Methods for potentiating antimicrobial agents

1. A method of treating a subject having a medical condition associated with a pathogenic microorganism, the method comprising:

(i) administering to said subject a potentiating effective amount of nitric oxide by inhalation; and

(ii) administering to said subject a therapeutically effective amount of an antimicrobial agent,

wherein said antimicrobial agent is other than said nitric oxide, and

wherein said antimicrobial agent is inactive when used alone against said pathogenic microorganism.

2. The method of claim 1 , wherein said potentiating effective amount is lower than a therapeutically effective amount of said nitric oxide with respect to said pathogenic microorganism.

3. The method of claim 2 , wherein said potentiating effective amount is lower than 1 MIC unit of nitric oxide with respect to said pathogenic microorganism.

4. The method of claim 1 , wherein said pathogenic microorganism exhibits a resistance to said antimicrobial agent prior to said administering said potentiating effective amount of nitric oxide.

5. The method of claim 1 , wherein (i) is affected prior to (ii).

6. The method of claim 1 , wherein (i) is affected concomitantly with (ii).

7. The method of claim 1 , wherein (ii) is affected prior to (i).

8. The method of claim 1 , wherein the pathogenic microorganism is selected from one or more of gram-negative bacteria, gram-positive bacteria, eubacteria, archaebacteria, eukaryotic organisms, yeast, fungi, algae, protozoa, and other parasites.

9. The method of claim 8 , wherein the pathogenic microorganism is selected from one or more of Plasmodium falciparum and related malaria-causing protozoan parasites, Acanthamoeb, Aeromonas hydrophila, Anisakis and related worms, Serracia sp., Enterobacter sp., Acinetobacter sp., Acinetobacter baumanii, Ascaris lumbricoides, Bacillus cereus, Brevundimonas diminuta, Campylobacter jejuni, Clostridium botulinum, Clostridium perfringens, Cryptosporidium parvum, Cyclospora cayetanensis, Diphyllobothrium, Entamoeba histolytica, Escherichia coli, Eustrongylides, Giardia lamblia, Klebsiella pneumoniae, Listeria monocytogenes, Nanophyetus, Mycobacterium smegmatis, Mycobacterium tuberculosis, Mycobacterium avium intracellularae, Plesiomonas shigelloides, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella, Serratia odorifera, Shigella, Staphylococcus aureus, Stenotrophomonas maltophilia, Streptococcus, Trichuris trichiura, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica, Yersinia pseudotuberculosis and Yersinia kristensenii.

10. The method of claim 1 , wherein the pathogenic microorganism is a bacteria, and the medical condition is a bacterial infection selected from one or more of actinomycosis, anthrax, aspergillosis, bacteremia, bacterial skin diseases, bartonella infections, botulism, brucellosis, burkholderia infections, campylobacter infections, candidiasis, cat-scratch disease, chlamydia infections, cholera, clostridium infections, coccidioidomycosis, cryptococcosis, dermatomycoses, diphtheria, ehrlichiosis, epidemic louse borne typhus, Escherichia coli infections, fusobacterium infections, gangrene, general infections, general mycoses, gonorrhea, gram-negative bacterial infections, gram-positive bacterial infections, histoplasmosis, impetigo, klebsiella infections, legionellosis, leprosy, leptospirosis, listeria infections, lyme disease, malaria, maduromycosis, melioidosis, mycobacterium infections, mycoplasma infections, necrotizing fasciitis, nocardia infections, onychomycosis, omithosis, pneumococcal infections, pneumonia, pseudomonas infections, Q fever, rat-bite fever, relapsing fever, rheumatic fever, rickettsia infections, Rocky-mountain spotted fever, salmonella infections, scarlet fever, scrub typhus, sepsis, sexually transmitted bacterial diseases, staphylococcal infections, streptococcal infections, surgical site infection, tetanus, tickborne diseases, tuberculosis, tularemia, typhoid fever, urinary tract infection, vibrio infections, yaws, yersinia infections, Yersinia pestis plague, zoonoses and zygomycosis.

