Introduction to

Antimicrobial Therapy
Rianto Setiabudy
Department of Pharmacology FKUI
Lecture for PPDS Farmakologi Klinik Smt 2, 2 Feb 2016

Introduction
The problems we are facing:
The ever increasing problem of
bacterial resistance (MRSA, VRE, ESBL
producing pathogens, MDR hospital
pathogens)
Spread of infections in hospital setting
Inappropriate use of antimicrobial
agents
2

Introduction

Lack of new antimicrobial agents

developed in recent years
Unnecessary financial burden to
the patients
Scarcity of objective information on
appropriate use of antimicrobial
agents
3

Outlines

Pharmacologic factors affecting

antimicrobial activity
Selecting an antimicrobial agent
Use of combinations
Prophylaxis
Duration of antimicrobial treatment

Outlines

Patterns of antimicrobial killing

activity
Penetration of antimicrobials
into CSF
Dosage adjustment in renal
failure
Factors responsible for
treatment failure
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Pharmacologic factors affecting

tissue penetration of
antimicrobials
1.
2.
3.
4.
5.

Antimicrobial concentration in blood

Molecular size of antimicrobials
Protein binding
Lipid solubility
Ionic charge

6.
7.
8.
9.

Binding to exudate or tissue

Presence of inflammation
Active transport mechanism
Pathway of excretion

Selecting an antimicrobial
agent

Establish a working diagnosis based

on clinical symptoms
Then establish the corresponding
etiological diagnosis:

Use educated guess or

Culture and sensitivity test, if
appropriate

Determine the drug of choice (DOC)

for the condition
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Selecting an antimicrobial
agent (contd)

If the DOC cannot be given for

certain reasons, choose one of the
alternatives (second liners) based on:

Efficacy
Safety
Suitability
Cost

Give the drug and evaluate its

efficacy and safety
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Selecting an antimicrobial agent

clinical signs &
symptoms
clinical diagnosis
Educated guess or
Culture and sensitivity
test

etiological diagnosis
Consider: safety,
efficacy, suitability, and
cost. Also: PK/PD
determine the drug of
10
choice

Selecting an antimicrobial agent

(contd)
determine the drug of
choice

give the drug

evaluate the result
stop or continue or
modify the treatment as
necessary
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Tips for selecting an

appropriate antimicrobial
If
a
sensitivity
test
indicates
that
a
agent
(1)
pathogen is sensitive to some

antibiotics, it does not mean all these

agents have equal clinical efficacy
If two or more antibiotics are equally
safe and effective, choose the one with
narrower antibacterial spectrum
In life-threatening condition, a deescalating therapy has to be applied if
the etiology is unknown
Generic antibiotics are not of low quality
but their price is much more affordable
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Tips for selecting an

appripriate antimicrobial
A
new generation
antibiotic is not
agent
(2)

always superior to its older generations

A slightly more potent antibiotic shown
in vitro, is not necessarily associated
with better clinical efficacy

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Use of antimicrobial
combinations (1)
Indications:
Empirical therapy of severe infections
in which the cause is unknown
Treatment of polymicrobial infections
Enhancement of antimicrobial activity
in treatment of specific infections
Prevention of emergence of
resistance
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Use of antimicrobial
combinations (2)
Examples of appropriate use of AM combinations:
Septic shock due to Gram negative pathogens
Life-threatening infection of undetermined
cause
Enterococcal endocarditis
Serious infections due to P. aeruginosa
Intra-abdominal infection
Tuberculosis and leprosy treatment

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Use of antimicrobial
combinations (3)

Disadvantages of AM combinations:
Increased risk of toxicity
Selection of multiple-drug-resistant
microorganisms
Increased cost
Possibility of unexpected antagonistic
effect
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Use of antimicrobial
combinations (4)
Examples of possible clinical
antagonistic effect:

Lepper & Dowling (Arch Int Med

1951;88:489-94)
Pneumococcal meningitis treated with:
Penicillin alone: fatality rate = 21%
Penicillin + chlortetracycline: fatality
rate = 79%
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Prophylaxis

Characteristics of successful
prophylaxis:

Aimed at a specific pathogen

The pathogen is highly sensitive to
the prophylactic agent used

Characteristics of unsuccessful
prophylaxis:

Aimed at any or all microorganism in

the environment of a patient
(Chambers, 2001)
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Duration of therapy
Determined by:
The ability of the pathogens to
resist hosts defense mechanism
Physical location of the pathogen
Potency of the AM agent
The frequency of development of
resistance
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Duration of therapy
Examples:

