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WO2024216070A1 - Compositions pharmaceutiques combinatoires pour traitement d'infections bactériennes - Google Patents

Compositions pharmaceutiques combinatoires pour traitement d'infections bactériennes Download PDF

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Publication number
WO2024216070A1
WO2024216070A1 PCT/US2024/024324 US2024024324W WO2024216070A1 WO 2024216070 A1 WO2024216070 A1 WO 2024216070A1 US 2024024324 W US2024024324 W US 2024024324W WO 2024216070 A1 WO2024216070 A1 WO 2024216070A1
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composition
active agent
antibacterial
topical pharmaceutical
weight ratio
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Rachel WOZNIAK
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University of Rochester
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University of Rochester
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Infectious keratitis is a devastating ophthalmic disease with the potential to cause severe ocular tissue damage and permanent vision loss (Ting, D. S. J., et al., 2021, Eye, 35(4):1084-1101; Cabrera-Aguas, M., et al., 2022, Clinical & Experimental Ophthalmology, 50(5):543-562; Austin, A., et al., 2017, Journal of Ophthalmology, 124(11):1678-1689).
  • infectious keratitis is the fifth leading cause of blindness, and the single most common cause of non-trachomatous corneal opacification (Cabrera-Aguas, M., et al., 2022, Clinical & Experimiental Ophthalmology, 50(5):543-562; Ung, L., et al., 2019, Survey of Ophthalmology, 64(3):255-271).
  • infectious keratitis including bacterial, fungal, viral, and protozoan, yet the ability to determine the causative organism based on clinical signs alone remains a significant challenge (Redd, T.
  • antibiotic resistance surveillance programs have revealed that resistance to moxifloxacin, a fourth-generation fluoroquinolone and current gold standard of keratitis treatment, routinely occurs in 40% to 60% methicillin resistant S. aureus (MRSA) ocular isolates within the U.S. (Ni, N., et al., 2015, Cornea, 34(8):870-875; Alexandrakis, G., et al., 2000, Ophthalmology, 107:1497-502; Asbell, P.
  • MRSA methicillin resistant S. aureus
  • a common treatment strategy is to provide patients with a combination of topical antimicrobials to ensure broad antimicrobial coverage and overcome circulating antibiotic resistance. Additionally, if the clinical history or presentation is suggestive of a non-bacterial etiology, patients may also receive additional antimicrobial agents such as antifungal agents (voriconazole, natamycin, amphotericin B) or anti-acanthamoeba agents (polyhexamethylene biguanide, chlorhexidine).
  • antifungal agents voriconazole, natamycin, amphotericin B
  • anti-acanthamoeba agents polyhexamethylene biguanide, chlorhexidine
  • drug-drug interactions can be classified as either neutral (no effect on efficacy when drugs are used in combination), additive (improved efficacy in combination), synergistic (improved efficacy beyond what might be predicted when in combination) or antagonistic (decreased efficacy when in combination)(Tyers, M., et al., 2019, Nature Reviews Microbiology, 17(3):141-155; Jawetz, E., et al., 1951, AMA Archives of Internal Medicine, 87(3):349-359).
  • Prior drug discovery efforts have shown that predicting advantageous combinations (those that display additive or synergistic antimicrobial activity) is neither obvious nor straightforward.
  • the present disclosure provides an antibacterial composition for use against Gram-positive and Gram-negative bacteria comprising as active agents: a) a composition A comprising polymyxin B and trimethoprim and a composition B comprising polyhexamethylene biguanide (PHMB); or b) a composition A comprising gentamicin and a composition B comprising ceftazidime or tobramycin.
  • active agents a) a composition A comprising polymyxin B and trimethoprim and a composition B comprising polyhexamethylene biguanide (PHMB); or b) a composition A comprising gentamicin and a composition B comprising ceftazidime or tobramycin.
  • the composition A comprises polymyxin B and trimethoprim and composition B comprises PHMB. In some embodiments, polymyxin B, trimethoprim, and PHMB are the only active agents. In some embodiments, the composition A comprises gentamicin and composition B comprises ceftazidime. In some embodiments, gentamicin and ceftazidime are the only active agents. In some embodiments, composition A comprises gentamicin and composition B comprises tobramycin. In some embodiments, gentamicin and tobramycin are the only active agents.
  • the disclosure provides an antibacterial composition for use against Gram-positive bacteria comprising as active agents a composition A comprising cefazolin and a composition B comprising vancomycin or erythromycin.
  • the Gram-positive bacteria is of the genus Staphylococcus. In some embodiments, the bacteria is Staphylococcus aureus.
  • composition A comprises cefazolin and composition B comprises vancomycin. In some embodiments, cefazolin and vancomycin are the only active agents. In some embodiments, composition A comprises cefazolin and composition B comprises erythromycin. In some embodiments, cefazolin and erythromycin are the only active agents.
  • the disclosure provides an antibacterial composition for use against Gram-negative bacteria comprising as active agents: a) a composition A comprising chlorhexidine and a composition B comprising polymyxin B and trimethoprim, or moxifloxacin; or b) a composition A comprising PHMB and a composition B comprising moxifloxacin or polymyxin B and trimethoprim.
  • the Gram-negative bacteria is of the genus Pseudomonas.
  • the bacteria is Pseudomonas aeruginosa.
  • composition A comprises chlorhexidine and composition B comprises polymyxin B and trimethoprim.
  • chlorhexidine, polymyxin B, and trimethoprim are the only active agents.
  • composition A comprises chlorhexidine and composition B comprises moxifloxacin.
  • chlorhexidine and moxifloxacin are the only active agents.
  • composition A comprises PHMB and composition B comprises moxifloxacin.
  • PHMB and moxifloxacin are the only active agents.
  • composition A comprises PHMB and composition B comprises polymyxin B and trimethoprim.
  • PHMB, polymyxin B, and trimethoprim are the only active agents.
  • the composition further comprises one or more pharmaceutically acceptable carriers or excipients.
  • the weight ratio between composition A and composition B is from about 1:1000 to about 1000:1. In some embodiments, the weight ratio between composition A and composition B is from about 1:500 to about 500:1. In some embodiments, the weight ratio between composition A and composition B is from about 1:100 to about 100:1. In some embodiments, the weight ratio between composition A and composition B is from about 1:100 to about 10:1.
  • the weight ratio between composition A and composition B is about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1, , about 12.6:
  • composition A and composition B are from about 1 wt% to about 50 wt%.
  • the disclosure provides a topical pharmaceutical composition comprising as active agents: a) a composition A comprising polymyxin B and trimethoprim and a composition B comprising polyhexamethylene biguanide (PHMB); or b) a composition A comprising gentamicin and a composition B comprising ceftazidime or tobramycin.
  • composition A comprises polymyxin B and trimethoprim and composition B comprises PHMB.
  • polymyxin B, trimethoprim, and PHMB are the only active agents.
  • composition A comprises gentamicin and composition B comprises ceftazidime. In some embodiments, gentamicin and ceftazidime are the only active agents. In some embodiments, composition A comprises gentamicin and composition B comprises tobramycin. In some embodiments, gentamicin and tobramycin are the only active agents.
  • the disclosure provides a topical pharmaceutical composition for use against Gram-positive bacteria comprising as active agents a composition A comprising cefazolin and a composition B comprising vancomycin or erythromycin. In some embodiments, the Gram-positive bacteria is of the genus Staphylococcus. In some embodiments, the bacteria is Staphylococcus aureus.
  • composition A comprises cefazolin and composition B comprises vancomycin. In some embodiments, cefazolin and vancomycin are the only active agents. In some embodiments, composition A comprises cefazolin and composition B comprises erythromycin. In some embodiments, cefazolin and erythromycin are the only active agents.
  • the disclosure provides a topical pharmaceutical composition for use against Gram-negative bacteria comprising as active agents: a) a composition A comprising chlorhexidine and a composition B comprising polymyxin B and trimethoprim or moxifloxacin; or b) a composition A comprising PHMB and a composition B comprising moxifloxacin or polymyxin B and trimethoprim.
  • the Gram-negative bacteria is of the genus Pseudomonas. In some embodiments, the bacteria is Pseudomonas aeruginosa.
  • composition A comprises chlorhexidine and composition B comprises polymyxin B and trimethoprim. In some embodiments, chlorhexidine, polymyxin B, and trimethoprim are the only active agents.
  • composition A comprises chlorhexidine and composition B comprises moxifloxacin. In some embodiments, chlorhexidine and moxifloxacin are the only active agents. In some embodiments, composition A comprises PHMB and composition B comprises moxifloxacin. In some embodiments, PHMB and moxifloxacin are the only active agents.
