Field of the Invention This invention relates to in-dwelling intravascular catheters. Background of the Invention

Blood compatibility is much more complex than the compatibility of a bio aterial with other body fluids or tissues. The extent of the compatibility of blood with a specific biomaterial depends on whether the blood is moving (as in a heart device or blood vessel) or static (as in a storage bag or bottle) ; whether the blood is arterial or venous; flow patterns and especially changes in flow patterns; and interactions with red cells, white cells, platelets, plasma proteins and other blood components. Blood is a heterogeneous, non-Newtonian fluid consisting of about 45% solids (red cells, white cells, platelets) and 55% plasma. The plasma contains a variety of inorganic ions and a series of soluble proteins which can be classified as albumins, fibrinogenc, and globulins.

Blood forms a clot or thrombus when injury occurs or when it is contacted by a foreign substance. Almost all biomaterials set off this clot-formation process and soon become coated with an irreversible clot of varying size that could have an adverse effect on the utility of the biomedical device and even be fatal to the patient. Blood compatibility of certain hydrophobic polymers, such as polydimethylsiloxane and the polyether polyuretha~ ^» e ureas (PEUU) is inversely related to the wettability of the polymers. But certain hydrophilic polymers, :;uch as hydrogels, are also blood compatible. Certain i no er-type polymers and electrets (charged polymers) are also compatible with blood. Blood compatibility is, to some extent, related to the nature of the prrteins that adsorb on the biomaterial surface.

Whenever the blood contacts a foreign surface various plasma proteins adsorb on this surface. With some classes of polymers, such as hydrophobic polyether polyurethane ureas and the hydrophilic hydrogels, surfaces that adsorb mostly cold insoluble globulins, (fibronectin) and fibrinogen tend to be more thrombogenic than those that adsorb albumin. Protein adsorption is a slow process, requiring many hours or days, whereas thrombus formation begins in a matter of minutes. Thus, some biomaterials show initial thromboresistance but develop clots after several weeks, possibly because of changes in the adsorbed protein layer. While various theories seem adequate to explain why one polymer in a given class is more or less blood compatible than another polymer of the same class, no theory is adequate to explain all the variations in blood compatibility for natural and synthetic materials. A number of biomaterials have limited utility in various extracorporal devices if a suitable anticoagulant, such as heparin, is added to the blood. However, administration of heparin reduces or prevents the . natural clotting of the blood. Heparin, a naturally occurring polyanionic mucopolysaccharide with a molecular weight of 12,000-16,000 has been attached to various surfaces by a variety of techniques. Although ionically bound heparin confers a significant degree of thromboresistance to the surface, the heparin desorbs and/or is inactivated with time and the basic thrombogenic nature of the surface prevails. Covalently bonded heparin maintains its thromboresistance longer, although the heparin is usually somewhat less active than the natural material. It appears likely that many experimental nonthrombogenic amido-amine polymers are thromboresistant because heparin is adsorbed at the amido-amin-s sites since many of the heparinization

techniques involve a quaternary ammonium compound and heparin do^s form complexes with amino groups. Several experimental polymer systems have shown promise. These include ths Ioplex materials and other hydrogels such as those based on 2-hydroxyethyl methacrylate or acrylamide. These materials may contain 50-80% water and it was claimed formerly that this was the basis of thromboresistance of hydrogels. More recent studies have shown that blood compatibility does not depend on the water content of hydrogels. Hydrogels normally lack physical or mechanical strength, a problem that has been partially solved by grafting hydrogels onto other substrates or by making a composite material with the hydrogel surface contacting the blood. Various lysing agents, such as urokinase or streptokinase, have been bonded to polymers with the intention of lysing any clotted material that might form on the surface. Certain polyether polyurethane ureas (PEUU) show good thromboresistance and are generally regarded as promising materials for internal use. The PEUU system, can be mac'e with a wide variety of alkyl and/or aryl polymer groups and is often referred to as a segmented polyurethane. Devices made from these hydrophobic polymers often show no evidence of thrombus build up on the surface, but emboli are noted in other parts of the test animal's body.

