Bradley A. Sharpe, M.D. Associate Professor Medicine Department of Medicine UCSF

Maximizing Care for Community- Acquired Pneumonia Bradley A. Sharpe, M.D. Associate Professor Medicine Department of Medicine UCSF sharpeb@medicine.ucsf.edu 1. In 1898, William Osler described community-acquired pneumonia as: a. An ailment that often leads to suffocation and death. b. A friend of the aged. c. A common and mortal disease which can be diagnosed by simple observation and percussion of the chest. d. Bad. Really bad. An ailment tha... 12% A friend of th... 51% A common and m... 37% 0% Bad. Really b... 1. In 1898, William Osler described community-acquired pneumonia as: a. An ailment that often leads to suffocation and death. b. A friend of the aged. c. A common and mortal disease which can be diagnosed by simple observation and percussion of the chest. d. Bad. Really bad. "Pneumonia may well be called the friend of the aged. Taken off by it in an acute, short, not often painful illness, the old man escapes those cold gradations of decay so distressing of himself and to his friends. -- William Osler, M.D., 1898 1

Update in CAP Brad, pneumonia sucks. -- Mary R. Sharpe November 2008 Roadmap Specific Goals: Background Etiology Diagnosis Treatment Prevention Describe the most common causes of community-acquired pneumonia in the outpatient setting. Order appropriate diagnostic tests for CAP. Initiate appropriate antibiotics in the treatment of community-acquired pneumonia (CAP). State the optimal duration of therapy in CAP. State the benefits and need for preventative measures for CAP. 2

Sources Caveats Guidelines for Community-Acquired Pneumonia IDSA/ATS Consensus Guidelines 2007 (IDSA = Infectious Disease Society of America) (ATS = American Thoracic Society) BTS: British Thoracic Society Practical, nuts and bolts (use it tomorrow ) Will not talk about healthcare-associated pneumonia (HCAP) Will not discuss admission decision (complex) Syllabus vs. all slides Updated Literature Review Community-Acquired Pneumonia Roadmap CAP: Background Background Etiology Diagnosis Treatment Prevention 5 million cases/year in the U.S. 80% of CAP is treated outpatient Sixth leading cause of death Inpatient mortality 10-35% One-year mortality = 40% (vs. 29% in controls) Outpatient mortality < 1% 3

CAP: Background CAP: Background Some evidence that quality of care for African-Americans with CAP is worse Higher mortality among Caucasians Cough 90%* Dyspnea 66% Sputum 66% Pleuritic chest pain 50% * Yet, only 4% of all visits for cough are pneumonia Mortensen EM, et al. BMC Health Serv Res. 2004;4:20. Mayr FB, et al. Crit Care Med. 2010;38:759. Halm EA, Teirstein AS. N Engl J Med 2002;347(25):2039. Roadmap Typical vs. Atypical Background Etiology Diagnosis Treatment Prevention Typical organisms S. pneumococcus, H. influenzae, M. catarrhalis, etc. 4

Typical vs. Atypical Atypical organisms M. pneumoniae, C. pneumoniae, Legionella spp, etc. Typical vs. Atypical Classic teaching is not supported by the literature Some general trends S. pneumococcus in older pts, co-morbidities Mycoplasma in patients < 50 years old But - no history, exam, laboratory, or radiographic features predict organism Walking pneumonia Classic lobar pneumonia Etiology of CAP Etiology of CAP Outpatients (mild) Non-ICU inpatients ICU inpatient Outpatients (mild) Non-ICU inpatients ICU inpatient GNRs S aureus (40-50%) GNRs S aureus File TM. Lancet 2003;362:1991. Metlay JP, et al. JAMA 1997;278(17):1440. File TM. Lancet 2003;362:1991. 5

Etiology of CAP Etiology of CAP Outpatients (mild) Non-ICU inpatients ICU inpatient Outpatients (mild) Non-ICU inpatients ICU inpatient (40-50%) GNRs S aureus (40-50%) GNRs S aureus File TM. Lancet 2003;362:1991. File TM. Lancet 2003;362:1991. CA-MRSA CA-MRSA Community-acquired MRSA CAP First reported in 2003; increasing Specific strain of MRSA -- Panton-Valentine Leukocidin (PVL) genes Clinical Features % of Patients Flu Prodrome 30-75% Shock 50-100% Multi-lobar 50-100% Necrotizing 33-100% Leukopenia 25-100% Ventilated 50-100% Mortality ~ 40% Lancet. 2009. 6

