Community-Acquired Bacterial Pneumonia: Is There Anything New? Steve Vacalis DO CaroMont Health Regional Medical Center Gastonia, North Carolina

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1 Community-Acquired Bacterial Pneumonia: Is There Anything New? Steve Vacalis DO CaroMont Health Regional Medical Center Gastonia, North Carolina

2 This presentation is sponsored by: and supported by an educational grant from Cempra Pharmaceuticals

3 Sign up for free membership at pcrg-us.org The Primary Care Respiratory Group (PCRG) is a national educational initiative providing comprehensive respiratory disease education. PCRG s mission is to provide a representative forum for primary care clinicians involved in respiratory disease management and raise standards of patient care through the dissemination of best practices, education programs, and communication among members.

4 Disclosure: Dr. Vacalis discloses that he is on the advisory board and speakers bureau for CEMPRA

5 Learning Objectives: Community Acquired Pneumonia (CAP) After participating in this activity, the clinician will be able to: Describe CAP microbial trends in the US and their impact on clinical outcomes Choose evidence-based empiric antibiotic therapy based on reported sensitivity patterns Identify patients who require broad-spectrum antibiotic therapy Modify therapy in patients who don t respond to initial antibiotic therapy List medications on the horizon for communityacquired bacterial pneumonia

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7 Only 2 Antibiotics Approved for Community-Acquired Bacterial Pneumonia Since 2007 Tigecycline (2009) Ceftaroline fosamil (2010) Both are injectable antibiotics

8 So is there really anything to talk about? Yes!

9 CAP Overview Epidemiologic Concerns Significant morbidity and mortality Costs and hospital length of stay New Dx tests for wider array of pathogens Pathogen sesnsitivy evolving New definition of CABP Collateral damage therapeutic change New antibiotics on the horizon

10 Case Study RD is a 59 y.o. male presenting with cough, fever (oral ) and DOE Hx & PE and CXR: probable CABP Rx: macrolide pending lab confirmation 4 days later: RD complaining of continued Sx including fever Do you admit or treat as an outpatient? If treated as an outpatient, Do you culture? What antibiotic(s) do you start? What do you do if he doesn t get better?

11 CAP Epidemiology and Burden Incidence (declined since PCV 13) 950,000 cases/year in adults age <65 y million cases/year in adults age 65 y 2 3-y prospective study ( n>900,000) Peds ED Incidence of CABP decreased 16% Pneumococcal CAP decreased 63% US health plan database ( ) 4 28,575 episodes: 72% outpatient Inpatient cost/duration: 31.8 d/$11k-51k Outpatient cost/duration: 10.2 d/1k-5.6k 1. Bonafede MM, et al. Am J Manag Care. 2012;18(7): Yu H, et al. J Am Geriatr Soc. 2012;60(11): Angoulvant F, et al. Clin Infect Dis. 2014;58(7): Sato R, et al. Appl Health Econ Health Policy. 2013;11:

12 Epidemiology and Burden In adults age 50 y 1 Time to resolution of symptoms >3 weeks Absenteeism 13 days 21 days before achieving full productivity 8 th leading cause of death* and leading cause of infection-related death in U.S. 2 Persons with CAP have a greater risk of 10- year mortality vs controls (hazard ratio 1.65) 3 *Pneumonia and influenza combined 1.Wyrwich KW, et al. Pat Relat Out Measures. 2015;6: Xu J, et al. Natl Vital Stat Rep. 2016;64(2): Eurich DT, et al Am J Respir Crit Care Med. 2015;192(5):

13 Etiology of CAP Bacterial only (11%) Fungal or mycobacterial (1%) Bacterial-viral (3%) Viral-viral (2%) Viral pathogen only (22%) No pathogen detected (62%) N=2259 adults hospitalized with radiographic evidence of CAP in 5 U.S. hospitals, January 2010 through June 2012 Jain S, et al. N Engl J Med. 2015;373:

14 Patients with a Positive Result (%) Etiology of CAP (cont) Single Pathogen Copathogen N=2259 adults hospitalized with radiographic evidence of CAP in 5 U.S. hospitals, January 2010 through June Jain S, et al. N Engl J Med. 2015;373:

15 Susceptibility (%) Susceptibility of S. pneumoniae, , United States PCN AMC ERY TCN SMX/TMP LVX Flamm RK, et al. Presented at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy and 28th International Congress of Chemotherapy Meeting (ICAAC/ICC); September 17-21, 2015; San Diego, CA. [Abstract C-554].

16 Macrolide-resistant S. pneumoniae, United States, 2012 Center for Disease Dynamics, Economics & Policy. Accessed August 3, 2016.