Notwithstanding the great advances in materials sciences, in the understanding of the clotting process and its relationship to various materials, in bactericides, viricides and fungicides, one of the major hazards of modern medical practice, especially in- hospital practice, is the risk of thrombus formation and infection associated with intravascular invasive devices, all classes and types of which are referred to here for convenience as catheters. The principal

feature and object of this invention is to provide an improved catheter which significantly reduces the risk of infection and, at the same time, reduces the risk of thrombus and embolus formation. Born into an environment laden with microbes, the body of man becomes infected from the moment of birth. Throughout life the skin and mucous membranes, exposed to the outside world, harbor a variety of bacterial, fungal and viral species, many of which establish more or less p rmanent residence on and in the superficial tissue. Some species cause no overt disturbance, some are symbiotic with man, some are essential to man's continued existence, and some place man's future health and life at risk. Some species may be inoffensive on the skin but become pathogenic in the blood stream. Some species may be nonpathogenic or so weakly pathogenic that they have no effect upon a healthy body with a strong immunological defense, but may become mildly or even fatally pathogenic in a body weakened by age, disease, radiation, chemotherapy or even by mental and emotioral depression.

As mere people with major diseases receive better treatment and thus live longer, and yet suffer from small or great debilitation of the immune system from the major disease or its treatment, and as more infections caused by virulent exogenous organisms are controlled by effective antimicrobial drugs, endogenous bacterial and other microbial diseases have become more common. Such diseases now constitute a major proportion of the serious bacterial diseases encountered in clinical practice.

The dramatic increase in the use of vascular invasive devices and the ready availability of a vast array of catheters and other such devices of new materials, have introduced higher risk factors to both

the patient and the medical practitioner. Some of the problems springing from this phenomena are described in a communication "Plastic Devices: New Fields for Old Microbes", The Lancet, p. 365, February 13, 1988. The brcterial flora found on human skin varies in degree and variety depending on which part of the skin is examined. A typical skin bacterial flora will include 5 t aphyl ococci , Streptococci viridans, Streptococci faecalis, Corynebacteri a , and Mycobacteri a , and may, depending upon which skin area is examined, include Pneumococci , Cl ostridi a , Enteric bacilli, spi rochetes , Mycopl as mas . Streptococci anaerobic , as well as other species. Fungi such as the yeasts, Candida, C. albicans especially, is frequently a constituent of skin or membrane flora.

Among the most common, and potentially most serious, pathogens frequently found on the skin are the Staphyloco ,ci. Staphylococci are spherical, gram- positive crganisms which cause a wide variety of suppurativ? diseases in man. Because staphylococci frequently become drug-resistant, they have risen to a position of special significance in clinical medicine.

Man is constantly exposed to staphylococci. The skin and nose of the infant are colonized within a few days of birth. 5. epidermidi s is a virtually constant inhabitant of the human skin and mucous membranes. Infection of the skin, nose, oropharynx and intestinal tract with 5. aureus is common. So long as the skin remains unbroken, large colonies of staphylococci may, and do, ir'iabit the skin without any adverse effect. A wound, a burn or any other breaking of the skin, however, invites infection.

One of .the major problems in the use of intravascular catheters and in the control of infections during hocpitalization is the tendency of some bacteria.

