Could combining drugs with different targets increase resistance?

Posted on June 22, 2015   by Anand Jagatia

Bacterial and viral infections are often treated using multiple drugs at once. This is thought to have many advantages, including a lower risk of drug resistance. But according to a new study in Proceedings of the National Academy of Sciences (PNAS), combining drugs that reach different parts of the body may speed up the evolution of multi-drug resistance, compared to using drugs that reach the same parts of the body.

When you receive an injection or swallow a tablet for an infection, the drug you’re given won’t reach every part of your body to the same extent. Certain parts of your anatomy or certain types of cell may be more difficult for drug molecules to reach than others, meaning there will always be areas in your body where the drug fails to reach therapeutic concentrations. This is known as “imperfect drug penetration”.

To get over this problem, doctors might prescribe you two drugs that, between them, have a greater overall coverage – ensuring that all parts of the body receive treatment. But combining drugs which have different penetrations could actually make multi-drug treatment less effective, by accelerating the emergence of drug resistance.

“Your intuition would be that more drug penetration is always better,” says Pleuni Pennings from San Francisco State University, co-author of the PNAS paper. “But our results suggest that this might not be the case.”

The team used a mathematical model to show how resistance develops more quickly when two drugs penetrate different areas of the body, compared to when they penetrate the same areas.

To understand why, consider the following hypothetical situation. Let’s say you’re given two drugs to fight off a virus: drug A and drug B. They have identical penetrations, and neither drug is able to reach the kidneys. This means that these organs represent a drug-free ‘sanctuary’ for the virus, where it can replicate unchecked. However when the virus leaves the kidneys and migrates to other areas of the body, it’s quickly snuffed out by the double combination of drugs.

Of course, the virus could mutate and become resistant, but in this scenario the chances are very small. For the virus to survive outside of the kidneys, resistance mutations would have to arise against both drugs simultaneously, which is unlikely.

Now imagine that you are given a different combination: drug A and drug C. Unlike in the previous example, drug C can penetrate the kidneys. So the virus can’t replicate here, meaning its overall growth is lower, which is good news for you. But it also means that the virus only has one drug to deal with in the kidneys – and the probability that it will evolve resistance to just drug C becomes much higher. If this drug C-resistant strain leaves the kidneys, it is now only attacked by drug A, meaning additional resistance against this drug is also much more likely to evolve. Once this happens, the virus becomes multi-drug resistant and alternative measures are needed to treat it.

Using drugs with different penetrations effectively leads to areas of the body where only one of the drugs is present, what the authors term “single-drug compartments”. These compartments can undermine the benefits of a multi-drug treatment by giving pathogens a ‘stepping stone’, allowing them to acquire resistance to drugs one at a time instead of all at once.

“It may not happen every day, but it may happen at some point during your treatment,” explains Pennings. “You then have a resistant mutant virus in that area which can replicate and form a stable population. And from this population, mutants could then emerge that are also resistant to the second drug, allowing them to invade areas where that drug is present, and so they start to conquer back the body, bit by bit.”

The model developed by the authors in this research is a simplification, using only two drugs and four compartments. However, they found that even a very small single-drug compartment was enough to markedly accelerate the evolution of resistance to both drugs. For this reason, the authors conclude that even if it means overall coverage is lower, it may still be better to use drugs with matching penetration profiles. Doing so has obvious drawbacks – it leaves a greater area of the body with no drugs at all, so pathogen replication is higher. But it also makes it much harder for resistance to evolve, because neither drug is ever present on its own.

“It’s a trade-off – what you decide depends on how bad on-going replication will be for the patient,” says Pennings. “But our results suggest that mismatched drug penetration is something clinicians and drug developers should be thinking about.”

While the model may be simple, the situation is much more complex in reality. Future work will involve extending the model and investigating whether matching drug penetrations in a clinical setting can actually improve treatment outcomes.

Combination drug therapy is almost always better than single drug therapy – but it’s not perfect, and multi-drug resistance is still of huge concern in the fight against infections like HIV, hepatitis and tuberculosis, which affect millions of people around the world. These results may help us to understand how pathogens are able to acquire resistance in the face of multiple drugs.

Moreno-Gamez, S., Hill, A., Rosenbloom, D., Petrov, D., Nowak, M., & Pennings, P. (2015). Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance Proceedings of the National Academy of Sciences, 112 (22) DOI: 10.1073/pnas.1424184112

Image: Jamie on Flickr under CC BY 2.0