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Avalox iv cap&sss is 1

  1. 1. Avalox® …IV Momentumin CAP and SSSI A jump ahead
  2. 2. The Goal of Antimicrobial TherapyHit Early! Hit Hard! Hit Appropriately!A jump ahead 2
  3. 3. Agenda Mode of Action Spectrum of Activity Tissue Concentration/In Vitro Activity Clinical Efficacy Important Safety Considerations A jump ahead 3
  4. 4. Avalox® … Novel Molecular Structure O OHMoxifloxacin F O H N N NH O 8-methoxy subgroup minimizes H3C ability of Gram-positive bacteria to H acquire resistance. 8-methoxy subgroup Avalox® acts at two target sites to exert its bactericidal action: • Topoisomerase II (DNA gyrase): mainly in Gram-negative bacteria • Topoisomerase IV: mainly in Gram-positive bacteriaA jump ahead 4
  5. 5. Avalox® … Dual Target Action Super coiled DNA Topoisomerase Ava Ava Relaxed DNA llox ox Topoisomerase Topoisomerase II (i.e. gyrase) in Gram-negative bacteria Topoisomerase IV in Gram-positive bacteriaA jump ahead 5
  6. 6. Avalox MIC90s Against Common Respiratory PathogensOrganism MoxifloxacinS. pneumoniae (PenS) 0.06-0.25S. pneumoniae (PenR) 0.12-0.25H. influenzae BL (–) 0.03-0.06H. influenzae BL (+) 0.03-0.06M. catarrhalis BL (–) 0.012-0.06M. catarrhalis BL (+) 0.012-0.06BL = β-lactamase; MIC = minimum inhibitory concentration (mg/L). Blondeau JM. J Antimicrob Chemother. 1999;43(suppl B):1-11. A jump ahead 6
  7. 7. Moxifloxacin: in vitro activity against common Respiratory pathogens MIC90 (mg/mL) Organism Avalox Amoxicillin/ Levofloxacin Amoxicillin clavulanic Clarithromycin Cefuroxime acid Moxifloxacin S. pneumoniae 0.06–0.25 1–2 0.03–0.06 0.03 0.03–0.25 0.06–0.25 (PenS) S. pneumoniae 0.12–0.25 1–2 8 4 32–>256 8–16 (PenR) H. influenzae BL 0.03–0.06 0.03–0.32 1 1–2 8–24 2–8 (–) H. influenzae BL 0.03–0.06 0.03–0.47 8–128 1–2 8–16 2–4 (+) M. catarrhalis BL 0.012–0.06 0.06 0.25 0.38 0.06–4 2 (–) M. catarrhalis BL 0.012–0.06 0.06–0.094 >16 0.38 <0.06–0.38 3 (+) PenS, penicillin-susceptible; PenR, penicillin-resistant; BL, β-lactamaseA jump ahead Blondeau. J Antimicrob Chemother 1999; 43(Suppl B): 1–11 7
  8. 8. Avalox® … Broad Spectrum of Activity In vitro activity of Avalox® against pathogens commonly implicated in uncomplicated SSSIs and cSSSIs. Micro-organism MIC90 Gram-positive bacteria S. aureus 0.03 S. Aureus (methicillin-sensitive)* 0.06 S. aureus (methicillin-resistant) 4 S. Pyogenes 0.25 S. Pyogenes 0.25 (constitutive resistance) S. 0.25 Pyogenes (inducible resistance) 0.25 S. pyogenes (M- phenotype) *Methicillin-sensitive = MIC ≤8.0 mg/l Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557 Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.A jump ahead 8
  9. 9. Avalox® … Broad Spectrum of Activity In vitro activity of Avalox® against pathogens commonly implicated in uncomplicated SSSIs and cSSSIs. Micro-organism MIC90 Enterobacteriaceae Escherichia coli 0.015 Klebsiella pneumoniae 0.125 Proteus mirabilis 0.25 Enterobacter cloacae 0.06 Enterobacter spp. 0.062 Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557 Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.A jump ahead 9
