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ERS Annual Congress Vienna

1–5 September 2012

Postgraduate Course 17 Clinical failure of treatment of respiratory infections

Saturday, 1 September 2012

14:00–17:30

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 Clínic 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 community- acquired 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 cost- assistance 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. Menéndez R, Torres A, Rodríguez de Castro F, et al. Reaching stability in community- acquired 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. Menéndez R, Torres A, Zalacaín 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. Rosón B, Carratalà J, Fernández-Sabé 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 fluoroquinolone- resistant 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. Pérez-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. Menéndez R, Torres A, Zalacaín 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):451-

7.

20. Fernández-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 factor- kappaB 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. Montón 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. Montón 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. Agustí C, Rañó 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 community- acquired 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, Ramírez P, Montull B, Menéndez 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

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

NAME OF SPEAKER

ANTONI TORRES

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, Astra- Zeneca, GSK

FACULTY DISCLOSURE

Advisory Boards and sponsored symposia: Bayer, Pfizer, Astra- Zeneca, GSK

FACULTY DISCLOSURE • Advisory Boards and sponsored symposia: Bayer, Pfizer, Astra- Zeneca, GSK
TREATMENT FAILURE OF COMMUNITY- ACQUIRED-PNEUMONIA: RISK FACTORS AND CONSEQUENCES ERS CONGRESS VIENNA 2012
TREATMENT FAILURE OF COMMUNITY-
ACQUIRED-PNEUMONIA: RISK FACTORS AND
CONSEQUENCES
ERS CONGRESS VIENNA 2012

30

INTRODUCTION AIMS • Aim 1 : To describe incidence ,risk factors and causes of treatment

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

characteristics of treatment failure in CAP • Aim 3: To describe outcomes of patients with treatment
CONTENTS • 1-Definitions and epidemiology • 2-Pneumofail and other studies • 3-Inflammatory response and

CONTENTS

1-Definitions and epidemiology

2-Pneumofail and other studies

3-Inflammatory response and Treatment failure

• 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

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 >38º and or clinical symptoms after at least 72 h of treatment

Arancibia et al Am J Respir Crit Care Med 2000

>38º and or clinical symptoms after at least 72 h of treatment – Arancibia et al

31

DEFINITIONS: CAP (II) • Non-responding: This term is used to define a situation in wich

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)

pneumonia: absence or delay in achieving clinical stability IDSA/ATS guidelines for CAP in adults. CID 2007:

INCIDENCE• 1-CAP – non- responding and progressive pneumonia : 10 % and 6 % of

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)

(Alvarez-Lerma) – 67% in VAP caused by P.aeruginosa (Brewer) – 61% in a follow-up study (Ioanas.Crit

INCIDENCE OF NON-RESPONSE IN CAP

INCIDENCE OF NON-RESPONSE IN CAP

32

CLASSIFICATION OF CAUSES OF NON-RESPONSE IN CAP • 1-Complications: Empyema,abscess. • 2-Inadequate antibiotic

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

Mycobacterias, fungi. • 4-Nosocomial infections • 5-Failure • 6-Non-infectious causes of pulmonary infiltrates

PEUMONIA: MORTALITYRespuesta tratamiento Kaplan AJRCCM 2003.

Respuesta tratamiento
Respuesta tratamiento

Kaplan AJRCCM 2003.

PEUMONIA: MORTALITY Respuesta tratamiento Kaplan AJRCCM 2003.
MORTALITY IN NON-RESPONDING PNEUMONIA • Mortality is clearly increased in both CAP and HAP non-responding

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

Crit Care Med 2004 – Consequently this is a target population to evaluate risk factors and

33

MORTALITY IN NON-RESPONDING CAP PATIENTS

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

< 100 bx min

HR

< 24 x min

RR

SBP

> 90 mm Hg

Halm et al. JAMA 1998

> 90 % or PaO2 > 60

O2S

mm

Hg room air

 

Ability to maintain oral

intake

Normal mental status

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 Área TIR-SEPAR
Clin Infect Dis 2004
Área TIR-SEPAR

RESULTS. MULTIVARIATE DAYS 1 AND DAY 3

 

HR day 1

HR day 1 + evolutive variab.

Dispnea

0.76 (0.7-0.8)

0.79

Confusión

0.6

0.61

Pleural effusion

0.6

---

PSI

0.73

0.73

Multilobar

0.7

0.84

Adherent Treat

1.2

 

RESULTS. MULTIVARIATE DAYS 1 AND 3

 

HR day 1 and evolutives

P

Treatment

0.31 (0.7-0.8)

<0.001

failure

Cardiac comp

0.66

0.001

Respirat comp

0.77

0.03

Empiema

0.57

0.01

ICU admission

0.57

0.003

35

Área TIR-SEPAR

Área TIR-SEPAR

Área 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

Early RR

Late RR

Influen Vacc.

