US 2010.001 6333A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0016333 A1 Flanner et al. (43) Pub. Date: Jan. 21, 2010

(54) ONCE-A-DAY (RNA-POLYMERASE Related U.S. Application Data INHIBITING ORPHENAZINE)- (60) Provisional application No. 60/836,026, filed on Aug. DHYDROPTEROATE SYNTHASE 7, 2006, provisional application No. 60/836,313, filed INHIBITING - DHYDROFOLATE on Aug. 8, 2006. REDUCTASE INHIBITING ANTIBOTC PHARMACEUTICAL PRODUCT, Publication Classification FORMULATION THEREOF, AND USE (51) Int. Cl. THEREOF INTREATING INFECTION A63/496 (2006.01) CAUSED BY METHCILLIN-RESISTANT A6IP3L/04 (2006.01) STAPHYLOCOCCUSAUREUS (52) U.S. Cl...... 514/254.11 (57) ABSTRACT (76) Inventors: Henry H. Flanner, Montgomery Disclosed are once-a-day antibiotic products for treating Village, MD (US); Donald Treacy, Methicillin-Resistant Staphylococcus aureus, or “MRSA.” Woodbine, MD (US); Sanna the products comprising: a combination of at least three dif Tolle-Sander, North Potomac, MD ferent antibiotics, wherein one of the at least three different (US); Beth A. Burnside, Bethesda, antibiotics is selected from the group consisting of RNA MD (US); Edward M. Rudnic, Polymerase Inhibiting antibiotics or Phenazine antibiotics, North Potomac, MD (US) wherein one of the at least three different antibiotics is selected from the group consisting of Dihydropteroate Syn Correspondence Address: thase Inhibiting antibiotics, and wherein one of the at least three different antibiotics is selected from the group consist Raymond E. Stauffer, Esq. ing of Dihydrofolate Reductase Inhibiting antibiotics (alter c/o Carella, Byrne, Bain, Gilfillan, Cecchi, natively any or all of the aforementioned RNA-Polymerase Stewart & Olstein, 5 Becker Farm Road Inhibiting antibiotics, Dihydropteroate Synthase Inhibiting Roseland, NJ 07068 (US) antibiotics, and Dihydrofolate Reductase Inhibiting antibiot ics may be in the form of analogues, derivatives, polymorphs, (21) Appl. No.: 11/890,747 metabolites, pro-drugs, salts, and/or hydrates of any of the foregoing); optionally in further combination with a resis tance inhibitor, preferably a Lex A protease cleavage inhibi (22) Filed: Aug. 7, 2007 tOr. US 2010/001 6333 A1 Jan. 21, 2010

ONCE-A-DAY (RNA-POLYMERASE hereinabove and hereinbelow, either of the terms “patient’ or INHIBITING ORPHENAZINE) - “subject' shall each individually denote any host of a bacte DHYDROPTEROATE SYNTHASE rial infection, or any organism suspected of hosting a bacterial INHIBITING - DHYDROFOLATE infection, including without limitation humans and animals. REDUCTASE INHIBITING ANTIBOTC As referred to hereinabove and hereinbelow, the terms “to PHARMACEUTICAL PRODUCT, treat,” “treating,” or “treatment” (of) such patient or subject FORMULATION THEREOF, AND USE shall mean that the hereinabove-described and/or hereinbe THEREOF INTREATING INFECTION low-described products and/or processes are administered to CAUSED BY METHCILLIN-RESISTANT and/or practiced upon the patient or subject, but shall neither STAPHYLOCOCCUSAUREUS necessarily imply nor foreclose actual treatment of Such patient or subject by a physician, clinician, investigator, par ent, custodian, or other caregiver; yet may include any act of 0001. This application claims the priority of U.S. Provi prescribing or otherwise directing that any of the herein sional Application Ser. No. 60/836,026, filed Aug. 7, 2006: above-described and/or hereinbelow-described products and/ and also claims the priority of U.S. Provisional Application or processes are administered to and/or practiced upon the Ser. No. 60/836,313, filed Aug. 8, 2006; the disclosures of patient or Subject, by any such person. Similarly, “to treat.” each of which are hereby incorporated by reference in their “treating,” or “treatment” (of) such patient or subject may entireties. include any act whereby the hereinabove-described and/or 0002 This invention relates to a once-a-day antibiotic hereinbelow-described products and/or processes are admin product, and to the use and formulation thereof. More spe istered to and/or practiced upon the patient or subject by the cifically this invention relates to a once-a-day antibiotic prod patient or subject himself/herself, or by an inanimate device uct comprising: a combination of at least three different anti or similar means. biotics, wherein one of the at least three different antibiotics 0004 Staphylococcus aureus, sometimes referred to sim is selected from the group consisting of RNA-Polymerase ply as 'staph, or 'staph A is a common bacterium typically Inhibiting antibiotics, one of the at least three different anti found on the skin and/or in the nasal passages of healthy biotics is selected from the group consisting of Dihy people. While the presence of Staphylococcus aureus on the dropteroate Synthase Inhibiting antibiotics, and one of the at skin and/or in the nasal passages is usually harmless to a least three different antibiotics is selected from the group person at those sites, 'staph' infections can occur as a result consisting of Dihydrofolate Reductase Inhibiting antibiotics of breaks in the skin, such as through abrasions, lacerations, (alternatively any or all of the aforementioned RNA-Poly and wounds; or by way of Surgical procedures or catheteriza merase Inhibiting antibiotics, Dihydropteroate Synthase tions. If staph gets into the body it can cause minor skin and Inhibiting antibiotics, and Dihydrofolate Reductase Inhibit Soft tissue infections, such as boils or pimples; or it can cause ing antibiotics may be in the form of analogues, derivatives, more serious conditions, such as pneumonia, empyema, polymorphs, metabolites, pro-drugs, salts, and/or hydrates of blood infections, bacteremia, sepsis, osteomyelitis, pyomy any of the foregoing), and to the use and formulation of Such tosis, necrotizing fascititis, purpura fulminans, infections of an antibiotic product. More specifically still this invention the bones and joints, urinary tract infections, toxic shock relates to a once-a-day antibiotic product comprising the syndrome, and even death. aforementioned combination of antibiotics (or analogues, 0005 Methicillin-Resistant Staphylococcus aureus is a etc.), to the formulation thereof, and to the use thereof in bacterial pathogen resistant to certain antibiotics, such as treating bacterial infection in a patient or Subject. In several methicillin and other beta-lactams, including oxacillin, peni embodiments the invention is directed to improving upon the cillin, nafcillin, amoxicillin, and the cephalosporins. (See eradication of antibiotic-resistant bacterial pathogens and/or Dellit et al., Interim Guidelines for Evaluation & Manage to reducing the emergence of any further resistant bacterial ment of Community-Associated Methicillin-Resistant Sta pathogens, while using the product to treat bacterial infection phylococcus Aureus Skin and Soft Tissue Infections. In Out in a patient or Subject (e.g., an infectious bacterial pathogen patient Settings, Sep. 2, 2004; Infectious Diseases Society of Such as Methicillin-Resistant Staphylococcus aureus, or Washington, pages 1-14). Another source explains that "Oll “MRSA). In still other embodiments, the above-described MRSA are characterized genotypically by the presence of invention is directed to a once-a-day antibiotic product com mecA, which encodes for altered penicillin binding proteins prising the aforementioned combination of antibiotics (or (PBPs) (PBP2A) on their cell walls. The low affinity binding analogues, etc.), in further combination with a resistance of PBP2A to antistaphylococcal penicillins results pheno inhibitor preferably a Lex A protease cleavage inhibitor; typically in resistance to all B-lactam antibiotics.” (See Bra and to the similarly above-described use, and formulation of dley S. Staphylococcus Aureus Pneumonia: Emergence of such an antibiotic product. In preferred embodiments, the MRSA in the Community, Semin Respir Crit Care Med. above-described invention is administered orally. However, 2005; 26(6):643-649). in other embodiments, the above-described invention may be 0006. In accordance with a first broad aspect of the inven delivered by a multitude of pharmaceutically acceptable tion, the RNA-Polymerase Inhibiting antibiotic, Dihy routes that are known in the art and described hereinbelow. dropteroate Synthase Inhibiting antibiotic, and Dihydrofolate 0003. As known in the art and as referred to herein the Reductase Inhibiting antibiotic pharmaceutical product is terms “once-a-day,” “one-a-day,” “once daily, and “Q.D.’ administered once-a-day in treating a patient or subject shall denote that the product of the hereinabove-described infected with Methicillin-Resistant Staphylococcus aureus and hereinbelow-described invention is to be administered (MRSA), an infection most traditionally acquired nosocomi only once during any given twenty-four hour period, after ally—in a hospital, clinic, dialysis center, or other healthcare which no further product or composition is administered dur associated setting; or through contact with persons associated ing that same given twenty-four hour period. As referred to with Such healthcare settings (e.g., through healthcare US 2010/001 6333 A1 Jan. 21, 2010 employed or healthcare exposed family members). Nosoco will appear red and inflamed around wound sites. Symptoms mially acquired MRSA is more commonly referred to as in serious cases may include fever, lethargy, and headache. healthcare-acquired (or healthcare-associated) MRSA, or Intravenous drug users and persons with long-term illnesses HA-MRSA or who are immuno-Suppressed are at increased risk for infec 0007. In divers embodiments of the invention the RNA tion by MRSA. Other non-healthcare related populations Polymerase Inhibiting antibiotic, Dihydropteroate Synthase most at risk for infection by CA-MRSA include prisoners, Inhibiting antibiotic, and Dihydrofolate Reductase Inhibiting athletes in contact sports, School children, daycare attendees, antibiotic pharmaceutical product is administered once-a-day military personnel, Pacific Islanders, Native Americans, in treating a patient or Subject infected with healthcare-ac Alaskan Natives, male homosexuals, and persons infected quired Methicillin-Resistant Staphylococcus aureus, or HA with HIV. MRSA. 0011. In the last several years the incidence of community 0008. In other divers embodiments of the invention the acquired-MRSA (CA-MRSA) has risen dramatically, and it RNA-Polymerase Inhibiting antibiotic, Dihydropteroate is becoming increasingly more common world-wide for Synthase Inhibiting antibiotic, and Dihydrofolate Reductase MRSA infection to occur in the community setting. Salmen Inhibiting antibiotic pharmaceutical product is administered linna et al. report that from 1997 to 1999 21% of all MRSA once-a-day in treating a patient or Subject infected with com positive persons hospitalized in Finland had community-ac munity-acquired Methicillin-Resistant Staphylococcus quired MRSA. (See Community-Acquired Methicillin aureus (CA-MRSA). Without limiting the scope of these, or Resistant Staphylococcus aureus, Finland; Infectious any other, embodiments of the herein-described invention, Diseases Vol. 8, No. 6, June 2002). In Los Angeles, Calif. one Applicants note that MRSA has been generally described as local Emergency Room has recently reported that 64% of skin being community-acquired (or community-associated) if the and soft-tissue infections (“SSTI) were caused by MRSA in MRSA-positive specimen is obtained outside hospital set 2003-2004, versus 29% in 2001-2002. (See Community tings or within2 days of hospital admission, and if it was from Associated Methicillin-Resistant Staphylococcus Aureus: an a person who had not been hospitalized within 2 years before Emerging Infectious Disease in Los Angeles County, The the date of MRSA isolation. (See Salmenlinna et al., Com Public's Health Volume 5, Number 7, pgs. 4-5; County of Los munity-Acquired Methicillin-Resistant Staphylococcus Angeles, Dept. of Health Services July-August 2005). aureus, Finland, Emerging Infectious Diseases, 2002 June; Though there is little in the way of nationwide U.S. statistics 8(6):602-7). Still, another source notes that patients develop regarding the actual incidence of CA-MRSA pneumonia, the ing infections within 48 to 72 hours of hospital (healthcare) art anticipates that “more cases of Staphylococcus pneumo admission are presumed to have acquired the infection from nia, and CA-MRSA in particular, will be seen in addition to the community. (See Bradley S. Staphylococcus Aureus those populations that were traditionally at risk for S. aureus Pneumonia: Emergence of MRSA in the Community, Semin respiratory tract infection.” (See Bradley S., Staphylococcus Respir Crit. Care Med. 2005; 26(6):643-649). Aureus Pneumonia: Emergence of MRSA in the Community, 0009. These art-recognized distinctions notwithstanding, Semin Respir Crit. Care Med. 2005; 26(6):643-649). As however, as reported cases of CA-MRSA become more wide many strains contain cytotoxins that exacerbate the necrotiz spread in the healthcare environment, definitions based on ing (cell death) aspects of the infections, and hence the sever exposure risk and/or location of acquisition may prove to be ity of the illnesses, and/or the rates of mortality of the ill of less epidemiological value. Under current modes of Sus nesses, the development of effective, reliable antibiotic ceptibility testing, an isolate is likely to be CA-MRSA if it is treatments for both CA-MRSA and HA-MRSA should be of resistant to all beta-lactamantibiotics and Susceptible to most paramount importance to their overall epidemiology. other antibiotic classes including the aminoglycosides, lin 0012. In the treatment of bacterial infections, antibiotics, cosamides, Sulfonamides, fluoroquinolones, and macrollides. Such as those commonly-used for treating MRSA, are gener In addition to being similarly resistant to the beta-lactams, ally dosed in formulations that require multiple administra HA-MRSA is also known to carry resistance elements for tions over the course of any given 24-hour period. As is several other antibiotic classes, including macrollides, ami known in the art, Such dosing regimens may be twice-a-day noglycosides, fluoroquinolones, tetracyclines, and Sulfona (b.i.d.), whereby the formulation is administered every 12 mides. While CA-MRSA is generally more susceptible to hours; three times daily (t.i.d.), whereby the formulation is each of gentamicin, clindamycin, ciprofloxacin, and erythro administered every 8 hours; four times daily (q.i.d.), whereby mycin than is HA-MRSA, it is expected that as CA-MRSA the formulation is administered every 6 hours; or Such dosing becomes more common it will similarly acquire resistance regimens may even conceive of dosing the formulation in genes that will make its detection by routine antibiotic sus excess of four administrations per day. Repeated administra ceptibility testing more difficult. (See Bradley S. Staphylo tions of a drug throughout a 24-hour period may be disruptive coccus Aureus Pneumonia: Emergence of MRSA in the Com to meals or sleep, thereby presenting a significant inconve munity, Semin Respir Crit. Care Med. 2005; 26(6):643-649). nience for patients. In the treatment of elderly or incapaci Additionally, “the prevalence of in vitro resistance to non tated patients multiple administration regimens can result in beta-lactam antimicrobial agents may be increasing among poor compliance, and hence an ineffective treatment of the MRSA strains associated with community transmission.” infection. (See Gorwitz et al.; Strategies for Clinical Management of 0013 Much of the existing guidelines and art relating to MRSA in the Community. Summary of an Experts' Meeting antibiotic treatments for MRSA requires repeated adminis Convened by the Centers for Disease Control and Prevention: trations of antibiotics over the course of a 24-hour period (i.e., Department of Health and Human Services; March 2006). at least twice-a-day or more—b.i.d. t.i.d., or q.i.d dosing). 0010. On the skin and soft tissues Methicillin-Resistant Those of the existing guidelines and art relating to antibiotic Staphylococcus aureus produces symptoms no different from treatments for MRSA that are touted for once daily adminis any other type of Staphylococcus aureus bacteria: the skin tration are generally directed to the use of beta-lactams (i.e., US 2010/001 6333 A1 Jan. 21, 2010