  10. 10. Avalox® … Broad Spectrum of Activity In vitro activity of Avalox® against pathogens commonly implicated in uncomplicated SSSIs and cSSSIs. Micro-organism MIC90 Anaerobes Bacteroides fragilis 1.0 Clostridium perfringens 0.5 Peptostreptococcus spp. 1.0 Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557 Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.A jump ahead 10
  11. 11. Avalox® … Broad Spectrum of Activity In vitro activity of Avalox® against aerobic and anaerobic isolates caused by animal and human bites. Micro-organism MIC90 Aerobes Eikenella corrodens 0.06 Pasteurella canis – P. multocida subsp. multocida 0.016 P. multocida subsp. septica 0.016 Pasteurella spp.* 0.03 Staphylococcus epidermidis 0.06 Staphylococcus spp.† – EF-4b 0.25 Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557A jump ahead 11
  12. 12. Avalox® … Broad Spectrum of Activity In vitro activity of Avalox® against aerobic and anaerobic isolates caused by animal and human bites. Micro-organism MIC90 Anaerobes F. nucleatum 4.0 Fusobacterium spp. 8.0 Prevotella heparinolytica 0.125 Prevotella spp. 0.5 Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557A jump ahead 12
  13. 13. Rapid Penetration of Moxifloxacin Into relevant Tissues 1000 100 Macrophages Conc. (mg/l. mg/kg) 10 Epithelial lining fluid (ELF) 1 Bronchial Mucosa Serum 0,1 MIC90 of S. pneumoniae and M. catarrhalis (0.12 mg/l) MIC90 of H. influenzae (0.06 mg/l) 0,01 3 12 24 TIME (h) Andrews J et al., 1998A jump ahead 13
  14. 14. Avalox® … Rapid Tissue Penetration 10 Concentration of Moxifloxacin (mg/l) 8 7.6 6 4.6 4 3.1 2 1.7 1.0 * 0 ** Bone, Muscle Skin blister Subcutaneous Serum level Spongiosa fluid tissue * MIC90 ==0.25 mg/l, Enterococcus agalactiae, P. mirabilis, S.pyogenes MIC90 0.5 mg/l, S. aureus, S. faecalis ** Gusinde A., et al., Klinik & Forschung 2004, 10 (suppl. 1):44-45A jump ahead 14
  15. 15. Avalox® … Higher Conc. in Infected Tissue Relative time (h) Concentration of Moxifloxacin (mcg/l) Relative time (h) Concentrations measured in inflamed and normal tissue at the start of a 1-hour infusion of 400mg moxifloxacin I.v. and at 30-minutes intervals thereafter in subjects with cSSSI (geometric means and SD, N=6) Stass et al. Eur Congress Clin Microbiol Infect April 24 – 27, 2002, Milan, Italy. Abstract O178A jump ahead 15
  16. 16. Avalox® … Optimum Pharmacokinetics Avalox® … Oral Elimination half-life: ~12 hours Bioavailability: ~ 91% Protein binding 48 ± 2.5% Tmax: 0.5 – 4 hours Cmax (high): 3.1 - 4.5 mg/l Following a 400 mg Oral single doseA jump ahead 16
  17. 17. Avalox® … Optimum Pharmacokinetics Avalox® … I.V. Administration: I.V. drip within 1 hour AUC value (high): 39 mg.h/L Cmax (high) : 4.1 - 5.9 mg/L Following a 400 mg Oral single doseA jump ahead 17
  18. 18. Avalox® … Optimum Pharmacokinetics Oral dose Urinary Cmax (mg/L) T1/2 (hours) (mg) recovery (%) Avalox® 1,2 400 4.5 12.7 19 Levofloxacin3 750 5.7 7.6 87 Ciprofloxacin4 500 3.6 4 40–50 † Data shown are for the doses used in ABS 1) AVALOX® tablets US prescribing information, 2007 2) AVALOX® tablets UK prescribing information, 2006 3) LEVAQUIN® tablets US prescribing information, 2007 4) CIPRO® tablets US prescribing information, 2007A jump ahead 18
  19. 19. Avalox® …Fast Bacterial Eradication Survival (%) Over 99% killing after 150 minutes 99% Time (min) Bactericidal activity of maxifloxacin at 1.0 mg/l against a clinical isolate of staphybcoocus aureus in nutrient broth, sensitive to moxi.oxacin (mic 0.05 mg/l) Lister et al. Clin Infect Dis 2001; 32 (suppl) : S33-8A jump ahead 19
