This document discusses new developments in the treatment of community-onset pneumonia. It notes that mortality from pneumonia has declined due to pneumococcal vaccines, timely administration of appropriate antibiotics, and avoiding overtreatment in low-risk patients. Viruses are now recognized as a common cause of adult pneumonia. Procalcitonin levels may help identify patients at low risk of deterioration who need only extremely short courses of antibiotics. While healthcare-associated pneumonia is associated with drug-resistant pathogens and worse outcomes, inappropriate antibiotics alone do not fully explain increased mortality.

1. New Developments in Community-
Onset Pneumonia
Richard G. Wunderink MD
Northwestern University Feinberg School of Medicine
Chicago, IL, USA

2. Conflicts of Interest
• bioMerieux – investigator-initiated grant
• Pfizer – data safety monitoring board
• Accelerate Diagnostics
• Curetis
• Genmark
• Nabriva
• Arsanis
Diagnostics companies

3. US Causes of Death
1
10
100
1000
Deathsper100,000population
Pneumonia Tuberculosis Sepsis AIDS 20/100K
Pediatric
Conjugate
Vaccine
Clinical use of penicillin starts
Effective anti-TB drugs

4. US Causes of Death
1
10
100
1000
Deathsper100,000population
Pneumonia Tuberculosis Sepsis AIDS 20/100K
CMS Public
reporting/Pediatric
ConjugateVaccine
Clinical use of penicillin starts
Effective anti-TB drugs

5. Paradigm change #1:
Outcome of many critical
illnesses, including CAP,
is determined by the
timely provision of
appropriate antibiotic(s)

6. Time to First Antibiotic Dose
in Septic Shock
Kumar, Crit Care Med, 2006
7.6%/hr increase
in mortality

7. ARDS Prevention Strategies:
Appropriate Antibiotics
Levitt JE and Matthay MA. Critical Care
2012;1:223
Septic
Shock
Pneumonia
Iscimen et
al,
Crit Care
Med
2008;36:151
8- 1522
Kojicic et al
Crit Care
2012;16:R46

8. “It’s the antibiotics,
stupid.”

9. What is (are) the correct
antibiotic(s)?

10. What is (are) the correct
antibiotic(s) in the era of
antibiotic stewardship?

11. JAMA, 2014

12. JAMA, 2014

14. July 14, 2015

15. CDC Etiology of Pneumonia in the
Community (EPIC) Study
 Both children (< 18
years) and adults
 4 sites: Chicago,
Nashville, Memphis,
Salt Lake City
 January 1, 2010 –
June 30, 2012
 2320 adults with
radiographic
pneumonia
Objective: Determine US population-based incidence
and etiology of CAP

17. Am J Respir Crit Care Med, 2015
319 patients with clinically suspected CAP in 4 EDs

18. 87% prior to
antibiotics
CDC EPIC Diagnostic Algorithm

19. CDC-EPIC Etiology of CAP:
Etiology Results
77
27
10 11
18
64
0
10
20
30
40
50
60
70
80
90
Pediatric Adult
Percentofpatients
Viral
Bacterial
None

20. Only 52/2320 (2%) of adults
enrolled in EPIC died
Slightly higher in eligible, un-
enrolled patients (4% at most)

21. Trends in Adult Community-
Acquired Pneumonia
Smith et al, JAMA Int Med, 2014
EPIC

23. 3rd Gen Cephalo
Aminoglycoside
B-lactam+Macro
Cephalo+Macro
Quinolone
Treatment Outcomes Data
Gleason, Arch
Intern Med, 1999

24. Macrolide Combination Therapy
0
2
4
6
8
10
Ceftriaxone Other Ceph Penicilln Quinolone
6.31
5.11
8.15
4.94
2.76
2.16 2.46
2.91
Mortality(%)
Monotherapy Macrolide Combination
p < 0.0001 p < 0.05
Brown, Chest, 2003
18,500 16,000 4,500 1800

25. Presumption of proponents of
narrow-spectrum therapy e.g.
β-lactam monotherapy, is that
S. pneumoniae is the
overwhelming cause of CAP

26. EPIC – Adult Pathogen
Detections
0
20
40
60
80
100
120
140
160
180
200
HRV Flu S. pn. HMPV RSV PIV G. ng.* CoV M. pn. S. au. AdV Leg. Strep
sp.
Other†
115/2320 (5%) S. pneumoniae

27. Changing Etiology of CAP
PCV7

29. CAP-START
Postma et al, NEJM, 2015

30. CAP-START Primary Endpoint :
90 Day Mortality
Postma et al, NEJM, 2015

31. CAP-START Endpoints
9 8.8
11.1
6.1
8.8
3.7
0
2
4
6
8
10
12
90-DayMortality Add Abs for failure
%
B-Lactam
BL/Macro
Quinolone
Postma et al, NEJM, 2015

32. JAMA Intern Med 2014
TCS difference at 7 days –
7.6% (95%CI:-0.8 to 16, p = .07)
HR PSI IV = 0.81 (0.59-1.10)
HR CURB65 >2 = 0.80 (0.61-1.06)
ICU transfer: 3 (Legionella) vs. 0
Death 2 (Mycoplasma) vs. 0
Significantly more readmissions

33. Viruses are a common cause
of adult CAP
Paradigm Change #2

34. EPIC – Pathogen Detections
0
20
40
60
80
100
120
140
160
180
200
HRV Flu S. pn. HMPV RSV PIV G. ng.* CoV M. pn. S. au. AdV Leg. Strep
sp.
Other†