cephalosporins, cephems, carbapenems, etc.) an antibiotic Services; March 2006). Accordingly, there is a need in the art class noted to have waning utility against MRSA, and/or are for anti-MRSA formulations that are not reliant on beta generally directed to injectable formulations. lactams, and that can provide the convenience of once-a-day 0014 U.S. Pat. Nos. 4,131,672 and 4,175,125 (Eli Lilly dosing, preferably by way of oral administration. and Company) disclose halogenated phenylthioacetamido 0020. The RNA-Polymerase Inhibiting antibiotics, Dihy cephalosporanic acids and derivatives such as 7-2'-(2".5"- dropteroate Synthase Inhibiting antibiotics, and Dihydro dichlorophenylthio)acetamidocephalosporanic acid, as being effective antibiotics against Staphylococcus aureus folate Reductase Inhibiting antibiotics are each individually cultures which show heterogeneous resistance to methicillin. known antibiotic classes, which are outside of the beta-lactam Administration of this beta-lactam is preferably by intramus antibiotic class. cular injection every four to six hours, or by oral tablet every 0021 Lex A is a protease found in bacteria, the cleavage of four to six hours. which protease is known in the art to promote mutations in 0015 U.S. Pat. No. 5,334,590 (Merck & Co., Inc.) dis response to DNA damage, leading to the development of the closes the use of 2-phenyl-carbapenems against MRSA. The bacteria's resistance to antibiotics. Cirzetal. “have shown, in preferred method of administration of this beta-lactam is Vivo, that preventing LeXA cleavage renders bacteria unable parenteral by i.v. infusion, i.V. bolus, ori.m. injection; 2, 3, or to evolve resistance to either ciprofloxacin or rifampicin in a 4 times per day. mouse thigh infection model.” (See Cirz et al.; Inhibition of 0016 U.S. Pat. No. 5,789,584 (Microcide Pharmaceuti Mutation and Combating the Evolution of Antibiotic Resis cals, Inc.) discloses (7R)-7-(acylamino)-3-(substituted-py tance; PLOS Biology June 2005/Vol. 3/Issue 6/e176, pages ridinyl)-3-cephem-4-carboxylic acids or their pharmacologi 1024-1033). cally acceptable salts, as exhibiting antibiotic activity against 0022. In accordance with an aspect of the invention there MRSA. The preferred method of administration of the beta is provided a once-a-day, anti-MRSA pharmaceutical prod lactam is intravenous or intraperitoneal, one to four times per uct providing a daily dosage of a combination of at least three day. differentantibiotics, wherein one of theat least three different 0017 U.S. Pat. No. 6,265,394 (Bristol-Myers Squibb antibiotics is selected from the group consisting of RNA Company) discloses gram-positive cephem derivatives as Polymerase Inhibiting antibiotics, one of the at least three being useful in the treatment of diseases caused by MRSA. different antibiotics is selected from the group consisting of The patent further discloses that in MRSA-infected mice, Dihydropteroate Synthase Inhibiting antibiotics, and one of against a Vancomycin control, the PDs (the dose of drug the at least three different antibiotics is selected from the given which protects 50% of mice from mortality) may range group consisting of Dihydrofolate Reductase Inhibiting anti from 0.8 to about 16.5 mg/kg when the beta-lactam is given biotics (or analogues, derivatives, polymorphs, metabolites, by intramuscular injection twice within the post-infection pro-drugs, salts, and/or hydrates of any of the foregoing). 24-hour period. 0023. In general, in those embodiments containing only 0018 U.S. Pat. No. 6,946,458 (University of South the three active ingredients selected from each of the RNA Florida) discloses N-thiolated beta-lactams, for use in the Polymerase Inhibiting, Dihydropteroate Synthase Inhibiting, treatment or inhibition of MRSA, but the patent discloses and Dihydrofolate Reductase Inhibiting antibiotic classes, nothing with regard to the daily frequency of dosing for each active ingredient accounts for about 5% to about 90% of treatment of this ever-more challenging to treat indication, the total compliment of active ingredient in the product. Pref with Such beta-lactams. erably each active ingredient accounts for about 10% to about 0019. The above referenced beta-lactam prior art to the 85% of the total compliment of active ingredient in the prod contrary notwithstanding, however, the present and future uct. More preferably each active ingredient accounts for utilities of beta-lactam oriented anti-MRSA regimens must about 15% to about 80% of the total compliment of active be seriously questioned insofar as MRSA is generally recog ingredient in the product. nized as being resistant to beta-lactams, including all penicil 0024. In general, the individual antibiotics are present in lins and cephaolsporins—this, according to a recent multi the product in the following amounts: about 20 mg. to about agency collaborative publication titled Interim Guidelines for 2000 mg. ofan RNA-Polymerase Inhibiting antibiotic, about Evaluation & Management of Community-Associated Methi 100 mg. to about 3000 mg. of a Dihydropteroate Synthase cillin-Resistant Staphylococcus Aureus Skin and Soft Tissue Inhibiting antibiotic, and about 20 mg. to about 2000 mg. of Infections in Outpatient Settings (Sep. 2, 2004, Infectious a Dihydrofolate Reductase Inhibiting antibiotic. Diseases Society of Washington Tacoma-Pierce County 0025. In accordance with a further aspect of the invention Health Department Public Health Seattle & King County— there is provided a once-a-day anti-MRSA pharmaceutical Washington State Department of Health). Gorwitz et al. have product providing a daily dosage of a combination of at least also noted that HA-MRSA isolates “are usually resistant in three different antibiotics, wherein one of the at least three Vivo to multiple classes of antimicrobial agents.” and have different antibiotics is selected from the group consisting of further noted the resistance of CA-MRSA “to beta-lactams RNA-Polymerase Inhibiting antibiotics, one of the at least (the antimicrobial class that includes penicillins and cepha three different antibiotics is selected from the group consist losporins) and macrollides/azalides (e.g., erythromycin, ing of Dihydropteroate Synthase Inhibiting antibiotics, and clarithromycin, azithromycin).' They additionally noted that one of the at least three different antibiotics is selected from “resistance to other classes of antimicrobial agents, such as the group consisting of Dihydrofolate Reductase Inhibiting fluoroquinolones and tetracyclines, occurs and may be antibiotics (or analogues, derivatives, polymorphs, metabo increasing in prevalence.” (Gorwitz et al.; Strategies for lites, pro-drugs, salts, and/or hydrates of any of the forego Clinical Management of MRSA in the Community. Summary ing), in further combination with a daily dosage of a resis of an Experts Meeting Convened by the Centers for Disease tance inhibitor, preferably a LexA protease cleavage Control and Prevention: Department of Health and Human inhibitor. US 2010/001 6333 A1 Jan. 21, 2010

0026. In general, in those embodiments containing the otic, Saphenamycin is included in the alternative embodiment three active ingredients selected from each of the RNA-Poly wherein a phenazine is used instead of an RNA-Polymerase merase Inhibiting, Dihydropteroate Synthase Inhibiting, and Inhibiting antibiotic. Dihydrofolate Reductase Inhibiting antibiotic classes, and 0031. As non-limiting examples of the Dihydropteroate additionally containing a resistance inhibitor (Such as a Lex A Synthase Inhibiting antibiotics (analogues, derivatives, poly protease cleavage inhibitor), each active ingredient accounts morphs, metabolites, pro-drugs, salts, and/or hydrates of any for about 2% to about 96% of the total compliment of active of the foregoing) that may be used in the invention there may ingredient in the product. Preferably each active ingredient be mentioned: Sulfamethoxazole; para-aminobenzene accounts for about 5% to about 90% of the total compliment Sulfonamide derivatives (aka Sulfanilamide-analogues); Sul of active ingredient in the product. More preferably each fanilamide; Sulfadiazine; Sulfamethoxazole; Sulfadoxine; active ingredient accounts for about 10% to about 85% of the Sulfisoxazole, Sulfisoxazole acetyl; Sulfacetimide, Sulfapyri total compliment of active ingredient in the product. dine, Sulfasalazine; mafenide; Sulfadimethoxine, Sulfaqui noxaline; silver Sulfadiazine; mafenide acetate; Sulfisoxazole 0027. In general, the combination of antibiotics and diolamine; phtalylsulfacetamide: phtalylsulfathiazole; sulf inhibitor are present in the product in the following amounts: aguanidine, Sulfamazole; sulfamazone; sulfametopirazine; about 20 mg. to about 2000 mg. of an RNA-Polymerase Sulfametoxypiridazine; Sulfametrol; Succinylsulfathiazole; Inhibiting antibiotic, about 100 mg. to about 3000 mg. of a 2,4-Diaminoquinazolines; Pyridopyrimidines; 2.3-a-pyrim Dihydropteroate Synthase Inhibiting antibiotic, about 20 mg. idines; 5-deaza-pteridine: Epiroprim; Brodimoprim: K-130; to about 2000 mg. of a Dihydrofolate Reductase Inhibiting SRI 8858; the class of the sulfones (aka diaminophenylsul antibiotic, and about 5 mg. to about 5000 mg. of an inhibitor. fones, such as dapsone and Sulfoxone); and any antibiotic 0028. As non-limiting examples of the RNA-Polymerase which may act synergistically with any, or each, of a Dihy Inhibiting antibiotics (analogues, derivatives, polymorphs, drofolate Reductase Inhibiting antibiotic (or analogue, metabolites, pro-drugs, salts, and/or hydrates of any of the derivative etc.), and/or a RNA-Polymerase Inhibiting antibi foregoing) that may be used in the invention there may be otic (or analogue, derivative etc.). mentioned: rifamycin; rifampin: rifampicin: rifabutin: rifap 0032. As non-limiting examples of the Dihydrofolate entin: rifapentine; rifaximin: rifalazil; the ansamycin antibi Reductase Inhibiting antibiotics (analogues, derivatives, otics (drug class); rifamycin SV: rifamycin B diethylamide: polymorphs, metabolites, pro-drugs, salts, and/or hydrates of rifamycin W: rifamycin S: rifamycin P: rifamycin O: rifamy any of the foregoing) that may be used in the invention there cin R; rifamycin U; rifamycin Y: rifamycin 3-iminomethyl may be mentioned: trimethoprim, pyrimethamine; iclaprim; enyl ( CH=N ) derivatives; rifamycin-imino-derivatives: ormetoprim; 2,4-diaminopyrimidine; Sulfanilic acid; rifamycin-C11-oxime derivatives; rifamycin-C11-oxime nitroSoisocytosines; monocyclic pteridines; proguanil; chlo cyclo derivatives; Spiro-rifamycin; C-25 carbamaterifamycin roguanide; cycloguanil; and any antibiotic which may act derivatives: rifamexil; rifamdin: rifamide: rifaprim; rifamet synergistically with any, or each, of a Dihydropteroate Syn (h)oprim; kanglemycin A; protorifamycin; rifamycin Verde; thase Inhibiting antibiotic (or analogue, derivative etc.) and/ ansamycin LM427; rifamazine; Streptolygidin; Sorangicin A; or a RNA-Polymerase Inhibiting antibiotic (or analogue, MDL473; GE23077; other (bacterial) RNA-Polymerase derivative etc.). inhibitors such as the CBR703 series (Artsimovitch I, et al., 0033. As non-limiting examples of the resistance inhibi Science. 2003 Oct. 24; 302(5645):650-4); Microcin J25 tors that may be used in the invention there may be men (Mukhopadhyay et al. 2004 Mol Cell 14:739; Adelman et al. tioned: any achaogen able to reduce the rate of induced 2004 Mol Cell 14:753); and any antibiotic which may act mutagenesis, which may include nucleic acids, peptide synergistically with any, or each, of: a Dihydrofolate Reduc nucleic acids, phages, phagemids, polypeptides, peptidomi tase Inhibiting antibiotic (or analogue, derivative etc.) and/or metics, antibodies, Small or large organic or inorganic mol a Dihydropteroate Synthase Inhibiting antibiotic (or ana ecules or any combination of the above; of natural or non logue, derivative etc.). natural origin; able to bind to or interact with gene products 0029. In addition to the above-mentioned non-limiting that increase the rate of mutations in a cell or organism. examples, and consistent with the broadest reasonable inter Examples of such gene products include RecA, RecB. RecC. pretation of this specification (M.P.E.P. S.2111), as used in the RecD, RecE. RecC., RecN, Lex A, UmuC, Umu), PolB, hereto-attached, or in any later-amended, claims the term PolIV, Poly, PriA, RuvA. RuvB, RuvC, UmuC, UmulD, RNA-Polymerase Inhibiting antibiotic is to be interpreted UvrA, UvrB, UvrD, or any homologs or analogs thereof. without regard to whether the manner by which any such Examples of Such polypeptides (and peptidomimetics antibiotic inhibits an RNA-Polymerase enzyme is allosteric thereof) include those comprising or consisting of dipeptide or competitive. Ala-Ala., tripeptide Val-Ala-Ala, or SEQID NO: 1, 2, or 3. In 0030 Although one of ordinary skill in the art may or may Some embodiments wherein the achaogen comprises an Ala not recognize Saphenamycin as being an RNA-Polymerase Gly bond, the bond may be modified so that it is not cleavable Inhibiting antibiotic, in an alternative embodiment of the under normal physiological conditions. In some embodi invention saphenamycin may be substituted for the RNA ments, the polypeptide or peptidomimetic is C-terminally Polymerase Inhibiting antibiotic of the instant invention, as modified, e.g., such that it is electrophilic. For further instruc such invention is hereinabove-described and hereinbelow tion on this aspect of the invention, the disclosures of U.S. described. In an alternative embodiment of the invention a Patent Application Publication 2006/011 1302 A1 and PCT/ phenazine may be substituted for the RNA-Polymerase US2004/039064 (WO 2005/056754A2) are hereby incorpo Inhibiting antibiotic of the instant invention, as Such inven rated by reference in their entireties. tion is hereinabove-described and hereinbelow-described. 0034 Generally, the once-a-day product comprises: at Saphenamycin is a phenazine and therefore, to the extent that least one component(s), wherein each component comprises saphneamycin is not an RNA-Polymerase Inhibiting antibi a pharmaceutically acceptable carrier and at least one antibi US 2010/001 6333 A1 Jan. 21, 2010

