ANTIMICROBIAL LOCKS
COMPRISING TAURINAMIDE DERIVATIVES AND
CARBOXYLIC ACIDS AND/OR SALTS THEREOF
The benefit of copending U.S. Provisional Application No. 60/091,491, filed July 2, 1998
is hereby claimed.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a composition and method for the flushing and coating of
catheters for the prevention of infection and blood coagulation.
2. Description of Related An
Hemodialysis access systems for access to a human or animal patient's vascular system for
exchange of blood between the vascular system and an external processing apparatus are well
known in the art. One method comprises a catheter placed in the patient with one end extending
into the central venous system. As with any invasive procedure, the prevention of infection has
been a problem, particularly with a device that must remain in place over protracted periods of
time. Coagulation of the blood in and around the catheter has also proven troublesome and
methods are needed for its prevention, particularly with regard to inhibiting the clogging of the
catheter, which can diminish or destroy its usefulness. A significant amount of research has been
directed to the alleviation of these problems.
It is standard procedure to flush catheters with an anticoagulant, such as heparin.
However, heparin is not an antibacterial and, in addition, if not carefully controlled, it can carry
the anti-coagulation process too far, thereby presenting a risk of hemorrhage.
U.S. Patent No. 4,096,241 discloses pharmaceutical compositions for the treatment and
for prophylaxis of tooth and gum infections, and in particular parodontosis, comprising derivatives
of thiadiaziπe as the active ingredient
U.S. Patent No 4, 107,305 discloses a method of combating endotoxaemia by
administering an effective amount of a taurolin composition.
U.S. Patent No 4,337,251 discloses the use of taurolin in humans or animals to eliminate
or reduce adhesions after surgery
U.S. Patent No 4,587,268 discloses a composition for the treatment of wounds
comprising a resorbable aqueous gel having dissolved or dispersed therein one or more water-
soluble medicaments, which are preferably an antibiotic or a methylol transfer antibacterial
U S. Patent No 4,587,284 discloses the preparation of an enhanced water-absorbency
hydrophilic polymer material, suitable for use in wound dressings by a process in which a water-
containing organic hydrogel comprising a gelable polysaccharide and/or protein or polypeptide
interspersed with a polymer of a hydrophilic acrylic or methacrylic acid derivative is permeated
with a base, the pH of said hydrogel being raised to at least 9 during treatment with said base
U S Patent No 4,604,3 1 discloses the administration of taurolin compounds
prophylactically to humans or warm-blooded animals to combat the occurrence of osteitis or
osteomyelitis, especially in patients suffering from bone injuries of traumatic origin
U.S. Patent No. 4,626,536 discloses the use of taurolin compounds to combat toxic
proteins or peptides, e.g., venoms, fungal toxins and bacterial exotoxins, in the bloodstream of
humans or warm-blooded animals.
U.S. Patent No. 4,772,468 discloses a pharmaceutical composition for filling into bone
cavities comprising an aqueous paste formed from powdered calcium phosphate and an antibacterial substance, if necessary together with one or more binders. The antibacterial
substance is preferably taurolidine and the calcium phosphate is preferably β-tricalcium phosphate.
U.S. Patent No. 4,797,282 discloses a drug depot, which can be implanted in the body, for
the controlled, delayed release of cytostatics, comprising a synthetic material based on
polyacrylates and/or polymethacryiates containing a cytostatic and at least one amino acid.
U.S. Patent No. 4,853,225 discloses an implantabie medicament depot useful for
combating infections comprising physiologically acceptable excipients and at least one delayed
release active compound that is a chemotherapeutic of the gyrase inhibitor type.
U.S Patent No 4,882, 149 discloses a pharmaceutical depot preparation for implantation
into base tissue comprising natural bone mineral from which the naturally associated fat and bone-
proteins have been removed whereby said bone is sterile and non-allergenic, said bone material
having adsorbed thereon and/or absorbed therein one or more physiologically active substances
The physiologically active substance is advantageously an antibiotic or taurolidine or taurultam or
a protein or polypeptide assisting bone regeneration
U.S. Patent No 4,905,700 discloses an acoustic coupling medium for transmitting ultra¬
sound The medium, which is of use in ultrasonic visualization of the human body, comprises a
sheet of hydrogel containing over 90% water, preferably over 95% water. The hydrogel
preferably comprises agar, the chains of which are interspersed with chains of polyacrylamide.
U.S. Patent No. 4,960,415 discloses a device for inserting in wounds and wound cavities
consisting of a container containing a pharmaceutically active substance, the walls of this
container consisting at least partly of a membrane , preferably a semi-permeable membrane, which
allows the active substance to escape into the wound area. The container is, more preferably, a
dialysis tube. In order to drain off wound secretions, the container containing the
pharmaceutically active substance, particularly taurolidine, is conveniently connected to a drainage
tube. Preferably, a drainage tube is used in which the end that leads into the wound is split into
filaments.
