Field of the Invention

Compositions and methods useful in providing antimicrobial effect to medical devices are numerous. This invention generally relates to articles of manufacture providing antimicrobial effect to urinary drainage systems. The specific province of this in¬ vention resides in compositions and an article of manufacture, generally for insertion into a urinary drainage bag, which pro- vide antimicrobial effect to the interior of the urinary drainage bag and the urine contained therein. The article can be used as part of a urinary drainage system having a urinary drainage bag, a urinary catheter, and a catheter adapter on the end of catheter tubing providing flow communication from catheter to bag. When placed directly in the urinary drainage bag, the compositions also can be used as part of a similar system. The article, catheter and catheter adapter of the system all would provide levels of antimicrobial effect.

Background of the Invention Indwelling urethra! catheterization is performed in approxi¬ mately 10 to 15 percent of hospitalized patients. About 25 percent of these patients contract bacterial infections of the urinary tract. Two studies of note are, Garibaldi, R. A.; Burke, J. P.; Dickman, M. L.. and Smith, C. B., "Factors Predisposing to Bacteriuria During Indwelling Urethral Catheterization". New England Journal of Medicine, 291:215, 1974, and Kunin, C. M. and McCor ack, R. C, "Prevention of Catheter-Induced Urinary-Tract Infections by Sterile Closed Drainage". New England Journal of Medicine, 274:1155, 1966.

OMPI

The incidence of catheter-induced urinary tract infections still remains a problem despite various prophylactic measures that have been tried. Attempts to reduce the incidence of urinary tract infections have included the application of antibiotic ointments or other bacteriocidal agents to the surface of the catheters, frequent bladder irrigation with concornmitant prophy¬ lactic administration of antibiotics, or inhibition of the growth of bacteria in urine drainage containers. See, Akiyama, H. and Okamoto, S. , "Prophylaxis of Indwelling Urethra! Catheter Infection: Clinical Experience with a Modified Foley Catheter and Drainage System". The Journal of Urology, 121:40, 1979.

Urinary drainage bags have been cited as one of the contami¬ nation routes through which a patient may obtain a urinary tract infection when catheterized. Two other predominant sites suscep- tible to contamination which can contribute to urinary tract infections are the catheter adapter at the end of a catheter drainage tube which connects the urinary drainage bag with a catheter and the catheter itself. • Microorganisms which have been introduced into the urinary drainage bag through the drainage conduit when the bag is emptied can colonize in the bag and mi¬ grate up the catheter drainage tubing and catheter and thereafter into a patient's bladder. Furthermore, microorganisms from an infected patient may proliferate in the urinary drainage bag and, when emptied, can lead to cross-contamination of other areas of the body, other patients, or both.

The patent literature is illustrative of attempts to el minate the urinary drainage bag as a source of contamination leading to urinary tract infection. U.S. Patent 4,193,403, Patient-Care Apparatus Housing Device for Controlling Presence of Pathogens, to Langston, et _. al. and U.S. Patent 4,241,733, Patient-Care Appara¬ tus With Device for Dispensing Anti-pathogenic Agent, to Langston, et al. describe a urinary drainage bag system where an antimicrobial agent is continuously released into the catheter drainage tubing

and the urinary drainage bag. The mode of release of the antimi¬ crobial agent involves the depolymerization of paraformaldehyde into formaldehyde in the presence of moisture. Formaldehyde is not a preferred antimicrobial agent because it is believed to be a mutagen and a carcinogen.

Introducing 3 percent U.S.P. hydrogen peroxide solution into a urinary drainage bag prior to each period of urine collection, significantly reduces the risk of urinary tract infection. This discovery is the subject of U.S. Patent 4,233,263, Method of Maintaining Bacterial Sterility in Urine Drainage Bags, to Schaeffer [hereinafter cited as Schaeffer]. The key to the effectiveness of the Schaeffer method is user compliance. Each time urine is drained from the urinary drainage bag, hydrogen peroxide must be reintroduced. Practical experience teaches that the hydrogen peroxide of the Schaeffer system must be actively mixed or agitated to disperse throughout the urine in the bag. Also, several urinary tract infection organisms are resistent to hydrogen peroxide.

