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References
1. Arancibia F, Ewig S, Martinez JA et al. Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic. Am J Respir Crit Care Med. 2000 Jul;162(1):154-60. 2. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of communityacquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27-72. 3. Kaplan V, Angus DC, Griffin MF et al. Hospitalized community-acquired pneumonia in the elderly: age- and sex-related patterns of care and outcome in the United States. Am J Respir Crit Care Med. 2002 Mar 15;165(6):766-72. 4. Ioanas M, Ferrer M, Cavalcanti M, et al. Causes and predictors of nonresponse to treatment of intensive care unit-acquired pneumonia. Crit Care Med. 2004 Apr;32(4):938-45. 5. Federman AD, Safran DG, Keyhani et al. Low levels of awareness of pharmaceutical costassistance programs among inner-city seniors. JAMA. 2008 Sep 24;300(12):1412-4. 6. Halm EA, Fine MJ, Kapoor WN. Instability on hospital discharge and the risk of adverse outcomes in patients with pneumonia. Arch Intern Med. 2002 Jun 10;162(11):1278-84. 7. Menndez R, Torres A, Rodrguez de Castro F, et al. Reaching stability in communityacquired pneumonia: the effects of the severity of disease, treatment, and the characteristics of patients.Clin Infect Dis. 2004 Dec 15;39(12):1783-90. Epub 2004 Nov 18. 8. Niederman MS. Understanding the natural history of community-acquired pneumonia resolution: vital information for optimizing duration of therapy. Clin Infect Dis. 2004 Dec 15;39(12):1791-3. Epub 2004 Nov 18. 9. Menndez R, Torres A, Zalacan R, et al. Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome. Thorax. 2004 Nov;59(11):960-5. 10. Lim WS. Identifying failure of empirical treatment for pneumonia: vigilance and common sense. Thorax. 2004 Nov;59(11):918-9. 11. Rosn B, Carratal J, Fernndez-Sab N et al. Causes and factors associated with early failure in hospitalized patients with community-acquired pneumonia. Arch Intern Med. 2004 Mar 8;164(5):502-8. 12. Yu VL, Chiou CC, Feldman C et al. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis. 2003 Jul 15;37(2):230-7. Epub 2003 Jul 7. 13. Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med. 2002 Mar 7;346(10):747-50.
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14. De la Campa AG, Ferrandiz MJ, Tubau F et al. Genetic characterization of fluoroquinoloneresistant Streptococcus pneumoniae strains isolated during ciprofloxacin therapy from a patient with bronchiectasis. Antimicrob Agents Chemother. 2003 Apr;47(4):1419-22 15. Anderson KB, Tan JS, File TM Jr, et al. Emergence of levofloxacin-resistant pneumococci in immunocompromised adults after therapy for community-acquired pneumonia. Clin Infect Dis. 2003 Aug 1;37(3):376-81. 16. Prez-Trallero E, Marimon JM, Iglesias L, Larruskain J. Fluoroquinolone and macrolide treatment failure in pneumococcal pneumonia and selection of multidrug-resistant isolates. Emerg Infect Dis. 2003 Sep;9(9):1159-62. 17. Menndez R, Torres A, Zalacan R et al. Guidelines for the treatment of community-acquired pneumonia: predictors of adherence and outcome. Am J Respir Crit Care Med. 2005 Sep 15;172(6):757-62. Epub 2005 Jun 3. 18. Aujesky D, Fine MJ. Does guideline adherence for empiric antibiotic therapy reduce mortality in community-acquired pneumonia? Am J Respir Crit Care Med. 2005 Sep 15;172(6):655-6. 19. Dean NC, Silver MP, Bateman KA, et al. Decreased mortality after implementation of a treatment guideline for community-acquired pneumonia. Am J Med. 2001 Apr 15;110(6):4517. 20. Fernndez-Serrano S, Dorca J, Coromines M et al. Molecular inflammatory responses measured in blood of patients with severe community-acquired pneumonia. Clin Diagn Lab Immunol. 