Community- Acquired Pneumonia (CAP); The Disease and its Management

1. Community- Acquired Pneumonia (CAP); The Disease and its Management Toronto, November 9, 2013 Lionel A. Mandell MD. FRCPC. FRCP(LOND) Professor Emeritus of Medicine McMaster University Hamilton, Canada

2. Pneumonia CAP HCAP HAP/VAP

4. Impact of the Disease • 5.6 million cases annually • 1.1 million hospitalizations • 55,477 deaths • Mortality - Out pt. :<1-5% - In pt. : 12% - ICU: approaches 40% • Cost is $12 billion

5. Pneumonia – Still the Old Man’s Friend? Kaplan V et al. Arch Internal Med 2003;163:317-323

6. Figure 3. Unadjusted and comorbidity-adjusted Kaplan-Meier survival estimates for age-, sex-, and race-matched cohorts of elderly patients hospitalized with community-acquired pneumonia (CAP) and for reasons other than CAP. Comorbidities were defined using the Charlson-Deyo comorbidity index. Unadjusted (A) and comorbidity-adjusted (B) survival estimates are presented for CAP patients and hospitalized controls. Expected survival in an age-, sex-, and race-matched US population is presented as a dotted line and was generated from US life tables. Unadjusted and comorbidity-adjusted 1-year mortality was higher for CAP patients than for hospitalized controls (P<.001).

7. ETIOLOGY

8. Ambulatory Pts Hosp. non-ICU Severe (ICU) S. pneumoniae S. pneumoniae S. pneumoniae M. pneumoniae M. pneumoniae S. aureus H. influenzae C. pneumoniae Legionella sp. C. pneumoniae H. influenzae Gram-negative bacilli Respiratory Viruses* Legionella spp. H. influenzae Aspiration Respiratory Viruses* Most Common Etiologies of Community-Acquired Pneumonia # *Influenza A and B; Adenovirus; RSV; Parainfluenza; # Based on collective data from recent studies [223]

10. CA-MRSA and HA-MRSA CMRSA – Canadian MRSA PVL – Panton-Valentine leukocidin SCCmec – Staphylococcal chromosomal cassette mec Barton M et al. Can J Infect Dis Med Microbiol . 2006;17 Suppl C. Klevens RM, et al.Emerg Infect Dis. Dec 2006;12(12):1991-1993.

11. SITE OF CARE

12. SOC Determines • Type and extent of diagnostic w/u • Antibiotics (spectrum,route) • Overall costs

13. Class I II III IV V CAP 14,199 adult pts Derivation cohort derived 2 step prediction rule stratifying pts. into 5 classes re: risk of death within 30 days Rule assigns points based on age coexisting illness abnormal physical findings abnormal lab findings

14. CURB - 65 C – Confusion U – Urea > 7 m mol/l R – Resp rate > 30/min B – BP: Systolic < 90 mm Hg Diastolic < 60 mm Hg 65 – Age > 65 Years

15. ____ PSI ……. CURB-65 _ _ _ CRB-65 Capelastegui A Eur Respir J 2006;27:151-157

16. Neither rule accurate for predicting need for ICU Ananda-Rajah, M et al. Scan J Infec Control 2008;40:293-300

17. RESISTANCE

18. Wild type 1st step 1st and 2nd

22. Relative Risk of Infection with Macrolide- resistant Pneumococci, by Prior Antibiotic Use1 P<0.001*†; P=0.004‡; P=0.02§; P<0.001*† For internal use only. Not for use in promotional speaker programs. *Significance vs. no prior antibiotic; †significance vs prior antibiotic (not Mac); ‡Significance vs. erythromycin; §Significance vs. clarithromycin (no prior antibiotic, n=1576; prior antibiotic [not macrolide], n=435; erythromycin, n=24; clarithromycin, n=57; azithromycin, n=37) Mac =macrolide; Ery = erythromycin; Clari = clarithromycin; Azi = azithromycin) Vanderkooi OG, et al. Clin Infect Dis. 2005;40:1288-1297.

23. DIAGNOSIS

24. Pretreatment blood cultures and expectorated sputum stain and culture should be obtained from hospitalized pts. with selected clinical conditions, but are optional for pts. without these conditions

25. Respiratory Tract Specimen Gram stain and culture • Yield of sputum cultures variable and strongly influenced by entire process; collection, transport, etc. • Even with bacteremia, yield of S. pneumoniae from sputum cultures only 40-50%. • Adequate specimen with predominant morphotype on Gram stain in only 14% of 1,669 hospitalized CAP patients.

