2. Acute Pneumonia “The most widespread and fatal of all acute diseases, pneumonia is now Captain of the Men of Death.” The Principals and Practice of Medicine Sir William Oscar, 1901

3. Principles and Practice of Infectious Diseases

4. Principals and Practice of Infectious Diseases

5. Diagnosis of CAP Chest radiograph is the most important diagnostic tool Clinical presentation is not diagnostic of an etiology Yield of pathogens from Gram stain of expectorated sputum from patients with CAP is only 30%–40%.

6. Diagnosis Chest Radiograph

7. Gram Stain’s Role in CAP Diagnosis

8. CAP Treatment Issues Causative pathogen frequently not found –Treatment predominantly empiric –Pneumococcal and atypical coverage important Increasing antibiotic resistance –Clinical significance in question Use double-coverage for pneumococci? If outcomes are similar, which agent do we choose?

9. CAP: Changing Presentation Aging of the population Increased number of nursing home beds Increased number of AIDS cases Increased number of organs transplanted

10. Clin Infect Dis 2000;31:347-82 Ramirez et al. IDSA 2000 Clin Infect Dis 2000;31:347-82 Ramirez et al. IDSA 2000 16% 6% 1% 10% 7% 20% 40% S. pneumoniae H. influenzae Legionella spp. M. pneumoniae C. pneumoniae M. catarrhalis Others Atypical Pathogens: 23% Key Bacterial Pathogens in CAP Up to 60% of cases have an unknown etiology Up to 15% with ≥ 2 etiologies

11. The reported age-related mortality per 100,000 US population from pneumonia and influenza in individuals >15 yr, 1982-1990

12. ASCAP Guidelines for Outpatient Treatment of CAP Otherwise healthy patients (all ages) –First-line Azithromycin PO –Alternative first-line Moxifloxacin PO (preferred) or levofloxacin PO or clarithromycin PO or gatifloxacin PO The ASCAP 2002 Consensus Panel. Hosp Med Consensus Rep. 2002:1-32; Emerman CL, Bosker G. In: Bosker G, ed. Textbook of Adult and Pediatric Emergency Medicine. 2nd ed. Atlanta, Ga: American Health Consultants. 2002:375-395.

13. Indications for Hospitalization Pulse >140, SBP 30/min Altered mental status Hypoxemia (PO  <60 mm Hg) Suppurative complication Metabolic abnormality

14. ASCAP Guidelines for Inpatient Treatment of CAP Hospitalized, non-ICU –First-line Ceftriaxone PLUS azithromycin IV –Alternative first-line Moxifloxacin or levofloxacin IV or gatifloxacin ICU Patients –First-line Ceftriaxone IV PLUS levofloxacin IV (±) aminoglycoside or ceftriaxone IV PLUS azithromycin IV (±) an antipseudomonal agent –Alternative first-line Ciprofloxacin IV PLUS an aminoglycoside IV PLUS azithromycin IV The ASCAP 2002 Consensus Panel. Hosp Med Consensus Rep. 2002:1-32; Emerman CL, Bosker G. In: Bosker G, ed. Textbook of Adult and Pediatric Emergency Medicine. 2nd ed. Atlanta, Ga: American Health Consultants. 2002:375-395.

15. ASCAP Guidelines for Inpatient Treatment of CAP – Special Considerations Nursing home acquired –First-line Ceftriaxone IV PLUS azithromycin IV –Alternative first-line Ceftriaxone PLUS doxycycline or moxifloxacin or levofloxacin IV or gatifloxacin Severe, bacteremic CAP with documented Streptococcus pneumoniae* –First-line Ceftriaxone PLUS moxifloxacin or ceftriaxone IV PLUS levofloxacin IV –Alternative first-line Vancomycin † PLUS azithromycin IV * Showing high-level or complete resistence to macrolides, cephalosporins and/or penicillin. † If S. pneumoniae demonstrates complete resistance to extended-spectrum quinolones (very rare), third generation cephalosporins and macrolides, then vancomycin may be required as part of initial therapy, although this would be necessary only in rare circumstances. The ASCAP 2002 Consensus Panel. Hosp Med Consensus Rep. 2002:1-32; Emerman CL, Bosker G. In: Bosker G, ed. Textbook of Adult and Pediatric Emergency Medicine. 2nd ed. Atlanta, Ga: American Health Consultants. 2002:375-395.

16. Infections caused by S. pneumoniae, USA 1997

17. Worldwide Prevalence Rates for Penicillin Resistant S.pneumoniae Unknown < 5% 5-10% 10-25% > 25% Doern CID 1998; Felmingham JAC 1996 and 2000. Zhanel Low and Hoban AAC 1999.

