Thursday, April 12, 2007

When a little fighting is good

Last week's Nature has a great paper in it that takes several readings before it makes sense. It's not that the paper is poorly written, it's just that the results take a while to burrow through a bunch of preconceptions.

The paper looks at the effects of combining two antibiotics which antagonize each others actions, primarily doxycycline and ciprofloxacin. What is interesting, and initially counter-intuitive, is that mixing the two antibiotics at low doses (all in culture) creates a very different selective environment than two antibiotics which show additive effects. If you look at the space of possible combinations, then if the antibiotics add a strain resistant to one of the antibiotics will always grow better than an otherwise identical strain which is sensitive to that antibiotic. However, if the antibiotics are antagonistic then there will be some combinations which favor growth (Figure 2). They go on to show that this theoretical analysis indeed holds true for mixed cultures (Figure 3).

The interesting possibility is that by dosing the two drugs appropriately, resistance mutations would be at a competitive disadvantage to their wild-type kin and would therefore not take over the population. The article is appropriately cautious in extrapolating these effects to clinical settings. This remains to be demonstrated in an animal setting, let alone a patient. But it is intriguing. In addition to some mouse experiments, an obvious next step would be a further exploration of whether resistance mutations do emerge in long-term cultures.

Even if the results were to get past such experiments, it is difficult to see this work escaping the economic trap which ensnares all antibiotic work. Any commercial activities must compete with cheap, highly effective existing antibiotics. Academics could try to develop such combinations, but the patients in true need of such drugs are desparately ill, making finding any clinical signal difficult.

However, this could be a very interesting strategy to explore for cancer. There are definitely examples of chemotherapy agents which conflict with each other. For example, topoisomerase inhibitors & bortezomib. Combinations using this strategy might be cytostatic -- aiming to keep the tumor in check -- but that could be sufficient in many settings. However, these bump against the challenge for any cytostatic chemotherapeutic agent: you can't use tumor shrinkage as a clinical measure but must measure survival. Survival is what really counts, but requires much longer and larger studies.

1 comment:

Frédéric said...

To me, it sounds like Hormesis i.e. depending on the dose of each antibiotic, you get an inverted response.
Also, I think this dose response behavior is found in anti-self tolerance in immunology