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WO2011008193A1 - Schémas posologiques de l’acide fusidique pour le traitement d’infections bactériennes - Google Patents

Schémas posologiques de l’acide fusidique pour le traitement d’infections bactériennes Download PDF

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Publication number
WO2011008193A1
WO2011008193A1 PCT/US2009/050353 US2009050353W WO2011008193A1 WO 2011008193 A1 WO2011008193 A1 WO 2011008193A1 US 2009050353 W US2009050353 W US 2009050353W WO 2011008193 A1 WO2011008193 A1 WO 2011008193A1
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Prior art keywords
staphylococus
infection
loading dose
hours
fusidic acid
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Inventor
Ronald Jones
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Cempra Pharmaceuticals Inc
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Cempra Pharmaceuticals Inc
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Priority to CA2767614A priority Critical patent/CA2767614C/fr
Priority to PCT/US2009/050353 priority patent/WO2011008193A1/fr
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Anticipated expiration legal-status Critical
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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

  • Fusidic acid is a tetracyclic triterpenoid or fusidane (steroidal) antibiotic derived from the fungus Fusidium coccineum that inhibits bacterial protein synthesis. FA is effective against gram-positive bacteria such as Staphylococcus species and
  • Cory neb acterium species L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and
  • FA was developed for clinical use in the 1960s and it is approved for human use outside of the United States, such as in the UK, Canada, Europe, Israel, Australia and New Zealand. It is typically prescribed at doses of 500 mg TID for treating skin and skin structure infections caused by Staphylococcus aureus (A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Collumble et al., Int'lJ. Antimicrobial Agents 12:S45-S58 (1999); D. Spelman, Int'lJ.
  • Antimicrobial Agents 12:S59-S66 (1999) although some physicians have routinely prescribed the compound at 500 mg BID for treating skin and skin structure infections due to the long half-life of the compound (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6 th ed. (Mandell et al. eds., Elsevier, 2006)).
  • FA Treatment using FA has been well studied and it is generally regarded as safe when administered to humans, as evidenced by the fact that the drug has been in continuous use for more than 40 years. There are, however, several characteristics of FA that have prevented use of the drug against a wider spectrum of bacteria and in the treatment in additional types of infection. For example, approved dosing regimens have been shown to select for bacterial resistance, such as in S. aureus. Approved dosing regimens provide low multiples of the MIC and as a result, S. aureus resistant mutants can be selected after the first day of dosing. Once resistance has developed, FA is not effective against the resistant strains.
  • the dosage of the drug cannot be simply increased as a means of avoiding development of resistance. It is difficult to achieve high concentrations of FA in the blood due to the substantial protein binding of the drug (approximately 95-97%) (K.
  • FA e.g. 1 gram TID
  • High doses of FA are required if the drug is to be used in the treatment of bone and joint infections, less susceptible bacteria and other serious infections.
  • treatment regimens using high doses of the drug induce nausea and vomiting and are rejected by patients (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6 th ed. (Mandell et al. eds., Elsevier, 2006); K.
  • the present invention is directed to a method of treating or preventing a bacterial infection in a subject comprising:
  • PK pharmacokinetic
  • the C max is not less than about 80 ug/ml, the minimum trough plasma concentration of (a) is not less than about 60 ug/ml and the minimum trough plasma concentration of (b) is not less than about 70 ug/ml. In a further preferred aspect, the C max is not less than about 100 ug/ml, the minimum trough plasma concentration of (a) is not less than about 80 ug/ml and the minimum trough plasma concentration of (b) is not less than about 80 ug/ml.
  • the loading dose comprises two loading doses, wherein the second loading dose is administered about 12 hours after administration of the first loading dose, and wherein each loading dose is between about 1000 mg and about 1850 mg.
  • the total loading dose administered to the subject is between about 2000 mg and about 3600 mg.
  • the maintenance dose comprises multiple maintenance doses of independently between about 500 mg and 1000 mg, administered about 12 hours apart, beginning about 12 hours after administration of the loading dose.
  • a minimum trough plasma concentration of not less than about 50 ug/ml is maintained for at least about 48 hours after administering of the loading dose. More preferably, a minimum trough plasma concentration of not less than about 50 ug/ml is maintained for at least about 72 hours. Even more preferably, a minimum trough plasma concentration of not less than about 50 ug/ml is maintained for at least about 96 hours.
  • the loading dose comprises two loading doses, wherein each loading dose is independently between about 1000 mg and about 1850 mg, and wherein the second loading dose is administered about 12 hours after administration of the first loading dose; and the maintenance dose comprises multiple maintenance doses of independently between about 500 mg and 1000 mg administered about 12 hours apart, beginning about 12 hours after administration of the second loading dose.
  • each loading dose is independently at least about 1500 mg.
  • each maintenance dose is independently at least about 600 mg.
  • the subject is a human.
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of staphylococci, including coagulase-negative staphylococci and coagulase-positive staphylococci, streptococci, including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Corynebacterium species.
  • staphylococci including coagulase-negative staphylococci and coagulase-positive staphylococci
  • streptococci including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Corynebacterium species.
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus,
  • bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus,
  • Staphylococus simulans Staphylococus warneri, Staphylococus hominis, Staphylococus intermedius, Staphylococcus pseudointermedius, Staphylococus lyricus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies dysgalactiae, Streptococcus anginosus, Streptococcus mitis, Streptococcus salivarius, Streptococcus bovis, Streptococcus mutans, Neisseria gonorrhoeae, Neisseria meningitidis, Bacillus anthracis, Bordetella pertussis, Clostridium difficile, Enterococcus faecalis, Enterococcus faecium and Cory neb acterium diphtheriae.
  • the bacterial infection is an infection selected from the group consisting of a skin and soft tissue infection, a bone infection, a joint infection, pneumonia, a wound infection, a burn infection, an infection of the blood, and an infection associated with cystic fibrosis.
  • the pharmaceutical composition comprising fusidic acid, or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition is in the form of a tablet, a capsule, an IV solution, an inhalable formulation, a powder formulation, or a formulated suspension.
  • the pharmaceutical composition is administered orally, by injection or by intravenous infusion.
  • the subject does not experience an adverse level of nausea.
  • the present invention is directed to a method of treating or preventing a bacterial infection in a subject comprising:
  • a minimum plasma concentration of fusidic acid of not less than about 60 ug/ml is achieved in (a) and a minimum plasma concentration of fusidic acid of not less than about 60 ug/ml is maintained in (b).
  • a minimum plasma concentration of fusidic acid of not less than about 80 ug/ml is achieved in (a) and a minimum plasma concentration of fusidic acid of not less than about 80 ug/ml is maintained in (b).
  • the loading dose comprises two loading doses, wherein the second loading dose is administered about 12 hours after the first loading dose, and wherein each loading dose is between about 1000 mg and about
  • the total loading dose administered to the subject is between about 2000 mg and about 3600 mg.
  • the maintenance dose comprises multiple maintenance doses of independently between about 500 mg and 1000 mg administered about 12 hours apart, beginning about 12 hours after administration of the loading dose.
  • a minimum plasma concentration of not less than about 50 ug/ml is maintained for at least about 48 hours after administering the loading dose, preferably a minimum plasma concentration of not less than about 50 ug/ml is maintained for at least about 72 hours, more preferably, a minimum plasma concentration of not less than about 50 ug/ml is maintained for at least about 96 hours.