U.S. Patent No. 5,077,281 discloses the use of taurolin compounds as blood coagulation-
inhibiting agents and as abacterial inflammation-inhibiting agents. According to the patent,
taurolin has outstanding coagulation-inhibiting action and is especially suitable for use in medical
conditions requiring dialysis and for vascular prostheses. It is also disclosed that these
compounds can be used together with other anti-coagulants such as coumarin or heparin.
U.S. Patent No. 5, 167,961 and 5,417,975 disclose processes for the preparation of high
purity bone mineral wherein the organic matter is degraded by heating with ammonia or a primary
amine, characterized in that the solubilized degradation products are extracted by washing with
flowing water at a temperature below 60° C, such heating with primary amine and washing steps
optionally being repeated, whereby substantially all organic matter removable by these steps is
removed, the bone mineral so treated being heated in air at temperatures up to 700° C.
U.S. Patent No. 5,210,083 discloses an aqueous solution containing a bacterially effective
concentration of taurolidine and/or taurultam together with a parenterally acceptable polyol. The
aqueous splution is said to be particularly suitable for parenteral administration.
U.S. Patent No. 5,362,754 discloses pharmaceutical compositions of a mixture of
minocycline and EDTA (M-EDTA) and methods of using the compositions in maintaining the
patency of a catheter port. Methods for inhibiting the formation of polysaccharide-rich glycocalyx
(such as the glycocalyx of staphyiococcal organisms) are also provided using an M-EDTA
solution. The M-EDTA solution may also be used to pretreat a medical device to prevent
adherence of infectious organisms, such as S. epidermis and S. aureous. The compositions
destroy and prevent the formation of polysaccharide-rich glycocalyx.
U.S. Patent No. 5,573,771 discloses a purified paniculate bone mineral product for use in
medicine, the panicles of said mineral being substantially free from all endogenous organic
material and having at least at the surface thereof resorbable, physiologically compatible, natural
or synthetic macromolecular material In particular, a bone mineral is provided that is
impregnated with a gel-forming protein or polysaccharide such as gelatin to provide an increase in
strength and a product comprising bone mineral in a matrix of collagen-fibers and a gel-forming
protein. Such products are intended as remodeling implants or prosthetic bone replacement.
U.S. Patent No. 5,593,665 discloses products containing tumor necrosis factor and
taurolidine and/or taurultam as a combined preparation for simultaneous, separate or sequential
use for treatment of patients suffering from medical conditions mediated by tumor necrosis factor.
U.S. Patent No. 5,603,921 discloses a medicated dental floss for controlling the bacterial
activity associated with gingivitis. The floss incorporates an antimicrobial agent which, as a result
of the flossing action, is deposited to the interdental area of the teeth. The slow dissolution of the
antimicrobial agent ensures that effective levels of medication are attained for sustained periods,
thereby reducing bacterial activity.
U.S. Patent No. 5,688,516 discloses compositions and methods of employing
compositions in flushing and coating medical devices. The compositions include selected
combinations of a chelating agent, anticoagulant, or antithrombotic agent, with a non-
glycopeptide antimicrobial agent, such as the tetracycline antibiotics. Methods for using these
compositions for coating a medical device and for inhibiting catheter infection are also disclosed.
Particular combinations include minocycline or other non-glycopeptide antimicrobial agent
together with EDTA, EGTA, DTP A, TTH, heparin and/or hirudin in a pharmaceutically
acceptable diluent.
Myers et al, J. Appl. Bacterial 7(9:89-96 (1980) reported that taurolin - bis(l, l-dioxo-
perhydro-1,2,4 thiadiazinyl) methane - is an antimicrobial compound formed by the condensation
of two molecules of taurine with three of formaldehyde. It had been previously suggested that
taurolin releases formaldehyde in contact with bacteria. The authors presented evidence that
indicated that taurolin is mostly hydrolyzed in aqueous solution to release one molecule of
formaldehyde and two monomeric molecules, l, l-dioxo-perhydro-l,2,4-thiadiazine and its
carbinolamine derivative. According to the article, a stable equilibrium was established. The
authors concluded that antibacterial activity was not entirely due to adsorption of free
formaldehyde, but also to reaction with a masked (or latent) formaldehyde, as the activity of
taurolin was found to be greater than formaldehyde. The monomer was found to be only slightly
active by comparison.
Gorman et al., J. Clin. Phar . Ther. /2:393-399 (1987) reported on the examination of
three antimicrobial agents, taurolidine, chlorhexidine, and povidone-iodine for microbial anti-
adherence activity. Two adherence systems were investigated: an oral isolate of Candida
albicans to human buccal epithelial cells and a urine isolate of E. coli to human uroepithelial cells.
Each of the three agents exhibited significant anti-adherence activity, which was concentration
dependent.
