U.S. patent application number 11/560300 was filed with the patent office on 2007-07-05 for methods for coating surfaces with antimicrobial agents.
Invention is credited to ISSAM RAAD.
Application Number | 20070154621 11/560300 |
Document ID | / |
Family ID | 38068007 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070154621 |
Kind Code |
A1 |
RAAD; ISSAM |
July 5, 2007 |
METHODS FOR COATING SURFACES WITH ANTIMICROBIAL AGENTS
Abstract
Disclosed are methods for coating or impregnating a surface with
an antimicrobial agent that involve contacting the surface with a
composition that includes an antimicrobial agent and a solvent, and
curing the surface by applying heat. Also disclosed are methods for
reducing the risk of development or progression of an infection in
a subject in need of a medical device, that involve coating or
impregnating a surface of the medical device with an antimicrobial
agent and then curing the surface by applying heat, wherein the
risk of development or progression of an infection is reduced.
Inventors: |
RAAD; ISSAM; (Missouri City,
TX) |
Correspondence
Address: |
FULBRIGHT & JAWORSKI L.L.P.
600 CONGRESS AVE.
SUITE 2400
AUSTIN
TX
78701
US
|
Family ID: |
38068007 |
Appl. No.: |
11/560300 |
Filed: |
November 15, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60738198 |
Nov 18, 2005 |
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Current U.S.
Class: |
427/2.1 |
Current CPC
Class: |
A61L 31/16 20130101;
A61L 2300/442 20130101; A61L 27/54 20130101; A61P 31/04 20180101;
A01N 25/24 20130101; A01N 25/34 20130101; A61L 2300/406 20130101;
A61L 29/16 20130101; A01N 25/34 20130101; A01N 37/44 20130101; A01N
43/90 20130101; A01N 47/44 20130101; A01N 25/24 20130101; A01N
37/44 20130101; A01N 43/90 20130101; A01N 47/44 20130101 |
Class at
Publication: |
427/002.1 |
International
Class: |
A61L 33/00 20060101
A61L033/00; B05D 3/00 20060101 B05D003/00 |
Claims
1. A method for coating or impregnating a non-organic surface with
an antimicrobial agent, comprising: a) contacting the non-organic
surface with an composition comprising an antimicrobial agent and a
solvent; and b) curing the non-organic surface at a temperature
that is at least about 40.degree. C., wherein at least some of the
solvent that was contacted with the surface is removed, and wherein
the antimicrobial agent coats or impregnates the surface.
2. The method of claim 1, further defined as a method for coating
or impregnating a medical device with an antimicrobial agent,
wherein the non-organic surface is the surface of a medical
device.
3. The method of claim 2, wherein the medical device is an
endotracheal tube, a tracheotomy tube, chest tube, a vascular
catheter, an urinary catheter, a nephrostomy tube, a biliary stent,
a peritoneal catheter, an epidural catheter, a central nervous
system catheter, an orthopedic device, a prosthetic valve, a
gastric tube, an intestinal tube, or drug-delivery implant.
4. The method of claim 3, wherein the medical device is a vascular
catheter selected from the group consisting of a central venous
catheter, an arterial line, a pulmonary artery catheter, a stent,
and a peripheral venous catheter, an infusion port, or a dialysis
catheter.
5. The method of claim 3, wherein the medical device is a central
nervous system catheter further defined as an intraventricular
shunt.
6. The method of claim 1, wherein the non-organic surface is a
surface of a glove, a condom, a gown, hospital equipment, a table,
a container, a countertop, a floor, a bag, a suture, a device used
in food-processing, a sponge, or a mop.
7. The method of claim 1, wherein the antimicrobial agent is
further defined as an antibiotic, an antiseptic, an antiviral
agent, an antifungal agent, or a disinfectant.
8. The method of claim 7, wherein the antimicrobial agent is an
antibiotic.
9. The method of claim 8, wherein the antibiotic is a tetracycline,
a macrocyclic antibiotic compound, or a combination thereof.
10. The method of claim 9, wherein the tetracycline is
minocycline.
11. The method of claim 9, wherein the macrocyclic antibiotic is
rifampin, rifampicin, or a combination thereof.
12. The method of claim 8, wherein the composition comprises
tetracycline and minocycline.
13. The method of claim 7, wherein the antimicrobial agent is an
antiseptic.
14. The method of claim 7, wherein the antimicrobial agent is a
disinfectant.
15. The method of claim 1, wherein the antimicrobial agent
comprises a dye, a basic reagent, or a combination thereof.
16. The method of claim 15, wherein the composition comprises a
basic reagent and a dye.
17. The method of claim 16, wherein the basic reagent is a
guanidium compound, a biguanide, a bipyridine, a phenoxide
antiseptic, an alkyl oxide, an aryl oxide, a thiol, a halide, an
aliphatic amine, or an aromatic amine.
18. The method of claim 17, wherein the basic reagent is a
guanidium compound.
19. The method of claim 18, wherein the guanidium compound is
chlorhexidine, alexidine, or hexamidine.
20. The method of claim 17, wherein the basic reagent is a
bipyridine.
21. The method of claim 20, wherein the bipyridine is
octenidine.
22. The method of claim 17, wherein the basic reagent is a
phenoxide antiseptic.
23. The method of claim 22, wherein the phenoxide antiseptic is
clofoctol, chloroxylenol, or triclosan.
24. The method of claim 16, wherein the dye is a triarylmethane
dye, a monoazo dye, a diazo dye, an indigoid dye, a xanthene dye,
an anthraquinone dye, a quinoline dye, an FD&C dye, a D&C
dye, or brilliant green.
25. The method of claim 24, wherein the dye is a triarylmethane dye
selected from the group consisting of gentian violet, crystal
violet, and ethyl violet.
26. The method of claim 25, wherein the FD&C dye is Blue No. 1
or Green No. 3.
27. The method of claim 24, wherein the monoazo dye is FD&C
Yellow No. 5 or FD&C Yellow No. 6.
28. The method of claim 24, wherein the diazo dye is D&C Red
No. 17.
29. The method of claim 24, wherein the indigoid dye is FD&C
Blue No. 2.
30. The method of claim 24, wherein the xanthene dye is FD&C
Red No. 3.
31. The method of claim 24, wherein the anthraquinone dye is
D&C Green No. 6.
32. The method of claim 24, wherein the quinoline dye is D&C
Yellow No. 1.
33. The method of claim 1, wherein the surface comprises a
micropore or a nanopore.
34. The method of claim 1, wherein curing comprises heating the
surface to a temperature that is about 40.degree. C. to about
100.degree. C.
35. The method of claim 24, wherein curing comprises heating the
surface to a temperature that is about 40.degree. C. to about
80.degree. C.
36. The method of claim 35, wherein curing comprises heating the
surface to a temperature that is about 40.degree. C. to about
60.degree. C.
37. The method of claim 36, wherein the surface is heated for about
1 hour to about 3 weeks.
38. The method of claim 37, wherein the surface is heated for about
12 hours to about 96 hours.
39. The method of claim 38, wherein the surface is heated for about
24 hours to about 72 hours.
40. The method of claim 1, wherein curing is further defined as
drying the surface.
41. The method of claim 1, further comprises washing the surface
after curing the surface.
42. The method of claim 41, wherein washing is further defined as
contacting the surface with a composition comprising a detergent
and water.
43. The method of claim 41, further comprising curing the surface
at a temperature of at least 40.degree. C. after washing the
surface.
44. The method of claim 43, wherein the surface is cured for at
least 1 hour to at least 96 hours.
45. The method of claim 44, wherein the surface is cured for at
least 24 hours to at least 72 hours.
46. The method of claim 1, wherein the surface is composed of a
polymer or silicone.
47. The method of claim 46, wherein the polymer is polyvinyl
chloride, polyurethane, polyethylene, silastic elastomers,
polytetrafluoroethylene, dacron, collodion, carboethane or
nylon.
48. The method of claim 2, further comprising packaging the medical
device in a container.
49. The method of claim 2, further comprising sterilizing the
medical device.
50. A method for coating or impregnating a medical device with an
antimicrobial composition, comprising the steps of: a) contacting
the medical device with a composition comprising an antimicrobial
agent and a solvent; b) curing the medical device at a temperature
of about 40.degree. C. to about 80.degree. C. for about 12 hours to
about 72 hours, wherein the medical device is dried; c) washing the
medical device with an aqueous composition; and d) repeating step
b), wherein the medical device becomes coated or impregnated with
an antimicrobial composition.
51. A method for reducing the risk of development or progression of
an infection in a subject in need of a medical device, comprising
coating or impregnating a surface of the medical device with an
antimicrobial agent in accordance with the method of claim 1 prior
to contacting the medical device with the subject, wherein the risk
of development or progression of an infection is reduced.
52. The method of claim 51, wherein the subject is a human.
53. The method of claim 51, wherein the antimicrobial agent is
further defined as an antibiotic, an antiseptic, an antiviral
agent, an antifungal agent, or a disinfectant.
54. The method of claim 53, wherein the antimicrobial agent is an
antibiotic.
55. The method of claim 54, wherein the antibiotic is a
tetracycline, a macrocyclic antibiotic compound, or a combination
thereof.
56. The method of claim 55, wherein the tetracycline is
minocycline.
57. The method of claim 55, wherein the macrocyclic antibiotic is
rifampin, rifampicin, or a combination thereof.
58. The method of claim 51, wherein the infection is pneumonia,
bacteremia, fungimia, candidemia, a urinary tract infection, a
catheter-exit site infection, or a surgical wound infection.
59. The method of claim 51, wherein the infection is a nosocomial
infection.
60. The method of claim 59, wherein the infection is caused by
methicillin-resistant staphylococci, vancomycin-resistant
enterococci, resistant Pseudomonas aeruginosa, or a combination
thereof.
61. The method of claim 59, wherein the infection is a fungal
infection secondary to Candida species.
62. The method of claim 51, wherein the antimicrobial agent is an
antibacterial agent, an antiviral agent, or an antifungal
agent.
63. The method of claim 62, wherein the antibacterial agent is
minocycline or rifampin.
64. The method of claim 51, wherein the composition comprises a
basic reagent and a dye.
65. The method of claim 51, wherein the medical device is an
endotracheal tube, a vascular catheter, an urinary catheter, a
nephrostomy tube, a biliary stent, a peritoneal catheter, an
epidural catheter, a central nervous system catheter, an orthopedic
device, a prosthetic valve, a silk suture, or a medical
implant.
66. The method of claim 65, wherein the medical device is a
vascular catheter further defined as a central venous catheter, an
arterial line, an pulmonary artery catheter, or a peripheral venous
catheter.
67. The method of claim 65, wherein said central nervous system
catheter is an intraventricular shunt.
Description
[0001] The present application is related to U.S. Provisional
Patent Application 60/738,198, filed on Nov. 18, 2005, which is
hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to the fields of
infectious disease control and medical devices. More particularly,
the invention provides methods for coating antiseptic and
antimicrobial compositions onto a surface, such as the surface of a
medical device.
[0004] 2. Description of Related Art
[0005] Medical devices, such as urinary catheters, endotracheal
tubes and central venous catheters (CVC), are the driving and
leading cause of hospital-acquired infections in high-risk
patients. These high-risk patients include critically ill patients
admitted to the Intensive Care Unit (ICU), cancer patients, or
patients with chronic diseases requiring long-term care, such as
those patients on total parenteral nutrition (TPN). Anti-infective
devices coated with antimicrobial agents have been shown to
significantly decrease the risk of device-related and
hospital-acquired infection.
[0006] Most nosocomial (hospital-acquired) infections are caused by
the contamination of medical devices. One class of nosocomial
infection is nosocomial pneumonia. Nosocomial pneumonias are
associated with a very high attributable mortality and morbidity.
Recent data have shown that at least 300,000 episodes of nosocomial
pneumonia occur annually in the United States (Official Statement,
American Thoracic Society). The attributable mortality of
nosocomial pneumonia is 33%-50%, hence, around 100,000 patients die
annually because of nosocomial pneumonia (CDC, 1993; Leu et al.,
1989). The risk of nosocomial pneumonia increases 6- to 20-fold
from the use of mechanical ventilation (Official Statement,
American Thoracic Society).
[0007] The endotracheal tube is considered a common vehicle for
colonization/contamination leading to nosocomial pneumonia. The
endotracheal tube connects the oropharyngeal environment with the
sterile bronchoalveolar space, significantly increasing the risk of
nosocomial pneumonia. Endotracheal tubes are typically constructed
of polyvinylchloride, which is known to be very difficult to
impregnate with antiseptic or antimicrobial agents. Thus, there are
no endotracheal tubes that are impregnated with antibiotics or
antiseptics currently in use.
[0008] Another class of nosocomial infections includes bloodstream
infections. The primary contributors to nosocomial bloodstream
infections are vascular catheters. It is estimated that around
400,000 vascular catheter-related bloodstream infections (CRBSI)
occur annually in the United States (Raad, 1998). The attributable
mortality of these infections in the intensive care unit (ICU) was
estimated in JAMA in 1994 to be 25% (Reiselman et al., 1994).
Hence, these infections are a major cause of morbidity and
mortality in hospitalized patients. Vascular catheters are mostly
polyurethane short-term catheters used in the ICU and long-term
silicone catheters used in cancer/AIDS patients.
