Current Perspectives on the Management of Community Acquired Pneumonia

Current Perspectives on the Management of Community Acquired Pneumonia Dr. Roland Leung MBBS MD FRACP FCCP FHKCP FHKAM(Med) Specialist in Respiratory Medicine

Outline of Presentation Diagnosis and its pitfalls Common pathogens in CAP Antibiotic resistance Management guidelines

Definition: Signs/symptoms of acute infection plus acute infiltrate on CXR or auscultatory findings Signs and symptoms: chill and/or fever, pleuritic chest pain, productive cough, tachypnea, tachycardia, crackles and/or consolidation Clinical sequelae: bacteremia, metastatic foci of infection, death No association between signs/symptoms and bacterial aetiology The Disease Process Bartlett JG, et al. Clin Infect Dis. 2000;31:347-82. Donowitz GR, Mandell GL. Principles and Practice of Infectious Diseases 1995:619-37. Fang GD, et al. Medicine (Baltimore). 1990;69:307-16.

Morbidity and Mortality Hospitalisations Deaths Bartlett et al, 500,000/year 45,000/year 2000 (USA) 0.27% of general population 2-30% of inpatients 1.0% of elderly < 1% of outpatients population ( 65 years) Huchon G et al, 22-51% of 7% of inpatients 1998 patients with CAP 29% of severe (North America/ infections Europe) Bartlett JG, et al. Clin Infect Dis. 2000;31:347-82. Huchon G, Woodhead M. Eur Resp Rev. 1998;8:391-426.

Pneumonia: X-Ray Normal not pneumonia Lobar pattern Bilateral Basal Bronchopneumonia Diffuse Cavitating Upper lobe

False-negative CXR first 24 hours of infection Dehydration Severe neutropenia Infection with P carinii - 10-30 % of cases of normal CXR J AIDS 1994;7:39

Pneumonia: Differential Diagnosis Pulmonary embolism Endobronchial obstruction/atelectasis Extrinsic Allergic alveolitis Cryptogenic Fibrosing Alveolitis Sepsis and ARDS

Pneumonia: Classification Lobar Bronchopneumonia Atypical Pneumonia Cavitating Pneumonia Viral pneumonia Nosocomial pneumonia Pneumonia in the immunosuppressed

Host Risk Factors for Infection Defective phagocytosis Advanced age Institutionalization Immune dysfunction Risk of infection Alcoholism Comorbidity Smoking Poor nutrition Huchon G, et al. Eur Resp Rev. 1998;8:391-426. Koivula I, et al. Am J Med. 1994;96:313-20. Baik I, et al. Arch Intern Med. 2000;160:3082-8.

Methods for aetiologic diagnosis Stains Culture Antibody detection Antigen detection Nucleic acid detection

Sputum Gram Stain Specific for infecting organism when >25PMN & <10 SEC/low power field Clearly predominant pathogen Most patients do not produce a diagnostic specimen Physicians are more likely than nurses to collect diagnostic sputum samples Common error of interpretation Interpretating poor specimen Missing influenza, other GNB Misinterpret oral flora as pneumococci

Sputum culture Sensitive but not specific Specialized media improves sensitivity Screening with gram stain improve sensitivity & specificity Diagnostic for organism that do not colonize respiratory tract MTB, Legionella, Mycoplasma, Chlamydia RNA viruses, Coccidioides, Histoplasma, Blastomyces

Difficulty in obtaining sputum About 10-30% of patients have non-productive cough 15-30% of patients have received antibiotics prior to evaluation Many possible important pathogens are not detected with conventional culture ie Legionella, C pneumoniae The quality of microbiologic studies is often substandard

Serologic Diagnosis Limited value: antibody rises occurs 2-4 weeks after onset symptoms A single elevated titre can be helpful in dx of infection caused by : M. pneumoniae C. pneumoniae Legionella spp. Coxiella burnetti Corona virus (SARS)

Key Pathogens Associated with Community- Acquired Pneumonia (CAP) USA M pneumoniae Legionella spp C pneumoniae Anaerobes/ aspiration 7% 8% Aerobic gramnegative rods Other 8% 7% 5% 10% 34% S pneumoniae 6% S aureus 15% H influenzae and M catarrhalis Eron JJ, et al. Hosp Formul. 1994;29:122-36.

