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RESPIRATORY TRACT
INFECTION :
PROBLEMA &
PENATALAKSANAANYA
Soedarsono
Lab-SMF Penyakit Paru
FK Unair- RSUD Dr. Soetomo
Surabaya
1
OUTLINE OF DISCUSSION
COMMUNITYACQUIRED
PNEUMONIA
(CAP)
ACUTE
EXACERBATION
CHRONIC
BRONCHITIS
(AECB)
ANTIMICROBIAL
THERAPEUTIC
2
IDENTIFICATION
IDENTIFICATION
RISK
RISKFACTORS
FACTORS
Comorbidity
MANAGEMENT
MANAGEMENT
NEW and
RESISTANT
PATHOGEN
OUTCOMES
OUTCOMES
COST
EFFECTIVE
CARE
3
BATASAN
COMMUNITY-ACQ. PNEUMONIA (CAP) :
INFEKSI AKUT PARENKIM PARU DI MASYARAKAT
INFILTRAT PADA FOTOTORAK DISERTAI 2 Gx :
- FEVER 380C
- LEKOSISITOSIS > 10.000 / mm3
- SPUTUM PURULEN
- BATUK, SESAK, NYERI DADA
- FISIS : TANDA KONSOLIDASI
RAWAT JALAN
DRAJAT SKOR
RISIKO
RAWAT INAP
4
CLASSIFICATION
CLASSIFICATION OF
OF PNEUMONIA
PNEUMONIA
By Source of
Infection
By Infectious
agent
By Site
Infection
Communiy-acquired
Hospital-acquired
Atypical pneum.
Bronchopneumo.
Aspiration
Viral pneum.
Interstitial pneum
Immunocompr. host
Lobar
pneumonia
Bacterial
pneumonia
Atypical
pneumonia
CAP
Bronchopneumonia
Interstitial
pneumonia
MORTALITY
COST- EFFECTIVE
PREVENTION OF OCCURANCE RESISTANCE OF PATHOGEN
7
Community-acquired pneumonia
EVALUASI SISTIM SKOR
FAKTOR DEMOGRAFI
PEMERIKSAAN FISIK
LABORATORIUM / RADIOLOGIK
TOTAL SKOR
RISK. I/II/III
(RENDAH)
RAWAT JALAN
RISK. IV
SEDANG
RAWAT INAP
RISK. V
BERAT
8
RAWAT INAP
YES
NO
Does the patient have aof any of the following comorbid
conditions :
YES
. Neoplastic disease
. Congestive heart failure
. Cerebrovascular disease
. Renal
disease
. Liver disease
Assign patient to
risk class II-V based
on prediction model
scoring system
NO
Does the patient have any of the following abnormalities on
physical examination ?
- Altered mental status
- Pulse 125 / BPM
- Respiratory rate 30/min - Systolic BP < 90 mm Hg
- Temperature < 350C (950F) or 400C(
1040F)
YES
NO
SCORING SYSTEM
SISTIM
SKOR
pada
CAP
berdasarkan
PORT
PATIENT CHARACTERISTIC
POINTS ASSIGNED*
Demographic factors
Age: Males
Age: Females
nursing-home resident
+ 10
COMORBID DISEASE
Neoplastic disease
Liver disease
+30
+ 20
+ 10
Cerebrovascular disease
+ 10
Renal disease
+ 10
+ 20
Pulse 125/BPM
+ 10
+ 20
+ 30
pH < 7.35
+ 30
+ 20
+ 20
+ 10
PO2< 60 mm Hg+
+ 10
Pleural effusion
+ 10
11
STRATIFICATION OF RISK
SCORE FOR CAP
Risk
Recommendation
for site of care
Low
Algorithm
Outpatient
Low
II
70 total points
Outpatient
Low
III
Moderate IV
Inpatient
Inpatient
High
Inpatient
13
EMPIRIC
Advantages w/ DIRECTED Tx :
Polypharmacy
Cost
Adverse drug reaction
14
The Pathogens
difficulty in finding pathogen
& culture
Serology
- too sensitive
- lacks specifity
- special skills
- adherence to protocol
- too costly
- patients cannot produce
sputum
- false negative on
antibiotic - cannot detect
atypical
- low sensitiity
- high specificity
- time delay
16
17
Mycoplasma
pneumoniae
7%
S. pneumoniae
66%
Global meta-analysis of
English-language studies
Study cohorts: N=127
Total patients: N= 33,148
Total patients reporting
data: N=6,866
Haemophilus
influenzae
12%
Fine MJ et al. JAMA 1996; 275:134.
