WO2001015695A1 - Methods of use of fluoroquinolone compounds against bacteria - Google Patents
Methods of use of fluoroquinolone compounds against bacteria Download PDFInfo
- Publication number
- WO2001015695A1 WO2001015695A1 PCT/US2000/023883 US0023883W WO0115695A1 WO 2001015695 A1 WO2001015695 A1 WO 2001015695A1 US 0023883 W US0023883 W US 0023883W WO 0115695 A1 WO0115695 A1 WO 0115695A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gemifloxacin
- mic
- pathogenic bacteria
- ciprofloxacin
- pneumoniae
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- 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
- This invention relates, in part, to newly identified methods of using quinolone antibiotics, particularly a gemifloxacin compound against bacteria, particularly pathogenic bacteria.
- Quinolones have been shown to be effective to varying degrees against a range of bacterial pathogens. However, as diseases caused by these pathogens are on the rise, there exists a need for antimicrobial compounds that are more potent than the present group of quinolones.
- Gemifloxacin mesylate (SB-265805) is a novel fluoroquinolone useful as a potent antibacterial agent.
- Gemifloxacin compounds are described in detail in patent application PCT/KR98/00051 published as WO 98/42705.
- Patent application EP 688772 discloses novel quinoline(naphthyridine)carboxylic acid derivatives, including anhydrous (R,S)-7-(3- aminomethyl-4-methoxyiminopyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 ,8- naphthyridine-3-carboxylic acid of formula I.
- PCT/KR98/00051 discloses (R,S)-7-(3-aminomethyl-4-5y/z-methoxyimino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 ,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof including the hemihydrate and sesquihydrate.
- An aspect of the invention is directed to the use of a gemifloxacin compound agianst Acinetobacter species, demonstrating the activity of the gemifloxacin compounds herein used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Prevotella denticola/loeschii group, Veillonella spp., Prevotella heparinolytica, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas spp. (Porphyromonas cangingivalis;
- a further aspect of the invention is directed to the use of a gemifloxacin compound against Salmonella spp. and Shigella spp. , demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- Another aspect of the invention is directed to the use of a gemifloxacin compound against pneumococcal bacteria, including penicillin-susceptible, intermediate and resistant (including ciprofloxacin-resistant) pneumococci., demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- Still another aspect of the invention is directed to the use of a gemifloxacin compound against maxillary sinus pathogens, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against
- An aspect of the invention is directed to the use of a gemifloxacin compound against Chlamy dia pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Legionella spp., demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against respiratory tract bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against bacterial meningitis, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against
- An aspect of the invention is directed to the use of a gemifloxacin compound against Gram positive or Gram negative aerobic bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Streptococci bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Mycoplasma bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Legionella spp., demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against
- Streptococcus pneumoniae demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Haemophilus influenzae and pneumococci bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Gram positive bacteria, such as streptococci and staphylococci, and Enterobacteriaceae bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Gram positive pneumococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against gonococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against pneumococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against aerobic bacteria, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against pneumococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- Another aspect of the invention is directed to the use of a gemifloxacin compound against Gram positive cocci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- Yet another aspect of the invention is directed to the use of a gemifloxacin compound against Streptococcus pneumoniae, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against enterococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against streptococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Acinetobacter spp., demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Chlamydia pneumoniae, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against streptococci, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against Bordetella spp., demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- An aspect of the invention is directed to the use of a gemifloxacin compound against
- Mycoplasma demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- Another aspect of the invention is directed to the use of a gemifloxacin compound against Streptococcus pneumoniae, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- Still another aspect of the invention is directed to the use of a gemifloxacin compound against Streptococcus pneumoniae, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
- gemifloxacin compounds are valuable compounds for the treatment of clinical conditions or indications caused by a range of bacteria of the invention, including those bacteria resistant to usual oral therapy.
- An object of the invention is a method for modulating metabolism of Ac intobacter pathogenic bacteria comprising the step of contacting Acintobacter pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Acintobacter pathogenic bacteria is selected from the group consisting of: A. baumannii, A. anitratus, A. Iwoffii, A. calcoaceticus or Acinetobacter spp. Also provided by the invention is a method of treating or preventing a bacterial infection by Acintobacter pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Acintobacter pathogenic bacteria. Further preferred methods are provided by the invention wherein said bacteria is selected from the group consisting of: A. baumannii, A. Iwoffii. or A. calcoaceticus.
- An object of the invention is a method for modulating metabolism of anaerobic pathogenic bacteria comprising the step of contacting anaerobic pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said anaerobic pathogenic bacteria is selected from the group consisting of: Prevotella denticola/loeschii group, Veillonella spp., Prevotella heparinolytica, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas spp.
- Prevotella bivia Prevotella buccae-oris group, Porphyromonas canoris, Porphyromonas gingivalis, Porphyromonas macaccae, Peptostreptococcus micros, Peptostreptococcus prevotii, Porphyromonas asaccharolyticus, Fusobacterium varium, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Fusobacterium spp group 1 (Fusobacterium gonidiaformans, Fusobacterium naviforme, Fusobacterium necrophorum,
- Fusobacterium nucleatum, and Fusobacterium nucleatum ss animalis Fusobacterium spp. group 2 (Fusobacterium mortiferum, Fusobacterium necrogenes, and Fusobacterium ulcerans), Fusobacterium russii, Clostridium difficile, Clostridium inocuum, Clostridium ramosum, Bacteroides ureolyticus, Bilophila wadsworthia, Clostridium clostridioforme, Anaerobiospirillum succiniciproducens, Bacteroides gracilis, Bacteroides tectum, Actinomyces odontolyticus, Actinomyces israelii, or Anaerobiospirillum thomasii.
- Also provided by the invention is a method of treating or preventing a bacterial infection by anaerobic pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with anaerobic pathogenic bacteria.
- bacteria is selected from the group consisting of: Prevotella denticola/loeschii group, Veillonella spp., Prevotella heparinolytica, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas spp. (Porphyromonas cangingivalis; Porphyromonas cansulci; Porphyromonas circumdentaria; and
- Porphyromonas levii Prevotella bivia, Prevotella buccae-oris group, Porphyromonas canoris,
- Porphyromonas gingivalis Porphyromonas macaccae, Peptostreptococcus micros,
- Peptostreptococcus prevotii Porphyromonas asaccharolyticus, Fusobacterium varium,
- Peptostreptococcus asaccharolyticus Peptostreptococcus magnus
- Fusobacterium spp group 1 Fusobacterium gonidiaformans, Fusobacterium naviforme, Fusobacterium necrophorum, Fusobacterium nucleatum, and Fusobacterium nucleatum ss animalis
- Fusobacterium russii Clostridium difficile, Clostridium inocuum, Clostridium ramosum, Bacteroides ureolyticus, Bilophila wadsworthia, Clostridium clostridioforme, Anaerobiospirillum succiniciproducens, Bacteroides gracilis, Bacteroides tectum, Actinomyces odontolyticus, Actinomyces israelii, or Anaerobiospirillum thomasii.
- An object of the invention is a method for modulating metabolism of pathogenic Enterococcal bacteria comprising the step of contacting pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: E. coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, Proteus vulgaris, Morganella morganii, Serratia spp., Providencia stuartii, Salmonella spp., Stenotrophomonas maltophila, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus MSSA, Staphylococcus aureus MRSA, Staphylococcus epidermidis MSSE, Staphylococcus epidermidis MRSE, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus lancefield Gp B, Streptococcus millerii, Strepto
- bacteria is selected from the group consisting of: Enterobacter spp., Staphylococcus aureus MSSA, Staphylococcus epidermidis MSSE, Staphylococcus epidermidis MRSE, Streptococcus pneumoniae, Quinolone- resistant Streptococcus pneumoniae, Moraxella catarrhalis, Peptostreptococcus anaerobius, Peptostreptococcus prevoti, and Bacteroides fragilis.
- An object of the invention is a method for modulating metabolism of Salmonella spp. and Shigella spp. pathogenic bacteria comprising the step of contacting Salmonella spp. and Shigella spp. pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Salmonella spp. and Shigella spp. pathogenic bacteria is selected from the group consisting of: Salmonella spp. and Shigella spp.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Salmonella spp. and Shigella spp. pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Salmonella spp. and Shigella spp. pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of pneumococcal pathogenic bacteria comprising the step of contacting pneumococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pneumococcal pathogenic bacteria is selected from the group consisting of: penicillin-susceptible, intermediate and resistant (including ciprofloxacin-resistant) pneumococci.
- Also provided by the invention is a method of treating or preventing a bacterial infection by pneumococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with pneumococcal pathogenic bacteria.
- bacteria is selected from the group consisting of: penicillin-susceptible, intermediate and resistant (including ciprofloxacin-resistant) pneumococci.
- An object of the invention is a method for modulating metabolism of maxillary sinus pathogenic bacteria comprising the step of contacting maxillary sinus pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said maxillary sinus pathogenic bacteria is selected from the group consisting of: Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus,
- Peptostreptococcus spp. Bacteroides ureolyticus, Enterobacteriaceae, non-fermentative Gram negative bacilli, Neisseria meningitidis, Bacteroides spp., beta-hemolytic Streptococcus and Gram negative rods.
- Also provided by the invention is a method of treating or preventing a bacterial infection by maxillary sinus pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with maxillary sinus pathogenic bacteria.
- bacteria is selected from the group consisting of: Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, Peptostreptococcus spp., Bacteroides urealyticus, Enterobacteriaceae, non-fermentative Gram negative bacilli, Neisseria meningitidis, Bacteroides spp., beta-hemolytic Streptococcus and Gram negative rods.
- An object of the invention is a method for modulating metabolism of Gram negative, non- fermenting pathogenic bacteria comprising the step of contacting Gram negative, non-fermenting pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Gram negative, non-fermenting pathogenic bacteria is selected from the group consisting of: Pseudomonas. Aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia and Burkholderia cepacia bacteria.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram negative, non-fermenting pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram negative, non-fermenting pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Chlamydia pneumoniae or other respiratory tract pathogenic bacteria comprising the step of contacting Chlamydia pneumoniae or respiratory tract pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Chlamydia pneumoniae or respiratory tract pathogenic bacteria is selected from the group consisting of: Chlamydia pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Legionella spp..
- Also provided by the invention is a method of treating or preventing a bacterial infection by Chlamydia pneumoniae or respiratory tract pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Chlamydia pneumoniae or respiratory tract pathogenic bacteria.
- bacteria is selected from the group consisting of: Chlamydia pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Legionella spp.
- An object of the invention is a method for modulating metabolism of respiratory tract pathogenic bacteria comprising the step of contacting respiratory tract pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said respiratory tract pathogenic bacteria is selected from the group consisting of: Streptococcus pneumoniae and Haemophilus influenzae.
- a method of treating or preventing a bacterial infection by respiratory tract pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with respiratory tract pathogenic bacteria.
- Further preferred methods are provided by the invention wherein said bacteria is selected from the group consisting of: Streptococcus pneumoniae and Haemophilus influenzae.
- An object of the invention is a method for modulating metabolism of bacterial meningitis pathogenic bacteria comprising the step of contacting bacterial meningitis pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said bacterial meningitis pathogenic bacteria is Streptococcus pneumoniae.
- Also provided by the invention is a method of treating or preventing a bacterial infection by bacterial meningitis pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with bacterial meningitis pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Gram negative pathogenic bacteria comprising the step of contacting Gram negative pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Gram negative pathogenic bacteria is selected from the group consisting of: Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Pseudomonas aeruginosa, Morganella morganii, Proteus spp., Stenotrophomonas maltophilia, Klebsiella oxytoca, Citrobacter freundii, Acinetobacter sp., and Serratia spp.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram negative pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram negative pathogenic bacteria.
- bacteria is selected from the group consisting of: Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Pseudomonas aeruginosa, Morganella morganii, Proteus spp., Stenotrophomonas maltophilia, Klebsiella oxytoca, Citrobacter freundii, Acinetobacter sp., and Serratia spp.
- An object of the invention is a method for modulating metabolism of Gram positive or
- Gram negative aerobic pathogenic bacteria comprising the step of contacting Gram positive or Gram negative aerobic pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Gram positive or Gram negative aerobic pathogenic bacteria is selected from the group consisting of: Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram positive or Gram negative aerobic pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram positive or Gram negative aerobic pathogenic bacteria.
- a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram positive or Gram negative aerobic pathogenic bacteria.