[0009] The most common class of nosocomial infection are urinary
tract infections (UTI), contributing to 34% of all nosocomial
infections (Klempner et al., 1998). Nosocomial UTI are usually
associated with contamination of urinary catheters. In addition,
nosocomial surgical wound infections are common complications of
surgical procedures, particularly in cancer and immunocompromised
patients with devitalized tissue and decreased immunity. Surgical
wound infections contribute to 17% of all nosocomial infections
(Platt and Bucknall, 1988). Many surgical wound infections are
associated with the contamination of sutures.
[0010] Antibiotics and antiseptics have been used to impregnate
vascular catheters. The concern with the use of antibiotics has
been that resistance might develop to antibiotics, preventing their
use therapeutically and systemically in hospitalized patients.
Furthermore, the durability of the existing antiseptics has been
limited. For example, the use of chlorhexidine/silver sulfadiazine
on polyurethane surfaces has had limited effectiveness. Moreover,
chlorhexidine/silver sulfadiazine impregnating the surface of
vascular catheters resulted in limited activity against
gram-negative bacilli, such as Pseudomonas (Raad et al. 1996).
[0011] U.S. Patent App. Pub. No. 20050197634 and 20030078242
describe certain antiseptic coatings on medical devices. These
applications have shown that antiseptics consisting of antiseptic
dyes (such as Gentian violet) and quadinium compounds (such as
chlorhexidine) are highly effective as a combination in coating
various medical devices and preventing the adherence of diverse
resistant bacteria and fungi (including gram-positive and
gram-negative bacteria as well as Candida spp.) U.S. Pat. No.
5,624,704 discloses methods for impregnating a non-metallic medical
implant with an antimicrobial agent.
[0012] Although highly effective from an antimicrobial perspective,
the drawback of antiseptic dyes is their high level of leaching
into body fluids (such as urine, serum or bronchoalveolar lavage)
as well as their staining potential. The leaching into body fluids
might lead to systemic toxicity clinically. The staining could lead
to a cosmetic problem, thus making these devices unmarketable.
Thus, there thus exists a need for improved methods for coating
medical devices with antiseptics that reduces the risk of
nosocomial infections.
SUMMARY OF THE INVENTION
[0013] The present invention provides for novel methods of coating
or impregnating a surface with an antimicrobial agent. For example,
the inventors have found that their method of coating or
impregnating a surface with an antimicrobial agent can be applied
in coating or impregnating a medical device with an antimicrobial
agent such that there is a decrease in staining potential of the
medical device, decrease in leaching of the antimicrobial into
tissue, and prolonged antimicrobial efficacy.
[0014] The present invention generally pertains to methods for
coating or impregnating a surface with an antimicrobial agent, that
involve (1) contacting the non-organic surface with an composition
that includes an antimicrobial agent and a solvent; and (2) curing
the surface at a temperature that is at least about 40.degree. C.,
wherein at least some of the solvent that was contacted with the
surface is removed, and wherein the antimicrobial agent coats or
impregnates the surface. An "antimicrobial agent" as used herein
refers to an agent that can prevent or reduce the growth or
reproduction of a microorganism or kill a microorganism. A
"microorganism" is defined herein to refer to a bacterium, a
fungus, a protozoan, or a virus. In particular embodiments, the
surface is a non-organic surface. A "non-organic surface" as used
herein refers to a superficial or external aspect of any object
other than a living organism. By way of example, the surface may be
the surface of medical device.
[0015] A "medical device" is defined herein to refer to an
instrument, apparatus, implement, machine, contrivance, implant, or
other similar or related article, including a component part, or
accessory which is intended for use in the diagnosis, treatment, or
prevention of disease or other health-related conditions in a
subject. The subject can be any vertebrate, such as a mammal. In
particular embodiments, the subject is a human. Non-limiting
examples of medical devices include a stent, a tube, a catheter, or
a valve. A "stent" as used herein refers to a thread, rod, or
catheter inserted into a tubular structure, such as a blood vessel,
to provide support during or after anastomosis. A "catheter" is
defined herein to refer to a hollow tube (which may or may not be
flexible) for insertion into a body cavity, duct, or vessel to
allow the passage of fluids or distend a passageway. Particular
non-limiting examples of medical devices include an endotracheal
tube, tracheotomy tube, ureteral stent, biliary stent,
ventriculostomy catheters, chest tube, a vascular catheter, an
urinary catheter, a gastric tube, an intestinal tube, a nephrostomy
tube, a biliary stent, a peritoneal catheter, an epidural catheter,
a central nervous system catheter, an orthopedic device, a
prosthetic valve, orthopedic devices, pacemakers, infusion pumps,
infusion ports, dialysis catheters, neurotransmitters,
drug-delivery implant, and gloves. Non-limiting examples of
vascular catheters include of a central venous catheter, an
arterial line, a pulmonary artery catheter, a stent, and a
peripheral venous catheter.
[0016] Other medical devices that can benefit from the present
invention include blood exchanging devices, vascular access ports,
cardiovascular catheters, extracorpeal circuits, stents,
implantable prostheses, vascular grafts, pumps, heart valves, and
cardiovascular sutures, to name a few. Regardless of detailed
embodiments, applicability of the invention should not be
considered limited with respect to the type of medical device,
implant location or materials of construction of the device.
[0017] Other examples of non-organic surfaces contemplated by the
present invention include surfaces of medical supplies and medical
equipment. Non-limiting examples of medical supplies and equipment
include gloves (such as disposable gloves), gowns, pads,
wheelchairs, stretchers, tables, swabs, sponges, sutures (such as
silk sutures), bags, surgical supplies, and packaging materials for
the packaging of sterile medical or hospital supplies. Further
examples of non-organic surfaces include the surfaces of a sponge,
wipe, pad, or mop.
[0018] Further examples of non-organic surfaces include floors,
countertops, the surface of a container (such as for food storage),
and the surfaces of food processing supplies and equipment, mopping
equipment or sponges. Still further examples of non-organic
surfaces include the surface of personal care products such as
gloves, condoms, diaphragms, sanitary napkins.
[0019] The antimicrobial agent can be any antimicrobial agent known
to those of ordinary skill in the art. For example, the
antimicrobial agent may be an antibiotic, an antiseptic, an
antiviral agent, an antifungal agent, or a disinfectant. An
"antibiotic" is defined herein to refer to a compound or agent that
can prevent or reduce the growth and reproduction of a bacterium or
kill a bacterium. Some antibiotics kill bacteria, whereas others
prevent or inhibit their growth. Antibiotics are applied in the
treatment of subjects with infections, such as bloodstream
infections. They are administered via any of a variety of routes,
such as through oral, intravenous, subcutaneous, or intramuscular
routes. Examples of antibiotics include penicillin, cephalosporins,
vancomycin, minocycline, and rifampin. In certain embodiments, the
antibiotic is a tetracycline or a macrocyclic antibiotic or a
combination thereof. The tetracycline can be any tetracycline known
to those of ordinary skill in the art, such as minocycline.
Non-limiting examples of macrocyclic antibiotics include rifampin,
rifampicin, or a combination thereof. Additional examples of
antibiotics are discussed in the specification below.
[0020] As used herein, the term "antifungal agent" is defined as a
compound having either a fungicidal or fungistatic effect upon
fungi contacted by the compound. As used herein, the term
"fungicidal" is defined to mean having a destructive killing action
upon fungi. As used herein, the term "fungistatic" is defined to
mean having an inhibiting action upon the growth of fungi. As used
herein, the term "antiviral agent" is defined as a compound that
can either kill viral agents or one that stops the replication of
viruses upon contact by the compound.
[0021] The antimicrobial agent may also be an antiseptic. An
"antiseptic" is defined herein to refer to an agent that can
prevent or reduce the growth and reproduction of any microorganism
(such as bacteria, fungi, protozoa, and viruses) or kill any
microorganism but which is generally not applied in the treatment
of a systemic infection in a subject usually because of limitations
related to absorption, penetration, or systemic toxicity. These
agents can generally be used on the skin and external mucosal
surfaces. Examples include chlorhexidine and povidone iodine.
"Disinfectants" operate only on nonliving objects, but are
otherwise similar to antiseptics.
[0022] In particular embodiments of the present invention, the
composition that is contacted with the non-organic surface includes
a basic reagent, a dye, or a basic reagent in combination with a
dye. The composition may include a single dye or a combination of
dyes. The composition may include a single basic reagent, or a
combination of basic reagents. In particular embodiments, the dye
and/or basic reagent has antimicrobial activity. In some
embodiments, the dye is bonded to the basic reagent to form a
compound that has antimicrobial activity. Non-limiting examples of
basic reagents contemplated by the present invention include a
guanidium compound, a biguanide, a bipyridine, a phenoxide
antiseptic, an alkyl oxide, an aryl oxide, a thiol, a halide, an
aliphatic amine, or an aromatic amine. In particular embodiments,
the basic reagent is a guanidium compound. For example, the
guanidium compound may be chlorhexidine, alexidine, or hexamidine.
In other embodiments, the basic reagent is a bipyridine. For
example, the bipyridine may be octenidine. In further embodiments,
the basic reagent is a phenoxide antiseptic. For example, the
phenoxide antiseptic may be clofoctol, chloroxylenol, or triclosan.
One of ordinary skill in the art would be familiar with basic
reagents that can be included in the context of the present
invention.
[0023] The dye can be any dye known to those of ordinary skill in
the art. Non-limiting examples of dyes include a triarylmethane
dye, a monoazo dye, a diazo dye, an indigoid dye, a xanthene dye,
an anthraquinone dye, a quinoline dye, an FD&C dye, a D&C
dye, or brilliant green. For example, the triarylmethane dye may be
a dye selected from the group consisting of gentian violet, crystal
violet, and ethyl violet. Non-limiting examples of FD&C dyes
include Blue No. 1 and Green No. 3. Non-limiting examples of
monoazo dyes include FD&C Yellow No. 5 or FD&C Yellow No.
6. A non-limiting example of a diazo dye is D&C Red No. 17. A
non-limiting example of an indigoid dye is FD&C Blue No. 2. A
non-limiting example of a xanthene dye is FD&C Red No. 3. A
non-limiting example of an anthraquinone dye is D&C Green No.
6. A non-limiting example of a quinoline dye is D&C Yellow No.
1.
[0024] The basic reagent may be bonded to the dye. The basic
reagent and the dye may be bonded ionically to form the antiseptic
compound. In other embodiments, the basic reagent and the dye are
bonded covalently to form the antiseptic compound. The basic
reagent and the dye can be combined in any amount to obtain the
antiseptic composition of the invention, however, in a particular
embodiment, an equimolar amount of the basic reagent is added to
the dye solution. The inventors also contemplate that the
antiseptic composition of the invention can be made by combining
other amounts of the dye and basic reagent for example, one may
combine, in molar ratios, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,
1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55,
1:60, 1:65, 1:70, 1:75, 1:80, 1.85, 1:90, 1:95, to 1:99 of either
dye : basic reagent or basic reagent : dye. This includes all the
intermediate ranges as well, for example it includes molar ratios
such as, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1,
1.9:1 and the like for other values listed. It also includes the
ranges in between these values such as 1.11:1, 1.12:1 and so on.
The skilled artisan will therefore recognize that the dye and basic
reagent can be combined in different molar ratio amounts to obtain
the antiseptic composition disclosed and that the invention is
therefore not limited to any particular molar ratio of dye:basic
reagent or basic reagent:dye.
[0025] A "solvent" as used herein refers to a compound or molecule
that exits as a liquid at a temperature of about 20.degree. C. to
about 60.degree. C. In some embodiments, the solvent has a boiling
point of over 35.degree. C. Non-limiting examples of solvent as
used herein may be an aqueous solvent or a nonaqueous solvent. In
particular embodiments, the solvent is inert in that it has no
ability to alter or modify the chemical structure of the
antimicrobial agent. Nonlimiting examples of solvents include
water, methylene chloride, alcohols (such as methanol and ethanol),
ketones (such as acetone, methylethylketone), esters (such as
tetrahydrofuran), aldehydes (such as formaldehyde), acetonitrile,
acetic acid, methylene chloride, chloroform, butyl acetate, or a
combination thereof. In some embodiments, the solvent is a dipolar
aprotic solvent, such as dimethylsulfoxide or
N,N-dimethylformamide. The solvent may also be a protic solvent or
an aprotic solvent. Additional examples of solvents are set forth
in the specification below.
[0026] The surface may be a smooth surface or an irregular surface.
In some particular embodiments, the surface comprises one or more
pores. The pores can be of any size. For example, the pore may be a
micropore (a pore with a diameter of about 100 nm to about 100
.mu.m) or a nanopore (a pore with a diameter in the range of from
about 1 nm to about 100 nm in a membrane or solid media.
[0027] The surface can be composed of any material known to those
of ordinary skill in the art. For example, the surface may be
composed of a polymer, silicone, or a mixture thereof. Any polymer
known to those of ordinary skill in the art is contemplated by the
present invention. Examples include polyvinyl chloride,
polyurethane, polyethylene, silastic elastomers,
polytetrafluoroethylene, dacron, collodion, carboethane and
nylon.