  20. 20. Avalox® Clinical Study in cSSSIA jump ahead 20
  21. 21. Sequential intravenous/oral moxifloxacin versus intravenous piperacillin-tazobactam followed by oral amoxicillin- clavulanate for the treatment of complicated skin and skin structure infectionGiordano P, Song J, Pertel P, Herrington J, Kowalsky S Int J Antimicrob Agents 2005; 26: 357–365A jump ahead 21 Dec-05
  22. 22. Study protocol Study design: Prospective, randomized, double-blind, double-dummy, multicenter study Treatments: Sequential IV/oral moxifloxacin, 400 mg once daily IV piperacillin-tazobactam, 3.0/0.375 g 6-hourly, followed by oral amoxicillin-clavulanate, 800 mg, b.i.d Duration: The total treatment duration: 7–14 days The IV treatments were given for at least 3 days Switch to oral therapy made at the discretion of the investigatorA jump ahead 22
  23. 23. Patients: Disposition: 617 patients randomized 367 satisfied the criteria for evaluation of efficacy 601 evaluable for safety Diagnosis: • Hospitalized patients aged ≥ 18 years • Complicated skin and skin structure infections - Ischemic ulcers - Diabetic foot, - Decubitus ulcers - Major abscesses, carbuncles - SSSIs needing surgery - Deep soft tissue infections (including surgical wounds), - Human or animal bite infections Expected to require ≥ 1 week of antibiotic treatment Over half had polymicrobial infectionsA jump ahead 23
  24. 24. Results: Clinical cure by infection type Moxifloxacin Control (n=187)* (n=180)*Overall 143/180 (79%) 153/187 (82%)Abscess 42/53 (79%) 52/56 (93%)Cellulitis 36/43 (84%) 38/43 (88%)Diabetic foot infection 25/37 (68%) 25/41 (61%)Ischemic/decubitus ulcer infection 10/13 (77%) 6/10 (60%)Surgical wound infection 11/12 (92%) 8/8 (100%)Complicated erysipelas 0/0 2/2 (100%)Infection with traumatic lesion 11/12 (92%) 10/13 (77%)Other 8/10 (80%) 12/14 (86%)*Efficacy-valid populationA jump ahead 24
  25. 25. Subset with Diabetic Foot Infections Moxifloxacin IV/PO Piperacillin-Tazobactam IV Amoxicillin-Clavulanate 80 75 PO 76 68 68 70 63 61 60 52 50 Patients (%) 50 40 30 20 10 0 Per investigator n/N Per investigator with Any foot infection + Any foot infection with 25/37 25/41 ulcer n/N 21/28 13/25 history of diabetes n/N ulceration + history of 28/41 29/46 diabetes n/N 22/29 *P=0.054 13/26 Efficacy-valid population. n=number of patients with response of clinical cure; N=total number of patients.A jump ahead 25
  26. 26. Results: Bacteriologic Eradication* Moxifloxacin ControlStaphylococcus aureus 50/64 (78%) 47/59 (80%)Streptococcus pyogenes 13/18 (72%) 8/12 (67%)Streptococcus agalactiae 7/13 (54%) 20/25 (80%)Enterococcus faecalis 12/18 (67%) 9/12 (75%)Escherichia coli 7/8 (88%) 11/12 (92%)Klebsiella pneumoniae 5/6 (83%) 4/7 (57%)Proteus mirabilis 3/5 (60%) 5/6 (83%)Enterobacter cloacae 4/5 (80%) 1 / 2 (50%)Peptostreptococcus spp. 6/10 (60%) 11/12 (92%)Bacteroides spp. 9/9 (100%) 9/10 (90%)Prevotella spp. 9/14 (64%) 9/11 (82%)Monomicrobial infection 50/59 (85%) 55/65 (85%)Polymicrobial infection 42/60 (70%) 41/53 (77%)*Confirmed and presumed eradicationData from selected causative pre-therapy skin organisms (microbiologically-valid population)A jump ahead 26
