Classifications

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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • 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
• • 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

• Cystic fibrosis lung disease is characterized by chronic respirator ⁇ ' tract infection with multiple bacterial species frequently dominated by Pseudomonas aeruginosa, which has been associated with accelerated lung disease progression, increased morbidity, and decreased survival.
• Chronic Pseudomonas aeruginosa infection is typically treated with chronic inhaled antibiotics to suppress infection, reduce risk of pulmonary exacerbations, improve quality of life, and preserve lung function.
• Antibiotic classes currently approved in many countries for use by inhalation include the aminoglycosides (tobramycin), monobactams (aztreonam) and polymyxins (colistimethate).
• a separate antibiotic class with high potency and a broad spectmm of action, fluoroquinolones, is used extensively as oral and intravenous formulations to treat cystic fibrosis lung disease.
• fluoroquinolones A separate antibiotic class with high potency and a broad spectmm of action, fluoroquinolones, is used extensively as oral and intravenous formulations to treat cystic fibrosis lung disease.
• Described herein are methods to treat cystic fibrosis in high-risk patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Described herein are methods to treat pulmonary bacterial infections in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Described herein are methods to treat Pseudomonas aeruginosa pulmonary infections in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Described herein are methods to treat pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Described herein are methods to reduce the incidents of pulmonary exacerbations in high- risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Described herein are methods to extend the time between the onset of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Described herein are methods to reduce a Pseudomonas aeruginosa sputum density in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone, such as levofloxacin or ofloxacin.
• Fig. 1 shows the proportion of patients who did not experience a pulmonary exacerbation over the course of the 28 day treatment, and beyond to 70 days, in the levofioxacin inhalation solution (LIS) treatment group and placebo group.
• LIS levofioxacin inhalation solution
• Fig. 2A shows the LS mean absolute change in FEVi over the course of the 28 day treatment (shaded area), and over the course of days 29-56 after treatment (non-shaded area), in the levofioxacin inhalation solution (LIS) treatment group and placebo group. Differences between treatment groups were statistically significant at Day 28.
• Fig. 2B shows the LS mean change sputum Pseudomonas aeruginosa over the course of the 28 day treatment (shaded area), and over the course of days 29-56 after treatment (non-shaded area) in the levofioxacin inhalation solution (LIS) treatment group and placebo group.
• an active agent refers not only to a single active agent but also to a combination of two or more different active agents
• a dosage form refers to a combination of dosage forms as well as to a single dosage form, and the like.
• Patient refers to mammals, preferably humans.
• the human is an adult.
• the human is an adolescent.
• the human is a child.
• the human is an infant.
• the patient has cystic fibrosis, preferably a human with cystic fibrosis.
• "Patient” also refers to a human with cystic fibrosis on an antibiotic treatment (other than levofioxacin or ofloxacin) who has symptoms or pulmonary bacterial infections that are not adequately controlled on the antibiotic treatment (other than levofioxacin or ofloxacin), such that the patent requires a new antibiotic therapy such as that described herein.
• High-risk patient or "high-risk cystic fibrosis patient” refers to a patient that experienced at least 2 occurrences of a pulmonan,' exacerbation in the prior year.
• a "high-risk patient” or “high-risk cystic fibrosis patient” refers to a patient that experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• a "high-risk patient” or “high-risk cystic fibrosis patient” refers to a patient that experienced at least 4 occurrences of a pulmonary exacerbation in the prior year.
• a "high-risk patient” or “high-risk cystic fibrosis patient” refers to a patient that experienced at least 5 occurrences of a pulmonary exacerbation in the prior year. In embodiments, a “high-risk patient” or “high-risk cystic fibrosis patient” refers to a patient that experienced at least 6 occurrences of a pulmonary exacerbation in the prior year. In embodiments, a “high-risk patient” or “high-risk cystic fibrosis patient” refers to a patient that experienced at least 7 occurrences of a pulmonary exacerbation in the prior year.
• the antibiotic can be an oral antibiotic, an intravenous antibiotic, or an inhaled antibiotic.
• the antibiotic is an intravenous antibiotic or an inhaled antibiotic.
• the antibiotic is an intravenous antibiotic.
• the antibiotic is an inhaled antibiotic.
• the "pulmonary illness" which results in a clinician's decision to treat the patient with an antibiotic can be any pulmonary illness caused by or related to cystic fibrosis.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic occurs when the patient is diagnosed as having at least four of the twelve Fuchs criteria.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a a pulmonary bacterial infection.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Pseudomonas pulmonary bacterial infection.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Pseudomonas aeruginosa pulmonary bacterial infection. In embodiments, the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Staphylococcus pulmonary bacterial infection. In embodiments, the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Burkholderia pulmonary bacterial infection.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Burkholderia cepacia pulmonary bacterial infection.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Pseudomonas pulmonary bacterial infection, Staphylococcus pulmonary bacterial infection, a Burkholderia pulmonary bacterial infection, or a combination of two or more thereof.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is a Pseudomonas aeruginosa pulmonary bacterial infection, a Staphylococcus aureus pulmonary bacterial infection, a Burkholderia cepacia pulmonary bacterial infection, or a combination of two or m ore thereof.
• the pulmonary ill ness which results in a clinician's decision to treat the patient with an antibiotic is a 10% or more decrease in a patient's forced expiratory volume in 1 second (FEVi) of the predicted value using Hankinson/NHANES III reference equations.
• the pulmonary illness which results in a clinician's decision to treat the patient with an antibiotic is any pulmonary disease, dysfunction, or disorder that can occur in a patient with cystic fibrosis.
• Fuchs criteria refers to the symptoms described in Fuchs et al, The New England Journal of Medicine, 331 :637-642 (1994).
• the twelve symptoms that fall within the scope of the Fuchs criteria include: (i) change in sputum; (ii) new or increased hemoptysis, (iii) increased cough; (iv) increased dyspnea; (v) malaise, fatigue, or lethargy; (vi) temperature above 38°C; (vii) anorexia or weight loss, (viii) sinus pain or tenderness; (ix) change in sinus discharge, (x) change in physical examination of the chest; (xi) decrease in pulmonary function by 10% or more from a previously recorded value, and (xii) radiographic change indicative of pulmonary infection.
• the change in sputum is an increase in sputum. In embodiments, the change in sputum is a decrease in sputum. In embodiments, the change in physical examination of the chest is a negative change, a deteriorating change, or a worsening change.
• pulmonary bacterial infection refers to any pulmonary bacterial infection that can occur in a patient with cystic fibrosis.
• the pulmonary bacterial infection is a
• the pulmonary bacterial infection is a Pseudomonas aeruginosa pulmonary bacterial infection.
