Susceptibility pattern of

Salmonella
Muh. Nasrum Massi
Lab. Mikrobiologi, Infection Center, RSUP Dr
Wahidin Sudirohusodo
Lab Mikrobiologi, RSP Universitas Hasanuddin
 Burden of Typhoid Fever
(WHO, 2008)
Annual typhoid incidence in 5 Asian
countries (per 100,000 person/year)

• 5-15 years age group

• Vietnam: 24.2
• China: 29.3
• Indonesia:180.3
• Pakistan: 412.9
• India: 493.5
 Antibiotic Therapy of Typhoid
• Ampicillin/Amoxicilin

• Chloramphenicol

• Trimethoprim-sulphamethoxazole

• Fluoroquinolones: NA, Ciprofloxacin, Levofloxacin,

Gatifloxacin

• Ceftriaxone or other 3rd Gen of Cephalosporin

• Azythromycin
 Strains Resistance to
Chloramphenicol
• Produced in 1948

• 1950: Chloramphenicol resistance S.Typhi

strains were reported from England

• Outbreak of Chloramphenicol and

Ampicillin Resistance S.Typhi stains:
– 1972: Mexico and India
– 1973: Vietnam
– 1977: Korea

SA.Zaki and S.Karande. J Infect Dev Ctries 2011; 5(5)

The use of chloramphenicol in the treatment
of typhoid fever has three disadvantages:
• The risk of developing aplastic anaemia,
which is a rare but potentially fatal
complication (9)
• A relapse rate of approximately 10%
• The prolonged course (2 weeks) of
treatment.
 Strains Resistance to Co-
Trimoxazole
• Co-trimoxazole was used in treating the resistance
strain

• 1975: Co-trimoxazole resistance S.Typhi strains

were reported from France

• Late 1980s: resistant to all three first-line drugs

(=MDR-TF)

• Fluoroquinolones became the drug of choice for

the treatment of MDR-TF worldwide

SA.Zaki and S.Karande. J Infect Dev Ctries 2011; 5(5)

SA.Zaki and S.Karande. J Infect Dev Ctries 2011; 5(5)
 Strains Resistance to
Fluoroquinolones
• 1992: first reported from the UK and India
and some countries in Asia

• 3rd-generation cephalosporins were used for

treatment

• Cause of resistance to fluoroquinolones:

– Alteration in target enzymes (DNA gyrase and
topoisomerase IV)
– Decrease in drug permeability
– Active efflux mechanism
SA.Zaki and S.Karande. J Infect Dev Ctries 2011; 5(5)
 MECHANISM OF BACTERIAL
RESISTANCE TO ANTIBIOTIC
• Antimicrobial inactivation by enzym activity
(Enzymatics inactivation)
• Resistance occur by change in bacterial cell wall
permeability.
• Change in target molecule.
• Bacteria alters synthetic pathway utilized by
antimicrobials.
• Antimicrobials is actively excreted out of
bacterial cell.
• Occurrence of tolerance
 A. Inactivation of antimicrobials by enzyme
activity (Enzymatics inactivation)
– Penicillin inactivation: hydrolysis of ß-lactam
ring by ß-lactamases.
– Aminoglycoside inactivation: alteration
caused by acetyltransferase and
phophorylase, nucleotidases activities →
unable to bind to ribosome.
– Chloramphenicol inactivation:
chloramphinecol acetyltransferases have
similar activity mechanism to aminoglycoside
transferases.
 B. Resistance by change in cell wall
permeability.
• Porin: outer membrane protein specific to Gram
negative bacteria → plays a role in entrance of
hydrophilic antimicrobials.
Porin mutation: antimicrobial transportation into the cell
is hindered → bacteria becomes resistent to multiple
antimicrobials (multi-resistant)
• Lipopolysaccharide (LPS): inhibit the entrance of
hydrophilic antimicrobials through the cell wall.
Mutant containing small amount of polysaccharide
capsules & small amount of LPS will be more permeable
to many antimicrobials.
– Membr. transport proteins. Mutation of
membrane transport protein causes bacterial
resistance to tetracycline as the result of
reduction of transportation into the cell.
– Electron transport. The entrance of
aminoglycosides into the cell is dependent on
electron transport into oxygen. That’s why
aminoglycoside is not effective against
anaerobic bacteria & facultative bacteria in
anaerobic environment, like abscess.
 D. Change in target molecule.
• Antimicrobial targets could be:
– Cytoplasm: penicillin-binding protein (PBP),
– Membr. Cytoplasm: ribosom 30S atau ribosom 50S.
• Change in target molecule → reduced bacterial affinity
towards antibacterial.
• Example
• Change of 30S ribosome → bacterial resistance to
aminoglyside.
• Change of 50S ribosome → bacterial resistance to
macrolide
• Change of DNA gyrase: → bacterial resistance to
quinolone.
 E. Bacteria changes synthetic pathway
utilized by antimicrobials.

