Typhoid Fever,

(Salmonella)

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 Typhoid fever

Infectious
Disease

Deepika Gupta1, Jayanti Tokkas2, Shalini Jain3 and Hariom Yadav3*

1Amity University,Noida, UP, India; 2Biochemistry Department, CCS-HAU, Hisar,
India
3NIDDK, NIH, Bethesda, MD, USA; *Email: yadavhariom@gmail.com
 Overview

Salmonella is a rod-
shaped, gram-
negative, facultative
anaerobe in the
family
Enterobacteriaceae

Rod togkat

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4
Salmonella enterica.
 Typhoid Fever
Typhoid fever is a systemic infection with the
bacterium Salmonella enterica serotype
typhi.
A subset of Salmonella serotypes that
includes S. typhi and S. paratyphi causes
enteric (typhoid) fever and is restricted to
growth in human hosts.
Clinically S. typhi > S. paratyphi

Restrc batsi
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 Classification
Enterobacteria
Gram-negative
Facultative anaerobes
Glucose-
fermenting/mmuai
Straight, rod
2-3 m in length
Flagellated
Many serovars
Typhi
Typhimurium
Enteriditis
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 /carrier

This is a membrane of S.
typhi. Other serovars do
not have the outer capsule.
Notice parts of
LPS/Lipopolysaccharide.
Lipid A (conserved)mkna.
Polysaccharide part is
variable, especially O
polysaccharide (what
antibodies bind to) 9
 Infection

Ingestion of contaminated
food or water
Passes through mucosa of
intestine to epithelial cells
Causes membrane ruffling/
mengkerut
Releases effector proteins
through Type III Secretion
system
Endocytosis

Ruffmgerut 10
 Salmonella
Salmonella can be further
divided into serovars based
on the detection of three
major antigenic
determinants:
the somatic O antigen
[lipopolysaccharide
(LPS) cell-wall
components]
the surface Vi antigen
(restricted to S. typhi
and S. paratyphi
C),/carrier
the flagellar H antigen.

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 Epidemiology
Endemic in developing contries
Incubation period : 3 d 3 m (1-3 wk)
Transmission :
most cases of disease result from
ingestion of contaminated food or water
anal-oral transmission
health care workers

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(grm(-)

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 Pathogenesis
Disebabkan ok S.typhi dan endotoksinnya merangsang
sintese.Penularan S.thypi terjadi melalui mulut,oleh makanan yg
tercemar.Sbgn akan dimusnahkan melalui lambung oleh asam
lambung,sgbn masuk ke usus halus,mencapai jaringan limfoid,lalu
berkembang biak.Kuman masuk aliran darah,mencapai sel-sel
retikuloendotelial : hati,limpa,organ lain.Proses ini terjadi pada masa
tunas,yg berakhir saat sel-sel retikulo endotelial melepaskan kuman
kedalam peredaran darah dan menimbulkan bakteriemi yg kedua
kalinya.Masuk limpa,usus,kandung empedu.Penelitian dahulu
mengira demam ok endotoksin.

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Salmonella typhi infecting the body via the
Peyer's patches of the small intestine. The
bacteria migrates to mesenteric lymph nodes and
arrive via the blood in the liver and spleen during
the first exposure. After multiple replication in
the above locations, the bacteria Migrates back
into the Peyer's patches of the small intestine for
the secondary exposure and consequently the
clinical symptoms are seen. Inflammation in the
small intestine leads to ulcers and necrosis.
How does the bacteria cause disease ?
 Pathogenesis
Penemuan berikutnya menyatakan endotoxin
bukan penyebab utama demam.Endotoksin
S.typhi berperan pd patogenesis typhoid,ok
membantu terjadinya proses inflamasi lokal pd
jaringan tempat dimana S.typhi berkembang
biak.
Demam pd tifoid disebabkan ok S.typhi dan
endotoksinnya merangsang sintesis dan
penglepasan zat pirogen oleh lekosit pd
jaringan yg meradang.
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 PATOLOGI
Kelainan patologi utama terjadi di usus halus,di ileum distal.
Pada minggu pertama penyakit,terjadi hiperplasi plaks Peyer
,disusul minggu kedua terjadi nekrosis,dalam minggu ketiga terjadi
ulserasi plak Peyer,minggu keempat terjadi penyembuhan
ulkus,meninggalkan sikatriks.Ulkus dpt menyebabkan
perdarahan,sampai perforasi usus.
Hepar mebesar dg infiltrasi limfosit,sel plasma dan sel mono
nukler,serta nekrosis fokal.
SRE menunjukkan hiperplasi dan kelenjar mesenterika dan limfe
membesar.
Kelaian patologik juga dpat dijumpai pd ginjal,paru,jantung,selaput
otak,otot,tulang.

