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ANTIBACTERIAL

CHEMOTHERAPY

Antibacterial chemotherapy OUT


COMES
By the end of the sessions, learners will
be able to:
Describe the mode of actions of antibacterial

chemotherapeutic agents

Discuss antibiotic susceptibility testing


Identify the complications of chemotherapy
Describe the mechanisms of bacterial

resistance to antimicrobial agents

Definitions:
- Antimicrobial chemotherapeutic agents:
chemically synthesized substances that are used to
treat infectious diseases by killing or inhibiting the
growth of microorganisms.

- Antibiotics:
antimicrobial substances that are produced as
secondary metabolites by certain groups of
microorganisms (Streptomyces, Bacillus, few moulds
as penicillum and Cephalosporium).

Types of antimicrobials (concerning the


nature)
Natural antibiotics: original source was micro-

organisms.
Semisynthetic antibiotics: by chemical
modification of certain antibiotics to achieve the
desired properties.
Fully synthetic antibiotics: higher generations.

Types of actions of antibiotics


1- Bacteriostatic agent:
Antimicrobial agent capable of inhibiting
bacterial multiplication.
2- Bactericidal agent:
Antimicrobial agent capable of killing
bacteria.

Selective toxicity
The ability of an antimicrobial agent to
harm a pathogen without harming the
host. It may be a function of:
1- A specific receptor or target (found in
microbe but not in human body)
2- Inhibition of a biochemical reaction
(essential for microbe but not for the host)

Spectrum of activity of antibiotic:


The range of microorganisms that are affected by a certain
antibiotic is expressed as its spectrum of action.

1- Broad spectrum antibiotics:


antibiotics that kill or inhibit the growth of a wide range of
Gm +ve & Gm ve bacteria.

2- Narrow spectrum antibiotics:


antibiotics that are effective mainly against either gm +ve or
Gm ve bacteria.

3- Limited or mono spectrum antibiotics:


antibiotics that are effective only against a single organism
or disease

MECHANISMS OF ACTION OF
ANTIMICROBIAL DRUGS
1- Inhibition of bacterial cell wall
synthesis
2- Interference with the cell membrane
function.
3- Inhibition of bacterial protein
synthesis.
4- Inhibition of bacterial nucleic acid
synthesis (DNA or RNA).

1- Inhibition of bacterial wall synthesis


These antibiotics are bactericidal with minimal tissue

toxicity.
Members: a - -lactam antibiotics

b - Glycopeptides
c - Cycloserine and bacitracin
- -lactams inhibit the last steps of PG synthesis, while
Glycopeptides & cycloserine inhibit the early steps.

2- interference with cell membrane function


These antibiotics are bactericidal & highly toxic.
Members: - Polymyxin, colistin

They cause cell membrane disruption &


interfere with its function

3- Inhibition of bacterial protein synthesis:


Bacteria have 70S ribosomes (with 30S & 50S subunits)
Agents acting on 30S subunit:

- Tetracycline
- Aminoglycosides (gentamycin, streptomycin, amikacin)
Agents acting on the 50S subunit:

- Macrolides (erythromycin, azethromycin)


- Lincomycins
- Streptogramins
- linezolid
- Chloramphenicol
- Fusidic acid

4- Inhibition of nucleic acid synthesis:


This may occur by:

A- Inhibition of mRNA synthesis (e.g. rifampin)


B- Inhibition of DNA synthesis (e.g. quinolones)
C- Inhibition of dihydrofolic acid reductase leading to
inhibition of folic acid which is important for purine synthesis
and consequently nucleic acid formation (e.g.
trimethoprim).
D- Inhibition of folic acid synthesis by competitive
antagonism (e.g. sulphonamides). This drug is a structural
analogue for PABA (para-amino benzoic acid) a compound
which is essential for the synthesis of folic acid.

MECHANISMS OF ACTION OF Antibiotics

Choice of an Antimicrobial Agent for


Therapy
1- Can penetrate to the site of infection in a proper
concentration.
2- Know the nature of the infection.
3- Give the appropriate dose of the antibiotic for the proper
duration
4- Choose the spectrum of antibiotic activity.
5- Know the potential of the drug to produce toxicity and
use antibiotics that are only safe for the pregnant and
lactating women and for infants and children.
6- Choose bactericidal antibiotics.

Microbial Susceptibilities to Antimicrobial


Agents
Ideally, the appropriate antibiotic to treat any infection

should be determined in vitro before being given.


The in vivo activity of an antimicrobial agent is not

always the same as its in vitro susceptibility due the


involvement of many host factors.
The activity of an antimicrobial agent against an

organism depends on its concentration.