11. The method of claim 1 , wherein the pathogenic microorganism is a fungi, and the medical condition is a fungal infection selected from one or more of endemic fungal infections, opportunistic fungal infections, histoplasmosis histoplasma associated with capsulatum , coccidioidomycosis associated with coccidioides immitis , blastomycosis blastomyces associated with dermatitidis , paracoccidioidomycosis paracoccidioides associated with brasiliensis , candidiasis associated with candida spp., aspergillosis associated with aspergillus spp., mucormycosis associated with mucor spp., infections associated with absidia , infections associated with rhizopus spp., and cryptococcosis associated with Cryptococcus neoformans.

12. The method of claim 1 , wherein the antimicrobial is selected from one or more of mandelic acid, 2,4-dichlorobenzenemethanol, 4-[bis(ethylthio)methyl]-2-methoxyphenol, 4-epitetracycline, 4-hexylresorcinol, 5, 12-dihydro-5, 7, 12, 14-tetrazapentacen, 5-chlorocarvacrol, 8-hydroxyquinoline, acetarsol, acetylkitasamycin, acriflavin, alatrofloxacin, ambazon, amfomycin, amikacin, amikacin sulfate, aminoacridine, aminosalicylate calcium, aminosalicylate sodium, aminosalicylic acid, ammoniumsulfobituminat, amorolfin, amoxicillin, amoxicillin sodium, amoxicillin trihydrate, amoxicillin-potassium clavulanate combination, amphotericin B, ampicillin, ampicillin sodium, ampicillin trihydrate, ampicillin-sulbactam, apalcillin, arbekacin, aspoxicillin, astromicin, astromicin sulfate, avermycin, azanidazole, azidamfenicol, azidocillin, azithromycin, azlocillin, aztreonam, bacampicillin, bacitracin, bacitracin zmc, bekanamycin, benzalkonium, benzethonium chloride, benzoxonium chloride, berberine hydrochloride, biapenem, bibrocathol, biclotymol, bifonazole, bismuth subsalicylate, bleomycin antibiotic complex, bleomycin hydrochloride, bleomycin sulfate, brodimoprim, bromochlorosalicylanilide, bronopol, broxyquinolin, butenafine, butenafine hydrochloride, butoconazol, calcium undecylenate, candicidin antibiotic complex, capreomycin, carbenicillin, carbenicillin disodium, carfecillin, carindacillin, carumonam, carzinophilin, caspofungin acetate, cefacetril, cefaclor, cefadroxil, cefalexin, cefalexin hydrochloride, cefalexin sodium, cefaloglycin, cefaloridine, cefalotin, cefalotin sodium, cefamandole, cefamandole nafate, cefamandole sodium, cefapirin, cefapirin sodium, cefatrizine, cefatrizine propylene glycol, cefazedone, cefazedone sodium salt, cefazolin, cefazolin sodium, cefbuperazone, cefbuperazone sodium, cefcapene, cefcapene pivoxil hydrochloride, cefdinir, cefditoren, cefditoren pivoxil, cefepime, cefepime hydrochloride, cefetamet, cefetamet pivoxil, cefixime, cefmenoxime, cefmetazole, cefinetazole sodium, cefininox, cefminox sodium, cefmolexin, cefodizime, cefodizime sodium, cefonicid, cefonicid sodium, cefoperazone, cefoperazone sodium, ceforanide, cefoselis sulfate, cefotaxime, cefotaxime sodium, cefotetan, cefotetan disodium, cefotiam, cefotiam hexetil hydrochloride, cefotiam hydrochloride, cefoxitin, cefoxitin sodium, cefozopran hydrochloride, cefpiramide, cefpiramide sodium, cefpirome, cefpirome sulfate, cefpodoxime, cefpodoxime proxetil, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftazidime, cefteram, cefteram pivoxil, ceftezole, ceftibuten, ceftizoxime, ceftizoxime sodium, ceftriaxone, ceftriaxone sodium, cefuroxime, cefuroxime axetil, cefuroxime sodium, cetalkonium chloride, cetrimide, cetrimonium, cetylpyridinium, chloramine T, chloramphenicol, chloramphenicol palmitate, chloramphenicol succinate sodium, chlorhexidine, chlormidazole, chlormidazole hydrochloride, chloroxylenol, chlorphenesin, chlorquinaldol, chlortetracycline, chlortetracycline hydrochloride, ciclacillin, ciclopirox, cinoxacin, ciprofloxacin, ciprofloxacin hydrochloride, citric acid, clarithromycin, clavulanate potassium, clavulanate sodium, clavulanic acid, clindamycin, clindamycin hydrochloride, clindamycin palmitate hydrochloride, clindamycin phosphate, clioquinol, cloconazole, cloconazole monohydrochloride, clofazimine, clofoctol, clometocillin, clomocycline, clotrimazol, cloxacillin, cloxacillin sodium, colistin, colistin sodium methanesulfonate, colistin sulfate, cycloserine, dactinomycin, danofloxacin, dapsone, daptomycin, daunorubicin, DDT, demeclocycline, demeclocycline hydrochloride, dequalinium, dibekacin, dibekacin sulfate, dibrompropamidine, dichlorophene, dicloxacillin, dicloxacillin sodium, didecyldimethylammonium chloride, dihydrostreptomycin, dihydrostreptomycin sulfate, diiodohydroxyquinolin, dimetridazole, dipyrithione, dirithromycin, DL-menthol, D-menthol, dodecyltriphenylphosphonium bromide, doxorubicin, doxorubicin hydrochloride, doxycycline, doxycycline hydrochloride, econazole, econazole nitrate, enilconazole, enoxacin, enrofloxacin, eosine, epicillin, ertapenem sodium, erythromycin, erythromycin estolate, erythromycin ethyl succinate, erythromycin lactobionate, erythromycin stearate, ethacridine, ethacridine lactate, ethambutol, ethanoic acid, ethionamide, ethyl alcohol, eugenol, exalamide, faropenem, fenticonazole, fenticonazole nitrate, fezatione, fleroxacin, flomoxef, flomoxef sodium, florfenicol, flucloxacillin, flucloxacillin magnesium, flucloxacillin sodium, fluconazole, flucytosine, flumequine, flurithromycin, flutrimazole, fosfomycin, fosfomycin calcium, fosfomycin sodium, framycetin, framycetin sulphate, furagin, furazolidone, fusafungin, fusidic acid, fusidic