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Pneumonia in ER

Pascal Van BleyenberghDepartment of Pneumology, UZ KULeuven

Global mortality due to infection:major impact of pneumonia

0 0,5 1 1,5 2 2,5 3 3,5

Respiratory infec ons

AIDS

Gastroenteri s

Tuberculosis

Malaria

Neonatal infec ons

Deaths (millions)

World Health Statistics, WHO 2010

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Pneumonia, a family…

• Community-acquired pneumonia (CAP)

• Health-care associated pneumonia (HCAP)

• Hospital-acquired pneumonia (HAP) Ventilator-associated pneumonia (VAP)

Even in developed countriesCAP mortality is not negligible…

1900 1950 2000

Mortality:- outpatients 1%- 5%- inpatients

- CAP III 6%-14%- CAP IV 36%-60%

- 18-44 year <1%- >65 year 12,5%

Feikin DR et al. Am J Public Health 2000; 90: 223-229National Center for Health Statistics 2000 (www.cdc.gov/nchs)

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Mixed patient populations in different settings and countries

*CAP=Community acquired pneumonia # average of 30-day and 90-day mortality in ICU vs ward patients, with average of 2 rates ~ 12%

Mortality for hospitalised patients with CAP has remained constant over time

Austrian R et al. Ann Intern Med 1964; 60: 759Fine MJ et al. JAMA 1996; 274: 134Feikin DR et al. Am J Pub Health 2000; 90: 223Restrepo MI et al. Chest 2008; 133: 610

CAP: assessment

History and clinical examination (vital signs!)

Routine laboratorium(PBC, electrolytes, liver and kidney function) severity

Oxygenation assessment (oximetry/ABG)

Chest X-ray- definate diagnosis of pneumonia (caveats!)- severity- underlying conditions or complicatins- no correlation with causal pathogen!!

Sputum stain & culture= controversial (colonisation / contamination !!)

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CAP: assessment

Blood cultures All hospitalised patients with CAP (11% positive)

(S. pneumoniae, H. influenzae, S. aureus, K. pneumoniae)

Serological testing(Influenza, Para-influenza, Adeno, RSV, Mycoplasma, Chlamydia,…)

- patients with severe pneumonia- no response to empirical therapy- specific epidemiologic circumstances

legionella antigen detection in urine all patients with severe pneumonia alle patients with pneumonia in epidemics

To admit or not? Ward or ICU?

IN- or OUT- hospital care ?

Severityscores

Common Sense

Pneumonia

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Severe CAP: severity scoring systems

• Pneumonia severity index (PSI)

• CURB-65

Score systems to stratify patients wit CAP into mortality risk groups⟶ management IN/OUT hospital

Severe CAP: severity scoring systems

• Pneumonia severity index (PSI) Accurately identify patients with CAP at low risk of

dying within 30 days of presentation.

• CURB-65 To predict mortality in individual hospitalized patients

Score systems to stratify patients wit CAP into mortality risk groups⟶ management IN/OUT hospital

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Pneumonia Severity Index – step 1

Mortality probability< 0.5%

Fine MJ, Auble TE, Yealy DM, et al. N Engl J Med 1997; 336: 243

Points Class

≤ 70 II < 1%

71-90 III 1-4 %

91-130 IV 4-10 %

> 130 V >10 %

Pneumonia Severity Index – step 2

Fine MJ, Auble TE, Yealy DM, et al. N Engl J Med 1997; 336: 243

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Neill AM et al. Thorax 1996; 51(10):1010-6Lim WS et al. Thorax 2003;58:377-382

ConfusionUrea >7mmol/l (42 mg/dL)Respiratory rate ≥30/minBlood pressure: Psyst <90mmHg

Pdias ≤60mmHgAge ≥65years

CURB-65 score system

BTS Guidelines. Lim WS et al.Thorax 2009; 64(3); 1-55

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CAP: treatment

• Pneumonia always antibiotics ASAP

• Which?→ criteria

- antibiotic spectrum

Target themost likely pathogens

CAP: causal pathogens

Welte T et al. Thorax 2012; 67: 71

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CAP: causal pathogensby country…

Welte T et al.Thorax 2012; 67: 71-79

CAP: causal pathogensby treatment setting…

Welte T et al.Thorax 2012; 67: 71-79

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Streptococcus pneumoniae

= most frequent pathogen= highest morbidity and mortality

CAP: etiology

Should always be covered when starting emperical therapy!

