Community-Acquired Bacterial Pneumonia:

Is There Anything New?

Steve Vacalis, D.O.

CaroMont Health Regional Medical CenterGastonia,

North Carolina

This presentation is sponsored by:

and supported by an educational

grant from

Cempra Pharmaceuticals

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.

Sign up for free membership at pcrg-us.org

Disclosures:

Dr. Vacalis discloses that he is on the advisory boards and speakers bureau for CEMPRA

CME:

This Live activity, “Community-Acquired Bacterial Pneumonia: Is There Anything New?,” from 10/06/2016 - 10/05/2017, has been reviewed and is acceptable for up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity

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

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!

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?

Pneumonia: Still a serious disease

Epidemiology and Burden

• Incidence• 950,000 cases/year in adults age

Epidemiology and Burden (cont)

• In adults age ≥50 y1

• Time to resolution of symptoms >3 weeks

• Absenteeism 13 days

• 21 days before achieving full productivity

• 8th 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

1.Wyrwich KW, et al. Pat Relat Out Measures. 2015;6:215-223.2. Xu J, et al. Natl Vital Stat Rep. 2016;64(2):1-118.3. Eurich DT, et al Am J Respir Crit Care Med. 2015;192(5):597-604.

*Pneumonia and influenza combined

Etiology of CAP

Jain S, et al. N Engl J Med. 2015;373:415-427.

N=2259 adults hospitalized with radiographic evidence of CAP in 5 U.S. hospitals, January 2010 through June 2012

Etiology of CAP

267 hospitalized patients in Norway with diagnosed CAP enrolled consecutively from January 2008 to January 2011

Holter JC, et al. BMC Infect Dis. 2015;15:64.

Etiology of CAP (cont)

Jain S, et al. N Engl J Med. 2015;373:415-427.

N=2259 adults hospitalized with radiographic evidence of CAP in

5 U.S. hospitals, January 2010 through June 2012

Etiology of CAP (cont)

• Etiology established in 167/267 (63%)

• 75 (45%) pure bacterial

• 41 (25%) pure viral

• 51 (31%) viral-bacterial

• 26% had ≥1 copathogen

• Viruses detected more frequently in

winter/spring than summer/fall (45% vs 28%)

and usually in combination with bacteria

(39%)

Holter JC, et al. BMC Infect Dis. 2015;15:64.

Susceptibility of S. pneumoniae, 2010-2014, United States

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. http://resistancemap.cddep.org/resmap/c/us/united%20states/. Accessed August 3, 2016.

Macrolide-resistant M. pneumoniae, United States, 2012-2014

City (number of M. pneumoniae respiratory isolates tested)Collection period: August 2012 – April 2014

Zheng X, et al. Emerg Infect Dis. 2015;21(8):1470-1472.

Although the number of isolates is small (N=91), it shows the wide geographic variability in susceptibility of M pneumoniae to a macrolide

Etiology of CABP

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

Does not include viruses, fungi, etc.

Definition of CABP

• Acute bacterial infection of the pulmonary

parenchyma1

• 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. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm123686.pdf. Accessed July 11, 2016.

CURB-65

• Confusion (based upon a specific mental test or new disorientation to person, place, or time)

• ●Urea (blood urea nitrogen in the United States) >7 mmol/L (20 mg/dL)

• ●Respiratory rate ≥30 breaths/minute

• ●Blood pressure (BP; systolic

Comparison of Care Recommendations Based on PSI vs CURB-65 ScoresPSI Risk Class1 No. of

Points%

MortalityRecommended Site of Care

I —* 0.1 Outpatient

II ≤70 0.6 Outpatient

III 71-90 2.8 Outpatient or brief inpatient

IV 91-130 8.2 Inpatient

V >130 29.2 Inpatient; consider ICU

CURB-65 Score2 0 or 1

Limited Value of Signs and Symptoms in Determining Etiology

Huijskens EGW, et al. J Med Microbiol. 2014;63:441-452.

P

Limited Association of Common Comorbidities with Etiology

N=408; age 68 y (20-94 y)Huijskens EGW, et al. J Med Microbiol. 2014;63:441-452.

P

Molecular Testing vs Culture Improves Pathogen Detection

From: Holter JC, et al. BMC Infect Dis. 2015;15:64 under Creative Commons Attribution 4.0 [https://creativecommons.org/licenses/by/4.0/].

Molecular Testing vs Culture Improves Pathogen Detection (cont)

Comprehensive molecular testing significantly improved pathogen detection, particularly in antimicrobial-exposed patients, with the possibility of narrowing treatment in 77.2%

Gadsby NJ, et al. Clin Infect Dis. 2016;62(7):817-823.

