Drug resistance limits the therapeutic uses of antibacterial agents in animals and man. Antibacterial drug resistance develops in bacteria rapidly due to their short generation time and easy genetic exchange mechanisms. Drug resistance is also observed with protozoa, helminthic parasites and malignant cells.
Resistance in bacteria spreads from animals to animals or from bacterium to bacterium by plasmids and from plasmid to plasmid by transposons. Understanding the mechanisms of resistance helps in avoiding resistance by sensible use of drugs and developing new drugs un-favouring resistance.
Genetic determinants for resistance in bacteria may be chromosomal (constitutive) or extra-chromosomal (acquired). Plasmids are examples of extra-chromosomal genetic determinants. Plasmids carrying gene for resistance (‘r’ genes) are known as R-plasmids or R-factors. Plasmid transfer takes place by three mechanisms namely transduction, transformation and conjugation.
Due to acquisition of resistant genes bacteria can defend themselves against antimicrobials by several ways as follows:
(i) Increased production of different antibiotic inactivating enzymes e.g. β-lactamases, acetyl transferases and kinases. Penicillins, cephalosporins, aminoglycosides and chloramphenicol are inactivated by enzymes.
(ii) Alteration of the specific configuration of binding sites e.g. cloxacillin, macrolides, lincomycin and streptomycin.
(iii) Development of impermeable cell walls. It has been observed with Pseudomonas aeruginosa and many antibiotics.
(iv) Increased production of metabolic intermediates e.g. PABA and sulfa drug resistance.
(v) Development of alternative pathways e.g. dihydrofolate reductase synthesis with no affinity to trimethoprim and dihydropteroate synthetase with poor affinity to sulfa drugs.
(vi) Induction of membrane transport system for elimination of anti-bacterials e.g. tetracyclines.
(vii) Inhibition of alteration in membrane transport system to prevent entry of anti-bacterials e.g. aminoglycosides.
(viii) Defective production of autolytic enzymes e.g. penicillins.
Beta lactamases are mainly produced by staphylococci by R-plasmids. They degrade penicillins and cephalosporins. Semi synthetic penicillins such as methicillin and new β lactam antibiotics e.g. monobactams and carbapenems are however, not degraded. Gram- negative bacteria can also produce β lactamase.
The enzyme is determined by chromosomal genes or plasmid genes. Acetyl transferase gene is carried on plasmid, whereas kinases inactivating aminoglycosides are coded by plasmid and transposons. Multiple drug resistance has been observed in staphylococci.
In addition to the resistance to β lactam antibiotics, staphylococci also acquire resistance to many drugs by plasmids and transposon genes namely streptomycin, aminoglycosides, chloramphenicol, trimethoprim, sulfa drugs and quinolones.
Cross resistance is also observed in bacteria. Bacteria resistant to one drug also show resistance to another drug. This has been seen in aminoglycosides and macrolides.
In veterinary practice emergence of drug resistance has been amply demonstrated in Salmonella typhimurium strains causing diseases in man and animals and enteric bacteria especially E. coli. Multiple antibiotic resistance has been recorded in S. typhimurium isolated from animals throughout the world.
Prevention of Drug Resistance:
Following approaches help in control of antibiotic resistance:
(i) Drugs should be used for short period at therapeutic doses.
(ii) Drug combination may overcome the emergence of drug resistance,
(iii) Antimicrobial sensitivity test is necessary to select drug for therapy.
(iv) Isolation of sick animals as preventive measures for spread of resistant bacteria.
(v) Broad spectrum drug should not be used if a narrow spectrum drug is effective against the causative organism.