UNSLAP: You reach for the antibiotic … and it’s not there!

Dear All (with thanks to Louise for co-authoring and with a wonkish alert … settle in for the ride!),

Today’s newsletter discusses the intersection of three themes around antibiotic access. Recall first how the paper by Baraldi et al. (1 Dec 2024 newsletter) taught us that there are at least six variations to the idea of access that can be summarized as UNSLAP: (U)nregistered, (N)ever registered (or, non-registered), (S)hort-term shortage, (L)ong-term shortage, (A)ffordability, and (P)hysical Presence of a Health Care Pfacility.

Thus, for example, the superb papers by Laxminarayan & colleagues about sustainable access in the sense of lack of infrastructure focus mainly on Affordability and Physical presence of healthcare infrastructure to deliver the drugs (see the 23 May 2024 newsletter entitled “Lancet: 10-20-30 targets to address AMR by 2030”). Note especially that the idea of “(P)hysical Presence of a Health Care Pfacility” covers the many challenges of connecting the patient with the drug and is sometimes called the “last mile problem” (excellent 27 May 2022 UN Trade & Development blog). It will need another newsletter!

But for today, we need to move to the other end of the acronym and in particular, the supply chains that manufacture and deliver the antibiotics we expect to find on the shelf. We’re going to take this in three layers — here are the papers you need:

• Access limitations from lack of local regulatory approval
  • [KEY FOCUS FOR THIS NEWSLETTER] Hillock NT, Cheng A, Bowskill A. Do policies that allow access to unregistered antimicrobials address the unmet need? Australia as a case study of a high-income country with universal healthcare. JAC Antimicrob Resist. 2025;7(1):dlae216. (https://doi.org/10.1093/jacamr/dlae216)
  • [Access limitations are not just in LMICs] Outterson K, Orubu ESF, Rex J, Årdal C, Zaman MH. Patient access in fourteen high-income countries to new antibacterials approved by the FDA, EMA, PMDA, or Health Canada, 2010-2020. Clinical Infectious Diseases. 2022 (doi: 10.1093/cid/ciab612) the 19 Aug 2021 newsletter about the paper, and a YouTube discussion of the paper.
• Access limitations due to supply chain shortages
  • [KEY FOCUS FOR THIS NEWSLETTER] Wells N, Nguyen V-K, Harbarth S. A pharmaceutical policy accident: collision of shareholder capitalism and Chinese state capitalism driving the shortage of an essential antibiotic. Journal of pharmaceutical policy and practice. 2024;17(1):2430441 (https://doi.org/10.1080/20523211.2024.2430441).
  • [A good overview] Bartoo AS, Gilmer MA, Tichy EM. Antimicrobial Shortages: A Global Issue Impacting Infectious Diseases. Clin Infect Dis. 2025;80(2):249-52 (https://doi.org/10.1093/cid/ciae498).
  • [Great graphics!] Also, you might want to review the report by Wellcome Trust and Boston Consulting Group that we discussed in the 4 May 2022 newsletter. Entitled Understanding the Antibiotic Manufacturing Ecosystem: A view of global supply chains, pressure points, and implications for antimicrobial resistance response, it contains some really good graphical illustrations of how supply chains work.
• The impact of tariffs being imposed by the current US White House administration
  • [KEY FOCUS FOR THIS NEWSLETTER] Murphy F. How Trump’s trade war will break global medicine supply chains. BMJ. 2025;389:r648 (https://doi.org/10.1136/bmj.r648).

Step 1: To start, let’s consider access limitations from lack of local regulatory approval — the “UN” of UNSLAP. Recall the 2022 paper by Outterson et al. (I am part of the et al.) in which we learned that regulatory approval (and hence) access to new antimicrobials was often delayed by years in high-income countries due  to the cost and complexity of obtaining and maintaining registration (19 Aug 2021 newsletter, YouTube discussion). 

Building on this, we have the fascinating paper by Hillock et al. in which the authors consider the specific consequences of lack of local regulatory approval in Australia. In brief, a significant number of both older and newer antimicrobials are not on the TGA’s ARTG (Therapeutic Goods Administration’s Australian Register of Therapeutics Goods). The reasons for this are probably multiple, but the cost of registration (~$200k in USD) is likely part of the challenge.