• pulmonary bacterial infection is a Staphylococcus pulmonary bacterial infection.
• the pulmonary bacterial infection is a Staphylococcus aureus pulmonary bacterial infection.
• the pulmonary bacterial infection is a Burkholderia pulmonary bacterial infection.
• the pulmonary bacterial infection is a Burkholderia cepacia pulmonary bacterial infection.
• the pulmonary bacterial infection is a Pseudomonas pulmonary bacterial infection, a Staphylococcus pulmonary bacterial infection, a Burkholderia pulmonary bacterial infection, or a combination of two or more thereof.
• the pulmonary bacterial infection is a Pseudomonas aeruginosa pulmonary bacterial infection, a Staphylococcus aureus pulmonary bacterial infection, a Burkholderia cepacia pulmonary bacterial infection, or a combination of two or more thereof.
• Chronic fibrosis refers to any person who can prescribe medications (e.g., antibiotics) or treat cystic fibrosis patients, such as doctors, physician assistants, nurses, clinical investigators, pharmacists, and the like.
• medications e.g., antibiotics
• cystic fibrosis patients such as doctors, physician assistants, nurses, clinical investigators, pharmacists, and the like.
• Prior year refers to the 12 months prior to initiation of treatment with a levofloxacin inhalation solution, ofloxacin inhalation solution, or fluoroquinolone inhalation solution as described herein.
• Levofloxacin inhalation solution refers to an aerosol of a solution of levofloxacin.
• levofloxacin inhalation solution is an aerosol of a solution of levofloxacin and a divalent or trivalent cation.
• levofloxacin inhalation solution is an aerosol of a solution of levofloxacin and a divalent cation.
• levofloxacin inhalation solution is an aerosol of a solution of about 75 mg/ml to about 150 mg/ml of levofloxacin and about 150 mM to about 250 mM of a divalent cation.
• levofloxacin inhalation solution is an aerosol of a solution of about 80 mg/ml to about 120 mg/ml of levofloxacin and about 180 mM to about 220 mM of a divalent cation. In embodiments, levofloxacin inhalation solution is an aerosol of a solution of about 90 mg/ml to about 110 mg/ml of levofloxacin and about 175 mM to about 225 mM of a magnesium cation. In embodiments, levofloxacin inhalation solution is an aerosol of a solution of about 100 mg/ml of levofloxacin and about 40 mg/ml of magnesium chloride.
• levofloxacin inhalation solution is an aerosol of an aqueous solution of about 102.50 mg/ml of levofloxacin hemihydrate and about 40.66 mg/ml magnesium chloride hexahydrate, e.g.,
• the levofloxacin inhalation solution may optionally contain pharmaceutically acceptable excipients.
• the levofloxacin inhalation solution is administered with a nebulizer (e.g., PARI eFlow® Rapid Nebulizer System).
• a nebulizer e.g., PARI eFlow® Rapid Nebulizer System.
• Exemplary levofloxacin inhalation solutions are described in US Patent No. 7,838,532, US Patent No. 8,629,139, and US Patent No. 8,815,838, the disclosures of which are incorporated by reference herein in their entirety.
• the levofloxacin inhalation solution is administered to patients whose symptoms or pulmonary bacterial infections are not adequately controlled by another antibiotic therapy. This administration can be in place of the other antibiotic therapy or in addition to the other antibiotic therapy.
• Oxidacin inhalation solution refers to an aerosol of a solution of ofloxacin.
• ofloxacin inhalation solution is an aerosol of a solution of ofloxacin and a divalent or trivalent cation.
• ofloxacin inhalation solution is an aerosol of a solution of about 75 mg/ml to about 150 mg/ml of ofloxacin and about 150 mM to about 250 mM of a divalent cation.
• ofloxacin inhalation solution is an aerosol of a solution of about 100 mg/ml of ofloxacin and about 200 mM magnesium chloride.
• the ofloxacin inhalation solution may optionally contain pharmaceutically acceptable excipients.
• the ofloxacin inhalation solution is administered with a nebulizer (e.g., PARI eFlow® Rapid Nebulizer System).
• a nebulizer e.g., PARI eFlow® Rapid Nebulizer System
• Exemplary ofloxacin inhalation solutions are described in US Patent No. 7,838,532, US Patent No. 8,629, 139, and US Patent No. 8,815,838, the disclosures of which are incorporated by reference herein in their entirety.
• the ofloxacin inhalation solution is administered to patients whose symptoms or pulmonary bacterial infections are not adequately controlled by another antibiotic therapy. This administration can be in place of the other antibiotic therapy or in addition to the other antibiotic therapy.
• Fluoroquinolone inhalation solution refers to an aerosol of a solution of a
• fluoroquinolone inhalation solution is an aerosol of a solution of levofloxacin and a divalent or trivalent cation.
• fluoroquinolone inhalation solution is an aerosol of a solution of about 50 mg/ml to about 300 mg/ml of a fluoroquinolone and about 50 mM to about 400 mM of a divalent or trivalent cation.
• the fluoroquinolone inhalation solution may optionally contain pharmaceutically acceptable excipients.
• the fluoroquinolone inhalation solution is administered with a nebulizer (e.g., PARI eFlow® Rapid Nebulizer System). Exemplary fluoroquinolone inhalation solutions are described in US Patent No. 7,838,532, the disclosure of which is incorporated by reference herein in its entirety.
• Divalent cation refers to cations of magnesium, calcium, zinc, copper, and iron. In one embodiment, divalent cation is a cation of magnesium.
• Trivalent cation refers to cations of aluminum and iron.
• Fluoroquinolone refers to fluoroquinolone antibiotics which include, e.g., levofloxacin, ofloxacin, ciprofloxacin, enoxacin, gatif!oxacin, gemif!oxacin, lomefloxacin, nioxifloxacin, norfloxacin, pefloxacin, sparfloxacin, garenoxacin, sitagloxacin, and DX-619 (i.e., 7 ⁇ [(3R)-3-(l ⁇ arninocyclopropyl)pyrrolidin-l-yl]-l -[(lR,2S)-2-fluorocyc]opropyl]-8-methoxy-4-oxoquinoline-3- carboxylic acid).
• fluoroquinolone is ievofloxacin or ofloxacin.
• fluoroquinolone is Ievofloxacin.
• the fluoroquinolone is ciprofloxacin, enoxacin, gatifloxacin, gemifloxaein, lomefloxacin, nioxifloxacin, norfloxacin, pefloxacin, sparfloxacin, garenoxacin, sitagloxacin, or DX-619.