  27. 27. Summary Overall clinical cure rates were similar in the moxifloxacin (79%) and comparator (82%) groups • Differences in the clinical cure/eradication rates within subgroups could not be attributed directly to the treatments Moxifloxacin was as effective as the comparator in eradicating the most common pathogens In the treatment of cSSSIs, IV/oral moxifloxacin once daily is at least as effective and well tolerated as IV piperacillin-tazobactam four times daily followed by oral amoxicillin-clavulanate twice daily Results from this study support the role of moxifloxacin as monotherapy for the treatment of patients with moderate to severe DFIA jump ahead 27
  28. 28. Avalox® …Fast Cure Rate Avalox® Amoxicillin Clavulanate 45% 20% 0% 10% 20% 30% 40% 50% Clinical cure rate on day 7 in patients with cSSSIs (%) n=29 patients; all diabetic foot infections, n.s. Bogner JR et al., Chemother Journal, 13 (26) 2004A jump ahead 28
  29. 29. Avalox® …Shorter Therapy Avalox® Amoxicillin Clavulanate 4.3 days I.V. therapy 7 days 15 days Hospitalization 19 days 17 daysGeneral therapy 32 days 0 5 10 15 20 25 30 35 Duration of therapy in patients with cSSSIs (days) n=29 patients; all diabetic foot infections, n.s. Bogner JR et al., Chemother Journal, 13 (26) 2004A jump ahead 29
  30. 30. Avalox® In Community AcquiredPneumonia.Hazem SharafProduct Specialist
  31. 31. Treatment with sequential (I.V. /oral) moxifloxacin was associated with fasterclinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral therapy Welte T, Petermann W, Schuermann D, Bauer TT, Reimnitz P and the MOXIRAPID Study Group Clin Infect Dis 2005; 41: 1697–1705
  32. 32. Study protocol Prospective, multicenter, randomized, open-label, controlled trial in Europe. Interventions: • Moxifloxacin, 400 mg, once daily, given IV for at least 3 days; switch to oral at discretion of clinician; overall treatment duration 7–14 days. • IV ceftriaxone, 2 g, once daily ± IV erythromycin, 1 g, every 6–8 hours (if ‘atypical’ pathogen was proven or suspected). Clinical responses assessed at days 3–5, 7–14 (end of treatment) and 5–20 (test of cure) after final dose.A jump ahead 32
  33. 33. Study Design Randomization Moxifloxacin 400 mg once daily IV or orally for 7-14 days Patients with community acquired 3-5 Days 7-10 Days 5-20 Days Pneumonia Ceftriaxone 2gm IV once daily + erythromycin 1 gm 3-4 times daily IV if atypical pathogen suspected for 7-14 days Time of End of Test of cure Base Line therapy 5-20 days after therapy switch 7-10 days the final dose 3-5 DaysClinical infectious disease 2005:41:1697-705 A jump ahead 33
  34. 34. Patients Aged ≥ 18 years. Admitted to hospital within the last 5 days, with a diagnosis of community-acquired pneumonia. Requiring initial IV treatment. 161 per protocol patients received moxifloxacin. 156 per protocol patients received ceftriaxone (59 also received erythromycin).A jump ahead 34
  35. 35. Results: clinical success at test of cure 100 87.6 88.5 80 Moxifloxacin Ceftriaxone ± 60 erythromycinPatients (%) 40 20 141/161 138/156 0 Clinical cure A jump ahead 35
  36. 36. Results: clinical success amongst elderly and more severe CAP patients Ceftriaxone ± Moxifloxacin erythromycin P value Fine class IV+V 77.8% 70.4% 0.534 (21/27) (19/27) Age >74 years 81.5% 70.6% 0.326 (22/27) (24/34)A jump ahead 36