[0028] "Curing" in the context of the present invention is defined
herein to refer to heating the surface such that some or all of the
solvent that was contacted with the surface is removed from the
surface. "Heating" as used herein refers to an increase in
temperature of the surface due to application of a heat source
compared to temperature of the surface in the absence of the heat
source. Heating can be by any method known to those of ordinary
skill in the art. Heat sources that may be used with the methods
set forth herein include but are not limited to a heat lamp,
heating incubator, heat from an electrical source, infrared
radiation, visible light, ultraviolet radiation, inductive heating,
laser illumination, high-frequency ultrasound or combinations
thereof.
[0029] Curing can comprising heating the surface to a temperature
that is at least about 30.degree. C., 36.degree. C., 37.degree. C.,
38.degree. C., 39.degree. C., 40.degree. C., 41.degree. C.,
42.degree. C., 43.degree. C., 44.degree. C., 45.degree. C.,
46.degree. C., 47.degree. C., 48.degree. C., 49.degree. C.,
50.degree. C., 51.degree. C., 52.degree. C., 53.degree. C.,
54.degree. C., 55.degree. C., 56.degree. C., 57.degree. C.,
58.degree. C., 59.degree. C., 60.degree. C., 61.degree. C.,
62.degree. C., 63.degree. C., 64.degree. C., 65.degree. C.,
66.degree. C., 67.degree. C., 68.degree. C., 69.degree. C.,
70.degree. C., 71.degree. C., 72.degree. C., 73.degree. C.,
74.degree. C., 75.degree. C., 76.degree. C., 77.degree. C.,
78.degree. C., 79.degree. C., 80.degree. C., 81.degree. C.,
82.degree. C., 83.degree. C., 84.degree. C., 85.degree. C.,
86.degree. C., 87.degree. C., 88.degree. C., 89.degree. C.,
90.degree. C., 91.degree. C., 92.degree. C., 93.degree. C.,
94.degree. C., 95.degree. C., 96.degree. C., 97.degree. C.,
98.degree. C., 99.degree. C., 100.degree. C., 105.degree. C.,
110.degree. C., 115.degree. C., 120.degree. C., or greater, or to
at least any intermediate temperature between one of the
specifically recited temperatures, or within any range of
temperature. For example, the surface may be heated to about 40 to
about 100.degree. C. In further embodiments, curing involves
heating the surface to a temperature that is about 40.degree. C. to
about 80.degree. C. In still further embodiments, curing involves
heating the surface to a temperature that is about 40.degree. C. to
about 60.degree. C.
[0030] In certain particular embodiments, curing occurs at a
temperature of from about 30.degree. C. to about 220.degree. C., at
a temperature of from about 40.degree. C. to about 100.degree. C.,
at a temperature of from about 45.degree. C. to about 100.degree.
C., at a temperature of from about 45.degree. C. to about
90.degree. C., at a temperature of from about 45.degree. C. to
about 80.degree. C., 45.degree. C. to about 70.degree. C., or at a
temperature of from about 50.degree. C. to about 60.degree. C.
[0031] The heating may occur before, after or during the time that
the medical device is contacted with an antibiotic or an
antiseptic. The heating may result in the fixation of the
antiseptic agent or the antibiotic to the medical device. In
certain embodiments, the heating may affect nanopores or micropores
which exist on the medical device (e.g., the heating may enlarge
and/or improve the ability of the micropore or nanopore to contain
or adhere an antiseptic or antibiotic). The heating may occur once
or more than once. In certain embodiments the medical device may be
heated 1, 2, 3, 4, 5 or more times.
[0032] The surface can be heated for any duration of time. For
example, the surface may be heated to remove some but not all of
the solvent that was contacted with the surface. Alternatively the
surface can be heated until the surface is dry. For example, the
surface may be heated for at least 5 minutes, 10 minutes, 15
minutes, 20 minutes 25 minutes 30 minutes 35 minutes 40 minutes 45
minutes, 50 minutes, 55 minutes, 1 hour, 1.25 hour, 1.5 hour, 1.75
hour, 2.0 hours 2.25 hours, 2.5 hours, 2.75 hours, 3.0 hours, 3.25
hours, 3.5 hours, 3.75 hours, 4.0 hours, 4.5 hours, 5.0 hours, 5.5
hours, 6.0 hours, 6.5 hours, 7.0 hours, 7.5 hours. 8.0 hours, 8.5
hours, 9.0 hours, 9.5 hours, 10.0 hours. 15 hours, 24 hours, 36
hours, 48 hours, 60 hours, 72 hours, 84 hours, 2 weeks, 2.5 weeks,
3 weeks, 1 month, or longer, or for at least any duration in
between one of the specifically recited durations, or within any
range of durations set forth herein. In further embodiments, the
surface is further heated after the surface is dry. In some
embodiments, the surface is heated for about 1 hour to about 3
weeks. In further embodiments, the surface is heated for about 12
hours to about 96 hours. In still further embodiments, the surface
is heated for about 24 hours to about 72 hours.
[0033] In particular embodiments set forth herein, the surface is
washed after it is cured. Washing is defined herein to refer to
application of a liquid for the purpose of removing a substance.
For example, washing may be further defined as contacting the
surface with a composition comprising a detergent and water. The
contacting may result in removal of antimicrobial agent not bound
to the surface of the medical device. Any method known to those of
ordinary skill in the art can be applied in washing the medical
device. Washing can, for example, include rinsing, dipping, or
immersing the device in a wash solution using any method known to
those of ordinary skill in the art.
[0034] In further embodiments, the method further involves curing
the surface at a temperature of at least 40.degree. C. after
washing the surface. The surface may be cured as discussed above.
For example, the surface may be cured for at least 1 hour to at
least 96 hours or for at least 24 hours to at least 72 hours.
[0035] When the surface is the surface of a medical device, the
method may further involve packing the medical device in a
container. The container can be any container known to those of
ordinary skill in the art that can be applied in packing the device
for shipping to a site where the device will be used. In some
embodiments, the method further involves sterilizing the medical
device. Any method known to those of ordinary skill in the art can
be used to sterilize the medical device. For example, the medical
device may be sterilized after it is heated using any method known
to those of ordinary skill in the art. Examples of such methods of
sterilization include heat sterilization, radiation sterilization,
including gamma irradiation, chemical sterilization, or gas
sterilization.
[0036] In a particular embodiments, the method is a method for
coating or impregnating a medical device with an antimicrobial
composition, involving the steps of: (1) contacting the medical
device with a composition comprising an antimicrobial agent and a
solvent; (2) curing the medical device at a temperature of about
40.degree. C. to about 80.degree. C. for about 12 hours to about 72
hours, wherein the medical device is dried; (3) washing the medical
device with an aqueous composition; and (4) repeating step (2),
wherein the medical device becomes coated or impregnated with an
antimicrobial composition.
[0037] Additional information regarding contacting an antimicrobial
agent with a medical device can be found in U.S. Pat. No.
5,624,704, herein specifically incorporated by reference in its
entirety. Additional information regarding antiseptic compositions
for coating medical devices can be found in U.S. Patent App. Pub.
Nos. 20050197634 and 20030078242, herein specifically incorporated
by reference in their entirety.
[0038] The present invention is also generally directed to a
medical device, personal product, or health care product coated
with an antimicrobial agent using any of the methods set forth
above. The medical device, personal product, food processing
supply, or health care product can be any of those items set forth
above. The antimicrobial agent can be any of those agents set forth
above and elsewhere in this specification.
[0039] The present invention also generally pertains to a method
for reducing the risk of development or progression of an infection
in a subject in need of a medical device, involving coating or
impregnating a surface of the medical device with an antimicrobial
agent in accordance with the method of claim 1 prior to contacting
the medical device with the subject, wherein the risk of
development or progression of an infection is reduced. The subject
can be any subject, such as a vertebrate. For example, the subject
may be a mammal. In particular embodiments, the mammal is a human.
For example, the human may be a subject in need of a medical
device.
[0040] The antimicrobial agent can be any of those agents discussed
above and elsewhere in this specification. As discussed above, the
antimicrobial agent may be an antibiotic, an antiseptic, an
antiviral agent, an antifungal agent, or a disinfectant. In
particular embodiments, the antibiotic is a tetracycline, a
macrocyclic antibiotic compound, or a combination thereof. For
example, the tetracycline may be minocycline. The macrocyclic
antibiotic may be a macrocyclic antibiotic such as rifampim,
rifampicin, or a combination thereof.
[0041] The infection can be any type of infection. Non-limiting
examples of types of infection include pneumonia, bacteremia,
fungimia, candidemia, a urinary tract infection, a catheter-exit
site infection, or a surgical wound infection. In particular
embodiments, the infection is a nosocomial infection. For example,
the infection may be an infection caused by methicillin-resistant
staphylococci, vancomycin-resistant enterococci, resistant
Pseudomonas aeruginosa, or a combination thereof. In some
embodiments, the infection is a fungal infection. For example, the
fungal infection may be an infection secondary to a Candida
species.
[0042] In some embodiments, the medical device has been contacted
with a composition comprising a basic reagent and a dye. The basic
reagent can be any of those reagents discussed above and elsewhere
in this specification. The dye can be any of those reagents
discussed above and elsewhere in this specification. In particular
embodiments, the dye is gentian violet, and the basic reagent is
chlorhexidine, clofoctol, chloroxylenol, or triclosan. Throughout
this application, the term "gendine" refers to a composition
comprising chlorhexidine and gentian violet, the term "genlosan"
refers to a composition comprising gentian violet and triclosan,
the term "genfoctol" refers to a composition comprising gentian
violet and clofoctol, and the term "genlenol" refers to a
composition comprising gentian violet and chloroxylenol.
[0043] The medical device can be any medical device known to those
of ordinary skill in the art, including any of those examples
discussed above. Non-limiting examples include an endotracheal
tube, a vascular catheter, an urinary catheter, a nephrostomy tube,
a biliary stent, a peritoneal catheter, an epidural catheter, a
central nervous system catheter, an orthopedic device, a prosthetic
valve, a silk suture, or a medical implant. In particular
embodiments, the medical device is a vascular catheter further
defined as a central venous catheter, an arterial line, an
pulmonary artery catheter, or a peripheral venous catheter. In
further embodiments, the medical device is a central nervous system
catheter, such as an intraventricular shunt.
[0044] An aspect of the present invention relates to a method for
coating a medical device with an antimicrobial composition
comprising: contacting said medical device with a solvent
comprising the antimicrobial composition, drying the medical device
and heating the medical device, wherein if the antimicrobial
composition does not comprise a basic reagent and a dye, then the
medical device is heated for at least about 12 hours. The
antimicrobial composition may be minocycline or rifampin.
[0045] In certain embodiments, the antimicrobial composition is an
antiseptic composition. The antiseptic may comprise a basic reagent
and a dye. The solvent may comprise water, methylene chloride,
alcohols (such as methanol and ethanol), ketones (such as acetone,
methylethylketone), esters (such as tetrahydrofuran), aldehydes
(such as formaldehyde), acetonitrile, acetic acid, methylene
chloride, chloroform, butyl acetate, or a combination thereof. The
medical device may be heated before, after or during contacting the
medical device with the solvent. In certain embodiments, the
medical device comprises a micropore or a nanopore. In certain
embodiments, the medical device is heated both before and after
contacting the medical device with the solvent.
[0046] The composition may include additional agents, such as
penetrating agents (i.e. agents used to promote impregnation of the
antimicrobial agent through the surface. Examples include esters
(e.g., ethyl acetate, propyl acetate, butyl acetate, amyl acetate,
and combinations therefore), ketones, methylene chloride, and
chloroform. The composition may also include one or more
alkalinizing agents (such as an organic or inorganic base such as
sodium hydroxide, potassium hydroxide, ammonia, diethylamine,
triethyleamine), and one or more high ionic strength salts, such as
sodium chloride, potassium chloride, or ammonium acetate.
[0047] The medical device may be heated to from about 40.degree. C.
to about 100.degree. C., more preferably from about 50.degree. C.
to about 80.degree. C. In certain embodiments, the medical device
is heated to about 60.degree. C. The medical device is heated for a
period of at least 30 minutes. In certain embodiments, the medical
device is heated for a period of time from about 12 hours to about
96 hours, more preferably from about 24 hours to about 96
hours.
[0048] In certain embodiments, the method further comprises washing
the medical device. The washing may be used to remove excessive
antiseptic composition. In certain embodiments, the medical device
is washed with a mild detergent and de-ionized water.
[0049] As used herein the specification and claim(s), the words "a"
or "an" when used in conjunction with the word "comprising" may
mean one or more.
[0050] Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0051] The use of the term "or" in the claims is used to mean
"and/or" unless explicitly indicated to refer to alternatives only
or the alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or."
[0052] As used herein the specification and claim(s), the words
"ionic bonding" or "ionically bound" refers to the electrostatic
interactions among ions which can be formed by the transfer of one
or more electrons from one atom or group of atoms to another, to
create an ionic bond between the basic reagent and the dye
comprising an antiseptic compound.
[0053] As used herein the specification and claim(s), the words
"covalent bonding" or "covalently bound" refers to the chemical
bond formed by the sharing of one or more pairs of electrons
between the basic reagent and the dye comprising an antiseptic
compound.
[0054] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0056] FIG. 1: Heating reduces Gendine leaching.