2003 Sep;10(5):813-20. 21. Root RK, Lodato RF, Patrick W et at. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med. 2003 Feb;31(2):367-73. 22. Desaki M, Takizawa H, Ohtoshi T, Kasama T, et al. Erythromycin suppresses nuclear factorkappaB and activator protein-1 activation in human bronchial epithelial cells.Biochem Biophys Res Commun. 2000 Jan 7;267(1):124-8. 23. Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother. 2001 Jan;45(1):44-7. 24. Waterer GW, Quasney MW, Cantor RM et al. Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med. 2001 Jun;163(7):1599-604. 25. Montn C, Ewig S, Torres A, et al. Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J. 1999 Jul;14(1):218-20. 26. Montn C, Torres A, El-Ebiary M, et al. Cytokine expression in severe pneumonia: a bronchoalveolar lavage study. Crit Care Med. 1999 Sep;27(9):1745-53. 27. Agust C, Ra A, Filella X, et al. Pulmonary infiltrates in patients receiving long-term glucocorticoid treatment: etiology, prognostic factors, and associated inflammatory response.Chest. 2003 Feb;123(2):488-98. 28. Meduri GU, Kanangat S, Bronze M, et al. Effects of methylprednisolone on intracellular bacterial growth. Clin Diagn Lab Immunol. 2001 Nov;8(6):1156-63. 29. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe communityacquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005 Feb 1;171(3):242-8. Epub 2004 Nov 19. 30. Dennesen PJ, van der Ven AJ, Kessels AG, et al. Resolution of infectious parameters after antimicrobial therapy in patients with ventilator-associated pneumonia. Am J Respir Crit Care Med. 2001 May;163(6):1371-5. 31. Meijvis SC, Hardeman H, Remmelts HH et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jun 11;377(9782):2023-30. 32. Torres A, Ramrez P, Montull B, Menndez R. Biomakers and community-acquired pneumonia: Tailoring Management with biological data. Semin Respir Crit Care Med. 2012 Jun;33(3):266-71.
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Evaluation
1. What is the crude incidence of non-responding hospitalized community-acquired pneumonia? a. 25% b. 5% c. 10-15% d. Zero e. 50% 2. Of the following causes, which one is not a cause of non-responding treatment? a. Empyema b. Resistant microorganisms c. Nosocomial infection d. Antibiotic allergy e. Unusual microorganism 3. Which one of the following variables is not included in the concept of clinical stability? a. Temperature b. C-reactive protein c. O2 Saturation d. Respiratory rate 4. Which one of the following factors is associated with risk of treatment failure in CAP? a. PSI I and II b. Multilobar involvement c. Fever d. COPD e. Asthma Please find all answers at the back of your handout materials. .
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ANTONI TORRES
FACULTY DISCLOSURE
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INTRODUCTION
AIMS Aim 1 : To describe incidence ,risk factors and causes of treatment failure in CAP Aim 2: To describe the clinical characteristics of treatment failure in CAP Aim 3: To describe outcomes of patients with treatment failure in CAP
CONTENTS
1-Definitions and epidemiology
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INCIDENCE
1-CAP non- responding and progressive pneumonia : 10 % and 6 % of hospitalized patients Ortqvist 1990, Ruiz 1999, Arancibia 2001, NACE study. Spanish CAP study in Elderly. 2-HAP: 36% lack of clinical response (Alvarez-Lerma) 67% in VAP caused by P.aeruginosa (Brewer) 61% in a follow-up study (Ioanas.Crit Care Med 2004)
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1-Complications: Empyema,abscess. 2-Inadequate antibiotic treatment including resistances 3-Unusual microorganisms: P.jiroveci, Mycobacterias, fungi.
