+

US20030148964A1 - Single dose azithromycin - Google Patents

Single dose azithromycin Download PDF

Info

Publication number
US20030148964A1
US20030148964A1 US10/224,903 US22490302A US2003148964A1 US 20030148964 A1 US20030148964 A1 US 20030148964A1 US 22490302 A US22490302 A US 22490302A US 2003148964 A1 US2003148964 A1 US 2003148964A1
Authority
US
United States
Prior art keywords
dose
body weight
azithromycin
day
infection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/224,903
Other languages
English (en)
Inventor
Michael Dunne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US10/224,903 priority Critical patent/US20030148964A1/en
Priority to US10/628,102 priority patent/US6987093B2/en
Publication of US20030148964A1 publication Critical patent/US20030148964A1/en
Priority to US11/172,012 priority patent/US7067493B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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

  • the present invention relates to a method of treating infection by administering a single dosage of azithromycin.
  • Azithromycin is the U.S.A.N. (generic name) for 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antimicrobial compound derived from erythromycin A.
  • Azithromycin was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No. 4,517,359. These patents disclose that azithromycin and certain derivatives thereof possess antibacterial properties and are accordingly useful as antibiotics.
  • Azithromycin may be made, formulated and administered according to procedures described in the following US patents, which are all incorporated herein in their entirety by reference: U.S. Pat. Nos. 6,268,489; 4,963,531; 5,633,006; 5,686,587; 5,605,889; 6,068,859; 4,328,334; and 5,498,699.
  • Azithromycin is administered for the treatment of infections, particularly respiratory infections, more particularly respiratory infections of the bronchial tract, lungs, and sinus, and still more particularly acute otitis media.
  • Acute otitis media is an inflammation of the area behind the eardrum (tympanic membrane) in the chamber called the middle ear.
  • Acute otitis media is an infection that produces pus, fluid, and inflammation within the middle ear.
  • Acute otitis media may be caused by a variety of pathogens, such as M. catarrhalis, S. pneumoniae, and H. influenzae.
  • Acute otitis media is particularly common in infants and children.
  • Azithromycin has been prescribed for the treatment of acute otitis media with a 30 mg/kg body weight total treatment dose given as a five day regimen in the US and as a three day regimen in Europe.
  • the multiple dosages prescribed to completely cure the infection have caused compliance problems, particularly in pediatric patients. Even in the adult population, compliance with multiple dosaging regimens is not complete because of forgetfulness and other reasons.
  • a method of treating and curing infection, particularly a microbial infection such as acute otitis media, by administering a single dose of azithromycin would significantly shorten courses of therapy and be of a great advantage to patient compliance.
  • a continual problem with antibiotic therapy is the emergence of resistant microbial strains.
  • a method of treating microbial infections with a reduced risk of developing treatment-resistant strains is desirable. It is believed that a single dose azithromycin treatment provides such as reduced risk.
  • the inflammatory cells provide a mode of transport of azithromycin to the infection site and provide a reservoir for azithromycin at the infection site.
  • azithromycin is characterized by high and sustained concentrations in a wide range of tissues, and a particularly increased concentration at sites of infection.
  • a single dose therapy with azithromycin by providing a higher initial concentration at the infection site, may help prevent less susceptible sub-populations of the pathogens initially present from becoming established. Also, a single-dose regimen will result in greater patient compliance, which should contribute to reduced emergence of less susceptible strains.
  • a related resistance problem is the problem of treating infection caused by pathogens having a high susceptibility threshold to most therapeutically available antiinfective agents.
  • Such resistant pathogens are characterized by being unlikely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable and other therapy is needed.
  • the other therapy involves anti-infective agents with undesirable side effects, such as severe gastrointestinal distress or heightened sensitivity to sun.
  • Arguedas reported on single-dose therapy in otitis media using azithromycin in infants and children.
  • Arguedas, A. “Single-dose therapy in otitis media”, Poster Presentation at 9 th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, Germany, Mar. 21-24, 1999, Clin. Microbiol. Infect. 1999:5 (Supp. 3 March):28 (Abstr).
