All Eyes on Antibiotics?

As scientists and medicine makers, we all know how crucial antibiotics are; indeed, sulfonamides and beta-lactam antibiotics have saved countless lives since their discovery in the 1930s. However, economic and regulatory challenges have led to disengagement from antibiotic research; though countless numbers of generic antibiotics are being manufactured globally, the number of large multinational pharmaceutical companies actively engaged in antibiotic research has fallen from 18 in 1990 to just four in 2011 – AstraZeneca, Novartis, GlaxoSmithKline and Sanofi-Aventis.

A worrying statistic: in 2011, a total of 262.5 million courses of antibiotics were prescribed in the US – that’s 842 per 1000 people (1). Misuse of antibiotics through overprescribing and suboptimal dosing fuels the development of resistance. But superbugs are not the only issue. The sheer volume of antibiotics sold daily and their relatively low production costs makes them vulnerable to counterfeiting and substandard manufacture.

When talking about counterfeit or falsified medicines in developing countries, a great deal of attention has focused on the quality of antimalarial drugs. Indeed, malaria medicine was featured in this magazine back in June (tmm.txp.to/0715/fake_medicine). I’ve also studied the quality of malaria medicines; our studies of over 10,000 drug samples found substandard formulations (containing less or more of the stated active pharmaceutical ingredients than the specified pharmacopeia limits) in all six of the malaria endemic countries (Cambodia, Ghana, Tanzania, Rwanda and Equatorial Guinea) (2). But substandard or counterfeit antibiotics are also a big problem, particularly in resource-constrained countries, and I believe that a concerted effort is needed to determine the quality of varying antibiotic brands. The threat of superbugs – coupled with the disengagement of pharmaceutical companies – makes the maintenance of good quality antibiotics even more important.

Drug quality monitoring requires effective tools and regulatory systems. Certainly, wherever possible, we need quality control (QC) laboratories equipped with high-performance liquid chromatography-photo diode array detection (HPLC-PDA) and in vitro dissolution testing. HPLC-PDA is seen as the ‘gold standard’ for drug quality analysis because it offers accuracy, specificity and precision in quantifying the amount of stated active pharmaceutical ingredients detected – or their absence. And in vitro dissolution testing is a valuable predictor of the in vivo bioavailability and bioequivalence of tablets and capsules. Investment in quality assured reference standards is also needed and highly trained staff. Of course, all of these elements are cost-intensive and not always achievable in resource-poor countries. But even in the absence of well-equipped QC laboratories, the screening of drugs can still be conducted at the point of purchase using portable laboratories. For example, one charitable organization – the Global Pharma Health Fund (GPHF) – has specifically developed the MiniLab as part of its mission to curb counterfeits in developing countries. The GPHF-MiniLab offers “simple drug quality verification in four steps,” including thin-layer chromatography (TLC), and though results from the MiniLab should not be relied upon for regulatory purposes, it is able to perform tests simply and inexpensively, without the need for electricity or extensive training (3). Moreover, it provides qualitative data which was found to have low sensitivity for a brand of antibiotic when compared with content analysis with HPLC-PDA plus dissolution testing (4).

We used both the MiniLab and HPLC-PDA (plus dissolution tests) to assess the quality of two brands of antibiotics: amoxicillin and co-trimoxazole. The drugs were stated to be manufactured in six countries and purchased in Ghana, Nigeria and England. All samples of amoxicillin complied with US Pharmacopeia tolerance limits, but 60 percent of co-trimoxazole tablets (purchased in Ghana and Nigeria) did not, when tested using HPLC-PDA and dissolution testing. There was also some disparity between results obtained from HPLC-PDA and MiniLab TLC for co-trimoxazole as 13.3 percent samples failed in the MiniLab TLC test, whereas the numbers increased to 60 percent on HPLC-PDA and dissolution testing. The MiniLab is a suitable screening tool in the absence of medicines QC laboratories, but it has been previously reported (5) to only detect grossly substandard or counterfeit drugs as illustrated with the results of our study with co-trimoxazole (4). This highlights the need for further investigation including other brands of antibiotics.

The take home message is that the results emphasize the importance of verifying the quality of antibiotics, particularly in developing countries where antibiotics can be obtained without a prescription. Developing nations must invest in capacity by building and integrating national QC laboratories that use reliable and accurate methods, such as HPLC-PDA and dissolution testing, as part of an integrated drug quality surveillance system.