acid sodium salt, gatifloxacin, gemifloxacin, gentamicin antibiotic complex, gentamicin cla, gentamycin sulfate, glutaraldehyde, gramicidin, grepafloxacin, griseofulvin, halazon, haloprogine, hetacillin, hetacillin potassium, hexachlorophene, hexamidine, hexetidine, hydrargaphene, hydroquinone, hygromycin, imipenem, isepamicin, isepamicin sulfate, isoconazole, isoconazole nitrate, isoniazid, isopropanol, itraconazole, josamycin, josamycin propionate, kanamycin, kanamycin sulphate, ketoconazole, kitasamycin, lactic acid, lanoconazole, lenampicillin, leucomycin A1, leucomycin A13, leucomycin A4, leucomycin AS, leucomycin A6, leucomycin A7, leucomycin A8, leucomycin A9, levofloxacin, lincomycin, lincomycin hydrochloride, linezolid, liranaftate, 1-menthol, lomefloxacin, lomefloxacin hydrochloride, loracarbef, lymecyclin, lysozyme, mafenide acetate, magnesium monoperoxophthalate hexahydrate, mecetronium ethylsulfate, mecillinam, meclocycline, meclocycline sulfosalicylate, mepartricin, merbromin, meropenem, metalkonium chloride, metampicillin, methacycline, methenamin, methyl salicylate, methylbenzethonium chloride, methylrosanilinium chloride, meticillin, meticillin sodium, metronidazole, metronidazole benzoate, mezlocillin, mezlocillin sodium, miconazole, miconazole nitrate, micronomicin, micronomicin sulfate, midecamycin, minocycline, minocycline hydrochloride, miocamycin, miristalkonium chloride, mitomycin c, monensin, monensin sodium, morinamide, moxalactam, moxalactam disodium, moxifloxacin, mupirocin, mupirocin calcium, nadifloxacin, nafcillin, nafcillin sodium, naftifine, nalidixic acid, natamycin, neomycin a, neomycin antibiotic complex, neomycin C, neomycin sulfate, neticonazole, netilmicin, netilmicin sulfate, nifuratel, nifuroxazide, nifurtoinol, nifurzide, nimorazole, niridazole, nitrofurantoin, nitrofurazone, nitroxolin, norfloxacin, novobiocin, nystatin antibiotic complex, octenidine, ofloxacin, oleandomycin, omoconazol, orbifloxacin, omidazole, ortho-phenylphenol, oxacillin, oxacillinsodium, oxiconazole, oxiconazole nitrate, oxoferin, oxolinic acid, oxychlorosene, oxytetracycline, oxytetracycline calcium, oxytetracycline hydrochloride, pampenem, paromomycm, paromomycm sulfate, pazufloxacine, pefloxacin, pefloxacin mesylate, penamecillin, penicillin G, penicillin G potassium, penicillin G sodium, penicillin V, penicillin V calcium, penicillin V potassium, pentamidine, pentamidine diisetionate, pentamidine mesilas, pentamycin, phenethicillin, phenol, phenoxyethanol, phenylmercuriborat, PHMB, phthalylsulfathiazole, picloxydin, pipemidic acid, piperacillin, piperacillin sodium, pipercillin sodium-tazobactam sodium, piromidic acid, pivampicillin, pivcefalexin, pivmecillinam, pivmecillinam hydrochloride, policresulen, polymyxin antibiotic complex, polymyxin B, polymyxin B sulfate, polymyxin Bl, polynoxylin, povidone-iodine, propamidin, propenidazole, propicillin, propicillin potassium, propionic acid, prothionamide, protiofate, pyrazinamide, pyrimethamine, pyridomycin, pyrithion, pyrrolnitrin, quinoline, quinupristin-dalfopristin, resorcinol, ribostamycin, ribostamycin sulfate, rifabutin, rifampicin, rifamycin, rifapentine, rifaximin, ritiometan, rokitamycin, rolitetracycline, rosoxacin, roxithromycin, rufloxacin, salicylic acid, secnidazol, selenium disulphide, sertaconazole, sertaconazole nitrate, siccanin, sisomicin, sisomicin sulfate, sodium thiosulfate, sparfloxacin, spectinomycin, spectinomycin hydrochloride, spiramycin antibiotic complex, spiramycin b, streptomycin, streptomycin sulphate, succinylsulfathiazole, sulbactam, sulbactam sodium, sulbenicillin disodium, sulbentin, sulconazole, sulconazole nitrate, sulfabenzamide, sulfacarb ami de, sulfacetamide, sulfacetamide sodium, sulfachlorpyridazine, sulfadiazine, sulfadiazine silver, sulfadiazine sodium, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaguanidine, sulfalene, sulfamazone, sulfamerazine, sulfamethazine, sulfamethazine sodium, sulfamethizole, sulfamethoxazole, sulfamethoxazol-trimethoprim, sulfamethoxypyridazine, sulfamonomethoxine, sulfamoxol, sulfanilamide, sulfaperine, sulfaphenazol, sulfapyridine, sulfaquinoxaline, sulfasuccinamide, sulfathiazole, sulfathiourea, sulfatol ami de, sulfatriazin, sulfi somi dine, sulfi soxazole, sulfisoxazole acetyl, sulfonamides, sultamicillin, sultamicillin tosilate, tacrolimus, talampicillin 15 hydrochloride, teicoplanin A2 complex, teicoplanin A2-1, teicoplanin A2-2, teicoplanin A2-3, teicoplanin A2-4, teicoplanin A2-5, teicoplanin A3, teicoplanin antibiotic complex, telithromycin, temafloxacin, temocillin, tenoic acid, terbinafine, terconazole, terizidone, tetracycline, tetracycline hydrochloride, tetracycline metaphosphate, tetramethylthiuram monosulfide, tetroxoprim, thiabendazole, thiamphenicol, thiaphenicol glycinate hydrochloride, 20 thiomersal, thiram, thymol, tibezonium iodide, ticarcillin, ticarcillin-clavulanic acid mixture, ticarcillin disodium, ticarcillin monosodium, tilbroquinol, tilmicosin, tinidazole, tioconazole, tobramycin, tobramycin sulfate, tolciclate, tolindate, tolnaftate, toloconium metilsulfat, toltrazuril, tosufloxacin, triclocarban, triclosan, trimethoprim, trimethoprim sulfate, triphenylstibinsulfide, troleandomycin, trovafloxacin, tylosin, tyrothricin, undecoylium chloride, undecylenic acid, vancomycin, vancomycin hydrochloride, viomycin, virginiamycin antibiotic complex, voriconazol, xantocillin, xibomol and zinc undecylenate.

