Dear All,
Although it seems entirely reasonable that the “Which came first?” chicken vs. egg riddle can be resolved in favor of the egg, a pair of papers in CID suggest that the answer to the parallel question of “drug vs. resistance to the drug” is changing in a way that is NOT in our favor! Here are the papers you need:
- [A case report] Senchyna et al., “Sequential Treatment Failure With Aztreonam-Ceftazidime-Avibactam Followed by Cefiderocol Due to Preexisting and Acquired Mechanisms in a New Delhi Metallo-β-lactamase–Producing Escherichia coli Causing Fatal Bloodstream Infection”, Clinical Infectious Diseases, 2024, https://doi.org/10.1093/cid/ciad759.
- [Accompanying editorial] Bonomo et al., “The Real Crisis in Antimicrobial Resistance: Failure to Anticipate and Respond”, Clinical Infectious Diseases, 2024, https://doi.org/10.1093/cid/ciad758.
In brief, the case report by Senchyna and colleagues describes how evolution of resistance over 40 days in a strain of E. coli led to death of the patient despite very careful attention to use of the best possible antibiotics at each step.
The accompanying editorial by Bonomo et al. considers the implications of this case regarding our ability to stay ahead of the pace of bacterial evolution. Their core thesis is that we are experiencing a change in the order of emergence of resistance.
In the early days (top half of the figure, “The Established Timeline”), resistance generally did not emerge until at least a few years after introduction of the drug. But in more recent years (bottom half of the figure, “The New Timeline”), resistance has consistently preceded licensure of new drugs:
A much more legible PowerPoint version of this image is available at https://doi.org/10.1093/cid/ciad758.
That resistance would emerge has been known from the beginning … Fleming himself predicted this in in his 1945 Nobel Prize acceptance speech when he said, ““It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.“
But it is the pace of the emergence of resistance that is so terrifying here! Every drug in that lower timeline required years of effort to bring to registration and availability. And yet, it is not enough as shown by the death of this patient. As Bonomo et al. write,
- “We no longer have the luxury of waiting years for resistance to emerge to a specific drug.
- “In fact, we now know that resistance can be demonstrated to even the most potent agents before they are even released.
- “This “collateral damage” is an inevitable result of years and years of indiscriminate antibiotic use and also of the “resistome” developed and shared by microorganisms over millennia, before the clinical use of antibiotics.”
So, what is to be done? Bonomo et al. point broadly to the need for use of diagnostics, integrated surveillance, and rapid development of new agents. I can only agree … and would add a plea for diversity in terms of new agents. The diversity of the current development candidates is well shown in the CARB-X portfolio: we need to be exploring everything from small molecules to phage to AI-based discovery.
Inhale, exhale. Onward! With all best wishes, –jr
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.
PS: In a related and somber way, I thought the paper by Karlin et al. entitled “State-of-the-Art Review: Use of Antimicrobials at the End of Life“, Clinical Infectious Diseases, 2024, https://doi.org/10.1093/cid/ciad735 was very timely. It’s a great summary of ways to approach the sad situation of not having drugs we need.
PPS: It also made me reflect on the idea of DTR (Difficult-to-Treat Resistance, 20 Feb 2020 newsletter, 5-minute YouTube explainer) and the famous “Deaf or Dead?” paper (Harvard & Garrod, Br Med J. 1959 Mar 14) regarding the choice that a patient had to make about use of streptomycin for bacterial endocarditis. It’s a brief 2-page read with an ending that is (all things considered) happy … but also a reminder of how hard it is to find drugs that are toxic to the microbes but not the patient.
- BARDA’s long-running BAA (Broad Agency Announcement) for medical countermeasures (MCMs) for chemical, biological, radiological, and nuclear (CBRN) threats, pandemic influenza, and emerging infectious diseases is now BAA-23-100-SOL-00004 and offers support for both antibacterial and antifungal agents (as well as antivirals, antitoxins, diagnostics, and more). Note especially these Areas of Interest: Area 3.1 (MDR Bacteria and Biothreat Pathogens), Area 3.2 (MDR Fungal Infections), and Area 7.2 (Antibiotic Resistance Diagnostics for Priority Bacterial Pathogens). Although prior BAAs used a rolling cycle of 4 deadlines/year, the updated BAA released 26 Sep 2023 has a 5-year application period that ends 25 Sep 2028 and is open to applicants regardless of location: BARDA seeks the best science from anywhere in the world! See also this newsletter for further comments on the BAA and its areas of interest.