- said bacteria is selected from the group consisting of: Staphylococcus aureus, Staphylococcus saprophyticus,
- Streptococcus pneumoniae Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa,
- Klebsiella pneumoniae Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- An object of the invention is a method for modulating metabolism of Streptococci pathogenic bacteria comprising the step of contacting Streptococci pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Streptococci pathogenic bacteria is Streptococcus spp.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Streptococci pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Streptococci pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Mycoplasma pathogenic bacteria comprising the step of contacting Mycoplasma pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Mycoplasma pathogenic bacteria is selected from the group consisting of: Mycoplasma pneumoniae, Mycoplasma hominis,
- Mycoplasma fermentans Mycoplasma genitalium, Mycoplasma penetrans and Ureaplasma urealyticum.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Mycoplasma pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Mycoplasma pathogenic bacteria.
- bacteria is selected from the group consisting of: Mycoplasma pneumoniae, Mycoplasma hominis, Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma penetrans and Ureaplasma urealyticum.
- An object of the invention is a method for modulating metabolism of Legionella spp. pathogenic bacteria comprising the step of contacting Legionella spp. pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Legionella spp. pathogenic bacteria is selected from the group consisting of: Legionella pneumophilia, Legionella bozemanii, Legionella wadsworthii, Legionella jordanis, Legionella dumoffli, Legionella longbeacheae,
- Legionella micdadei, and Erithromycin-resistant strains of Legionella spp. are Legionella micdadei, and Erithromycin-resistant strains of Legionella spp..
- Also provided by the invention is a method of treating or preventing a bacterial infection by Legionella spp. pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Legionella spp. pathogenic bacteria.
- bacteria is selected from the group consisting of: Legionella pneumophilia, Legionella bozemanii, Legionella wadsworthii, Legionella jordanis, Legionella dumoffli, Legionella longbeacheae, Legionella micdadei, Erithromycin-susceptible strains of Legionella spp and Erithromycin-resistant strains of Legionella spp.
- An object of the invention is a method for modulating metabolism of Streptococcus pneumoniae pathogenic bacteria comprising the step of contacting Streptococcus pneumoniae pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is
- Also provided by the invention is a method of treating or preventing a bacterial infection by Streptococcus pneumoniae pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Streptococcus pneumoniae pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Haemophilus influenzae or pneumococci pathogenic bacteria comprising the step of contacting Haemophilus influenzae or pneumococci pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: Haemophilus influenzae and pneumococci.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Haemophilus influenzae and pneumococci pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Haemophilus influenzae or pneumococci pathogenic bacteria.
- bacteria is selected from the group consisting of: Haemophilus influenzae and pneumococci bacteria.
- An object of the invention is a method for modulating metabolism of Gram positive bacterial pathogens, such as streptococci and staphylococci, and Enterobacteriaceae pathogenic bacteria comprising the step of contacting the pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: Gram positive bacterial pathogens, such as streptococci and staphylococci, and Enterobacteriaceae bacteria.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram positive bacterial pathogens, such as streptococci and staphylococci, or
- Enterobacteriaceae pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram positive bacterial pathogens, such as streptococci and staphylococci, or Enterobacteriaceae pathogenic bacteria.
- Gram positive bacterial pathogens such as streptococci and staphylococci, or Enterobacteriaceae pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Gram positive pneumococcal pathogenic bacteria comprising the step of contacting Gram positive pneumococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Gram positive pneumococcal pathogenic bacteria is Streptococcus pneumoniae.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram positive pneumococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram positive pneumococcal pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of gonococcal pathogenic bacteria comprising the step of contacting gonococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said gonococcal pathogenic bacteria is selected from the group consisting of: Neisseria gonorrhoeae, including Ciprofloxacin- resistant strains of Neisseria gonorrhoeae.
- Also provided by the invention is a method of treating or preventing a bacterial infection by gonococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with gonococcal pathogenic bacteria.
- bacteria is selected from the group consisting of: Neisseria gonorrhoeae, including Ciprofloxacin-resistant strains of Neisseria gonorrhoeae.
- An object of the invention is a method for modulating metabolism of pneumococcal pathogenic bacteria comprising the step of contacting pneumococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pneumococcal pathogenic bacteria is selected from the group consisting of: pneumococcal pathogenic bacteria.
- Also provided by the invention is a method of treating or preventing a bacterial infection by pneumococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with pneumococcal pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of aerobic pathogenic bacteria comprising the step of contacting aerobic pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said aerobic pathogenic bacteria is selected from the group consisting of: Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- said aerobic pathogenic bacteria is selected from the group consisting of: Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- Also provided by the invention is a method of treating or preventing a bacterial infection by aerobic pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with aerobic pathogenic bacteria.
- bacteria is selected from the group consisting of: Staphylococcus aureus, Staphylococcus saprophyticus,
- Streptococcus pneumoniae Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- An object of the invention is a method for modulating metabolism of pneumococcal pathogenic bacteria comprising the step of contacting pneumococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pneumococcal pathogenic bacteria is S. pneumoniae.
- Also provided by the invention is a method of treating or preventing a bacterial infection by pneumococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with pneumococcal pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Gram positive coccal pathogenic bacteria comprising the step of contacting Gram positive coccal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Gram positive coccal pathogenic bacteria is selected from the group consisting of: Enterococcus faecalis, Enterococcus faecium, Enterococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Coagulase-negative staphylococci, Streptococcus pneumoniae, Streptococcus ⁇ -hemolytic, Streptococcus viridans group, Bacillus spp., and Corynebacterium spp.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram positive coccal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Gram positive coccal pathogenic bacteria.
- bacteria is selected from the group consisting of: Enterococcus faecalis, Enterococcus faecium, Enterococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Coagulase-negative staphylococci, Streptococcus pneumoniae, Streptococcus ⁇ -hemolytic, Streptococcus viridans group, Bacillus spp., and Corynebacterium spp.
- An object of the invention is a method for modulating metabolism of Streptococcus pneumoniae pathogenic bacteria comprising the step of contacting Streptococcus pneumoniae pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: Streptococcus pneumoniae .
- Also provided by the invention is a method of treating or preventing a bacterial infection by Streptococcus pneumoniae pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Streptococcus pneumoniae pathogenic bacteria.
- An object of the invention is a method for modulating metabolism of Escherichia coli,
- Staphylococcus aureus or Streptococcus pneumoniae pathogenic bacteria comprising the step of contacting Escherichia coli, Staphylococcus aureus or Streptococcus pneumoniae pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Escherichia coli, Staphylococcus aureus or Streptococcus pneumoniae pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Escherichia coli, Staphylococcus aureus or Streptococcus pneumoniae pathogenic bacteria.
- bacteria is selected from the group consisting of: Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae.
- An object of the invention is a method for modulating metabolism of enterococcal pathogenic bacteria comprising the step of contacting enterococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said enterococcal pathogenic bacteria is selected from the group consisting of: Enterococcus faecalis and Enterococcus faecium
- enterococcal pathogenic bacteria is selected from the group consisting of: Enterococcus faecalis and Enterococcus faecium
- a method of treating or preventing a bacterial infection by enterococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with enterococcal pathogenic bacteria.
- said bacteria is selected from the group consisting of: Enterococcus faecalis and Enterococcus faecium.
- An object of the invention is a method for modulating metabolism of streptococcal pathogenic bacteria comprising the step of contacting streptococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said streptococcal pathogenic bacteria is selected from the group consisting of: Streptococcus pyogenes, Streptococcus agalactiae and viridans streptococci.
- Also provided by the invention is a method of treating or preventing a bacterial infection by streptococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with streptococcal pathogenic bacteria.
- bacteria is selected from the group consisting of: Streptococcus pyogenes, Streptococcus agalactiae and viridans streptococci.
- An object of the invention is a method for modulating metabolism of Acinetobacter spp. pathogenic bacteria comprising the step of contacting Acinetobacter spp. pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Acinetobacter spp. pathogenic bacteria is selected from the group consisting of: Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, and Acinetobacter anitratus. Also provided by the invention is a method of treating or preventing a bacterial infection by Acinetobacter spp. pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Acinetobacter spp. pathogenic bacteria. Further preferred methods are provided by the invention wherein said bacteria is selected from the group consisting of: Acinetobacter baumannii, Acinetobacter calcoaceticus,
- Acinetobacter Iwoffli and Acinetobacter anitratus.
- An object of the invention is a method for modulating metabolism of Chlamydia pneumoniae pathogenic bacteria comprising the step of contacting Chlamydia pneumoniae pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: Chlamydia pneumoniae.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Chlamydia pneumoniae pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Chlamydia pneumoniae pathogenic bacteria.
- bacteria is selected from the group consisting of: Chlamydia pneumoniae.
- An object of the invention is a method for modulating metabolism of streptococcal pathogenic bacteria comprising the step of contacting streptococcal pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said streptococcal pathogenic bacteria is selected from the group consisting of: Streptococcus pyogenes, Streptococcus agalactiae and viridans streptococci.
- Also provided by the invention is a method of treating or preventing a bacterial infection by streptococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with streptococcal pathogenic bacteria.
- bacteria is selected from the group consisting of: Streptococcus pyogenes, Streptococcus agalactiae and viridans streptococci.
- An object of the invention is a method for modulating metabolism of Bordetella spp. pathogenic bacteria comprising the step of contacting Bordetella spp. pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Bordetella spp. pathogenic bacteria is selected from the group consisting of: B.pertussis, B. parapertussis, and B. bronchiseptica.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Bordetella spp. pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Bordetella spp. pathogenic bacteria.
- bacteria is selected from the group consisting of: B.pertussis, B. parapertussis, and B. bronchiseptica.
- An object of the invention is a method for modulating metabolism of Mycoplasma pathogenic bacteria comprising the step of contacting Mycoplasma pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said Mycoplasma pathogenic bacteria is selected from the group consisting of: Mycoplasma pneumoniae, Mycoplasma hominis,
- Mycoplasma fermentans Mycoplasma genitalium, Mycoplasma penetrans and Ureaplasma urealyticum.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Mycoplasma pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Mycoplasma pathogenic bacteria.
- a composition comprising a quinolone, particularly a gemifloxacin compound
- said bacteria is selected from the group consisting of: Mycoplasma pneumoniae, Mycoplasma hominis, Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma penetrans and Ureaplasma urealyticum.
- An object of the invention is a method for modulating metabolism of Streptococcus pneumoniae pathogenic bacteria comprising the step of contacting Streptococcus pneumoniae pathogenic bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
- a further object of the invention is a method wherein said pathogenic bacteria is selected from the group consisting of: Streptococcus pneumoniae .
- Also provided by the invention is a method of treating or preventing a bacterial infection by Streptococcus pneumoniae pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with Streptococcus pneumoniae pathogenic bacteria.
- a preferred method is provided wherein said modulating metabolism is inhibiting growth of said bacteria or killing said bacteria.
- a further preferred method is provided wherein said contacting said bacteria comprises the further step of introducing said composition into a mammal, particularly a human.
- Still further preferred methods comprise a gemifloxacin compound selected from the group consisting of gemifloxacin mesylate, gemifloxacin mesylate hydrate, gemifloxacin mesylate hemihydrate and gemifloxacin mesylate sesquihydrate.
- Figure 1 shows MICsoand MIC 90 values ( ⁇ g/ml) for 5 species of Acinetobacter.
- Figure 2 shows percentage of isolates with MICs above the breakpoint.
- Figure 3 shows ranges of MICs ( ⁇ g/ml).
- Figures 4a-4g show bactericidal activity of gemifloxacin against A. baumannii ATCC 19606.
- Figure 4 shows the bactericidal activity of trovafloxacin against A. baumannii ATCC
- Figure 4c shows the bactericidal activity of moxifloxacin against A. baumannii ATCC 19606.
- Figure 4d shows the bactericidal activity of levofloxacin against A. baumannii ATCC 19606.
- Figure 4e shows the bactericidal activity of ciprofloxacin against A. baumannii ATCC 19606.
- Figure 4f show the bactericidal activity of grepafloxacin against A. baumannii ATCC 19606.
- Figure 4g shows the bactericidal activity of sparfloxacin against A. baumannii ATCC
- Figure 5 shows a scattergram of MIC vs zone of inhibition for a 1 ⁇ g gemifloxacin disk content for all genera except Pseudomonas species using the BSAC standardized method of disk testing.
- Figure 6 shows a scattergram of MIC vs zone of inhibition for a 5 ⁇ g gemifloxacin disk content to Pseudomonas species using the BSAC standardized method of disk testing
- Figure 7 shows a graphical depiction of gemifloxacin time-kill activity against a penicillin- resistant pneumococcus.
- Figure 8 shows the MIC distribution of four quinolones against P. aeruginosa.
- Figure 9 shows the MIC distribution of four quinolones against Acinetobacter spp.
- Figure 10 shows the efficacy of Gemifloxacin (SB 265805) and comparator agents against RTI in rats caused by 5. pneumoniae 622286
- Figure 11 shows the efficacy of Gemifloxacin and comparator agents against RTI in rats caused by S. pneumoniae 305313.
