Combining drugs with different penetration profiles can accelerate development of multidrug resistance

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What scares you? As a kid, I hid behind couch cushions while watching Jurassic Park and could never finish a Goosebumps book. Nowadays, I am terrified of the growing epidemic of antimicrobial resistance. And I’m not the only one. Last year, as part of a five-year strategy to combat drug resistance, British Prime Minister David Cameron commissioned a review to examine the economic and health costs of antimicrobial resistance. In their first report published last December, the panel predicted that left unchecked, antimicrobial resistance will lead an extra 100 million deaths by 2050 and cost the world economy up to $100 trillion USD.

Efforts to halt the spread of antimicrobial resistance have focused on removing antibiotics from animal feed and curtailing the overzealous and oftentimes unnecessary use of antibiotics in humans. Another strategy to prevent resistance from developing is combination therapy, when two or more drugs with unique modes of action are taken together to treat an infection. In a paper published this week in the Proceedings of the National Academy of Sciences, a team of mathematicians and biologists led by Dr. Pleuni Pennings at San Francisco State University examined how differences in drug penetrance can impact the effectiveness of combination therapy and subsequent emergence of multidrug resistance.

Combination therapy reduces the risk of drug resistance because in theory, the pathogen needs to acquire multiple mutations at the same time to withstand the assault of multiple drugs. In reality, combination therapies fail to stem the development of resistance for a number of reasons. For example, some patients are started on a single drug first before a second drug is added. This type of treatment regiment facilitates resistance development because bacteria can acquire singular mutations in a stepwise fashion. Another reason is that different drugs have different staying power, which means that even though you may be taking both drugs at the same time, one could pass through your body much faster than the other. This creates periods of “effective monotherapy” where resistance can develop easily to the single long-lived drug. While a lot of attention has been paid to how drugs with different half-lives impact resistance, not a lot is known about how the spatial distribution of drugs influence the evolution of multidrug resistance. That’s where this paper comes in.  Continue reading