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`US 20050013836Al
`
`(19) United States
`(12) Patent Application Publication
`Raad
`
`(10) Pub. No.: US 2005/0013836 Al
`Jan. 20, 2005
`( 43) Pub. Date:
`
`(54) ANTIMICROBIAL FLUSH SOLUTIONS
`
`Publication Classification
`
`(75)
`
`Inventor:
`
`Issam Raad, Missouri City, TX (US)
`
`Correspondence Address:
`FULBRIGHT & JAWORSKI L.L.P.
`600 CONGRESS AVE.
`SUITE 2400
`AUSTIN, TX 78701 (US)
`
`(51)
`
`Int. Cl.7 ....................... A61K 38/14; A61K 31/704;
`A61K 31/65; A61K 31/545;
`A61K 31/397; A61K 31/407
`(52) U.S. Cl. ................. 424/400; 514/35; 514/8; 514/37;
`514/39; 514/152; 514/154;
`514/192; 514/200; 514/210.09;
`514/253.08; 514/312
`
`(73) Assignee: Board of Regents, The University of
`Texas System
`
`(57)
`
`ABSTRACT
`
`(21) Appl. No.:
`
`10/862,830
`
`(22) Filed:
`
`Jun. 7, 2004
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/476,555, filed on Jun.
`6, 2003.
`
`The present invention provides antimicrobial solutions that
`comprise at least one alcohol, at least one antimicrobial
`agent and at least one chelator and/or anticoagulant. Also
`provided are methods for rapidly reducing a microbe or a
`virus from surfaces including surfaces of indwelling medical
`devices and organic surfaces such as skin and sutures, and
`inorganic surfaces such as hospital equipment, pipelines etc.
`
`BAXTER EXHIBIT 1016
`Page 1 of 17
`
`

`

`.... 0 =
`~ ....
`O' -....
`~
`.... 0 =
`~ ....
`~ "Cl -....
`~ .... ~ = ....
`
`(')
`
`(')
`
`""C
`
`'""" ~
`0
`0
`~
`0
`0
`N
`'JJ.
`d
`
`O'I
`~
`00
`
`'"""
`>
`
`FIG. 1
`
`control
`
`30/Mlno 3
`EtOH/EDTA
`
`25%
`
`Drug Combination Tested
`
`EDTA30
`25%EtOH I
`
`24 hour growth
`
`Mlno3
`
`N ~=
`?
`~
`~
`
`Ul
`0
`0
`N
`
`and then plated
`for an additional 24 hours,
`placed in TSB and Incubated
`these pieces were then
`drug solution for 15 minutes,
`the pieces In their respective
`24 hour growth: After soaking
`
`plated
`were scraped, sonicated, and
`for 15 minutes, these pieces
`their resectlve drug solution
`15 minutes: After soaking in
`
`15 minutes (cid:127)24 hour growth I
`
`I(cid:127)
`
`EtOH In combination with M-EDTA as a 15 minute flush solution
`
`(.) :5
`u. 0::
`::, u,
`'o<
`
`350.0
`
`400.0
`
`450.0
`
`500.0
`
`BAXTER EXHIBIT 1016
`Page 2 of 17
`
`

`

`US 2005/0013836 Al
`
`Jan.20,2005
`
`1
`
`ANTIMICROBIAL FLUSH SOLUTIONS
`
`[0001] The present application claims the benefit of the
`filing date of U.S. Provisional Patent Application Ser. No.
`60/476,555, filed on Jun. 6, 2003. The entire text of the
`above-referenced disclosure is specifically incorporated
`herein by reference without disclaimer.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 1. Field of the Invention
`
`[0003] The present invention relates generally to the fields
`of medicine and microbiology. More particularly, it concerns
`methods of reducing microbial organisms from indwelling
`medical devices, medical equipment and other surfaces.
`
`[0004] 2. Description of Related Art
`
`[0005] Medical devices, such as vascular catheters, have
`improved the quality of medical care. However, infections
`resulting from the colonization of organisms embedded in
`biofilm are the most frequent complication associated with
`the use of these and other indwelling and/or prosthetic
`devices. In fact, infections are the most serious complica(cid:173)
`tions associated with indwelling central venous catheters
`(CVCs) (Maki et al., 1998). It is estimated that more than
`200,000 catheter-related bloodstream infections (CRBSI)
`occur annually in the United States alone (Kluger et al.,
`1999). Staphylococcus epidermidis, Staphylococcus aureus
`and Candida species are the leading organisms causing
`CRBSI (Maki et al., 1998; Raad et al., 2002).
