Pneumonia in ER Pneumonia, a family. Postgraduate course Even in developed countries CAP mortality is not negligible

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1 Pneumonia, a family Community-acquired pneumonia (CAP) Pneumonia in ER Health-care associated pneumonia (HCAP) Postgraduate course Hospital-acquired pneumonia (HAP) Ventilator-associated pneumonia (VAP) Pascal Van Bleyenbergh Department of Pneumology, UZ KULeuven Even in developed countries CAP mortality is not negligible Mortality for hospitalised patients with CAP has remained constant over time Mortality: - outpatients 1%- 5% - inpatients - CAP III 6%-14% - CAP IV 36%-60% Mixed patient populations in different settings and countries year <1% - >65 year 12,5% *CAP=Community acquired pneumonia # average of 30-day and 90-day mortality in ICU vs ward patients, with average of 2 rates ~ 12% Feikin DR et al. Am J Public Health 2000; 90: National Center for Health Statistics 2000 ( Austrian R et al. Ann Intern Med 1964; 60: 759 Fine MJ et al. JAMA 1996; 274: 134 Feikin DR et al. Am J Pub Health 2000; 90: 223 Restrepo MI et al. Chest 2008; 133: 610 1

2 CAP: assessment 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!!) 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, Chlamydophila, ) - 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? Pneumonia IN- or OUT- hospital care? Severe CAP: severity scoring systems Pneumonia severity index (PSI) CURB-65 Severity scores Common Sense Score systems to stratify patients wit CAP into mortality risk groups management IN/OUT hospital 2

3 Severe CAP: severity scoring systems Pneumonia Severity Index step 1 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 Mortality probability < 0.5% Score systems to stratify patients wit CAP into mortality risk groups management IN/OUT hospital Fine MJ, Auble TE, Yealy DM, et al. N Engl J Med 1997; 336: 243 Pneumonia Severity Index step 2 CURB-65 score system Points Class 70 II < 1% III 1-4 % IV 4-10 % > 130 V >10 % Confusion Urea >7mmol/l (42 mg/dl) Respiratory rate 30/min Blood pressure: P syst <90mmHg P dias 60mmHg Age 65years Fine MJ, Auble TE, Yealy DM, et al. N Engl J Med 1997; 336: 243 Neill AM et al. Thorax 1996; 51(10): Lim WS et al. Thorax 2003;58:

4 To admit or not? Ward or ICU? Pneumonia IN- or OUT- hospital care? Severity scores Common Sense BTS Guidelines. Lim WS et al.thorax 2009; 64(3); 1-55 To admit or not: common sense CAP: treatment Pleural fluid Bilateral pneumonia Need for supplemental oxygen Oral therapy possible? Compliance Socio-economic situation Recurrent pneumonia Co-morbidity (immune status,...) Diagnostic uncertainty Pneumonia always antibiotics ASAP Which? criteria - antibiotic spectrum Target the most likely pathogens 4

5 CAP: causal pathogens CAP: causal pathogens by country Welte T et al. Thorax 2012; 67: 71 Welte T et al. Thorax 2012; 67: CAP: causal pathogens by treatment setting CAP: etiology Streptococcus pneumoniae = most frequent pathogen = highest morbidity and mortality Should always be covered when starting emperical therapy! Welte T et al. Thorax 2012; 67:

6 Typical vs. atypical pneumonia Atypical Typical History younger age older age no co-morbidity productive cough dry cough high fever viral syndrome dyspnea no pleural pain pleural pain insidious onset acute onset CAP: not always caused by difficult pathogens Coverage for Pseudomonas aeruginosa and MRSA only when specific risk factors are present Clinical not always crackles crackles minor complaints consolidation Lab low WBC count high WBC count no neutrophilia neutrophilia Radiology ill-defined alveolar filling interstitial lobar - multilobar Pseudomonas risk factors Risk factors for infection by multidrug resistant (MDR) pathogens 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 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 days Nursing home residence Home intravenous therapy Chronic dialysis within 30 days Chronic wound care Close contacts to MDR pathogens Eller et al. Chest 1998; 157: 1542 Miravitlles et al. Chest 1999; 116: 40 Woodhead et al. ERS Task force. Eur Resp J 2005; 26: 1138 Trouillet et al. AJRCCM 1998; 157:

7 CAP: treatment Antibiotics: which route to choose? Pneumonia always antibiotics ASAP Which? criteria - antibiotic spectrum - route of administration - bio-equivalence Parenteral administration is widely and often unnecessarily used only 30-50% of patients admitted to hospital will initially require treatment with parenteral antibiotics Parenteral therapy High severity pneumonia Impaired consciousness Loss of swallowing reflex Functional or anatomical reasons for malabsorption Chan R et al. BMJ 1995; 310: Macgregor RR et al. Clin Infect Dis 1997; 24: IV vs. PO: bio-equivalent antibiotics IV vs. PO: when to switch? Levofloxacin Moxifloxacin Clarithromycin Clindamycin Linezolid Metronidazole Ornidazole Fluconazole SMX/TMP No rigid recommendations Any decision should be individualised based on assessing all factors Oral therapy should be considered in a patient who has shown clear evidence of improvement Ward pharmacists could play an important role Mandell LA et al. Can J Infect Dis 1995; 6:

8 IV vs. PO: when to switch? IV vs. PO: how to switch? -lactam fluoroquinolone -lactam fluoroquinolone cefalosporine cefalosporine fluoroquinolone amoxycillinclavulanate Lim WS et al. Thorax 2009; 64(3); 1-55 Halm EA, Fine MJ, Marrie TJ, et al. JAMA 1998; 279; CAP: treatment Antibiotics: daily cost (in euro) Pneumonia always antibiotics ASAP Which? criteria - antibiotic spectrum - route of administration - bio-equivalence - interactions, side effects -cost - 8

9 CAP: treatment Penicilline resistance 2014: I+R Pneumonia always antibiotics ASAP Which? we follow the guidelines BUT - local epidemiology! - local resistance patterns! EARSS ECDC report. Antimicrobial resistance surveillance in Europe 2014 Penicilline resistance 2014: R Macrolide resistance 2014: R EARSS EARSS ECDC report. Antimicrobial resistance surveillance in Europe 2014 ECDC report. Antimicrobial resistance surveillance in Europe

10 Resistance in Belgium, CAP: guidelines for AB therapy 40 S. pneumoniae, invasive isolates ,1 23,8 10,8 0,2 0,1 J. Verhaegen, referentie-laboratorium Leuven, 2015 Peni tetra ofl ery cefotax Woodhead M et al. Eur Respir J 2005; 26: Lim WS et al. Thorax 2009; 64(3);

11 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: moxifloxacin If 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 Mandell LA et al. Clin Infect Dis 2007; 44: Sanford Guide to Antimicrobial Therapy Antibioticagids UZ Leuven 2014: Question: how long antibiotics? No Pseudomonas risk factors amoxicillin-clavulanate or cefuroxime + clarithromycin or fluoroquinolone cefotaxime or ceftriaxone + clarithromycin or fluoroquinolone If infection with Legionella suspected: fluoroquinolones > macrolides Pseudomonas risk factors cefepime or carbapenem or ceftazidim or pipera/tazobactam + ciprofloxacin Sanford Guide to Antimicrobial Therapy Antibioticagids UZ Leuven 2014: 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!! 11

12 Duration of antibiotic therapy 8 vs 15 days of antibiotics for treatment of pneumonia 5-7 days S. pneumoniae 7-14 days Enterobacteriaceae Pseudomonas aeruginosa 14 days Staphylococci days Mycoplasma spp. Chlamydophila spp. Legionella spp. Li JZ et al. Am J Med 1997; 120: BTS Guidelines. Lim WS et al. Thorax 2009; 64(3); iii1-55 Chastre et al. JAMA 2003; 290: 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!! Health-care associated pneumonia (HCAP) BUT - very heterogenous group of patients - pneumonia not always severe - pathogens not always MDR - intravenous therapy not always necessary Management has to be individualized Determining subgroups is warranted MDR coverage not always necessary combination therapy not always necessary Mylotte JM. Clin Infect Dis 2002; 35: ATS/IDSA Guidelines. Am J Respir Crit Care Med 2005; 171; Brito V, Niedermann MA. Curr Opin Inf Dis 2009; 22;