Acute uncomplicated cystitis: one dose 3 days

Acute gonococcal urethritis: one dose
Pneumococcal pneumonia: until afebrile 3
days, at least 5 days
Bacterial endocarditis: 4 weeks
Pulmonary tuberculosis: 6 months
Extra pulmonary tuberculosis: 12-24 months

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Time-kill curves of P.
aeruginosa with exposure to
tobramycin
10
9

Control

1/ 4 MI C

1 MI C

Log
CFU/ml

6
5

4 MI C

16 MI C

64 MI C

2
1
0
0

Time (h)
(Craig, 1991)
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Patterns of antibiotic
killing activity
Pattern 1: concentration-dependent
killing
E.g.: aminoglycosides,
fluoroquinolones
Strategy of dosing regimen: maximize
concentrations
Parameters determining efficacy:
ratios of Cmax/MIC or AUC/MIC
(Deziel-Evans, 1986)
22

Log
CFU/ml

Time-kill curves of P.
aeruginosa with exposure to
ticarcillin

Time (h)
(Craig, 1991)
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Patterns of antibiotic
killing activity
Pattern 2: time-dependent killing
E.g.: betalactams, macrolides,
oxazolidinedinones
Strategy of dosing regimen: maximize
duration of exposure to antibiotics
Parameters determining efficacy:
length of time of above-MIC antibiotic
blood level
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Pharmacokinetic/Pharmac
o-dynamic (PK/PD)
For concentration-dependent killing
parameters

pattern:
AUC/MIC (required: 125 and
30 for Gram negative and Gram
positive pathogens, respectively )
Cmax/MIC
(required: 10)
For time-dependent killing pattern:
Time above MIC (required: 40%)
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Pharmacokinetics and pharmacodynamics of antimicrobial agents

CONC.

Cmax

AUC/MIC
Cmax/MIC
Time above MIC
Area
Under the
Curve

MIC
Time

Time above-MIC

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Penetration of
antimicrobials into
Excellent:
cerebrospinal
fluid

Trimethoprim
Sulfonamides
Chloramphenicol
INH
Rifampicin
Flucytocin

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Penetration of
antimicrobials into
Good with inflamedfluid
meninges:
cerebrospinal

Penicillin G
Ampicillin
Cloxacillin
Ticarcillin
Piperacillin
Mezlocillin

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Penetration of
antimicrobials into
Ceftriaxone
cerebrospinal fluid

Ceftazidime
Aztreonam
Imipenem
Fluoroquinolones

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Penetration of
antimicrobials into
Poor penetration:
cerebrospinal
fluid

Aminoglycosides
First generation cephalosporins
Lincomycin
Clindamycin
Vancomycin
Cefoxitin
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Dosage adjustment in
renal failure

Initial dose: Give without any

reduction.
Initial dose is determined by the
equation:
Dose = Vd x target concentration
Subsequent maintenance dose:
reduce in accordance to total body
clearance of the drug
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Dosage adjustment in
renal failure

Weight = Vol. x Conc.

Dose = Vd x Drug conc.

32

Dosage adjustment in
renal failure
Dose reduction can be determined
by using:
Calculation
Nomogram
Prescribing information in
product insert

33

Dosage adjustment in
renal failure

The basic principles for calculating

maintenance dose for an individual
patient :
Rinf = Cltot x Csteady state
Cltot = Clrenal + Clnon-renal

34

Dosage adjustment in renal

failure
IN

IN = OUT

IN

OU
T

OU
T
R inf = Cl tot x Css
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Dosage adjustment in
renal failure

Example:
Normal dose of vancomycin is 1 g/12 hours by
continuous infusion. Urinary excretion is 80%.
What is the dose for a man with creatinine clearance
of 25 mL/min?
Answer:
Total clearance = renal clearance + non-renal
clearance
= (25/100 x 80%) + 20% = 40%
The dose for this patient is 40% x 1 g/12 hours = 0.4
g/12 hours by continuous infusion
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Factors responsible for

treatment failure (1)

Poor antimicrobial activity

Active antimicrobial agent fails to be delivered
to the site of infection in sufficient
concentration
Inaccessible site of infection
Inadequate host defenses
Treatment is too short to prevent relapse
Serious toxicity necessitates discontinuation
of therapy
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Factors responsible for

treatment failure (2)

Development of resistance
Superinfection occurred
Foreign body or necrotic tissues
Patients incompliance

THANK YOU
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