Root et al.. Antimicrobial Agents and Chemotherapy 32(11) \621-\63 \ (1988) reported
that granulocytopenic patients with an intravascular catheter are at increased risk for infection
with S. epidermis. During the intervals when the catheters are not being used for infusions, it is
customary to maintain patency of the catheter lumen with a solution containing heparin. The
authors showed that heparin does not inhibit the growth of S. epidermis isolated from the
catheter of an infected patient A 20-mg/mL solution of disodium EDTA, a chelating agent that
effectively anticoagulates blood at this concentration, was shown to be bactericidal for an initial
inoculum of 103 CFU of staphylococci per mL in 24 hours Vancomycin, an antibiotic that is
often employed to treat Staphylυcυccits infections was also found to be bactericidal for initial
inocula of 103 CFU/mL at doses of 6 7 μg/mL, a drug concentration in the therapeutic range. The
authors recommended that EDTA be studied as a replacement for heparin solutions for the
maintenance of intravenous catheters in granulocytopenic patients, in view of its low cost,
effectiveness as an anticoagulant, and bactericidal activity
Jones et al , J Appl Bacteriol 71 218-227 ( 1991 ) examined the effects of three non-
antibiotic, antimicrobial agents - taurolidine, chlorhexidine acetate, and povidone-iodine - on the
surface hydrophobicity of the clinical strains E. coli, S. saprophyticiis, S. epidermidis, and C
albicans. At concentrations reported to interfere with microbial-epithelial cell adherence, all three
agents were found to alter the cell surface hydrophobicity. However, these effects failed to
exhibit a uniform relationship. Generally, taurolidine and povidone-iodine treatments decreased
the hydrophobicity of the strains examined, whereas chlorhexidine acetate effects depended upon
the micro-organism treated.
Traub et al. Chemotherapy 39 322-330 (1993) examined taurolidine for bactericidal
activity against a representative number of multiple-antibiotic-resistant bacterial isolates in broth
as well as in the presence of bovine and human serum and fresh defibrinated human blood. The
authors suggested that this antimicrobial substance might be employed for topical treatment of
patients colonized or superficially infected by glycopeptide-resistant strains ofE. faeciitm, S.
aureus (GRMRSA), or by Enterobacteriaceae producing wide-spectrum β-lactamases.
Willatts et al, Crit. Care Mcd. 23(6) 1033-1039 ( 1995) reported that taurolidine had no
beneficial therapeutic effect on the outcome of patients admitted to the intensive therapy unit of a
university teaching hospital with sepsis syndrome, using clinical, bacteriologic outcomes,
progression of endotoxemia, resolution of organ failure, and 28-day mortality rate as end points.
Darouiche et al. Nutrition 13(-t)(sιιppl) 26S-29S (1997) reported that the prevention of
vascular catheter-related infection mostly centers around inhibiting the adherence to the catheter
of microorganisms originating from either the skin or the catheter hub. They described two
general approaches that can be used non-exclusively for the successful prevention of vascular
catheter-related infection The first approach does not use antimicrobial agents and includes
measures such as placement and maintenance of vascular catheters by a skilled infusion therapy
team and use of maximal sterile barriers The second approach uses antimicrobial agents and
involves the application of topical disinfectants such as chlorhexidine, use of silver-impregnated
subcutaneous cuffs (for short-term central venous catheters), flushing catheters with a
combination of antimicrobial and antithrombic agents, and coating of catheters with either
antiseptic (chlorhexidine and silver sulfadiazine) or antimicrobial agents (minocycline and
rifampin).
In a talk presented at the 30lh annual meeting of the American Society of Nephrology, held
November 2-5, 1997 in San Antonio, Texas, Sodemann et al reported on a four year trial of a
gentamicin/sodium citrate mixture as an antibiotic-lock technique for salvage and prevention of
catheter-related infections. They concluded that the replacement of catheters due to infection can
be avoided by routine application of the concentrated gentamicin/citrate mixture and that even the
salvage of intraluminally contaminated catheters is possible.
Notwithstanding the above-described contributions to the art, a need continues to exist for
a safe and effective method for the prevention of infection and blood coagulation in patients
whose illness requires the implantation of atrial catheters.
SUMMARY OF THE INVENTION
In accordance with the present invention, compositions are provided that comprise an
anticoagulant and a non-antibiotic biocide, neither of which have the properties of (a) inducing
bacterial resistance and (b) causing systemic effects in the event of accidental overdose, i.e., there
are no systemic anti-clotting and no systemic biocidal effects.
As employed herein, the term "anticoagulant" is intended to mean any composition that
has the ability, either directly or indirectly, to prevent the coagulation of blood or to dissolve
blood clop or other coagulated species once formed.
The biocide employed in the practice of the present invention is one that is a "non-
antibiotic," i.e. , it is not an antibiotic. For purposes of the present invention, the term
"antibiotic" is defined as a chemical substance produced by a microorganism that has the
capacity, in dilute solutions, to inhibit the growth of or to kill other microorganisms. It is an
object of the present invention to avoid these antibiotics - although they may, if desired, be
present in addition to the non-antibiotics of the invention - in order to minimize the probability
of producing microorganisms that are genetically immune thereto. antimicrobial/anti-coagulant compositions are provided for use in flushing and coating medical
prosthetic devices, especially catheters and ports.