• “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a patient and can be included in the inhalation solutions described herein without causing a significant adverse toxicologicai effect on the patient.
• Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, tillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxvmethycelluiose, polyvinyl pyrrolidine, and colors, and the like.
• Such preparations can be sterilized and, if desired, mixed with auxiliaiy agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliaiy agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliaiy agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliaiy agents such as lubricants, preservatives
• salts are meant to include salts of the active compounds, divalent cations, and trivalent cations that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, nialeic, maionic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesuifonic, and the like.
• inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
• divalent and trivalent cations are in the form of pharmaceutically acceptable salts, e.g., magnesium chloride, magnesium sulfate, and the like.
• treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline, making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
• certain methods herein may treat cystic fibrosis by treating a pulmonary exacerbation and/or treating a pulmonary illness, such as a pulmonary bacterial infection (e.g., Pseudomonas aeruginosa pulmonary bacterial infections), reducing the incidents of pulmonary exacerbations, extending the time between the occurrence of pulmonary exacerbations, and/or reducing the severity of pulmonary exacerbations.
• a pulmonary bacterial infection e.g., Pseudomonas aeruginosa pulmonary bacterial infections
• reducing the incidents of pulmonary exacerbations or equivalent phrase means that a patient will have fewer incidents of pulmonary exacerbations in the future compared to a similar patient in the same situation (or the same patient) who does not receive the treatments described herein, compared to the absence of treatment, or compared to some other acceptable control.
• “Reducing the incidents of pulmonary exacerbations” includes reducing the incidents during the course of the treatments described herein, reducing the incidents after the course of the treatments described herein ends, or reducing the incidents during the course of treatments described herein and after the course of the treatments end,
• the phrase "extend the time between the occurrence of pulmonary exacerbations" or equivalent phrase means that a patient will experience a longer period of time between the occurrence of future pulmonary exacerbations compared to a similar patient in the same situation (or the same patient) who does not receive the treatments described herein, compared to the absence of treatment, or compared to some other acceptable control.
• "Extending the time between the occurrences of pulmonary exacerbations” or equivalent phrase includes extending the time during the course of the treatments described herein, extending the time after the course of the treatments described herein ends, or extending the time during the course of treatments described herein and after the course of the treatments end.
• the phrase "reducing the severity of pulmonary exacerbations" or equivalent phrase means that a patient may experience a pulmonary exacerbation, but the duration of the pulmonary exacerbation will be for a shorter period of time (e.g., compared to a similar patient in the same situation (or the same patient) who does not receive the treatments described herein, compared to the absence of treatment, or compared to some other acceptable control) and/or the number of Fuchs criteria that they experience will be lower (e.g., compared to a similar patient in the same situation (or the same patient) who does not receive the treatments described herein, compared to the absence of treatment, or compared to some other acceptable control) and/or the course of treatment for the pulmonary exacerbation will be for a shorter period of time (e.g., compared to a similar patient in the same situation (or the same patient) who does not receive the treatments described herein, compared to the absence of treatment, or compared to some other acceptable control).
• Reducing the severity of pulmonary exacerbations includes reducing the severity during the course of the treatments described herein, reducing the severity after the course of the treatments described herein ends, or reducing the severity during the course of treatments described herein and after the course of the treatments end.
• administration refers to the methods of providing the levofloxacin inhalation solutions, ofloxacin inhalation solutions, or fluoroquinolone inhalation solutions to a patient.
• the solutions described herein are administered topically.
• the solutions described herein are administered to the lungs of the patient, e.g., by pulmonary administration through the use of an appropriate device, such as a nebulizer.
• fluoroquinolone inhalation solutions are administered to a patient whose symptoms or pulmonary bacterial infections are not adequately controlled by a different antibiotic therapy.
• Dosing regimen refers to the time between administration of two doses of a levofloxacin inhalation solution, ofloxacin inhalation solution, or a fluoroquinolone inhalation solution to a patient.
• levofloxacin inhalation solution, ofloxacin inhalation solution, or a fluoroquinolone inhalation solution are administered daily for one month (e.g., 28 days) of treatment, then the patient stops treatment for one month (e.g., 28 days), and then resumes treatment for another month (e.g., 28 days). Treatment cycles may be repeated for as long as the patient benefits.
• the levofloxacin inhalation solution, ofloxacin inhalation solution, or a fluoroquinolone inhalation solution are administered once daily or twice daily.
• Dose refers to the amount (e.g., mg) or concentration (e.g., mg/ml) of a fluoroquinolone (e.g., levofloxacin or ofloxacin) that is administered to a patient or that is contained in a formulation.
• the dose of the fluoroquinolone is from about 25 mg to about 400 mg; about 25 mg to about 300 mg; about 25 mg to about 200 mg; or from about 50 mg to about 150 mg; or from about 75 mg to about 125 mg; or from about 90 mg to about 110 mg.
• the dose of the fluoroquinolone is about 100 nig. In embodiments, the dose of the fluoroquinolone (e.g., levofloxacin or ofloxacin) is from about 100 mg to about 300 mg; or from about 200 mg to about 300 mg; or from about 210 mg to about 270 mg. In embodiments, the dose of the fluoroquinolone (e.g., levofloxacin or ofloxacin) is about 220 mg to about 260 mg. In embodiments, the dose of the fluoroquinolone (e.g., levofloxacin or ofloxacin) is about 230 mg to about 250 mg. In embodiments, the dose of the fluoroquinolone (e.g., levofloxacin or ofloxacin) is about 240 mg.
• the disclosure provides methods to treat pulmonary bacterial infections in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the methods to treat the pulmonary bacterial infections further comprise reducing the incidents of future pulmonary bacterial infections in the high-risk cystic fibrosis patients.
• the methods to treat the pulmonary bacterial infections further comprise increasing or extending the time between the onset of future pulmonary bacterial infections in the high-risk cystic fibrosis patients.
• the methods to treat the pulmonary bacterial infections further comprise reducing the incidents of future pulmonary bacterial infections and increasing or extending the time between the onset of future pulmonary bacterial infections in the high-risk cystic fibrosis patients. In embodiments, the methods to treat the pulmonary bacterial infections further comprise reducing the severity of the pulmonary bacterial infections in the high-risk cystic fibrosis patients. In embodiments, the methods to treat pulmonary bacterial infections further comprise reducing the incidents of future pulmonary exacerbations in the high-risk cystic fibrosis patients.
