Update Community Respiratory Tract Infections

1. Update Community Respiratory Tract Infections Thomas M File, Jr MD MSc MACP FIDSA FCCP Chair, Infectious Disease Division Summa Health System Akron, Ohio; Professor of Internal Medicine, Chair ID Section Northeast Ohio Medical University Rootstown, Ohio

2. Acute Respiratory Tract Infections • Most common reason for antimicrobials • Many infections Unspecified URI Otitis Common Cold Acute Bronchitis Sinusitis Chronic Bronchitis Pharyngitis Pneumonia • Challenge • What infections warrant antimicrobial therapy? • What etiology (viral vs bacterial)?

3. Use of Procalcitonin for Antimicrobial Stewardship for RTIs File TM Jr. Clin Cherst Med. 2011; modified from Schuetz P. et al. Eur Respir J 2011;37(2): 384–92.

4. 20 year old afebrile college student with non-exudative acute sore throat. What is your approach?

5. Pharyngitis • Most pharyngitis is viral • S. pyogenes (GAS)—only common etiology of pharyngitis for which antimicrobials are indicated • accounts for up to 25% in children, much less in adults • Concern for severe post-streptococcal complications • Acute rheumatic fever (risk is low in developed countries) • Acute glomerulonephritis (no evidence ATB prevents) • Local suppurative (low risk) • Other causes: GC, Mono, Mycoplasma, Grp C/G Strep, Arcanobacterium hemolyticus (unresponsive to PCN), Fusobacterium necrophorum (Lemierres syndrome) • Inf Dis Soc Am Guidelines, Clin Inf Dis. 2012: available www.idsociety .org

6. Pharyngitis • Indications for antimicrobial therapy • Base on rapid antigen test or throat culture • Newer antigen tests have sensitivity approx 90% • No need to do culture for adults if antigen neg. • vs syndromic approach (adenopathy, exudate, fever, lack of cough….) • Low predictability • Consider if high risk; ie, history of recurrent GAS-pharyngitis or ARF; epidemic) • Inf Dis Soc Am Guidelines, Clin Inf Dis. 2012: available www.idsociety .org .

7. Grp A Strep vs Viral Pharyngitis Grp A Strep Viral • Inf Dis Soc Am Guidelines, Clin Inf Dis. 2012: available www.idsociety .org .

8. IDSA Guideline: Grp A Strep therapy b. Avoid if immediate PCN hypersensitivity; c. Resistance variable • Inf Dis Soc Am Guidelines, Clin Inf Dis. 2012: available www.idsociety .org

9. Pharyngitis in University Health Clinic • 312 students (age 15-30) • Etiology: • Fusobacterium necrophorum 20.5% • Grp A Strep 10.3% • Grp C/G Strep 9.0% • Mycoplasma 1.9% • Infection with F necrophorum and Grp A Strep more severe Centor et al. Ann Intern Med 2015; 162: 241-

10. F necrophorum casues pharyngitis in adolescents/young adults as common as Grp A Strep • Use a penicillin or cephalosporin or clindamycin (not macrolide) if a consideration in Strept-negative pharyngitis • Pharyngitis normally resolves in 3-5 days • 2 major flags are worsening sore throat and neck swelling • Often bacteremic and toxic; may require surgical intevention Centor R. Annals Intern Med. 2009; 151: 812-815 (Dec 1)

11. Who of the following warrant antimicrobial therapy for sinusitis? • 35 year old afebrile female with signs of acute sinusitis of three days duration • 40 y/o female with sinus drainage and tenderness for 10 days • 25 y/o female with sinus pressure and drainage for 3 days with initial improvement followed by onset of fever, increasing sinus drainage and tenderness

12. Management of Sinusitis • Acute sinusitis is generally viral • 0.5%-2% develop secondary bacterial sinusitis • Predictors of bacterial sinusitis (acute maxillary) • Symptoms >7 days; severe • Facial pain/tenderness, fever, dental pain, abnormal transillumination, intranasal pus, unresponsive to decongestants • Imaging studies not suggested for initial Rx • Most common bacterial pathogens: S. pneumoniae, H. influenzae • Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg. 2004;130(Suppl 1):1-45.

