Avalox iv cap&sss is 1

Avalox® …IV Momentumin CAP and SSSI

A jump ahead

2A jump ahead

Hit Early!Hit Early! Hit Hard!Hit Hard!

Hit Appropriately!Hit Appropriately!

The Goal of Antimicrobial Therapy

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Agenda

Mode of Action

Spectrum of Activity

Tissue Concentration/In Vitro Activity

Clinical Efficacy

Important Safety Considerations

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Avalox® … Novel Molecular Structure

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 bacteria

8-methoxy subgroup minimizes ability of Gram-positive bacteria to

acquire resistance.

8-methoxy subgroup minimizes ability of Gram-positive bacteria to

acquire resistance.

8-methoxy subgroup

MoxifloxacinMoxifloxacin

N

NH

H

N

O

F

H

H3C

O

O

OH

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Avalox® … Dual Target Action

Topoisomerase II (i.e. gyrase) in Topoisomerase II (i.e. gyrase) in Gram-negativeGram-negative bacteria bacteriaTopoisomerase IV in Topoisomerase IV in Gram-positiveGram-positive bacteria bacteria

Relaxed DNA

Super coiled DNA

Topoisomerase

Topoisomerase

Avalo

xA

valox

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Avalox MIC90s Against Common Respiratory Pathogens

BL = -lactamase; MIC = minimum inhibitory concentration (mg/L).

0.012-0.06M. catarrhalis BL (+)

0.012-0.06M. catarrhalis BL (–)

0.03-0.06H. influenzae BL (+)

0.03-0.06H. influenzae BL (–)

0.12-0.25S. pneumoniae (PenR)

0.06-0.25S. pneumoniae (PenS)

MoxifloxacinOrganism

Blondeau JM. J Antimicrob Chemother. 1999;43(suppl B):1-11.

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Moxifloxacin: in vitro activity against common Respiratory pathogens

Organism

MIC90 (mg/mL)

AvaloxAvalox

Moxifloxacin

Levofloxacin AmoxicillinAmoxicillin/ clavulanic

acidClarithromycin Cefuroxime

S. pneumoniae (PenS)

0.06–0.25 1–2 0.03–0.06 0.03 0.03–0.25 0.06–0.25

S. pneumoniae (PenR)

0.12–0.25 1–2 8 4 32–>256 8–16

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

Blondeau. J Antimicrob Chemother 1999; 43(Suppl B): 1–11

PenS, penicillin-susceptible; PenR, penicillin-resistant; BL, β-lactamase

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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

S. Aureus (methicillin-sensitive)*

S. aureus (methicillin-resistant)

S. Pyogenes

S. Pyogenes

(constitutive resistance)

S. Pyogenes (inducible resistance)

S. pyogenes

(M-phenotype)

0.03

0.06

4

0.25 0.25 0.25

0.25

*Methicillin-sensitive = MIC ≤8.0 mg/l

Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.

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Enterobacteriaceae

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Enterobacter cloacae

Enterobacter spp.

0.015

0.125

0.25

0.06

0.062


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Anaerobes

Bacteroides fragilis

Clostridium perfringens

Peptostreptococcus spp.

1.0

0.5

1.0


13A jump aheadAndrews J et al., 1998

Co

nc.

(m

g/l

. m

g/k

g)

Macrophages

Bronchial Mucosa

Serum

MIC90 of S. pneumoniae and M. catarrhalis (0.12 mg/l) MIC90 of H. influenzae (0.06 mg/l)

0,01

0,1

1

10

100

1000

3 12 24 TIME (h)

Epithelial lining fluid (ELF)

Rapid Penetration of Moxifloxacin Rapid Penetration of Moxifloxacin Into Into relevant Tissuesrelevant Tissues

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4.6

7.6

1.71.0

3.1

0

2

4

6

8

10

Bone,Spongiosa

Muscle Skin blisterfluid

Subcutaneoustissue

Serum level

Co

nc

en

tra

tio

n o

f M

ox

iflo

xa

cin

(m

g/l)

Avalox® … Rapid Tissue Penetration

***

*** MIC90 = 0.25 mg/l, S. aureus, S. agalactiae, P. mirabilis, S.pyogenes

Gusinde A., et al., Klinik & Forschung 2004, 10 (suppl. 1):44-45

MIC90 = 0.5 mg/l, Enterococcus faecalis

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Avalox® … Higher Conc. in Infected Tissue

Re

lati

ve

tim

e (

h)

Co

nc

en

tra

tio

n o

f M

ox

iflo

xa

cin

(m

cg

/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 O178

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Avalox® … Optimum Pharmacokinetics

Avalox® … Oral

Elimination half-life:

Bioavailability:

Protein binding

Tmax:

Cmax (high):

~12 hours

~ 91%

48 ± 2.5%

0.5 – 4 hours

3.1 - 4.5 mg/l

Following a 400 mg Oral single dose

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Avalox® … I.V.