The minimal inhibitory concentration (MIC) is


defined as the lowest concentration of the drug that
prevents the growth of a test organism.

The routine in vitro susceptibility testing can


be done by one of the following methods:
1.

Disc diffusion methods.

2. Dilution methods such as tube broth


dilution.
3. Gradient diffusion (E-test) methods.

Disc Diffusion
method

E test method

Empiric therapy
It is the

best guess procedure based upon a

provisional diagnosis made by the physician that a patient


has a bacterial infection which requires treatment.

Depending on the type of infection, there will be a short list


of bacteria probably causing that infection.

Depending on the type of bacteria, there will be an antibiotic

most likely to successfully treat that infection.

Indications:
1- In seriously ill patients empiric therapy should be started
without delay but after collecting specimens for culture.
2- In closed lesions where there is no available sample.

Combined Therapy
- Definition:
the use of more than one antibiotic in order to
achieve successful clinical response.
- N.B.: The rule in treatment is monotherapy.

- Indications of combined chemotherapy:


1- Serious infections (e.g. meningitis).
2- Infection with Mycobacterium tuberculosis.
3- Febrile neutropenia.
4-To delay development of drug-resistant mutants.
5- Mixed infections.

Complications of Chemotherapy
1- Toxicity:
- tetracycline may cause staining of teeth in infants.
- Streptomycin may affect the 8th cranial nerve.
- Aminoglycosides may cause nephrotoxicity.
- Chloramphenicol can cause bone marrow depression.

2- Allergy (hypersetivinsity):
- Penicillin may cause urticaria, anaphylactic shock.
- Local application of sulphonamides may result in contact dermatitis.

3- Emergence of resistant strains:


- The abuse of antibiotics (low dosage, interrupted course, no
real indication, improper choice) encourage the emergence of resistant
mutants.

4- Superinfection:
- Occurs as a result of outgrowth of resistant members of normal
flora when the sensitive ones are eradicated during antibiotic therapy.

RESISTANCE TO ANTIMICROBIAL AGENTS


Antibiotic resistant is a global problem faced today in the treatment
of infectious diseases.
It is more prevalent in hospitals especially intensive care units due to

higher antibiotic use.

Categories of Resistance to antimicrobial agents:

I- Intrinsic (inherent or natural) resistance.


- Bacteria are insensitive naturally to antibiotics without acquisition
of resistance factors.
- It is consistent & can be expected once the organism is known.

- Examples: - Streptomycetes are protected from the antibiotics they


produce.
- An organism lacks the target for the antibiotic as in wallless bacteria to cell wall inhibitor antibiotica.

RESISTANCE TO ANTIMICROBIAL AGENTS


II- Acquired resistance:
It results from altered bacterial physiology and structure due

to changes in the genome of the organism.


It is inconsistent and unpredictable.
The acquired resistance mechanisms are driven by 2 genetic

processes in bacteria:
(1) Mutation: the more frequent the exposure to the
antibiotic, the greater the potential resistance.
(2) Exchange of genes between strains and species that can
be encoded on plasmid, phage or others.

PLASMID
Extrachromosomal, small,
cicular, double-stranded DNA
Function:
Antibiotic resistance

Mechanisms of Acquired Resistance to


antimicrobial agents
1-Reduction of the intracellular concentration of the
antibiotic:
- either by decrease in influx of antibiotic via the bacterial cell
wall or
- Efflux pumps: the antibiotic is pumped out through the cell
membrane faster than it can diffuse in which reduces its
concentration.

2-Inactivation of the antibiotic: e.g.:


- Production of -lactamases that hydrolyse -lactam ring in
penicillins & cephalosporins.
- Production of aminoglycoside modifying enzymes.

Mechanisms of Acquired Resistance to


antimicrobial agents

3-Target modification: modification of the target site


for the antibiotic results in reduced affinity for this
receptor, e.g.:
- Alteration of the PBPs leads to resistance to -lactam
antibiotics.
- Alteration of the 50S or 30S ribosomal subunits
reduces the affinity of the antibiotics targeting
these structures.

4-Target elimination by developing new


metabolic pathways:
- These bacteria have the ability to create new
metabolic pathway that bypass the original target

ANTIMICROBIAL CHEMOPROPHYLAXIS
- Definition:
Administration of an effective antimicrobial agent to
prevent infection with a certain microbe.

- Indications:
1- Examples of Surgical indications:
Preoperative in some surgical operations.
2- Examples of Medical indications:
a- In rheumatic fever.
b- In meningococcal meningitis.
c- In subacute bacterial endocarditis.

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