Transcript S pneumoniae

Traitements des
infections broncho pulmonaires
ou en sommes nous en 2006 ?
JR Zahar
CHU Necker Enfants – Malades
Service de Microbiologie - Hygiène
Unité de microbiogie clinique et de conseil antibiotique
4 ème Journée Franco-Libanaise de Pneumologie
Hôtel Bristol Beyrouth - LIBAN
Vendredi 7 avril 2006
Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens

Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens

CAP Epidemiology
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In United States:
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In United Kingdom
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annual incidence : 5.6 million cases
20% required hospitalization
50 000 annually admission
Mortality : 2 to 21%
>50% in patients with severe disease
Epidemiology
Pathogens
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Virus
Clinical situations
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COPD
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Bacteria
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S pneumoniae
H influenzae
M catarrhalis
L pneumophila
M pneumoniae
C pneumoniae
Enterobacteria
S aureus
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Virus
S pneumoniae
H influenzae
M catarrhalis
Community acquired pneumonia
 Outpatients
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S pneumoniae
M pneumoniae
Inpatients
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Not critical ill
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S pneumoniae
M pneumoniae
Critical ill
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S pneumoniae
L pneumophila
S aureus
Special situations
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Immunosuppression
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Diabetes mellitus, Corticotherapy, Chemotherapy, solid organ
transplantation, ABMT,…. Others
HIV
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Comorbidities ?
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Community acquired (?) « but »in nursing home
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Prospective study including 95 patients (2000 – 2003)
Living in « nursing home »
67 isolated pathogens
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49% Enterobacteria (E coli and K pneumoniae)
16% anaerobic
12% Staphylococcus aureus
El Solh, AJRCCM 2003
Epidemiology: CAP
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Microbiologically documented : 30 – 84%
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Streptococcus pneumoniae
Mycoplasma pneumoniae
Haemophilus influenzae
Legionella pneumophila
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In hospital
Severe community acquired
30 – 60%
7 – 10%
5 – 22 %
7%
15%
10%
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Chlamydia pneumoniae
5 – 10%
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Viral etiology
10 – 23% (hospital)
22 – 30% (outpatient)
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Prospective study, including 493 patients with CAP
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223 > 65 years old
265 > one comorbidity
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COPD (20.1%), Diabetes (19.9%), dementia (10.5%), Immunosuppresion
(5.3%), Neoplasia (4.3%), Congestive heart failure (4.1%), Chronic renal
failure (3.4%)
Previous antibiotic therapy : 114 patients (23.1%)
Microbiological investigations :
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Sputum samples
2 blood samples
Urine sample (S pneumoniae, L pneumophila urinary antigen)
Serological testing
CMI 2005, 11 : 788
Gutierrez, CMI 2005, 11 : 788
Gutierrez, CMI 2005, 11 : 788
Gutierrez, CMI 2005, 11 : 788
Gutierrez, CMI 2005, 11 : 788
Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens

Spread of resistance
Pathogen
Antibiotics
Major resistance mecanism
S pneumoniae
b- lactams
Mosaicism in DNA-encoding PBP
Macrolides
Methylation of ribosomal RNA targets
(erm)
Efflux by mef-A gene products
Fluoroquinolones
Mutations in genes encoding for DNA
topoisomérase IV, and DNA gyrase
Hyperexpression of multidrug efflux
H influenzae
b- lactams
b- lactamase production
Altered PBPs, or diminished permeability
M catharralis
b- lactams
b- lactamase production
Mc Geer A, Nat Med 2003; 9:390
Spread of resistance (France)
Pathogen
% Resistance
H influenzae
b- lactamin : 41,3%
macrolides : 98,2%
M catarrhalis
amino pénicillins: 98%
S pneumoniae
PSDP = 48%
cephalosporin = 13,7%
Macrolides = 50%
mécanismes
26% b- lactamase production
Efflux
b- lactamase production
(I+R %) co-résistance aux autres antibiotiques
selon le niveau de sensibilité à la pénicilline G
90
82,2
80
73
70
60
50
PSDP
PRP
PS
53
48,5
41,7
40
30,1
30
39,8
31,8
24,6
18,3
20
17
10,8
10
0
ERY
G. Laurans et al. BEH; Août
2001.
TET
SXT
C
What about Lebanon
?
What about Lebanon
?
Can we predict antimicrobial resistance in
invasive pneumococcal infection ?
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Prospective cohort study of invasive pneumococcal
infection
3339 patients (1995-2002)
Risk factors for infection with antibiotic resistant in multivariate
analysis :
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Erytrhomycin
TMP-SMX
Ceftriaxone
Penicillin
Vanderkooi, CID 2005, 40 : 1288
Vanderkooi, CID 2005, 40 : 1288
Decreased susceptibility of S. pneumoniae
to fluoroquinolones in Canada
 15-64 ans
 > 65 ans
(aucune souche R
isolée avant 15 ans)
[Chen et al. N Engl J Med 1999;341]
NEJM 2002, 346: 747
CID 2005, 41 : 118
CID 2001, 32 : 701
Risk factors by multivariate analysis :
COPD (OR, 10.3)
Nosocomial acquired (OR, 16.2)
Resident in nursing home (OR, 7.4)
Prior exposure to FQ (OR, 10.7)
CID 2005, 40 : 1288
Prospective study
3339 patients include with Pneumococcal
pneumonia
Risk factors by multivariate analysis :
Previous use of FQ (OR, 12.1)
Resident in nursing home (OR, 12.9)
Nosocomial infection (OR, 994)
Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens

Pharmacokinetics
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b lactamines :
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activity time dependent
Goal : 40% Time > MIC
macrolides :
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activity time depemdent
Azithromycin and ketolides : ASC/CMI
Goal for telithromycin : ASC/CMI (if > 25 99%
eradication of S pneumoniae and M catarrhalis and 90%H
influenzae
fluoroquinolones
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ASC/CMI
Goal to achieve : 48 - 125
Paramètres
pharmacocinétiques/pharmacodynamiques
Antibiothérapie
S. pneumoniae sensible à
la pénicilline
CMI 90
( 5µg/ml)
Amoxicilline 1g x3
Céfuroxime axétil
500mg x2
S. pneumoniae résistant à la
pénicilline
T> CMI (%)
CMI 50-90
(µg/ml)
T> CMI (%)
0,03
58
1-2
30-25
0,06
42
4-8
11-7
D’après B Fantin
Paramètres
pharmacocinétiques/pharmacodynamiques
Antibiothérapie
S. pneumoniae sensible à la
pénicilline
CMI 90
( 5µg/ml)
Cefpodoxime proxétil
200 mg x2
S. pneumoniae résistant à la
pénicilline
T> CMI (%)
CMI 50-90
(µg/ml)
T> CMI (%)
0,06
59
4-4
6
Cefotiam hexétil
400 mg x2
0,25
19
4-4
5
Cefixime 200 mg x 2
0,25
72
32-32
0
Cefotaxime 1g x3 ivd
0,03
53
1-2
18-15
Ceftriaxone 1 g x 1 im
0,03
100
1-2
84-71
Ceftriaxone 1 gx1 iv
0,03
100
1-2
84-71
D’après B Fantin
Paramètres
pharmacocinétiques/pharmacodynamiques
Molécule
Secrétions
bronchiques
Muqueuse
bronchique
Film
alvéolaire
Parenchyme
pulmonaire
Macrophage
alvéolaire
Ciprofloxacine
x 0,33-0,66
x 1-1,5
x 0-0,64
x 1,5-3,5
x2-10
x 3,5-3,9
x3
Ofloxacine
x 0,5-0,9
x1,7-3,4
Non
disponible
Lévofloxacine
x 1,2
x 0,9-1,8
x2
x 2-5
x 10
Moxifloxacine
x 0,89-1,13
x 1,7-2,1
x 5-7
x 3,5-4,4
x 9-70
D’après B Fantin
Paramètres
pharmacocinétiques/pharmacodynamiques
Molécule
Lévofloxacine
500 mg per
os
500x2 per os
Moxifloxacine
400 per os
CMI90
µg/ml
CPM90
µg/ml
Cmax
µg/ml
ASCO-24h
µg/mlxh
Cmax/
CMI90
Temps
>
CPM
(h)
ASC/CMI90
1
8
5.7
48
96
5.7
0
48
96
0.25
2
4.5
48
18
18
190
D’après B Fantin
Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens

Pneumococcal bacteremia with especial reference to bacteremic
pneumococcal pneumonia.
R Austrian, J Gold, Annals of Internal Medicine, 1964, 60: 759-776.
N Engl J Med 1995; 333: 474
Am J Med 2002, 113 : 120
N Engl J Med 1995; 333: 474
429 episodes of monomicrobial pneumococcal infection
30-day mortality, Cephalosporin S vs Cephalosporin R
•
Intermediate strains (MIC= 1µg/ml): OR= 0.64, 95% CI : 0.27 – 1.5, p=0.3
•
Resistant strains (MIC=2µg/ml) : OR= 0.65, 95% CI: 0.19-2.3, p=0.5
Am J Med 2002, 113 : 120
-Case control study (matched for age, sex, location and year that
bacteremia developped)
-Bacteriemic pneumococcal infection
-Case (76) : Erythromycin intermediate or resistant pneumococcus
-Control (136): Erythromycin susceptible pneumococcus
-Receiving macrolides therapy : 22% (cases) vs 0 (control), p<0.0001
CID 2002, 35: 558
Impact of penicillin susceptibility on mortality
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7 études contrôlées
4 ne montrent pas de différence de mortalité (après
ajustement sur la gravité initiale, l’adéquation de
l’antibiothérapie )
3 montrent une différence de mortalité
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Etude chez les patients VIH
Aucun ajustement sur la gravité initiale
Mortalité augmentait au-delà du 4 ième jour si CMI > 4 à la
pénicilline, ou > 2 au céfotaxime
-Prospective study including, 844 hospitalized patients with Streptococcus
pneumoniae blood cultures
CID 2003, 37 : 230
CID 2003, 37 : 230
Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens

Legionellosis
Données de l’INVS
Données de l’INVS
MIC of active antibiotic on atypical
pathogens
Drug
M
pneumoniae
C
pneumoniae
L
pneumophila
Erythromycin
<0.002 – 0.004
0.06 – 0.25
0.25
Tetracycline
0.25
0.06 – 0.125
Azitrhromycin <0.001 – 0.004
0.06 – 0.25
0.25
Clarythromyci <0.004 – 0;125
n
0.004 – 0.03
0.06
Levofloxacin
0.5
0.5
0.125
Ciprofloxacin
2
1
0.12 – 0.25
Ofloxacin
2
1
0.06 – 0.25
Macrolides or Fluoroquinolones
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Macrolides :
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Antiinflamatory properties
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They reduce the production of IL8
They reduce Tumor necrosis factor a
They reduce adherence of S pneumoniae to repiratory
epithelial cells.
Inhibition of protein synthesis
Bacteriostatic activity
High resistance prevalence
Fluoroquinolones
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Bactericidal activity
Low resistance prevalence
Secondary effect
-Etude prospective observationnelle
130 patients
-76 macrolides (33 Erythromycine, 43 Clarithromycine)
-54 fluoroquinolones (50 levofloxacine, 4 ofloxacine)
Chest 2005, 128 : 1401
Chest 2005, 128 : 1401
-Etude prospective
-139 patients , 120 traitements adéquats
-40 fluoroquinolones (levofloxacine)
-80 macrolides (53 Erythromycine, 27 Clarithromycine)
-48 des patients traités par macrolides ( + rifampicine)
CID 2005, 40: 794
CID 2005, 40: 794
-Etude observationnelle, prospective
-292 patients inclus ,
-143 fluoroquinolones (levofloxacine)
-65 macrolides (35 azithromycine, 30clarithromycine)
-Comparaison de 45 patients levofloxacine vs 45 levo +
rifampicine
CID 2005, 40: 800
CID 2005, 40: 800
CID 2005, 40: 800
Gacouin et al, Int Care Med 2002
From Françis et al, CID 2005, 40
MRSA-CA Pneumonia
Françis et al, CID 2005, 40
MRSA-CA Pneumonia
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Community acquired
Genes encoding PVL
Type IV SCC mec elements
MRSA-CA Pneumonia
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Severe community acquired pneumonia
Necrotizing pneumonia
Shock
Hempotysis (38%)
High fever
Leukopenia
Community acquired (Jails,Soldiers, football team….)
High case fatality (35%)
Clinical and microbiological epidemiology
 Spread of resistance
 Pharmacokinetic/Pharmacodynamic
 Impact of resistance
 Emerging infectious disease
 Should we cover atypical pathogens ?

Do we need specific antibiotic coverage for
atypical pathogens ?
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Meta-analysis including 18 trials
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Randomised double blind monotherapy comparing antibiotics
active against atypical pathogens (flouroquinolones (9 different),
macrolides (2), ketolides (1) ) with any b lactams (penicillin,
cephalosporins)
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Totalling 6749 patients
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Mild to moderate community acquired pneumonia
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Intention to treat and per protocol
Mills, BMJ 2005; 330 : 456
Do we need specific antibiotic coverage for
atypical pathogens ?
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Failure to achieve clinical cure or improvement
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Mortality (all cause)
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Active antibiotics against atypical pathogens # b lactams
RR=0,97, CI 95%, 0.87 – 1.07
No differences
RR= 1.2, CI 95%, 0.84 – 1.71
Subgroup analysis
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Mycoplasma pneumoniae (RR= 0.6, CI 95%, 0,31 – 1.17)
Chlamydia pneumoniae (RR = 2.32, CI 95%, 0.67 – 8.03)
Legionella spp (RR = 0.4, CI 95% 0.19 – 0.85)
Mills, BMJ 2005; 330 : 456
Do we need specific antibiotic coverage for
atypical pathogens ?
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Systematic review and meta –analysis of randomized
controlled trials
Comparing treatment regimens with or without coverage of
atypical pathogens
24 trials, 5015 patients (b lactams vs fluoroquinolones or
macrolides)
Outcome:
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Primary : overall mortality up to 30 days after the end of treatment
Secondary :
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Clinical treatment failure
Bacteriological eradication
Development of superinfections
Adverse events resulting in discontinuation
Shefet, Arch Intern Med 2005; 165 : 1992
Do we need specific antibiotic coverage for
atypical pathogens ?