18
Etiology of CAP
(Persahabatan Hosp. 2000)
19
Pathogens in CAP :
Dr. Soetomo Hospital ( 1998 )
20
S. PNEUMONIAE PENYEBAB
TERBANYAK
22
APPROACH
G. IIIA
CPD and / or
modifiers
Hospitalize patient
G. II
CPD and/or
modifiers
G. IIIB
No CPD, no
modifiers
Mild to moderate
infection
(general ward)
G. IVA
No risk of
P. aeruginosa
Severe
infection
(ICU)
G. IVB
No risk of
23
P. aeruginosa
MODIFYING FACTORS
RISK OF INFECTION WITH
SPESIFIC PATHOGENS
Enteric gram-negatives
Pseudomonas aeruginosa
24
MODIFYING FACTORS
Penicillin resistant &
drug resistant pneumococci
Age > 65 year
Betalaktam therapy within the past 3
months Alcoholsm
Immune-suppressive illness
Multiple medical comorbdities
25
Exposure to a child in a day
MODIFYING FACTORS
Enteric gram-negatives
MODIFYING FACTORS
Pseudomonas aeruginosa
KRITERIA MINOR :
KRITERIA MAYOR :
- Ventilasi mekanik
- Serum kreatinin - Infiltrat
> 50%
- Septik syok
> 2 mg/dl
atau pean > 2 md/dl
Minimal
Minimal ::22 dari
dari33MINOR
MINORtertentu
tertentu
11 dari
dari22MAYOR
MAYORtertentu
tertentu
ICU
28
Group I :
-S. pneumoniae
-M. pneumoniae
-C . pneumoniae
Group 3A :
=
group 2 plus
H. influenzae
mixed infection
Group 4A :
= group 3 plus
- Legionella
spp
Group 2. :
-S. pneumoniae
( DRSP)
M.
pneumoniae
C. pneumoniae
PATHOGEN
Group 3B :
= group 2 plus
H. influenzae
mixed infection
Group 4B :
=group 4A plus
- P.
aeruginosa
29
.Group I :
- Azithromicin
Clarithromicin
- Doxicycline
Group 3A :
- IV BL plus
IV/oral Macrolide /
Doxicycline OR
- IV New FQ
(monotherapy)
Group 2. :
-- BL plus Macrolide /
Doxicycline OR
- New FQ ( monotherapy)
ANTIMICROBIAL
Group 4A :
-IV BL plus
IV Azithromicin
OR
-IV New
FQ
Group 3B :
= group
3A
Group 4B :
- IV BL antipseudomonal
plus
- IV FQ
30
ATS 2001
BTS 2001
Group I:
Minimal Risk:
Generally Preferred:
No CP disease
< 65 yrs, Stable VS
No Modifying Factors
No Co-morbidity
Macrolide
Adv. Gen. Macrolide
Amoxycillin OR
OR
(Azithromycin/Clarithromycin) Extended Macrolide OR
Doxycycline
Cotrimoxazole
OR
OR
Fluoroquinolone (FQ) Doxycycline
Older Patients or w/
underlying disease:
Fluoroquinolone
Low Risk:
Group II: w/ CP disease
< 65 yrs., Stable VS
& /or Modifying Factors
Stable Co-morbidity
B-Lactam
Cotrimoxazole OR
+
Sultamicillin OR
Macrolide or Doxycycline Co-Amoxyclav OR
OR
2nd Gen Oral Ceph OR
31
Antipneumococcal FQ
Extended Macrolide
alone
ATS 2001
BTS 2001
Moderate Risk:
> 65 yrs, Unstable VS ,
Complicated CXR,
Aspiration, Extrapulmo.