18. 0 5 10 15 20 25 30 35 40 1979-871988-891990-911992-931994-951997-981999-00 Percent Resistant (MICs >2) Intermediate (MICs 0.12-1) 5589 487 524 799 1527 1601 1531 1940 35 15 17 19 30 34 33 45 2001-02 1980’s1990’s Penicillin Resistance with S pneumoniae in the United States Antimicrob Agents and Chemother 2001;45:1721 and submitted

19. S. pneumoniae Resistance Rates Selected Agents, 1999-2000* * n=1,531 isolates; 33 U.S. medical centers, winter (1999-2000) Antimicrobial% Resistance Macrolides25.9 Clindamycin 8.8 Tetracycline16.4 Chloramphenicol 8.6 TMP/SMX30.3 Fluoroquinolones 1.2 Antimicrob Agents and Chemother 2001;45:1721 Clin Infect Dis 2002;34:330

20. PBP alterations - not  -lactamase production - mediate penicillin resistance in pneumococcus thus  - lactamase inhibitors do not enhance activity of  -lactam agents against penicillin- resistant pneumococci PRSP-Mechanism

21. Drug-Resistant S. pneumoniae Age > 65 years or < 5 years Exposure to a child in a day care center Multiple medical comorbidities Alcoholism Recent use of antibiotics Immunosuppression Recent hospitalization

22. MIC Interpretive Criteria for S. pneumoniae Susceptibility to Ceftriaxone Effective January 1, 2002 Meningeal BreakpointsNonmeningeal Breakpoints Sensitive  0.5  g/mL  1  g/mL Intermediate1  g/mL2  g/mL Resistant  2  g/mL  4  g/mL For cerebrospinal fluid isolates, report only meningitis interpretations. For all other isolates, report interpretations for both meningitis and nonmeningitis. NCCLS. 2002. M100.

23. Mortality of Hospitalized Patients With Invasive Pneumococcal Disease YearsNMortalityReference Austrian & Gold Kings County Brooklyn Hospital 1952-62113013% Annals Int Med 1964 Fine Meta-analysis of 127 cohorts 1966-95443212%JAMA 1996 Feikin Population-based, active surveillance 1995-97583712% Am J Public Health 2000

24. Mortality Due to Pneumococcal Pneumonia / Sepsis LocationYear Patients with DRSP (%) Mortality (%) PStudy Pen-SPen-NS Ohio1991-9439/499 (8)1921NS Plouffe, JAMA 1996 Israel1987-9267/293 (23)1116NS Rahav, Medicine 1997 Barcelona1984-93145/504 (29)2438NS Pallares, NEJM 1995 South Africa ‡ 1993-9435/108 (32)1624NS Friedland PIDJ 1995 Atlanta199444/192 (23)1123NS Metlay, CID 2000 Barcelona1996-98 49/101-Pen (49) 12/101-Mac (12) 6 14* 16 7 † NS Ewig, AJRCCM 1999 N. America1995-97741/4193 (18)11%14NSFeikin AJPH 2000 * Mac-S; † Mac-NS ‡ Children Bishai, JAC 2001

25. New NCCLS Breakpoints for Streptococcus pneumoniae Overall Rates of Resistance (I + R) DrugOld BreakpointsNew Breakpoints Amoxicillin24.2%6.3% Amoxicillin/clavulanate24.2%6.3% Ceftriaxone/cefotaxime24.0%4.0% Cefuroxime29.1%27.3% Antimicrob Agents Chemother 2001;45:1721-29 NCCLS, M100 document January 2002

26. Time > MIC 90 for Selected  -Lactams vs. S. pneumoniae T>MIC 90, % of dosing interval  -lactam Pen SPen IPen R Amoxicillin 23 mg/kg bid 1006146 Amoxicillin 13 mg/kg bid 1005941 Cefotaxime/ceftriax one 100 71 Cefuroxime75350 Clin Infect Dis 2000;31(Suppl 2):S29-34

27. Antibiotic Activity Against H. influenzae

28. H. influenzae Increasing  -Lactamase Production

29. Slide28 Atypical Pneumonia AP encompasses pneumonias due to Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp* Prospective studies have failed to identify the cause of 40% to 60% of CAP cases ‡ Today, AP implies –An often benign course (ambulatory)* –Gradual onset § –Systemic complaints often greater than respiratory complaints § AP often a “mixed” infection* * File TM Jr, et al. Infect Dis Clin North Am. 1998;12:572,570,579. † Reimann HO. JAMA. 1938;111:2377,2384. ‡ Bartlett JG, et al. Clin Infect Dis. 1998;26:813. § Levison ME. Harrison’s Principles of Internal Medicine. McGraw-Hill; 1998:1439.