[0057] FIG. 2: Heating reduces bacteria (Pseudomonas aerugenosa)
adherence.
[0058] FIG. 3: Zones of inhibitions formed by Gendine coated PVC
endotracheal tubes in methicillin resistant Staphylococcus
aureus.
[0059] FIG. 4: Effects of heating on the leaching of Gendine from
coated polyurethane CVC.
[0060] FIG. 5: Adherence of bacteria to polyurethane CVC
surfaces.
[0061] FIG. 6: Zones of inhibitions formed by Gendine coated cook
polyurethane catheters in methicillin resistant Staphylococcus
aureus.
[0062] FIG. 7: Zones of inhibitions formed by Gendine coated cook
polyurethane catheters in Pseudamonas aeruginosa.
[0063] FIG. 8: Zones of inhibitions formed by Gendine coated cook
polyurethane catheters Candida parapsilosis.
[0064] FIG. 9: Effects of heating on the leaching of Gendine from
coated cook silicone urinary catheters.
[0065] FIG. 10: Adherence of bacteria to silicone urinary catheter
surfaces.
[0066] FIG. 11: Zones of inhibitions formed by Gendine coated cook
silicone urinary catheters in vancomycin resistant Enterococcus
(VRE).
[0067] FIG. 12: Zones of inhibitions formed by Gendine coated cook
silicone urinary catheters in E. coli.
[0068] FIG. 13: Zones of inhibitions formed by Gendine coated cook
silicone urinary catheters in Candida parapsilosis.
[0069] FIG. 14. Durability of Spectrum (unheated Mino-Rifampin
catheters) compared to heated mino-rifampin catheters over 12
weeks--tested against MRSA 4798.
[0070] FIG. 15. Durability of Spectrum compared to heated
Mino-Rifampin catheters over 12 weeks--tested against S. malto
5075.
[0071] FIG. 16. Durability of Spectrum compared to heated
Mino-Rifampin catheters over 12 weeks--tested against S. malto
4807.
[0072] FIG. 17. Durability of Spectrum compared to heated
Mino-Rifampin catheters over 12 weeks--tested against S. malto
4709.
[0073] FIG. 18. Adherent of biofilm to coated polymers.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0074] The present invention provides for novel methods of coating
or impregnating a surface with an antimicrobial agent. By way of
example, the inventors have found that coating a medical device
with a composition that includes an antimicrobial agent and a
solvent following by curing the medical device at a temperature of
greater than 40.degree. C. results in a decrease in staining
potential of the medical device, decrease in leaching of the
antimicrobial into tissue, and prolonged antimicrobial efficacy.
Medical devices, such as indwelling catheters, are used routinely
in hospitals on a diverse group of patients. A common cause of
failure of these medical devices is infection. Pathogens often
attach to and proliferate in such devices and eventually invade the
patient leading to nosocomial infections. Microorganisms usually
migrate along the surfaces of devices to invade sterile
environments, such as the bronchoalveolar space leading to
pneumonia, the bloodstream leading to bacteremia, or the urinary
bladder leading to urinary tract infections.
[0075] For example, in certain embodiments, the present invention
relates to the use of antiseptic compositions with broad-spectrum
activity against various nosocomial microorganisms, including
resistant bacteria and fungi. For example, the antiseptic
compositions are effective against resistant staphylococci,
vancomycin-resistant enterococci, resistant Pseudomonas aeruginosa
and Candida species. These antiseptics also have unique properties
that enable penetration/impregnation of various polymers, such as
polyvinyl chloride, polyethylene, silastic elastomers,
polytetrafluoroethylene, dacron, collodion, carboethane, nylon,
polymers used in the formation of endotracheal tubes, silicone and
polyurethane polymers used in the formation of vascular catheters
and surgical silk sutures. Thus, they are suitable for coating a
wide range of device surfaces.
[0076] The present invention provides safe antimicrobial-treated
surfaces wherein the coated or impregnated surface has a durability
that may last through the life-span of the device. For example,
with regard to medical devices, this significantly decreases
patient mortality and morbidity associated with the various
nosocomial infections such as nosocomial pneumonias, nosocomial
bacteremias, nosocomial urinary tract infections and nosocomial
surgical wound infections.
A. Antimicrobial Agents
[0077] For the purposes of this disclosure, the phrase "effective
amount" or "therapeutically effective amount" is defined as a
dosage sufficient to induce a microbicidal or microbistatic effect
upon the microbes contacted by the composition on a surface.
[0078] In some embodiments of the invention, the antimicrobial
agent is an antibacterial agent. While any antibacterial agent may
be used in the preparation of the instant antimicrobial solutions,
some non-limiting exemplary antibacterial agent(s) include those
classified as aminoglycosides, beta lactams, quinolones or
fluoroquinolones, macrolides, sulfonamides, sulfamethaxozoles,
tetracyclines, streptogramins, oxazolidinones (such as linezolid),
clindamycins, lincomycins, rifamycins, glycopeptides, polymxins,
lipo-peptide antibiotics, as well as pharmacologically acceptable
sodium salts, pharmacologically acceptable calcium salts,
pharmacologically acceptable potassium salts, lipid formulations,
derivatives and/or analogs of the above.
[0079] Each of these classes of antibacterial agents have different
mechanisms of action and are represented by several antibiotics a
discussion of which is presented below. However, the skilled
artisan will recognize that the invention is in no way limited to
the agents set forth here and that these agents are described
merely as examples.
[0080] The aminoglycosides are bactericidal antibiotics that bind
to the 30S ribosome and inhibit bacterial protein synthesis. They
are typically active against aerobic gram-negative bacilli and
staphylococci. Exemplary aminoglycosides that may be used in some
specific aspects of the invention include amikacin, kanamycin,
gentamicin, tobramycin, or netilmicin.
[0081] Beta lactams are a class of antibacterials that inhibit
bacterial cell wall synthesis. A majority of the clinically useful
beta-lactams belong to either the penicillin group (penam) or
cephalosporin (cephem) groups. The beta-lactams also include the
carbapenems (e.g., imipenem), and monobactams (e.g., aztreonam).
Inhibitors of beta-lactamase such as clavulanic acid and its
derivatives are also included in this category.
[0082] Non-limiting examples of the penicillin group of antibiotics
that may be used in the solutions of the present invention include
amoxicillin, ampicillin, benzathine penicillin G, carbenicillin,
cloxacillin, dicloxacillin, piperacillin, or ticarcillin, etc.
Examples of cephalosporins include ceftiofur, ceftiofur sodium,
cefazolin, cefaclor, ceftibuten, ceftizoxime, cefoperazone,
cefuroxime, cefprozil, ceftazidime, cefotaxime, cefadroxil,
cephalexin, cefamandole, cefepime, cefdinir, cefriaxone, cefixime,
cefpodoximeproxetil, cephapirin, cefoxitin, cefotetan etc. Other
examples of beta lactams include mipenem or meropenem which are
extremely active parenteral antibiotics with a spectrum against
almost all gram-positive and gram-negative organisms, both aerobic
and anaerobic and to which Enterococci, B. fragilis, and P.
aeruginosa are particularly susceptible.
[0083] Examples of beta lactamase inhibitors include clavulanate,
sulbactam, or tazobactam. In some aspects of the present invention,
the antibacterial solutions may comprise a combination of at least
one beta lactam and at least one beta lactamase inhibitor.
[0084] Macrolide antibiotics are another class of bacteriostatic
agents that bind to the 50S subunit of ribosomes and inhibit
bacterial protein synthesis. These drugs are active against aerobic
and anaerobic gram-positive cocci, with the exception of
enterococci, and against gram-negative anaerobes. Exemplary
macrolides include erythromycin, azithromycin, clarithromycin.
[0085] Quinolones and fluoroquinolones typically function by their
ability to inhibit the activity of DNA gyrase. Examples include
nalidixic acid, cinoxacin, trovafloxacin, ofloxacin, levofloxacin,
grepafloxacin, trovafloxacin, sparfloxacin, norfloxacin,
ciprofloxacin, moxifloxacin and gatifloxacin.
[0086] Sulphonamides are synthetic bacteriostatic antibiotics with
a wide spectrum against most gram-positive and many gram-negative
organisms. These drugs inhibit multiplication of bacteria by acting
as competitive inhibitors of p-aminobenzoic acid in the folic acid
metabolism cycle. Examples include mafenide, sulfisoxazole,
sulfamethoxazole, and sulfadiazine.
[0087] The tetracycline group of antibiotics include tetracycline
derivatives such as tigecycline which is an investigational new
drug (IND), minocycline, doxycycline or demeclocycline and analogs
such as anhydrotetracycline, chlorotetracycline, or
epioxytetracycline. The present inventors have previously shown
that minocycline has a higher penetration of the microbial biofilm
layer than vancomycin and that EDTA is unique in effectively
preventing and dissolving polysaccharide-rich microbial glycocalyx
(U.S. Pat. No. 5,362,754).
[0088] The streptogramin class of antibacterial agents is
exemplified by quinupristin, dalfopristin or the combination of two
streptogramins.
[0089] Drugs of the rifamycin class typically inhibit DNA-dependent
RNA polymerase, leading to suppression of RNA synthesis and have a
very broad spectrum of activity against most gram-positive and
gram-negative bacteria including Pseudomonas aeruginosa and
Mycobacterium species. An exemplary rifamycin is rifampicin.
[0090] Other antibacterial drugs are glycopeptides such as
vancomycin, teicoplanin and derivatives thereof. Yet other
antibacterial drugs are the polymyxins which are exemplified by
colistin.
[0091] In addition to these several other antibacterial agents such
as prestinomycin, chloramphenicol, trimethoprim, fusidic acid,
metronidazole, bacitracin, spectinomycin, nitrofurantion,
daptomycin or other leptopeptides, oritavancin, dalbavancin,
ramoplamin, ketolide etc. may be used in preparing the compositions
described herein. Of these, metronidazole is active only against
protozoa, such as Giardia lamblia, Entamoeba histolytica and
Trichomonas vaginalis, and strictly anaerobic bacteria.
Spectinomycin, is a bacteriostatic antibiotic that binds to the 30S
subunit of the ribosome, thus inhibiting bacterial protein
synthesis and nitrofurantoin is used orally for the treatment or
prophylaxis of UTI as it is active against Escherichia coli,
Klebsiella-Enterobacter species, staphylococci, and
enterococci.
[0092] In other embodiments, the antimicrobial agent is an
antifungal agent. Some exemplary classes of antifungal agents
include imidazoles or triazoles such as clotrimazole, miconazole,
ketoconazole, econazole, butoconazole, omoconazole, oxiconazole,
terconazole, itraconazole, fluconazole, voriconazole (UK 109,496),
posaconazole, ravuconazole or flutrimazole; the polyene antifungals
such as amphotericin B, liposomal amphoterecin B, natamycin,
nystatin and nystatin lipid formulation; the cell wall active
cyclic lipopeptide antifungals, including the echinocandins such as
caspofungin, micafungin, anidulfungin, cilofungin; LY121019;
LY303366; the allylamine group of antifungals such as terbinafine.
Yet other non-limiting examples of antifungal agents include
naftifine, tolnaftate, mediocidin, candicidin, trichomycin,
hamycin, aurefungin, ascosin, ayfattin, azacolutin, trichomycin,
levorin, heptamycin, candimycin, griseofulvin, BF-796, MTCH 24,
BTG-137586, pradimicins (MNS 18184), benanomicin; ambisome;
nikkomycin Z; flucytosine, or perimycin.
[0093] In still other embodiments of the invention, the
antimicrobial agent is an antiviral agent. Non-limiting examples of
antiviral agents include cidofovir, amantadine, rimantadine,
acyclovir, gancyclovir, pencyclovir, famciclovir, foscarnet,
ribavirin, or valcyclovir. In some embodiments the antimicrobial
agent is an innate immune peptide or proteins. Some exemplary
classes of innate peptides or proteins are transferrins,
lactoferrins, defensins, phospholipases, lysozyme, cathelicidins,
serprocidins, bacteriocidal permeability increasing proteins,
amphipathic alpha helical peptides, and other synthetic
antimicrobial proteins.
[0094] In other embodiments of the invention, the antimicrobial
agent is an antiseptic agent. Several antiseptic agents are known
in the art and these include a taurinamide derivative, a phenol, a
quaternary ammonium surfactant, a chlorine-containing agent, a
quinaldinium, a lactone, a dye, a thiosemicarbazone, a quinone, a
carbamate, urea, salicylamide, carbanilide, a guanide, an amidine,
an imidazoline biocide, acetic acid, benzoic acid, sorbic acid,
propionic acid, boric acid, dehydroacetic acid, sulfurous acid,
vanillic acid, esters of p-hydroxybenzoic acid, isopropanol,
propylene glycol, benzyl alcohol, chlorobutanol, phenylethyl
alcohol, 2-bromo-2-nitropropan-1,3-diol, formaldehyde,
glutaraldehyde, calcium hypochlorite, potassium hypochlorite,
sodium hypochlorite, iodine (in various solvents), povidone-iodine,
hexamethylenetetramine, noxythiolin, 1-(3-choroallyl)-3,5,7-triazo
1-azoniaadamantane chloride, taurolidine, taurultam,
N(5-nitro-2-furfurylidene)-1-amino-hydantoin, 5-nitro-2-furaldehyde
semicarbazone, 3,4,4'-trichlorocarbanilide,
3,4',5-tribromosalicylanilide,
3-trifluoromethyl-4,4'-dichlorocarbanilide, 8-hydroxyquinoline,
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecar-
boxylic acid,
1,4-dihydro-1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyli-
c acid, hydrogen peroxide, peracetic acid, phenol, sodium
oxychlorosene, parachlorometaxylenol,
2,4,4'-trichloro-2'-hydroxydiphenol, thymol, chlorhexidine,
benzalkonium chloride, cetylpyridinium chloride, silver
sulfadiazine, or silver nitrate.