Specifically, the present invention relates to a method of inhibiting or preventing infection
and blood coagulation in or near a medical prosthetic device after said device has been inserted in
a patient comprising administering to the device a pharmaceutically effective amount of a
composition comprising:
(A) at least one taurinamide derivative, and
(B) at least one compound selected from the group consisting of biologically
acceptable acids and biologically acceptable salts thereof, whereby there are no systemic anti-
clotting and no systemic biocidal effects.
More particularly, the present invention is directed to a method of inhibiting or preventing
infection and blood coagulation in or near a medical prosthetic device after said device has been
inserted in a patient comprising administering to the device a pharmaceutically effective amount of
a composition comprising:
(A) at least one antimicrobial compound of the formula
wherein R1 is hydrogen or alkyl and R2 is hydrogen, alkyl, or a group of the formula
and
(B) at least one compound selected from the group consisting of biologically
acceptable acids and biologically acceptable salts thereof.
In another embodiment, the present invention is directed to a medical prosthetic device
coated with a composition comprising:
(A) at least one antimicrobial compound of the formula
wherein R
1 is hydrogen or alkyl and R
2 is hydrogen, alkyl, or a group of the formula
and
(B) at least one compound selected from the group consisting of biologically
acceptable acids and biologically acceptable salts thereof,
wherein the composition is included in a pharmaceutically effective amount for preventing or
inhibiting infection and blood coagulation
In still another embodiment, the present invention is directed to a medical prosthetic
device prepared by a process comprising exposing the medical prosthetic device to a composition
comprising:
(A) at least one antimicrobial compound of the formula
wherein R is hydrogen or alkyl and R" is hydrogen, alkyl, or a group of the formula
(B) at least one compound selected from the group consisting of biologically
acceptable acids and biologically acceptable salts thereof,
wherein the composition is included in a pharmaceutically effective amount for preventing or
inhibiting infection and blood coagulation .
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As stated above, the present invention is directed to a method of inhibiting or preventing
infection and blood coagulation in or near a medical prosthetic device after said device has been
inserted in a patient comprising administering to the device a pharmaceutically effective amount of
a composition comprising:
(A) at least one antimicrobial compound of the formula
wherein R1 is hydrogen or alkyl and R.2 is hydrogen, alkyl, or a group of the formula
and
(B) at least one compound selected from the group consisting of biologically
acceptable acids and biologically acceptable salts thereof.
The preparation of representative examples of the compounds of formula I is described in
U.K. Patent No. 1, 124,285. Basically, these compounds are condensation products of
taurinamide and formaldehyde and, therefore, will be referred to herein as "taurinamide
derivatives." They are active not only against both gram-positive and gram-negative bacteria,
but also against exotoxins and endotoxins produced by these organisms.
Where R' and/or R: are alkyl. they may be either straight or branched chain alkyl and are
preferably independently selected from those alkyls having from 1 to 8 carbon atoms, i.e., methyl,
ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomers thereof. More preferably, where R1
and/or R2 are alkyl, they are independently selected from those alkyls having from 1 to 6 carbon
atoms, i e , methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof; most preferably, the
alkyl group(s) have from 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl, butyl, and isomers
thereof It is, however, most preferred that R1 be hydrogen and that R2 be hydrogen or a group of
formula II
In the present invention, of the compounds of formula I, the compounds taurolidine (R1 =
H, R2 = formula II) and taurultam (R1 = R = H) are particularly preferred. Taurolidine is bis-( 1 , 1 -
dioxo-perhydroxy- 1 ,2,4-thiadiazin-4-yl)methane.
The antimicrobial compound employed in the practice of the present invention is a
formaldehyde carrier, i.e., a non-toxic derivative containing formaldehyde in combination.
The mode of action of taurolidine has been shown to include the transfer of methylol
groups to hydroxyl or amino groups present on the above toxins or on the mureine of the bacterial
cell walls. In solution, taurolidine exists in equilibrium with taurultam and N-methylol taurultam,
taurolidine being greatly predominant. Taurultam is itself in equilibrium with methylol
taurinamide, the equilibrium being greatly in favor of taurultam. When the above methylol
derivatives, methylol taurultam and methylol taurinamide. contact the toxins or bacteria, methylol
groups are transferred. Methylol taurultam is thereby converted to taurultam , while methylol
taurinamide is converted to taurine, a naturally occurring aminosulfonic acid that is extremely well
tolerated in the human body. It will thus be appreciated that taurolidine and taurultam act in
essentially the same way and produce the same final products.
Bacterial infections by gram-negative organisms are commonly accompanied by
endotoxaemia, that is, by the reaction of the patient to the endotoxin liberated by the organisms.
Endotoxin is a complex lipopolysaccharide constituent of the O-somatic antigen and is
loosely attached to the cell walls of gram-negative bacteria. Irrespective of the bacterial source,
all endotoxins exhibit similar toxic properties - in contradistinction to the exotoxins of gram-
positive bacteria, which exert a wide range of individual effects. In man, it can produce the
syndrome of endotoxin shock when large numbers of gram-negative bacteria are lysed. This
syndrome is encountered in about 30% of patients with gram-negative septicaemia. It is known
that endotoxins can be inactivated by taurinamide derivatives.