  • a single oral dose of 2 g azithromycin was administered to healthy male subjects in tests of gastrointestinal side effects reported in U.S. Pat. No. 6,068,859.
  • the present invention provides a method of treating a respiratory infection in a human comprising administering to a human in need thereof a single dose of azithromycin wherein the dose is about 30 mg/kg body weight or greater.
  • the invention is directed to a method of treating a respiratory infection in a human comprising administering to a human in need thereof a single dose of azithromycin wherein the dose is within the range of about 0.15 to 4.5 g.
  • a further embodiment is directed to a method of treating a respiratory infection caused by S. pneumoniae isolates in a human comprising administering to a human in need thereof a single dose of azithromycin.
  • a further embodiment involves the treatment of a respiratory infection in a human in which the respiratory infection is caused by an S. pneumoniae isolate containing a mef A gene.
  • the invention is directed to a method of treating a respiratory infection caused by H. influenzae in a human comprising administering to a human in need thereof a single dose of azithromycin.
  • a further embodiment is directed to a method of treating an infection caused by S. pyogenes in a human comprising administering to a human in need thereof a single dose of azithromycin.
  • the invention is directed to a method of treating an infection caused by E. faecalis in a human comprising administering to a human in need thereof a single dose of azithromycin.
  • the invention is also directed to a method of treating a respiratory infection caused by M. catarrhalis in a human comprising administering to a human in need thereof a single dose of azithromycin.
  • FIG. 1 shows Day 28 Outcome and MIC Distribution for azithromycin.
  • Baseline susceptibility data for azithromycin was available for 66 subjects with S. pneumonia who had a clinical outcome on day 28.
  • Clinical cure is shown in gray and clinical failures in black.
  • Isolates with an MIC of 8 ⁇ l/ml to azithromycin contained the mef A gene and isolates with an MIC>256 ⁇ l/mi contained the erm B gene.
  • FIG. 2 shows H. influenzae Clinical Outcome—Test of Cure Visit day 21-35.
  • the data is presented as clinical success (cure+improvement) or cure alone as shown in the label.
  • the vertical dashed lines mark the limits of the 95% confidence interval for single dose azithromycin. No attempt was made to adjust outcomes by important demographic variables.
  • FIGS. 3 a and 3 b show the eradication of H. influenzae in a gerbil model of middle ear infection.
  • FIG. 4 shows the impact of different dosage regimens of Augmentin® amoxicillin/clavulanate potassium (from GlaxoSmithKline, Inc.) on an infection of H. influenzae in a gerbil model of middle ear infection.
  • FIG. 5 shows azithromycin mouse serum concentrations following dosage of azithromycin administered over one, two or three days.
  • the invention provides a method of treating infections, particularly respiratory infections such as acute otitis media, in a human in need thereof by administering a single dose of azithromycin.
  • the human patient may be an adult sixteen years of age or older, a child under sixteen years of age, or a young child twelve years of age or younger.
  • single dose is meant a dosage that is administered only once over a 28-day period.
  • the dosage may be administered in a single dosage form, such as one capsule or tablet, or may be divided, e.g. constituted by more than one dosage form, such as by multiple capsules or tablets that are taken at or about the same time. Any type of dosage form may be used, such as capsule, tablet, liquid suspension for oral administration, or liquid for intravenous administration.
  • the “single dose” of the invention is formulated for immediate release and is not formulated for controlled, sustained or delayed release.
  • an orally administered azithromycin single dose administered according to the present invention is preferably in a form such that it releases azithromycin to the human gastrointestinal tract at a rate such that the total amount of azithromycin released therein is more than 4 mg of azithromycin per kg of patient weight in the first fifteen minutes after ingestion and more preferably is more than 30 mg of azithromycin per kg of weight in the first six hours after ingestion.
  • Azithromycin can be employed in its pharmaceutically acceptable salts and also in anhydrous as well as hydrated forms, such as the di- and mono-hydrates. All such forms are within the scope of this invention.
  • the azithromycin employed is preferably the dihydrate, which is disclosed in published European Patent Application 0 298 650 A2.
