Transcript Document 7227126

Role of Zithromax in
The Treatment of CAP
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CAP and Atypical
Pathogens
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Annual Incidence of CAP in General Population:
Community-Based Survey in USA, 1988-94
Incidence (% population)
3
2.5
2
1.5
1
0.5
0
All
< 17 years
17-64 years
 65 years
National Center for Health Statistics. Third National Health and Nutrition Examination Survey,
1988-1994. Washington DC: US Department of Health and Human Services; 1995.
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Problems in Identifying
Bacterial Pathogens
• Accuracy of etiologic studies is limited by:
– Testing methods (scope, specificity, sensitivity)
– Geographic location and time
– Sample contamination (eg, oral flora)
– Site of care
• Frequency of specific pathogens varies with:
– Patient risk factors (age, comorbidity,
immunocompetence)
– Season (eg, S pneumoniae and H influenzae
more common in winter)
– Occupation
– Environmental factors
Bartlett JG et al. Clin Infect Dis. 2000;31:347-82. Mandell LA et al. Clin Infect Dis. 2000;31:383-421.
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Common pathogens in communityacquired pneumonia (CAP)
U.S. Etiology
Other
C. pneumoniae
M. pneumoniae
Legionella spp
5%
7%
10%
34%
S. pneumoniae
7%
8%
Anaerobes/
Aspiration
Aerobic Gramnegative Rods
8%
15%
6%
H. influenzae and
M. catarrhalis
S. aureus
Eron et al. Hospital Formulary 1994;29:122-36
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Aetiology of community-acquired
pneumonia (CAP)
Pathogen
Total, n (%)
Age >70 years
Without aetiology
82 (40)
48 (48)
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Other Gram-positive cocci
Other Gram-negative bacilli
Atypical pathogens
Legionella spp.
Others
38 (31)
12 (10)
2 (2)
8 (7)
14 (12)
28 (23)
11 (9)
9 (7)
17 (33)
5 (10)
1 (2)
3 (6)
5 (10)
10 (20)
4 (8)
4 (8)
Ewig et al. Eur Respir J 2002;20:1254–1262
Aetiology of CAP
 359 patients with CAP admitted
to hospital in Pittsburgh
 Antibiotic administration before
admission was significantly
associated with unknown
aetiology (p<0.003)
Pathogen
Patients
infected (%)
S. pneumoniae
15.3
H. influenzae
10.9
 No distinctive clinical feature
was diagnostic for any
aetiological agent
Legionella spp.
6.7
Chlamydia spp.
 Mortality was highest for
Staphylococcus aureus infection
and lowest for Mycoplasma spp.
6.1
Unknown aetiology
32.9
Fang et al. Medicine (Baltimore) 1990;69:307–316
Are Pneumococcus spp. the leading cause
of CAP with unknown aetiology?
•
109 patients with CAP who were diagnosed using a conventional approach (sputum, blood culture, serology)
vs cultures and genetic and antigen testing in transthoracic lung aspirates
Rank
1
2
3
4
5
6
7
8
9
10
11
12
13
Conventional testing
(n=54)
Mycoplasma pneumoniae
Chlamydia pneumoniae
Streptococcus pneumoniae
Influenza A virus
Chlamydia psittaci
Mycobacterium tuberculosis
Pneumocystis carinii
Coxiella burnetii
n (%)
19 (35)
9 (17)
9 (17)
5 (9)
4 (7)
3 (6)
3 (6)
2 (4)
Conventional testing plus transthoracic needle
aspiration (n=90)
S. pneumoniae
M. pneumoniae
C. pneumoniae
P. carinii
H. influenzae
Influenza A virus
M. tuberculosis
C. psittaci
C. burnetii
Escherichia coli
Streptococcus viridans
Enterococcus faecium
Cryptococcus neoformans
n (%)
27 (30)
20 (22)
12 (13)
7 (8)
6 (7)
5 (6)
4 (4)
4 (4)
2 (2)
1 (1)
1 (1)
1 (1)
1 (1)
There were 55 patients with pneumonia of unknown aetiology after conventional diagnostic methods and 19 patients whose
cause of pneumonia remained undiagnosed after the addition of transthoracic aspiration antigen testing
Ruiz-Gonzalez et al. Am J Med 1999;106:385–390
Chong-Jen Yu; Post-SARS Era:Clinical Review and Prospective Symposium 2003 Sep.