  • composition A comprises PHMB and composition B comprises polymyxin B and trimethoprim.
  • PHMB, polymyxin B, and trimethoprim are the only active agents.
  • the composition further comprises one or more pharmaceutically acceptable carriers or excipients.
  • the weight ratio between composition A and composition B is from about 1:1000 to about 1000:1. In some embodiments, the weight ratio between composition A and composition B is from about 1:500 to about 500:1. In some embodiments, the weight ratio between composition A and composition B is from about 1:100 to about 100:1. In some embodiments, the weight ratio between composition A and composition B is from about 1:100 to about 10:1.
  • the weight ratio between composition A and composition B is about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1, , about 12.6:
  • the total concentration of composition A and composition B is from about 1 wt% to about 50 wt%.
  • the disclosure provides a method of treating a bacterial infection in a subject comprising administering to the subject a therapeutically effective amount of an antibacterial or topical pharmaceutical composition of the disclosure.
  • the method comprises administering to the subject an antibacterial or topical pharmaceutical composition for use against Gram-positive bacteria of the disclosure, wherein the bacterial infection is associated with a Gram- positive bacteria.
  • the Gram-positive bacteria is of the genus Staphylococcus.
  • the bacteria is Staphylococcus aureus.
  • the method comprises administering to the subject an antibacterial or topical pharmaceutical composition for use against Gram-negative bacteria of the disclosure, wherein the bacterial infection is associated with a Gram-negative bacteria.
  • the Gram-negative bacteria is of the genus Pseudomonas.
  • the bacteria is Pseudomonas aeruginosa.
  • the bacterial infection is ocular, otic, nasal, skin, wound, or systemic infection.
  • the bacterial infection is selected from the group consisting of bacterial keratitis, acute bacterial conjunctivitis, bacterial endophthalmitis, blepharoconjunctivitis, abscesses, boils, cellulitis, folliculitis, impetigo, sepsis, pneumonia, endocarditis, osteomyelitis, infectious arthritis, toxic shock syndrome, bacteremia, and meningitis.
  • the bacterial infection is characterized with colonization or biofilm formation of a bacterium.
  • the disclosure provides a method of decolonizing a bacterial organism comprising contacting the bacterial organism with the composition of the disclosure.
  • the method is for decolonizing a Gram-positive bacterial organism, comprising contacting the bacterial organism with an antibacterial or topical pharmaceutical composition for use against Gram-positive bacteria of the disclosure.
  • the method is for decolonizing a Gram-negative bacterial organism comprising contacting the bacterial organism with an antibacterial or topical pharmaceutical composition for use against Gram-negative bacteria of the disclosure.
  • the disclosure provides a method of destroying, disrupting, inhibiting, or reducing biofilm formation a bacterial organism comprising contacting the bacterial organism with the composition of the disclosure.
  • the method is for destroying, disrupting, inhibiting, or reducing biofilm formation a Gram-positive bacterial organism, comprising contacting the bacterial organism with an antibacterial or topical pharmaceutical composition for use against Gram-positive bacteria of the disclosure.
  • the method is for destroying, disrupting, inhibiting, or reducing biofilm formation a Gram-negative bacterial organism comprising contacting the bacterial organism with an antibacterial or topical pharmaceutical composition for use against Gram-negative bacteria of the disclosure.
  • Figure 1 depicts the results of representative experiments demonstrating the minimum inhibitory concentration (MIC) of a panel of ophthalmic antimicrobials toward S. aureus and P. aeruginosa.
  • Figure 2 depicts the results of representative experiments demonstrating the fractional inhibitory concentration (FIC) testing resulting in synergistic, additive, or antagonistic drug-drug interactions toward S. aureus UAMS-1. Synergistic interactions are bolded and underlined, while all other interactions in normal font are additive.
  • Figure 3 depicts the results of representative experiments demonstrating the fractional inhibitory concentration (FIC) testing resulting in synergistic, additive, or antagonistic drug-drug interactions toward P. aeruginosa PA01.
  • FIG. 4 depicts the results of representative experiments demonstrating the fractional inhibitory concentration (FIC) testing resulting in improved activity of indicated drug towards either S. aureus or P. aeruginosa in the case where one of the drug components has no antimicrobial activity towards the indicated species.
  • Figure 5 depicts the results of representative experiments demonstrating the fractional inhibitory concentration (FIC) testing resulting in synergistic (bolded and underlined) or additive combinations (normal font) toward both S. aureus and P. aeruginosa.
  • Figure 6 depicts representative kill curves of S. aureus and P.
  • the present invention generally relates to compositions and methods for combating bacterial infections.
  • the present invention is based, in part, on the unexpected discovery that certain combinations of compounds, that individually display antibacterial activity, exhibit antibacterial activity beyond a simple additive effect.
  • the invention is further based, partly, on the unexpected discovery that the antibacterial efficacy of certain compounds can be drastically increased upon combination with a compound that, on its own, has no antibacterial activity. Accordingly, in certain embodiments the present disclosure provides compositions comprising combinations of antibacterial, anti-fungal, and/or anti-acanthamoeba agent compositions and methods of treating bacterial infections using said combinations. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, each of the following terms has the meaning associated with it in this section.
  • an element means one element or more than one element.
  • microbial organism or “microbe,” or “microbial,” or “microorganism” refers to a domain (Bacteria) of prokaryotic round, spiral, or rod-shaped single-celled, multi-celled, or celled microorganisms that may lack cell walls or are Gram-positive or Gram-negative or alteration thereof (i.e. Mycobacterium) if they have cell walls, that are often aggregated into colonies or motile by means of flagella, that typically live in soil, water, organic matter, or the bodies of plants and animals, that are usually autotrophic, saprophytic, or parasitic in nutrition, and that are noted for their biochemical effects and pathogenicity.
  • flagella that typically live in soil, water, organic matter, or the bodies of plants and animals, that are usually autotrophic, saprophytic, or parasitic in nutrition, and that are noted for their biochemical effects and pathogenicity.
  • the term is intended to encompass prokaryotic or eukaryotic cells or organisms having a microscopic size and includes bacteria, viruses, archaea and eubacteria of all species as well as eukaryotic microorganisms such as yeast and fungi.
  • the term also includes cell cultures of any species that can be cultured for the production of a biochemical.
  • the activity of a microbial organism can be measured by calculating the log reduction in number of the microorganism.
  • bacteria includes, but is not limited to, references to organisms of the following classes and specific types: 1) Gram-positive cocci, such as Staphylococci (e.g., Staph. aureus, Staph.
  • Staph. saprophyticus Staph. auricularis
  • Staph. capitis capitis Staph. c. ureolyticus
  • Staph. caprae Staph. cohnii cohnii
  • Staph. c. urealyticus Staph. equorum, Staph. gallinarum, Staph. haemolyticus, Staph. hominis hominis, Staph. h. novobiosepticius, Staph. hyicus, Staph. intermedius, Staph. lugdunensis, Staph. pasteuri, Staph. saccharolyticus, Staph.
  • Streptococci e.g. beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept. canis, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae equisimilis, Strept. equi equi, Strept. equi zooepidemicus, Strept. iniae, Strept. porcinus and Strept.
  • Streptococci e.g. beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept. canis, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae equisimilis, Strept. equi equi, Strept. equi zooepidemicus, Strept. iniae, Strept. porcinus and Strept.
  • streptococcus "milleri” such as Strept. anginosus, Strept. constellatus constellatus, Strept. constellatus pharyngidis and Strept. intermedius
  • oral streptococci of the "mitis” alpha-haemolytic-- Streptococcus “viridans”, such as Strept. mitis, Strept. oralis, Strept. sanguinis, Strept. cristatus, Strept. gordonii and Strept. parasanguinis
  • "salivarius” non-haemolytic, such as Strept. salivarius and Strept.
  • mutans teeth-surface streptococci, such as Strept. criceti, Strept. mutans, Strept. ratti and Strept. sobrinus
  • Strept. acidominimus Strept. bovis, Strept. faecalis, Strept. equinus, Strept. pneumoniae and Strept.
  • Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava and Neisseria weaveri;
  • Bacillaceae such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus
  • Enterobacteriaceae such as Escherichia coli, Enterobacter (e.g., Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae), Citrobacter (such as Cit
  • Hafnia e.g., Hafnia alvei
  • Erwinia e.g., Erwinia persicinus
  • Morganella morganii Salmonella (Salmonella enterica and Salmonella typhi)
  • Shigella e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei
  • Klebsiella e.g., Klebs. pneumoniae, Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. terrigena, Klebs.