  37. 37. Results: speed of defervescence 100 98 100 Moxifloxacin (n=82) Patients with fever (%) 81 80 Ceftriaxone ± 65 61 erythromycin (n=74) 60 42 40 40 38 22 20 18 0 1 2 3 4 5 Duration of treatment (days)Defervescence was more rapid for moxifloxacin (median 3 days) than withceftriaxone ± erythromycin (median 4 days; P < 0.003)Fever: body temperature > 38.5°CA jump ahead 37
  38. 38. Results: patient-reported relief from symptoms Compared to ceftriaxone + erythromycin, moxifloxacin-treated patients reported a consistently faster improvement in signs and symptoms specific to CAP • Chest pain (P = 0.021) • Weakness (P = 0.015) • Sputum color (P = 0.002) Median time to feeling better: • Moxifloxacin: 3 days • Ceftriaxone + erythromycin: 4 daysA jump ahead 38
  39. 39. Results: duration of hospitalization Shorter mean duration of hospitalization with moxifloxacin (P < 0.001) • Moxifloxacin: 9.8 days. • Ceftriaxone + erythromycin: 11.1 days.A jump ahead 39
  40. 40. Equivalent tolerability and safety Number (%) of patients Moxifloxacin Ceftriaxone + (n = 200) erythromycin Variable (n = 197) Treatment emergent AE 114 (57.0) 125 (63.5) Drug-related AE 65 (32.5) 76 (38.6) Serious AE 31 (15.5) 29 (14.7) Drug-related serious AE 5 (2.5) 4 (2.0) Drug-related AEs with an incidence > 3% - Gastrointestinal symptoms 24 (12.0) 34 (17.3) - Phlebitis 3 (1.5) 12 (6.1) - Elevated γ- glutamyl transferase 2 (1.0) 7 (3.6) - Abnormal liver function tests 16 (8.0) 26 (13.2)A jump ahead 40
  41. 41. Conclusion Sequential moxifloxacin is at least as effective in terms of clinical cure as ceftriaxone ± erythromycin in the treatment of community-acquired pneumonia requiring initial parenteral therapy. Moxifloxacin is superior to ceftriaxone ± erythromycin in terms of: • Speed of defervescence. • Duration of hospital stay. Moxifloxacin has advantages over ceftriaxone ± erythromycin in terms of relief from symptoms like chest pain, weakness and sputum colour.A jump ahead 41
  42. 42. Summary of clinical moxifloxacin experience in patients with CAP: Moxifloxacin; Covers all the key pathogens including atypical and typical species. Accumulates in alveolar macrophages and epithelial lining fluids. Maintains bactericidal activity in macrophages. Achieves clinical response 94.4% bacteriological response 91% with 400 mg once daily given for 10 days.A jump ahead 42
  43. 43. Summary of clinical moxifloxacin experience in patients with CAP (2) Moxifloxacin Has excellent clinical and bacteriological efficacy independent from resistance to beta-lactams or macrolides. Has high clinical cure rates in polymicrobial community- aquired pneumonia. Offers clinical hints for a rapid onset of action.A jump ahead 43
  44. 44. Avalox® … Metabolism & Elimination Metabolites EliminationSulfo-compound (M-1) LIVER Hepatic ~ 60%Acyl-glucuronide (M-2) inactive Renal ~ 40% BILE Parent + M-1, M-2 STOMACH Enterohepatic cycling: Parent + M-2 BLOOD KIDNEY Fecal excretion: M-1 (35% of dose) Fecal excretion: unchanged Urine: 26% of dose M-1 (2.5% of dose) M-2 (14% of dose) Urinary excretion: ~ 20% of dose unchanged A jump ahead 44