Atypical Typical

History younger age older ageno co-morbidity productive coughdry cough high feverviral syndrome dyspneano pleural pain pleural paininsidious onset acute onset

Clinical not always crackles cracklesminor complaints consolidation

Lab low WBC count high WBC countno neutrophilia neutrophilia

Radiology ill-defined alveolar fillinginterstitial lobar - multilobar

Typical vs. atypical pneumonia

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CAP: not always caused bydifficult pathogens…

• Coverage for Pseudomonas aeruginosaand MRSA only when specific risk factors are present

Pseudomonas risk factors

1. Recent hospitalisation

2. Frequent use of antibiotics/steroids (>4 in previous

year) or recent use of antibiotics/steroids (previous

3 months)

3. Very severe COPD (i.e. GOLD IV)

4. Isolation van P. aeruginosa during a previous AECOPD

of known kolonisation during stable periods

5. Presence of bronchiectasis

Eller et al. Chest 1998; 157: 1542Miravitlles et al. Chest 1999; 116: 40Woodhead et al. ERS Task force. Eur Resp J 2005; 26: 1138

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Risk factors for infection by multidrug resistant (MDR) pathogens

• Antibiotic therapy in previous 90 days• High frequency of resistance in community• Immunosuppression by disease or medication• Risk factors for HCAP

Hospitalisation for ≥2 days in previous 90 daysNursing home residenceHome intravenous therapyChronic dialysis within 30 daysChronic wound careClose contacts to MDR pathogens

Trouillet et al. AJRCCM 1998; 157: 531-539

CAP: treatment

• Pneumonia always antibiotics ASAP

• Which?→ criteria

- antibiotic spectrum- route of administration- bio-equivalence

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Antibiotics: which route to choose?

• Parenteral administration is widely andoften unnecessarily used

→ only 30-50% of patients admitted tohospital will initially require treatmentwith parenteral antibiotics

Parenteral therapyHigh severity pneumoniaImpaired consciousnessLoss of swallowing reflexFunctional or anatomical reasons for malabsorption

Chan R et al. BMJ 1995; 310: 1360-1362Macgregor RR et al. Clin Infect Dis 1997; 24: 457-467

IV vs. PO: bio-equivalent antibiotics

Levofloxacin

Moxifloxacin

Clarithromycin

Clindamycin

Linezolid

Metronidazole

Ornidazole

Fluconazole

SMX/TMP

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IV vs. PO: when to switch?

• No rigid recommendations

• Any decision should be individualised basedon assessing all factors

• Oral therapy should be considered in a patient who has shown clear evidence ofimprovement

• Ward pharmacists could play an important role…

Mandell LA et al. Can J Infect Dis 1995; 6: 306-315

IV vs. PO: when to switch?

Lim WS et al. Thorax 2009; 64(3); 1-55Halm EA, Fine MJ, Marrie TJ, et al. JAMA 1998; 279; 1452-1457

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IV vs. PO: how to switch?

-lactam -lactamfluoroquinolone fluoroquinolone

cefalosporine fluoroquinolonecefalosporine amoxycillin-

clavulanate

CAP: treatment

• Pneumonia always antibiotics ASAP

• Which?→ criteria

- antibiotic spectrum- route of administration- bio-equivalence- interactions, side effects- cost- …

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Antibiotics: daily cost (in euro)

CAP: treatment

• Pneumonia always antibiotics ASAP

• Which? we follow the guidelines…

BUT- local epidemiology!- local resistance patterns!