Key Pathogens Associated with Community- Acquired Pneumonia (CAP) Europe (5,961 Adult Hospitalized CAP Patients in 26 Prospective Studies from 10 European Countries) S pneumoniae C pneumoniae Viral M pneumoniae Legionella spp Atypicals: 25% H Influenzae G-neg Enterobacteria 0 5 10 15 20 25 30 Proportion of Cases (%) Woodhead MA. Chest 1998;113:183S 187S

Etiology of CAP in Hong Kong - 1994 No. of case (%) H influenzae 11 15.7 M pneumoniae 7 10 S pneumoniae 3 4.3 Klebsiella 3 4.3 Pseudomonas aeruginosa 2 2.9 TB 1 1.4 MSSA 1 1.4 Acinetobacter 1 1.4 Branhamella Catarrhalis 1 1.4 No identifiable agent 40 57.1

Prince of Wales Hospital Antibiogram 2008 Top 10 Isolates from All Units in Respiratory Specimens Eterobacter sp. 3% M. catarrhalis 4% Others 17% P. aeruginosa 18% H. influenzae 15% Acietobacter sp. 5% Candida sp. 10% M. tuberculosis 5% S. pneumoniae Klebsiella sp. 8% S. aureus 7% 8% Specimens no.: 2745

HK West Cluster Antibiogram 2008 Top 7 Isolates from All Units in Respiratory Specimens P. aeruginosa 12% H. influenzae 9% S. aureus 9% Others 55% S. peumoniae 3% E. coli 3% Klebsiella sp. 6% M. catarrahlis 3%

Pathogens by underlying disease Conditions Infectious agents None S. pneum, Mycoplasma, Chamydia, H. flu. Age>60 S. pneum, H. flu, S. aureus, GNR, influenza COPD S. pneum, H. flu, M. cat ETOH S. pneum, GNR, anaerob, S. aur, H. flu CRF/DM S. pneum, S. aureus, GNR Bronchiectasis H. flu, S. aureus, P. aerug Influenza S. pneum, H. flu, S aureus

Pathogens by underlying disease

Prevalence of Atypical Pathogens N Mp (%) Cp (%) Leg (%) Marrie et al, 1996 (Canada) 149 26 14 1 File et al, 1997 (USA) 456 9 22 2 Sopena et al, 1998 (Spain) 173 3 24 28 Steinhoff et al, 1996 (Germany) 237 9 11 2 Lieberman et al, 1996 (Israel) 346 29 18 16 Neill et al, 1996 (New Zealand) 251 16 3 11 Bohte et al, 1994 (Netherlands) 334 6 3 2 N, number of patients; Mp, Mycoplasma pneumoniae; Cp, Chlamydia pneumoniae; Leg, Legionella species. Lieberman D. Clin Chest Med. 1999;20:489-97. Marrie TJ, et al. Am J Med. 1996;101:508-15. File TM, et al. Antimicrob Agents Chemother. 1997;41:1965-72. Sopena N, et al. Chest. 1998;113:1195-200. Steinhoff D, et al. Clin Infect Dis. 1996;22:958-64. Lieberman D, et al. Eur Respir J. 1996;9:2630-4. Neill AM, et al. Thorax. 1996;51:1010-6. Bohte R, et al. Thorax. 1995;50:543-7.

