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ERS Annual Congress Vienna

15 September 2012

Postgraduate Course 17 Clinical failure of treatment of respiratory infections

Saturday, 1 September 2012 14:0017:30 Room: C6

Treatment failure of community-acquired pneumonia: risk factors and consequences

Prof. Antoni Torres Head of Intensive Care Unit Dept of Pneumology and Allergy Respiratory Hospital Clnic de Barcelona Villarroel, 170 8036 Barcelona atorres@.ub.edu Aims
To describe incidence, risk factors and causes of treatment failure in CAP To describe the clinical characteristics of treatment failure in CAP To describe outcomes of patients with treatment failure in CAP

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.

27

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.

28

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. .

29

NAME OF PRESENTATION Treatmant Failure in CAP: risk factors and consequences

NAME OF SPEAKER

ANTONI TORRES

FACULTY DISCLOSURE

Advisory Boards and sponsored symposia: Bayer, Pfizer, AstraZeneca, GSK

TREATMENT FAILURE OF COMMUNITYACQUIRED-PNEUMONIA: RISK FACTORS AND CONSEQUENCES

ERS CONGRESS VIENNA 2012

30

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

2-Pneumofail and other studies

3-Inflammatory response and Treatment failure

DEFINITIONS: CAP (I)

Progressive pneumonia: clinical deterioration in terms of the development of ARF requiring MV and or septic shock after at least 72 h of treatment Non responding pneumonia: persistent fever >38 and or clinical symptoms after at least 72 h of treatment Arancibia et al Am J Respir Crit Care Med 2000

31

DEFINITIONS: CAP (II)

Non-responding: This term is used to define a situation in wich an inadequate clinical response is present despite antibiotic treatment TWO PATTERNS: Progressive pneumonia: Actual clinical deterioration with ARF requiring ventilatory support and or septic shock usually occurring within the first 72 h of hospital admission Persistent non-responding pneumonia: absence or delay in achieving clinical stability
IDSA/ATS guidelines for CAP in adults. CID 2007: 44 (Suppl2)

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)

INCIDENCE OF NON-RESPONSE IN CAP

32

CLASSIFICATION OF CAUSES OF NON-RESPONSE IN CAP

1-Complications: Empyema,abscess. 2-Inadequate antibiotic treatment including resistances 3-Unusual microorganisms: P.jiroveci, Mycobacterias, fungi.

4-Nosocomial infections 5-Failure 6-Non-infectious causes of pulmonary infiltrates

PEUMONIA: MORTALITY

Respuesta tratamiento

Kaplan AJRCCM 2003.

MORTALITY IN NON-RESPONDING PNEUMONIA

Mortality is clearly increased in both CAP and HAP non-responding pneumonia: CAP: The NACE study (22% vs 3.5%) HAP: Ioanas et al. (51% vs 7%) Crit Care Med 2004 Consequently this is a target population to evaluate risk factors and new interventional strategies

33

MORTALITY IN NON-RESPONDING CAP PATIENTS

Overall mortality: 43% Prognosis factors: APACHE II >14; RR:9 NOSOCOMIAL INFECTION; RR: 17

Arancibia et al Am J Respir Crit Care Med 2000

CLINICAL STABILITY IN CAP

IDSA/ATS Definition: T < 37.8 C HR < 100 bx min RR < 24 x min SBP > 90 mm Hg O2S > 90 % or PaO2 > 60 mm Hg room air Ability to maintain oral intake Normal mental status

Halm et al. JAMA 1998

CID 2007: 44: Suppl 2

CLINICAL STABILITY IN CAP

Clinical stability temperature Heart rate Respiratory rate BP O2 saturation Correlation with PSI

Halm et al. Arch Intern Med 2002

34

Clin Infect Dis 2004

rea TIR-SEPAR

RESULTS. MULTIVARIATE DAYS 1 AND DAY 3

HR day 1

Dispnea Confusin Pleural effusion PSI Multilobar Adherent Treat

0.76 (0.7-0.8) 0.6 0.6 0.73 0.7 1.2

HR day 1 + evolutive variab. 0.79 0.61 --0.73 0.84 .....