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Penicilline resistance, 2011

Macrolide resistance, 2011

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Resistance in Belgium, 1986-2012

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28,9

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25,8

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Peni tetra ofl ery cefotax

J. Verhaegen, referentie-laboratorium Leuven, 2013

S. pneumoniae, invasive isolates

CAP: guidelines for AB therapy

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Lim WS et al. Thorax 2009; 64(3); 1-55

Woodhead M et al.Eur Respir J 2005; 26: 1138–1180

Mandell LA et al. Clin Infect Dis 2007; 44: 27-72

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Outpatient, no comorbidity Outpatient, + comorbidity

amoxicillin amoxicillin-clavulanate

If no improvement after 3d., atypical pathogens may be considered:consider using moxifloxacin or combining β-lactam with macrolide

Hospitalized patient

If oral treatment possible: moxifloxacinIf parenteral treatmant: amoxicillin-clavulanate (or cefuroxime)

If no improvement after 3d., atypical pathogens may be considered:consider using moxifloxacin or combining β-lactam with macrolide

Sanford Guide to Antimicrobial Therapy 2012-2013Antibioticagids UZ Leuven 2013: www.uzleuven.be/antibioticagids

No Pseudomonas risk factors Pseudomonas risk factors

amoxicillin-clavulanate orcefuroxime+clarithromycin or fluoroquinolone

cefepime or carbapenem orceftazidim or pipera/tazobactam+ciprofloxacin

cefotaxime or ceftriaxone+clarithromycin or fluoroquinolone

If infection with Legionella suspected:fluoroquinolones > macrolides

Sanford Guide to Antimicrobial Therapy 2012-2013Antibioticagids UZ Leuven 2013: www.uzleuven.be/antibioticagids

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Question: how long antibiotics?

• No robust data to support any guideline→ subject to clinical judgement

• AB eliminate target pathogen» quite rapidly (within 3d.) in uncomplicated

infections» longer for intracellular organisms and

Enterobacteriaceae

• Resolution of pneumonia is also the subsidence of the host inflammatory response

→ this takes much longer!!

Duration of antibiotic therapy

5-7 days S. pneumoniae

7-14 days EnterobacteriaceaePseudomonas aeruginosa

14 days Staphylococci

14-21 days

Mycoplasma spp.Chlamydophila spp.Legionella spp.

Li JZ et al. Am J Med 1997; 120: 783-790BTS Guidelines. Lim WS et al. Thorax 2009; 64(3); iii1-55

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8 vs 15 days of antibioticsfor treatment of pneumonia

Chastre et al. JAMA 2003; 290: 2588-2598

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Health-care associated pneumonia(HCAP)

• Nursing home residents

• Hospitalisation for ≥2days within 90days

• Treatment with intravenous antibiotics, chemotherapy or wound care within 30 days

• Ambulatory treatment in day care centre or dialysis ward

Treat like HAP !!

Mylotte JM. Clin Infect Dis 2002; 35: 1205-1211ATS/IDSA Guidelines. Am J Respir Crit Care Med 2005; 171; 388-416

Health-care associated pneumonia(HCAP)

BUT- very heterogenous group of patients- pneumonia not always severe- pathogens not always MDR- intravenous therapy not always necessary

Brito V, Niedermann MA. Curr Opin Inf Dis 2009; 22; 316-325

Management has to be individualizedDetermining subgroups is warranted MDR coverage not always necessary combination therapy not always necessary

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Something about “severe CAP”

Severe CAP = CAP that necessitatesadmission to an intensive care unit

Mandell LA et al. Clin Infect Dis 2007; 44: 27-72Kamath AV et al. Br J Hosp Med 2006; 26: 76-78

6,6% - 16,7% of hospitalized CAP pts

- No objective measurements- ICU admittance policies differ…

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Severe CAP has a somewhatdistinct microbial etiology

• (methicillin-resistant) S. aureus• Pseudomonas (+ other nonfermenting Gr-negatives)

Common Rare

S. pneumoniae (incl. DRSP) Chlamydophila

Legionella spp. C. burnetii

Pseudomonas aeruginosa Respiratory viruses

S. aureus (incl. MRSA) Endemic fungi

Enteric Gram-negative bacilli(esp. Klebsiella spp.)

