathode was the same copper wire. The current stability graph reflects this.
Test 18 consisted of prototype A425, a silicone catheter with two Ag wires, each ø.020″, running down the shaft in separate lumens. The electrodes were created by exposing approx. 10 mm of wire length on each side. Both sides of the wire exposure was potted with silicone to prevent saline ingress to the lumens. This is the same prototype construction that was challenged with bacteria for 7.5 hrs. in test TR0070. The current stability test was run for 7 days.
A silicone catheter prototype was constructed by potting each side lumen with conductive 2-part epoxy, and “burying” a copper wire into the epoxy for a distance of approx. 300 mm on the proximal end of the catheter to make a connection to the power box cable, and burying a ø.020″×30 mm Ag wire to create the electrodes on the distal end (10 mm buried in epoxy, 10 mm exposed to surface, and another 10 mm buried in epoxy). The construction resulted in a desirable flexible shaft catheter; however the smaller dia. lumen did not have continuity, whereas the larger lumen did. Therefore, the current stability test was setup as a single pole catheter anode with a copper “hanging wire” cathode.
Several hanging wire test samples were constructed with the intent of exposing progressively more anode surface area or volume to saline to develop a baseline surface area versus volume profile. Anode exposure to saline were 2, 3, 4, 5, 6, 7, 8, 9, 10 mm length of ø.008″ Ag wire. To increase the surface area the same Ag wire lengths were flattened. A ø.020″ Cu cathode was also used.
Attachment 20 shows that the round anodes for all sizes (smaller surface) have a quicker decrease in current, but the overall time until a sudden drop is longer than the flat anodes (larger surface). For the flat anodes the decrease in current is slower but the sudden drop in current appears earlier than the round samples of the same exposed wire length. As expected the longer the anode (e.g. 10 mm versus 5 mm) the longer the period of steady decline until the steep drop in current.
A catheter prototype was created by the same methods as Test 19, but with no silver wire electrode attached. The goal of this study was to evaluate the silver-based conductive epoxy as an electrode. The anode (epoxy) was extracted from the catheter to be used in a hanging wire setup. Prior to the test, the epoxy was checked for electrical continuity, and it was confirmed very low and erratic. A scalpel was used to strip a layer from the top surface of the anode to improve continuity. It is likely that an electrical connection with the underlying copper wire was made after around 4 hrs.
Two sets of 5 mm hanging wire samples were energized with approx. 60 μA over a period of 14 hrs. One set maintained its current direction throughout the test, while the current of the second set alternated its direction every 2 hrs by swapping the catheter poles. The alternating set lasted longer with no steep decline after 14 hrs. It also appeared that, after the initial period, the current much is more stable when alternating, and becomes more steady over time.
A silicone catheter with silicone potted lumens, and wire electrodes was tested for >72 hrs. Test 23 consisted of prototype A425, a silicone catheter with two Ag wires, each ø.020″, running down the shaft in separate lumens. The electrodes were created by exposing approx. 10 mm of wire length on each side. Both sides of the wire exposure was potted with silicone to prevent saline ingress to the lumens. This is the same prototype construction that was challenged with bacteria for 7.5 hrs. in test TR0070. The current stability test was run for 5 days.
Test 24 used the previously mentioned prototype A425 with 10 mm silver wire exposed on two sides and potted lumens. The test was run for about 26 hours. This prototype was an untested catheter from the previous batch. The purpose of the test was to study the current stability of the catheter in TSB and 0.9% Saline. During the test, the catheter was switched alternatively between TSB and Saline. This test was a reaction to some poor current results during TR0074.
The main purpose of this test was to verify that current levels will be maintained beyond a 24 hr time period and in TSB solution, and in preparation for TP0087. Additionally and after 2 days, the poles were briefly swapped and the solution was changed to saline. These time points are indicated on the graph.
A duty cycle where electrodes were energized for 10 minutes (positive) before swapping the pole for 10 minutes (negative) was run for approx 24 hrs. (10-0-10-0 duty cycle). These HW Ag electrodes were ø0.008″×5 mm long. An identical electrode pair was run with continues current as a control.
Test No. 27-5 mm HW with 5-5-5-5 Duty Cycle
Test 27 was similar to Test No. 26 but with the introduction of “all offs” in the cycle (5-5-5-5 duty cycle). The assay was in a 0.09% saline solution. The test lasted about 3 days. The control electrodes lasted approximately 10-12 hrs, whereas the duty cycle lasted over 3 days with no signs of current degradation. The posts are insulated from each other the full length, with exception to the top of the screw within the insulator tubing.
Materials and Methods
Results
E. coli
2 Hr
E. coli
E. coli
S. aureus
E. coli
E. coli
E. coli
Klebsiella
Klebsiella
Acinetobacter
Pseudomonas
Acinetobacter
Enterococcus
Pseudomonas
Enterococcus
E. coli
Ecoli
Klebsiella
Pseudomonas
Klebsiella
Pseudomonas
E. coli
This application claims benefit of U.S. Provisional Application No. 62/256,541 filed Nov. 17, 2015, which is incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62256541 | Nov 2015 | US |