  • the loading dose comprises two loading doses, wherein each loading dose is independently between about 1000 mg and about 1850 mg, and wherein the second loading dose is administered about 12 hours after administration of the first loading dose; and multiple maintenance doses of independently between about 500 mg and 1000 mg are administered, about 12 hours apart, beginning about 12 hours after administration of the second loading dose.
  • each loading dose is independently at least about 1500 mg. Equally preferably, each
  • maintenance dose is independently at least about 600 mg.
  • the subject is a human.
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of staphylococci, including coagulase-negative staphylococci and coagulase-positive staphylococci, streptococci, including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Corynebacterium species.
  • staphylococci including coagulase-negative staphylococci and coagulase-positive staphylococci
  • streptococci including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Corynebacterium species.
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus,
  • bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus,
  • Staphylococus simulans Staphylococus warneri, Staphylococus hominis, Staphylococus intermedius, Staphylococcus pseudointermedius, Staphylococus lyricus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies dysgalactiae, Streptococcus anginosus, Streptococcus mitis, Streptococcus salivarius, Streptococcus bovis, Streptococcus mutans, Neisseria gonorrhoeae, Neisseria meningitidis, Bacillus anthracis, Bordetella pertussis, Clostridium difficile, Enterococcus faecalis, Enterococcus faecium and Corynebacterium diphtheriae.
  • the bacterial organism Str
  • the bacterial infection is an infection selected from the group consisting of a skin and soft tissue infection, a bone infection, a joint infection, pneumonia, a wound infection, a burn infection, an infection of the blood, and an infection associated with cystic fibrosis.
  • the pharmaceutical composition comprising fusidic acid, or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition is in the form of a tablet, a capsule, an IV solution, an inhalable formulation, a powder formulation, or a formulated suspension.
  • the pharmaceutical composition is administered orally, by injection or by intravenous infusion.
  • the subject does not experience an adverse level of nausea.
  • the present invention is directed to a method of treating or preventing a bacterial infection in a subject comprising:
  • each loading dose is independently between about 1000 mg and about 1850 mg, and wherein the second loading dose is administered about 12 hours after administration of the first loading dose;
  • each maintenance dose is independently between about 500 mg and 1000 mg, wherein a first maintenance dose is administered about 12 hours after administration of the second loading dose, and wherein subsequent maintenance doses are administered about 12 hours apart.
  • each loading dose is
  • each maintenance dose is independently at least about 600 mg. In related aspects, at least three, four, five or six maintenance doses are administered to the subject.
  • the subject is a human.
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of staphylococci, including coagulase-negative staphylococci and coagulase-positive staphylococci, streptococci, including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Corynebacterium species.
  • staphylococci including coagulase-negative staphylococci and coagulase-positive staphylococci
  • streptococci including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Corynebacterium species.
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus, Staphylococus simulans, Staphylococus warneri, Staphylococus hominis, Staphylococus intermedius, Staphylococcus pseudointermedius, Staphylococus lyricus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies dysgalactiae, Streptococcus anginosus
  • the bacterial infection is an infection selected from the group consisting of a skin and soft tissue infection, a bone infection, a joint infection, pneumonia, a wound infection, a burn infection, an infection of the blood, and an infection associated with cystic fibrosis.
  • the pharmaceutical composition comprising fusidic acid, or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition is in the form of a tablet, a capsule, an IV solution, an inhalable formulation, a powder formulation, or a formulated suspension.
  • the pharmaceutical composition is preferably administered orally, by injection or by intravenous infusion to the subject.
  • the subject does not experience an adverse level of nausea.
  • the present invention is directed to a method of reducing development of an antibiotic-resistant strain of bacteria in a subject having a bacterial infection comprising:
  • PK pharmacokinetic
  • the C max is not less than about
  • the minimum trough plasma concentration of (a) is not less than about 60 ug/ml, and the minimum trough plasma concentration of (b) is not less than about 70 ug/ml.
  • the C max is not less than about 100 ug/ml, the minimum trough plasma concentration of (a) is not less than about 80 ug/ml and the minimum trough plasma concentration of (b) is not less than about 80 ug/ml.
  • the loading dose comprises two loading doses, wherein the second loading dose is administered about 12 hours after the first loading dose, and wherein each loading dose is between about 1000 mg and about
  • the total loading dose administered to the subject is between about 2000 mg and about 3600 mg.
  • the loading dose comprises two loading doses, wherein the second loading dose is administered about 12 hours after the first loading dose, and wherein each loading dose is between about 1000 mg and about
  • the maintenance dose comprises multiple maintenance doses of independently between about 500 mg and 1000 mg administered about 12 hours apart, beginning about 12 hours after administration of the loading dose.
  • a minimum trough plasma concentration of not less than about 50 ug/ml is maintained for at least about 48 hours after administering the loading dose, more preferably a minimum trough plasma concentration of not less than about 50 ug/ml is maintained for at least about
  • the loading dose comprises two loading doses, wherein each loading dose is independently between about
  • each loading dose is independently at least about 1500 mg.
  • each maintenance dose is independently at least about 600 mg.
  • the subject is a human.
  • the bacterial infection is caused by a bacteria selected from the group consisting of staphylococci, including coagulase-negative staphylococci and coagulase-positive staphylococci, streptococci, including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Cory neb acterium species.
  • staphylococci including coagulase-negative staphylococci and coagulase-positive staphylococci
  • streptococci including Group A beta hemolytic streptococci, non-Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and Cory neb acterium species.
  • the infection is caused by a bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus, Staphylococus simulans, Staphylococus warneri, Staphylococus hominis, Staphylococus intermedius,
  • a bacteria selected from the group consisting of Staphylococcus aureus (methicillin-resistant and -susceptible), Staphylococus epidermidis, Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphy
  • Staphylococcus pseudointermedius Staphylococus lyricus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies dysgalactiae,
  • Streptococcus anginosus Streptococcus mitis, Streptococcus salivarius, Streptococcus bovis, Streptococcus mutans, Neisseria gonorrhoeae, Neisseria meningitidis, Bacillus anthracis, Bordetella pertussis, Clostridium difficile, Enterococcus faecalis, Enterococcus faecium and Cory neb acterium diphtheriae.
  • the infection is caused by Enterococcus faecalis or Enterococcus faecium.
  • Figure 1 Mean plasma concentrations of fusidic acid after a single dose of sodium fusidate (semi-log plot).
  • Figure 2 Mean plasma concentrations of fusidic acid after a single dose of sodium fusidate (linear plot).
  • Figure 3 Mean plasma concentrations of CEM- 102 (Sodium fusidate) after 13 doses - semi-log plot.
  • Figure 4 Mean plasma concentrations of CEM- 102 (Sodium fusidate) after 13 doses - linear plot.
  • Figure 5 Mean CEM- 102 (Sodium fusidate) single and multiple dose plasma concentrations (linear scale). Cohort 1 (550 mg), cohort 2 (1100 mg), cohort 3 (1650 mg), and cohort 4 (2200 mg - single dose only).
  • Figure 6 Mean CEM- 102 (Sodium fusidate) plasma concentrations in loading dose regimens (linear scale).
  • FIG. 8 CEM- 102 pharmacodynamics in hollow fiber.
