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1 Community-Acquired Bacterial Pneumonia: Is There Anything New? Hans Liu, M.D., FACP Infectious Disease Specialist Bryn Mawr Medical Specialists Bryn Mawr, Pennsylvania Professor of Medicine Sidney Kimmel School of Medicine Thomas Jefferson University Philadelphia, Pennsylvania This presentation is sponsored by: and supported by an educational grant from Cempra Pharmaceuticals 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.

2 Disclosure: Dr. Liu discloses that he is on the advisory board for Cempra and Daiichi Sankyo CME: Learning Objectives After participating in this activity, the primary care physician will be able to: Describe trends in the microbiology of community-acquired pneumonia in the United States and the impact on clinical outcomes Select evidence-based empiric antibiotic therapy based on national susceptibility trends and ideally on local patterns Initiate broad-spectrum antibiotic therapy in appropriate patients Modify therapy in patients who don t respond to initial antibiotic therapy List medications on the horizon for community-acquired bacterial pneumonia

3 Following an episode of CABP, it takes an adult age 50 years an average of days to achieve full productivity? Retrospective analysis of adults with CAP initially managed in a primary care clinic showed all of the following to predict non-responsiveness except? 1. Bilateral rales 2. Former smoker 3. Initial presentation to urgent care 4. Myalgia Several systematic reviews and meta-analyses since 2007 show which of the following is preferred as initial empiric therapy in the outpatient management of CABP? 1. Macrolide 2. β-lactam + macrolide 3. β-lactam + respiratory fluoroquinolone 4. There is no preferred empiric therapy as the data are inconsistent?

4 Only 2 Antibiotics Approved for Community- Acquired Bacterial Pneumonia Since 2007 Tigecycline (2009) Ceftaroline fosamil (2010) Both are injectable antibiotics So is there really anything to talk about? Yes!

5 Overview Epidemiology of community-acquired pneumonia Still significant cause of morbidity and mortality Costs and hospital length of stay are concerns New diagnostic tests for wider array of pathogens Pathogen susceptibility continues to change New definition of community-acquired bacterial pneumonia Collateral damage driving therapeutic change New antibiotics on the horizon Case Study RD is a 59 year-old male who presents to his primary care physician with dyspnea on exertion and cough History, physical examination, and chest X-ray suggest a diagnosis of community-acquired bacterial pneumonia A macrolide antibiotic is prescribed pending laboratory confirmation Four days later, RD returns complaining of continued symptoms that now include 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? Epidemiology and Burden Incidence 950,000 cases/year in adults age <65 y million cases/year in adults age 65 y 2 Incidence has declined since introduction of PCV y prospective study of nearly 1 million pediatric ED visits Incidence of CABP decreased 16% Incidence of pneumococcal CAP decreased 63% Review of US health plan database ( ) 4 28,575 episodes- 72% managed as outpatient Episode length d (inpatient), 10.2 d (outpatient) Cost (all-cause total) Inpatient: $11,148 to $51,219 Outpatient: $1,048 to $5, 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:

6 Epidemiology and Burden (cont) 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): Etiology of CAP Bacterial only ([VALUE]) Bacterial-viral Viral-viral (3%) ([VALUE]) Fungal or mycobacterial (1%) Viral pathogen only ([VALUE]) No pathogen detected ([VALUE]) 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: Etiology of CAP (cont) Patients with a Positive Result (%) Single Pathogen Copathogen 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:

7 Susceptibility of S. pneumoniae, , United States Susceptibility (%) [VALUE] 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]. Macrolide-resistant S. pneumoniae, United States, 2012 Center for Disease Dynamics, Economics & Policy. Accessed August 3, Macrolide-resistant M. pneumoniae, United States, Percent of M. pneumoniaeisolates resistant 60% 50% 40% 30% 20% 10% 0% 17% 17% Birmingham, AL (6) Chicago, IL (23) 50% Hackensack, NJ (2) Although the number of isolates is small (N=91), it shows the wide geographic variability in susceptibility of M pneumoniae to a macrolide 8% Kansas City, MO (40) 40% New York, NY (5) 7% 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):

8 Etiology of CABP Does not include viruses, fungi, etc. Common bacteria S. pneumoniae H. influenza S. aureus Group A streptococci M. catarrhalis Atypical bacteria C. pneumoniae M. pneumoniae L. pneumophila Other Community-associated MRSA Gram-negative bacilli K. pneumoniae Ps. aeruginosa Definition of CABP Acute bacterial infection of the pulmonary parenchyma 1 Associated with chest pain, cough, sputum production, difficulty breathing, chills, rigors, fever, or hypotension Accompanied by the presence of a 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, A patient with a Pneumonia Severity Index of II 1. Can be managed as an outpatient 2. Should be admitted to the ICU 3. Has an average mortality rate of 7% 4. Is most likely infected with a Gram-negative pathogen?