13. New Guideline Recommendations (pending review and approval) The following clinical criteria (any of three) are recommended for identifying patients with acute bacterial vs. viral rhinosinusitis: • Onset with persistent symptoms (nasal discharge of any quality or daytime cough or both) lasting for >10 days without any evidence of clinical improvement); • Onset with severe symptoms (purulent nasal discharge and fever or facial pain) lasting for at least 3-4 days at the beginning of illness; or • Onset with initial improvement followed by worsening of respiratory symptoms (nasal discharge or cough or new onset fever or headache) lasting for 3-4 days. Clin Infect Dis. April, 2012

14. New Recommendations (pending approval) • Amoxicillin-clavulanate rather than amoxicillin alone is recommended as empiric therapy in both children and adults. • “high-dose” amoxicillin-clavulanate recommended for children and adults from geographic regions with high endemic rates of penicillin-nonsusceptible S. pneumoniae, severe infection, a recent history (within 3 months) of hospitalization or antibiotic use, or those with co-morbidities • Either doxycycline (not suitable for children) or a respiratory fluoroquinolones (levofloxacin or moxifloxacin) are recommended as alternative agents for empiric initial antimicrobial therapy in patients allergic to penicillin. (macrolides or SXT/TMP NOT listed) • Recommended duration of therapy for uncomplicated ABRS in adults is 5-7 days. (Children 10-14d)

15. New Recommendations • Intranasal saline irrigations recommended as an adjunctive treatment in patients with ABRS. Either physiologic or hypertonic saline is recommended. • Intranasal corticosteroids may be used as an adjunct to antibiotics in the empiric treatment of ABRS, particularly in those with a history of allergic rhinitis. This recommendation places a relatively high value on a small additional relief of symptoms and a relatively low value on avoiding increased resource cost. • Neither topical nor oral decongestants and/or anti-histamines are recommended as adjunctive treatment in patients with ABRS (in placebo trials no significant benefit and causes increase in inflammation)

16. NASAL IRRIGATION:recipe • Use a one-quart clean glass jar • Fill with water that has been distilled, boiled, or sterilized. Plain tap water is not recommended because it is not sterile. • Add 1 to 1½ heaping teaspoons of pickling/canning salt. Do NOT use table salt because it contains a large number of additives. • Add 1 teaspoon baking soda (pure bicarbonate) • Mix ingredients together and store at room temperature. Discard after one week. from: Diseases of the Sinuses: Diagnosis and Management. Kennedy DW, Bolger WE, Zinreich SJ (Eds), BC Decker, Hamilton, Ontario 2001.

17. COPD Airflow limitation/obstruction present Emphysema Bronchiectasis • Chronic bronchitis • Chronic productive cough for 3 monthsin each of 2 successive years • 85% of COPD • AECB • Increaseddyspnea • Increased sputum volume • Increased sputum purulence COPD = chronic obstructive pulmonary disease; AECB = acute exacerbations of chronic bronchitis McCrory et al. Chest. 2001 Apr;119(4):1190-209

18. A vicious cycle of infection and inflammation in AECB MicrobialInfection Impaired LungDefences Inflammation Tissue Damage Cole and Wilson

19. GOLD Recommendation for antibiotic use in Exacerbations of COPD • Antibiotics recommendations: • Patients with 3 cardinal symptoms • 2 symptoms if increased purulence is one • Length 5-10 days. • Choice based on local bacterial resistance pattern. Global Initiative for Chronic Obstructive Lung Disease Vestbo J et al. Am J Resp Crit Care Med. 2013 187: 347-65

20. Guidelines for management of AECB III, Chronic suppurative bronchitis II, Chronic bronchitis w Risk factors (Complicated) I, Chronic bronchitis w/o risk factors (Simple) < 4 exacerbations/yr No comorbid illness FEV1 >50% As in group II FEV1 usually<35% Multiple risk factors >4 exacerbations/yr Cardiac disease FEV1 <50% Home O2 Chronic oral steroids Ab use in past 3 mo Plus GNRs Fluoroquinolone b-lactam/b-lactamase inhibitor Hemophilus, S. pneumoniae, Moraxella 2nd generation macrolide 2nd/3rd cephalosporin, Amoxicillin; Doxycycline Trimethoprim/sulfameth Plus Pseudomonas Tailor to pathogen Ciprofloxacin Balter et al Can Respir J 2003; 10 (Suppl B): 3B-32B