U.S. Patent 3,312,221, Urinary Drainage Apparatus, to Overment describes a urinary drainage bag having a porous plastic pouch containing an antimicrobial agent. The pouch is suspended so that incoming urine cascades over and through the pouch so that the antimicrobial agent will dissolve in the urine. Adequate dwell time of antimicrobial agent in the urine is not always assured, however. Undersaturation of the urine is a possibility when there is a high flow rate of urine. Also, potential exists for restrict¬ ing the flow of urine into the bag by the placement of the pouch in the urine flow path. This situation may become critical espe¬ cially when there is high flow of urine or when a patient drains bloody or viscous urine. It would be advantageous to have an article of manufacture for a urinary drainage bag which releases antimicrobial agent only when wet or humidified and not necessarily on a continuous basis.

Such selective release of antimicrobial agent would insure effec¬ tiveness for longer periods of time without excessively high con¬ centrations or pressures of antimicrobial vapors.

A desirable antimicrobial agent would be less toxic than formaldehyde. The agent desirably would have high enough solubility in urine to exert antimicrobial effect, and it desirably would provide antimicrobial effect to those portions of the interior of the urinary drainage bag not contacting the urine.

Good dispersion qualities of the antimicrobial agent and an adequate dwell time in urine would be desirable. Undersaturation of the urine in high flow rate conditions would be obviated.

Also, it would be expedient to have a system which did not require introduction of antimicrobial agent into the urinary drainage bag each time after a bag is emptied. Placement of the antimicrobial agent desirably would be away from urine flow to avoid restricting urine flow.

Description of the Invention

An antimicrobial urinary drainage system and an article of manufacture having antimicrobial effect constitute this invention. A method of this invention comprises introducing a halogenating agent into a urinary drainage bag in order to provide antimicrobial effect to the urinary drainage bag interior and to urine in the bag. The article of manufacture comprises an antimicrobial gas- generating agent, for example, trichloroisocyanuric acid (TCCA), contained within a gas permeable material. The general configura- tion may be that of a pouch, a coated solid, a solid mixture or the like. A preferred embodiment is a pouch which may be seg¬ mented into compartments. The article also may be variously shaped as sheets, rods, tubes or the like. When the article, for example the pouch, is placed in a urinary drainage bag, ft is exposed to humidity or wetness when urine is present. Water vapor diffuses through the material forming the pouch walls to activate the anti-microbial gas-generating agent. Chlorine gas or other vapor having antimicrobial effect is thus released through the pouch walls into the urine which contacts the pouch and is thus released into the drainage bag.

The material forming the pouch walls is permeable to at least water vapor and chlorine gas. Preferably it is a hydro- phobic material permeable to gases but impermeable to fluids such as urine. When urine is drained from the urinary drainage bag, the pouch containing the antimicrobial agent remains in the bag. Chlorine gas or other vapor having antimicrobial effect is again released into the urine and drainage bag when fresh urine enters the bag. By pouch we also contemplate an agent coated by a gas permeable material and a solid mixture of antimicrobial agent and gas permeable material.

Solid, halogenating agents providing antimicrobial effect and suitable for direct introduction into the urinary drainage bag as a step in the method of this invention include, but are not limited to, the classes of N-halo-amines, N-halo-amides, N-halo-sulfonamides and hypochlorites, such as the following:

trichloroisocyanuric acid (TCCA), dichloroisocyanuric acid (DCCA) and al kal i metal salts thereof, such as [(monotrichloro)-tetra- (monopotassium dichloro)] penta-isocyanurate, sodium dichloro- isocyanurate, sodium dichloroisocyanurate di ydrate and potassium dichloroisocyanurate; N-chlorinated-hydantoins, N-brominated- hydantoins and N-chlorinated-N-brominated-hydantoins, such as 1 ,3-dichloro-5, 5-dimenthyl hydantoin; chlorinated melamine, bro inated melamine, and chlorobromomel amines, such as tri- chl oromelamine, dichloromel amine and monochloromelamine; N, N'-dichloroazodicarbonamidine; sodium p-tol uenesul fonchloramide; p-toluenesul fondichloramides ; sodium benzenesulfonchloramide; succinchlorimide; p-sul fondichloramidobenzoid acid; calcium hypochlorite; chlorinated trisodiu phosphate. Quantities of these agents, not contained within a gas permeable material , ' are introduced into a urinary drainage bag before each period of urine col lection in the method of this invention.

