Wonkish – AMR.Solutions https://amr.solutions Antimicrobial Resistance Solutions with Dr. John H. Rex Mon, 20 Jul 2026 18:17:02 +0000 en-US hourly 1 https://amr.solutions/wp-content/uploads/2022/04/Fire-Extinguisher-icon-70x70.png Wonkish – AMR.Solutions https://amr.solutions 32 32 DTR Gram-negative infections: Are new antibiotics making a difference? https://amr.solutions/2026/04/24/dtr-gram-negative-infections-are-new-antibiotics-making-a-difference/ Fri, 24 Apr 2026 18:18:53 +0000 https://amr.solutions/?p=25457

Dear All (and with thanks to Aaron Dane for co-authoring this newsletter AND inhale, exhale … this is going to be a long, wonkish, but VERY important note! Get coffee! Get to a calm place! Clear your head! Read on!),

Provoked by a recent paper on the idea of DTR (Difficult-to-Treat Resistance) by Walker et al. (from the group led by Sameer Kadri at the NIH Clinical Center, full details on the paper are below), we are today going to visit the intersection of a set of intertwined themes. Deep, deep down, this conversation is about how we know whether (or not) new drugs really work for bad bugs. Yes, we can see the favorable microbiology in the laboratory. Yes, we can see the favorable results of animal models. But, what about in human infections? “I want to see data on new drugs for bad bugs in people,” you cry! “Why are you bringing me these confusing non-inferiority results? Why aren’t you studying bad bugs? And, superiority studies would be cleaner! They can be smaller! Why aren’t we instead seeing superiority data on treatment of bad infections?”

Well, there are good explanations for (i) why we can know that new antibiotics will work on bad bugs and (ii) why superiority studies are NOT routine. These ideas have been covered in prior newsletters, but it seems a good time to draw all these threads into an updated, comprehensive summary. 

Our tour today is going to have 7 stops:

  1. (Context) How do we classify resistant bacteria? I’ve heard of MDR and XDR, but what are UDR, PDR, and DTR?
  2. (Use of new agents) Since the idea of DTR emerged in the mid-20-teens, we have at least some new, safe beta-lactam antibiotics. Are these newer agents being used for DTR infections?
  3. (Impact of new agents: the new paper is discussed here!) What is the impact of these newer agents on outcome in DTR infections?
  4. (One step further) How much of a mortality improvement is actually plausible?
  5. (Implications, Part 1) Can we ever show that new drugs are better?
  6. (Implications, Part 2) What does this mean for calls to improve outcomes through alternative approaches such as host-directed therapies?
  7. (Implications, Part 3) Rapid diagnostics and access to DTR-active agents are the keys to taking action!

Know that as we write we will sometimes be repeating materials from prior newsletters … you can see the full list of sources below our signatures. With that, here we go!

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Stop #1 (Context): How do we classify resistant bacteria? I’ve heard of MDR and XDR, but what are UDR, PDR, and DTR?

It’s helpful to see the spectrum of resistance as having 5 categories:

  • UDR (Usual Drug Resistance): Any resistance profile that is not MDR, XDR, or PDR. This is the current expected pattern of susceptibility to available agents. There will be non-susceptibility to some agents but first-line therapies are reliably active.
  • MDR (Multi-Drug Resistance): non-susceptibility to at least one agent in three or more antimicrobial categories.
  • XDR (eXtensive Drug Resistance): non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories).
  • PDR (Pan Drug Resistance): non-susceptibility to all agents in all antimicrobial categories.
  • DTR (Difficult-to-Treat Resistance): non-susceptibility to all of the typical first-line, lower toxicity agents.
  • Sources:

The first 4 categories (UDR to PDR) are step-wise variants of each other. UDR is, well, the usual thing — what you expect. The organism may have some resistance mechanisms but standard first-line therapies are reliable. Therapeutic choices are narrowed as you go from MDR (choose carefully!) to XDR (only 1 or 2 choices) to PDR (no choices).

The concept of DTR is, however, different from the stepwise ladder of UDR-MDR-XDR-PDR. The idea is that the UDR-MDR-XDR-PDR definitions make no distinction between strengths and weaknesses of the individual antibiotics: agents with higher efficacy and lower toxicity are counted in the same way as agents with lower efficacy and higher toxicity. So, DTR  is defined as resistance to all of the typical first-line, lower toxicity agents. The organism might really be just MDR if you just count active drugs, but Kadri et al. argue resistance to fluoroquinolones and the beta-lactams (including carbapenems and beta-lactamase inhibitor combinations) is DTR in that you are forced to use less desirable agents with either toxicity (e.g., the nephrotoxic aminoglycosides) or other pharmacology limitations.

If you’d like a bit more detail on this key idea, there’s a 5-minute YouTube explainer of the concept as well as this diagram:

Kadri 2018 - Graphical view of UDR-MDR-XDR-PDR-DTR

Diagram of the concept of DTR from Kadri 2018. Note that DTR includes only portions of MDR or XDR.

The idea of discriminating among the qualities of the agents was shown to be important by Kadri et al. 2018. Based on data from the Premier Healthcare Database from 173 US institutions on 46,521 Gram-Negative Blood Stream Infection (GNBSI) isolates from the period 2009-2013, about 1.5% of isolates were DTR. Critically, patients with DTR GNBSI isolates had a 40% higher adjusted mortality risk than those with non-DTR GNBSI. These findings were consistent in a variety of sensitivity analyses including by-species analyses and were also further validated using detailed clinical data in Kadri et al. OFID 6:ofz110, 2019.



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Stop #2 (Use of new agents): Since the idea of DTR emerged in the mid-20-teens, we have at least some new, safe beta-lactam antibiotics. Are these newer agents being used for DTR infections?

OK, so DTR is associated with increased mortality! But when you have an active beta-lactam, things should improve. The DTR data above were for the period 2009-2013. Since then, we’ve had new agents, especially new beta-lactams reach approval. Are these agents being used?

Well, sometimes. For data, we need to consider 2 papers and a related editorial:

  • Outterson K et al. (2021): Patient access in fourteen high-income countries to new antibacterials approved by the FDA, EMA, PMDA, or Health Canada, 2010-2020. Clinical Infectious Diseases. 2021;74:1183-90. https://doi.org/10.1093/cid/ciab612.
  • Strich et al. (2024): Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals: A Retrospective Cohort Study. Ann Intern Med. 2024;177:559-72, https://doi.org/10.7326/M23-23
  • And the excellent associated commentary on Strich 2024 by Howard-Anderson and Boucher (2024): New Antibiotics for Resistant Infections: What Happens After Approval? Annals of Internal Medicine. 2024:177:674-5, https://doi.org/10.7326/M24-0192).

The first paper (Outterson 2021) has an associated newsletter entitled “Ex-US new antibiotic access: Multi-year delays, even in Europe!”. In brief, this paper found that access to newer antibiotics was often delayed for years, even in high-income countries. Only 3 countries (United States, United Kingdom, and Sweden), tended to have relatively prompt access to all new antibiotics

The 2nd paper (and paper #3, the related editorial) focus on use of newer antibiotics in the US. As essentially all new antibiotics were approved in the US (and thus theoretically available), were they used? Analyzing data for the period Jan 2016 to Jun 2021, Strich et al. found limited use of safer, newer agents (ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, plazomicin, eravacycline, imipenem–relebactam–cilastatin, and cefiderocol). Specifically, 1091 of 2631 DTR infection episodes (41.5%) were treated exclusively using traditional agents. This included use of antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%)..


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Stop #3 (Impact of new agents — the new paper!): What is the impact of these newer agents on outcome in DTR infections?

Well, some use is better than none! So, are outcomes better when the newer agents are used? Here’s where we come to the new paper:

  • Walker MK, Yek C, Sarzynski S, Warner S, Harris AD, Baghdadi JD, et al. Survival trends in patients with difficult-to-treat, antibiotic-resistant, Gram-negative infections in the era of next-generation antibiotics in the USA: a retrospective cohort study. The Lancet Infectious Diseases 2026. DOI: 10.1016/S1473-3099(26)00020-4.
  • (and an editorial about the paper) Kabbani S, McDonald LC. Treatment of multidrug-resistant Gram-negative infections: A stewardship imperative. The Lancet Infectious Diseases 2026. DOI doi.org/10.1016/S1473-3099(26)00113-1.


Across an overlapping timeframe to that of the Strich 2024 study (1Jan2016 to 31Aug2023), Walker et al. retrieved electronic data on 8,319,398 adult inpatient encounters at 471 US hospitals. Across these inpatient events,

  • There were 9,384 encounters (0.11%) with evidence of a DTR pathogen.
  • Of these 9,384 encounters, the electronic data were consistent with a DTR infection in 5,065 (54.0%) of the encounters (rather than just colonization).
    • NB: Pay close attention to the fact that overall # of DTR infections is small: only ~5,000 at ~500 hospitals (rounding a bit). That’s 1 DTR infection for every 1,643 inpatient encounters. We’ll need this later!
  • Antibiotics used for these 5,065 DTR infections were broken down into 3 categories:
    • New DTR-active antibiotics (cefiderocol, ceftazidime-avibactam, ceftolazane/tazobactam, eravacycline, imipenem/relebactam, meropenem/vaborbactam, omadacycline, and plazomicin)
    • Traditional DTR-active antibiotics (amikacin, chloramphenicol, colistin, doxycycline, fosfomycin, gentamicin, minocycline, tetracycline, tigecycline, and tobramycin)
    • Non-DTR-active antibiotics (everything else)
  • Further, initial antibiotic therapy (therapy given on or before the day of the DTR culture) was classified as in vitro discordant if susceptibility data suggested the antibiotic (even a new DTR-active antibiotic) was inappropriate


So, let’s start by looking at physical availability of the new DTR-active antibiotics in the survey. As you’ll recall from the 1 Dec 2024 newsletter (“The 6 meanings of ‘Lack of Access’ (UNSLAP)”) and the related 7 Apr 2025 newsletter (“UNSLAP: You reach for the antibiotic … and it’s not there!”), if the antibiotic is not in your local pharmacy, it might as well not exist! The electronic data did not show what was actually on pharmacy shelves, but the authors were able to infer access by looking at use and susceptibility testing:

  • In 2016-18, only 12% of hospitals reported use of a new DTR-active antibiotic and only 4% did susceptibility testing for the newer antibiotics.
  • By 2021-23, the numbers had risen to 63% of hospitals using a newer antibiotic and 71% doing susceptibility testing.


OK, so far so good … a nice rise (but still only to about 2/3rds of hospitals). But, what therapy was actually given for those infections? Here’s where things go off the rails. See below Figure 3 from Walker et al.:

The x-axis is time (2016 to 2023) and the y-axis is % of DTR infections with the given type of initial antibiotic treatment. Critically, initial therapy is defined here as that given before the culture result is known — the therapy was empirical. We’ll look in a moment to see what happened when the culture result returns, but keep in mind that the initial period is critical to survival … we know from multiple studies that time to effective therapy makes a difference (as one example, see Liu XV et al., Amer J Resp Crit Care Med 2017, DOI: 10.1164/rccm.201609-1848oc)..

On the left of the figure, we have the raw data — a DTR-active antibiotic was initial therapy in only ~30% of DTR infections (total by eyeball of the red and blue lines at bottom). Ugh! But wait … it gets worse … when you further analyze (right-hand panel) the selected drug by whether it was actually active in vitro (that is, was there in vitro concordance or discordance), the authors found in vitro discordance in about half of the uses of a DTR antibiotic (total of the dotted red/blue lines at bottom). The net effect is is shown at the top of the right-hand panel … the percent of initial therapy predicted ineffective (either because the antibiotic used was non-DTR-active or was DTR-active but discordant) actually rose over the study period, peaking at 84% in 2023!

