A new analysis of pharmaceutical sales data from 75 countries shows that fixed-dose combinations (FDCs) account for more than a fifth of total antibiotic consumption, and that most of these combinations are not compatible with the World Health Organization’s (WHO’s) Essential Medicines List and have not been approved by the US Food and Drug Administration (FDA).
In the study, published yesterday in PLOS One, a team led by researchers in the United Kingdom looked at data from a multinational pharmacy retail sales database and found that FDCs—formulations comprising two or more antibiotics, or antibiotics combined with another drug, in a fixed ratio of doses—accounted for 22.5% of total antibiotic consumption in 75 countries in 2015. But 92% of the 119 FDCs identified were not FDA-approved, and 80% were not compatible with the WHO’s 2017 Essential Medicines List.
Overall, 70.7% of countries sold at least one FDC that was not FDA-approved, and 58.4% of those were low- and middle-income countries. The highest amount of non–FDA-approved FDCs were sold in India, where they accounted for roughly 16% of overall antibiotic sales, followed by China, Francophone West Africa, and Vietnam.
Questions about appropriate combinations
Antibiotic FDCs are not inherently a problem, and can have several benefits. Certain combinations act synergistically to produce increased efficacy against a bacterial infection, while other combinations can broaden the spectrum of activity.
In some cases, combining antibiotics can reduce the risk for the development of resistance against each individual antibiotics. While lack of FDA approval doesn’t necessarily indicate an FDC is inappropriate, FDA regulation is widely considered a benchmark of evidence-based safety and efficacy.
The two highest-selling FDCs found in the analysis were amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, both FDA-approved combinations that are on the WHO’s Essential Medicines List—a list of the medications the agency considers to be the most effective and safe in meeting the health needs of a population. The two FDCs are recommended for treating a variety of common bacterial infections, such as community-acquired pneumonia, ear infections, and urinary tract infections.
Other widely sold FDA-approved FDCs include piperacillin/tazobactam, ampicillin/sulbactam, and clavulanic acid/ticarcillin.
But the authors of the study say that there is limited evidence supporting the use of the three highest-selling non-FDA-approved FDCs (ampicillin/cloxacillin, cefixime/ofloxacin, and metronidazole/spiramycin), while other FDCs appear to be no more beneficial than the individual antibiotics on their own. They note that while countries with different health priorities than the United States may have reason to investigate and approve these combinations, and clinically appropriate reasons for doing so, there is reason to question the use of such combinations.
For example, they point out that ampicillin/cloxacillin combines two antibiotics from the same class that have overlapping spectra of activity—and infections that require both of these antibiotics for empiric therapy are uncommon.
In addition, 10 antibiotic FDCs on the list, all sold in India, were combinations of two antibiotics considered critically important antibiotics by the WHO, the highest priority the agency gives to antibiotics.
The authors say that, in addition to having concerns about the clinical efficacy and safety of some of these combinations, they are also concerned that non–FDA-approved FDCs could contribute to antimicrobial resistance (AMR).
“Antibiotic FDCs may contribute to AMR by exposing bacteria to sub-therapeutic concentrations of one or both antibiotic components since sub-therapeutic concentrations can exert non-lethal selective pressures,” they wrote. “This selection of resistant strains may further contribute to a reduction in clinical effectiveness.”
The authors suggest that the WHO Essential Medicines List could be helpful in determining which FDCs are clearly inappropriate, and that international initiatives may be needed to regulate the manufacturing and sale of these medications.