• the methods to treat pulrnonan,' bacterial infections further comprise increasing or extending the time between the onset of future pulmonary exacerbations in the high-risk cystic fibrosis patients, in embodiment, the methods to treat pulmonary bacterial infections further comprise reducing the incidents of future pulmonary exacerbations and increasing or extending the time between the onset of future pulmonary exacerbations in the high-risk cystic fibrosis patients. In embodiments, the methods to treat pulmonary bacterial infections further comprise reducing the severity of pulmonary exacerbations in the high-risk cystic fibrosis patients.
• the pulrnonan,' bacterial infection is a chronic pulmonary bacterial infection.
• the fluoroquinolone is levofloxacin.
• the fluoroquinolone is ofloxacin.
• the high-risk patient experienced at least 3 occurrences of a pulrnonan,' exacerbation in the prior year.
• the aerosol of the solution i administered to a patient whose symptoms or pulmonary bacterial infections are not adequately controlled by a different antibiotic therapy.
• the disclosure provides methods to treat Pseudomonas aeruginosa pulmonary infections in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the methods to treat the Pseudomonas aeruginosa pulmonary infection further comprise reducing the incidents of future Pseudomonas aeruginosa pulmonary infections in the high-risk cystic fibrosis patients.
• the methods to treat the Pseudomonas aeruginosa pulmonary infection further comprise increasing or extending the time between the onset of future Pseudomonas aeruginosa pulmonary infections in the high-risk cystic fibrosis patients.
• the methods to treat the Pseudomonas aeruginosa pulmonary infection further comprise reducing the incidents of future Pseudomonas aeruginosa pulmonary infections and increasing or extending the time between the onset of future Pseudomonas aeruginosa pulmonary infections in the high-risk cystic fibrosis patients.
• the methods to treat the Pseudomonas aeruginosa pulmonary infection further comprise reducing the severity of the Pseudomonas aeruginosa pulmonary infections in the high- risk cystic fibrosis patients. In embodiments, the methods to treat the Pseudomonas aeruginosa pulmonary infection further comprise reducing the incidents of future pulmonary exacerbations in the high-ri sk cystic fibrosis patients. In embodiments, the methods to treat the Psendomonas aeruginosa pulmonary infection further comprise increasing or extending the time between the onset of future pulmonary exacerbations in the high-risk cystic fibrosis patients.
• the methods to treat the Psendomonas aeruginosa pulmonary infection further comprise reducing the incidents of future pulmonary exacerbations and i ncreasing or extending the time between the onset of future pulmonary exacerbations in the high-risk cystic fibrosis patients.
• the methods to treat the Psendomonas aeruginosa pul monary infection further comprise reducing the severity of pulmonary exacerbations in the high-risk cystic fibrosis patients.
• the Psendomonas aeruginosa pulmonary infection is a chronic Pseud.om.onas aeruginosa pu l monary infection.
• the fluoroquinolone i s levofloxacin is reducing the pulmonary exacerbations and i ncreasing or extending the time between the onset of future pulmonary exacerbations in the high-risk cystic fibrosis patients.
• fluoroquinolone is ofloxacin.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year. In embodiments, the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the aerosol of the solution i administered to a patient whose symptoms or pulmonary bacterial infections are not adequately controlled by a different antibiotic therapy.
• the disclosure provides methods to treat Staphylococcus aureus pulmonary infections in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the methods to treat the Staphylococcus aureus pulmonary infection further compri se reducing the incidents of future Staphylococcus aureus pulmonary infections in the high-risk cystic fibrosis patients.
• the methods to treat the Staphylococcus aureus pulmonary infection further comprise increasing or extending the time between the onset of future Staphylococcus aureus pulmonary infections in the high-risk cystic fibrosis patients.
• the methods to treat the Staphylococcus aureus pulmonary infection further comprise reducing the incidents of future Staphylococcus aureus pulmonary infections and increasing or extending the time between the onset of future Staphylococcus aureus pulmonary infections in the high-risk cystic fibrosis patients. In embodiments, the methods to treat the Staphylococcus aureus pulmonary infection further comprise reducing the severity of the
• the methods to treat the Staphylococcus aureus pulmonary infection further comprise reducing the incidents of future pulmonary exacerbations in the high-risk cystic fibrosis patients.
• the methods to treat the Staphylococcus aureus pulmonary infection further compri se increasing or extending the time between the onset of future pulmonary exacerbations in the high- risk cystic fibrosis patients.
• the methods to treat the Staphylococcus aureus pulmonary infection further comprise reducing the incidents of future pulmonary exacerbations and increasing or extending the time between the onset of future pulmonaiy exacerbations in the high- risk cystic fibrosis patients.
• the methods to treat the Staphylococcus aureus pulmonaiy infection further comprise reducing the severity of pulmonary exacerbations in the high- risk cystic fibrosis patients.
• the Staphylococcus aureus pulmonary infection is a chronic Staphylococcus aureus pulmonaiy infection.
• the fluoroquinolone is levofloxacin.
• the fluoroquinolone is ofloxacin.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the aerosol of the solution i administered to a patient whose symptoms or pulmonary bacterial infections are not adequately controlled by a different antibiotic therapy.
• the disclosure provides methods to reduce the incidents of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the fluoroquinolone is levofloxacin.
• the fluoroquinolone is ofloxacin.
• the cystic fibrosis patient has a pulmonary bacterial infection, such as a Pseudomonas aeruginosa pulmonary infection.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the disclosure provides methods to extend the time between the onset of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the disclosure provides methods to extend the time between the onset of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the disclosure provides methods to extend the time between the onset of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• fluoroquinolone is levofloxacin. In embodiments, the fluoroquinolone is ofloxacin. In
• the cystic fibrosis patient has a pulmonary bacterial infection, such as a Pseudomonas aeruginosa pulmonary infection.
• the high-risk patient experienced at least 3 occurrences of a pulmonaiy exacerbation in the prior year.
• the disclosure provides methods to reduce the severity of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the fluoroquinolone is levofloxacin.
• the fluoroquinolone is ofloxacin.
• the cystic fibrosis patient has a pulmonary bacterial infection, such as a Pseudomonas aeruginosa pulmonary infection.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the disclosure provides methods to achieve one or more of the following: (a) reduce the incidents of pulmonary exacerbations in high-risk cystic fibrosis patients; (b) extend the time between the onset of pulmonary exacerbations in high-risk cystic fibrosis patients, and (c) reduce the severity of pulmonary exacerbations in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the fluoroquinolone is levofloxacin.
• the fluoroquinolone is ofloxacin.
• the cystic fibrosis patient has a pulmonary bacterial infection, such as a Pseudomonas aeruginosa pulmonary infection.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the disclosure provides methods to reduce a Pseudomonas aeruginosa sputum density in high-risk cystic fibrosis patients by administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone.
