Here's a paper in PNAS that says that we're probably treating infectious disease the wrong way - and perhaps cancer as well. The authors go over the currently accepted doctrines: multiple-mechanism therapies, when possible, and restricted use to patients who really need antibiotics. But there's a third assumption that they say is causing trouble:
A third practice thought to be an effective resistant management strategy is the use of drugs to clear all target pathogens from a patient as fast as possible. We hereafter refer to this practice as “radical pathogen cure.” For a wide variety of infectious diseases, recommended drug doses, interdose intervals, and treatment durations (which together constitute “patient treatment regimens”) are designed to achieve complete pathogen elimination as fast as possible. This is often the basis for physicians exhorting their patients to ﬁnish a drug course long after they feel better (long-course chemotherapy). Our claim is that aggressive chemotherapy cannot be assumed to be an effective resistance management strategy a priori. This is because radical pathogen cure necessarily confers the strongest possible evolutionary advantage on the very pathogens that cause drugs to fail.
The harder you hit a population of infectious disease organisms, the harder you're selecting for resistance. The key, they say, is that in many cases there's genetic diversity among these organisms even inside single patients. So you can start off with a population of bacteria, say, that could be managed by less aggressive therapy and the patient's own immune system. But then aggressive treatment ends up killing off the great majority of the bacterial population, which you'd think would be a step forward. But what you're left with are the genotypes that are hardest to kill with antibiotics. They were in a minority, and might well have died out under competition from their less-genetically-burdened cohorts. But killing those off gives the resistant organisms an open field to work in.
The other problem here is a public-heath one. You want to cure the individual patient, and you want to keep their disease from spreading, and you want to keep from encouraging resistance among the infectious organisms. Optimizing for all three at once is probably not possible.
The paper goes into detail with the example of malaria, pointing out that it may well be the norm for people to be infected with several different lineages of malaria parasites at the same time. They seem to be in there competing for nutrients and for red blood cells, and some of them appear to be keeping the others in check. Antimalarial drugs alter the cost/benefit ratio (for the parasites) of carrying resistance genes.
So what should we do? The problem is, they say, that there are probably no general rules that can be recommended:
Thus, aggressive chemotherapy is a double-edged sword for resistance management. It can reduce the chances of high-level resistance arising de novo in an infection. But when an infection does contain resistant parasites, either from de novo mutation or acquired by transmission from other hosts, it gives those parasites the greatest possible evolutionary advantage both within individual hosts and in the population as a whole. How do the opposing evolutionary pressures generated by radical cure combine in different circumstances to determine the useful life span of a drug? There will be circumstances when overwhelming chemical force retards evolution and other times when it drives things very rapidly. We contend that for no infectious disease do we have sufﬁcient theory and empiricism to determine which outcome is more important. It seems unlikely that any general rule will apply even for a single disease, let alone across disease systems.
For more on such ideas as applied to bacterial infections, see here and here. But near the end of this paper, the authors apply similar reasoning to cancer. (That analogy has come up around here before, I should note).
An analogous situation also occurs in cancer therapy, where cell lineages within a tumor compete for access to space and nutrients. There, the argument has recently been made that less aggressive chemotherapy might sustain life better than overwhelming drug treatment, which simply removes the competitively more able susceptible cell lineages, allowing drug-resistant lineages to kill the host. Mouse experiments support this: Conventionally treated mice died of drug-resistant tumors, but less aggressively treated mice survived (95).
So maybe too many of us have been thinking about these questions the wrong way. If we switch over to favoring whatever strategy minimizes resistance, both in individual patients and thus across the population, we could be in better shape. . .