otic(s); such that the product on whole, regardless of whether of an antibiotic combination comprising at least three differ it contains one component or a plurality of components, fur ent antibiotics, wherein one of the at least three different ther comprises: a combination of at least three different anti antibiotics is selected from the group consisting of RNA biotics, wherein one of the at least three different antibiotics Polymerase Inhibiting antibiotics, wherein one of the at least is selected from the group consisting of RNA-Polymerase three different antibiotics is selected from the group consist Inhibiting antibiotics, wherein one of the at least three differ ing of Dihydropteroate Synthase Inhibiting antibiotics, and ent antibiotics is selected from the group consisting of Dihy wherein one of the at least three different antibiotics is dropteroate Synthase Inhibiting antibiotics, and wherein one selected from the group consisting of Dihydrofolate Reduc of the at least three different antibiotics is selected from the tase Inhibiting antibiotics (alternatively any or all of the group consisting of Dihydrofolate Reductase Inhibiting anti aforementioned RNA-Polymerase Inhibiting antibiotics, biotics (alternatively any or all of the aforementioned RNA Dihydropteroate Synthase Inhibiting antibiotics, and Dihy Polymerase Inhibiting antibiotics, Dihydropteroate Synthase drofolate Reductase Inhibiting antibiotics may be in the form Inhibiting antibiotics, and Dihydrofolate Reductase Inhibit of analogues, derivatives, polymorphs, metabolites, pro ing antibiotics may be in the form of analogues, derivatives, drugs, salts, and/or hydrates of any of the foregoing). In some polymorphs, metabolites, pro-drugs, salts, and/or hydrates of embodiments of the invention each of the at least three dif any of the foregoing); Such that the product is administered to ferent antibiotics may be present in each component of the a patient once-a-day; and Such that the product contains a product. In other embodiments of the invention each of the at therapeutically-effective, anti-MRSA daily dosage of an anti least three different antibiotics may be present in a separate biotic combination comprising the aforementioned three dif component of the product either independent of, or to the ferent antibiotics, so selected from among the RNA-Poly exclusion of the presence therein of any other, or all other, merase Inhibiting, Dihydropteroate Synthase Inhibiting, and antibiotic(s). In yet other embodiments of the invention com Dihydrofolate Reductase Inhibiting antibiotic classes. The at binations of all, or less than all, of the at least three different least one component(s) may be an immediate release compo antibiotics may be in all, or less than all, of the components of nent, a modified release component, or a combination of the product. thereof. As used herein and as known in the art, immediate 0036 Consistent with the above-delimited component release components shall include any component from which permutations, in several embodiments of the present inven the initiation of release, and/or the rate of release, of active tion there is provided a once-a-day, therapeutically-effective, ingredient is not substantially delayed, and/or slowed, and/or anti-MRSA pharmaceutical product providing a daily dosage Sustained, after administration of the product. As used herein of a combination comprising at least three different antibiot and as known in the art, modified release components shall ics, wherein one of the at least three different antibiotics is include any component which is not considered as herein selected from the group consisting of RNA-Polymerase above defined as an immediate release component. Non-lim Inhibiting antibiotics, wherein one of the at least three differ iting examples of Such modified release components shall ent antibiotics is selected from the group consisting of Dihy include: delayed release component(s), Sustained (or dropteroate Synthase Inhibiting antibiotics, and wherein one extended) release component(s), and/or combinations of the of the at least three different antibiotics is selected from the foregoing. Accordingly, Such Sustained (or extended) release group consisting of Dihydrofolate Reductase Inhibiting anti components may be formulated so that initiation of release of biotics; wherein the product comprises a single component the individual antibiotic or combination of antibiotic(s) and/ containing all three of the at least three different antibiotics so or inhibitor(s) therefrom is not substantially delayed after selected; wherein the single component is an immediate administration of the antibiotic product, or it may be formu release component or a modified release component; and lated so that initiation of release of the individual antibiotic or from which any of the initiation, rate, or duration, of the combination of antibiotic(s) and/or inhibitor(s) therefrom is release of any of the at least three different antibiotics so substantially delayed after administration of the antibiotic selected may be the same or different as respectively com product. The formulating of the aforementioned components pared to any of the initiation, rate, or duration, of the release will be apparent to those of ordinary skill in the art in view of of any other of the at least three different antibiotics so the disclosures herein, further guided by the disclosures of selected. U.S. patent application Ser. Nos. 10/894,787: 10/894,786; 0037 Similarly consistent with the above-delimited com 10/894,994; 10/917,059; 10/922,412; and 10/940,265; and ponent permutations, in several embodiments of the present by the disclosures of U.S. Pat. Nos. 6,544,555; 6,623,757; and invention there is provided a once-a-day, therapeutically-ef 6,669,948; all of which are hereby incorporated by this ref fective, anti-MRSA pharmaceutical product providing a daily erence in their entireties. dosage of a combination comprising at least three different 0035. In some embodiments of the invention the product antibiotics, wherein one of the at least three different antibi will contain a single component, wherein the single compo otics is selected from the group consisting of RNA-Poly nent comprises: either an immediate release component or a merase Inhibiting antibiotics, wherein one of the at least three modified release component. In some embodiments of the different antibiotics is selected from the group consisting of invention the product will contain a plurality of components, Dihydropteroate Synthase Inhibiting antibiotics, and wherein wherein the plurality of components comprises: immediate one of the at least three different antibiotics is selected from release components; modified release components; or com the group consisting of Dihydrofolate Reductase Inhibiting binations of the foregoing. Regardless of whether the once antibiotics; wherein the product comprises two components, a-day product contains only a single component (modified in one containing at least one of the at least three different its release or not), or contains a plurality of components antibiotics so selected and the other containing at least two of (modified in their release(s) or not); it is an aspect of every the at least three different antibiotics so selected; wherein the embodiment of the invention that the product as a whole two components are each independently selected from the contains atherapeutically-effective, anti-MRSA daily dosage group consisting of immediate release components and modi US 2010/001 6333 A1 Jan. 21, 2010

fied release components; and from which any of the initiation, 0040. In some embodiments of the present invention there rate, or duration, of the release of any of the at least three is provided a once-a-day, therapeutically-effective, anti different antibiotics so selected may be the same or different MRSA pharmaceutical product providing a daily dosage of a as respectively compared to any of the initiation, rate, or combination comprising at least three different antibiotics, duration, of the release of any other of the at least three wherein one of the at least three different antibiotics is different antibiotics so selected, irrespective of either compo selected from the group consisting of RNA-Polymerase nent. In several such embodiments both of the components Inhibiting antibiotics, wherein one of the at least three differ ent antibiotics is selected from the group consisting of Dihy are immediate release components. In several other Such dropteroate Synthase Inhibiting antibiotics, and wherein one embodiments both of the components are delayed release of the at least three different antibiotics is selected from the components. In still several other such embodiments both of group consisting of Dihydrofolate Reductase Inhibiting anti the components are Sustained release components. In yet still biotics; wherein the product comprises an immediate release several other such embodiments both of the components are a component that contains rifampin; and in either order, an combination of any of immediate, delayed, and Sustained immediate-release and/or Subsequent modified-release com release components. ponent(s) containing Sulfamethoxazole, and an immediate 0038. Further consistent with the above-delimited compo release and/or Subsequent modified-release component(s) nent permutations, in several embodiments of the present containing trimethoprim. invention there is provided a once-a-day, therapeutically-ef 0041. In another embodiment of the present invention fective, anti-MRSA pharmaceutical product providing a daily there is provided a once-a-day, anti-MRSA pharmaceutical dosage of a combination comprising at least three different product, which is comprised of at least two, preferably at least antibiotics, wherein one of the at least three different antibi three, components (at least one of which is a modified release otics is selected from the group consisting of RNA-Poly component). Such components are formulated so that each of merase Inhibiting antibiotics, wherein one of the at least three the components has a different release profile and so that the different antibiotics is selected from the group consisting of composition provides a daily dosage of a combination com Dihydropteroate Synthase Inhibiting antibiotics, and wherein prising at least three different antibiotics, wherein one of the one of the at least three different antibiotics is selected from at least three different antibiotics is selected from the group the group consisting of Dihydrofolate Reductase Inhibiting consisting of RNA-Polymerase Inhibiting antibiotics, antibiotics; wherein the product comprises three components wherein one of the at least three different antibiotics is each containing a different one of each of the at least three selected from the group consisting of Dihydropteroate Syn different antibiotics so selected; wherein the three compo thase Inhibiting antibiotics, and wherein one of the at least nents are each independently selected from the group con three different antibiotics is selected from the group consist sisting of immediate release components and modified ing of Dihydrofolate Reductase Inhibiting antibiotics (orana release components; and from which any of the initiation, logues, derivatives, polymorphs, metabolites, pro-drugs, rate, or duration, of the release of any of the at least three salts, and/or hydrates of any of the foregoing). different antibiotics so selected may be the same or different 0042. In another embodiment of the present invention as respectively compared to any of the initiation, rate, or there is provided a once-a-day, anti-MRSA pharmaceutical duration, of the release of any other of the at least three product, which is comprised of at least two, preferably at least different antibiotics so selected, irrespective of any compo three, components (at least one of which is a modified release nent. In several Such embodiments all three components are component). Such components are formulated so that each of immediate release components. In several other such embodi the components has a different release profile and so that the ments all three components are delayed release components. composition provides a daily dosage of a combination com In still several other such embodiments all three components prising at least three different antibiotics, wherein one of the are Sustained release components. In yet still several other at least three different antibiotics is selected from the group Such embodiments all three components are a combination of consisting of RNA-Polymerase Inhibiting antibiotics, any of immediate, delayed, and Sustained release compo wherein one of the at least three different antibiotics is nentS. selected from the group consisting of Dihydropteroate Syn 0039. In some embodiments of the present invention there thase Inhibiting antibiotics, and wherein one of the at least is provided a once-a-day, therapeutically-effective, anti three different antibiotics is selected from the group consist MRSA pharmaceutical product providing a daily dosage of a ing of Dihydrofolate Reductase Inhibiting antibiotics (orana combination comprising at least three different antibiotics, logues, derivatives, polymorphs, metabolites, pro-drugs, wherein one of the at least three different antibiotics is salts, and/or hydrates of any of the foregoing), in further selected from the group consisting of RNA-Polymerase combination with a daily dosage of a resistance inhibitor, Inhibiting antibiotics, wherein one of the at least three differ preferably a Lex A protease cleavage inhibitor. ent antibiotics is selected from the group consisting of Dihy 0043. In another embodiment of the invention there is dropteroate Synthase Inhibiting antibiotics, and wherein one provided a once-a-day, anti-MRSA pharmaceutical product, of the at least three different antibiotics is selected from the wherein there are at least two, preferably at least three com group consisting of Dihydrofolate Reductase Inhibiting anti ponents (at least one of which is a modified release compo biotics; wherein the product comprises in any order at least nent), each of which has a different release profile, the release three components: an immediate release component or a profile of each of the components being such that the com modified release component containing at least rifampin, an ponents each start release of the individual antibiotic or com immediate release component or a modified release compo bination of antibiotic(s) contained therein at different times nent containing at least Sulfamethoxazole, and an immediate after administration of the product, and the product provides release component or a modified release component contain a daily dosage of a combination comprising at least three ing at least trimethoprim. differentantibiotics, wherein one of theat least three different US 2010/001 6333 A1 Jan. 21, 2010