• the fluoroquinolone is levofloxacin.
• the fluoroquinolone is ofloxacin.
• the high-risk patient experienced at least 3 occurrences of a pulmonary exacerbation in the prior year.
• the high-risk cystic fibrosis patient has, at the time of the pulmonary exacerbation (e.g., diagnosis for treatment of a pulmonary bacterial infection), a forced expiratory volume in 1 second (FEV 1 ) between 10% and 95% or between 25%> and 85% of their predicted values using Hankinson/NHANES III reference equations.
• FEV 1 forced expiratory volume in 1 second
• the high risk cystic fibrosis patient has a forced expiratory volume in 1 second (FEVi) of 10% to 55%; of 55% to 85%; of 60% to 85%; or greater than 75% of the predicted value using Hankinson/NHANES III reference equations at the time of the pulmonary exacerbation.
• FEVi forced expiratory volume in 1 second
• the Hankinson/NHANES III reference equations are well-known in the art, and described in Hankinson et al, Am J Respir Crit Care Med, 159: 179-187 (1999).
• the high-risk cystic fibrosis patient has a chronic airway infection with Pseudomonas aeruginosa and received at least three 28 -day courses of an inhaled antibiotic in the prior year (e.g., an inhaled aminoglycoside formulation; an inhaled monobactam formulation; an inhaled polymyxin formulation;or a combination of two or more thereof).
• the high-risk cystic fibrosis patient has a chronic airway infection with Pseudomonas aeruginosa and had received at least three 28-day courses of an inhaled tobramycin formulation in the prior year.
• Inhaled tobramycin formulations are known in the art and are commercially available, such as TORI® (Novartis, East Hanover, NJ) and BETHKIS® (Chiesi,
• the high-risk cystic fibrosis patient had at least three 28-day courses of intravenous antibiotic treatments for a pulmonary Pseudomonas aeruginosa infection in the prior year. In other embodiments of the methods described herein, the high-risk cystic fibrosis patient had at least three 28-day courses of intravenous antibiotic treatments for a pulmonary bacterial infection in the prior year.
• the intravenous antibiotic can be any known in the art, including, for example, a beta-lactam antibiotic or an aminoglycoside antibiotic.
• a fluoroquinolone inhalation solution, levofloxacin inhalation solution, and ofloxacin inhalation solution may be administered using an inhaler.
• a fluoroquinolone (including levofloxacin and ofloxacin) is produced as a pharmaceutical composition suitable for aerosol formation, good taste, storage stability, and patient safety and tolerability.
• the isoform content of the manufactured fluoroquinolone may be optimized for tolerability, antimicrobial activity and stability.
• the inhalation solutions can include a divalent or trivalent cation.
• the divalent or trivalent cation can include, for example, magnesium, calcium, zinc, copper, aluminum, and iron.
• the solution comprises magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride.
• the solution comprises magnesium chloride.
• the divalent or trivalent cation concentration can be from about 25 mM to about 400 ffiM, from about 50 mM to about 400 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 125 mM to about 250 mM, from about 150 mM to about 250 mM, from about 175 mM to about 225 mM, from about 180 mM to about 220 mM, and from about
• the concentration is about 200 mM.
• the magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride can have a concentration from about 5% to about 25%, from about 10% to about 20%, and from about 15% to about 20%.
• the ratio of fluoroquinolone to divalent or trivalent cation can be 1 : 1 to 2: 1 or 1 : 1 to 1 :2.
• the inhalation solution can have a fluoroquinolone concentration, for example, levofloxacin or ofloxacin, greater than about 50 mg/ml, about 60 mg/ml, about 70 mg/mi, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 1 10 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about 180 mg/ml, about 190 mg/ml, and about 200 mg/ml.
• levofloxacin or ofloxacin greater than about 50 mg/ml, about 60 mg/ml, about 70 mg/mi, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 1 10 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg
• the inhalation solution can have a fluoroquinolone concentration, for example, levofloxacin or ofloxacin, from about 50 mg/ml to about 200 mg/ml, from about 75 mg/ml to about 150 mg/ml, from about 80 mg/ml to about 125 mg/ml, from about 80 mg/ml to about 120 mg/ml, from about 90 mg/ml to about 125 mg/ml, from about 90 mg/ml to about 120 mg/ml, and from about 90 mg/ml to about 1 10 mg/ml.
• the concentration is about 100 mg/ml.
• the inhalation solution can have an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg, from about 325 mOsmol/kg to about 450 mOsmol/kg, from about 350 mOsmol/kg to about 425 mOsmol/kg, and from about 350 mOsmol/kg to about 400 mOsmol/kg.
• the osmolality of the inhalation solution is greater than about 300 mOsmol/kg, about 325 mOsmol/kg, about 350 mOsmol/kg, about 375 mOsmol/kg, about 400 mOsmol/kg, about 425 mOsmol/kg, about 450 mOsmol/kg, about 475 mOsmol/kg, and about 500 mOsmol/kg.
• the inhalation solution can have a pH from about 4.5 to about 8.5, from about 5.0 to about 8.0, from about 5.0 to about 7.0, from about 5.0 to about 6.5, from about 5,5 to about 6.5, and from 6.0 to about 6.5.
• the inhalation solution can optionally comprise a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like), or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanol amine acetate, triethanolamine oleate, and the like).
• a conventional pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like
• auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents,
• the inhalation solution can lack a conventional pharmaceutical carrier, excipient or the like. Some embodiments include a formulation lacking lactose. Some embodiments comprise lactose at a concentration less than about 10%, 5%, 1 %, or 0. 1%. In some embodiments, the inhalation solution can consist essentially of levofloxacin or ofloxacin and a divalent or trivalent cation.
• an inhalation solution can comprise a levofloxacin concentration between about 75 mg/ml to about 150 mg/ml, a magnesium chloride concentration between about 150 mM to about 250 mM, a pH between about 5 to about 7; an osmolality of between about 300 mOsmol/kg to about 600 mOsmol/kg, and lacks lactose.
• an inhalation solution comprises a levofloxacin concentration of about 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH of about 6.2, an osmolality of about 383 mOsmol/kg.
• a formulation consists essentially of a levofloxacin concentration of about 90 mg/ml to about 1 10 mg/ml, a magnesium chloride concentration of about 180 mM to about 220 mM, a pH of about 5 to about 7, an osmolality of about 300 mOsmol/kg to 500 mOsmol/kg.
• the amount of active compound administered will be dependent on the subject and disease state being treated, the severity of the affl iction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a likely dose range for aerosol administration of levofloxacin would be about 20 to 300 mg per day, the active agents being selected for longer or shorter pulmonary half-lives, respectively. In some embodiments, a likely dose range for aerosol administration of levofloxacin would be about 100 to 300 mg twice daily.
