Pneumonia considerations 2017

Galia Rahav Infectious diseases unit Sheba medical center

Sir William Osler (1849 –1919) "Father of modern medicine“ Pneumonia: • “The old man's friend” • “The captain of the men of death” (most common cause of infections related death) Osler died with pneumonia without benefit of a

proper chest radiograph, antimicrobial therapy, or vaccine

Epidemiology • Sixth leading cause of death – number one cause of death from infectious

disease • 5.6 million cases per year in U.S

– >10 million physician visits – 1.1 million hospitalizations – 12/1000 all ages, 36/1000 2-5y, 30/1000 >65y

• Average rate of mortality for hospitalized patients

12% • It cost $40 billion to care for patients with

pneumonia • Seasonal variation (winter months) • M>F, black persons > Caucasians

Pathophysiology

PresenterPresentation NotesHCAP - לפני כעשר שנים הוגדרה קבוצה ביינים חדשה = חולים שאינם מאושפזים בבית חולים ברם קשורים למערכת הבריאות עם חיידקים עמידים ועליה בתחלואה ותמותה.

Diagnosis • Physical examination: Sensitivity 58% Specificity 67% • Chest Imaging: CXR, CT

Air Bronchogram

CT not routine, is abnormal in 30% of those with normal CXR

PresenterPresentation NotesIn a normal chest x-ray, the tracheobronchial tree is not visible beyond 4th order. As the bronchial tree branches, the cartilagineous rings become thinner and eventually disappears in respiratory bronchioles. The lumen of bronchus contains air and the surrounding alveoli contain air. Thus there is no contrast to visualize bronchi. The air column in bronchi beyond 4th order becomes recognizable if the surrounding alveoli is filled, providing a contrast or if the bronchi get thickened. The term air bronchogram is used for the former state and signifies alveolar disease.Note branching radioluscent columns of air corresponding to bronchi, in RUL consolidation in the adjacent CXR.

Rationale for establishing an etiologic Dx (ID vs Pulmonary physicians)

• Optimal antibiotic selection • Limit broad spectrum antibiotics • Identify organisms of epidemiologic

significance • Identify drug resistant bacteria and

monitor trends • Identify new or emerging pathogens

Inadequate sputum

saliva

S. pneumopniae

Haemophilus influenzae

Staphylococcus aureus

Solitaire -52%!

Add -10-15%

PresenterPresentation Notesשיטות סטנדרטיות גם במחקרים קליניים שפורסמו בעיתונים מגיעים לאבחון בכרבע מהמקרים. מעניין שבעבודת הסוליטר של סוליטרומיצין הם הצליחו לזהות 52% את הפתוגנים.AG מוסיף בהחלט, כל חולה נותן שתן ולא ליחה טובה

PresenterPresentation NotesPCR PNA FISH – שעות, מלדי צריך לחכות עד צמיחה

PresenterPresentation Notesהמטרה שיהיה מכשיר ליד מיטת החולה ב POC שיתן תשובה תוך 15 דקות תראו כמה חברות

PresenterPresentation Notesכמה השיטות המולקולריות עוזרותזו עבודה משבדיה על 184 מקרים של CAP נעשתה אבחנה ב 67% מהחולים.

Chicago and Nashville

Age -57y ICU-21% Death-2%

PresenterPresentation Notes Etiology of Pneumonia in the Community (EPIC) study CDC- רק ב 38% יש אבחנה. נורא מעט פנוימוקוקס חיסון??

PresenterPresentation Notesמקרים של מיקופלסמה עמיד לאזיטרומיצין מסין מחלה קשה נזקקה לאשפוז

Treatment CAP (IDSA, ATS, CTS, CDC, BTC…)

• Outpatients, inpatients, ICU • Administration of antibiotics within 4 hours

reduces mortality & LOS • S. pneumoniae is the major pathogen

(PRSP) • Penicillin-resistant pneumococci may be

resistant to macrolides and/or doxycycline • All major guidelines recommend coverage

for both “typical" and “atypical" organisms

PresenterPresentation Notesהיו בעשר שנים אחרונות שלוש מטאנליזות על הנושא, האחרונה מ 2012 של הקבוצה של לייבוביץ. מצאו שאין כל יתרון במתן כיסוי לפתוגנים אטיפיים ב CAP בחולים שמתאשפזים – לא באפקטיביות הקלינית ולא ב SURVIVALהבעיה עם כל המחקרים שה END POINT הוא TOC בדרכ יום 7 10. כשמסתכלים יום 4 רואים שטיפול באטיפיים כן הביא לקיצור במשך החום ומשך האשפוז

PresenterPresentation Notesפוקוס 1 ו2 אלו עבודות שבדקו יעילות צפטרולין מול צפטריאקסון ב 1 – עם מקרוליד קלריתרו ליום. ובשני בלי מקרוליד. ה FDA דרש לבדוק יעילות בנקודת זמן מוקדמת שבדרכ לא מבצעים אותה במחקרים קליניים – ביום 4. ומצאו שאכן ביום 4 שיעור התגובה היה גבוה יותר באלו שקבלו מקרוליד. אם בודקים ב TOC – אין הבדל