  • respiratory infections in humans are treated by administering azithromycin in a single dose of about 30 mg/kg body weight or greater.
  • the single dose is between about 30 mg/kg and 90 mg/kg.
  • Other preferred dosages are between about 30 mg/kg and 35 mg/kg body weight, between about 31 mg/kg and 35 mg/kg body weight, between about 35 mg/kg and 40 mg/kg body weight, between about 40 mg/kg and 45 mg/kg body weight, between about 45 mg/kg and 50 mg/kg body weight, between about 50 mg/kg and 55 mg/kg body weight, between about 55 mg/kg and 60 mg/kg body weight, between about 60 mg/kg and 65 mg/kg body weight, between about 65 mg/kg and 70 mg/kg body weight, between about 70 mg/kg and 75 mg/kg body weight, between about 75 mg/kg and 80 mg/kg body weight, between about 80 mg/kg and 85 mg/kg body weight, and between about 85 mg/kg and 90 mg/kg body weight.
  • Other preferred doses are the following doses: 31 mg/kg or greater, 32 mg/kg or greater, 33 mg/kg or greater, 34 mg/kg or greater, 35 mg/kg or greater, 36 mg/kg or greater, 37 mg/kg or greater, 38 mg/kg or greater, 39 mg/kg or greater, 40 mg/kg or greater, 41 mg/kg or greater, 42 mg/kg or greater, 43 mg/kg or greater, 44 mg/kg or greater, 45 mg/kg or greater, 46 mg/kg or greater, 47 mg/kg or greater, 48 mg/kg or greater, 49 mg/kg or greater, 50 mg/kg or greater, 51 mg/kg or greater, 52 mg/kg or greater, 53 mg/kg or greater, 54 mg/kg or greater, 55 mg/kg or greater, 56 mg/kg or greater, 57 mg/kg or greater, 58 mg/kg or greater, 59 mg/kg or greater, 60 mg/kg or greater, 61 mg/kg or greater, 62 mg/kg or greater, 63 mg/kg or greater, 64 mg/kg or greater,
  • the single dose of azithromycin is administered as a single dose within the range of about 0.15 to 4.5 g, preferably a dose within the range of about 0.15 to 1.5 g or about 1.5 to 4.5 g.
  • Other preferred doses are a single dose within the range of about 0.7 to 1.5 g, a single dose within the range of about 1.5 to 2.5 g, a single dose within the range of about 2.5 to 3.5 g, and a single dose within the range of about 3.5 to 4.5 g.
  • the single dose is selected from the group consisting of 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, and 4.5 g.
  • the methods of the invention may be used to treat infections caused or mediated by different pathogens.
  • the pathogen is selected from S. aureaus, S. pneumoniae, H. influenzae, M. catarrhalis, E. faecalis, and S. pyrogenes, and more preferably is selected from S. pneumoniae isolates having a mef A gene, H. influenzae and M. catarrhalis.
  • the invention preferably is directed to treating a respiratory infection such as acute otitis media caused or mediated in whole or part by one of these specified pathogens.
  • Azithromycin has a long half-life in infected tissues. On pharmocokinetic grounds, it is not the duration but rather the total dose of azithromycin that is predicted to correlate most closely with clinical efficacy. Craig, W. A., “Postantibiotic effects and the dosing of Macrolides, azalides, and streptogramins”, In: Zinner, S. H. et al. (editor) Expanding Indications for New Macrolides, Azalides, and Streptogramins, New York: Marel Dekker (1997), pp.27-38. A study was undertaken to examine the efficacy of a single 30 mg/kg oral dose of azithromycin in the treatment of acute otitis media in children.
  • a trial was performed using a single 30-mg/kg dose of azithromycin in the treatment of otitis media in pediatric patients. Children six months to twelve years were enrolled if they had symptoms and signs of acute otitis media (“AOM”) for less than four weeks and middle ear effusion by acoustic reflectometry. Symptoms necessary for enrollment included ear pain or fullness, discharge from the external auditory canal, decreased hearing or fever. On physical examination they must have had one or more of the following: bulging or marked erythema of the tympanic membrane, loss of the normal light reflex or tympanic membrane landmarks, or impaired tympanic mobility on biphasic pneumatic otoscopy.
  • the effusion was to be documented by acoustic reflectometry with an abnormal reading of 3 or higher. Patients were excluded if they had a history of hypersensitivity to macrolides or azithromycin, had been treated with antibiotics in the prior thirty days, had symptoms of otitis media for longer than four weeks, had tympanostomy tubes present, or had been receiving antimicrobial prophylaxis.
  • Middle ear fluid samples were obtained by tympanocentesis or, in the case of a perforated tympanic membrane, by swab. Middle ear fluid samples were obtained for culture at baseline. Patients then received azithromycin 30 mg/kg as a single dose. Children who vomited within thirty minutes of dosing were redosed.