Now, it did turn out that therapy began to be changed as culture results were known. But, the delay in standard culture and susceptibility testing meant that those 5,065 patients were switched only slowly to a better DTR-active drug. We see that in this graphic of therapy by day relative to culture collection:

Walker 2026 - Time to effective antibiotics (annotated)

In the figure above (Figure 2 from Walker et al.), the x-axis is days relative to collection of the culture that yielded the DTR pathogen. Data by row are for 3 successive time periods (2016-18, 2019-20, 2021-23) and by column are for Acinetobacter baumannii, Enterobacterales, and Pseudomonas aeruginosa.

In the figure, now focus on the 3rd column from the left in each sub-figure … this is the time (1 day after culture collection) when new information might become available. You can see that therapy begins to change on that day … but that’s a long time to wait for effective therapy. 

Well, at least some patients did get a potentially better therapy. So (cue drumroll), did better therapy make a difference for the population as a whole over the study period? Given that either a DTR antibiotic or (worse) an ineffective antibiotic was given in more than three quarters of the population, the effect of the newer antibiotics would be expected to be diluted out. Thus, you will be unsurprised to hear that the answer is no, a reduction in mortality was not seen. The overall estimated mortality probability for DTR infections was 20% for Enterobacterales, 20% for P. aeruginosa, and 25% for A. baumannii … and this really did not change over the study period. Aside: There was a hint of a reduction in patients with P. aeruginosa bloodstream infections, but the authors feel this is a weak observation (small N and hints in the data of unexplained confounding).

In discussing their data, the authors focus on two factors that could have obscured the benefits of newer therapies:

  • Competing causes of mortality (age, other diseases) would obscure effects on the infection.
  • Delay in appropriate therapy, especially in the subset (~25%) with sepsis.

And I would agree that both of these make sense … but I’d like to take this one step further and consider the amount of improvement that is even plausible given that there are multiple causes of mortality.

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Stop #4 (One step further): How much of a mortality improvement is actually plausible?

Note: At this point in the newsletter, we have to assume that you are familiar with the study design ideas of superiority and non-inferiority. If not, please pause and (i) read the 19 Sep 2020 newsletter entitled “In Praise of Non-Inferiority” and (ii) watch its associated YouTube video. 

We start in this analysis by looking at the overall estimated mortality probability for DTR infections: ~20% for Enterobacterales, ~20% for P. aeruginosa, and ~25% for A. baumannii.

So, if we’re going to find an improvement (a reduction in mortality), we have to find it in the 20-25% who died … the other 75-80% survived and we can’t further improve their outcomes.

And, let’s also recognize that some mortality is doubtless unrelated to the infection and thus unpreventable: this would be the idea of attributable vs. non-attributable mortality. It’s hard to know an exact figure, we but know from Table 1 of Walker et al. that 12-13% of patients in the survey had a do-not-resuscitate order … so perhaps we can use 10% as a conservative estimate for non-attributable mortality. 

So now our zone for improvement (reduction) in mortality is limited to the attributable mortality subset … that’s a window from ~20% to (say) ~10%. And, it would take a 100% reduction in attributable mortality to reduce the mortality from 20% to 10%! That’s a tall order!

So, perhaps you are a bit less ambitious and think a better therapy could produce a reduction from 20% to 15% … effectively, a 50% relative reduction in the plausible zone for improvement. Well, that would be a stunning effect but it would take a study of about 1,250/arm to have 90% power to show that much change at P < 0.05. And if you thought you were going to show something a bit less (perhaps 40% relative reduction, the amount of mortality increase suggested by Kadri 2018), you’d need ~2,000/arm for a change from 20% to 16%. You could reduce the sample size to ~1,600/arm by accepting a P < 0.10 for your design, but that’s still a big study!

Ouch! But, you say, “I thought superiority studies were supposed to be small!” Well, that’s true for a really big effect — you only need 63/arm to show a change from 65% to 35% — but here we’re dealing with much smaller changes. Even if you said you’d recover all the mortality by moving the needle from 20% mortality to 10%, you’d need 286/arm. Not vast but not a small study either.

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Stop #5 (Implications, Part 1): Can we ever show that new drugs are better?

So, let’s return to the opening statements. Deep, deep down, this conversation is about how we know whether (or not) new drugs really work for bad bugs. Yes, we can see the favorable in vitro microbiology. Yes, we can see the favorable results of animal models. But, what about in human infections? “I want to see data on new drugs for bad bugs in people,” you cry! “Why are you bringing me these confusing non-inferiority results? Why aren’t you studying bad bugs? And, superiority studies would be cleaner! They can be smaller! Why aren’t we instead seeing superiority data on treatment of bad infections?”

Hopefully, the answers to these questions are now clear:

  • Unlike animal model studies, we can’t directly show the benefit of a new therapy over no treatment (placebo) in human studies because we can’t deliberately do placebo-controlled studies of new therapies … we always seek active therapy in all study arms.
    • Infections can be fatal if not treated promptly! Placebo just is not an option!
    • 25 Apr 2026 addendum: This was extensively debated 2007-08 (see Spellberg et al. Clin Investig (Lond). 2011;1:19-32; https://doi.org/10.4155/cli.10.1 for a good summary). Ultimately, FDA explicitly stated that placebo was not ethical in its guidance document for community-acquired bacterial pneumonia.
  • Situations where superiority studies have the potential to succeed are rare because we work hard to control the rate of DTR, MDR, XDR, and PDR pathogens.
    • We do sometimes run studies in which highly resistant pathogens are sought but these studies tend to be smaller and hard to enroll because we work hard to make resistant pathogens rare and thus …
    • … Walker et al. needed data from 471 hospitals spanning 8 years to find the 5,000 DTR infections in their report! That size and duration is obviously not feasible for a drug development program.
  • Finally, superiority studies are most feasible when there is a VERY large effect to be measured. Small effects require huge studies … and small changes are often not very compelling even when shown.
  • Now, you would correctly argue that perhaps we’re using the wrong endpoint … mortality is a blunt measure. Would measures that incorporate a range of non-mortality clinical measures be helpful?
    • This is the idea, for example, of DOOR (Desirability Of Outcome Rating) that has been championed over the years by Scott Evans and colleagues. Yes,  this could be a helpful path forward, especially if those endpoints can be shown to be clinical relevant and if superiority can be shown on a non-mortality component of an endpoint.
    • For an introduction to this literature, see Evans SR et al. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR), Clinical Infectious Diseases, 61:800–806, 2015, https://doi.org/10.1093/cid/civ495.
    • But, mortality is such an obvious and powerful endpoint that it’s hard to get away from it, especially in settings like infection where the course of the illness is often rapid and obvious. Even though it can be argued that other endpoints are clinically relevant and potentially more sensitive, the fundamental data that justify many of our standard designs depend on ACM as the primary endpoint because this is the measure that can be used to justify a non-inferiority margin.

And so, this is why we use non-inferiority studies:

  • We know from non-clinical data that the new antibiotic could work.
  • We show in a UDR setting that the new agent is non-inferior to an existing agent when the existing agent still works.
  • When resistance arises to the existing agent, the new agent’s activity is unaffected … it still works.
  • We can supplement the non-inferiority study with salvage studies in patients with MDR, XDR, PDR, or DTR infections but these studies are (hopefully) almost impossible to enroll if we are doing a good job with infection control.
  • The key to approval lies in the non-inferiority study done in the UDR setting
  • And, this is what allows us to develop new agents before the need for them becomes acute!
  • For more on this critical theme, see this YouTube video explainer or the 19 Sep 2020 newsletter entitled “In praise of non-inferiority.”

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Stop #5 (Implications, Part 2): What does this mean for calls to improve outcomes through alternative approaches such as host-directed therapies?

Well, you should by now be realizing that the news is not great. Unless your approach has a simply stunning effect, the ability to show a benefit in clinical studies is very limited. We say this with sadness as we think many of those ideas make good scientific sense. Unfortunately, it is very, very hard to show such effects consistently unless the effect is dramatic. For more on this (really, we have got to get to the end here!!), please see the 6 Aug 2019 newsletter entitled “Non-traditional antibiotics: A pipeline review and an analysis of key development challenges”. It’s a relatively old newsletter, but it’s one that covered in depth the problem of developing non-traditional therapies (such as host-directed therapies) and one where new material has been added as it has arisen.

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(Implications, Part 3) Rapid diagnostics and access to DTR-active agents are the keys to taking action!

So, there two strong, clear action items that come from Walker et al.: The first is to make a diagnosis, and make it quickly! This one is quite obvious …if antibiotics are the #FireExtinguishersOfMedicine, then diagnostics are surely the #SmokeDetectorsOfMedicine! But as noted in the paper, “Diagnosis of a DTR pathogen by conventional antimicrobial susceptibility testing methods is estimated to take a mean of 92.2 hours (SD 27.8) and can result in a significant delay in the time to initiation of an appropriate antibiotic.” That’s 4 days — much too long! Quoting further from Walker et al.:

  • “…rapid diagnostics could enable earlier yet stewardly initiation of newer over traditional antibiotics in this patient population with a high burden of sepsis.
  • “However, current rapid diagnostic platforms focus on enzyme-mediated resistance mechanisms, such as Klebsiella pneumoniae carbapenemases or New Delhi metallo-β-lactamases, despite the fact that such mechanisms are present in only a small fraction of resistant isolates and DTR isolates often have nonenzyme-mediated resistance mechanisms.
  • “Empirical antibiotic therapy could also be guided by predictive algorithms that estimate the likelihood of resistant pathogens, but this approach warrants further investigation.”

Is “stewardly” really a word? Well, it works for us and the message is clear. Also clear is the comment about the limitations on current diagnostics — we need tools for detection of more than just beta-lactamases! In further support of the #SmokeDetectorsOfMedicine, see these recent newsletters on the power of diagnostics:

And the second is, of course, ensure your healthcare system has access to all the DTR-active agents, especially the newer ones! Here again we remind you of the 1 Dec 2024 newsletter (“The 6 meanings of ‘Lack of Access’ (UNSLAP)” and the related 7 Apr 2025 newsletter (“UNSLAP: You reach for the antibiotic … and it’s not there!”). The titles of those newsletters are self-explanatory: if the antibiotic is not in your local pharmacy, it might as well not exist!

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Whew! That was a lot! Apologies for going on such a long tour, but it seemed helpful. Thanks for listening! All best wishes, John & Aaron

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.

Aaron Dane, CStat | DaneStat Consulting Limited | aarondane@danestat.com | www.linkedin.com/in/aaronldane | All opinions are my own.

Summary of prior newsletters on DTR and key related topics:

  • 13 Jan 2019: “Categories of resistance: MDR, XDR, PDR, UDR, and (new!) DTR”
  • 20 Feb 2020: “Language matters: CRE vs. CPE; SDD vs. I; and MDR, XDR, PDR, UDR vs. DTR”
  • 7 Jun 2020: “Assessing antibiotic value: DTR, fire extinguishers, and a view from Australia”
  • 19 Sep 2020: “In praise of non-inferiority”
  • 17 Mar 2021: “Where’s the innovation? / Indian Priority Pathogen List / DTR video explainer”
    • UDR vs. MDR/XDR YouTube video explainer — see below!
  • 25 Apr 2025: “Evolving the idea of DTR (Difficult-to-Treat Resistance) to include antibiotic access”

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, the small meeting format of BEAM’s AMR Conference (March) and GAMRIC (September-October; formerly, the ESCMID-ASM conference series) creates excellent global networking. IDWeek (October) and ECCMID (April) are much larger meetings but also provide opportunities for networking with a substantial, focused audience via their Pipeline sessions. Hope to see you there!

