1. Community Acquired Pneumonia (CAP) Bradley K. Harrison, M.D.

2. CAP defined Pneumonia not acquired in a hospital or a long-term care facility –Hospital acquired pneumonia –Healthcare associated pneumonia: other healthcare facilities such as nursing homes, dialysis centers, and outpatient clinics

3. Introduction Estimated 5.6 million cases of CAP occur annually in the United States Estimated total annual cost for CAP in the United States is $8.4 billion –92% of cost with inpatient therapy Because CAP is the only acute respiratory tract infection in which there is increased mortality if antibiotic therapy is delayed, diagnostic and treatment decisions need to be made accurately and efficiently Mortality rate among hospitalized patients with CAP varies each year and can reach 35%

4. Epidemiology Unclear because few population-based statistics for CAP alone are available Center for Disease Control and Prevention (CDC) combines pneumonia with influenza when collecting data on morbidity and mortality In 2001, influenza and pneumonia combined were the 7 th leading cases of death in the U.S. –Down from 6 th in previous years Death rate of 21.8 per 100,000 patients

5. Clinical Presentation Pneumonia is an inflammation or infection of the lungs that causes them to function abnormally Classified as typical or atypical, although the clinical presentations are often similar Several symptoms commonly present in patients with pneumonia Approximately 20-33% of episodes result in hospitalization

6. Etiology Typical: up to 70% –Usually caused by Streptococcus pneumoniae Atypical: 30-40% –“My Lungs Contain Viruses” Mycoplasma pneumoniae Legionella pneumophila Chlamydia pneumoniae Viruses: Influenza, Adenovirus –May be co-pathogens in other cases

7. Symptoms Cough, fever, chills, fatigue, dyspnea, rigors, and pleuritic chest pain Depending on the pathogen, cough may be persistent and dry, or it may produce sputum Other presentations may include headache and myalgia Certain etiologies, such as legionella, also may produce gastrointestinal symptoms –Symptoms at presentation are not useful in distinguishing CAP from respiratory illnesses with other causes

8. Diagnosis: Physical Examination Dullness to percussion of chest, crackles or rales on auscultation, bronchial breath sounds, tactile fremitus, and egophany (“E” to “A” changes) Patient may also be tachypneic Patients with typical pneumonia are more likely to present with dyspnea and bronchial breath sounds on auscultation

9. Diagnosis: Radiography CXR (PA and Lateral): –American Thoracic Society (ATS) guidelines, “all patients with suspected CAP should have a chest radiograph to establish the diagnosis and identify complications (pleural effusions, multilobar disease)” –Lobar consolidation – more common in typical pneumonia –Bilateral, diffuse infiltrates – commonly seen in atypical pneumonia However, radiologists cannot reliably differentiate bacterial from nonbacterial pneumonia on the basis of the radiographic appearance –If performed early in the course of the disease, may be negative The sensitivity of chest radiography depends greatly on pretest probability

10. 47-year-old smoker presented after just a few hours of rigors and productive cough Despite clinical signs of right upper zone consolidation, chest x-ray showed only minor abnormalities Empirical therapy for community-acquired pneumonia was begun

11. 12 hours later Chest x-ray showed consolidation in the right upper lobe consistent with the earlier clinical signs S. pneumoniae was isolated from blood cultures The patient recovered fully

12. Diagnosis: Radiography (cont.) CT –CT scan could be performed in patients with a negative chest radiograph when there is a high clinical suspicion for pneumonia –CT scan, especially high resolution CT (HRCT), is more sensitive than plain films for the evaluation of interstitial disease, bilateral disease, cavitation, empyema, and hilar adenopathy –This technology is not generally recommended for routine use because the data for its use in CAP are limited, the cost is high, and there is no evidence that this improves outcome –Thus, a chest radiograph is the preferred method for initial imaging, with CT scan or MRI reserved for further anatomical definition

13. Diagnosis: Laboratory Tests Historically: WBC, sputum cultures, two sets of blood cultures, and urine antigens –Sputum samples are adequate in only 52% of patients with CAP, and only 44 % of those samples contain pathogens Likely due to problems with retrieving samples from lower respiratory tract, previous antibiotics, contamination from upper airways, or viral etiology –Positive blood cultures obtained in only 5-10% of patients, including those with severe disease Positive blood culture has no correlation with severity of illness or outcome –Current ATS guidelines recommend that patients hospitalized for suspected CAP receive 2 sets of blood cultures