Administration:

AUC value (high):

Cmax (high) :

I.V. drip within 1 hour

39 mg.h/L

4.1 - 5.9 mg/L

Following a 400 mg Oral single dose

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Oral dose (mg)

Cmax (mg/L) T1/2 (hours)Urinary

recovery (%)

Avalox® 1,2 400 4.5 12.7 19

Levofloxacin3 750 5.7 7.6 87

Ciprofloxacin4 500 3.6 4 40–50

1) AVALOX® tablets US prescribing information, 20072) AVALOX® tablets UK prescribing information, 20063) LEVAQUIN® tablets US prescribing information, 20074) CIPRO® tablets US prescribing information, 2007

†Data shown are for the doses used in ABS

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Avalox® …Fast Bacterial Eradication

Over 99% killing after 150 minutes

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)

Su

rviv

al (

%)

Lister et al. Clin Infect Dis 2001; 32 (suppl) : S33-8

99%

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Avalox® Clinical Study in cSSSI

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Sequential intravenous/oral moxifloxacin versus intravenous piperacillin-tazobactam followed by oral amoxicillin-clavulanate for the treatment of complicated skin and skin structure infection

Giordano P, Song J, Pertel P, Herrington J, Kowalsky S Int J Antimicrob Agents 2005; 26: 357–365

Dec-05Dec-05

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Study protocol

The IV treatments were given for at least 3 days

Switch to oral therapy made at the discretion of the investigator

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

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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 infections

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Results:

Moxifloxacin (n=180)*

Control (n=187)*

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 population*Efficacy-valid population

Clinical cure by infection type

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Subset with Diabetic Foot Infections

6875

6876

61

52

63

50

0

10

20

30

40

50

60

70

80

Per investigator n/N25/37 25/41

Per investigator withulcer n/N 21/28 13/25

Any foot infection +history of diabetes n/N

28/41 29/46

Any foot infection withulceration + history of

diabetes n/N 22/2913/26

Pat

ien

ts (

%)

Moxifloxacin IV/PO

Piperacillin-Tazobactam IV Amoxicillin-ClavulanatePO

*P=0.054 Efficacy-valid population. n=number of patients with response of clinical cure; N=total number of patients.

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Results:

Moxifloxacin Control

Staphylococcus 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 eradication*Confirmed and presumed eradication

Data from selected causative pre-therapy skin organisms (microbiologically-valid population)Data from selected causative pre-therapy skin organisms (microbiologically-valid population)

Bacteriologic Eradication*

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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 DFI

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Avalox® …Fast Cure Rate

45%

20%

0% 10% 20% 30% 40% 50%

Clinical cure rate on day 7 in patients with cSSSIs (%)

Avalox®

Amoxicillin Clavulanate

Bogner JR et al., Chemother Journal, 13 (26) 2004

n=29 patients; all diabetic foot infections, n.s.

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Avalox® …Shorter Therapy

0 5 10 15 20 25 30 35

General therapy

Hospitalization

I.V. therapy

Duration of therapy in patients with cSSSIs (days)

Avalox®

Amoxicillin Clavulanate4.3 days

7 days

15 days

17 days

19 days

32 days

Bogner JR et al., Chemother Journal, 13 (26) 2004

n=29 patients; all diabetic foot infections, n.s.

Avalox® In Community Acquired Pneumonia.

Hazem Sharaf Product Specialist

Treatment with sequential (I.V. /oral) moxifloxacin was associated with faster clinical 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

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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.

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Study Design

Randomization

Base LineTime of therapy switch3-5 Days

End of therapy 7-10 days

Test of cure 5-20 days after the final dose

Patients with community acquired Pneumonia

Moxifloxacin 400 mg once daily IV or orally for 7-14 days

Ceftriaxone 2gm IV once daily + erythromycin 1 gm 3-4 times daily IV if atypical pathogen suspected for 7-14 days

3-5 Days 5-20 Days 7-10 Days

Clinical infectious disease 2005:41:1697-705

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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).