such as Staph . ep idermidi s , for example, to mutate when challenged with antibiotics to produced a strain which is resistant to the antibiotic. Thus, infection control techniques which rely upon traditional antibiotic treatment tend to be only temporarily effective. Staph . and other infectious organisms are not known to mutate or form strains which are resistant to polymyxin. It is possible, but not known for certain, that such resistance is not developed toward polymyxin B because it is an outer membrane-disorganizing agent which lyses and inactivates the organism rather than attacking internally. Thus, it is believed, the organism is destroyed without triggering the mutation-protection mechanism which is inherent in some bacteria. The prior art includes many needles, catheters and other devices for insertion into the body. The present invention is suitable for use with and may comprise as a element or as elements thereof such devices. For example, the assembly of breakaway needle and catheter is disclosed by , Luther et al in US patent 4702735, who also disclose the assembly of stylet and catheter, Luther, US patents 4668221 and 4610671, the assembly of stylet and catheter, Luther, US patent 4610671, the assembly with septum fitting for connecting adaptor and fluid tube, Luther et al, US patent 4559043, a small gauge, prn-split cannula and process for manufacture, Luther e l, US patent 4449973, apparatus for advancing oversized catheter through cannula, and the like, Luther, UJ patent 4401433, and cannula needle for catheter. Trey et al, US patent 4377165.

Pepti e antibiotics produced by Bacillus species include several that are chemically closely related although produced by taxonomically different species: bacitracin from Baci l l us l ichen i formis and Baci l l us sub t i i i s and polymyxins from Bac i 1 1 us po lymyxa , Bac i l l us

aerosporus , Bacillus colistinus , and Bacillus circulans. Of this class of antibiotics, the subclass of antibiotics of principal, but not exclusive, interest in this invention are the Polymyxins. Polymyxins are antibiotics with a detergent like action, containing basic groups of the amino acid α,7-diaminobutyrate plus a fatty acid side chain, which destroys the integrity of the membranes of gram-negative but commonly thought not to have such effect on gram-positive bacteria. Because of their nεuro- and nephrotoxicity the use of polymyxins is limited to serious infections caused by susceptible organisms which have built up resistance to or have natural resistance to other biocidal materials. Polymyxins are, for example, among . the few drugs effective against Pseudo onas aeruginosa which is a frequent and persistent secondary invader in patients under prolonged chemotherapy. The polymyxins inhibit the growth of a number of . gram-negative organisms including Pseudomonas , Escheri chi a , K1 ebsi el 1 a , Enterobacter , Salmonel 1 a , Shigella, and Haemophi 1 us species, and are not inhibitors of growth of Proteus and gram-positive bacteria. Preparations of sulfates of polymyxin B and of colistin (polymyxin E) are used for local, topical, oral, and intravenous medication, and the sodium N-sulfomethyl derivatives are used for intramuscular and intrathecal administration. A wide range of mixed antibiotic formulations is marketed.

Ainsworth and co-workers , Shepherd and co-workers, and Benedict and Langlykke announced in 1947 aerosporin and polymyin from Bacillus polymyxa strains.This led to an understanding that a group of closely related antibiotics of interest here referred to by the generic name polymyxin. Aerosporin was renamed polymyxin A and polymyxin became polymyxin D. Both of these antibiotics were nephrotoxic and this clinical defect led to the

search for other antibiotic-producing strains of B. o lymyxa and the development of four new polymyxins B, C, E, and F. Polymyxins B and E produced negligible toxic effects within the limits of the therapeutic dosage rang. Other polymyxins were discovered during evaluation of other strains of Bac i l l us po lymyxa . Example include the antibiotic class identified as colistin from a microorganism initially identified as a strain of Ba c i l l us co l is t inus and now classified Bac i l l us po lymyxa var. garyph a l us and a strain of B . po lymyxa from a soil sample taken in Moscow yielded an antibiotic which was designated as polymyxin M. Bac i l l us b revis produces an antibiotic mixture of which tyrothricin is a major constituent. . J . B i o l . Chem . 141:155, 163 (1941). Tyrothricin has been separated into three quite well known cationic cyclic polypeptide antibiotics, Tyrocidine A, B, and C. Other cationic cyclic polypeptide antibiotics, which are presently considered equivalent include the gramicidins, viomycins, capreomycins. Cationic cyclic polypeptide antibiotics, of which the polymyxins are the best known and including the colistins, gramicidins, viomycins, capreomycins and tyrothricins, are useful in the present invention; Polymyxin B, being used in what is presently considered the best mode of carrying out the invention. Because the polymyxins are the best known, the term "polymyxin" as used here will, unless specified differently, means the general family of polymyxins and the equivalent, related cationic cyclic polypeptide antibiotic.'., the specific species Polymyxin B being the preferred compound.