Etiology of CAP Roadmap Outpatients (mild) Non-ICU inpatients ICU inpatient GNRs S aureus Background Etiology Diagnosis Treatment Prevention File TM. Lancet 2003;362:1991. Metlay JP, et al. JAMA 1997;278(17):1440. 2. A 65-year old man presents to urgent care complaining of subjective fever, chills, and productive cough x 3 days. He reports mild shortness of breath. His temperature is 38.6 o C, RR 20, O 2 saturation 95% on RA. He has crackles at the right base on lung exam. You should: a. Treat for community-acquired pneumonia. b. Send him for a PA and lateral CXR. 39% 39% c. Send him for blood and sputum cultures. d. Prescribe sudafed and robitussin and send him home. e. Perform trans-tracheal aspiration f. B and C g. B, C, and D 7% 0% 0% 15% 0% Diagnosis of CAP 1) Select clinical features (e.g. cough, fever, sputum, pleuritic chest pain) AND 2) Infiltrate by CXR or other imaging Treat for comm... Send him for a... Send him for b... Prescribe suda... Perform trans-... B and C B, C, and D IDSA/ATS Guidelines. CID. 2007;44:S27-72. 7

Chest Radiograph Gold Standard Chest Radiograph Gold Standard? All expert guidelines state should have positive CXR to make diagnosis History, exam, etc. not good enough In outpt setting, should see an infiltrate. Order CXR if you are concerned about CAP (urgent care, clinic) Should order CXR in all patients with suspected pneumonia. In the hospital, a positive CXR is not necessary to treat as CAP (but consider other diagnoses). In the inpatient setting, can you see pneumonia with a negative CXR??? Community-Acquired Pneumonia Community-Acquired Pneumonia 2. A 65-year old man presents to urgent care complaining of subjective fever, chills, and productive cough x 3 days. He reports mild shortness of breath. His temperature is 38.6 o C, RR 26, O 2 saturation 95% on RA. He has crackles at the right base on lung exam. You should: 2. A 65-year old man presents to urgent care complaining of subjective fever, chills, and productive cough x 3 days. He reports mild shortness of breath. His temperature is 38.6 o C, RR 26, O 2 saturation 95% on RA. He has crackles at the right base on lung exam. You should: a. Treat for community-acquired pneumonia. b. Send him for a PA and lateral CXR. c. Send him for blood and sputum cultures. d. Prescribe sudafed and robitussin and send him home. e. Perform trans-tracheal aspiration f. B and C g. B, C, and D a. Treat for community-acquired pneumonia. b. Send him for a PA and lateral CXR. c. Send him for blood and sputum cultures. d. Prescribe sudafed and robitussin and send him home. e. Perform trans-tracheal aspiration f. B and C g. B, C, and D 8

Blood Cultures Provides a specific diagnosis The data: Cultures within 24 hours of arrival are associated with 10% lower odds of 30d mortality No evidence of benefit in outpatient setting Blood Cultures in CAP Limitations Positive in < 10% of cases Medicare database of 13,000 patients Determined predictors of blood-culture positivity The sicker you are... Meehan TP, et al. JAMA 1997;278. Metersky ML, et al. Am J Respir Crit Care Med 2004;169(3):342-7 Blood Cultures in CAP Blood Cultures in CAP Limitations Positive in < 10% of cases High percentage of contaminants Cultures change antibiotics in < 5% of patients Costly Metersky ML, et al. Am J Respir Crit Care Med 2004;169(3):342-7 Metersky ML, et al. Am J Respir Crit Care Med 2004;169(3):342-7 9

Blood Cultures in CAP In general, blood cultures are not indicated in the management of outpatient CAP. For inpatient CAP, blood cultures are optional unless clear risk factors for positive blood cultures: ICU, severe liver disease, cavitary infiltrates, Pleural effusion Sputum for CAP Complicated and Controversial Simple, inexpensive, specific for pneumococcus Problems include: Up to 30% could not produce adequate sputum Good quality available in only 14% Most don t narrow antibiotics IDSA/ATS Guidelines. CID. 2007;44:S27-72. Sputum Cultures in CAP Diagnostic testing for CAP In general, sputum cultures are not indicated in the management of outpatient CAP For inpatient CAP, sputum is indicated: High-quality specimen, right to the lab ICU, Cavitary infiltrates, Underlying lung disease Get the CXR (esp. outpatient) Blood and sputum cultures generally discouraged in outpatient CAP General trend away from blood and sputum in non-icu patients with CAP IDSA/ATS Guidelines. CID. 2007;44:S27-72. 10