21. From Sethi S. personal communication

22. Community-acquired Pneumonia (CAP) Leading cause of morbidity and mortality 40,000 deaths/year in US Esp. elderly and patients with comorbidities No. I cause due to infection Incidence General pop.: 1−12/1000/year > 65 years: 25−44/1000/year 5-6 million cases/year Approx. 1 million admissions/year (40% one year mortality; Kaplan et al. Arch Intern Med 2003; 163: 317-323) > 75% treated as outpatients Cost of treating CAP exceeds $17 billion/year Performance Measures File T. Lancet 2003; File and Tan JAMA 2005 File T and Marrie T Postgrad Med. 2010

23. Types and Spectrum of Pneumonia Hospital-acquired pneumonia (HAP)/ ventilator-acquired pneumonia (VAP) Risk of MDR Pathogens Healthcare-associated pneumonia (HCAP) Community-acquired pneumonia (CAP) Morbidity and Mortality Craven D. CurrOpin Infect Dis. 2006;19:153-160.

24. HCAP: are all at risk for MDRO? • Inclusion of healthcare related pneumonia1 • Hospitalized in the preceding 90 days • Nursing home/extended care facility residence • Home infusion therapy (including antibiotics) • Chronic dialysis; Home wound care • Treat for MDR pathogens, regardless of when in hospital stay pneumonia begins1(But this is overgeneralization) • Increasing evidence many NOT at risk for MDRO2-4 • 23.5% of HCAP patients over treated for MDRO5 • Underlying patient characteristics important independent determinants • New guidelines pending 1. Am J respir Crit Care Med. 2005; 171: 388; 2.Chambers et al. Clin Infect Dis 2014; 58:330; 3. Gross et al AAC 2014; 58:5262; 4. Yap et al. Inf Dis Clinics NA 2013; 27: 1; 5. Webb, BJ et al. IDWeek Poster #47798, 2014

25. Inclusion of healthcare related pneumonia1 • Hospitalized in the preceding 90 days • Nursing home/extended care facility residence • Home infusion therapy (including antibiotics) • Chronic dialysis • Home wound care • Family member with multidrug-resistant pathogen • Treat for MDR pathogens, regardless of when in hospital stay pneumonia begins1(But this is overgeneralization) • Increasing evidence many with HCAP NOT at risk for MDRO2-4 • 23.5% of HCAP patients over treated for MDRO5 • Underlying patient characteristics important independent determinants • New guidelines pending 1. Am J respir Crit Care Med. 2005; 171: 388; 2.Chambers et al. Clin Infect Dis 2014; 58:330; 3. Gross et al AAC 2014; 58:5262; 4. Yap et al. Inf Dis Clinics NA 2013; 27: 1; 5. Webb, BJ et al. IDWeek Poster #47798, 2014

26. Community-acquired pneumonia (CAP): Case 26 Y/O FEMALE Healthy Headache, Fever, Nonproductive Cough for 7 days T-100.80 F; P-100; RR-24; Ausc-Bilateral hi-pitched rhonchi O2 sat-98% Room Air SHOULD SHE BE ADMITTED? What antimicrobial(s)

27. Site of Care Decision Determines Cost of care Intensity of diagnostic testing Empiric choice of antibiotics Advantages of outpatient therapy Cost Patient preference Faster convalescence and avoidance of nosocomial complications Science and Art Mortality prediction rules (PSI, CURB-65) Social circumstances Co-existing conditions

28. Pneumonia Prediction Rule for Mortality Risk Assessment STEP 1 STEP 2 Yes Is the patient >50 years of age? Class II(70 points) Assign points for: Demographic variables Comorbid conditions Physical observations Laboratory and radiographic findings No Does the patient have any of the following coexisting conditions: Neoplastic disease; congestive heart failure; cerebrovascular disease; renal disease; liver disease Class III(71–90 points) Yes Class IV(91–130 points) No Yes Does the patient have any of thefollowing abnormalities: Altered mental status; pulse 125/min; respiratory rate 30/min; systolic blood pressure <90 mm Hg; temperature <35ºC or 40ºC Class V(>130 points) No Class I Fine MJ, et al. N Engl J Med. 1997;336:243-50.

29. Prediction Rule Step 2: Algorithm Pt CharacteristicPoints Age No. of years (-10 for female) Cancer 30 Liver disease 20 CHF, CVD, Renal disease 10 RR >30/min, SBP <90 mmHg, Confusion 20 Temp <35ºC, >50ºC 15 Pulse, beats/min 10 BUN; Sodium <130 mmol/l 20 Glucose >250 mg/dl; Hct < 30% 10 pO2 < 60 mmHg 10

30. Prediction Rule: Risk Categories Risk categories according to two validation cohorts (38,039 inpatients and 2287 in- and outpatients) Fine MJ, et al. N Engl J Med. 1997;336:243-50.