  • 22-24 Sep 2026 (Lisbon, Portugal): The 2nd GAMRIC, the Global AMR Innovators Conference (London, UK). Formerly the ESCMID-ASM (or ASM-ESCMID depending on location) Joint Conference on Drug Development for AMR, 2026 will be the 11th year for this series that is now under the joint sponsorship of CARB-X, ESCMID, BEAM Alliance, GARDP, LifeArc, Boston University, and AMR.Solutions. The ongoing series employs the successful format of prior meetings with a single-track meeting and substantial networking time. The 2025 meeting was a sell-out success! A written summary of the 2025 meeting is here and the videos from the sessions are now available here. Registration for the 2026 meeting is now open and you can view the preliminary program here. Abstract submissions are open through Fri 10 Apr at noon CET; note as well that travel grants are available for attendees with accepted abstracts. A late-breaker window be announced for July.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026, the annual meeting of the Infectious Diseases Society of America. I would expect the program to continue to provide a substantial opportunity to present a product to a large audience (see also adjacent note about ESCMID) as well as opportunities to present at an IDWeek Pipeline Session.
  • 23-24 Mar 2027 (Basel, Switzerland): The 10th AMR Conference (3-4 Mar 2026) is now over and offered a rich program that included a 10-year retrospective (we’ve done a lot!), regulatory updates, discussions of how to pursue development in China, and much more … in addition to being a superb opportunity for networking! I am told the session videos will soon be available on the conference website. Mark your calendars for next year’s 11th AMR Conference!
  • 9-13 April 2027 (Stockholm, Sweden): ESCMID Global 2027, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Details won’t be out for some months, but the website is here. I do know that the meeting schedule will again include a Science Policy Forum on Friday 9 April 2027 (see here the newsletter about the 2026 science policy forum) and all who are interested in Pull incentives and the antibiotic ecosystem should plan to be there!)..

  Upcoming meetings of interest to the AMR community:

  • 28 Apr 2026 (9:30-11:00 CET, virtual): REVIVE (GARDP)-sponsored webinar: “Natural product-inspired antibiotics: Successes and future prospects.” Go here for details and to register.
  • 4-8 June 2026 (Washington, DC): ASM Microbe, the annual meeting of the American Society for Microbiology. The meeting format is evolving and next year will combine 3 meetings (ASM Health, ASM Applied and Environmental Microbiology, and ASM Mechanism Discovery) into one event. Go here for details.
  • 11-12 Jun 2026 (Washington, DC): The Second Annual Unite for Sepsis Symposium, presented by the Sepsis Alliance. The event seeks to accelerate progress in sepsis research and care. Go here for details and to register.
  • 22-24 Sep 2026 GAMRIC (Lisbon, Portugal), the Global AMR Innovators Conference (London, UK; formerly the ESCMID-ASM Joint Conference on Drug Development for AMR). See list of Top Recurring meetings, above..
  • 10-18 Oct 2026 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2026 will be the 10th year for this program. Patrice Courvalin orchestrates content 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! Registration for 2026 will be during March 16–July 3, 2026. You can go here for more details and you should put a reminder in your calendar register on / after 16 March.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026. See list of Top Recurring meetings, above.
  • 10-13 November 2026 (Madrid, Spain): The International Society for Infectious Diseases (ISID) has announced its 21st International Congress on Infectious Diseases (ICID). Register and view the preliminary program here (Early bird closes 30 July 2026); abstract deadline is 28 April 2026.
  • 23-24 Mar 2027 (Basel, Switzerland): The 11th AMR Conference sponsored by the BEAM Alliance. See list of Top Recurring meetings, above.
  • 9-13 April 2027 (Stockholm, Sweden): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • ??? Mar 2028 (yes, that’s 2028, with location TBD): The 2028 Gordon Research Conference (GRC, https://www.grc.org/) entitled “Antibacterials of Tomorrow to Combat the Global Threat of Antimicrobial Resistance” and its related Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers will be sometime in March 2028. The organizers hope to coordinate dates and location with the 2028 BEAM-AMR meeting. Details to follow — mark your calendar!

Self-paced courses, online training materials, and other reference materials:

Current funding opportunities

  • [NEW] Wellcome Leap have announced a $50m funding round to support development of technologies that would spare the gut, focus the delivery of the antibiotic to the site of infection, and (thereby) reduce the rate of emergence of resistance. The application timeline is soon and short: 8-15 May 2026. See the 19 Apr 2026 newsletter for details.
  • CARB-X have announced a funding round that will be open 8-22 April 2026 (there will also be a round during 4Q 2026). There are 4 funding themes as below. Informational webinars have been announced for 9 and 10 April 2026.
    • Direct-acting therapeutics for infections caused by Gram-negative bacteria
    • Novel Chemistry for AMR Challenge – target-based therapeutics.
    • Non-vaccine approaches to prevent neonatal sepsis
    • Diagnostics for neonatal sepsis
  • The Horizon Europe Work Programme 2026-2027 includes at least 3 calls of interest within its Cluster 1 — see the list below.  The application window starts 10 Feb 2026 and closes on 16 Apr 2026. See also the 12 Dec 2025 newsletter about the call. Note as well that there calls for agents to prevent and/or treat viral infections.
    • HORIZON-HLTH-2027-01-DISEASE-08: Development of innovative antimicrobials against pathogens resistant to antimicrobials
    • HORIZON-HLTH-2027-02-IND-02: Portable point-of-care diagnostics
    • HORIZON-HLTH-2026-01-DISEASE-03:Advancing research on the prevention, diagnosis, and management of post-infection long-term conditions. 
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • 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.
  • 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
    • 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. See also the 7 Feb 2026 newsletter (“The global funding pipeline, 2017-2023: A review”) about an excellent deep dive by the Hub team into patterns of funding over time.
    • Antimicrobial Resistance Research and Innovation in Australia is an actively updated summary that covers Australia’s AMR research and patent landscape. It is provided via collaboration between The Lens (an ambitious project seeking to discover, analyse, and map global innovation knowledge) and CSIRO (Commonwealth Scientific and Industrial Research Organisation, an Australian Government agency responsible for scientific research). Lots to explore here!
    • 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).
]]> Mirror Bacteria: An AMR threat of unprecedented magnitude https://amr.solutions/2024/12/12/mirror-bacteria-an-amr-threat-of-unprecedented-magnitude/ Thu, 12 Dec 2024 19:51:36 +0000 https://amr.solutions/?p=17573

Dear All (wonkish but stick with it … I’m going to try very hard to de-wonk it; addendum: see also the follow-up newsletters, most recently on 22 Dec 2025),

In an absolutely terrifying paper and technical report in today’s issue of Science, we are introduced in detail to the concept of “mirror” bacteria in which all chiral elements of the bacterium are replaced by their enantiomeric counterparts. And if that’s completely unintelligible to you, please stick with me and read just a bit further — you really will want to understand this. To get us started, here are the links and ideas you need:

  • The 4-page article itself: Adamala KP et al., “Confronting risks of mirror life.” Science 2024, DOI: 10.1126/science.ads9158.
  • The Mirror Biology Dialogues Fund (MBDF) that has been created “to advance a global discussion to chart the path forward for mirror biology research.”
  • General articles
  • Some words that matter in following the story:
    • Chiral / Chirality: An object is chiral (or has chirality) if it can be distinguished from its mirror image. Your left and right hands are chiral.
      • Enantiomer: Each object of a mirror-image chiral pair is called an enantiomer. Your left and right hands are enantiomers.
      • Racemic mixture (or racemate): A 50-50 mixture of the enantiomers of a chiral pair. The clapping left and right hands of the audience are a racemic mixture.
    • Achiral: An object is achiral (NOT chiral) if it cannot be distinguished from its mirror image. A solid white sphere is achiral.

OK, so what’s going on here? What is a mirror bacterium? The core concept begins with understanding that most molecules have a natural property that can be called “handedness” or chirality. Your left and right hands are great example of this. Further, think about a pair of gloves … the left glove won’t work very well (if at all) on your right hand. 

Extending this a bit, it turns out that all living things on our lovely planet have agreed to use a consistent set of choices when molecules are sufficiently complex to be chiral. All proteins and all DNA/RNA strands use the same set of choices for their underlying amino acids and nucleotides. The opposite chirality would have worked, but it’s not what was chosen.

  • 12 Dec 2024 addendum: The origins of our planetary agreement on homochirality are unknown, but if you are curious you can see Ozturk et al. (DOI: 10.1126/sciadv.adg8274) for a “prebiotically plausible way of achieving system-level homochirality from completely racemic starting materials, in a shallow-lake environment on early Earth where sedimentary magnetite deposits are expected to be common.” So there!
  • 2 Sep 2025 addendum: These same authors have now published a very approachable 4-page summary of their core argument in PNAS (https://doi.org/10.1073/pnas.2505126122). In brief, the argument is that ribose aminooxazoline (RAO), a ribose precursor, crystallizes enantiomerically on magnetic surfaces. This, in turn, provides a starting point for the preference for D-nucleotides and then L-peptides. Seriously cool!)
  • 8 June 2026 addendum: Building on theme that our agreed homochirality is based on the effect of magnetic fields, Paltiel et al. (Sci Adv 2026; doi: 10.1126/sciadv.aec9325) have reported that magnetic fields can select enantiomers by effects on spin. There’s as well a helpful discussion in this news article in Chemistry World: “Elusive electronic effect could explain the origins of chirality for all life on Earth.” 

A reasonable parallel would the concept of left-hand vs. right-hand traffic. Most of the world drives on the right … but the mirror image of driving on the left works just fine with a little practice (as I learned while living in the UK some years ago).

And that (drum roll) brings us at last to the idea of a mirror bacterium (or organism). If you could replace every chiral molecule in an E. coli with its enantiomer, you’d have a mirror E. coli. If put in a growth medium that contained achiral simple sugars as its carbon source, it would grow and divide normally.

So what’s the fuss? Why is this report creating such news? Although the idea of mirror life is known (at least to sci-fi fans), the potential to actually make a mirror organism has gone from speculative fiction to the possibility of near-term reality based (in particular, but not exclusively) on work exploring ways to make non-mirror organisms from basic chemical building blocks (see this ACS 2021 article for a very deep dive). The ability to actually do this is still at least a decade away, but it is coming … and once we can make a normal (non-mirror) bacterium from scratch, then making a mirror version would also be possible.

And with this, we come to the point of the paper and technical report in Science: All life on earth is in balance (even apex predators have each other as predators) but mirror bacteria would interact with existing life in profoundly different ways from non-mirror bacteria. The mirror bacteria would have many advantages that would mean that the mirror bacteria could easily come to dominate the global ecosystem:

  1. The natural innate immune defenses that all living things possess are designed to work against pathogens of the agreed (standard) chirality. A mirror bacterium might go unscathed.
  2. Similarly, adaptive immunity (e.g., the antibodies you make when you get vaccinated) will usually have a chiral nature and might well not work vs. a mirror bacterium.
    • We might be able to develop vaccines for the mirror bacterium, but that would be a new vaccine.
  3. Natural predators of bacteria (bacteriophage and the protists that prey on bacteria) would be ineffective vs. mirror bacteria.
  4. Many antibiotics are chiral and would be ineffective vs. mirror bacteria.
    • A handful of achiral (or racemic) antibiotics would still work: sulfas, quinolones, metronidazole, nitrofurantoin, and trimethoprim. 
    • But we’d lose the penicillins, the cephalosporins, the aminoglycosides, the tetracyclines, vancomycin, linezolid, and others.
    • We could directly synthesize the mirror version of some compounds (e.g., linezolid) as it is readily made by direct synthesis.
    • But anything that starts with a natural product (a large molecule made by bacteria or yeast; vancomycin would be an example) would be very hard to convert to a mirror form.

Or as the authors note, “We cannot rule out a scenario in which a mirror bacterium acts as an invasive species across many ecosystems, causing pervasive lethal infections in a substantial fraction of plant and animal species, including humans.”

Ugh! I encourage you to read the paper and the technical report for more details, but hopefully this paints the picture with clarity: Pandora’s Box for real!