17 Percent of M. pneumoniae isolates resistant Macrolide-resistant M. pneumoniae, United States, % 50% 50% Although the number of isolates is small (N=91), it shows the wide geographic variability in susceptibility of M pneumoniae to a macrolide 40% 40% 30% 20% 17% 17% 10% 8% 7% 0% Birmingham, AL (6) Chicago, IL (23) Hackensack, NJ (2) Kansas City, MO (40) New York, NY (5) Seattle, WA (15) City (number of M. pneumoniae respiratory isolates tested) Collection period: August 2012 April 2014 Zheng X, et al. Emerg Infect Dis. 2015;21(8):

18 Etiology of CABP Common bacteria S. pneumoniae H. influenza S. aureus Group A strep M. catarrhalis Atypical bacteria C. pneumoniae M. pneumoniae L. pneumophila Other MRSA Gram-negative bacilli K. pneumoniae Ps. aeruginosa

19 Definition of CABP Acute bacterial pulmonary parenchymal infection 1 With chest pain, cough, sputum production, dyspnea, chills, rigors, fever, or hypotension Accompanied by new lobar or multilobar infiltrate on a chest radiograph Acquired in the community vs hospital or healthcare facility 1. U.S. Food and Drug Administration. df. Accessed July 11, 2016.

20 Comparison of Care Recommendations Based on PSI vs CURB-65 Scores PSI Risk Class 1 No. of Points % Mortality I * 0.1 Outpatient II Outpatient Recommended Site of Care III Outpatient or brief inpatient IV Inpatient V > Inpatient; consider ICU CURB-65 Score 2 0 or 1 <3 Likely suitable for home treatment 2 9 Consider hospital-supervised treatment Inpatient PSI, Pneumonia Severity Index *Absence of risk factors; Options may include short inpatient stay or as hospitalsupervised outpatient; Assess for ICU admission, especially if CURB-65 score=4 or 5 1. Bartlett JG, et al. Clin Infect Dis. 2000;31: Lim WS, et al. Thorax. 2009;64(suppl III):iii1-iii55.

21 CAP Care Recommendations PSI vs CURB-65 Scores PSI Risk Points Mortality Class 1 % I * 0.1 Outpatient II Outpatient Recommended Site of Care III Outpatient or brief inpatient IV Inpatient V > Inpatient; consider ICU CURB-65 0 or 1 <3 Likely suitable for home treatment Score Consider hospital-supervised treatment Inpatient PSI, Pneumonia Severity Index *Absence of risk factors; Options may include short inpatient stay or as hospitalsupervised outpatient; Assess for ICU admission, especially if CURB-65 score=4 or 5 1. Bartlett JG, et al. Clin Infect Dis. 2000;31: Lim WS, et al. Thorax. 2009;64(suppl III):iii1-iii55.

22 Units Percent of Patients Limited Value of Signs and Symptoms in Determining Etiology Signs Symptoms 250 P< P= No Etiology Bacterial Viral Bacterial-Viral N=408; age 68 y (20-94 y) Huijskens EGW, et al. J Med Microbiol. 2014;63:

23 Percent of Patients Limited Association of Common Comorbidities with Etiology P< No Etiology Bacterial Viral Bacterial-Viral Huijskens EGW, et al. J Med Microbiol. 2014;63: N=408; age 68 y (20-94 y)

24 Cases Positive (%) Molecular Testing vs Culture Improves Pathogen Detection Bars are percentages of cases with a positive test result relative to the number of cases with a valid test Bacteria Viruses Pleural Fluid Culture Sputum OP Swab Urine Culture PCR Antigen Assay NP Swab Culture NP Swab PCR Serology Blood Culture BAL NP Swab PCR OP SwabSerology PCR From: Holter JC, et al. BMC Infect Dis. 2015;15:64 under Creative Commons Attribution 4.0 [

25 Outpatient Rx Recommendations IDSA Guidelines, 2007 Healthy; no risk for resistant S. pneumoniae Macrolide Doxycycline Comorbidities or risks for resistant S. pneumoniae Respiratory fluoroquinolone -lactam + macrolide Macrolide-resistant (MIC 16 mcg/ml) S. pneumoniae >25% Respiratory fluoroquinolone, ceftriaxone, cefpodoxime, cefuroxime, doxycycline Mandell L, et al. Clin Infect Dis. 2007;44:S27-S72.

26 Monotherapy vs Combination Therapy -lactam vs - lactam/macrolide 1,2 -lactam vs - lactam/macrolide vs FQ 3 FQ vs -lactam/macrolide 4 FQ vs macrolide vs FQ/ lactam vs macrolide/ lactam 5,6 Macrolide vs nonmacrolide 7,8 Similar outcomes and no clear best regimen for empiric therapy 9 1. Nie W, et al. J Antimicrob Chemother. 2014;69: ; 2. Ambroggio L, et al. Pediatr Pulmonol. 2016;51(5): Postma DF, et al. N Engl J Med. 2015;372(14): ; 4. Lodise TP, et al. Antimicrob Agents Chemother. 2007;51(11): ; 5. Raz-Pasteur A, et al. Int J Antimicrob Agents. 2015;46(3): ; 6. Skalsky K, et al. Clin Microbiol Infect. 2013;19: ; 7. Asadi L, et al. Clin Infect Dis. 2012;55(3): Ambroggio L, et al. Pediatr Infect Dis J. 2015;34(8): Pakhale S, et al. Cochrane Database Syst Rev. 2014;10:CD

27 Antibiotic Collateral Damage? Ecological adverse effects of antibiotics 1 Selection of drug-resistant organisms Colonization or infection with multidrugresistant organisms Should it include other unintended, serious consequences of antibiotic therapy? FLQ: tendinopathy, QTc prolongation 2 Macrolide: hepatotoxicity, QTc prolongation 3 Clostridium dificile 1. Paterson DL. Clin Infect Dis. 2004;38(Suppl 4):S341-S US FDAhttp:// Accessed August 5, US FDA. Accessed August 5, 2016.