Incidence of M. pneumoniae Acute Infection in Children with Lower Respiratory Tract Diseases Age Group (years) Diagnosis 2-4 (%) 5-7 (%) >7 (%) All (%) Acute bronchitis 14/62 (22.5) 10/34 (29.4) 12/17 (70.5) 36/113 (31.8) Wheezing 12/53 (22.6) 5/15 (33.3) 7/14 (50.0) 24/82 (29.2) Pneumonia 43/209 (20.5) 56/123 (45.5) 51/86 (59.3) 150/418 (35.8) All 67/324 (21.3) 71/172 (41.3) 70/117 (59.8) 210/613 (34.3) Principi N, et al. Clin Infect Dis 2001

Incidence of C. pneumoniae Acute Infection in Children with Lower Respiratory Tract Diseases Age Group (years) Diagnosis 2-4 (%) 5-7 (%) >7 (%) All (%) Acute bronchitis 5/62 (8.0) 12/34 (35.2) 5/17 (29.4) 22/113 (19.4) Wheezing 8/53 (15.0) 7/15 (46.6) 4/14 (28.5) 19/82 (23.1) Pneumonia 18/209 (8.6) 13/123 (10.5) 15/86 (17.4) 46/418 (11.0) All 31/324 (9.6) 32/172 (18.6) 24/117 (20.5) 87/613 (14.1) Principi N, et al. Clin Infect Dis 2001

Implications of Atypical Pneumonia Clinical and radiographic features of atypical infection similar to those of typical infections Classification into atypical and typical syndromes 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.

Treatment Guidelines for CAP Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality, and internationally is the leading cause of death from an infectious disease and the sixth leading cause of death overall. Over the past decade international societies have published and revised guidelines for the management of patients with CAP. e.g. ATS-IDSA (2007), European Respiratory Society (ERS) (2005), IMPACT(2005), etc.

Rationale for Antibiotic Therapy Guidelines Ensure appropriate prescribing Promote 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.

Risk Stratification The goals of stratification include Avoiding antimicrobial treatment when it is not indicated (e.g., for viral infections), To support use of the 3 D s the right Drug, at the right Dose, for the right Duration One of the most important considerations in patient stratification is determining the site of care Evaluating the severity of the patient s illness and Deciding whether the patient can be treated safely as an outpatient

Site-of-Care Decisions Site-of-care decisions are important areas for improvement in CAP i.e. hospital vs. outpatient i.e. intensive care unit vs. general ward Severity-of-illness scores Pneumonia Severity Index (PSI), also known as the Pneumonia Patient Outcomes Research Team (PORT) Effective, but requires consideration of many variables CURB-65 Simple, does not require a blood test CRB-65 More simplify version of CURB-65

CURB-65

CRB-65

Respiratory Tract Infections Hong Kong Hospital Authority IMPACT guideline Second Edition (version 2.2) Updated 10 Feb 2003

Respiratory Tract Infections RTI Usual organism Preferred regimens Acute bacterial exacerbation of COPD respiratory viruses; S. pneumoniae; H. influenzae; B. catarrhalis b IV/PO Augmentin or Unasyn CAP, not hospitalized CAP, hospitalized in general ward CAP, hospitalized in ICU or serious pneumonia S. pneumoniae; H. influenzae; Mycoplasma pneumoniae; Chlamydia pneumoniae; C. psittaci (Influenza A; M. tuberculosis) As above As above + Enterobacteriaceae PO Augmentin or Unasyn ± macrolide IV/PO Augmentin or Unasyn ± macrolide (IV piperacillin-tazobactam or cefotaxime ceftriaxone) + a macrolide Bronchiectasis; acute bacterial exacerbation or pneumonia P. aeruginosa (most) (PO ciprofloxacin or IV ticarcillin-clavulana piperacillin-tazobactam) ± an aminoglycos Aspiration pneumonia oral anaerobes : bacteroides, peptostreptococci, fusobacterium, S. milleri (IV penicillin G + PO metronidazole) or PO clindamycin

Hospitalacquired pneumonia (HAP) HAP; onset < 4 days after admission + no previous antibiotics HAP; onset < 4 days after admission + had antibiotics recently; OR onset 5 days after admission OR mechanical ventilation Respiratory Tract Infections Usual organisms S. pneumoniae; H. influenzae; B. catarrhalis; S. aureus MRSA; P. aeruginosa; acinetobacters; Klebsiella spp.; Enterobacter spp. Preferred regimens IV/PO ampicillinsulbactam or amoxycillinclavulanate (IV ticarcillinclavulanate or piperacillintazobactam) ± an aminoglycoside Alternatives cefuroxime if patient is penicillinallergic --