evidence of sepsis,
Unstable Co-morbidity
Doxycycline
OR
IV Antipneumo-FQ alone
Group III b : No CP disease
No Modifying Factors
IV Azithromycin alone
If macrolide intolerant:
Doxycycline + B-Lactam
OR
Antipneumo- FQ alone
IV -lactam
with or without
anerobic coverage
+/IV Macrolide
(or alternatives)
OR
Fluoroquinolone alone
32
ATS 2001
Group IV a :
No Risks for P. aeruginosa
IV -lactam
+
IV Macrolide(azithromycin)
OR
IV Fluoroquinolone
Group IV b :
Risks for P. aeruginosa
IV Antipseudo. -lactam
+
IV Fluoroquinolone
OR
IV Antipseudo. -Lactam
+ IV Aminoglycoside
+ IV Macrolide
or IV Non-pseudo FQ
BTS 2001
High Risk:
Shock or signs of
hypoperfusion or
Respiratory failure
IV Antipseudo. -lactam
+/IV Aminoglycoside
OR
IV Fluoroquinolone
+
IV Macrolide
33
or
or
34
alternative
Intravenous -lactam
Ampicilin plus sulbactam (3 x 1,5-3 g)
Cefotaxim ( 3 x 2g ) or ceftriaxone ( 2 x 1g)
4th-generation cephalosporine (Cefepime 3 x 2g)
Consider combination with IV or oral macrolide
( azithromycin or clarithromycin)
or
Recommended of
New oral/IV fluoroquinolone
(e.g. GATIFLOXACIN)
GATIFLOXACIN
Alergy to one of
lactam, macrolide or
doxycycline
36
Acute Exacerbation of
Chronic Bronchitis
(AECB)
DEFINITIONS
Host
Microbial
load
Inflammatory
Response
Fig. Test tube model
of bacterial
bronchial infection
Cough
Purulent sputum
38
PREVALENCE OF MAJOR
RESPIRATORY PATHOGENS IN AECB
39
Antibiotics in AECB
INDICATIO
N
AT LEAST 2 OF 3
FOLLOWING SYMPTOMS :
MUST INCLUDE
COVERAGE :
- H. influenzae
- S.
pneumoniae
- Moraxella
catarrhalis
SPUTUM PRODUCTION
SPUTUM PURULENCE
DYSPNEA
40
Baseline
clinical status
Acute
tracheobronchitis
II
Simple cronic
bronchitis
III
Complicated
chronic bronchitis
IV
Chronic bronchial
suppuration
Recommended
first-line
tharapy
None
Exacerbation in
Amoxicillin or
tetracycline
established : dyspnea /
sputum / sputum
= Classpurulence
II plus 1 :
Fluoroquinolone
or
-lactam/
-lactamase
inhibitor
combination
Ciprofloxacin
(oral)
41
Beta-lactams
They are virtually all inactives againts the
atypical pathogens : M. pneumoniae, C.
pneumoniae, Legionella sp.
Current problems with beta-lactams:
Trend Penecillin-Resistant S. pneumoniae
H. influenzae (>40%)
,
produce betalactamase
M. catarrhalis (>95%)
S. aureus (>90%)
43
BETA LACTAMs
MAIN LIABILITY as EMPIRIC
THERAPY in PNEUMONIA
NOT EFFECTIVE AGAINST INTRACELLULAR
PATHOGEN e.g. ATYPICAL PATHOGEN :
M. PNEU & CHL. PNEU
RISING RESISTANCE TO STR.PNEU , WITH IS
ASSOCIATED TO MACROLIDE RESISTANCE
44
Prevalence of Penicillin
Non-Susceptible* Pneumococci:
Asia/Pacific and the Americas
Macrolides
ADVANTAGES
HIGH TISSUE PENETRATION
EFFECTIVE against ATYPICALS
NO CROSS HYPERS. With PEN.
MACROLIDEs
LOW/NEGLIGIBLE SERUM CONC.
=> NOT SUITABLE FOR SEVERE
INFECTION / SEPSIS
INEFFECTIVE against H.INFLUEN.
NO ANAEROB ACTIVITY
47
DISADVANTAGES
TETRACYCLINE
2 groups :
naturally molecule (TETRACYCLINE) &
semisynthetic molecule ( DOXYCYCLINE &
MINOCYCLINE)
TETRACYCLINE : poor activity ~ H. influenzae
DOXYCYCLINE : especially active ~ M. catarrhalis
MINOCYCLINE : > active ~ H. influenzae & S.
pneumoniae
The most important imitation use of this class :
increasing emergence of microbial resistance
48
Quinolone
49
Nalidixic Acid
Expanded
gram negatives
Ciprofloxacin, Norfloxacin,
Ofloxacin
Grampositives
Levofloxacin, Sparfloxacin
GATIFLOXACIN, Gemifloxacin,
Moxifloxacin
Anaerobes
Trovafloxacin, Clinafloxacin
50
51
Structure of Gatifloxacin
O
F
COOH
[1-1/2 H2O]
OCH3
HN
CH3
Pharmacokinetic/Pharmacodynamic
Relationships: Surrogate Markers
Concentration (mg/L)
T>MIC
Cmin = Trough
Time (h)
53
Concentration (mg/L)
Pharmacodynamic Relationships:
AUC : MIC Ratio
Proposed Target Ratios
AUC:MIC >125 Gram-negative organisms
AUC:MIC ~ 30 Gram-positive organisms
AUC = Area under the
curve
MIC = Minimal inhibitory
concentration
Time (h)
54
55
SPEKTRUM KUINOLON
terhadap RESP.PATOGEN
STR.
