Curriculum

Vitae
Dr. Adityo Susilo, SpPD, K-PTI, FINASIM

• PENDIDIKAN
Dokter Umum : FKUI
Dokter Spesialis : FKUI
Dokter Konsultan : FKUI

• PEKERJAAN
Staf Pengajar dan Staf Medis Divisi Penyakit Tropik dan Infeksi
Departemen Ilmu Penyakit Dalam, FKUI/RSCM

• ORGANISASI
IDI : Anggota
PB PAPDI : Wakil SekJen
PP PETRI : Wakil SekJen (demisioner)
 Update on Typhoid Fever Management

KoNas PETRI 2019 – Malang

Adityo Susilo

Division of Tropical and Infectious Diseases, Internal Medicine

FMUI/Cipto Mangunkusumo Hospital/Universitas Indonesia Hospital
 Introduction
• Typhoid and paratyphoid fevers, collectively referred to as enteric
fever, are caused by systemic infection with Salmonella enterica
subspecies serovars Typhi and Paratyphi A, B, and C.

• Whereas most non-typhoidal Salmonella spp infections typically

produce diarrhoeal illness and less commonly cause bloodstream
infection, typhoid and paratyphoid infections produce primarily
bacteraemic febrile illnesses, with prolonged high fever, headache,
and malaise being characteristic symptoms.

• Without effective treatment, typhoid and paratyphoid fevers can

lead to altered mental states (termed the typhoid state), ileus,
gastrointestinal bleeding, intestinal perforation, septic shock, and
death.

• GBD 2017 Typhoid and Paratyphoid Collaborators. Lancet Infect Dis 2019; 19: 369–81
• Harris JB, Brooks WA. Typhoid and paratyphoid (enteric) fever.
In: Magill AJ, Ryan ET, Hill DR, Solomon T, eds. Hunter’s tropical medicine and emerging infectious diseases, 9th ed. Elsevier, 2013:
 Epidemiologic Distribution of Enteric Fever

Wain et al. Typhoid fever. Lancet 2015; 385: 1136–45

GBD 2017 Typhoid and Paratyphoid Collaborators. Lancet Infect Dis 2019; 19: 369–81
 Causes of deaths worldwide

Wain et al. Typhoid fever. Lancet 2015; 385: 1136–45

 Pathogenesis :
Non-Typhoidal vs Typhoidal Salmonella (Enteric Fever)

Dougan G, Baker S. Salmonella enterica serovar typhi and the pathogenesis of typhoid fever. Annu Rev Microbiol. 2014;68:316-36.
Pegues DA, Miller SJ. Salmonellosis. Dalam: Harrison’s principle of internal medicine. 19th edition. McGraw-Hill. 2015.
 Disease Course and Clinical Manifestation

de Jong HK, Parry CM, van der Poll T, Wiersinga WJ (2012) Host– Pathogen Interaction in Invasive Salmonellosis. PLoS Pathog 8(10): e1002933. doi:10.1371
Published Guidelines
Standard case definitions/classifications of
Typhoid fever
 Diagnostic approaches
• Clinical
– History taking, symptoms and signs
– Physical examination)

• Laboratories
– Culture/PCR
– Serology

• Case definition – Typhoid Fever/Paratyphoid Fever

 General Management
• Supportive measures are important in the management of
typhoid fever.
– Oral or intravenous hydration
– Antipyretics
– Appropriate nutrition and blood transfusions if indicated.

• More than 90% of patients can be managed at home with

oral antibiotics, reliable care and close medical follow-up
for complications or failure to respond to therapy

• Patients with persistent vomiting, severe diarrhoea and

abdominal distension may require hospitalization and
parenteral antibiotic therapy.

WHO Guidelines. 2003

 The importance of Antipyretics
• Reduction of fever not only offers substantial
benefit to a patient’s well-being but the
metabolic compromise of sustained fever may
potentiate risks associated with common co-
morbidities encountered in hospitalized patients.

• Options :
– Acetaminophen/Paracetamol
• oral, iv
– Methampyrone
• oral, iv
– Ibuprofen
• oral, iv ?
Bookstaver et al. Journal of Pain Research 2010:3 67–79
 Ibuprofen
• The antipyretic effects of
NSAIDs are well documented

• Inhibition of COX-1 to block

the conversion of
arachidonic acid to
prostaglandins such as PGE
in the immune response
pathway.

• Oral ibuprofen is a COX-1 blockage

commonly used NSAID with
antipyretic,
antiinflammatory, and
analgesic properties.
Mainstay in the treatment of
acute pain and fever(OTC).

• iv prep. ?

Bookstaver et al. Journal of Pain Research 2010:3 67–79

Bunga rampai Tropik Infeksi.
 Safety issues NSAIDs
• Gastrointestinal
• Renal
• Cardiovascular
• Hepatotoxicity
• Soft tissue
infections

Favors PCT Favors IBP

Kanabar DJ. A clinical and safety review of paracetamol and ibuprofen in children. Inflammopharmacol (2017) 25:1–9
 Platelets
Renal Fx.

Southworth et al. Journal of Pain Research 2015:8 753–765

 Dosing and Administrations
• The lowest effective dose should be used for the shortest duration
consistent with individual patient treatment goals.
– Maximum daily dose is 3200 mg.
– Patients should be hydrated prior to administration (renal risk)

• For analgesia 400 mg to 800 mg should be administered (iv) every 6

hours as necessary.

• For fever 400 mg (iv) followed by 400 mg every 4 to 6 hours or 100

to 200 mg every 4 hours should be administered as necessary.
– Minimum infusion time is 30 minutes.
– Rapid infusion (5-7 min) risk of phlebitis

Bookstaver et al. Journal of Pain Research 2010:3 67–79

 Definitive treatment : Antibiotics
• Antimicrobial susceptibility testing is crucial for the guidance of
clinical management. Isolates from many parts of the world are
now multidrug-resistant (MDR)

• First line drugs : ampicillin, chloramphenicol, trimethoprim-

sulfamethoxazole

• Alternative drugs that are used for treatment include:

fluoroquinolones (e.g. ciprofloxacin), third-generation
cephalosporins (e.g. ceftriaxone, cefotaxime), a monobactam beta-
lactam (aztreonam) and a macrolide (azithromycin).

• Even though resistance has been noted they nevertheless remain

useful.
Rowe B, Ward LR, Threlfall EJ. Multidrug-resistant Salmonella typhi: a worldwide epidemic. Clinical Infectious Diseases 1997; 24(Suppl 1): S106-9.
Bhutta ZA. Impact of age and drug resistance on mortality in typhoid fever. Archives of Disease in Childhood 1996; 75: 214-7.
Gupta A. Multidrug-resistant typhoid fever in children: epidemiology and therapeutic approach. The Pediatric Infectious Disease Journal 1994; 13: 124-40.
Saha SK, Talukder SY, Islam M, Saha S. A highly ceftriaxone resistant Salmonella. typhi in Bangladesh. The Pediatric Infectious Disease Journal 1999; 18(3): 297-303.
Murdoch DA, Banatvala N, Shoismatulloev BI, Ward LR, Threlfall EJ, Banatvala NA. Epidemic ciprofloxacin-resistant Salmonella typhi in Tajikistan. Lancet 1998; 351: 339.
Saha SK, Saha S, Ruhulamin M, Hanif M, Islam M. Decreasing trend of multiresistant Salmonella typhi in Bangladesh. The Journal of Antimicrobial Chemotherapy 1997; 39: 554-6.
Antibiotics : Site of Action
 The Fluoroquinolones
• The fluoroquinolones are widely regarded as optimal for the
treatment of typhoid fever in adults
– Relatively inexpensive, well tolerated and more rapidly and reliably
effective than the former first-line drugs.
– The majority of isolates are still sensitive.

• The fluoroquinolones attain excellent tissue penetration.

– Penetrates monocytes/macrophages
– Higher active drug levels in the gall bladder

• Produce rapid therapeutic response and very low rates of post-

treatment carriage

• Bactericidal action
The Cephalosporines
• Inhibition of bacterial cell
wall syntehsis, similar to
penicillin mechanisms

• Transpeptidases enzyme is
inhibited leading to failure
of cross linking in peptide
chains of strands, no
stability to cell wall

• Bactericidal action
Resistance issue

• Emergence of MDR strains has reduced the choice of

antibiotics in many areas.

• Two categories of drug resistance

– Resistance to antibiotics such as chloramphenicol, ampicillin and
trimethoprim-sulfamethoxazole (MDR strains)
– Resistance to the fluoroquinolone drugs (nalidixic-acid-resistant S.
typhi/NARST)

• There is a significant number of MDR strains from the Indian

subcontinent and some other Asian countries
– Indonesia ? ------ Culture-Resistance Data
 Worldwide S. typhi resistance to antimicrobials

Wain et al. Lancet. 2015

Rowe et al. Clinical Infectious Diseases 1997; 24(Suppl 1):S106-9
 Choice of Antibiotics : Uncomplicated typhoid

WHO: Guidelines for Typhoid Fever

 Choice of Antibiotics : Severe typhoid

WHO: Guidelines for Typhoid Fever

What Do the Clinical Trials Say?
• To review evidence supporting use of fluoroquinolones as first line agents over
other antibiotics for treating typhoid and paratyphoid fever (enteric fever).

• 20 metanalysis
FQ vs Cefixime
• Adult and children
FQ vs Chloramphenicol
FQ vs Ceftriaxone
 Conclusion
• Typhoid fever is still a major problem in developing
countries

• Early recognition and diagnosis is warranted in defining

patients outcome

• Ibuprofen in iv prep. is a new option with good antipyretics

properties

• Fluoroquinolones, ceftriaxone and first line ABs such as

chloramphenicols are still suitable for treating typhoid fever
Thank You