- FDA have released a BAA covering a wide variety of regulatory topics. See this newsletter for general details; also note in particular an RFP for work on urine-specific breakpoints for uUTI. Early concept papers are due 6 Nov 2023; full proposals are due 19 Feb 2024.
- NIAID have a BAA open through 13 Mar 2024 for projects covering vaccines, therapeutics vs. selected pathogens (specific viruses, fungi, and bacteria), and sequencing-based diagnostics. See this newsletter for further details.
- JPIAMR have an AMR Interventions call that is open for pre-applications through 14 Mar 2024. The call covers interventions for both fungi and bacteria. Go here for full details. Note that there is an informational 24 Jan 2024 webinar for applicants.
- ARPA-H have an Open BAA that is accepting applications through 14 March 2024. It is quite wide-ranging in its scope and definitely includes AMR-related projects. See this newsletter for discussion of the BAA and an AMR project that it now supports.
- HERA Invest was launched August 2023 with €100 million to support innovative EU-based SMEs in the early and late phases of clinical trials. Part of the InvestEU program supporting sustainable investment, innovation, and job creation in Europe, HERA Invest is open for application to companies developing medical countermeasures that address one of the following cross-border health threats: (i) Pathogens with pandemic or epidemic potential, (ii) Chemical, biological, radiological and nuclear (CBRN) threats originating from accidental or deliberate release, and (iii) Antimicrobial resistance (AMR). Non-dilutive venture loans covering up to 50% of investment costs are available. A closing date is not posted insofar as I can see — applications are accepted on a rolling basis; go here for more details.
- The AMR Action Fund is open on an ongoing basis to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
- INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
- These things aren’t sources of funds but would help you develop funding applications
- AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
- The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
- Diagnostic developers would find valuable guidance in this 6-part series on in vitro diagnostic (IVD) development. Sponsored by CARB-X, C-CAMP, and FIND, it pulls together real-life insights into a succinct set of tutorials.
- In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).
John’s Top Recurring Meetings
Virtual meetings are easy to attend, but regular attendance at annual in-person events is the key to building your network and gaining deeper insight. My personal favorites for such in-person meetings are below. Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!
- 6-7 Mar 2024 (Basel, Switzerland): The 8th AMR Conference 2024. Go here to register!
- 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details.
- 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. Go here for the meeting’s general website. You can’t register (yet) for the 2024 event, but save the date!
- 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. Save the date! More details to come!
Upcoming meetings of interest to the AMR community:
- 6-7 Feb 2024 (online): Antimicrobial Chemotherapy Conference. This is an annual, free of charge conference that is co-organized by GARDP and the British Society for Antimicrobial Chemotherapy (BSAC). Go here to register.
- [NEW] 7 Feb 2024 (virtual, noon-1.30p CET): WHO-sponsored webinar entitled “One Health Priority Research Agenda: Intervention Pillar.” As context, the WHO Quadripartite launched its One Health Priority Research Agenda (OHPRA) on 28 June 2023 (launch webinar recording is here). This new webinar covers one of its five pillars (Transmission; Integrated Surveillance; Interventions; Behavioural insights and change; and Economics and policy). Go here to register.
- 8 Feb 2024 (in person, Liverpool, UK, 8.30a – 4p): 2024 BioInfect Conference. A full-day AMR conference that includes a keynote from Lord Jim O’Neill (Chairman of the UK AMR Review). Go here for details and to register.
- [NEW] 9 Feb 2024 (in person, London): “Exploring AI’s impact on AMR,” a workshop co-organised by Imperial’s Institute of Infection, AI Network, NIHR HPRU in Healthcare Associated Infections and Antimicrobial Resistance, and the Centre for Antimicrobial Optimisation (CAMO). Go here for more details and to register.
- 14 Feb 2024 (virtual, 8-9a EST): GARDP’s “SECURE: Improving access to antibiotics through new economic models” webinar about the SECURE project. Click here to register.