• Pulmonary drug delivery may be accomplished by inhalation of an aerosol through the mouth and throat.
• Particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed.
• Particles having diameters of about 2 to about 5 microns are small enough to reach the upper- to mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Smaller particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region.
• Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles may be exhaled.
• a nebulizer is selected on the basis of allowing the aerosol of a solution of a fluoroquinolone disclosed herein having an MMAD predominantly between about 2 to about 5 microns.
• the delivered amount of fluoroquinolone provides a therapeutic effect for pulmonary infections.
• the nebulizer can deliver an aerosol comprising a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns, a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns, and a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
• the aerosol can be produced using a vibrating mesh nebulizer.
• An example of a vibrating mesh nebulizer includes the PARI E-FLOW® nebulizer or a nebulizer using PARI eFlow technology.
• nebulizers More examples are provided in US Patent Nos. 4,268,460; 4,253,468, 4,046, 146; 3,826,255; 4,649,91 1 ; 4,510,929; 4,624,251; 5, 164,740; 5,586,550; 5,758,637; 6,644,304; 6,338,443;
• nebulizers that can be used with the formulations described herein include Respirgard II®, Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen; AERx® and AERx Essence® produced by Aradigm; Porta-Neb®, Freeway Freedom®, Sidestream, Ventstream and I-neb produced by Respironics, Inc.; and PARI LC-Plus® PARI LC-Start, produced by P ARI, GmbH.
• Respirgard II®, Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen
• AERx® and AERx Essence® produced by Aradigm
• Porta-Neb® Freeway Freedom®, Sidestream, Ventstream and I-neb produced by Respironics, Inc.
• PARI LC-Plus® PARI LC-Start produced by P ARI, GmbH.
• RDD Respirable delivered dose
• the RDD is estimated from the inspiratory phase of a breath simulation device programmed to the European Standard pattern of 15 breaths per minute, with an inspiration to expiration ratio of 1 : 1, and measurement of particles emitted from a nebulizer with a size of about 5 microns or less.
• the amount of levofloxacin or ofloxacin that can be administered to the lungs with an aerosol dose, such as the RDD, can include at least about 20 mg, about 30 nig, about 40 mg, about 50 mg, about 60 nig, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg
• the amount of levofloxacin or ofloxacin that can be administered to the lungs with an aerosol dose such as a respirable drug dose (RDD)
• an aerosol dose such as a respirable drug dose (RDD)
• RDD respirable drug dose
• the aerosol can be administered to the lungs in less than about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, and about 1 minute.
• Methods and inhalation solutions described herein can be used to treat pulmonary infections and disorders.
• disorders can include cystic fibrosis, pneumonia, and chronic obstructive pulmonary disease, including chronic bronchitis, and some asthmas.
• the disorder is cystic fibrosis.
• Some embodiments include treating an infection comprising one or more bacteria selected from the group consisting of Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas niaitophilia, Aeronionas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganelia morganii, Proteus mirabilis, Proteus vulgaris,
• the infection is a Pseudomonas infection.
• the infection is Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaiigenes, or Pseudomonas putida.
• the infection is Pseudomonas aeruginosa,
• the lung infection is caused by a gram-negative anaerobic bacteria.
• the lung infection comprises one or more of the bacteria selected from the group consisting of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vuigatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.
• the lung infection is caused by a gram-positive bacteria.
• the lung infection comprises one or more of the bacteria selected from the group consisting of Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes,
• the lung infection is caused by a Staphylococcus bacteria.
• the Staphylococcus bacteria is Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophvticus, Staphylococcus intermedius, Staphylococcus hyicus subsp, hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharoiyticus.
• the Staphylococcus bacteria is Staphylococcus aureus.
• the lung infection is caused by a gram-positive anaerobic bacteria.
• the lung infection is caused by one or more bacteria selected from the group consisting of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.
• the lung infection is caused by an acid-fast bacteria.
• the lung infection is caused by one or more bacteria selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae. In embodiments, the lung infection is caused by an atypical bacteria. In embodiments, the lung infection is caused by one or more bacteria selected from the group consisting of Chlamydia pneumoniae and Mycoplasma pneumoniae.
• Embodiment I A method for treating a Pseudomonas aeruginosa pulmonary infection in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levofloxacin to the high-risk cystic fibrosis patient,
• Embodiment 2 A method for reducing the incidents of a pulmonary exacerbation in a high- risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levofloxacin to the high-risk cy stic fibrosis patient.
• Embodiment 3 A method for extending the time between the onset of pulmonary exacerbations in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 4 A method for treating a pulmonary bacterial infection in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levofloxacin to the high-risk cystic fibrosis patient
• Embodiment 5 A method of treating a pulmonary exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levofloxacin to the high-risk cystic fibrosis patient
• Embodiment 6 A method of treating cystic fibrosis in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levoiloxacin to the high-risk cystic fibrosis patient.
• Embodiment 7 A method of reducing a Pseudomonas aeruginosa sputum density in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising levoiloxacin to the high-risk cystic fibrosis patient.
• Embodiment 8 The method of any one of Embodiments 1-7, wherein the high-risk patient had at least 3 occurrences of a pulmonary exacerbation in the prior year.
• Embodiment 9 The method of any one of Embodiments 1 -7, wherein the high-risk patient had at least 4 occurrences of a pulmonary exacerbation in the prior year.
• Embodiment 10 The method of any one of Embodiments 1-7, wherein the high-risk patient had at least 5 occurrences of a pulmonary exacerbation in the prior year.
• Embodiment 11 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation comprises at least four of the following: (i) a change in sputum; (ii) a new or increased hemoptysis, (iii) an increased cough, (iv) increased dyspnea; (v) malaise, fatigue, or lethargy; (vi) a temperature above 38°C; (vii) anorexia or weight loss; (viii) sinus pain or tenderness; (ix) a change in sinus discharge; (x) a change in physical examination of the chest; (xi) a decrease in pulmonary function by 10% or more from a previously recorded value, and (xii) a radiographic change indicative of pulmonary infection.
• Embodiment 12 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation is a pulmonary bacterial infection
• Embodiment 13 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation is a Pseudomonas aeruginosa pulmonary infection
• Embodiment 14 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation is a Pseudomonas pulmonary infection
• Embodiment 15 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation is a Staphylococcus aureus pulmonary infection.
• Embodiment 16 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation is a Staphylococcus pulmonary infection.
