Community Acquired Pneumonia, Prof Antoni Torres Marti

Community Acquired Pneumonia, Prof Antoni Torres Marti

Community Acquired Pneumonia:
Current & Future Best Practice
Prof. Antoni Torres
University of Barcelona. Spain
Sir William Osler
One of the most frequent
and severe acute illness is
pneumonia:
“THE CAPTAIN OF THE
MEN OF DEATH”
Alexander Fleming MD
• “The greatest danger...
• that people will consume
antibiotics too often…
• at too low of doses…so that
instead of eradicating the
microbes, a host of antibioticfast organisms will be bred
out; and we will no longer be
able to treat pneumonia with
penicillin.”*
• *A. Fleming, New York Times,
1945 in The Antibiotic
Paradox by S. Levy
Respiratory Infections are the most frequent
cause of death caused by infectious diseases
4.0
3.5
Millions of deaths
3.0
Over age five
Under age five
2.5
2.0
1.5
1.0
* HIV-positive
people who have
died with TB
have been
included among
AIDS deaths
0.5
0
Acute
AIDS* Diarrhoeal TB
Malaria Measles
respiratory
diseases
infections
Estimates for adults 2002; under 5’s 2000-2003;
World Health Report 2004/5
Mortality of pneumonia/100.000
patients
200
180
Morts/100,000
160
140
120
100
Antibiótics
80
60
40
20
0
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2020
YEAR
Any
Adapted from Gilbert K, Fine MJ: Sem Respir Inf 1994; 9:140-52
Normativas SEPAR
Normativas para el diagnóstico y el tratamiento de la
neumonía
Adquirida en la comunidad of Infectious
Grupo de Estudio de a NAC
Área TIR de la SEPAR
Arch Bronconeumol 2005; 41 (5): 272-289
Pneumologie. 2010 Mar;64(3):149-54.
Guidelines of the Paul-Ehrlich-Society of Chemotherapy, the
German Respiratory Diseases Society, the German Infectious
Diseases Society and of the Competence Network CAPNETZ
for the Management of Lower Respiratory Tract Infections and
Community-acquired Pneumonia.
Paul-Ehrlich-Society of Chemotherapy.
General Aspects
• Implementation:
– Emergency Departments
– Internal Medicine
– Primary Care
– Specialists
• Exclusion of “Health-care associated
pneumonia” patients
• Stratification of microorganisms by severity
Adherence, severity and specialty
95
% Adherence
90
85
80
75
70
65
60
55
I
II
III
IV
V
Fine
Pulmonol
Other specilist
Menéndez et al. AJRCCM 2005
Pulmonol Resident
Other resident
Controversial or not covered issues
in CAP guidelines
• Health-Care associated Pneumonia
• Elderly
• Mixed pneumonias
HCAP: original definition
ATS / IDSA guidelines for HA, VAP and HCAP, Am J Respir Crit Care Med 2005
Health–Care–Associated Pneumonia: It is a different CAP?
Author
Micek1
Kollef2
El-Sohl3
El-Sohl4
Carratalà5
Polverino6
Martinez
Moragón7
Lim8
Journal
Antim Ag
Chemother
2007
Chest
2005
Am J Resp
Crit Care
Med 2002
Am J Resp
Crit Care
Med 2001
Arch Int Med
2007
Thorax
2010
Arch Bronc
2004
ERJ
2001
Design
Retrosp.
Cultivos +
Retrosp.
Cultivos +
Prosp.
“Severe” NH
Prosp.
>75aa NH
Prosp.
HCAP
Prosp.
NH
Prosp.
NH
Prosp.
NH
Number
431
988
52
47
126 (NH:32)
155
25 (Et:6)
40 (Et:15)
MSSA
14%
21%
0%
23%
5%
7%
50%
0%
MRSA
31%
27%
33%
6%
2%
5%
0%
Enterobact.
20%
16%
24%
16%
5%
10%
17%
P. aeruginosa
26%
25%
14%
4%
3%
3%
3%
8%
Atypical
1.
2.
3.
4.
2%
S. pneumoniae
10%
6%
9%
54%
57%
H. influenzae
4%
6%
2%
23%
3%
Micek S, et al. Antimicrob Agents Chemother. 2007;51:3568-3573.
Kollef M, et al. Chest. 2005;128:3854-3862.
El-Solh A, et al. Am J Respir Crit Care Med. 2002;166:1038-1043.
El-Solh A, et al. Am J Respir Crit Care Med. 2001;163:645-651.