antibiotics is selected from the group consisting of RNA 0046. In accordance with another embodiment of the Polymerase Inhibiting antibiotics, wherein one of the at least invention, the antibiotic product may be comprised of at least three different antibiotics is selected from the group consist four different components, each of which has a different ing of Dihydropteroate Synthase Inhibiting antibiotics, and release profile, and the product provides a daily dosage of a wherein one of the at least three different antibiotics is combination comprising at least three different antibiotics, selected from the group consisting of Dihydrofolate Reduc wherein one of the at least three different antibiotics is tase Inhibiting antibiotics (or analogues, derivatives, poly selected from the group consisting of RNA-Polymerase morphs, metabolites, pro-drugs, salts, and/or hydrates of any Inhibiting antibiotics, wherein one of the at least three differ of the foregoing). ent antibiotics is selected from the group consisting of Dihy dropteroate Synthase Inhibiting antibiotics, and wherein one 0044. In another embodiment of the invention there is of the at least three different antibiotics is selected from the provided a once-a-day, anti-MRSA pharmaceutical product, group consisting of Dihydrofolate Reductase Inhibiting anti wherein there are at least two, preferably at least three com biotics (or analogues, derivatives, polymorphs, metabolites, ponents (at least one of which is a modified release compo pro-drugs, salts, and/or hydrates of any of the foregoing); or nent), each of which has a different release profile, the release provides a daily dosage of a combination comprising at least profile of each of the components being such that the com three different antibiotics, wherein one of the at least three ponents each start release of the individual antibiotic or com different antibiotics is selected from the group consisting of bination of antibiotic(s) and/or inhibitor(s) contained therein RNA-Polymerase Inhibiting antibiotics, wherein one of the at at different times after administration of the product, and the least three different antibiotics is selected from the group product provides a daily dosage of a combination comprising consisting of Dihydropteroate Synthase Inhibiting antibiot at least three different antibiotics, wherein one of the at least ics, and wherein one of the at least three different antibiotics three different antibiotics is selected from the group consist is selected from the group consisting of Dihydrofolate Reduc ing of RNA-Polymerase Inhibiting antibiotics, wherein one tase Inhibiting antibiotics (or analogues, derivatives, poly of the at least three different antibiotics is selected from the morphs, metabolites, pro-drugs, salts, and/or hydrates of any group consisting of Dihydropteroate Synthase Inhibiting of the foregoing), in further combination with a daily dosage antibiotics, and wherein one of the at least three different of a resistance inhibitor, preferably a LeXA protease cleavage antibiotics is selected from the group consisting of Dihydro inhibitor. folate Reductase Inhibiting antibiotics (or analogues, deriva 0047. In accordance with another embodiment of the tives, polymorphs, metabolites, pro-drugs, salts, and/or invention, the antibiotic product may be comprised of at least hydrates of any of the foregoing), in further combination with five different components, each of which has a different a daily dosage of a resistance inhibitor, preferably a Lex A release profile, and the product provides a daily dosage of a protease cleavage inhibitor. combination comprising at least three different antibiotics, 004.5 Thus, in accordance with such embodiments of the wherein one of the at least three different antibiotics is present invention, there is provided a single or unitary anti selected from the group consisting of RNA-Polymerase biotic product that has contained therein at least two, prefer Inhibiting antibiotics, wherein one of the at least three differ ably at least three components (at least one of which is a ent antibiotics is selected from the group consisting of Dihy modified release component); each of which has a different dropteroate Synthase Inhibiting antibiotics, and wherein one release profile, whereby the individual antibiotic or combi of the at least three different antibiotics is selected from the nation of antibiotic(s) and/or inhibitor(s) contained in each of group consisting of Dihydrofolate Reductase Inhibiting anti Such components is released at different times, and the anti biotics (or analogues, derivatives, polymorphs, metabolites, biotic product provides a daily dosage of a combination com pro-drugs, salts, and/or hydrates of any of the foregoing); or prising at least three different antibiotics, wherein one of the provides a daily dosage of a combination comprising at least at least three different antibiotics is selected from the group three different antibiotics, wherein one of the at least three consisting of RNA-Polymerase Inhibiting antibiotics, different antibiotics is selected from the group consisting of wherein one of the at least three different antibiotics is RNA-Polymerase Inhibiting antibiotics, wherein one of the at selected from the group consisting of Dihydropteroate Syn least three different antibiotics is selected from the group thase Inhibiting antibiotics, and wherein one of the at least consisting of Dihydropteroate Synthase Inhibiting antibiot three different antibiotics is selected from the group consist ics, and wherein one of the at least three different antibiotics ing of Dihydrofolate Reductase Inhibiting antibiotics (orana is selected from the group consisting of Dihydrofolate Reduc logues, derivatives, polymorphs, metabolites, pro-drugs, tase Inhibiting antibiotics (or analogues, derivatives, poly salts, and/or hydrates of any of the foregoing); or provides a morphs, metabolites, pro-drugs, salts, and/or hydrates of any daily dosage of a combination comprising at least three dif of the foregoing), in further combination with a daily dosage ferent antibiotics, wherein one of the at least three different of a resistance inhibitor, preferably a LeXA protease cleavage antibiotics is selected from the group consisting of RNA inhibitor. Polymerase Inhibiting antibiotics, wherein one of the at least 0048. In accordance with one embodiment of the inven three different antibiotics is selected from the group consist tion, there are at least three components (at least one of which ing of Dihydropteroate Synthase Inhibiting antibiotics, and is a modified release component). One of the at least three wherein one of the at least three different antibiotics is components is an immediate release component whereby selected from the group consisting of Dihydrofolate Reduc initiation of release of the individual antibiotic or combina tase Inhibiting antibiotics (or analogues, derivatives, poly tion of antibiotic(s) and/or inhibitor(s) therefrom is not sub morphs, metabolites, pro-drugs, salts, and/or hydrates of any stantially delayed after administration of the antibiotic prod of the foregoing), in further combination with a daily dosage uct. The second and third of the at least three components are of a resistance inhibitor, preferably a LeXA protease cleavage delayed release components (each of which may be a pH inhibitor. sensitive or a non-pH sensitive delayed component, depend US 2010/001 6333 A1 Jan. 21, 2010 ing on the type of antibiotic product), whereby the individual range of about 100 mg. to about 400 mg. and the trimethoprim antibiotic or combination of antibiotic(s) and/or inhibitor(s) is present in a range of about 20 mg. to about 80 mg., and a released therefrom is delayed until after initiation of release second (in time to release) delayed release component con of the individual antibiotic or combination of antibiotic(s) taining a combination of Sulfamethoxazole and trimethoprim and/or inhibitor(s) from the immediate release component. (SMX-TMP), wherein the sulfamethoxazole is present in a 0049. In one embodiment, the second of the at least three range of about 100 mg. to about 400 mg. and the trimethprim components initiates release of the individual antibiotic or is present in a range of about 20 mg. to about 80 mg. combination of antibiotic(s) and/or inhibitor(s) contained 0054. In several embodiments of the present invention therein at least one hour after the first component, with the there is provided a once-a-day, therapeutically-effective, anti initiation of the release therefrom generally occurring no MRSA pharmaceutical product providing a daily dosage of a more than six hours after initiation of release of individual combination of the antibiotics rifampin, Sulfamethoxazole, antibiotic or combination of antibiotic(s) and/or inhibitor(s) and trimethoprim (or analogues, derivatives, polymorphs, from the first component of the at least three components. metabolites, pro-drugs, salts, and/or hydrates of any of the 0050. As hereinabove indicated, some embodiments of the foregoing) wherein the product comprises: an immediate antibiotic product may contain three, four, or more different release component containing rifampin in a range of about components. 150 mg. to about 600 mg., an immediate release component 0051. In a preferred embodiment, the antibiotic product is containing a combination of sulfamethoxazole and trimetho a once-a-day product, whereby after administration of the prim (SMX-TMP), wherein the sulfamethoxazole is present antibiotic product, no further composition is administered in a range of about 200 mg. to about 800 mg. and the trime during the day; i.e., the preferred regimen is that the product thoprim is presentina range of about 40 mg. to about 160 mg.: is administered only once over a twenty-four hour period. a delayed release component containing a combination of Thus, in accordance with this preferred embodiment, there is sulfamethoxazole and trimethoprim (SMX-TMP), wherein a single administration of an antibiotic product with the anti the Sulfamethoxazole is present in a range of about 50 mg. to biotic combination (and the optional inhibitor). The term about 200 mg. and the trimethoprim is present in a range of single administration means that the total daily dosage of a about 10 mg. to about 30 mg., and a Sustained release com combination comprising at least three different antibiotics, ponent containing a combination of Sulfamethoxazole and wherein one of the at least three different antibiotics is trimethoprim (SMX-TMP), wherein the sulfamethoxazole is selected from the group consisting of RNA-Polymerase present in a range of about 150 mg. to about 600 mg. and the Inhibiting antibiotics, wherein one of the at least three differ trimethoprim is present in a range of about 30 mg. to about 90 ent antibiotics is selected from the group consisting of Dihy ng. dropteroate Synthase Inhibiting antibiotics, and wherein one 0055. In several embodiments of the present invention of the at least three different antibiotics is selected from the there is provided a once-a-day, therapeutically-effective, anti group consisting of Dihydrofolate Reductase Inhibiting anti MRSA pharmaceutical product providing a daily dosage of a biotics (or analogues, derivatives, polymorphs, metabolites, combination of the antibiotics rifampin, Sulfamethoxazole, pro-drugs, salts, and/or hydrates of any of the foregoing), with and trimethoprim (or analogues, derivatives, polymorphs, or without the further combination of a daily dosage of a metabolites, pro-drugs, salts, and/or hydrates of any of the resistance inhibitor, preferably a Lex A protease cleavage foregoing) wherein the product comprises: an immediate inhibitor, administered over a twenty-four hour period, is release component containing rifampin in a range of about administered at the same time, which can be a single tablet or 150 mg. to about 600 mg.; a first (in time to release) delayed capsule or sachet or two or more thereof, provided that they release component containing a combination of sulfamethox are administered at essentially the same time. azole and trimethoprim (SMX-TMP), wherein the sul 0052. In general, each of the components in the antibiotic famethoxazole is present in a range of about 130 mg. to about product may have one or more individual antibiotics or a 540 mg. and the trimethoprim is present in a range of about 20 combination of antibiotic(s) and/or inhibitor(s), and each of mg. to about 80 mg., a second (in time to release) delayed the components may have the same individual antibiotic or release component containing a combination of sulfamethox the same combination of antibiotic(s) and/or inhibitor(s) or a azole and trimethoprim (SMX-TMP), wherein the sul different individual antibiotic or a different combination of famethoxazole is present in a range of about 130 mg. to about antibiotic(s) and/or inhibitor(s). 540 mg. and the trimethoprim is present in a range of about 20 0053. In several embodiments of the present invention mg. to about 80 mg., and a Sustained release component there is provided a once-a-day, therapeutically-effective, anti containing a combination of sulfamethoxazole and trimetho MRSA pharmaceutical product providing a daily dosage of a prim (SMX-TMP), wherein the sulfamethoxazole is present combination of the antibiotics rifampin, Sulfamethoxazole, in a range of about 130 mg. to about 540 mg. and the trime and trimethoprim (or analogues, derivatives, polymorphs, thoprim is present in a range of about 20 mg. to about 80 mg. metabolites, pro-drugs, salts, and/or hydrates of any of the 0056. As long as the product as a whole contains a com foregoing) wherein the product comprises: an immediate bination comprising at least three different antibiotics, release component containing rifampin in a range of about wherein one of the at least three different antibiotics is 150 mg. to about 600 mg., an immediate release component selected from the group consisting of RNA-Polymerase containing a combination of sulfamethoxazole and trimetho Inhibiting antibiotics, wherein one of the at least three differ prim (SMX-TMP), wherein the sulfamethoxazole is present ent antibiotics is selected from the group consisting of Dihy in a range of about 200 mg. to about 800 mg. and the trime dropteroate Synthase Inhibiting antibiotics, and wherein one thoprim is presentina range of about 40 mg. to about 160 mg.: of the at least three different antibiotics is selected from the a first (in time to release) delayed release component contain group consisting of Dihydrofolate Reductase Inhibiting anti ing a combination of Sulfamethoxazole and trimethoprim biotics, it is within the scope of the invention that the product (SMX-TMP), wherein the sulfamethoxazole is present in a may be comprised of various types of individual components US 2010/001 6333 A1 Jan. 21, 2010

or combinations of various types of individual components. 0061. In addition, the antibiotic product may be formu Non-limiting embodiment examples may include: a single lated for use in the eye or ear or nose, for example, as a liquid immediate release component, a single modified release com emulsion. For example, the component may be coated with a ponent, a plurality of immediate release components, a plu hydrophobic polymer whereby a component is in the oil rality of modified release components, and a plurality of phase of the emulsion, and a component may be coated with components comprising combinations of immediate release hydrophilic polymer, whereby a component is in the water components and modified release components; wherein any phase of the emulsion. of the here-mentioned modified release components can each 0062. Furthermore, the antibiotic product may be formu be any of the aforementioned delayed release component(s), lated for rectal or vaginal administration, as known in the art. Sustained (or extended) release component(s), and/or combi This may take the form of a cream, an emulsion, a Supposi nations of the foregoing. In some embodiments the product tory, or other dissolvable component similar to those used for comprises an immediate release component in combination topical administration. with a delayed release component. In some embodiments the 0063. In an embodiment, the antibiotic product is formu lated in a manner Suitable for oral administration. Thus, for a product comprises an immediate release component in com non-limiting example, for oral administration, each of the bination with a Sustained release component. In some components may be used as a pellet or a particle, with a pellet embodiments the product comprises a plurality of immediate or particle then being formed into a unitary pharmaceutical release components. In some embodiments the product com composition, for example, in a capsule, or embedded in a prises a plurality of delayed release components. In some tablet, or Suspended in a liquid for oral administration. Simi embodiments the product comprises a plurality of Sustained larly, for a further non-limiting example, for oral administra release components. In some embodiments the product com tion, each of the components may be used as pluralities of prises combinations of the foregoing. pellets or particles, with pluralities of pellets or particles then 0057. It is to be understood that when it is disclosed herein being formed into a unitary pharmaceutical composition, for that a component initiates release after another component, example, in a capsule, or embedded in a tablet, or Suspended Such terminology means that the component is designed and in a liquid for oral administration. is intended to produce Such later initiated release. It is known 0064. Alternatively, in formulating an oral delivery sys in the art, however, notwithstanding Such design and intent, tem, each of the components of the composition may be that some “leakage' of antibiotic may occur. Such “leakage” formulated as a single layer or multilayer tablet or similar is not “release' as used herein. unit, and each tablet or similar unit may be administered 0058. The antibiotic product of the present invention, as once-a-day, as individual tablets or similar units provided that hereinabove described, may beformulated for administration they are administered at essentially the same time; or each of by a variety of routes of administration. For example, the the tablets or similar components may be put into a capsule to antibiotic product may be formulated in a way that is suitable produce a unitary antibiotic composition to be administered for topical administration; administration in the eye or the ear, once-a-day. Thus, as a non-limiting example, a three compo rectal or vaginal administration; as a nasal preparation; by nent antibiotic composition may include a first component in inhalation; as an injectable; or for oral administration. In a the form of a tablet that is an immediate release tablet, and preferred embodiment, the antibiotic product is formulated in may also include two or more additional tablets, each of a manner Such that it is Suitable for oral administration. which provides for a delayed release or a sustained release of 0059 For example, in formulating the antibiotic product any or all of a combination comprising at least three different for topical administration, Such as by application to the skin, antibiotics, wherein one of the at least three different antibi the components, each of which contains an individual antibi otics is selected from the group consisting of RNA-Poly otic or combination of antibiotic(s) and/or inhibitor(s), may merase Inhibiting antibiotics, wherein one of the at least three be formulated for topical administration by including Such different antibiotics is selected from the group consisting of components in an oil-in-water emulsion, or a water-in-oil Dihydropteroate Synthase Inhibiting antibiotics, and wherein emulsion. In Such a formulation, an immediate release com one of the at least three different antibiotics is selected from ponent may be in the continuous phase, and a delayed release the group consisting of Dihydrofolate Reductase Inhibiting component may be in a discontinuous phase. The formulation antibiotics, as hereinabove described. may also be produced in a manner for delivery of three com 0065. The formulation of an antibiotic product including ponents as hereinabove described. For example, there may be at least three components with different or similar release provided an oil-in-water-in-oil emulsion, with oil being a profiles for different routes of administration is deemed to be continuous phase that contains the immediate release com within the skill of the art from the teachings herein. As known ponent, water dispersed in the oil containing a first delayed in the art, with respect to delayed release, the time of release release component, and oil dispersed in the water containing can be controlled by a variety of mechanisms such as pH, a third delayed release component. The topical formulation coating thickness, choice of polymer, and combinations of the may contain penetration enhancers. The topical formulation foregoing. may contain long-lasting polymers that are Generally Recog 0066. In formulating an antibiotic product in accordance nized As Safe (GRAS) in the various pharmacopoeial com with one embodiment of the invention, an immediate release pendia, such as those used in topically applied Sun-screens. component of the composition generally provides from about The release of the various active ingredients of the invention 10% to about 100% of the total dosage of individual antibiotic may also be initiated by means of a mechanical device. or combination of antibiotic(s) and/or inhibitor(s) to be deliv 0060. It is also within the scope of the invention to provide ered by the composition, with Such immediate release com an antibiotic product in the form of a patch, which includes ponent generally providing at least 25% of the total dosage of antibiotic components having different release profiles, as individual antibiotic or combination of antibiotic(s) and/or hereinabove described. inhibitor(s) to be delivered by the composition. In many US 2010/001 6333 A1 Jan. 21, 2010