PNE
OFLO
STA.
AUR
H.
INFL
M.
CATA
M.PNE CHL.
PNE
ENTE
RO B.
KL.
PNE
CIPRO
LEVO
GATI
56
PHARMACODYNAMIC
PROFILE OF THE
FLUOROQUINOLONES
Drug
Cmax
(mg/L)
AUC
(mg/L)
MIC90
AUC/MIC
S. pneumoniae
90
Cmax/
MIC90
Moxifloxacin
4.5
48
0.25
192
18
Gatifloxacin
4.2
34.4
0.5
68.8
8.4
Levofloxacin
5.7
47.5
1.0
47.5
5.7
57
AUC
(mgh/L)
MIC90
(mg/L)
AUC:MIC90
Moxifloxacin
400
48
0.25
192
Gatifloxacin
400
51.3
0.5 *
103
Levofloxacin
500
72.5
2.0 *
36
Ciprofloxacin
750
20.2
1.0 *
20
58
RESISTENSI
LEVOFLOX
RESIST.
MECH.
FAKTA DI
LAPANGAN
MOXIFLOX
GATIFLOX
1 STEP
MUTATION
2 STEP
MUTATION
2 STEP
MUTATION
DOSIS
MAKIN
TIDAK/
BELUM ADA
TIDAK/
BELUM ADA
59
ADVANTAGES
DiSADVANTAGES
Inexpensie, safe,
widely used
PRP, BL +, inactive
againts atypical
Amox/clavulanate
Broadspectrum. Actie
agains H. influenzae,
safe & well tolerated
PRP. Inactive
againts atypical ,
GI sideeffects
Broad spectrum,
active againts H.
influenzae
PRP, inactive
againts atypical
Cephalosporins
eg. Cefaclor,
cefdinir, cefixime
60
ADVANTAGES
DiSADVANTAGES
Inexpensie, active
againts atypical
Dose od., active
againts atypical
Short-cource therapy,
active againts atypical
Macrolides
Erythromycin
Clarithromycin
Azithromycin
H. influenzae, GI side ef
Fluoroquinolone
Ciprofloxacin
Newfluoroquinolone
( gatiflox., moxiflox.)
Active againts P.
aeruginosa
Broad spectrum, active
againts PRP, H. influenzae,
atypical, anerobes, dose od
Isolated report of
failure in PP
Limited activity
againts P.
61
aeruginosa
Pcn
Cep
ACTIVITY
IN AECB
RISK
PROFILE
(GROUP)
RESISTANCE
RESPIRATORY
PENETRATION
DOSING
AMOXICILLIN
ADEQUATE
HIGH (MOST)
LOW
tid / qid
AMOXICILLIN /
CLAVULANATE
GOOD/
EXCELENT
3&4
LOW
LOW
bid / tid
CEPHALEXIN /
CEFACLOR
POOR
NR
RELATIVELY
HIGH
VERY LOW
tid / qid
ADEQUATE
MODERATE
LOW
qd / bid
TETRACYCLINE
POOR
NR
HIGH
LOW
qid
DOXYCLINE
GOOD
MODERATE-HIGH
LOW
bid
POOR
NR
HIGH
MODERATE
qid
CEFUROXIME /
LORACARBEF
CEFIXIME /
CEFPODOXIME
Tetr
MINOCYCLINE
Mac
ERYTHROMYCIN
AZITHROMYCIN /
DIRITHROMYCIN
qd
GOOD
MODERATE
VERY HIGH
CLARITHROMYCIN
Quinol
bid
CIPROFLOXACIN
GOOD
3&4
LOW
VERY HIGH
LEVOFLOXACIN
GOOD
3&4
LOW
VERY HIGH
GATIFLOXACIN
GOOD
3&4
LOW
VERY HIGH
bid
62
qd
qd
HEALTH ECONOMICS
STREAMLINING
PARENTERAL
ORAL
COMBINATION
BROAD
MONO-TX
NARROW SPECTR.
