Antibiotic therapy for

Pneumonia in the ICU

Outline

Pneumonia dan Pneumonia berat

Peta Kuman RS
Antibiotik untuk Pneumonia
Kombinasi antibiotik untuk
pneumonia

Pneumonia
Pneumonia: Radang paru yang disebabkan oleh bakteri dengan
gejala panas tinggi disertai batuk berdahak, napas cepat
(frekuensi nafas >50 kali/menit), sesak, dan gejala lainnya
(sakit
kepala, gelisah dan nafsu makan berkurang)

Riskesdas 2013

Epidemiologi Pneumonia di
Indonesia
Prevalensi Pneumonia di 2013: 4,5%

Grafik perbandingan period prevalence 2007 vs 2013

Riskesdas 2013

Kasus Pneumonia yang dirawat

di ICU

CAP berat
HCAP berat
HAP onset dini, tetapi berat
HAP late onset
VAP

Komplikasi terkait CAP

Pediatric Community Pneumonia Guidelines d CID 2011:53 (1 October) d e28

Kriteria CAP berat pada pasien

anak

Pediatric Community Pneumonia Guidelines d CID 2011:53 (1 October) d e28

Kriteria CAP berat pada pasien

dewasa

IDSA/ATS Guidelines for CAP in Adults CID 2007:44 (Suppl 2) S27

Mortality, Hospital and ICU Stay

Pneumonia Patients with VAP vs
Non VAP
Parameters

Patients with VAP

Patients Non-VAP

Hospital Stay (days)

41

41

ICU Stay (days)

24

18

42%

36%

Mortality

Esperatti M, et al. Am J Respir Crit Care Med Vol 182. pp 15331539, 2010

Mikroorganisme Penyebab
Pneumonia Derajat Berat

Curr Opin Pulm Med. 2012;18(3):213-221.

Faktor risiko Patogen

multiresisten menyebabkan
HAP, HCAP, dan VAP

American Journal of Respiratory and Critical Care Medicine Vol 171 2005

Pola Kuman ICU RS Persahabatan 2014

P. aeruginosa
P aeruginosa has emerged as the epitome of MDR
gram-negative bacilli causing hospital-acquired
pneumonia (HAP).
Possesses at least five distinct mechanisms for
inducing antibiotic resistance

Antibiotik untuk Pneumonia

Early, appropriate, broad-spectrum antibiotics in
adequate doses, while avoiding excessive antibiotics
by de-escalation of initial antibiotic therapy, based
on microbiologic cultures and the clinical response of
the patient, and shortening the duration of therapy
to the minimum effective period.
An empiric therapy regimen should include agents
that are from a different antibiotic class than the
patient has recently received.
Combination therapy for a specific pathogen should
be used judiciously in the therapy of HAP, and
consideration should be given to short-duration (5
days) aminoglycoside therapy, when used in
combination with a -lactam to treat P. aeruginosa
pneumonia.
American Journal of Respiratory and Critical Care Medicine Vol 171 2005

Faktor yang harus dipertimbangkan

dalam pemberian antibiotik

Data mikrobiologi
Monoterapi vs kombinasi terapi
Dosis obat
Penetrasi
Waktu
Toksisitas
Risiko Resisitensi
Pemakaian antibiotik sebelumnya
Cost effectiveness
Kollef MH. Clin Infect Dis 2000;31(suppl 4): S131-S138
22
Ibrahim EH et al. Chest 2000; 118:146-155

What factors should be

considered when choosing an
antibiotic?

Mandell et al. Clin Infect Dis 2007; 44: S2772

Woodhead et al. Clin Microbiol Infect 2011; 17(Suppl 6): E1E59
Lim et al. Thorax 2009: 64 (Suppl 3): iii1iii55

Resistance Potential:
All Antibiotics Are Not the Same
Antibiotic
Piperacillintazobactam
Ceftazidime
Cefepime
Imipenem
Meropenem
Gentamicin
Amikacin
Levofloxacin
Ciprofloxacin

Anti-P.
aeruginosa
Activity
++++
++++
++++
++++
++++
+
++
++
+++

P. aeruginosa
Resistance
Potential
+
++++
+
++++
+
++++
+
+
++++

Cunha BA. Semin Respir Infect. 2002;17:231-239.