13 Something about severe CAP Severe CAP = CAP that necessitates admission to an intensive care unit 6,6% - 16,7% of hospitalized CAP pts - No objective measurements - ICU admittance policies differ Mandell LA et al. Clin Infect Dis 2007; 44: Kamath AV et al. Br J Hosp Med 2006; 26: Severe CAP has a somewhat distinct microbial etiology (methicillin-resistant) S. aureus Pseudomonas (+ other nonfermenting Gr-negatives) Severe CAP has a somewhat distinct microbial etiology 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 S. pyogenes (esp. Klebsiella spp.) Mycoplasma pneumoniae M. tuberculosis H. influenzae Pneumocystis jeroveci Restrepo MI et al. Curr Opin Infect Dis 2001; 14: Lim WS et al. Thorax 2009; 64:

14 How can we improve outcome of severe CAP? Severe CAP: major outcome determinants Major outcome determinants?? Waterer GW et al. Am J Resp Crit Care Med 2011; 183: 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 14

15 Severe CAP: risk factors Severe CAP: risk factors Co-morbidities COPD renal insufficiency chronic heart failure ishemic heart disease diabetes mellitus chronic liver disease alcoholism malignancy immunosuppression Co-morbidities COPD ICU mortality 39% (50% if no response to NIPPV) Rello J et al. Eur Resp J 2006; 27: renal insufficiency chronic heart failure ishemic heart disease diabetes mellitus chronic liver disease alcoholism malignancy immunosuppression Severe CAP: risk factors Co-morbidities Pathogens - most lethal: S. pneumoniae Legionella pneumophila Pseudomonas aeruginosa Radiology: progression of infiltrates >50% in the first 48hrs Bacteremia Lisboa T et al. Chest 2008; 135: Bodi M et al. Clin Infect Dis 2005; 41: Severe CAP: criteria for ICU admission IDSA/ATS criteria identification of severe CAP better discriminatory capacity for ICU admission than PSI, CURB, and CURB : 9 criteria 2001: major and minor criteria 2007: reappraisal of minor criteria IDSA/ATS Guidelines. Clin Infect Dis 2007; 44: Mandell LA. Clin Infect Dis 2009; 48:

16 Severe CAP: IDSA/ATS criteria Severe CAP: IDSA/ATS criteria 3 minor Mandell LA et al. Clin Infect Dis 2007; 44: Liapikou A et al.clin Infect Dis 2009; 48: Biomarkers for identification of severe CAP Pro-adrenomedullin (proadm) 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) = peptide expressed in vascular endothelium (and adrenal medulla, heart, kidneys, lungs, ) vasodilatation bactericidal activity anti-inflammatory activity - rapid circulation clearance -more stablepart: midregional proadm Christ-Crain M, Müller B. Eur Resp J 2007; 30: Menendez R et al. Thorax 2009; 64: Waterer GW et al. Am J Resp Crit Care Med 2011; 183: Samson WK. Front Neuroendocrinol 1998; 19: Becker KL et al. J Clin Endocrinol Metabol 2004; 89:

17 Pro-adrenomedullin (proadm) 1. Strong discriminatory power of proadm for predicting serious complications short-, mid- and long-term mortality 2. Adding proadm to clinical scoring systems enhanced such predictions and significantly improved classification of pts into predefined risk groups independent of etiology also in nonpneumonic lower respiratory infections 3. proadm consistently more accurate than other studied blood biomarkers (eg. PCT) Christ-Crain M et al. Crit Care 2005; 9: Kruger S et al. Am J Resp Crit Care Med 2010; 182: Schuetz P et al. Crit Care 2010; 14: R106 Huang DT et al. Chest 2009; 136: Guertler C et al. Eur Resp J 2011; 37: Bello S et al. Eur Resp J 2012; 39: consecutive adult pts, admitted to ED with diagnosis of CAP Power of biomarkers to discriminate between low (PSI I-III) and highrisk (PSI IV-V) pts Pro-ADM 0,811 PCT 0,620 CRP 0,588 (optimal cut-off: 0,646nmol/L) Bello S et al. Eur Resp J 2012; 39: Bello S et al. Eur Resp J 2012; 39: % of pts suffered significant complications Optimal cut-off: 0,833nmol/L - sens.: 67% - spec.: 66% Optimal cut-off: 1,066nmol/L (0,959-1,800nmol/L) 17