28 Case Study RD is a 59 y.o. male presenting with cough, fever (oral ) and DOE Hx & PE and CXR: probable CABP Rx: macrolide pending lab confirmation 4 days later: RD complaining of continued Sx including fever Do you admit or treat as an outpatient? If treated as an outpatient, Do you culture? What antibiotic(s) do you start? What do you do if he doesn t get better?

29 Factors Associated with Non- Responsive CAP in Primary Care Retrospective analysis 250 adult CAP (n = 250) initially managed in primary care clinic 85 cases (ie, non-responsive), 165 controls Non-responsive CAP defined as worsening symptoms after 4 days or no improvement within 10 days Rx Non-responder initial Rx macrolide (33%), quinolone (35%), no antibiotic (11%), amoxicillin/amox-clav (6%) Factors predicting non-responsiveness Former smoker (odds ratio 2.27) Initial presentation to urgent care (OR 2.10) Myalgia (odds ratio 2.79) Vander Wyst KB, et al. J Patient Cent Res Rev. 2016;3:79-89.

30 CAP: Common Management Strategies Dx based on symptoms, lab, radiography Severity Scores; PSI, CURB-65 Potential lab: CBC, CMP, CXR, Gram stain, culture Anitbiotics: range from none/mono/combo If patient not improving: Broaden further (vancomycin, 3 rd generationcephalosporin, carbapenem???) Perform diagnostic procedure Broader Rx, hospital stay more collateral damage

31 Antibiotics on the Horizon Lefamulin - pleuromutilin Omadacycline - tetracycline Sitafloxacin - fluoroquinolone Solithromycin - fluoroketolide

32 Omadacycline Oral and IV tetracycline 1 Potent activity against resistant Grampositive bacteria, including S. pneumoniae and MRSA 2,3 Comparable to tigecycline Good oral bioavailability 1 No significant nausea/vomiting 1 1. Honeyman L, et al. Antimicrob Agents Chemother. 2015;59(11): Draper MP, et al. Antimicrob Agents Chemother. 2014;58(3): Macone AB, et al. Antimicrob Agents Chemother. 2014;58(2):

33 Sitafloxacin Oral fluoroquinolone High activity against S. pneumoniae, ESBLproducing E. coli and K. pneumoniae 1,2 7 days of treatment resulted in clinical improvement (94.2%) and bacteriologic cure (95.4%) in S. pneumoniae CABP (N=72) 1 Photosensitivity in Caucasians a concern 3 1. Fujita J, et al. J Infect Chemother. 2013;19(3): Nakamura T, et al. J Infection Chemother. 2014;20(1): Ghebremedhin B. Clin Med Insights Ther. 2012;4;

34 Lefamulin Oral and IV pleuromutilin antibiotic Potent activity against multi-drug-resistant strains of S. pneumoniae 1 macrolide-sensitive and macrolide-resistant M. pneumoniae 2 Granted qualified infectious disease product/fast track status by FDA LEAP2 study- comparison with moxifloxacin in moderate CABP (in progress) 1. Mendes RE, et al. Antimicrob Agents Chemother. 2016;60(7): Waites K, et al. American Society for Microbiology 2016 Scientific Program; June 16-20, 2016, Boston, MA

35 Solithromycin Oral and IV fluoroketolide Highly active against macrolide-resistant S. pneumoniae 1,2 M. catarrhalis 2 2X less active than azithromycin for H. influenzae 2 Good activity against S. aureus, including MRSA 2 Clinical trial mod-moderately severe CABP; outcome: Sx response at 72 hrs solithromycin vs levofloxacin: non-inferior solithromycin vs moxifloxacin: non-inferior 1. Farrell DJ, et al. Antimicrob Agents Chemother. 2015;59(4): ; 2. Farrell DJ, et al. Antimicrob Agents Chemother. 2016;60(6): ; 3. Oldach D, et al. Antimicrob Agents Chemother. 2013;57(6): ; 4. Barrera CM, et al. Lancet Infect Dis. 2016;16(4):

36 Summary and Conclusions CAP: still a significant cause of morbidity and mortality, demanding substantial health care resources Wide array of CAP pathogens, with frequent inability to confirm a pathogen S pneumoniae & mycoplasma susceptibility continues to evolve Antibiotic selection difficult: etiology often uncertain, concern about collateral damage Few new antibiotics for CAP: some pending

37 Thank you Questions & Answers