CAP admitted to non-ICU wards 90-day mortality: Beta-lactam monotherapy was noninferior to Beta-lactam–macrolide combination or Fluoroquinolone monotherapy

IDSA/ATS recommendations for empiric therapy of CAP

Ertapenem, ceftaroline

1. Riedel S, et al. Eur J Clin Microbiol Infect Dis. 2007;26(7):485-490; 2. Richter SS, et al. Clin Infect Dis. 2009;48(3):e23-e33. 3. Regev-Yochay G. Plos one. 2014; e88406

Antibiotic Resistance S. pneumoniae EU & U.S; Israel 2010

% of Drug Resistant S. pneumoniae Isolates

Antibiotic Europe1 (N=1974)

US2 (N=1647)

Israel3 (N=980)

Penicillin 24.0 14.6 25.9

Ceftriaxone --- 5.9 5.5

Erythromycin

24.6 29.1 14

TMP-SMX 26.7 21.0

Tetracycline 19.8 15.8

Clindamycin --- 11.2

Chloramphenicol --- 4.9

Levofloxacin 2.0 1.1 1.6

PresenterPresentation NotesVoiceover:Emergence of antibiotic-resistant strains of S. pneumoniae is a major concern.1 The chart shows the relatively high prevalence of antibiotic-resistant pneumococcal isolates recovered from patients with community-acquired respiratory tract infections during the winter of 2004-2005 in 15 European countries (n = 1974 isolates) and the same annual period in the United States (n=1647 isolates).1,2 As of 2004, the incidence of multi-drug resistance in the U.S. had remained stable from the previous 2 years (2002 and 2003) at approximately 28% to 29% nationally, with a prevalence reaching 38% in the South-central region of the nation.3

Outpatients without comorbidity PO therapy

(1) Macrolides • Erythromycin • Clarithromycin (Klacid) • Roxithromycin (Rulid) • Azithromycin (azenil)

(2) Doxycycline

(3) Respiratory Quinolones

• Levofloxacin (tavanic)

• Moxifloxacin

• Gatifloxacin

Outpatients with comorbidity PO therapy

• Respiratory fluoroquinolone • Macrolide plus high-dose amoxicillin • Macrolide plus high-dose amoxicillin-

clavulanate

Some authorities prefer macrolides or doxycycline for patients 50 y or have comorbidities

Hospitalized patients General medical ward

• Extended spectrum cephalosporin

(Ceftriaxone) (IV) combined with a macrolide / doxycycline (IV/PO) or

• ß -lactam / ß -lactamase inhibitor (augmentin) (IV) combined with a macrolide / doxycycline (IV/PO) or

• Fluoroquinolone (IV/PO)

Hospitalized patients – ICU IV therapy

• Extended-spectrum cephalosporin (IV)

plus either fluoroquinolone or macrolide (IV)

• ß lactam / ß -lactamase inhibitor (IV) plus either fluoroquinolone or macrolide (IV)

Duration of therapy

• No controlled trials to assess • Good outcomes with 5-7 days total • Consider 10-14 days if sick . . .

• S pneumoniae 7-10 days • M. pneumoniae 10-14 days • L. pneumophila 14-21 days

Prevention • Pneumococcal vaccine pneumococcal polysaccharide

vaccine (PPV) (pneumovax) 23-valent: > 65y, comorbidity, ineffective

PPV23- Efficacy and effectiveness

“Despite multiple studies conducted during >30 years, the efficacy and effectiveness of PPV23 in children and adults remain poorly defined and the subject of controversy”

Capsular polysaccharide vaccine lack potency, durability, memory

Limitations: • No immune memory

– Does not induce T cell response – Antibody titers and efficacy appear to wane after 5 years – Effectiveness is very low in immunocompromised

patients – Poorly immunogenic in children younger than two years – Induce Hypo responsiveness to either another dose of