30. Pharmacokinetics and Pharmacodynamic Parameters Concentration Time (hours) MIC 0 Peak/MIC AUC/MIC Time > MIC

32. Schentag J and Tillotson, G.S. (1997). Chest. 112(6 Suppl):314S-319S C max (peak) Time above MIC AUIC = AUC MIC 90 Time (h) Antibiotic serum concentration MIC Pharmacodynamic parameters as a guide to antibiotic decision makingAUC For optimal antimicrobial effect: – C max /MIC should be > 8-10 – AUIC should be > 50- 125 For optimal antimicrobial effect: – C max /MIC should be > 8-10 – AUIC should be > 50- 125 To minimize resistance: – AUIC ratio should be > 50-125

33. AUC/MIC 90 Ratio of Major FQ for S. pneumoniae

34. FQ Prescription per Capita and Frequency of Pneumococci with Reduced Susceptibility to FQs in Canada According to Patient’s Age (Bars)

35. Treatment for 7 to 14 days  2 days Newly Hospitalized CAP Patients (  18 years) Gatifloxacin IV 400 mg QD n=141 Gatifloxacin PO 400 mg QD Ceftriaxone IV 1 or 2 g (32%) QD ± Erythromycin IV 0.5 or 1 g (39%) q6h n=142 Clarithromycin PO 500 mg BID Fogarty C et al. J Respir Dis. 1999;20(suppl 11):S60-S69. Please see IMPORTANT SAFETY INFORMATION slides. Please see full Prescribing Information. Gatifloxacin vs Ceftriaxone ± Macrolide in Hospitalized CAP Patients

36. Gatifloxacin vs Ceftriaxone ± Macrolide* in CAP: Clinical and Bacteriologic Response *Macrolides were erythromycin IV and clarithromycin PO step-down. † No. cured/total of clinically evaluable patients; ‡ No. eradicated/total of microbiologically evaluable patients. NSD=not statistically different Fogarty C et al. J Respir Dis. 1999;20(suppl 11):S60-S69. Gatifloxacin efficacy rates in CAP from clinical trials used as a basis for approval—up to 90% Please see IMPORTANT SAFETY INFORMATION slides. Please see full Prescribing Information. 97 90 92 GatifloxacinCeftriaxone ± erythromycin/clarithromycin Clinical Cure † Microbiologic Eradication ‡ 0 70 80 90 100 96/9996/10669/7173/79 Patients with Cure or Eradication (%) NSD

37. *Macrolides were erythromycin IV and clarithromycin PO step-down; † ATS severity scores; ‡ No. cured/total of clinically evaluable patients. NSD=not statistically different Niederman MS et al. Am Rev Respir Dis. 1993;148:1418-1426; Fogarty C et al. J Respir Dis. 1999; 20(suppl 11):S60-S69. Gatifloxacin efficacy rates in CAP from clinical trials used as a basis for approval—up to 90% Please see IMPORTANT SAFETY INFORMATION slides. Please see full Prescribing Information. Gatifloxacin vs Ceftriaxone ± Macrolide* in CAP: Clinical Response by Pneumonia Severity † GatifloxacinCeftriaxone ± erythromycin/clarithromycin NSD All PatientsMild/Moderate CAP ‡ Patients with Cure (%) Severe CAP ‡ 0 70 80 90 100 97 91 100 92 96 90 96/9996/10628/2824/2668/7172/80

38. Role of FQ in Treatment of CAP To limit the emergence of FQ-resistant strains, the new FQ should be limited to adults:To limit the emergence of FQ-resistant strains, the new FQ should be limited to adults: For whom one of the above regimens has already failed, Who are allergic to alternative agents, OR Who have documented infection with highly drug- resistant pneumococci (MIC ≥4 µg/ml)

39. Pneumococcal Vaccine Older than 2 years with: functional or anatomic asplenia** immunocompromise or immunosuppression** HIV infection** malignancy** chronic renal failure, HD, nephrotic syndrome** chronic cardiovascular or pulmonary illness** Alaskan natives, American Indians Revaccination if >65 years, consider revaccination in 5 yr**

40. CDC Recommendations: Who Should Receive Influenza Vaccine? Persons at increased risk (age  6 mos) Hospital and outpatient employees Nursing home employees with patient contact Home health care providers working with high-risk persons Household members of high-risk persons Persons desiring to avoid influenza infection MMWR. 1999;48:5-7.

41. Guidelines for CAP GuidelineInpatientOutpatient IDSA  -lactam + macrolide or Fluoroquinolone Macrolide or Doxycycline or Fluoroquinolone ATS IV azithromycin or  -lactam + macrolide or Fluoroquinolone Macrolide or doxy  -lactam + macrolide Fluoroquinolone CDC  -lactam + macrolide or Fluoroquinolone  -lactam or macrolide or doxycycline (reserve quinolones) Clin Infect Dis 2000;31:347-82 Am J Resp Crit Care Med 2001;163:1730-54 Arch Int Med 2000;160:1399-1408

42. I prefer to decide my prescription strategies for CAP on the basis of severity of the patient’s condition, the presence of comorbidities, and the epidemiologic pattern in each geographical area. J. Rello - Chest (May 98)

43. Results of Influenza Vaccination Among Staff & Patients in 12 Scottish Geriatric Long-Term Care Facilities

44. Acknowledgements Dr Naiel Nassar MD FACP Assistant professor of Medicine UTSW Dallas