This article is taken from European Biopharmaceutical Review April 2022, pages 23-26. © Samedan Ltd

While the over-prescription of antibiotics is causing increasing levels of antimicrobial resistance  (AMR) within the developed world, the lack of access to treatments in lower income countries is just  as much of a global concern 

By Mark Chataway at Hyderus 

Most discussion of AMR focuses on the overuse or  inappropriate use of broad spectrum antibiotics. But  too little diagnosis and inadequate treatment is just as  important. The lack of access to antibiotics is the cause  of 5.7 million deaths annually, the majority in low- and  middle-income countries. We have to find ways to reduce  these deaths and to limit treatment-linked resistance. 

Today’s Burden 

Low-resource countries are worst affected by limited  access to antibiotics. This is, in part, because people  in these countries are more vulnerable to infections.  

For example, infections associated with ventilators and catheters in low-resource countries are up to 13 times  higher than in the US, while hospital infections amongst newborns in low-income countries are up to 20 times  higher than in high-income countries. The antibiotics  needed to treat these infections are often difficult or  impossible to access. 

antibioticsHowever, deaths are on a downward trend, thanks to  antibiotics. A 2018 paper in the Proceedings of the  National Academy of Sciences of the USA said, “The  worldwide mortality attributable to infectious agents  dramatically decreased from around 13 million deaths in  1990 to around 10 million deaths in 2016. This decrease  was mainly driven by the yearly decline of mortality  caused by antibiotic-susceptible bacterial infections,  including lower respiratory tract infections, especially  in [lower-middle income countries] (1).” In context, this  decline is not, maybe, as “dramatic” as the article says  or as it might have been: deaths from malaria and HIV,  

two other infectious diseases, over roughly the same  two decades fell far faster. And we should not forget  that resistance to medicines to combat parasitic and  viral infections are an often-neglected part of the AMR agenda – one we will neglect here as well. 

Back in 2010, a Duke University literature review of  Sub-Saharan African papers showed that nearly one in  13 hospitalised patients across Africa may have had a  bacterial bloodstream infection (2). Many were never  treated with antibiotics, either because the illness was  never diagnosed or because there were no treatments.  

Barriers to accessing antibiotics are complex, particularly  in low- and middle-income countries. A 2018 Access To  Medicines Foundation (ATMF) report said, “Shortages  of generic antibiotic products have been reported on  a global and national scale and many formulations of  antibiotics for specific populations, including children,  have limited availability (3).” Things were so bad that in  2017, only four companies were producing the active  pharmaceutical ingredient (API) for penicillin; three were  in China (4). Brazil’s tough and respected drug regulator  gave permission for its producers to buy the API from  a Chinese producer that European regulators said had  falsified data and posed a high risk of contamination.  There was, apparently, no alternative.  

These shortages are getting worse. “The increasingly  common shortages of antimicrobials are an additional  threat to the emergence of AMR. While the threat of  such drug shortages is most acutely experienced in low income and middle-income settings, their consequences impact the quality and effectiveness of antimicrobials worldwide,” Shafiq et al. said in a November 2021 article in BMJ Global Health (5).
Stockouts in resource-poor countries happen sometimes because there just isn’t enough money to buy medicines; more usually, for generics, they are caused by bureaucratic bottlenecks in tendering, awarding contracts, releasing payments, import clearances, or distribution. That ATMF report explained another cause: “Governments with high purchasing power are using increasingly stringent tendering processes focused on price, creating competition among producers that puts further pressure on already slim margins.” Fewer and fewer companies are involved in producing active product ingredients and finished antibiotic treatments.

The orthodox view that intellectual property is the biggest hindrance to medicines availability is clearly wrong, at least in this context. The lack of availability in the public sector along with steep out-of-pocket costs often pushes patients or parents into the private sector. In many countries, prescribers and dispensers in this sector have strong incentives to use more expensive products, rather than the ones indicated by clinical guidelines. A 2021 paper in Antibiotics reported that “although the per-capita consumption of antibiotics in India is lower than that in several other countries, the proportion of broad-spectrum antibiotic consumption which are recommended for restricted use by the WHO is high (6).” Patients cannot afford the full course, and the paper reported that, according to interviews involving 36 pharmacies in two states, pharmacists often dispensed antibiotics – including ones on WHO’s watchlist for resistance – without a prescription and with only enough pills for one or two days of treatment.

