avalox iv cap&sss is 1
DESCRIPTION
By Bayer CompanyTRANSCRIPT
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
3A jump ahead
Agenda
Mode of Action
Spectrum of Activity
Tissue Concentration/In Vitro Activity
Clinical Efficacy
Important Safety Considerations
4A jump ahead
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
5A jump ahead
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
6A jump ahead
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.
7A jump ahead
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
8A jump ahead
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.
9A jump ahead
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
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter cloacae
Enterobacter spp.
0.015
0.125
0.25
0.06
0.062
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.
10A jump ahead
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
Clostridium perfringens
Peptostreptococcus spp.
1.0
0.5
1.0
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.
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
14A jump ahead
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
15A jump ahead
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
16A jump ahead
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
17A jump ahead
Avalox® … Optimum Pharmacokinetics
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
18A jump ahead
Avalox® … Optimum Pharmacokinetics
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
19A jump ahead
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%
20A jump ahead
Avalox® Clinical Study in cSSSI
21A jump ahead
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
22A jump ahead
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
23A jump ahead
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
24A jump ahead
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
25A jump ahead
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.
26A jump ahead
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*
27A jump ahead
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
28A jump ahead
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.
29A jump ahead
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
32A jump ahead
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.
33A jump ahead
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
34A jump ahead
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).
35A jump ahead
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
36A jump ahead
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
37A jump ahead
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
38A jump ahead
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
39A jump ahead
Results: duration of hospitalization
Shorter mean duration of hospitalization with moxifloxacin (P < 0.001)
• Moxifloxacin: 9.8 days.• Ceftriaxone + erythromycin: 11.1 days.
40A jump ahead
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)
41A jump ahead
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.
42A jump ahead
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.
44A jump ahead
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
45A jump ahead
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
46A jump ahead
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
47A jump ahead
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
48A jump ahead
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
49A jump ahead
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
50A jump ahead
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
51A jump ahead
Avalox® … Contraindications
Known hypersensitivity to moxifloxacin or other quinolones.
Pregnancy and lactation.
Children and adolescents.
Impaired liver function.
QTc-related contraindications.
52A jump ahead
Avalox® … Dosage
Tablets 400 mg
I.V. 400 mg, 250 ml
53A jump ahead
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
54A jump ahead