All cf the polymyxins are basic polypeptides whose basicities are.associated with the uncommon basic amino acid, α,7-diaminobutyric acid. They form water-soluble salts wit! mineral acids with only the phosphates being

isolated in crystalline form. The normal form of pharmaceutical presentation of the sulfates and the hydrochlorides is amorphous solids. The water insolubility of the naphthalene-2-sulfonates and azobenzene-4-sulfonates is of advantage in purification of the polymyxins and crystalline forms can be obtained from aqueous alcohols. The picrates, reineckates, helianthates. Polar Yellow and other acid dyestuff salts, lcng-chain alkyl sulfates, etc, are very insoluble in water and are useful in the various purification procedures.

Intramuscular injection of polymyxins is painful and tends to result in an inflammatory reaction at the site of injection. When polymyxins are treated with formaldehyde and sodium birulfite they are converted into their sodium N-sulfomet'iyl derivatives, which are relatively free from causi ⁿ g pain upon injection and still retain most of their antibacterial activities. The potency of these derivatives depends on regeneration in vivo to the parent compound so the nephrotoxicity is not significantly reduced. The degree of N-sulfomethylation varies: mc.-st preparations of Coli-Mycin have about 50% of the maximum 7 sulfomethyl groups. Polymyxins A and D each contain two D-amino acid residues, *rtιile polymyxins B and E have one. This difference may be responsible for the higher nephrotoxicity with the A and D compounds. The higher proportions of hydroxyamino acids found in A and D are reflected in the water solubility of the bases of these polymyxins, in contrast with that of polymyxins B and E and circulin A, which precipitate when aqueous solutions are neutralized.

The sulfates of polymyxin B and colistin have been used orally for gastrointestinal infections and bowel

sterilization prior to surgery, but because of poor absorption, they are not used for systemic infections. Tyrocidine A, Tyrocidine B and Tyrocidine C are closely related polypeptides which are known to possess antimicrobial action comparable to that of the better known Polymyxin B.

Polymyxin B in isotonic saline (0.5%) is used intrathecally and sterile, pyrogen-free polymyxin B sulfate is available for intravenous infusion in cases of sever ^p . systemic infection (usually requiring hospitalization) . Although the acute intravenous toxicity is reduced by sulfomethylation with formaldehyde and sodium metabisulfite, this toxicity is of little therapeutic importance because the polymyxin B sulfates have a satisfactory therapeutic index. The main advantage of the sulfomethyl derivatives is the reduction cf pain at the site of intramuscular injection and thus making parenteral therapy tolerable to the patient. A correlation of the intravenous LD50 values of various preparations and their therapeutic efficiency has been observed. The data showed that detoxification by sulfomel-hylation is minimal and that derivatives with LD50 (iv in mice) of the order of 100 mg/kg are a reasonable compromise. Polymyxins are useful when administered intramuscularly or intrathecally to combat acute er'.eritis, urinary and respiratory tract infections.:, bacteremia, peritonitis, and meningitis caused by Pseudomonas sp Escherich ia co l i , Enterobacter aerogenes , and Kl eb s i e l l a sp . An endotoxin detoxifying process which includes contacting ^* blood with fibrous carrier having Polymyxin fixed thereon is disclosed by Hanazawa Kazuyoshi, et al, US patent no. 4661260. he endotoxin detoxifying material comprising a ^" fibrous carrier to which Polymyxin is fixed. A r3thod of removing endotoxin .from> a fluid by

contacting the fluid with the endotoxin detoxifying material comprising a carrier to which Polymyxin is fixed is also disclosed. The disclosed method it possible to contact blood with polymyxin directly and safely and gives a new method of therapy of endotoxemia or prophylaxis of endotoxemia, and compounds for use in antibacterial therapy are disclosed by Vaara Martti in U.S. Patent 4510132.