Toxic proteins, such as, exotoxins, can similarly be inactivated and methylol transfer
antibacterials can be administered to combat toxic proteins in the absence of lipopolysaccharide
toxins. Toxins that may be concerned include the exotoxins of such gram-negative bacteria as E.
coli and Bacteroides fragilis. It is known that intravenous administration to mice of 0.2 mL of a
20% solution of taurolidine in sterile 5% polyvinyl pyrrolidone can very significantly reduce the
mortality rate on intraperitoneal administration of pathogenic strains of both E. coli and B.
fragilis.
Other toxic proteins include venoms such as mellitin and fungal toxins such as amanitin
and cc-bungarotoxin, which have been shown to be substantially detoxified by taurolidine.
A particular advantage of taurolidine is its very low toxicity; it has been shown to be non-
teratogenic in mice, the intraperitoneal LD50 being on the order of 1.5g/kg. As mentioned above,
these compounds exhibit methyloi transfer activity that results in the production of taurine, which
is found naturally in the body and is particularly nontoxic. A further advantage of taurolidine is its
stability in aqueous solution, enabling the solutions to be pre-packed and stored over relatively
long periods
The taurinamide derivatives employed in the practice of the present invention will normally
be administered as an aqueous solution by injection into the medical prosthetic device. Such
solutions may contain, in addition to a given taurinamide derivative, gentamycin sulfate or
chondroitin sulfate and also may commonly contain a solubilizing agent, such as, polyvinyl
pyrrolidone (PVP), to help maintain the taurinamide derivative in solution and to contribute to the
isotonicity of the solution. The concentration of the taurinamide derivatives in such solutions can
range from greater than zero to about 2 wt%; concentrations in the range of from about 0.01 to
about 1.5 wt % are preferred; and a concentration of about 1 wt% is most preferred. Higher
concentrations than these would be useful, but in such cases, solubility becomes a problem.
Where PVP is incorporated into the solution, it will commonly be employed at a
concentration in the range of from 4 to 7% by weight in order to achieve relatively high
concentrations of the taurinamide derivatives, especially taurolidine, which have low water
solubility. The molecular weight of the PVP should not be greater that about 30,000 and is
preferably less than 10,000, e.g., between about 200 and 3500. Kollidone® 17, sold by BASF is
especially suitable. Such PVP is fairly quickly absorbed and excreted through the kidneys.
The amount of solution of taurinamide derivative injected into a medical prosthetic device
will be enough to fill it. Such devices, when they are hemodialysis catheters, typically have
internal volumes in the range of from about 0.1 mL to about 10 mL, such quantities will, of course, vary with the length and diameter of the tubing of the device, which, inter alia, can be a
function of the size of the individual patient
The concentration of the taurinamide derivative in such solutions is preferably in the range
of from about 0 4 to about 5% by weight, depending, at the maximum, upon the solubility of the
compound. Solutions of about 0 4 to about 2.0 weight % taurolidine, i.e., about 4 to about 20 grams per liter, are particularly preferred
An example describing the preparation of a stock solution of taurolidine has appeared in
several patents, for example, U S Patent No 4,337,251.
15 Liters of double distilled pyrogen free water are filled into a 25 liter glass vessel
equipped with a stirrer and an intensive reflux device and heated to 50 °C with stirring.
Taurolidine (400 g) is added followed by PVP (Kollidone 17; lOOOg) After dissolution, the
solution is cooled and the pH is adjusted to 6.0 with a few drops of 0. 1 N hydrochloric acid. The
solution is then passed through an adsorption filter to remove microorganisms and pyrogens and
through a sterilizing Millipore filter before being filled into 100 mL vials, which are finally
autoclaved
If desired, some or all of the PVP may be replaced by a parenterally acceptable polyol
This use for polyols has been disclosed in U S Patent No 5,210,083, the disclosure of which is
incorporated herein by reference in its entirety There, it is pointed out that at higher
concentrations of taurolidine. crystallization can occur, which can render the solution unuseable
In the case of bacteπa and their endo- and exotoxins, it has been found that after the
methylol transfer, as descπbed above, there is a further irreversible step involving dehydration
Thus, in the case of bacteπal endotoxins, which are lipopolysaccharides, it was found that an irreversible cross-linking reaction takes place that prevents the endotoxin from exerting its lethal
effect Similarly, in the case of bacterial exotoxins, which are proteins or polypeptides and do not
contain lipopolysaccharide material of the kind found in the endotoxins , the detoxification
reaction has been found to be irreversible However, it is disclosed in U S Patent No 5,210,083
that the transfer of methylol groups by the mechanism set out above is reversible in the case of
many hydroxyl or amino compounds so that an equilibrium can be established that does not
significantly interfere with the availability of taurolidine Thus, polyols, such as, sugars and sugar
alcohols, can also be used to maintain relatively high concentrations of taurolidine and/or
taurultam in aqueous solution without significantly affecting their antibacterial and antitoxin
activity Preferred polyols include carbohydrates, e g , hexoses, such as, glucose, fructose, and
mixtures thereof, pentoses. such as, xviose, polysaccharides, such as, dextran or hydrolyzed
starch, glycerol, and sugar alcohols, uch as, sorbitol, mannitol, and xylitol Glucose is most
preferred
The concentration of the polyol is typically in the range of from about 3 to about 40% by
weight. In the case of glucose, the concentration is preferably in the range of from about 10 to
about 30% by weight, more preferably about 20%.