  • granulomatis Calymmatobacterium granulomatis and Klebs. rhinoscleromatis
  • Proteus e.g., Pr. mirabilis, Pr. rettgeri and Pr. vulgaris
  • Providencia e.g., Providencia alcalifaciens, Providencia rettgeri and Providencia stuartii
  • Serratia e.g., Serratia marcescens and Serratia liquifaciens
  • Yersinia e.g., Yersinia enterocolitica, Yersinia pestis and Yersinia pseudotuberculosis
  • Enterococci e.g., Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus fa
  • Pseudomonas e.g., Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps.
  • Pseudomonas e.g., Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena,
  • Clostridium e.g., C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C. camis, C. celatum, C. clostridioforme, C. cochlearium, C. cocleatum, C. fallax, C.
  • Mycobacteria e.g., Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gas
  • Pasteurella e.g., Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis
  • Bordetella e.g., Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum
  • Nocardiaceae such as Nocardia (e.g., Nocardia asteroides
  • Chlamydia e.g., Chlamydia trachomatis
  • Cryptosporidium e.g., C. parvum, C. hominis, C. canis, C. felis, C.
  • Chlamydophila e.g., Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae (Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittaci)
  • Leuconostoc e.g., Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides and Leuconostoc pseudomesenteroides
  • Gemella e.g., Gemella bergeri, Gemella haemolysans, Gemella morbillorum and Gemella sanguinis
  • Ureaplasma e.g., Ureaplasma parvum and Ureaplasma urealyticum.
  • microbial colonization refers to the formation of compact population groups of the same type of microorganism (such as bacteria), such as the colonies that develop when a microbial (such as bacterial) cell begins reproducing.
  • the microbial colonization (such as bacterial colonization) may or may not cause disease symptoms.
  • Decolonization refers to a reduction in the number of microbial (such as bacterial) organisms present. When the microbial organisms are completely decolonized, the microbial organisms have been eradicated and are non-detectable.
  • biofilm refers to matrix-enclosed microbial (such as bacteria) accretions to biological or non-biological surfaces in which microorganisms are dispersed and/or form colonies.
  • the biofilm typically is made of polysaccharides and other macromolecules. Biofilm formation represents a protected mode of growth that allows cells to survive in hostile environments.
  • biofilm formation is intended to include the formation, growth, and modification of microbes contained with biofilm structures, as well as the synthesis and maintenance of a polysaccharide matrix of the biofilm structures. Also within the scope of this term is formation of protein-based biofilms that do not secrete polysaccharide in the matrix, but which comprise proteins that permit bacteria to form biofilm architecture.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated, the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • a disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
  • an analog is meant to refer to a chemical compound or molecule made from a parent compound or molecule by one or more chemical reactions.
  • an analog can be a structure having a structure similar to that of the small molecule therapeutic agents described herein or can be based on a scaffold of a small molecule therapeutic agents described herein, but differing from it in respect to certain components or structural makeup, which may have a similar or opposite action metabolically.
  • An analog or derivative can also be a small molecule that differs in structure from the reference molecule, but retains the essential properties of the reference molecule. An analog or derivative may change its interaction with certain other molecules relative to the reference molecule.
  • An analog or derivative molecule may also include a salt, an adduct, tautomer, isomer, or other variant of the reference molecule.
  • tautomers are constitutional isomers of organic compounds that readily interconvert by a chemical process (tautomerization).
  • isomers or stereoisomers refer to compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • prodrug refers to compounds that differ in structure from the reference molecule, but is chemically modified by a particular cellular process to ultimately become modified to retain the essential properties of the reference molecule or become the reference molecule.
  • the term “synergistic” refers to the effect obtained by combining compounds and/or agents that is greater than the effect obtained by the separate addition of each compound.
  • a synergistic effect can be measured by, for example, the extent of the response, the duration of response, the response rate, the stabilization rate, the duration of stabilization, the time to reduce or clear the infections, the time to eradicate the microorganisms, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.
  • treating a disease or disorder means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient.
  • Disease and disorder are used interchangeably herein.
  • therapeutically effective amount refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition, including alleviating symptoms of such diseases.
  • topical administration refers to the delivery to a subject by contacting the formulation directly to a surface or localized region of the subject.
  • topical composition As used herein, the term “topical composition” (synonymously, “topical formulation”) is used herein to refer to a pharmaceutical preparation intended for topical or local application to an afflicted region of a subject in need thereof, and includes such dosage forms as gel, cream, ointment, emulsion, suspension, solution, drops, lotion, paint, pessary, douche, suppository, troche, spray, sponge, film, or foam.
  • topical formulation is in the form of a cream, a gel, or an ointment.
  • the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic.
  • pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and/or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • “Measuring” or “measurement,” or alternatively “detecting” or “detection,” means assessing the presence, absence, quantity, or amount (which can be an effective amount) of either a given substance within a sample, including the derivation of qualitative or quantitative concentration levels of such substances, or otherwise evaluating the values or categorization of the substance or the sample.
  • Ranges throughout this disclosure, various embodiments of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6.
  • Description The present invention is based, in part, on the unexpected discovery that specific antibacterial compositions, in combination, yield greatly improved antibacterial properties.
  • the present disclosure provides antibacterial compositions comprising two or more antibacterial compositions which exhibit increased antibacterial activity.
  • the disclosure provides compositions comprising one or more antibacterial composition and one or more compositions which, individually, demonstrate no antibacterial activity but in combination increase the antibacterial activity of the one or more antibacterial compositions.
  • the disclosure provides methods of treating or preventing a disease or disorder associated with a bacterial infection in a subject.
  • the disease or disorder is a bacterial infection.
  • the bacterial infection is an ocular bacterial infection.
  • the infection is selected from the group consisting of keratitis, acute bacterial conjunctivitis, bacterial endothalmitis, and blepharoconjunctivitis.
  • the method comprises administering an antibacterial composition to the subject.
  • the composition comprises a combination of antibacterial compositions.
  • compositions comprising one or more compositions or compounds with antibacterial properties.
  • compositions comprising one or compositions or compounds with antibacterial properties and one or more non-antibacterial compositions which enhance the antibacterial activity of the antibacterial compositions or compounds.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. In one embodiment, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • the composition is an antibacterial composition.
  • the composition is a topical pharmaceutical composition.
  • the composition comprises a composition A and a composition B.
  • the composition comprising the composition A and composition B is synergistic. For example, the effect of the composition A and composition B is synergistic if the dosages required in combination are significantly less than the minimum inhibitory concentration (MIC) of the compositions individually.
  • MIC minimum inhibitory concentration
  • this may be determined through a fractional inhibitory concentration index (FICI), where a composition is synergistic if the FICI is less than 0.5, wherein the FICI is calculated by the following equation: ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ h ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ + ⁇ individually have MIC values of 100 ⁇ g/mL and 50 ⁇ g/mL, respectively.
  • FICI fractional inhibitory concentration index
  • a and composition B is additive if the FICI is 0.5-1.0.
  • a composition A and composition B may individually have MIC values of 100 ⁇ g/mL and 50 ⁇ g/mL, respectively.
  • the composition comprising the composition A and composition B is synergistic for one type of bacteria and additive for another type of bacteria.
  • a composition of the present disclosure is synergistic for both Gram-positive and Gram-negative bacteria if it has a fractional inhibitory concentration index (FICI) that is less than 0.3 for both Gram-positive and Gram-negative bacteria.
  • FICI fractional inhibitory concentration index
  • Another composition may be synergistic for Gram-positive bacteria, with an FICI of 0.3, but additive for Gram-negative bacteria, with an FICI of 0.65.
  • the composition A comprises one or more antibiotic agent, one or more antifungal agent, and/or one or more anti-acanthamoeba agent.
  • the composition A comprises one or more antibiotic agents.
  • the composition A comprises one or more antibiotic agents selected from the group consisting of vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B, trimethoprim, ceftazidime, cefazolin, erythromycin, and rifampin.
  • the composition A comprises polymyxin B and trimethoprim.
  • the composition A comprises gentamicin.
  • the composition A comprises cefazolin.
  • the composition A comprises erythromycin.
  • the composition A comprises one or more antifungal agents.
  • the composition A comprises one or more antifungal agents selected from the group consisting of natamycin, amphotericin B, and voriconazole. In some embodiments, the composition A comprises voriconazole. In some embodiments, the composition A comprises one or more anti- acanthamoeba agents. In some embodiments, the composition A comprises one or more anti-acanthamoeba agents selected from the group consisting of chlorhexidine and polyhexamethylene biguanide (PHMB). In some embodiments, the composition A comprises chlorhexidine. In some embodiments, the composition A comprises PHMB.
