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Antibiotic Resistance

M. R. Reddy, M M. Chawak, M. V. L. N. Raju, and S. V. Rama Rao
Project Directorate on Poultry, Hyderabad .

The introduction of antibiotics into clinical use has almost invariably been followed by the emergence ofresistance to these drugs in bacteria| populations. Resistance is seen when microorganisms fail to respond to medication, either because they are naturally resistant (i.e. non-susceptible) or because they have acquired resistance. Acquired resistance bybacteria is common and has become a serious problem because it reduces or prevents the opportunities for effective use of some antibiotics. With an increasing u e of antibiotics, opportunities for resistance to arise are greater. This is especially so where continuous exposure to one antimicrobial is applied under circumstances of mass medication. Resistance arises most frequently in organisms with high multiplication rates, such as bacteria (both pathogens and commensals) and cocacidia.

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Bacterial resistance Is often seen in the poultry industry. It gives cause for concern, not only regarding poultry medication but also from possible public health Hazards resulting from human consumption of products.

MECHANISMS OF RESISTANCE :

There are three major mechanisms that mediate bacterial resistance to drugs.

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  • Bacteria produce enzymes that inactivate the drugs; eg. Beta laciamases can inactivate penicillin’s and cephalosporins by cleaving the beta-lactan ring of drug.
  • Bacteria synthesize modified targets against which the drug has no effect; eg. a mutant protein in the 30s ribosomal subunits can result is resistance to streptomycin and a mentholated 23srRNA can result in resistance to erythromycin.
  • Bacteria alter their permeability so that an effective intracellular concentration of the drug is not achieved; eg. Tetracyclines are concentrated less in resistant bacteria than in susceptible once.

GENETIC BASIS OF RESISTANCE:

Most drug resistance is due to a genetic change in the organism, either as a chromosomal mutation or the acquisition of a plasmid ortransposon.

a) CHROMOSOME-MEDIATED-RESISTANCE:

Chromosomal resistance is due to a mutation in the gene that codes for either the target of the drug or the transport system in the membrane that controls the uptake of the drug. The frequency of spontaneous mutations usually ranges from 10~ 7 to 10 ~ 9 which is much lower then the frequency of acquisition of resistance plasmids. Therefore, chromosomal resilience is less of a clinical problem than plasmid. Mediated resistance.

b) PLASMID-MED1ATED RESISTANCE:

Plasmid-mediated resistance is very important from clinical point of view for 3 reasons:

1) It occurs in many different species, especially gram negative rods.

2) Plasmida frequently madiate resistance to multiple drugs.

3) Plasmids have a high rate of trans. for from one cell to another, usually by conjugation.

Resistance plasmids (resistance factors, R factors) are extrachromosomal. Circular, double standard DNA molecules that carry the genes for a variety of enzyme that can degrade antibiotics and modify membrane transport system.

In addition to producing drug resistance. R factors have two very important properties:

1) They can replicate independently of the bacterial chromosome, sothat a cell can contain many copies.

2) They can be transferred not only to cells of the same species but also to other species and genera.

In addition to conveying antibiotic resistance, R factors impart two other

Traits: (1) resistance to metal ions (eg, they coda. for an enzyme that reduces mercuric ions to elemental mercury) and (2) resistance to certain bacterial viruses (bacteriophages) by coding for restriction and nucleases that degrade the DNA of the infecting bacteriephages.

c) TRANSPOSON-MEDIATED RESISTANCE:

Transposons are genes that are transferred either within or between larger pieces of DNA such as the bacterial chromosome and plasmid.s. A typical drug resistance transposon is composed of three genes blanked on both sides by shorter DNA sequences usually a series of inverted repeated bases that mediate the interaction of the transposon with the larger DNA. The three genes codes for (1) transposase, the enzyme that catalyzes excision and reintegration of the trans­poson; (2) a repressor that regulates synthesis, of the transposase and (3) the drug resistance gene.

NON-GENETIC BASIS OF RESISTANCE:

There ere several non genatic reasons for the failure of drugs to inhibit the growth of bacteria.