Liquid antimicrobi al halogenating agents suitable for direct introduction into the urinary drainage bag as a step in the method of this invention are aqueous solutions of hypochlorous acid, sodium hypochlorite, calcium hypochlorite or the agents li sted in the paragraph above. Al so, these l iquid agents may be contained in non-porous , gas permeable containers made from, for example, polyetfiylenevinyl acetate or silicone rubber. One embodiment of the urinary drainage system of the present invention compri ses a urinary drainage bag, catheter drainage tubing connected to the urinary drainage bag and terminating at one end in a catheter adapter, a catheter connected to the catheter adapter, and an antimicrobi al agent contained by material to form a pouch or the like. The pouch easily can provide antimicrobi al effect to the urinary drainage bag interior and urine col lected therein. Portions of the catheter adapter, urinary catheter, or both are coated with

the antimicrobial composition of U.S. Patent Application Serial No. 439,506, Antimicrobial Compositions, to Laurin and Stupar, filed November 5, 1982 [hereinafter cited as the '506 application], commonly owned with this application by Baxter Traveno! Laboratories, Inc., which material included therein is incor¬ porated by reference.

Another embodiment of the urinary drainage system of the present invention is similar to the embodiment just described except that quantities of the solid halogenating agents or liquid halogenating agents, not contained within a material, are directly introduced into the urinary drainage bag before each period of urine collection.

The material forming the article, for example the pouch, of the present invention preferably is a hydrophobic, gas - permeable material. The pouch is closed so that an antimicrobial agent contained therein is prevented from spilling out. TYVEK ^® non-woven, spun wound, microporous polyolefin fabric (TYVEK ^® is a registered trademark of E. I, du Pont de Nemours and Company), a hydrophobic, polyolefin paper material or the like, may be used as the material for the pouch or the like. Also, the material for containing the agent may be polyethylenevinyl- acetate or silicone rubber. Indeed, useful hydrophilic gas permeable materials may be used for containing the antimicrobial agent, for example, cellophane and polyvinylalcohol. Antimicro- bial agent may be contained directly between layers of the material.to form a closed pouch or the like. The agent may be contained in elongated gas barrier capsules in the pouch which protect the agent during storage and which can be broken later to expose the antimicrobial agent during urine collection use. The antimicrobial agent also may be coated by the material or formed into a solid mixture with the material. The solid mixture then can be formed into configurations desired.

Alternatively, the urinary drainage bag may be manufactured with a polyolefin paper material window or other gas permeable ma- terial. An antimicrobial agent-containing pouch then may be attached

OMPI -

at the window area. This embodiment pouch preferably would have one side covered with metal foil or other gas impermeable material while the edges of the opposite face would contain an adhesive. This layered pouch then would seal in face-to-face engagement with the window on the urinary drainage bag.

An antimicrobial agent which preferably is contained in a TYVEK® material pouch is trichloroisocyanuric acid (TCCA). The other solid halogenating agents listed hereinabove also can be contained in the TYVEK ^® pouch. Gaseous chlorinating compounds from the TCCA or halogen gases from the other antimicrobial agent, would be released only in the presence of humidity or wetness. A sufficient quantity of agent to release antimicrobial gas for 10 to 14 days could be contained in the pouch.

One benefit of the present invention is that halogenating gases, such as chlorine, and hypochlorous acid, as the antimicrobial agent, are released only in the presence of humidity or wetness and not necessarily continuously released. It is contemplated that gaseous chlorinating compounds released in this way are less toxic than other antimicrobial agents introduced into urine. Another benefit achieved by the present invention is that the solubility of the antimicrobial agent in urine is high enough to render the urine antimicrobial. Gas generated can render interior surfaces, not in contact with urine, antimicrobial as well. Impediments to urine flow from the catheter drainage tube are not present because the pouch or article does not reside in the urine flow path. Flow of urine is not restricted, and urine need not contact the pouch to render it antimicrobial.

