5 Mar 2013 ... no response to empirical therapy ... Frequent use of antibiotics/steroids (>4 in
previous .... Sanford Guide to Antimicrobial Therapy 2012-2013.
3-5-2013
Pneumonia in ER
Pascal Van Bleyenbergh Departlent of Pneumology, UZ KULeuven
Global mortality due to infection: major impact of pneumonia
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 countries CAP mortality is not negligible… Mortality: - outpatients - inpatients - CAP III - CAP IV - 18-44 year - >65 year
1900
1950
1%- 5% 6%-14% 36%-60% 130
V
>10 %
Fine MJ, Auble TE, Yealy DM, et al. N Engl J Med 1997; 336: 243
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CURB-65 score system
Confusion Urea >7mmol/l (42 mg/dL) Respiratory rate ≥30/min Blood pressure: Psyst4 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: 1542 Miravitlles et al. Chest 1999; 116: 40 Woodhead 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 days Nursing home residence Home intravenous therapy Chronic dialysis within 30 days Chronic wound care Close 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 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: 1360-1362 Macgregor 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 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: 306-315
IV
vs.
PO: when to switch?
Lim WS et al. Thorax 2009; 64(3); 1-55 Halm EA, Fine MJ, Marrie TJ, et al. JAMA 1998; 279; 1452-1457
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IV
vs.
PO: how to switch?
-lactam fluoroquinolone
-lactam fluoroquinolone
cefalosporine cefalosporine
fluoroquinolone amoxycillinclavulanate
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 S. pneumoniae, invasive isolates
J. Verhaegen, referentie-laboratorium Leuven, 2013
CAP: guidelines for AB therapy
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Woodhead M et al. Eur Respir J 2005; 26: 1138–1180
Lim WS et al. Thorax 2009; 64(3); 1-55
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: 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
Sanford Guide to Antimicrobial Therapy 2012-2013 Antibioticagids UZ Leuven 2013: www.uzleuven.be/antibioticagids
No Pseudomonas risk factors
Pseudomonas risk factors
amoxicillin-clavulanate or cefuroxime + clarithromycin or fluoroquinolone
cefepime or carbapenem or ceftazidim or pipera/tazobactam + ciprofloxacin
cefotaxime or ceftriaxone + clarithromycin or fluoroquinolone If infection with Legionella suspected: fluoroquinolones > macrolides Sanford Guide to Antimicrobial Therapy 2012-2013 Antibioticagids 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
Enterobacteriaceae Pseudomonas aeruginosa
14 days
Staphylococci
14-21 days
Mycoplasma spp. Chlamydophila spp. Legionella spp.
Li JZ et al. Am J Med 1997; 120: 783-790 BTS Guidelines. Lim WS et al. Thorax 2009; 64(3); iii1-55
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8 vs 15 days of antibiotics for treatment of pneumonia
Chastre et al. JAMA 2003; 290: 2588-2598
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: 1205-1211 ATS/IDSA Guidelines. Am J Respir Crit Care Med 2005; 171; 388-416
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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
Brito V, Niedermann MA. Curr Opin Inf Dis 2009; 22; 316-325
HCAP: treatment algorithm
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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: 27-72 Kamath AV et al. Br J Hosp Med 2006; 26: 76-78
Severe CAP has a somewhat distinct 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
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Severe CAP has a somewhat distinct microbial etiology Pseudomonas (+ other nonfermenting Gr-negatives)
Lim WS et al. Thorax 2009; 64: 1-55
How can we improve outcome of severe CAP?
Major outcome determinants??
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Severe CAP: major outcome determinants
Waterer GW et al. Am J Resp Crit Care Med 2011; 183: 157-164
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
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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
Severe CAP: risk factors • Co-morbidities • • • • • • • • •
COPD renal insufficiency chronic heart failure ishemic heart disease diabetes mellitus chronic liver disease alcoholism malignancy immunosuppression
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Severe CAP: risk factors • Co-morbidities • COPD
ICU mortality 39% (50% if no response to NIPPV) Rello J et al. Eur Resp J 2006; 27: 1210-1216
• • • • • • • •
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: 165-172 Bodi M et al. Clin Infect Dis 2005; 41: 1709-1716
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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: 27-72 Mandell LA. Clin Infect Dis 2009; 48: 386-388
Severe CAP: IDSA/ATS criteria ≥3 minor
Mandell LA et al. Clin Infect Dis 2007; 44: 27-72
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Severe CAP: IDSA/ATS criteria
Liapikou A et al.Clin Infect Dis 2009; 48: 377-385
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: 556-573 Menendez R et al. Thorax 2009; 64: 587-591 Waterer GW et al. Am J Resp Crit Care Med 2011; 183: 157-164
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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 Rello J et al. Chest 2009; 136: 832-840 Peters RP et al. J Clin Microbiol 2009; 47: 3308-3312 Kee C et al. Chest 2010; 137: 243-244
Sepsis, shock, …death not only an exagerated host response but also related to bacterial factors!
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
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Therapy for severe CAP • Combination therapy >> monotherapy Mufson MA et al. Am J Med 1999; 107:34-43 Waterer GW et al. Arch Intern Med 2001; 161:1837-1842 Baddour LM et. Am J Respir Crit Care Med 2004; 170:440–444
Nonsevere CAP
Severe CAP
Therapy for severe CAP • Coverage for S. pneumoniae and Legionella species should be ensured Ruiz M et al. Am J Respir Crit Care Med 1999; 160:923–9
• Parenteral administration is recommended • Coverage for Pseudomonas aeruginosa and MRSA when specific risk factors are present
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Adjunctive therapy for severe CAP 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
Sprung CL et al. N Engl J Med 2008;358:111-24
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Adjunctive therapy: corticosteroids • No evidence to support use of corticosteroids in severe CAP without septic shock
Snijders D et al. Am J Resp Crit Care Med 2010; 181: 975-982
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 200-300mg/d
Annane D et al. JAMA 2009; 301: 2362-2375
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
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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
(macrolide) Combination therapy in adult pts with (severe) CAP
1999 2001 2003 2003 2004 2007 2006 2007
2009 2009 2010
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Eur Respir J 2009; 33: 153-159
All pts
Culture NEG
Culture POS
Macrolide RES
Martin-Loeches I et al. Intensive Care Med 2010; 36: 612–620
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Why macrolides may contribute to better outcome in severe CAP 1. Synergistic antibacterial mechanism 2. Atypical pathogen coverage
3. Immunomodulatory/anti-inflammatory effect
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
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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: 12-20
Beneficial affect of macrolides in the inflamed airways
Kanoh S, Rubin BK. Clin Microbiol Rev 2010; 23:590-615
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“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: 157-164
Questions?
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