  • the composition B comprises one or more antibiotic agents, one or more antifungal agents, and/or one or more anti-acanthamoeba agents. In some embodiments, the composition B comprises one or more antibiotic agents. In some embodiments, the composition B comprises one or more antibiotic agents selected from the group consisting of vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B, trimethoprim, ceftazidime, cefazolin, erythromycin, and rifampin. In some embodiments, the composition comprises a combination of cefazolin and another antibiotic agent. In some embodiments, the composition B comprises ceftazidime. In some embodiments, the composition B comprises tobramycin.
  • the composition B comprises vancomycin. In some embodiments, the composition B comprises erythromycin. In some embodiments, the composition B comprises gentamicin. In some embodiments, the composition B comprises polymyxin B and trimethoprim. In some embodiments, the composition B comprises moxifloxacin. In some embodiments, the composition B comprises one or more antifungal agents. In some embodiments, the composition B comprises one or more antifungal agents selected from the group consisting of natamycin, amphotericin B, and voriconazole. In some embodiments, the composition B comprises one or more anti- acanthamoeba agents.
  • the composition B comprises one or more selected from the group consisting of chlorhexidine and polyhexamethylene biguanide (PHMB). In some embodiments, the composition B comprises PHMB. In some embodiments, the composition comprises a composition A comprising one or more antibiotic agents and a composition B comprising one or more antibiotic agents. In some embodiments, the composition A and composition B comprise, independently, one or more antibiotic agents selected from the group consisting of vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B, trimethoprim, ceftazidime, cefazolin, erythromycin, and rifampin.
  • the composition A comprises cefazolin and the composition B comprises one or more antibiotic agents. In one embodiment, the composition A comprises cefazolin and the composition B comprises erythromycin and/or vancomycin. In one embodiment, the composition A comprises cefazolin and the composition B comprises erythromycin. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:200, about 1:180, about 1:160, about 1:140, about 1:120, about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises cefazolin and the composition B comprises vancomycin.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises gentamicin and the composition B comprises one or more antibiotic agents.
  • the composition A comprises gentamicin and the composition B comprises one or more selected from the group consisting of tobramycin and ceftazidime. In one embodiment, the composition A comprises gentamicin and the composition B comprises tobramycin. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises gentamicin and the composition B comprises ceftazidime.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises vancomycin and the composition B comprises one or more antibiotic agents.
  • the composition A comprises vancomycin and the composition B comprises one or more selected from the group consisting of erythromycin and ceftazidime. In one embodiment, the composition A comprises vancomycin and the composition B comprises erythromycin. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises vancomycin and the composition B comprises ceftazidime.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a composition A comprising one or more antibiotic agents and a composition B comprising one or more anti-acanthamoeba agents.
  • the composition A comprises one or more antibiotic agents selected from the group consisting of vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B, trimethoprim, ceftazidime, cefazolin, erythromycin, and rifampin.
  • the composition B comprises one or more selected from the group consisting of chlorohexidine and PHMB.
  • the composition A comprises polymyxin B and trimethoprim and the composition B comprises one or more anti-acanthamoeba agents.
  • the composition A comprises polymyxin B and trimethoprim and the composition B comprises PHMB.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises one or more antifungal agents and the composition B comprises one or more antibiotic agents.
  • the composition A comprises one or more antifungal agents selected from the group consisting of natamycin, amphotericin B, and voriconazole.
  • the composition B comprises one or more antibiotic agents selected from the group consisting of vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B, trimethoprim, ceftazidime, cefazolin, erythromycin, and rifampin.
  • the composition A comprises voriconazole and the composition B comprises one or more antibiotic agents.
  • the composition A comprises voriconazole and the composition B comprises gentamicin and/or tobramycin.
  • the composition A comprises voriconazole and the composition B comprises gentamicin.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises voriconazole and the composition B comprises tobramycin.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises one or more anti- acanthamoeba agents and the composition B comprises one or more antibiotic agents.
  • the composition A comprises PHMB and/or chlorhexidine.
  • the composition B comprises one or more antibiotic agents selected from the group consisting of vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B, trimethoprim, ceftazidime, cefazolin, erythromycin, and rifampin.
  • the composition A comprises chlorhexidine and the composition B comprises one or more selected from the group consisting of vancomycin, polymyxin B, trimethoprim, and moxifloxacin.
  • the composition A comprises chlorhexidine and the composition B comprises vancomycin.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises chlorhexidine and the composition B comprises polymyxin B and trimethoprim.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises chlorhexidine and the composition B comprises moxifloxacin.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises PHMB and the composition B comprises one or more antibiotic agents.
  • the composition A comprises PHMB and the composition B comprises one or more selected from the group consisting of polymyxin B, trimethoprim, and moxifloxacin.
  • the composition A comprises PHMB and the composition B comprises polymyxin B and trimethoprim.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition A comprises PHMB and the composition B comprises moxifloxacin.
  • the composition comprises the composition A and composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the composition A and composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the composition A and composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 12.5:1,
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:1000 and about 1000:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:500 and about 500:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active(s) agent of composition B in a weight ratio between about 1:100 and about 100:1. In some embodiments, the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio between about 1:100 and about 10:1.
  • the composition comprises the active agent(s) of composition A and the active agent(s) of composition B in a weight ratio of about 1:100, about 1:90, about 1:80; about 1:70, about 1:68, about 1:67; about 1:66, about 1:60, about 1:50; about 1:40, about 1:30; about 1:20; about 1:15; about 1:10, about 1:9, about 1:8, about 1:7.7, about 1:7.6, about 1:7, about 1:6, about 1:5, about 1:4.9, about 1:4.8, about 1:4.7, about 1:4, about 1:3; about 1:2.2, about 1:2.1, about 1:2, about 1:1.5, about 1:1.25, about 1:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 4.3:1, about 4.4:1, about 5:1, about 6:1, about 6.1:1, about 6.2:1, about 6.3:1, about 7:1, about 8:1, about 9:1, about
  • the composition comprises a concentration of composition A and composition B between about 0.01 weight percent (wt%) to about 99 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of composition A and composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of composition A and composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.01 wt% to about 99 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 0.1 wt% to about 90 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B between about 10 wt% to about 30 wt%.
  • the composition comprises a concentration of the active agent(s) of composition A and the active agent(s) of composition B of about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition comprises the specified antibiotic agents, antifungal agents, and/or anti-acanthamoeba agents as active agents in combination with one or more additional active agents.
  • Additional active agents include, but are not limited to, additional antibiotic agents, additional antifungal agents, additional anti-acanthamoeba agents, anthelminthics, antivirals, antiseptics, disinfectants, adjuvants, polymers, nucleic acids, proteins, peptides, carbohydrates, small molecules, and additional therapeutic compositions that may be useful in relieving symptoms of infection.
  • the specified antibiotic agents, antifungal agents, and/or anti-acanthamoeba agents are the only active agents in the composition.
  • the composition comprises the active agents between about 0.01 wt% to about 99 wt%. In some embodiments, the composition comprises the active agents between about 0.1 wt% to about 90 wt%.
  • the composition comprises the active agents between about 1 wt% to about 50 wt%. In some embodiments, the composition comprises the active agents between about 5 wt% to about 40 wt%. In some embodiments, the composition comprises the active agents between about 10 wt% to about 30 wt%.
  • the composition comprises the active agents at about 50 wt%, about 40 wt%, about 30 wt%, about 25 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 9 wt%, about 8 wt%, about 7 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1 wt%.
  • the composition is effective against a broad range of bacteria.
  • the composition is effective for treating a bacterial infection associated with Gram-positive and Gram-negative bacteria.
  • the bacterial infection is from one selected from Staphylococcus spp., e.g., Staphylococcus aureus, Staphylococcus epidermidis; Enterococcus spp., e.g., Enterococcus faecalis; Klebsiella spp., e.g., Klebsiella pneumoniae; Acinetobacter spp., e.g., Acinetobacter baumannii; Pseudomonas spp., e.g., Pseudomonas aeruginosa; Enterobacter spp.; Streptococcus pyogenes; Listeria spp.; Pseudomonas spp.; Mycobacterium spp., e.g., Mycobacterium tuberculosis; Enterobacter spp.; Campylobacter spp.; Salmonella spp.; Strepto
  • the infection is from one of the ESKAPE pathogens including Enterococcus spp., e.g., Enterococcus faecalis; Staphylococcus spp., e.g., Staphylococcus aureus, Staphylococcus epidermidis; Klebsiella spp., e.g., Klebsiella pneumoniae; Acinetobacter spp., e.g., Acinetobacter baumannii; Pseudomonas spp., e.g., Pseudomonas aeruginosa; Enterobacter spp., or the combination thereof.