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Chong-Jen Yu; Post-SARS Era:Clinical Review and Prospective Symposium 2003 Sep.
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Percentage of atypical pneumonia
identified in pneumonic patients
during SARS epidemic
•Mycoplasma Pneumoniae
50%
•Chlamydia pneumoniae
30%
•Legionella Pneumophilia
7%
-CDC, Taiwan, June 2003-
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Implications of Atypical Pneumonia
• Clinical and radiographic features of atypical infection
are similar to those of typical infections
• Classification into “atypical” and “typical” syndromes
clinically does not accurately predict etiology
• Atypical pathogens are a frequent cause of CAP
• Clinical outcomes similar for atypical and typical
pathogens
• Empiric therapy must include coverage of atypical
pathogens
• Empiric therapy should include an agent that
penetrates intracellularly and attains high intracellular
concentrations
Reimann HA. JAMA. 1938;111:2377-82. Liebermann D. Clin Chest Med. 1999;20:489-97. Marrie TJ et al.
Am J Med. 1996;101:508-15.
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Pathogens by Disease Severity
Outpatient,
no modifiers
Outpatient,
modifiers
S pneumoniae
M pneumoniae
C pneumoniae
H influenzae
S pneumoniaea
M pneumoniae
C pneumoniae
H influenzae
Enteric GNB
< 5%
mortality
< 5% mortality,
 20%hospitalization
Hospitalized,
general ward
S pneumoniaea
M pneumoniae
C pneumoniae
H influenzae
Enteric GNB
Legionella spp
Anaerobes
5-25%
mortality
GNB, gram-negative bacilli.
aIncluding drug-resistant pneumococci.
American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.
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Hospitalized,
ICU
S pneumoniaea
M pneumoniae
H influenzae
Enteric GNB
Legionella spp
S aureus
P aeruginosa
 50%
mortality
Response to Treatment
• Adequate clinical response:
– Clinical improvement within 48-72 h (ATS, ERS)
– Subjective response within 1-3 days (IDSA) or 3-5 days
(CIDS/CTS)
– Fever usually persists for longer than other signs and
symptoms
• Clinical resolution can be delayed by:
– Old age
– Comorbidity
– Severe infection
– Other host factors
• Radiographic deterioration common during first several days of
treatment (reflecting continued inflammatory change in absence
of viable bacteria)
Huchon G et al. Eur Resp Rev. 1998;8:391-426. Bartlett JG et al. Clin Infect Dis. 2000;31:347-82. Mandell LA et al. Clin Infect
Dis. 2000;31:383-421. American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.
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Rationale for Antibiotic Therapy
Guidelines
• Ensure appropriate prescribing
• Encourage the rational use of antibiotics
• Limit the emergence of resistance
• Conserve new agents
• Ensure cost-effective practice
• Educate physicians
but
• Are only a starting point
Niederman MS. Curr Opin Pulm Med. 1996;2:161-5.
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Rationale for Empirical Antibiotic
Therapy for CAP
• Causative pathogen is often unknown
(50%) but is predictable
• Limited value in current diagnostic
testing
• Delay in therapy, in order to find an
etiology, may be harmful
• Outcome in severe CAP is improved
with timely and appropriately treatment
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Fluoroquinolones and Macrolides
General Concept in Taiwan
Fluoroquinolones
-Antipseudomonal: ciprofloxacin
-Respiratory: levofloxacin, moxifloxacin, gatifloxacin
Macrolides (active)
-Clarithromycin: S. pheumoniae, C. pneumoniae
-Azithromycin: Legionella, H. influenzae, M.
pneumoniae
-H. influenzae: erythromycin, clarithromycin (poor)
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Zithromax- 更優的 New Macrolide
Pharmocokinetic Profile
1. T1/2: 72小時=> QD
2. H. influenzae 殺菌效果
3. 不經由P450酵素代謝
4. 腸胃副作用較小
5. 懷孕安全級數 “B”
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Phagocytic Delivery of
Azithromycin
Phagocytes absorb azithromycin (A)
Phagocytes migrate to infected tissue
Adapted from: Schentag JJ and Ballow CH. Am J Med. 1991;91(Suppl 3A):5S-11S.