  • the primary endpoint of the trial was the investigator designated cure rate at Day 24-28 for which a 95% confidence interval was computed using the normal approximation to the binomial distribution.
  • Other endpoints analyzed included the clinical response rate by baseline pathogen at Day 24-28, the overall clinical response at Day 10, the percentage of subjects with individual signs and symptoms, as well as findings from pneumatic otoscopy and acoustic reflectometry. Only Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were considered baseline pathogens for the purposes of these analyses.
  • pneumoniae isolate recovered on day 4 from the opposite ear. This second isolate had an MIC of >256 ⁇ g/ml, was resistant to clindamycin and contained the erm B gene. The two isolates also differed by pulsed field electrophoresis. Nine children had isolates of S. pneumoniae that were penicillin resistant (MIC ⁇ 2 ⁇ g/ml). Clinical cure at day 28 was seen in 6 of these children. The 3 children who failed therapy had isolates with an MIC>256 ⁇ g/ml to macrolides and contained the erm B gene.
  • the amount of drug delivered in the first 24 hours is higher with a single dose regimen compared with either the three day or five day treatment options. While the contribution of Cmax cannot be excluded, it is felt that outcome is likely to be best predicted by AUC 24 /MIC, supporting the overall comparability of these results to the three and five day regimens.
  • AUC 24 /MIC the efficacy in 6/7 patients, whose S. pneumoniae isolates were found to contain the mef A gene, responsible for efflux-mediated resistance.
  • the S. pneumoniae isolates having a mef A gene are known as resistant to macrolides.
  • Azithromycin which is a macrolide, surprisingly was able to effectively treat infections caused or mediated by S. pneumoniae isolates having a mef A gene when administered as a single dose of 30 mg/kg.
  • efflux pump resistance could be overcome by exposing resistant organisms to higher concentrations of drug earlier in the course of therapy was noteworthy.
  • influenzae 30/42 (71%) Day 24-28 Clinical Cure All Subjects 206/242 (85%) 80%, 90% Age ⁇ 2 years 64/83 (77%) 68%, 87% Age > 2 years 142/159 (89%) 84%, 94% By pathogen identified at baseline 100/124 (81%) S. pneumoniae 67/76 (88%) PC 23140 10 M. catarrhalis 10/10 H. influenzae 28/44 (64%)
  • inflammatory cells provide a mode of transport to the infection site and a reservoir for azithromycin at the infection site
  • superior delivery to the infection site is believed to occur when one administers large azithromycin doses as early as practical during the period where maximal inflammation is associated with the infection.
  • the higher initial concentration at the infection site may help prevent less susceptible sub-populations of the pathogens initially present from becoming established. This has been proposed as the reason for less in vivo emergence of resistance to azithromycin compared with clarithromycin in patients who received either drug for treatment or prophylaxis against M. avium.
  • a shorter oral dosage regimen would also result in greater patient compliance, which should contribute to reduced emergence of less susceptible strains.
  • H. influenzae strains 54A1100 and 54A1218 are non-typable isolates; 54A1218 also carries a TEM-1 ⁇ -lactamase.
  • colony-forming units (CFU) are assessed from the bulla wash of five gerbils per time point. The ED 50 values reflect the dose in which the CFU recoverable from the bulla wash is 50% of the non-treated animals.
  • azithromycin was the only one that was efficacious after a single oral 10 mg/kg dose in a Mycoplasma pneumoniae pulmonary infection model in hamsters. This efficacy correlated with the high Cmax and prolonged exposure for azithromycin in uninfected lungs compared with other macrolides.
  • azithromycin ⁇ an anti-inflammatory agent was superior to doxycycline and ofloxacin combinations in preserving fertility.
  • Azithromycin and clarithromycin are both active against the susceptible Streptococcus pneumoniae 02J1016 that produces a more slowly developing disease relative to other pneumococcal strains in the in vivo panel. In this pulmonary infection model 100% mortality in no-drug controls is not observed until 7 days post-infection. Clarithromycin was chosen as a comparator to azithromycin because the pharmacokinetics for these two macrolides are quite different. While clarithromycin achieves relatively high blood levels quickly and is cleared fairly rapidly, azithromycin accumulates in tissues and leeches out slowly over time into the bloodstream yielding overall lower blood levels than clarithromycin but a much longer exposure time. Additionally, the research of Craig et al.