Notwithstanding the long usage of polymyxins in a great vari.ty of applications, the risks associated with the insertion of in-dwelling intravascular catheters has not been greatly reduced for many years. It is, therefor, an object of this invention to provide a catheter which not only reduces the frequency and seriousness: of thrombus or embolus formation but also greatly reduces the risk of infection at the site of the invasion of the body by the catheter and in the vascular • system.

Summary of the Invention The present invention is embodied in an intravascular device the surface of which is coated with a cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known examples, to render the surface non-thrombogenic. The principle of the invention is applicable to any device which is designed or intended to reside in contact with blood for a period of time which would, without special precaution, result in the formation of thrombus on the surface, ^• hich may either attach to the surface or slough off as emboli.

Invasive devices for dwelling in contact with fibrinogen-fibrin containing fluid of a patient which contains fibrinogen-fibrin capable of forming clots generally are within the contemplated applications of the presei.l process and invention. Such devices would

include, for example, tubes introducing medication into or draining fluid from hydrencephaloceles and cavities in connection with the treatment of pleurisy and peritonitus and other diseases and infections, and in similar applications where it is important to avoid fibrin deposition and clotting are included within the devices referred to herein. The principal applications being, of course, vascular devices such as catheters.

In itr most common form, and one most of the useful forms, the invention is embodied in an intravascular catheter comprising a cannula constructed and dimensioned for insertion into an vascular system of a patient which is coated so as to be non-thrombogenic with a coating of cationic cyclic polypeptide antibiotic?., of which the polymyxins are the best presently known examples.

Typically, the catheter includes or comprises a cannula th*≥ inner and outer walls of which are coated with the rationic cyclic polypeptide antibiotic. If a non-cannulated catheter is used, then the coating is on the outsidα of the catheter.

A cationic cyclic polypeptide antibiotic, e.g. the polymyxins, Polymyxin B is used in what is presently considered the best mode of carrying out the invention. The cationic cyclic polypeptide antibiotic is coated onto the "surface(s) of the device which come into contact wiLh the blood.

In the following discussion, the exemplary embodiment, a catheter, will be referred for simplicity in describing the invention, but with the express understanding that the invention is directed to in¬ dwelling vascular devices more generally.

The principal limitation upon the application of the present invention to all vascular devices is that the surfa-e of the device must be capable of being

coated with the cationic cyclic polypeptide antibiotic and retaining the coating on the surface for a significant period of time.

Virtually any polymeric surface can be coated or can be treated to accept a coating of the cationic cyclic polypeptide antibiotic in sufficient amounts and with sufficient retention time to make the surface non- thrombogenic.

The advantageous and unexpected features of this invention include the discovery that providing a level of cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known examples, in or on the surface of a catheter not only inhibits the growth of pathogenic gram negative bacteria, but also inhibits the growth of gram positive bacteria, inhibits the replicrtion of virus, inhibits the growth of fungal infection sites, prevents the development of tolerance to the antibiotic, and creates a non-thrombogenic surface on the catheter. Description of the Preferred Embodiment

The intravascular, device, e.g. a catheter is constructed and dimensioned for insertion into an vascular system of a patient and coated with the cationic cyclic polypeptide antibiotic by dipping, spraying cr other application techniques. Cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known examples, may be used. Polymyxin B is used here to exemplify the invention.