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 Pathogenesis
The bacteria traverse the gastrointestinal tract, including the acidic
environment of the stomach, to colonize the small intestines.
Salmonellae cross the intestinal barrier, where phagocytosis by
macrophages results in their dissemination throughout the
reticuloendothelial system.
Once salmonellae reach the small intestine, the bacteria resist/melawan
a variety of innate immune factors before penetrating the mucus layer.
The organisms enter the intestines through phagocytic microfold or M
cells overlying the Peyer's patches.
Salmonellae (S. typhi or S. paratyphi) undergo/mngalami phagocytosis
by macrophages after crossing the epithelial layer of the small intestine.

undergmngalam 19
 Pathogenesis
Once phagocytosed, the bacteria are protected from PMNs)
the complement system, and antibodies.
After phagocytosis, salmonellae disseminate throughout the
body in macrophages via the lymphatics and colonize
reticuloendothelial tissues (liver, spleen, lymph nodes, and
bone marrow).
Signs and symptoms, including fever and abdominal pain,
probably result from secretion of cytokines by macrophages
when a critical number of organisms have replicated. .

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Patofisiologi

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 GAMBARAN KLINIS
Masa tunas 10-14 hari.
Gejala amat bervariasi,dari yg ringan,tdk terdiagnosis sp
yg khas,komplikasi sp kematian.Seorang yg ahli pun dpt
mengalami kesulitan untk mendiagnosis.
Minggu pertama,spt flu like syndrome,demam,nyeri
kepala,pusing,nyeri
otot,anoraksi,mual,muntah,obstipasi,diare dll.
Px suhu meningkat
Minggu kedua gejala lebih jelas,demam,relatif bradi
kardi,lidah kotor(kotor ditengah,tepi dan ujung
merah,tremor),hepatomegali,splenomegali,meteorismus,
ggn mental,stupor,koma,delirium.
Roseolae di Indonesia jarang dtemukan.

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Rose spot

Prolonged fever, rose spots, relative

bradycardia and leucopenia make typhoid
strongly suggestive.

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Rose spots

Prolonged fever, rose spots,

relative bradycardia and
leucopenia
make typhoid strongly
suggestive.
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 Symptoms

No symptoms - if only a mild exposure; some people become "carriers" of

typhoid.
Poor appetite,
Headaches,
Generalized aches and pains,
Fever, Lethargy, Lethargy,
Lethargy,
Diarrhea,
Have a sustained fever as high as 103 to 104 degrees Fahrenheit (39 to 40
degrees Celsius),
Chest congestion develops in many patients, and abdominal pain and
discomfort are common,
Constipation, mild vomiting, slow heartbeat.
Rose spots Aches and pains High fever

Diarrhea

Chest congestion
Typhoid Meningitis
 Time frame
Occurs gradually over a few weeks after exposure to the bacteria.
Sometimes children suddenly become sick.
The condition may last for weeks or even a month or longer without
treatment.

First-Stage Typhoid Fever

The beginning stage is characterized by high fever,fatigue, weakness,
headache, sore throat, diarrhea, constipation, stomach pain and a skin
rash on the chest and abdominal area. According to the Mayo Clinic,
adults are most likely to experience constipation, while children usually
experience diarrhea.
 Second stage
Second-stage typhoid fever is characterized by weight loss, high fever,
severe diarrhea and severe constipation. Also, the abdominal region
may appear severely distended.