cases, an immediate release component provides from about administration to release the individual antibiotic or combi 20% to about 70% of the total dosage of individual antibiotic nation of antibiotic(s) and/or inhibitor(s). This can take the or combination of antibiotic(s) and/or inhibitor(s) to be deliv form of either a discretepellet or granule that is mixed in with, ered by the composition; however, in Some cases it may be or compressed with, the other components. desirable to have an immediate release component provide for about 25% to about 50% of the total dosage of individual 0074 The materials to be added to the individual antibiotic antibiotic or combination of antibiotic(s) and/or inhibitor(s) or combination of antibiotic(s) and/or inhibitor(s) for the to be delivered by the composition. immediate release component can be, but are not limited to, 0067. The remaining components deliver the remainder of microcrystalline cellulose, corn starch, pregelatinized starch, the individual antibiotic or combination of antibiotic(s) and/ potato starch, rice starch, Sodium carboxymethyl starch, or inhibitor(s). If more than one component is used each of the hydroxypropylcellulose, hydroxypropylmethylcellulose, components may provide about equal amounts of individual hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychi antibiotic or combination of antibiotic(s) and/or inhibitor(s): however, they may also be formulated so as to provide differ tosan, hydroxymethylated chitosan, cross-linked chitosan, ent amountS. cross-linked hydroxymethyl chitosan, maltodextrin, manni 0068. In accordance with the present invention, each of the tol, Sorbitol, dextrose, maltose, fructose, glucose, levulose, components contains a single individual antibiotic or a com Sucrose, lactose, dicalcium phosphate, polyvinylpyrrolidone bination of antibiotic(s) and/or inhibitor(s); however, each of (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), the components may contain more than one individual anti polyethylene glycols (PEG200-20000). biotic or combination of antibiotic(s) and or inhibitor(s). 0075. It may be useful to have these materials present in 0069. In one embodiment, where the composition con the range of 1.0 to 60% (W/W). tains one immediate release component and two modified release components, the immediate release component pro 0076. In addition, it may be useful to have other ingredi vides from 15% to 75% (preferably 20% to 65%), by weight, ents in this system to aid in the dissolution of the drugs, or the of the total individual antibiotic or combination of antibiotic breakdown of the components after ingestion or administra (s) and/or inhibitor(s); where there are three modified release tion, or drug stability or dissolution. These ingredients can be components, the immediate release component provides Surfactants, such as Sodium lauryl Sulfate, Sodium monoglyc from 15% to 75%, by weight, of the total individual antibiotic erate, Sorbitan monooleate, polyoxyethylene Sorbitan or combination of antibiotic(s) and/or inhibitor(s); and where monooleate, glyceryl monostearate, glyceryl monooleate, there are four modified release components, the immediate release component provides from 15% to 75%, by weight, of glyceryl monobutyrate, one of the non-ionic Surfactants such the total individual antibiotic or combination of antibiotic(s) as the Pluronic line of surfactants, Vitamin E-TPGS or any and/or inhibitor(s). other material with Surface active properties, or any combi 0070. With respect to the modified release components, nation of the above. Further additives may be from the group where there are two modified release components, the first of stabilizers and antioxidants, e.g. ascorbic acid and vitamin modified release component (the one released earlier in time) E. BHT buffers like citric acid or phosphate salts; and disin provides from 15% to 85%, by weight, of the total individual tegrants like crosslinked polyvinyl pyrrolidone, crosslinked antibiotic or combination of antibiotic(s) and/or inhibitor(s) hydroxypropylcellulose, sodium starch glycolate, or sodium provided by the two modified release components with the carboxymethylcellulose. second modified release component providing the remainder 0077. These materials may be present in the range of 0.05 of the individual antibiotic or combination of antibiotic(s) and/or inhibitor(s). 15% (W/W). 0071. Where there are three modified release components, the earliest released component provides 10% to 70% by The Non-pH Sensitive Delayed Release Component weight of the total individual antibiotic or combination of 0078. The components in this composition are the same as antibiotic(s) and/or inhibitor(s) provided by the three modi the immediate release unit, but with additional polymers inte fied release components, the next in time modified release grated into the composition, or as coatings over the pellet or component provides from 10% to 70%, by weight, of the granule. individual antibiotic or combination of antibiotic(s) and/or inhibitor(s) provided by the three modified release compo (0079. Several methods to affect a delayed release with nents and the last in time provides the remainder of the indi non-pH dependent polymers are known to those skilled in the vidual antibiotic or combination of antibiotic(s) and/or art. These include soluble or erodible barrier systems, enzy inhibitor(s) provided by the three modified release compo matically degraded barrier systems, rupturable coating sys nentS. tems, and plugged capsule systems among others. These sys 0072. When there are four modified release components, tems have been thoroughly described in the literature (see 'A the earliest modified release component provides from 10% Review of Pulsatile Drug Delivery” by Bussemer and Bod to 70%, by weight, the next in time modified release compo meier in the Winter 2001 issue of American Pharmaceutical nent provides from 10% to 70%, by weight, the next in time Review) and the formulations and methods (described modified release component provides from 10% to 70%, by therein) for their manufacture are hereby incorporated by weight, and the last in time modified release component pro reference. vides from 10% to 70%, by weight, in each case of the total 0080 Materials that can be used to obtain a delay in individual antibiotic or combination of antibiotic(s) and/or release suitable for this component of the invention can be, inhibitor(s). but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax), Polyeth The Immediate Release Component ylene Oxides (Polyox), waxes such as white wax or beeswax, 0073. The immediate release portion of this system can be paraffin, acrylic acid derivatives (Eudragit), propylene gly a mixture of ingredients that breaks down quickly after col, and ethylcellulose. US 2010/001 6333 A1 Jan. 21, 2010

0081 Typically these materials can be present in the range pH-dependent or pH-independent polymers as listed herein). of 0.5-40% (W/W) of this component. Further examples are listed in U.S. Provisional Patent Appli cation Ser. No. 60/755,043; U.S. patent application Ser. No. The pH Sensitive (Enteric) Release Component 11/173,929; and U.S. patent application Ser. No. 1 1/021.309; the disclosures of each of which are hereby incorporated by 0082. The components in this composition are the same as reference in their entireties. the immediate release component, but with additional poly 0094. The antibiotic product of the present invention may mers integrated into the composition, or as coatings over the be administered, for example, by any of the following routes pellet or granule or tablet. of administration: Sublingual, transmucosal, transdermal, 0083. The kind of materials useful for this purpose can be, parenteral, etc., and preferably is administered orally. The but are not limited to, cellulose acetate pthalate, Eudragit L. composition includes a therapeutically effective amount of a Eudragit S, Eudragit FS, and other pthalate salts of cellulose combination comprising at least three different antibiotics, derivatives. wherein one of the at least three different antibiotics is 0084. These materials can be present in concentrations selected from the group consisting of RNA-Polymerase from 3-30% (W/W). Inhibiting antibiotics, wherein one of the at least three differ ent antibiotics is selected from the group consisting of Dihy Sustained Release Component dropteroate Synthase Inhibiting antibiotics, and wherein one 0085. The components in this composition are the same as of the at least three different antibiotics is selected from the the immediate release component, but with additional poly group consisting of Dihydrofolate Reductase Inhibiting anti mers integrated into the composition, or as coatings over the biotics (or analogues, derivatives, polymorphs, metabolites, pellet or granule. pro-drugs, salts, and/or hydrates of any of the foregoing), with I0086. The kind of materials useful for this purpose can be, or without the further combination of a therapeutically effec but are not limited to, ethylcellulose; hydroxypropylmethyl tive amount of a resistance inhibitor, preferably a Lex A pro cellulose; hydroxypropylcellulose; hydroxyethylcellulose; tease cleavage inhibitor, which amounts may vary in relation carboxymethylcellulose; methylcellulose; nitrocellulose; to each other, and in relation to the number of times that the Eudragit R: Eudragit RS; and Eudragit R L. Carbopol; poly composition is to be delivered in a day. In preferred embodi ethyleneoxide or polyethylene glycols with molecular ments the product is to be administered once-a-day. The com position is administered to a patient or Subject in an amount weights in excess of 8,000 daltons. effective for treating infection caused by MRSA. 0087. These materials can be present in concentrations (0095. The RNA-Polymerase Inhibiting antibiotic, Dihy from 4-20% (W/W). dropteroate Synthase Inhibiting antibiotic, and Dihydrofolate 0088. When it is desired to delay initiation of release of the Reductase Inhibiting antibiotic (and optional inhibitor) prod Sustained release component, an appropriate coating may be uct should be administered for a sufficient amount of time to used to delay initiation of the Sustained release, Such as a pH treat the MRSA infection. In one embodiment the RNA sensitive or a non-pH sensitive coating. Polymerase Inhibiting antibiotic, Dihydropteroate Synthase Inhibiting antibiotic, and Dihydrofolate Reductase Inhibiting The Non-pH Sensitive Coating for Sustained Release Com antibiotic (and optional inhibitor) product is administered for ponent about 10 days, but may vary depending on severity of infec 0089 Materials that can be used to obtain a delay in tion and clinical response. The product may benefit from release suitable for this component of the invention can be, being administered with or without food. but are not limited to, polyethylene glycol (PEG) with (0096. The invention will be further described with respect molecular weight above 4,000 daltons (Carbowax), polyeth to the following examples; however, the scope of the inven yleneoxides (Polyox), waxes such as white wax or bees wax, tion is not limited thereby. All percentages in this specifica paraffin, acrylic acid derivatives (Eudragit RS or RL), cellu tion, unless otherwise specified, are by weight. lose acetate, and ethylcellulose. 0090 Typically these materials can be present in the range EXAMPLES of 0.5-40% (W/W) of this component. Preferably the mate 0097. In general, the product may consist of any of the rials are present in an amount just enough to provide the following immediate release (IR), delayed release (DR), and/ desired in vivo lag time and T. or Sustained release (SR) components. The manufacture of each component is described below. The components are The pH Sensitive Coating for Sustained Release Component combined into unit products known to those skilled in the art 0091. The kind of materials useful for this purpose can be, but not limited to capsules, tablets or Sachets, in the appro but are not limited to, cellulose acetate phthalate, Eudragit L. priate ratio to achieve the proper dose to be administered; the Eudragit S, Eudragit FS, and other pthalate salts of cellulose dose may be divided into one or multiple unit products of the derivatives. same or varying composition. 0092. These materials can be present in concentrations Unit products containing varying amounts of IR, DR, and/or from 4-20% (W/W) or more. Preferably the materials are SR components can be manufactured by techniques known to present in an amount just enough to provide the desired in those skilled in the art, but are not limited to: Vivo lag time and T. 0.098 compression using a suitable tablet press, such as 0093. As hereinabove indicated, the units comprising the a rotary tablet press or bilayer/trilayer/multilayer tablet antibiotic product of the present invention can be in the form press, or of discrete pellets or particles contained in a capsule, or 0099 filling into a capsule with a suitable encapsulator, particles embedded in a tablet or Suspended in a liquid Sus O pension. Furthermore, mintablets may be combined with or 0.100 filling into a sachet with a suitable filler. withoutpellets or powders into a capsule or larger tablet form: 0101. As used in the following examples the term RNAPi/ the tablet may be multilayer coated with coating layers con RIFA shall indicate any RNA-Polymerase Inhibiting antibi taining active ingredients and/or functional excipients (e.g. otic, or any rifamycin antibiotic (or any derivatives, ana US 2010/001 6333 A1 Jan. 21, 2010 12 logues, etc. of any RNA-Polymerase Inhibiting antibiotic or of any rifamycin antibiotic) or any compounds that may act -continued by the same mechanism of action, including but not limited to Hydroxypropyl Cellulose (e.g. Klucel LF) 59% the non-limiting examples of RNA-Polymerase Inhibiting Vitamin ETPGS 190 antibiotics as are listed and/or mentioned hereinabove and/or 5. hereinbelow. 0102. As used in the following examples the term SMX/ Fiasco 8OOO 5.0. (W/W) TMP shall indicate the fixed combination of a Dihy- Polyvinyl Pyrrollidone (K30) 59% dropteroate Synthase Inhibiting antibiotic with a Dihydro- -- folate Reductase Inhibiting antibiotic (or the combination of - - SMXTMP 65% (WW) any Dihydropteroate Synthase Inhibiting antibiotic with any Microcrystalline Cellulose (e.g. Avicel 20%0. derivative, analogue, etc. of a Dihydrofolate Reductase Inhib- PH101) iting antibiotic, or the combination of any Dihydrofolate Polyvinyl Pyrrollidone (K30) 10% Reductase Inhibiting antibiotic with any derivative, analogue, Creatmellose sodium i. etc. of a Dihydropteroate Synthase Inhibiting antibiotic, or 7 .0 the combination of any derivative, analogue, etc. ofany Dihy- o dropteroate Synthase Inhibiting antibiotic with any deriva- Sulfamethoxazole?Trimethoprim 5:1 55% (W/W) tive, analogue, etc. of a Dihydrofolate Reductase Inhibiting Microcrystalline Cellulose (e.g. Avicel 25% antibiotic, or the combination of any other compounds that Siy Pyrrollidone (K30) 10% may act by the same respective mechanisms ofaction, includ- Croscarmellose sodium 9% ing but not limited to the non-limiting examples of Dihy- Polyoxyl 35 Castor Oil 190 dropteroate Synthase Inhibiting antibiotics and Dihydro- -- folate Reductase Inhibiting antibiotics as are listed and/or 0. mentioned hereinabove and/or hereinbelow. Preferably, this SMXTMP 65% (WW) combination consists of Sulfamethoxazole and trimethoprim MicrocrystallinePH101) Cellulose (e.g. Avicel 20% in the ratio 5:1, but is not limited to this specific ratio or to Hydroxypropyl Cellulose (e.g. Klucel LF) 10% these specific compounds. Croscarmellose sodium 4% 9. I. IR Components SMXTMP 75% (WW) 0103 Mix the ingredients in a suitable pharmaceutical PolyethyleneE. glycolE. 40002OOO 10%o mixer or granulator Such as a planetary mixer, high-shear Hydroxypropyl Cellulose (e.g. Klucel LF) 59% granulator, fluid bed granulator, or extruder, in the presence of O. water or other solvent, or in a dry blend, optionally followed 0. by dry granulation techniques (slugging, roller compaction) N.ise glycol 8000 5. (W/W) or other methods known to those skilled 1. the art. If water or Polyvinyl Pyrrollidone (K30) 59%0. other solvent is used, dry the blend in a suitable pharmaceu- 1. tical drier, Such as a vacuum oven or forced-air oven. The product may be milled, sieved or further granulated, and/or Rifapentin 85% (W/W) compressed using a Suitable tablet press, such as a rotary Miftaline Cellulose (e.g. Avicel 7.5%0. tablet press. Polyvinyl Pyrrollidone (K30) 4% Crosscarmellose Sodium 2.5% Polyoxyl 35 Castor Oil 190 2. 1. Sulfamethoxazole:Trimethoprim 5:1 85% (W/W) Rifapentin 65% (W/W) Microcrystalline Cellulose (e.g. Avicel 7.5% Microcrystalline Cellulose (e.g. Avicel 20% PH101) PH101) Polyvinyl Pyrrollidone (K30) 4% Polyvinyl Pyrrollidone (K30) 10% Crosscarmellose Sodium 2.5% Croscarmellose sodium 59 Polyoxyl 35 Castor Oil 190 2. 3. RNAPSRIFA 55% (W/W) RNAPSRIFA 95% (W/W) Microcrystalline Cellulose (e.g. Avicel 25% Polyvinyl Pyrrollidone (K30) 4% PH101) Polysorbate 80 190 Polyvinyl Pyrrollidone (K30) 10% 4. Croscarmellose sodium 10% 3. SMXTMP 95% (W/W) Polyvinyl Pyrrollidone (K30) 4% Rifampin 65% (W/W) Polysorbate 80 190 Microcrystalline Cellulose (e.g. Avicel 20% 5. PH101) Hydroxypropyl Cellulose (e.g. Klucel LF) 10% RNAPSRIFA 40% (WW) Croscarmellose sodium 5% Microcrystalline Cellulose (e.g. Avicel 23% 4. PH101) Lactose Monohydrate 20% RNAPSRIFA 75% (W/W) Polyvinyl Pyrrollidone (K30) 10% Polyethylene glycol 4000 10% Crosscarmellose Sodium 59% Polyethylene glycol 2000 10% Polyoxyl 35 Castor Oil 2% US 2010/001 6333 A1 Jan. 21, 2010 13