In mr-t cases, it is sufficient to dip the device in an aqueous or alcoholic solution of the cationic cyclic polypeptide antibiotic. Other solvents may, of course, br used of course, and are advantageously used with particular polymers. Polyurethane intravascular devices are effectively coated by being dipped in the solution cf cationic cyclic polypeptide antibiotic at

normal room temperatures. Teflon ^® polytetrafluoro- ethylene .'..urfaces did not retain sufficient cationic cyclic polypeptide antibiotic to be non-thrombogenic when dipped into an aqueous solution at room temperature; however, when dipped in an aqueous solution of cationic cyclic polypeptide antibiotic, Polymyxin B, at 80°C. for half an hour, the surface became antimicrobial and non-thrombogenic. The time- temperaturo relationships have not been fully developed but it is known that dipping the Teflon ^® into aqueous cationic cyclic polypeptide antibiotic solutions of from about 70°C. to boiling for periods for from a minute to five minutes at higher temperatures and up to half an hour to an hour at lower temperatures coats the surfaces with effective amounts of the cationic cyclic polypeptide antibiotic. Longer dipping times (or coating times using spraying or other application techniques) are not detrimental but are not required.

If a particular polymer surface is naturally resistant to uptake of an adherent coating of the cationic cyclic polypeptide antibiotic from aqueous or alcoholic solution, any of several approaches are available to prepare the surface for the coating. In some instances, for example, the polymer surface may be pre-treated with a softening or swelling solvent. The acrylic acid and acrylate based polymers, for example, may be pre-treated with acetone or another ketone, dipped in the cationic cyclic polypeptide antibiotic solution, and then dried, in vacua if necessary, to remove all solvent. Olefin based polymers may be swelled w:'.th many non-polar solvents and nearly all polymers ~.re softened or swelled in some of the very strong solvents such as methylene chloride or dimethyl sulfoxide. The antibiotics useful in this invention have more than adequate solubility in polar solvents

generally to prepare solutions for carrying out the present invention. Great care must be taken, of course, to assure complete removal of any solvent which is not fully compatible with the tissue and blood of the patient; thus, no particular solvent system is critical to the invention and suitable solvents can be selected based upon the data on polymer solubility, softening and swelling in many handbooks. In extreme cases, the surface y be subjected to electron bombardment or other high energy radiation to break some of the surface bonds of the polymer and produce active sites to which the cationic cyclic polypeptide antibiotic may attach.

It is also quite well known to prepare polymers which have activie sites on the backbone of the polymer or side chains. The cationic cyclic polypeptide antibiotics being very strong Lewis bases are commonly prepared and handled as salts. By using the basic form directly, or converting the salt to the basic form, the cationic cyclic polypeptide antibiotics become quite reactive and can be made to attach to naturally occurring or induced active sites on the polymer, as well as to dissolve into the polymer or form a physico- chemical b nd on the surface of the polymer.

Solutions of from 0.1 percent (by weight) to a saturated solution in water, glycerol, water-glyceral, ehtylene rlycol, water-ethylene glycol solutions, etc. may be used. Solutions in the range of about one weight percent in concentration have been found most convenient . Cationic cyclic polypeptide antibiotic, e.g polymyxin, is thus introduced as a coating in amount which is determined empirically to be effective to substantially prevent the growth of polymyxin- sensitive microorganisms and to inhibit thrombus formation on the catheter. The precise parameters as to the amount, of the antibiotic necessary to achieve this

result have not been determined, nor are these parameters critical. Immersion of polyurethane catheter in a 1 ^w /o solution of Polymyxin B for a few minutes, is sufficient to accomplish the necessary loading of the cationic cyclic polypeptide antibiotic onto the polymer surface. Very little effort is required to determine optimum tiae-temperature-concentration parameters for a particular polymer - solvent system.

As pointed out, several results which were not and could not- have been expected have been discovered. These unexpected results include the discovery that providing a level of cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known examples, in or on the surface of a catheter nnt only inhibits the growth of pathogenic gram negative bacteria, but also inhibits the growth of gram positive bacteria, inhibits the replication of virus, inhibits the growth of fungal infection sites, prevents the development of tolerance to the antibiotic, and creates a non-thrombogenic surface on the catheter.