26. TREATMENT

27. CAP 80%20% outpts inpts <1% die 14% die

28. Outpatient Treatment • Previously healthy and no use of antimicrobials within the previous 3 months: A macrolide Doxycyline • Presence of comorbidities or use of antimicrobials within the previous 3 months (in which case, an alternative from a different class should be selected) Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, levofloxacin [750 mg]) Beta lactam PLUSa macrolide • In regions with a high rate of “high-level” macrolide-resistant S. pneumoniae, consider use of alternative agents listed above in 2 for patients with comorbidities

29. Septic Shock in PCR +ve Waterer G. Rello J. ATS 2008

30. Mortality in PCR +ve Waterer G. Rello J. ATS 2008

31. Inpatients, non-ICU Treatment • Respiratory fluoroquinolone • Beta-lactam PLUS a macrolide

32. Inpatients, ICU Treatment A beta-lactam (cefotaxime, ceftriaxone, ampicillin-sulbactam) PLUS either azithromycinOR a respiratory fluoroquinolone (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended)

33. Special Concerns Pseudomonas a consideration: an antipneumococcal, anti-pseudomonal beta-lactam (piperacillin/tazobactam, cefepime, imipenem, meropenem) plus either ciprofloxacin or levofloxacin (750 mg dosage) the above beta-lactam plus an aminoglycoside and azithromycin the above beta-lactam plus an aminoglycoside and an anti-pneumococcal fluoroquinolone (For penicillin-allergic patients, substitute aztreonam for above beta-lactam) CA-MRSA a consideration:add linezolid or vancomycin

34. Duration of Treatment

35. Duration of Therapy • Patients with CAP should be treated a minimum of 5 days (I), should be afebrile for 48-72 hours and should have no more than one CAP-associated sign of clinical instability before stopping therapy.

36. Consider Longer Duration of Treatment • If initial therapy was not effective • If there is extra pulmonary infection e.g., meningitis or endocarditis • If there is bacteremia especially S.aureus, S.pneumoniae, P.aeruginosa • Most cases of severe CAP

37. gyrB gyrB gyrA gyrA 5’ DNA Replicating Complex parE parE parC parC 5’ Mechanisms of Fluoroquinolone Resistance DNA gyrase: Mutations confer resistance to moxifloxacin Most fluoroquinolones bind to the 2 enzymes with varying affinities in different species, inhibiting DNA replication Topoisomerase IV: Mutations confer resistance to levofloxacin and ciprofloxacin Hooper DC. Lancet Infect Dis. 2002; 2:530-8. 37

38. Mechanisms of Fluoroquinolone Resistance gyrB gyrB gyrA gyrA 5’ DNA Replicating Complex parE parE parC parC 5’ DNA gyrase: Mutations confer resistance to moxifloxacin Gemifloxacin has a high binding affinity for both and at therapeutic levels Most fluoroquinolones bind to the 2 enzymes with varying affinities in different species, inhibiting DNA replication Topoisomerase IV: Mutations confer resistance to levofloxacin and ciprofloxacin Hooper DC. Lancet Infect Dis. 2002; 2:530-8. 38

39. Predictors of Bacterial Eradication& Clinical Efficacy PK/PD Profile for Quinolones • AUC/MIC - target > 25-30 • Cmax/MIC - target > 10 C (µg/ml) AUC Cmax Cmax MIC 1 Time (h) U34 Adapted from Craig, et al. PIDJ 1996; Zhanel. Curr Infect Dis Report 2001

40. Highest Plasma AUC/MIC90 Ratio for S. pneumoniae Compared With Other Quinolones*†1 • Resistance emerges more readily for agents with lower AUC/MIC ratios, such as ciprofloxacin and levofloxacin2 AUC/MIC90 ([g•h/mL]/[g/mL]) *Total drug AUC data are from each manufacturer’s product prescribing information. †In vitro activity does not establish clinical effectiveness. 1. Jacobs MR, et al. J Antimicrob Chemother. 2003; 52:229-246. 2. Fuller JD, Low DE. Clin Infect Dis. 2005; 41:118-121.