“In many countries, prescribers and dispensers in this sector have strong incentives to use more expensive products, rather than the ones indicated by clinical guidelines”

To conserve the antibiotics we have, we need to make sure that professionals working in the public sector can reliably get the antibiotics they need. This will mean challenging some shibboleths of activist groups and building sustainable public private partnerships to produce and distribute high-quality medicines.

Resistance Is Already a Major Problem

Treating bacterial infections with medicines that are not ideal in courses that are too short is accelerating antibiotic resistance. So is the widespread and unnecessary use of broad spectrum antibiotics, especially in courses or at doses that are too low.

AMR is already an issue in resource-poor countries. Elsewhere in this special edition, there are many references to a 2019 paper in The Lancet. It is a complex piece of modelling, but overall it is clear that low-resource countries are disproportionately affected by deaths associated with and attributable to AMR.

The authors of that The Lancet paper conclude: “Many might expect that with higher antibiotic consumption in high resource settings, the burden of bacterial AMR would be correspondingly higher in those settings. We found, however, that the highest rates of death were in Sub-Saharan Africa and South Asia. High bacterial AMR burdens are a function of both the prevalence of resistance and the underlying frequency of critical infections such as lower respiratory infections, bloodstream infections, and intra-abdominal
infections, which are higher in these regions. Other drivers of the observed higher burden in [resource-poor countries] include the scarcity of laboratory infrastructure making microbiological testing unavailable to inform treatment to stop or narrow antibiotics.

“The higher burden in low-resource health systems highlights the importance – both for the management of individual patients and for the surveillance of AMR – of well-developed national action plans and laboratory infrastructure in all regions and countries.”

Lab facilities are very unlikely to be available to most treaters and, where they are, treaters face the same dilemmas as their counterparts in advanced economies: Do they wait for a sample to be cultured and analysed? Or do they treat the patient now, with no risk of loss to follow up, based on the pathogen probably involved and what professionals know about resistance patterns in the area?

A doctor treating a patient with a potentially life-threatening infection will, of course, not wait and will use whatever is available. However, even in those circumstances, they might prescribe differently if the full range of essential antibiotics were available. The Shafiq et al. paper reported: “Global antimicrobial supply chains are inefficient and fragmented… scarcely available and poorly functioning forecasting systems [in resource-poor countries] contribute to the problem of disrupted supply chains (5).”

 

Preparing for the Future 

Medicine will have to work harder because resistant microbes have changed the world in which patients are treated. Julian and Dorothy Davies pointed out in 2010: “The planet is saturated with these toxic [antibiotics used since the 1940s], which has of course contributed significantly to the selection of resistant strains. The development of generations of antibiotic-resistant microbes and their distribution in microbial populations throughout the biosphere are the results of many years of unremitting selection pressure from human applications of antibiotics, via underuse, overuse, and misuse. This is not a natural process, but a man-made situation superimposed on nature; there is perhaps no better example of the Darwinian notions of selection and survival (7).”

New antibiotics must only be used in those infections which cannot be cured, at therapeutic doses, with older antibiotics. As Davies and Davies put it, “If well-considered restrictions and rules for usage were supported by a pipeline of structurally novel antibiotics and semi-synthetics designed to be refractory to resistance mechanisms, one could expect some significant and lasting improvements in the treatment of infectious diseases (7).” The restrictions do not work well in some advanced economies or in some resource-poor ones. Some of the causes are similar, but the solutions are very different.