  • Azithromycin performs the best when given once rather than the total dose being spread out over 3 days. It is important to note that while the azithromycin one day dosing PD 50 (20.4 mg/kg/regimen) is significantly different than the 3 day dosing PD 50 (49.4 mg/kg/regimen), both are within the 95% confidence limits of the 2 day dosing regimen PD 50 (27.6 mg/kg/regimen).
  • Clarithromycin fails (PD 50 >200 mg/kg/regimen) using the q.d. regimen regardless as to the duration of therapy. This is puzzling since clarithromycin has a MIC equivalent to that of azithromycin against 02J1016 (0.01-0.06 ⁇ g/ml). However, since clarithromycin is cleared more rapidly from the animal and this infection takes longer to manifest itself and cause mortality, this is most likely an accurate result. Previous efficacy data with clarithromycin in this pneumococcal pneumonia model was generated following BID administration over two days of therapy where clarithromycin therapy is successful with PD 50 s ranging from 5-25 mg/kg.
  • Azithromycin and clarithromycin were administered P.O. in diluent q.d. for 1, 2 or 3 days after an I.N. challenge with Streptococcus pneumoniae (02J1016).
  • Dose Mice (mg/kg/ Surviving/ PD50 Compound day)
  • Total (mg/kg/regimen)
  • Azithromycin P.O. 33.3 9/10
  • Lot #17419-64-1F 8.3 1/10 49.4 MIC 0.02-0.13 ⁇ g/ml 2.1 0/10 (28.1-70.8)* 3 day regimen 0.52 0/10 Azithromycin P.O.
  • Azithromycin and clarithromycin are both active against the susceptible Streptococcus pyogenes 02C0203.
  • the outcomes for various lengths of therapy were compared in this infection model, because the peritonitis caused by this strain lends itself to prolonged therapy as 100% mortality doesn't occur until 2-3 days post-challenge.
  • Clarithromycin was chosen as a comparator to azithromycin because the pharmacokinetics for these two macrolides are quite different. While clarithromycin achieves relatively high blood levels quickly and is cleared fairly rapidly, azithromycin accumulates in tissues and leeches out slowly over time into the bloodstream yielding overall lower blood levels than clarithromycin but a much longer exposure time. Additionally, the research of Craig et al.
  • azithromycin performs the best when given once rather than the total dose being spread out over 3 days.
  • the azithromycin 1 day dosing PD 50 (1.0 mg/kg/regimen) is significantly different than the 2 and 3 day dosing PD 50 s (2.5 and 3.8 mg/kg/regimen, respectively).
  • the 2 and 3 day dosing regimen PD 50 s are also significantly different from each other.
  • Clarithromycin has the best activity when given more often (2-days and 3-days dosing versus 1-day dosing).
  • the PD 50 s for the 2 and 3-day dosing regimens (3.1 and 2.2 mg/kg/regimen) are equivalent, while the PD 50 for the 1-day dosing regimen, 11.3 mg/kg/regimen), is clearly higher.
  • the 95% confidence limits for all three regimens are taken into account, it appears as though all three regimens are equivalent.
  • the 2 and 3-day therapies are more consistent with historical data for clarithromycin administered b.i.d. for 1-day.
  • Azithromycin and clarithromycin were administered P.O. in diluent q.d. for either 1, 2 or 3 days after an I.P. challenge with Streptococcus pyogenes (02C0203) starting 1.0 hour after infection.
  • Dose Mice (mg/kg/ Surviving/ PD50 Compound day) Total (mg/kg/regimen)
  • Azithromycin P.O. 12.5 10/10 Lot #17419-64-1F 3.12 10/10 3.8 MIC 0.01-0.10 ⁇ g/ml 0.78 3/10 (3.8-3.9)* 3 day regimen 0.20 0/10 Azithromycin P.O.
  • Clarithromycin (with a one day dose regimen and an MIC of 8 ⁇ g/ml) failed (PD50: >200 mg/kg s.c.).
  • Dose Mice (mg/kg/ Surviving/ PD50 Compound day) Total (mg/kg/regimen) Azithromycin s.c. 200 10/10 25.3 (17419-064-1F) 50 9/10 (14.3-36.2) 1 MIC: 0.5-1 ⁇ g/ml 12.5 1/10 Q.D. [1 day] 3.12 0/10 Azithromycin 100 10/10 49.9 (17419-64-1F) 25 5/10 (41.5-58.5) Q.D.
  • the same total therapeutic dose i.e., 200 mg/kg/therapeutic regimen
  • Q.D. on day one i.e., 200 mg/kg on day 1
  • Q.D. on day one and two i.e., 100 mg/kg on day 1 and 3
  • Q.D. on day one, two and three i.e., 67 mg/kg on day 1, 2 and 3
  • efficacy was best with one dose (14.8 mg/kg s.c.) and this accelerated dosing regimen was significantly better (p ⁇ 0.05).
  • a kinetic kill curve could be constructed which was designed to visually elucidate the observed in vivo therapeutic efficacy by examining the dose/time-kill relationship (FIG. 3 a ).
  • MIC Determinations Streptococcus pneumoniae, S. pyogenes, E. faecalis, and H. influenzae MICs were determined using the broth microdilution procedure recommended by the NCCLS. Test trays were incubated at 35C without carbon dioxide. For testing of streptococci, the cation-adjusted Mueller-Hinton broth was supplemented with 2-3% lysed horse blood. For testing H. influenzae, freshly prepared Haemophilus Test Medium broth was used.
  • S. pneumoniae 02J1016 serotype 3, originally isolated from blood culture (strain P 4241) (MLS- and penicillin-susceptible).