2011 European Respiratory

Society guidelines
Initial empirical treatment/treatment options for non-ICU hospitalised
patients:
PenicillinG macrolide, aminopenicillin macrolide, aminopenicillin
/ -lactamase inhibitor macrolide, non-antipseudomonal 2nd or 3rd
generation cephalosporin macrolide, levofloxacin, moxifloxacin#
Severe CAP
No P. aeruginosa risk factors:
non-antipseudomonal 3rd generation cephalosporin + macrolide,
non-antipseudomonal 3rd generation cephalosporin + moxifloxacin or
levofloxacin
P. aeruginosa risk factors:
anti-pseudomonal cephalosporin or acylureidopenicillin/-lactamase inhibitor
or carbapenem (meropenam preferred) + ciprofloxacin + macrolide +
aminoglycoside
#

Antibiotic must be effective against S. pneumoniae within the fluroquniolones moxifloxacin has highest anti-pneumococcal activity

Woodhead et al. Clin Microbiol Infect 2011; 17(Suppl 6): E1E59

Adherence to guidelines and

CAP outcome (length of stay)
Prospective
observational
study of 780 pts
Shorter length of
stay in pts
receiving adherent
regimens (7.6 vs
10.4days

Dambrava PG, et al, Eur Respir J 2008; 32:892-901

Adherence to guidelines and

CAP outcome (mortality)
mortality less in
pts that received
adherent regimens
(3% vs 10.6%)

Dambrava PG, et al, Eur Respir J

2008; 32:892-901

Risk factors associated with

early death

Odds Ratio (multivariate analysis)

Garcia-Vidal C, et al, Eur Respir J 2008; 32:733-739

Early initiation of appropriate

antibiotic therapy for septic
shock and survival

Deresinski S Clin Infect Dis. 2007;45:S177-S183

Retrospective cohort study of

161 CAP ICU patients

MVA using Cox proportional

hazard model

Primary outcome: 30-day

mortality adjusted for severity

Late ICU-admitted patients

had a 30-day mortality
(47.4%) compared with early
admitted patients (23.2%)
(P=0.02)

Similar result after adjusting

in MVA (HR 2.6; 95% CI 1.25.5; P=0.02)

Restrepo M I et al. Chest 2010; 137:552-557

Cumulative Survival

Survival of CAP patients with

early ICU
admission vs late admission

EUCUA (Direct or <2d)

LICUA (>2d)

Time to death at 30 days

2007 ATS-IDSA guidelines ICU

CAP
CAP Inpatient
Inpatient Therapy
Therapy
Intensive
Intensive Care
Care Unit
Unit

No
No Pseudomonas
Pseudomonas Risk
Risk

No
No -lactam
-lactam
Allergy
Allergy

-lactam
-lactam ++
Either
Either advanced
advanced
macrolide
macrolide
OR
OR
Respiratory
Respiratory
Fluoroquinolone
Fluoroquinolone

-lactam
-lactam
Allergy
Allergy

Respiratory
Respiratory
Fluoroquinolone
Fluoroquinolone
++
Aztreonam
Aztreonam

Mandell LA, et al. Clin Infect Dis

2007; 44: S27-72

Pseudomonas
Pseudomonas Risk
Risk

No
No -lactam
-lactam Allergy
Allergy
Anti-pseudomonal,
Anti-pseudomonal, antipneumococcal
antipneumococcal
lactam
/
carbapenem
lactam / carbapenem
++
Cipro
Cipro // Levo
Levo 750
750
OR
OR
Anti-pseudomonal,
Anti-pseudomonal, antipneumoccal
antipneumoccal
lactam
lactam // carbapenem
carbapenem
++
Aninoglycoside
Aninoglycoside
++
Azithromycin
Azithromycin