An additional benefit of the present invention is that a pouch or article containing the antimicrobial agent need be in- troduced into the urine drainage bag only once. Treatment with additional antimicrobial agent after every emptying of the bag is not necessary with the pouch embodiment.

-'gURE

OMPI

Brief Description of the Drawings

For a more complete understanding of this invention, reference should now be had to the embodiments illustrated in greater detail in the accompanying drawings. In the drawings:

Figure 1 is a plan view of a urinary drainage bag, partially broken away, showing the antimicrobial agent-containing article in the form of a pouch inside the drainage bag.

Figure 2 is a partial plan view illustrating the pouch of the present invention being inserted into a urinary drainage bag.

Figure 3 is a plan view showing a urinary drainage bag with a gas permeable window and antimicrobial agent-containing pouch being affixed thereto.

Figure 4 illustrates, in perspective, an embodiment of the antimicrobial agent-containing pouch.

Figure 5 is a plan view of another embodiment of an antimicro¬ bial agent-containing pouch having breakable, gas-impermeable ampules therein for containing ^* the antimicrobial agent prior to use. Figure 6 is a cross-section taken at 6--6 of Figure 5, showing the breakable ampules contained in the pouch.

Figure 7 illustrates, in a plan view, the urinary drainage system of this invention comprising a urinary drainage bag contain¬ ing an antimicrobial agent-containing pouch, a catheter drain tube, a catheter adapter coated with an antimicrobial compound and a catheter coated with an antimicrobial compound.

OMPI

Detailed Description of the Drawings

Turning now to the drawings, Figure 1 illustrates urinary drainage bag 10 of general ly conventional configuration. Catheter drainage tubing 12 drains urine from an indwel l ing catheter to drainage bag 10. Drainage conduit 14, residing in the bottom of drainage bag 10, al lows urine periodical ly to be emptied from bag 10. Port 16 i s provided for insertion of an article, a pouch or the l ike comprised of material which contains an antimicrobial agent. Port 16 can be capped at its end 18 by a cap of appro- priate configuration.

Pouch 20, containing an antimicrobial agent, i s shown in the interior of urinary drainage bag 10. Pouch 20 is general ly of rectangul ar configuration tapering to a pointed end 22. Pouch 20 i s comprised of opposing layers of a gas permeable, ^' urine impermeable, material . The material forming the layers is permeable to at least water vapor and chlorine gas. Prefer¬ ably, pouch 20 i s constructed of a hydrophobic material permeable to gases but impermeable to fluids such as urine. A preferred material for the layers is a non-woven, spun wound, m croporous polyolefin material such as TYVEK ^® fabric. Pouch 20 i s shown having two separate compartments 24, 26 each containing an antimicrobial , gas-generating agent, preferably trichloroiso- cyanuric acid (TCCA) .

Other material s, both hydrophobic and hydrophilic, can be used to contain antimicrobial , gas-generating agents. These material s incl ude po lye thy! enevinyl acetate, sil icone rubber, cel lophane and polyvinylal cohol . Sol id halogenating agents al so can be coated by or mixed with these materials.

Other antimicrobi al agents which rel ease gases having anti- microbial effect at the bag interior can be contained within pouch 20 or coated or mixed with the gas permeable, urine im¬ permeable material s. For example, the sol id halogenating agents earl ier identified can be used.

ra_|

OMPI

Urine from a patient drains through catheter drainage tubing 12 into urinary drainage bag 10. In the presence of humidity or wetness, a gas having antimicrobial effect at the bag interior is released. When TCCA is contained in pouch 20, chlorine gas and vaporous hypochlorous acid are released.

As earlier mentioned, pouch 20 may be made from a microporous, hydrophobic, polyolefin paper material such as TYVEK ^® fabric or nonporous highly gas permeable material such as polyethylene- vinylacetate or silicone rubber. Pouch 20 may be closed using conventional heat sealing techniques to form seal 28 at its periphery and to form seal 30 which separates pouch 20 into compartments 24, 26.