The future in CAP Pneumococcal urinary antigen Rapid test, specificity > 90% If positive, tx for pneumococcal disease May not reduce antibiotic spectrum -- > 70% with no change The future in CAP - biomarkers Procalcitonin: precursor of calcitonin No hormonal activity Inflammatory marker Increased in sepsis, bacterial infection Sorde R, et al. Arch Intern Med. 2011;171:166. Diagnosing Pneumonia Procalcitonin: Bacterial vs. Non-bacterial Intl J. Lung Dz. 2006 Procalcitonin: Diagnosis Procalcitonin Based Management Swiss RCT: 1360 pts with CAP, COPD, bronchitis, etc. 93% admitted; 50% PSI risk VI or V Usual care vs. PCT assay PCT validated algorithm for stopping antibiotics Schuetz, et al. JAMA. 2010;302:1059. 11

Procalcitonin: Diagnosis Procalcitonin Based Management Control PCT Group Adverse events* 20.2% 16.1% Abx Given 90% 78% Abx duration 10.7 days 7.2 days Abx reaction 33.1% 23.5% Roadmap Background Etiology Diagnosis Treatment Prevention * Defined as death, ICU admit, complications, recurrent infection Schuetz, et al. JAMA. 2010;302:1059. Roadmap Treatment of CAP Background Etiology Diagnosis Treatment Prevention 12

4. A healthy 48 year-old woman who was recently treated (1 month ago) for cystitis with cipro presents to your clinic with fever, cough, sob. Her CXR reveals RLL infiltrate and you diagnose community-acquired pneumonia and decide to treat as an outpatient. Etiology of CAP Outpatients (mild) Non-ICU inpatients ICU inpatient Which of the following is the best treatment regimen? A. Levofloxacin PO B. Azithromycin PO C. Ertapenem IV D. Augmentin PO and Azithromycin PO E. Doxycycline PO and penicillin PO Levofloxacin P... 14% Azithromycin P... 57% Ertapenem IV 0% Augmentin PO a... 20% 10% Doxycycline PO... File TM. Lancet 2003;362:1991. GNRs S aureus Treatment Principle #1 Treatment Principle #2 Outpatients (mild) Outpatients (mild) Must cover all these organisms Wimpy pneumococcus Drug-resistant angry S. pneumoniae (DRSP) Penicillin, erythromycin, macrolides, etc. 13

Risk Factors for DRSP Treatment Principle #2 Age > 65 years old Chronic disease Heart, lung, renal, liver Diabetes mellitus Alcoholism Malignancy (active) Immunosuppression Antibiotics in the last 3 months Outpatients (mild) Wimpy pneumococcus Drug-resistant S. pneumoniae (DRSP) Treatment CAP Treatment of CAP 14

Treatment CAP Treatment CAP Outpatient, healthy, no DRSP risk factors Doxycycline or macrolide Macrolide = azithro, clarithro, erythro Risk Factors for DRSP Age > 65 years old Chronic disease Heart, lung, renal, liver Diabetes mellitus Alcoholism Malignancy Immunosuppression Antibiotics in the last 3 months Treatment CAP Outpatient, DRSP risk factors (DRSP = drug-resistant angry strep pneumo) Oral fluoroquinolone OR Oral β-lactam + doxy or β- lactam + macrolide NOTE: macrolides are no longer indicated for outpatients with DRSP risk factors 15