14. Sensitivity and Specificity of Diagnostic Tests for CAP Diagnostic tests by pathogenSensitivity (%)Specificity (%) Chlamydia Rapid PCR (sputum, BAL fluid)30 to 95> 95 Serology (fourfold rise in serum and convalescent titers) 10 to 100- Sputum culture10 to 80> 95 Gram-negative rods Sputum Gram stain15 to 10011 to 100 Haemophilus influenzae, Moraxella catarrhalis, Pneumoniae Sputum cultureDiagnostic yield 20 to 79* Influenza Rapid DFA (sputum, BAL fluid)22 to 7590 Legionella pneumophila DFA (sputum, BAL fluid)22 to 7590 PCR (sputum, BAL fluid)83 to 100> 95 Serum acute titer10 to 27> 85 Urinary antigen55 to 90> 95 Mycoplasma pneumoniae Antibiotic titers75 to 95> 90 Cold agglutinins50 to 60- PCR (sputum, BAL fluid)30 to 95> 95 Pneumococcal pneumoniae Chest radiography (lobar infiltrate)40†- Sputum cultureDiagnostic yield 20 to 79* Sputum Gram stain15 to 10011 to 100 Diagnosis and treatment of community-acquired pneumonia: Am Fam Physician. 2006 Feb 1;73(3):442-50.

15. Treatment Initial treatment of CAP is based on physical examination findings, laboratory results, and patient characteristics –Age, chronic illnesses, smoking history, history of the illness Therapy for pneumonia is empiric because specific pathogens usually are not identified at the time treatment is initiated Physicians should begin their treatment decisions by assessing the need for hospitalization using a prediction tool for increased mortality, combined with clinical judgment –Pneumonia Severity Index

16. Pneumonia Severity Index (PSI) PSI was derived and validated as part of the Pneumonia Patient Outcomes Research Team (PORT) prospective cohort study for the purpose of identifying patients with CAP at low risk for mortality –The Pneumonia PORT prediction rule used a derivation cohort of 14,199 inpatients with CAP; it was independently validated in 38,039 inpatients with CAP and in 2,287 inpatients and outpatients prospectively –The PSI rule stratified adults with radiographic evidence of pneumonia into five classes for risk of death from all causes within 30 days of presentation One limitation in the derivation of this rule was that it included mostly patients seen in a hospital emergency department, and included few outpatients who were evaluated in a physician's office and sent home

17. Demographics MaleAge (years) FemaleAge (years) − 10 Nursing home resident+ 10 Comorbid illness Neoplastic disease+ 30 Liver disease+ 20 Congestive heart failure+ 10 Cerebrovascular disease+ 10 Renal disease+ 10 Physical examination findings Altered mental status+ 20 Respiratory rate > 30 breaths per minute+ 20 Systolic blood pressure < 90 mm Hg+ 20 Temperature 40˚C (104˚F)+ 15 Pulse rate > 125 beats per minute+ 10 Laboratory and radiographic findings Arterial pH < 7.35+ 30 Blood urea nitrogen > 64 mg per dL (22.85 mmol per L) + 20 Sodium < 130 mEq per L (130 mmol per L)+ 20 Glucose > 250 mg per dL (13.87 mmol per L)+ 10 Hematocrit < 30 percent+ 10 Partial pressure of arterial oxygen < 60 mm Hg or oxygen percent saturation < 90 percent + 10 Pleural effusion+ 10 Pneumonia Severity Index (PSI) Point total Risk Risk classRisk class Recommended site of care No predictorsLowIOutpatient ≤ 70LowI Outpatient 71 to 90LowIIIIII Inpatient (briefly) 91 to 130ModerateIVIV Inpatient > 130HighVInpatient

18. Treatment: Outpatient vs. Inpatient Choosing between outpatient and inpatient treatment is a crucial decision because of the possible risk of death Decision influences diagnostic testing and medication choices, as well as a psychological impact on patients and families Average cost –Inpatient: $7,500 –Outpatient: $150-350 Based on age, co-morbidities, and the severity of presenting disease