`
`[0006] Because intralumenal colonization is the major
`source for the migration of organisms leading to blood(cid:173)
`stream infections in long-term silicone catheters (Raad et al.,
`1993), recent guidelines by the CDC and Infectious Diseases
`Society of America have proposed the use of intralumenal
`antimicrobial lock solutions for the prevention and treatment
`of CRBSI (Mermel et al., 2001; Centers for Disease Control
`and Prevention, 2002). Most long-term CVCs are typically
`flushed with heparin. An antimicrobial/anticoagulant com(cid:173)
`bination consisting of vancomycin/heparin with and without
`ciprofloxacin was shown to reduce the risk of catheter(cid:173)
`related bacteremia caused by gram-positive organisms (Car(cid:173)
`ratala et al., 1999; Henrickson et al., 2002; Schwartz et al.,
`1990). However, with the rise of incidences of infection by
`vancomycin resistant gram-positive bacteria, concerns have
`been raised over the use of vancomycin flush solutions and
`their potential for increasing the risk of vancomycin resis(cid:173)
`tance (Spafford et al., 1994).
`
`[0007] Recently the present inventor demonstrated that a
`flush
`solution
`compnsmg minocycline
`and EDTA
`(M-EDTA) is highly efficacious in preventing catheter(cid:173)
`related colonization, bacteremia and endocarditis in rabbits
`(Raad et al., 2002). When compared to a heparin flush
`solution, M-EDTA was found to decrease the risk of cath(cid:173)
`eter-related colonization and infection in hemodialysis
`patients as well as pediatric cancer patients (Bleyer et al.,
`2000; Chatzinikolaou et al., 2002). EDTAhas an equivalent
`anticoagulant activity to heparin (Reardon et al., 1991). An
`anticoagulant in flush solutions is necessary to prevent the
`thrombotic occlusion of the catheter lumen.
`
`[0008] Although M-EDTA has been found to be effica(cid:173)
`cious in preventing CRBSI, this solution may not be appli(cid:173)
`cable given some of the limitations of the real world of
`
`clinical practice. In the animal and clinical studies, the
`M-EDTA lock solution was required to be exposed to the
`surface of the indwelling medical device, such as the lumen
`of catheters, for at least 4 hours. In vitro studies have also
`shown that M-EDTA requires at least 4 hours of dwell time
`to eradicate organisms that colonize the lumen of the cath(cid:173)
`eter (see in particular data in U.S. Pat. No. 5,362,754,
`columns 11 and 12, and Tables 3, 4 and 5 as well as in U.S.
`Pat. No. 5,688,516, columns 15 and 16, and Tables 3, 4, and
`5). Providing a four hour exposure time to reduce microbes
`using the M-EDTA solution is usually not possible in
`critically ill patients who require continuous infusion
`therapy, including parenteral nutrition.
`
`[0009] Thus, there is an acute need in the art to develop
`compositions and methods for rapid reduction and/or eradi(cid:173)
`cation of microbes from indwelling medical devices without
`interruption of the use of the device in patients for too long
`a period. In addition, there is also a need for better and
`improved antimicrobial compositions.
`
`SUMMARY OF THE INVENTION
`[0010] The present invention overcomes these and other
`limitations in the art and provides compositions that reduce
`or eradicate microbial agents from surfaces wherein the
`compositions comprise at least one antimicrobial agent, at
`least one chelator and/or anticoagulant, and at least one
`alcohol. The present invention also provides methods to
`rapidly reduce or eradicate microbial agents from surfaces.
`
`[0011] Therefore, provided are antimicrobial solutions
`comprising at least one alcohol, at least one antimicrobial
`agent and at least one chelator and/or anticoagulant. "Anti(cid:173)
`microbial agents" that are comprised in the solutions of the
`present invention include antibacterial agents, antifungal
`agents, antiviral agents as well as antiseptic agents. These
`components are present in effective amounts to reduce
`microbial growth.
