ANALISIS PENGGUNAAN

ANTIBIOTIK PADA DEMAM

TIFOID
DEFINISI
Demam Tyfoid merupakan penyakit
sistemik akut yang disebabkan oleh
infeksi kuman Salmonella typhi.
Prevalensi Demam Tyfoid

Nasronudin, 2011
 Etiologi Demam Tyfoid
Salmonella
Merupakan bakteri gram negatif, bersifat aerobik,
thypi
bergerak dengan rambut getar, dan bersifat tidak
berspora

Nasronudin, 2011
Patofisiologi Demam Tyfoid

Djoko Widodo, Buku Ajar IPD 2009

TYPHOID
MANAGEMENT
(WHO)
Typhoid Fever Management (WHO)
 Treatment of uncomplicated Thypoid fever

WHO 2003
Typhoid Fever Management (WHO)
 Treatment of severe Thypoid fever

WHO 2003
TYPHOID
MANAGEMENT IN
INDONESIA

KEPMENKES RI NO 364/MENKES/SK/V/2006
TENTANG PEDOMAN PENGENDALIAN DEMAM
TIFOID
Antibiotik Dosis Keuntungan & Kelebihan

First Line Dewasa: 4x500mg (2 gr) selama 14 hari - Merupakan obat yang sering digunakan dan telah lama dike
1. Khloramfenicol Anak: 50-100 mg/Kg/hr efektif untuk tifoid
Max: 2 gr selama 10- 14 hr dibagi 4 dosis -Murah dan dapat diberi peroral dan sensitifitas masih tinggi
- Pemberian PO/IV
-Tidak diberikan bila leukosit˂2000/mm3
2. Ampicillin & Dewasa: 3-4 gr/hr selama 14 hr -Aman untuk penderita hamil
Amoxcillin Anak: 100 mg/Kg BB/hr selama 10 hr -Sering dikombinasi dengan Khloramfenicol pada pasien krit
-Tidak mahal
-Pemberian PO/IV
3. TMP-SMX Dewasa: 2 x(160-800 mg) selama 2 -Tidak mahal
(Kotrimoxazol) minggu -Pemberian PO
Anak: TMP 6-10 mg /Kg BB/hr atau
SMX 30-50 mg/Kg BB/hr selama 10 hr

Second Line Ciprofloxacin: 2x500 mg 1 minggu -Pefloxacin dan fleroxacin lebih cepatmenurunkan suhu
Quinolon Ofloxacin: 2x(200-400) 1 minggu -Efektif mencegah relaps dan karrier
Pefloxacin: 1x400 mg selama 1 minggu -Pemberian peroral
Fleroxacin: 1x400 mg selama 1 minggu -Anak tidak dianjurkan karena efek samping pada pertumbuh
tulang
Third Line Dewasa: 2-4 gr/hr selama 3-5 hr Cepat menurunkan suhu, lama pemberian pendek dan dapat d
Ceftriaxone Anak: 80 Kg/BB/hr , Dosis tunggal tunggal serta cukup aman untuk anak
selama 5 hr - Pemberian IV
Cefixim Anak: 15-20 mg/Kg BB/hr dibagi dosis Aman untuk anak, Efektif, pemberian peroral
selama 10 hr
Thiamfenicol Dewasa: 4x500mg -Dapat untuk anak dan dewasa
Anak: 50mg/KgBB/hr selama 5-7 hr -Dilaporkan cukup sensitif pada beberapa daerah
bebas panas
 Guideline RSUD. Soetomo
Antibiotik Dosis

First Line 1. Chloramfenicol 3-4 x50 mg/KgBB/hr

Oral/IV, selama 14 hr

2. Ampicillin 3-4 x 200 mg/Kg BB/hr

Iv, selama 21 hari

3. Amoxycillin 3-4 x sehari 100 mg/Kg BB/hr

Oral atau IV , selama21 hari

4. Cotrimoxazol 2 x sehari 8 mg/Kg BB/hr

Oral. Selama 14 hari
Second line Ceftriaxone 2x sehari 50 mg/Kg BB/hr atau 80
mg/Kg BB/hr sekali sehari selama
5-7 hari
Third Line Meropenem
(Px yang Azitromisin
mengalami MDR) Fluoroquinolon
PDT ANAK 2008
Mekanisme Kerja Antibiotik
Chloramphenicol vs Thiamphenicol