  • Enterococcus spp. e.g., Enterococcus faecalis
  • Staphylococcus spp. e.g., Staphylococcus aureus, Staphylococcus epidermidis
  • Klebsiella spp.
  • the bacteria are selected from Acidothermus cellulyticus, Actinomyces odontolyticus, Alkaliphilus metalliredigens, Alkaliphilus oremlandii, Arthrobacter aurescens, Bacillus amyloliquefaciens, Bacillus clausii, Bacillus halodurans, Bacillus licheniformis, Bacillus pumilus, Bacillus subtilis, Bifidobacterium adolescentis, Bifidiobacterium longum, Caldicellulosiruptor saccharolyticus, Carboxydothermus hydrogenoformans, Clostridium acetobutylicum, Clostridium beijerinckii, Clostridium botulinum, Clostridium cellulolyticum, Clostridium difficile, Clostridium reteyveri, Clostridium leptum, Clostridium novyi, Clostridium perfringens, Clos
  • the composition for use against Gram-positive and Gram-negative bacteria comprising as active agents: a) a composition A comprising polymyxin B and trimethoprim and a composition B comprising polyhexamethylene biguanide (PHMB); or b) a composition A comprising gentamicin and a composition B comprising ceftazidime or tobramycin.
  • the composition A comprises polymyxin B and trimethoprim and composition B comprises PHMB.
  • polymyxin B, trimethoprim, and PHMB are the only active agents.
  • the composition A comprises gentamicin and composition B comprises ceftazidime.
  • composition A comprises gentamicin and composition B comprises tobramycin. In some embodiments, gentamicin and tobramycin are the only active agents. In some embodiments, the composition is effective for treating a bacterial infection associated with Gram-positive bacteria.
  • the Gram- positive bacteria are of the phylum Bacillota (a.k.a., Firmicutes). In some embodiments, the Gram-positive bacteria are of the class Bacilli. In some embodiments, the Gram- positive bacteria are of the order Bacillales. In some embodiments, the Gram-positive bacteria are of the family Staphylococcaceae.
  • the Gram-positive bacteria are of the genus Staphylococcus. In some embodiments, the Gram-positive bacteria are Staphylococcus aureus. In some embodiments, the Gram-positive bacteria are selected from the group consisting of Mycobacterium avium, Mycobacterium marinum, and Mycoplasma pneumoniae.
  • composition for use against Gram-positive bacteria comprising as active agents a composition A comprising cefazolin and a composition B comprising vancomycin or erythromycin. In some embodiments, composition A comprises cefazolin and composition B comprises vancomycin. In some embodiments, cefazolin and vancomycin are the only active agents.
  • composition A comprises cefazolin and composition B comprises erythromycin.
  • cefazolin and erythromycin are the only active agents.
  • the composition is effective for treating a bacterial infection associated with Gram-negative bacteria.
  • the Gram- negative bacteria are of the phylum Pseudomonadota.
  • the Gram- negative bacteria are of the class Gammaproteobacteria.
  • the Gram-negative bacteria are of the order Pseudomonadales.
  • the Gram-negative bacteria are of the family Pseudomonadaceae.
  • the Gram-negative bacteria are of the genus Pseudomonas.
  • the Gram- negative bacteria are Pseudomonas aureginosa.
  • the Gram- negative bacteria is selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Citrobacter freundii, Citrobacter koseri, Enterobacter aerogens, Enterobacter cloacae, Escherichia coli, Haemophius influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Pseudomonas stutzeri, Chlamydia pneumoniae, Chlamydia trachomatis, and Legionella pneumophila.
  • the composition for use against Gram-negative bacteria comprising as active agents: a) a composition A comprising chlorhexidine and a composition B comprising polymyxin B and trimethoprim, or moxifloxacin; or b) a composition A comprising PHMB and a composition B comprising moxifloxacin or polymyxin B and trimethoprim.
  • composition A comprises chlorhexidine and composition B comprises polymyxin B and trimethoprim.
  • chlorhexidine, polymyxin B, and trimethoprim are the only active agents.
  • composition A comprises chlorhexidine and composition B comprises moxifloxacin.
  • composition A comprises PHMB and composition B comprises moxifloxacin. In some embodiments, PHMB and moxifloxacin are the only active agents. In some embodiments, composition A comprises PHMB and composition B comprises polymyxin B and trimethoprim. In some embodiments, PHMB, polymyxin B, and trimethoprim are the only active agents.
  • the antibacterial composition or the topical pharmaceutical composition as described herein is for treating ocular, otic, nasal, skin, or wound infection in a subject. In one embodiment, the infection is bacterial infection.
  • the bacterial ocular infection is bacterial keratitis, bacterial conjunctivitis, or bacterial endophthalmitis.
  • the antibacterial composition or the topical pharmaceutical composition is for treating surface ocular bacterial infections, including acute bacterial conjunctivitis, and blepharoconjunctivitis, caused by susceptible strains of the following microorganisms: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumonia, Streptococcus viridans, Haemophilus influenza and Pseudomonas aeruginosa, etc..
  • the antibacterial composition or the topical pharmaceutical composition of the present invention may take the form of a cream, a lotion, an ointment, a hydrogel, a colloid, a gel, a foam, an oil, a milk, a suspension, a wipe, a sponge, a solution, an emulsion, a paste, a patch, a pladget, a swab, a dressing, a spray or a pad.
  • the topical composition of the present invention comprises one or more pharmaceutically acceptable carrier.
  • Examples of the pharmaceutically acceptable carriers that are usable in the context of the present invention include carrier materials such as a solvent, a stabilizer, a solubilizer, a filler, a tonicity enhancing agent, a structure-forming agent, a suspending agent, a dispersing agent, a chelating agent, an emulsifying agent, an anti-foaming agent, an ointment base, an emollient, a skin protecting agent, a gel-forming agent, a thickening agent, a pH adjusting agent, a preservative, a penetration enhancer, a complexing agent, a lubricant, a demulcent, a viscosity enhancer, a bioadhesive polymer, or a combination thereof.
  • carrier materials such as a solvent, a stabilizer, a solubilizer, a filler, a tonicity enhancing agent, a structure-forming agent, a suspending agent, a dispersing agent, a
  • solvents are water or purified water, alcohols (e.g., ethanol, benzyl alcohol), vegetable, marine and mineral oils, polyethylene glycols, propylene glycols, glycerol, and liquid polyalkylsiloxanes.
  • Inert diluents or fillers may be sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate.
  • buffering agents include citric acid, acetic acid, lactic acid, hydrogenophosphoric acid, diethylamine, sodium hydroxide and tromethane (/.e., tris(hydroxymethyl)aminomethane hydrochloride).
  • Suitable suspending agents are, for example, naturally occurring gums (e.g., acacia, arabic, xanthan, and tragacanth gum), celluloses (e.g., carboxymethyl-, hydroxyethyl-, hydroxypropyl-, and hydroxypropylmethyl-cellulose), alginates and chitosans.
  • dispersing or wetting agents are naturally occurring phosphatides (e.g., lecithin or soybean lecithin), condensation products of ethylene oxide with fatty acids or with long chain aliphatic alcohols (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate).
  • Preservatives may be added to a topical composition of the invention to prevent microbial contamination that can affect the stability of the formulation and/or cause infection in the patient.
  • Suitable examples of preservatives include parabens (such as methyl, ethyl, propyl, /p-hydroxybenzoate, butyl, isobutyl, and isopropylparaben), potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDM hydantoin, iodopropynyl butylcarbamate, benzalconium chloride, cetrimide, and benzylalcohol.
  • Examples of chelating agents include sodium EDTA and citric acid.
  • gel bases or viscosity-increasing agents are liquid paraffin, polyethylene, fatty oils, colloidal silica or aluminum, glycerol, propylene glycol, propylene carbonate, carboxyvinyl polymers, magnesium-aluminum silicates, hydrophilic polymers (such as, for example, starch or cellulose derivatives), water-swellable hydrocolloids, carragenans, hyaluronates, alginates, and acrylates.
  • Ointment bases suitable for use in the compositions of the present invention may be hydrophobic or hydrophilic, and include paraffin, lanolin, liquid polyalkylsiloxanes, cetanol, cetyl palmitate, vegetal oils, sorbitan esters of fatty acids, polyethylene glycols, and condensation products between sorbitan esters of fatty acids, ethylene oxide (e.g., polyoxyethylene sorbitan monooleate), polysorbates, white petrolatum and white wax.
  • humectants are ethanol, isopropanol glycerin, propylene glycol, sorbitol, lactic acid, and urea.
  • Suitable emollients include cholesterol and glycerol.
  • thickening agents are generally used to increase viscosity and improve bioadhesive properties of pharmaceutical or cosmetic compositions.