27%
33%
80%
0%
5. Caratalà J, et al. Arch Intern Med. 2007;167:1393-1399.
6. Polverino E, et al. Thorax. 2010. In press.
7. Martinez-Moragón E, et al. Arch Bronconeumol. 2004;40:547-552.
8. Lim WS, Macfarlane JT. Eur Respir J. 2001;18:362-368.
13
This is a patient with HCAP!
HCAP: what you get is what you put in
NHome
Previous
hospitalization
Antibiotics
Immunosuppression
Dialysis
MDR
Infusions
Incidence of hospitalized CAP patients in Germany
Ewig Thorax 2010
This is a very elderly patient
Community Acquired Pneumonia in the Elderly
Age
<65 years
>65 years
N patients
N pathogens detected
n = 1298
n = 271
n = 1349
n = 268
p-value
Streptococcus pneumonia
42,10%
43,30%
0.85
Gram negative bacilli
3,70%
7,10%
0.17
Staphyloccocus aureus
1,50%
2,20%
0.74
Hemophilus influenzae
4,80%
3,40%
0.53
Chlamydia pneumoniae
1,10%
0%
0.26
Mycoplasma pneumoniae
14,00%
0,70%
0.0005
Legionella spp.
16,60%
17,50%
0.87
Respiratory syncytial virus
1,80%
3,70%
0.29
Influenza Virus A
5,90%
14,90%
0.001
Kothe H. ERJ 2008;
Etiology in the very elderly
Fernández-Sabé et al. Medicine 2003
Mortality of CAP is increased in elderly and nursing-home
patients
Ewig Thorax 2009
Etiology (%) of Community-Acquired Pneumonia
by Site of Care (1474/3523 patients)
S.pneumo
Outpatiens
162/514
Atypical Legionella
Virus
Mixed
35
30
6
9
9
Ward
1050/2521
43
8
8
11
13
ICU
262/488
42
6
8
3
22
Mixed: Bacteria+ virus: 29% out of 208 mixed; atypical + virus: 6%
Cillóniz C et al. Thorax.In press
Outside Patients
• IDSA/ATS 2007
– No risk of DRSP: macrolide (level I) or doxicyclin (level III)
– Risk for DRSP or regions with >25% of high level resistance of
macrolide resistance S.pneumoniae :
• Moxi or levo monotherapy (level I)
• -Beta-lactam (high dose amoxicillin, amoxicillin-clavulanate ,
ceftriaxone, cefpodoxime, cefuroxime)+macrolide (level II)
•
BTS 2009
– Amoxicillin 500 mg three times daily (A+)
– Doxicyclin or clarithromycin (A-)
Erythromycin/penicillin-nonsusceptible
invasive S. pneumoniae in 2007  Europe
% Penicillin Resistance
13%
10%
2% 3%
10%
35%
30%
25%
20% 10%
11%
15%
10%
3%
2%
5%
0%
13%
2%
2%
Au
s
% Resistant Penicillin & Erythromycin
40%
35%
30%
25%
20%
15%
10%
5%
0%
EARSS Annual Report.
13%
3%
6%
11%
4%
5%
6%
9%
7%
12%
t
Bu ria
lg
a
Sl ria
ov
en
ia
Tu
rk
Ro ey
m
an
ia
Po
la
nd
Cr
oa
ti
Li
th a
ua
n
Hu ia
ng
ar
Cy y
pr
us
Is
ra
el
15% 16%
A
us
tr
i
B
ul a
ga
Sl ria
ov
en
ia
Tu
rk
e
R
om y
an
i
Po a
la
n
C d
ro
at
Li
t h ia
ua
ni
H
un a
ga
r
C y
yp
ru
s
Is
ra
el
25%
20%
15%
10%
5%
0%
% Erythromycin Resistance
20%
14% 16%
1%
3%
3%
8%
5%
Hospitalized Patients
• 1- IDSA/ATS:
-Levofloxacin, moxifloxacin or
gemifloxacin in monotherapy (I)
-Cefotaxime, ceftriaxone, ertapenem
(in selected patients) + macrolide (I)
• 2-BTS:-Oral amoxicillin+macrolide (D)
– IV amoxicillin or benzyl penicillin +
clarithromycin (D)
– Alternatives: doxyciclin, levofloxacin,
moxifloxacin
Unknown Etiology:
Is S. pneumoniae Hidden?