  • CEM- 102 (Sodium fusidate) 600 mg ql2h vs. USA 300.
  • FIG. 9 CEM- 102 pharmacodynamics in hollow fiber.
  • CEM- 102 (Sodium fusidate) 1200 mg x 2 then 600 mg ql2h vs. USA 300.
  • FIG. 10 Figure 10 - CEM- 102 pharmacodynamics in hollow fiber.
  • CEM- 102 (Sodium fusidate) 1500 mg x 2 then 600 mg ql2h vs. USA 300.
  • the doses given during the maintenance phase are sufficient to maintain a minimum trough plasma concentration of FA for sufficient time in which to treat or prevent the bacterial infection, but not so great as to cause an unacceptable degree of nausea or to induce vomiting.
  • a loading dose regimen of 1100 mg BID FA for the first day, followed by 550 mg BID FA for five days as the maintenance dose showed that the drug was well tolerated and that a trough level of at least 74 ug/ml in the plasma was achieved, much higher than the MIC of 2.5 ug/ml of S. aureus in humans.
  • the present invention is directed to methods for treating or preventing bacterial infections in a subject.
  • the methods are based on the novel dosing regimens disclosed herein.
  • the novel dosing regimens comprise two phases, a loading dose phase followed by a maintenance dose phase.
  • the loading dose phase is the period of time over which a high dose of FA is administered to a subject.
  • the loading dose phase is defined by the administration of fusidic acid to a subject in an amount sufficient to reach a
  • PK profile for fusidic acid defined by three variables: (i) a maximum plasma concentration (C max ), (ii) a time to maximum plasma concentration (T max ) of fusidic acid, and (iii) a minimum trough plasma concentration of fusidic acid.
  • the maximum plasma concentration (C max ) of fusidic acid is not less than about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115 or 120 ug/ml, or a value within this range, preferably not less than about 80 ug/ml, more preferably not less than about 100 ug/ml.
  • the time to maximum plasma concentration (T max ) of fusidic acid is no more than about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 hours, preferably no more than about 24 hours.
  • the minimum trough plasma concentration of fusidic acid is not less than about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 ug/ml, or a value within this range, preferably not less than about 60 ug/ml, more preferably not less than about 80 ug/ml.
  • the loading dose administered to the subject may also be defined based on the amount of FA sufficient to achieve a minimum plasma concentration within a particular period of time.
  • the minimum plasma concentration of fusidic acid is not less than about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 ug/ml, or a value within this range, preferably not less than about 60 ug/ml, more preferably not less than about 80 ug/ml.
  • the period of time in which the minimum plasma concentration of fusidic acid is achieved is within about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 hours, preferably within about 24 hours.
  • the loading dose of fusidic acid is an amount sufficient to achieve a minimum plasma concentration of not less than about 50 ug/ml fusidic acid within about 24 hours of administration to the subject.
  • the loading dose may be split into discrete loading doses that are administered to a subject over a particular period of time. Therefore, in addition to a single loading dose, the loading dose may comprise two, three, four, five, six or more discrete loading doses.
  • the total amount of FA administered to a subject as the loading dose is about 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000 mg or more of FA, or a value within this range.
  • the total loading dose is between about 2000 mg and 3600 mg of FA.
  • the loading dose is administered to a subject as two discrete loading doses, where each discrete loading dose is about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800 or 1850 mg, or a value within this range.
  • each loading dose is between about 1000 mg and 1850 mg of FA
  • the entirety of the loading dose will be administered to the subject within about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more hours. In a preferred aspect, the entirety of the loading dose will be
  • the time periods between administrations of the discrete loading doses may be equal or unequal. Preferably, the time periods are equal.
  • the loading dose administered to the subject may further be defined simply based on the amount of FA administered to the subject.
  • the total amount of FA may be defined simply based on the amount of FA administered to the subject.
  • the administered to a subject as the loading dose may be about 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000 mg or more of FA, or a value within this range.
  • the total loading dose is between about 2000 mg and 3600 mg of FA.
  • the loading dose may be split into discrete loading doses that are administered to a subject over a particular period of time, such as two, three, four, five, six or more discrete loading doses.
  • any fraction of the total loading dose may be used in each discrete loading dose, whether the discrete doses are equal in concentration or unequal (e.g., two-thirds of the total loading dose in a first dosage, and one-third of the total loading dose in a second dosage).
  • the loading dose is administered to a subject as two discrete loading doses, where each discrete loading dose is about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800 or 1850 mg, or a value within this range.
  • the loading dose is administered to a subject as two discrete loading doses, where each discrete loading dose is about 1000 mg, and where in the second loading dose is administered about 12 hours after administration of the first loading dose.
  • the loading dose is administered to a subject as two discrete loading doses, where each discrete loading dose is about 1500 mg, and where in the second loading dose is administered about 12 hours after administration of the first loading dose.
  • the maintenance dose phase is the period of time following the loading dose phase where a particular minimum trough plasma concentration or plasma concentration of the FA is maintained in the subject.
  • the skilled artisan will understand that the particular concentration of FA in the plasma, and the length of time needed to maintain the desired concentration, will depend on the condition that is being treated or prevented. While the methods of the invention may be practiced through the use of a single maintenance dose, the methods of the present invention will generally require that two or more maintenance doses be administered to a subject in order to maintain the desired minimum trough plasma concentration or plasma concentration of fusidic acid for a particular period of time.
  • the maintenance dose is defined by the administration of fusidic acid to the subject in an amount sufficient to maintain a minimum trough plasma concentration of fusidic acid for a particular period of time.
  • the minimum trough plasma concentration is maintained for a sufficient period of time to achieve the goal of the method being practiced (treatment or prevention) and will vary depending on the identity of the bacterial infection. However, it is considered that the minimum trough plasma concentration will need to be maintained at least about 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240 or more hours, beginning from the time at which the last loading dose was administered to the subject.
  • the first maintenance dose may be administered about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more hours after the last loading dose.
  • the specific amount of FA administered to a subject will depend on the characteristics of the subject, including age, weight, and general health.
  • discrete maintenance doses will generally be about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200 mg or more, or a value within this range.
  • each maintenance dose is between about 500 mg and 1000 mg.
  • the amount of FA in each maintenance dose may be the same, or the doses may increase or decrease with time.
  • the maintenance doses will be
  • the maintenance doses may be administered to the subject 1, 2, 3, 4, 5, 6 or more times per day, or a value within this range.
  • a minimum trough plasma concentration of not less than about 50 ug/ml is maintained for at least about 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240 or more hours, or a value within this range, in particular at least about 24, 48 or 96 hours, after the last loading dose was administered to the subject.
  • the maintenance dose in the methods of the present invention may also be simply defined by the amount of fusidic acid in a discrete dose that is administered to a subject.
  • Each discrete maintenance dose is individually about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200 mg or more, or a value within this range.
  • each maintenance dose is between about 500 mg and 1000 mg.
  • the discrete maintenance doses of FA may be administered 1, 2, 3, 4, 5, 6 or more times per day, or a value within this range.
  • the first maintenance dose may be administered about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more hours after the last loading dose.
  • the maintenance dose phase is maintained for at least about 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240 or more hours, or a value within this range, beginning from the time at which the last loading dose was administered to the subject.