31. Applying the CURB-65 Rule Group 1 Mortality Low (1.5%) (n=324, died=5) Treatment Options CURB-65 Score Likely suitable for home treatment 0 or 1 • Any of: • Confusion* • Urea >7 mmol/l • Respiratory Rate ≥30/min • Blood pressure (SBP <90 mmHg or DBP ≤60 mm Hg) • Age ≥65 years Consider hospital supervised treatment Options may include: Short stay inpatient; Hospital-supervised outpatient Group 2 Mortality Intermediate (9.2%) (n=184, died=17) 2 3 + Group 3 Mortality High (22%) (n=210, died=47) Manage in hospital as severe pneumonia Assess for ICU admission especially if CURB-65 score = 4 or 5 Lim WS, et al. Thorax. 2003;58:377-82.

32. Diagnostic Tests for Etiologyin CAP Management • Standard culture methods (blood, sputum) • Low yield, time to results • Gram stain, urinary antigen testing • S pneumoniae, Legionella spp • Newer molecular tests (PCR, MALDI-TOF) • Potential for more rapid diagnosis, greater sensitivity • Allows for pathogen-directed therapy • Biomarkers (Procalcitonin) • Differentiate Bacterial vs virus • Timely response to bacterial load • PCR, polymerase chain reaction; MALDI-TOF, matrix-assisted laser desorption/ionization Time of Flight mass spectrometry

33. CAP: EMPIRICAL THERAPYPrinciples • TREAT EARLY • TREAT MOST LIKELY PATHOGENS • S. pneumoniae (?Drug resistance*); H. influenzae • Atypicals—studies in North America show high prevalence (even though may not be severe, therapy reduces illness) • Others (local epidemiology) • Cannot differentiate etiology based on initial findings *Recent ATB (Following of ? Relevance: Recent Hospitalization; DayCare; Multiple comorbidities; Age)

34. Most Common Etiologies of CAP Based on collective data from recent studies; †Excluding Pneumocystis spp. ‡ Influenza A and B, adenovirus, respiratory syncytial virus, parainfluenza File TM. Lancet. 2003;362:1991-2001.

35. Empiric Therapy in CAP: IDSA/ATS 35 *Includes healthy patients in regions with high rates of macrolide resistance. †Treatment of Pseudomonas or MRSA is the main reason to modify standard therapy for ICU patients. ICU = intensive care unit Mandell L, et al. Clin Infect Dis. 2007;44(Suppl 2):S27-S72.

36. Azithromycin Cardiovascular events (QT effect) • NEJM 2012 (Ray et al. Tennessee, USA) • Older population; Azithro associated with higher mortality • NEJM 2013 (Svanstrom et al. Denmark) • General population; no association with mortality • JAMA 2014 (Mortensen et al. VA database, USA) • Azithro associated with slight increase of MI but overall reduced mortality in hospitalized patients • J AM Coll Cardiology 2015 ( Cheng et al) • Metaanalysis: higher risk sudden cardiac death • MY TAKE: Risk small; Azithro safe for general population and associated with better outcomes for hospitalized patients. Need to consider risk-benefit for patients with CV disease (QT prolongation). Avoid 2 drugs that prolong QT

37. Clinical Infectious Diseases 2010; 51(2):189–194

38. CAP in 24 y/o female from China • 3 days of progressive cough, fever, chills, dyspnea • T-103.2 F (39.5 C); R-24; HR-128 • WBC 9,100; 21% bands • Pulse Ox-94%

39. CAP: Ceftarolinevs Ceftriaxone • Meta-analysis 3 Phase 3 RCT, DB; 1900+ patients; PORT III or IV1 • Clinical Cure for S. pneumoniae (FOCUS): • Ceftaroline 59/69 (85.5%); Ceftriaxone 48/70 (68.6%)2 • (Ceftaroline has greater affinity for PBP 2X) 1. Taboada M et al. L-1748a ICAAC 2014; 2. File TM Jr. et al. Clin Infect Dis. 2010; 51; 1395-405

40. Community-acquired pneumonia (CAP): Case 66 Y/O MALE Smoke, Diabetes, CHF Treated with macrolide for ‘sinusitis’ 8 weeks ago Headache, Fever, Cough for 3 days, New Confusion T-101.80 F; P-110; RR-28; Ausc-rhonchi RLL O2 sat-92% Room Air SHOULD HE BE ADMITTED? WHAT ANTIMICROBIAL CXR courtesy of T. File MD

