Biological Basis for Antibacterial Action

Question 1

Why are two antibiotics sometimes better than one?

Answer 1

Mutations conferring resistance to some antibiotics occur with frequencies of 106-109 per generation. Thus, because of the rapid growth of bacteria in human infection, outgrowth of resistant mutants can easily take place and become a significant clinical risk. However, two antibiotics given simultaneously can theoretically reduce the chance that a bacterium will completely evade antibiotic destruction. For example, assume that resistance to drug A arises with a frequency of 106 per generation. If drug B has a similar frequency of resistant mutants and is given simultaneously, the chance of a single bacterium becoming resistant to both antibiotics is 106 × 106, or 1012, which is vanishingly small.

Question 2

Name two clinical examples of using two antibiotics at once?

Answer 2

An excellent example of this concept currently in practice is combination therapy with sulfamethoxazole and trimethoprim. Although both drugs act on one-carbon metabolism, their sites of action are different, and resistance to one does not influence resistance to the other.

Another example is the obligatory combination of drugs used to treat tuberculosis and HIV infection. Treatment of active tuberculosis with a single agent is invariably associated with clinical failure and the emergence of drug-resistant strains. Similarly, HIV is typically treated with three-drug regimens to avoid rapid emergence of resistant viruses. Multidrug therapy for these diseases is therefore considered essential.

Question 3

What are three possible outcomes of the use of multi-drug therapies?

Answer 3

Synergism: The effectiveness of the drugs together is greater than that of either drug alone. For example, enterococci are naturally tolerant to penicillins and resistant to gentamicin. However, when penicillin is given along with gentamicin, the bacteria become permeable to gentamicin, which exerts a bactericidal effect in the cytoplasm.

Antagonism: The action of one drug reduces the effectiveness of the other. Thus, when tetracycline is given with penicillin, it blocks protein synthesis, preventing the cell growth required for penicillin to cause lysis. The result is dominance by the weaker bacteriostatic drug.

Indifference: Each drug works no better and no worse alone or in combination.

Question 4

What are some reasons to be cautious about using multiple drugs?

Answer 4

1. Drugs can show synergism in toxicity as well as in antimicrobial action (an example is the heightened damage to the kidney by the joint administration of vancomycin and an aminoglycoside).
2. In a hospital setting, the main sources of drug resistance are the members of the resident microbiota (not bacterial flora). Therefore, the decision to administer multiple drugs and which ones to choose should be governed by the spectrum of multidrug resistance of the dominant organisms in that hospital.