Table 1 lists the presumed advantages and disadvantages of FDCs. Some of these advantages and disadvantages are important in the context of AMR.

We might infer from the circumstantial evidence presented in this Table that FDCs may be better than free combinations in slowing or even eliminating AMR. It is well documented in TB treatment⁷ that multiple interruptions when using free dose combinations of pills creates the risk of monotherapy on some drugs and not in others. This fact, coupled with the in vivo mutation rates of the mycobacterial genome, rapidly leads to drug resistance to one or more of the free combination drugs. Fixed-dose combinations make the possibility of monotherapy even more remote. Effectiveness of FDCs, however, really depends on detailed knowledge of the epidemiology and microbial ecology of the particular pathogen. Since in HIV, malaria, or TB, development of AMR commonly occurs by rapid genetic mutations, deletions and insertions ^20, if evolution of AMR is occurring within a host during course of therapy (which in the case of HIV or TB is quite long), then FDCs would theoretically be effective if more than one drug is present in therapeutic concentration at any one time. Jordan et al²¹ did a systematic review and meta-analysis to assess the evidence for the effectiveness of increasing numbers of drugs in antiretroviral combination therapy. Evidence from randomised controlled trials supports the use of triple therapy but more research is needed on the relative effectiveness of specific combinations of drugs. Unfortunately, to reduce the potential for confounding by established drug resistance, Jordan et al. looked only at those patients who had not previously received antiretroviral therapy.

There are several ways that the different components of free or fixed-dose combinations produce their antimicrobial effect. The different drugs may attack the same biochemical target by different mechanisms (e.g., cotrimoxazole). Strictly speaking, use of different drugs with potentially incompatible pharmacokinetics is irrational because of the different elimination ½ lives of the individual components. Yet in combination therapy for dapsone-resistant leprosy²² and malaria⁶, it is often the case that individual drugs have different ½. lives in the blood. Alternately, combination therapy may use drugs with completely different modes of action (e.g., artemether-mefloquine for malaria) and which in theory do not share the same resistance mechanism. Both these strategies lie at the heart of the value of combination drugs in the context of treating infectious diseases and, in theory, combating antimicrobial drug resistance. The “leprosy” rationale for using combination drugs is based on the concept that a strong drug (e.g., rifampicin) with a short ½ life will reduce the number of pathogens to a level at which a second, more slowly acting drug (e.g., dapsone) will kill the rest^{22 23}. The second rationale follows from the discussion in Section 2. Drug resistance in many microbes arises from mutations and the probability that resistance to two different drugs will emerge is the product of the mutation rates per microbe (e.g., bacteria, virus, protozoan) for the individual drugs, multiplied by the number of microbes in an infection that are exposed to the drugs⁶. For instance, if one in 10⁹ microbes are resistant to drug. A and one in 10¹³ are resistant to drug B, and the genetic mutations that confer resistance are not linked, only 1 in 10²² will be simultaneously resistant to both A and B. If correctly given, combination drug treatments should in theory retard emergence of resistance compared with sequential use of single drugs²⁴. We note, of course, that if the dosages of the components of either FDCs or free combinations are incorrect there may be long periods where the concentration of drug is below levels needed to inhibit the pathogen-thus providing selection pressure for mutations.