`
`[0012]
`In some embodiments of the invention, the antimi(cid:173)
`crobial agent is an antibacterial agent. While any antibac(cid:173)
`terial agent may be used in the preparation of the instant
`antimicrobial solutions, some non-limiting exemplary anti(cid:173)
`bacterial agent(s) include those classified as aminoglyco(cid:173)
`sides, beta lactams, quinolones or fluoroquinolones, mac(cid:173)
`rolides, sulfonamides, sulfamethaxozoles,
`tetracyclines,
`streptogramins, oxazolidinones (such as linezolid), clinda(cid:173)
`mycins, lincomycins, rifamycins, glycopeptides, polymxins,
`lipo-peptide antibiotics, as well as pharmacologically
`acceptable sodium salts, pharmacologically acceptable cal(cid:173)
`cium salts, pharmacologically acceptable potassium salts,
`lipid formulations, derivatives and/or analogs of the above.
`
`[0013] 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.
`
`[0014] The aminoglycosides are bactericidal antibiotics
`that bind to the 30S ribosome and inhibit bacterial protein
`synthesis. They are typically active against aerobic gram(cid:173)
`negative bacilli and staphylococci. Exemplary aminoglyco(cid:173)
`sides that may be used in some specific aspects of the
`invention include amikacin, kanamycin, gentamicin, tobra(cid:173)
`mycin, or netilmicin.
`
`BAXTER EXHIBIT 1016
`Page 3 of 17
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`

`US 2005/0013836 Al
`
`Jan.20,2005
`
`2
`
`[0015] Beta lactams are a class of antibacterials that
`inhibit bacterial cell wall synthesis. A majority of the clini(cid:173)
`cally useful beta-lactams belong to either the penicillin
`group (penam) or cephalosporin (cephem) groups. The beta(cid:173)
`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.
`
`[0016] Non-limiting examples of the penicillin group of
`antibiotics that may be used in the solutions of the present
`invention include amoxicillin, ampicillin, benzathine peni(cid:173)
`cillin G, carbenicillin, cloxacillin, dicloxacillin, piperacillin,
`or ticarcillin, etc. Examples of cephalosporins include ceft(cid:173)
`iofur, ceftiofur sodium, cefazolin, cefaclor, ceftibuten, cefti(cid:173)
`zoxime, cefoperazone, cefuroxime, cefprozil, ceftazidime,
`cefotaxime, cefadroxil, cephalexin, cefamandole, cefepime,
`cefdinir, cefriaxone, cefixime, cefpodoximeproxetil, cepha(cid:173)
`pirin, cefoxitin, cefotetan etc. Other examples of beta lac(cid:173)
`tams include mipenem or meropenem which are extremely
`active parenteral antibiotics with a spectrum against almost
`all gram-positive and gram-negative organisms, both aero(cid:173)
`bic and anaerobic and to which Enterococci, B. fragilis, and
`P. aeruginosa are particularly susceptible.
`
`[0017] Examples of beta lactamase inhibitors include cla(cid:173)
`vulanate, 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.
`
`[0018] Macrolide antibiotics are another class of bacterio(cid:173)
`static agents that bind to the SOS 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 anaer(cid:173)
`obes. Exemplary macrolides include erythromycin, azithro(cid:173)
`mycin, clarithromycin.
`
`[0019] Quinolones and fluoroquinolones typically func(cid:173)
`tion by their ability to inhibit the activity of DNA gyrase.
`Examples include nalidixic acid, cinoxacin, trovafloxacin,
`ofloxacin, levofloxacin, grepafloxacin, trovafloxacin, spar(cid:173)
`floxacin, norfloxacin, ciprofloxacin, moxifloxacin and gati(cid:173)
`floxacin.
`
`[0020] Sulphonamides are synthetic bacteriostatic antibi(cid:173)
`otics with a wide spectrum against most gram-positive and
`many gram-negative organisms. These drugs inhibit multi(cid:173)
`plication of bacteria by acting as competitive inhibitors of
`p-aminobenzoic acid in the folic acid metabolism cycle.
`Examples include mafenide, sulfisoxazole, sulfamethox(cid:173)
`azole, and sulfadiazine.
`
`[0021] The tetracycline group of antibiotics include tetra(cid:173)
`cycline derivatives such as tigecycline which is an investi(cid:173)
`gational new drug (IND), minocycline, doxycycline or
`demeclocycline and analogs such as anhydrotetracycline,
`chlorotetracycline, or epioxytetracycline. The present inven(cid:173)
`tors 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).