1. Bacteria can be walled off within an abscess cavity which the drug cannot penetrate effectively.

2. Bacteria can be in a resting state, i.e. not growing, they are therefore insensitive to cell wait inhibitor such as penicillin’s and cephalosporins.

3. Under certain circumstances, organisms that would ordinarily be kitted by penicillin’s can lose their cell walls, survive as protoplasts and be insensitive to cell wall active drugs. Later, if such organisms resyanthesize their cell walls, they are fully susceptible to these drugs.

4. There are several artifacts that can make it appear that the organisms are resistant,

eg, administration of the wrong drug or the wrong dose, failure of the drug to reach the appropriate site in the body or failure of administration of drug.

SELECTION OF RESISTANT BACTERIA Br OVERUSE AND MISUSE OF ANTIBIOTICS:

Serious outbreaks of diseases caused by gram negative rods resistant to multiple antibiotics are more common in poultry, especially in developing countries. There are three main foci points, of overuse and misuse of antibiotics that increase the likelihood of these problems by enhancing the selection of resistant mutants.

  • Antibiotics are used in poultry feed, to prevent infections and promote growth. This selects for resistant organisms in the poultry and may contribute to the pool of resistant organisms in humans.
  • In many countries antibiotics are sold in the market to the general public. Some producers administer drugs without consulting the veterinarian. This practice leads to inappropriate and indiscriminate use of the drugs.
  • Some veterinarians use multiple antibiotics when one would be sufficient, prescribe unnecessarily long courses of antibiotic therapy. use antibiotics in self limited infections for which they are not needed, and overuse antibiotics for prophylaxis.

SPECIFIC MECHANISMS OF RESISTANCE:

1. Penicillins and cephalosporins:

There are several mechanisms ofresistance to these drugs. Cleavage by Beta-lactamases (penicillin’s and cephaloeporinases) is by for the most important. Beta-lactamases produced by various organisms have different properties. For example staphyloccal penicillinase is inducible by penicillin end is secreted into the medium. In contrast, some Beta-lactamases produced by several gram negative rods are located in periplasmic space near the peptidoglycan, and are not secreted in to the medium.

Resistance to Penicillins can also be due to changes in the penciling-binding proteins in the bacterial cell membrane. These changes probably account for low-level and high level resistance. Low - level resistance Is due to the presence of a plasmid coding for penicillinase.

Another form of resistance to Penicillins is tolerance in which growth of the organism is inhibited by Penicillins but the organism is not killed. This is attributed to a failure of activation of the autolytic enzymes, murein hydrolases. Which degrade the peptidoglycan-can.

2. Aminoglycosides: Resistance to aminoglycosides occurs by three mechanisms: (1) modification of the drugs by plasmid encoded phosphorylating, adenylylating, and acetylating enzymes (the most important mechanism). (2) Chromo­somal mutation, eg, a mutation in the gene that codes for target protein in the 30s submit of the bacterial ribosome, end (3) decreased permeability of the bacterium to the drug.

3. Tetracyclines: Resistance to tetracyclines is the result of failure of the drug to reach

An in­hibitory concentration inside the bacteria. This is due to plasmid-encoded processes,

that either reduce uptake of the drug or enhan­ce its transport out of the cell.

4. Chloramphenical: Resistance to chloramphenical is due to plasmid-encoded

acetyl transfers that acetylates the drug thus inactiva­ting it

5. Erythromycin: Resistance to erythromycin is due primarily to a plasmid-encoded

Enzyme that methytaies the 23s rRNA, thereby blocking binding of the drug.

6. Sulfonamides: Resistance to sulfonamides is mediated primarily by 2 mechanisms:

(1) a plasmiuencoded transport system that actively exports the drug out of cell; and

(2) a chromosomal muta­tion in the gene coding for the target enzyme, dihydropteroate

Synthesis, which reduces the binding affinity of the drug.

7. Ouinolones: Resistance to quino- lones due primarily to chromoso­mal mutations

that modify the bacterial DNA gyrate.