36. RCT of PCT in LRTI
Christ-Crain, Lancet, 2004

37. Admission Procalcitonin in EPIC
< .25 ng/dl,
1042, 59%
> .25 ng/dl,
728, 41%

38. Admission Procalcitonin in EPIC
Viral
18%
Unknown
36%
Atypical
2%
Bacterial
2%
Bacterial
7%
Atypical
2%
Unknown
25%
Viral
8%
< .25 ng/dl> .25 ng/dl

39. Antibiotics in CHF Admissions
Maisel et al, Eur J Heart Fail, 2011

40. Antibiotics in CHF Admissions
Maisel et al, Eur J Heart Fail, 2011

41. Phase III RCT of Daptomycin
vs. Ceftriaxone in CAP
• Daptomycin subsequently
found to be inactivated by
pulmonary surfactant
• Essentially placebo-
controlled study of
ceftriaxone
• Re-analyzed based on
whether received prior
antibiotic dose
– usually cephalosporin
60
65
70
75
80
85
90
95
All Prior No Prior
79.4
90.7
75.4
87.9 88 87.8
ClinicalSuccess(%)
Daptomycin Ceftriaxone
Pertel, Clin Infect Dis, 2008 Clinically Evaluable

42. It is OK to avoid or use
ultra-short course antibiotics
for some suspected CAPs
Paradigm Change #3

43. 10 days 5 days
• Antibiotic of
physician’s choice
• Placebo after 5 days
10 days 5 days
Higher
readmissions in
10-day treatment
also
Sept 2016

44. Healthcare-Associated
Pneumonia (HCAP)
HCAP
Hospital
-acquired
Community
-acquired

45. Epidemiology Of HCAP
Culture-positive cases from large database
0
5
10
15
20
25
30
MRSA Pseudomonas Acinetobacter Enterics
8.9
17.1
1.6
21.3
26.5 25.3
2.6
25.8
22.9
18.4
2
19.8
14.6
21.2
3
26.6
CAP HCAP HAP VAP
Kollef, Chest, 2005
%ofisolates

46. 7
22.6
37.8
4
9.9
19.8
5
20.1
32.7
0
5
10
15
20
25
30
35
40
LOS 30-Day 90-Day
GC-HCAP
GC-CAP
Non-GC
Mortality
p = 0.001
p = 0.001
p = 0.001

47. EPIC Adult Exclusions
Recent hospitalization
30 days for immunocompetant
90 days for immunosuppressed
Functionally dependent nursing home
patients
Tracheostomy or PEG
Cystic Fibrosis
Severe immunosuppression
Language barrier to consent

48. EPIC:
Severe Immunosuppression
Cancer with neutropenia
Solid organ or stem cell transplant
within 90 days
Graft vs. Host Disease or Bronchiolitis
obliterans
HIV with CD4 < 200 mm3

49. EPIC – Pathogen Detections
0
20
40
60
80
100
120
140
160
180
200
HRV Flu S. pn. HMPV RSV PIV G. ng.* CoV M. pn. S. au. AdV Leg. Strep
sp.
Other†
7/2320 (0.3%) Pseudomonas
38/2320 (1.6%) S. aureus
115/2320 (5%) S. pneumoniae

50. CAP-Drug Resistant Pathogens
618
36%
219
57120
162
74
286
14
79
5%
22 77
Unknown
S. pneumoniae
Other Strep
MSSA
H. flu/Morax
Atypicals
GNB - sens
GNB - resist
Pseudo
Other Nonferm
MRSA
Shindo, Am J Respir Crit Care Med, 2013

51. Independent Risk Factors for Pneumonia Secondary to:
CAP-DRP MRSA
Hospitalization > 2 days in
previous 90 days
Hospitalization > 2 days in
previous 90 days
Use of antibiotics in
previous 90 days
Use of antibiotics in
previous 90 days
Immunosuppression Chronic hemodialysis in
previous 30 days*
Non-ambulatory status Prior MRSA colonization*
Tube feedings Congestive heart failure*
Gastric acid suppression Gastric acid suppression
* MRSA- specific risk factors
Shindo, Am J Respir Crit Care Med, 2013

52. 2/12

53. Gross Findings: The Lung

54. Wunderink RG, Waterer GW. N Engl J Med
2014;370:543-551.

55. Risk for CAP-Drug Resistant
Pathogens
439 122 57
20
25
32
12
9
32
0
50
100
150
200
250
300
350
400
450
500
<=1 2 >=3
CAP-DRP Risk Factors
Negative
MRSA
Other CAP-DRPs
Shindo, Am J Respir Crit Care Med, 2013

56. Treatment Response for Patients
with < 1 Risk for CAP-DRPs
2.1
10.2
13.2
9.7
0
2
4
6
8
10
12
14
CAP Mono β-lactam Broad Spec Inappropriate
Mortality
Empirical Treatment
p = 0.00001
284 380 266 72
Shindo, Am J Respir Crit Care Med, 2013

57. Paradigm Change #4:
Should have good reasons to not
treat with traditional CAP drugs
 CAP-DRG make up 13.6% of all CAP
 Increased mortality in HCAP is likely not
due to inappropriate antibiotics alone

58. Summary
Falling CAP mortality rates can result from:
Pneumococcal conjugate vaccine
Early traditional CAP antibiotics
Avoiding overtreatment of patients at low risk for DRPs
Viral CAP is much more common than previously
believed
Greater availability of multiplex RVPs
Procalcitonin may identify patients at low risk for
deterioration with extremely short course antibiotics

59. “Not everything that counts can
be measured and not everything
that can be measured counts.”
Albert Einstein