Rational Usage of

Antibiotics in Typhoid
Fever
SUDIRMAN KATU
Division of Tropical Medicine and Infectious Diseases
Departement of Internal Medicine
Medical Faculty of Hasanuddin Univesity
2013

Antibiotic Resistance
A worldwide problem1
Associated with
increased morbidity,
mortality, and
hospital costs1
Occurs in both
hospitals and the
community2
1: R. A. Kulkarni et al. Indian J Surg. 2005: Volume 67(6): 308-315.
2 Ben-David D, Rubenstein E. Curr Opin Infect Dis 2002;15:151-156.

Current Problems of
Bacterial Resistance
Policy & Advocacy of IDSA; July 2004
B AD B UGS , N O D RUGS
As Antibiotic Discovery Stagnates A Public Health Crisis Brews

Consideration When Choosing

an Antibacterial Agent
Outcome

Microbiology
Mechanism of action

Drug

Antibacterial spectrum Concentration

Bacterial mapping at infection site

PK
Absorption

Distribution
Metabolism
Excretion
Optimal dosing
regimen

(Scaglione, 2002)

Pathogen MIC

Clinical efficacy
Bacterial eradication
Compliance with
dosing regimen
Tolerability
Rate of resolution
Prevention of resistance

PD
Time vs. concentration
dependent killing
Bactericidal vs. bacteriostatic
activity
Tissue penetration
Persistence of antibacterial effect

Klasifikasi & Mekanisme

Kerja AM
Dinding kuman
Penisilin,
Sefalosporin,
Monobaktam,
Karbapenem,
Glikopeptida,
Fosfomisin,
Oxasolidine

Membran sitoplasma
Aminoglikosida, Polimiksin B,
Kolistin, Amfoterisin B

Sintesis As nukleat
Inhibisi biosintesis protein
Aminoglikosida,
Linkosamida,
Makrolid,
Tetrasiklin/Tygecyclin
Kloramfenikol,
As. Fusidik

As.folat antagonis
Sulfa-Trimethoprim,
Kotrimoksasol

Rifampisin,
As. Fusidik,
Quinolon.

Inhibisi b-laktam
As.klavulanat,
Sulbaktam,
Tasobaktam

Rational Antimicrobial
Therapy
Patient
Clinician/
Farmakologis

Drug

Microorganism
Microbiologist

Factors in Choices of Antibiotics:

Drug Interactions
IV fluids:
incompatible
drug mixtures

Kidney:
Effect on passive
readsorbtion &
active secretion

Bowel:
Other drug or food
modifies absorbtion

Drug interaction

Plasma:
Competitition for
protein binding
sites

Liver:
Receptor sites:
Induction of liver enzymes -Drugs may compete
modified excretion
at binding site

Examples of
Antibiotics-Drugs Interactions
Site
IV fluids
GI tract

Antimicrobial Interacting drug/effects

Many

Many - Do not mix IV fluids

Tetracyclines Absorbtion by food

Quinolones
Absorbtion reduced by iron

Protein bindingChloramphenicol
Warfarin (antiocoagulant), SulphoCo-trimoxazoleureas effects
Liver enzyme
induction
Kidney

Rifampicin

Aminoglycosides

Oral contraceptive, warfarin, antidia

betics, cyclosporin, etc, metabolism
, i.e., effect
Loop diuretics (frusemide)
ototoxicity

Antibiotic Usage in
Clinical Practice
Empirical therapy
Definite therapy
Prophylaxis
Pre-emptive

Who is the Host ?

1. Immunocompetence
2. Immunodeficiency / immunocompromized :
Imunocompromise Primer :
Immunocompromized Secunder :
Neutropenia
Neoplasm
Cytotoxic agent
Diabetes
Drugs user, Alcoholic
Elderly, neonatal, pregnancy and purpureum
Dialysis, implants/ prostheses

Factors Involved in
Optimal Initial Antibiotic Therapy
Correct
dose
Pathoge
n
coverag
e

Timely
initiatio
n

Optima
l
Therap
y

Increased

Correct
route

Impact of the appropriateness of antibiotics

therapy on mortality of Gram-negative
bacteremia
NS

P<0.001
P<0.001

P<0.001

Bochud PY. Intensive Care Med 2001;27:s33-8

Antimicrobial Treatment based on

Microbiological Culture Results
Microbiological culture results

Colonization
No treat
Resistant

Pathogen
Sensitive

Treat with

Antibiotics

Recommended

Combination

Optimized
PKPD

Control of Antibiotic Usage

Avoid antibiotic homogeneity
Promote appropriate use of multiple
drug class
Apply formulary control and restrict
of specific agent or drug class that
resistant
Consider antibiotic cycling, rotation
or mixed use of antibiotic classes
Develop and promote antibiotic
guidelines and protocol based on

Antibiotic Policy
Classification of antibiotics
Class A : Not restricted
Class B : Not restricted, under
supervision
Class C : Restricted
Implementation
Evaluation and surveillance
Auditing