oven or forced-air oven. Allow the product to cool. The prod -continued uct produced may be milled, sieved or further granulated, and compressed using a suitable tablet press, such as a rotary 6. tablet press, or filled into capsules using a suitable capsule SMXTMP 40% (W/W) filler such as an MG2 Futura, or filled into Sachets with a Microcrystalline Cellulose (e.g. Avicel 23% suitable filler. PH101) Lactose Monohydrate 20% 0107. One skilled in the art will realize that the coating Polyvinyl Pyrrollidone (K30) 10% level, polymer type, matrix agent type and level can be Crosscarmellose Sodium 59 Polyoxyl 35 Castor Oil 296 adjusted to obtain the desired release characteristics. 7. Rifapentin 70% (W/W) Polyethylene Gycol 2000 10% 21. Microcrystalline Cellulose 10% Polyvinyl Pyrrollidone (K30) 8% Core from Examples 1-20 65% (WW) Vitamin ETPGS 296 Eudragit L Polymer 25% 8. Talc 8% Triethyl Citrate 2% Sulfamethoxazole:Trimethoprim 5:1 70% (W/W) 22. Polyethylene Gycol 2000 10% Microcrystalline Cellulose 10% Core from Examples 1-20 60% (WW) Polyvinyl Pyrrollidone (K30) 8% Citric Acid 10% Vitamin ETPGS 296 Polyvinyl Pyrrollidone (K30) 59% 19 Eudragit RS Polymer 20% Talc 4% Rifampin 27.1% (WW) Triethyl Citrate 190 Sulfamethoxazole 36.2% 23. Trimethoprim 7.2% Microcrystalline Cellulose 18.1% Core from Examples 1-20 93% (WW) Crosspovidone S.2% Cellulose Acetate 6.75% Polyvinyl Pyrrollidone K30 S.2% Polyethylene Glycol 400 O.25% Sodium Lauryl Sulfate 1.0% 24. Magnesium Stearate O.0% 2O. Core from Examples 1-20 65% (WW) Cellulose Acetate Phthalate 30% Rifampin 21.3% (WW) Triethyl Citrate 59% Sulfamethoxazole 42.7% 25. Trimethoprim 10.7% Polyethylene Glycol 2000 14.2% Core from Examples 1-20 75% (W/W) Crosspovidone S.0% Cellulose Acetate Phthalate 20% Polyvinyl Pyrrollidone K30 S.0% Triacetin 59% Sodium Lauryl Sulfate 1.0% 26. Core from Examples 1-20 65% (WW) Eudragit FS Polymer 28% II. Delayed Release Components Talc 59% Triethyl Citrate 2% 0104 Immediate release core pellets or tablets manufac 27. tured in accordance with section 1 are coated with pH-depen Core from Examples 1-20 65% (WW) dent or pH-independent polymers to generate the delayed Eudragit S Polymer 28% release components of the formulation per compositions Talc 59% listed in examples 21-32. These are examples of modified Triethyl Citrate 2% release components. 28. 0105. The coatings are applied by film coating techniques Core from Examples 1-20 80% (WW) commonly known to those skilled in the art. The delayed Eudragit L Polymer 12.5% Talc 6% release component is created by layering of polymers onto an Triethyl Citrate 1.5% active core. In general, the steps involve first making a coating 29. dispersion or Solution in organic or aqueous solvent. Second, the coating is applied at the proper conditions to produce an Core from Examples 1-20 75% (W/W) Eudragit L Polymer 20% acceptably uniform film. This is done in a suitable coating Talc 3.5% apparatus such as a pan coater or a fluid bed Wurster column Triethyl Citrate 1.5% coater. Optionally the product may be further cured if neces Sary. Core from Examples 1-20 60% (WW) 0106. In addition to coating techniques, matrix type Eudragit L Polymer 35% enteric components may be formulated with ingredients of Talc 4% examples 33 to 42 by mixing the ingredients in a Suitable Triethyl Citrate 190 pharmaceutical mixer or granulator Such as a planetary mixer, 31. high-shear granulator, fluid bed granulator, or extruder, in the Core from Examples 1-20 65% (WW) presence of water or other solvent, or in a hot melt or dry Cellulose Acetate Pthalate 32.5% granulation process. If water or other solvent was used, dry Triethyl Citrate 2.5% the blendina Suitable pharmaceutical drier, Such as a vacuum US 2010/001 6333 A1 Jan. 21, 2010 14

release components. In general, the steps involve first making -continued a coating dispersion or solution in organic or aqueous solvent. Second, the coating is applied at the proper conditions to 32. produce an acceptably uniform film. This is done in a Suitable Core from Examples 1-20 82% (WW) coating apparatus Such as a pan coater or a fluid bed Wurster Hydroxypropyl Methylcellulose Acetate 11% Succinate (e.g. Aqoat HF) column coater. Optionally the product may be further cured if Talc necessary. Curing studies are recommended with Sustained Triethyl Citrate release membranes. Sodium Lauryl Sulphate 0109 To create a matrix type sustained release compo 33. nent, formulate the ingredients of example 50-67 by mixing RNAPSRIFA 75% the ingredients in a Suitable pharmaceutical mixer or granu Microcrystalline Cellulose (e.g. Avicel 59% lator Such as a planetary mixer, high-shear granulator, fluid PH101) Hydroxypropyl methylcellulose 20% bed granulator, or extruder, in the presence of water or other phthalate solvent, or in a hot melt process. If water or other solvent was 34. used, dry the blend in a Suitable pharmaceutical drier, such as RNAPSRIFA 60% a vacuum oven or forced-air oven. Allow the product to cool. Lactose Monohydrate 10% 0110. The product produced may be milled, sieved or Eudragit L Polymer 30% granulated, and compressed using a Suitable tablet press, Such 35. as a rotary tablet press, or filled into capsules using a suitable RNAPSRIFA 70% capsule filler such as an MG2 Futura. Polyethylene glycol 4000 10% 0111. One skilled in the art will realize that any of the Cellulose acetate phthalate 20% coating level, polymer type, matrix agent type and level can 36. be adjusted to obtain the desired release rate. RNAPSRIFA 60% Polyethylene glycol 2000 10% Lactose Monohydrate 20% Eudragit L Polymer 10% 43. 37. Core from Examples 1-20 75% (WW) RNAPSRIFA 70% Ethylcellulose (e.g. Ethocel Std 7FP) 20% Microcrystalline Cellulose (e.g. Avicel 20% HPC 59% PH101) 44. Cellulose acetate phthalate 10% 38. Core from Examples 1-20 80% Eudragit RS Polymer 10% SMXTMP 75% Eudragit RL Polymer 59% Microcrystalline Cellulose (e.g. Avicel 59% Talc 3% PH101) Triethyl Citrate 2% Hydroxypropyl methylcellulose 20% phthalate 39. Core from Examples 1-20 90% Ethylcellulose (e.g. Ethocel Std 7FP) 9% SMXTMP 60% Triacetin 190 Lactose Monohydrate 10% 46. Eudragit L Polymer 30% 40. rom Examples 1-20 90% (WW) 10% SMXTMP 70% Polyethylene glycol 4000 10% Cellulose acetate phthalate 20% Core from Examples 1-20 85% 41. Kollicoat SR 10% TBC 5 SMXTMP 60% 48. Polyethylene glycol 2000 10% Lactose Monohydrate 20% Core from Examples 1-20 80% Eudragit L Polymer 10% Polyethylene glycol 8000 59% 42. Eudragit RS Polymer 15% 49. SMXTMP 70% Microcrystalline Cellulose (e.g. Avicel 20% Core from Examples 1-20 93% PH101) Cellulose Acetate 6.75% Cellulose acetate phthalate 10% PEG 400 O.25% SO.

RNAPFRIFA 75% III. Sustained Release Component Hydroxyethylcellulose 10% Polyethylene glycol 4000 10% 0108 Examples 43-49 utilize film coating techniques Hydroxypropyl Cellulose (e.g. Klucel LF) 59% commonly known to those skilled in the art to create the S1. Sustained release component by layering of Such Sustained SMXTMP 75% release polymers onto an active core such that the desired Hydroxyethylcellulose 10% release rate is obtained. These are examples of modified US 2010/001 6333 A1 Jan. 21, 2010 15

-continued -continued Polyethylene glycol 4000 10% Polyvinyl Pyrrollidone (K30) 10% Hydroxypropyl Cellulose (e.g. Klucel LF) 59 Hydroxypropyl Cellulose (e.g. Klucel HF) 59% 52. 65.

RNAPSRIFA 75% SMXTMP 75% (W/W) Lactose Monohydrate 10% Polyethylene glycol 4000 10% Polyvinyl Pyrrollidone (K30) 10% Polyvinyl Pyrrollidone (K30) 10% Polyethylene glycol 2000 59 Hydroxypropyl Cellulose (e.g. Klucel HF) 59% 53. 66.

SMXTMP 75% Rifapentin 75% (W/W) Lactose Monohydrate 10% Hydroxypropyl cellulose (e.g. Klucel GF) 15% Polyviny Pyrrollidone (K30) 10% Polyvinyl Pyrrollidone (K30) 8% Polyethy ene glycol 2000 59 Vitamin ETPGS 2% 54. 67.

RNAPSRIFA 75% Sulfamethoxazole:Trimethoprim 5:1 75% (W/W) Polyethy ene glycol 4000 10% Hydroxypropyl cellulose (e.g. Klucel GF) 15% Polyviny Pyrrollidone (K30) 10% Polyvinyl Pyrrollidone (K30) 8% Hydroxy propyl Cellulose (e.g. Klucel LF) 59 Vitamin ETPGS 2% 55.

SMXTMP 75% Polyethy ene glycol 4000 10% Specific Example Formulations Polyviny Pyrrollidone (K30) 10% Hydroxy propyl Cellulose (e.g. Klucel LF) 59 Combination 1 56.

RNAPSRIFA 75% 0112 Combination 1 consists of one bilayer tablet unit Lactose Monohydrate 15% product containing IR and SR portions as listed in the follow Polyethy ene glycol 4000 59 ing table. The dose is administered in multiple units of 1, 2, 3 Polyviny Pyrrollidone (K30) 59 or more tablets as directed by a physician to treat MRSA 57. infections. Sulfame hoxazole:Trimethoprim 5:1 75% Lactose Monohydrate 15% Polyethy ene glycol 4000 59 Polyviny Pyrrollidone (K30) 59 Total Unit Dose S8. Drug (mg) IR SR RNAPSRIFA 75% Rifampin 3OO 300 Polyethy ene Oxide (e.g. Polyox WSR 301) 20% Sulfamethoxazole 400 400 Hydroxy propyl Cellulose (e.g. Klucel LF) 59 Trimethoprim 8O 8O 59.

SMXTMP 75% Polyethy ene Oxide (e.g. Polyox WSR 301) 20% Hydroxy propyl Cellulose (e.g. Klucel HF) 4.5% Product Combination 1 Concept. Polyoxyl 35 Castor Oil O.S90 0113 Rifampin micronized in IR granulation (per 60. Example # 3) RNAPSRIFA 559, 0114 Sulfamethoxaxole?Trimethoprim SR granulation Polyethy ene Oxide (e.g. Polyox WSR 301) 40% (per Example #55) Hydroxy propyl Cellulose (e.g. Klucel HF) 59 0115 Blend each granulation with magnesium stearate 61. and Subsequently compress into bilayer tablets SMXTMP 559, ene Oxide (e.g. Polyox WSR 301) 39.5% Hydroxy propyl Cellulose (e.g. Klucel HF) 59 Composition Per Bilayer Tablet 1: Polyoxyl 35 Castor Oil O.S90 62. 0116

RNAPSRIFA 75% Lactose Monohydrate 59 Polyviny | Pyrrollidone (K30) 10% %/bilayer Hydroxypropyl methylcellulose (K4M) 10% tab TOTAL 63. Granulation #57 57.5% SMXTMP 75% Sulfamethoxazole 36.0% Lactose Monohydrate 59 Trimethoprim 7.2% Polyviny | Pyrrollidone (K30) 10% Lactose Monohydrate 8.6% Hydroxypropyl methylcellulose (K4M) 10% Polyethylene glycol 4000 2.9% 64. Polyvinyl Pyrrollidone (K30) 2.9% Blend with Mag Stearate O.S9/o O.S9/o RNAPSRIFA 75% Granulation #3 41.5% Polyethylene glycol 4000 10% Rifampin 27.0% Jan. 21, 2010 16

-continued -continued

%/bilayer % combo tab TOTAL tablets TOTAL Microcrystalline Cellulose 8.3% Polyvinyl Pyrrollidone (K30) 1.5% (e.g. Avicel PH101) Croscarmellose sodium 1.3% Hydroxypropyl Cellulose 4.1% Polyoxyl 35 Castor Oil O.1% (e.g. Klucel LF) Eudragit L Polymer 2.3% Croscarmellose sodium 2.1% Talc 1.1% Blend with Mag Stearate O.4% O.4% Triethyl Citrate O.3% 29 (DR-2 portion) 19.7% TOTAL per bilayer tablet 100.00% 100.00% Core from Example 7 Sulfamethoxazole 6.8% Trimethoprim 1.4% Microcrystalline Cellulose (e.g. Avicel 3.7% Combination 2 PH101) Polyvinyl Pyrrollidone (K30) 1.5% 0117 Combination 2 consists of one unit product tablet Croscarmellose sodium 1.3% Polyoxyl Castor Oil O.1% containing IR and DR portions as listed in the following table. Eudragit L Polymer 3.9% The dose is administered in multiple units of 1, 2, 3 or more Talc O.7% tablets as directed by a physician to treat MRSA infections. Triethyl Citrate O.3% Blend with Mag Stearate 1.0% 1.0%