DOSE REDUCTION
63
SWITCH THERAPY
atau
TERAPI SULIH
64
Community-Acquired Pneumonia
High risk
High Risk Pneumonia
- IV antibiotic treatment
- Hospital admission
Complicated pneumonia
- Prolonged IV antibiotic
treatment
Continued instability
Strategies for early discharge
of the hospitalized patient
Low risk
Low Risk Pneumonia
- Oral antibiotic treatment
- Out patient therapy
Unstable Pneumonia
- IV antibiotic
treatment
Observation
24 - 72 hours
Clinical Stability
- Rapid switch to oral antibiotic
- Hospital discharge65
66
GOAL
DAY 7-10
SWITCH day 3
DISCHARGE day 4
I.V.
to
ORAL
SWITCH
DAY 3
EASY
CRITERIA: IV to ORAL
RAMIREZ J.A.: 21 st IUATLD, MANILA, 2001
STABLE CLINICAL
CONDITION
IMPROVING COUGH & S.O.B.
AFEBRILE > 8 hrs
NORMALIZING WBC
ORAL INTAKE & G.I. ABSORPTION :
ADEQUATE
69
5. Low
acquisition cost
1. Coverage
= intravenous agent
4. No adverse
side effect
3. High
Bioavailability
2. OD or
BID dosing
to improve
compliance
70
EVALUATION : 48 - 72 hrs
DEFERVESCENCE
day 2 - 4
RHONCHI (-)
day 7 ( 60-80%)
CLINICAL
IMPROVEMENT
NORMALIZING WBC
day 4
X- RAY RESOLV.
2 wks ( 50.6 %)
4 wks ( 66.7 %)
71
Do NOT CHANGE Tx < 72 hrs, w.o. CLINICAL DETERORIATION
DIAGNOSIS
SALAH
- Gagal
jantung
- Emboli
Keganasan
Sarkoidosis
- Reaksi
Obat
Perdarahan
DIAGNOSIS
BENAR
FAKTOR
PENDERITA
FAKTOR
OBAT
- Kelainan
lokal
- Respon yg
tidak
adekuat
Komplikasi
- Salah
pilih
obat
- Salah
dosis/cara
pemberia
FAKTO
R
KUMA
N
Resiste
nKuman
patoge
n
72
lain
-
5 - 14 days
DURATION of TREATMENT
SHORT TREATMENT
CLINICAL CURE
BACTERIAL
ERADICATION ?
RESISTANCE
(dead bugs do not mutate)
73
PILIHAN EMPIRIK
ANTIBIOTIKA
KONSENSUS
ASIA-PASIFIK:
#MENGATASI > 90 %
PATOGEN
#POLA RESISTENSI
POLA KUMAN
> 80 %
1. H. INFL.
2. M. CATARRH.
3. S.. PNEU
4 ATYPICAL
RESISTENSI > 20 %
GANTI PILIHAN EMPIRIK
74
COMBINED
ONLY INDICATION:
IF NO SINGLE AGENT
COVERS ALL PROBABLE
PATHOGENS
MONO IS PREFERED :
LESS DRUG INTERACTION
LESS ADVERSE EFFECTS
LESS EXPENSIVE
LESS CHANCE OF FORGETTING
MONO TX
CAP
(ATS-guideline)
BETA LACT.
+
MACROL
COVERED by
MONO
RESPIR.QUIN !!
75
F. KUINOLON
-LAKTAM MAKROLID
LEVO
GATI
KECENDERUNGAN RESISTENSI
RENDAH
76
KESIMPULAN
80 %
KUMAN
AECB/CAP
H.INFL
M.CATARR
S.PNEU
ATYPICAL
RESISTENSI TINGGI
terhdp BETA LAKTAM
+
RESISTENSI SILANG
terhdp MAKROLID
GATIFLOX.
PILIHAN
EMPIRIK
1 DD 400 mg
7 - 1477hr
Summary :
Moxifloxacin in Patients with CommunityAcquired Pneumonia /AECB
Sebagai obat empirik CAP kelompok II / IIIa/IIIb & AECB, dapat
mencover semua patogen penyebabnya
Monoterapi
Kemampuan eradikasi kuman yang tinggi
Cara bekerjanya pada 2 tempat ( DNA gyrase & topoisomerase IV )
kemungkinan resistensi rendah
Memungkinkan sequential terapi ~ cost effective
Memenuhi
78
EMPIRICAL CHOICE:
PNEUMONIA : ALL GR.
A(b)ECB : ALL CLASSES
BACTERICIDAL+++
ACQ.RESIST. LOW
(dead bugs do not mutate)
RESUME
GATIFLOXACIN
COST of Tx
SEQUENTIAL
EASY
I.V.= ORAL
HOSPITALIZATION
MEDICINE
ROUTE of ADM.
79
80