Division Tropical Medicine and Infectious Diseases

Department of Internal Medicine

Medical Faculty Veteran National Development University

Gatot Soebroto Central Army Hospital

Permission and Adapted from Umar Zein, Tropical and Infectious Diseases Division Internal Medicine Department

AdamMalik Hospital Medan

BIO DATA

Nama : Dr. Soroy Lardo, SpPD FINASIMPangkat/Nrp : Letkol CKM/1920013110563Kesatuan : Departemen Penyakit Dalam RSPADStatus : K-3Riwayat Penugasan :Dokter Yonif 132/BS Kodam I/BB Pasiwatkes Rumkit Putri Hijau Kodam I/BBKa Rumkitban Binjai Kodam I/BBKa Bangsal Paviliun Rumkit Putri Hijau Kodam I/BBKasidiklitbang Departemen Paru RSPAD Gatot SoebrotoKabagyanmed Departemen Penyakit Dalam RSPAD Gatot

SoebrotoKasub SMF Penyakit Tropik dan Infeksi DepartemenPenyakit

DalamRiwayat Pendidikan :Fakultas Kedokteran UNPAD 1991Spesialis Penyakit Dalam Fakultas Kedokteran USU 2005

Term : Typhoid fever

Paratyphoid fever

Also known as : Enteric fever

It is an acute generalized infection of the

reticuloendothelial system, intestinal lymphoid tissue,

and gall bladder

Are severe systemic and life-threatening illnesses

characterized by sustained fever and abdominal

Symptoms

*

Etiology / Microbiology

Clinical Manifestations

Pathogenesis

Diagnosis

Treatment

Complications

SALMONELLOSIS Taxonomy : SALMONELLAE sp. : 2000 serotypes

Human infection : S. enterica subspesies enterica

which three serotypes :1. S. typhi 2. S. typhimurium (S. paratyphi A

and B), now called : S. schottmulleri

3. S. choleraesuisCHAMBERS. Infectious Diseases. In: Lawrence, et al. Current MD&T,34th Edition. A Lange medicalbook Int’l Ed. 1995;1173-9.

(Infections caused by Gram-negative bacteria)

Clinical Patterns of Infection

1. Enteric fever (typhoid fever), due to serotype typhi.

2. Acute enterocolitis, caused by serotype typhimurium.

3. Septicemic type, due to serotype choleraesuis, characterized by :

- bacteremia- focal lesions

This is responsible for 75% of reported cases of food poisoning in UKHow in INDONESIA ?

Microbiology :

Most commonly caused by Salmonella typhiSalmonella paratyphi A, B, CThe other serotypes : S.choleraesuis

S.enteretidis S.arizonae

Salmonellosis : Enteric fever Gastroenteritis

Sepsis

Facultative anaerobic/aerobic

Gram (-) bacteria

Rods shape

Family Enterobacteriaceae

Motile

Somatic

Flagelar

Viantigen

Susceptibility to Disinfectants :

1. 1 % Sodioum hypochlorite

2. 2 % Glutaraldehyde

3. Iodine

4. Phenolics

5. Formaldehyde

Physical Inactivation :

1. Sensitive to moist heat (1210C) for at least 15 min

2. Dry heat (160 – 1700C) for at least 1 hour

Survival outside Host :

Ashes – 130 days

Rabbit carcass – 17 days

Dust – up to 30 days

Feces – up to 62 days

Linoleum floor – 10 hours

Ice – 240 days

Epidemiology :Worldwide, except in industrialized regions such us the United State, Canada, western Europe, Australia, and Japan

In the developing world, it affects about 12.5 million persons each year

Over the past 10 years, travelers from the United States to Asia, Africa, and Latin America have been especially at risk

Typhoid fever can be prevented and can usually be treated with antibiotics

Multi-drug resistant strains have appeared in several areas of word

Indonesia 760 – 810 cases / 100.000 / year with death rate 3.1-10.4 %

Infectious Dose : 100,000 organism – ingestion

variable with gastric acidity

and size inoculum

Mode of Transmission :