  • thickening agents include, but are not limited to, celluloses, polyethylene glycol, polyethylene oxide, naturally occurring gums, gelatin, karaya, pectin, alginic acid, povidone, and Carbopol ® polymers.
  • Particularly interesting are thickening agents with thixotropic properties (i.e., agents whose viscosity is decreased by shaking or stirring).
  • Bioadhesive polymers are useful to hydrate the skin and enhance its permeability. Bioadhesive polymers can also function as thickening agents. Examples of bioadhesive polymers include, but are not limited to, pectin, alginic acid, chitosan, polysorbates, poly(ethyleneglycol), oligosaccharides and polysaccharides, cellulose esters and cellulose ethers, and modified cellulose polymers.
  • Permeation enhancing agents are vehicles containing specific agents that affect the delivery of active components through the skin.
  • Permeation enhancing agents are generally divided into two classes: solvents and surface active compounds (amphiphilic molecules).
  • solvent permeation enhancing agents include alcohols (e.g., ethyl alcohol, isopropyl alcohol), dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, l-dodecylazocyloheptan-2-one, N-decyl-methylsulfoxide, lactic acid, N,N-diethyl-m-toluamide, N-methyl pyrrolidone, nonane, oleic acid, petrolatum, polyethylene glycol, propylene glycol, salicylic acid, urea, terpenes, and trichloroethanol.
  • Surfactant permeation enhancing agents may be nonionic, amphoteric, cationic, or zwitterionic.
  • Suitable nonioinic surfactants include poly(oxyethylene)- poly(oxypropylene) block copolymers, commercially known as poloxamers; ethoxylated hydrogenated castor oils; polysorbates, such as Tween 20 or Tween 80.
  • Amphoteric surfactants include quaternized imidazole derivatives, cationic surfactants include cetypyridinium chloride, and zwitterionic surfactants include the betaines and sulfobetaines.
  • Suitable permeation enhancers include pentadecalactone, 2-pyrrolidine, l-dodecal-azacycloheptane-2-one, calcium thioglycolate, hexanol, derivatives of 1,3-dioxanes (i.e., 1,3-dioxacyclohexanes) and 1,3-dioxalanes (i.e., 1,3-dioxacyclopentanes), l-N-dodecyl-2-pyrrolidone-5-carboxylic acid, 2-pentyl-2- oxo-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, and l- azacycloheptan-2-one-2-dodecylacetic acid among others.
  • the topical pharmaceutical composition of the present invention is a topical ophthalmic pharmaceutical composition in the form of a solution or suspension, an emulsion, an ointment, a cream, a gel, or a sustained release vehicle, such as an ocular insert.
  • the topical ophthalmic pharmaceutical composition of the present invention is a sterile liquid or gel, such as a solution or suspension, contained within a multi-use or single-use eye drop dispensing bottle or vial.
  • the ophthalmic pharmaceutical composition is provided as a sterile liquid comprising from about 0.0015 to about 10.0 wt. % of the antibacterial composition described herein contained within a multi-use eye drop dispensing bottle or vial.
  • the eye drop formulation comprises an aqueous buffered saline solution such as phosphate or borate buffered saline from about pH 4 to about 8, typically from about pH 7.0 to about 8.0, and more typically from about pH 7.2 to about pH 7.4.
  • the osmolality of the formulation is typically in the range of about 200, 250, or 270 mOsm/kg up to about 310, 350, or 400 mOsm/kg.
  • a liquid formulation packaged in a multi-use eye drop dispensing bottle may contain an added preservative, such as benzalkonium chloride. However, in some examples, the ophthalmic composition may be preservative-free.
  • preservative-free means that the composition comprises no preservative agent in addition to the antibacterial composition.
  • the ophthalmic pharmaceutical composition when formulated as a liquid, such as a solution or a suspension for dispensing by eye dropper, may contain an excipient that extends the period of time that a dose of the composition remains in contact with the cornea.
  • the excipient may be a viscosity-increasing agent and/or a mucoadhesive agent.
  • excipients include high molecular weight hydrophilic polymers including, but not limited to, polyvinyl alcohol, polyethylene glycol, carbomers, polycarbophil, polyoxyethlene-polyoxypropylene block copolymers (e.g. Poloxamer 407), cellulose derivatives (e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose), natural polysaccharides (e.g. hyaluronic acid, dextran, chondroitin sulfate, gellan gum, xanthan gum, guar gum, trehalose, and tamarind seed polysaccharide).
  • high molecular weight hydrophilic polymers including, but not limited to, polyvinyl alcohol, polyethylene glycol, carbomers, polycarbophil, polyoxyethlene-polyoxypropylene block copolymers (e.g. Poloxamer 407), cellulose derivatives (e.g
  • compositions are described in the literature (see e.g. Yadav et al. J. Chem. Pharm. Res., 2010, 2(5):418-432, incorporated herein by reference). Any combination of two or more of the foregoing polymers may be included in composition.
  • a high molecular weight polymer has a molecular weight of at least 100,000 daltons.
  • the composition comprises a cyclodextrin (e.g.2-hydroxypropyl-beta-cyclodextrin).
  • the composition is formulated as a sustained release liquid.
  • the composition may be in the form of an ophthalmic suspension comprising mucoadhesive microspheres which sustain release of the antibacterial composition.
  • the microspheres comprise a mucoadhesive polymer and the antibacterial composition.
  • Methods of making mucoadhesive microspheres for ophthalmic suspensions are described in the literature (see e.g., Dandagi et al., Sci Pharm (2013) 81(l):259-280).
  • the ophthalmic pharmaceutical composition is formulated as unit dose ocular insert for placement in the eye's cul de sac. Methods of making ocular inserts are described in the literature (see e.g. U.S. Patent No.4,730,013, U.S.
  • An ocular insert is a solid unit dosage form comprising of a biodegradable matrix containing the active agent.
  • the matrix is typically made from a high molecular weight polymer or a combination of high molecular weight polymers, such as the aforementioned hydrophilic polymers and additional polymers disclosed in the aforementioned patent publications that describe ocular inserts.
  • the ocular insert may additionally comprise a lubricant to enhance comfort. Upon placement in the eye, the ocular insert dissolves or erodes over a period of several hours to a day, and in some cases over several days.
  • the disclosure provides methods of treating a bacterial infection in a subject.
  • the method comprises administering to the subject separately, simultaneously, or sequentially, therapeutically effective amount of an antibacterial composition of the present disclosure
  • the antibacterial composition is formulated into a topical pharmaceutical composition of the present disclosure.
  • the topical pharmaceutical composition is formulated for treating ocular, otic, nasal, skin, or wound infections.
  • the method is effective for treating a bacterial infection associated with a broad range of bacteria.
  • the method is effective for treating a bacterial infection associated with Gram-positive and Gram-negative bacteria.
  • the method is effective for treating an infection associated with one or more of the ESKAPE pathogens including Enterococcus spp., e.g. Enterococcus faecalis; Staphylococcus spp., e.g. Staphylococcus aureus, Staphylococcus epidermidis; Klebsiella spp., e.g. Klebsiella pneumoniae; Acinetobacter spp., e.g. Acinetobacter baumannii; Pseudomonas spp., e.g. Pseudomonas aeruginosa; Enterobacter spp., or the combination thereof.
  • Enterococcus spp. e.g. Enterococcus faecalis
  • Staphylococcus spp. e.g. Staphylococcus aureus, Staphylococcus epidermidis
  • Klebsiella spp.
  • the method is effective for treating a bacterial infection associated with Gram-positive bacteria.
  • the Gram- positive bacteria are of the phylum Bacillota (a.k.a., Firmicutes).
  • the Gram-positive bacteria are of the class Bacilli.
  • the Gram- positive bacteria are of the order Bacillales.
  • the Gram-positive bacteria are of the family Staphylococcaceae.
  • the Gram-positive bacteria are of the genus Staphylococcus.
  • the Gram-positive bacteria are Staphylococcus aureus.
  • the Gram-positive bacteria is selected from the group consisting of Mycobacterium avium, Mycobacterium marinum, and Mycoplasma pneumoniae.
  • the method is effective for treating a bacterial infection associated with Gram-negative bacteria.
  • the Gram- negative bacteria are of the phylum Pseudomonadota.
  • the Gram- negative bacteria are of the class Gammaproteobacteria.
  • the Gram-negative bacteria are of the order Pseudomonadales.
  • the Gram-negative bacteria are of the family Pseudomonadaceae.
  • the Gram-negative bacteria are of the genus Pseudomonas.
  • the Gram- negative bacteria are Pseudomonas aureginosa.
