Section VIII

Chemotherapeutic drugs
Chapter 1: Introduction
to Antimicrobial Drugs
Learning Objectives

 By the end of the chapter you should be able to:

Define terms related to antimicrobial drugs

Explain about selective toxicity

Classify antimicrobial drugs based on there MOA

Describe the time dependent & conc dependent PD of

antibiotics
Discuss about mechanisms by which microbes develop
resistance to antimicrobial drugs

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Outline

 Definitions

 Selective toxicity

 Major targets of antimicrobial agents

 Antimicrobial pharmacodynamics

 Super-infections

 Antimicrobial resistance

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I. Definitions

 Antibiotic agents:
Chemicals that are produced by one microbe &
have the ability to harm other microbes
 Antimicrobial agents:
Any agent, natural or synthetic, that has the
ability to kill or suppress microorganisms
 Chemotherapeutic agents:
 Any agent, natural or synthetic, that has the
ability to kill or suppress microorganisms or
cancer cells

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II. Selective toxicity

 Selective toxicity: it means that a chemical

produces injury to one kind of living matter without
harming another form of life even though the two may
exist in intimate contact

 They may be related to each other as parasite & host

or may be two tissues in one organism

 By taking advantage of the biological diversity, it is

possible to develop chemicals that are lethal for an
undesired species & harmless for other species

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Selective toxicity …

 Drugs & other chemicals used for selective toxic

purposes are selective for one of 2 reasons
The chemical is equally toxic to both forms
(desired & undesired) but is accumulated mainly
by undesired cells

The chemical reacts fairly specifically with a

cytological or a biochemical feature that is absent
from or does not play an important role in the
desired form

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Selective toxicity …

 Antimicrobial therapy takes advantage of the

biochemical differences that exist b/n MOs & human
beings

 Example:
The fact that bacteria contain cell walls &
humans do not has been utilized in developing
selective toxic antibiotics, such as penicillin &
cephalosporins, that kill bacteria but are relatively
nontoxic to mammalian cells

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Selective toxicity …

 In most instances, the selective toxicity is relative

rather than absolute, requiring that the conc of the
drug be carefully controlled to attack the
microorganism while still being tolerated by the host

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II. Major targets of antimicrobial agents

 Different antibiotics have different modes of action,

owing to the nature of their structure & degree of
affinity to certain target sites within bacterial cells
a) Inhibitors of cell wall synthesis
• A drug that targets cell walls can selectively
kill or inhibit bacterial organisms
• Examples: penicllins, cephalosporins,
bacitracin & vancomycin

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Major targets of antimicrobial agents…

b) Inhibitors of cell membrane function

B/c this structure is found in both eukaryotic &
prokaryotic cells, the action of this class of
antibiotic are often poorly selective & can
often be toxic for systemic use in the
mammalian host
Most clinical usage is therefore limited to
topical applications
Examples: polymixin B & colistin

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Major targets of antimicrobial agents…

c) Inhibitors of protein synthesis

Several types of antibacterial agents target
bacterial protein synthesis by binding to either
the 30S or 50S subunits of the ribosomes

Examples: Aminoglycosides, macrolides,

lincosamides, streptogramins, chloramphenicol,
tetracyclines

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Major targets of antimicrobial agents…

d) Inhibitors of nucleic acid synthesis

Some antibiotics work by binding to
components involved in the process of DNA or
RNA synthesis, which causes interference of
the normal cellular processes which will
ultimately compromise bacterial multiplication &
survival
Examples: quinolones, metronidazole, &
rifampin

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Major targets of antimicrobial agents…

e) Inhibitors of other metabolic processes

Other antibiotics act on selected cellular
processes essential for the survival of the
bacterial pathogens

Example: Both sulfonamides & trimethoprim

disrupt the folic acid pathway, which is a
necessary step for bacteria to produce
precursors important for DNA synthesis

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III.Anti bacterials pharmacodynamics

 Bacteriostatic Vs Bactericidal activity

Bacteriostatic agents:
• Act primarily by arresting bacterial multiplication
• Inhibitory drug conc are much lower than
bactericidal drug conc
 Bactericidal agents:
Those that act primarily by killing bacteria

