Role of Zithromax in

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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
PopulationCommunity-Based Survey in USA, 1988-94
All
lt 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.
200031347-82. Mandell LA et al. Clin Infect
Dis. 200031383-421.
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Common pathogens in community-acquired pneumonia
(CAP)
U.S. Etiology
Other
C. pneumoniae
7
5
M. pneumoniae
S. pneumoniae
10
34
7
Legionella spp
8
15
8
Anaerobes/Aspiration
6
H. influenzae and M. catarrhalis
Aerobic Gram-negative Rods
S. aureus
Eron et al. Hospital Formulary 199429122-36
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Aetiology of community-acquired pneumonia (CAP)
Pathogen Without aetiology Streptococcus
pneumoniae Haemophilus influenzae Moraxella
catarrhalis Other Gram-positive cocci Other
Gram-negative bacilli Atypical pathogens Legionell
a spp. Others
Total, n () 82 (40) 38 (31) 12 (10) 2 (2) 8
(7) 14 (12) 28 (23) 11 (9) 9 (7)
Age gt70 years 48 (48) 17 (33) 5 (10) 1 (2) 3
(6) 5 (10) 10 (20) 4 (8) 4 (8)
Ewig et al. Eur Respir J 20022012541262
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Aetiology of CAP

• 359 patients with CAP admitted to hospital in
  Pittsburgh
• Antibiotic administration before admission was
  significantly associated with unknown aetiology
  (plt0.003)
• No distinctive clinical feature was diagnostic
  for any aetiological agent
• Mortality was highest for Staphylococcus aureus
  infection and lowest for Mycoplasma spp.

Patients infected () 15.3 10.9 6.7 6.1 32.9
Pathogen S. pneumoniae H. influenzae Legionella
spp. Chlamydia spp. Unknown aetiology
Fang et al. Medicine (Baltimore) 199069307316
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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

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 1999106385390
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Chong-Jen Yu Post-SARS EraClinical Review and
Prospective Symposium 2003 Sep.
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Chong-Jen Yu Post-SARS EraClinical 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. 19381112377-82. Liebermann D.
Clin Chest Med. 199920489-97. Marrie TJ et al.
Am J Med. 1996101508-15.
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Pathogens by Disease Severity
Outpatient,no modifiers
Hospitalized,ICU
Outpatient,modifiers
Hospitalized, general ward
S pneumoniaeM pneumoniaeC pneumoniaeH
influenzae
S pneumoniaea M pneumoniaeC pneumoniae
H influenzaeEnteric GNB
S pneumoniaea M pneumoniae C pneumoniae H
influenzaeEnteric GNB Legionella spp Anaerobes
S pneumoniaea M pneumoniaeH influenzae
Enteric GNBLegionella spp S aureusP aeruginosa
lt 5mortality
lt 5 mortality,? 20hospitali-zation
5-25 mortality
? 50 mortality
GNB, gram-negative bacilli.aIncluding
drug-resistant pneumococci.
American Thoracic Society. Am J Respir Crit Care
Med. 20011631730-54.
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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. 19988391-426.
Bartlett JG et al. Clin Infect Dis.
200031347-82. Mandell LA et al. Clin Infect
Dis. 200031383-421. American Thoracic Society.
Am J Respir Crit Care Med. 20011631730-54.
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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. 19962161-5.
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Rationale for Empirical AntibioticTherapy 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- ??? New Macrolide
Pharmocokinetic Profile
1. T1/2 72??gt QD 2. H. influenzae ????? 3.
???P450???? 4. ??????? 5. ?????? 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. 199191(Suppl 3A)5S-11S.
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Phagocytic Delivery of Azithromycin
Phagocytes migrate to infected tissue
Bacteria
Fusion of the azithromycin-laden lysosomes with
the phagocytic vacuole
Phagocytes release azithromycin in presence of
bacteria
Adapted from Schentag JJ and Ballow CH. Am J
Med. 199191(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. 199626-34.
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Azithromycin Uptake and Release by Macrophages
azithromycin
erythromycin
azithromycin
erythromycin
Adapted from Amsden GW. Int J Antimicrob Agents.
199911(Suppl 1)S7-S14. Gladue RP, et al.
Antimicrob Agents Chemother. 198933277-82.
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Azithromycin Concentration in Monocytes
3d azithromycin 500mg qd VS 10d clarithromycin
500mg bid
Azithromycin
Clarithromycin
1000
100
Monocyte concentration (mg/L)
32.0 mg/l
10
16.0 mg/l
8.0 mg/l
2.0 mg/l
1
10
12
Time (days)
Adapted from Amsden GW. Int J Antimicrob Agents
199911(Suppl 1)S714
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• Stahl Study Length of hospital stay