Typhoid State
When typhoid fever continues untreated for more than two or three
weeks, the effected individual may be delirious or unable to stand and
move, and the eyes may be partially open during this time. At this point
fatal complications may emerge.
Relative bradicardia

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Widal Test

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Widal Test
Adalah reaksi aglutinasi antara antigen anti
bodi(aglutinin).
Aglutinin yg spesifik thd salmonela tdpt pd serum
penderita tyfoid,juga pd yg pernah ketularan
salmonela.atau yg pernah divaksinasi.thd tifoid.
Antigen yg digunakan pd reaksi Widal adalah suspensi
salmonella yg sdh dimatikan dan diolah di lab.
Maksud reaksi Widal dalah untk menetukan adanya
aglutinin dlmserum penderita yg diduga menderita
typhoid.

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Widal Test

Pada infeksi yg aktif,titer Widal akan meningkat

pd pemeriksaan ulang yg dilakukan selang 5
hari.
Kenaikan titer empat kali lipat pd pemeriksaan
ulang dpt memastikan diagnosis.
Pada pndrta yg sembuh,aglutinin akan berada
dlam darah dl wkt lama,mk reaksi Widal bukan
menrupakan para meter kesembuhan
penderita.
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 Medication
Antibiotics

Antibiotics, such as ampicillin, chloramphenicol, fluoroquinolone

trimethoprim-sulfamethoxazole, Amoxicillin and ciprofloxacin etc used to
treat typhoid fever.

Prompt treatment of the disease with antibiotics reduces the case-fatality

rate to approximately 1%.
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 Fluoroquinolones

Optimal for the treatment of typhoid fever

Relatively inexpensive, well tolerated and more rapidly and reliably

effective than the former first-line drugs, viz. chloramphenicol, ampicillin,
amoxicillin and trimethoprim-sulfamethoxazole.

The majority of isolates are still sensitive.

Attain excellent tissue penetration, kill S.typhi in its intracellular stationary

stage in monocytes/macrophages and achieve higher active drug levels in
the gall bladder than other drugs.

Rapid therapeutic response, i.e. clearance of fever and symptoms in three

to five days, and very low rates of post-treatment carriage.
 Chloramphenicol

Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth

by inhibiting protein synthesis.

The recommended dosage is 50 - 75 mg per kg per day for 14 days

divided into four doses per day, or for at least five to seven days after
defervescence.

Oral administration gives slightly greater bio availability than

intramuscular (i.m.) or intravenous (i.v.) administration of the succinate
salt.

The disadvantages of using chloramphenicol include a relatively high

rate of relapse (57%), long treatment courses (14 days) and the frequent
development of a carrier state in adults.
 Cephalosporins

Ceftriaxone: 50-75 mg per kg per day one or two doses

Cefotaxime: 40-80 mg per kg per day in two or three doses

Cefoperazone: 50-100 mg per kg per day

 Amoxicillin (Trimox, Amoxil, Biomox)

Interferes with synthesis of cell wall mucopeptides during active

multiplication, resulting in bactericidal activity against susceptible bacteria.
At least as effective as chloramphenicol in rapidity of defervescence and
relapse rate.
Convalescence carriage occurs less commonly than with other agents when
organisms are fully susceptible.
Usually given PO with a daily dose of 75-100 mg/kg tid (three times a day)
for 14 d.
Adult
1 g PO q8h
Pediatric
20-50 mg/kg/d PO divided q8h for 14 d
 Trimethoprim and sulfamethoxazole
Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Antibacterial activity of TMP-SMZ includes common urinary tract
pathogens, except Pseudomonas aeruginosa.
As effective as chloramphenicol in defervescence and relapse rate.
Trimethoprim alone has been effective in small groups of patients.
Dosing
Adult
6.5-10 mg/kg/d PO bid/tid; can be given IV if necessary; 160 mg
TMP/800 mg SMZ PO q12h for 10-14 d
Pediatric
<2 months: Do not administer
>2 months: 15-20 mg/kg/d PO, based on TMP, tid/qid for 14 d
 Dexamethasone (Decadron)

Prompt administration of high-dose dexamethasone reduces mortality in

patients with severe typhoid fever without increasing incidence of
complications, carrier states, or relapse among survivors.

Initial dose of 3 mg/kg by slow i.v. infusion over 30 minutes.