  • E. faecalis 03A1085, vancomycin susceptible clinically derived strain [0106] E. faecalis 03A1085, vancomycin susceptible clinically derived strain.
  • H. influenzae 54A1100 (43095 ATCC Fulghum strain) non-serotype B strain originally isolated from otitis media (macrolide and penicillin susceptible).
  • H. influenzae 54A1218 clinically derived non-serotype B strain (macrolide-susceptible, penicillin-resistant, TEM-1 beta-lactamase).
  • mice Female Swiss (CF-1) mice, 5-6 weeks of age (18-20 g): S. pneumoniae/pyogenes.
  • mice Female DBA/2 mice, 5-6 weeks of age (18-20 g): H. influenzae.
  • mice Female CF-1 mice were orally administered azithromycin at 100 mg/kg QD for one day, 50 mg/kg QD for two days and 33 mg/kg QD for three days.
  • Azithromycin was formulated in a 0.5% methylcellulose vehicle.
  • Blood and pulmonary tissue samples were taken starting at 0.5 h post-dose and at predetermined intervals over a 96 h period. Plasma and lung samples were prepared and maintained at ⁇ 70C. Plasma and pulmonary tissue concentrations of azithromycin were determined by a non-validated LC/MS assay using Turbo IonSpray mass spectrometry detection.
  • the lower limit of quantification (LLOQ) was 50 ng/ml.
  • the upper limit of quantification (ULOQ) was 1.25 ⁇ g/ml. Interassay variability was ⁇ 7%.
  • Pharmacokinetic parameters were calculated using the non-compartmental method by WinNonlin 2.1 (Scientific Consulting, Inc.).
  • the serum and pulmonary tissue pharmacokinetics of azithromycin were characterized at a total dose of 100 mg/kg dose administered over one, two, and three days (Table 8 and FIG. 5).
  • the serum and pulmonary tissue exposures are independent of dosing regimen. T max varies significantly.
  • C max is dependent on the dosing interval with the one-day regimen resulting in the highest C max .
  • the susceptibility breakpoints for azithromycin were defined as follows: Susceptible Intermediate Resistant Zone Zone Zone Pathogen MIC Diameter MIC Diameter MIC Diameter Streptococcus ⁇ 0.5 ⁇ 18 1 14-17 ⁇ 2 ⁇ 13 H. influenzae ⁇ 4 ⁇ 12 * * * M. catarrhalis ⁇ 2 ⁇ 18 4 14-17 ⁇ 8 ⁇ 13
  • H. influenzae has been a difficult organism to culture from the middle ear.
  • the use of PCR primers specific for this organism (and others) has been shown to have detection limits equivalent to 6-7 organisms and to be 85% concordant with traditional culture methods with no false positives.
  • the protocol was further validated by using reverse transcriptase-polymerase chain reaction to detect the presence of bacterial mRNA in a significant percentage of culturally sterile middle ear effusions, thereby establishing the presence of viable, metabolically active, intact organisms in patients with otitis media with effusion that are culture-negative. Using this methodology, seventeen additional patients were identified as having an H.
  • H. influenzae Historical Response Rates to Other Antibiotics Primary Antibiotic Response Comparator Response Endpoint Azithromycin 28/44 (64%) N/A N/A Clinical cure at TOC (1015) visit (day 24-28) Azithromycin 30/47 (64%) N/A N/A Presumptive (historical) bacterial/clinical cure outcomes (i.e., clinical success) at day 30 Cefpodoxime 50/76 (66%) Cefixime 61/81 (75%) Presumptive proxetil bacterial/clinical success outcomes (i.e., cured and improved) at 4-21 day post-therapy follow-up Clarithromycin 10/14 (71%) Oral 3/4 (75%) Presumptive Cephalosporin bacterial/clinical eradication/clinical cure outcomes (i.e., clinical success
  • the MITT subject had to have a positive culture from the middle ear for S. pneumoniae, H influenzae, or M. catarrhalis. Eradication was defined as presumed eradication of pretreatment pathogen(s) based on signs/symptoms or unavailability of culturable material. All evaluable patients had only one of the bacterial species present at baseline. There was no bacteriological response data collected for 95-001. However, the clinical outcome by bacterial pathogen at follow-up (approximately 28 days after first visit) was collected. For patients with S. pneumoniae as the baseline pathogen, all treatment arms yielded 100% clinical cure when the investigators' evaluations that were missing are not included in the analysis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
US10/224,903 2001-08-21 2002-08-21 Single dose azithromycin Abandoned US20030148964A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US10/224,903 US20030148964A1 (en) 2001-08-21 2002-08-21 Single dose azithromycin
US10/628,102 US6987093B2 (en) 2001-08-21 2003-07-25 Single dose azithromycin
US11/172,012 US7067493B2 (en) 2001-08-21 2005-06-29 Single dose azithromycin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31386701P 2001-08-21 2001-08-21
US10/224,903 US20030148964A1 (en) 2001-08-21 2002-08-21 Single dose azithromycin