- Figure 12 shows the efficacy of Gemifloxacin compared with that of Grepafloxacin
- GRP Levofloxacin
- TRV Trovafloxacin
- Figure 13 shows the efficacy of Gemifloxacin and comparator agents against RTI in rats caused by H. influenzae HI43.
- Figure 14 shows the efficacy of Gemifloxacin and comparator agents against S. pneumoniae 1629.
- Figure 15 shows the efficacy of Gemifloxacin and comparator agents against S. pneumoniae 1629.
- Figure 16 shows the mean post antibiotic effects (PAEs) of ciprofloxacin, trovafloxacin, and gemifloxacin in evaluable strains of S. pneumoniae
- Figure 17 shows the PAEs of ciprofloxacin, trovafloxacin, and gemifloxacin in susceptible strains of S. pneumoniae
- Figure 18 graphically illustrates percent inhibition by ciprofloxacin.
- Figure 19 graphically illustrates percent inhibition by ciprofloxacin.
- Figure 20 shows the effect of gemifloxacin administration on the intestinal aerobic microflora of 10 volunteers.
- Figure 21 shows the effect of gemifloxacin administration on the intestinal anaerobic microflora of 10 volunteers.
- Figure 22 shows the selection of mutant S. pneumoniae strains with gemifloxacin.
- Figure 23 shows the survival of Escherichia coli KL16 treated with gemifloxacin for 3 h at 37 °C.
- Figure 24 shows the survival of Staphylococcus aureus E3T treated with gemifloxacin for
- Figure 25 shows the survival of Streptococcus pneumoniae C3LN4 treated with gemifloxacin for 3 h at 37 °C.
- Figure 26 shows the dose response of A. baumannii ATCC 19606 to Gemifloxcain.
- Figures 27 shows the bactericidal activity of gemifloxacin against A. baumannii ATCC
- Figure 28 shows the bactericidal activity of trovafloxacin against A. baumannii ATCC
- Figure 29 shows the bactericidal activity of moxifloxacin against A. baumannii ATCC 19606
- Figure 30 shows the bactericidal activity of levofloxacin against A. baumannii ATCC
- Figure 31 shows the bactericidal activity of ciprofloxacin against A. baumannii ATCC
- Figure 32 shows the bactericidal activity of grepafloxacin against A. baumannii ATCC 19606.
- Figure 33 shows the bactericidal activity of sparfloxacin against A. baumannii ATCC 19606.
- Figure 34 shows the bactericidal activity of sparfloxacin against A. baumanii ATCC
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against A. baumannii, A. anitratus, A. Iwoffii, A. calcoaceticus or Acinetobacter spp.
- Gemifloxacin is a fluoroquinolone with a spectrum including activity against both Gram positive and Gram negative aerobic bacteria, among other bacteria.
- an agar dilution method has been used to determine the MICs of 100 clinical isolates of Acinetobacter species (47 A. baumannii, 18 A. anitratus, 18 A. Iwoffii, 13 A.
- Table 1 shows that gemifloxacin has good activity against the four species of Acinetobacter and is over eight-fold more potent than ciprofloxacin.
- the data in Table 1 also demonstrates that gemifloxacin is 2-8-fold more active than grepafloxacin, moxifloxacin, levofloxacin, ofloxacin and gatifloxacin, and within one dilution of the comparator quinolones, sparfloxacin and trovafloxacin. Cross-resistance was seen only within the quinolones and did not extend to the non-quinolone antimicrobials.
- Organisms from the genus Acinetobacter are increasingly being found in the nosocomial environment where they are responsible for causing secondary infection in the immunocompromised, in particular nosocomial pneumonia. These organisms are innately resistant to much of the antimicrobial armoury available to the clinician, thus, giving them a selective advantage in areas of high antimicrobial usage such as intensive care units. Resistance to ciprofloxacin has been found in the Acinetobacter strains within the hospital environment and the search for newer, more potent quinolones continues. Gemifloxacin (SB-265805) is one such quinolone which has shown a good spectrum of activity against both Gram positive and Gram negative organisms.
- Breakpoint values were taken from the BSAC guidelines and are as follows: cefuroxime 2 ⁇ g/ml; ciprofloxacin 4 ⁇ g/ml; imipenem 8 ⁇ g/ml; ofloxacin 4 ⁇ g/ml; levofloxacin 4 ⁇ g/ml; azithromycin 0.5 ⁇ g/ml. Where not published, the breakpoints were arbitrarily taken to be 4 ⁇ g/ml but may later have been found to be higher. Results for the MIC determination are in Table 1 and are summarized in Figures 1, 2 and 3.
- gemifloxacin has good activity against Gram positive respiratory organisms such as Streptococcus pneumoniae and Staphylococcus aureus with MIC 50 and MIC 90 values 32-64-fold more active than ciprofloxacin. In this study it was shown that this high activity is retained against a genus of Gram negative organisms, Acinetobacter, with an MIC 50 and MIC 90 of gemifloxacin that is 8- and 16-fold less, respectively, than that of ciprofloxacin, and is comparable to trovafloxacin and sparfloxacin. At a species to species level, gemifloxacin is most potent against A. calcoaceticus and A.
- Gemifloxacin has activity against Acinetobacter, a genus of Gram negative organisms. It has considerably better activity than ciprofloxacin and comparable activity to trovafloxacin and sparfloxacin. Gemifloxacin is most potent against A. calcoaceticus and A. Iwoffii. Although the levels of quinolone resistance are similar for the antimicrobial agents tested (19-25%), gemifloxacin demonstrates activity against all but the most ciprofloxacin-resistant isolates.
- a further objective of these analyses was to compare the in vitro killing activity of gemifloxacin on A baumannii ATCC 19606 against comparitor quinolones TRO, MOX, LEV, CTP, GREand SPA at their respective optimum bactericidal concentration (OBCs) and at four times their MIC.
- OBCs optimum bactericidal concentration
- the bactericidal activity of gemifloxacin has been compared to that of trovafloxacin, moxifloxacin, levofloxacin, ciprofloxacin, grepafloxacin and sparfloxacin in a time- kill study at the concentrations of four times the MIC (0.5, 0.25, 1, 2, 2, 0.5, 0.5 ⁇ g/ml respectively) and at their optimum bactericidal concentration (OBC) (4, 4, 4, 4, 4, 4, 8, 8 ⁇ g/ml, respectively) against the standard Acinetobacter baumannii ATCC 19606.
- OBC optimum bactericidal concentration
- gemifloxacin has excellent bactericidal activity against A. baumannii at a concentration eight-fold less than its OBC.
- Acinetobacter baumannii is an important opportunistic pathogen that is frequently found in the nosocomial environment where it is responsible for bacteremias, secondary meningitis, urinary tract infections and pneumonias in the immunocompromised. With these patients, a bactericidal drug is usually preferable to a bacteriostatic one. Quinolones are bactericidal but exhibit a bi-phasic dose response, whereby the lethality of a drug increases with its concentration until its optimum bactericidal concentration (OBC) is reached, after which the bactericidal activity decreases with concentration.
- OBC optimum bactericidal concentration
- the standard A. baumannii ATCC 19606 laboratory strain is used throughout the study. Prior to time-kill experiments, the MICs of seven quinolones for A. baumannii ATCC 19606 is determined using the agar dilution method following the BSAC guidelines for susceptibility testing. (See The British Society for Antimicrobial Chemotherapy. A guide to sensitivity testing. J Antimicrob Chemother 1991; 27(Suppl D)). To determine the OBC, nutrient broth is inoculated with A. baumannii ATCC 19606 and incubated overnight.
- Doubling dilutions of antimicrobial agent ranging from 0.03-256 ⁇ g/ml in nutrient broth are inoculated with the overnight culture and incubated for a further 3 hours.
- the resulting cultures are serial diluted and plated onto nutrient agar, incubated overnight and the colonies are counted (See Lewin CS, Howard BMA, Ratcliffe NT, Smith JT. 4-Quinolones and the SOS response. J Med Microbiol 1989; 29: 139-144).
- Log-phase cultures are challenged with a fixed concentration of antimicrobial that corresponded with its OBC or four times MIC.
- An overnight culture is used to inoculate nutrient broth and incubated for 3 hours.
- the antimicrobial agent was then added and samples are taken every 30 minutes for 3 hours, serially diluted and plated for viable count. A final sample is taken after 24 hours, diluted and plated for viable counting.
- Gemifloxacin demonstrates good bactericidal activity when compared with ciprofloxacin: at four times the MIC, the killing kinetics are almost equal to that of its OBC even though it is one- eighth the concentration. At both the OBC and at four times the MIC, gemifloxacin killed over 99% of microrganisms in 24 hours. Gemifloxacin at four times the MIC killed >2 log )0 compared to ciprofloxacin, sparfloxacin and trovafloxacin. This data suggests that gemifloxacin has the potential to treat Acinetobacter infections even at low concentrations or multiples of MIC.
- Antimicrobial agent OBC ( ⁇ g ml) MIC ( ⁇ g/ml) 4 x MIC ( ⁇ g/ml)
- the invention provides a method for modulating metabolism of Acinetobacter pathogenic bacteria. Skilled artisans can readily choose Acinetobacter pathogenic bacteria or patients infected with or suspected to be infected with these organisms to practice the methods of the invention. Alternatively, the bacteria useful in the methods of the invention may be those described herein.
- a method of treating or preventing a bacterial infection by Acinetobacter pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with Acinetobacter pathogenic bacteria.
- Acinetobacter pathogenic bacteria is selected from the group consisting of: A. baumannii, A. anitratus, A. Iwoffii, A. calcoaceticus or Acinetobacter spp.
- Other Acinetobacter pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention also provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against Prevotella denticola/loeschii group, Veillonella spp., Prevotella heparinolytica, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas spp.
- a composition comprising a quinolone, particularly a gemifloxacin compound against Prevotella denticola/loeschii group, Veillonella spp., Prevotella heparinolytica, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas spp.
- Prevotella bivia Prevotella buccae-oris group, Porphyromonas canoris, Porphyromonas gingivalis, Porphyromonas macaccae, Peptostreptococcus micros, Peptostreptococcus prevotii, Porphyromonas asaccharolyticus, Fusobacterium varium, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Fusobacterium spp group 1 (Fusobacterium gonidiaformans, Fusobacterium naviforme, Fusobacterium necrophorum, Fusobacterium nucleatum, and Fusobacterium nucleatum ss animalis), Fusobacterium spp.
- Clostridium ramosum Bacteroides ureolyticus, Bilophila wadsworthia, Clostridium clostridioforme, Anaerobiospirillum succiniciproducens, Bacteroides gracilis, Bacteroides tectum, Actinomyces odontolyticus, Actinomyces israelii, or Anaerobiospirillum thomasii..
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various anaerobic pathogens.
- An objective of these analyses was to determine the activities of gemifloxacin and comparator agents by an agar dilution method against 419 clinical strains of less commonly identified species of anaerobes.
- Gemifloxacin is generally more active than trovafloxacin against Gram positive strains by one to two dilutions.
- Peptostreptococci such as Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus micros and Peptostreptococcus prevotii and Porphyromonas spp., such as, Porphyromonas asaccharolytica, Porphyromonas canoris, Porphyromonas gingivalis, Porphyromonas macaccae are all susceptible to ⁇ 0.25 ⁇ g/ml of gemifloxacin.
- Fusobacterium naviforme and Fusobacterium necrophorum are also susceptible to ⁇ 2 ⁇ g/ml, while Fusobacterium varium strains exhibit a bimodal pattern; the other Fusobacterium species, such as Fusobacterium ulcerans, Fusobacterium russii, as well as Veillonella spp., Prevotella melaninogenica group, Prevotella bivia, Clostridium difficile, and Bilophila wadsworthia are relatively resistant to gemifloxacin [MIC 90 s >4 ug/ml].
- the activity of gemifloxacin was determined against the large variety of less usual anaerobic species that are encountered in human clinical infections and compared its activity with that of other commonly used oral agents.
- the strains are previously isolated from human clinical specimens from a variety of sources, and are identified by standard criteria. Almost all of these isolates are different from those strains used in a prior study when the same genus and species was used.
- Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC 29741 are tested simultaneously as control strains. The numbers and species of isolates tested are given in Table 3.
- Standard laboratory powders are supplied as follows: gemifloxacin and amoxicillin clavulanate, SmithKline Beecham Pharmaceuticals, Philadelphia, PA; trovafloxacin and azithromycin, Pfizer Inc., New York, NY; clarithromycin, Abbott Laboratories, Abbott Park, IL.; clindamycin, Pharmacia Upjohn Co., Kalamazoo, Mich.; metronidazole, Searle Research & Development, Skokie, IL.; erythromycin, Eli Lilly & Co., Indianapolis, IN; and penicillin G, Sigma Chemical Co., St. Louis, MO, USA.