1. Person-to-person

2. By contaminated food or water

3. By food contaminated by hand of carriers

4. Food contaminated by materials

5. Flies can infect food mechanical vector

Chronic carrierPatient

Healthysubject

StoolVomitUrine

Typhoid fever

IndirectInfection> 90 %

Direct Infection< 10 %

InfectedWaterFood

Route of Transmission of Typhoid Fever

Faktor Penentu Virulensi Salmonella thypi

Somatik (O) ada 2 determinanAntigen (endotoksin – LPS, aceltylated glucosamine dissaccharide lipid A

Capsular Vi (Polysaccharide (Vi) ada 2 determinan antigen (O)- acetyl – N acetyl carboxyl)

Flagella protein (H) antigen (fase 1 dan II)

Outer Membran Proteins (OMPS)

Porin (Omp B,C,D dan OmpR)

Non Porin

PatofisiologiMakanan yg

tercemar

Menembus

mukosa usus

Kelenjar limfe usus

(replikasi)

Duktus Torasiku

s

Masuk PD ke RES (hati, limpa, SST)

Ke Pembul

uh darah

Kapsul Vigagal

fagositosis Replikasi pesat

(7-10hari)

BAKTEREMIA 1

(24-72jam)

BAKTEREMIA2

Bakteremia ke-2

Endotoksin (LPS)

C3a, C5a

pirogen

Hipotalamus demam

IL-1

T-helperIL 2Limfosit BSel Plasma

& Agglutinin O

Limfosit T

Sel Plasma & Agglutinin H & Agglutinin Vi

Limfosit B

agglutinin O terbentuk lebih dahulu daripada agglutinin H dan agglutinin Vi. Aglutinin O cepat menghilang dalam beberapa tahun. Sedangkan agglutinin Vi menghilang setelah penderita sembuh tetapi cenderung menetap pada karrier.

Imunopatogenesis

Terdapat 4 komponen antigenic penting pada S typhi: 1. Kapsular Vi2. Lapisan luar (antigen O)3. Flagella protein (antigen H)4. Outer Membrane Protein (OMP) 3

2

14

S typhi

Resists the low pH of stomach

Reach SMALL INTESTINE

Membrane bound vacuoles enterocytes, SpiC

Bac must survive the antimiCrobial environment of macrophage, which includes the production of antimicrobial peptides and hydrolytic enzyme

Salmonella next penetrate the mucous layer of the gut

Bacterial proteins mediate in the ACTIN, a-actinin, trombomyosin, talin

Microfold cell (M cell)

Peyers patches, multiply in mononuclear phagocyte

Spread to the phagocyte of the liver, gallbladder & spleen

Bacteremia, endotoxin releaseCytokines, IL16, IL6, TNF-

alfa, TNF-R, p55

Clinical manifestation

Incubation Period : 1 – 3 weeks

depends on :

size of infecting dose

age

gastric acidity

immunologic status

Communicability :

As long as typhoid bacilli appear in excreta

Usually 1st week throughout convalescence

10 % of patients discharge bacilli for 3 months after onset

2 – 5 % become chronic carriers may shed bacteria for years

Clinical Manifestations (1):

Febril illness 5 to 21 days

Abdominal pain

chills

constitutional symptoms

in developed country : travelers or visitors from

endemic area

Clinical Manifestations (2):

Anorexia

Nausea

Vomiting

Diarrhea Pea soup stool

Enteric fever syndrome

Fever Chills

Headache Malaise Abdominal pain

Anorexia Weight loss weakness

Rose spots DIC Hepatomegaly

Splenomegaly

Bacteremia hypotension

Typhoid fever ( enteric fever )

Classic presentations :

First week of illness : “stepwise” fever &

bacteriemia

Second week : abdominal pain and rash

Third week : hepatosplenomegaly, intestinal

bleeding and perforation, secondary bacteriemia

and peritonitis

Clinical type of Vital Sign

Incubation periode Week1

Week2Week3 Week4 Chronic

periode

--- Blood pressure --- Temperature--- Pulse

Adapted from Syafruddin ARL RSPAD 2005

Tripple Cross

Normal

High

PATHOGENESIS :

10-12 daysS. Typhi Mouth Peyer’s patch Blood stream V.Velea Intestine Peyer’s patch

Small intestine :Plaque Peyeri Necrosis separation of slough Perforation

or healing ( ulceration, hemorrhages up to perforation ) or healed

Relaps orCarrier

(Stepwise fashion fever)