- [HIGHLY RECOMMENDED] 15 Feb 2024 (virtual, 8.30a-10.00a EST, 2.30-4p CET, 10.30p-12.00a JST): Entitled “AMR Preparedness Index: 2024 Progress Report”, this will be the launch of a major report by the Global Coalition on Aging (GCOA) and IDSA, and sponsored by IFPMA. Speakers are global (US, EU, Brazil) and feature Dame Sally Davies (UK Special Envoy for AMR) plus a panel moderated by Andrew Jack (Financial Times, creator of a marvelous 5-minute AMR video explainer); the discussion will to cover the new report (it updates the 2021 AMR Preparedness Index), including high-level policy insights from the report in advance of the eagerly anticipated High-Level Meeting on AMR at UNGA 2024 (see 15 Apr 2023 newsletter for background on the HLM). Go here to register.
- 27 Feb 2024 (virtual, 8.30a-9.30a EST): GARDP’s “What does the future look like if pull incentives to support antibiotic R&D are insufficient?” webinar. Go here for details.
- [Updated contact details] 27 Feb 2024 (in person, New York City, 3-6.30p ET): Hosted by the AMR Industry Alliance (AMRIA), “A Call-to-Action in the Fight Against AMR: Priorities for Progress at the 2024 UN High-level Meeting on AMR” is a symposium (3-5.30p) and reception (5.30-6.30p). For additional information on the event, please contact J.Schumacher@AMRIndustryAlliance.org.
- [NEW and HIGHLY RECOMMENDED] 4-5 Mar 2024 (virtual, noon-4.15p ET on both days): “Assessing the Burden and Potential Strategies to Address Antimicrobial Resistance” is a 2-day workshop sponsored by the National Academies that takes a deep dive into what we do and do not know about the costs (clinical and financial) of AMR. Chaired by Jomana Musmar, the deeply knowledgeable Designated Federal Officer who oversees PACCARB, it is no surprise that the agenda is excellent and includes an all-star cast of speakers. Go here to register.
- 6-7 Mar 2024 (Basel, 6-7 Mar 2024): See Recurring Meetings list, above.
- 17-22 Mar 2024 (Ventura Beach, CA, in person): Gordon Research Conference (GRC) entitled “New Antibacterial Discovery and Development” with a 16-17 Mar 2024 pre-conference Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers. An intensive residential meeting, GRCs are highly recommended for networking and deep research insights. Apply here for the GRC and here for the GRS.
- [NEW] 25-26 Mar 2024 (In person, London): “Novel Diagnostics for Infectious Diseases,” a 2-day workshop co-organised and funded by Imperial College London’s Institute of Infection, JPIAMR-funded B2B2B Network, London In Vitro Diagnostics Co-operative, NIHR Imperial Biomedical Research Centre, and DIAMONDS consortium. Go here for details and to register.
- 26 Apr 2024 (Barcelona, Spain): ESCMID workshop entitled “Using Data Science and Machine Learning for Infection Science: A Hands-on Introduction.” Click here to register or here for more details.
- 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
- 26-31 May 2024 (Montreal, Canada): EDAR7, the McGill AMR Centre’s 7th edition of their Environmental Dimension of Antimicrobial Resistance conference. Go here for details; final abstract deadline is 21 Dec 2023.
- 9-13 June 2024 (in person, Ascona, Switzerland): “New Approaches to Combat Antibiotic-Resistant Bacteria, 2nd Edition” is a Sunday-Thursday residential workshop focused on the deep biology of AMR. Sponsored by NCCR AntiResist (a Swiss National Science Foundation consortium), the scientific program has the feel of a Gordon Conference. Space is limited, so you are encouraged to apply promptly — go here for details.
- 13-17 June 2024 (Atlanta, Georgia): ASM Microbe, the annual meeting of the American Society for Microbiology. You can’t register yet, but you can go here for general details.
- 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. See Recurring Meetings list, above.
- 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. See Recurring Meetings list, above.
- 19-27 Oct 2024 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance). Now in its 8th year, Patrice Courvalin directs the program with the support of an all-star scientific committee and faculty. The resulting soup-to-nuts training covers all aspects of antimicrobials, is very intense, and routinely gets rave reviews! Seating is limited, so mark your calendars now if you are interested. Applications open in March 2024 — go here for more details.
- [NEW] 4-5 Dec 2024 (in person, Washington, DC): “Fungal Dx 2024: Fungal Diagnostics in Clinical Practice” is a 2-day in-person workshop organized by ISHAM‘s Fungal Diagnostics Working Group. The program and registration links are available at https://fungaldx.com/; the agenda is comprehensive and features an all-star global list of speakers.