`
`[0022] The streptogramin class of antibacterial agents is
`exemplified by quinupristin, dalfopristin or the combination
`of two streptogramins.
`
`[0023] Drugs of the rifamycin class typically inhibit DNA(cid:173)
`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.
`
`[0024] Other antibacterial drugs are glycopeptides such as
`vancomycin, teicoplanin and derivatives thereof. Yet other
`antibacterial drugs are the polymyxins which are exempli(cid:173)
`fied by colistin.
`
`[0025]
`In addition to these several other antibacterial
`agents such as prestinomycin, chloramphenicol, trimethop(cid:173)
`rim, fusidic acid, metronidazole, bacitracin, spectinomycin,
`nitrofurantion, daptomycin or other leptopeptides, oritavan(cid:173)
`cin, dalbavancin, ramoplamin, ketolide etc. may be used in
`preparing the compositions described herein. Of these, met(cid:173)
`ronidazole is active only against protozoa, such as Giardia
`lamblia, Entamoeba histolytica and Trichomonas vaginalis,
`and strictly anaerobic bacteria. Spectinomycin, is a bacte(cid:173)
`riostatic 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(cid:173)
`Enterobacter species, staphylococci, and enterococci.
`
`[0026]
`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, omo(cid:173)
`conazole, oxiconazole, terconazole, itraconazole, flucona(cid:173)
`zole, voriconazole (UK 109,496), posaconazole, ravucona(cid:173)
`zole or flutrimazole;
`the polyene antifungals such as
`amphotericin B, liposomal amphoterecin B, natamycin, nys(cid:173)
`tatin and nystatin lipid formualtions; 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, can(cid:173)
`dimycin, griseofulvin, BF-796, MTCH 24, BTG-137586,
`pradimicins (MNS 18184), benanomicin; ambisome; nikko(cid:173)
`mycin Z; flucytosine, or perimycin.
`
`[0027]
`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, famciclo(cid:173)
`vir, foscamet, ribavirin, or valcyclovir. In some embodi(cid:173)
`ments the antimicrobial agent is an innate immune peptide
`or proteins. Some exemplary classes of innate peptides or
`proteins are transferrins, lactoferrins, defensins, phospholi(cid:173)
`pases, lysozyme, cathelicidins, serprocidins, bacteriocidal
`permeability increasing proteins, amphipathic alpha helical
`peptides, and other synthetic antimicrobial proteins.
`
`[0028]
`In other embodiments of the invention, the antimi(cid:173)
`crobial 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, salicy(cid:173)
`lamide, carbanilide, a guanide, an amidine, an imidazoline
`biocide, acetic acid, benzoic acid, sorbic acid, propionic
`
`BAXTER EXHIBIT 1016
`Page 4 of 17
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`

`US 2005/0013836 Al
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`Jan.20,2005
`
`3
`
`acid, boric acid, dehydroacetic acid, sulfurous acid, vanillic
`acid, esters of p-hydroxybenzoic acid, isopropanol, propy(cid:173)
`lene glycol, benzyl alcohol, chlorobutanol, phenylethyl alco(cid:173)
`hol, 2-bromo-2-nitropropan-1,3-diol, formaldehyde, glut(cid:173)
`araldehyde, calcium hypochlorite, potassium hypochlorite,
`sodium hypochlorite, iodine (in various solvents), povidone(cid:173)
`iodine, hexamethylenetetramine, noxythiolin, l-(3-choroal(cid:173)
`lyl)-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'-trichlorocarba(cid:173)
`nilide, 3,4',5-tribromosalicylanilide, 3-trifluoromethyl-4,4'(cid:173)
`dichlorocarbanilide, 8-hydroxyquinoline, l-cyclopropyl-6-
`fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
`quinolinecarboxylic acid, 1,4-dihydro-l-ethyl-6-fluoro-4-
`oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, hydrogen
`peroxide, peracetic acid, phenol, sodium oxychlorosene,
`parachlorometaxylenol,
`2,4,4'-trichloro-2'-hydroxydiphe(cid:173)
`nol, thymol, chlorhexidine, benzalkonium chloride, cetylpy(cid:173)
`ridinium chloride, silver sulfadiazine, or silver nitrate.