- Frozen cultures are transferred at least twice on Brucella agar supplemented with hemin, vitamin Ki, and 5% sheep blood to ensure purity and good growth. Susceptibility testing was performed according to NCCLS standards. Brucella agar supplemented with hemin, vitamin K and 5% laked sheep blood was the basal medium used. For Bilophila wadsworthia, the agar is also supplemented with pyruvate. Antimicrobial agents are reconstituted according to the manufacturers' instructions. Serial twofold dilutions of antimicrobial agents are prepared on the day of the test and added to the media in varying concentrations ( ⁇ g/ml).
- the agar plates are inoculated with a Steers replicator (Craft Machine Inc., Chester, PA, USA).
- the inoculum used was 10 5 CFU/spot.
- Control plates without antimicrobial agents are inoculated before and after each set of drug-containing plates.
- the MIC was defined as the lowest concentration of an agent that yielded no growth, or a marked change in the appearance of growth as compared to the growth control plate.
- the comparative activity of gemifloxacin and other antimicrobial agents is shown in
- Gemifloxacin exhibits activity against Gram positive anaerobes, especially the four Peptostreptococcus species and the Porphyromonas species. Gemifloxacin is also active against more unusual isolates.
- MIC 50 Minimal inhibitory concentration for 50% and 90% of isolates tested, respectively.
- c Fusobacterium mortiferum (2); Fusobacterium necrogenes (3); Fusobacterium ulcerans (7).
- e Prevotella buccae (20); Prevotella oris (2).
- a method of treating or preventing a bacterial infection by anaerobic pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with anaerobic pathogenic bacteria.
- anaerobic pathogenic bacteria is selected from the group consisting of: Prevotella denticola/loeschii group, Veillonella spp., Prevotella heparinolytica, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas spp.
- Prevotella bivia Prevotella buccae-oris group, Porphyromonas canoris, Porphyromonas gingivalis, Porphyromonas macaccae, Peptostreptococcus micros, Peptostreptococcus prevotii, Porphyromonas asaccharolyticus, Fusobacterium varium, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Fusobacterium spp group 1 (Fusobacterium gonidiaformans, Fusobacterium naviforme, Fusobacterium necrophorum, Fusobacterium nucleatum, and Fusobacterium nucleatum ss animalis), Fusobacterium spp.
- Fusobacterium russii Clostridium difficile, Clostridium inocuum, Clostridium ramosum, Bacteroides ureolyticus, Bilophila wadsworthia, Clostridium clostridioforme, Anaerobiospirillum succiniciproducens, Bacteroides gracilis, Bacteroides tectum, Actinomyces odontolyticus, Actinomyces israelii, or Anaerobiospirillum thomasii.
- the present invention further provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against E.
- This aspect of the instant invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various pathogens.
- An objective of these analyses was to determine the in vitro activity of gemifloxacin (GFX) (SB-265805) to that of ciprofloxacin (CIP), trovafloxacin (TRX) and levofloxacin (LEV) against 782 recent clinical isolates.
- GFX inhibit 90% of Enterobacteriaceae at ⁇ 0.5 ⁇ g/ml (except Serratia spp., MIC 90 I ⁇ g/ml) and display similar activity to CIP, TRX and LEV.
- Pseudomonas aeruginosa is moderately susceptible to GFX (MIC 90 4 ⁇ g/ml ).
- GFX Against Streptococcus pneumoniae GFX (MIC 90 0.06 ⁇ g/ml) is 2-4-fold more active than TRX and 16-32-fold more active than CIP. GFX is the most active agent against quinolone-resistant 5. pneumoniae tested; of 16 strains resistant to CIP (MIC 4—8 ⁇ g/ml) all are susceptible to ⁇ 0.12 ⁇ g/ml of GFX. Four strains susceptible to >128 ⁇ g/ml CIP are susceptible to 0.5-2 ⁇ g/ml GFX. MSSA are equally susceptible to GFX and TRX (MIC 90 0.06 ⁇ g ml) but MRSA are less susceptible (GFX MIC 90 8 ⁇ g/ml).
- Haemophilus influenzae, Moraxella catarrhalis are susceptible to GFX (MIC 90 ⁇ 0.06 ⁇ g/ml). Enterococcus spp. are more susceptible to GFX than to other agents.
- GFX and TRX have high activity against Bacteroides fragilis (MIC 90 0.5 ⁇ g/ml) and peptostreptococci (MIC 90 0.25 ⁇ g/ml).
- a tentative breakpoint of 0.5 ⁇ g/ml was suggested following regression analysis of disk zone size plotted against MIC. A 1 ⁇ g disk is suggested and a zone diameter of >20 mm indicating susceptibility. The false sensitivity and resistance rates are 0% and 5.6% respectively.
- Gemifloxacin has been reported as having enhanced activity against Gram positive cocci (See Oh JI, Paek K-S, Ahn M-J et al. In vitro and in vivo evaluation of LB20304, a new fluoronaphthyridinone. Antimicrob Agents Chemother 1996; 40: 1564-1568; Comican MG, Jones RN. Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone. Antimicrob Agents Chemother 1997; 41: 204-211). In this study, the activity of gemifloxacin with commonly used antimicrobials against 782 recently isolated bacteria was compared. The techniques of the British Society for Antimicrobial
- BSAC Chemotherapy
- Gemifloxacin has been compared to ciprofloxacin, trovafloxacin, levofloxacin, nalidixic acid and amoxicillin/clavulanic acid. Susceptibilities were performed in accordance with the techniques of the BSAC Working Party (See Working Party of the British Society for Antimicrobial Chemotherapy. A guide to sensitivity testing. J Antimicrob Chemother 1991 ; 27 (Suppl D)).
- the final inoculum was approximately 10 4 CFU.
- the media was Unipath Iso-Sensitest agar (supplemented as required) or Wilkin-Chalgren agar. Incubation was performed in an appropriate atmosphere at 35°-37°C.
- gemifloxacin against Streptococcus pneumoniae gemifloxacin is 2-4-fold more active than trovafloxacin and 16- 32-fold more active than ciprofloxacin.
- a total of 10 strains of S. pneumoniae are resistant to ciprofloxacin (MIC 4-8 ⁇ g/ml); these are susceptible to 0.06-0.12 ⁇ g/ml of gemifloxacin.
- a total of 4 strains are highly ciprofloxacin resistant (MIC >128 ⁇ g/ml), these are susceptible to 0.5-2 ⁇ g/ml of gemifloxacin. Table 4.
- FIG. 5 shows the MICs and zone diameters for a 1 ⁇ g disk of gemifloxacin.
- the 2 and 5 ⁇ g disks gave zone diameters of 30-4-5 mm for susceptible isolates and would cause unacceptably large zones. Utilizing a zone diameter of 20 mm as breakpoint, the false resistance rate is 6% and a false susceptibility rate of around 1%.
- 8 were enterococci (MIC 0.12-0.5 ⁇ g/ml)
- 17 were Enterobacteriaceae with reduced susceptibility to ciprofloxacin
- 11 were Serratia, Acinetobacter and Stenotrophomonas spp with MICs close to the breakpoint.
- Figure 6 shows the scattergram of a 5 ⁇ g disk and P. aeruginosa. Tentative recommendations are shown in Table 5.
- While a preferred object of the invention provides a method wherein said pathogenic bacteria is selected from the group consisting of: E. coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, Proteus vulgaris, Morganella morganii, Serratia spp., Providencia stuartii, Salmonella spp., Stenotrophomonas maltophila, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus MSSA, Staphylococcus aureus MRSA, Staphylococcus epidermidis MSSE, Staphylococcus epidermidis MRSE, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus lancefleld Gp B, Streptococcus millerii
- Peptostreptococcus prevoti and Bacteroides fragilis.
- Other pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention still further provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against E. coli,
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various pathogens.
- An objective of these analyses was to determine the in vitro activity of gemifloxacin (GFX) to that of ciprofloxacin (CIP), trovafloxacin (TRX) and levofloxacin (LEV) against 782 recent clinical isolates.
- GFX inhibit 90% of Enterobacteriaceae at ⁇ 0.5 ⁇ g/ml (except Serratia spp., MIC 90 I ⁇ g/ml) and display similar activity to CTP, TRX and LEV.
- Pseudomonas aeruginosa is moderately susceptible to GFX (MIC 9 o 4 ⁇ g/ml ).
- GFX Against Streptococcus pneumoniae GFX (MlCgo 0.06 ⁇ g/ml) is 2-4-fold more active than TRX and 16-32-fold more active than CTP.
- GFX is the most active agent against quinolone-resistant S. pneumoniae tested; of 16 strains resistant to CIP (MIC 4-8 ⁇ g/ml) all are susceptible to ⁇ 0.12 ⁇ g/ml of GFX.
- MSSA are equally susceptible to GFX and TRX (MIC90 0.06 ⁇ g ml) but MRSA are less susceptible (GFX MIC 90 8 ⁇ g/ml).
- Haemophilus influenzae, Moraxella catarrhalis are susceptible to GFX (MIC 90 0.06 ⁇ g/ml). Enterococcus spp. are more susceptible to GFX than to other agents.
- GFX and TRX have high activity against Bacteroides fragilis (MIC 90 0.5 ⁇ g ml) and peptostreptococci (MIC 90 0.25 ⁇ g/ml).
- a tentative breakpoint of 0.5 ⁇ g/ml was suggested following regression analysis of disk zone size plotted against MIC. A 1 ⁇ g disk is suggested and a zone diameter of >20 mm indicating susceptibility. The false sensitivity and resistance rates are 0% and 5.6% respectively.
- Gemifloxacin has been compared to ciprofloxacin, trovafloxacin, levofloxacin, nalidixic acid and amoxicillin clavulanic acid. Susceptibilities were performed in accordance with the techniques of the BSAC Working Party (See Working Party of the British Society for Antimicrobial Chemotherapy. A guide to sensitivity testing. J Antimicrob Chemother 1991; 27 (Suppl D)). The final inoculum was approximately 10 4 CFU. The media was Unipath Iso- Sensitest agar (supplemented as required) or Wilkin-Chalgren agar. Incubation was performed in an appropriate atmosphere at 35°-37°C.
- Against Streptococcus pneumoniae gemifloxacin is 2-4-fold more active than trovafloxacin and 16- 32-fold more active than ciprofloxacin.
- a total of 4 strains are highly ciprofloxacin resistant (MIC >128 ⁇ g/ml), these are susceptible to 0.5-2 ⁇ g/ml of gemifloxacin.
- Certain other respiratory pathogens are extremely susceptible to gemifloxacin.
- Bacteroides fragilis are all susceptible to ⁇ 0.5 ⁇ g/ml of gemifloxacin.
- FIG. 1 shows the MICs and zone diameters for a 1 ⁇ g disk of gemifloxacin.
- the 2 and 5 ⁇ g disks gave zone diameters of 30-45 mm for susceptible isolates and would cause unacceptably large zones. Utilizing a zone diameter of 20 mm as breakpoint, the false resistance rate is 6% and a false susceptibility rate of around 1%.
- 8 were enterococci (MIC 0.12-0.5 ⁇ g/ml)
- 17 were Enterobacteriaceae with reduced susceptibility to ciprofloxacin
- 11 were Serratia, Acinetobacter and Stenotrophomonas spp with MICs close to the breakpoint.
- Figure 2 shows the scattergram of a 5 ⁇ g disk and P. aeruginosa. Tentative recommendations are shown in Table 7.
- a prefe ⁇ ed object of the invention provides a method wherein said pathogenic bacteria is selected from the group consisting of: E. coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, Proteus vulgaris, Morganella morganii, Serratia spp., Providencia stuartii, Salmonella spp., Stenotrophomonas maltophila, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus MSSA, Staphylococcus aureus MRSA, Staphylococcus epidermidis MSSE, Staphylococcus epidermidis MRSE, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus lancefleld Gp B, Streptoc
- Peptostreptococcus prevoti and Bacteroides fragilis.
- Other pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against pneumococcal bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various pneumococci pathogens.
- An objective of these analyses was to determine the activities of gemifloxacin (SB-265805), ciprofloxacin, levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, amoxicillin, cefuroxime, azithromycin and clarithromycin against 4 penicillin-susceptible, 4 -intermediate and 4 -resistant (including 2 ciprofloxacin-resistant) pneumococci by time-kill. .
- Broth MICs are: gemifloxacin: 0.016-0.5; ciprofloxacin: 0.5-32; levofloxacin: 1-32, sparfloxacin: 0.125-32; grepafloxacin: 0.06-16; trovafloxacin: 0.06-8; amoxicillin: 0.016-2; cefuroxime: 0.016-4; azithromycin: 0.008->64; clarithromycin: 0.008-64. Results are shown below at MIC/2 x MIC (number of strains with -1, -2, -3 log 10 decrease in count compared to 0 hours):
- Clarithromycin 3/3 1/2 0/0 5/5 0/2 1/2 5/5 5/5 2/4 7/7 7/7 5/7
- Gemifloxacin has the lowest MICs and, at twice the MIC, is uniformly bactericidal, irrespective of penicillin or ciprofloxacin MICs. Gemifloxacin is the only quinolone active against ciprofloxacin-resistant strains at achievable MICs. Other quinolones and ⁇ -lactams had similar kinetics relative to MIC and macrolides show slower kinetics.
