Daniel Gilmer
predoctoral fellow
The Rockerfeller University

Ramiro, Mexico

Antibiotic resistance is blamed on people not taking the whole course of treatment. But how does that select for resistance? Wouldn't completing an antibiotic course of treatment be an even stronger selection for the rare, resistant bacteria?

Daniel Gilmer
HHMI Gilliam Fellow,
predoctoral fellow,
The Rockerfeller University
This is a great question that involves some controversy. I will start by explaining the nature of antibiotics and antibiotic resistance, which will inform the discussion of your question.

All organisms seek to grow and replicate. Sometimes, bacteria grow and replicate at the expense of other organisms. These hosts have developed molecules to kill bacteria, called antibiotics. Antibiotics are specific types of antimicrobials derived from living sources (e.g., plants, molds, bacteria) (1). The battle between bacteria and other organisms (including other bacteria) has been fought for billions of years.

In the last century, scientists discovered these incredible defenses against bacteria and began using antibiotics to kill bacteria that caused human diseases (2). This method of treatment has been very effective, nearly eradicating certain types of bacterial infections. However, we have stepped into a battle that has raged on for eons; while antibiotics have evolved to become very effective at killing bacteria, bacteria have also evolved many ways around antibiotics.

Bacteria can take many paths to establish resistance to antibiotics (3). Bacteria may inactivate the antibiotics, change the target site/pathway, export the antibiotics, or prevent the antibiotics from entering the cell. Some bacteria may upregulate export systems during exposure to antibiotics (4). Nonetheless, in many cases, bacteria acquire these capabilities through horizontal gene transfer—the sharing of genes (capabilities) among bacteria. They may also spontaneously acquire such mutations through single-point mutations, which occur at a rate of ~1/108 per replication cycle. Resistant bacteria are able to survive and reproduce in the presence of antibiotics, leading to the development of a resistant population.

When doctors prescribe antibiotics, they aim to eradicate the pathogen before resistance occurs. Therefore, the regimen is intense, consisting of a high dose of antibiotics taken over a long period to kill off all bacteria, including those most likely to develop resistance. When resistance is generated in the lab, a species of bacteria is exposed to low concentrations of an antibiotic, enabling it to adjust to the presence of the antibiotic and survive (5). In the same way, resistance can be generated in the human body. When a patient doesn't follow a complete antibiotic regimen, bacteria are exposed to only low levels of the antibiotic. Therefore, bacteria may remain in the body where the antibiotic never reached concentrations high enough to kill them. Further, bacteria other than the targeted pathogen may develop resistance. These other bacteria could then pass resistance genes to the pathogen through horizontal gene transfer, as mentioned previously.

Other problems can occur when either a resistant population has emerged or when the pathogen has been cleared before the end of the regimen. The ability of bacteria to develop resistance to antibiotics typically comes at the sacrifice of fitness (an organism's ability to live and replicate), because they spend energy on this extra function while other bacteria are functioning more efficiently (unless these other bacteria are being killed by the antibiotics, of course). When a population becomes resistant to a particular antibiotic, further use of that antibiotic may remove competing bacteria, enabling the resistant bacteria to flourish and cause serious illness.

When a pathogen has been cleared before completion of the regimen, taking additional antibiotic only exposes other bacteria in the body to antibiotic unnecessarily. In addition, a patient may feel better and stop using an antibiotic before the pathogen is completely under control, so it is safest to finish the prescription as recommended.

Taking antibiotics for a prolonged period of time can lead to many problems (e.g., clearing out good bacteria, multidrug resistance). However, taking an antibiotic for the full length of the prescribed regimen is unlikely to lead to a super-resistant species of bacteria. It usually takes prolonged exposure to very high concentrations of antibiotics for super-resistant bacteria to emerge. These are the high-level concerns addressed in your question, but there are many details below this cursory overview. This area of research is incredibly important, and you could make the next major discovery in antibiotic resistance.

References

1. Waksman, S. A., and Woodruff, H. B. 1941. Actinomyces antibioticus, a new soil organism antagonistic to pathogenic and non-pathogenic bacteria. J. Bacteriol., 42:231–249.

2. Zaffiri, L., Gardner, J., and Toledo-Pereyra, L. H. 2012. History of antibiotics. From salvarsan to cephalosporins. Journal of Investigative Surgery, 25(2):67–77.

3. Lederberg, J., and Lederberg E. 1952. Replica plating and indirect selection of bacterial mutants. Journal of Bacteriology, 63(3):399–406.

4. Howden, B.P., et al. 2010. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: Resistance mechanisms, laboratory detection, and clinical implications. Clin. Microbiol. Rev., 23(1):99–139.

5. Rouse, M. S., et al. 2005. In vitro and in vivo evaluations of the activities of lauric acid monoester formulations against Staphylococcus aureus. Antimicrob. Agents Chemother., 49(8):3187–3191.

12/27/12 18:24