  • at least three maintenance doses of 500 mg or 600 mg are administered to a subject during the maintenance dose phase, more preferably at least four doses, even more preferably at least five doses, wherein the maintenance doses are administered about 12 hours apart beginning about 12 hours after the last loading dose.
  • the method of treating or preventing a bacterial infection in a subject comprises:
  • PK pharmacokinetic
  • fusidic acid comprising a maximum plasma concentration (C max ) of fusidic acid of not less than about 70 ug/ml, a time to maximum plasma concentration (T max ) of fusidic acid of no more than about 20 hours and a minimum trough plasma concentration of fusidic acid of not less than about 50 ug/ml, and
  • the PK profile comprises (i) a C max of not less than about 80 ug/ml, (ii) a minimum trough plasma concentration of not less than about 60 ug/ml and (iii) a T max of no more than 20 hours, with the minimum trough plasma concentration being maintained at not less than about 70 ug/ml.
  • the PK profile comprises (i) a C max of not less than about 100 ug/ml, (ii) a minimum trough plasma concentration of not less than about 80 ug/ml and (iii) a T max of no more than 20 hours, with the minimum trough plasma concentration being maintained at not less than about 80 ug/ml.
  • the method of treating or preventing a bacterial infection in a subject comprises:
  • a minimum plasma concentration of fusidic acid of not less than about 60 ug/ml is achieved in (a) and a minimum plasma concentration of fusidic acid of not less than about 60 ug/ml is maintained in (b).
  • a minimum plasma concentration of fusidic acid of not less than about 80 ug/ml is achieved in (a) and a minimum plasma concentration of fusidic acid of not less than about 80 ug/ml is maintained in (b).
  • the method of treating or preventing a bacterial infection in a subject comprises: (a) administering a first and a second loading dose of fusidic acid, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment or prevention, wherein each loading dose is independently between about 1000 mg and about 1850 mg, and wherein the second loading dose is administered about 12 hours after the first loading dose; and
  • each maintenance dose is independently between about 500 mg and 1000 mg, wherein a first maintenance dose is administered about 12 hours after administration of the second loading dose, and wherein subsequent maintenance doses are administered about 12 hours apart.
  • each loading dose is administered to the subject.
  • each maintenance dose is independently at least about 600 mg.
  • the present invention is also directed to methods for reducing development of antibiotic-resistant strains of bacteria in a subject undergoing antibiotic therapy. These methods are also based on the novel dosing regimens disclosed herein. As in the methods of treating or preventing bacterial infections described herein, the methods for reducing development of antibiotic-resistant strains of bacteria are based on the novel dosing regimens comprising a loading dose phase and a maintenance dose phase. All aspects of the loading dose phase and the maintenance dose phase described above for the methods of treating or preventing bacterial infections are the same for the loading dose phase and the maintenance dose phase of the methods for reducing development of antibiotic-resistant strains of bacteria and are specifically incorporated herein.
  • the method for reducing development of antibiotic-resistant strains of bacteria in a subject having a bacterial infection comprises:
  • PK pharmacokinetic
  • fusidic acid comprising a maximum plasma concentration (C max ) of fusidic acid of not less than about 70 ug/ml, a time to maximum plasma concentration (T max ) of fusidic acid of no more than about 24 hours and a minimum trough plasma concentration of fusidic acid of not less than about 50 ug/ml, and
  • the C max is not less than about 80 ug/ml, the minimum trough plasma concentration of (a) is not less than about 60 ug/ml, and the minimum trough plasma concentration of (b) is not less than about 70 ug/ml. In a further preferred aspect, the C max is not less than about 100 ug/ml, the minimum trough plasma
  • concentration of (a) is not less than about 80 ug/ml and the minimum trough plasma concentration of (b) is not less than about 80 ug/ml.
  • Fusidic Acid (FA) has the following structure.
  • the term "pharmaceutically acceptable salt” refers to non-toxic base addition salts derived from inorganic and organic bases.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as alkylamine and organic amino salts, such as an ethanolamine salt.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • sodium fusidate is a pharmaceutically acceptable salt that is used in the methods of the present invention.
  • Sodium fusidate also termed CEM- 102 herein, has the following structure.
  • the subject being subjected to treatment or prevention is a human, non-human primate, bird, horse, cow, goat, sheep, a companion animal, such as a dog, cat or rodent, or other mammal.
  • the subject may have a bacterial infection, such as where the present invention is directed to methods for treating a bacterial infection in a subject.
  • the subject may also be at risk for developing a bacterial infection, such as where the present invention is directed to methods for preventing a bacterial infection in a subject.
  • subjects at risk for developing bacterial infections include patients undergoing treatment for bacterial infections whereby normal gut flora is inhibited by antimicrobial therapy, patients with impaired immune function (e.g.
  • immunoglobulin deficiency e.g., immunoglobulin deficiency, splenic dysfunction, splenectomy, HIV infection, impaired leukocyte function, hemoglobinopathies
  • the elderly, children people with certain malignancies (e. g., multiple myeloma, chronic lympocytic leukemia, lymphoma), people at increased occupational risk (e.g., public services workers, such a fire, water, sanitary, police, medical, and laboratory workers, hospital workers), people in closed populations (e.g., hospitals and medial clinics, prisons, military, nursing homes), people having cystic fibrosis, people that have immunological deficiencies that might enhance their susceptibility to bacterial infection, people entering an emergency room, such as those with wounds or cellulitis, and patients leaving a hospital on step-down therapy after having been on intravenous therapy
  • the bacterial infection being treated or prevented is an infection caused by bacteria selected from the group consisting of staphylococci, including coagulase-negative staphylococci and coagulase- positive staphylococci, streptococci, including Group A beta hemolytic streptococci, non- Group A beta hemolytic streptococci and viridans group streptococci, enterococci, Nesseria species, Clostridium species, Bordetella species, Bacillus species and
  • the bacterial infection is an infection caused by bacteria selected from the group consisting of Staphylococcus aureus
  • Staphylococus epidermidis Staphylococus hemolyticus, Staphylococus saprophyticus, Staphylococus lugdunensis, Staphylococus capitis, Staphylococus caprae, Staphylococus saccharolyticus, Staphylococus simulans, Staphylococus warneri, Staphylococus hominis, Staphylococus intermedius,
  • Staphylococcus pseudointermedius Staphylococus lyricus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies dysgalactiae,
  • the bacterial infection is an infection caused by Enterococcus faecalis or Enterococcus faecium.
  • the bacterial infection may also be defined based on the type of infection that it causes.
  • each of the embodiments of the present invention may be used to treat or prevent an infection selected from the group consisting of a skin and soft tissue infection, a bone infection, a joint infection, pneumonia, a wound infection, a burn infection, an infection of the blood, and an infection associated with cystic fibrosis.
  • the fusidic acid may be administered to a subject in conjunction with a second therapeutic agent, such as a second antibiotic.
  • the second therapeutic agent may be administered before, concurrent with or after administration of the fusidic acid, whether in the same formulation or in a separate formulation. Suitable second therapeutic agents include rifampin, rifamycin, a
  • sulfonamide a beta-lactam, a tetracycline, a chloramphenicol, an aminoglycoside, a macrolide, a streptogramin, a quinolone, a fluoroquinolone, an oxazolidinone and a lipopeptide.