 NB: Bacteriostatic & bactericidal agents are

equivalent for the Tx of most infectious diseases in
immunocompetent hosts

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 Bacteriostatic vs. Bactericidal Examples
•Bacteriostatic • Bactericidal
• Chloramphenicol • Pencillins & Cephalosporins
• Clindamycin • Isoniazid, Metronidazole, Polymyxins
• Macrolides • Rifampin, Vancomycin,
• Sulfonamides Aminoglycosides
• Tetracyclines • Bacitracin, Quinolones
• Trimethoprim

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Antimicrobial Pharmacodynamics…

 MIC: The MIC is the lowest conc that completely

inhibits visible growth of the organism as detected by
the unaided eye after a 18-24 hour incubation period
with a standard inoculum of approx 105 CFU/ml

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Fig. Time course of systemic drug conc. following drug administration

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Antimicrobial Pharmacodynamics…

 Conc-dependent vs. Time-dependent killing

 Bactericidal drugs can be divided into 2 groups:
a) Conc-dependent killing:
• E.g. aminoglycosides, fluoroquinolones
• Show a significant ↑ in the rate of bacterial killing as the
concentration of antibiotic increases from 4-64 fold the
MIC of the drug for the infecting organism
• These drugs exhibit a ”post-antibiotic effect” (PAE):
persistent suppression of bacterial growth after limited
exposure to an antibiotic

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Antimicrobial Pharmacodynamics…

 Conc- dependent killing (Cont…)

Proposed MZMs for the PAE include:
• Slow recovery of bacteria after non-lethal damage to
cell structures
• Persistence of the antibiotic at its binding site or
within the periplasmic space
• A need for bacteria to synthesize new proteins before
growth can continue
Giving drugs that exhibit this conc-dependent killing
by a once-a-day bolus infusion achieves high peak
levels, favoring rapid killing of the infecting pathogen

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Antimicrobial Pharmacodynamics…

b) Time-dependent killing:
E.g. β-lactams & vancomycin

Bactericidal activity continues as long as the

plasma conc is > the MBC
Efficacy for these antibiotics is maximized by
the percentage of time that blood conc of a
drug remain above the MIC

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Antimicrobial Pharmacodynamics…

 Applying the PD & PK principles

3 PD properties of antibiotics are used to describe
their patterns of microbiologic & bactericidal activity:
• Conc. dependence

• Time dependence &

• Persistence of effect or post-antibiotic

suppression of bacterial growth

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Antimicrobial Pharmacodynamics…

 Applying the PD & PK principles (Cont…)

The 3 PK parameters that are most important for
evaluating antibiotic efficacy:
• The peak serum level (Cmax)
• The trough level (Cmin), &
• The Area Under the serum conc time Curve
(AUC)
While these parameters quantify the serum level
time course, they do not describe the killing
activity of an antibiotic

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Antimicrobial Pharmacodynamics…

 Applying the PD & PK principles (Cont…)

Integrating the PK parameters with the MIC
gives us 3 PK/PD parameters which quantify
the activity of an antibiotic:
• The Peak/MIC ratio
• The T>MIC, &
• The 24h-AUC/MIC ratio

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Antimicrobial Pharmacodynamics…

 Applying the PD & PK principles (Cont…)

The Peak/MIC ratio is simply the Cpmax divided
by the MIC
The T>MIC (time above MIC) is the percentage
of a dosage interval in which the serum level
exceeds the MIC
The 24h-AUC/MIC ratio is determined by
dividing the 24-hour-AUC by the MIC

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Antimicrobial Pharmacodynamics…

 Antimicrobial Patterns
The 3 PD properties of antibiotics that best
describe killing activity are time-dependence, conc-
dependence, & persistent effects
The rate of killing is determined by either the
length of time necessary to kill (time-dependent),
or the effect of increasing conc (conc-dependent)
Persistent effects include the PAE
Using these parameters, antibiotics can be divided
into 3 categories

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 Table. Patterns of antimicrobial activity
Pattern of Activity Antibiotics Goal of Therapy PK/PD Parameter