19. Treatment: Outpatient vs. Inpatient (cont.) Physicians tend to overestimate a patient’s risk of death; many low-risk patients could be treated safely as outpatients By using Pneumonia Severity Index (PSI), 26- 31% of hospitalized patients were good outpatient candidates –An additional 13-19% only needed brief hospital observation PSI can serve as a general guideline, clinical judgment should always supersede prognostic score

20. Pharmacotherapy: Outpatient Consensus guidelines –ATS, Infectious Disease Society of America, and Canadian Guidelines for the Initial Management of Community-Acquired Pneumonia Empiric oral therapy with macrolides, doxycycline, or an oral beta lactam (amoxicillin, cefuroxime [ceftin], or amoxicillin/clavulanate [augmentin]), or a flouroquinolone –Therapeutic Working Group of the CDC Use flouroquinolones sparingly because of resistance concerns Duration of therapy –S. pneumoniae: 7-10 days or until afebrile 3 days Bacteremic: 10-14 days –Mycoplasma/Chlamydia pneumoniae: 10-14 days, up to 21 days –Legionella: 10-21 days

21. Pharmacotherapy: Outpatient (cont.) Several classes of antibiotics are effective against atypical pathogens C. pneumoniae and Legionella species are intracellular organisms and M. pneumoniae lacks a cell wall, beta lactams are not effective –Erythromycin and tetracycline have been traditional choices for atypical CAP –Newer macrolides (azithromycin [zithromax] and clarithromycin [biaxin]) have good atypical activity and are generally are better tolerated than erythromycin –Doxycycline (Vibramcyin) is effective, associated with fewer gastrointestinal side effects, and is a less expensive alternative –Flouroquinolones have demonstrated excellent activity against atypicals and have one-daily dosing and excellent bioavailability

22. Pharmacotherapy: Outpatient (cont.) The Sanford Guide to Antimicrobial Therapy 2006 – 36 th Ed. –CAP, not hospitalized, no comorbidities* Azithro 0.5g PO x 1, then 0.25g PO QD Azithro-ER 2g x 1 (2g /60mL single dose bottle) Clarithro 500mg PO BID Clarithro-ER 1g PO Q24h Doxy 100mg PO BID * Alcoholism, bronchiectasis, COPD, IVDU, Post- CVA aspiration, post-obstruction of bronchi, post-viral

23. Pharmacotherapy: Outpatient (cont.) The Sanford Guide to Antimicrobial Therapy 2006 – 36 th Ed. –CAP, not hospitalized, with comorbidities Respiratory flouroquinolone –Gati 400mg PO q24h, Gemi 320mg PO q24h, Levo 750mg PO q24h, Moxi 400mg PO q24h Telithro 800mg PO q24h Azithro/Clarithro + HD Amox, HD AM-CL, cefdinir, cefpodoxime, cefprozil

24. Pharmacotherapy: Inpatient Antibiotic therapy should be initiated within 4 hours of hospitalization Intravenous beta lactam (cefotaxime [claforan] or ceftriaxone [rocephin]) plus a macrolide or a combination of ampicillin/sulbactam (unasyn) plus a macrolide or a fluoroquinolone alone After clinically stable (T 90, O2 sat>90%) and able to tolerate oral intake, may be switched to oral antibiotics for remainder of therapy –Save money, earlier discharge, minimizes risk of nosocomial infections

25. Pharmacotherapy: Inpatient (cont.) The Sanford Guide to Antimicrobial Therapy 2006 – 36 th Ed. –CAP, hospitalized, NOT in ICU, no comorbidities Ceftriaxone 2g IV q24h + Azithro 500mg IV q24h –Age >65: Ceftriaxone 1g IV q24h –CAP, hospitalized, NOT in ICU, comorbidities Gati 400mg IV q24h, Levo 750mg IV q24h, Moxi 400mg IV q24h

27. Flouroquinolones Conservative use is recommended to minimize resistance patterns New flouroquinolones (levofloxacin, gatifloxacin, moxifloxacin) should be used only when patients have failed recommended first-line regimens, are allergic to alternative agents, or have a documented infection with highly drug- resistant pneumococci