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Phagocytic Delivery of Azithromycin
Phagocytes migrate to infected tissue
Bacteria
Phagocytes release
azithromycin in presence of
bacteria
Fusion of the azithromycinladen lysosomes with the
phagocytic vacuole
Adapted from: Schentag JJ and Ballow CH. Am J Med. 1991;91(Suppl 3A):5S-11S. and
Pechère JC. Intracellular Bacterial Infections. Chapter 5: Survival Strategies of Salmonella in Macrophages.
Worthing, West Sussex, UK: Cambridge Medical Publications. 1996:26-34.
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Internal/External
Conc
Azithromycin Uptake and Release by
Macrophages
Uptake
120
100
80
60
40
20
0
azithromycin
erythromycin
Release (%)
0
4
8
12
16
20
24
Time (h)
0
20
Release
40
60
80
100
azithromycin
erythromycin
0
4
8
12
16
20
24
Time (h)
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Adapted from Amsden GW. Int J Antimicrob Agents. 1999;11(Suppl 1):S7-S14.
Gladue RP, et al. Antimicrob Agents Chemother. 1989:33:277-82.
Azithromycin Concentration in Monocytes
Monocyte concentration (mg/L)
3d azithromycin 500mg qd VS 10d clarithromycin 500mg bid
Azithromycin
1000
Clarithromycin
100
32.0 mg/l
10
16.0 mg/l
8.0 mg/l
2.0 mg/l
1
0
2
4
6
8
10
12
Time (days)
Adapted from: Amsden GW. Int J Antimicrob Agents 1999;11(Suppl 1):S7–14
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Stahl Study: Length of hospital stay
住院天數
Mean length of hospital
stay (days)
6
5
5.3
4
3
2
2.75

2.55天
1
0
Rochephin +
macrolide
Rocephin Alone
In a study of 76 hospitalized patients with CAP, the correlation between initial antibiotic
therapy with ceftriaxone or a macrolide and hospital length of stay and mortality was
assessed using hospital discharge data. (Adapted from Stahl JE et al. Arch Intern Med,
1999.)
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Gleason Study: 30-day mortality
0.20
Adjusted mortality
死亡率
Rocephin
0.18

0.16
0.14
Rocephin + macrolide
0.12
0.10
26%
0.08
0.06
0.04
0.02
0.00
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
Days from hospital admission
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In this study, combining a macrolide with a third-generation cephalosporin resulted in
a 26% lower incidence of mortality vs monotherapy with a third-generation
cephalosporin (Gleason PP et al. Arch Intern Med, 1999)
Case fatality rate by antibiotic regimen
Bacteremic Pneumococcal Pneumonia
Am J Med. 1999; 107(1A):34S-43S.
Number of Cases
Case Fatality Rate (%)
50
100
No. of Patients Who Died
40
No. of Patients Who Lived
80
30
60
20
40
10
20
0
’78-’82 ’83-’87 ’88-’92 ’93-’97
Beta-lactame
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’78-’82 ’83-’87 ’88-’92 ’93-’97
Beta-lactam + non-macrolide
’78-’82 ’83-’87 ’88-’92 ’93-’97
0
Beta-lactam + macrolide
Dudas Study
Predictors of Mortality: Multivariate Analysis
Variable
p Value
Odds Ratio
(95% Cl)
Change in Initial Antibiotic
0.0001
3.3 (2.1 to 5.1)
ICU Admission
0.003
2.5 (1.4 to 4.7)
>8 h to Administration
of First Antibiotic
0.004
2.6 (1.3 to 4.9)
 Age (Decades)
0.0001
1.5 (1.3 to 1.8)
SCr (1.0 mg/dL)
0.04
1.2 (1.0 to 1.4)
RR (10 Breaths/Min)
0.0001
1.9 (1.5 to 2.4)
WBC 10,000 Cells / mm3
0.02
1.4 (1.1 to 1.9)
2nd / 3rd Generation CEPH
or -Lactam / -Lactamase Inhibitor +
Macrolide (non-ICU)
0.009
0.4 (0.2 to 0.8)
2nd / 3rd Generation CEPH
or -Lactam / -Lactamase Inhibitor +
Macrolide (ICU)
0.26
0.5 (0.2 to 1.6)
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死亡率

Source: Dudas et al. The Annals of Pharmacotherapy, 2000; 34:446-452
Explaining the Clinical Benefits of
Adding Macrolides
• Mixed infections: S. pneumoniae +
atypical pathogens
• Anti-inflammatory effect:  cytokines,
IL-6, IL-8 etc.