What’s to be done? The authors get us started with these arguments. Note in particular the call for public conversation — the accompanying Mirror Biology Dialogue Fund (MBDF) website gives an initial view on how those conversations would be organized:

  • “Unless compelling evidence emerges that mirror life would not pose extraordinary dangers, we believe that mirror bacteria and other mirror organisms, even those with engineered biocontainment measures, should not be created.
  • “We therefore recommend that research with the goal of creating mirror bacteria not be permitted, and that funders make clear that they will not support such work.
  • …
  • “We believe that there is a productive path ahead in which a range of stakeholders collaboratively consider the risks from mirror life and develop appropriate governance without unnecessarily impeding scientific research.
  • “Drawing inspiration from the Tianjin Biosecurity Guidelines and other relevant frameworks, we invite the global research community, policy-makers, research funders, industry, civil society, and the public to join this discussion.
  • “To facilitate greater understanding of the risks associated with mirror life and further progress on governance, we plan to convene discussions on these topics in 2025.”

Nice ideas … but can we really stop this speeding train? At the very least, the science is still some years from reality and (provided we don’t delay) there’s time for the AMR development community to develop adequate responses: The current crisis of antimicrobial resistance (AMR) that has developed from the natural emergence of superbugs already threatens health worldwide and this report shows that mirror bacteria would sharply accelerate this crisis.

While hoping to keep this Pandora’s Box closed as long as possible, we should prepare for the day that mirror bacteria become a reality — and perhaps this would help us address the AMR crisis that is already afoot.

Critically, we have lamented in prior newsletters the lengthening R&D timelines for new antibacterial agents (e.g., the 30 June 2020 newsletter discussing Dheman et al., FDA’s analysis of 40 years of antibacterial development). The current typical time lags of a decade or more from start to approval would be much too slow to be an effective response: we really should start now to develop dramatically accelerated pathways for discovery, development, and manufacturing of innovative antimicrobials.

Yow! Terrifying, no? Put on your thinking caps. We’ll be talking about this again.

Meditatively yours, –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.

Current funding opportunities

  • NIAID’s RFA-AI-24-069 is a notice of funding opportunity (NOFO) soliciting applications to establish Centers for Accelerating Phage Therapy to Combat ESKAPE Pathogens (CAPT-CEP). The CAPT-CEPs will focus on developing preclinical assays, tools, and models for robust phage therapy research and development (R&D) and advancing phage clinical research. Applications are due by 28 Jan 2025; letters of intent must be received 30 days prior to the due date. See also the 23 Oct 2024 newsletter about the RFA for a discussion of issues with developing phage-based products.
  • The 2026 NIAID DMID Omnibus Broad Agency Announcement (HHS-NIH-NIAID-BAA2025-1) seeks applications in its Research Area 001 for (i) therapeutics for bacterial and fungal infections, (ii) vaccines for bacterial infections, and in vitro diagnostics for fungal pathogens. Applications are due by 21 Feb 2025. See also the 26 Nov 2024 newsletter discussing the BAA.
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • CARB-X has open calls at intervals that span four areas: (i) Therapeutics for Gram-Negatives, (ii) Prevention for Invasive Disease, (iii) Diagnostics for Neonatal Sepsis, and (iv) Proof-Of-Concept for Diagnosing Lower-Respiratory-Tract Infections. See this 6 Mar 2024 newsletter for a discussion of the call and go here for the CARB-X webpage on the call. There are multiple opportunities to submit — see the CARB-X webpage for details.
  • 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.
  • 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!

  • 25-26 February 2025 (Basel, Switzerland): The 9th AMR Conference 2025. Go here to register! 
  • 11-15 April 2025 (Vienna, Austria): ESCMID Global 2025, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details. 
  • (no date as yet) 2025 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. Go here to see details of the outstanding 2024 meeting!
  • 19-22 Oct 2025 (Georgia, USA): IDWeek 2025, the annual meeting of the Infectious Diseases Society of America. Details pending; go here for the general meeting website.

  Upcoming meetings of interest to the AMR community:

  • 23 Jan 2025 (virtual, 1700-1830 CET / 1100-1230 EST): GARDP REVIVE webinar entitled “The importance of chemical synthesis for antimicrobial R&D.” Go here to register.
  • 28-29 Jan 2025 (online and in-person, Washington, DC): PACCARB (US Presidential Advisory Council on Combatting Antimicrobial Resistant Bacteria): This particular meeting of PACCARB is unusually important as it will seek (i) public input into NAP for CARB 2025-2030 and (ii) work to sustain the momentum regarding the commitments at the High-Level Meeting on AMR at the 2024 UN General Assembly (UNGA HLM AMR). Go to http://hhs.gov/paccarb for details and to register.
  • 4-5 Feb 2025 (online, 1-5p GMT timing on both days): Antimicrobial Chemotherapy Conference by GARDP and BSAC in collaboration with CEPID-ARIES and Fiocruz. Now in its 6th year, the free program offers a good review of antimicrobial R&D, ranging from drug discovery to preclinical and clinical activities. Go here to register; the abstract deadline is 15 Nov 2024.
  • [NEW] 5 Feb 2025 (The Spine, Liverpool): BioInfect 2025, Bionow’s annual north of England meeting for AMR researchers and industry professionals. The agenda includes a keynote lecture from Erin Duffy, Chief of Research & Development, CARB-X. Go here to register. 
  • 25-26 February 2025 (Basel, Switzerland): The 9th AMR Conference 2025. See list of Top Recurring meetings, above.
  • 27 Feb 2025 (virtual, 1700-1830 CET / 1100-1230 EST): GARDP REVIVE webinar entitled “In vitro and in vivo correlations for prediction of human pharmacokinetics and dose of antimicrobials.” Go here to register.
  • 11-15 April 2025 (Vienna, Austria): ESCMID Global 2025, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 19-22 Oct 2025 (Georgia, USA): IDWeek 2025, the annual meeting of the Infectious Diseases Society 
  • 11-15 April 2025 (Vienna, Austria): ESCMID Global 2025. See list of Top Recurring meetings, above.
  • 30 June-1 July 2025 (virtual and in Washington, DC): BID2025: BARDA Industry Days — Enhancing Health Security With a Sustainable Future.  BID provides the opportunity to discuss U.S. government medical countermeasure (MCM) priorities, provide the private sector an informal opportunity to interact with BARDA and ASPR teams, and identify potential areas of collaboration in the field of MCM research and development. Go here for details.
  • 19-22 Oct 2025 (Georgia, USA): IDWeek 2025. See list of Top Recurring meetings, above.
  • 11-19 Oct 2025 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2025 will be the 9th year for this program. Patrice Courvalin orchestrates content 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 should open ~March 2025 — go here for more details.

 Noteworthy self-paced courses and training materials (this is a new section — comments or builds would be appreciated!):

]]> Chemical vs. drugs (Part 2): How do you discriminate? / More on halicin https://amr.solutions/2020/02/24/chemical-vs-drugs-part-2-how-do-you-discriminate-more-on-halicin/ Mon, 24 Feb 2020 18:32:01 +0000 https://13.43.35.2/?p=2044

This newsletter is part of a series — here are the links to Part 1, (this one is Part 2), Part 3, Part 4, and Part 5. Also relevant is the 5 April 2024 newsletter entitled “48,015 → 0: Antibacterial Discovery Is Hard. Really, Really Hard.“ You might also enjoy the discussion of AI-supported discovery in this May 2026 video from Nature. 

Dear All (wonkish note alert!),

The recent newsletter on chemicals, drugs, and halicin (link, see also a follow-up newsletter here) generated significant discussion and new insights that I thought I would share in a follow-up newsletter. Our theme in Part 2 is “Trust, but verify!” 

Let’s start by considering comments on the newsletter. A number of you wrote to add support for the idea that the specific antibacterial candidate identified by Stokes et al. (link, SU3227/halicin) is very unlikely to be a safe systemic human medicinal:

  • As noted in the first newsletter, c-Jun N-terminal kinases are involved in many critical biological pathways and inhibitors of same (such as SU3227) would need to be highly selective.
  • Indeed, the idea of seeking a novel antibacterial from a screen of human drug candidates from other therapy areas must by definition find compounds with effects on some aspect of human biology. Thus, such compounds would have two diverse activities (the antibacterial effect as well as the intrinsic effect on some human system) and hence be at risk for being toxic depending on the nature of the effect on that human system. It might be possible to make derivatives that would lose those effects, but the compound series starts with that liability.
  • Finally, and going on a limb a bit as I am not a chemist, the specific molecule (see its structure as the inset to Figure 2H from the paper) contains a nitro group attached to an aromatic ring, something that I’ve been taught is a mutagencity risk (link to a comment by Derek Lowe entitled “I Want A New Nitro” and link to a longer in-depth 2019 paper by Kepali et al. in J Med Chem).

So, SU3227/halicin might be topical medicinal (and they do show that in their paper) but it is unlikely to go further than that for this particular molecule. That said, the comments also noted that the idea of applying machine learning to antibiotic discovery is noteworthy and we all hope that continued work will refine the approach and identify useful new areas of chemical space. 

So, we now come to the deeper question that is the focus of this newsletter: How can we distinguish toxic chemicals from possible new antibacterial drugs? And this may not be easy as we are asking something special of these molecules: we want them to kill a living organism, but to do so selectively!  So, there is a perspective from which we may need to be willing to consider molecules that carry some risk. That noted, the quip “It’s easy to kill bacteria — steam, fire, and bleach are consistently effective — but those aren’t drugs!” provides no help at all with finding a path forward. For example, what about the further 23 candidate antibacterial molecules identified by their screening of the 1.5 billion compound ZINC15 database (Figure 6D)? Those compounds do have antibacterial activity — might they be drugs?

There are no perfect tools here and the problem is complicated by the fact that antibacterial compounds are often not “drug-like” from the perspective of Lipinski’s Rule of 5 (link). Reinforcing the notion that antibiotics often defy typical medicinal chemistry rules, some antibiotics even have reactive elements (e.g., fosfomycin is an epoxide). So, what can be done? Well, we do have some practical suggestions to hand. 

Our initial Chemical-vs-Drug signpost comes from the Instructions to Authors for Antimicrobial Agents and Chemotherapy (AAC, link). As part of guideline #6 on the first page of the instructions, we have:

  • “Manuscripts dealing with novel small molecular antimicrobials must provide at least some data showing that the proposed new agents or scaffolds have the potential to become therapeutic agents.
  • “Appropriate demonstrations will vary but generally should be some combination of data on physical properties (solubility, protein binding, log P [logarithm of the ratio of the concentrations of un-ionized solutes in solvents]), pharmacological properties (Caco2 predictions of bioavailability, pharmacokinetics in an animal species), or tolerability (mammalian cell toxicity, likelihood of hepatic metabolism, potential for receptor interactions, potential for human ERG liability).
  • “Initial presentations of compounds are not expected to address all these areas but rather to show an appropriate initial subset.
  • “For example, the first publication of a novel compound or compound series might address selected physical properties plus mammalian cell toxicity.
  • “Subsequent publications are expected to add progressively to the proof of the agent’s therapeutic potential.
  • “For cationic peptide molecules, an additional expectation is that the molecule demonstrates a profile that is distinct from previously reported similar molecules and that it demonstrates reasonable pharmacokinetics or credible efficacy in an in vivo tissue model of infection (e.g., thigh or lung).”

Our second Chemical-vs-Drug signpost comes from the pragmatic screening approach for novel antibiotics that is being implemented by CO-ADD (https://www.co-add.org/, Community for Open Antimicrobial Drug Discovery), a global open-access screening initiative. Launched in February 2015 and funded for nearly 5 years by the Wellcome Trust supplemented by support from the Institute for Molecular Bioscience (UQ IMB) and The University of Queensland (UQ), CO-ADD provides free antimicrobial screening with no encumbrances (in particular, no impact on IP with the proviso that structures should ultimately be published in CO-ADD’s database) for compound collections from any interested academic researcher..