In advanced economies, patients often demand medicines that are tolerable and virtually certain to work or refuse to wait for the outcome of lab testing to determine the best treatment for a specific infection. Doctors in resource-poor countries face very similar dilemmas. A 2021 paper in Antibiotics looked at the prescription of broad spectrum antibiotics (BSAs) in South Africa, Sri Lanka, and the UK (8). In all, doctors said that they recognised the need to restrict use of broad-spectrum antibiotics but, “universally across settings, participants described how using BSAs provided a solution to diagnostic uncertainty, reassured them that their patients would be safe, and reduced their own risk of censure from colleagues or of litigation.”

If patients don’t like what they are prescribed, they can buy something else in much of the world. Periodic efforts by national governments and WHO to limit over-the-counter dispensing of antibiotics have met with very limited success in resource-poor countries. For example, India introduced a new H1 schedule, which was designed to require that pharmacists keep a copy of antibiotic prescriptions, thus reducing sales without prescriptions. A 2020 study in the Indian Journal of Pharmacology found that mystery shoppers in one state were still able to buy antibiotics, mostly broad-spectrum ones, in almost eight out of ten attempts (9). There is no reason to think that regulation will be any more effective in the future.

Many patients will get antibiotics in the private sector for many years to come and planning that does not include private pharmacies and hospitals is an exercise in dangerous wishful thinking. It would, of course, be completely invidious to make new antibiotics available only to those rich enough to afford them in the private sector. There have to be solutions that work in every setting.

What needs to be done is often painfully obvious; the challenge lies in how to do it. Initiatives such as SECURE – led by the Global Antibiotic Research and Development Partnership and WHO – use pilots to generate real-world experience on issues such as:

• Surveillance and developing a flow of reliable data on resistance, susceptibility and clinical practice
• Country-specific (or even locality-specific) guidelines, based on good data, to use the narrowest-possible antibiotics • Access to fast, affordable, reliable lab facilities to help clinicians to prescribe better
• Access to the right antibiotics at affordable prices, or at no cost, in these high-burden countries
• Mechanisms for access to broad-spectrum and novel antibiotics that actually restrict their use to cases known, or strongly suspected, to be resistant to other agents
• Public-private partnerships to assure supply at fair but sustainable prices

Much more must be done, though. Abstract discussions about how to conserve new agents need to become honest
discussions about the real challenges. The diagnostics industry must be given a central role in developing new ways to test quickly and easily for pathogens and for the susceptibility of those pathogens to treatments.

COVID-19 has reminded us that we share one planet; unless our approach to managing infectious diseases is global, it will fail.

References
1. Abat C, Gautret P, Raoult D, Benefits of antibiotics burden in low-income countries. Proc Natl Acad Sci
U S A. 115(35):E8109–E8110, 2018. doi:10.1073/
pnas.1809354115
2. Visit: globalhealth.duke.edu/news/bacterial-infections common-cause-illness-death-africa
3. Visit: accesstomedicinefoundation.org/media/atmf/Antibiotic Shortages-Stockouts-and-Scarcity_Access-to-Medicine Foundation_31-May-2018.pdf
4. Visit: www.aljazeera.com/features/2017/5/21/why-is-the world-suffering-from-a-penicillin-shortage
5. Shafiq N et al, Shortage of essential antimicrobials: a major challenge to global health security, BMJ Global Health, 6: e006961, 2021.
6. Kotwani A, Joshi J, Lamkang AS, Over-the-Counter Sale of Antibiotics in India: A Qualitative Study of Providers’ Perspectives across Two States. Antibiotics (Basel), 10(9): p1,123, 2021. doi:10.3390/antibiotics10091123
7. Visit: Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev, 74(3): pp417–433, 2010. doi:10.1128/MMBR.00016-10
8. Tarrant C et al, Drivers of Broad-Spectrum Antibiotic Overuse across Diverse Hospital Contexts—A Qualitative Study of Prescribers in the UK, Sri Lanka and South Africa. Antibiotics, 10(1): p94, 2021. doi.org/10.3390/antibiotics10010094
9. Chadalavada V, Babu SM, Balamurugan K, Nonprescription sale of schedule H1 antibiotics in a city of South India. Indian J Pharmacol, 52(6): pp482–487, 2020. doi:10.4103/ijp. IJP_244_19