New Developments in Community Onset Pneumonia

New Developments in Community-

Onset Pneumonia

Richard G. Wunderink MD

Northwestern University Feinberg School of Medicine

Chicago, IL, USA

Conflicts of Interest

• bioMerieux – investigator-initiated grant

• Pfizer – data safety monitoring board

• Accelerate Diagnostics

• Curetis

• Genmark

• Nabriva

• Arsanis

Diagnostics companies

US Causes of Death

1

10

100

1000

Dea

ths

per

100,0

00 p

op

ula

tion

Pneumonia Tuberculosis Sepsis AIDS 20/100K

Pediatric

Conjugate

Vaccine

Clinical use of penicillin starts

Effective anti-TB drugs

US Causes of Death

1

10

100

1000

Dea

ths

per

100,0

00 p

op

ula

tion

Pneumonia Tuberculosis Sepsis AIDS 20/100K

CMS Public

reporting/Pediatric

ConjugateVaccine

Clinical use of penicillin starts

Effective anti-TB drugs

Paradigm change #1:

Outcome of many critical

illnesses, including CAP,

is determined by the

timely provision of

appropriate antibiotic(s)

Time to First Antibiotic Dose

in Septic Shock

Kumar, Crit Care Med, 2006

7.6%/hr increase

in mortality

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

“It’s the antibiotics,

stupid.”

What is (are) the correct

antibiotic(s)?

What is (are) the correct

antibiotic(s) in the era of

antibiotic stewardship?

JAMA, 2014

JAMA, 2014

July 14, 2015

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

Am J Respir Crit Care Med, 2015

319 patients with clinically suspected CAP in 4 EDs

87% prior to

antibiotics

CDC EPIC Diagnostic Algorithm

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

Perc

en

t o

f p

ati

ents

ViralBacterialNone

Only 52/2320 (2%) of adults

enrolled in EPIC died

Slightly higher in eligible, un-

enrolled patients (4% at most)

Trends in Adult Community-

Acquired Pneumonia

Smith et al, JAMA Int Med, 2014

EPIC

3rd Gen Cephalo

Aminoglycoside

B-lactam+Macro

Cephalo+Macro

Quinolone

Treatment Outcomes Data

Gleason, Arch

Intern Med, 1999

Macrolide Combination Therapy

0

2

4

6

8

10

Ceftriaxone Other Ceph Penicilln Quinolone

6.31

5.11

8.15

4.94

2.762.16 2.46

2.91

Mo

rtali

ty (

%)

Monotherapy Macrolide Combination

p < 0.0001 p < 0.05

Brown, Chest, 2003

18,500 16,000 4,500 1800

Presumption of proponents of

narrow-spectrum therapy e.g.

β-lactam monotherapy, is that

S. pneumoniae is the

overwhelming cause of CAP

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

Changing Etiology of CAP

PCV7

CAP-START

Postma et al, NEJM, 2015

CAP-START Primary Endpoint :

90 Day Mortality

Postma et al, NEJM, 2015

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

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

Viruses are a common cause

of adult CAP

Paradigm Change #2

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†

RCT of PCT in LRTI

Christ-Crain, Lancet, 2004

Admission Procalcitonin in EPIC

< .25 ng/dl,

1042, 59%

> .25 ng/dl,

728, 41%

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

Antibiotics in CHF Admissions

Maisel et al, Eur J Heart Fail, 2011

Antibiotics in CHF Admissions

Maisel et al, Eur J Heart Fail, 2011

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 cephalosporin60

65

70

75

80

85

90

95

All Prior No Prior

79.4

90.7

75.4

87.9 88 87.8

Cli

nic

al

Su

cces

s (%

)

Daptomycin Ceftriaxone

Pertel, Clin Infect Dis, 2008 Clinically Evaluable

It is OK to avoid or use

ultra-short course antibiotics

for some suspected CAPs

Paradigm Change #3

10 days 5 days

• Antibiotic of

physician’s choice

• Placebo after 5 days

10 days 5 daysHigher

readmissions in

10-day treatment

also

Sept 2016

Healthcare-Associated

Pneumonia (HCAP)

HCAPHospital

-acquired

Community

-acquired

Epidemiology Of HCAPCulture-positive cases from large database

0

5

10

15

20

25

30

MRSA Pseudomonas Acinetobacter Enterics

8.9

17.1

1.6

21.3

26.525.3

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

% o

f is

ola

tes

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

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

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

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

CAP-Drug Resistant Pathogens

618

36%

219

57120

162

74

286

1479

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

Independent Risk Factors for Pneumonia Secondary to:

CAP-DRP MRSAHospitalization > 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

2/12

Gross Findings: The Lung

Wunderink RG, Waterer GW. N Engl J Med

2014;370:543-551.

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

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

Mo

rta

lity

Empirical Treatment

p = 0.00001

284 380 266 72

Shindo, Am J Respir Crit Care Med, 2013

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

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

“Not everything that counts can

be measured and not everything

that can be measured counts.”

Albert Einstein