9 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-65Score 2 0 or 1 <3 Likely suitable forhome 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. Limited Value of Signs and Symptoms in Determining Etiology Signs Symptoms 250 P< P= Units Percent of Patients No Etiology Bacterial Viral Bacterial-Viral N=408; age 68 y (20-94 y) Huijskens EGW, et al. J Med Microbiol. 2014;63: Limited Association of Common Comorbidities with Etiology 50 Percent of Patients P< No Etiology Bacterial Viral Bacterial-Viral Huijskens EGW, et al. J Med Microbiol. 2014;63: N=408; age 68 y (20-94 y)

10 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 Cases Positive (%) Bacteria Viruses 5 0 Pleural Sputum OP Swab Urine NP NP Serology Blood Fluid Culture PCR Antigen Swab Swab Culture Culture Assay Culture PCR BAL NP OP SwabSerology Swab PCR PCR From: Holter JC, et al. BMC Infect Dis. 2015;15:64 under Creative Commons Attribution 4.0 [ Outpatient Treatment, 2007 Previously healthy and no risk for drug-resistant S. pneumoniae Macrolide Doxycycline Presence of comorbidities or other risks for drug-resistant S. pneumoniae Respiratory fluoroquinolone β-lactam + macrolide High rate (>25%) of macrolide-resistant S. pneumoniae (MIC 16 mcg/ml) Respiratory fluoroquinolone, ceftriaxone, cefpodoxime, cefuroxime, doxycycline Mandell L, et al. Clin Infect Dis. 2007;44:S27-S72. Monotherapy vs Combination Therapy β-lactam vs β- lactam/macrolide 1,2 β-lactam vs β- lactam/macrolide vs FQ 3 FQ vs β-lactam/macrolide 4 FQ vs macrolide vs FQ/βlactam vs macrolide/βlactam 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

11 Collateral Damage Typically refers to ecological adverse effects of antibiotic therapy 1 Specifically, the selection of drug-resistant organisms and the unwanted development of colonization or infection with multidrug-resistant organisms Should it also include other unintended, serious consequences of antibiotic therapy? Fluoroquinolone- tendinopathy, QTc prolongation 2 Macrolide- hepatotoxicity, QTc prolongation 3 1. Paterson DL. Clin Infect Dis. 2004;38(Suppl 4):S341-S US FDAhttp:// Accessed August 5, US FDA. Accessed August 5, Case Study RD is a 59 year-old male who presents to his primary care physician with dyspnea on exertion and cough History, physical examination, and chest X-ray suggest a diagnosis of community-acquired bacterial pneumonia A macrolide antibiotic is prescribed pending laboratory confirmation Four days later, RD returns complaining of continued symptoms that now include 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? Factors Associated with Non- Responsive CAP in Primary Care Retrospective analysis of 250 adults with CAP initially managed in primary care clinic 85 cases (ie, non-responsive), 165 controls Non-responsive CAP was defined as worsening symptoms after 4 days or no improvement within 10 days of starting antibiotic therapy In the 85 cases at initial visit 80% had a chest X-ray, 39% additional testing Initial treatment- 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 (odds ratio 2.10) Myalgia (odds ratio 2.79) Vander Wyst KB, et al. J Patient Cent Res Rev. 2016;3:79-89.

12 What is the state of the art in CAP/CABP Management? Suspect diagnosis based on symptoms Know risk factors for poor outcome (clinical; PSI, CURB-65) Send labs: CBC, CMP, CXR, sputum or other cultures Outpatient management or admit to hospital? Choose antibiotics: No antimicrobial (healthy host, viral, likely self-limited) Narrow (macrolide?) if viral vs. mycoplasma (but resistance?) Narrowish (amox-clav, TMP-SMX) Broad-spectrum (fluoroquinolone or macrolide + beta-lactam) If patient not improving: Broaden further (vancomycin, 3 rd generation-cephalosporin, carbapenem???) Perform diagnostic procedure Broader Rx, hospital stay more collateral damage Antibiotics on the Horizon Cethromycin - ketolide Omadacycline - tetracycline Sitafloxacin - fluoroquinolone Lefamulin - pleuromutilin Solithromycin - fluoroketolide Cethromycin Oral ketolide Potent activity against S. pneumoniae 1 FDA denied approval in 2009 Review used updated efficacy standards 2 Phase III studies vs clarithromycin in mild/moderate CAP with clinical cure rates (ITT) of 2 CL (N=584): 83.1% vs 81.1% CL (N=522): 82.9% vs 88.5% 1. Wierzbowski AK, et al. J Antimicrob Chemother. 2009;63: English ML, et al. Antimicrob Agents Chemother. 2012;56:

13 Omadacycline Oral and IV tetracycline 1 Potent activity against resistant Gram-positive 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): 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; 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

14 Solithromycin Oral and IV fluoroketolide Highly active against macrolide-resistant S. pneumoniae 1,2 M. catarrhalis 2 2-fold less active than azithromycin against H. influenzae 2 Good activity against S. aureus, including MRSA 2 In patients with moderate/moderately severe CABP, solithromycin demonstrated non-inferiority vs levofloxacin 3 and moxifloxacin 4 in achieving symptom response at 72 hours 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): Summary and Conclusions Community-acquired pneumonia (CAP) remains a significant cause of morbidity and mortality in the U.S.; this entails high use of health care resources There is new appreciation of a wider array of CAP pathogens, notably viruses (some treatable) In community-acquired bacterial pneumonia (CABP) pathogen susceptibility is changing (e.g., Streptococcus pneumoniae, mycoplasma) Antibiotic selection driven by difficulty diagnosing pathogen, need to optimize coverage AND avoid toxicity Few new antibiotics over last 10 years for CABP; new antibiotics are on the horizon Following an episode of CABP, it takes an adult age 50 years an average of days to achieve full productivity?

15 Retrospective analysis of adults with CAP initially managed in a primary care clinic showed all of the following to predict non-responsiveness except? 1. Bilateral rales 2. Former smoker 3. Initial presentation to urgent care 4. Myalgia Several systematic reviews and meta-analyses since 2007 show which of the following is preferred as initial empiric therapy in the outpatient management of CABP? 1. Macrolide 2. β-lactam + macrolide 3. β-lactam + respiratory fluoroquinolone 4. There is no preferred empiric therapy as the data are inconsistent? Thank you Questions & Answers