18 Am J Emerg Med 2013; 31: Am J Emerg Med 2013; 31: consecutive pts with CAP, admitted to ED PSI IV-V: 56% (61pts) Mortality 8,3% 109 consecutive pts with CAP, admitted to ED PSI IV-V: 56% (61pts) Mortality 8,3% proadm >> CRP, PCT proadm >> CRP, PCT good correlation with PSI improves accuracy of risk stratification AUC PSI 0,710 AUC proadm 0,803 BMC Infect Dis 2011; 11: 112 BMC Infect Dis 2011; 11: consecutive LRTI pts, admitted to ED Multicenter study (6 Swiss hospitals) CAP 68% -- AECOPD 17% -- Bronchitis 11% Combination of proadm and CURB65 in a novel risk score (CURB65A) showed improved performance for triaging pts with regard to expected risks for mortality and adverse outcomes 18

19 Severe CAP & bacterial load BMC Infect Dis 2011; 11: 112 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 Rello J et al. Chest 2009; 136: Peters RP et al. J Clin Microbiol 2009; 47: Kee C et al. Chest 2010; 137: Sepsis, shock, death not only an exagerated host response but also related to bacterial factors! Severe CAP & bacterial load Therapy for severe CAP 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 Combination therapy >> monotherapy Mufson MA et al. Am J Med 1999; 107:34-43 Waterer GW et al. Arch Intern Med 2001; 161: Baddour LM et. Am J Respir Crit Care Med 2004; 170: Nonsevere CAP Severe CAP 19

20 Therapy for severe CAP Adjunctive therapy for severe CAP Coverage for S. pneumoniae and Legionella species should be ensured Parenteral administration is recommended Ruiz M et al. Am J Respir Crit Care Med 1999; 160:923 9 Coverage for Pseudomonas aeruginosa and MRSA when specific risk factors are present 1. Corticosteroids 2. Macrolides 3. Activated Protein C 4. Tissue Factor Pathway Inhibitor Adjunctive therapy: corticosteroids No improved survival or reversal of shock in patients with septic shock (hydrocortisone 50mg qid, 5d.) Adjunctive therapy: corticosteroids No evidence to support use of corticosteroids in severe CAP without septic shock Sprung CL et al. N Engl J Med 2008;358: Snijders D et al. Am J Resp Crit Care Med 2010; 181:

21 Adjunctive therapy: corticosteroids Meta-analysis JAMA 2009: - overall no effect on 28-day mortality - moderate beneficial effect on mortality in subgroup with septic shock low-dose corticosteroids 5 days = hydrocortisone mg/d Annane D et al. JAMA 2009; 301: Corticosteroids not recommended for routine use in severe CAP (BTS, IDSA/ATS) Need for prospective studies to evaluate low-dose regimen in pts with septic shock Torres A, Ferrer M. Int Care Med 2015; Sept 14 (Epub ahead of print) Torres A et al. JAMA 2015; 313(7): 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: (macrolide) Combination therapy in adult pts with (severe) CAP

22 Eur Respir J 2009; 33: All pts Culture NEG Martin-Loeches I et al. Intensive Care Med 2010; 36: Culture POS Macrolide RES Why macrolides may contribute to better outcome in severe CAP 1. Synergistic antibacterial mechanism 2. Atypical pathogen coverage Why macrolides may contribute to better outcome in severe CAP 1. Synergistic antibacterial mechanism Gram-positive pathogens not the only cause of severe CAP 2. Atypical pathogen coverage 3. Immunomodulatory/anti-inflammatory effect 3. Immunomodulatory/anti-inflammatory effect 22

23 Why macrolides may contribute to better outcome in severe CAP 1. Synergistic antibacterial mechanism Gram-positive pathogens not the only cause of severe CAP 2. Atypical pathogen coverage Atypicals not a very common cause of severe CAP No beneficial effect of tetracyclines nor fluoroquinolones 3. Immunomodulatory/anti-inflammatory effect success in noninfectious but immune-related conditions animal studies Giamarellos-Bourboulis E. Int J Antimicrob Agents 2008; 31: Beneficial affect of macrolides in the inflamed airways Kanoh S, Rubin BK. Clin Microbiol Rev 2010; 23: Questions? We believe that current evidence supports obligatory macrolide therapy in all cases of CAP with physiological compromise, especially those with or deemed at risk for septic shock or mechanical ventilation Grant W. Waterer, Jordi Rello, and Richard G. Wunderink Am J Respir Crit Care Med 2011; 183: