Typhoid Fever : 3rd Gen

Cephalosphorin vs Quinolone , what is

your choice?

Djoko Widodo

Division of Tropical Medicine and Infectious Diseases

Departement of Internal Medicine
Medical Faculty Univesity of Indonesia

MANIFEST0 Maret 2012

History of Typhoid fever
 1884 Scientist including George
Gafky (1850-1918) isolate and
culture the typhoid bacillus
 1894 The diagnostic Widal test
was introduced
 1904 Case of Marry Mallon
(typhoid Marry) as healthy carrier
of tyhoid
 1933 Bacterial of typhoid named
as Salmonella typhi by Daniel
Elmer Salmon (1850-1941)
 1948 Introducing of
chloramphenicol reducing
mortality of typhoid
Alexander The Great died when he was 34 years old due to acute fever
illness possibly due to typhoid fever or malaria
Prince Albert (1819-1861) husband of Queen Victoria dies due to Bowel fever
(typhoid fever)
 Typhoid Fever
 Typhoid fever is an acute systemic
infection caused by Salmonella enterica
serotype typhi or paratyphi which is also
known as Salmonella typhi
 Typhoid fever
 Global health problem and highly endemic in
Indonesia
 Global annual incidence 33 million cases and
15 million deaths.
 Incidence in Indonesia estimated 350-810
cases/100.000 population per year
 Case fatality rate 2.8-16%
 3 % of all mortality (50.000 death/year)

Seowandojo E, 1998
Epidemiologic Distribution of Typhoid Fever

♦ Strongly endemic
♦ Endemic
♦ Sporadic cases

J of Antimicrobial Chemoth 2009 ; J Infect Dev Ctries 2011

 Salmonella:
Structure, Classification, & Antigenic Types
1. Gram-negative, flagellated and
facultative anaerobic bacteria

2. The cell envelope contains a complex

lipopolysaccharide (LPS) structure.
(an outer O-polysaccharide coat, a
middle portion, the R core, and an
inner lipid A coat)

3. This LPS structure is thought as an

endotoxin, and important in
determining virulence of the
organisms.
 Some example of commonly
Occuring Salmonella serotypes and groups

Group Serotype
A S. paratyphi A
B S. paratyphi B
S. stanley
S. saintpaul
S. agona
S. typhimurium
C S. paratyphi C
S. choleraesuis
S. virchow
S. thompson
D S. typhi
S. enteritidis
S. dublin
S. gallinarium
 Method of Transmission:

 Ingestion of contaminated food or water

 The stools and urine of chronic carriers

usually contains from 106 to 109 organisms/g

 Raw shell fish from polluted water presents

with an enormous dose of S. typhi
 Factors that Influence Infectivity
 Ingestion of
– 105 organism cause clinical disease in 25%
– 107 organisms caused disease in 50%
– 109 organisms caused disease in 95%

 Strains that do not have ‘Vi antigen’ are less

infective and less virulent
Patterns of disease in Community:

 Developed Countries:
• Good sewage and water supply system
• Most cases are sporadic or imported or can be
traced to contact with chronic carriers
 Developing World:
• Chronic carriers are less important in transmission
• Peak in hot dry months or rainy season
• The incidence of typhoid fever is 2- 3 times that of
paratyphoid fever
 Risk factors for Typhoid & Paratyphoid Fever
in Jakarta

 Among 1019 subjects with fever, S.typhi was identified in

88 (9%) and S.paratyphi A in 26 (3%) patients
 Paratyphoid fever was independently associated with:
–consumption of food from street vendors
–and flooding.
 Typhoid fever using the community control group were
mostly related to the household, ie, to recent typhoid fever in
the household:
–no use of soap for handwashing;
–sharing food from the same plate,
–and no toilet in the household.
–also, typhoid fever was associated with young age in
years.
Vollaard, AM., JAMA. 2004;291(21):2607-2615
Pathogenesis
Pathogenesis (continue)
Pathology of typhoid fever
 Clinical Picture

• Fever • confusion, delirium

• Headache • psychosis
• malaise • convulsion
• myalgia • coated tongue
• nausea • bradicardia relative
• abdominal discomfort • tender abdomen
• constipation • hepatomegaly
• diarrhea • splenomegaly
• dry cough • rose spots
• epistaxis • erythmatous muco
papular lesion
Fever pattern in Typhoid Fever

Leucopenia
High fever Mild thrombocytopenia
Headache Relative neutrofilia
Abdominal discomfort Aneosinofilia
Diarrhea or constipation
Relative bradicardia

0 5 7 14
 Fever pattern : typhoid fever
Typhus Inversus Pattern
Lowest early in the morning
Highest about 5.30 to 6.30 pm
Can be found in typhoid fever
tuberculosis
Pulse Temperature dissosiation
In normal temperature 37oC (99oF) pulse 80 beats/min
Increased 9 beats/min every 1o C
Relative bradicardia can be found in
enteric/typhoid fever
mycoplasma, malaria falciparum
Devervescence : 3-7 days after treatment
usually on 2nd or 3rd weeks
 Laboratory Examination

Peripheral blood count leucopenia, leucocytosis

normal WBC count
mild anemia
thrombocytopenia
increased ESR
Inflammatory increased CRP
Serum transaminase increased ALT and AST
Albumin Hypoalbuminemia
Serology Widal,Typhidot
Tubex (Salmonella IgM)
Culture :b / m / s / u Gall culture
PCR Salmonella typhi
 Laboratory Diagnosis: Culture
 Culture: is essential for diagnosis.
• Blood culture
• Bone marrow aspirate culture
• Urine culture
• Stool culture
 Failure to isolate the organism usually due to:
• the limitations of laboratory media.
• the presence of antibiotics due to early empiric treatment
• small volume of the specimen cultured
• the time of collection
 Diagnostic criteria
 Definite :
Positive gall culture or PCR Salmonella typhi
Widal serology agglutinin O titer > 1/640
or H titer >1/1280
Increased of O titer twice or more
 Probable :
Widal serology agglutinin O titer 1/320
or H titer 1/640.
Blood culture and PCR results in diagnosis
of Typhoid Fever
 Diagnostic criteria
 Relapse of typhoid fever:
 1~3 weeks after temperature has reached normal.
 milder pattern to the primary attack.
 Blood culture is positive.
 Recurrence of typhoid fever:
 3~4 months after the illness.
 Blood culture is positive.
 Antibiotic resistance of typhoid fever: the ability
of a salmonella typhi to survive and reproduce in
the presence of antibiotic doses that were
previously thought effective against them
26
TYPHOID CLASSIFICATION WHO 2003

 Uncomplicated Typhoid fever

 Complicated Typhoid fever
 Confirmed case of typhoid fever
 Probable case of typhoid fever
 Chronic carrier of typhoid fever
 DIFFERENTIAL DIAGNOSIS
 Malaria
 ”Enteric fever-like” syndrome
 Enteric fever caused by Salmonella non-typhi
 Infectious hepatitis
 Atypical pneumonia
 Infectious mononucleosis
 Subacute bacterial endocarditis
 Tuberculosis
 Brucellosis
 Q fever
 Treatment
 Non Pharmacologic : Bed rest, Nutrition
 Pharmacologic
Symptomatic
Antibiotic :
Ampicillin/Amoxicillin
Chloramphenicol 4x500mg
Cephalosporin : Ceftriaxone 3-4 g/days
Fluoroquinolones : Ciprofloxaxin 2x500 mg
Ofloxacin 2x400 mg
Pefloxacin 1x400 mg
Fleroxacin 1x500 mg
Levofloxacin 1x500mg
 Treatment
Chloramphenicol
 The recommended dose is 50 - 75 mg / kg BW / day ,divided
into four doses ,for 14 days , or for at least 5 to 7 days after
defervescence.
 Oral administration gives slightly greater bioavailability than IM
or IV route.
 Chloramphenicol has been for decades the drug of choice for
typhoid fever and is still used in many endemic areas
 The disadvantages of its use include a relatively high rate of
relapse (57%), long treatment courses (14 days) and the
frequent development of a carrier state in adults.
 Treatment
Fluoroquinolones
 Optimal treatment for typhoid fever
 Relatively inexpensive, well tolerated and more rapidly and
reliably effective than the former first-line drugs ie .
chloramphenicol, ampicillin, amoxicillin and trimethoprim-
sulfamethoxazole. Microbial resistance is increasing against
these agents especially in India and Southeast Asia.
 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 3 to 5 days, and very low rates of post-treatment carriage.
 Treatment
Fluoroquinolones
 Ofloxacin 400mg BID, ciprofloxacin 750mg BID, Levofoxacin
500mg OD. Quinolones are contraindicated in children (<17y old)
and pregnant women. Resistance to quinolones is emerging.
Cephalosporins
 Ceftriaxone: 50-75mg/kg/day one or two doses
 Cefotaxime: 40-80mg/kg/day in 2-3 doses
 Cefoperazone: 50-100mg/kg/day
Other antibiotics:
- Trimethoprim-sulfamethoxazole is still considered by some the
drug of choice.
- Azithromycin has been shown effective in uncomplicated cases
and can be used for multiresistant strains.
 Clinical Trials of Fluoroquinolones
in Typhoid fever

Invest Year Medication Treatment number Clinical Bacterial

Igator duration cases efficacy efficacy

Arnold 1993 FLX 14 35 100 96

Nelwan 1993 PEF 7 20 100 100
Hien 1994 FLX 7 16 100 100
Nelwan 1994 OFL 7 12 100 100
Nelwan 1995 CIP 6 31 100 100
Duong 1995 FLX 5 41 97.5 94
Duong 1995 FLX 3 22 100 100
Nelwan 1997 FLX 3 4 100 100
COMPARISON OF DEFERVESCENCE IN TYPHOID FEVER

Name of Drug Dosage Duration Fever

Clearance

Ciprofloxacine(5) 500 BID 6 days 3,60 days

Ofloxacine(6) 600 mg OD 7 days 3,40 days

Pefloxacine(7) 400 mg OD 7 days 3,10 days

Fleroxacine(8) 400 mg OD 5 days 3,4 days

Acta Med Indones 2007;39 (1):22
South East Asia J Trop Med Pub Health 2006; 37 (1):126
Resistance pattern of S. typhi isolates

Deepak Arora. African J of Microbiology Research Vol. 4 (3), 2010

Resistance pattern of S. paratyphi ‘A’.

Deepak Arora. African J of Microbiology Research Vol. 4 (3), 2010

 Global distribution of MDRST
(Multi Drug Resistant Salmonella Typhi)
USA (1996-2003) Nalidixic Acid Canada (2009) Cefoxitin- Viet Nam (1997)
Resistance S. Typhi resistant Salmonella Quinolone-Resistant
USA (2005) Ceftiofur-Resistant S. typhi
Salmonella

Makassar (2007) :
resistant of S.typhi
infection 6,8%.

Cuba (2006), Jakarta FKUI/RSCM

Mexico (2007) (1990-1994 ) :
Multidrug-resistant resistant of S.typhi
salmonella infection 9,5%.

Ethiopia(2011) ; 86.5% multiply resistant Australia (2006) Antibiotic

to trim-sulpha, ceftr, chloram and genta, resistant Salmonella
ciprofl. infections

Clin.Infect.Diseases 1997; J of Antimicrobial Chemoth 2009 ;

Commun Dis Intell 2006; Antimicrobial agents and chemoth. 2005;
Antimicrobial agents and chemoth.
40 2007
J Infect Dev Ctries 2011
Antimicrobial Sensitivity in Typhoid fever
(RSCM/FMUI Januari - Juni 2011
 Group beta-lactam non-cephalosphorins
– Ampicillin : 4 (50%)
– Aztreonam : 4 (75%)
 Group cephalosphorins
– Cephalothin : 4 (0%)
– Cephopherazone : 3 (100%)
– Cefotaxime : 4 (75%)
– Ceftriaxon : 4 (100%)
 Quinolones
– Ciprofloxacin : 4 (100%)
– Levofloxacin : 4 (100%)
 Others antibiotic
– Chloramphenicol : 3 (100%)
– Cotrimoksazole : 4 (100%)
– Azythromycin : tidak ada data
Antimicrobial Sensitivity :
Salmonella Typhi/Paratyphi
Premier Hospital, Jatinegara,
Jakarta Timur
2009 – 2010
 Sensitivity (%)
2009 2010
oiAM ST 25 SPT 19 ST 19 SPT 16
AMC 100 100 100 100
AMK 0 0 0 0
AMX 100 100 100 100
CAZ 100 100 100 100
CHL 100 100 100 100
CIP 100 100 100 65
CTX 100 100 100 100
CXM 0 0 0 0
GEN 0 0 0 0
MEM 100 100 100 100
SXT 100 100 100 100
TZP 100 100 100 100

Premier Hospital, Jatinegara

Treatment of uncomplicated typhoid
Christopher , NEJM 2002
Treatment of severe typhoid
Christopher NEJM 2002
Treatment for Typhoid in
Pregnancy
 Chloramphenicol :Avoid in 3rd smst
- Prematurity, IUFD, Grey Syndrome
 Thiamphenicol ; Avoid in 1st smst :
- Teratogenic
 Avoid Fluoroquinolone & Co
Trimoxazole
 Suggestion : Ampicillin, Amoxicillin, &
Ceftriaxone
Treatment of Chronic Carriers of S. typhi:
 No Gall-Stones:
Oral Ampicillin/amoxicillin/TMP-SMX for 3
months
 Presence of Gall-stones:
Try above regimen prior to surgery
In most cases antibiotic plus
cholecystectomy required
Ciprofloxacin 750mg PO BID or Norfloxacin
400mg BID for 28 days
 Chronic urinary carriers:
Treat schistosomiasis first, if present,
before antibiotics
 Prevention

• Avoid risky food or drinks

• Hand washing
• Vaccination
• Detection of carrier state in food handler
Indication for hospitalization :

Severe Manifestations
Poor intake
Toxic typhoid
Perforation symptoms
 Conclusions
 Typhoid fever : acute systemic illness due to
Salmonella typhi and paratyphi
 Transmission : fecal oral : food – water
 Clinical manifestation :
Fever, GI symptoms, systemic symptoms
 Treatment : Supportive and symptomatic
Antimicrobial : FQ : Ciprofloxacin, etc
3rdG Cephalosporine :ceftriaxone
 Prevention : hand washing, avoiding non hygiene
food, vaccination and detection carrier
Thank you