- the problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread from country to country, and from continent to continent (See, Munoz R, Musser JM, Crain M, et al. Geographic distribution of penicillin-resistant clones of Streptococcus pneumoniae: characterization by penicillin-binding protein profile, surface protein A typing, and multilocus enzyme analysis. Clin Infect Dis 1992; 15: 112-118).
- a further study examined the anti-pneumococcal activity of gemifloxacin compared to ciprofloxacin, levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, amoxicillin, cefuroxime, azithromycin and clarithromycin by time-kill testing of 12 pneumococcal strains of varying quinolone and penicillin susceptibilities.
- time-kill studies 4 penicillin- susceptible, 4 -intermediate and 4 -resistant strains (2 quinolone resistant, obtained courtesy of David Felmingham from the Alexander Project collection) are tested.
- Gemifloxacin susceptibility powder was obtained from SmithKline Beecham Laboratories, Harlow, UK; other antimicrobials are obtained from their respective manufacturers. Broth MICs for 12 strains tested by time-kill and 6 tested by PAE have been performed according to NCCLS recommendations using cation-adjusted Mueller-Hinton broth with 5% lysed defibrinated horse blood (See, National Committee for Clinical Laboratory Standards. In: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically (3 rd edition; approved standard. NCCLS publication no. M7-A4) National Committee for Clinical Laboratory Standards :Villanova, PA, 1997).
- Standard quality control strains including Streptococcus pneumoniae ATCC 49619, were included in each run of agar and broth dilution MICs.
- glass tubes containing 5 ml cation-adjusted Mueller-Hinton broth (Difco) + 5% lysed horse blood with doubling antimicrobial concentrations are inoculated with 5 x 10 5 to 5 x 10 6 CFU/ml and incubated at 35°C in a shaking water bath.
- Antimicrobial concentrations were chosen to comprise 3 doubling dilutions above and 3 dilutions below the agar dilution MIC.
- Lysed horse blood was prepared as described previously.(See, Pankuch , Jacobs et al and Pankuch, Lichtenberger et al, supra).
- the bacterial inoculum was prepared by suspending growth from an overnight blood agar plate in Mueller-Hinton broth until turbidity matched a no. 1 McFarland standard. Dilutions required to obtain the co ⁇ ect inoculum (5 x 10 5 -5 x 10 6 CFU/ml) were determined by prior viability studies using each strain.(See See Pankuch , Jacobs et al and Pankuch, Lichtenberger et al, supra).
- Viability counts of antimicrobial-containing suspensions were performed by plating 10-fold dilutions of 0.1 ml aliquots from each tube in sterile Mueller-Hinton broth onto trypticase soy agar 5% sheep blood agar plates (BBL). Recovery plates were incubated for up to 72 hours. Colony counts were performed on plates yielding 30-300 colonies. The lower limit of sensitivity of colony counts was 300 CFU/ml.(See See Pankuch , Jacobs et al and Pankuch, Lichtenberger et al, supra).
- Time-kill assays were analyzed by determining the number of strains which yielded a ⁇ logio CFU/ml of -1, -2 and -3 at 0, 3, 6, 12 and 24 hours, compared to counts at time 0 hours.
- Antimicrobial agents are considered bactericidal at the lowest concentration that reduced the original inoculum by >3 logio CFU/ml (99.9%) at each of the time periods, and bacteriostatic if the inoculum is reduced by 0- ⁇ 3 log 10 CFU/ml. With the sensitivity threshold and inocula used in these studies, no problems are encountered in delineating 99.9% killing, when present.
- Microbroth dilution MIC results of the 12 strains tested by time-kill are presented in Table 8. Microdilution MICs are all within one dilution of agar MICs. For the two quinolone resistant strains (both penicillin susceptible), gemifloxacin microbroth MICs are 0.5 and 0.25 ⁇ g/ml, respectively. Time-kill results (Table 9) show that levofloxacin at the MIC, gemifloxacin and sparfloxacin at 2 x MIC and ciprofloxacin, grepafloxacin and trovafloxacin at 4 x MIC, are bactericidal after 24 hours. Various degrees of 90% and 99% killing by all quinolones is detected after 3 hours.
- Gemifloxacin and trovafloxacin are both bactericidal at 2 x MIC for the two quinolone resistant pneumococcal strains.
- Gemifloxacin is uniformly bactericidal after 24 hours at ⁇ 0.5 ⁇ g/ml. Amoxicillin, at 2 x MIC and cefuroxime at 4 x MIC, are bactericidal after 24 hours, with some degree of killing at earlier time periods. By contrast, macrolides gave slower killing against the 7 susceptible strains tested, with 99.9% killing of all strains at 2-4 x MIC after 24 hours.
- Time-kill kinetics of gemifloxacin against a penicillin-resistant pneumococcal strain is depicted graphically in Figure 7.
- gemifloxacin is also highly active against most members of the family
- Gemifloxacin is the most active agent against Gram positive species resistant to other quinolones and glycopeptides. Gemifloxacin has variable activity against anaerobes, and is very active against the Gram positive group (See, Cormican MG, Jones RN. Antimicrobial activity and spectrum of LB 20304, a novel fluoronaphthyridone. Antimicrob Agents Chemother 1997; 41: 204; Hohl AF, Frei R, Punter V, et al. International multicenter investigation of LB 20304, a new fluoronaphthyridone.
- Gemifloxacin gives the lowest quinolone MICs against all pneumococcal strains tested followed by trovafloxacin, grepafloxacin, sparfloxacin, levofloxacin and ciprofloxacin. MICs are similar to those described previously (See, Pankuch GA, Jacobs MR, Appelbaum PC. Activity of CP 99,219 compared to DU-6859a, ciprofloxacin, ofloxacin, levofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and grepafloxacin against penicillin-susceptible and -resistant pneumococci.
- Killing rates relative to MICs are similar to those of other quinolones, with significant killing occurring earlier than with ⁇ -lactams and macrolides (See, Pankuch GA, Jacobs MR, Appelbaum PC supra; Pankuch GA, Jacobs MR, Appelbaum PC. Comparative activity of ampicillin, amoxycillin, amoxycillin/clavulanate and cefotaxime against 189 penicillin- susceptible and -resistant pneumococci. J Antimicrob Chemother 1995; 35: 883-888.; Visalli MA, Jacobs MR, Appelbaum PC.
- gemifloxacin is the most potent quinolone tested by MIC and time- kill against both quinolone-susceptible and -resistant pneumococci. While the incidence of quinolone-resistant pneumococci is cu ⁇ ently very low, the introduction of broad-spectrum quinolones into clinical practice, particularly in the pediatric population, can lead to the selection of quinolone- resistant strains. Quinolones such as gemifloxacin may be used in the pediatric environment using appropriate doses determined by a physician.
- gemifloxacin can be employed as a theraputic option.
- Gemifloxacin is a promising new anti-pneumococcal agent, i ⁇ espective of the strains' susceptibility to quinolones and other agents.
- Antimicrobial agent l (S) a 2 (S) 3 (S) b 4 (S) b 5 (1) 6 (1) 7 (1) 8 (1) 9 (R) 10 (1) 11 ( ) 12 (R)
- Penicillin G 0.06 0.03 0.016 0.016 0.25 0.25 1 0.5 4 2 4 4
- Ciprofloxacin 1 0.5 32 32 2 1 4 0.5 1 1 2 1
- Levofloxacin 2 1 32 32 1 2 1 1 2 2 1 2
- Also provided by the invention is a method of treating or preventing a bacterial infection by pneumococcal pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with pneumococcal pathogenic bacteria.
- pneumococcal pathogenic bacteria is selected from the group consisting of: penicillin- susceptible, intermediate and resistant (including ciprofloxacin-resistant) pneumococci.
- Other pneumococcal pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against maxillary sinus.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various bacterial pathogens.
- An objective of these analyses was to determine the efficacy of the novel fluoroquinolone, gemifloxacin, (SB-265805) compared with that of ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, grepafloxacin, moxifloxacin, sparfloxacin, amoxicillin and amoxicillin/clavulanic acid against a total of more than 250 strains isolated from recently acute or chronic maxillary sinusitis.
- the MICs were determined by agar dilution technique.
- gemifloxacin MIC 90 0.06 ⁇ g/ml
- the activity of gemifloxacin is superior to that of ciprofloxacin, ofloxacin, levofloxacin, grepafloxacin, moxifloxacin and sparfloxacin (MIC 90 >0.25 ⁇ g/ml) against the Streptococcus pneumoniae isolates.
- gemifloxacin and grepafloxacin MIC 90 ⁇ 0.02 ⁇ g/ml are the most active antimicrobial agents tested.
- gemifloxacin, trovafloxacin and moxifloxacin are more effective (MIC 90 0.06 ⁇ g/ml) than ciprofloxacin, amoxicillin and amoxicillin/clavulanic acid (MIC 90 >1 ⁇ g/ml).
- MIC 90 0.25 ⁇ g/ml was observed with gemifloxacin and moxifloxacin against anaerobic strains tested.
- gemifloxacin The activity of gemifloxacin is similar to that of ofloxacin, trovafloxacin, moxifloxacin and sparfloxacin (MIC 90 0.5 ⁇ g/ml) against various other strains, such as some Enterobacteriaceae or non-fermentative Gram negative bacilli. Combined with favorable pharmacokinetics in humans, gemifloxacin can be a valuable oral compound for the treatment of acute or chronic sinusitis caused by isolates resistant to usual oral therapies.
- gemifloxacin works by inhibiting the normal function of the A subunit of DNA gyrase, a bacterial DNA topoisomerase. In susceptibility studies, gemifloxacin is appreciably more potent than most fluoroquinolones against many Gram positive organisms, including Streptococcus pneumoniae, Streptococcus pyogenes and methicillin-resistant Staphylococcus spp. Gemifloxacin retains activity against a range of resistant Gram negative bacilli. It has potent activity against various anaerobic and atypical respiratory pathogens like Legionella pneumophila, Mycoplasma spp. and Chlamydia spp.
- the objective of a study described herein was to determine the MIC of gemifloxacin, ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, grepafloxacin, moxifloxacin, sparfloxacin, amoxicillin and amoxicillin/clavulanic acid against a variety of strains such as Haemophilus spp., S. pneumoniae and Moraxella catarrhalis, isolated recently from acute or chronic maxillary sinus infections.
- Antibiotic was dissolved in water or co ⁇ esponding dissolution solutions for the preparation of stock solutions.
- Antimicrobial stock solutions were prepared at concentrations of 1000 ⁇ g/ml or ten times the highest concentration tested whichever was greater. Small volumes of the sterile stock solutions were dispensed in sterile polypropylene vials, sealed carefully and were stored at -20°C or below -60°C Vials were removed as needed and were used the same day. Any unused drug was discarded .
- M-H Mueller-Hinton agar was used for routine susceptibility testing of aerobic and facultative anaerobic bacteria. M-H agar was supplemented with 5% defibrinated sheep blood for testing those organisms that do not grow on the unsupplemented medium.
- the medium used for testing Haemophilus was Haemophilus Test Medium (HTM).
- the medium used for testing anaerobes is Wilkins-Chalgren agar.
- Mueller-Hinton agar, HTM or Wilkins-Chalgren agar were prepared from dehydrated base according to the manufacturer's recommendations. After it was autoclaved, the agar was allowed to cool to 48-50°C in a water bath before addition of antimicrobial solutions. The pH of each batch of agar was checked after autoclaving. The pH of the medium was 6.9-6.95 at 25°C. The measurement is done with a standard combination pH electrode or with a surface electrode.
- agar and antimicrobial solution were added to M-H agar, HTM or Wilkins-Chalgren which were allowed to equilibrate to 48-50°C in a water bath.
- the agar and antimicrobial solution was mixed thoroughly and poured into petri dishes on a level surface.
- the petri were poured as quickly as possible after the mixing to prevent cooling and partial solidification in the container.
- the agar depth was between 3 and 4 mm.
- the agar was allowed to solidify at room temperature.
- the plates were used immediately or were stored in plastic freezer bags at 4°C for up to 4 weeks. Following storage, the plates were allowed to equilibrate to room temperature before use. The surface was dried before inoculation.
- the standardized inoculum was prepared by inoculating 4-5 colonies of a single type into a tube containing 5.0 ml of M-H broth. This bacterial suspension was incubated at 35°C until it was visibly turbid. The density of this inoculum was adjusted to a turbidity of 0.5 McFarland standard by addition of M-H broth. The adjusted suspension was diluted 1 : 10 in sterile sodium chloride solution to obtain the desired inoculum concentration of 10 7 CFU/ml. With the replicating device, the final inoculum on the agar contained 10 4 CFU in an area of 5- 8 mm.