  45. 45. Avalox - Metabolism ® • Avalox® is metabolised by conjugate formation (Phase II metabolism), not by cytochrome P450 • The conjugates of Avalox® are pharmacologically inactive (M1 and M2) Hence, there is minimal risk of drug–drug interactions duringA jump ahead combination/concomitant therapy 45
  46. 46. Renal impairmentPharmacokinetics of moxifloxacin p.o. Mild-to-moderate renal dysfunction • no clinically significant effect on PK* Renally-impaired patients undergoing hemodialysis or peritoneal dialysis • PK after single-dose and at steady-state comparable to healthy subjects and renally-impaired patients No adjustments to dose or timing relative to hemodialysis or peritoneal dialysis required Stass et al 2002a,b,cA jump ahead 46
  47. 47. Important Safety Considerations Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antimicrobial agents. Anaphylactic reactions, some following the first dose, have been reported in patients receiving quinolone therapy including moxifloxacin. The safety and effectiveness of moxifloxacin in pediatric patients, adolescents (less than 18 years of age), pregnant women, and lactating women have not been established.A jump ahead 47
  48. 48. Moxifloxacin use in the elderly Low risk of toxicity expected with MXF use in the elderly • No CYP450 interactions, thus reduced risk of common drug- drug interactions • No need for dose adjustment in presence of mild-moderate hepatic or severe renal dysfunction MXF PK are unaffected by age and no dosage adjustments are necessaryA jump ahead 48
  49. 49. Moxifloxacin Interactions No interaction with • calcium • food / dairy products • glyburide • p.o. contraceptives • ranitidine • morphine • theophylline • itraconazole • warfarin • digoxin Not metabolized by, nor affect, CYP 450 system Decreased absorption with antacids (↓60% AUC) and iron (↓40% AUC)**MXF should be taken at least 4 h before or 8 h after these agentsA jump ahead 49
  50. 50. Avalox® … Safety & Tolerability Dose adjustment Dose adjustment CYP450 for mild/moderate for severe renal metabolism hepatic impairment impairment Avalox® 1 No No No Levofloxacin2 Not stated No Yes Caution and Amoxicillin/ clavulanate 3 Not stated monitoring Yes recommended Cefuroxime axetil4 Not stated Not stated in SPC No 1) AVALOX® tablets UK prescribing information, 2006 2) TAVANIC® tablets UK prescribing information, 2006 3) AUGMENTIN® tablets US prescribing information, 2006 4) ZINNAT® tablets UK prescribing information, 2007A jump ahead 50
  51. 51. Avalox® … Contraindications Known hypersensitivity to moxifloxacin or other quinolones. Pregnancy and lactation. Children and adolescents. Impaired liver function. QTc-related contraindications.A jump ahead 51
  52. 52. Avalox® … Dosage Tablets 400 mg I.V. 400 mg, 250 mlA jump ahead 52
  53. 53. Avalox® … A jump ahead in the treatment of SSSIs Avalox® has many of the ideal features of an emperical treatment of CAP&SSSIs Effective: Broad spectrum of activity  Eradicates bacteria Fast  Highly active at sites of infection for 24 hrs.  High cure rates  Safe: • Minimal interactions  • Low resistance potential  • Suitable for all adult patient types  • Well tolerated  Simple: • Once-daily administration  • Short treatment duration  • Cost effectiveness A jump ahead 53
  54. 54. A jump ahead 54
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