Pathogenesis :

Ingestion of S.typhi

Infection carried in theLymphoid follicle

Draining mesentericLymph node

Entering thoracic ductsPassed through the heart

Primary bacteremia

Liver, GB, Spleen,BMMultiply within MNPC

Secondary bacteremia

Enter the small intestine

Excreted in stool and Urine

Inflammation, necrosis,Ulceration Payer’s patches

MULTIPLICATION

End incubation period

Pathology :

Payer’s patches :

Hyperplasia during the first week Necrosis in second week Ulceration during third week Healing takes place without scarring during forth week The ulcer are oval shaped, in the long axis of lower ileum Separation of the sloughs hemorrhage and perforation

1.Isolation of Organism :

- Blood cultures : positive in 40 – 80 % patients

during the first 7 – 10 days

- Culturing stool

- urine

- rose spots

- duodenal contents via string capsule : positive in

30 – 40 % patients

- bile

- faeces

2. Detection of antigen in body fluid :

- Coagglutination

- Latex agglutination

- ELISA

- CIEP

Urine test Typhidot

3. Detection of antibodies :

- Widal tube test

- Widal slide test

- IHA

- CIEP

- RIA

- ELISA

Anemia

Leucopenia or leucocytosis

Thrombocytopenia

Abnormal liver function

1.Clinical Signs and Symptoms

2.Laboratory findings

3. Isolation of the organism

4.Detection of microbial antigen

5.Titration of antibody against causative agent

Skor Nelwan (Demam Tifoid) Dari hasil pemeriksaan klinis pada saat penderita masuk RS diambil data-data

sesuai dengan yang diajukan oleh Nelwan (1991). Ketepatan diagnosis demam tifoid dihitung dengan skor:

No Gejala Klinis Skor

1 Demam < 1minggu 1

2 Sefalgia (pusing) 1

3 Rasa lemah 1

4 Mual 1

5 Gangguan motilitas saluran cerna 1

6 Nyeri perut 1

7 Anoreksia 1

8 Susah tidur 1

9 Splenomegali 1

Skor Nelwan (2)

No Gejala Klinis Skor

10 Hepatomegali 1

11 Muntah 1

12 Demam > 1minggu 2

13 Apatis 2

14 Lidah tifoid 2

15 Bradikardi relatif 2

16 Feses hitam 2

Skor Maksimal 20

Nilai ramal demam tifoid = skor/20 x 100% menunjukkan persentase kemungkinan terjangkitnya pasien dengan salmonella typhi atau paratyphi. Dari studi yang dilakukan skor 13 ke atas sudah mengarah ke diagnosis demam tifoid, sedangkan skor di bawah 7 kecil kemungkinan penderita terjangkit demam tifoid.

Kesimpulan Penelitian : SENSITIFITAS DAN SPESIFISITAS DIAGNOSIS KLINIS DALAM

MENDIAGNOSIS DEMAM TIFOID PENDERITA RAWAT INAP DI BANGSALPENYAKIT DALAM RSUP SARDJITO (TAHUN 1998-2000)

 Sri Wahyuni, Soebagjo Loehoeri, Nurfaita Mislihar

Subbagian Penyakit Tropik dan Infeksi, Bagian Ilmu Penyakit DalamFK-UGM/RSUP Dr. Sardjito Yogyakarta

Konas Petri Malang 2005

1.      Gejala yang dominan pada kasus demam tifoid adalah demam, nausea, lidah tifoid dan bradikardi relatif.

2.      Hasil perbandingan diagnosis klinis terhadap diagnosis laboratoris memiliki sensitifitas sangat rendah (18,18%), spesifisitas tinggi (87,5%), nilai ramal positif rendah (25%) dan nilai ramal negatif tinggi (84%). Berdasarkan indikator-indikator tersebut dapat dinyatakan kurang efektif untuk digunakan sebagai pegangan diagnosis. Perlu pendukung yang lain

yaitu dengan pemeriksaan laboratoris.