RESULTS. MULTIVARIATE DAYS 1 AND 3

HR day 1 and evolutives Treatment failure Cardiac comp Respirat comp Empiema ICU admission 0.31 (0.7-0.8) 0.66 0.77 0.57 0.57 P

<0.001 0.001 0.03 0.01 0.003

35

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

RISK FACTORS OF FAILURE

Failure RR 0,3 0,6 0,5 4,1 2 2,1 2,7 1,3 3,7 Early RR 0,2 Late RR

Influen Vacc. COPD Quinolones Cavitation Hepatic Dis Multilobar Pleural eff PSI Leucopenia

5,1 2,2 1,2 5,8 2,4 1,7 2,6 1,4

36

NEUMOFAIL: NON-RESPONDING CAP AND PSI SCORE

RISK FACTORS FOR EARLY FAILURE

OR (95% CI) <65 yrs Fine IV-V Multilobar Legionella GramDiscordant Atb Treatment 0.35 (0.2-0.6) 2.75 (1.6-4.8) 1.8 (1.1-2.8) 2.7 (1.4-5.3) 4.3(1.1-18) 2.5(1.6-3.94)

Rosn et al Arch Inter Med 2004

NEUMOFAIL: RATES OF NON-RESPONDING AND INITIAL ANTIBIOTIC TREATMENT

37

NEUMOFAIL: MORTALITY AND CAUSE OF NON-RESPONSE

Prognosis factors: Non-response: 11.7 No adherence to Spanish Guidelines: 3.7

FACTORS EVALUATED FOR MORTALITY IN 360 PATIENTS RECEIVING ANTIBIOTIC MONOTHERAPY IN MULTIVARIATE ANALYSIS

Yu V et al. CID 2003;37:230

*Pitt bacteremia score >4

MACROLIDE-RESISTANT PNEUMOCOCCI SUMMARY

- Increasing worldwide; associated with penicillin-resistance - Two main mechanisms of R Efflux pump (mef)- M phenotype Ribosomal methylase (erm)-MLSB phenotype - Therapeutic implications of the type of resistance Level of R Concentration of new macrolides at the site of infection (ELF, AM) - Recent data suggest that both mechanisms may be associated with failures - Emergence of resistance while on therapy

The prevalence of R will dictate the need to reassess current recommendations for the treatment of CAP.

38

EMERGENCE OF FQ-RESISTANT S. PNEUMONIAE IN VIVO (DURING OR AFTER THERAPY)

REFERENCE
N EPISODE
INITIAL ISOLATE LEVO MIC(g/ml) ANTIBIOTIC TREATMENT (mg/day) FINAL ISOLATE LEVO MIC(g/ml)

MUTATION(S)

Davidson et al. NEJM 2002

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

Pneumonia Pneumonia Pneumonia Pneumonia

LEVO (500)

LEVO (500)

LEVO (500)

LEVO (500) CIPRO (400 IV)

30-DAY CRUDE MORTALITY, HOSPITALIZED PATIENTS BEFORE/AFTER GUIDELINE IMPLEMENTATION

Dean Am J Med. 2001;110:451

39

ADHERENCE, SEVERITY AND SPECIALITY

NO ADHERENCE AND PROGNOSIS

PROGNOSTIC FACTORS. MULTIVARIATE ANALYSIS

Failure Independent variables Adherence Pulmonol + residents vs other PSI IV-V vs I-III OD (95%IC) 0.65(0.5-0.9) 0.6(0.4-0.9) 10.8(5-21) Adherence OD (95%IC) 0.55(0.3-0.9)