S. pyogenes

Mycoplasma pneumoniae M. tuberculosis

H. influenzae Pneumocystis jeroveci

Restrepo MI et al. Curr Opin Infect Dis 2001; 14: 703-709

Severe CAP has a somewhatdistinct microbial etiology

Pseudomonas (+ other nonfermenting Gr-negatives)

Lim WS et al. Thorax 2009; 64: 1-55

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How can we improve outcome of severe CAP?

Major outcome determinants??

Waterer GW et al. Am J Resp Crit Care Med 2011; 183: 157-164

Severe CAP: major outcome determinants

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How can we improve outcome of severe CAP?

• Optimization of ICU admission timely recognition of patients at risk correct indication for admission

• Optimization of antibiotic therapy

• Adjunctive therapy

Timely recognition and correct indication for ICU admission

1. Risk factors for severe CAP

2. Severity scoring systems

3. Criteria for severe CAP

4. Biomarkers

5. Bacterial load

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Severe CAP: risk factors

• Co-morbidities• COPD• renal insufficiency• chronic heart failure• ishemic heart disease• diabetes mellitus• chronic liver disease• alcoholism• malignancy• immunosuppression

Severe CAP: risk factors

• Co-morbidities• COPD ICU mortality 39% (50% if no response to NIPPV)

• renal insufficiency• chronic heart failure• ishemic heart disease• diabetes mellitus• chronic liver disease• alcoholism• malignancy• immunosuppression

Rello J et al. Eur Resp J 2006; 27: 1210-1216

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Severe CAP: risk factors

• Co-morbidities

• Pathogens- most lethal: S. pneumoniae

Legionella pneumophilaPseudomonas aeruginosa

• Radiology: progression of infiltrates>50% in the first 48hrs

• BacteremiaLisboa T et al. Chest 2008; 135: 165-172

Bodi M et al. Clin Infect Dis 2005; 41: 1709-1716

Severe CAP: criteria for ICU admission

• IDSA/ATS criteria

identification of severe CAP

better discriminatory capacity for ICU admission than PSI, CURB, and CURB-65

– 1993: 9 criteria– 2001: major and minor criteria– 2007: reappraisal of minor criteria

IDSA/ATS Guidelines. Clin Infect Dis 2007; 44: 27-72Mandell LA. Clin Infect Dis 2009; 48: 386-388

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Severe CAP: IDSA/ATS criteria

Mandell LA et al. Clin Infect Dis 2007; 44: 27-72

≥3 minor

Liapikou A et al.Clin Infect Dis 2009; 48: 377-385

Severe CAP: IDSA/ATS criteria

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Biomarkers for identification of severe CAP

• Ideal marker has not yet been found• One marker panel of markers

CRP (c-reactive protein)

PCT (procalcitonine )

IL-6 (>>IL-8)

Pro-adrenomedullin

Pro-natriuretic peptide (proANP)

sTREM-1 (triggering receptor expressed on myeloid cells)

Pro-vasopressin (proAVP)

Christ-Crain M, Müller B. Eur Resp J 2007; 30: 556-573Menendez R et al. Thorax 2009; 64: 587-591Waterer GW et al. Am J Resp Crit Care Med 2011; 183: 157-164

Severe CAP & bacterial load

• PCR-based pneumococcal assay– sensitivity: 2x blood culture sensitivity– specificity ≈100%– load (copies/mL) strong predictor of the

risk of shock and risk of deathRello J et al. Chest 2009; 136: 832-840

Peters RP et al. J Clin Microbiol 2009; 47: 3308-3312Kee C et al. Chest 2010; 137: 243-244

Sepsis, shock, …death not only an exagerated host response

but also related to bacterial factors!