B. Solvents
[0095] Non-limiting examples of solvents are set forth in Table 1.
TABLE-US-00001 TABLE 1 Examples of Solvents Name Structure water
H--OH methanol CH.sub.3--OH ethanol CH.sub.3CH.sub.2--OH 1-propanol
CH.sub.3CH.sub.2CH.sub.2--OH 1-butanol
CH.sub.3CH.sub.2CH.sub.2CH.sub.2--OH formic acid ##STR1## acetic
acid ##STR2## formamide ##STR3## ##STR4## ##STR5## acetone ##STR6##
tetrahydrofuran (THF) ##STR7## methyl ethyl ketone ##STR8## ethyl
acetate ##STR9## acetonitrile H.sub.3C--C.ident.N
N,N-dimethylformamide (DMF) ##STR10## diemthyl sulfoxide (DMSO)
##STR11## ##STR12## ##STR13## hexane
CH.sub.3(CH.sub.2).sub.4CH.sub.3 benzene ##STR14## diethyl ether
CH.sub.3CH.sub.2OCH.sub.2CH.sub.3 methylene chloride
CH.sub.2Cl.sub.2 carbon tetrachloride CCl.sub.4
C. Dyes
[0096] In some embodiments of the present invention, the surface is
contacted with a composition that includes a dye. A "dye" is
defined herein to refer to an agent that is used to impart color.
The dye may or may not have antimicrobial activity. In some
embodiments, the composition includes a dye and a basic reagent.
The dye may or may not be bonded to the basic reagent. The dye may
be ionically or covalently bonded to the basic reagent. The dye
bonded to the basic reagent may or may not have antimicrobial
activity
[0097] The dye may be obtained from any source known to those of
ordinary skill in the art. The dye may be obtained, for example,
from natural sources, from commercial sources, or may be chemically
synthesized.
[0098] The dyes that may be used to synthesize certain antiseptic
compounds of the invention include but are not limited to, gentian,
or crystal violet, ethyl violet, brilliant green, etc., and the
FD&C dyes such as Blue No. 1 and Green No. 3. In addition,
other dyes include the following FD&C and D&C colors: (1)
monoazo dyes such as, but not limited to, FD&C Yellow No. 5,
FD&C Yellow No. 6, (2) diazo dyes such as, but not limited to,
D&C Red No. 17, (3) indigoid dyes such as, but not limited to,
FD&C Blue No. 2, (4) xanthene (Fluorescein) dyes such as, but
not limited to, FD&C Red No. 3, (5) anthraquinone dyes such as,
but not limited to, D&C Green No. 6, (6) quinoline dyes such
as, but not limited to, D&C Yellow No. 1. An extensive list of
dyes and stains that may be employed is also provided in Table 1.
TABLE-US-00002 TABLE 1 The Color Index (C.I.) Number and/or
Chemical Abstracts Service Registry CAS) Number for Selected Dyes
and Stains: No. C.I. # CAS # 1 15670 2092-55-9 2 26370 3071-73-6 3
20460 5850-35-1 4 62130 2666-17-3 5 61585 4474-24-2 6 26360
3351-05-1 7 62058 6397-02-0 8 42685 3244-88-0 9 61580 6408-57-7 10
15575 5850-86-2 11 22870 15792-50-4 12 18050 3734-67-6 13 14900
4787-93-3 14 18070 12167-45-2 15 22890 10169-02-5 16 23635
6459-94-5 17 18800 6408-31-7 18 18055 4321-69-1 19 18965 6359-98-4
20 18900 6359-91-7 21 25135 13390-47-1 22 22910 6375-5-9 23 18850
6359-88-2 24 .sup. 46005:1 494-38-2 25 8048-52-0 26 58000 72-48-0
27 3952-78-1 28 61710 6408-63-5 29 42750 30586-13-1 30 569-58-4 31
52417-22-8 32 520-10-5 33 48035 3056-93-7 34 4431-00-9 35 50090
25360-72-9 36 52010 531-55-5 37 61111 12217-43-5 38 42500 569-61-9
39 11460 42373-04-6 40 23500 992-59-6 41 298-95-3 42 21010
5421-66-9 43 1871-22-3 44 28440 2519-30-4 45 42660 6104-59-2 46
27290 5413-75-2 47 24890 3051-11-4 48 76-60-8 49 115-40-2 50
115-39-9 51 65005 1328-24-1 52 62055 6408-78-2 53 62125 6424-85-7
54 63010 2861-02-1 55 13390 3861-73-2 56 26400 3529-01-9 57 15706
12392-64-2 58 61570 4403-90-1 59 62560 4430-16-4 60 26550 8003-88-1
61 18745 10127-27-2 62 14710 5858-39-9 63 17045 6360-07-2 64 15620
1658-56-6 65 18110 6844-74-2 66 26900 6406-56-0 67 18125 10130-48-0
68 42650 4129-84-4 69 18835 6359-85-9 70 18890 6359-90-6 71 18950
6372-96-9 72 14170 6408-90-8 73 13900 10343-58-5 74 46025 135-49-9
75 12840 61968-76-1 76 63615 1324-21-6 77 58005 130-22-3 78 14025
584-42-9 79 42080 3486-30-4 80 16185 915-67-3 81 42780 82 1668-00-4
83 41000 2465-27-2 84 43810 13186-45-3 85 52005 531-53-3 86 51004
33203-82-6 87 11075 94233-04-2 88 42510 632-99-5 89 48055 4208-80-4
90 26905 4196-99-0 91 2315-97-1 92 21000 10114-58-6 93 16180
5858-33-3 94 42655 6104-58-1 95 81029-05-2 96 42040 633-03-4 97
102185-52-4 98 62625-32-5 99 62625-30-3 100 62625-28-9 101
14337-53-2 102 76-59-5 103 40070-59-5 104 3147-14-6 105 24410
2610-05-1 106 43825 1667-99-8 107 16575 548-80-1 108 43820
3564-18-9 109 24895 2870-32-8 110 18972 50662-99-2 111 596-27-0 112
2303-01-7 113 1733-12-6 114 10510-54-0 115 15970 1934-20-9 116
15391-59-0 117 76-54-0 118 4727-50-8 119 54-88-6 120 6473-13-8 121
23655 6420-03-7 122 25380 2829-43-8 123 27905 5489-77-0 124 13950
10190-68-8 125 29025 3214-47-9 126 64500 2475-45-8 127 61500
2475-44-7 128 1005 730-40-5 129 31482-56-1 130 11115 3180-81-2 131
11855 2832-40-8 132 26090 6300-37-4 133 45400 548-24-3 134 45380
548-26-5 135 15086-94-9 136 14640 3564-14-5 137 42090 3844-45-9 138
.sup. 45430:2 15905-32-5 139 45386 6359-05-3 140 76058-33-8 141
23860 314-13-6 142 11160 97-56-3 143 13015 2706-28-7 144 11285
6416-57-5 145 .sup. 45350:1 2321-07-5 146 596-09-8 147 3326-34-9
148 51030 1562-85-2 149 1634-82-8 150 3737-95-9 151 165660-27-5 152
16574-43-9 153 34722-90-2 154 617-19-6 155 51050 1562-90-9 156
4430-20-0 157 14720 3567-69-9 158 16570 4197-07-3 159 11270
532-82-1 160 18105 17681-50-4 161 22120 573-58-0 162 2411-89-4 163
62625-31-4 164 62625-29-0 165 41830-80-2 166 42555 548-62-9 167
.sup. 45370:1 596-03-2 168 620-45-1 169 .sup. 45425:1 31395-16-1
170 73688-85-4 171 34140 4399-55-7 172 29160 3441-14-3 173 28160
2610-11-9 174 13920 10130-29-7 175 19556 6537-66-2 176 36900
6409-90-1 177 61505 2475-46-9 178 11080 2581-69-3 179 26080
6253-10-7 180 11110 2872-52-8 181 11130 2734-52-3 182 12790
6439-53-8 183 518-82-1 184 56360-46-4 185 .sup. 45380:2 15086-94-9
186 14645 1787-61-7 187 18760 3618-63-1 188 45430 568-63-8 189
1239-45-8 190 62758-12-7 191 42600 2390-59-2 192 37190 64071-86-9
193 42053 2353-45-9 194 12010 6535-42-8 195 18820 6359-82-6 196
45350 518-47-8 197 3326-32-7 198 51649-83-3 199 42085 4680-78-8 200
75290 517-28-2 201 90-33-5 202 73000 482-89-3 203 73015 860-22-0
204 12210 4569-88-4 205 11050 2869-83-2 206 44090 3087-16-9 207
42000 2437-29-8 208 13065 587-98-4 209 52041 2516-05-4 210 45385
23391-49-3 211 13025 547-58-0 212 32469-43-5 213 14855 3624-68-8
214 11335 6247-27-4 215 11880 6370-46-3 216 11300 6232-53-7 217
26520 3564-27-0 218 18735 1934-24-3 219 14010 6054-99-5 220 44530
5715-76-4 221 11350 131-22-6 222 16255 2611-82-7 223 52030
6586-05-6 224 7385-67-3 225 74-39-5 226 60760 6409-77-4 227 26120
4477-79-6 228 16230 1936-15-8 229 15705 2538-85-4 230 19010
10127-05-6 231 42045 129-17-9 232 34487-61-1
233 101-75-7 234 11800 1689-82-3 235 45410 18472-87-2 236 16680
1058-92-0 237 27190 6226-78-4 238 49000 30113-37-2 239 16593-81-0
240 85531-30-2 241 45005 92-32-0 242 58500 81-61-8 243 47000
8003-22-3 244 20505 17095-24-8 245 61205 13324-20-4 246 17908
25489-36-5 247 635-78-9 248 45170 81-88-9 249 45160 989-38-8 250
45440 632-69-9 251 50240 477-73-6 252 61552 6994-46-3 253 7423-31-6
254 3599-32-4 255 146-68-9 256 42095 5141-20-8 257 .sup. 42000:1
510-13-4 258 129-16-8 259 52015 61-73-4 260 50206 4569-86-2 261
42590 7114-03-6 262 13020 493-52-7 263 11020 60-11-7 264 20110
3564-15-6 265 11875 6247-28-5 266 13250 3618-62-0 267 14030
2243-76-7 268 26560 6406-37-7 269 6408-91-9 270 14045 6470-98-0 271
20470 1064-48-8 272 50040 553-24-2 273 42520 3248-91-7 274 51180
3625-57-8 275 14890 5423-07-4 276 56431-61-9 277 61555 2646-15-3
278 26125 1320-06-5 279 15510 633-96-5 280 15711 5610-64-0 281
12070 6410-10-2 282 143-74-8 283 11000 60-09-3 284 16201-96-0 285
975-17-7 286 2768-90-3 287 27195 6226-79-5 288 67627-18-3 289 58205
81-54-9 (75410) 290 115-41-3 291 45010 2150-48-3 292 117-92-0 293
58050 81-64-1 294 47005 8004-92-0 295 61211 12236-82-7 296 17757
12225-82-1 297 61200 2580-78-1 298 123333-76-6 299 .sup. 45170:1
509-34-2 300 13161-28-9 301 43800 603-45-2 302 61554 17354-14-2 303
61565 128-80-3 304 12055 842-07-9 305 12140 3118-97-6 306 26105
85-83-6 307 11920 2051-85-6 308 123359-42-2 309 23647-14-5 310
45100 3520-42-1 311 19140 1934-21-0 312 108321-10-4 313 62637-91-6
314 6262-21-1 315 632-73-5 316 42798-98-1 317 19540 1829-00-1 318
52000 78338-22-4 319 81012-93-3 320 123359-43-3 321 12120 2425-85-6
322 23850 72-57-1 323 44045 2580-56-5 324 42595 2390-60-5 325
125-31-5 326 16150 3761-53-3 327 135-52-4 328 26100 85-86-9 329
26150 4197-25-5 330 26050 6368-72-5 331 68504-35-8 332 123333-78-8
333 45220 5873-16-5 334 4430-25-5 335 1301-20-8 336 123333-63-1 337
386-17-4 338 4430-24-4 339 1719-71-7 340 49005 2390-54-7 341
76-61-9 342 125-20-2 343 52040 92-31-9 344 14270 547-57-9 345
14541-90-3 346 44040 2185-86-6 347 45190 6252-76-2 348 63721-83-5
349 14936-97-1 350
D. Basic Reagents
[0099] Some embodiments of the present invention involve contacting
a surface, such as a medical device, with a composition that
includes a basic reagent. Any basic reagent known to those of
ordinary skill in the art is contemplated. For example, the basic
reagents can be alkyl and aryl oxides, thiols, sulfides,
phosphorous, aliphatic and aromatic amines, guanidines and halides
such as F.sup.-, Br.sup.- and I.sup.-. Some examples of the basic
reagents that can be used include phenoxide antiseptics (such as
clofoctol, chloroxylenol, triclosan) or guanidium compounds (such
as chlorhexidine, alexidine, hexamidine) or bipyridines (such as
octenidines).