1 mg/kg 6 hourly for 2 days.

 Antibiotic resistance

MDR is mediated by plasmid The genes for antibiotic resistance in S

typhi and S paratyphi are acquired into a region called an integron from
Escherichia coli and other gram-negative bacteria via plasmids.

Quinolone resistance is frequently mediated by single point mutations in the

quinolone-resistancedetermining region of the gyrA gene.

Nalidixic acid resistant: MIC of fluoroquinolones for these strains was 10

times that for fully susceptible strains.
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 Complications
Complications occur in 10 to 15 percent of patients
Gastrointestinal bleeding, intestinal perforation, and
typhoid encephalopathy are the most important.
Gastrointestinal bleeding is the most common,
occurring in up to 10 percent of patients. It results
from erosion of a necrotic Peyers patch through the
wall of an enteric vessel.

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Complications

Intestinal bleeding or
perforation

The most serious complication

of typhoid fever

Other, less common

Myocarditis
Pneumonia
pancreatitis
UTI
Osteomyelitis
Meningitis
Psychiatric problems
Complications

Intestinal hemorrhage
Commonly appear during the second-third week
may be mild or severe bleeding
often caused by unsuitable food, and diarrhea

serious bleeding in about 2~8%

clues: sudden drop in temperature, rise in pulse, and
signs of shock followed by dark or fresh blood in the
stool.
Intestinal perforation:
more serious. Incidence:1-4%
Commonly appear during 2nd-3rd week.
Take place at the lower end of ileum.
Before perforation,abdominal pain or
diarrhea,intestinal bleeding .
When perforation: abdominal pain, sweating, drop in temperature,
and increase in pulse rate, then rebound tenderness +ve
reduce or disappear in the dullness of liver, leukocytosis .
Temperature rise when peritonitis appear.
free air in abdominal x-ray.
 Toxic hepatitis:
common,1-3 weeks
hepatomegaly, ALT elevated
get better with improvement of disease in 2~3 weeks
Toxic myocarditis.
seen in 2nd-3rd week, usually severe toxemia.
Bronchitis, bronchopneumonia.
seen in early stage
 TREATMENT
1-General :
Isolation and rest
suitable diet include easy digested food or
half-liquid food and drinking more water
IV fluid to maintain water and acid-base and
electrolyte balance
Symptomatic : antipyretic
 Drug treatment
Ciprofloxacin: 15 mg/kg/d for 7 days
For quinolone-resistant: azithromycin
10mg/kg/d for 7 days OR ceftriaxone
75mg/kg/d for 10-14 days
 steroids
dexamethasone: initial dose 3 mg/kg by slow
i.v. infusion over 30 minutes and after six hours,
1 mg/kg is administered and subsequently
repeated at six-hourly intervals on seven further
occasions, mortality can be reduced by some 80-
90% in high-risk patients (high fever with
obtundation and meningeal irritation signs)
 Carrier
Asymptomatic and have positive stool or rectal
swab cultures for S. typhi a year following
recovery from acute illness.
Treatment: co-trimoxazole 2 tab twice/d for 6
wk, OR
ciprofloxacin 750 mg twice/d for 4 wk
 Carrier
Carriers should be excluded from activities
involving food preparation and serving/porsi.
Food handlers should not resume their duties
until they have had three negative stool cultures
at least one month apart.
Vi Ab is used as a screening technique to
identify carriers among food handlers and in
outbreak investigations. Vi Abs are very high in
chronic S. typhi carriers
 Relapse

Apparent recovery can be followed by

relapse in 5 10 % of untreated patient
culture +ve of S.typhi after 1-3 wks of
defervescence
Symptom and signs reappear
the bacilli have not been completely
removed
Prognosis:
Case fatality 0.5-1%.
but high in old ages, infant, and serious
complications
immunity long lasting
About 3% of patients become fecal
carriers .
Prophylaxis

Wash your hands.

Avoid drinking untreated

water.

Avoid raw/mentah fruits and

vegetables

Choose hot foods.

THE END
 Terima kasih

Helai ilalang jadi pena, dan lautan jadi tinta, takkan cukup untuk menulis ilmuMU

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