  • the Gram- negative bacteria is selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Citrobacter freundii, Citrobacter koseri, Enterobacter aerogens, Enterobacter cloacae, Escherichia coli, Haemophius influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Pseudomonas stutzeri, Chlamydia pneumoniae, Chlamydia trachomatis, and Legionella pneumophila.
  • the bacterial infection is an ocular, otic, nasal, skin, wound, or systemic infection. In some embodiments, the bacterial infection is an ocular infection. In some embodiments, the ocular infection is a surface ocular bacterial infection. In some embodiments, the surface ocular bacterial infection is one or more selected from the group consisting of bacterial keratitis, acute bacterial conjunctivitis, bacterial endophthalmitis, and blepharoconjunctivitis. In some embodiments, the bacterial infection is a skin infection. In some embodiments, the skin infection is one or more selected from the group consisting of an abscess, a boil, cellulitis, folliculitis, and impetigo.
  • the infection is a systemic infection.
  • infection is one or more selected from the group consisting of sepsis, pneumonia, endocarditis, osteomyelitis, infectious arthritis, toxic shock syndrome, bacteremia, and meningitis.
  • the bacterial infection is characterized with colonization or biofilm formation.
  • the method is effective to decolonize the bacteria.
  • the method comprises contacting the bacterial organism separately, simultaneously, or sequentially with an antibacterial or topical pharmaceutical composition of the present disclosure. Examples of effective decolonization of bacteria include, but are not limited to, reduction in colony size, quantity, or a combination thereof by between about 0.001% and about 100%.
  • the method reduces colony size, quantity, or a combination thereof by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 96%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%.
  • the method is effective to destroy, disrupt, inhibit, or reduce the formation of a bacterial biofilm.
  • the method comprises contacting the bacterial organism separately, simultaneously, or sequentially with an antibacterial or topical pharmaceutical composition of the present disclosure. Examples of destruction, disruption, or inhibition of a bacterial biofilm include, but are not limited to, reducing biofilm area, thickness, volume, quantity, stability, or a combination thereof by between about 0.001% and about 100%.
  • a bacterial biofilm is destroyed, disrupted, or inhibited by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 96%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%.
  • Examples of inhibition or reduction of biofilm formation include, but are not limited to, slowing the formation of one or more biofilms, decreasing the number of biofilms formed, decreasing the area, thickness, or volume of biofilms formed, decreasing stability of biofilms formed, or a combination thereof by between about 0.001% and about 100%.
  • biofilm formation is inhibited or reduced by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 96%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%.
  • the method is performed alone. In some embodiments, the method is performed in conjunction with another therapy.
  • the combination therapy of the present invention may be used in conjunction with a disinfectant, antiseptic, antibiotic, or biocide on a surface such as medical devices and indwelling devices including stents, catheters, peritoneal dialysis tubing, draining devices, joint prostheses, dental implants and the like.
  • Pharmaceutical compositions and formulations The invention also encompasses the use of pharmaceutical compositions to practice the methods of the invention.
  • a pharmaceutical composition may consist of at least one composition of the invention or a salt thereof in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one composition of the invention or a salt thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
  • the compound or conjugate may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
  • Pharmaceutical compositions that are useful in the methods of the invention may be suitably developed for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, or another route of administration.
  • a composition useful within the methods of the invention may be directly administered to the skin, vagina, or any other tissue of a mammal.
  • Other contemplated formulations include liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
  • compositions suitable for administration to humans are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist may design and perform such modification with merely ordinary, if any, experimentation.
  • compositions utilized in the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions comprise a therapeutically effective amount of a compound or conjugate of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers that are useful include, but are not limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, are included in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
  • the pharmaceutically acceptable carrier is not DMSO alone.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, vaginal, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotic agents; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
  • compositions utilized in the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition.
  • the preservative is used to prevent spoilage in the case of exposure to contaminants in the environment.
  • preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof.
  • An exemplary preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.
  • the composition includes an antioxidant and a chelating agent that inhibits the degradation of the compound.
  • Exemplary antioxidants for some compounds are BHT, BHA, alpha-tocopherol, and ascorbic acid in the range of about 0.01% to 0.3%.
  • the BHT is in the range of 0.03% to 0.1% by weight by total weight of the composition.
  • the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition.
  • Exemplary chelating agents include edetate salts (e.g., disodium edetate) and citric acid in the weight range of about 0.01% to 0.20%. In one embodiment, chelating agents may be in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are the exemplary antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art. Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle.
  • Aqueous vehicles include, for example, water, and isotonic saline.
  • Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
  • Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.
  • Oily suspensions may further comprise a thickening agent.
  • suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
  • Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively).
  • Known emulsifying agents include, but are not limited to, lecithin, and acacia.
  • Known preservatives include, but are not limited to, methyl, ethyl, or n- propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid.
  • Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
  • Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol. Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent.
  • an “oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
  • Liquid solutions of the pharmaceutical composition for use in the invention may comprise each of the components described regarding liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent.
  • Aqueous solvents include, for example, water, and isotonic saline.
  • Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Powdered and granular formulations of a pharmaceutical preparation of the composition utilized in the invention may be prepared using known methods.
  • Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto.
  • Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
  • a pharmaceutical composition for use in the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion.
  • the oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these.
  • Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
  • Methods for impregnating or coating a material with a chemical composition include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after a diagnosis of disease. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection.
  • the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • Administration of the compositions of the present invention to a subject, such a mammal, including a human, may be carried out using known procedures, at dosages and for periods of time effective to prevent or treat disease.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well-known in the medical arts.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non- limiting example of an effective dose range for a therapeutic compound for use in the invention is from about 1 and 5,000 mg/kg of body weight/per day.
  • the invention may be practiced as frequently as several times daily, or it may be practiced less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less.
  • the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
  • a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease in a subject.
  • the composition of the present invention provides for a controlled release of a therapeutic agent.
  • controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology, using for example proteins equipped with pH sensitive domains or protease-cleavable fragments.
  • the dosage forms to be used can be provided as slow or controlled release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, micro-particles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention.
  • single unit dosage forms suitable for oral administration such as tablets, capsules, gel-caps, lozenges, and caplets, which are adapted for controlled-release are encompassed by the present invention.
  • Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.
  • controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time.
  • the controlled-release formulation of the composition described herein allows for release of a therapeutic agent precisely when the agent is most needed.
  • the controlled-release formulation of the composition described herein allows for release of a therapeutic agent precisely in conditions in which the therapeutic agent is most active. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • the composition provides for an environment- dependent release, when and where the therapeutic agent is triggered for release.
  • the composition invention releases at least one therapeutic agent when and where the at least one therapeutic agent is needed.
  • the triggering of release may be accomplished by a variety of factors within the microenvironment of the treatment or prevention site, including, but not limited to, temperature, pH, the presence or activity of a specific molecule or biomolecule, and the like.
  • Controlled release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water or other physiological conditions or compounds.
  • controlled-release component in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient.
  • the formulations of the present invention may be, but are not limited to, short-term, rapid offset, as well as controlled, for example, sustained release, delayed release, and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release that is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds.
  • the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the compositions are administered to a subject, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the invention is practiced in dosages that range from one to five times per day or more.
  • the invention is practiced in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any subject will be determined by the attending physical taking all other factors about the subject into account.
  • Routes of administration of include ophthalmic, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, liquid drops for ophthalmic administration, dry powder or aerosolized formulations for inhalation, compositions, and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • Example 1 Antimicrobial Drug-Drug Interactions in the Treatment of Infectious Keratitis
  • Infectious keratitis is a serious disease requiring immediate, intensive, and broad-spectrum empiric treatment to prevent vision loss.
  • current guidelines recommend treatment with several antimicrobial agents simultaneously to provide adequate coverage while awaiting results of microbiology cultures.
  • Bacterial Strains and Growth Conditions Bacterial strains Staphylococcus aureus strain UAMS-1(Gillaspy, A.
  • the antibiotic agents used in this study include vancomycin (Acros Organics), gentamicin (Sigma), moxifloxacin (Alcon), polymyxin B-trimethoprim ( Pacific Pharma), erythromycin (Fisher Biotech), tobramycin (Acros Organics), ceftazidime (Acros Organics), cefazolin (Acros Organics), and rifampin (Ala Aesar).
  • Anti-fungal agents include voriconazole (Acros Organics), natamycin (Alfa Aesar) and amphotericin B (Fisher BioReagents), and anti-acanthamoeba drugs include polyhexamethylene biguanide (PHMB) (Matrix Scientific) and chlorhexidine (Acros Organics).
  • PHMB polyhexamethylene biguanide
  • MIC Minimum Inhibitory Concentration Following the Clinical and Laboratory Standards Institute guidelines for minimum inhibitory concentration (MIC) ((CLSI) CLSI. CLSI supplement M100.