- the surface of the agar was dried before inoculation.
- the plates were placed in an incubator with the lids open.
- the tubes containing the adjusted and diluted bacterial suspensions (10 7 CFU/ml) were a ⁇ anged in order in a rack.
- An aliquot of each suspension was placed into the co ⁇ esponding well in the replicator block.
- the inocula was applied to the agar surface with inocula replicating device.
- a control plate first and a second plate last were inoculated to insure that no contamination or antimicrobial carryover occu ⁇ ed during the inoculating process.
- the inoculated plate was left at room temperature until the moisture in the inoculum was absorbed into agar.
- the plates were inverted and were incubated at 35°C for 24 hours in aerobic atmosphere for aerobes or facultative anaerobes, in atmosphere containing 5-7% C0 2 for Haemophilus and in anaerobic atmospheres for anaerobes .
- the susceptibility results are presented in Tables 11-14.
- the susceptibility of Gram positive cocci to gemifloxacin compared with those of oral compounds is shown in Table 11.
- gemifloxacin against Gram positive cocci is significantly superior (p ⁇ 0.05) to some common oral compounds tested such as levofloxacin, ofloxacin, amoxicillin or amoxicillin/ clavulanic acid.
- Gemifloxacin inhibits 90% of Gram positive cocci at a concentration of 0.06 ⁇ g/ml.
- the activity of gemifloxacin (MIC 90 0.06 ⁇ g/ml) is similar to trovafloxacin, but it is superior to ciprofloxacin, ofloxacin, levofloxacin, and sparfloxacin (MIC 90 >0.5 ⁇ g/ml).
- S. pneumoniae the activity of gemifloxacin (MIC 90 0.06 ⁇ g/ml) is similar to trovafloxacin, but it is superior to ciprofloxacin, ofloxacin, levofloxacin, and sparfloxacin (MIC 90 >0.5 ⁇ g/ml).
- aureus sinus pathogens gemifloxacin, moxifloxacin, trovafloxacin (MIC 90 0.06 ⁇ g/ml) and sparfloxacin (MIC ⁇ 0.12 ⁇ g/ml) are the most active compounds tested.
- the activity of gemifloxacin is more important than the activity of ciprofloxacin, amoxicillin (MIC 90 I ⁇ g/ml) and amoxicillin/clavulanic acid (MlCcr ⁇ 2 ⁇ g/ml) against S. aureus.
- Table 12 shows the susceptibility of Haemophilus spp. to gemifloxacin.
- the strains of H. influenzae are susceptible to gemifloxacin at a MlCgo of ⁇ 0.02 ⁇ g/ml. This activity is significantly superior to ofloxacin, moxifloxacin, sparfloxacin, amoxicillin and amoxicillin/clavulanic acid.
- gemifloxacin MIC 90 0.12 ⁇ g/ml is still superior to ofloxacin (MIC 90 0.5 ⁇ g/ml), moxifloxacin (MIC 90 0.5 ⁇ g/ml), sparfloxacin (MIC 90 1 ⁇ g/ml), amoxicillin (MIC 90 1 ⁇ g/ml) and amoxicillin/clavulanic acid (MIC 90 0.5 ⁇ g/ml).
- Table 13 shows the susceptibility of strains of M. catarrhalis to gemifloxacin.
- gemifloxacin and grepafloxacin are the most active compounds tested.
- the activity of gemifloxacin is significantly superior to sparfloxacin, amoxicillin/clavulanic acid (MIC 90 0.5 ⁇ g/ml) and amoxicillin 8 ⁇ g/ml).
- the susceptibility of various strains isolated from maxillary sinus is shown in Table
- gemifloxacin MIC ⁇ 0.25 ⁇ g/ml
- moxifloxacin MIC 90 0.25 ⁇ g/ml
- gemifloxacin is as active as ofloxacin
- trovafloxacin MIC ⁇ 4 ⁇ g/ml
- grepafloxacin MIC 90 8 ⁇ g/ml
- sparfloxacin MIC 90 16 ⁇ g/ml
- gemifloxacin is as active as ofloxacin, trovafloxacin, moxifloxacin and sparfloxacin (MIC 90 0.5 ⁇ g/ml).
- Gemifloxacin shows a broad spectrum of antimicrobial activity against most strains isolated from acute or chronic maxillary sinusitis. Moreover, gemifloxacin appears to have a better and constant activity than most beta-lactams such as amoxicillin and amoxicillin/clavulanic acid against many maxillary sinus isolates such as S. aureus, Haemophilus spp., M. catarrhalis and anaerobic strains. The overall in vitro activity of gemifloxacin is significantly greater than ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin against strains of S. pneumoniae.
- gemifloxacin Another attractive attribute of gemifloxacin is that the drug has significant activity against Haemophilus spp., M. catarrhalis, some anaerobic strains and other various strains tested such as non-fermentative Gram negative bacilli, Neisseria meningitidis and beta-hemolytic Streptococcus.
- Gemifloxacin, ciprofloxacin, grepafloxacin and trovafloxacin were the most active agents tested against Haemophilus spp. and Moraxella sinus isolates. This particular activity is markedly important against beta-lactamase producing strains of H. influenzae and also in patients who are allergic to penicillins.
- gemifloxacin could be a valuable oral compound for the treatment of acute or chronic sinusitis caused by microrganisms resistant to usual oral therapy.
- Antimicrobial agent MIC ( ⁇ g/ml) and isolate (number tested)
- Streptococcus pneumoniae (85) Staphylococcus aureus (31 )
- Range MIC 50 MIC 90 Range MIC 50 MIC 90
- Trovafloxacin ⁇ 0.02-0.12 0.06 0.12 ⁇ 0.02-0.06 0.03 0.03
- Levofloxacin 0.12-2 1 1 0.12-0.5 0.25 0.25
- Antimicrobial agent MIC ( ⁇ g/ml) and isolate (No. tested)
- Haemophilus influenzae 45
- Haemophilus parainfluenzae 10
- Range MIC 50 MIC 90 Range MIC 50 MIC 90
- Trovafloxacin ⁇ 0.02-0.06 ⁇ 0.02 0.03 ⁇ 0.02-0.12 0.03 0.12
- Grepafloxacin ⁇ 0.02-0.03 ⁇ 0.02 ⁇ 0.02 ⁇ 0.02-0.12 0.06 0.12
- Ciprofloxacin ⁇ 0.02 ⁇ 0.02 ⁇ 0.02 ⁇ 0.02 ⁇ 0.02-0.06 0.03 0.06
- Also provided by the invention is a method of treating or preventing a bacterial infection by maxillary sinus pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with maxillary sinus pathogenic bacteria.
- a preferred object of the invention provides a method wherein said maxillary sinus pathogenic bacteria is selected from the group consisting of: Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, Peptostreptococcus spp., Bacteroides ureolyticus, Enterobacteriaceae, non-fermentative Gram negative bacilli, Neisseria meningitidis, Bacteroides spp., beta-hemolytic Streptococcus and Gram negative rods.
- Other maxillary sinus pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various Gram negative, non-fermenting bacterial pathogens, especially especially Pseudomonas. Aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia.
- Gemifloxacin is highly potent activity against a wide range of Gram negative and Gram positive bacteria.
- An aspect of the invention is based, in part, on a further analysis examined the susceptibility of clinically relevant, non-fermentative, Gram negative bacilli to gemifloxacin in comparison with other fluoroquinolones, gentamicin and co-trimoxazole.
- Table 15 shows the in vitro antibacterial activities of gemifloxacin and other antimicrobials against Gram negative, non-fermentative bacteria.
- Tables 16 and 17 present the MIC distributions of gemifloxacin and ciprofloxacin, respectively. MIC distributions of gemifloxacin, ciprofloxacin, levofloxacin and trovafloxacin against P. aeruginosa, Acinetobacter spp. and S. maltophilia are illustrated in Figures 8 and 9, respectively. Gemifloxacin and ciprofloxacin are more active than trovafloxacin and levofloxacin against P. aeruginosa.
- Acinetobacter isolates are most susceptible to trovafloxacin and gemifloxacin, and 80% or more of the strains are inhibited by 1 ⁇ g/ml of all fluoroquinolones tested.
- Gemifloxacin and trovafloxacin are the most active compounds tested against 5. maltophilia.
- Ciprofloxacin was the least active agent, although more than 50% of 5.
- maltophilia strains had MICs of >2 ⁇ g/ml. All the quinolones tested demonstrate poor activity against B. cepacia.
- Microrganism MIC ( ⁇ g/ml)
- Microrganism MIC ( ⁇ g/ml)
- Microrganism % of isolates inhibited at MIC ( ⁇ g/ml)
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram negative, non-fermenting pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with Gram negative, non-fermenting pathogenic bacteria.
- Gram negative, non-fermenting pathogenic bacteria is selected from the group consisting of: Pseudomonas. Aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia and Burkholderia cepacia bacteria.
- Other Gram negative, non-fermenting pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against Chlamydia pneumoniae or respiratory tract bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various Chlamydia pneumoniae or respiratory tract pathogens.
- An objective of these analyses was to determine the in vitro activity of gemifloxacin as compared with that of levofloxacin, moxifloxacin, trovafloxacin, erythromycin and doxycycline against 20 isolates of C. pneumoniae, including recent clinical isolates.
- Gemifloxacin has potent activity against respiratory tract pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Legionella spp.
- the activity of gemifloxacin, levofloxacin, moxifloxacin, trovafloxacin, erythromycin and doxycycline was compared against 20 isolates of Chlamydia pneumoniae, including the prototype strain TW183, four other laboratory strains from the US and Japan plus 15 recent US clinical isolates from adults with community- acquired pneumonia. Testing was carried out in cycloheximide-treated HEp-2 cells. The results are summarized in Table 18.
- Gemifloxacin is the most active quinolone against C. pneumoniae, but is less active than erythromycin and doxycycline.
- the potent, broad- spectrum activity of gemifloxacin indicates that it has a role in the treatment of respiratory tract infections, including those caused by C. pneumoniae.
- Chlamydia pneumoniae is a frequent cause of community-acquired respiratory tract infection (RTI), including pneumonia and bronchitis in adults and children.
- RTI community-acquired respiratory tract infection
- Quinolones have attracted interest as potential therapy for community-acquired RTI because they are active against a wide range of pathogens responsible for these infections, such as Mycoplasma pneumoniae, Streptococcus pneumoniae (including penicillin-resistant strains) and C. pneumoniae.
- C. pneumoniae isolates tested were: TW-183 (Washington Research Foundation, Seattle, WA, USA), CM-1 (ATCC 1360), J21 (from Japan, ATCC VR1435), W6805, T2219 and 15 recent clinical isolates from adults enrolled in a multicenter community- acquired pneumonia treatment study.
- Tests were performed in HEp-2 cells grown in 96-well microtiter plates. Each well was inoculated with 0.1 ml of the test strain diluted to yield 10 3 — 10 4 inclusion-forming units (IFU) per ml, centrifuged at 1700 x g for 1 h and incubated at 35°C for 1 h. Wells were then aspirated and overlaid with 0.2 ml of medium containing 1 ⁇ g of cycloheximide per ml and serial twofold dilutions of the test drug.
- IFU inclusion-forming units
- MBC minimal bactericidal concentration
- gemifloxacin is the most active quinolone.
- the MICs obtained for gemifloxacin against C. pneumoniae are consistent from strain to strain. Data on the activity of gemifloxacin against C. pneumoniae are limited, in part due to the relatively small number of clinical isolates available for testing.
- a MIC range of 0.06-0.12 ⁇ g/ml was obtained.
- An aspect of the invention provides a method for modulating metabolism of Chlamydia pneumoniae or respiratory tract pathogenic bacteria.
- Skilled artisans can readily choose Chlamydia pneumoniae or respiratory tract pathogenic pathogenic bacteria or patients infected with or suspected to be infected with these organisms to practice the methods 0 of the invention.
- the bacteria useful in the methods of the invention may be those described herein.
- a quinolone, particularly a gemifloxacin compound or composition of the invention may be administered by injection to achieve a systemic effect against relevant bacteria, preferably a Chlamydia pneumoniae or respiratory tract pathogenic bacteria, shortly before insertion of an in-dwelling device. Treatment may be continued after surgery during the in- body time of the device.
- the composition could also be used to broaden perioperative cover for any surgical technique to prevent bacterial wound infections caused by or related to Chlamydia pneumoniae or respiratory tract pathogenic bacteria.