Mortality : no significant difference between the arms
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
RR = 1.13, 95%CI, 0.82 -1.54
No difference when evaluating
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Fluoroquinolones, RR = 0.98, 95%CI, 0.69 -1.41
Macrolides, RR = 1.25, 95%CI, 0.52 -3.01
Clinical failure : no difference between study arms

RR= 0.92, 95%CI, 0.82 -1.03
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Fluoroquinolones : RR = 0.89, 95%CI, 0.77 -1.02
Macrolides, RR = 1.17, 95%CI, 0.77 -1.77
Microbiologically documented infections
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Pneumococcal (906), RR = 1.15, 95% CI, 0.81 – 1.63
Atypical (158), RR = 0.52, 95%CI, 0.24 -1.10
Legionella (20), RR = 0.17, 95%CI, 0.05 – 0.63
Shefet, Arch Intern Med 2005; 165 : 1992
Should we use a combination therapy in
severe pneumonia?

Empiric use of b lactams alone is associated with
increased mortality
Frequency of co-infection (>10%)
Difficulty to make the diagnosis of legionella

If Yes, should we use fluooquinolones or macrolides?

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Impact of antimicrobial therapy with b lactams and
fluoroquinolones on mortality for patients
hospitalized with severe pneumonia
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Retrospective observational study
172 subjects with severe CAP (PSI V)
Assessing the association between 30-day mortality and the
use of b lactams and fluoroquinolones compared with other
guideline concordant therapy.
Multivariable analysis after adjustement for potentiel
confounders
Mortality rate = 19,8%
62% admitted in intensive care unit
33% received antibiotics within the 4 first hours and 58% within
the 8 first hours
Mortensen et al, Crit Care, 2006
Impact of antimicrobial therapy with b lactams and
fluoroquinolones on mortality for patients hospitalized with
severe pneumonia
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26% : Ceftriaxone + azithromycin
7% : Cefotaxime + azithomycin
8% : Piperacilline-tazobactam + azithromycin
12% : Piperacilline-tazobactam + levofloxacin
5% : Piperacilline – tazobactam + gatifloxacin
7% : Ceftriaxone + levofloxacin
3.5% : Ceftriaxone + gatifloxacin
30-day mortality
 b lactams + fluoroquinolone : 30%
 b lactams + macrolides : 17,2%
Multivariable analysis after adjustement for confounders
OR = 2.71, 95% CI 1.2 – 6.1
Mortensen et al, Crit Care, 2006
What about combination therapy in
pneumococcal infection
844 consecutive adults with pneumococcal bacteremia
Retrospective study
592 patients, analysis of combination therapy versus monotherapy
14 days mortality in all patients :
10,4 % vs 11,5 %, NS
AJRCCM 2004, 170: 440
Monotherapy :
b lactams (43)
Third generation Cephalosporins (25)
azithromycin (2), ciprofloxacin (1), clindamycin (1)
Combination therapy
b lactams + macrolides (14), Vancomycin + b lactams (12)
b lactams + aminoglycoside (7) , b lactam + quinolones (4)
Mortality according to in vitro activity
All treatment active in vitro : 19, 4% vs 60% (p=0,0006)
One the drugs was active in vitro : 18, 2 vs 60% (p=0,0003)
AJRCCM 2004, 170: 440
Not critical ill patients
Critical ill patients
14 days mortality
23,4 % vs 55,3 %, p=0,0015
AJRCCM 2004, 170: 440
Whatever is your choice think about the flora
-222 patients with nosocomial acquired MRSA
-163 patients with nosocomial acquired MSSA
-343 patients admitted served as controls
Emerging Inf Dis 2003, 11:1415
Results : (multivariate analysis)
Exposure to levofloxacin increased the risk (OR= 3.4, p<0.0001)
Exposure to Ciprofloxacin increased the risk (OR= 2,5,p< 0.005)
Emerging Inf Dis 2003, 11:1415
CID 2005, 41: 435
Conclusion
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To treat we have to know
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Clinical situations (Comorbidity, Immunosuppression)
Out or In patient
% of resistance in your area
To treat we have to think

Pharmacokinetic/Pharmacodynamic
Never Forget Flora
Merci