Conventional Testing
Undetermined: 55/109: 50.5%
Conventional Testing
+ Transthoracic Needle Aspiration
Undetermined: 19/109: 17.4%
Pathogen
N (%)
Pathogen
N (%)
M. pneumoniae
C. pneumoniae
S. pneumoniae
Influenza A virus
C. psittaci
Mycobacterium tuberculosis
Pneumocystis carinii
C. burnetii
19 (35)
9 (17)
9 (17)
5 (9)
4 (7)
3 (6)
3 (6)
2 (4)
S. pneumoniae
M. pneumoniae
C. pneumoniae
P. carinii
H. influenzae
Influenza A virus
M. tuberculosis
C. psittaci
C. burnetii
Enterococcus coli,
Streptococcus viridans,
Escherichia faecium,
Cryptococcus neoformans
27 (30)
20 (22)
12 (13)
7 (8)
6 (7)
5 (6)
4 (4)
4 (4)
2 (2)
1 (1)
Ruiz-Gonzáles A, et al. Am J Med. 1999;106:385-390.
Streptococcus pneumoniae
Overall results worldwide (n=7465)
100
90
80
% (CLSI)
70
60
50
98,6
98,8
93,6
40
78,4
70
30
68
68,1
68
66,3
73,1
20
10
0
LE
V
M
O
X
PE
N
Susceptible
AM
C
CX
M
ER
Y
Intermediate
CL
AR
AZ
I
SX
T
TE
T
I
Resistant
LEV levofloxacin, MOX moxifloxacin, PEN penicillin, AMC amoxi + clav, CXM
cefuroxime, ERY erythromycin, CLARI clarithromycin, AZI azithromycin, SXT
cotrimoxazole, TET tetracycline
Streptococcus pneumoniae: activity of antibiotics on
Multidrug-resistant strains worldwide (n=2359)
100
90
80
% (CLSI)
70
60
50
96,5
96,6
79,7
40
30
20
34,9
23,3
10
13,4
13,5
13,5
24,3
22,7
0
LE
V
M
O
X
PE
N
Susceptible
AM
C
CX
M
ER
Y
Intermediate
CL
AR
AZ
I
SX
T
TE
T
I
Resistant
LEV levofloxacin, MOX moxifloxacin, PEN penicillin, AMC amoxi + clav, CXM cefuroxime,
ERY erythromycin, CLARI clarithromycin, AZI azithromycin, SXT cotrimoxazole, TET
tetracycline
Mortality from CAP through PA
“Definite” and “indeterminate”
resp. sample
availabe, no EB/PA
(n = 1840)
definite EB
indeterminate EB
(n = 22)
(n = 27) *
age (mean, yrs)
58 ± 18
64 ± 17
68 ± 11
nursing home
resident (%)
2
23
7
chronic resp.
disease
37
68
52
enteral tube
feeding
0.6
23
11
mortality
4
18
4
* 55% of all EB isolates were indeterminate
Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.
Enterobacteriaceae - Europe
Proportion of K. pneumoniae
resistant to 3GC
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© European Communities, 1995 - 2007
Reprinted from EARSS Annual Report 2005.
Proportion of E. coli
resistant to 3GC
Ertapenem efficacy in the treatment of CommunityAcquired Pneumonia in the elderly
 Results
Cure rates in clinically evaluable CAP patients
Cure rates in each group
Evaluation
Age
Ertapenem
n/N (%)
Ceftriaxone
n/N (%)
(confidence interval 95%)*
P value for
Treatment
Evidence of
cure
≤ 65
139/148 (93,9)
113/125 (90,4)
1.56 (0,63-3,87)
0,34
≥ 75
63/67 (94,0)
56/64 (87,3)
1.83 (0,65-8,20)
0,18
1.83 (0,63-5,36)
0,26
1.83 (0,58-17,27)
0,16
End of IV
≤ 65 115/147 (95,9)
115/124 (92,7)
*Odds ratio comparing Ertapenem with Ceftriaxone
Treatment
† P values based on a linear regression model with treatment and study factors
≥ 75
65/67 (97,0)
58/63 (92,1)
n clinically cured patients
Odds Ratio
 Conclusion
 Ertapenem was at least as efficient as ceftriaxone in the treatment of CAP for patients
aged 65 or older who required IV treatment.
