Review of Pharmacology - 9E (2015)

CHAPTER
13
Chemotherapy A: General
Considerations and Non-specific
Antimicrobial Agents
Antibiotics are the substances produced by microorganisms, which suppress the growth of or
kill other microorganisms at very low concentrations.
General Considerations
Drug Resistance
Drug resistance in bacteria may be natural or acquired. Development of acquired resistance
may be due to single step mutation (as seen with streptomycin and rifampicin) or multi step
mutation (erythromycin, tetracycline and chloramphenicol).
Drug resistance can be transferred from one microorganism to other by gene transfer (also
called infectious resistance) via conjugation, transduction or transformation.
• Conjugation: It is due to the physical contact between bacteria and is responsible
for multidrug resistance. This is a very important mechanism for the development
of resistance against chloramphenicol and streptomycin.
• Transduction: It is the transfer of resistance gene through bacteriophage e.g.
penicillin, erythromycin and chloramphenicol.
• Transformation: It is the transfer of resistance gene through environment and is
not significant clinically e.g. penicillin G.
Transfer of antimicrobial drug
resistance
Conjugation
– Multiple drug resistance
Transduction
– Staph. aureus
Transformation
– Pneumococci
– Neisseria
Resistance once acquired becomes prevalent due to selection pressure of a widely used
antimicrobial agent i.e. antimicrobials allow resistant organisms to grow preferentially.
Mechanism of Resistance
Microorganism may develop resistance due to
• Decreased affinity for the target e.g. pneumococci and staphylococci may develop
altered penicillin binding proteins.
• Development of alternative metabolic pathway e.g. sulfonamide resistant
organisms start utilizing preformed folic acid in place of synthesizing it from
PABA.
• Elaboration of the enzymes which inactivate the drug e.g. β-lactamases (penicillins
and cephalosporins), chloramphenicol acetyl transferase (chloramphenicol) and
aminoglycoside inactivating enzymes (aminoglycosides).
• Decreased drug permeability due to the loss of specific channels e.g. aminoglycosides
and tetracyclines attain much lower drug concentration in the resistant organisms
than in the sensitive organisms.
• Development of efflux pumps (tetracyclines, erythromycin and fluoroquinolones)
results in active extrusion of the drug from the resistant microorganisms.
Drug resistance by Inactivating
enzymes
A – Aminoglycosides
B – Beta lactams
C – Chloramphenicol
Superinfection
It refers to the appearance of a new infection as a result of antimicrobial therapy. Normal
microbial flora contributes to host defense by development of bacteriocins. Pathogens also
have to compete with the normal flora for nutrients. Broad spectrum antibiotics (tetracyclines,
chloramphenicol, clindamycin, aminoglycosides and ampicillin) may kill the normal flora and
result in the development of new infection. Superinfection is more commonly seen in
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