13. The method of claim 1 wherein the antimicrobial is selected from one or more of polyenes, amphotericin B, liposomal amphotericin, nystatin, and pimaricin; azoles, fluconazole, itraconazole, ketoconazole, itraconazole, voriconazole, posaconazole, anidulafungin, caspofungin, micafungin, allylamines, naftifine, binafine, amorolfine, 5-fluorocytosine, amoxicillin, amoxicillin sodium, amoxicillin trihydrate, amoxicillin-potassium clavulanate combination, aztreonam, azithromycin, azlocillin, clofazimine, cloxacillin, cloxacillin sodium, dicloxacillin, cefdinir, cefditoren, cefditoren pivoxil, cefepime, cefepime hydrochloride, colistin, colistin sodium methanesulfonate, colistin sulfate, clarithromycin, cefprozil, cefaclor, cefuroxime, cefuroxime axetil, cefuroxime sodium, dicloxacillin sodium, amikacin, amikacin sulfate, flucloxacillin, flucloxacillin magnesium, flucloxacillin sodium, doxycycline, doxycycline hydrochloride, imipenem, levofloxacin, linezolid, minocycline, minocycline hydrochloride, mezlocillin, mezlocillin sodium, nafcillin, nafcillin sodium, oxacillin, piperacillin, penicillin G, ciprofloxacin, ciprofloxacin hydrochloride, erythromycin, sulfisoxazole, sulfisoxazole acetyl, sulfamethoxazole, sulfamethoxazol-trimethoprim, tazobactam, tazobactam sodium, tetracycline, tobramycin, tobramycin sulfate, ticarcillin, ticarcillin-clavulanic acid mixture, ticarcillin disodium, ticarcillin monosodium, gentamicin, vancomycin and methicillin.