Where such polyols are used, the concentration of taurolidine in the solution is preferably
in the range of from about 0.5 to about 5%, more preferably in the range of from about 2 to about
3% by weight. The concentration of taurultam is preferably in the range of from about 1 to about
7.5%, more preferably in the range of from about 3 to about 5% by weight.
Since gram-negative organisms will frequently be present and since the bacteriostatic
activity of the taurinamide derivatives is lower than that of many conventional antibiotics, it may be advantageous to administer the compositions employed in the practice of the present invention
in conjunction with a broad spectrum antibiotic substance, more especially, a substance strongly
active against both gram-positive and gram-negative pathogens that, preferably, induces no or
only delayed resistance, for example, a β-lactam antibiotic, such as, penicillin, ampicillin, or
cephalosporin; a tetracycline antibiotic; a macrolide antibiotic, such as, erythromycin; a
polypeptide antibiotic, such as, bacitracin or novobiocin; or, more preferably, an aminoglycoside
antibiotic, such as, amikasin, butirosin, fortimycin, streptomycins, neomycin, linkomycins, such
as, clindamycin and lincomycin, kanamycin, dideoxykanamycin B (DKP), lividomycin, netilmicin,
ribostamycin, sagamycins, seldomycins and their epimers, sisomycin, sorbistin, tobramycin,
vancomycin, gentamicin, and rifamycins, such as, rifampicin and rifamycin; and the like. Of these,
gentamicin is prefened.
However, antibiotics are often contraindicated for use in surgical treatment, owing to their
tendency to produce resistant strains, and, except in unusual cases, it is preferred that the
taurinamide derivative be relied upon solely for antibacterial action, since such derivatives do not
produce resistant strains.
The composition employed in the practice of the present invention preferably also contains
a pharmacologically acceptable carrier solution, such as, water, Ringer's solution, or saline.
Additionally, the compositions of the present invention can also contain other dissolved additives
that can favorably influence their physical and biochemical properties, for example, amino acids,
sugar, common salt, fats, lipids, and the like.
The antimicrobial taurinamide derivatives employed in the practice of the present invention
are used in combination with a biological acceptable acid or a biologically acceptable salt thereof.
It is preferred that the acid be a carboxylic acid and more preferred that it be an anticoagulant.
U.S. Patent No 5,077,281 teaches that taurolin compounds exhibit outstanding coagulation-
inhibiting action in their own right and are especially suitable for use in medical conditions
requiring dialysis and for vascular prostheses, either alone or in combination with other anti¬
coagulants such as coumarin or heparin As pointed out in the patent, this is contrary to the
teaching of "Taurolin", published by W L. Bruckner and R.W. Pfirrmann, Verlag Urban und
Schwarzenberg, Munich, 1985, which expressly states that taurolin does not influence blood
coagulation and displays no anti-phlogistic action. It is the belief of the present inventor that the
taurinamide derivatives employed in the practice of the present invention do exhibit a degree of
anticoagulant activity, although to a lesser extent than is found with better known anticoagulants,
such as heparin. Accordingly, it is beneficial to employ the taurinamide derivatives in combination
with an anticoagulant, preferably one that is a biologically acceptable acid or salt thereof.
In accordance with the present invention, beneficial results are achieved when the
antimicrobial taurinamide derivatives are combined with a biologically acceptable acid or
biologicaljy acceptable salt thereof so as to produce a pH for the ultimate composition that is no
higher than 7, preferably in the range of from about 3 5 to about 6 5, more preferably in the range
of from about 4 5 to about 6 5 Exemplary of such acids are acetic acid, dihydroacetic acid,
benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid,
hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, vanillic acid, tartaric acid, ascorbic
acid, boric acid, lactic acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-{β- aminoethyl ether} -N,N,N',N'-tetraacetιc acid, and diethylenetπamine pentaacetic acid, esters of
p-hydroxybenzoic acid (Parabens), and the like, and biologically acceptable salts of the foregoing, such as, ammonium phosphate, potassium citrate, potassium metaphosphate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate, and the like A blood anticoagulating amount
of an acid selected from the group consisting of citπc acid, phosphoric acid,
ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bιs-{β-amιnoethyl ether}-N,N,N',N'-
tetraacetic acid, and diethylenetriamine pentaacetic acid and biologically acceptable salts thereof is
preferred It is preferred that the acid employed in the practice of the present invention be an
organic acid, especially one having at least one carboxyl group, particularly citric acid or EDTA
It is more preferred that the acid be citric acid and most preferred that it be used in combination
with a citrate salt, e g , sodium citrate, since, in addition to its pH loweπng and anticoagulation
capabilities, it is also known to be an antiseptic at the 3% level
Mermel, L A et al, in a talk entitled Taurolidine Activity Against Vancomycm-
Intermediate Susceptibility Staphylυcoccus Aureus (VISA) and Methicillm-Resistant
Staphylococctts Aureus (MRSA) presented at the Interscience Conference on Antimicrobial
Agents and Chemotherapy (1998), disclosed that taurolidine activity increases with decreasing pH
in the range of from pH 7.0 to pH 5.0.
