Not recommended fixed-dose antibiotic combinations in low- and middle-income countries - the example of Tanzania

Fixed-dose combinations (FDC) are medicine formulations that combine two or more ingredients in fixed ratios in a single dose form. Although advantageous in tuberculosis and malaria (efficacy, adherence, protection against resistance), only a few antibiotic FDC (FDC-AB) have been developed along full microbiological, pharmacological and clinical validation and safety studies. The World Health Organization (WHO) database of Access, Watch and Reserve (AWaRe) antibiotics contains, since 2021, a list of "Not Recommended" FDC-AB (n = 103) which are rejected for use in clinical practice. BODY: The share of non-recommended FDC-AB in global antimicrobial use (2000-2015) was < 3% but substantially higher in middle income countries. The share increases over time, but recent data particular concerning sub-Saharan Africa are rare. Along three non-recommended FDC-AB listed in the Tanzanian National Essential Medicine List (ampicillin-cloxacillin, flucloxacillin-amoxicillin and ceftriaxone-sulbactam) we discuss the concerns and reasons behind use of these products. Non-recommended FDC-AB have poor rationale (ratios of both ingredients), lack evidence of efficacy (pharmacological, microbiological and clinical), have difficulties in dosing (underdosing of the single ingredients, absence of pediatric dosing) and risks of safety (additive toxicity). They are expected to fuel antimicrobial resistance (unnecessary broad spectrum coverage) and are incompatible with antimicrobial stewardship. The specific context of low- and middle-income countries contributes to their increased use: at the side of prescriber and supplier are the lack of diagnostics, poor training in antibiotic prescribing, patients' preferences, role-model of senior prescribers and pharmaceutical promotion. International market mechanisms include economic motivation for development, branding and promotion, poor access to the single antibiotic forms and weak national regulatory capacity.

There is an urgent need for monitoring consumption of non-recommended FDC-AB in low- and middle-income countries, particular in Sub-Saharan Africa. A multinational and multisectoral antimicrobial stewardship strategy is needed in order to abolish the use of non-recommended FDC-AB.