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Severe CAP & bacterial load

• PCR-based pneumococcal assay– sensitivity: 2x blood culture sensitivity– specificity ≈100%– load (copies/mL) strong predictor of the

risk of shock and risk of death

Therapy for severe CAP

• Combination therapy >> monotherapyMufson MA et al. Am J Med 1999; 107:34-43

Waterer GW et al. Arch Intern Med 2001; 161:1837-1842Baddour LM et. Am J Respir Crit Care Med 2004; 170:440–444

Nonsevere CAP Severe CAP

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Therapy for severe CAP

• Coverage for S. pneumoniae and Legionella species should be ensured

• Parenteral administration is recommended

• Coverage for Pseudomonas aeruginosaand MRSA when specific risk factors are present

Ruiz M et al. Am J Respir Crit Care Med 1999; 160:923–9

Adjunctive therapy for severe CAP

1. Corticosteroids

2. Macrolides

3. Activated Protein C

4. Tissue Factor Pathway Inhibitor

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• No improved survival or reversal of shock in patients with septic shock

Adjunctive therapy:corticosteroids

Sprung CL et al. N Engl J Med 2008;358:111-24

(hydrocortisone 50mg qid, 5d.)

• No evidence to support use of corticosteroidsin severe CAP without septic shock

Adjunctive therapy:corticosteroids

Snijders D et al. Am J Resp Crit Care Med 2010; 181: 975-982

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• Meta-analysis JAMA 2009:- overall no effect on 28-day mortality- moderate beneficial effect on mortality

in subgroup with septic shock

Adjunctive therapy:corticosteroids

“low-dose” corticosteroids ≥5 days= hydrocortisone 200-300mg/d

Corticosteroids not recommended forroutine use in severe CAP (BTS, IDSA/ATS)

Need for prospective studies to evaluatelow-dose regimen in pts with septic shock

Annane D et al. JAMA 2009; 301: 2362-2375

Adjunctive therapy:macrolides

• Combination of antibiotics >> single agent

• Benefit of combination therapy in severe CAP only when macrolides part of the regimen

• Mortality benefit seen largely in those with the most severe disease

Waterer GW et al. Am J Respir Crit Care Med 2011; 183: 157-164

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(macrolide) Combination therapy in adult pts with (severe) CAP

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2010

Eur Respir J 2009; 33: 153-159

All pts Culture NEG

Culture POS

Macrolide RES

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Martin-Loeches I et al. Intensive Care Med 2010; 36: 612–620

Why macrolides may contribute tobetter outcome in severe CAP

1. Synergistic antibacterial mechanism

2. Atypical pathogen coverage

3. Immunomodulatory/anti-inflammatoryeffect

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Why macrolides may contribute tobetter outcome in severe CAP

1. Synergistic antibacterial mechanismGram-positive pathogens not the only causeof severe CAP

2. Atypical pathogen coverage

3. Immunomodulatory/anti-inflammatoryeffect

Why macrolides may contribute tobetter outcome in severe CAP

1. Synergistic antibacterial mechanismGram-positive pathogens not the only causeof severe CAP

2. Atypical pathogen coverage‘Atypicals’ not a very common cause of severe CAPNo beneficial effect of tetracyclines nor fluoroquinolones

3. Immunomodulatory/anti-inflammatoryeffect

success in noninfectious but immune-related conditionsanimal studies

Giamarellos-Bourboulis E. Int J Antimicrob Agents 2008; 31: 12-20

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Beneficial affect of macrolidesin the inflamed airways

Kanoh S, Rubin BK. Clin Microbiol Rev 2010; 23:590-615

“We believe that current evidence supports obligatorymacrolide therapy in all cases of CAP with physiologicalcompromise, especially those with or deemed at risk forseptic shock or mechanical ventilation”

Grant W. Waterer, Jordi Rello, andRichard G. WunderinkAm J Respir Crit Care Med 2011; 183: 157-164

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Questions?