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/628,102 Continuation US6987093B2 (en) 2001-08-21 2003-07-25 Single dose azithromycin

Publications (1)

Publication Number Publication Date
US20030148964A1 true US20030148964A1 (en) 2003-08-07

Family

ID=23217490

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/224,903 Abandoned US20030148964A1 (en) 2001-08-21 2002-08-21 Single dose azithromycin
US10/628,102 Expired - Fee Related US6987093B2 (en) 2001-08-21 2003-07-25 Single dose azithromycin
US11/172,012 Expired - Fee Related US7067493B2 (en) 2001-08-21 2005-06-29 Single dose azithromycin

Family Applications After (2)

Application Number Title Priority Date Filing Date
US10/628,102 Expired - Fee Related US6987093B2 (en) 2001-08-21 2003-07-25 Single dose azithromycin
US11/172,012 Expired - Fee Related US7067493B2 (en) 2001-08-21 2005-06-29 Single dose azithromycin

Country Status (25)

Country Link
US (3) US20030148964A1 (fr)
EP (1) EP1418924A2 (fr)
JP (1) JP2005501862A (fr)
KR (1) KR20040032942A (fr)
AP (1) AP1729A (fr)
BG (1) BG108537A (fr)
BR (1) BR0211830A (fr)
CA (1) CA2458135A1 (fr)
CZ (1) CZ2004232A3 (fr)
EA (1) EA200400214A1 (fr)
EC (1) ECSP044985A (fr)
GE (1) GEP20063812B (fr)
HR (1) HRP20040163A2 (fr)
HU (1) HUP0401332A2 (fr)
IL (1) IL159585A0 (fr)
IS (1) IS7092A (fr)
MA (1) MA27059A1 (fr)
MX (1) MXPA04001605A (fr)
OA (1) OA12845A (fr)
PL (1) PL367888A1 (fr)
SK (1) SK1012004A3 (fr)
TN (1) TNSN04035A1 (fr)
WO (1) WO2003018031A2 (fr)
YU (1) YU8804A (fr)
ZA (1) ZA200400804B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050209172A1 (en) * 2004-03-17 2005-09-22 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US9895385B2 (en) * 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10064882B2 (en) 2007-05-07 2018-09-04 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US10328071B2 (en) 2005-12-08 2019-06-25 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7572773B2 (en) * 2003-07-24 2009-08-11 Pliva Hrvatska D.O.O. Single dose fast dissolving azithromycin
CN1889932A (zh) 2003-12-04 2007-01-03 辉瑞产品公司 制备药用多颗粒的方法
WO2005053651A1 (fr) 2003-12-04 2005-06-16 Pfizer Products Inc. Compositions multiparticulaires a stabilite amelioree
WO2005053656A1 (fr) 2003-12-04 2005-06-16 Pfizer Products Inc. Procede d'atomisation/congelation faisant appel a une extrudeuse pour la preparation de compositions medicamenteuses cristallines multiparticulaires contenant de preference un poloxamere et un glyceride
US6984403B2 (en) 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
US20090005326A1 (en) * 2007-06-26 2009-01-01 Idexx Laboratories, Inc. Single dose roxithromycin
US20090197956A1 (en) * 2008-02-04 2009-08-06 Arbor Pharmaceuticals, Inc. Treatment of acute otitis media with xylitol and n-acetylcysteine
US20110105421A1 (en) * 2008-03-14 2011-05-05 The Florida International University Board Of Trustees Ellagitannins as inhibitors of bacterial quorum sensing
US20130156803A1 (en) 2011-06-04 2013-06-20 Rochester General Hospital Research Institute Compositions and methods related to p6
EP4103725A4 (fr) * 2020-02-14 2024-03-27 Asklepios Biopharmaceutical, Inc. Procédé de traitement d'une toxicité associée à une thérapie génique avec des antibiotiques

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US53264A (en) * 1866-03-20 Improved ditching-machine
YU43116B (en) 1979-04-02 1989-04-30 Pliva Pharm & Chem Works Process for preparing 11-aza-4-o-cladinosyl-6-o-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one(11-aza-10-deox
SI8110592A8 (en) 1981-03-06 1996-06-30 Pliva Pharm & Chem Works Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof
US4474768A (en) 1982-07-19 1984-10-02 Pfizer Inc. N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor
MX12213A (es) 1987-07-09 1993-05-01 Pfizer Metodo de preparacion de dihidrato de azitromicina cristalino
WO1989002271A1 (fr) 1987-09-10 1989-03-23 Pfizer Azithromycine et derives utilises comme agents anti-protozoaires
YU45590A (sh) 1990-03-07 1992-07-20 PLIVA FARMACEVTSKA, KEMIJSKA, PREHRAMBENA I KOZMETIČKA INDUSTRIJA s.p.o. Novi kompleksi odnosno helati antibiotika s dvovalentnim i/ili trovalentnim metalima i postupci za njihovo dobijanje
TW271400B (fr) 1992-07-30 1996-03-01 Pfizer
WO1994026758A1 (fr) 1993-05-19 1994-11-24 Pfizer Inc. Intermediaire s'appliquant a l'azithromycine
US5605889A (en) 1994-04-29 1997-02-25 Pfizer Inc. Method of administering azithromycin
SI9520049A (en) 1994-05-06 1997-12-31 Pfizer Controlled-release dosage forms of azithromycin
HRP980189B1 (en) * 1998-04-06 2004-04-30 Pliva Pharm & Chem Works Novel 15-membered lactams ketolides
US6239113B1 (en) * 1999-03-31 2001-05-29 Insite Vision, Incorporated Topical treatment or prevention of ocular infections
US20040053264A1 (en) * 2002-02-01 2004-03-18 Park Sung Sup Clinical panel assay using DNA chips

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US7468428B2 (en) 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
US20050209172A1 (en) * 2004-03-17 2005-09-22 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US10328071B2 (en) 2005-12-08 2019-06-25 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US10064882B2 (en) 2007-05-07 2018-09-04 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US10471149B2 (en) 2012-11-29 2019-11-12 Insmed Incorporated Stabilized vancomycin formulations
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US10751355B2 (en) 2014-05-15 2020-08-25 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11395830B2 (en) 2014-05-15 2022-07-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10398719B2 (en) 2014-05-15 2019-09-03 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9895385B2 (en) * 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10588918B2 (en) 2014-05-15 2020-03-17 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10238675B2 (en) 2014-05-15 2019-03-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10828314B2 (en) 2014-05-15 2020-11-10 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10251900B2 (en) 2014-05-15 2019-04-09 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11446318B2 (en) 2014-05-15 2022-09-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US12168022B2 (en) 2014-05-15 2024-12-17 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US12016873B2 (en) 2014-05-15 2024-06-25 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US12168021B2 (en) 2014-05-15 2024-12-17 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products
US12290600B2 (en) 2018-03-30 2025-05-06 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

