1-24 Mechanisms of Resistance to Antibiotics

Question 1

How do intrinsic, mutational, and acquired resistance differ?

Answer 1

• Intrinsic resistance is the innate, chromosomally mediated, and predictable ability of a bacterial species to resist the activity of a particular antimicrobial agent, perhaps through inherent structural or functional characteristics.
• Mutational resistance is chromosomally mediated but not predictable. Resistance granted by a random mutation may occur spontaneously or due to exposure to an antibiotic during therapy.
• Acquired resistance occurs when a particular microorganism gains the ability to resist specific antimicrobial activity to which it was previous susceptible. This process may occur through transformation, transduction, or conjugation.

Question 2

What are some factors that increase antibiotic resistance mutation rates?

Answer 2

• Unstable sequences surrounding the bases for the resistance phenotype
• Transposable elements
• Low antibiotic concentrations/short time of exposure
• Low/high copy # of each R gene (depending on dominant/recessive mutation)
• Stress (starvation, antibiotic stress, pathogenic stress)
• Large variety of resistance genes
• Large # sites in resistant gene

Question 3

What are the seven mechanisms of antibiotic resistance in bacteria?

Answer 3

1. Enzymatic inactivation
2. Decreased permeability
3. Efflux (ejection of antibiotic from bacterium)
4. Alteration of target site
5. Protection of target site
6. Overproduction of target
7. Metabolic bypass of inhibited process

Question 4

What are two examples of groups that resist antibiotics through enzymatic inactivation?

Answer 4

1. β-lactamases
2. Carbapenemases

Question 5

How do bacteria become resistant to β-lactams?

Answer 5

Enyzme inactivaiton, through the production of β-lactamases. β-lactamases are enzymes that split the amide bond of the β-lactam ring, and they can be encoded by chromosomal genes or transferable genes.

Question 6

How are β-lactamases classified?

Answer 6

By amino acid structure, in classes A through D. Additional classification is based on the spectrum of activity with respect to the destruction of β-lactam antibiotics:

• Extended-spectrum β-lactamases (ESBLs): enzymes that mediate resistance to extended-spectrum cephalosporins and monobactams. Usu. found in Klebsiella, E. coli, and Proteus.
• Amp C β-lactamases: primarily chromosomal enzymes that confer resistance to penicillins, narrow-spectrum cephalosporins, oxymino-β-lactams, and cephamycins. Usu. found in members of Enterobacteriaceae OTHER than Klebsiella and E. coli.

Question 7

What are carbapenemases?

Answer 7

Enzymes that confer the largest antibiotic resistance spectrum. Found worldwide in many Gram(-) species.

Question 8

What are the four ways to overcome the action of β-lactamase enzymes?

Answer 8

1. Pencicillinase-resistant penicillins
2. β-lactamase inhibitors and inhibitor combinations
3. Extended-spectrum cephalosporins
4. Carbapenems

Question 9

What are penicillinase-resistant penicillins?

Answer 9

A semisynthetic class of drugs that is the choice treatment for penicillin-resistant S. aureus (OTHER than MRSA) and S. epidermidis. Active against Gram(+) only.

Question 10

What are β-lactamase inhibitors?

Answer 10

Drugs with weak antibacterial activity but potent inhibition of many class A β-lactamases. They bind irreversibly to β-lactamase, neutralizing its activity and preventing hydrolysis of β-lactam antibiotics. There are three β-lactamase inhibitors in clinical use:

1. Clavulanic acid (Augmentin = amoxicillin + clavulanic acid)
2. Sulbactam (Unasyn = ampicillin + sulbactam)
3. Tazobactam (Zosyn = piperacillin + tazobactam)

They can be used in combination, as shown above, or singly.

Question 11

What are extended-spectrum cephalosporins?

Answer 11

3rd or 4th generation cephalosporins resistant to the action of many β-lactamases.

Note: NOT effective on ESBL and carbapenase producers.

Question 12

What are carbapenems?

Answer 12

A class of broad-spectrum β-lactam antibiotics. They are structurally resistant to most β-lactamases, including ESBLs.

Question 13

What are extended-spectrum β-lactamases (ESBLs)?

Answer 13

Enzymes that mediate resistance to extended-spectrum penicillins and cephalosporins. They are usually found in Klebsiella, E. coli, and Proteus.

Susceptible to β-lactamase inhibitors, carbapenems, and cephamycins.