ProCalcitonin

• Precursor of calcitonin

• From C cells of thyroid, neuro-endocrine cells of lung and intestine

• Bacterial infection - increased production from intestines and lungs

• Downregulated in patients with viral infections

• Detectable in the serum within 4 hours

• Normal PCT level < 0.01 mcg/L

• Since the levels reflect bacterial replication it can facilitate the decision to stop antibiotics

• Assay recently approved by FDA

Procalcitonin Algorithm

ProcalcitoninLevel

µg/L = ng/mL

Use ofAntibiotics

0.5 µg/L Strongly Recommended

Drozdov D et al Antibiotics 2013;2:1-10

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

• -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

• -lactam vs -lactam/macrolide1,2

• -lactam vs -lactam/macrolide vs FQ3

• FQ vs -lactam/macrolide4

• FQ vs macrolide vs FQ/-lactam vs macrolide/-lactam5,6

• Macrolide vs non-macrolide7,8

Similar outcomes and no clear best regimen for empiric therapy9

1. Nie W, et al. J Antimicrob Chemother. 2014;69:1441-1446; 2. Ambroggio L, et al. Pediatr Pulmonol. 2016;51(5):541-548. 3. Postma DF, et al. N Engl J Med. 2015;372(14):1312-1323; 4. Lodise TP, et al. Antimicrob Agents Chemother. 2007;51(11):3977-3982; 5. Raz-Pasteur A, et al. Int J Antimicrob Agents. 2015;46(3):242-248; 6. Skalsky K, et al. Clin Microbiol Infect. 2013;19:370-378; 7. Asadi L, et al. Clin Infect Dis. 2012;55(3):371-380. 8. Ambroggio L, et al. Pediatr Infect Dis J. 2015;34(8):839-842. 9. Pakhale S, et al. Cochrane Database Syst Rev. 2014;10:CD002109.

Collateral Damage

• Typically refers to ecological adverse effects of antibiotic therapy1

• 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

prolongation2

• Macrolide- hepatotoxicity, QTc prolongation3

1. Paterson DL. Clin Infect Dis. 2004;38(Suppl 4):S341-S345.2. US FDAhttp://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed August 5, 2016.3. US FDA. http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm. Accessed August 5, 2016.

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?

Patterns and Etiologies of Types of Failure to Respond

Failure to improve

• Early (

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.

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, 3rd 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. pneumoniae1

• 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) of2

• CL05-001 (N=584): 83.1% vs 81.1%

• CL06-001 (N=522): 82.9% vs 88.5%

1. Wierzbowski AK, et al. J Antimicrob Chemother. 2009;63:620-622.2. English ML, et al. Antimicrob Agents Chemother. 2012;56:2037-2047.

Omadacycline

• Oral and IV tetracycline1

• Potent activity against resistant Gram-positive bacteria, including S. pneumoniaeand MRSA2,3

• Comparable to tigecycline

• Good oral bioavailability1

• No significant nausea/vomiting1

1. Honeyman L, et al. Antimicrob Agents Chemother. 2015;59(11):7044-7053.2. Draper MP, et al. Antimicrob Agents Chemother. 2014;58(3):1279-1283. 3. Macone AB, et al. Antimicrob Agents Chemother. 2014;58(2):1127-1135.

Sitafloxacin

• Oral fluoroquinolone

• High activity against S. pneumoniae, ESBL-producing E. coli and K. pneumoniae1,2

• 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 concern3

1. Fujita J, et al. J Infect Chemother. 2013;19(3):472-479.2. Nakamura T, et al. J Infection Chemother. 2014;20(1):48-51.3. Ghebremedhin B. Clin Med Insights Ther. 2012;4;185-200.

Lefamulin

• Oral and IV pleuromutilin antibiotic

• Potent activity against• multi-drug-resistant strains of S. pneumoniae1

• macrolide-sensitive and macrolide-resistant M. pneumoniae2

• 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. a Agents Chemother. 2016;60(7):4407-4411.2. Waites K, et al. American Society for Microbiology 2016 Scientific Program; June 16-20, 2016, Boston, MA

Solithromycin

• Oral and IV fluoroketolide

• Highly active against• macrolide-resistant S. pneumoniae1,2

• M. catarrhalis2

• 2-fold less active than azithromycin against H. influenzae2

• Good activity against S. aureus, including MRSA2

• In patients with moderate/moderately severe CABP, solithromycin demonstrated non-inferiority vs levofloxacin3 and moxifloxacin4 in achieving symptom response at 72 hours

1. Farrell DJ, et al. Antimicrob Agents Chemother. 2015;59(4):2432-2434; 2. Farrell DJ, et al. Antimicrob Agents Chemother. 2016;60(6):3662-3668; 3. Oldach D, et al. Antimicrob Agents Chemother. 2013;57(6):2526-2534; 4. Barrera CM, et al. Lancet Infect Dis. 2016;16(4):421-430.

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

Thank youQuestions & Answers