0,3

0,2

 

COPD

0,6

   

Quinolones

0,5

   

Cavitation

4,1

5,1

 

Hepatic Dis

2

 

2,4

Multilobar

2,1

2,2

1,7

Pleural eff

2,7

 

2,6

PSI

1,3

1,2

1,4

Leucopenia

3,7

5,8

 

36

NEUMOFAIL: NON-RESPONDING CAP AND PSI SCORE

%
%

RISK FACTORS FOR EARLY FAILURE

 

OR (95% CI)

<65 yrs

0.35

(0.2-0.6)

Fine IV-V

2.75

(1.6-4.8)

Multilobar

1.8

(1.1-2.8)

Legionella

2.7

(1.4-5.3)

Gram-

4.3(1.1-18)

Discordant Atb Treatment

2.5(1.6-3.94)

Rosón 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
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; associat ed with penicillin-resistance - Two main

MACROLIDE-RESISTANT PNEUMOCOCCI SUMMARY

- Increasing worldwide; associated with penicillin-resistance

- Two main mechanisms of R Efflux pump (mef)- M phenotype Ribosomal methylase (erm)-MLS B 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.

while on therapy The prevalence of R will dictate the need to reassess current recommendations for

38

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

REFERENCE

N

EPISODE

INITIAL ISOLATE

ANTIBIOTIC

FINAL ISOLATE

MUTATION(S)

LEVO MIC(µg/ml)

TREATMENT

LEVO MIC(µg/ml)

(mg/day)

 

Davidson et al. NEJM 2002

1

Pneumonia

1

LEVO (500)

8

parC(S79F)

gyrA(S81F)

 

2

Pneumonia

4

LEVO (500)

16

parC(S79F)

gyrA(S81F)

De la Campa A et al.

3

Bronchiectasis

1

CIPRO (1000)

16

parC(S79F)

AAC 2003

For months,

gyrA(S81F)

intermittently

Anderson KB et al.

4

Pneumonia

1

LEVO (500)

16

parC(S79Y)

CID 2003

gyrA(S81F)

5

Pneumonia

1

LEVO (500)

8

parC(D83Y)

gyrA(S81Y)

6

Pneumonia

1

LEVO (500)

16

parC(S79F)

gyrA(S81F)

7

Pneumonia

1

LEVO (500)

16

parC(S79F)

gyrA(S81F)

Perez-trallero E et

8

Pneumonia

2

LEVO (500)

16

parC(S79F)

al. EID 2003

CIPRO (400 IV)

gyrA(S81F)

a l . EID 2003 CIPRO (400 IV) gyrA(S81F) 30-DAY CRUDE MORTALITY, HOSPITALIZED PATIENTS BEFORE/AFTER
a l . EID 2003 CIPRO (400 IV) gyrA(S81F) 30-DAY CRUDE MORTALITY, HOSPITALIZED PATIENTS BEFORE/AFTER
a l . EID 2003 CIPRO (400 IV) gyrA(S81F) 30-DAY CRUDE MORTALITY, HOSPITALIZED PATIENTS BEFORE/AFTER

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

Dean Am J Med.

Dean Am J Med.

2001;110:451

2001;110:451

39

ADHERENCE, SEVERITY AND SPECIALITY

ADHERENCE, SEVERITY AND SPECIALITY
NO ADHERENCE AND PROGNOSIS

NO ADHERENCE AND PROGNOSIS

NO ADHERENCE AND PROGNOSIS

PROGNOSTIC FACTORS. MULTIVARIATE ANALYSIS

 

Failure

Adherence

Independent variables

OD (95%IC)

OD (95%IC)

Adherence

0.65(0.5-0.9)

0.55(0.3-0.9)

Pulmonol + residents vs other

0.6(0.4-0.9)

 

PSI IV-V vs I-III

 

10.8(5-21)

40

EVOLUTION AND OUTCOME OF NON- RESPONDING AND RESPONDING CAP   NR* R • Clinical stability

EVOLUTION AND OUTCOME OF NON-

RESPONDING AND

RESPONDING CAP

 

NR*

R

Clinical stability (dys)

11+8

4+3

Complications (%)

69

23

ICU admission (%)

26

4

Length of Stay (dys)

18+14

9+6

Death (%)

25

2

* p<001 for all comparisons

(%) 26 4 • Length of Stay (dys) 18+14 9+6 • Death (%) 25 2 *
PATIENTS WITH SEVERE CAP MAY DIE DESPITE EARLY AND APROPIATE ANTIBIOTIC THERAPY
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 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

and nonspecific immune cells at the site of infection and activate them to eradicate bacteria and
SYSTEMIC INFLAMMATION AND PROGNOSIS IN CAP Non-survivors had a persistent increase of blood IL6 and

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: 813–820

had a persistent increase of blood IL6 and IL10 levels Fernandez-Serrano S, et al. Clin Diag

FILGRASTIM (GCSF) IN SEVERE PNEUMONIA
%

Root R et al. Crit Care Med 2003

42

FACTORS INFLUENCING THE INFLAMMATORY RESPONSE • 1-Host Factors • 4-Corticosteroids – Pulmonary –
FACTORS INFLUENCING THE
INFLAMMATORY RESPONSE
• 1-Host Factors
• 4-Corticosteroids
– Pulmonary
– Extrapulmonary
• 5-Genetics :TNF
polymorphisms
• 2-Type of
microorganisms and
• 6-Mechanical
bacterial burden
ventilation
MANY FACTORS
• 3-Antibiotics used
HAVE TO BE TAKEN
INTO ACCOUNT!