Pouch 20 is inserted into urinary drainage bag 10 as shown in Figure 2. Opposing layers of material 27, 29 comprise pouch 20. Pouch 20 conveniently can be folded along sealing line 30. Angled front portion 22 of pouch 20 allows its easy insertion through port 16. Pouch 20 can be packaged in aluminum or other metal foil, polymers of vinylidene chloride or the like to provide a vapor barrier for pouch 20 prior to use. Also, pouch 20 can be coated with a dissolvable material functioning as a vapor barrier; gelatins, polyvinylalcohol , inorganic salts or the like which dissolve ^' in urine would be preferable.

Figure 5 illustrates another embodiment of the present inven¬ tion. Urinary drainage bag 10a is substantially similar to urinary drainage bag 10 except as herein noted. The back 11 of urinary drainage bag 10a is illustrated in Figure 3. Window portion 32, of generally rectangular configuration, has been removed from back 11 of bag 10a. The bag material has been replaced by panel 34 generally made from a gas permeable, hydrophobic material such as a polyolefin paper, TYVEK ^® fabric or the like. Panel 34 is sealed along line 36 to the bag material.

Figure 4 illustrates an antimicrobial agent-containing pouch 20a substantially similar to pouch 20 except as hereinafter noted. Pouch 20a can be made from the same layers of opposing material

as pouch 20 with the exception that side 38 is backed with a gas and water impermeable material such as a metal foil, polyvinylidene chloride or the like. Also, pouch 20a can be made from one layer of gas permeable, hydrophobic material and an opposing layer of gas and water impermeable material. Pouch 20a is of generally rectangular configuration and is shown with two compartments 24a, 26a. Compartments 24a, 26a are filled with an antimicrobial agent such as TCCA or the like which can release an antimicrobial gas such as chlorine gas into the interior of bag 10a through gas permeable panel 34.

Still another embodiment of the antimicrobial agent-containing pouch 20b is illustrated in Figure 5. Pouch 20b is substantially similar to pouch 20 except as hereinafter noted. Compartments 24b, 26b of pouch 20b are shown separated by sealing line> 30b. Elongated, breakable gas-impermeable ampules 40 are contained in compartments 24b, 26b. Ampules 40 contain an antimicrobial agent such as TCCA, or the like. When ready for use, ampules 40 in pouch 20b can be broken thereby providing the intended antimicrobial effect. Figure 6 illustrates a cross-section taken at 6—6 in Figure 5 showing ampules 40 containing anti¬ microbial agent 42. Ampules 40 can be made of glass, polymers of acrylonitrile or vinylidene chloride, other brittle plastics or metal foil-plastic laminates.

A particular advantage in using the embodiment of pouch 20b resides in its ease of storage. When antimicrobial agent 42 is TCCA or another chlorine gas releasing agent which functions in the presence of humidity or wetness, the agent 42 can be stored indefinitely. Chlorine gas will be released only when the ampules are shattered thereby exposing the antimicrobial agent to the atmosphere. Furthermore, pouch 20b conveniently may be placed in a urinary drainage bag at a manufacturing facility, prior to sterilization of the urinary drainage bag. Insertion of an anti¬ microbial agent-containing pouch into the urinary drainage bag

at a hospital by a nurse or other trained individual is obviated. All that needs to be done is the shattering of ampules 40.

Similarly, other problems are obviated by containing TCCA in ampules in pouch 20 before use. Chlorine gas released from TCCA reacts with polyvinyl chloride in urinary drainage bags causing yellowing in 7 to 10 days and a more severe tackiness over a period of months. Ethylene oxide sterilization of the urinary drainage bag could involve a vigorous reaction with TCCA and the production of toxic ethylene chlorohydrin. Encapsulated TCCA in a pouch would overcome these disadvantages thereby allowing pouches to be inserted as a manufacturing step.