PEUMONIA: MORTALITY
Respuesta tratamiento
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Overall mortality: 43% Prognosis factors: APACHE II >14; RR:9 NOSOCOMIAL INFECTION; RR: 17
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rea TIR-SEPAR
HR day 1
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rea TIR-SEPAR
NEUMOFAIL STUDY
-Prospective multicenter study:14 hospitals in Spain
-228 out of 1502 patients recruited with CAP (15%) -25% mortality in non-responding compared to 2%in responding CAP
-31 % vs 17 % mortality comparing early vs late failure
Influen Vacc. COPD Quinolones Cavitation Hepatic Dis Multilobar Pleural eff PSI Leucopenia
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FACTORS EVALUATED FOR MORTALITY IN 360 PATIENTS RECEIVING ANTIBIOTIC MONOTHERAPY IN MULTIVARIATE ANALYSIS
The prevalence of R will dictate the need to reassess current recommendations for the treatment of CAP.
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MUTATION(S)
1
2
Pneumonia Pneumonia
Bronchiectasis
1 4 1 1 1 1 1
2
LEVO (500)
8 16 16 16 8 16 16
16
parC(S79F) gyrA(S81F) parC(S79F) gyrA(S81F) parC(S79F) gyrA(S81F) parC(S79Y) gyrA(S81F) parC(D83Y) gyrA(S81Y) parC(S79F) gyrA(S81F) parC(S79F) gyrA(S81F) parC(S79F) gyrA(S81F)
LEVO (500)
De la Campa A et al.
AAC 2003
Anderson KB et al.
CIPRO (1000)
For months, intermittently
CID 2003
Pneumonia
LEVO (500)
5 6 7
Perez-trallero E et al. EID 2003
LEVO (500)
LEVO (500)
LEVO (500)
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PATIENTS WITH SEVERE CAP MAY DIE DESPITE EARLY AND APROPIATE ANTIBIOTIC THERAPY
The host defense reaction is usually localized by the presence of regulatory mechanisms that contain the inflammatory response to the site of infection (compartimentalization), where it is needed and is appropriate, and rarely does this response "spill over" into the serum. When inflammation is localized to the site of infection, it is beneficial.
379726
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4-Corticosteroids 5-Genetics :TNF polymorphisms 6-Mechanical ventilation MANY FACTORS HAVE TO BE TAKEN INTO ACCOUNT!
B-lactam
PBP 1
lisis
4, 5 ...
philaments
sferoplasts
++
+
Endotoxin Release
+++
NF-B TNF-
mRNA
IL-8
1
Antibacterial effect
2
Inhibition of transcription
3
Inhibition of translation
Desaki M, Biochem Biophys Res Commun. 267:124-128, 2000. Ichiyama T, et al, Antimicrob Agents Chemother. 45:44-47, 2001. Kikuchi T, et al, Antimicrob Agents Chemother. 49:745-755, 2002.
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% Septic Shock
P=0.01 AA vs no AA
100
p=NS 75 p<0.0001
2000 p=0.013
50
1000 p<0.0001
25
Mortality: 93%
200
27%
p=0.013
60%
2000 p<0.0001
150
100
p=NS
50
p=0.021
500
p=0.001
CONTROL
CGCT
AGCT
NGCT
CONTROL
CGCT
AGCT
NGCT
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No Methylprednisolone
No methylprednisolone
Methylprednisolone 150 g
Methylprednisolone 250 g
p=0.03
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MAIN OUTCOME PARAMETERS AT& AND 60 DAYS Placebo Hydrocort PaO2/FIO2 Chest-X ray score MOF score CRP mg/dl Patients on MV Length of stay (days)
60 day mortality
Corticosteroids in CAP
Conclusions
1-Treatment failure in CAP accounts for 10-15% of hospitalized cases and it is followed by a higher mortality 2-There are host, microbial and management causes of treatment failure (risk factors) 3-In some cases an exagerated inflammatory response is associated with treatment failure. Modulation of the inflammatory response is a promising therapy
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47
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