To date, CO-ADD has screened about 300,000 compounds from 47 countries by following this 3-step process (https://web.archive.org/web/20210417025918/https://www.co-add.org/content/free-screening):

  • Step 1: Primary Screening
    • In the primary screening we test compound libraries against key ESKAPE pathogens, E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus (MRSA), as well as the fungi C. neoformans and C. albicans.
    • The screen will be at a single concentration (32 µg/mL) and will provide initial activity data to select compounds for further more detailed screening.  
  • Step 2: Hit Confirmation
    • Active compounds from the primary screening will be tested in dose response antimicrobial assays to confirm their activity.
    • Active compounds will be screened for adverse effects, such as cytotoxicity, critical micelle concentration and membrane depolarization, as well as for their purity.
    • The Hit confirmation process will evaluate the basic drug qualities of actives, and which of the actives have the best potential for further development.    
  • Step 3: Hit Validation
    • The next step of the CO-ADD process is to test the hit against a broader panel of microbes with multidrug-resistant (MDR) and pan-resistant bacterial strains and clinical isolates, with different co-factors (such as serum or lung surfactant).
    • The Hit validation will also include initial ADMET screening, including haemolysis, microsome and plasma stability and protein binding.
    • In addition, structural analogues could be included to evaluate any structure-activity relationship.

If you look at this sequence of tests, it is readily seen to parallel the ideas in AAC’s suggestions for initial data. Testing vs. both bacteria and fungi in Step 1 is a simple way to spot general toxins: if something kills both prokaryotes and eukaryotes, it is probably not a drug! Step 2 does simple tests to look for indiscriminate activity such as being a detergent. Finally, things get serious in Step 3 with a broader look at the activity of the compound series.

As a demonstration of the potentially utility of this approach to mine novel chemical space, CO-ADD has recently published a paper (Frei et al., link) in which they observe that metal-containing compounds have an unusually high validated hit rate. The authors conclude, “This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combating antimicrobial resistance.”

I’m sure that the real chemists in our community can suggest other ideas (e.g., the idea of PAINS, link), but I think that’s enough for a general path. Putting it all together, the core idea is that we always need to remember that “It’s easy to kill bacteria — steam, fire, and bleach are consistently effective” and balance this with the adage “Trust, but verify.” 

Many thanks to all who wrote! All best wishes, –jr

PS: This newsletter has a follow-up here.

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/

Current funding opportunities:

  • Open now through 28 Feb 2020: FDA call for applications to create rabbit models of ventilator-associated bacterial pneumonia (VAP or VABP, depending on your preferred abbreviation) due to carbapenem-resistant strains of A. baumannii and P. aeruginosa. Go here for details.
  • Open now through 16 Mar 2020: CC4CARB, NIAID’s call for applications to fund an innovative Chemistry Center for Combating Antibiotic-Resistant Bacteria (CC4CARB). Go here for details.
  • Open now through 9 Apr 2020: NIAID Broad Agency Announcement (BAA) soliciting contract proposals for preclinical and clinical development of vaccines, therapeutic, and diagnostics for microbial pathogens. Go here for more.
  • Dates for the 2020 funding rounds for Novo REPAIR Impact Fund will be announced May 2020. Go here for current details.
  • 2020 funding rounds for CARB-X have not been announced.

Upcoming meetings of interest to the AMR community:

  • Unclear dates. University of Sheffield (UK). Applications are being taken for a new 1-year (full-time) or 2-year (part-time) Masters of Science course in Antimicrobial Resistance. The program appears to start Fall 2020. The course webpage is here. Further details when I have them!
  • 26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
  • 27 Feb 2020 (1700-1830 CET, online): GARDP-sponsored webinar entitled “PK/PD murine infection models: Focus on study elements, variability, and interpretation of results.” Go here to register.
  • 1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): Gordon Research Conference (GRC) on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
  • 5 Mar 2020 (FDA, White Oak Campus, 8.30a-5.00p EST): FDA workshop entitled “Advancing Animal Models for Antibacterial Drug Development.” FR notice is here and registration is here. The workshop will be webcast.
  • 12-13 Mar 2020 (Basel): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Details are here, poster deadline is 12 Dec 2019.  
  • 16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details. 
  • [UPDATED – REGISTRATION IS NOW OPEN] 20 Mar 2020 (Boston, MA): 7th annual BAARN (Boston Area Antimicrobial Resistance Network) Meeting. Chaired by Lawson Ung and Michael Gilmore, talks start at 9am and end with a reception at the Harvard Museum of Natural History. Go here to register; you can also contact Lawson Ung (lawson_ung@meei.harvard.edu) for other inquiries.
  • 26-30 Mar 2020 (Atlanta, GA): CDC- and SHEA-sponsored 6th International Conference on Healthcare Associated Infections. Go here for details.
  • 30 Mar 2020 (everywhere): Deadline for applications for the Molecular Mycology pathogenesis course at Marine Biological Laboratory, Woods Hole. Now in its 24th year, the hands-on residential course runs 17 July to 2 Aug and gets rave reviews. Go here for more.
  • 9 Apr 2020 (everywhere): Final date for applications for NIAID/DMID call (link) for AMR-related vaccines, therapeutics, and diagnostics.
  • 17 Apr 2020 (Paris): Pre-ECCMID workshop entitled “Machine Learning for Clinical Microbiology.” This meeting has been cancelled. 
  • 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
  • 25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
  • 18-22 Jun 2020 (Chicago), ASM Microbe 2020. Go here for details.
  • 27-28 Jun 2020 (Bryant University, Rhode Island): Drug Resistance Gordon Research Seminar entitled “Mechanisms and Approaches to Overcoming Drug Resistance in Cancer, Infectious Disease and Agriculture” for graduate students and postdoctoral scientists. Go here for details … this immediately precedes the GRC listed just next
  • 28 Jun-3 Jul 2020 (Bryant University, Rhode Island): Gordon Research Conference (GRC) entitled “Strategies to Disrupt Drug Resistance in Infectious Disease, Cancer and Agriculture.” Go here for details.
  • 1-4 Sep 2020 (Dublin): Annual ASM-ESCMID Conference on Antibiotic Development #5! Mark your calendar now and go here for details.
  • 9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
  • 22-25 Sep 2020 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
  • 17-25 Oct 2020 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics, antibiotic resistance, and antibiotic R&D. The course is very intense, very detailed, and gets rave reviews. The date is set for 2020 and the program will ultimately appear here. Registration is limited to 40 students and opens 15 Mar 2020.
  • 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)
  • 3-7 Jun 2021 (Anaheim), ASM Microbe 2021. Go here for details.
]]> Limits on measuring the impact of rapid antimicrobial susceptibility testing (AST) https://amr.solutions/2026/05/27/limits-on-measuring-the-impact-of-rapid-antimicrobial-susceptibility-testing-ast/ Wed, 27 May 2026 20:55:55 +0000 https://amr.solutions/?p=25514

Dear All (and with thanks to Arjun Srinivasan for co-authoring this wonkish newsletter — prepare yourself! Know also that we’ve written a parallel newsletter entitled “Economic modeling of the value of rapid diagnostics” that discusses the use of modeling to estimate the value of diagnostics in general):

Driven by ongoing work to encourage use as part of good medical practice and stewardship, discussions of the value of diagnostics have been increasingly prominent in past issues of this newsletter:

  • 18 Jun 2025: “Extending STEDI to diagnostics: STRIDES”
  • 4 Oct 2025: “WHO: Reviews of antibacterial therapeutics and diagnostics”
  • 17 Feb 2026: “Workshop on diagnostics: Can we drive use by making value visible?”
  • 9 Apr 2026: “GO-Dx: Global One Health Diagnostics Access Compact”

While a lot of this discussion is focused on simply ensuring access to diagnostics (any diagnostic!), the push for use of diagnostics would be greatly aided by data showing that their use makes a difference in clinical outcomes and improved health system efficiencies. And as a build on that, the idea that rapid initiation of effective therapy improves outcomes drives a push for rapid AST. It would all seem to make perfect sense: the mortality of serious infections can be reduced by an effective antibiotic and this would imply benefits from rapid adjustments to antibiotic therapy (if needed).

Perhaps surprisingly, however, studies of the value of rapid AST have consistently struggled to demonstrate this theoretical value. A recently published study sponsored by the ARLG (Antibiotic Resistance Leadership Group) was both a very good effort to generate such data and a demonstration of the limitations on randomized demonstrations of the utility of diagnostics. To follow the discussion, here are the links you need: 

  • Papers evaluating the clinical impact of rapid AST methods:
    • Banerjee R et al. Fast Antimicrobial Susceptibility Testing for Gram-Negative Bacteremia: The FAST Randomized Clinical Trial. JAMA. 2026, doi: 10.1001/jama.2026.5487. This article prompted this newsletter. It concludes that “Among patients with gram-negative bacilli BSIs, rapid blood culture AST was not superior to standard testing by DOOR.”
    • Srinivasan A. A Multinational Trial of Rapid Antimicrobial Susceptibility Testing: Is FASTer Better? JAMA. 2026, doi: 10.1001/jama.2026.5504. Accompanying editorial by Arjun, co-author of this newsletter.
    • Anton-Vazquez V et al. Rapid versus standard antimicrobial susceptibility testing to guide treatment of bloodstream infection. Cochrane Database Syst Rev. 2021, doi: 10.1002/14651858.cd013235.pub2. A Cochrane review that concludes “The theoretical benefits of rapid susceptibility testing have not been demonstrated to directly improve mortality, time-to-discharge, or time-to-appropriate antibiotic in these randomized studies.”
    • A comparison of six recent prospective studies of rapid AST (Antimicrobial Susceptibility Testing) methods. With Banerjee 2026, there are six such studies. This is a comparative summary that John generated with the assistance of one of the AI models.
  • Papers evaluating the clinical impact of delayed antibiotic therapy:
    • Kumar A. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–96, doi: 10.1097/01.ccm.0000217961.75225.e9. A classic paper on this topic – one of my favorites.
    • Zasowski EJ et al. A Systematic Review of the Effect of Delayed Appropriate Antibiotic Treatment on the Outcomes of Patients with Severe Bacterial Infections. Chest. 2020;158(3):929–38, doi: 10.1016/j.chest.2020.03.087. A recent, well-written systematic review of the literature on this topic.
  • Papers evaluating the impact of parachutes on gravitational injury:
    • What? Yes, you read that correctly — this is not an April Fool’s Day joke or a review from The Onion! We’ll make use of these papers when get to topics 2 and 3, below!
    • Smith GCS, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: Systematic review of randomised controlled trials. BMJ. 2003;327:1459–61, doi: 10.1136/bmj.327.7429.1459. No surprise — a systematic review failed to find any RCTs showing that parachutes work.
    • Yeh RW et al. Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial. BMJ. 2018, doi: 10.1136/bmj.k5094. To address the gap identified by Smith & Pell, we’ll see that Yeh et al. conducted an RCT … details below!

So, we’re off on a tour of these 3 topics:

  1. Why did Banerjee 2026 conclude that “Among patients with gram-negative bacilli bloodstream infections, rapid blood culture AST was not superior to standard testing by DOOR.”?
  2. So, does time to prompt initiation of antimicrobial therapy actually matter?
  3. What does all this say about showing superiority outcomes in studies of AST (whether rapid or not) and of antimicrobial agents?

Here we go!

Topic 1: Why did Banerjee 2026 conclude that “Among patients with gram-negative bacilli bloodstream infections, rapid blood culture AST was not superior to standard testing by DOOR.”?