- a gemifloxacin compound or composition used in the methods of this invention may be used generally as a wound treatment agent to prevent adhesion of bacteria to matrix proteins, particularly Chlamydia pneumoniae or respiratory tract pathogenic bacteria, exposed in wound tissue and for prophylactic use in dental treatment as an alternative to, or in conjunction with, antibiotic prophylaxis.
- a quinolone, particularly a gemifloxacin compound or composition of the invention may be used to bathe an indwelling device immediately before insertion.
- the active agent will preferably be present at a concentration of 1 ⁇ g/ml to lOmg/ml for bathing of wounds or indwelling devices.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Chlamydia pneumoniae or respiratory tract pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with Chlamydia pneumoniae or respiratory tract pathogenic bacteria. While a prefe ⁇ ed object of the invention provides a method wherein said
- Chlamydia pneumoniae or respiratory tract pathogenic bacteria is selected from the group consisting of: Chlamydia pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Legionella spp.
- Other Chlamydia pneumoniae or respiratory tract pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against respiratory tract bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various respiratory tract pathogens. An objective of these analyses was to determine the effect of gemifloxacin against ciprofloxacin-resistant (cip r ) strains of Streptococcus pneumoniae and Haemophilus influenzae.
- Gemifloxacin was compared to amoxycillin/clavulanate, ciprofloxacin, cefuroxime, grepafloxacin, levofloxacin, azithromycin, trovafloxacin or tosufloxacin.
- Gemifloxacin a fluoroquinolone agent with a broad spectrum of antibacterial activity, has excellent in vivo efficacy against ciprofloxacin-susceptible (cip s ) strains of Streptococcus pneumoniae and Haemophilus influenzae.
- Animals were infected via intrabronchial instillation to produce pneumonia and oral therapy was initiated at 1 h or 24 h with amoxycillin/clavulanate, ciprofloxacin, cefuroxime, grepafloxacin, levofloxacin, azithromycin, trovafloxacin or tosufloxacin.
- the doses were chosen to approximate, in the rat serum or tissue, concentrations measured in man following therapeutic dosing. Therapy continued o.d. or b.i.d. for 3 days, and at 96 h post-infection the lungs were excised for the recovery and enumeration of viable bacterial numbers.
- RTI Respiratory tract infections
- Streptococcus pneumoniae is an important pathogen in upper and lower RTI.
- ⁇ -Lactam and macrolide antimicrobials have been the treatment of choice for RTI, but recently new quinolones have become available for clinical and or investigational use.
- These agents have a broad spectrum of antibacterial activity, including against penicillin-resistant S. pneumoniae. However, their use may be limited by the increasing incidence of resistance against them found in strains of S. pneumoniae.
- Gemifloxacin is a fluoroquinolone antimicrobial currently under development for the treatment of community-acquired infections and has excellent in vivo efficacy against ciprofloxacin-sensitive strains of S. pneumoniae and H. influenzae.
- the studies described here demonstrate the efficacy of gemifloxacin mesylate in comparison with ciprofloxacin, grepafloxacin, levofloxacin, trovafloxacin, amoxycillin/clavulanate, cefuroxime and azithromycin against experimental RTI in rats caused by ciprofloxacin-resistant S. pneumoniae and H. influenzae.
- Bacterial inocula for S. pneumoniae were prepared by harvesting growth from blood agar plates and suspending it in phosphate-buffered saline (PBS). H. influenzae was grown as an overnight culture in Mueller-Hinton broth with the addition of 5% Fildes extract. Tenfold dilutions of each organism were prepared into cooled (41 °C) molten nutrient agar. Animals were anesthetized and infected by intrabronchial instillation of a 50 ⁇ l inoculum for S. pneumoniae (6.0-6.7 logio CFU) and 100 ⁇ l for H. influenzae (5.2 logio CFU) via intratracheal intubation (Smith, et al., Antimicrob.
- PBS phosphate-buffered saline
- gemifloxacin produces a response and reduces bacterial counts significantly compared with untreated animals (2.4 ⁇ 1.1 and 6.4 ⁇ 1.3 logio CFU/lungs; p - ⁇ 0.01).
- Gemifloxacin affords protection against ciprofloxacin-resistant strains of S. pneumoniae and H. influenzae, and bacterial numbers are reduced significantly compared with those in untreated animals. Overall, gemifloxacin demonstrates a superior effect compared with comparator quinolones against ciprofloxacin-resistant S. pneumoniae strains. Against ciprofloxacin-resistant strains of H. influenzae gemifloxacin has equivalent efficacy to amoxycillin/clavulanate, azithromycin, cefuroxime and levofloxacin, whereas ciprofloxacin, grepafloxacin, trovafloxacin and tosufloxacin are ineffective. The data presented here indicate a high benefit for the use of gemifloxacin in the treatment of RTI caused by ciprofloxacin-resistant strains of S. pneumoniae and H. influenzae.
- Microrganism MIC ( ⁇ g/ml)
- Ciprofloxacin b.i.d. 200 13.8 750 14.9 2
- Also provided by the invention is a method of treating or preventing a bacterial infection by respiratory tract pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with respiratory tract pathogenic bacteria.
- respiratory tract pathogenic bacteria is selected from the group consisting of: Streptococcus pneumoniae and Haemophilus influenzae.
- Other respiratory tract pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against bacterial meningitis bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various bacterial meningitis pathogens. An objective of these analyses was to determine the efficacy of gemifloxacin in comparison with vancomycin, cefotaxime, cefuroxime, ciprofloxacin, levofloxacin and trovafloxacin against infant rat meningitis caused by S. pneumoniae 1629..
- Gemifloxacin 100 mg/kg is highly effective against S.
- Gemifloxacin is a broad-spectrum fluoroquinolone with excellent potency in vitro against strains of S. pneumoniae.
- the studies described here demonstrate the efficacy of gemifloxacin mesylate in comparison with vancomycin, cefotaxime, cefuroxime, ciprofloxacin, levofloxacin and trovafloxacin against infant rat meningitis caused by S. pneumoniae 1629.
- the in vivo activity of gemifloxacin was evaluated in an experimental meningitis model in infant rats caused by Streptococcus pneumoniae .
- Cerebral spinal fluid was obtained from the rats 15 h after infection by puncture of the cisterna magna for confirmation of meningitis.
- Therapy 50 and/or 100 mg/kg i.p.
- gemifloxacin vancomycin
- cefotaxime cefuroxime
- ciprofloxacin levofloxacin
- trovafloxacin trovafloxacin or ceftriaxone.
- Treatment continued o.d. or b.i.d. for a further 3 days and survival was monitored for up to 7 days post-infection.
- Meningitis was established based on a method described previously. (Delaplane, et al, J. Antimicrob. Chemother., 11 : 69-73 (1983)). Briefly, S. pneumoniae 1629 (20-80 CFU/rat) was injected i.p. into 5-day-old rats. At 15 h after infection, a sample was taken from the cerebrospinal fluid (CSF) of each rat to determine meningitic status. Therapy was initiated immediately after the 15 h sample and was continued o.d. or b.i.d for 3 days.
- CSF cerebrospinal fluid
- the survival rates for rats administered gemifloxacin compares favorably with those obtained with the competitor quinolones tested.
- Gemifloxacin is as effective as the cephalosporin antimicrobials cefuroxime and cefotaxime against S. pneumoniae meningitis.
- No comparator agent at co ⁇ esponding doses was shown to result in significantly greater protection against S. pneumoniae meningitis in infant rats than gemifloxacin.
- the efficacy demonstrated in these studies with S. pneumoniae indicates a benefit for the use of gemifloxacin in the treatment of bacterial meningitis.
- the invention provides a method for modulating metabolism of bacterial meningitis pathogenic bacteria.
- Skilled artisans can readily choose bacterial meningitis pathogenic bacteria or patients infected with or suspected to be infected with these organisms to practice the methods of the invention.
- the bacteria useful in the methods of the invention can be those described herein. Table 21. MICs of the Test Antimicrobials to S. pneumoniae 1629
- Also provided by the invention is a method of treating or preventing a bacterial infection by bacterial meningitis pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with bacterial meningitis pathogenic bacteria.
- bacterial meningitis pathogenic bacteria is Streptococcus pneumoniae.
- Other bacterial meningitis pathogenic bacteria can also be included in the methods. The skilled artisan can identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against Gram negative bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various Gram negative pathogens. An objective of these analyses was to determine the MIC of the fluoroquinolone gemifloxacin against a panel of 895 recent clinical isolates consisting of both Enterobacteriaceae and non-Enterobacteriaceae.
- Gemifloxacin was compared to trovafloxacin, grepafloxacin, levofloxacin, ciprofloxacin, ofloxacin, nalidixic acid, gentamicin, cefuroxime, amoxycillin/clavulanate, penicillin, ampicillin, clarithromycin, azithromycin and trimethoprim/sulfamethoxazole. Isolates were collected in hospital laboratories from three geographically distributed regions in the US.
- MICs for gemifloxacin and comparator compounds consisting of six quinolones, four ⁇ -lactams, two macrolides, one aminoglycoside and trimethoprim/sulfamethoxazole were determined by broth microdilution using NCCLS recommended procedures. With the exception of gentamicin, the quinolones were consistently more active than the other compounds tested.
- the antibacterial activity of gemifloxacin was equal to that of levofloxacin and ciprofloxacin, and generally better than that of ofloxacin, grepafloxacin, trovafloxacin and naladixic acid.
- MIC 90 s ( ⁇ g/ml) obtained for gemifloxacin were: Escherichia coli, 0.016; Klebsiella pneumoniae, 0.25; Enterobacter aerogenes, 0.25; Enterobacter cloacae, 1; Pseudomonas aeruginosa, 8; Morganella morganii, 0.12; Proteus spp., 4; Stenotrophomonas maltophilia, 4; Klebsiella oxytoca, 0.25; Citrobacter freundii, 2; Acinetobacter sp., 32; and Serratia spp., 1.
- the antibacterial activities of the following 14 comparator compounds were also determined: trovafloxacin, grepafloxacin, levofloxacin, ciprofloxacin, ofloxacin, nalidixic acid, gentamicin, cefuroxime, amoxycillin/clavulanate, penicillin, ampicillin, clarithromycin, azithromycin and trimethoprim/sulfamethoxazole.
- Microtiter susceptibility plates were obtained from Sensititre (AccuMed International Ltd, Westlake, OH, USA; lot # CMP5ASMK-8342, -8423, -8331 and CMP4BSMK-8334A, -8451, -8351).
- Plates contained the following compounds in serial twofold doubling dilutions (concentration range, ⁇ g/ml): gemifloxacin, 0.001-256; trovafloxacin, 0.016-16; grepafloxacin, 0.016-16; levofloxacin, 0.016-16; ciprofloxacin, 0.016-16; ofloxacin, 0.06-64; nalidixic acid, 0.06-64; gentamicin, 0.06-64; cefuroxime, 0.06-64; amoxycillin/clavulanate, 0.03/0.016-32/16; penicillin, 0.016-16; ampicillin, 0.06- 64; clarithromycin, 0.016-16; azithromycin, 0.06-64; and trimethoprim/sulfamethoxazole, 0.06/1.14-64/1216.
- the plates were covered with a microtiter plate lid and incubated at 35°C in air for 20-24 h.
- the MIC was determined as the lowest concentration of drug that inhibited visible growth of the test isolates.
- trimethoprim/sulfamethoxazole the MIC was determined as the concentration that produced an 80-90% decrease in growth compared with the positive growth control.
- Individual MIC data were summarized and reported using the following parameters: MIC range , MIC 50 and MICw.
- ATCC American Type Culture Collection
- These NCCLS recommended quality control organisms were obtained from the SmithKline Beecham Anti-infectives Research Culture Collection, Collegeville, PA, USA. Quality control organisms were included on each day of testing. The results for that day were only accepted if the quality control values were within the acceptable limits as established by the NCCLS. (National Committee for Clinical Laboratory Standards 1999. Approved Standard M100-S9, ninth ed., Wayne, PA, USA). Quality control limits, tentatively approved by the NCCLS in January 1999 were used for gemifloxacin.
- Gemifloxacin has in vitro antibacterial activity that is comparable to or better than that of quinolones cu ⁇ ently available for the treatment of infections caused by Gram negative pathogens.
- Microrganism and antimicrobial MIC ( ⁇ g/ml)
- Ciprofloxacin ⁇ O.Ol 6-4 ⁇ 0.016 0.25
- Trovafloxacin 0.03-16 0.5 4 Microrganism and antimicrobial MIC ( ⁇ g/ml)
- the invention provides a method for modulating metabolism of Gram negative pathogenic bacteria. Skilled artisans can readily choose Gram negative pathogenic bacteria or patients infected with or suspected to be infected with these organisms to practice the methods of the invention. Alternatively, the bacteria useful in the methods of the invention may be those described herein.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram negative pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with Gram negative pathogenic bacteria.