• Embodiment 17 The method of any one of Embodiments 2, 3, 5, and 8-10, wherein the pulmonary exacerbation is a decrease of 10% or more in the FEV j of the predicted value using Hankinson/NHANES III reference equation.
• Embodiment 18 The method of any one of Embodiments 1 -17, wherein the high-risk patient has a forced expiratory volume in 1 second (FEV 1 ) between 25 and 85 percent of their predicted values using Hankinson/NHANES III reference equation.
• FEV 1 forced expiratory volume in 1 second
• Embodiment 19 The method of any one of Embodiments 1-17, wherein the high-risk patient had a chronic airway infection with Psendomonas aeruginosa and had received at least three 28-day courses of an inhaled tobramycin formulation in the prior year,
• Embodiment 20 The method of any one of Embodiments 1 -17, wherein the high-risk patient had a chronic airway infection with Psendomonas aeruginosa and had received at least three 28-day courses of an inhaled aminoglycoside formulation in the prior year, an inhaled monobactam formulation in the prior year, an inhaled polymyxin formulation in the prior year, or a combination of two or more thereof.
• Embodiment 21 The method of any one of Embodiments 1 -20, wherein the solution comprises levofloxacin or ofloxacin and a divalent or trivalent cation.
• Embodiment 22 The method of Embodiment 21, wherein the trivalent cation is aluminum or iron.
• Embodiment 23 The method of any one of Embodiments 1-20, wherein the solution comprises levofloxacin and a divalent cation.
• Embodiment 24 The method of Embodiment 23, wherein the divalent cation is magnesium, calcium, zinc, copper, or iron,
• Embodiment 25 The method of Embodiment 23, wherein the divalent cation is magnesium.
• Embodiment 26 The method of any one of Embodiments 1-20, wherein the solution comprises about 75 mg/ml to about 150 mg/ml of levofloxacin and about 150 mM to about 250 mM of a divalent cation.
• Embodiment 27 The method of Embodiment 26, wherein the divalent cation is magnesium, calcium, zinc, copper, or iron.
• Embodiment 28 The method of Embodiment 26, wherein the divalent cation is magnesium.
• Embodiment 29 The method of any one of Embodiments 1 -20, wherein the solution comprises about 90 mg/ml to about 1 10 ma ml of levofloxacm and about 190 mM to about 210 mM of a divalent cation.
• Embodiment 30 The method of Embodiment 29, wherein the divalent cation is magnesium, calcium, zinc, copper, or iron.
• Embodiment 31 The method of Embodiment 29, wherein the divalent cation is magnesium.
• Embodiment 32 The method of any one of Embodiments 1 -20, wherein the solution comprises about 80 mg/ml to about 120 ma ml of levofloxacm and about 180 mM to about 220 mM of a divalent cation.
• Embodiment 33 The method of Embodiment 32, wherein the divalent cation is magnesium, calcium, zinc, copper, or iron.
• Embodiment 34 The method of Embodiment 32, wherein the divalent cation is magnesium.
• Embodiment 35 The method of any one of Embodiments 1 -20, wherein solution comprises about 100 mg/ml of levofloxacin and about 200 mM magnesium chloride.
• Embodiment 36 A method for treating a Pseudomonas aeruginosa pulmonary infection in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 37 A method for reducing the incidents of a pulmonary exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 38 A method for extending the time between the onset of pulmonary exacerbations in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 39 A method for treating a pulmonary bacterial infection in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 40 A method of treating a pulmonary exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 41 A method of treating cystic fibrosis in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 42 A method of reducing a Pseudomonas aeruginosa sputum density in a high-risk cy stic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising ofloxacin to the high-risk cystic fibrosis patient.
• Embodiment 43 The method of any one of Embodiments 36-42, wherein the high-risk patient had at least 3 occurrences of a pulmonary exacerbation in the prior year.
• Embodiment 44 A method for treating a Pseudomonas aeruginosa pulmonary infection in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 45 A method for reducing the incidents of a pulmonary exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 46 A method for extending the time between the onset of pulmonary exacerbations in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 47 A method of reducing a Pseudornonas aeruginosa sputum density in a high-risk cy stic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 48 A method for treating a pulmonary bacterial infection in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 49 A method of treating a pulmonary exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 50 A method of treating cystic fibrosis in a high-risk cystic fibrosis patient in need thereof comprising administering a therapeutically effective amount of an aerosol of a solution comprising a fluoroquinolone to the high-risk cystic fibrosis patient.
• Embodiment 51 The method of any one of Embodiments 44-50, wherein the
• fluoroquinolone is ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, iomefloxacin, moxifloxacin, norfloxacin, pefloxacin, sparfloxacin, garenoxacin, sitagloxacin, or DX-619.
• Embodiment 52 The method of any one of Embodiments 44-50, wherein the high-risk patient had at least 3 occurrences of a pulmonary exacerbation in the prior year.
• Embodiment 53 A method for treating a Pseudornonas aeruginosa pulmonary infection in a high-risk cystic fibrosis patient in need thereof comprising administering by inhalation a therapeutically effective amount of a pharmaceutical composition comprising an antibiotic to the high-risk cystic fibrosis patient.
• Embodiment 54 A method for reducing the incidents of a pulmonary' exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering by inhalation a
• Embodiment 55 A method for extending the time between the onset of pulmonary exacerbations in a high-risk cystic fibrosis patient in need thereof comprising administering by inhalation a therapeutically effective amount of a pharmaceutical composition comprising an antibiotic to the high-risk cystic fibrosis patient.
• Embodiment 56 A method for treating a pulmonary bacterial infection in a high-risk cystic fibrosis patient in need thereof comprising administering by inhalation a therapeutically effective amount of a pharmaceutical composition comprising an antibiotic to the high-risk cystic fibrosis patient.
• Embodiment 57 A method of treating a pulmonary exacerbation in a high-risk cystic fibrosis patient in need thereof comprising administering by inhalation a therapeutically effective amount of a pharmaceutical composition comprising an antibiotic to the high-risk cystic fibrosis patient.
• Embodiment 58 A method of treating cystic fibrosis in a high-risk cystic fibrosis patient in need thereof compri sing administering by inhalation a therapeutically effective amount of a pharmaceutical composition comprising an antibiotic to the high-risk cystic fibrosis patient.
• Embodiment 59 The method of any one of Embodiments 53-58, wherein the high-risk patient had at least 3 occurrences of a pulmonary exacerbation in the prior year.
• Embodiment 60 The method of any one of Embodiments 53-59, wherein the antibiotic is tobramycin.
• Embodiment 61 The method of any one of Embodiments 53-59, wherein the antibiotic is aztreonam.