ERS IDSA CIDS/CTS *Preferred option. Outpatients Treatment Options (1) Penicillin*, aminopenicillin ± β-lactamase inhibitor (especially if H influenzae suspected), macrolide, tetracycline, cephalosporin, quinolone, oral streptogramin Macrolide, doxycycline, fluoroquinolone Macrolide*, doxycycline COPD, no recent R X COPD, recent R X Macrolide*, doxycycline Fluoroquinolone*, amoxicillin/clavulanate + macrolide Suspected Amoxicillin/clavulanate ± macroaspiration macrolide*, fluoroquinolone + macrolide Nursing home Fluoroquinolone, amoxicillin/clavulanate + macrolide 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.

Outpatients Treatment Options (2) CDCP Macrolide*, doxycycline*, antipneumococcal β-lactam ATS No CPD, no Advanced-generation macrolide*, modifiers doxycycline With CPD and/or other modifier β-lactam a + (macrolide*, doxycycline), antipneumococcal fluoroquinolone *Preferred option. a Oral cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanate or parenteral ceftriaxone then oral cefpodoxime. Heffelfinger JD, et al. Arch Intern Med. 2000;160:1399-408. American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.

Hospitalized General Ward Patients Treatment Options (1) ERS IDSA CIDS/CTS ([β-lactam/β-lactamase inhibitor, 2nd- or 3rd-gen. cephalosporin, benzylpenicillin, amoxicillin, ampicillin] ± [macrolide, 2nd-gen. fluoroquinolone]), 3rd-gen. fluoroquinolone Pulmonary abscess, cavitated pneumonia, suspected macroaspiration Amoxicillin/clavulanate, clindamycin (Cefotaxime, ceftriaxone) + macrolide, fluoroquinolone Respiratory fluoroquinolone*, 2nd- to 4th-generation cephalosporin + macrolide *Preferred option. 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.

CDCP Hospitalized General Ward Patients Treatment Options (2) β-lactam + macrolide*, newer fluoroquinolone ATS No CPD, no Azithromycin*, doxycyline + modifiers β-lactam, antipneumococcal fluoroquinolone CPD and/or other modifier *Preferred option. a Cefotaxime, ceftriaxone, ampicillin/sulbactam, high-dose ampicillin. Intravenous β-lactam a + (macrolide, doxycycline), antipneumococcal fluoroquinolone Heffelfinger JD, et al. Arch Intern Med. 2000;160:1399-408. American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.

Empirical Antibiotics for CAP Sanford 2010 IDSA 2007 IMPAC 2005 Outpatient: no cardiopulmonary disease or modifying factors Azithro Azithro-ER Macrolide (Azithro) Unasyn +/- macrolide (Azithro) Outpatient: cardiopulmonary disease +/- modifying factors Azithro + AM-CL Macrolide (Azithro) + ß lactam Inpatient, non-icu Ceftriaxone + Azithro Macrolide (Azithro) + ß lactam (Tazocin/ Sulperazon) AM-CL +/- Macrolide (Azithro) Inpatient, ICU Tazocin + Azithro If CA-MRSA is a consideration, add Linezolid ß lactam (Tazocin/ Sulperazon) + Azithro Tazocin + Macrolide (Azithro)

Effect of Macrolide Inclusion on Mortality Gleason et al, 1999 Gleason PP, et al. Arch Intern Med. 1999;159:2562-72. 30-d Mortality, % (95% CI) Community LCF Total study Initial antimicrobial dwelling dwelling cohort regimens (n = 9751) (n = 3194) (n = 12,945) 2nd-generation 9.3 23.5 11.7 cephalosporin only 2nd-generation 7.8 13.0 8.4 cephalosporin plus macrolides Nonpseudomonal 3rd- 10.7 26.2 14.9 generation cephalosporins only Nonpseudomonal 3rd- 6.8 24.3 9.1 generation cephalosporins plus macrolides

Effect of Macrolide Inclusion on Mortality Dudas et al, 2000 Predictors of mortality: multivariate analysis Odds ratio Variable P value (95% CI) 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/mm 3 0.02 1.4 (1.1 to 1.9) 2 nd -/3 rd -Generation CEPH or β-lactam/ 0.009 0.4 (0.2 to 0.8) β-lactamase inhibitor + macrolide (non-icu) 2 nd -/3 rd -Generation CEPH or β-lactam/ 0.26 0.5 (0.2 to 1.6) β-lactamase inhibitor + macrolide (ICU) Dudas V, et al. Ann Pharmacother. 2000;34:446-52.