28. Pneumococcal Resistance S. pneumoniae accounts for 60-70% of all bacterial CAP –Affects all patient groups and can be fatal Alarming rate of resistance to many commonly used antibiotics –PCN uncommon before 1990 Resistance classified as intermediate or high- level –Intermediate: 28% –High-level: 16% Nation-wide

29. Patterns of Resistance to Antibiotics in North America Antibiotic Resistance (%) Penicillins Amoxicillin/clavulanate (Augmentin)4.1 Penicillin21.3 Cephalosporins Cefepime (Maxipime)0.4 Cefprozil (Cefzil)23.9 Ceftriaxone (Rocephin)1.9 Cefuroxime (Ceftin)24.7 Macrolides Azithromycin (Zithromax)23.0 Clarithromycin (Biaxin)26.6 Erythromycin28.3 Fluoroquinolones Gatifloxacin (Tequin)0.7 Levofloxacin (Levaquin)0.7 Moxifloxacin (Avelox)0.4 Miscellaneous Clindamycin (Cleocin)9.2 Tetracycline18.8 Trimethoprim/sulfamethoxazole (Bactrim, Septra) 29.9 Vancomycin (Vancocin)0.0 Antibiotics tested against Streptococcus pneumoniae isolates Resistance rates averaged across all patient groups

30. Cost-effective Care When choosing a treatment, it is essential to compare costs and outcomes of all recommended drug therapies Evaluation should lead to a decision that will maximize the value of health care services, not simply reduce the costs of drug therapy –Overall cost of each therapy should be obtained by comparing the end cost with the probability of achieving a positive outcome

31. Antimicrobial Therapies for CAP AgentDosage Cost per course (generic)Common adverse reactions Cefotaxime (Claforan) Cefpodoxime (Vantin) Cefprozil (Cefzil) Ceftriaxone (Rocephin) Cefuroxime (Ceftin) 1 g IV every six to eight hours 200 mg orally twice per day 500 mg orally twice per day 1 g IV every 24 hours 500 mg orally twice per day 0.75 to 1.5 g IV every eight hours $355 (330) 124 (110) 192 392 219 oral 250 to 358 IV Mild diarrhea Rash Clindamycin (Cleocin)300 mg orally every six hours 600 mg IV every eight hours 238 (148 to 168) oral 250 IV Mild diarrhea Abdominal pain Pseudomembranous colitis Rash Gatifloxacin (Tequin) Levofloxacin (Levaquin) Moxifloxacin (Avelox) 400 mg orally or IV once per day 500 mg orally or IV once per day 400 mg orally once per day 98 oral, 382 IV 56 oral, 438 IV 107 Mild diarrhea Nausea Vomiting Constipation Dizziness Headache Azithromycin (Zithromax) Clarithromycin (Biaxin) Erythromycin 500 mg orally for one dose, then 250 mg once per day for four doses 500 mg IV every 24 hours 500 mg orally twice per day 500 mg orally every six hours 500 to 1,000 mg IV every six hours 49 to 60 oral 295 IV 96 17 (8 to 10) oral (167) IV Mild diarrhea Nausea Vomiting Abdominal pain Rash Amoxicillin Amoxicillin/clavulanate (Augmentin) Penicillin G Penicillin V 500 mg orally every eight hours 875 mg orally every 12 hours 875 mg/125mg orally every 12 hours 1 to 3 mU IV every four hours 500 mg orally four times per day 4 (4 to 8) 20 (18 to 19) 166 (110 to 115) (273) 15 (9 to 15) Mild diarrhea Nausea Vomiting Rash Doxycycline (Vibramycin)100 mg orally twice per day102 (16 to 21)Mild diarrhea Nausea Vomiting Phototoxicity

32. Prevention More people die from pneumococcal infections (an estimated 40,000 annually in the United States) than from any other vaccine preventable disease PPV23 is recommended for all adults ≥65 years of age and in younger patients with a number of conditions that increase the risk of invasive pneumococcal disease –Adults who have been diagnosed with invasive pneumococcal disease should also be vaccinated because infection with one serotype does not necessarily provide protection against other serotypes A single revaccination is recommended in adults ≥65 years of age if they were vaccinated more than 5 years previously at a time when they were <65 years of age, and in immunocompromised patients five years or more after the first dose