Also Published As

Publication number Publication date
US6987093B2 (en) 2006-01-17
WO2003018031A2 (fr) 2003-03-06
AP1729A (en) 2007-03-26
AP2004002968A0 (en) 2004-03-31
CA2458135A1 (fr) 2003-03-06
BG108537A (bg) 2005-02-28
BR0211830A (pt) 2004-09-08
YU8804A (sh) 2006-08-17
MA27059A1 (fr) 2004-12-20
MXPA04001605A (es) 2004-07-08
PL367888A1 (en) 2005-03-07
EA200400214A1 (ru) 2004-06-24
US20040023898A1 (en) 2004-02-05
HRP20040163A2 (en) 2005-02-28
OA12845A (en) 2006-09-15
TNSN04035A1 (fr) 2006-06-01
IL159585A0 (en) 2004-06-01
SK1012004A3 (sk) 2005-04-01
HUP0401332A2 (hu) 2004-11-29
ECSP044985A (es) 2004-04-28
US7067493B2 (en) 2006-06-27
JP2005501862A (ja) 2005-01-20
WO2003018031A3 (fr) 2003-10-02
US20050250712A1 (en) 2005-11-10
ZA200400804B (en) 2005-05-03
KR20040032942A (ko) 2004-04-17
EP1418924A2 (fr) 2004-05-19
CZ2004232A3 (cs) 2005-10-12
IS7092A (is) 2003-12-23
GEP20063812B (en) 2006-05-10

Similar Documents

Publication Publication Date Title
US6987093B2 (en) Single dose azithromycin
O'doherty et al. Randomized, multicentre study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of adults with mild to moderate community-acquired pneumonia
Nord The role of anaerobic bacteria in recurrent episodes of sinusitis and tonsillitis
Hagberg et al. Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia
Arguedas et al. Single-dose extended-release azithromycin versus a 10-day regimen of amoxicillin/clavulanate for the treatment of children with acute otitis media
JP5782615B2 (ja) オリタバンシンの単回用量を用いる治療の方法
Garau Clinical failures: the tip of the iceberg?
Azoulay-Dupuis et al. In vivo efficacy of a new fluoroquinolone, sparfloxacin, against penicillin-susceptible and-resistant and multiresistant strains of Streptococcus pneumoniae in a mouse model of pneumonia
Hammerschlag Activity of gemifloxacin and other new quinolones against Chlamydia pneumoniae: a review
Mobs et al. A comparative study of azithromycin and amoxycillin in paediatric patients with acute otitis media
Clement et al. A comparison of the efficacy, tolerability and safety of azithromycin and co-amoxiclav in the treatment of sinusitis in adults
Onyeji et al. Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus pneumoniae in a mouse model of experimental septicaemia
Marchi Comparative efficacy and tolerability of clarithromycin and amoxycillin in the treatment of out-patients with acute maxillary sinusitis
Herron Roxithromycin in the therapy of Streptococcus pyogenes throat infections
Leibovitz et al. Acute otitis media in children: current epidemiology, microbiology, clinical manifestations, and treatment
Müller An open comparative study of azithromycin and roxithromycin in the treatment of acute upper respiratory tract infections
Lauvau et al. An open, multicentre, comparative study of the efficacy and safety of azithromycin and co-amoxiclav in the treatment of upper and lower respiratory tract infections in children
Brook A pooled comparison of cefdinir and penicillin in the treatment of group A β-hemolytic streptococcal pharyngotonsillitis
Maesen et al. Pulse dosing with bacampicillin in treatment of acute exacerbations of chronic bronchitis
Johnson et al. Efficacy and tolerability of moxifloxacin in the treatment of acute bacterial sinusitis caused by penicillin-resistant Streptococcus pneumoniae: a pooled analysis
EP0225329B1 (fr) Vaccin sans adjuvant
Pozzi Clinical efficacy of dirithromycin versus miocamycin in the treatment of acute bronchitis or acute exacerbations of chronic bronchitis
Cazzola et al. A five-day course of dirithromycin in the treatment of acute exacerbation of severe chronic obstructive pulmonary disease
Hotomi et al. Efficacy of a novel oral carbapenem, tebipenem pivoxil (TBM-PI), against experimental otitis media caused by penicillin resistant Streptococcus pneumoniae in chinchilla
KIZILAY PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF MOXIFLOXACIN

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载