  • tetracycline, tetracycline derived antibacterial agents, glycylcycline, glycylcycline derived antibacterial agents, minocycline, minocycline derived antibacterial agents, oxazolidinone antibacterial agents, aminoglycoside antibacterial agents, quinolone antibacterial agents, vancomycin, vancomycin derived antibacterial agents, teicoplanin, teicoplanin derived antibacterial agents, eremomycin, eremomycin derived antibacterial agents, chloroeremomycin, chloroeremomycin derived antibacterial agents, daptomycin, and daptomycin derived antibacterial agents are preferred.
  • rifampin is administered concurrently with the fusidic acid.
  • an adverse level of nausea is considered to be a level of nausea severe enough that at least 15% of subjects in a population of subjects being treated with fusidic acid discontinue treatment.
  • compositions of the present invention comprise fusidic acid, a hemihydrate form thereof, or pharmaceutically acceptable salts, other hydrates, solvates, or mixtures thereof, and one or more of a carrier, diluent and excipient.
  • a carrier diluent and excipient.
  • the terms specifically exclude cell culture medium.
  • Suitable diluents are well known to those skilled in the art and include saline, buffered saline, dextrose (e.g., 5% dextrose in water), water, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80TM), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g.
  • Cremophor EL Cremophor EL
  • poloxamer 407 and 188 a cyclodextrin or a cyclodextrin derivative (including HPCD ((2-hydroxypropyl)-cyclodextrin) and (2- hydroxyethyl)-cyclodextrin; see, e.g., U.S. patent application publication 20060194717).
  • Carriers are compounds and substances that improve and/or prolong the delivery of an active ingredient to a subject in the context of a pharmaceutical formulation.
  • Carrier may serve to prolong the in vivo activity of a drug or slow the release of the drug in a subject, using controlled-release technologies. Carriers may also decrease drug metabolism in a subject and/or reduce the toxicity of the drug. Carrier can also be used to target the delivery of the drug to particular cells or tissues in a subject.
  • Common carriers include fat emulsions, lipids, PEGylated phospholids, liposomes and lipospheres, microspheres (including those made of biodegradable polymers or albumin), polymer matrices, biocompatible polymers, protein- DNA complexes, protein conjugates, erythrocytes, vesicles and particles.
  • Excipients included in a pharmaceutical composition have different purposes depending, for example on the nature of the drug, and the mode of administration.
  • excipients include, without limitation: stabilizing agents, solubilizing agents and surfactants, buffers and preservatives, tonicity agents, bulking agents, lubricating agents (such as talc or silica, and fats, such as vegetable stearin, magnesium stearate or stearic acid), emulsif ⁇ ers, suspending or viscosity agents, inert diluents, fillers (such as cellulose, dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate), disintegrating agents (such as crosslinked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose), binding agents (such as starches, gelatin, cellulose, methyl cellulose or modified cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, sugars such as sucrose and lactose, or sugar alcohols such
  • the pharmaceutical compositions may contain common carriers and excipients, such as microcrystalline cellulose, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silica, all-rac- ⁇ -tocopherol, talc and titanium dioxide.
  • common carriers and excipients such as microcrystalline cellulose, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silica, all-rac- ⁇ -tocopherol, talc and titanium dioxide.
  • composition compatible excipients also include tonicity agents that make the composition compatible with blood. Tonicity agents are particularly desirable in injectable formulations.
  • compositions of the present invention may be formulated, for example, for oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, pulmonary, topical or parenteral administration.
  • Parenteral modes of administration include without limitation, intradermal, subcutaneous (s.c, s.q., sub-Q, Hypo),
  • intramuscular i.m.
  • intravenous i.v.
  • intraperitoneal i.p.
  • intra-arterial intramedulary
  • intracardiac intra-articular
  • joint intrasynovial
  • joint fluid area intracranial, intraspinal, and intrathecal (spinal fluids).
  • Spinal fluids any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration.
  • Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions, suspensions or fat emulsions.
  • the parenteral form used for injection must be fluid to the extent that easy syringability exists.
  • These solutions or suspensions can be prepared from sterile concentrated liquids, powders or granules.
  • Excipients used in parenteral preparations also include, without limitation, stabilizing agents (e.g. carbohydrates, amino acids and polysorbates, such as 5% dextrose), solubilizing agents (e.g. cetrimide, sodium docusate, glyceryl monooleate,
  • stabilizing agents e.g. carbohydrates, amino acids and polysorbates, such as 5% dextrose
  • solubilizing agents e.g. cetrimide, sodium docusate, glyceryl monooleate
  • PVP polyvinylpyrolidone
  • PEG polyethylene glycol
  • surfactants e.g. polysorbates, tocopherol PEG succinate, poloxamer and CremophorTM
  • buffers e.g. acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like
  • preservatives e.g.
  • BHA, BHT, gentisic acids vitamin E, ascorbic acid, sodium ascorbate and sulfur containing agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like), tonicity agents (for adjusting physiological compatibility), suspending or viscosity agents, antibacterials (e.g. thimersol, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol), chelating agents, and administration aids (e.g. local anesthetics, anti-inflammatory agents, anti-clotting agents, vasoconstrictors for prolongation and agents that increase tissue permeability), and combinations thereof.
  • agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like
  • tonicity agents for adjusting physiological compatibility
  • suspending or viscosity agents e.g.
  • Parenteral formulations using hydrophobic carriers include, for example, fat emulsions and formulations containing lipids, lipospheres, vesicles, particles and liposomes.
  • Fat emulsions include in addition to the above-mentioned excipients, a lipid and an aqueous phase, and additives such as emulsif ⁇ ers (e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose).
  • emulsif ⁇ ers e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil
  • osmotic agents e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose.
  • Liposomes include natural or derived phospholipids and optionally stabilizing agents
  • the parenteral unit dosage form can be a ready-to-use solution of the active ingredient in a suitable carrier in sterile, hermetically sealed ampoules or in sterile pre-loaded syringes.
  • the suitable carrier optionally comprises any of the above-mentioned excipients.
  • the unit dosage of the pharmaceutical composition can be in a concentrated liquid, powder or granular form for ex tempore reconstitution in the appropriate pharmaceutically acceptable carrier, such as sterile water, at the time of delivery.
  • the appropriate pharmaceutically acceptable carrier such as sterile water
  • powder forms optionally include bulking agents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants.
  • compositions of the present invention and optionally one or more additives, including solubilizers or surfactants, can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
  • Intravenous fluids include, without limitation, physiological saline, phosphate buffered saline, 5% dextrose in water or Ringer'sTM solution.
  • fusidic acid is dissolved in a buffered solution (pH 7.4 - 7.6) containing disodium hydrogen phosphate, citric acid, disodium edetate and water for injections.
  • the buffered solution is then added to a suitable infusion, such as a sodium chloride intravenous infusion, a dextrose intravenous infusion, a compound sodium lactate intravenous infusion ("Ringer-lactate solution”), a sodium lactate intravenous infusion, sodium chloride and dextrose intravenous infusion, or potassium chloride and dextrose intravenous infusion.
  • a suitable infusion such as a sodium chloride intravenous infusion, a dextrose intravenous infusion, a compound sodium lactate intravenous infusion (“Ringer-lactate solution”), a sodium lactate intravenous infusion, sodium chloride and dextrose intravenous infusion, or potassium chloride and dextrose intravenous infusion.