[0100] Other examples include a guanidium compound, a biguanide, a
bipyridine, a phenoxide antiseptic, an alkyl oxide, an aryl oxide,
a thiol, a halide, an aliphatic amine, or an aromatic amine.
Non-limiting examples of guanidium compounds include chlorhexidine,
alexidine, hexamidine. In other specific embodiments, the basic
reagent is a bipyridine. One example of a bipyridine is octenidine.
In yet other aspects, the basic reagent is a phenoxide
antiseptic.
E. Antiseptics
[0101] In some embodiments set forth herein, the antimicrobial is
an antiseptic. The composition that includes an antiseptic agent
may be applied to the surface by any method known to those of
ordinary skill in the art. For example, if the surface is a surface
of a medical device the device may be immersed in the composition,
or the composition may be painted or sprayed onto the device. The
composition may include a dye, as set forth above. The
self-impregnating property of the dyes such as for example, the
triarylmethane dyes, removes the need for another binding agent.
This is another feature of the composition provided by this
invention which is a considerable improvement over certain other
known compositions. Certain previously known compositions require
other impregnating/coating agents and/or must typically be extruded
into the device as it is made. Both these methods are time
consuming and involve additional steps and techniques.
[0102] For example, one method of coating devices first requires
application or absorption of a layer of surfactant, such as
tridodecylmethyl ammonium chloride (TDMAC) followed by the
antibiotic coating layer, to the surface of the medical device.
Another method used to coat surfaces of medical devices with
antibiotics involves first coating the selected surfaces with
benzalkonium chloride followed by ionic bonding of the antibiotic
composition (Solomon and Sherertz, 1987; U.S. Pat. No. 4,442,133).
Other methods of coating surfaces of medical devices with
antibiotics are taught in U.S. Pat. No. 4,895,566 (a medical device
substrate carrying a negatively charged group having a pH of less
than 6 and a cationic antibiotic bound to the negatively charged
group); U.S. Pat. No. 4,917,686 (antibiotics are dissolved in a
swelling agent which is absorbed into the matrix of the surface
material of the medical device); U.S. Pat. No. 4,107,121
(constructing the medical device with ionogenic hydrogels, which
thereafter absorb or ionically bind antibiotics); U.S. Pat. No.
5,013,306 (laminating an antibiotic to a polymeric surface layer of
a medical device); and U.S. Pat. No. 4,952,419 (applying a film of
silicone oil to the surface of an implant and then contacting the
silicone film bearing surface with antibiotic powders).
Furthermore, most of the methods previously employed to coat the
surfaces of medical devices use antibiotics such as tetracyclines,
penicillins, cephalosporins and the beta-lactam antibiotics. The
main drawback with antibiotics is the emergence of resistant
strains.
[0103] In certain embodiments, antiseptic derivative compounds with
broad-spectrum antiseptic activity against bacteria and fungi
including nosocomial and multidrug-resistant varieties may be used
to impregnate, bind, coat, adhere and/or attach to various device
surfaces without the assistance of impregnating vehicles such as
tridodecylmethylammonium chloride (TDMAC). Furthermore, antiseptic
compounds of the invention also have an extended antimicrobial
efficacy that can cover the life of the device.
[0104] One example of the a broad-spectrum antiseptic is a
composition that includes a combination of gentian violet and
chlorhexidine ("Gendine"). Gentian violet, on its own, is a good
impregnating triarylmethane dye. Bhatnager et al., 1993 have shown
in an in vitro study that gentian violet alone can be used to
impregnate the surface of CSF silicone shunts and prevent the
colonization of S. epidermis on these surfaces. However, after
impregnating the surfaces of various polymers, including
polyvinylchloride, gentian violet on its own has no activity
against Pseudomonas aeruginosa, which is the second most common
cause of nosocomial pneumonia and the third most common cause of
nosocomial urinary tract infections. Antiseptics such as
chlorhexidine cannot attach on their own onto the surfaces of
polyvinylchloride tubes or silicone catheters and silk sutures.
They require an impregnating vehicle. Furthermore, on their own
they are not highly active against Pseudomonas aeruginosa. On the
other hand, upon the binding of gentian violet with chlorhexidine,
the new antiseptic agent synthesized, is a potent and effective
broad-spectrum antiseptic and has the additional ability to
coat/impregnate various device surfaces. Gendine is unique in its
ability to impregnate various device polymers, such as
polyvinylchloride used in the formation of endotracheal tubes,
silicone and polyurethane polymers used in the formation of
vascular, as well as peritoneal, epidural, urinary and
intraventricular catheters. In addition, gendine is able to
impregnate the silk sutures used in surgical wounds.
[0105] Compositions with antiseptic properties that are
specifically contemplated for use in the invention include, but are
not limited to Gendine, Genlenol and Genfoctol.
F. Microorganisms
[0106] In some embodiments, the methods set forth herein pertain to
methods of reducing the risk of development or progression of an
infection in a subject. For example, the subject may be a subject
in need of a medical device. The infection to be prevented may be,
for example bacteremia, pneumonia, meningitis, osteomyelitis,
endocarditis, sinusitis, arthritis, urinary tract infections,
tetanus, gangrene, colitis, acute gastroenteritis, bronchitis, an
abscess, an opportunistic infection, or a nosocomial infection.
Examples of bacterial pathogens include Gram-positive cocci such as
Staphylococcus aureus, coagulase negative staphylocci such as
Staphylococcus epidermis, Streptococcus pyogenes (group A),
Streptococcus spp. (viridans group), Streptococcus agalactiae
(group B), S. bovis, Streptococcus (anaerobic species),
Streptococcus pneumoniae, and Enterococcus spp.; Gram-negative
cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, and
Branhamella catarrhalis; Gram-positive bacilli such as Bacillus
anthracis, Corynebacterium diphtheriae and Corynebacterium species
which are diptheroids (aerobic and anerobic), Listeria
monocytogenes, Clostridium tetani, Clostridium difficile,
Escherichia coli, Enterobacter species, Proteus mirablis and other
spp., Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella,
Shigella, Serratia, and Campylobacter jejuni. The antibiotic
resistant bacteria that can be killed by the antiseptic coated
devices of the present invention include Staphylococci
(methicillin-resistant strains), vancomycin-resistant enterococci
(Enterococcus faecium), and resistant Pseudomonas aeruginosa.
[0107] Fungal infections may have cutaneous, subcutaneous, or
systemic manifestations. Superficial mycoses include tinea capitis,
tinea corporis, tinea pedis, onychomycosis, perionychomycosis,
pityriasis versicolor, oral thrush, and other candidoses such as
vaginal, respiratory tract, biliary, eosophageal, and urinary tract
candidoses. Systemic mycoses include systemic and mucocutaneous
candidosis, cryptococcosis, aspergillosis, mucormycosis
(phycomycosis), paracoccidioidomycosis, North American
blastomycosis, histoplasmosis, coccidioidomycosis, and
sporotrichosis. Fungal infections include opportunistic fungal
infections, particularly in immunocompromised patients such as
those with AIDS. Fungal infections contribute to meningitis and
pulmonary or respiratory tract diseases.
[0108] Other pathogenic organisms include dermatophytes
(Microsporum canis and other M. spp.; and Trichophyton spp. such as
T. rubrum, and T. mentagrophytes), yeasts (e.g., Candida albicans,
C. Parapsilosis, C. glabrata, C.Tropicalis, or other Candida
species including drug resistant Candida species), Torulopsis
glabrata, Epidermophyton floccosum, Malassezia fuurfur
(Pityropsporon orbiculare, or P. ovale), Cryptococcus neoformans,
Aspergillus fumigatus, and other Aspergillus spp., Zygomycetes
(Rhizopus, Mucor), hyalohyphomycosis (Fusarium Spp.),
Paracoccidioides brasiliensis, Blastomyces dermatitides,
Histoplasma capsulatum, Coccidioides immitis, and Sporothrix
schenckii. Other examples include Cladosporium cucumerinum,
Epidermophyton floccosum, and Microspermum ypseum.
G. Medical Devices
[0109] Non-limiting examples of medical devices are set forth
herein. These include vascular devices such as grafts (e.g.,
abdominal aortic aneurysm grafts, etc.), stents, catheters
(including arterial, intravenous, blood pressure, stent graft,
etc.), valves (e.g., polymeric or carbon mechanical valves,),
embolic protection filters (including distal protection devices),
vena cava filters, aneurysm exclusion devices, artificial hearts,
cardiac jackets, and heart assist devices (including left ventricle
assist devices), implantable defibrillators, electro-stimulation
devices and leads (including pacemakers, lead adapters and lead
connectors), implanted medical device power supplies, peripheral
cardiovascular devices, atrial septal defect closures, left atrial
appendage filters, valve annuloplasty devices, mitral valve repair
devices, vascular intervention devices, ventricular assist pumps,
and vascular access devices (including parenteral feeding
catheters, vascular access ports, central venous access catheters);
surgical devices such as sutures of all types, anastomosis devices
(including anastomotic closures), suture anchors, hemostatic
barriers, screws, plates, clips, vascular implants, tissue
scaffolds, cerebro-spinal fluid shunts, shunts for hydrocephalus,
drainage tubes, catheters including thoracic cavity suction
drainage catheters, abscess drainage catheters, biliary drainage
products, and implantable pumps; orthopedic devices such as joint
implants, acetabular cups, patellar buttons, bone
repair/augmentation devices, spinal devices (e.g., vertebral disks
and the like), bone pins, cartilage repair devices, and artificial
tendons; dental devices such as dental implants and dental fracture
repair devices; drug delivery devices such as drug delivery pumps,
implanted drug infusion tubes, drug infusion catheters, and
intravitreal drug delivery devices; ophthalmic devices such as
scleral buckles and sponges, glaucoma drain shunts and intraocular
lenses; urological devices such as penile devices (e.g., impotence
implants), sphincter, urethral, prostate, and bladder devices
(e.g., incontinence devices, benign prostate hyperplasia management
devices, prostate cancer implants, etc.), urinary catheters
including indwelling ("Foley") and non-indwelling urinary
catheters, and renal devices; synthetic prostheses such as breast
prostheses and artificial organs (e.g., pancreas, liver, lungs,
heart, etc.); respiratory devices including lung catheters;
neurological devices such as neurostimulators, neurological
catheters, neurovascular balloon catheters, neuro-aneurysm
treatment coils, and neuropatches, splints, nasal tampons, ear
wicks, ear drainage tubes, tympanostomy vent tubes, otological
strips, laryngectomy tubes, esophageal tubes, esophageal stents,
laryngeal stents, salivary bypass tubes, and tracheostomy tubes;
oncological implants; and pain management implants.
[0110] Classes of suitable non-implantable devices can include
dialysis devices and associated tubing, catheters, membranes, and
grafts; autotransfusion devices; vascular and surgical devices
including atherectomy catheters, angiographic catheters,
intraaortic balloon pumps, intracardiac suction devices, blood
pumps, blood oxygenator devices (including tubing and membranes),
blood filters, blood temperature monitors, hemoperfusion units,
plasmapheresis units, transition sheaths, dialators, intrauterine
pressure devices, clot extraction catheters, percutaneous
transluminal angioplasty catheters, electrophysiology catheters,
breathing circuit connectors, stylets (vascular and non-vascular),
coronary guide wires, peripheral guide wires; dialators (e.g.,
urinary, etc.); surgical instruments (e.g. scalpels and the like);
endoscopic devices (such as endoscopic surgical tissue extractors,
esophageal stethoscopes); and general medical and medically related
devices including blood storage bags, umbilical tape, membranes,
gloves, surgical drapes, wound dressings, wound management devices,
needles, percutaneous closure devices, transducer protectors,
pessary, uterine bleeding patches, PAP brushes, clamps (including
bulldog clamps), cannulae, cell culture devices, materials for in
vitro diagnostics, chromatographic support materials, infection
control devices, colostomy bag attachment devices, birth control
devices; disposable temperature probes; and pledgets.
H. EXAMPLES
[0111] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
Example 1
Method of Coating Medical Device Results in Superior Properties
Materials and Methods
[0112] Preparation of pieces. Gendine was prepared as described in
U.S. Patent App. Pub. No. 20030078242. One-centimeter segments of
endotracheal tube (ETT) made of polyvinylchloride (PVC-ETT) and
urinary catheter (UC) made of silicone (SilUC) and central venous
catheter (CVC) made of polyurethane (CVC-PU) were dipped into the
Gendine solution, so that both internal and external surfaces were
coated. The pieces were left to dry overnight, at 60.degree. C. The
pieces were then washed using mild detergent and de-ionized water
to remove any possible loosely attached antiseptic off the surface
of the coated segments. Some of the pieces were then left to dry
for and additional 48 hours at a temperature of 60.degree. C.
