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Intuitively the standard practice of using only 1 antibiotic for a standard (non-resistant) infection poses the highest risk of developing resistance (because the bacterial population only has to beat the antibiotic it faces).

What if every antibiotic prescription had to be a mix of 2 or more antibiotics with different modes of action?

Assuming all the bacteria in a given population have to "develop" (mutate) antibiotic resistance on their own (could be as a plasmid or part of the bacterial genome, no cheating allowed via plasmid or gene transfer from bacteria outside the population), then resistance mutations would occur randomly with a low but significant chance per replication. If the bacterial population has to face 2 fundamentally different antibiotics at the same time, then bacteria that want to survive have to develop resistance to both (at the same time) which would be another order of difficulty.

Mathematically, if the chance per replication of developing resistance to each of the 2 antibiotics can be written as 1/A and 1/B respectively (where A and B are large numbers), then the chance of a bacterial cell replicating a mutant that survives the 2-antibiotic mix is (1/A) * (1/B). For a 3-antibiotic mix the chance becomes (1/A) * (1/B) * (1/C). As more are added to the mix, the survival chances quickly get astronomically stacked against the bacteria, with none of them surviving or getting a chance to spread resistance. Importantly, this formula assumes that all antibiotics in the mix use different enough modes of action that resistance to 1 of them doesn't significantly confer resistance to any other in the mix.

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  • Somewhat on-topic: the new cancer treatment described in jpost.com/HEALTH-SCIENCE/… seems to take the same approach, hitting 3 common cancer targets at the same time to make it statistically "impossible" that a cancer will mutate around all of them.
    – user1258361
    Jan 31, 2019 at 18:13
  • A better way: Research at Case Western Reserve University has shown that by turning off the toxic excretion mechanism of the bacteria, the bacteria become essentially harmless. With this technique, the body can clear the infection whenever it gets around to it! Worked on MRSA, Staph, Strep so far. Case Western Reserve researchers cure drug-resistant infections without antibiotics
    – Heart Tropix
    Feb 20, 2019 at 22:28

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The issue is that antibiotics are not without side effects and the use of most antibiotics carry a risk for developing Clostridium Difficile. If you take more than one class of antibiotic, your risk increases based on the risk associated with the second antibiotic if not more.

Furthermore, there's the deleterious effect on the human biome when using antibiotic therapy in the first place:

Mounting evidence shows that antibiotics influence the function of the immune system, our ability to resist infection, and our capacity for processing food. Therefore, it is now more important than ever to revisit how we use antibiotics.

On the other hand, certain bacterial infections are known to develop resistance during the course of treatment, and that's why current antituberculosis therapy uses 4 drugs concurrently.

Given the complications observed in treatment with streptomycin and the efficacy observed for both streptomycin and PAS individually, the MRC decided to extend their first RCT to include the first combination antimicrobial regimen using both of these agents. In this new trial, the MRC found that, in contrast to streptomycin monotherapy, which yielded streptomycin resistance in 70% of cases after 120 days, combination therapy yielded streptomycin resistance in at most 9% of cases and in 0% of cases in regimens with intermittent streptomycin administration every 3 days

http://mbio.asm.org/content/8/2/e01586-16.full

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    Wouldn't adding antibiotics for regular, everyday use also give rise to more superbugs? (MRSA etc). I think that is what you are alluding to in your second quote.
    – JohnP
    Oct 19, 2018 at 15:45

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