  • Fractional Inhibitory Concentration According to Clinical and Laboratory Standards Institute guidelines for fractional inhibitory concentration (FIC) testing ((CLSI) CLSI, 2021, CLSI supplement M100, Wayne, PA, Clinical and Laboratory Standards Institute), a standard checkerboard assay was done to determine the efficacy of every combination of vancomycin, gentamicin, moxifloxacin, polymyxin B-trimethoprim, erythromycin, tobramycin, ceftazidime, cefazolin, and rifampin with 1) each other (36 antibiotic-antibiotic combinations), 2) voriconazole, amphotericin B and natamycin (27 antibiotic-antifungal combinations), and 3) PHMB and chlorhexidine (18 antibiotic-anti-acanthamoeba combinations) against both UAMS-1 and PAO1 in biological triplicate.10 ⁇ L of the indicated bacterial culture prepared as described above was added to 88 ⁇ L MH media and 2 ⁇ L of antibiotic agents in individual wells of a
  • FICI fractional inhibitory concentration index
  • the minimum inhibitory concentrations (MICs) of a panel of commonly used ophthalmic antimicrobial drugs (9 antibiotic agents: vancomycin, gentamicin, moxifloxacin, polymyxin B-trimethoprim, erythromycin, tobramycin, ceftazidime, cefazolin, and rifampin, 3 antifungal agents: natamycin, amphotericin B and voriconazole, and 2 anti-acanthamoeba agents: chlorhexidine and PHMB) were determined for both S. aureus and P. aeruginosa ( Figure 1). Among antibiotic agents, S. vancomycin, gentamicin, moxifloxacin, polymyxin B-trimethoprim, erythromycin, tobramycin, ceftazidime, cefazolin, and rifampin, 3 antifungal agents: natamycin, amphotericin B and voriconazole, and 2 anti-acant
  • ceftazidime (1.26 ⁇ 0.627 ⁇ g/ml), gentamicin (0.301 ⁇ 0.102 ⁇ g/ml), moxifloxacin (7.55 ⁇ 1.22 ⁇ g/ml), polymyxin B/trimethoprim (0.407 ⁇ 0.134 ⁇ g/ml), and tobramycin (0.179 ⁇ 0.179 ⁇ g/ml).
  • ceftazidime displayed moderate antimicrobial activity towards S. aureus (16.8 ⁇ 4.85 ⁇ g/ml), and towards P.
  • aeruginosa rifampin displayed moderate antimicrobial activity (17.23 ⁇ 4.32 ⁇ g/ml), erythromycin displayed poor activity (119 ⁇ 39.2 ⁇ g/ml), and cefazolin and vancomycin had no antimicrobial activity.
  • amphotericin B, natamycin and voriconazole none displayed antimicrobial activity when tested individually against either S. aureus or P. aeruginosa.
  • anti-acanthamoeba drugs did display efficacy towards both bacterial species. The MIC of chlorhexidine towards S. aureus and P.
  • aeruginosa was 0.723 ⁇ 0.141 ⁇ g/ml and 3.01 ⁇ 0.417 ⁇ g/ml, respectively.
  • PHMB displayed potent activity towards S. aureus (1.76 ⁇ 0.597 ⁇ g/ml) and moderate activity towards P. aeruginosa (17.6 ⁇ 6.26 ⁇ g/ml).
  • 36 antibiotic-antibiotic combinations, 27 antibiotic-antifungal combinations and 18 antibiotic- anti-acanthamoeba combinations were evaluated in standard FIC checkerboard format for both S. aureus and P. aeruginosa (Table 1).
  • gentamicin has a baseline MIC of 0.833 ⁇ 0.289 ⁇ g/ml towards S. aureus, yet when in combination with voriconazole, the MIC decreased 3-fold to 0.25 ⁇ 0 ⁇ g/ml ( Figure 4).
  • tobramycin alone has an MIC of 0.333 ⁇ 0.144 ⁇ g/ml towards S. aureus, yet in combination with voriconazole, the MIC decreased to 0.0833 ⁇ 0.036 ⁇ g/ml, representing a 4-fold improvement in activity (Figure 4).
  • antibiotic-acanthamoeba drug combinations 18 antibiotic-acanthamoeba drug combinations were tested to evaluate whether the presence of either chlorhexidine or PHMB would alter the efficacy of ophthalmic antibiotic agents towards either S. aureus or P. aeruginosa. With regards to S. aureus, there were no synergistic or antagonistic drug-drug interactions and 16 drug- drug combinations resulted in neutral activity (Table 1).
  • Additive combinations included rifampin + chlorhexidine (0.542 ⁇ 0.219), erythromycin + chlorhexidine (0.563 ⁇ 0.063), ceftazidime + chlorhexidine (0.604 ⁇ 0.036), and rifampin + PHMB (0.75 ⁇ 0).
  • vancomycin itself does not have any intrinsic antibiotic activity toward P.
  • the MIC of PHMB decreased 2-fold from 1.56 ⁇ g/ml to 0.781 ⁇ g/ml when in combination with PT.
  • the MIC of PT decreased 16-fold from 0.372 ⁇ g/ml to 0.0232 ⁇ g/ml when in combination with PHMB, and the MIC of PHMB also decreased 16-fold from 25 ⁇ g/ml to 1.56 ⁇ g/ml when in combination with PT (Table 1, Figure 5).
  • Tobramycin + gentamicin displayed additive antimicrobial activity towards both S. aureus (0.896 ⁇ 0.295) and P. aeruginosa (0.563 ⁇ 0.225). In this combination, towards S.
  • the ceftazidime MIC decreased 5.4-fold and gentamicin MIC decreased 2-fold in combination vs alone.
  • the ceftazidime MIC decreased 2.7-fold and gentamicin MIC decreased 2.4-fold.
  • these drug combinations show improved broad-spectrum activity toward both S. aureus and P. aeruginosa, they may represent ideal combinations for the empiric treatment of keratitis.
  • Bacterial kill curves were also completed for the combinations of ceftazidime + gentamicin, tobramycin + gentamicin, and PT + PHMB, evaluating the kill rate of each antibiotic in isolation compared to the combination, As shown in Figure 6, each of these combinations displayed superior, rapid killing of both S. aureus and P, aeruginosa cells compared to the agents individually.
  • Combination therapy on the efficacy of antibiotic agents toward either S. aureus or P. aeruginosa Keratitis is a devastating disease, requiring immediate, broad spectrum antimicrobial therapy to prevent vision loss. Given the aggressive nature of these infections, patients are often subject to intensive treatment with multiple antimicrobial agents administered by drops every 30 minutes – 1 hour around the clock.
  • aeruginosa could represent favorable choices when selecting therapeutics for corneal infections.
  • drug-drug combinations including polymyxin B/trimethoprim + rifampin, polymyxin B/trimethoprim + PHMB, tobramycin + gentamicin and ceftazidime + gentamicin, that displayed this improved activity towards both S. aureus and P. aeruginosa, suggesting that these combinations may be particularly advantageous in the empiric treatment of keratitis.
  • aureus 1 1.67 0.5 0.833 1 ⁇ 0 Vancomycin Moxifloxacin Vancomycin Moxifloxacin P. aeruginosa --- 8 --- 8 --- S. aureus 0.833 0.125 0.833 0.125 2 ⁇ 0 Vancomycin PT Vancomycin PT P. aeruginosa --- 0.388 --- 0.310 --- S. aureus 1.17 1.61 0.833 1.61 2.33 ⁇ 0.577 Vancomycin Ceftazidime Vancomycin Ceftazidime P. aeruginosa --- 1.67 --- .5 --- S.
  • aureus 1 16 0.5 3.33 0.708 ⁇ 0.072 Vancomycin Cefazolin Vancomycin Cefazolin P. aeruginosa --- --- --- --- --- --- --- --- --- S. aureus 1 1 0.25 0.167 0.417 ⁇ 0.072 Vancomycin Erythromycin Vancomycin Erythromycin P. aeruginosa --- 125 --- 15.63 --- S. aureus 0.833 0.5 1 0.5 2.33 ⁇ 0.578 Vancomycin Rifampin Vancomycin Rifampin P. aeruginosa --- 16 --- 21.3 --- S.

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  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions et des méthodes de traitement d'infections bactériennes. Dans certains cas, les présentes compositions et méthodes sont utiles pour traiter des infections bactériennes oculaires telles que la kératite.
PCT/US2024/024324 2023-04-14 2024-04-12 Compositions pharmaceutiques combinatoires pour traitement d'infections bactériennes Pending WO2024216070A1 (fr)

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