????
?
Mean length of hospital stay (days)
2.55?
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

???
Rocephin Rocephin macrolide
?
Adjusted mortality
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Days from hospital admission
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)
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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
80
No. of Patients Who Lived
30
60
20
40
10
20
0
0
Beta-lactame Beta-lactam
non-macrolide Beta-lactam macrolide
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Dudas Study
Predictors of Mortality Multivariate Analysis
Odds Ratio(95 Cl)
Variable
p Value
3.3 (2.1 to 5.1) 2.5 (1.4 to 4.7) 2.6 (1.3 to
4.9) 1.5 (1.3 to 1.8) 1.2 (1.0 to 1.4) 1.9 (1.5
to 2.4) 1.4 (1.1 to 1.9) 0.4 (0.2 to 0.8) 0.5
(0.2 to 1.6)
0.0001 0.003 0.004 0.0001 0.04 0.0001 0.02 0.009
0.26
Change in Initial Antibiotic ICU Admission gt8 h
to Administration of First Antibiotic ? Age
(Decades) SCr (1.0 mg/dL) RR (10 Breaths/Min) WBC
10,000 Cells / mm3 2nd / 3rd Generation CEPH or
?-Lactam / ?-Lactamase Inhibitor Macrolide
(non-ICU) 2nd / 3rd Generation CEPH or ?-Lactam
/ ?-Lactamase Inhibitor Macrolide (ICU)
???
?
Source Dudas et al. The Annals of
Pharmacotherapy, 2000 34446-452
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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
  Empiric therapy
• High drug concentrations Once-daily, 3-day
  dosingin respiratory tissues (azithromycin only)
• Monotherapy for mild-to-moderate infections Use
  in outpatientscombination therapy for and
  inpatientssevere infections
• Intravenous and oral Simplified
  IV-to-oralformulations therapy
• Good safety profile Good compliance
• Effective combined Potential to reducewith
  cephalosporin 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
PORTPneumonia Patient Outcome Research Team
Sanchez et al.CID 200336(15 May)
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gt Pateints treated with azithromycin, the LOS
was shorter and the mortality rate was lower
Sanchez et al.CID 200336(15 May)
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Zithromax ???P450????!!
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? 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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?????Antimicrobial agentsmacrolides (?
erythromycin?azithromycin?clarithromycin?roxithrom
ycin)?????(90/11/1)??????????????????(mycoplasm
a)????(chlamydia)???????(legionella)?????????????m
acrolides????????(??????????,????)???erythromyc
in(??????)??????????????????????(????????????--??)
???
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Zithromax ? Competitor??
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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 drugdrug interactions

Barry AL et al. Antimicrob Agents Chemother.
1994382419-25. Fung-Tomc JC et al. Antimicrob
Agents Chemother. 199539533-8. Hammerschlag MR
et al. Antimicrob Agents Chemother.
1992361573-4. Ishida K et al. Antimicrob Agents
Chemother. 199438790-8. Nimmo GR et al. J
Antimicrob Chemother. 199536219-23. Schentag JJ
et al. Am J Med. 199191(Suppl 3A)S5-S11.
Baldwin DR et al. Eur Resp J. 19903886-90.
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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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