• Embodiment 62 The method of Embodiment 61 , wherein the aztreonam is aztreonam lysine.
• Pulmonary exacerbations are important events among persons with cystic fibrosis and are a significant risk factor for future pulmonary exacerbations and pulmonary deterioration.
• Levof!oxacin inhalation solution was evaluated in an open-label study with tobramycin inhalation solution over three 28-day cycles, with intervals of 28-days off treatment.
• levofloxacm inhalation solution refers to an aerosol of a solution containing about 100 mg/ml of levofloxacin and about 200 mM magnesium chloride.
• a pulmonary exacerbation occurred when a patient met at least four of the twelve Fuchs criteria and was prescribed an antibiotic treatment.
• Prior-year pulmonary exacerbation categories were defined as 0, 1 -2, or >3 pulmonary exacerbations.
• Endpoints The primary efficacy endpoint was the time to a pulmonary exacerbation of cystic fibrosis lung disease (i.e., pulmonary illness).
• cystic fibrosis lung disease i.e., pulmonary illness.
• patients must have had changes in >4 of the 12 Fuchs criteria, independent of a clinician's decision to treat the patient with an antibiotic.
• Use of the term "pulmonary exacerbation" in this manner is a modification of the above definition, which requires a clinician's decision to affirmatively treat with antibiotics (e.g. IV antibiotics) for a respiratory (as opposed to other) event.
• modified pulmonan,' exacerbation endpoint or “modified pulmonary exacerbation” or “protocol-defined pulmonary exacerbation” is used because the clinician may or may not have made a decision to treat a patient with an antibiotic when the patient had at least 4 of the 12 Fuchs criteria.
• Additional endpoints included absolute change from baseline in FEV 1 percent predicted, change from baseline in CF Questionnaire -Revised (CFQ-R) respirator ⁇ ' symptom score, and change from baseline in sputum Pseudomonas aeruginosa density (log 10 colony-forming units (CFU) per gram sputum).
• CFQ-R CF Questionnaire -Revised
• CFU colony-forming units
• Respiratory secretions throat swabs or sputum
• Respiratory secretions were collected at ail study visits for selective bacterial culture by central laboratories.
• Distinct Pseudomonas aeruginosa morphotypes from patients were analyzed separately.
• Bacterial densities in sputum specimens were determined by dilution plating.
• Pseudomonas aeruginosa sputum density for change in Pseudomonas aeruginosa sputum density and Baseline score for change in the Respiratory Domain of the CFQ-R.
• a post-hoc analysis of time to pulmonary exacerbation i.e., as defined by either the modified pulmonary exacerbation endpoint or by administration of antipseudomonal antibiotics was performed among patient subgroups defined by the number of pulmonary exacerbations treated with intravenous antibiotics they had experienced in the prior year.
• Hazard ratios levofloxacin inhalation solution/placebo
• log rank P values were determined by Kaplan-Meier survival analysis.
• sample sizes were estimated based upon time-to-need for systemic or inhaled antimicrobials observed for placebo patients of a previous levofloxacin inhalation solution study. In that prior stiidy, an event-free rate of 0.50 at Day 56 was observed.
• a 2: 1 (levofloxacin inhalation solution: placebo) randomization, a maximum follow-up time of 56 day s, and use of a 2- sided log rank test at the 5% level of significance was determined to require 261 patients to obtain 90% power to detect a hazard ratio (FIR) of 0,52 (ratio of the risk of use of a systemic or inhaled antimicrobial for a pulmonary exacerbation in the levofloxacin inhalation solution arm to the risk of same for a pulmonary exacerbation in the placebo arm).
• FIR hazard ratio
• the sample size was subsequently increased to account for a secondary endpoint of interest, relative change in FEVi percent predicted, in keeping with the primary endpoint of a Phase 3, open-label, randomized trial to compare the safety and efficacy of levofloxacin inhalation solution with TIS over 3 consecutive cycles.
• Elborn et ai Journal of Cystic Fibrosis, 14(4):507-514 (2015).
• the planned sample size was increased to 330 patients to obtain >90% power to detect an 8.0 percentage point treatment difference in relative change in FEVi percent predicted, assuming a 2-sided test at the 5% level of significance, a standard deviation of 20%, and 2: 1 randomization to levofloxacin inhalation solution: placebo.
• Approximately 415 patients were to be screened to enroll approximately 330 patients, assuming a 20% screening failure rate.
• MIC Levofloxacin minimum inhibitory concentrations
• CFQ-R Respiratory Domain Scores on the Respirator ⁇ ' Domain of the CFQ-R were similar in the treatment groups at Baseline and both treatment groups had a similar mean increase in CFQ-R Respiratory Domain score from Baseline to Day 28. The results were similar at ail time points. The between-group difference was not significant in the ITT population.
• this post hoc analysis shows that a levofloxacin inhalation solution treatment effect (as measured by hazard of antibiotic treatment for pulmonary symptoms) was more likely to be observed among patients at higher risk for exacerbation at study entry.
• a comparable relationship between prior-year levofloxacin inhalation solution exacerbation group and apparent levofloxacin inhalation solution treatment effect was not observed for the modified pulmonary exacerbation endpoint (Table 2).
• Table 2 Patients Meeting the Modified Pulmonary Exacerbation (PE) Endpoint or Treated with Antibiotics for Pulmonary Symptoms by Prior- Year Exacerbation History.
• PE Pulmonary Exacerbation
• the Hazard Ratio is based on levofloxacin inhalation solution (LIS)/Plaeebo, Kaplan Meier survival method.
• LIS demonstrated clinical efficacy by a reduction in bacterial density and an increase in lung function.
• levofloxacin inhalation solution demonstrates effective therapy for some patients with cystic fibrosis and chronic Pseiidomonas aeruginosa infection of the airways, particularly those patients with 3 or more pulmonary exacerbations in the prior year.
• Levofloxacin inhalation solution was approved by the EMA after a three on/off cycle 168- day study demonstrated clinical non-inferiority to tobramycin inhalation solution.
• a concern with extended levofloxacin inhalation solution use is a potential for reduction in levofloxacin-susceptible Pseiidomonas aeruginosa isolate prevalence.
• levofloxacin inhalation solution refers to an aerosol of a solution containing about 100 mg/ml of levofloxacin and about 200 mM magnesium chloride.
• Sputum or throat swabs were cultured for Pseiidomonas aeruginosa and other cystic fibrosis airway bacterial opportunists. Multiple Pseudomonas aeruginosa morphotypes were isolated when present and susceptibility was tested using microdilution with EUCAST breakpoints.

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