`[0029]
`In some embodiments of the invention, the anti(cid:173)
`septic agent is as set forth in the specification of U.S.
`Provisional Application Ser. No. 60/261,447, U.S. Provi(cid:173)
`sional Application Ser. No. 60/316,165, and U.S. Non(cid:173)
`Provisional patent application Ser. No. 10/044,842, incor(cid:173)
`porated herein by reference in their entirety. Thus, in some
`embodiments the antiseptic agent comprises a basic reagent
`and a dye.
`[0030] The basic reagent may be 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 some specific aspects, the basic
`reagent is a guanidium compound. 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.
`[0031] The dye may be 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. Non(cid:173)
`limiting examples of triarylmethane dye include gentian
`violet, crystal violet, ethyl violet, or brilliant green. Exem(cid:173)
`plary monoazo dyes inlude FD&C Yellow No. 5, or FD&C
`Yellow No. 6. Other non-limiting examples of FD&C dye
`include Blue No. 1 or Green No. 3. One non-limiting
`example of diazo dyes is D&C Red No. 17. An example of
`an indigoid dye is FD&C Blue No. 2. An examples of a
`xanthene dye is FD&C Red No. 3; of an anthraquinone dye
`is D&C Green No. 6; and of an quinoline dye is D&C
`Yellow No. 1.
`[0032] Other examples of antiseptics that may be used to
`prepare the antimicrobial solutions of the invention are the
`phenoxide antiseptics such as clofoctol, chloroxylenol or
`triclosan. Still other antiseptic agents that may be used to
`prepare the amntimicrobial solutions of the invention are
`gendine, genlenol, genlosan, or genfoctol.
`[0033] One of skill in the art will appreciate that one can
`use one or more of the antimicrobial agents including one or
`more antibacterial agent, and/or one or more antifungal
`agent, and/or one or more antiviral agent, and/or one or more
`antiseptic agent, and/or combinations thereof.
`[0034] A wide variety of chelator agents are contemplated
`as useful in preparing the antimicrobial solutions of the
`
`invention. This includes chelators such as EDTA free acid,
`EDTA2Na, EDTA3Na, EDTA4Na, EDTA2K, EDTA2Li,
`EDTA 2NH4 , EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA,
`Co(II)-EDTACu(II)-EDTA, Dy(III)-EDTA, Eu(III)-EDTA,
`Fe(III)-EDTA,
`In(III-EDTA, La(III)-EDTA, CyDTA,
`DHEG, diethylenetriamine penta acetic acid (DTPA),
`DTPA-OH, EDDA, EDDP, EDDPO, EDTA-OH, EDTPO,
`EGTA, HEED, HDTA, HIDA, IDA, Methyl-EDTA, NTA,
`NTP, NTPO, O-Bistren, TTHA, EGTA, DMSA, deferoxam(cid:173)
`ine, dimercaprol, zinc citrate, a combination of bismuth and
`citrate, penicillamine, succimer or Etidronate. It is contem(cid:173)
`plated that any chelator which binds barium, calcium,
`cerium, cobalt, copper, iron, magnesium, manganese, nickel,
`strontium, or zinc will be acceptable for use in the present
`invention.
`
`[0035] Alternatively, one may use at least one anticoagu(cid:173)
`lant such as heparin, hirudin, EGTA, EDTA, urokinase,
`streptokinase, hydrogen peroxide etc., in the preparation of
`the antimicrobial solutions of the invention.
`
`[0036] A variety of alcohols are contemplated as useful in
`the preparation of the instant antimicrobial solution, and
`include any antimicrobially active alcohol. Non-limiting
`examples of alcohols include ethanol, methanol, isopro(cid:173)
`panol, propylene glycol, benzyl alcohol, chlorobutanol, phe(cid:173)
`nylethyl alcohol, and the like. The concentration of the
`alcohol is preferably in the range of 5%-80% (v/v), more
`preferably in the range of 10% to 50%, more preferably in
`the range of 15% to 40%, more preferably in the range of
`20% to 30%, with the most preferable being about 25%.
`Thus, the more preferred concentration of alcohol will
`include 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,
`35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%
`(v/v) of the alcohol in the preparation of the instant antimi(cid:173)
`crobial solutions. This includes the use of intermediate
`concentrations of alcohol such as 11 %, 22.5%, 26% and the
`like.