  • Suitable amounts of fusidic acid to be dissolved in the buffered solution range from about 10 to about 4000 mg, with preferred amounts including about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750,
  • the final concentration of fusidic acid in the intravenous infusion is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35 or 40 mg/ml or more.
  • Suitable periods of time over which the fusidic acid-containing intravenous infusion may be administered include 15, 30, 45 or 60 minutes, or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 or more hours.
  • a sterile formulation of the pharmaceutical composition of the present invention can be dissolved and administered in a
  • a suitable insoluble form of the pharmaceutical compositions may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate.
  • Suitable amounts of fusidic acid to be administered in a formulation for injection range from about 10 to about 4000 mg, with preferred amounts including about 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of fusidic acid, or a value within this range.
  • the oral pharmaceutical composition may be made in the form of a unit dosage containing a therapeutically-effective amount of the pharmaceutical composition.
  • Solid formulations such as tablets and capsules are particularly useful.
  • Sustained released or enterically coated preparations may also be devised.
  • suspension, syrups, slow release and chewable tablets are especially suitable.
  • the pharmaceutical compositions are in the form of, for example, tablets, capsules, suspensions or liquid syrups or elixirs, wafers and the like.
  • excipient or additives include, but are not limited to inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • the tablets and capsules can contain, in addition to fusidic acid, inert diluents (e.g., sodium and calcium carbonate, sodium and calcium phosphate, and lactose), binding agents (e.g., acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, tragacanth methylcellulose, sodium fusidic acid, inert diluents (e.g., sodium and calcium carbonate, sodium and calcium phosphate, and lactose), binding agents (e.g., acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, tragacanth methylcellulose, sodium
  • carboxymethylcellulose, hydroxypropyl methylcellulose, and ethylcellulose fillers (e.g., calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose), wetting agents, lubricating agents (e.g., metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid or talc), disintegrating agents (e.g., potato starch, corn starch and alginic acid), flavoring (e.g. peppermint, oil of wintergreen, fruit flavoring, cherry, grape, bubblegum, and the like), and coloring agents.
  • the tablets and capsules may also include coating excipients such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • compositions of the present invention may be in the form of a tablet containing microcrystalline cellulose,
  • crospovidone hypromellose, lactose monohydrate, magnesium stearate, silica, all-rac- ⁇ - tocopherol, talc and titanium dioxide, and optionally one or more other inactive
  • Suitable amounts of fusidic acid in a tablet may range from about 10 to about 4000 mg, with preferred amounts including about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of fusidic acid per tablet, or a value within this range.
  • Oral liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents.
  • additives for liquid preparations include acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methyl cellulose, microcrystalline cellulose, methyl or propyl para- hydroxybenzoate, propylene glycol, sorbitol, or sorbic acid.
  • the pharmaceutical composition comprises fusidic acid and the following inactive ingredients: acesulfame potassium, flavor, citric acid, disodium phosphate dihydrate, hydroxyethylcellulose, glucose liquid, methylcellulose, sodium benzoate, sorbitol, and purified water.
  • Suitable amounts of fusidic acid in an oral formulation may range from about 10 to about 4000 mg, with preferred amounts including about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of fusidic acid in the oral formulation, or a value within this range.
  • the pharmaceutical compositions of present invention can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of creams, ointments, nasal drops, liquid sprays or inhalants, lozenges, or throat paints.
  • Such formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient.
  • DMSO dimethylsulfoxide
  • the pharmaceutical compositions can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.
  • DMSO dimethylsulfoxide
  • compositions can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.
  • a cream may be prepared comprising fusidic acid and the following inactive ingredients: steareth-21, cetostearyl alcohol, white soft paraffin, liquid paraffin, hypromellose, citric acid monohydrate, methyl parahydroxybenzoate, propyl
  • an eye drop may be prepared comprising fusidic acid and the following inactive ingredients: benzalkonium chloride, disodium edetate, mannitol, carbomer, sodium hydroxide, and water.
  • Suitable amounts of fusidic acid in an eye drop formulation may range from about 1 to about 100 mg, with preferred amounts including about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of fusidic acid in the formulation, or a value within this range.
  • the pharmaceutical compositions of present invention can be prepared in suitable forms for inhalation (an inhalable formulation; for nasal or buccal inhalation).
  • the compounds may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of this invention in suitable propellants, such as fluorocarbons or hydrocarbons.
  • MDI me
  • the terms “dose”, “dosage”, “unit dose”, “unit dosage”, “effective dose” and related terms refer to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. These terms are synonymous with the therapeutically effective amounts and amounts sufficient to achieve the stated goals of the methods disclosed herein.
  • the skilled artisan will understand that the term “maintenance dose” can refer to single discrete dose, as well as more than one discrete dose.
  • the maintenance dose is the total amount of FA administered during the maintenance dose phase.
  • the term “loading dose” can refer to single discrete dose, as well as more than one discrete dose.
  • the loading dose is the total amount of FA administered during the loading dose phase.
  • the terms "treating” and “treatment” have their ordinary and customary meanings, and include one or more of, ameliorating a symptom of a bacterial infection in a subject, blocking or ameliorating a recurrence of a symptom of a bacterial infection in a subject, decreasing in severity and/or frequency a symptom of a bacterial infection in a subject, stasis, decreasing, or inhibiting growth of bacteria in a subject, killing bacteria in a subject, inhibiting bacterial sporulation, inhibiting activation of a bacterial spore in a subject, inhibiting germination of a bacterial spore in a subject, and inhibiting outgrowth of a bacterial spore in a subject.
  • Treatment means ameliorating, blocking, reducing, decreasing or inhibiting by about 1% to about 100% versus a subject to which a pharmaceutical composition has not been administered.
  • the ameliorating, blocking, reducing, decreasing or inhibiting is about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or 1% versus a subject to which a pharmaceutical composition has not been administered.
  • the terms "preventing” and “prevention” have their ordinary and customary meanings, and include one or more of preventing bacterial colonization in a subject, preventing an increase in the growth of a bacterial population in a subject, preventing activation, germination or outgrowth of bacterial spores in a subject, preventing bacterial sporulation in a subject, preventing development of a disease caused by a bacterial infection in a subject, and preventing symptoms of a disease caused by a bacterial infection in a subject.
  • the prevention lasts at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50 or more days after administration of a pharmaceutical composition.
  • the MIC 50 for CEM- 102 was 0.12 ⁇ g/mL and the MIC 90 was 0.25 ⁇ g/mL, which is only slightly higher than strains in the US (MIC 90 0.12 ⁇ g/mL).
  • the MIC population distribution study showed that only 6.5% of the Canadian S. aureus isolates had MICs of >2.0 ⁇ g/mL and would be classified as resistant.
  • ciprofloxacin, clindamycin, and erythromycin resistance rates were 41.5, 30.9, and 52.1% respectively).
  • FA activity against GN species was limited (all MIC values >2 ⁇ g/ml) except for E. brevis, M. catarrhalis and iV. meningitidis (MICs, 0.12-0.5 ⁇ g/ml).
  • Example 2 Antimicrobial Activity of CEM-102 (Fusidic Acid) Against Canadian Isolates of Staphylococci and Streptococci.