Antimicrobial urinary drainage System 44 is illustrated in Figure 7. System 44 comprises urinary drainage bag 10, antimicro¬ bial agent-containing pouch 20, catheter drainage tubing 12/ catheter adapter 46 and urinary catheter 48. Urinary catheter 48 communicates with catheter adapter 46 which communicates with urinary drainage bag 10 through urinary drainage tube 12. Catheter 48 and catheter adapter 46 are shown having surfaces co'ated with a composition having antimicrobial effect. The antimicrobial composition preferably is chosen from among the compositions disclosed in our prior patent application, the '506 patent ap¬ plication. In System 44, either catheter adapter 46, catheter 48 or both may have surfaces coated with an antimicrobial composition. A method of this invention involves directly introducing an uncoated solid or aqueous halogenating agent into the urinary drainage bag. Referring again to Figure 1, instead of intro¬ ducing a pouch into the interior of urinary drainage bag 10, a halogenating agent is introduced into bag 10 through port 16 prior to each period of urine collection. For example, the solid and liquid antimicrobial agents earlier identified can

be used. Antimicrobial effect is provided to urine contained therein and to interior portions of bag 10 not directly contacting urine.

The examples below are offered for illustrative purposes only and are not intended to limit the scope of the invention of this application, which is defined in the claims below.

EXAMPLE 1

A urinary drainage bag of conventional configuration was opened and a pouch made from TYVEK ^® polyolefin fabric material was placed thereinto. The pouch measured 8-1/2 inches by 4 inches and was segmented into 12 equally sized compartments. Each of the 12 compartments contain approximately 1 gram of ' powdered trichloroisocyanuric acid. The drainage was sealed closed. Over an 8-hour period, 500 i l l il i ters of urine con- taining -lO^-lO ⁵ E. Col i per mil l iliter was infused into the bag. Urine drained from the bag was filtered, and the filter was cul ¬ tured for bacterial growth. No organisms grew on the filter after 16 of the 8-hour challenges described above.

EXAMPLE 2

A TYVEK ^® polyolefin fabric material pouch measuring approxi¬ mately 8 inches by 3 inches and divided into two compartments containing a total of 20 grams of TCCA was inserted into a urinary drainage bag. 500 mi l l il i ters of urine containing 10 -10 E. Col i per mil l i l iter was then infused into the bag over an 8-hour period . Urine drained from the bag was fil tered and cul tured for bacterial growth. No bacteria grew on the fi lters after six such chal lenges.

EXAMPLE 3

A tablet, approximately 1 inch diameter and 1 1/2 inch thick,

made from one part powdered TCCA (less than 100 mesh size parti- cals) and one part silicone rubber (alkoxy-cured RTV) was placed into a urinary drainage bag. One ml. of urine challenge contain¬ ing 10 organisms (E.Coli or Candida albicans) was added through the dra.inage port at the bottom of the bag. Urine was added to the bag at a rate of 500 ml. per 8 hours. After 8 hours of col¬ lection, urine was drained and filtered. The filters were cul¬ tured. No growth of bacteria occurred on the filters after 14 of these challenges and bag fillings.

EXAMPLE 4

Quantities of various halogen-releasing agents were added to 50 ml. of urine. Prior to the addition of the agents, the urine was sterilized by microporous filtration. Samples were left at room temperature for more than 8 hours. The samples then were contaminated with microorganisms to the level of 10 ⁴ organisms per milliliter. Periodically, urine from the samples was streaked on agar plates and incubated to detect the amount of surviving organisms compared to urine with no antimicrobial agents added thereto. Separate populations of microorganisms introduced into the samples were E.Coli, Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus. Results of the separate challenges were generally identical and are tabulated in Table 1 below. As used below, cidal means no surviving organisms detectable, and static means no organisms multiplied in the treated urine.

JJRI OMPI

TABLE 1 z

Agent Concentration Appearance Activity Appearance in Urine Initially Against After (w ϊ) all 1-2 days Organisms

TCCA 0.02 Clear 30 min. Clear - Cidal

Br ₃ Cl- 1.0 Slightly Less than Slightly turbi 1 hr. - turbid dimenthyl Cidal hydantoin

Chloramine 1.0 Slightly Less than Slightly -T turbid 1 hr. - turbid Cidal

Trichloro- 0,2 Clear, si. 30 min. - Clear, mel amine orange Cidal si. orange

Ca(0Cl ) 0,04 Clear 24 hr. - Clear static (no growth)