`
`[0037] One of skill in the art will appreciate that the
`solutions of the instant invention can comprise various
`combinations of at least one alcohol, at least one antimicro(cid:173)
`bial agent, and at least one chelator/anticoagulant. In some
`specific embodiments, the solution of the invention com(cid:173)
`prises at least one alcohol, at least one tetracycline and at
`least one chelator/anticoagulant. In a specific aspect, such an
`antimicrobial solution comprises ethanol, at least one tetra(cid:173)
`cycline and EDTA or heparin.
`
`[0038]
`In other specific aspects, such a solution comprises
`ethanol, minocycline and EDTA or heparin. In one embodi(cid:173)
`ment of this aspect, the concentration of minocycline is
`0.001 mg/ml to 100 mg/ml. In another embodiment, the
`concentration of minocycline is about 3 mg/ml. In another
`aspect, the concentration of EDTA is in the range of 10-100
`mg/ml. In one embodiment of this aspect, the concentration
`of EDTA is about 30 mg/ml.
`
`[0039] The invention also provides methods for reducing
`microbial organisms from a surface comprising: a) obtaining
`an antimicrobial solution of the invention as set forth above;
`and b) contacting the surface with the antimicrobial solution,
`whereby said contacting reduces microbial organisms from
`the surface.
`
`[0040]
`In one embodiment of the method, the contacting is
`performed for 4 hours or less. In other embodiments of the
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`method, the contacting is performed for 2 hours or less, for
`1 hour or less, for 30 minutes or less, or for 15 minutes or
`less.
`
`[0041]
`In another aspect, the method further comprises
`eradicating microbes from the surface wherein the contact(cid:173)
`ing is performed for about 15 minutes or more.
`
`[0042] The methods of the invention can be used to reduce
`microbial agents from the surface of a medical device such
`as a catheter, an endotracheal tube, a nephrostomy tube, a
`biliary stent, an orthopedic device, a prosthetic valve, a
`medical implant, dental devices or dental implants, cardiac
`assist devices, vascular grafts, tracheostomy, ventriclulos(cid:173)
`tomy devices, or intrathecal devices. In some aspects, the
`catheter is an indwelling catheter such as a central venous
`catheter, a peripheral intravenous catheter, an arterial cath(cid:173)
`eter, a Swan-Ganz catheter, a hemodialysis catheter, an
`urinary catheter, a peritoneal catheter, an umbilical catheter,
`a percutaneous nontunneled silicone catheter, a cuffed tun(cid:173)
`neled central venous catheter or a subcutaneous central
`venous port.
`
`[0043]
`In other embodiments, the methods of the inven(cid:173)
`tion are useful in reducing microbial agents from a surface
`such as an organic surface or an inorganic surface. An
`organic surface is exemplified by skin, surgical sutures,
`mucosal membrane surface, or an epithelial surface. An
`inorganic surface may be the surface of a pipe or pipeline,
`a floor, a table-top, a counter-top, hospital equipment, or a
`wheel chair, etc. Non-limiting examples of a pipe is an oil
`pipeline, a water pipeline, an ice machine pipe, or a beverage
`dispensing pipe.
`
`[0044]
`It is contemplated that the antimicrobial solutions
`of the present invention will find particular usefulness as
`antimicrobial mouthwash solutions. Such mouthwash solu(cid:173)
`tions are contemplated to be useful both in conjunction with
`dental procedures and oral sterilization as well as in general
`dental and oral hygiene applications. Antimicrobial mouth(cid:173)
`wash is becoming extremely important in the prevention of
`oral cavity infections as well as aspiration pneumonia.
`Microbial organisms in the mouth particularly around the
`teeth, embed themselves in biofilm and the pathogenesis of
`infection and colonization is similar to that seen in, for
`example, vascular catheters. In this regard, it is contem(cid:173)
`plated that one will preferably apply the triple combinations
`of the present invention, that will include an antimicrobial
`(possibly antiseptic) with EDTA and low concentration
`alcohol as a mouthwash or mouth flush solution.