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Results: clinical success at test of cure

87.6 88.5

0

20

40

60

80

100

Clinical cure

Pat

ien

ts (

%)

MoxifloxacinMoxifloxacin

Ceftriaxone ± Ceftriaxone ± erythromycinerythromycin

141/161141/161 138/156138/156

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Results: clinical success amongst elderly and more severe CAP patients

MoxifloxacinCeftriaxone ± erythromycin P value

Fine class IV+V 77.8%

(21/27)

70.4%

(19/27)

0.534

Age >74 years 81.5%

(22/27)

70.6%

(24/34)

0.326

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Results: speed of defervescence

98 100

65

81

38

61

22

42

18

40

0

20

40

60

80

100

Pa

tie

nts

wit

h f

ev

er

(%)

1 2 3 4 5

Duration of treatment (days)

Moxifloxacin Moxifloxacin (n(n=82)=82)

Ceftriaxone ± Ceftriaxone ± erythromycin erythromycin ((nn=74)=74)

Defervescence was more rapid for moxifloxacin (median 3 days) than Defervescence was more rapid for moxifloxacin (median 3 days) than with ceftriaxone with ceftriaxone erythromycin (median 4 days; erythromycin (median 4 days; PP < 0.003) < 0.003)

Fever: body temperature > 38.5°CFever: body temperature > 38.5°C

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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 days

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Results: duration of hospitalization

Shorter mean duration of hospitalization with moxifloxacin (P < 0.001)

• Moxifloxacin: 9.8 days.• Ceftriaxone + erythromycin: 11.1 days.

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Equivalent tolerability and safety

Variable

Number (%) of patients

Moxifloxacin (n = 200)

Ceftriaxone + erythromycin (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 - glutamyl transferase 2 (1.0) 7 (3.6)

- Abnormal liver function tests 16 (8.0) 26 (13.2)

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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.

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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.

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MetabolitesSulfo-compound (M-1)Acyl-glucuronide (M-2)

Avalox® … Metabolism & Elimination

Fecal excretion: unchanged 26% of dose

Urinary excretion:~ 20% of dose unchanged

STOMACH

KIDNEY

Parent + M-1, M-2

Enterohepatic cycling:Parent + M-2

Fecal excretion:M-1 (35% of dose)

Urine: M-1 (2.5% of dose)M-2 (14% of dose)

BILE

LIVER

BLOOD

EliminationHepatic ~ 60%Renal ~ 40%inactive

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Avalox®

- Metabolism

• Avalox®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 Hence, there is minimalminimal risk of risk of drug–drug interactions duringdrug–drug interactions during

combination/concomitant therapycombination/concomitant therapy

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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,c

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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.

Important Safety Considerations

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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 necessary

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Moxifloxacin

Interactions

No interaction with• food / dairy products• glyburide• ranitidine• theophylline• warfarin

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 agents

• calcium

• p.o. contraceptives

• morphine

• itraconazole

• digoxin

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Avalox® … Safety & Tolerability

CYP450metabolism

Dose adjustment for mild/moderate

hepatic impairment

Dose adjustment

for severe renalimpairment

Avalox®1 No No No

Levofloxacin2 Not stated No Yes

Amoxicillin/ clavulanate3

Not statedCaution and monitoring

recommendedYes

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, 2007

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Avalox® … Contraindications

Known hypersensitivity to moxifloxacin or other quinolones.

Pregnancy and lactation.

Children and adolescents.

Impaired liver function.

QTc-related contraindications.

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Avalox® … Dosage

Tablets 400 mg

I.V. 400 mg, 250 ml

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Once-daily administration Short treatment duration Cost effectiveness

Avalox® … A jump ahead in the treatment of SSSIs

Broad spectrum of activity Eradicates bacteria Fast Highly active at sites of infection for 24 hrs. High cure rates

Avalox® has many of the ideal features of an emperical treatment of CAP&SSSIs

Effective:Effective:

Safe: Safe:

Simple:Simple:

Minimal interactions Low resistance potential Suitable for all adult patient types Well tolerated

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Health & Medicine

Avalox iv cap&sss is 1