American Thoracic Society 2001 Approach Evaluate prognostic factors and social factors Treat as outpatient Hospitalize patient No CPD, no modifiers CPD and/or modifiers Mild-to-moderate infection (general ward) Severe infection (ICU) No CPD, no modifiers CPD and/or modifiers No risk of P aeruginosa Risk of P aeruginosa American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.

Pathogens by Disease Severity Outpatient, no modifiers Outpatient, modifiers Hospitalized, general ward Hospitalized, ICU S pneumoniae M pneumoniae C pneumoniae H influenzae < 5% mortality GNB, gram-negative bacilli. a Including drug-resistant pneumococci. S pneumoniae a M pneumoniae C pneumoniae H influenzae Enteric GNB < 5% mortality, 20%hospitalization S pneumoniae a M pneumoniae C pneumoniae H influenzae Enteric GNB Legionella spp Anaerobes 5-25% mortality S pneumoniae a M pneumoniae H influenzae Enteric GNB Legionella spp S aureus P aeruginosa 50% mortality American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.

Switch from Intravenous to Oral Therapy Guideline criteria for switch to oral therapy: Clinically and hematologically stable Able to tolerate oral drug administration (no gastrointestinal disturbance) Usually appropriate after ~3 days of parenteral therapy Ramirez criteria for switch to oral therapy: Improvement in cough and shortness of breath White blood cells normalizing Afebrile for 8 h No abnormal gastrointestinal absorption 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. Ramirez JA. Diagn Microbiol Infect Dis. 1995;22:219-23.

IV-to-Oral Azithromycin versus Cefuroxime + Erythromycin Vergis et al, 2000 (1) Prospective, comparative, non-blinded, multicenter study at 4 centers in USA (1994-96) Adults (age 18 years) hospitalized with CAP Two treatment regimens: Azithromycin 500 mg IV od for 2-5 days Azithromycin 500 mg PO od to complete 7-10 days Cefuroxime 750 mg IV tid for 2-7 days + Erythromycin 0.5-1.0 g IV qid for 2-7 days Cefuroxime axetil 500 mg PO bid to complete 7-10 days Erythromycin 0.5-1.0 g PO qid up to 21 days Vergis EN, et al. Arch Intern Med. 2000;160:1294-300.

IV-to-Oral Azithromycin versus Cefuroxime + Erythromycin Vergis et al, 2000 (2) 100 80 Azithromycin IV then PO 91% Cefuroxime + erythromycin IV then PO 91% Patients (%) 60 40 20 P = NS 0 n = 67 n = 78 Clinical cure Vergis EN, et al. Arch Intern Med. 2000;160:1294-300.

IV-to-Oral Azithromycin versus Cefuroxime + Erythromycin Vergis et al, 2000 (4) No. of patients (%) Treatment-related adverse event Azithromycin Cef + ery P All events 8/67 (12%) 38/78 (49%) < 0.001 Infusion site reactions 4/67 (6%) 28/78 (36%) < 0.001 Gastrointestinal tract 1/67 (1%) 18/78 (23%) 0.002 Abnormal liver 5/67 (7%) 2/78 (3%) NS injury markers Ototoxic effects 0/67 (0%) 1/78 (1%) NS Cef + ery, cefuroxime + erythromycin; NS, P > 0.02. Vergis EN, et al. Arch Intern Med. 2000;160:1294-300.