• The formation of mutant enzyme → change

in synthetic pathway. Exp. Bacteria
resistant to vancomycin produce an enzyme
with low affinity to vancomycin.
F. Antimicrobials are actively excreted from the
bacteria.
Bacterial resistance to tetracycline is caused by
the formation of a new transport protein which
could actively excreted antimicrobials out of
bacterial cell.
G. Occurrence of tolerance
With the lost of outer membrane permeability &
autolytic enzyme inactivation, changes of
bactericidal substance into bacteriostatic
substance would occur.
Walker RA, International Journal of Antimicrobial Agents 22 (2003) 622-625
 Antibiotics Susceptibility Pattern
in Nepal, 2004-2006

Note: 7 strains of S.Typhi are MDR

Tamang MD, International Journal of Antimicrobial Agents 30 (2007) 330-335

 Antibiotics Susceptibility Pattern,
North India

Nath G., P.Maurya. International Journal of Antimicrobial Agents 35 (2010)

 In Vitro Efficacy of Combination
Therapy

Kim DL., et al. International Journal of Antimicrobial Agents 36, 2010

A study of typhoid fever in five Asian countries:
disease burden and implications for controls
 Antimicrobial agent resistance pattern of S. enterica
serotype Typhi isolates by study site

Bulletin of the World Health Organization , Volume 86: 2008, Number 4, April 2008, 241-320
 S. Typhi in South Sulawesi,
Indonesia
• Prevalence in Indonesia in 2007:
– 358-810/100.000 population
– 64% of enteric fever in 3 to 19 year olds
– Mortality rate varies from 3.1-10.4%

• Case detection rate in South Sulawesi:

– 1991 was 257/100,000 population
– 2007 was 386/100,000 population
Hatta and Ratnawati. J Infect Dev Ctries 2008; 2(4)
Incidence and MDR Cases

Hatta and Ratnawati. J Infect Dev Ctries 2008; 2(4)

 MDR-S.Typhi

Hatta and Ratnawati. J Infect Dev Ctries 2008; 2(4)

Laboratorium Mikrobiologi Klinik (LMK) - FKUI
Specimen : Blood

Year 1992* 2001- 2004- 2007-2010

2003** 2006**
Isolates
Salmonella 161 4 3 1
Paratyphi A
Salmonella Typhi 40 23 19 9

•Mardiastuti HW et al. Mikr Klinik Ind vol.6 no.3 1994

**Anis Karuniawati, Slide Presentation in 4th NS-IARW, 2007
 LMK-FKUI, 2007-2010
S.Typhi (9 isolates)
120

100
% SUSCEPTIBLE

80

60

40

20

0
AMX CRO CHL CIP FEP TZP SXT
ANTIBIOTICS
Anis Karuniawati, Slide Presentation in PIT PAMKI Makassar, 2011
 Conclusion
• MDR-S.Typhi remains a major public health
problem in some countries in Asia and Africa

• First-line recommended antibiotics for typhoid

fever in Makassar are still susceptible

• Isolation and characterization of MDR-

S.Typhi from all regions in Indonesia for
effective epidemiologic surveillance and
control should be done
THANKS