[0113] Absorbance and Quantitation of Leaching. To determine
leaching of the dye, sets of standards with known concentrations of
Gentian violet were made in each biological fluid (bronchoalveolar
lavage, plasma, and artificial urine). Absorbances were read for
each of the standards and a standard curve was plotted. Absorbances
were also read from 200 .mu.L biological fluids of each coated
segments. Quantitation of leaching (in .mu.g/L) was derived from
the regression line in the standard curve. Unknown absorbances were
read at 550 nm and then figured into the standard curve equation to
determine amount of leaching in .mu.g/L.
[0114] Adherence testing. The inventors evaluated bacterial
adherence to the surface of Gendine-coated and control uncoated
segments, as well as that of silver hydrogel urinary catheter and
other antiinfective approved CVC, such as the antibiotic-coated CVC
(Spectrum, Cook Critical Care, Bloomington, Ind.--coated with
minocycline and rifampin), CVC coated with chlorhexidine/silver
sulfadiazine (Arrow Guard Plus, Arrow, Reading, Pa.) and
silver/platinum CVC (Edwards, Edwards Life Sciences, Irvine,
Calif.). Six segments of each device were tested per organism. A
modification of a previously published method for testing adherence
and biofilm formation on silicone disks was used (Chaiban et al.,
2005).
[0115] The sterile device segments were placed into sterile 5 mL
snap top tubes containing 1 mL of plasma. The tubes were then
placed into the incubator for 24 hours at 37.degree. C. The plasma
was then removed from the tubes, leaving the pieces inside the
tubes, and was replaced with 1 mL of Mueller Hinton Broth (MHB),
that was inoculated with bacteria. The inoculum was prepared as
follows: Five colonies of freshly subbed bacteria were placed in 50
mLs of MHB (0.5 McFarland, approximately 1.3.times.108 CFU/mL), and
used immediately. The tubes were then placed in the incubator for
24 hours at 37.degree. C. The MHB was then removed and replaced
with 1 mL of 0.9% saline solution and the tube was placed in the
37.degree. C. incubator for 30 minutes as a washing step. The
catheter segments were then removed from the washing saline, and
placed into sterile 15 mL tubes containing 5 mLs of 0.9% sterile
saline solution and sonicated for 15 minutes. After sonication, the
tubes containing the catheters were vortexed for 60 seconds. A 100
.mu.L volume of the sample was pipetted and spread onto a
trypticase soy agar plate with 5% sheep blood (this was the 1:50
dilution). The plates were placed in the incubator for 24 hours,
and then the colonies were counted. A value of 100 CFU was used for
any plate that had at least 100 counted colonies.
[0116] Zones of inhibition and antimicrobial durability. Using a
modified Kirby-Bauer method, baseline antimicrobial activity was
assessed by measuring the zones of inhibition created by duplicates
of impregnated segments that were vertically embedded in Mueller
Hinton agar plates coated with one of the following organisms:
Methicillin-resistant staphylococcus aureus (MRSA), C. albicans, C.
parapsilosis, Vancomycin-resistant Enterococci (VRE), P.
aeruginosa, and E. coli. The zones of inhibition were measured and
recorded as the diameter (mm) across the center of the embedded
segments.
[0117] The antimicrobial durability of Gendine-coated ETT
(GND-ETT), Gendine-coated UC (GND-UC) and Gendine-coated CVC
(GND-CVC) segments was assessed over time by testing zones of
inhibitions of segments soaked in body fluids. The antimicrobial
durability of that GND-CVC was compared with other anti-infective
CVC described above (Arrow Guard Plus, Edwards and Spectrum). The
segments were placed in sterile 50 mL polystyrene tubes (Falcon),
containing 10 mL sterile bronchoalveolar lavage (ETT) or urine
(UC), or serum (CVC), respectively, and were incubated at
37.degree. C. The 10 mL volume was used to ensure the complete
immersion of all of the pieces contained in the tube. Segments were
tested in duplicates at weekly intervals, as the soaking fluids
were replaced with fresh fluids. Zones of inhibition were
determined using the modified Kirby-Bauer method against the same
organisms mentioned above.
[0118] Abbreviations. MRSA (bacteria)=multidrug-resistant
Staphylococcus aureus. PS (bacteria)=Pseudomonas aeruginosa. EC
(bacteria)=Escherichia coli. VRE (bacteria)=vancomycin-resistant
Enterococcus. CA (fungi)=Candida albicans.
Results
[0119] Endotracheal Tubes (ETT). As shown in FIG. 1, heating of the
Gendine-coated ETT decreased leaching of the antiseptic dye
(Gendine) progressively and substantially (P<0.01). More than
three-fold decrease in leaching of Gendine was quantitatively noted
after three days of heating (Gendine H3) and by more than two-fold
after one day of heating (Gendine H1). Furthermore, heating of the
Gendine-coated ETT improved anti-infective anti-adherence effect of
the Gendine-coated ETT against multidrug-resistant Pseudomonas
aeruginosa as shown in FIG. 2. This improvement was significant
(P<0.001) after one day of heating (Gendine H1) and three days
of heating (Gendine H3). Heating did not compromise the
antimicrobial durability of the Gendine-coated ETT against MRSA
through the series of zones of inhibitions performed. This high
level of antimicrobial durability was hence maintained as shown in
FIG. 3.
[0120] Central Venous Catheters (CVC). As shown in FIG. 4 below,
heating progressively decreased the leaching of Gendine-coated CVC
into the serum (P<0.05). Heating of Gendine-coated CVC for one
day (Gendine H1) resulted in almost 1.6-fold decrease in leaching
whereas three days of heating (Gendine H3) was associated with
3.5-fold decrease leaching into the serum when compared to unheated
Gendine-coated CVC. Furthermore, as shown in FIG. 5, three-day
heating of Gendine-coated CVC (Gendine H3) maintained a
significantly improved anti-adherence effect of multidrug-resistant
bacteria, such as Pseudomonas aeruginosa and MRSA when compared
with uncoated CVC or other antimicrobial CVC, such as the spectrum
coated with antibiotics (minocycline and rifampin) or Arrow Guard
(coated with chlorhexidine and silver sulfadiazine) or the Edwards
catheter (with electric silver and platinum ions) (p<0.04).
Three day heating (Gendine H3) also maintained a significantly
superior anti-adherence effect compared to uncoated CVC with the
Spectrum and the Edwards catheter against fungi, (p<0.02) such
as Candida albicans and Candida parapsilosis, which are known to be
associated with catheter-related candidemia (FIG. 5). In addition,
the heating of Gendine-coated CVC (Gendine H1 and Gendine H3)
continued to maintain a superior antimicrobial durability against
MRSA, multidrug-resistant Pseudomonas aeruginosa and Candida
parapsilosis when compared to other antimicrobial catheters, such
as the Spectrum, Arrow Guard and Edwards, as shown in FIG. 6, FIG.
7 and FIG. 8.
[0121] Urinary Catheters (UC). FIG. 9 shows that heating of
Gendine-coated UC (Gendine H1 and Gendine H3) progressively and
substantially decreased leaching (P<0.001). The one-day heating
(Gendine H1) decreased the leaching of silicone UC by 1.6-fold,
whereas the three-day heating (Gendine H3) decreased the leaching
into urine of the Gendine by 2.5-fold. Furthermore, as shown below,
heating of Gendine-coated UC (Gendine H3-UC) maintained a
significantly (P.ltoreq.0.025) improved anti-adherence effect,
compared to unocated to uncoated urinary catheters or silver-coated
UC against two isolates of multidrug-resistant Pseudomonas and two
isolates of E. coli (FIG. 10). It should be noted that the
silver-coated UC has been shown effective in decreasing bacteruria
clinically. In addition, as shown in FIG. 11, FIG. 12 and FIG. 13,
heating of Gendine-coated silicone UC maintained a high level of
antimicrobial durability over a 56-day period against
vancomycin-resistant Enterococci (VRE), resistant E. coli and
Candida parapsilosis tested through zones of inhibtion and
urine.
[0122] Heating of Gendine-coated ETT was associated with a
significant decrease in leaching into bronchoalveolar lavage
(p<0.05) and a significant improvement in the
anti-adherence/antimicrobial activity of Gendine-coated ETT against
multidrug-resistant Pseudomonas aeruginosa (p<0.001). The high
level of antimicrobial durability of Gendine-coated ETT against
methicillin resistant staphylococcus aureus (MRSA) was maintained
through heating.
[0123] Heating of Gendine-coated CVC was progressively and
substantially associated with decreased leaching of this antiseptic
dye into serum while maintaining a significant anti-adherence
activity against resistant bacteria and fungi compared to other
antimicrobial catheters on the market. Furthermore, the
antimicrobial durability of the heated Gendine-coated CVC was
maintained in a superior fashion to other antimicrobial catheters
placed in serum.
[0124] The heating of silicone UC coated with Gendine was
associated with a progressive and substantial decrease of this
antiseptic dye into urine while maintaining a significantly
superior anti-adherence/antimicrobial activity against
Multidrug-resistant gram-negative bacteria, such as Pseudomonas
aeruginosa and E. coli compared to the only available
anti-infective urinary catheter on the market, which is the silver
hydrogel-coated Bard UC. Furthermore the high level of
antimicrobial durability of Gendine-coated UC was maintained
through heating for up to 56 days against fungi, such AS Candida
parapsilosis, multidrug-resistant organisms, such as VRE and E.
coli.
[0125] All medical devices coated with antiseptic dyes or
antiseptic/antimicrobial agents including.
Example 2
Studies Demonstrating that Heating Enhances the Durability of
Antimicrobial Efficacy and Adherence of Biofilm to
Minocycline/Rifampin-Coated and Heated Silicone and CVCs
Materials and Method
[0126] Antimicrobial coating procedure. Constantly stirring, 450 mg
of NaOH was dissolved in a beaker containing 45 mL of methanol
heated to 45.degree. C. Once completely dissolved, 4.5 g of
minocycline was added to the solution in small aliquots over 15
minutes and stirred until completely dissolved. Then, 9 g of
rifampin were added to the solution in small aliquots over 15
minutes. Solution was stirred at 45.degree. C. until completely
clear. Finally 255 mL of prewarmed (45.degree. C.) butyl acetate
was added to the solution and stirred until thoroughly mixed.
[0127] Whole catheters (Cook silicone CVC) were coated for 1 hour
at 45.degree. C. Catheters were removed and allowed to dry for 1
day as described below.
[0128] 1 day heating--Dried at 60.degree. C. overnight (14-24
hours). Washed twice (ddH.sub.2O, ddH.sub.2O+detergent for 1 minute
then dried for an additional 4 hours at 60.degree. C. After drying,
the catheters were cut into 0.5 cm segments for in vitro durability
and adherence testing. Uncoated catheters and commercially
available Spectrum catheters (coated catheters which were not
heated) were also tested for comparison.
[0129] Efficacy and Durability of antiseptic activity in Coated
CVCs. Using the modified Kirby-Bauer method, coated catheter
segments were vertically inserted in agar plates inoculated with a
0.5 McFarland dilution of microorganisms. Organisms to be tested
against included: [0130] 1. methicillin resistant Staphlococcus
aureus (MRSA 4978)--clinical isolate [0131] 2. Stenotrophomonas
maltophilia (5075, 4709, 4807)--catheter site isolate
[0132] Plates were incubated overnight then zones of inhibition
(ZOI) were measured in millimeters (mm). Remaining coated segments
were incubated in donor calf serum. Weekly segments were removed
for durability testing and the donor calf serum was replaced with
fresh.
[0133] Adherence of biofilm to coated CVCs. Following a modified
Kuhn's method, coated catheter segments were incubated for 24 hours
in plasma. The plasma was then replaced with 5.0.times.105 cells in
Muller Hinton Broth of either methicillin resistant Staphlococcus
aureus (MRSA 4798) or Stenotrophomonas maltophilia (5075, 4709,
4807) and incubated for an additional 24 hours. After incubation,
the bacterial innoculum was discarded and segments were washed
shaking for 30 minutes in 1 mL of 0.9% sterile saline. The segments
were then removed with sterile sticks placed in 5 mL of 0.9%
sterile saline and sonicated for 15 minutes. After sonication, 100
.mu.L of liquid from each segment was spread onto trypticase soy
agar with 5% sheep blood and incubated at 37.degree. C. inverted
for 24 hours. Plates were then counted for colony growth.
[0134] Statistical Methods. For each bacterium strain, the numbers
of viable organisms adhering to the catheter segments indicated by
CFU were compared by Kruskal-Wallis test (P<0.05 was regarded
statistically significant). If a significant result was detected
for the test, a Wilcoxon rank sum tests for the following pairwise
comparisons was made: comparing PU-Mino/Rifam (H1=heated) with
PU-Spectrum (not heated) and comparing each of them with control,
respectively; comparing Silicone -Mino/Rifam (H1=heated) with
Silicone-Spectrum(not heated) and comparing each of them with
control, respectively. The .alpha. levels of the post-hoc pairwise
comparisons were adjusted using a sequential Bonferroni adjustment
to control type I error.
Results
[0135] Table 2 demonstrates results of studies evaluating the
efficacy and durability of antiseptic activity in coated CVCs.