-lactam
-lactam
Allergy
Allergy

Aztreonam
Aztreonam
++
Respiratory
Respiratory
Fluoroquinolone
Fluoroquinolone
++
Aminoglycoside
Aminoglycoside

Terapi Antibiotik
Semua Terapi Awal Empirik, pilihan
mencakup > 90% patogen penyebab,
perhitungkan pola resistensi setempat
Pada kasus berat, butuh dosis dan cara
pemberian adekuat. Terapi IV, sulih terapi
bila klinis dan saluran cerna baik
De-eskalasi setelah ada hasil kultur dari sal
nafas bawah dan perbaikan klinis
Kombinasi AB bila kemungkinan MDR
Jangan mengganti sebelum 72 jam, kecuali
klinis memburuk
Data mikroba dan sensitivitas untuk
mengubah pilihan empirik apabila klinis awal
tidak memuaskan
32

 Non MDR : S. pneumonia, H.influenza, MSSA

Bacteria classified as MDR Pathogens are:

Pseudomonas aeruginosa
MRSA, Acinetobacter spp.
Enterobacteriaceae
EnterobacteriaceaeEnterobacter spp.
ESBL-positive strains
Klebsiella spp.
Legionellapneumophila
Burkholderiacepacia
Aspergillus spp.

Benefit of Combination
therapy?
Sinergi in Vitro
Mengcover sebagian besar jenis
kuman
Mempercepat deeskalasi
Mempercepat kesembuhan
Memperpendek lama perawatan
Munurunkan biaya rawat inap

Benefit of combination
therapy
Had activity against the major
causes of CAP, including drugresistant Streptococcus pneumonia
Evidences showed the superiority of
combination therapy compared with
monotherapy for subset population
(severe CAP, bacteremic
penumococcal CAP, intubated CAP)

Studi yang mendukung

kombinasi antibiotik vs
monoterapi untuk CAP

Ann Intensive Care. 2011; 1: 48.

Studi yang mendukung

kombinasi antibiotik vs
monoterapi untuk CAP (2)

Ann Intensive Care. 2011; 1: 48.

Studi di mana tidak ada

perbedaan bermakna
kombinasi antibiotik vs
monoterapi untuk CAP

Ann Intensive Care. 2011; 1: 48.

Risks
Do the patient had comorbid disease?
Renal impairment do dose
adjustment
Hepatic impairment choose nonexcreted drugs via hepatic and biliary
Q-T interval prolongation caution
with fluoroquinolone drugs
DM

Do patient had drug allergy?

Ask the patient if they had drug(s) allergy
Change to not allergy drug (s)
Think about cross reactivity penicillin
allergy to cephalosporin drug (?)

40

 What are the choices of the

combination?
When to use this combination
considering the risk and benefit?
(refer to Levo-Meropenem)

ATSD & IDSA 2004 Recommendations

Initial EMPIRIC therapy for HAP, CAP, and HCAP in patients with late-onset disease or risk factor
for MDR pathogens and all disease severity
Potential Pathogen
Pathogens listed in previous table and
MDR pathogens
P. aeruginosa
K. pneumoniae (ESBL+)1
Acinetobacter species1

1.

2.