Classification of Antibiotics
Class A
Aminoglicoside
Penicillin
Cephalosporin
gen.I,II
Chloramphenicol
Fucidic acid
Lincosamide
Macrolide
Nitroimidazol
Fluoroquinolone
gen.I,II
Tetracyline
TMP-SMX
Fosfomicin
Polypeptide

Class B
Cephalosporin
e
gen III
Fluoroquinolo
ne
gen III-IV
Sulperazone
Ertapenem
Aztreonam

Vancomycin

Class C
Teicoplanin
Linezolide
Cefepime
Cefpirome
Ceftazidime
Pip-Tazo
Carbapenem
Tygecicline

Implementation of Antimicrobial
Policy in Hospital
Outpatient

Community

Hospital

Class A

Class A

Class B

Class C

Class B/C

Class C

Inpatient
WAR
D
ICU

Mild
Moderat
e Severe

Evaluation category of
Antibiotics Usage by Gyssens
I.
II.

Correct Usage
Incorrect due to:
a) Incorrect dose b) Incorrect interval c) Incorrect route

III.

Incorrect due to:

a) duration too long b) duration too short

IV.

Incorrect due to: Alternative drug that is

a) more effective b) less toxic c) cheaper d) more specific

V.
VI.

No Indication
Medical record is insufficient to be
evaluated

Evaluation and Surveillance

Surveillance of every inpatient ward,
intensive care ward, and surgery
room periodically, e.g. monthly
surveillance in internal medicine
ward
Report of surveillance periodically,
e.g. report of surveillance in internal
medicine ward every 6 months

Auditing
Periodically done by antibiotic team
(multi department), commissioned
by management of hospital
Audit of medical records, copy of
prescriptions
Percentage of compliance to
antibiotic guideline
Reward and punishment

ANTIBIOTICS FOR TYPHOID FEVER

(KONSENSUS PETRI 2010)
AB

DOSE

FRE
K

ROUT
E

DURATION
MILD

SE

SEVERE

KLORAMF 50-100
4
ENICOL
mg/kgBB/h
r
30 mg/kg
BB /hr
(fever -)

O/IM/IV Fever &

7 days
fever (-)

Fever &
7 days
fever (-)

Bone
marrow
deppres
sion

THIAMFE
NICOL

Tidak
direkom
endasik
an

AMPISILLI
N & AMO

50 100
mg/kgBB/hr

Fever &
7 days
fever (-)

Treatment
Chloramphenicol

The recommended dose is 50 - 75 mg divided into four doses

per kg per day 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 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 trimethoprimsulfamethoxazole. 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

BID. 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
Igator

Year

Arnold
Nelwan
Hien
Nelwan
Nelwan
Duong
Duong
Nelwan

1993
1993
1994
1994
1995
1995
1995
1997

Medication Treatment
duration
FLX
PEF
FLX
OFL
CIP
FLX
FLX
FLX

14
7
7
7
6
5
3
3

number
cases
35
20
16
12
31
41
22
4

Clinical
efficacy

Bacterial
efficacy

100
100
100
100
100
97.5
100
100

96
100
100
100
100
94
100
100

Antimicrobial Sensitivity in Typhoid fever

(RSCM/FMUI Januari - Juni 2011

Group beta-lactam non-cephalosphorins

Ampicillin
Aztreonam

Group cephalosphorins

: 4 (50%)
: 4 (75%)

Cephalothin
: 4 (0%)
Cephopherazone
: 3 (100%)
Cefotaxime
: 4 (75%)
Ceftriaxon
: 4 (100%)

Quinolones
Ciprofloxacin
Levofloxacin

: 4 (100%)
: 4 (100%)

Others antibiotic
Chloramphenicol
Cotrimoksazole
Azythromycin

: 3 (100%)
: 4 (100%)
: tidak ada data

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

Treatment of uncomplicated typhoid

Treatment of severe typhoid

TREATMENT OF MDRST
MDRST

1:

Ciprofloxacin / Levofloxacin
Third generation cephalosporin
MDRST

2:

Monobactam (Aztreonam) -> India , Korsel

Carbapenem

John Wine, J Infect Developing Countries 2008

Yonsei Med J 50(1):147 - 151, 2009

Conclusions
Types of antibiotic usage in typhoid fever:
definite and prophylaxis
Rational antibiotic therapy: rapid,
appropriate, cost effective
The implementation of antibiotic policy to
promote:

rational use of antibiotics,

cost-effective therapy,
prevent collateral damage
Prevent of MDRST

Thank You

Antimicrobial Combination:
When we need?
Unknown focus of infection
Polymicrobial infection, eg: abscess
caused by multiple aerob and anaerob
organisms
Decrease resistance rate, eg: Tb
treatment
Decrease dose related toxicity
Increase antimicrobial potency
Chambers HF. Antimicrobial agents. 2001

Strategy in Managing MDR

Treat pathogen not colonization
Based on local susceptibility data
Monotherapy or combination
Optimalization PK/PD
Considered comorbidities, organ
function
Prevent transmission