Activity of 9 oral agents against various bacterial strains MIC 90 (µg/ml) and (%) of strains sensitive at PK/PD breakpoint Agent PK/PD Breakpoint (µg/ml) Penicillin-Susceptible Pneumococci (70 strains) Penicillin-Intermediate Pneumococci (68 strains) Penicillin-Resistant Pneumococci (69 strains) Augmentin 2.00 <0.015(100%) 0.50(100%) 4(90%) Cefpodoxime 0.50 0.120(97%) 1.00(89%) 4(3%) Cefdinir 0.50 0.120(97%) 2.00(78%) 8(2%) Cefditoren 0.25 0.03(99%) 0.25(94%) 1(7%) Cefprozil 1.00 0.12(97%) 2.00(76%) 16(1%) Cefuroxime 1.00 0.12(97%) 2.00(85%) 8(0%) Cefixime 1.00 1.00(90%) >4(40%) >4(0%) Azithromycin 0.12 0.12(92%) >16(89%) >16(43%) Clarithromycin 0.25 0.03(94%) >16(84%) >16(45%) Peric M, Browne FA, Jacobs MR et al. Activity if nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: use of pharmacokinetic / pharmacodynamic breakpoints in the comparative assessment of beta-lactam and macrolide antimicrobial agents. Clin Therap 2003 Jan 25(1): 169-177

Activity of 9 oral agents against various bacterial strains MIC 90 (µg/ml) and (%) of strains sensitive at PK/PD breakpoint Agent β-lactamase +ve Haemophilus influenza (46 strains) β-lactamase -ve Haemophilus influenza (54 strains) Moraxella catarrhalis (49 strains) Methicillin-Sensitive Stapylococcus aureus (100 strains) Augmentin 2.0(96%) 1.0(100%) 0.06(100%) 0.5(100%) Cefpodoxime 0.06(98%) 0.12(100%) 0.51(94%) 2(3%) Cefdinir 0.50(89%) 1.0(87%) 0.12(100%) 0.25(100%) Cefditoren 0.015(100%) 0.015(100%) 0.25(96%) 0.5(50%) Cefprozil 32(7%) 8(20%) 2(73%) 1.0(99%) Cefuroxime 2(78%) 4(68%) 1.0(90%) 1(91%) Cefixime 0.06(100%) 0.06(100%) 0.12(100%) >4(2%) Azithromycin 2(0%) 2(0%) 0.12(100%) >16(0%) Clarithromycin 16(0%) 16(0%) 0.12(100%) >16(45%) Peric M, Browne FA, Jacobs MR et al. Activity if nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: use of pharmacokinetic / pharmacodynamic breakpoints in the comparative assessment of beta-lactam and macrolide antimicrobial agents. Clin Therap 2003 Jan 25(1): 169-177

Pricing Comparison (Oral) Product Presentations Dosage Daily cost Augmentin 375mg tds $4.5 Augmentin 1g bd $5.4 Klacid 250mg bd $5.6 Zinnat 250mg bd $5.5 Unasyn 375mg bd $5.0 Zithromax 250mg od $7.0

Pricing Comparison (IV) Product Presentations Dosage Daily cost Augmentin 1.2g Q8H $68 Klacid 500mg Q12H $125 Zinacef 750mg Q8H $62 Unasyn 750mg Q8H $105 Zithromax 500mg Q24H $245

Role of Macrolides in Treatment of CAP (1) Inpatients Outpatients Mild Severe ERS 98 Mono Adj* Comb* IDSA 00 Mono* Comb* Comb* CDCP 00 Mono* Comb* Comb* Mono, monotherapy; Adj, optional add-on (adjunctive) therapy; Comb, combination therapy; *, recommended first-line use. Huchon G, et al. Eur Resp Rev. 1998;8:391-426. Bartlett JG, et al. Clin Infect Dis. 2000;31:347-82. Heffelfinger JD, et al. Arch Intern Med. 2000;160:1399-408.

Rationale for Clinical Use of Azithromycin Broad-spectrum activity Gram-positive respiratory pathogens Gram-negative respiratory pathogens, including β-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.