PPV23 or to a dose of conjugate vaccine

• Not effective in preventing pneumococcal pneumonia

• No reduction in carriage, no reduction in transmission

Surveillance of IPD in children in US following implementation of PCV7 in 2000

Surveillance of IPD in adults found Herd protection

Incidence rate of antibiotic resistant isolates in Israel

0

0.5

1

1.5

2

2.5

320

09-1

0

2010

-11

2011

-12

2012

-13

2009

-10

2010

-11

2011

-12

2012

-13

2009

-10

2010

-11

2011

-12

2012

-13

2009

-10

2010

-11

2011

-12

2012

-13

AB Penicillin Ceftriaxone Erythromycin Quin

Penicillin MIC≥2.0 µg/ml MIC>0.06 µg/ml

Ceftriaxone MIC≥4.0 µg/ml MIC> 1 µg/ml 29.7%

11%

18%

5%

1.5%%

PCV Implementation in Israel

PCV7 - 7/2009

PCV13 – 11/2010

Chart1

ABABAB

2009-10Penicillin2009-10Penicillin2009-10Penicillin

2010-112010-112010-11

2011-122011-122011-12

2012-132012-132012-13

2009-10Ceftriaxone2009-10Ceftriaxone2009-10Ceftriaxone

2010-112010-112010-11

2011-122011-122011-12

2012-132012-132012-13

2009-10Erythromycin2009-10Erythromycin2009-10Erythromycin

2010-112010-112010-11

2011-122011-122011-12

2012-132012-132012-13

2009-10Quin2009-10Quin2009-10Quin

2010-112010-112010-11

2011-122011-122011-12

2012-132012-132012-13

0

0

1

0.291

2.107

0.474

1.1964

0.25

0.704

0.35

0.9181

0.0896

0.3796

0.0691

0.09142

0.04313

0.091

0.04315

0.0647

1.2987

0

1.16815

0

1.18174

0

1.0572

0

0.357

0

0.34537

0

0.28465

0

0.1309

0

Sheet1

ABResistantIntermediate

Penicillin2009-100.2912.107

2010-110.4741.1964

2011-120.250.704

2012-130.350.9181

Ceftriaxone2009-100.08960.3796

2010-110.06910.09142

2011-120.043130.091

2012-130.043150.0647

Erythromycin2009-101.29870

2010-111.168150

2011-121.181740

2012-131.05720

Quin2009-100.3570

2010-110.345370

2011-120.284650

2012-130.13090

Penicillin13.883.8

Ceftriaxone0.9598.7

Erythromycin0.687.5

Ofloxacin296.6

Levofloxacin0.4898.1

Moxyfloxacin1.6197.6

GHQ scoreNo chronic painChronic pain

0-3All30.810.6

Male36.615.3

Female24.77.3

4-7All32.821.1

Male33.121.9

Female32.520.5

8 or moreAll36.468.3

Male30.362.8

Female42.872.2

CAPiTA trial (Community-Acquired Pneumonia Immunization Trial in Adults)

One of the largest double-blind, randomized, placebo-controlled vaccine

efficacy trials conducted in adults

Primary and Secondary Objectives: Per Protocol

49 90 45.6 (21.8,62.5)

ACIP Sequential administration and recommended intervals for PCV13 and PPSV23 for aged ≥65y

Influenza vaccine - efficacy

Risk Reduction

variable

56%* Respiratory illness

50%* Hospitalization

53%* Pneumonia

68%* NNT=118

All cause death *p

TYPICAL ATYPICAL

• Pathogens S. pneumoniae M. pneumoniae H. influenaze C. pneumoniae K. pneumoniae L. pneumophilla

• Onset Abrupt insidious • Fever high (39-40) low grade (38) • Chills yes no • Cough productive (rusty) dry • Sputum PMN & bacteria few PMN • Extra rare common Pulmonary signs

• CXR lobar interstitial

consolidation infiltrates

• WBC leukocytosis normal count • General condition sick walking pneumonia • Mortality high (20%) low (1-2%)

CAP

Admission decision (X20 cost…)

Pneumonia severity index (PSI) (PORT study) • Scoring system to risk stratify and to

identify outpatient vs. inpatient treatment

Fine MJ, et al. N Engl J Med 1997

years

F -10

+10

+30

+20

+10

+10

+10

+20

+20

+20

+10

+20

+10

+20

+20 +30

+10

+10

CURB - 65 • Confusion • Uremia > 20mg/ml • Respiration > 30/min • Blood pressure (SBP < 90 mmHg or DBP

65y

CURB - 65

Pneumonia considerations 2017Sir William Osler Slide Number 3EpidemiologyPathophysiologySlide Number 6Slide Number 7DiagnosisRationale for establishing an etiologic Dx (ID vs Pulmonary physicians)Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Treatment CAP �(IDSA, ATS, CTS, CDC, BTC…)Slide Number 27Slide Number 28Slide Number 29Slide Number 30IDSA/ATS recommendations for empiric therapy of CAPAntibiotic Resistance S. pneumoniae EU & U.S; Israel 2010Outpatients without comorbidity�PO therapyOutpatients with comorbidity�PO therapy��Hospitalized patients�   General medical ward���Hospitalized patients – ICU�IV therapy�Slide Number 37Duration of therapySlide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43PreventionPPV23- Efficacy and effectivenessCapsular polysaccharide vaccine�lack potency, durability, memory Surveillance of IPD in children in US following implementation of PCV7 in 2000Surveillance of IPD in adults found Herd protectionIncidence rate of antibiotic resistant isolates in Israel CAPiTA trial (Community-Acquired Pneumonia Immunization Trial in Adults)One of the largest double-blind, randomized, placebo-controlled vaccine efficacy trials conducted in adultsPrimary and Secondary Objectives: �Per ProtocolSlide Number 53Influenza vaccine - efficacySlide Number 55Slide Number 56Slide Number 57Admission decision (X20 cost…)Slide Number 59Slide Number 60CURB - 65CURB - 65Slide Number 63