Recommended Antibiotic
Antipseudomonal cephalosporin
(cefipime, ceftazidime)
or
Antipseudomonal carbepenem
(imipenem or meropenem)
or
-Lactam/-lactamase inhibitor
(piperacillin-tazobactam)
plus
Antipseudomonal Fluroquinolone1
(Levofloxacin or ciprofloxacin)2
or
Aminoglycoside
(amikacin, gentamicin, or tobramycin)
plus
Linezolid or vancomycin3

MRSA
If an ESBL+
strain, such as K. pneumoniae, or an Acinetobacter species is suspected, a carbepenem is a
reliable choice.
If L. pneumophila
is1 suspected, the combination antibiotic regimen should include a
Legionella
pneumophila
macrolide (e.g. azithromycin) or a fluoroquinolone (e.g. levofloxacin or ciprofloxacin) should be used rather
than an aminoglycoside
Levofloxacin 750mg q12h, ciprofloxacin 400mg q8h

ATSD & IDSA 2004 Recommendations

Initial empiric therapy in patients with late onset or
risk factors for MDR pathogens, and any disease
severity

Pathogens listed
previously
(S. pneumoniae, H.
influenzae, MSSA,
antibiotic-susceptible
EGNB)
MDR pathogens

P. aeruginosa
K. pneumoniae ESBL
Acinetobacter spp.
MRSA

Anti-pseudomonal cephalosporin
(cefepime, ceftazidime) OR
anti-pseudomonal carbapenem
(imipenem or meropenem)
OR -lactam/-lactamase inhibitor
(piperacillin/tazobactam)
PLUS
Anti-pseudomonal fluoroquinolone
(ciprofloxacin or levofloxacin)
OR aminoglycoside
(amikacin, gentamicin or tobramycin)
PLUS
Linezolid or vancomycin
(if MRSA risk factors are present or
there is a high incidence locally)

Resume rekomendasi
monoterapi atau kombinasi
antibiotik untuk pneumonia

Ann Intensive Care. 2011; 1: 48.

Kuman ESBL banyak terdapat di ruang ICU

termasuk NICU, bagian bedah dan bagian ortopedi.

IJIB 2008; 2 (2): 12

Meropenem
Antibiotik golongan carbapenem
Aktif terhadap kuman penghasil ESBL (Klebsiella
pneumonia, Escherichia coli, Enterobacteriaceae)
Secara in vitro Meropenem mempunyai aktivitas
terhadap mikroba penghasil ESBL yang lebih
tinggi
dibandingkan Imipenem (MIC Meropenem: 0,030,12 g/mL vs Imipenem: 0,06-0,5 g/mL).
Stabil terhadap DeHidroPeptidase-1 di ginjal
(tidak perlu
dikombinasi dengan cilastatin seperti imipenem)

http://www.medscape.com/viewarticle/409761_5

KEPEKAAN MEROPENEM

Trends in antimicrobial susceptibility of gram negative isolates from

a paediatrics intensive care unit in Warsaw: results from the MYSTIC proggr
(1997-2007). JAC 2008: 1-7.

MEKANISME KERJA
Menghambat sintesis
dinding sel bakteri

Bakterisidal
(kematian bakteri)

Pneumonia, termasuk
pneumonia nosokomial

Infeksi saluran
kemih

Infeksi intraabdominal

Indikasi Meropenem

Infeksi ginekologi

Septikemia
Meningitis

Infeksi kulit dan

struktur kulit

MEROFEN/Product Profile, PT Kalbe Farma

Usia
DEWASA

DOSIS

Jenis Infeksi

Dosis

Pneumonia, ISK, infeksi

ginekologi, infeksi kulit
dan struktur kulit

500 mg IV tiap 8 jam

Pneumonia nosokomial,
peritonitis, infeksi pd
pasien neutropenia,
septikemia

1 g IV tiap 8 jam

Meningitis

2 g IV tiap 8 jam

BAYI > 3 bulan

ANAK 12
tahun

ANAK > 50 kg
Bolus lambat (5 menit), infus (15 - 30 menit)

10 20 mg/kgBB tiap
8 jam
40 mg/kgBB tiap 8
jam (meningitis),
maksimum 2 g tiap 8
jam
= dewasa
MEROFEN/Product Profile, PT Kalbe Farma

PENYESUAIAN DOSIS
Klirens Kreatinin
(mL/menit)