Total Dose TOTAL 100.0% 100.0% Drug (mg) IR DR-1 DR-2 Rifapentin 3OO 3OO Sulfamethoxazole 400 2OO 100 1OO Combination 3 Trimethoprim 8O 40 2O 2O I0123 Combination 3 consists of one unit product tablet containing IR and DR portions as listed in the following table. Product Combination 2 Concept. The dose is administered in multiple units of 1, 2, 3 or more tablets as directed by a physician to treat MRSA infections. 0118 Rifapentin micronized in IR granulation (per example if 1) 0119 Sulfamethoxazole?Trimethoprim granulation with solubilizer (per example #7) Total Dose I0120 coat Sulfamethoxazole?Trimethoprim IR gran Drug (mg) IR DR-1 DR-2 ules for DR (per example # 26 and 27) Rifapentin 3OO 3OO I0121 Blend with magnesium stearate and compact Sulfamethoxazole 400 2OO 100 100 granules into tablets Trimethoprim 8O 40 2O 2O Composition Per Tablet 2 0122) Product Combination 3 Concept: 0.124 Rifapentin micronized in IR granulation (per example it 11) 0.125 Sulfamethoxazole?Trimethoprim granulation % combo tablets TOTAL with solubilizer (per example #12) 0126 coat Sulfamethoxazole/Trimethoprim IR gran 1 (IR) 31.3% Rifapentin 20.3% ules for DR (per example # 22 and 23) Microcrystalline Cellulose (e.g. Avicel 6.3% O127 Blend with magnesium Stearate and Crosscar PH101) mellose Sodium and compact granules into tablets Polyvinyl Pyrrollidone (K30) 3.1% Croscarmellose sodium 1.6% 7 (IR portion) 29.6% Composition Per Tablet 3 SMXTMP 5:1 Sulfamethoxazole 13.5% 0128 Trimethoprim 2.7% Microcrystalline Cellulose (e.g. Avicel 7.4% PH101) Polyvinyl Pyrrollidone (K30) 3.0% % combo Croscarmellose sodium 2.7% tablet TOTAL Polyoxyl 35 Castor Oil O.3% 28 (DR-1 portion) 18.5% Example 11 (IR) 32.8% Core from Example 7 Rifapentin 27.9% Sulfamethoxazole 6.8% Microcrystalline Cellulose (e.g. Avicel 2.5% Trimethoprim 1.4% PH101) Microcrystalline Cellulose (e.g. Avicel 3.7% Polyvinyl Pyrrollidone (K30) 1.6% PH101) Croscarmellose sodium O.8% US 2010/001 6333 A1 Jan. 21, 2010

0.134 coat Sulfamethoxazole/Trimethoprim IR minit -continued abs for DR 0.135 Blend IR granulations, fill coated minitab and % combo tablet TOTAL granulation into capsule Example 12(IR portion) 26.3% SMXTMP 5:1 Sulfamethoxazole 18.6% % combo Trimethoprim 3.7% capsule Total Microcrystalline Cellulose (e.g. Avicel 2.0% PH101) Example 11 (IR) 32.8% Polyvinyl Pyrrollidone (K30) 1.1% Rifapentin 27.9% Croscarmellose sodium O.7% Microcrystalline Cellulose (e.g. 2.5% Polyoxyl Castor Oil O.3% Avicel PH101) 28(DR-1 portion) 18.2% Polyvinyl Pyrrollidone (K30) 1.6% Core from Example 7 80% (WW) Croscarmellose sodium O.8% Sulfamethoxazole 9.3% Example12 (IR portion) 47.2% Trimethoprim 1.9% SMXTMP 5:1 Microcrystalline Cellulose (e.g. Avicel 1.0% Sulfamethoxazole 33.4% PH101) Trimethoprim 6.7% Polyvinyl Pyrrollidone (K30) O.S90 Microcrystalline Cellulose (e.g. 3.5% Croscarmellose sodium O.3% Avicel PH101) Polyoxyl Castor Oil O.1% Polyvinyl Pyrrollidone (K30) 1.9% Eudragit L Polymer 3.2% Croscarmellose sodium 1.2% Talc 1.5% Polyoxyl Castor Oil O.S90 Triethyl Citrate O.4% (DR-1 portion) 20.1% 29 (DR-2 portion) 19.9% Sulfamethoxazole 11.1% Core from Example 7 Trimethoprim 2.2% Sulfamethoxazole 9.3% Microcrystalline Cellulose (e.g. 1.2% Trimethoprim 1.9% Avicel PH101) Microcrystalline Cellulose (e.g. Avicel 1.0% Polyvinyl Pyrrollidone (K30) O.6% PH101) Croscarmellose sodium O.4% Polyvinyl Pyrrollidone (K30) O.S90 Polyoxyl Castor Oil O.2% Croscarmellose sodium O.3% Blend granulation with Polyoxyl Castor Oil O.1% Crosscarmellose Sodium O.6% Eudragit L Polymer 5.4% Mag Stearate O.2% Talc O.9% compress and coat with 7% wtgain on tab Triethyl Citrate O.4% COGS Blend all 4 granular portions with 2.7% Eudragit L Polymer 2.7% Crosscarmellose Sodium 1.7% Talc O.6% Mag Stearate 1.0% Triethyl Citrate O.3%

TOTAL 100.00% 100.00% TOTAL 100.00% 100.00%

Combination 4 Combination 5 0129. Combination 4 consists of one unit product capsule 0.136 Combination 5 consists of one unit product tablet containing IR and DR portions as listed in the following table. containing IR and SR portions as listed in the following table. The dose is administered in multiple units of 1, 2, 3 or more The dose is administered in multiple units of 1, 2, 3 or more capsules as directed by a physician to treat MRSA infections. tablets as directed by a physician to treat MRSA infections.

Total Dose Total Dose Drug (mg) IR SR Drug (mg) IR DR-1 Rifapentin 3OO 3OO Rifampin 250 250 Sulfamethoxazole 400 2OO 2OO Sulfamethoxazole 400 300 1OO Trimethoprim 8O 40 40 Trimethoprim 8O 60 2O

Product Combination 5 Concept. Product Combination 4 Concept. 0.137 Rifapentin in IR granulation (per exampleil 11) 0.130 1 dose-2 capsules of equal composition: 1 DR 0.138 Sulfamethoxazole?Trimethoprim IR granulation minitab and IR granulation(s) with solubilizer (per example # 12) I0131 Rifampin micronized in IR granulation (per 0.139 Sulfamethoxazole?Trimethoprim SR granulation exampleil 11) with solubilizer (per example #57), blend with Magne I0132) Sulfamethoxazole?Trimethoprim granulation sium Stearate with solubilizer (per example #12) 0140 Blend IR granulations with Crosscarmellose 0.133 Compress Sulfamethoxazole?Trimethoprim IR Sodium and Magnesium Stearate minitabs with Mag Stearate 0.141 Compress into bilayer tablets US 2010/001 6333 A1 Jan. 21, 2010 18

Composition Tablet #5: 0142 -continued % combo tab Total

% combo Microcrystalline cellulose 3.6% tab Total Polyvinyl Pyrrollidone K30 2.9% Vitamin ETPGS O.7% Example 11 (IR) 32.7% Example 18(IR portion) 57.8% Rifapentin 27.8% SMXTMP 5:1 Microcrystalline cellulose 2.5% Sulfamethoxazole 33.7% Povidone 1.6% Trimethoprim 6.7% Croscarmellose sodium O.8% Polyethylene Glycol 2000 5.8% Example 12(IR portion) 28.1% Microcrystalline cellulose 5.8% SMXTMP 5:1 Polyvinyl Pyrrollidone K30 4.6% Sulfamethoxazole 18.5% Vitamin ETPGS 1.2% Trimethoprim 3.7% O.0% Microcrystalline cellulose 2.9% Blend granulation with 6.1% Povidone 1.6% Crosscarmellose Sodium S.1% Croscarmellose sodium 1.0% Mag Stearate 1.0% Polyoxyl Castor Oil O.4% O.0% 100.0% 100.0% Blend granulation with 6.6% Crosscarmellose Sodium 1.5% Mag Stearate S.1% Example 59/SR 29.6% Combination 7 SMXTMP Sulfamethoxazole 18.5% 0148 Combination 7 consists of one unit product tablet Trimethoprim 3.7% containing SR portions as listed in the following table. The Polyethyleneoxide 5.9% Hydroxypropylcellulose 1.3% dose is administered in multiple units of 1,2,3 or more tablets Polyoxyl 35 Castor Oil O.1% as directed by a physician to treat MRSA infections. Blend granulation with 3.0% Mag Stearate 3.0%

100.0% 100.0% Total SRDOse Drug (mg) Rifapentin 3OO Combination 6 Sulfamethoxazole 400 Trimethoprim 8O 0143 Combination 6 consists of one unit product tablet containing IR portions as listed in the following table. The dose is administered in multiple units of 1,2,3 or more tablets as directed by a physician to treat MRSA infections. Product Combination 7 Concept: 0.149 Rifapentin in SR granulation (per exampleil 66) 0150. Sulfamethoxazole?Trimethoprim SR granulation with solubilizer (per example #67) Total IRDose 0151. Blend SR granulations with Magnesium Stearate Drug (mg) 0152 Compress into tablets Rifapentin 300 Sulfamethoxazole 400 Trimethoprim 8O % combo tab Total Example 66 (SR) 38.0% Product Combination 6 Concept: Rifapentin 28.5% Hydroxyproppyl Cellulose (Klucel 5.7% 0144) Rifapentin in IR granulation (per exampleil 17) GF) 0145 Sulfamethoxazole?Trimethoprim IR granulation Polyvinyl Pyrrollidone K30 3.0% Vitamin ETPGS O.8% with solubilizer (per example #18) Example 67 (SR portion) 60.8% 0146 Blend IR granulations with Crosscarmellose SMX/TMP 5:1 75% (W/W) Sodium and Magnesium Stearate Sulfamethoxazole 38.0% Trimethoprim 7.6% 0147 Compress into tablets Hydroxyproppyl Cellulose (Klucel 9.1% GF) Polyvinyl Pyrrollidone K30 4.9% Vitamin ETPGS 1.2% % combo O.0% tab Total Blend granulations with 1.1% Mag Stearate 1.1% Example 17(IR) 36.1% Rifapentin 25.3% 100.0% 100.0% Polyethylene Glycol 2000 3.6% US 2010/001 6333 A1 Jan. 21, 2010 19

Combination 8 dose is administered in multiple units of 1,2,3 or more tablets 0153 Combination 8 consists of one unit product tablet as directed by a physician to treat MRSA infections. containing IR portions as listed in the following table. The dose is administered in multiple units of 1,2,3 or more tablets as directed by a physician to treat MRSA infections. Total IRDose Drug (mg) Total IRDose Drug (mg) Rifampin 3OO Rifampin 300 Sulfamethoxazole 600 Sulfamethoxazole 600 Trimethoprim 150 Trimethoprim 150

Product Combination 8 Concept: 0154 Blend all dry ingredients; add Magnesium Stear- % ate and blend (O155 Compress into tablets Rifampin 21.1 Sulfamethoxazole 423 Trimethoprim 10.6 Polyethylene Glycol 14.1 2OOO % Crosspovidone S.O Polyvinyl Pyrrollidone S.O Rifampin 26.9 K30 sulfamethoxazole 35.8 Sodium Lauryl Sulfate 1.O Trimethoprim 7.2 Magnesium Stearate 1.O Microcrystalline 17.9 Cellulose 1OOO Crosspovidone S.1 Polyvinyl Pyrrollidone 5.1 K30 Sodium Lauryl Sulfate 1.O Magnesium Stearate 1.O Further Examples 1OOO Example Compositions

Combination 9 See Table Below 0156 Combination 9 consists of one unit product tablet containing IR portions as listed in the following table. The O157

Active Ex1 Ex2 Ex3 Ex4 Ex5 Ex 6 Ex 7 Ex8 Ex9 Pulse Ingredient (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)

IR RNAPSRIFA 150 3OO 600 1SO 600 1SO 600 1 SO 600 analogue IR SMX 200 400 800 200 800 200 800 O O TMP 40 80 120 40 120 40 12O O O DR-1 SMX 100 2OO 400 SO 200 O O 133.3 S33.3 TMP 2O 40 60 10 30 O O 26.6 80 DR-2 SMX 100 2OO 400 O O SO 200 1333 S33.3 TMP 2O 40 60 O O 10 30 26.6 8O SR SMX 1SO 600 1SO 600 O O TMP 30 90 30 90 O O DR-3 SMX O O O O 133.3 S33.3 TMP O O O O 26.6 80 US 2010/001 6333 A1 Jan. 21, 2010 20

0158. In general, the finished product can be manufactured We claim: in a variety of ways. The pulses can be combined to create 1. A once-a-day anti-MRSA antibiotic product compris from 1 up to as many as 5 individual units, dosed simulta ing: a therapeutically-effective anti-MRSA daily dosage of a neously. The individual pulses can be combined for simulta combination of at least three different antibiotics, wherein neous administration, in a package Such as a Sachet, capsule, one of the at least three different antibiotics is selected from etc., or compressed as one or more tablets to be administered simultaneously. the group consisting of RNA-Polymerase Inhibiting antibiot 0159. Numerous modification and variations of the ics, wherein one of the at least three different antibiotics is present invention are possible in light of the above teachings selected from the group consisting of Dihydropteroate Syn and therefore within the scope of the appended claims the thase Inhibiting antibiotics, and wherein one of the at least invention may be practiced otherwise than as particularly three different antibiotics is selected from the group consist described. The present invention also extends to formulations ing of Dihydrofolate Reductase Inhibiting antibiotics; said which are bioeduivalent to the pharmaceutical formulations daily dosage being the total dosage of said so selected anti of the present invention, in terms of both rate and extent of biotic combination for a twenty-four hour period. absorption, for instance as defined by the US Food and Drug 2. The product of claim 1, further comprising at least one Administration and discussed in the so-called “Orange Book” component(s) selected from the group comprising immediate (Approved Drug Compositions with Therapeutic Equiva release components and modified release components; each lence Evaluations, US Dept of Health and Human Services, component comprising a pharmaceutically acceptable carrier 19th edn, 1999). and at least one antibiotic.

SEQUENCE LISTING

<16O NUMBER OF SEO ID NOS: 3

<210 SEQ ID NO 1 <211 LENGTH: 4 &212s. TYPE : PRT <213> ORGANISM: Artificial &220s FEATURE: <223> OTHER INFORMATION: Synthetic peptide corresponding to LexA cleavage site

<4 OO SEQUENCE: 1

Val Ala Ala Gly 1.