EDTA is a known anticoagulant that is used in blood collection tubes. It is also known to
have the ability to form chelates with calcium. Since calcium is one factor that is known to have a
role in the coagulation of blood, it is believed possible that at least part of EDTA's efficacy in
anticoagulant activity may be brought about by this means. Sodium citrate is also believed to
have anticoagulation properties by virtue of its ability to generate insoluble calcium citrate.
Ethylene glycol-bis-{β-aminoethyl ether}-N,N,N',N'-tetraacetic acid (EGTA) and
diethylenetriamine pentaacetic acid (DTPA) and salts thereof are other known cheiating agents
that can be used in place of, or in addition to, EDTA or citric acid/citrate.
The foregoing anticoagulants can be used alone in the free acid state, but, more often will
be employed with some or all of their carboxylic acid groups neutralized with an appropriate base
or combined with a similar salt. Generally, it will be desirable to employ a cation that will form a
salt that is soluble in aqueous solution, such as alkali metal ions, e.g., sodium, potassium, or
lithium. Zinc citrate may also be employed. Sodium or potassium salts are normally preferred,
especially sodium, and the disodium salt of EDTA and sodium citrate and most preferred.
The acid and/or salt will be used in a concentration effective to bring about the desired
anticoagulation effect and, at the same time, bring about, or help to bring about, an appropriate
pH for biological use. Typically, the combined antimicrobial and anticoagulant composition of the
present invention will have a pH in the range of from about 3.0 to about 7, preferably from about
3.5 to about 6.5 and, most preferably from about 4.5 to about 6.5. The composition will normally
be at a physiological pH. If necessary, the pH can be adjusted by additional acid or base, such as
a mineral acid, for example hydrochloric acid, or, preferably, one that will not cause acidosis, such
as, for example, acetic, malic, or lactic acid. Other methods for adjusting the pH, familiar to those
of skill in the art, can also be employed. Where, as is preferred, trisodium citrate and citric acid
are employed in the practice of the present invention, the trisodium citrate will typically be used in
a concentration range of from about 5 to about 50 grams per liter. The citric acid will then be
added in sufficient amount to bring the pH to the desired level.
Although the process of the present invention is primarily concerned with introducing the
antimicrobial/anticoagulant compositions into catheters that are already in place, those skilled in
the art will understand that contacting an artificial surface outside the body with these
compositions can prevent the deposition of blood coaguia on such surface after its implantation and aid in the elimination of sites for bacterial growth. Thus, the surfaces of medical devices,
such as hemodialysis catheters, can be pre-treated by the compositions employed in the practice of
the present invention to prevent the blockage due to blood coaguia that present a favorable site
for bacteria growth and thereby prevent the infection that may ensue The apparatus can be
treated with a composition initially and then, after insertion, repeated periodic flushing as referred
to above.
Although the process of the present invention is primarily and preferably directed to
maintaining the patency and asepsis of implanted hemodialysis catheters, beneficial effects may
also be obtained in applying the process to other, similar, devices, such as, central venous
catheters, peripheral intervenous catheters, arterial catheters, Swan-Ganz catheters, umbilical
catheters, percutaneous nontunneled silicone catheters, cuffed tunneled central venous catheters
as well as with subcutaneous central venous ports
Various features and aspects of the present invention are illustrated further in the examples
that follow While these examples are presented to show one skilled in the art how to operate
within the scope of the invention, they are not intended in any way to serve as a limitation upon
the scope of the invention
EXAMPLE 1 A 0 5% solution of taurolidine in Ringer-Iactate solution (Thomae, Biberach, Germany)
was introduced into each of four polyethylene bottles having a 30 mL volume Filling volumes
were 5, 10, and 15 L One bottle was filled with 5 mL of the taurolidine solution and 2 mL ACD-A (Fresenius, Bad Homburg, Germany) solution ACD-A solution is used for the
conservation of whole blood and contains per liter 22 0 grams of sodium citrate dihydrate, 7 3
grams of citnc acid and 34 5 grams of glucose monohydrate
Blood was collected at the slaughter house from a female pig directly from the slaughter
wound into the containers that were then filled up to the 30 mL level The containers were
capped and gently moved to mix blood with the solution The containers were inspected after 30
minutes Blood in the containers containing only taurolidine was clotted, but the blood in the
container containing the mixture of taurolidine and ACD-A was not clotted Thus, it is concluded
that the use of sodium citrate and citric acid anticoagulants in combination with taurolidine
provides substantially enhanced anticoagulation properties in whole blood
EXAMPLE 2
A subcutaneously implantable titanium port-system of the type described in U.S. Patent
Application No. 08/485,498 is used in this example. It is connected with two 12 French silastic
catheters introduced with the tips into the right atrium. The valves of the port are opened by two
special needles allowing a blood flow of about 300 mL/min.
