Table 1 lists the presumed advantages and disadvantages of FDCs. Some of these advantages and disadvantages are important in the context of AMR.
TABLE 1: ADVANTAGES AND DISADVANTAGES OF FIXED-DOSE COMBINATIONS
Simpler dosage schedule improves compliance and therefore improves treatment outcomes
Reduces inadvertent medication errors
Prevents and/or slows attainment of antimicrobial resistance by eliminating monotherapy (i.e, one drug is never by itself in circulation)
Allows for syngergistic combinations (i.e., trimethoprim/sulfamethoxazole combination allows each drug to selectively interfere with successive steps in bacterial folate metabolisms
Eliminates drug shortages by simplifying drug storage and handling, and thus lowers risk of being “out of stock”
Only 1 expiry date simplifies dosing (single products may have different expiry dates)
Procurement, management and handling of drugs is simplified
Lower packing and shipping costs
Less expensive than single ingredient drugs
Side effects are reduced by using one drug of the combination for this purpose
Potential for drug abuse can be minimized by using one drug of the combination for this purpose (i.e., excessive use of the antidiarrheal narcotic diphenoxylate is discouraged by side effects of atropine in the FDC atropine + diphenoxylate)
FDCs are (possibly) more expensive than separate tablets
Potential quality problems, especially with rifampicin in FDCs for TB, requiring bio-availability testing
If a patient is allergic or has a side-effect to 1 component, the FDC must be stopped and replaced by separate tablets
Dosing is inflexible and cannot be regulated to patient’s needs (each patient has unique characteristics such as weight, age, pharmacogenetics, co-morbidity, that may alter drug metabolism and effect).
Incompatible pharmacokinetics is irrational because of different elimination ½ lives of individual components
Reaction of one of the components (e.g., a rash to sulfamethaoxazole in cotrimoximzole) may result in patient avoiding the “innocent” trimethoprim in the future
Drug interactions may lead to alteration of the therapeutic effect.
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 rest22 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.