Suspect Typhoid cases

General Nursing care and Diet

Specific antibiotic therapy

Treatment of Chronic carriers

Management of complications

Antibiotic Therapy :

Chlaramphenicol 4 X 500 mg 11-14 days Ampicillin 50 -100 mg /kg BW/ day Trimetropin – sulfametoksazole 2 x 2 tab Ceftriaxone 50 – 100 mg/ kg BW / day Cefoperazone 100 mg/kg BW/ day Cefotaxim 2 – 3 x 1 gr Ciprofloxacin 2 x 500 mg Fleroksasin 1 x 400 mg Ofloxacin 1 x 600 mgPerfloxacin 1 x 400 mg Levofloxacin 1 x 500 mg

DISKUSI

• Tabel 1. Perbandingan Reda Demam (Defervescence) Demam Tifoid Non-Komplikata FluorokuinolonNama Obat Disis Lama

PemberianPenurunan Demam

Siprofloksasin (5) 500 BID 6 hari 3,60 hari

Ofloksasin (6) 600 mg OD 7 hari 3,40 hari

Pefloksasin (7) 400 mg OD 7 hari 3,10 hari

Fleroksasin (8) 400 mg OD 5 hari 3,40 hari

Levofloxacine (9) 500 mg OD 7 hari 2,43 hari

DISKUSI

• Tabel 2. Betalaktam untuk pengobatan demam tifoid

Beta Laktam Dosis Lama Pemberian

Ampisilin 4x1 gram IV atau Oral

Dua minggu

Amoksisilin 50-150mg/kgBB/hari

Dua minggu

Sefiksim 10-15mg/kgBB/hari Sepuluh hari

Seftriakson 4 gram/hari Tiga hari

3 gram/hari Empat hari

2 gram/hari Enam hari

DISKUSI

• Tabel 3. Berbagai jenis antimikroba untuk demam tifoid

Antimikroba Dosis Lama Pemberian

Kloramfenikol Hari ke 1 4x250 IV/oral

Hari ke 2 4x500 IV/oral

2 minggu

Kotrimoksazol 2 x 2 tab oral 2 minggu

Azitromisin 2 x 500 mg IV/oral 1 minggu

Aztreonam 3 x 1 gram IV 1 minggu

Multi drugs Resistance Salmonella typhi (MDRST)

Resistance to :

• Chloramphenicol

• Amoxycillin

• Cotrimoxazole

Komplikasi ( Dikutip dari Butler dan Scheld, 2004)

Abdomen Perforasi usus terutama ilium , terjadi pada 1- 3 %Pendarahan saluran cerna, terjadi pada 10 % pasienHepatitisKholesistitis

Kardiovaskuler Perubahan elektrokardiografi asimptomatisMiokarditisSyok

Neuropsikiatri Ensefalopati, Delirium, Psikotik, MeningitisGangguan Koordinasi

Respirasi BronkhitisPneumonia

Hematologi AnemiaKoagulasi intravaskular Diseminata (KID)

Lain lain Abses LokalFaringitisRelapsKarier khronis

Penelitian Kompilasi Tifoid dari RS Sanglah Denpasar:

Pada 49 penderita dengan komplikasi tersebut 43 (87,7) orang datang dengan keluhan utama demam, 38 (77,5) orang datang ke rumah sakit pada akhir minggu pertama hingga minggu kedua setelah demam. Sebanyak 7 (14,2) datang pada minggu ketiga setelah demam. Keluhan utama penderita lainnya : kesadaran menurun 1 (2,0) , nyeri ulu hati 1 (2,0), mual muntah 1 (2,0) dan 3 (6,1) dengan berak darah. Komplikasi yang terjadi pada penderita baik intestinal (24,4) maupun ekstra intestinal (75,5), adapun jenis komplikasi yang terjadi pada penderita dapat dilihat pada grafik 1.

24.4

24.436.7

16.710.2 2.1 Hepatitis tifosa

Perdarahan usus

Tifoid toksik

Pneumonia

Meningitis

Artritis

Tabel 1. Komplikasi demam tifoid di beberapa RS di Indonesia.5-10

Komplikasi

(%)

Nama peneliti

Hendarwanto

1979

Loehoeri

1994

Yogya

Darmanik

1994

Herdiman

1997

Ratih

2002

Denpasar

PerdarahanPerforasiSyok septikPneumoniaDICHepatitisMeningitisTifoid toksikArtritis