The study by Banerjee 2026 was a substantial and well-considered effort to show the value of rapid AST. Building on challenges with prior studies, its key features were: 

  • It was an open-label randomized clinical trial comparing rapid AST with standard AST as guidance for antibiotic therapy in patients with bloodstream infection due to Gram-negative bacilli (E. coli, etc.)
  • It was conducted at 7 medical centers in countries with a high endemicity for resistant organisms: Greece (2), India (1), Israel (3), and Spain (1).
  • It was a big study: it randomized 850 subjects: 413 to rapid AST, 437 to standard AST
  • Rather than a blunt endpoint of all-cause mortality, its primary outcome was focused on overall clinical response by use of a desirability of outcome ranking (DOOR, Evans 2015) at day 30 based on 3 categories that are ranked from better to worse: (i) alive without deleterious events, (ii) alive with deleterious events, and (iii) death.

 Frustratingly, the authors found that:

  • Rapid AST did not improve the likelihood of a more favorable DOOR category outcome.
  • Rapid AST did reduce the time to antibiotic escalation or de-escalation, but
  • … there was no difference in time to effective antibiotic therapy.

The lack of impact of rapid AST on time to effective antibiotic therapy is almost certainly the core issue and can be seen in Figure 4 from the paper where we have antibiotic therapy over time for the two groups. The bottom two bars in each column (purple and blue) are the roll-up of overtreatment (purple) and appropriate treatment (blue): both would be expected to be effective, of course:

Walker's Figure 4, Sankey diagram of antibiotic use

To make it a little easier to see, this next figure shows the sum of appropriate treatment + overtreatment (the purple and blue bars, above. As you can see, the % on adequate therapy was essentially identical over time:

Walker, Figure 4, graph showing effective antibiotic use over time

So, that explains the lack of impact of rapid AST … effective antibiotics were used essentially equally well in both arms — or equally poorly, with INappropriate antibiotics used about 40% of the time! Eh? What is going on?

Well, the answer turns out to be related to the theme of these prior newsletters in which we explored the lack of use of newer (less toxic) antibiotics:

  • 24 Apr 2026: “DTR Gram-negative infections: Are new antibiotics making a difference?”
  • 1 Dec 2024: “The 6 meanings of ‘Lack of Access’ (UNSLAP)”
  • 7 Apr 202: “UNSLAP: You reach for the antibiotic … and it’s not there!”

While there are multiple contributing factors (most importantly, rapid molecular ASTs do not [and cannot] detect all forms of resistance), a fundamental issue noted by the authors in their discussion is the lack of access to newer (less toxic agents). Better (rapid) AST is useless if no action is possible!

As a further concern, prior analyses (e.g., Vogler S et al. Health Policy OPEN. 2024;7:100129, doi: 10.1016/j.hpopen.2024.100129) have found that modification of provider behavior requires substantial educational efforts. The manuscript does indicate that the antibiotic stewardship team at each institution would contact the provider if treatment changes were thought needed but it’s not clear how readily or rapidly that advice was utilized at the study sites.

Finally, and further obscuring any potential impact of rapid AST, over half of the subjects had infections due to organisms that were NOT highly resistant thus, they received appropriate therapy without difficulty. Stated differently, if therapy is already appropriate, rapid AST might permit de-escalation but can’t be expected to produce clinical improvement. And it thus follows that measurement of the strength of benefit from rapid AST in the subset really needing AST was diluted by / obscured by the larger pool of patients who received acceptable therapy as part of standard practice.

In summary, and although this trial did find process benefits such as reductions in time to first antibiotic change, the negative result of this trial is readily understood from lack of the ability of an AST (whether rapid or not) to alter selection of (and time to) administration of an appropriate antibiotic unless that antibiotic is available and unless providers are also motivated to act on new data. There are also practical limits on the impact of AST devices, but the foremost problem is that the better agents were often either not available or not used in the study sites!

—–
Topic 2: So, does time to prompt initiation of antimicrobial therapy actually matter? (And we’re soon going to use the bit about gravitational injury — hang in there!)

So, what does this say about the value of AST, whether rapid or not? Well, that’s a separate issue from the impact of initiation of antimicrobial therapy. Overall, there’s little doubt that prompt administration of an effective antibiotic makes a difference … and that lack of effective therapy causes bad outcomes.

The primary data on the impact of early therapy is the extensive observational literature cited above. One can also point at specific bits of data such as the impact of a single prior dose of an effective therapy early in the course of community-acquired bacterial pneumonia (Pertel et al. Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia. CID 2008;46(8):1142–51, doi: 10.1086/533441).

And if you want more proof, this population-level figure showing the case fatality rate for erysipelas (a skin infection) in Norway illustrates the dramatic effect of the introduction of first sulfas and then penicillin:

Madsen 1973 - Annotated figure showing mortality due to erysipelas

Source: Figure 6 from Madsen ST. Scarlet fever and erysipelas in Norway during the last hundred years. Infection. 1973;1(2):76–81, https://doi.org/10.1007/bf01638479. Note the timescale on the x-axis (1880 to 1960): mortality fell from a steady rate of 20-50/1,000 cases to < 1 death per million cases from the mid-1950s.
 
While the effect might be less dramatic in LMICs with limited medical resources (see the final paper by the UK AMR Review in May 2016), all serious infections progress through stages of clinical severity. Inevitably, there is a point at which it doesn’t look so bad, then it’s a bit worse, and then it’s awful, and finally it’s too late. This is obvious on its face from the pathophysiology of disease and is supported by the personal experience of anyone who’s cared for such patients.
 
And it’s here (finally!) that the two papers on parachutes to prevent gravitational injury become relevant. The first (Smith 2003) was a snarky commentary on the desire for an RCT for everything and is included mainly for completeness: “As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials.”
 
It’s the second paper (Yeh 2018) that provides the key message about feasibility and context for RCTs in some situations. In this study, the authors measured the rate of injury or death following a jump from an aircraft (airplane or helicopter) while wearing either a parachute or an empty backpack. The twist was that the jump was from an aircraft that was parked. On the ground. Not moving. Thus (and no surprise), this randomized study of 23 subjects found that:

  • “Parachute use did not reduce death or major traumatic injury when jumping from aircraft in the first randomized evaluation of this intervention.
  • “However, the trial was only able to enroll participants on small stationary aircraft on the ground, suggesting cautious extrapolation to high altitude jumps.”

 
OK … so that’s pretty snarky … but the point is that demonstrations of superiority require a plausible difference in outcomes between the arms. At the same time, we must also always protect study subjects to the maximum extent possible, and so there are limits on plausible designs. Like the parachute study, the circumstances at Banerjee’s study sites were such that it can be seen (in retrospect) that the lack of plausible scope for improvement in most subjects obscured any improvement in the subset of patients who actually could have benefited.
 
And we now need to connect this idea to topic 3…
 
—–
Topic 3: What does all this say about showing superiority outcomes in studies of (i) AST (whether rapid or not) and (ii) antimicrobial agents?
 
Following on from parachutes in Topic 2, we now need to loop back to a perennial question: Why don’t we routinely have randomized superiority data on novel anti-infective agents or AST? And actually, is it even plausible to expect to have such data?
 
Hopefully, you’ll now understand that the answer is “No, not unless something really bad has happened!” Good (and ethical) medical practice in studies of potentially lethal infections demands that we always ensure that we are trying to deliver effective therapy to participants in both arms.
 
With respect to this idea for trials of novel therapies, please review these sources:

  • Nambiar S, Laessig K, Toerner J, Farley J, Cox E. Antibacterial drug development: challenges, recent developments, and future considerations. Clin Pharmacol Ther. 2014;96(2):147–9, doi: 10.1038/clpt.2014.116.  An excellent discussion by five colleagues from FDA of the issues with doing superiority studies.
  • 19 Sep 2020 newsletter: “In praise of non-inferiority” This newsletter, along with its associated YouTube explainer, provides a deep dive into the tension between superiority studies and non-inferiority studies.

 
And for AST (whether rapid or not), the exceptional effort by Banerjee et al. to produce such data is noteworthy and instructive. As discussed in the primary paper and the accompanying editorial, it might be possible to find a subset in which a difference could be shown, but (from Arjun’s editorial):

  • “…trying to focus rapid AST on a subset of patients where it might have clear mortality benefit seems impractical and unnecessary.
  • “Nearly every hospital in the US, and many globally (including all the hospitals in the FAST trial), have antibiotic stewardship programs focused on ensuring that patients receive optimal antibiotic therapy.
  • “If we have a tool that will help antibiotic stewardship programs support clinicians in optimizing therapy faster, an outcome that is consistent across all studies of rapid AST, should we not work toward making that tool available?
  • “The answer from a patient-centric perspective is clearly yes.”

 
—
In summary, our ability to measure the differential impact of more rapid forms of AST is always going to be limited. A difference is certain to exist for patients with rapidly progressive, severe forms of infection but modern therapeutic approaches work to reduce such differences. Further, it just doesn’t make sense to try to triage use of rapid AST as infections that seem mild at the start can progress very rapidly to death.
 
Thus, arguments around use of (rapid) AST will need to be built around economic modeling of the cost and value of different approaches. On that point, see the parallel newsletter entitled “Economic modeling of the value of rapid diagnostics”!
 
Best wishes,

John & Arjun
 
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.
 
Arjun Srinivasan, MD | Deputy Chief Medical Officer, Joint Commission | formerly, Deputy Director, Division of Healthcare Quality Promotion, US CDC | Follow me at linkedin.com/in/arjun-srinivasan-28951b355. All opinions are my own.

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, the small meeting format of BEAM’s AMR Conference (March) and GAMRIC (September-October; formerly, the ESCMID-ASM conference series) creates excellent global networking. IDWeek (October) and ECCMID (April) are much larger meetings but also provide opportunities for networking with a substantial, focused audience via their Pipeline sessions. Hope to see you there!

  • [UPDATED INFO] 22-24 Sep 2026 (Lisbon, Portugal): The 2nd GAMRIC, the Global AMR Innovators Conference (London, UK). Formerly the ESCMID-ASM (or ASM-ESCMID depending on location) Joint Conference on Drug Development for AMR, 2026 will be the 11th year for this series that is now under the joint sponsorship of CARB-X, ESCMID, BEAM Alliance, GARDP, LifeArc, Boston University, and AMR.Solutions. The ongoing series employs the successful format of prior meetings with a single-track meeting and substantial networking time. The 2025 meeting was a sell-out success: a written summary is here and the videos are here. Registration for the 2026 meeting is now open and the near-final program is here: in addition to a keynote lecture by Karen Bush on the threat to beta-lactams due to the emergence of PBP3 mutations, there are sessions on funding, access, program design for narrow-spectrum agents such as phage, development for pediatrics, and more. The main abstract submission window is closed but late-breaker abstracts will be accepted 8-22 July 2026.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026, the annual meeting of the Infectious Diseases Society of America. I would expect the program to continue to provide a substantial opportunity to present a product to a large audience (see also adjacent note about ESCMID) as well as opportunities to present at an IDWeek Pipeline Session.
  • 23-24 Mar 2027 (Basel, Switzerland): The 10th AMR Conference (3-4 Mar 2026) is now over and offered a rich program that included a 10-year retrospective (we’ve done a lot!), regulatory updates, discussions of how to pursue development in China, and much more … in addition to being a superb opportunity for networking! I am told the session videos will soon be available on the conference website.
  • 9-13 April 2027 (Stockholm, Sweden): ESCMID Global 2027, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Details won’t be out for some months, but the website is here. I do know that the meeting schedule will again include a Science Policy Forum on Friday 9 April 2027 (see here the newsletter about the 2026 science policy forum) and all who are interested in Pull incentives and the antibiotic ecosystem should plan to be there!)..