14. A method of treating a subject having a medical condition associated with a pathogenic microorganism in which an antimicrobial resistance has been uncovered following treating said subject with said antimicrobial agent, the method comprising:

(i) administering to said subject, following a treatment with said antimicrobial agent and uncovering said antimicrobial resistance, a re-sensitizing effective amount of nitric oxide;

(ii) administering to said subject a therapeutically effective amount of said antimicrobial agent,

wherein said antimicrobial agent is other than said nitric oxide and said re-sensitizing effective amount of nitric oxide is lower than a therapeutically effective amount of nitric oxide with respect to said microorganism.

15. A method for sensitizing or re-sensitizing a microorganism to an antimicrobial agent, comprising:

(i) contacting said microorganism with a sensitizing or re-sensitizing effective amount of nitric oxide; and

(ii) contacting said microorganism with a therapeutically effective amount of said antimicrobial agent, wherein said antimicrobial agent is other than said nitric oxide and said sensitizing or re-sensitizing effective amount being lower than a therapeutically effective amount of said nitric oxide with respect to said pathogenic microorganism; and

wherein said pathogenic microorganism exhibits a resistance to said antimicrobial agent prior to said administering said potentiating effective amount of nitric oxide.

16. The method of claim 15 , wherein said sensitizing or re-sensitizing effective amount is lower than 1 MIC unit of nitric oxide with respect to said pathogenic microorganism.

17. The method of claim 15 , wherein contacting said microorganism with said nitric oxide comprises administering to a subject having a medical condition associated with said microorganism, said sensitizing or re-sensitizing effective amount of said nitric oxide; and wherein contacting said microorganism with said therapeutically effective amount of said antimicrobial agent comprises administering to said subject said antimicrobial agent.

18. The method of claim 15 , wherein said antimicrobial agent is inactive when used against said pathogenic microorganism.