Oral Azithromycin Pooled Analysis Study Designs No. patients Therapy Dose Frequency Duration treated Azithromycin 500 mg od 3 days 299 Clarithromycin 250 mg bid 10 days 164 Roxithromycin 150 mg bid 10 days 53 od, once daily; bid, twice daily. O'Doherty B, et al. Eur J Clin Microbiol Infect Dis. 1998;17(Suppl 2):828-33. Rizzato R, et al. Eur Resp J. 1995;8:398-402. Pontani D, et al. Program & Abstracts 5th ICMAS, 2000; Seville. Abstract no. 4.43. Schönwald S, et al. Scand J Infect Dis. 1994;26:706-10. Schönwald S, et al. Infection. 1999;27:46-50.

Clinical success* (% patients) 100 80 60 40 20 0 Oral Azithromycin Pooled Analysis Clinical Efficacy Azithromycin (3 days, 500 mg, od) Roxithromycin (10 days, 150 mg, bid) *Cure plus improvement at end of treatment. Clarithromycin (10 days, 250 mg, bid) 97% 93% 94% n = 299 n = 164 n = 53 O'Doherty B, et al. Eur J Clin Microbiol Infect Dis. 1998;17(Suppl 2):828-33. Rizzato R, et al. Eur Resp J. 1995;8:398-402. Pontani D, et al. Program & Abstracts 5th ICMAS, 2000; Seville. Abstract no. 4.43. Schönwald S, et al. Scand J Infect Dis. 1994;26:706-10. Schönwald S, et al. Infection. 1999;27:46-50.

Oral Azithromycin Pooled Analysis Bacteriologic Efficacy Bacteriologic success* (% isolates) 100 80 60 40 20 0 Azithromycin (3 days, 500 mg, od) 98% n = 80 Clarithromycin (10 days, 250 mg, bid) 91% n = 35 *Eradication or presumed eradication at end of study. O'Doherty B, et al. Eur J Clin Microbiol Infect Dis. 1998;17(Suppl 2):828-33. Schönwald S, et al. Infection. 1999;27:46-50. Schönwald S, et al. Scand J Infect Dis. 1994;26:706-10.

100 Oral Azithromycin Pooled Analysis Treatment-Related Adverse Events Azithromycin (3 days, 500 mg, od) Roxithromycin (10 days, 150 mg, bid) Clarithromycin (10 days, 250 mg, bid) 80 Patients (%) 60 40 20 8% 13% 6% 0 *All treated patients. n = 332 n = 192 n = 53 O'Doherty B, et al. Eur J Clin Microbiol Infect Dis. 1998;17(Suppl 2):828-33. Rizzato R, et al. Eur Resp J. 1995;8:398-402. Pontani D, et al. Program & Abstracts 5th ICMAS, 2000; Seville. Abstract no. 4.43. Schönwald S, et al. Scand J Infect Dis. 1994;26:706-10. Schönwald S, et al. Infection. 1999;27:46-50.

IV-to-Oral Azithromycin versus Cefuroxime ± Erythromycin Plouffe et al, 2000 (1) Prospective, comparative, open-label, parallel-group, multicenter study Adults (age 16 years) hospitalized with CAP Two treatment regimens: Azithromycin 500 mg IV od for 2-5 days Cefuroxime 750 mg IV tid for 2-7 days +/ +/ Erythromycin 0.5-1.0 g IV qid for 2-7 days Plouffe J, et al. Antimicrob Agents Chemother. 2000;44:1796-802. Azithromycin 500 mg PO od to complete 7-10 days Cefuroxime axetil 500 mg PO bid to complete 7-10 days Erythromycin 500 mg PO qid up to 21 days

IV-to-Oral Azithromycin versus Cefuroxime ± Erythromycin Plouffe et al, 2000 (2) 100 Azithromycin IV then PO Cefuroxime +/ erythromycin IV then PO Patients (%) 80 60 40 77% 74% 75% P > 0.05 P > 0.05 71% 20 0 n = 137 n = 131 n = 130 n = 122 10-14 days posttherapy 4-6 weeks posttherapy Clinical success Plouffe J, et al. Antimicrob Agents Chemother. 2000;44:1796-802.