B-lactam

PBPPBP 11 22 33 4,4, 55
PBPPBP
11 22
33
4,4, 55

lisislisis

sferoplastssferoplasts

philamentsphilaments

++++ ++ ++++++ EndotoxinEndotoxin ReleaseRelease
++++
++
++++++
EndotoxinEndotoxin ReleaseRelease
Macrolides: Mechanism of Action Mechanisms of Anti-inflammatory Activity Cytokine Production by Host Cells IL-8 gene
Macrolides: Mechanism of Action
Mechanisms of Anti-inflammatory Activity
Cytokine Production by Host Cells
IL-8 gene
Transcription
IL-8 gene
↓ NF-кB
↓ mRNA
Translation
TNF-α
↓ IL-8
Macrolides modulate inflammation by inhibiting NF-кB activation
1
2 3
Antibacterial
Inhibition of
Inhibition of
effect
transcription
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

GENETIC INFLUENCE ON CAP SEVERITY % Septic Shock P=0.01 AA vs no AA Waterer et al.

%

Septic

Shock

P=0.01 AA vs no AA
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

Cytokines in Severe Pneumonia: Corticosteroids SERUM No GC GC p-value   (n = 9) (n =

SERUM

No GC

GC

p-value

 

(n = 9)

(n = 11)

TNF-

43 ± 7 4 ± 2 1089 ± 342 34 ± 5

28 ± 4 1 ± 0.4 630 ± 385 19 ± 5

0.15

IL-1ß

0.50

IL-6

0.03*

CRP

0.03*

BAL

TNF-

118 ± 50 91 ± 35 1569 ± 965

24 ± 5 57 ± 17 889 ± 432 57 ± 16

0.05*

IL-1ß

0.31

IL-6

0.49

Neutrophil, % 93 ± 3

0.03*

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

Steroids in Severe Pneumonia 3000 125 p=0.003 100 p=NS 75 p<0.0001 50 25 Mortality: 93%

Steroids in Severe Pneumonia

3000

125 p=0.003 100 p=NS 75 p<0.0001 50 25 Mortality: 93% 27% 60% 200 p=0.013 150
125
p=0.003
100
p=NS
75
p<0.0001
50
25
Mortality: 93%
27%
60%
200
p=0.013
150
100
p=NS
p=0.021
50
CONTROL
CGCT
AGCT
NGCT
BAL TNF-  ( pg/ml)
BAL neutrophils (%)
BAL IL-6
( pg/ml)
Serum IL- 6 ( pg/ mL)

2000

1000

(%) BAL IL-6 ( pg/ml) Serum IL- 6 ( pg/ mL) 2000 1000 2000 1500 1000

2000

1500

1000

500

p=0.005

p=0.013 p<0.0001 p<0.0001 p=NS p=0.001 CONTROL CGCT AGCT NGCT
p=0.013
p<0.0001
p<0.0001
p=NS
p=0.001
CONTROL
CGCT
AGCT
NGCT

Montón et al. Crit Care Med 1999; Agustí et al.Chest 2003.

44

No Methylprednisolone

Methylprednisolone 150  g No methylprednisolone Methylprednisolone 250  g

Methylprednisolone 150 g

No methylprednisolone

Methylprednisolone 250 g

 g No methylprednisolone Methylprednisolone 250  g Meduri et al. Clin Diag Lab Inmunol 2001;

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

RESULTS: BAL AND LUNG BACTERIAL BURDEN

p=0.03
p=0.03
AJRCCM 2005; 171: 242-248
AJRCCM 2005; 171: 242-248

AJRCCM 2005; 171: 242-248

45

MAIN OUTCOME PARAMETERS AT& AND 60 DAYS Placebo Hydrocort PaO2/FIO2 237+92 332+80 Chest-X ray score
MAIN OUTCOME PARAMETERS AT& AND 60 DAYS
Placebo
Hydrocort
PaO2/FIO2
237+92
332+80
Chest-X ray score
MOF score
CRP mg/dl
Patients on MV
Length of stay (days)
2.6+1.3
1.1+0.7
1.0+0.9
0.3+0.5
34
(0-225)
18 (0-44)
65%
26%
18
(3-45)
13 (10-53)
60 day mortality
38%
0%
P significant for all
comparisons
Confalonieri et al. AJRCCM 2005 171: 242-248
Corticosteroids in CAP
Corticosteroids in CAP
Corticosteroids in CAP
Conclusions • 1-Treatment failure in CAP a ccounts for 10-15% of hospitalized cases and it

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

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
PaO2/FIO2

* Leucocytes, oxigenation,fever,bacterial growth

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