  • S susceptibility
  • 153 GP isolates 123 S. aureus, 15 coagulase-negative staphylococci [CoNS] and 15 S. pyogenes [SPYO]
  • BMD Reference broth microdilution
  • Example 3 In Vitro Activity of CEM-102 (Fusidic acid) Against Resistant Strains of Staphylococcus aureus [00127] The activity of CEM- 102 (fusidic acid) against a variety of resistant strains of Staphylococcus aureus was investigated.
  • CEM-102 (MIC90 0.25 mg/L) was significantly superior to linezolid (MIC90 2 mg/L), levofloxacin (MIC90 4 mg/L), telithromycin (MIC90 4 mg/L), azithromycin (MIC 90 >32 mg/L), and erythromycin (MIC 90 >32 mg/L) against macrolide-resistant S. aureus (ermA, B, C genotype or MLSb-resistant). Against cipro floxacin-resistant (gyrA and parC genotype) S.
  • aureus erythromycin (MIC90 >32 mg/L), levofloxacin (MIC90 >32 mg/L), azithromycin (MIC90 16 mg/L), linezolid (MIC90 2 mg/L), and doxycycline (MIC 90 1 mg/L) were less active than CEM-102 (MIC 90 0.25 mg/L) and telithromycin (MIC 90 0.06 mg/L).
  • the primary objective of the study was to evaluate the relative bioavailability of single oral doses of CEM-102 (sodium fusidate) 500 mg (2 x 250 mg) tablets and Fucidin® (sodium fusidate) 500 mg (2 x 250 mg) tablets in healthy subjects in a fed or fasted state.
  • Study Period 1, 2, and 3 Days 1, 15, and 29: One dose of study drug 500 mg (2 x 250 mg) of CEM- 102 or Fucidin® was given at 8:00 AM (-30 minutes). On Day 1 of Study Periods 1 and 2 (Days 1 and 15), subjects fasted overnight for at least 10 hours prior to dosing. On Day 1 of Study Period 3 (Day 29), subjects were given a high fat caloric meal which was to be entirely consumed within 30 minutes prior to study drug
  • Plasma concentrations were assayed at MicroConstants, Inc. in San Diego, CA using a validated liquid chromatography with dual tandem mass spectrometry
  • Plasma concentrations of CEM-102 were assayed at MicroConstants, Inc. in
  • PK pharmacokinetics
  • safety, and tolerability of single and multiple doses of CEM- 102 were evaluated in a single-center, Phase 1, double-blind, randomized, placebo-controlled, dose-escalating study in 32 healthy adult subjects enrolled in 4 dosage groups (550, 1100, 1650, and 2200 mg).
  • CEM- 102 sodium fusidate
  • 4 dosage groups 550, 1100, 1650, and 2200 mg.
  • six subjects were to receive CEM- 102 and two were to receive placebo in a single dose (Period 1) and then multiple doses BID for a total of 11 doses over 5.5 days (Period 2).
  • the two dosing periods were separated by a seven-day washout period between the single dose in Period 1 and the first dose in Period 2.
  • Cohort 4 received only the single dose of 2200 mg (Period 1), because dose-limiting gastrointestinal intolerance was observed after multiple doses of 1650 mg BID in Cohort 3.
  • Period 2 for Cohort 4 evaluated an initial loading dose regimen, and a second loading dose regimen was evaluated in an additional cohort (Cohort 5) per a protocol amendment.
  • CEM- 102 was considered safe and generally well tolerated. No serious or life- threatening adverse events (AEs) occurred. Seventy-four AEs were reported in 19 of the 32 study subjects, all of which were mild or moderate in severity. Of the 70 treatment- emergent AEs reported all except 7 were in Period 2, in which subjects received multiple daily doses over 5.5 days. Most of the AEs were considered possibly related to study drug.
  • AEs adverse events
  • PK results from single and multiple dose administration of CEM- 102 are shown in Table 8 and Figure 5.
  • the increases in C max and AUC appear to be more than dose proportional from the 550 mg to the 1100 mg dose, but then approximately dose proportional from the 1100 mg to the 2200 mg dose (only single doses).
  • CEM-102 demonstrated higher PK exposures after 5.5 days of dosing in Period 2 compared to a single dose on Day 1 in Period 1 , indicating that accumulation occurs over the dosing period.
  • the protocol was amended for assessment of the safety, tolerability, and PK of front- loaded dose regimens comprised of a higher dose of CEM- 102 on Day 1 followed by lower doses for the subsequent 6.5 days. All loading dose regimens employed multiple doses lower than the maximum tolerated dose (MTD) established in the first part of the study (1650 mg administered as multiple doses).
  • MTD maximum tolerated dose
  • PK results of the loading dose regimens are shown in Figure 6.
  • the 1100 mg BID loading dose followed by 550 mg BID for 6.5 days resulted in a mean trough plasma concentration of approximately 74 ⁇ g/mL at 24 hours and approximately 105 ⁇ g/mL after 7 days of dosing.
  • the 1650 mg BID loading dose followed by 825 mg BID for 6.5 days resulted in a mean trough plasma concentration of approximately 150 ⁇ g/mL at 24 hours and approximately 200 ⁇ g/mL after 7 days of dosing.
  • Figure 7 is a compilation of the period 2 portion of Figure 5 and the 1100/550 mg BID loading dose regimen data.
  • Figure 7 demonstrates that, in contrast with the conventional BID regimens, near steady state plasma concentrations are reached at 24 hours after the first dose on Day 1 and these plasma concentrations are maintained at or above this level throughout the remainder of the 7 day treatment course.
  • CEM- 102 was safe and well tolerated in single doses up to 2200 mg, with a threshold for symptoms of gastrointestinal intolerance between 1650 mg and 2200 mg.
  • CEM-102 administered in doses up to 1650 mg BID for 5.5 days was safe and generally well tolerated; however, as 4 subjects had vomiting at the 1650 mg dose level, escalation to the 2200 mg dose level was limited to single doses.
  • AEs appeared to be related to dose and duration of exposure, with gastrointestinal symptoms reported more frequently after 3-5 days of dosing and at higher doses. Loading dose regimens of CEM-102 1100/550 mg and 1650/825 mg for a total of 7.5 days were very well tolerated.
  • Loading dose regimens appeared to be generally better tolerated than the conventional BID dosing regimens for similar levels of overall plasma exposure. There were no clinically significant changes in physical examinations, vital signs, ECGs, or laboratory parameters after single doses of CEM-102 up to 2200 mg, multiple doses up to 1650 mg for 5.5 days, or loading dose regimens of 1100/500 mg or 1650/825 mg for a total of 7.5 days.
  • C max and AUC showed more than dose proportional increases from 550 mg to 1100 mg, then approximately dose proportional increases from 1100 to 2200 mg (single dose only for 2200 mg). Accumulation of CEM-102 occurred from Day 1 to Day 6 of dosing at all dose levels.
  • the 1100 mg BID loading dose followed by a 550 mg BID maintenance dose resulted in mean trough plasma concentrations of approximately 74 ⁇ g/mL at 24 hours and approximately 105 ⁇ g/mL after 7 days of dosing.