Treatment CAP Outpatient, DRSP risk factors Oral fluoroquinolone OR Oral β-lactam + doxy or macrolide Oral fluoroquinolone: moxi, gemi, levofloxacin β-lactam: High-dose amoxicillin (1mg PO tid) Augmentin (875mg PO bid) 4. A healthy 48 year-old woman who was recently treated (1 month ago) for cystitis with cipro presents to your clinic with fever, cough, sob. Her CXR reveals RLL infiltrate and you diagnose community-acquired pneumonia and decide to treat as an outpatient. Which of the following is the best treatment regimen? A. Levofloxacin PO B. Azithromycin PO C. Ertapenem D. Augmentin PO and Azithromycin PO E. Doxycycline PO and penicillin PO Risk Factors for DRSP Age > 65 years old Chronic disease Heart, lung, renal, liver Diabetes mellitus Alcoholism Malignancy Immunosuppression Antibiotics in the last 3 months Treatment of CAP 4. A healthy 48 year-old woman who was recently treated (1 month ago) for cystitis with cipro presents to your clinic with fever, cough, sob. Her CXR reveals RLL infiltrate and you diagnose community-acquired pneumonia and decide to treat as an outpatient. Which of the following is the best treatment regimen? A. Levofloxacin PO B. Azithromycin PO C. Ertapenem D. Augmentin PO and Azithromycin PO E. Doxycycline PO and penicillin PO 16

Treatment CAP Treatment Inpatient, Non-ICU Outpatient, healthy, no DRSP risk factors Outpatient, DRSP risk factors Doxycycline or macrolide Oral fluoroquinolone OR Oral β-lactam + doxy or β- lactam + macrolide Non-ICU inpatients Treatment Inpatient, ICU Treatment CAP ICU inpatient (resistant) GNRs S aureus Inpatient, non-icu Fluoroquinolone OR β-lactam + macrolide Inpatient, ICU IV β-lactam + macrolide + vancomycin OR IV β-lactam + fluoroquinolone + vancomycin 17

Treatment Inpatient, ICU Treatment CAP ICU inpatient (resistant) GNRs MRSA Inpatient, non-icu Fluoroquinolone OR β-lactam + macrolide Inpatient, ICU IV β-lactam + macrolide + vancomycin OR IV β-lactam + fluoroquinolone + vancomycin Guideline Concordant Abx Benefits Frei CR, et al. Am J Med. 2006;119:865 - Retrospective study of 631 pts with CAP - Early switch to orals, shorter LOS, lower mortality Mortensen EM, et al. Am J Med. 2006;119:859. - Retrospective study of 787 pts with CAP - Decreased mortality at 48 hours Guideline Concordant Abx Benefits Arnold FW, et al. Arch Intern Med. 2009;169:1515. - Retrospective study of 1725 pts with CAP; - Shorter LOS, mortality 10% lower (NNT = 10) Mccabe C, et al. Arch Intern Med. 2009;169:1525. - Retrospective study of > 50,000 with CAP - Decreased mortality by 30% Mortensen EM, et al. Am J Med. 2004;117:726-31 - Improved 30-day mortality 18

Duration of therapy Duration of therapy? Meta-analysis of 15 RCTs, 2796 patients with mild to moderate CAP Compared short-course (< 7 days) with longer courses. Looked at clinical failure, bacterial eradication, and mortality. Li JZ, et al. Am J Med. 2007;120:783. Risk of Clinical Failure Relative Risk of Mortality 19

Duration of therapy? Duration of therapy No difference in clinical failure No difference in bacterial eradication No difference in mortality In subgroup analysis, trend toward favorable efficacy with short-course. Patients with CAP should be treated for a minimum of 5 days (level I evidence) -- IDSA/ATS Guidelines Li JZ, et al. Am J Med. 2007;120:783. Duration of therapy Minimum of 5 days If afebrile for 48-72 For most, 7 days total Following at home? Have pts take temp q8 hours & report if > 101 o F or if > 99 o F after 48 hours Encourage pts to drink 1-2 quarts of liquid daily If they respond appropriately, have them follow-up within 10-14 days Niederman M. Ann Intern Med. 2009 20

Follow-up CXR? Roadmap Standard practice? Prior ATS guidelines said yes, recent guidelines do not address CXR resolution: At 28 days, ~ 50% had not resolved Can consider in high-risk patients Significant smoking history, etc. Probably should wait > 3 months Background Etiology Diagnosis Treatment Prevention Bruns AH. CID. 2007;45:983. Pneumovax Vaccine against Streptococcus pneumoniae, most common cause of CAP Polysaccharide vaccine with 23 antigens Covers 85-95% of serotypes causing invasive disease in U.S. Pneumococcal Vaccine:High Risk Pts Effective? Study Design CAP Invasive Dz Mortality Fine 94 Meta-analys No No No 9 RCTs Hutchison 99 Meta-analys 47% 73% NA 13 RCTs Moore 00 Meta-analys No No No 13 RCTs Cornu 01 Meta-Analys No N/A No 14 RCTs Watson 02 Meta-Analys No No No 16 RCTs Holden 03 Cochrane No 53% No ACIP Recs. MMWR 1997;46:1. 21