Spectrum catheters are those coated with minocycline and rifampin
without any heating to determine the antimicrobial durability of
catheters coated with minocycline and rifampin. Segments of
spectrum silicone catheters coated with minocycline and rifampin
(without heating) and other silicone catheters coated with
minocycline and rifampin that were heated were immersed in serum.
Catheter segments were removed at weekly intervals and we
determined zones of inhibition (ZOI) against resistant bacteria
such as methicillin resistant staphylococci (MRSA) and
strenotrophomas maltophilia (S. malta) strains. A ZOI of .gtoreq.10
mm is predictive of in vivo and clinical efficacy. It was found
that heating of the catheters treated with Mino/Rifampin increased
the efficacy (ZOI.gtoreq.10) of coating against MRSA from 28 days
to 70 days (Table 2). It was also found that heating of the
catheters treated with Mino/Rifampin increased the efficacy
(ZOI.gtoreq.10) of coating against Stenotrophomonas maltophilia by
1 week. TABLE-US-00003 TABLE 2 Efficacy and Durability of
antiseptic activity in Coated CVCs as determined by zones of
inhibition: S. malto S. malto S. malto MRSA 4798 5075 4807 4709
Silicone-Specturm 21 Feb. 2006 Baseline 27 27 18 18 20 19 18 18
(Day 0) 28 Feb. 2006 Day 7 21 21 0 0 12 12 12 12 7 Mar. 2006 Day 14
18 16 0 0 0 0 0 0 14 Mar. 2006 Day 21 15 14 0 0 0 0 0 0 21 Mar.
2006 Day 28 13 13 0 0 0 0 0 0 28 Mar. 2006 Day 35 8 8 0 0 0 0 0 0 4
Apr. 2006 Day 42 8 7 0 0 0 0 0 0 11 Apr. 2006 Day 49 7 7 0 0 0 0 0
0 18 Apr. 2006 Day 56 5 5 0 0 25 Apr. 2006 Day 63 0 0 0 0 2 May
2006 Day 70 0 0 0 0 9 May 2006 Day 77 0 0 0 0 Day 84
Silicone-Mino/Rifampin 1 day heat 21 Feb. 2006 Baseline 32 30 20 20
22 21 21 20 (Day 0) 28 Feb. 2006 Day 7 25 24 8 7 16 15 15 12 7 Mar.
2006 Day 14 22 21 0 0 12 12 8 7 14 Mar. 2006 Day 21 21 21 0 0 0 0 0
0 21 Mar. 2006 Day 28 20 19 0 0 0 0 0 0 28 Mar. 2006 Day 35 14 14 0
0 0 0 0 0 4 Apr. 2006 Day 42 10 10 0 0 0 0 0 0 11 Apr. 2006 Day 49
10 10 0 0 0 0 0 0 18 Apr. 2006 Day 56 10 10 0 0 25 Apr. 2006 Day 63
10 10 0 0 2 May 2006 Day 70 10 10 0 0 9 May 2006 Day 77 7 7 0 0 Day
84
[0136] Table 3 demonstrates results of studies pertaining to an
evaluation of the adherence of biofilm forming bacteria biofilm to
coated CVCs.
[0137] Adherence of biofilm to coated CVC's:
[0138] Following a modified Kuhn's method coated silicone catheter
segments were incubated for 24 hours in plasma. The plasma was then
replaced with 5.0.times.10.sup.5 cells in Muller Hinton Broth of
either methicillin resistant Staphlococcus aureus (MRSA 4798) or
Stenotrophomonas maltophilia (5075, 4709, 4807) and incubated for
an additional 24 hours. After incubation, the bacterial innoculum
was discarded and segments were washed by shaking for 30 minutes in
1 mL of 0.9% sterile saline. The segments were then removed with
sterile sticks placed in 5 mL of 0.9% sterile saline and sonicated
for 15 minutes. After sonication, 100 .mu.L of liquid from each
segment was spread onto trypticase soy agar with 5% sheep blood and
incubated at 37.degree. C. inverted for 24 hours. Plates were them
counted for colony growth.
[0139] It was found that heating of polyurethane and silicone CVCs
increased the inhibition of biofilm forming bacteria when tested
against MRSA and S. malto. When tested against MRSA Sil
Mino/Rifampin-1 (heated at 60.degree. C. for one day) significantly
decreased adherence (p=0.0047) when compared to CVCs coated with
minocycline and rifampin without heating. All coated catheters
showed significant decrease of adherence of biofilm forming
bacteria (p<0.0001) when compared to uncoated control catheters.
TABLE-US-00004 TABLE 3 Adherence of biofilm forming bacteria to
coated CVCs: PU Control Sil- Control Control Mino/Rifampin
Silicone- Control Mino/Rifampin PU-Uncoated PU Spectrum 1 day heat
Uncoated Sil-Spectrum 1 day heat Plate Plate Plate Plate Plate
Plate count Dilution count Dilution count Dilution count Dilution
count Dilution count Dilution Tested against adherence of
methicillin resistant Staph aureus (MRSA 4798) 1 100 5000 0 0 0 0
100 5000 1 50 0 0 2 100 5000 4 200 1 50 100 5000 1 50 0 0 3 100
5000 5 250 4 200 100 5000 4 200 1 50 4 100 5000 13 650 10 500 100
5000 4 200 4 200 5 100 5000 45 2250 27 1350 100 5000 5 250 0 0 6
100 5000 6 300 46 2300 100 5000 5 250 0 0 7 100 5000 73 3650 14 700
100 5000 6 300 4 200 8 100 5000 49 2450 0 0 100 5000 11 550 4 200 9
100 5000 92 4600 2 100 100 5000 3 150 0 0 10 100 5000 47 2350 5 250
100 5000 31 1550 0 0 Average 5000 1670 545 5000 355 65 St Dev 0.00
1626.04 745.15 0.00 443.13 94.43 Tested against adherence of
Stenotrophomas Maltophilia (PS 4807 & 4709) 1 100 5000 0 0 3
150 100 5000 0 0 0 0 2 100 5000 0 0 4 200 100 5000 0 0 0 0 3 100
5000 2 100 22 1100 100 5000 0 0 0 0 4 100 5000 15 750 42 2100 100
5000 1 50 2 100 5 100 5000 100 5000 14 700 100 5000 100 5000 0 0 6
100 5000 67 3350 3 150 100 5000 100 5000 0 0 7 100 5000 100 5000 6
300 100 5000 100 5000 6 300 8 100 5000 100 5000 2 100 100 5000 100
5000 11 550 9 100 5000 100 5000 6 300 100 5000 100 5000 4 200 10
100 5000 3 150 9 450 100 5000 100 5000 7 350 Average 5000 2435 555
5000 3005 150 St Dev 0.00 2415.81 624.26 0.00 2575.57 194.37
1) Results Pertaining to Adherence of S. maltophilia (PS 4807):
[0140] The Kruskal-Wallis test detected a significant difference
for PS4807 CFU among the 3 types of CVCs
(.psi..sup.2.sub.(5)=43.97, p<0.0001).
[0141] According to the Wilcoxon rank sum tests, there was no
significant difference in CFU between PU Mino/Rifam (H1=heated) and
PU-Spectrum (not heated) (p=0.45), but both catheters significantly
reduced CFU compared to the control (p<0.0001 for PU Mino/Rifam
(H1=heated) vs control; p=0.0059 for PU-Spectrum (not heated) vs
control). The CFU of Si-Mino/Rifam (H1=heated) was significantly
less than that of Si-Spectrum (not heated) (p=0.022), which in turn
was less than that of the control (p<0.0001). TABLE-US-00005
TABLE 4 S. maltophilia 4807 biofilm CFU among different catheters
Catheter Mean Median (Min-Max) N PU - Uncoated 5000 5000
(5000-5000) 10 PU - Spectrum 2435 2050 (0-5000) 10 PU - Mino/Rifam
(H1) 555 300 (100-2100) 10 Silicone - Uncoated 5000 5000
(5000-5000) 10 Silicone - Spectrum 240 125 (0-1250) 10 Silicone -
Mino/Rifam (H1) 30 0 (0-150) 10 Comparisons: (PS4807) Catheters:
p-value 1. PU-Mino/Rifam (H1) vs Pu-Spectrum 0.45 2. PU-Mino/Rifam
(H1) vs PU-Uncoated <.0001 3. PU-Spectrum vs PU-Uncoated 0.0059
1. Si-Mino/Rifam (H1) vs Si-Spectrum 0.022 2. Si-Mino/Rifam (H1) vs
Si-Uncoated <.0001 3. Si-Spectrum vs Si-Uncoated <.0001
Kruskal-Wallis test: Chi-square statistic with 5 d.f. = 43.97, p
< .0001 PU = Cool Polyurethane Spectrum = CVC coated with
minocycline & rifampin without heating. Mino/Rifam (H1) = CVC
coated with minocycline & rifampin with 1 day heating at
60.degree. C.
2) Results Pertaining to Adherence of S. maltophilia (PS 4709):
[0142] The Kruskal-Wallis test detected a significant difference
for PS4709 CFU among the 3 types of CVCs
(.psi..sup.2.sub.(5)=34.36, p<0.0001).
[0143] According to the Wilcoxon rank sum tests, there was no
significant difference in CFU between PU Mino/Rifam (H1=heated) and
PU-Spectrum (not heated) (p=0.85), and between a trend towards
reducing adherence when we compared Silicone-Mino/Rifam (H1=heated)
and to Silicone- Spectrum (coated with minocycline and rifampin but
not heated)(p=0.081), respectively. However all the Mino/Rifam
coated catheters significantly reduced CFU than their corresponding
controls, respectively (Table 4). TABLE-US-00006 TABLE 5 S.
maltophilia 4709, Biofilm CFU among different catheters Catheter
Mean Median (Min-Max) N PU - Uncoated 5000 5000 (5000-5000) 10 PU -
Spectrum 650 525 (0-2900) 10 PU-Mino/Rifam (H1) 1600 600 (0-5000)
10 1. Silicone - Uncoated 5000 5000 (5000-5000) 10 2. Silicone -
Spectrum 3005 5000 (0-5000) 10 3. Silicone - Mino/Rifam (H1) 150 50
(0-550) 10 Comparisons: (PS4709) Catheters: p-value 1.
PU-Mino/Rifam (H1) vs Pu-Spectrum 0.85 2. PU-Mino/Rifam (H1) vs
PU-Uncoated 0.0007 3. PU-Spectrum vs PU-Uncoated <.0001 1.
Si-Mino/Rifam (H1) vs Si-Spectrum 0.081 2. Si-Mino/Rifam (H1) vs
Si-Uncoated <.0001 3. Si-Spectrum vs Si-Uncoated 0.034
Kruskal-Wallis test: Chi-square statistic with 5 d.f. = 34.36, p
< .0001
3) Results Pertaining to MRSA 4798
[0144] The Kruskal-Wallis test detected a significant difference
for MRSA 4798 CFU among the 6 CVCs (.psi..sup.2.sub.(5)=47.86,
p<0.0001). According to the Wilcoxon rank sum tests (see Table
6), there was no significant difference in CFU between PU
Mino/Rifam (H1=heated) and PU-Spectrum (not heated) ((p=0.088), but
both catheters significantly reduced CFU compared to the control
(p<0.0001, respectively). The CFU of Si-Mino/Rifam (H1=heated)
was significantly less than that of Si-Spectrum (not heated)
(p=0.0047), which in turn was less than that of the control
(p<0.0001). TABLE-US-00007 TABLE 6 MRSA 4798 Biofilm CFU among
different catheters Catheter Mean Median (Min-Max) N PU - Uncoated
5000 5000 (5000-5000) 10 PU - Spectrum 1670 1450 (0-4600) 10 PU -
Mino/Rifam (H1) 545 225 (0-2300) 10 Silicone - Uncoated 5000 5000
(5000-5000) 10 Silicone - Spectrum 355 225 (50-1550) 10 Silicone -
Mino/Rifam (H1) 65 0 (0-200) 10 Comparisons: (MRSA 4798))
Catheters: p-value 1. PU-Mino/Rifam (H1) vs Pu-Spectrum 0.088 2.
PU-Mino/Rifam (H1) vs PU-Uncoated <.0001 3. PU-Spectrum vs
PU-Uncoated <.0001 4. Si-Mino/Rifam (H1) vs Si-Spectrum 0.0047
5. Si-Mino/Rifam (H1) vs Si-Uncoated <.0001 6. Si-Spectrum vs
Si-Uncoated <.0001 Kruskal-Wallis test: Chi-square statistic
with 5 d.f. = 47.86, p < .0001
[0145] All of the methods disclosed and claimed herein can be
executed without undue experimentation in light of the present
disclosure. While the of this invention have been described in
terms of preferred embodiments, it will be apparent to those of
skill in the art that variations may be applied to the methods or
in the sequence of steps of the method described herein without
departing from the concept, spirit and scope of the invention. More
specifically, it will be apparent that certain agents which are
both chemically and physiologically related may be substituted for
the agents described herein while the same or similar results would
be achieved. All such similar substitutes and modifications
apparent to those skilled in the art are deemed to be within the
spirit, scope and concept of the invention as defined by the
appended claims.
REFERENCES
[0146] The following references, to the extent that they provide
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forth herein, are specifically incorporated herein by reference.
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[0153] U.S. Pat. No. 5,362,754 [0154] U.S. Pat. No. 5,624,704
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