  Upcoming meetings of interest to the AMR community:

  • 4-8 June 2026 (Washington, DC): ASM Microbe, the annual meeting of the American Society for Microbiology. The meeting format is evolving and next year will combine 3 meetings (ASM Health, ASM Applied and Environmental Microbiology, and ASM Mechanism Discovery) into one event. Go here for details.
  • 11-12 Jun 2026 (Washington, DC): The Second Annual Unite for Sepsis Symposium, presented by the Sepsis Alliance. The event seeks to accelerate progress in sepsis research and care. Go here for details and to register.
  • 22-24 Sep 2026 GAMRIC (Lisbon, Portugal), the Global AMR Innovators Conference (London, UK; formerly the ESCMID-ASM Joint Conference on Drug Development for AMR). See list of Top Recurring meetings, above..
  • [REGISTRATION IS OPEN] 10-18 Oct 2026 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2026 will be the 10th year for this program. Patrice Courvalin orchestrates content 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! Registration for 2026 is now open and runs through June 21, 2026. Go here to register!
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026. See list of Top Recurring meetings, above.
  • 10-13 November 2026 (Madrid, Spain): The International Society for Infectious Diseases (ISID) has announced its 21st International Congress on Infectious Diseases (ICID). Register and view the preliminary program here (Early bird closes 30 July 2026); abstract deadline is 28 April 2026.
  • 23-24 Mar 2027 (Basel, Switzerland): The 11th AMR Conference sponsored by the BEAM Alliance. See list of Top Recurring meetings, above.
  • 9-13 April 2027 (Stockholm, Sweden): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • ??? Mar 2028 (yes, that’s 2028, with location TBD): The 2028 Gordon Research Conference (GRC, https://www.grc.org/) entitled “Antibacterials of Tomorrow to Combat the Global Threat of Antimicrobial Resistance” and its related Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers will be sometime in March 2028. The organizers hope to coordinate dates and location with the 2028 BEAM-AMR meeting. Details to follow — mark your calendar!

Self-paced courses, online training materials, and other reference materials:

Current funding opportunities

  • CARB-X have had one funding round (8-22 April 2026); a further round is expected during 4Q 2026. There are 4 funding themes for these rounds as below.
    • Direct-acting therapeutics for infections caused by Gram-negative bacteria
    • Novel Chemistry for AMR Challenge – target-based therapeutics.
    • Non-vaccine approaches to prevent neonatal sepsis
    • Diagnostics for neonatal sepsis
  • The Horizon Europe Work Programme 2026-2027 includes at least 3 calls of interest within its Cluster 1 — see the list below.  The application window starts 10 Feb 2026 and closes on 16 Apr 2026. See also the 12 Dec 2025 newsletter about the call. Note as well that there calls for agents to prevent and/or treat viral infections.
    • HORIZON-HLTH-2027-01-DISEASE-08: Development of innovative antimicrobials against pathogens resistant to antimicrobials
    • HORIZON-HLTH-2027-02-IND-02: Portable point-of-care diagnostics
    • HORIZON-HLTH-2026-01-DISEASE-03:Advancing research on the prevention, diagnosis, and management of post-infection long-term conditions. 
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • 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.
  • 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
    • 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. See also the 7 Feb 2026 newsletter (“The global funding pipeline, 2017-2023: A review”) about an excellent deep dive by the Hub team into patterns of funding over time.
    • Antimicrobial Resistance Research and Innovation in Australia is an actively updated summary that covers Australia’s AMR research and patent landscape. It is provided via collaboration between The Lens (an ambitious project seeking to discover, analyse, and map global innovation knowledge) and CSIRO (Commonwealth Scientific and Industrial Research Organisation, an Australian Government agency responsible for scientific research). Lots to explore here!
    • 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).
]]> Economic modeling of the value of rapid diagnostics https://amr.solutions/2026/05/27/economic-modeling-of-the-value-of-rapid-diagnostics/ Wed, 27 May 2026 21:11:11 +0000 https://amr.solutions/?p=25519

Dear All (and again with thanks to Arjun Srinivasan for co-authoring this pair of newsletters):

In parallel with the newsletter discussing a recent paper on the impact of rapid antimicrobial susceptibility testing (27 May 2026 newsletter, “Limits on measuring the impact of rapid AST”), we have release of an exceptionally well-done classic economic approach showing that rapid diagnostics rapid could save thousands of lives per year and hundreds of millions of dollars in health care savings in the G7. The comprehensive economic analysis goes beyond AST devices to cover both diagnostics that (i) identify the pathogen and/or (ii) provide AST data. Here are the links you need:

  • (the report itself) Hassan S, Hamlyn T, Fong H, Hampson G. 2026. The Value of Fast Diagnostics in Time-Critical Infections. OHE Contract Research Report, London: Office of Health Economics. Available at: https://www.ohe.org/publications/the-value-of-fast-diagnostics-in-time-critical-infections/
  • (related press release) “First-of-its-Kind Health Economic Analysis Shows Early Use of Fast Diagnostics in Sepsis Care Could Save Thousands of Lives and Reduce Health System Costs Across G7 Countries.” Available at https://www.biomerieux.com/us/en/journalists/press-releases/health-economic-analysis-sepsis-g7.html
    • As the press release makes clear, the study was sponsored by Biomérieux. But, the analysis is not specific to their products — rather the results would apply to any tools in the general category of rapid tests for either organism identification or susceptibility testing.
  • And these two for context:
    • 18 Jun 2025 newsletter, “Extending STEDI to diagnostics: STRIDES”:  We’ll mention this again below as an example of ongoing work that will build on the ideas in the OHE report.
    • 9 Apr 2026 newsletter: “GO-Dx: Global One Health Diagnostics Access Compact”: And, this newsletter discusses an industry-wide approach to ensuring that diagnostics, the cornerstones of both surveillance and proper antibiotic utilization, are accessible and utilized

In brief, this report uses a decision tree-based analysis to estimate outcomes for adults with bloodstream infections where are at high risk of progressing to sepsis. Note that the timeframe for the analysis is 13 months: 1 month of hospitalization and then a 1-year follow-up period:

OHE analysis of the impact of rapid diagnostics, model flow chart

Source: Figure 1 from the OHE paper.

The modeling considers differences in clinical outcomes and cost for rapid diagnostics vs. current standard of care (SOC) tools for diagnosis and AST for these at-risk patients based on these assumptions regarding the difference in time for these tools:

OHE analysis of the impact of rapid diagnostics, model flow chart

Source: Figure 2 from the OHE paper based on data from Peri AM et al. (BMC ID 2022, doi: 10.1186/s12879-022-07772-x), Schifman RB et al. (Arch Pathology Lab Med 2015, doi: 10.5858/arpa.2014-0258-CP), Yuceel-Timur I et al. (JAC 2024, 10.1093/jac/dkae280), and Caspar Y et al. (Eur J Clin Micro ID, 2024, doi: 10.1007/s10096-024-04820-z).

To make the analysis concrete in economic terms, the analysis focuses on data for 7 countries (Canada, France, Germany, Italy, Japan, UK, and USA). The potential for both clinical impact and health care savings was substantial. Shown here are the results for Japan and US:

OHE, QALY and dollar value of rapid diagnostics in Japan and the US

At left (Figure 4 from the OHE paper), we have population-level estimates of the number of QALYs gained (top-bar, light blue) and then the # of patients in whom a long-term consequence of sepsis is avoided (“averted LTC”, see list of LTCs in the decision tree figure, above)), # of averted deaths, and finally # of averted cases of sepsis. At right (Figure 5), we have a cost-savings estimate both at the population level (green gar) and per patient (orange line).
 
Overall, rapid identification and AST devices were predicted to have costs savings ranging from EUR 500/patient (Canada) to EUR 3,800/patient (Japan). When scaled up to the population level, annual national savings were predicted to range from EUR 26m (Canada) to EUR 2.5b (United States). The authors explain that:

  • “The improvements are achieved through shortening time to appropriate treatment and reducing the number of BSI patients progressing to sepsis and septic shock.
  • “In the longer term, fewer patients are projected to experience long-term complications related to sepsis, resulting in further savings in readmission and long-term management of these conditions.” 

The results were consistent across the 7 countries but (no surprise) differed in magnitude due to:

  • Differences in sepsis progression rates (higher in Japan due to an older population)
  • Differences in costs of acute care avoided (greater in the United States)
  • Differences in the size of the high‑risk BSI population.
  • Differences in how sepsis and BSI cases are coded in national databases.

 
Impressive! As discussed in the companion newsletter (the 27 May 2026 Banerjee paper newsletter entitled “Limits on measuring the impact of rapid antimicrobial susceptibility testing (AST)”), this type of modeling is going to be our best approach to estimating the value of improved identification and AST systems as it is not reasonable to expect to be able to measure these differences in clinical trials for the reasons discussed in the companion newsletter.
 
And this is certainly a springboard for future work. Think about the kind of papers we now have on the economics of AMR in general:

  • 29 Nov 2022: “Impact of PASTEUR: 9.9m lives saved, ROI of 125:1”
  • 8 Dec 2022: “Lives saved + ROI of PASTEUR-like pull in Canada, UK, EU, Japan!”
  • 27 Sep 2024: “Without action, AMR costs go from $66b to $159b/yr by 2050”
  • 14 Aug 2025: “$ Impact of AMR in your country: Interactive web tool!”

 
We’re already starting to see bridging from therapeutics to diagnostics with the work on STRIDES (18 Jun 2025, “Extending STEDI to diagnostics: STRIDES”) and as well the recent conversation on the value of diagnostics during last year’s Panmure House workshop (17 Feb 2026 newsletter).  We certainly look forward to more of this type of work in future. Well done to the team at OHE for organizing such an exhaustive analysis!
 
Best wishes,
 
John & Arjun
 
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.
 
Arjun Srinivasan, MD | Deputy Chief Medical Officer, Joint Commission | formerly, Deputy Director, Division of Healthcare Quality Promotion, US CDC | Follow me at linkedin.com/in/arjun-srinivasan-28951b355. All opinions are my own.

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, the small meeting format of BEAM’s AMR Conference (March) and GAMRIC (September-October; formerly, the ESCMID-ASM conference series) creates excellent global networking. IDWeek (October) and ECCMID (April) are much larger meetings but also provide opportunities for networking with a substantial, focused audience via their Pipeline sessions. Hope to see you there!

  • [UPDATED INFO] 22-24 Sep 2026 (Lisbon, Portugal): The 2nd GAMRIC, the Global AMR Innovators Conference (London, UK). Formerly the ESCMID-ASM (or ASM-ESCMID depending on location) Joint Conference on Drug Development for AMR, 2026 will be the 11th year for this series that is now under the joint sponsorship of CARB-X, ESCMID, BEAM Alliance, GARDP, LifeArc, Boston University, and AMR.Solutions. The ongoing series employs the successful format of prior meetings with a single-track meeting and substantial networking time. The 2025 meeting was a sell-out success: a written summary is here and the videos are here. Registration for the 2026 meeting is now open and the near-final program is here: in addition to a keynote lecture by Karen Bush on the threat to beta-lactams due to the emergence of PBP3 mutations, there are sessions on funding, access, program design for narrow-spectrum agents such as phage, development for pediatrics, and more. The main abstract submission window is closed but late-breaker abstracts will be accepted 8-22 July 2026.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026, the annual meeting of the Infectious Diseases Society of America. I would expect the program to continue to provide a substantial opportunity to present a product to a large audience (see also adjacent note about ESCMID) as well as opportunities to present at an IDWeek Pipeline Session.
  • 23-24 Mar 2027 (Basel, Switzerland): The 10th AMR Conference (3-4 Mar 2026) is now over and offered a rich program that included a 10-year retrospective (we’ve done a lot!), regulatory updates, discussions of how to pursue development in China, and much more … in addition to being a superb opportunity for networking! I am told the session videos will soon be available on the conference website.
  • 9-13 April 2027 (Stockholm, Sweden): ESCMID Global 2027, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Details won’t be out for some months, but the website is here. I do know that the meeting schedule will again include a Science Policy Forum on Friday 9 April 2027 (see here the newsletter about the 2026 science policy forum) and all who are interested in Pull incentives and the antibiotic ecosystem should plan to be there!)..

