Anti-infective drugs
Anti-infectives…Introduction
Are agents used to combat infectious
agents (bacteria, virus, fungus,
parasites, protozoans)
Antibacterial
Antiviral
Antifungal
Antiparasitic
antiprotozoals
INTRODUCTION …General Principles
There are principles that are more pertinent to the use of
antimicrobial agents as a group.
1. Mechanisms of actions of different groups of antibiotics.
2. Mechanisms by which pathogens acquire and express
resistance to antibiotics.
3. Combination therapy (use of two or more drugs
concomitantly).
4. Host determinants that influence the selection and
efficacy of antibiotics.
Antimicrobial Chemotherapy
Majority of antibiotics are based on
naturally occurring compounds or may be
semi-synthetic or synthetic
Differential toxicity: based on the
concept that the drug is more toxic
to the infecting organism than to the
host
The Ideal antibiotics
Have the appropriate spectrum of activity for the
clinical setting.
Have no toxicity to the host, be well tolerated.
Low propensity for development of resistance.
Not induce hypersensitiveness in the host.
Have rapid and extensive tissue distribution
Have a relatively long half-life.
Be free of interactions with other drugs.
Be convenient for administration.
Antibacterial
chemotherapy…principles/definitions
Antibacterial spectrum
Range of activity of an antimicrobial
against bacteria.
A broad-spectrum antibacterial drug
can inhibit a wide variety of gram-
positive and gram-negative bacteria,
whereas a narrow-spectrum drug is
active only against a limited variety of
bacteria
Principles/definitions
Bacteriostatic activity—The level of
antimicrobial activity that inhibits the growth
of an organism.
This is determined in vitro by testing a
standardized concentration of organisms
against a series of antimicrobial dilutions.
The lowest concentration that inhibits the
growth of the organism is referred to as the
minimum inhibitory concentration
Principles/definitions
Bactericidal activity—The level of
antimicrobial activity that kills the test
organism
This is determined in vitro by exposing a
standardized concentration of organisms to a
series of antimicrobial dilutions
The lowest concentration that kills 99.9% of
the population is referred to as the minimum
bactericidal concentration (MBC).
Principles / Definitions
Ideally, before beginning antibiotic therapy, the
suspected areas of infection should be cultured to identify
the causative organism and potential antibiotic
susceptibilities
Empiric therapy: treatment of an infection before specific
culture information has been reported or obtained
Prophylaxis - antimicrobial agents are administered to
prevent infection
Treatment - antimicrobial agents are administered to cure
existing or suspected infection
MECHANISMS OF ACTION OF ANTIBACTERIAL
DRUGS
Mechanism of action
include:
Inhibition of cell wall
synthesis
Inhibition of protein
synthesis
Inhibition of nucleic acid
synthesis
Inhibition of metabolic
pathways
Interference with cell
membrane integrity
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Inhibition of Cell wall synthesis
Bacteria cell wall is unique in
construction
Contains peptidoglycan
These drugs have very high
therapeutic index
Low toxicity with high effectiveness
Antimicrobials of this class include
β lactam drugs
Vancomycin
Bacitracin
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Penicillins and cephalosporins
Part of group of drugs called β –lactams
Have shared chemical structure called β-lactam ring
Competitively inhibits function of penicillin-binding proteins
Inhibits peptide bridge formation between glycan molecules
This causes the cell wall to develop weak points at the growth sites
and become fragile.
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
The weakness in the cell wall causes the cell to
lyze.
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Inhibition of protein synthesis
Structure of prokaryotic ribosome acts as a target for
many antimicrobials of this class
Differences in prokaryotic and eukaryotic ribosomes is
responsible for selective toxicity
Drugs of this class include
Aminoglycosides
Tetracyclins
Macrolids
Chloramphenicol
Streptogramins
Lincosamides
Oxazolidinones
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Inhibition of nucleic acid synthesis
These include
Fluoroquinolones
Rifamycins
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Fluoroquinolones
Inhibit action of topoisomerase DNA gyrase
Topoisomerase maintains supercoiling of DNA
Effective against Gram + and Gram -
Examples include
Ciprofloxacin and ofloxacin
Resistance due to alteration of DNA gyrase
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Rifamycins
Block prokaryotic RNA polymerase
Block initiation of transcription
Rifampin most widely used rifamycins
Effective against many Gram + and some Gram - as well
as members of genus Mycobacterium
Primarily used to treat tuberculosis and preventing
meningitis after exposure to N. meningitidis
Resistance due to mutation coding RNA polymerase
Resistance develops rapidly
Mechanism of Action
Inhibition of metabolic pathways
Sulfonamides
an analog of PABA, works by competitive
inhibition
Trimethoprim
Mechanism of Action (cont’d)
ANTIMETABOLITE ACTION
tetrahydrofolic acid
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Interference with cell membrane integrity
Few damage cell membrane
Polymixn B most common
Common ingredient in first-aid skin ointments
Binds membrane of Gram - cells
Alters permeability
Leads to leakage of cell and cell death
Also bind eukaryotic cells but to lesser extent
RESISTANCE TO ANTIMICROBIAL DRUGS
Resistance: the inability to kill or inhibit the
organism with clinically achievable drug
concentrations
Resistance may be innate (naturally resistant)
Resistance may be acquired
- mutation
- acquisition of foreign DNA
RESISTANCE TO ANTIMICROBIAL DRUGS
Factors which may accelerate the
development of resistance
- inadequate levels of antibiotics at the site
of infection
- duration of treatment too short
- overwhelming numbers of organisms
- overuse / misuse of antibiotics
RESISTANCE TO ANTIMICROBIAL
DRUGS
Mechanisms of resistance
Drug inactivating enzymes
Someorganisms produce enzymes that
chemically modify drug
Penicillinase breaks β-lactam ring of penicillin
antibiotics
Alteration of target molecule
Minorstructural changes in antibiotic target
can prevent binding
Changes in ribosomal RNA prevent macrolids from
binding to ribosomal subunits
Mechanisms of resistance
Decreased uptake of the
drug
Alterations in porin proteins
decrease permeability of cells
Prevents certain drugs from
entering
Increased elimination of
the drug
Some organisms produce
efflux pumps
Increases overall capacity of
organism to eliminate drug
Enables organism to
resist higher
concentrations of drug
Tetracycline resistance
EFFECTS OF COMBINATIONS OF DRUGS
Sometimes the chemotherapeutic effects
of two drugs given simultaneously is
greater than the effect of either given
alone.
This is called synergism. For example,
penicillin and streptomycin in the
treatment of bacterial endocarditis.
Damage to bacterial cell walls by
penicillin makes it easier for
streptomycin to enter.
EFFECTS OF COMBINATIONS OF DRUGS
Other combinations of drugs can be
antagonistic.
For example, the simultaneous use of
penicillin and tetracycline is often less
effective than when either drugs is used
alone. By stopping the growth of the
bacteria, the bacteriostatic drug
tetracycline interferes with the action of
penicillin, which requires bacterial
growth.
Antibiotic combinations
Combinations of antibiotics may be used
1. to broaden the antibacterial spectrum for
empiric therapy or the treatment of
polymicrobial infections
2. to prevent the emergence of resistant
organisms during therapy, and
3. to achieve a synergistic killing effect.
Important Host Determinants
a) Hepatic function:
Erythromycin, clindamycin, rifampin, Chloramphenicol, etc
depend on liver metabolisms for the inactivation of
antimicrobial mechanisms. Patients with impaired liver
function may accumulate in the body active form of the
drugs to a toxic level if the dosage adjustment is not made.
b) Kidney function:
Normal kidney function is essential for disposal of -lactams,
aminoglycosides, vancomycin, etc. Active form of these
drugs may accumulate in the patient with renal diseases.
Important Host Determinants…
c. Host defense mechanism:
A chemotherapeutic regimen that is perfectly
adequate for immuno-competent patient may be
totally ineffective for immuno-incompetent patient.
Immuno-incompetence may be due to deficiencies in
(1) immunoglobulin,
(2) phagocytic cells and
(3) cellular immune system.