Type I Aminoglycosides Cmax/MIC

Conc-dependent killing Daptomycin Maximize drug
& Prolonged persistent Fluoroquinolones conc
effects Ketolides
Maximize T>MIC
Type II Cephalosporins duration of drug
Time-dependent killing Erythromycin exposure
& Minimal persistent Linezolid
effects Penicillins
Maximize amount AUC24/MIC
Type III Azithromycin of drug
Time-dependent killing Clindamycin
& Moderate to Oxazolidinones
prolonged persistent Tetracyclines
effects Vancomycin
Question

• The mechanism by which beta -lactams (such as Question

penicillins & cephalosporins) kill bacteria is

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characterized as time -dependent killing
– This means that the antibacterial effect • The mechanism by which aminoglycosides &
depends on the % of time during the dosing fluoroquinolones kill bacteria is characterized as
interval that the antibiotic conc remain above conc-dependent killing
the MIC for the organism
– This means that for these drugs, it is better for
• Based on this principle of requiring the conc of the higher peak drug level conc to be achieved
antibiot ic to exceed the MIC of the organism for a compared to the MIC
substantial period of time, w hich dosing strategy • Based on the importance of achieving an
w oul d maximize bacterial kill in a pt with
antibiotic conc substantially above the MIC, which
impaired renal function?
dosing strategy would be most effective in a pt
with impaired renal function?
IV. Super-infections

 Antibacterial drugs are designed to kill bacteria,

but no drug kills all bacteria

 Killing of normal flora removes the inhibitory effect of

the normal flora
Which produce antibacterial substances & compete for
essential nutrients
This allows for uninhibited growth of potentially
pathogenic bacteria & fungi
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Super-infections…

 The more broad-spectrum the antibiotic & the more

prolonged the therapy, the greater is the change in
the normal micro-flora, & the greater the chance
that a single drug-resistant microorganism will
proliferate & cause infection
 The most specific & narrow spectrum antimicrobial
drug should be selected to treat infections
whenever possible

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Super-infections…

 Common organisms in superinfection include:

C. difficile

MDR G-(-) rods

MRSA

Candida or other fungi

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 Drugs Vs. Bacteria

 Imagine you're outside playing soccer & you get a

V. Antimicrobial resistance
cut on your leg. You put a bandage on it & wait for it
to get better. But within a few days, you notice that
the skin around the cut is getting red, swollen &
painful to the touch, so you decide to get a doctor to
look at it.

 It is the major problem threatening the continued

success of antimicrobial drugs
 Overuse & inappropriate use of antibiotics in pts has
fueled a major ↑ in prevalence of MDR pathogens
 Antibacterial antibiotics are misused by providers in
a variety of ways, including:
Use in pts who are unlikely to have bacterial
infections
Use over unnecessarily prolonged periods, &
Use of multiple agents or broad spectrum agents
when not needed
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Antimicrobial resistance…

 It can develop at any one or more of steps in the processes

by which a drug reaches & combines with its target
 Thus, resistance development may develop due to:
Reduced entry of antibiotic into pathogen
Enhanced export of antibiotic by efflux pumps
Release of microbial enzymes that destroy the antibiotic
Alteration of microbial proteins that transform pro-drugs to
the effective moieties
Alteration of target proteins
Development of alternative pathways to those inhibited by
the antibiotic

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Antimicrobial resistance…

 MZMs by which such resistance develops can

include:
Acquisition of genetic elements that code for the
resistant MZM, via:
• Conjugation, Transduction, Transformation

Mutations that develop under antibiotic pressure,

or constitutive induction

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Antimicrobial resistance…

 Ways to limit resistance:

Avoidance of indiscriminate use

• By ensuring that the indication for, the

dose & duration of Tx are appropriate

Using antimicrobial combinations in

appropriate circumstances; e.g. TB

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Antimicrobial resistance…

 Ways to limit resistance…

Constant monitoring of resistance patterns

Restricting drug use

• E.g. Limiting the use of the newest

member of a group of antimicrobials so
long as the currently-used drugs are
effective

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