So, what do you do in Australia if you need, say, bedaquiline as part of the antimycobacterial regimen for a patient with MDR tuberculosis? It’s approved by FDA but not TGA and hence not readily available. Well, you can apply for the drug under TGA’s Special Access Scheme (SAS). Hillock et al. report that there were 36k such applications during 2018-2023 for antimicrobials other than antivirals with most being for an antibacterial or an antimycobacterial. This equates to 15-16 patients per day requiring such access in Australia. The requests for access do appear to be approved promptly for urgent cases however supply is not guaranteed.

The authors conclude that Australia should consider steps that would ensure local access (waived fees, as suggested by a recent HTA plan from Australia, 20 Sep 2024 newsletter): “Whilst the Australian market alone is insufficient to encourage the development of new antimicrobials, as a high- income country, Australia can play an important role in contributing to a global response to the AMR crisis by addressing regulatory and economic barriers to the registration of antibacterials needed for otherwise untreatable infections.”

Step 2: Waived fees might help a bit, but this assumes that the antibiotic is even available for purchase. So now let’s consider access limitations due to supply chain shortages — the “SL” of UNSLAP. The paper by Bartoo et al. provides a general view of the problem of antibiotic shortages but the excellent deep dive by Wells, Nguyen, and Harbarth into shortages of piperacillin-tazobactam really brings the problem to life. Take a moment now to download and read this one. Well, it will take more than a moment — but it will be worthwhile! In brief, here’s the story:

• During the period ~2000-2010, pip-tazo manufacturing gradually became reliant on outsourced production.
• In China, API manufacturing was encouraged by the government as an important activity for China. With this, stricter rules for manufacturing quality and clean product gradually forced consolidation of API manufacturing. Ultimately, this led to most production of the API (Active Pharmaceutical Ingredient) being from one company in China.
• Elsewhere, a confluence of factors caused other manufacturing sites to go off-line (e.g., a delayed renovation in Italy, a production ban in India following a regulatory inspection)
• With these events, the single manufacturer in China became the sole global source of pip-tazo API!
• And then, an accidental explosion in 2016 at that manufacturer halted all production and hence shut down the global pip-tazo supply chain.
• The resulting shortage was not fully resolved until 2020!

Good grief! No one had visibility into the vulnerability that was building, and you can easily see that there is no one governing body that would have had the ability to spot the brewing problem. And when a shortage hits, the idea of access takes on a really different flavor — there is no access for anyone, anywhere, at any price!

Step 3: And finally, the risk of shortages is further reinforced by the excellent commentary by Murphy in which he explores the impact of tariffs being imposed by the current US White House administration. Murphy reviews the complexity of the drug supply chains, noting that manufacturing almost always crosses national boundaries. Citing the paper by Wells et al. as well as calls to exempt pharmaceuticals from tariffs, he concludes that tariffs would disrupt supplies of vital medicines — moving supply chains from one location to another is a complex process that will not happen overnight. As of the date of this newsletter, it is not clear how all this will play out but the risk certainly exists.

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So, what to do? Well, awareness is the first step! The introspection by the Australian HTA is a good start and is a recognition that supply chains collapse partly due to a lack of economic incentives to invest in resilience. Effectively, what is needed for antibiotics are Pull incentives (purchase models) along the lines of the UK’s subscription model (19 Aug 2024 newsletter) in which antibiotics are purchased to ensure both availability (all antibiotics) and adequate reimbursement for innovation (new antibiotics). It is critical that we all keep working on reimbursement models of these types!

Finally, none of us are safe until we are all safe! We need to work to address all the elements of the long and delicate supply chain from manufacturing to local registration to bringing the tablet across the last mile to a patient in need. 

All best wishes, John & Louise

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Louise Norton-Smith, MA (Hons). Director of External Affairs, CARB-X (these views are personal and do not necessarily reflect the views of CARB-X or any of its funders) lnortons@bu.edu