IV-to-Oral Azithromycin versus Cefuroxime ± Erythromycin Plouffe et al, 2000 (3) 100 Azithromycin IV then PO Cefuroxime +/ erythromycin IV then PO Patients (%) 80 60 40 87% 74% 80% 80% 20 0 n = 30 S pneumoniae n = 27 n = 15 H influenzae n = 10 Clinical success Plouffe J, et al. Antimicrob Agents Chemother. 2000;44:1796-802.

IV-to-Oral Azithromycin versus Cefuroxime ± Erythromycin Plouffe et al, 2000 (4) 5 Duration of IV therapy (days) 4 3 2 1 3.6 P < 0.05 4.0 4.0 0 Azithromycin (n = 150) Cefuroxime + erythromycin (n = 68) Cefuroxime only (n = 73) Treatment Plouffe J, et al. Antimicrob Agents Chemother. 2000;44:1796-802. Data on file, Pfizer Inc.

IV-to-Oral Azithromycin versus Cefuroxime ± Erythromycin Plouffe et al, 2000 (5) Duration of total therapy (days) 12 10 8 6 4 2 0 8.6 Azithromycin (n = 150) P < 0.05 10.3 Cefuroxime + erythromycin (n = 68) 9.2 Cefuroxime only (n = 73) Treatment Plouffe J, et al. Antimicrob Agents Chemother. 2000;44:1796-802. Data on file, Pfizer Inc.

IV-to-Oral Azithromycin versus Cefuroxime ± Erythromycin Plouffe et al, 2000 (6) Plouffe J, et al. Antimicrob Agents Chemother. 2000;44:1796-802. No. of patients (%) Treatment-related adverse event Azithromycin Cef ± Ery P All events 39 (19%) 49 (24%) NS Diarrhea 11 (5%) 16 (8%) NS Nausea 4 (2%) 16 (8%) 0.006 Abdominal pain 2 (1%) 2 (1%) NS Vomiting 0 (0%) 4 (2%) NS Insertion site pain 11 (5%) 12 (6%) NS Insertion site infection 7 (3%) 14 (7%) NS or inflammation Cef ± Ery, cefuroxime ± erythromycin; NS, P > 0.05.

Case Fatality Rate by Antibiotic Regimen Mufson and Stanek, 1999 Bacteremic pneumococcal pneumonia Number of cases Case fatality rate (%) 50 No. of patients who died No. of patients who lived 40 100 80 30 60 20 40 10 20 0 78-82 83-87 88-92 93-97 78-82 83-87 88-92 93-97 78-82 83-87 88-92 93-97 β-lactam β-lactam + non-macrolide β-lactam + macrolide 0 Mufson MA, Stanek RJ. Am J Med. 1999;107:34S-43S.

Effect of Macrolide Inclusion on Length of Hospital Stay 6 Length of stay (days) 4 2 4.76 P = 0.80 4.96 2.75 P = 0.01 5.3 4.6 P = 0.51 5.1 0 Yes No (n = 51) (n = 25) Ceftriaxone sodium within first 24 h Yes No (n = 12) (n = 64) Macrolide within first 24 h Yes No (n = 27) (n = 49) Macrolide at any time Stahl JE, et al. Arch Intern Med. 1999;159:2576-80.

Role of Macrolides in Treatment of CAP Broad antimicrobial activity Empiric therapy High drug concentrations Once-daily, 3-day dosing in respiratory tissues (azithromycin only) Monotherapy for mild-tomoderate infections; Use in outpatients combination therapy for and inpatients severe infections Intravenous and oral Simplified IV-to-oral formulations therapy Good safety profile Good compliance Effective combined Potential to reduce with cephalosporin treatment costs

Susceptibility to Antibiotic Agents: SENTRY Program, Canada, 1997 Susceptibility (% isolates) a S pneumoniae H influenzae M catarrhalis Agent (n = 151) (n = 74) (n = 28) Penicillin 66.7 11.1 Amoxicillin 88.9 64.9 11.1 Amoxi/clav 88.9 98.6 100 Cefotaxime 90.7 100 100 a Isolates from 8 Canadian centers; susceptibility according to NCCLS break points. Amoxi/clav, amoxicillin/clavulanate. Jones RN, et al. Diagn Microbiol Infect Dis. 2000;37:115-25.