`
`[0045] The invention also provides a kit for disinfecting a
`surface to reduce microorganisms thereon, wherein the kit
`comprises components including at least one antimicrobial
`agent, at least one anticoagulant/chelator, and at least one
`alcohol, contained in a suitable container. The components
`may be combined in a single container, or powdered com(cid:173)
`ponents may be lyophilized, combined and separately com(cid:173)
`partmentalized, or all of the components may be placed in
`separate containers. In some embodiments, only the antimi(cid:173)
`crobial agent(s) is included as a dried powder. In aspects
`comprising powdered components, the kit may optionally
`include a second carrier solution for reconstituting the
`lyophilized antibiotic agent(s).
`
`[0046]
`In preferred aspects, the kit will include a unit dose
`of a pharmacologically effective amount of minocycline and
`
`EDTA ( or heparin), either provided separately as a lyo(cid:173)
`philized or powdered dose or already mixed in an ethanol
`solution. In a specific embodiment, the unit dose contains at
`least about 9 mg of minocycline and at least about 90 mg of
`EDTA. Such a kit may further comprise a preselected
`amount of an ethanol solution such that when the ethanol
`solution is mixed with the lyophilized unit dose, the con(cid:173)
`centration of minocycline is 3 mg/ml and the concentration
`of EDTA is 30 mg/ml.
`[0047] Kits in accordance with the present invention may
`be used to reduce/eliminate microbes on the surface of a
`medical device, a pipe or pipeline, a floor, a table-top, a
`counter-top, hospital equipment, or a wheel chair. It is also
`contemplated that the kits of the invention will further
`comprise a means for introducing the kit components into
`the medical device, the pipe or surface.
`[0048]
`In some specific aspects of the invention, a syringe
`or vial comprising a lyophilized unit dose of a pharmaco(cid:173)
`logically effective amount of one or more of the three
`components of the flush solutions of the present invention.
`For example, such a syringe may comprise minocycline and
`EDTA( or heparin) mixed in an ethanol solution. In a specific
`embodiment, the unit dose contains at least about 9 mg of
`minocycline and at least about 90 mg of EDTA. Such a
`syringe or vial may further comprises a preselected amount
`of an ethanol solution such that when the ethanol solution is
`mixed with the lyophilized unit dose, the desired concen(cid:173)
`tration of the particular agent is obtained, such as about 3
`mg/ml in the case of minocycline and about 30 mg/ml. in the
`case of EDTA.
`[0049]
`In other embodiments of the invention, a locking
`solution for filling and/or flushing a medical indwelling
`device such as, but not limited to, an implanted catheter is
`contemplated. The locking solution may comprise at least
`one antimicrobial agent, at least one chelator and/or antico(cid:173)
`agulant, and at least one alcohol.
`[0050] Some of the terms used in the present application
`are defined below:
`[0051] An "antimicrobial agent" is defined herein as an
`agent that has antibiotic properties against bacteria, fungi,
`viruses and other pathogens and includes antibacterial
`agents, antifungal agents, antiviral agents and antiseptic
`agents.
`[0052] As used herein, the term "antifungal agent" is
`defined as a compound having either a fungicidal or fungi(cid:173)
`static 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.
`[0053] As used herein, the term "antibacterial agent" is
`defined as a compound having either a bactericidal or
`bacteriostatic effect upon bacteria contacted by the com(cid:173)
`pound. As used herein, the term "bactericidal" is defined to
`mean having a destructive killing action upon bacteria. As
`used herein, the term "bacteriostatic" is defined to mean
`having an inhibiting action upon the growth of bacteria.
`[0054] 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.
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`[0055] 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.
`
`[0056] The phrase "a chelator" denotes one or more chela(cid:173)
`tors. As used herein, the term "chelator" is defined as a
`molecule comprising nonmetal atoms, two or more of which
`atoms are capable of linking or binding with a metal ion to
`form a heterocyclic ring including the metal ion.
`
`[0057] As used herein the terms "contact", "contacted",
`and "contacting", or "exposed" and "exposure" are used to
`describe the process by which any of the compositions
`disclosed in the present invention, comes in direct juxtapo(cid:173)
`sition with the surface of a medical device or any other
`surface from which microbial growth is to be reduced or
`eradicated.
`
`[0058] As used herein in the specification, "a" or "an" may
`mean one or more. As used herein in the claim(s), when used
`in conjunction with the word "comprising", the words "a" or
`"an" may mean one or more than one. As used herein
`"another" may mean at least a second or more.
`
`[0059] 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
`
`[0060] 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