  • the 1650 mg BID loading dose followed by an 825 mg BID maintenance dose resulted in mean trough plasma
  • aureus and beta hemolytic streptococci These high blood levels are sufficient to inhibit the bacterium as well as to prevent the selection of resistant bacteria. Keeping the growth to below detectable levels for a period of 72 hours without selection of resistant strains has been noted to be sufficient time in which to allow for clearance by neutrophils and macrophages, and it is sufficient to prevent the selection of resistant strains (Louie et al., Antimicrob. Agents Chemother. 52:2486-2496 (2008)). Thus, after the loading dose, the 600 mg as the maintenance dose was sufficient to maintain a steady state level of 80 micrograms per ml throughout the dosing period.
  • MRSA methicillin-resistant S. aureus
  • USA 300 Network of Antimicrobial Resistance in Staphylococcus aureus (NARSA), Chantilly, VA). USA 300 is a highly virulent strain of MRSA and is the most common community-associated MRSA isolate in the USA. MIC values were determined in accordance with Clinical and Laboratory Standards Institute (CLSI).
  • the hollow fiber model comprised a two-compartment hollow fiber model (Louie et al. Antimicrob Agents Chemother 52:2486-2496(2008)) consisting of a volume of 15 mL in the central compartment, with multiple ports for the removal of broth, delivery of antibiotics, and collection of bacterial and antimicrobial samples.
  • a peristaltic pump was used to continually replace antibiotic-containing medium with fresh media (Mueller Hinton Broth, supplemented with calcium, magnesium, and human albumin to a final concentration of 4 g/dL, simulating human physiologic levels) at a rate to simulate the half-life of CEM- 102 based on human PK data. All experiments were performed in duplicate.
  • Hollow fibers contain 15 ml of media was prepared and inoculated with 10 6 colony forming units (CFU)/mL USA 300 bacteria.
  • CFU colony forming units
  • One of three different dosing regimens of CEM- 120 was then applied to the fibers: (1) 600 mg/ml ql2h; (2) 1200 mg/ml x 2, followed by 600 mg/ml, ql2h; (3) 1500 mg/ml x 2, followed by 600 mg/ml, ql2h.
  • Figure 8 shows the growth of samples withdrawn from 600 mg/ml ql2h fibers at the different time points on plates without CEM-102 (solid circles), with 1 ug/ml CEM- 102 (open circles), with 2 ug/ml CEM-102 (solid triangle), and with 4 ug/ml CEM-102 (open triangle).
  • the results in Figure 8 show that treatment using 600mg FA ql2h resulted in regrowth and development of resistance by 24h and 48h.
  • Figure 9 shows the growth of samples withdrawn from 1200 mg/ml x 2, 600 mg/ml, ql2h, fibers at the different time points on plates without CEM-102 (solid circles), with 1 ug/ml CEM-102 (open circles), with 2 ug/ml CEM-102 (solid triangle), and with 4 ug/ml CEM-102 (open triangle).
  • the results in Figure 9 show that treatment using 1200 mg x2 then 600 mg ql2h suppressed bacterial counts and reduced bacterial counts by ⁇ 2 logs, with rebound at 72h.
  • Figure 10 shows the growth of samples withdrawn from 1500 mg/ml x 2, 600 mg/ml, ql2h, fibers at the different time points on plates without CEM-102 (solid circles), with 1 ug/ml CEM-102 (open circles), with 2 ug/ml CEM-102 (solid triangle), and with 4 ug/ml CEM-102 (open triangle).
  • the results in Figure 10 show that treatment using 1500 mg x2 then 600 mg ql2h suppressed resistance until > 72h and resulted in killing over 2.5 log and even approached the threshold of bactericidal activity, and rebounded at 144h.

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Abstract

La présente invention concerne de nouveaux schémas posologiques pour le traitement et la prévention d’infections bactériennes à l’aide d’acide fusidique. Il a été découvert que l’utilisation d’une dose de charge élevée d’acide fusidique, suivie de doses d’entretien modérées du médicament, prévient le développement de souches de bactéries résistant au médicament, augmente le spectre efficace du médicament, et évite les nausées et vomissements associés à un traitement prolongé avec des quantités élevées du médicament.
PCT/US2009/050353 2009-07-13 2009-07-13 Schémas posologiques de l’acide fusidique pour le traitement d’infections bactériennes Ceased WO2011008193A1 (fr)

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US9072759B2 (en) 2008-10-24 2015-07-07 Cempra Pharmaceuticals, Inc. Biodefenses using triazole-containing macrolides
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US9345717B2 (en) 2013-09-25 2016-05-24 Zavante Therapeutics, Inc. Method for improving drug treatments in mammals
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US9480679B2 (en) 2009-09-10 2016-11-01 Cempra Pharmaceuticals, Inc. Methods for treating malaria, tuberculosis and MAC diseases
US9751908B2 (en) 2013-03-15 2017-09-05 Cempra Pharmaceuticals, Inc. Convergent processes for preparing macrolide antibacterial agents
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9200026B2 (en) 2003-03-10 2015-12-01 Merck Sharp & Dohme Corp. Antibacterial agents
US10131684B2 (en) 2007-10-25 2018-11-20 Cempra Pharmaceuticals, Inc. Process for the preparation of macrolide antibacterial agents
US9453042B2 (en) 2007-10-25 2016-09-27 Cempra Pharmaceuticals, Inc. Process for the preparation of macrolide antibacterial agents
US9669046B2 (en) 2008-10-24 2017-06-06 Cempra Pharmaceuticals, Inc. Biodefenses using triazole-containing macrolides
US9072759B2 (en) 2008-10-24 2015-07-07 Cempra Pharmaceuticals, Inc. Biodefenses using triazole-containing macrolides
US9439918B2 (en) 2008-10-24 2016-09-13 Cempra Pharmaceuticals, Inc. Methods for treating gastrointestinal diseases
US9901592B2 (en) 2008-10-24 2018-02-27 Cempra Pharmaceuticals, Inc. Methods for treating resistant diseases using triazole containing macrolides
US9937194B1 (en) 2009-06-12 2018-04-10 Cempra Pharmaceuticals, Inc. Compounds and methods for treating inflammatory diseases
US9480679B2 (en) 2009-09-10 2016-11-01 Cempra Pharmaceuticals, Inc. Methods for treating malaria, tuberculosis and MAC diseases
US9051346B2 (en) 2010-05-20 2015-06-09 Cempra Pharmaceuticals, Inc. Process for preparing triazole-containing ketolide antibiotics
US9815863B2 (en) 2010-09-10 2017-11-14 Cempra Pharmaceuticals, Inc. Hydrogen bond forming fluoro ketolides for treating diseases
US10188674B2 (en) 2012-03-27 2019-01-29 Cempra Pharmaceuticals, Inc. Parenteral formulations for administering macrolide antibiotics
US9861616B2 (en) 2013-03-14 2018-01-09 Cempra Pharmaceuticals, Inc. Methods for treating respiratory diseases and formulations therefor
US9751908B2 (en) 2013-03-15 2017-09-05 Cempra Pharmaceuticals, Inc. Convergent processes for preparing macrolide antibacterial agents
US10086006B2 (en) 2013-09-25 2018-10-02 Zavante Therapeutics, Inc. Method for improving drug treatments in mammals
US9345717B2 (en) 2013-09-25 2016-05-24 Zavante Therapeutics, Inc. Method for improving drug treatments in mammals
CN116650399A (zh) * 2023-04-13 2023-08-29 福元药业有限公司 一种夫西地酸乳膏及其制备方法

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