Dosis
(dosis
rekomendasi : 500
mg -2 g)

Frekuensi

26 - 50

Dosis rekomendasi

Tiap 12 jam

10 - 25

dosis
rekomendasi

Tiap 12 jam

< 10

dosis
rekomendasi

Tiap 24 jam

Pasien gangguan fungsi hati TIDAK perlu penyesuaian dosis

MEROFEN/Product Profile, PT Kalbe
Farma

EFEK SAMPING

Norbi S, et. al. Scan.J of Infect Dis. 1999:31:3-10

KLASIFIKASI QUINOLONES DAN CAKUPAN

AKTIVITAS ANTIBAKTERI
Generasi 1
Nalidixic acid,
Oxolinic acid,
Cinoxacin

Generasi 2
Lomefloxacin,
Norfloxacin

Ofloxacin,
Ciprofloxacin

Generasi 3

Generasi 4

Levofloxacin,
Grepafloxacin

Trovafloxacin,
Moxifloxacin

Aktivitas mikrobiologi
Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae Enterobacteriaceace

+ P. aeroginosa

+
Atipikal
P. aeruginosa

P. aeruginosa (+/-)
Atipikal
+Streptococci

P.aeruginosa (+/-)
Atipikal
Streptococci
+anaerob

Tempat infeksi
Hanya saluran
kemih

Hanya saluran
kemih

Sistemik +
sal.kemih

Sistemik sal.
kemih

Sistemik sal. kemih

Am Fam Physician 2000; 61: 2741-8

FARMAKODINAMIK
LEVOFLOXACIN

Enzim DNA
gyrase dan
topoisomerase
IV dari bakteri

Bakteri mati
PI Cravit. 2001

MIC90 Levofloxacin terhadap Bakteri Penyebab

Infeksi
Bakteri

MIC90 (mg/L)

Streptococcus pneumoniae
-Penicillin susceptible
-Penicillin intermediate
-Penicillin resistant

0,5 - 16
1
1
1

Escherichia coli

0,06 - > 8

Haemophilus influenzae

0,008 - 0,06

Haemophilus parainfluenzae

0,06

Klebsiella pneumoniae

0,5 - > 8

Moraxella catarrhalis

0,03 0,06

Proteus mirabilis

0,05 2

Pseudomonas aeruginosa

0,5 - 64

Salmonella spp

0,03-0,25

Drugs 2008; 68(4): 535-65, Thauvin-Eliopoulos C, Eliopoulos GM. Quinolone antimicrobial agent. 3 rd ed. 2003

METABOLISME DAN EKSKRESI

LEVOFLOXACIN
Metabolisme: terbatas
Ekskresi: melalui ginjal terutama dalam
bentuk utuh (87 % dalam 48 jam)
melalui feses (< 4 % dalam 72 jam)

PI Cravit. 2001

DOSIS UMUM

Typhoid fever

500 mg

7
www.rxlist.com

PERBANDINGAN EFEK SAMPING

PADA ANTIBIOTIKA QUINOLONE

KESIMPULAN
Meropenem & Levofloxacin
Meropenem

Meropenem adalah gol

carbapenem yang stabil terhadap
enzim beta-lactamase & DHP-1
Mempunyai spektrum antibakteri
yang luas
Merofen diindikasikan untuk
penanganan infeksi berat
Dapat digunakan baik pada
dewasa maupun anak (> 3 bulan)

Levofloxacin

Quinolone generasi ketiga dengan

spektrum anti-bakteri luas

Dosis praktis 1x/hr

Kombinasi Meropenem dan Lfx

direkomendasikan untuk infeksi
berat (seperti sepsis atau
pneumonia nosokomial) yang
disebabkan bakteri MDR seperti
Pseudomonas, Acinetobacter sp,
atau Klebsiella Pneumoniae.

TERIMA KASIH
SEMOGA SUKSES