<210 SEQ ID NO 2 <211 LENGTH: 7 &212> TYPE: PRT <213> ORGANISM: Artificial &220s FEATURE: <223> OTHER INFORMATION: Synthetic peptide corresponding to LexA cleavage site

<4 OO SEQUENCE: 2

Val Ala Ala Gly Glu Pro Lieu 1. 5

<210 SEQ ID NO 3 <211 LENGTH: 9 &212> TYPE: PRT <213> ORGANISM: Artificial &220s FEATURE: <223> OTHER INFORMATION: Synthetic peptide corresponding to LexA cleavage site

<4 OO SEQUENCE: 3

Val Ala Gly Glu Pro Lieu. Lieu Ala Trp 1. 5 US 2010/001 6333 A1 Jan. 21, 2010

3. The product of claim 2, wherein said modified release tives, polymorphs, metabolites, pro-drugs, salts, and/or component(s) is/are selected from the group consisting of hydrates thereof are selected from the group consisting of delayed release component(s), Sustained (or extended) trimethoprim, pyrimethamine; iclaprim; ormetoprim; 2,4-di release component(s), and combinations of the foregoing. aminopyrimidine, Sulfanilic acid; nitroSoisocytosines; mono 4. The product of claim 3, wherein said modified release cyclic pteridines; proguanil; chloroguanide; cycloguanil; and component(s) is/are a delayed release component(s). any antibiotic which may act synergistically with any, or 5. The product of claim 5, wherein said modified release each, of a Dihydropteroate Synthase Inhibiting antibiotic, a component(s) is/are a Sustained release component(s). RNA-Polymerase Inhibiting antibiotic, or an any analogue 6. The product of claim 2, wherein said at least one antibi (derivative etc.) of a Dihydropteroate Synthase Inhibiting otic component(s) is/are an immediate release component(s). antibiotic, or a RNA-Polymerase Inhibiting antibiotic. 7. The product of claim 1, wherein any of said RNA 11. The product of claim 1, wherein said combination of Polymerase Inhibiting antibiotics, Dihydropteroate Synthase antibiotics are present in the product in the following Inhibiting antibiotics, and Dihydrofolate Reductase Inhibit amounts: about 20 mg. to about 2000 mg. of a RNA-Poly ing antibiotics comprise analogues, derivatives, polymorphs, merase Inhibiting antibiotic, about 100 mg. to about 3000 mg. metabolites, pro-drugs, salts, and/or hydrates thereof. of a Dihydropteroate Synthase Inhibiting antibiotic, and 8. The product of claim 7, wherein any of said RNA about 20 mg. to about 2000 mg. of a Dihydrofolate Reductase Polymerase Inhibiting antibiotics, analogues, derivatives, Inhibiting antibiotic. polymorphs, metabolites, pro-drugs, salts, and/or hydrates 12. The product of claim 1, wherein said product is thereof are selected from the group consisting of rifamycin; designed for oral administration. rifampin: rifampin: rifabutin: rifapentin: rifapentine; rifaxi 13. The product of claim 1, further comprising at least one min: rifalazil; rifaximin; the ansamycin antibiotics (drug resistance inhibitor. class); rifamycin SV: rifamycin B diethylamide: rifamycin 14. The product of claim 13, wherein said resistance inhibi W: rifamycin S: rifamycin P: rifamycin O: rifamycin R; rifa tor is selected from the group consisting of any achaogen mycin U; rifamycin Y; rifamycin 3-iminomethylenyl able to reduce the rate of induced mutagenesis, nucleic acids, (—CH=N ) derivatives; rifamycin-imino-derivatives; rifa peptide nucleic acids, phages, phagemids, polypeptides, pep mycin-C11-oxime derivatives: rifamycin-C11-oxime cyclo tidomimetics, antibodies, Small or large organic or inorganic derivatives; spiro-rifamycin; C-25 carbamate rifamycin molecules, and combinations of the foregoing; whether of derivatives: rifamexil; rifamdin: rifamide: rifaprim; rifamet natural or non-natural origin; wherein they are able to bind to, (h)oprim; kanglemycin A; protorifamycin; rifamycin Verde; or interact with, gene products that increase rate of mutations ansamycin LM427; rifamazine; Streptolygidin; Sorangicin A; in a cellor organism; wherein such gene products are selected MDL473; GE23077; other (bacterial) RNA-Polymerase from the groups consisting of RecA, RecB. RecC. Rec), inhibitors such as the CBR703 series (Artsimovitch I, et al., RecE. RecC., RecN, Lex A, UmuC, UmuD, PolB, PolIV, Poly, Science. 2003 Oct. 24; 302(5645):650-4); Microcin J25 PriA, RuvA. RuvB, RuvC, UmuC, UmuD, UvrA, UvrB, (Mukhopadhyay et al. 2004 Mol Cell 14:739; Adelman et al. UVrD, and homologs and analogs of the foregoing; and 2004 Mol Cell 14:753); and any antibiotic which may act wherein said polypeptides are selected from the group con synergistically with any, or each, of a Dihydrofolate Reduc sisting of dipeptide Ala-Ala., tripeptide Val-Ala-Ala, and SEQ tase Inhibiting antibiotic, a Dihydropteroate Synthase Inhib ID NO: 1, 2, or 3. iting antibiotic, oran any analogue (derivative etc.) of a Dihy 15. The product of claim 13, wherein said at least one drofolate Reductase Inhibiting antibiotic, or a resistance inhibitor is a LeXA protease cleavage inhibitor. Dihydropteroate Synthase Inhibiting antibiotic. 16. The product of claim 1, wherein said therapeutically 9. The product of claim 7, wherein any of said Dihy effective anti-MRSA daily dosage of said combination is an dropteroate Synthase Inhibiting antibiotics, analogues, amount that is therapeutically-effective against infections derivatives, polymorphs, metabolites, pro-drugs, salts, and/or caused by healthcare-acquired Methicillin-Resistant Staphy hydrates thereof are selected from the group consisting of lococcus aureus (HA-MRSA). Sulfamethoxazole; para-aminobenzenesulfonamide deriva 17. The product of claim 1, wherein said therapeutically tives (aka Sulfanilamide-analogues); Sulfanilamide; Sulfadi effective anti-MRSA daily dosage of said combination is an azine; Sulfamethoxazole; Sulfadoxine; Sulfisoxazole; amount that is therapeutically-effective against infections Sulfisoxazole acetyl; Sulfacetimide; Sulfapyridine; Sulfasala caused by community-acquired Methicillin-Resistant Sta Zine; mafenide; Sulfadimethoxine; Sulfaquinoxaline; silver phylococcus aureus (CA-MRSA). Sulfadiazine; mafenide acetate; sulfisoxazole diolamine; 18. The product of claim 1, wherein said therapeutically phtalylsulfacetamide, phtalylsulfathiazole, Sulfaguanidine; effective anti-MRSA daily dosage of said combination is an Sulfamazole; SulfamaZone; Sulfametopirazine, Sulfametox amount that is therapeutically-effective for treating a patient ypiridazine; Sulfametrol; Succinylsulfathiazole; 2,4-Diami suffering from a disease caused by a Methicillin-Resistant noquinazolines; Pyridopyrimidines; 2.3-a-pyrimidines; Staphylococcus aureus infection. 5-deaza-pteridine: Epiroprim; Brodimoprim: K-130; SRI 19. The product of claim 18, wherein said disease is 8858; the class of the sulfones (aka diaminophenylsulfones, selected from the group selected from: skin and Soft tissue Such as dapsone and Sulfoxone); and any antibiotic which infections; boils; pimples; pneumonia, empyema, blood may act synergistically with any, or each, of a Dihydrofolate infections, bacteremia, sepsis, osteomyelitis, pyomytosis, Reductase Inhibiting antibiotic, a RNA-Polymerase Inhibit necrotizing fasciitiitis, purpura fulminans, infections of the ing antibiotic, or an any analogue (derivative etc.) of a Dihy bones and joints, urinary tract infections, toxic shock syn drofolate Reductase Inhibiting antibiotic, or a RNA-Poly drome; and pluralities of the foregoing. merase Inhibiting antibiotic. 20. The product of claim 2, wherein said at least one com 10. The product of claim 7, wherein any of said Dihydro ponent(s) comprises: an immediate release component con folate Reductase Inhibiting antibiotics, analogues, deriva taining rifampin in a range of about 150 mg. to about 600 mg.: US 2010/001 6333 A1 Jan. 21, 2010 22 an immediate release component containing a combination of 27. A process for treating Methicillin-Resistant Staphylo sulfamethoxazole and trimethoprim (SMX-TMP), wherein coccus Aureus infection in a host comprising: administering the Sulfamethoxazole is present in a range of about 200 mg. to to a host the antibiotic product of claim 5, once-a-day. about 800 mg. and the trimethoprim is present in a range of 28. A process for treating Methicillin-Resistant Staphylo about 40 mg. to about 160 mg.; a first (in time to release) coccus Aureus infection in a host comprising: administering delayed release component containing a combination of Sul to a host the antibiotic product of claim 6, once-a-day. famethoxazole and trimethoprim (SMX-TMP), wherein the 29. A process for treating Methicillin-Resistant Staphylo Sulfamethoxazole is present in a range of about 100 mg. to coccus Aureus infection in a host comprising: administering about 400 mg. and the trimethoprim is present in a range of to a host the antibiotic product of claim 7, once-a-day. about 20 mg. to about 80 mg., and a second (in time to release) 30. A process for treating Methicillin-Resistant Staphylo delayed release component containing a combination of Sul coccus Aureus infection in a host comprising: administering famethoxazole and trimethoprim (SMX-TMP), wherein the to a host the antibiotic product of claim 8, once-a-day. Sulfamethoxazole is present in a range of about 100 mg. to 31. A process for treating Methicillin-Resistant Staphylo about 400 mg. and the trimethprim is present in a range of coccus Aureus infection in a host comprising: administering about 20 mg. to about 80 mg. to a host the antibiotic product of claim 9, once-a-day. 21. The product of claim 2, wherein said at least one com 32. A process for treating Methicillin-Resistant Staphylo ponent(s) comprises: an immediate release component con coccus Aureus infection in a host comprising: administering taining rifampin in a range of about 150 mg. to about 600 mg.: to a host the antibiotic product of claim 10, once-a-day. an immediate release component containing a combination of 33. A process for treating Methicillin-Resistant Staphylo sulfamethoxazole and trimethoprim (SMX-TMP), wherein coccus Aureus infection in a host comprising: administering the Sulfamethoxazole is present in a range of about 200 mg. to to a host the antibiotic product of claim 11, once-a-day. about 800 mg. and the trimethoprim is present in a range of 34. A process for treating Methicillin-Resistant Staphylo about 40 mg. to about 160 mg., a delayed release component coccus Aureus infection in a host comprising: administering containing a combination of sulfamethoxazole and trimetho to a host the antibiotic product of claim 12, once-a-day. prim (SMX-TMP), wherein the sulfamethoxazole is present 35. A process for treating Methicillin-Resistant Staphylo in a range of about 50 mg. to about 200 mg. and the trime coccus Aureus infection in a host comprising: administering thoprim is present in a range of about 10 mg. to about 30 mg.: to a host the antibiotic product of claim 13, once-a-day. and a Sustained release component containing a combination 36. A process for treating Methicillin-Resistant Staphyllo of sulfamethoxazole and trimethoprim (SMX-TMP). coccus Aureus infection in a host comprising: administering wherein the Sulfamethoxazole is present in a range of about to a host the antibiotic product of claim 14, once-a-day. 150 mg. to about 600 mg. and the trimethprim is present in a 37. A process for treating Methicillin-Resistant Staphylo range of about 30 mg. to about 90 mg. coccus Aureus infection in a host comprising: administering 22. The product of claim 2, wherein said at least one com to a host the antibiotic product of claim 15, once-a-day. ponent(s) comprises: an immediate release component con 38. A process for treating Methicillin-Resistant Staphylo taining rifampin in a range of about 150 mg. to about 600 mg.: coccus Aureus infection in a host comprising: administering a first (in time to release) delayed release component contain to a host the antibiotic product of claim 16, once-a-day. ing a combination of Sulfamethoxazole and trimethoprim 39. A process for treating Methicillin-Resistant Staphylo (SMX-TMP), wherein the sulfamethoxazole is present in a coccus Aureus infection in a host comprising: administering range of about 130 mg. to about 540 mg. and the trimethoprim to a host the antibiotic product of claim 17, once-a-day. is present in a range of about 20 mg. to about 80 mg., a second 40. A process for treating Methicillin-Resistant Staphylo (in time to release) delayed release component containing a coccus Aureus infection in a host comprising: administering combination of sulfamethoxazole and trimethoprim (SMX to a host the antibiotic product of claim 18, once-a-day. TMP), wherein the sulfamethoxazole is present in a range of about 130 mg. to about 540 mg.and the trimethprim is present 41. A process for treating Methicillin-Resistant Staphylo in a range of about 20 mg. to about 80 mg., and a Sustained coccus Aureus infection in a host comprising: administering release component containing a combination of sulfamethox to a host the antibiotic product of claim 19, once-a-day. azole and trimethoprim (SMX-TMP), wherein the sul 42. A process for treating Methicillin-Resistant Staphylo famethoxazole is present in a range of about 130 mg. to about coccus Aureus infection in a host comprising: administering 540 mg. and the trimethprim is present in a range of about 20 to a host the antibiotic product of claim 20, once-a-day. mg. to about 80 mg. 43. A process for treating Methicillin-Resistant Staphylo 23. A process for treating Methicillin-Resistant Staphylo coccus Aureus infection in a host comprising: administering coccus Aureus infection in a host comprising: administering to a host the antibiotic product of claim 21, once-a-day. to a host the antibiotic product of claim 1, once-a-day. 44. A process for treating Methicillin-Resistant Staphylo 24. A process for treating Methicillin-Resistant Staphylo coccus Aureus infection in a host comprising: administering coccus Aureus infection in a host comprising: administering to a host the antibiotic product of claim 22, once-a-day. to a host the antibiotic product of claim 2, once-a-day. 45. The product of claim 1, wherein said RNA-Polymerase 25. A process for treating Methicillin-Resistant Staphylo Inhibiting antibiotic is Saphenamycin. coccus Aureus infection in a host comprising: administering 46. A process for treating Methicillin-Resistant Staphylo to a host the antibiotic product of claim 3, once-a-day. coccus Aureus infection in a host comprising: administering 26. A process for treating Methicillin-Resistant Staphylo to a host the antibiotic product of claim 45, once-a-day. coccus Aureus infection in a host comprising: administering 47. A once-a-day anti-MRSA antibiotic product compris to a host the antibiotic product of claim 4, once-a-day. ing: a therapeutically-effective anti-MRSA daily dosage of a US 2010/001 6333 A1 Jan. 21, 2010

combination of at least three different antibiotics, wherein 48. A process for treating Methicillin-Resistant Staphylo one of the at least three different antibiotics is selected from coccus Aureus infection in a host comprising: administering the group consisting of Phenazine antibiotics, wherein one of to a host the antibiotic product of claim 47, once-a-day. the at least three different antibiotics is selected from the 49. The product of claim 47, wherein said Phenazine anti group consisting of Dihydropteroate Synthase Inhibiting biotic is Saphenamycin. antibiotics, and wherein one of the at least three different 50. A process for treating Methicillin-Resistant Staphylo antibiotics is selected from the group consisting of Dihydro coccus Aureus infection in a host comprising: administering folate Reductase Inhibiting antibiotics; said daily dosage to a host the antibiotic product of claim 49, once-a-day. being the total dosage of said so selected antibiotic combina tion for a twenty-four hour period. c c c c c