- Gram negative pathogenic bacteria is selected from the group consisting of: Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Pseudomonas aeruginosa, Morganella morganii, Proteus spp., Stenotrophomonas maltophilia, Klebsiella oxytoca, Citrobacter freundii, Acinetobacter sp., and Serratia spp.
- Other Gram negative pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against Gram positive or Gram negative aerobic bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various Gram positive or Gram negative aerobic pathogens.
- An objective of these analyses was to determine the post-antibiotic effect (PAE) of gemifloxacin compared with that of ciprofloxacin against 10 isolates comprising Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- PAE post-antibiotic effect
- T is the time for the antimicrobial-exposed culture to increase in viable count by 1 logio
- C is the time for the growth control to increase in viable count by 1 logio-
- a measurable PAE was observed with both compounds at 2 and 4x MIC.
- PAEs of gemifloxacin are comparable to those of ciprofloxacin, and for both compounds exposure to 2 x MIC results in shorter PAEs than exposure to 4 x MIC.
- the PAE of gemifloxacin at 4 x MIC is >6 h against P. aeruginosa, P. vulgaris and H. influenzae, and ranges from 0.1 to 2.5 h against the other isolates tested.
- the post-antibiotic effect is defined as the persistent suppression of bacterial growth after brief exposure of a bacterial culture to an antimicrobial.
- the measurement of a PAE can be useful in the design of an appropriate dosing regimen for an antimicrobial.
- An antimicrobial with a long PAE would require a less frequent dosing regimen than one with a short PAE.
- the PAE was determined for gemifloxacin and ciprofloxacin against 10 isolates representing a broad spectrum of Gram positive or Gram negative aerobic organisms.
- Trypticase soy agar containing 5% sheep blood (BBL, Cockeysville, MD, USA) was used to subculture frozen isolate stocks and for S. pneumoniae colony counts.
- Mueller- Hinton II agar (BBL) was used for colony counts of the non-fastidious organisms.
- chocolate II agar (BBL) was used for colony counts of the H. influenzae isolate.
- Cation- adjusted Mueller-Hinton broth (CAMHB) (BBL) was used to test the non-fastidious organisms.
- CAMHB supplemented with 5% lyzed horse blood (BBL) was used to test the S. pneumoniae isolate.
- Haemophilus Test Medium (BBL) was used to test the H. influenzae isolate.
- Organisms were subcultured from a frozen stock (-80°C) onto a trypticase agar plate containing 5% sheep blood and incubated for 20-24 h at 35°C. A 5 ml tube of saline was inoculated with a sufficient number of colonies from the overnight culture to obtain a turbidity equivalent to a 0.5 McFarland standard. This inoculum was diluted 100-fold into 18 ml of the appropriate media (contained in a 50 ml flask) to produce a final test inoculum of approximately 1 x 10 6 CFU/ml. The MICs of gemifloxacin and ciprofloxacin were determined using the NCCLS recommended procedure for broth microdilution.
- the PAE effect was determined using a filtration method as previously described.(Thornburn, et al. Antimicrob. Agents Chemother., 40: 2796-2801 (1996)).Each test isolate was added to a 50 ml flask containing the antimicrobial (at 2 or 4 x MIC) in 20 ml of the appropriate broth. After addition of the isolate, a colony count was performed to determine the density (CFU/ml) of the starting inoculum. Flasks were incubated on a shaker at 35°C.
- T is the time required for the test isolate count to increase by 10-fold (1 x logio) above the count observed immediately after removal of the antimicrobial
- C is the time required for the control to increase by 10-fold above the count observed immediately after removal of the antimicrobial
- a measurable PAE is observed for both compounds against all of the isolates tested. In general, a shorter PAE is observed at 2 x MIC as opposed to 4 x MIC.
- the gemifloxacin PAE is >6 h against H. influenzae, P. aeruginosa and P. vulgaris, and ranges from 0.1 to 2.5 h against the other isolates tested.
- the ciprofloxacin PAE values obtained at 4 x MIC range from 0.3 to 5.1 h, with the exception of E. faecalis ATCC 29212, where no effect is observed.
- the PAE of gemifloxacin is comparable to that of ciprofloxacin against all isolates tested. A shorter PAE is observed for both compounds at 2 x MIC compared with 4 x MIC. At 4 x MIC, a longer PAE for gemifloxacin (>6 h) than ciprofloxacin is observed against H. influenzae, P. aeruginosa and P. vulgaris. Overall, the results of this study indicate that gemifloxacin has a pronounced PAE against a broad spectrum of organisms.
- Microrganism MIC ( ⁇ g/ml)
- Staphylococcus saprophyticus 662 0.016 0.25
- Staphylococcus aureus ATCC 29213 1.1 1.0 1.3 1.5 Staphylococcus saprophyticus 662 1.9 2.5 2.4 3.9 Streptococcus pneumoniae ATCC 49619 0.7 1.5 0.9 1.5
- the invention provides a method for modulating metabolism of Gram positive or Gram negative aerobic pathogenic bacteria.
- Skilled artisans can readily choose Gram positive or Gram negative aerobic pathogenic bacteria or patients infected with or suspected to be infected with these organisms to practice the methods of the invention.
- the bacteria useful in the methods of the invention can be those described herein.
- Also provided by the invention is a method of treating or preventing a bacterial infection by Gram positive or Gram negative aerobic pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with Gram positive or Gram negative aerobic pathogenic bacteria.
- Gram positive or Gram negative aerobic pathogenic bacteria is selected from the group consisting of: Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Proteus vulgaris.
- Other Gram positive or Gram negative aerobic pathogenic bacteria can also be included in the methods. The skilled artisan can identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
- the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against Streptococci bacteria.
- This invention was based, in part, on analyses evaluating the comparative activity of gemifloxacin against various Streptococci bacteria pathogens. An objective of these analyses was to determine the in vitro activity of gemifloxacin compared with that of 11 other antimicrobials against 400 Streptococci isolates.
- Gemifloxacin was compared to gemifloxacin, ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, grepafloxacin, penicillin, ampicillin, erythromycin, clarithromycin, tetracycline and vancomycin.
- the MIC ⁇ s ( ⁇ g/ml) of all streptococci to various quinolones were: gemifloxacin 0.008-0.06, ciprofloxacin 0.125-2.0, levofloxacin 0.5-4, sparfloxacin 0.06-1.0, trovafloxacin ⁇ 0.016-0.25 and grepafloxacin ⁇ 0.016-1.
- the MIC ranges for other standard antibiotics were: penicillin ⁇ 0.008-4, ampicillin ⁇ 0.008-8, erythromycin ⁇ 0.016->32, clarithromycin ⁇ 0.016->32, tetracycline 0.06->64 and vancomycin 0.125-2.
- gemifloxacin was the most potent quinolone tested.
- Gemifloxacin has enhanced activity against streptococci compared with other quinolones and is a promising agent for use against Gram positive infections.
- Quinolones are used to treat a variety of clinical indications including respiratory, abdominal, skin and soft tissue, and genito-urinary infections.
- Gemifloxacin (SB-265805) is a broad spectrum 6-fluoronaphthyridone with an oxime-derivatized (aminomethyl) py ⁇ olidinyl substituent at position 7. Compared with quinolones in current use, gemifloxacin displays potent activity against Streptococcus pneumoniae and other Gram positive pathogens.
- Streptococci species selected in this study represent primary pathogens or 'passenger organisms'.
- passenger organisms are streptococci present as normal flora, and thus are affected by antimicrobial therapy.
- antimicrobials can influence the normal flora directly via eradication and/or by super colonization, or indirectly through the selection of resistant organisms, which can lead to difficulties in the treatment of Streptococci infections.
- a total of 400 distinct clinical isolates of Streptococcus spp. were studied.
- the majority of the strains tested were recent isolates from the last three years.
- the control strains used were Staphylococcus aureus NCTC 6571, S. aureus ATCC 29213, Streptococcus pneumoniae ATCC 49619.
- the minimum inhibitory concentration (MIC) of the strains was determined by agar dilution based on British Society for Antimicrobial Chemotherapy methods, 1 (Working Party of the British Society for Antimicrobial Chemotherapy, Journal of Antimicrobial Chemotherapy, 27(Suppl. D): 1-50 (1991)).using Iso-Sensitest agar (CM471 Oxoid, Basingstoke, UK) supplemented with lysed horse blood (5% v/v). Colonies were taken directly from the plate into broth to match 0.5 McFarland standard and diluted to 1:10.
- the antimicrobial-containing agar was inoculated with 1 ⁇ l of diluted broth culture to give a final inoculum of 10 4 CFU/spot. Plates were incubated at 35-37°C in 5% C0 2 for 18-20 hours, as some strains of
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| AU69479/00A AU6947900A (en) | 1999-09-01 | 2000-08-31 | Methods of use of fluoroquinolone compounds against bacteria |
| JP2001519909A JP2004507440A (ja) | 1999-09-01 | 2000-08-31 | 細菌に対するフルオロキノロン化合物の使用法 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6703512B1 (en) | 1999-09-03 | 2004-03-09 | Sb Pharmco Puerto Rico Inc. Of The United States Corporation Company | Intermediates for the production of quinolone carboxylic acid derivatives |
| US7199242B2 (en) | 2001-08-02 | 2007-04-03 | Lg Life Sciences Limited | Processes for the production of amino-protected derivatives of 4-aminomethylene-pyrrolidin-3-one and/or 4-aminomethylene-pyrrolidin-3-alkoxyimino derivatives and/or gemifloxacin or a salt thereof |
| US7232907B2 (en) | 1999-09-03 | 2007-06-19 | Lg Life Sciences Limited | Process for production of naphthyridine-3-carboxylic acid derivatives |
| US7361762B2 (en) | 2002-04-08 | 2008-04-22 | Lg Life Sciences Ltd. | Process for preparing acid salts of Gemifloxacin |
-
2000
- 2000-08-31 JP JP2001519909A patent/JP2004507440A/ja active Pending
- 2000-08-31 EP EP00993844A patent/EP1401440A4/en not_active Withdrawn
- 2000-08-31 WO PCT/US2000/023883 patent/WO2001015695A1/en active Application Filing
- 2000-08-31 AU AU69479/00A patent/AU6947900A/en not_active Abandoned
Non-Patent Citations (7)
| Title |
|---|
| DATABASE BIOSIS [online] HEATON V. ET AL.: "Gemifloxacin is highly active against both penicillin and ciprofloxacin resistant streptococcus pneumoniae", XP003000813, accession no. STN Database accession no. 1999:404565 * |
| DATABASE DRUGU [online] HARDY D. ET AL.: "Comparative in vitro activity of gemifloxacin, moxifloxacin, trovafloxacin, sparfloxacin, grepafloxacin, ofloxacin, ciprofloxacin and other antimicrobial agents against bloodstream isolates of gram-positive cocci", XP003000812, accession no. STN Database accession no. 2000-05860 * |
| DATABASE DRUGU [online] KING A. ET AL.: "The comparative in vitro activity of gemifloxacin, a new fluoroquinolone against selected clinical isolates", XP003000811, accession no. STN Database accession no. 2000-05866 * |
| J. ANTIMICROB. CHEMOTHER., vol. 44, no. SUPPL. A, July 1999 (1999-07-01), pages 140 * |
| J. ANTIMICROB. CHEMOTHER., vol. 44, no. SUPPL. A, July 1999 (1999-07-01), pages 146 * |
| J. ANTIMICROB. CHEMOTHER., vol. 44, no. SUPPL. A, July 1999 (1999-07-01), pages 147 * |
| See also references of EP1401440A4 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6703512B1 (en) | 1999-09-03 | 2004-03-09 | Sb Pharmco Puerto Rico Inc. Of The United States Corporation Company | Intermediates for the production of quinolone carboxylic acid derivatives |
| US6803467B2 (en) | 1999-09-03 | 2004-10-12 | Lg Life Sciences Limited | Intermediates for the production of quinolone carboxylic acid derivatives |
| US7232907B2 (en) | 1999-09-03 | 2007-06-19 | Lg Life Sciences Limited | Process for production of naphthyridine-3-carboxylic acid derivatives |
| US7199242B2 (en) | 2001-08-02 | 2007-04-03 | Lg Life Sciences Limited | Processes for the production of amino-protected derivatives of 4-aminomethylene-pyrrolidin-3-one and/or 4-aminomethylene-pyrrolidin-3-alkoxyimino derivatives and/or gemifloxacin or a salt thereof |
| US7361762B2 (en) | 2002-04-08 | 2008-04-22 | Lg Life Sciences Ltd. | Process for preparing acid salts of Gemifloxacin |
Also Published As
| Publication number | Publication date |
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| EP1401440A1 (en) | 2004-03-31 |
| EP1401440A4 (en) | 2006-07-05 |
| AU6947900A (en) | 2001-03-26 |
| JP2004507440A (ja) | 2004-03-11 |
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