Reliable access to antibiotics is an essential part of a functioning modern healthcare system, meaning that infections can be treated and advanced procedures like chemotherapy and organ transplants can be performed at acceptable risk levels.
Globally, an estimated 1.3 million people die every year from resistant bacterial infections.1 This doesn’t mean that these infections are resistant to all antibiotics, rather that most of these patients did not receive the right antibiotic at the right time. Yet there is a worryingly increasing number of multidrug resistant infections as well.2
In high-income countries, antibiotic resistance is mainly caused by overconsumption. The more an antibiotic is used, the more likely that resistance will develop and be transmitted.3 This is the rationale for antibiotic stewardship – to ensure that antibiotics are only used when they are needed (to treat susceptible bacterial infections). Antibiotic stewardship also calls for the use of the narrowest spectrum of antibiotic that will effectively treat the infection. Different antibiotics have different spectrums, meaning the breadth of bacteria that they kill. Taking a broad-spectrum antibiotic kills not only the bacteria causing the infection but also other harmless bacteria, thereby increasing the likelihood of resistance.
Unfortunately, in at least nine European countries as of 2022, clinicians are increasingly prescribing broader spectrum antibiotics.4 This not only negatively impacts antibacterial resistance levels, but also jeopardizes the availability of narrow-spectrum antibiotics, as these markets become smaller and less economically attractive. When a supplier determines that a market is no longer viable, it will withdraw its antibiotic, meaning that it is no longer available when a physician prescribes it. As a result, many older, narrow-spectrum antibiotics have become “forgotten” – unavailable and thus not included in national antibiotic prescribing guidelines.5
As a part of the second European Union Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI-2), www.eu-jamrai.eu, a work package focuses on improving access to select antibiotics, particularly older, narrow-spectrum antibiotics, both for human and veterinary use. This is an effort to look at interventions tailored to the specific access barriers of select antibiotics. Fourteen countries have selected focus antibiotics – those that are both medically important but also those with a vulnerable supply chain, i.e., those often in shortage, withdrawn from the market, or never marketed in the first place. The aim is to work with regional, national, and European stakeholders on demand- and supply-side interventions expected to strengthen access to the specific antibiotic, thereby expanding the arsenal of antibiotics reliably available to physicians.
One example is phenoxymethylpenicillin (aka penicillin v), a narrow-spectrum penicillin first marketed in the 1950s, the consumption of which is decreasing across Europe.6 While in the Scandinavian countries it remains a first-line treatment for many infections, in some European countries this may be no longer possible – resistance levels are too high. Yet this doesn’t hold true for all bacteria. For example, Streptococcus (strep) A infections may be safely treated with phenoxymethylpenicillin across many countries.7 Yet clinicians cannot prescribe this narrow-spectrum, effective antibiotic if it is not available in local pharmacies.
Access to phenoxymethylpenicillin is further complicated as the Scandinavian countries use different strengths, historical artefacts of marketing authorizations from a half century ago, which fragment the market. To improve access to this antibiotic, EU-JAMRAI-2 is examining how strengths can be harmonized across Europe (and beyond) to consolidate the existing market. At the same time, European primary care physicians need to be convinced that this is an important and useful antibiotic for their patients and start prescribing it, rather than the broader spectrum alternatives. This will demonstrate to companies that a reliable European market exists beyond the borders of Scandinavia.
Another “forgotten” antibiotic is pivmecillinam, another narrow-spectrum penicillin, first marketed in the 1970s for the treatment of urinary tract infections. While consumption of this antibiotic is low across Europe6, it has recently been approved in the United States as a “new” antibiotic, receiving a special designation meant to stimulate antibiotic innovation which includes market exclusivity, i.e., prohibition from competitive production.8 Yet, this US attention may be positive, awakening European primary care physicians to the utility of this antibiotic which can be made more widely available in Europe at inexpensive, generic prices. EU-JAMRAI-2 plans to alert European physicians to this new evidence while simultaneously encouraging companies to expand access across Europe.
Lack of reliable access to important antibiotics increases the likelihood of the development of antibacterial resistance. If the right antibiotic is not available at the right time, physicians will prescribe suboptimal and often broader spectrum antibiotics. If the inaccessibility is persistent, physicians change prescribing habits, resulting in the withdrawal of the antibiotic from the market. Narrow-spectrum antibiotics are especially vulnerable, with low returns and increasingly diminishing market sizes. EU-JAMRAI-2 is attempting to demonstrate that these trends can be changed. Countries can secure reliable access to narrow-spectrum antibiotics, especially if regional and European interventions can be applied.
References
1. Murray CJ, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 2022; 399(10325): 629-55. 2. European Centre for Disease Prevention and Control. Risk Assessment: Emergence of hypervirulent Klebsiella pneumoniae ST23 carrying carbapenemase genes in EU/EEA countries – first update. Stockholm: ECDC, 2024. 3. Holmes AH, Moore LS, Sundsfjord A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. The Lancet 2016; 387(10014): 176-87. 4. European Centre for Disease Prevention and Control. Antimicrobial consumption in the EU/EEA (ESAC-Net). Stockholm: ECDC, 2023. 5. Pulcini C, Mohrs S, Beovic B, et al. Forgotten antibiotics: a follow-up inventory study in Europe, the USA, Canada and Australia. International journal of antimicrobial agents 2017; 49(1): 98-101. 6. Bruyndonckx R, Adriaenssens N, Hens N, et al. Consumption of penicillins in the community, European Union/European Economic Area, 1997–2017. Journal of Antimicrobial Chemotherapy 2021; 76(Supplement_2): ii14-ii21. 7. Van Driel ML, De Sutter AI, Thorning S, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database of Systematic Reviews 2021; (3). 8. US Food & Drug Administration. FDA Approves New Treatment for Uncomplicated Urinary Tract Infections. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-uncomplicated-urinary-tract-infections (accessed May 6 2024).
Author
Christine Oline Årdal
Senior Scientist at the Norwegian Institute of Public Health, Oslo, Norway