Woods GL et al. Ertapenem Therapy for Community-Acquired Pneumonia in the Elderly. JAGS. 2003, 51 (11): 1256-1532
Proportion of patients who died
Total and CAP-related In-hospital Mortality for Patients
With and Without Coverage for Atypical Pathogens
20%
18%
16%
P < 0.01
14%
12%
10%
8%
6%
P = 0.05
4%
2%
0%
217/2,220
110/658
Total Mortality
101/2,220
41/658
CAP-related Mortality
Patients with atypical coverage (n = 2,220)
Patients without atypical coverage (n = 658)
Arnold FW, et al. AJRCCM. 2007; 1086-93
Early admission to ICU improves
survival in severe CAP
Patients admitted into ICU (%)
ICU mortality (%)
75
75
59
0
<2
***
58
59
21.5
19.5
2–7
>7
21.5
0
<2
2–7
>7
Days in hospital prior to ICU admission
***p<0.001
• Patients who require ICU admission are often initially admitted into
a non-ICU setting
Woodhead et al, Crit Care 2006; 10(S2): S1–S9
Mandell et al, Clin Infect Dis 2007; 44(S2): S27–S72
Mortality According to Etiology in Severe
CAP
250
Mortality
n of pathogens
70
60
50
150
40
100
30
Mortality (%)
Pathogens (n)
200
80
20
50
10
0
0
Etiology
Adapted from Cilloniz et al. Complicated pneumococcal pneumonia in adults. Presented at: The American Thoracic Society
Annual Meeting. San Diego, CA; May 15-20, 2009. Abstract A1711. Thorax in press
37
ICU admitted patients IDSA/ATS
BTS UPDATE Thorax 2009
-Broad spectrum B-lactamase (amoxi-clav)+ macrolide
(clarithromycin) (C)
-If allergy to penicillin: cefuroxime, cefotaxime,ceftriaxone+
clarithromycin (C)
Cox regression analysis
• Macrolide use was
associated with lower ICU
mortality (HR 0.48 95%CI
0.23-0.97, p = 0.04) when
compared to the use of
fluoroquinolones.
1,0
macrolides
,8
,6
,4
quinolones
,2
0,0
0
20
40
60
Días UCI
• Patients with severe sepsis
or septic shock (n=92):
Similar results (HR 0.44
95%CI 0.20-0.95, p =
0.03)
1,0
macrolides
,8
,6
quinolones
,4
,2
0,0
0
20
40
60
Días UCI
I. Martin-Loeches et al, Intensive Care Med 2010
Other recommendations for
treatment
• First dosage while in the ED (III).
• Oral : Clinical stability + oral tolerance (II).
• Discharge when stability is reached (II).
• Minimum of 5 days of treatment if: no fever
48-72 h and no more that one criteria of
instability (II).
• Prolonged treatment: initial inadequacy or
extrapulmonary complications (III).
Bacteremic pneumococcal CAP
125 episodes
1,0
0,9
Adecuate antibitic
dose
Survival
0,8
Before 4 hours
After 4 hours
0,7
0,6
0,5
0,4
0,3
0
10
20
30
40
50
60
days
• The use of combination therapy was not included in these
models but was a protective factor for delayed adequate therapy
[aHR 0.53 (95% CI 0.29-0.95); p=0.033]
Garnacho-Montero J. Scand J Infect Dis 2010
The new concept
Community-acquired pneumonia
CAP in younger patients
(18-64 years)
CAP in elderly
CAP in elderly
(>= 65 years)
(>= 65 years)
with moderate to good functional status with severe disabled functional status
(ADL <14)
(ADL >=14)
Ewig , Welte, Chastre and Torres. Lancet Infect Dis 2010;10:279
More virulent IPD is being observed in adults caused
by serotypes not covered by PCV-7: serotype 3 and shock (Garcia –
vidal. Thorax 2010, serotype 19ª and pulmonary complications
Stratification of microbial etiology
Likely
microorganism
Severity
Treatment
Group 1
S. pneumoniae
M.pneumoniae
Mild-moderate
Out-site care
Group 2
S. Pneumoniae
H.Influenzae
Atypical
GNB
Severe
Hospital
Group 3
S. pneumoniae
Legionella spp
P. aeruginosa
GNB
Very severe
ICU
Normativas NAC SEPAR. Arch Bronconeumol 2005, 41(5): 272-89
Macrolides and pneumolysin
production
• Pneumolysin is one of the most important
virulence factors of S. pneumoniae.
– It augments intrapulmonary growth and dissemination
during the early pathogenesis of S. pneumoniae.
– It disrupts epithelial tissues that form a mechanical
barrier, and allow S. pneumoniae to penetrate into the
blood stream.
• Macrolides attenuate the production of
pneumolysin by both macrolide-susceptible and
macrolide-resistant strains of Streptococcus
pneumoniae
Eur Respir J. 2006;27:1020-5
J Antimicrob Chemother. 2007; 59:224-9
No differences in mortality comparing PVL to non-PVL
Vardakas Int J Tuberc Lung Dis 2009
Conclusions
• There are some aspects not well covered by
guidelines: HCAP, elderly, mixed CAP
• Guidelines differ between them in
antibiotic recommendations. Outcome
studies are needed
Delay of antimicrobial therapy and
mortality
Arch Intern Med 2004; 164: 637-644