• Different killing rate on S. pneumoniae
• Synergistic effect
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Role of Macrolides in Treatment of CAP
• Broad antimicrobial activity
• High drug concentrations
dosing
in respiratory tissues
Empiric therapy
Once-daily, 3-day
(azithromycin only)
• Monotherapy for mild-tomoderate infections;
combination therapy for
severe infections
Use in outpatients
and inpatients
• Intravenous and oral
formulations
Simplified IV-to-oral
therapy
• Good safety profile
Good compliance
• Effective combined
with cephalosporin
Potential to reduce
treatment costs
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Azithromycin: The First-Choice Macrolide for
Treatment of Community-acquired Pneumonia
Prospective CAP study Protocol
500mg bidX10d
500mg qdX3d
*PORT:Pneumonia Patient Outcome Research Team
Sanchez et al.CID 2003:36(15 May)
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=> Pateints treated
with azithromycin, the
LOS was shorter and
the mortality rate was
lower…
Sanchez et al.CID 2003:36(15 May)
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Zithromax 不經由P450酵素代謝!!
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或 1ml /4kg qd
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Azithromycin Pharmacokinetics
in Special Populations
No significant variation from normal health volunteers
has been noted in:
• Hepatically-impaired patients
• Renally-impaired patients
• The elderly
• Children
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抗微生物劑Antimicrobial agents
macrolides (如 erythromycin、azithromycin、
clarithromycin、roxithromycin）之給付規定：
(90/11/1)
限用於經臨床診斷或實驗室診斷為黴漿菌
(mycoplasma)或披衣菌(chlamydia)或退伍軍人桿菌
(legionella)引起之感染、或經培養證實為macrolides
有效之致病菌感染（需於病歷記載診
斷依據，俾利審查）。
※將erythromycin（口服、注射劑）自全民健康保險醫療常用
第一線抗生物製劑品名表（全民健康保險藥品給付規定--附表）
刪除。
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Rationale for Clinical Use of Azithromycin
• Broad-spectrum activity
– Gram-positive respiratory pathogens
– Gram-negative respiratory pathogens, including -lactamase
producers
– Highly active against atypical respiratory pathogens
• High levels in respiratory tissue
• Infected tissue targeted
• Tissue levels sustained beyond duration of therapy
• Simple dosing regimen
– Once daily
– 3 days
• Well tolerated
• Few drug–drug interactions
Barry AL et al. Antimicrob Agents Chemother. 1994;38:2419-25. Fung-Tomc JC et al. Antimicrob Agents Chemother.
1995;39:533-8. Hammerschlag MR et al. Antimicrob Agents Chemother. 1992;36:1573-4. Ishida K et al. Antimicrob
Agents Chemother. 1994;38:790-8. Nimmo GR et al. J Antimicrob Chemother. 1995;36:219-23. Schentag JJ et al. Am J
Med. 1991;91(Suppl 3A):S5-S11. Baldwin DR et al. Eur Resp J. 1990;3:886-90.
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Consider Zithromax
•
•
•
•
•
•
H. influenzae (91%)
M. catarrhalis ~100%
Atypical pathogens: ~ 100%
QD for 3 days: ~ 100% compliance
Alternative to -lactam hypersensitivity
Elimination: non P450 enzyme system
• Combination therapy in CAP (empirical)
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Thank You for Your Attention
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