Pneumovax Pneumovax - Efficacy Updated meta-analysis of 22 trials, > 100,000 patients Only high-quality, blinded studies Relative Risk All-cause mortality 0.97 (0.87-1.09) All-cause pneumonia 1.19 (0.95-1.49) So, it doesn t prevent CAP or decrease mortality from CAP. Pneumovax likely prevents invasive disease. Should we be giving it at all? ** No difference for elderly or chronic illness Huss A, et al. CMAJ. 2009;180:48. Pneumovax - Efficacy Pneumovax - Efficacy Four different trials looking at benefits of pneumovax in patients hospitalized with CAP. Compared vaccinated vs. non-vaccinated Looked at impact on ICU admission, inpatient mortality, inpatient complications, and LOS. Variable ICU admission Inpt complications LOS Inpt mortality Outcome Decreased Decreased Decreased Decreased 22

Pneumovax - Efficacy Pneumococcal vaccine likely prevents invasive pneumococcal disease. Probably reduces death, ICU admission, complications, and LOS in patients hospitalized with CAP. Quality Improvement Influenza Vaccine - Efficacy Adults aged < 65 years Prevents influenza illness in ~ 70-90% Adults aged > 65 years Prevents influenza illness in ~ 30-70% Influenza Vaccine - Efficacy Hospitalization Risk Reduction Resp. Illness 56%* Hospitalization 50%* Pneumonia 53%* All cause death 68%* (NNT = 118) * All p values < 0.001 ACIP Recs. MMWR 2003;52:1. Gross PA, et al. Ann Intern Med. 1995;123:518-27. 23

Influenza Vaccine - Efficacy Smoking Cessation Counseling Hospitalization Risk Reduction Hospitalization for pna/flu 27%* All cause death 48%* Should provide it to all of our patients that smoke Some evidence that tobacco is a risk factor for pneumonia * All p values < 0.001 Nichol KL, et al. N Engl J Med 2007;357:1373. (Oct 4, 2007) Prevention Smoking and Invasive Pneumococcus Cigs / d OR Current Smokers 1-14 2.3 15-24 3.7 25 5.5 All 4.1 (2.4-7.3) Hrs / d OR Passive Smokers 4 2.4 > 4 3.9 All 2.5 (1.2-5.1) Roadmap Background Etiology Diagnosis Treatment Prevention No PPI for you Nuorti, NEJM, 2000 24

Proton Pump Inhibitors Gulmez, et al. Arch Intern Med. 2007. -- Current use of PPI: CAP OR = 1.5 -- Recent start: CAP OR = 5.0 Sarkar, et al. Ann Intern Med. 2008. -- Recent PPI start: CAP OR = 3.8 Herzig, et al. JAMA. 2009. -- 52% of hosp pts got PPI, HAP OR = 1.3 Eurich, et al. Am J Med. 2010. -- Rates recurrent CAP after CAP admit -- Starting PPI: OR 2.1% (7% abs risk) Anti-psychotics Knol W, et al. JAGS. 2009. -- Recent anti-psychotic start (1 wk); OR 4.3** Trifiro, et al. Ann Intern Med. 2010. -- Population based study, 2000 patients. Current Use Risk of pneumonia Typical anti-psychotic OR = 2.6 (1.4-4.6) Atypical OR = 1.8 (1.2-5.3) Roadmap Take-Home Points Background Etiology Diagnosis Treatment Prevention Etiology: No predictors for typical or atypical need to treat both Etiology: Recognize CA-MRSA as a cause for severe CAP Diagnosis: Do not routinely get blood or sputum cultures in outpt CAP 25

Take-home Points Treatment: doxycycline or macrolide for healthy outpatient with no DRSP risk-factors Treatment: fluoroquinolone or β-lactam + macrolide/doxy for outpt with DRSP risk factors Treatment: most 7 days Prevention: pneumovax, flu vax, smoking, avoid PPIs Maximizing Care for Community- Acquired Pneumonia Bradley A. Sharpe, M.D. Associate Professor Medicine Department of Medicine UCSF sharpeb@medicine.ucsf.edu 26