41. CMS 2014 CAP Quality Measures for Inpatients • Empiric antimicrobials according to guidelines • Exceptions: pathogen-directed therapy, clinical trials, diagnostic uncertainty • CAP mortality • 30-d readmission rate for pneumonia* *Complements Core Measures as part of the Hospital Readmissions Reduction Program—hospitals with higher than expected 30-d readmission rates for AMI, heart failure, and pneumonia will incur penalties against their total Medicare payments beginning in FFY 2013. http://www.cms.gov/Regulations-and-Guidance/Legislation/EHRIncentivePrograms/2014_ClinicalQualityMeasures.html File TM Jr, personal communication, Sept. 2013. CMS community-acquired pneumonia Technical Expert Panel, 9/19/13.

42. CAP CASE: Assuming this patient does not have bronchiectasis or advanced COPD, which of the following regimens is NOT recommended in the IDSA/ATS guidelines and is considered in variance with the CMS Performance Indicator? Moxifloxacin Cefriaxone plus azithromycin Piperacillin/tazobactam plus azithromycin Ampicillin/sulbactam plus azithromycin Levofloxacin

43. CAP CASE: Assuming this patient does not have bronchiectasis or advanced COPD, which of the following regimens is NOT recommended in the IDSA/ATS guidelines and is considered in variance with the CMS Performance Indicator? Moxifloxacin Cefriaxone plus azithromycin Piperacillin/tazobactam plus azithromycin Ampicillin/sulbactam plus azithromycin Levofloxacin

44. CAP: JC/CMS Antimicrobial Recommendations by Site of Care1,2 aceftriaxone, cefotaxime, amp/sulbactam, ertapenem, ceftaroline bIf aged <65 y with no risk factors for drug-resistant Pneumococcus. 1. JC, CMS. http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx. Good through 12/31/2013. 2. File TM Jr et al. Clin Infect Dis. 2011;53(suppl 1):S15-S22, by permission of Oxford University Press.

45. CAP Case: Assuming he was treated with ceftriaxone + azithromycin and it is now Day 3-Afebrile, other VS stable, alert, no unstable comorbidity; O2 sat-96%; sputum culture obtained on admission + for S. pneumoniae ( PCN susceptible). What is your course of action? • Change to po amoxicillin discharge on next day • Change to po fluoroquinolone and discharge now • Change to po amoxicillin and discharge now • Continue IV ATB • Add IV Vancomycin

46. SWITCH THERAPY (IV to po) and DISCHARGE CRITERIA • Switch Therapy • When good clinical response, comobidities stabilized, can take po • If pathogen identified, ‘Directed’ Therapy • If empiric, can utilize ‘negative’ lab results to simplify therapy (e.g. if urinary antigen and blood cultures negative) • Discharge • If VS and O2 status stable, and no unresolved comorbidities, can discharge at time of oral switch • No value to observe in hospital for 24 h after switch • (Dunn et al. Am J Med. 1999; 106:6)

47. CAP Case: How long do you treat? • 5-7 days • 7-10 days • 10-14 days • 14-21 days

48. Short- vs Long-course Therapy for CAP • Meta-analysis (≤ 7 days vs longer) Conclusion: No difference in efficacy and safety • Based on available data • Minimum of 5 days if afebrile by 48-72 hrs for ‘core pathogens’ • Longer for other pathogens or evidence of extrapulmonary infection • S. aureus, Pseudomonas • Shorter course Therapy • Reduced resistance, AE, cost Dimopoulos 2008, p1848; Drugs; 2008: 68: 1841-

49. Adjunctive Therapy:Glucocorticoids for CAP • Systemic adjunctive corticosteroid therapy may attenuate the inflammatory response, and by doing so decrease the frequency of ARDS, reduce the length of illness and of hospital stay, and possibly even reduce mortality. • Previous systematic reviews of randomized clinical trials have, however, failed to establish a conclusive benefit and current clinical practice guidelines do not recommend systemic corticosteroid therapy for CAP 49

50. Adjunctive Therapy:Glucocorticoids for CAP Impact of corticosteroids on all-cause mortality in patients hospitalized with community-acquired pneumonia , by severity of pneumonia Siemieniuk R et al. Ann Intern Med. 2015; 163: 519-28