Ports were implanted by an experienced nephrologist, after their informed consent, in 10
female and 6 male patients, whose mean age was 68 ± 9 years Nine of the sixteen patients were
diabetics Patient inclusion criterion for the study was vessel exhaustion resulting in no blood
access sites in the arms available for hemodialysis Eight of the sixteen suffered from severe
congestive heart failure and all had a high comorbidity Nine of the patients started hemodialysis
just after implantation, the others were on chronic hemodialysis and switched from catheter to the port system (four patient exchange by guidewire) No peri-operative complications occurred
The preferred vessel was the right internal jugular vein, but the external jugular and
subclavian veins were also used The device has, thus far, been used for a total duration of 1 1 0
patient years The ports were used for all planned IID sessions (n= 1200)
In order to avoid intraluminal contamination of the device, an antimicrobial lock was
applied between the sessions and removed before the next treatment The aqueous antimicrobial
lock solution comprised 13 3 grams/liter of taurolidine, 6 7 grams per liter of tri-sodium citrate,
and approximately 3 3 grams per liter of citnc acid The citric acid was added to adjust the pH
range to 4 75-5 25 By virtue of the citric acid and sodium citrate, clotting of the catheters was
prevented and application of heparin was unnecessary
During the period of the study, two episodes of bacteriaemia (S. aureous) were observed
and successfully treated without loss of the device (0.5 infection per 1000 days). The results of
this study are shown in Table 1.
EXAMPLE 3
Comparative Example
In four separate facilities, two in the United States and two in Europe, A B, C, and D,
studies similar to those described above in Example 2 were carried out, except that the lock used
was heparin or heparinized saline in concentrations in the range of from 2,000 to 10,000
international units per mL. In the studies in the United States, A and B, benzyl alcohol was also
present as a standard presevative. The results of these comparative studies are shown in Table 1.
1 Mean interval without infection.
2 Mean interval without clotting.
EXAMPLE 4
In this example, which is a more detailed description of the trial of Example 2, the
subcutaneously implantable titanium port-system described in Example 2 was used.
In a prospective multi-center pilot trial starting June, 1998, 31 ports were implanted in 19 female and 12 male patients (mean age 66, min. 30, max. 81 years). In addition to the acceptance
of the new device, the aim of the study was the avoidance of infection supported by the completely atoxic mixture (heparin-free lock solution containing taurolidine as an anti-infective
substance and citric acid/sodium citrate for inhibition of coagulation) with excellent efficacy
against any germs, even those with multi-resistance.
In ten participating centers, no port was lost since the start of the study (3,847 days of
implantation). Despite high comorbidity, only two patients experienced blood-stream related
infections (S. aureus). Total observed infection was 0.5 per 1000 days. Systemic antibiotic
treatment was successful. Pre-existing catheter-related sepsis occurred in 5/31 patients; no
relapse occurred in the patients using the subcutaneously implantable titanium port-system.
Hospitalization was short and access was used just after implantation. The acceptance
was high even in patients who switched from catheter to port (12/31). In 6/31 patients an
exchange by guide-wire was possible. The usual placement technique was Seldinger applied by
three nephrologists. The preferred vessel was the right internal jugular vein (18/31), but all other
central veins were used.
Compared to the disadvantages of catheters, the port system allows bathing and is very
safe. Combined with the lock solution of the present invention, the risk of infection is low and
allows a puncture technique similar to a graft. The lifetime of the device has yet to be established.
EXAMPLE 5
An experiment was conducted to determine the minimum tauroiidine/citrate lock solution
acidity that will function well when in contact with human blood. Various lock solution acid
concentrations were mixed 50/50 by weight with fresh whole human blood. The pH was
experimentally varied from pH 3.0 to pH 7.0. At a lock solution acidity level of 4.0 and below,
the resulting blood mixture becomes hard and concretionary after one hour of contact with the
lock solution. This hardening was apparently due to the acid level of the lock solution and normal
blood clotting, since the clot appears very dark in color and dry in nature, not normal in color or
physical properties. When acidity of the lock solution was maintained above pH 5.0, no blood
clotting occurred and blood color remained a healthy red color. Thus, the most preferred lower
limit for the acidity of the taurolidine lock solution is about 5.0.
In view of the many changes and modifications that can be made without departing from
principles underlying the invention, reference should be made to the appended claims for an
understanding of the scope of the protection afforded the invention.