Antimicrobial chemotherapy

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ANTIMICROBIAL CHEMOTHERAPY
A. Antimicrobial Agents
B. Chemotherapeutic Agents
C. Antibiotics
A) ANTIBIOTICS
Natural substances produced by various species of microorganisms
 bacteria
 fungi
 actinomycetes
suppress growth / kill other microorganisms
B) ANTIMICROBIAL AGENTS
Synthetic analogues
includes synthetic as well as naturally obtained drugs that attenuate microorganisms
C) CHEMOTHERAPEUTIC AGENTS
 Drugs in this class differ from all others in that they are
 Designed to inhibit/kill the infecting organism and have no/minimal effect on the recipient.
 The drugs also known as agents that are known to be used in chemotherapy for cancer
(wikipedia)-most specifically any how they also includes drugs used as antibiotics.
Microorganisms of medical improtance fall into four categories
 Bacteria
 Viruses
 Fungi
 Parasites
Antimicrobial chemotherapy
Use of drugs to combat infectious agents
 Anti-bacterial
 Anti-viral
 Anti-fungal
 Anti-parasitic agents

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Antimicrobial Chemotherapy
 Differential ( Selective) toxicity: Based on the concept that the drug is more toxic to the infecting
organism than to the host.
 Majority of antibiotics are based on naturally occurring compounds.
 Or may be semi-synthetic or synthetic.
What is the ideal antibiotic?
 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 hypersensitivities. In the host.
 Have rapid and extensive tissue distribution.
 Have a relatively long life.
 Be free of interactions with other drugs.
 Be convenient for administration.
 Be relatively inexpensive.
Principles / Definitions.
Spectrum of Activity:
 Narrow spectrum -Drug is effective against a limited number of species.
 Broad Spectrum – Drug is effective against a wide variety of species.
 Gram negative agent.
 Gram positive agent
 Anti-anaerobic activity.
 Minimum in hibitory concentration ( MIC)
 Minimum concentration of antibiotic required to inhibit the growth of the test organisms.
 Minimum Bacterial Concentration ( MBC)
 Minimum Concentration of antibiotic required to kiss the test organisms.
 Bacteriostatic.
 Bactericidal.
 Time dependent killing.
 Concentration dependent killing.
 Treatment and Prophylaxis
 Prophylaxis- Antimicrobial agent are administered to prevent infection.
 Treatment - Antimicrobial agents are administered to cure existing or suspected infections.
Combination Therapy
 To prevent the emergence of resistance .
 Mycobacterium tuberculosis

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 To treat polymicrobial infections.
 Initial empiric therapy.
 Synergy.
Why not use 2 antibiotics all the time?
 Antagonism.
 Cost .
 Increased risk of side effects.
 May actually enhance development of resistance inducible resistance.
 Interactions between drugs of different classes.
 Often unnecessary for maximal efficacy.
How do antimicrobial agents work?
 Must bind or interfere with an essential target.
 May inhibit or interfere with essential metabolic process.
 May cause irreparable damage to cell.
Target of antimicrobial agents.
 Inhibit cell wall production.
 Penicillin binding proteins.
 Inhibit protein synthesis .
 Bind 30s Or 50s ribosomal subunits.
 Inhibit nucleic acid synthesis.
 Binding topoisomerases / RNA polymerase.
 Block biosynthetic pathways.
 Interfere with folate metabolism.
 Disrupt bacterial membrane.
 Polymixins.

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Antimicrobial Resistance
 Factors which may accelerate the development of resistance.
 Inadequate levels of antibiotics at the site of infections.
 During of treatment too short.
 Overwhelming numbers of organisms.
 Overuse / misuse of antibiotics.
Antimicrobial Resistance
 General mechanisms of resistance.
 Altered permeability .
 Inactivation / destruction of antibiotic.
 Altered binding site.
 Novel ( new) binding site.
 Efflux ( pumps) mechanisms.
 Bypass of metabolic pathways.
Bacterial Resistance to ANTIMICROBIAL AGENTS
3 general categories
 Drug does not reach its target
 Drug is not active
 Target is altered
Drug does not reach its target
Porins
 Absence/mutation
 Reduce drug entry
 Reduced effective drug concentration at the target site.
Efflux pumps
 Transport drugs out of the cell
 Resistance to tetracyclines & β-lactam antib
Inactivation of Drug
Second general mechanism of drug resistance
β-lactam antibiotics - β-lactamase
Aminoglycosides - Aminoglycoside modifying enzymes

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Variant: failure of bacterial cell to convert an inactive drug to its active metabolite. Resistance to INH
(isoniazed) in mycobacterium TB.
Alteration of the Target
 Mutation of natural target
 Target modification
The new target does not bind the drug for native target
Resulting in resistance to antibiotic.
Components mediating resistance to β –lactam antibiotics in Psuedomonas aeruginosa
 β –lactam antibiotics hydrophilic
 Must cross outer membrane barrier of the cell via outer membrane protein (Omp) channel or
porins
 Mutation/missing/deleted

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 Drug entry slow or prevented.
 β - lactamase concentrated between the inner & outer membrane in the periplasmic space
 constitutes an enzymatic barrier
 Drug destroyed
 Effective concentration not achieved
 Target: PBP penicillin binding protein
 Low affinity for drug
 Altered
 Efflux transporter
 Mex A, Mex B & Opr F
 Pumps the antibiotic across the outer membrane
 Reduced intracellular concentration of active drug Resistance.
Mutations
 May occur in
 Target protein
 Drug transport protein
 Protein important for drug activation
 Random events
 Survival advantage upon re-exposure to the drug.
Resistance is acquired by horizontal transfer of resistance determinants from a donor cell, often of
another bacterial species by
 Transduction
 Transformation
 Conjugation
Insatiable need for new antibiotics
 Emergence of antibiotic resistance in bacterial pathogens both nosocomially & in the community
setting is a very serious development that threatens the end of antibiotic era.
 Responsible approach to the use of antibiotics
 That are now available & new agents that might be developed in future
 Is essential
 If the end of antibiotic era is to be averted.
CROSS RESISTANCE
 Acquisition of resistance to one AMA conferring resistance to another antimicrobial agent to
which the organism has not been exposed,is called cross resistance
 Seen b/w chemically or mechanistically related drugs.
 Resistance to one sulphonamide means resistance to all others
 Resistance to one tetracyclines means insenstivity to all others

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Complete cross resistance
Resistance to one aminoglycoside may not extend to others, Gentamycin resistant strains may respond to
amikacin.
partial cross resistance
 Sometimes unrelated drugs show partial cross resistance,
o e.g. Tetracyclines
o & Chloramphenicol
Prevention Drug Resistance
 Use of AMAs should not be:
 indiscriminate
 inadequate
 unduly prolonged
 Use rapidly acting & narrow spectrum (Selective) AMA whenever possible.
 Combination AMA
 whenever prolonged therapy is undertaken. Tuberculosis, SABE
 Infection by organism notorious for developing resistance Staph, E. Coli, M.
Tuberculosis must be treated intensively.
Prepared By ;
Amjad Khan Afridi
Date: 18March, 2017