The mechanism and chemistry by which these results are accomplished are not understood. Without being limited to any particular theory, it is believed likely that the anticoagulant action of cyclic polypeptides of this invention is related to the binding of thrombo- plastic ar 1 platelet phospholipids which are essential in clotting.

The nonthrombogenic surface effects resulting from the use of the cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known examples, of this invention may be enhanced by the additional use of known anticoagulants such as heparin and chelating .agents for calcium and magnesium, e.g. EDTA and citric acid. A typical manufacturing process includes the steps.

of forming the catheter, by extrusion of a cannula of appropriate size for example, coating the catheter by dipping or spraying or otherwise applying the polymyxin B, or other cationic cyclic polypeptide antibiotic, to the polymπr, usually by dipping the catheter in a solution of polymyxin B, or passing the catheter through a bath or r.pray of such a solution.

The polymer may contain or be modified to include moieties or sites which can accept an electron pair and brought into contact with free (non-salt) polymyxin, which is _:asic, which will form a covalent bond with such moieties or sites.

Other anticoagulants, e.g. heparin, may be added also, and various chelating and other agents may also be included i the solution or added separately. Other specific antimicrobials may, for example, be included in the polymer, as is known in the prior art. Indeed, virtually any constituent which does not interfere with the described action of the cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known examples, may be included in the polymer. Hence, the invention is described as a vascular J rvasive device of any kind which is used in contact with blood having a coating on the polymer containing an antimicrobial anticoagulant consisting essentially of cationic cyclic polypeptide antibiotics, of which t e polymyxins are the best presently known examples.

The preferred form of the invention includes the polymyxin B, or other cationic cyclic polypeptide antibiotics, of which the polymyxins are the best presently known.

Catheters prepared as described herein were compared with -the same type of catheter which differed only in tϊ ^* e absence of the cationic cyclic, polypeptide

antibiotic treated surface. Both catheters were dipped in whole b ood for various periods of time. In one such test, the catheters were compared for clotting after one hour in t ~ blood. The catheters treated according to this invention were virtually free of blood on the outside, and were free-flowing and free of clots on the inside. An identical catheter, absent the cationic cyclic polypeptide, when removed from the blood was coated on the outside and plugged substantially or entirely on the inside. A representative sample of commercially available catheters were used as controls. In all instances, they were coated with blood clots and were fully or partially block inside the lumen.

While one would expect that a polymyxin B coating on a catheter would exhibit the usual microbicidal characteristics of polymyxin B, i.e. anti-gram-negative bactericidal effects, but would also expect that the pain and trauma associated with intravenous polymyxin B therapy would be exhibited. One would not expect or predict, however, that a catheter coated with polymyxin B would also prevent the growth of gram-positive bacteria such as, for example, slime producing S t aphyl occcus ep idermid is . Surprisingly, however, gram-positive bacterial infections, at least by some species of staphylococci, are prevented by using the polymyxin ϊ\ coated catheters of this invention.

Still more surprising was the discovery that the polymyxin B coated catheters of this invention were very substantially less thrombogenic than identical catheters without thn polymyxin B constituent.

There ^* are several indirect advantages resulting from the use of the catheter's of this invention, in addition to the more startling direct advantages referred to. The catheters, when removed, are generally quite clean and free of the large clots and coating of

blood whici are normally found. The small amount of blood which remains coupled with the antimicrobial action of the coating reduces the risk of infection to medical works, e.g. nurses, doctors and technicians, the most serio's of which is the risk of infection with the HIV (AIDS) virus.

Thus, the catheters of this invention exhibit a number of surprising and unpredictable characteristics, and accomplish results not previously accomplished, which grec.tly reduce the risks in using intravascular catheters.

Industrial Application This invention finds application in the medical device industry, in hospitals and in the practice of medicine generally.