40

EVOLUTION AND OUTCOME OF NONRESPONDING AND RESPONDING CAP

Clinical stability (dys) Complications (%) ICU admission (%) Length of Stay (dys) Death (%) NR* R 11+8 4+3 69 23 26 4 18+14 9+6 25 2
* p<001 for all comparisons

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

41

CYTOKINES AND INNATE IMMUNITY

Cytokines - in optimal concentration - recruit both specific and nonspecific immune cells at the site of infection and activate them to eradicate bacteria and restore homeostasis

SYSTEMIC INFLAMMATION AND PROGNOSIS IN CAP

Non-survivors had a persistent increase of blood IL6 and IL10 levels

Fernandez-Serrano S, et al. Clin Diag Lab Immunol 2003: 813820

FILGRASTIM (GCSF) IN SEVERE PNEUMONIA

Root R et al. Crit Care Med 2003

42

FACTORS INFLUENCING THE INFLAMMATORY RESPONSE

1-Host Factors
Pulmonary Extrapulmonary

4-Corticosteroids 5-Genetics :TNF polymorphisms 6-Mechanical ventilation MANY FACTORS HAVE TO BE TAKEN INTO ACCOUNT!

2-Type of microorganisms and bacterial burden 3-Antibiotics used

B-lactam

PBP 1
lisis

4, 5 ...
philaments

sferoplasts

++

+
Endotoxin Release

+++

Macrolides: Mechanism of Action

Mechanisms of Anti-inflammatory Activity
Cytokine Production by Host Cells
IL-8 gene Transcription

NF-B TNF-

mRNA

IL-8 gene Translation

IL-8

Macrolides modulate inflammation by inhibiting NF-B activation

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.

43

GENETIC INFLUENCE ON CAP SEVERITY

% Septic Shock

P=0.01 AA vs no AA

Waterer et al. Am J Respir Crit Care Med 2001

Lt alpha + 250 Genotype

Cytokines in Severe Pneumonia: Corticosteroids

SERUM TNF- IL-1 IL-6 CRP BAL TNF- IL-1 IL-6 Neutrophil, % 118 50 91 35 1569 965 93 3 24 5 57 17 889 432 57 16 No GC (n = 9) 43 7 42 1089 342 34 5 GC (n = 11) 28 4 1 0.4 630 385 19 5 p-value 0.15 0.50 0.03* 0.03* ______ 0.05* 0.31 0.49 0.03*

Montn C, Ewig S, Torres A. Eur Respir J 1999; 14:218-220

Steroids in Severe Pneumonia

125 p=0.003 3000 p=0.005

BAL neutrophils (%)

100

BAL IL-6 ( pg/ml)

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

Serum IL- 6 ( pg/ mL)

BAL TNF- ( pg/ml)

150

1500 p=NS 1000

100

p=NS

50

p=0.021

500

p=0.001

CONTROL

CGCT

AGCT

NGCT

CONTROL

CGCT

AGCT

NGCT

Montn et al. Crit Care Med 1999; Agust et al.Chest 2003.

44

No Methylprednisolone
No methylprednisolone

Methylprednisolone 150 g

Methylprednisolone 250 g

Meduri et al. Clin Diag Lab Inmunol 2001; 1156-1163

RESULTS: BAL AND LUNG BACTERIAL BURDEN

p=0.03

AJRCCM 2005; 171: 242-248

45

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

237+92 2.6+1.3 1.0+0.9 34 (0-225) 65% 18 (3-45) 38%

332+80 1.1+0.7 0.3+0.5 18 (0-44) 26% 13 (10-53) 0%

P significant for all comparisons

Confalonieri et al. AJRCCM 2005 171: 242-248

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

46

RESOLUTION OF INFECTIOUS PARAMETERS AFTER ADEQUATE ANTIMICROBIAL THERAPY IN VAP

Significant improvements for all parameters* were observed within 6 days Newly acquired colonization occurred in the second week
Dennesen et al Am J Respir Crit Care Med 2001
PaO2/FIO2

* Leucocytes, oxigenation,fever,bacterial growth

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