The emergence of previously unreported infectious diseases and the re-emergence of infectious disease thought to have been on the way to elimination has recently occupied the energies of scientists and policymakers1. Moreover, this increasing burden of disease must be viewed against the backdrop of the rapid evolution of infectious pathogens exhibiting antimicrobial resistance (“AMR”) and in particular, multiple-drug resistance (“MDR”)2. These two issues have created a major clinical and public health threat of global dimensions3 4 5.
The idea that AMR can be delayed or even prevented by combining drugs with different targets as so-called “free” combinationsi or “fixed-dose” combinationsii has been the subject of continuing interest (see Section 3). The underlying pharmacological theories as to why combination therapies should delay or prevent clinical resistance are intellectually satisfying6 but not rigorously proven in the field. Outside of some work in tuberculosis (“TB”)7 and malaria8 9, little attention has been given to identifying obstacles to the promotion, availability, and rational use of FDCs in the context of AMR.
i Simultaneous dosing of more than one drug contained in several different tablets or pills.
ii Simultaneous dosing of more than one drug contained in a single formulation, in which each drug has an independent mode of action, or the combination of which are synergistic or additive or complementary in their effect.
In this paper, we briefly summarize the biological basis for clinical antimicrobial resistance in TB, malaria and HIV/AIDS (Section 2) and review the pharmacotherapeutic reasons for using combination drugs to eliminate or slow development of AMR (Section 3). In particular, in Section 4 we summarize the available information regarding two hypotheses:
1) use of FDCs will ameliorate or inhibit clinical resistance to TB, HIV/AIDs and malaria, and 2) use of separate dispensing and/or co/blistering is equally as effective as FDCs in ameliorating or inhibiting this clinical resistance.
We then attempt to identify future research needs.