 Broad spectrum  broad-spectrum

 Bacteriostatic, but may be
bactericidal in high
concentrations or against
highly susceptible organisms
Chloramphenicol vs Thiamphenicol
 Widely distributed into most  Like chloramphenicol, it is
body tissues and fluids: insoluble in water, but highly
saliva, ascitic fluid, pleural soluble in lipids.
fluid, synovial fluid, and  Protein binding ≤ 10%
aqueous and vitreous humor.  Plasma half life: 5 hours
Highest concentrations in
liver and kidneys.
 CSF concentrations may be
21-50% (uninflamed
meninges) and 45-89%
(inflamed meninges)
 Protein binding: 60%
 Plasma half-life 1.5-4.1 hours
Chloramphenicol vs Thiamphenicol
 Usual dosing range: I.V.: 50-  I.V.: 2 g once daily (or 50-
100 mg/kg/day in divided 100mg/kg BW/day) for 10-14
doses every 6 hours; days
maximum daily dose: 4 g/day,  Defervescence achieved
for 10-14 days. within 5-6 days
 Defervescence achieved  Haematologic complication
within 2-5 days less frequent
 A relatively high rate of
relapse (57%), long treatment
courses (14 days) and the
frequent development of a
carrier state in adults.
Side effect of Chloramphenicol
 Aplastic anaemia is the most dangerous effect produced
by chloramphenicol, although its occurrence is rare. It
is usually fatal. Numerous publications have appeared,
most of them case reports describing the development
of aplastic anaemia.
 The mechanism is not understood. There may be a
genetic element involved, as the effect has been seen in
families and in identical twins exposed to
chloramphenicol (Flach, 1982; Nagao & Maner, 1969;
Silver & Zuckerman, 1980; Yunis, 1978c).
 In in vitro experiments, chloramphenicol and its
postulated metabolite, nitrosochloramphenicol, have
shown adverse effects on bone marrow cells.
 Resistance of S. Typhi in Asia -
2008

Ochiai R.L. et al, 2008, A study of typhoid fever in five Asian countries: disease burden and
implications for controls. Bulletin of the World Health Organization. 86:260–268.
RESISTENSI S. TYPHI DI
INDONESIA
Resistance Mechanism of S.typhi
Cotrimoxazole
Dosis: 30-40 mg/kg BB/hari
Sulfametoksasol dan 6-8 mg/kg BB/hari
untuk trimetoprim, diberikan dalam 2 kali
pemberian, selama 10-14 hari
Efektifitas kotrimoksasol terhadap demam
tifoid masih kontroversial.
Kemungkinan timbulnya kekambuhan
pengobatan cukup kecil jika dibandingkan
kloramfenikol
Ampisillin and Amoxicillin
Merupakan derivat penisilin yang digunakan
pada demam tifoid terutama pada kasus yang
resisten thd kloramfenikol
Dosis Ampisilin: I.V.: 200-400 mg/kg/day in
divided doses every 6 hours (maximum: 6-12
g/day) selama 0-14 hari
Dosis Amoksisilin: 100mg/kgBB/hari selama
10-14 hari
Pengobatan demam tifoid yang
menggunakan obat kombinasai tidak
memberikan keuntungan yang lebih baik
dibandingkan obat tunggal
Structure
PK profile
Parameter Ampicillin Amoxicillin
Oral: 250-500 mg < 3 tahun : Oral: 20-30 mg/kg/day
every 6 hour divided every 12 hours.
Dosis
I.M., I.V.: 250-500 > 3 tahun : Oral: 20-50 mg/kg/day
mg every 6 hours in divided doses every 8-12 hours
Oral: 50% Rapid and nearly complete; food
Absorption
does not interfere
T½ Children and Adults: Neonates : 3.7 hours
1-1.8 hours Infants and Children : 1-2 hours
Clcr <10 mL/minute: 7-21 hours
Onset of action Oral: Within 1-2 hours 2 hours
Protein binding 15% to 25% 17% to 20%
Excretion Urine (90% as Urine (80% as unchanged drug)
unchanged drug)
within 24 hours
Lacy et al, 2009. Drug Information Handbook 17th
Edition
Cephalosporin 3rd Generation
Ceftriaxone
Dose 50-100 mg/kg BW/d, single or
divided every 12h
Cefotaxime
Dose 150-200 mg/kg BW/d, divided into
3-4 dose
Perbandingan Dosis
CEFTRIXONE CEFIXIME
 Oral: 20 mg/kg/day for 10-14 days; maximum 400  Dose 150-200 mg/kg BW/d, divided into 3-4 dose.
mg  Acute infections due to sensitive Gram-positive
 Infections due to sensitive Gram-positive and
and Gram-negative bacteria, but see notes above
Gram-negative bacteria By mouth
 Infus over 60 minutes Child 6 months–1 year 75 mg daily
 Neonate 20–50 mg/kg once daily Child 1–5 years 100 mg daily
IM , or bIV i over 2–4 minutes, or infus Child 5–10 years 200 mg daily
 Child 1 month–12 years Child 10–18 years 200–400 mg daily or 100–
 Body-weight under 50 kg 50 mg/kg once daily; 200 mg twice daily
up to 80 mg/kg daily in severe infections and
meningitis; doses of 50 mg/kg and over infus.
 Body-weight 50 kg and over dose as for child
12–18 years
 Child 12–18 years 1 g daily; 2–4 g daily in
severe
infections and meningitis; i.m doses over 1 g
divided between more than one site; single i.v
doses above 1 g infus