14,1-

5,42,22,21,1---

3,070,444,334,38

-18,4

---

81,80,97,1-

1,8---

44,411,1

-16.611,127,7

---

24,4--

16,3-

24,410,236,7

2

Komplikasi Demam Tifoid Pada Penderita Dewasa di Bangsal Menular RS Sanglah Denpasari.a.ratih wulansari manuaba*, tuti parwati merati**, sjaiful I biran**

**Divisi Tropik dan Infeksi *Lab/SMF. Penyakit Dalam, FK UNUD/RS Sanglah, Denpasar Konas Petri Malang 2004

10.2

57.1

22.4

4

6.1

0 10 20 30 40 50 60

> 20 hari

16 - 20 hari

11 - 15 hari

6 - 10 hari

1 - 5 hari

Lama perawatan penderita dengan komplikasi.

Biliary carriers

Urinary carriers

Intestinal carriers (faecal)

1- 5 % thypoid patient

Problem : cholelitiasis dan nephrolitiasis

Tifoid carrier treatmentAntibiotic treatment of tifoid carrier fever

Without cholelithiasis complication1. Ampicillin 100 mg/kgbw/day + probenecid 30 mg/kgbw/day2. Amoxicillin 100 mg/kgbw/day + probenecid 30 mg/kgbw/day3. Trimethroprim Sulphametoxazol 2 tabs twice/day

With cholelithiasis complicationCholesistektomi + regimen above for 28 days, 80 %

curable or cholesistektomi with one of the regimen below:

1. Ciprofloxacin 750mg/ twice perday 2. Norfloxacon 400 mg/ twice /dayCefixime 400 mg bid for 6 days for MDR or non MDR

Prevention

Decontamination : HospitalizationLouse control: Bathing and laundering of clothes

in hot water with detergent Reduction of exposure Identification and eradication Prevention of transmission Protection of the risk infection

Typhoid Vaccines :

1. Parenteral killed whole cell vaccines

* Heat and phenol killed

* Acetone killed and dried

2. Live attenuated Ty21a vaccine (TYPHORAL@ )

3. Polysaccharide subunit vaccine (TYPHIM V@)

Vaksinasi Tifoid Tsunami NAD 3-4 Januari 2005

Vaskinasi Tifoid di Tsunami NAD 2-4 Januari 2005

Tsunami NAD 3-4 Januari 2005

TERIMA KASIH

References :

1. Hohmann, L.E : Approach to the patient with typhoid fever, @2000 UpToDate.www.uptodate.com.(800)998-6374.(781)273-4788

2. Salmonella typhi, From : http://www.medinfo.ufl.edu/year2/mmid/bms5300/bugs/saltyphi.html

3. Material Safety Data Sheet – Infections Substances, Section I : Infectious Agent, From : http://www.hc-sc.gc.ca/pphb-dgspsp/msds-ftss/msds134e.html

4. Typhoid Fever, From : http://www.cdc.gov/ncidod/dbmd/diseaseinfo/typhoidfever_g.htm

5. Ichhpujani, R.L , Bhatia, R : Typhoid Fever, Top Publications, 4093, Nai Sarak, Delhi 110 006, India, 1997.

6. Zulkarnaen,I : Pola Kepekaan Salmonella typhi terhadap beberapa antibiotika,Demam Tifoid, Peran Mediator, Diagnosis dan Terapi, Subbgian Penyakit Tropik dan Infeksi FK UI, Jakarta, 2000

7. Suhendro, Inada,K , Hendarwanto, Zulkarnain,I : Patterns of Cytokine and Nitric Oxide in Typhoid Fever, Demam Tifoid, Peran Mediator, Diagnosis dan Terapi, Subbgian Penyakit Tropik dan Infeksi FK UI, Jakarta, 2000

8. Nasronudin. Demam Tifoid. Dalam Penyakit Infeksi di Indonesia dan Solusi Kini dan Mendatang. Edisi ke 2. Airlangga University Press. 2011 , Surabaya. h: 187 -190

9. Nasronudin. Imunopatogenesis, Diagnosis dan Tata Laksana Demam Tifoid Masa Kini. Dalam Penyakit Infeksi di Indonesia dan Solusi Kini dan Mendatang. Edisi ke 2. Airlangga University Press. 2011 , Surabaya. h: 191-208