In a paper in British Journal of Clinical Pharmacology, McGettigan et al present findings from the Indian pharmaceutical market, where 58 fixed combinations containing at least two antibiotics were found. Fixed dose combinations are pharmaceutical products such as tablets, ointments or suspensions where two or more drugs are combined in one product. In this science spotlight, we focus on the use of combinations of at least two antibiotics. In theory, this may sound like a good idea, but in practice it is generally not so.
Photo: Gareth Bentley, Photoshare.
Why Fixed Dose Combinations?
In general, there are three reasons to use antibiotic combinations:
- To increase efficacy. Mostly, this is linked with a search for synergy – combinations were the combined effect is greater than the added effects of single therapy. The most successful combination in this respect is perhaps Co-trimoxazole, a combination of Trimethoprim and Sulfametoxazole.
- To broaden spectrum. If the infection pathogen is unknown and there are several possibilities to choose from, a combination can be used to broaden spectrum. A typical example would be some topical ointments that may contain one or two antibiotics, an antifungal and perhaps an anti-inflammatory steroid. The idea is that any skin infection, regardless of cause, can be treated with one drug.
- To reduce the risk for resistance development. This is the rationale behind Tuberculosis (TB) and HIV therapy: if you give at least two antibiotics and the pathogen develops resistance to one of them, the other(s) will still be able to kill the resistant clone.
Experiences from other fields of infectious diseases – TB, HIV and malaria
TB, HIV and Malaria are three major infectious diseases of global health importance where predefined combinations of drugs is standard recommendation for treatment. For example, for drug sensitive TB the recommended treatment is a four-drug combination of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol for two months, followed by 4 months of Isoniazid and Rifampicin (2HRZE/4HR). For multidrug-resistant TB, recommendations include six drugs for 4-6 months followed by four drugs during 5 months. Similarly, HIV is treated with a combination of four antiretrovirals and Malaria is treated with combinations with Artemisin. In these cases fixed dose combinations are recommended in the World Health Organization (WHO) treatment guidelines, and several generics have been pre-qualified by WHO as well.
As the treatment periods are long with several drugs, recommendations include using fixed dose combinations or daily dose bags to improve compliance to treatment. This has indeed been a very important mantra in these disease areas: Fixed dose combinations are vital for treatment success as they improve compliance and reduce development of resistance.
ABR = Antibiotic resistance
AMR = Antimicrobial resistance
Avoid Fixed Dose Combinations in the context of antibiotic resistance
It seems intuitive to learn the lesson of fixed combinations from TB and HIV and to apply it to antibiotic resistance (ABR). However, in most other areas of infectious diseases this mantra does not apply, and it is one of the reasons to keep antimicrobial resistance (AMR; which includes HIV, malaria and bacterial infections) conceptually separated from ABR (which encompasses bacterial infections, including TB). In other bacterial infections, combination therapy generally does not improve patient outcome (on the population level), that is, it neither increases efficacy nor decreases resistance development.
While the rise of antibiotic resistance has sparked lots of research on combination therapy to either overcome resistance, decrease resistance development or improve patient outcomes, results are ambiguous at most. The current knowledge implies that these kinds of effects are highly strain specific, which means that each patient case needs to be evaluated separately. This is, however, not possible to do reliably with current methods.
Downsides of fixed dose combinations
Using antibiotic combinations has several possible downsides:
- Use of any drugs, including antibiotics, bring with them a risk for adverse reactions. They may be of different degrees of severity, but in addition to the individual risks, a combination of two drugs may cause additional risks by interaction of the drugs.
- Unforeseen combination effects, such as antagonism. Just as some combinations of antibiotics can cause synergistic, increasing effects, others may cause antagonistic effects that cancel a part or all of the effect of the drugs.
- Increase in the total amount of antibiotics used. Instead of a proper diagnosis a broad-spectrum cocktail can be used. This results in a more severe impact on the patients microbiome with increased risk for e.g. antibiotic associated diarrhea as well as increasing selection of resistant bacteria.
In addition, antibiotics are often combined with non-antibiotic drugs in e.g. cough syrups. Data from 2009 from the private health sector in Latin America showed that 20% of marketed products were fixed dose combinations with at least one antibiotic. Of the products identified in the study, 70% lacked evidence for the combined use.
International drug companies are undermining efforts to control drug resistance through production of fixed dose combinations
Of the 118 types of FDCs, 75 (64%) had no approval from either the Indian Central Drugs Standard Control Organization (CDSCO), U.S. Food and Drug administration or European Medicines Agency. Twelve multinational companies were responsible for making 53 of the 118 types of FDCs. These included Abbott, Astra Zeneca, Baxter, Bayer, Eli Lilly, GlaxoSmithKline (GSK), Merck/MSD, Novartis, Pfizer, Sanofi-Aventis, and Wyeth. Of the 53 FDCs, only four were approved by the FDA and/or the EMA, and 20 were not approved by India’s CDSCO. Of these 20 unapproved drugs 18 was produced by Abbott. The role of Abbott in the senseless production of fixed dose combinations by international pharmaceutical companies in India is not a new problem and was widely covered by reporters in 2015.
Old problem with old but still effective solutions
“It is discouraging and disquieting that, in spite of repeated expositions of the defects of the fixed combinations and the potential or actual dangers of their application, they are still being prescribed in sufficient quantity […] to encourage the manufacturers in continuing their production and in promoting their use. It cannot be too strongly emphasized that the best interest of the individual patient is served and the least harm done when antibiotics are prescribed, each in its optimum dosage and only for infections in which it is specifically indicated. Their possible curative and life-saving properties will also best be preserved for other patients if they are always used only in this manner.”
Editorial, New England Journal of Medicine, 1960.
Fixed dose combinations certainly have their well deserved place in the treatment of Tuberculosis, HIV and Malaria both for efficacy and for reduction of resistance development and efforts to develop such drugs are worth every effort. However, for the other bacterial infections, fixed dose combinations are more akin to Pandoras box than the Holy Grail. As the quote above shows, already 60 years ago the scientific community was aware of many of the problems caused by fixed dose combinations. But still they prevail, apparently unless strict regulations are in place.
Actions are needed on several levels to deal with the problem:
- Countries need to adopt and enforce strict regulations for the production and use of fixed dose combinations. There are examples of well-studied and effective combinations, such as Trimethoprim and Sulfametoxazole.
- Companies need to realize that the short-term economic gains are counter-productive in the long run. Also, multinational companies should be expected to employ the highest scientific standards in all countries where they operate.
- Prescribers need to remember their core ethical guideline: Primum non nocere – and realize that use of fixed dose combinations cause more harm than good.