BNF In PEDIATRIC 2011-2012

Farmakokinetik
 CEFTRIAXONE  CEFIXIME
 Accumulation of ceftriaxone in plasma was around
40% after 12-hourly intravenous injection, but
only 8% when administered at 24-hour
Ciprofloxacin

Bactericidal
Dose Dependent Antibiotics
Broad Spectrum (have more activity
againts gram negative bacteria)
Dosage in Typhoid fever : Oral : 500
mg every 12 hours for 10 days

AHFS
 PHARMACO CIPROFLOXACIN OFLOXACIN
KINETIC
Structure

Absorption Absorbed well in small intestinal their bioavailability is quite high, ranging
from 70 to 95 %. Oral absorptions is impaired by divalent cations, Including
those in antacids.
Peak Plasma 2.4 mcg/mL 2.9 mcg/mL
Concentration
t ½ elimination 3 – 5 hours 5 – 7 hours
Plasma Protein 16-43% 20-32%
Binding
Metabolized In Liver In Liver
 FLUOROQUINOLONE IN PAEDIATRICS
Ciprofloxacin safety in paediatrics: a systematic review

(Adefurin et al, 2011)

The use of ciprofl oxacin in paediatrics has been limited due to the
possibility of arthropathy
BUKTI ILMIAH
ANTIBIOTIK PADA
DEMAM TIFOID
Life Science Journal, 2011;8(2)
Kesimpulan
 Pedoman pemberian antibiotik empirik demam tifoid
setiap negara berbeda, tergantung dari pola resistensi
kuman Salmonella typhi
 Di Indonesia, terapi lini pertama menggunakan
kloramfenikol. Berdasarkan penelitian yang ada kuman
S.typhi masih sensitif terhadap antibiotik kloramfenikol
 Kuman S.typhi yang resisten terhadap kloramfenikol
dan beberapa antibiotik lain juga sudah ditemukan di
Indonesia
 Perlu penelitian lebih lanjut mengenai pola resistensi
kuman S.typhi di Indonesia untuk menentukan antibiotik
empirik yang tepat
Rekomendasi Choramfenycol
Kemenkes 2006 , penialian kemajuan terapi
Azithromycin in a dose of 500 mg (10
mg/kg) given once daily for seven days
has proved effective in the treatment of
typhoid fever in adults and children with
defervescence times similar to those
reported for chloramphenicol. A dose of 1
g per day for five days was also effective
in adults (42).
 Antibiotik empiris yang tepat sangat bermakna
menurunkan morbiditas dan mortalitas. Pemberian
seftriakson sebagai terapi empiris pada pasien demam
tifoid secara bermakna dapat mengurangi lama
pengobatan dibandingkan dengan pemberian jangka
panjang kloramfenikol. Hal lain yang menguntungkan
adalah efek samping dan angka kekambuhan yang lebih
rendah, serta lama demam turun yang lebih cepat.
Pengetahuan dan penilaian klinis yang baik diperlukan
dalam memilih terapi empiris yang tepat terutama
bila fasilitas uji resistensi tidak memadai. Seftriakson
terbukti dapat dijadikan sebagai antibiotik pilihan
utama pada kasus MDRST.
Antibiotik Umur Alasan
Siprofloksasin Kurang dari 12 tahun Merusak tulang rawan
(cartillage disgenesis)
Kotrimoksazol Kurang dari 2 bulan Tidak ada data
efektivitas dan
keamanan
Tiamfenikol Neonatus Menyebabkan Grey baby
syndrome
Azitromisin Neonatus Tidak ada data
keamanan