  Upcoming meetings of interest to the AMR community:

  • 4-8 June 2026 (Washington, DC): ASM Microbe, the annual meeting of the American Society for Microbiology. The meeting format is evolving and next year will combine 3 meetings (ASM Health, ASM Applied and Environmental Microbiology, and ASM Mechanism Discovery) into one event. Go here for details.
  • 11-12 Jun 2026 (Washington, DC): The Second Annual Unite for Sepsis Symposium, presented by the Sepsis Alliance. The event seeks to accelerate progress in sepsis research and care. Go here for details and to register.
  • 22-24 Sep 2026 GAMRIC (Lisbon, Portugal), the Global AMR Innovators Conference (London, UK; formerly the ESCMID-ASM Joint Conference on Drug Development for AMR). See list of Top Recurring meetings, above..
  • [REGISTRATION IS OPEN] 10-18 Oct 2026 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2026 will be the 10th year for this program. Patrice Courvalin orchestrates content 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! Registration for 2026 is now open and runs through June 21, 2026. Go here to register!
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026. See list of Top Recurring meetings, above.
  • 10-13 November 2026 (Madrid, Spain): The International Society for Infectious Diseases (ISID) has announced its 21st International Congress on Infectious Diseases (ICID). Register and view the preliminary program here (Early bird closes 30 July 2026); abstract deadline is 28 April 2026.
  • 23-24 Mar 2027 (Basel, Switzerland): The 11th AMR Conference sponsored by the BEAM Alliance. See list of Top Recurring meetings, above.
  • 9-13 April 2027 (Stockholm, Sweden): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • ??? Mar 2028 (yes, that’s 2028, with location TBD): The 2028 Gordon Research Conference (GRC, https://www.grc.org/) entitled “Antibacterials of Tomorrow to Combat the Global Threat of Antimicrobial Resistance” and its related Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers will be sometime in March 2028. The organizers hope to coordinate dates and location with the 2028 BEAM-AMR meeting. Details to follow — mark your calendar!

Self-paced courses, online training materials, and other reference materials:

Current funding opportunities

  • CARB-X have had one funding round (8-22 April 2026); a further round is expected during 4Q 2026. There are 4 funding themes for these rounds as below.
    • Direct-acting therapeutics for infections caused by Gram-negative bacteria
    • Novel Chemistry for AMR Challenge – target-based therapeutics.
    • Non-vaccine approaches to prevent neonatal sepsis
    • Diagnostics for neonatal sepsis
  • The Horizon Europe Work Programme 2026-2027 includes at least 3 calls of interest within its Cluster 1 — see the list below.  The application window starts 10 Feb 2026 and closes on 16 Apr 2026. See also the 12 Dec 2025 newsletter about the call. Note as well that there calls for agents to prevent and/or treat viral infections.
    • HORIZON-HLTH-2027-01-DISEASE-08: Development of innovative antimicrobials against pathogens resistant to antimicrobials
    • HORIZON-HLTH-2027-02-IND-02: Portable point-of-care diagnostics
    • HORIZON-HLTH-2026-01-DISEASE-03:Advancing research on the prevention, diagnosis, and management of post-infection long-term conditions. 
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • 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.
  • 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
    • 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. See also the 7 Feb 2026 newsletter (“The global funding pipeline, 2017-2023: A review”) about an excellent deep dive by the Hub team into patterns of funding over time.
    • Antimicrobial Resistance Research and Innovation in Australia is an actively updated summary that covers Australia’s AMR research and patent landscape. It is provided via collaboration between The Lens (an ambitious project seeking to discover, analyse, and map global innovation knowledge) and CSIRO (Commonwealth Scientific and Industrial Research Organisation, an Australian Government agency responsible for scientific research). Lots to explore here!
    • 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).
]]> In Praise of Non-Inferiority https://amr.solutions/2020/09/19/in-praise-of-non-inferiority/ Sat, 19 Sep 2020 17:00:13 +0000 https://13.43.35.2/?p=3484

Dear All (wonkish but intended for everybody to read and absorb):

27 Jan 2021 update: This topic now has its own YouTube video! As the ideas here are VERY confusing, I suggest you make the time to watch the video, read the newsletter, and then watch the video one more time. I have yet to find a short, simple way to explain this but I’ll keep trying!

8 July 2025 further update: Since the 2021 update, there have been guidance documents from FDA and EMA on antibacterial development that included good discussions of non-inferiority trials. Start with the 8 July 2025 newsletter and read backwards.

There’s been a lot of recent discussion about “lessons learned from COVID-19.” Indeed, there are many valuable points: global cooperation, preparedness, supply chains, and so forth. As an example, I note the 17 Sep 2020 communique from the G20 Health Ministers (link): it was heavily focused on COVID-19 but it did note the need to deliver on “previous G20 commitments to tackle antimicrobial resistance.” All good stuff!

Among these important ideas, I would like to draw out today the lesson learned from COVID-19 about the importance of non-inferiority (NI) trials as tools for developing new antimicrobial agents of all types (antibacterial, antiviral, etc.) in advance of widespread need.

Unless otherwise cited, the text below draws from two papers that I co-authored in 2017 and 2019 (link and link, see full cites below my signature). In outline, there are five key ideas:

  1. There are two types of trials: Superiority and non-inferiority (NI)
  2. Infections can be lethal: Placebo is a bad idea!
  3. Antibiotics are best developed before we need them!
  4. NI trials are the public good that allows us to avoid COVID-19-like situations.
  5. Superiority efficacy is (hopefully) unattainable, but superior utility is possible.

1) There are two kinds of clinical trials: All pharmaceutical products must (a) show which individuals can benefit from the product, (b) demonstrate a way to identify those individuals, and (c) document the benefit received from the product. Clear answers to these questions are required for product approval and acceptance. To achieve this, one of two types of trial designs can be used:

  • In a superiority trial, the goal is to show that NEW is measurably superior to EXISTING or to a placebo.
  • In a non-inferiority (NI) trial (sometimes formerly referred to as an “equivalence trial”), the goal is to show that NEW has efficacy similar (within the bounds of a pre-specified non-inferiority margin) to that of EXISTING.

2) Infections can be lethal: From a public health perspective, new antimicrobial agents with an improved microbiologic spectrum of activity should be developed before widespread bacterial resistance emerges. This desire leads immediately, however, to a paradox: although it is easy to demonstrate that a novel test agent has an improved spectrum both in vitro and in preclinical animal infection models, rigorous demonstrations of the NEW agent’s superior clinical efficacy over EXISTING drugs both are and should be difficult to implement on a routine basis in trials of human infections:

  • Infections move quickly and can be fatal! As inadequately treated acute infections can be rapidly fatal and enrollment into a trial must often be undertaken empirically before culture results are known, it is obviously desirable that the control arm be predicted to be efficacious in all studies, including studies of potentially superior new agents.
  • We always seek to give effective therapy to all patients! Indeed, if resistance is known or suspected to the control arm, then the control arm should always be adapted to offer some form of best available therapy that is predicted to be efficacious. In short, it is important from an ethical viewpoint that the trial make every attempt to use an efficacious control and not anticipate showing superiority relative to an ineffective or substandard control.

3) The time to develop new antimicrobial agents is before we need them: When we lack ANY effective therapies, placebo-controlled trials are possible … at least in theory:

  • COVID-19 highlights the only exception to the prior rule! The only exception to the above-noted ethical imperative would be if there were either no efficacious options whatsoever for the infecting strain (or if all forms of best available therapy were meaningfully suboptimal). It is of course obvious that such a situation would imply a situation with grim public health implications.
  • For (fatal!) infections, study enrollment is made challenging by both (i) the impact of infection control efforts and (ii) the desire to avoid placebo (link): Again COVID-19 has shown us that trials may not run as quickly as you’d expect. If local control measures are able to reduce the spread of the target infection (good for the community!), infected patients can become hard to find (bad for the study!). And the desire to be treated with something (anything!) can overwhelm the ability to enroll even in properly designed and ethical trials.
  • And once you definitively have an effective therapy, the rules change! The window of opportunity to reliably design trials to show superiority because of a complete lack of therapeutic options would close with emergence of a new efficacious therapy. Would you be willing to be randomized to placebo if you were in the ICU with COVID-19?

4) NI trials are a public good: By using NI trials to develop new antibiotics in advance of the (next) pandemic, we can save lives and avoid panic. Think about how different the world would be right now if we (as a global community) had substantially completed the development a few years ago of one or more therapies and vaccines for the coronaviridae (SARS, COVID-19, etc.) based on measures of immune response and perhaps even controlled human infection models (CHIMs, link to NEJM editorial on this approach).

5) Superior utility is possible: Although superior efficacy is thus hopefully something we rarely see, superior utility is entirely possible. Oral rather than IV? Shorter course of therapy? Fewer associated side-effects? Better taste in a pediatric formulation? All of these are entirely possible and could be pursued — the only thing that is off the table is superior efficacy. Indeed, the ARLG (Antibiotic Resistance Leadership Group) is pursuing studies of this type based on the Desirability Of Outcome Ranking (DOOR) suggested by Scott Evans and colleagues (link).

—
There we have the lesson of COVID-19: Antibiotics are the #FireExtinguishersOfMedicine and need to be developed, purchased, and installed in our pharmacies around the world before the fire breaks out. NI studies give us the opportunity to make this happen – provided we are willing to pay for them in advance (and that’s a topic for another day).

In praise of non-inferiority!

Best wishes, John

Key papers:

  • Nambiar S, Laessig K, Toerner J, Farley J, Cox E. Antibacterial drug development: challenges, recent developments, and future considerations. Clin Pharmacol Ther. 2014;96(2):147–9, doi: 10.1038/clpt.2014.116.  An excellent discussion by colleagues at the FDA of the issues with doing superiority studies for antimicrobial agents.
  • 26 May 2017 newsletter: Rex JH, Talbot GH, Goldberger MJ, Eisenstein BI, Echols RM, Tomayko JF, Dudley MN, and Dane A. Progress in the fight against multidrug-resistant bacteria 2005-2016: Modern non-inferiority trial designs enable antibiotic development in advance of epidemic bacterial resistance. Clinical Infectious Diseases. 2017;65:141-6.
  • 6 Aug 2019 newsletter: Rex JH, Fernandez Lynch H, Cohen IG, Darrow JJ, Outterson K. Designing development programs for non-traditional antibacterial agents. Nature Communications. 2019;10(1):3416.

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.

Current funding opportunities (most current list is here):

  • Novo REPAIR Impact Fund closed its most recent round on 31 Jul 2020. Go here for current details.
  • 2020 funding rounds for CARB-X have not been announced.
  • The Global AMR R&D Hub’s dynamic dashboard (link) summarizes funders and projects by geography, stage, and more.
  • It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
  • You might also be interested in the most current lists of R&D incentives (link) and priority pathogens (link)


Upcoming meetings of interest to the AMR community (most current list is here):

  • (it’s over now, but you can still watch it!) 24-28 Aug 2020 BEAM Alliance-sponsored AMR Conference. Go here to access the recorded sessions. This was a very, very good meeting! In particular, please note these two sessions from the final day … both are free on YouTube:
    • “Spotlight on UK | The Investor Action on AMR” (link). Chaired by Louise Norton-Smith (Head of Global AMR Strategy & Delivery, UK Dept of Health) with a key note by Dame Sally Davies (UK Special Envoy on AMR) in which we learn why we should #SaveTheLobster (see notes in this newsletter).
    • “The future of AMR – How a new post COVID19 policy roadmap could look like” (link). Chaired by Marc Gitzinger (CEO BioVersys and VP of BEAM Alliance, the core sponsor of the AMR Conference), this session has speakers from the Government of India (Renu Swarup), the UK (Dame Sally), FIND (a global non-profit focused on diagnostics), EU Parliament (Tiemo Woelken, MEP), and the US (Evan Loh, CEO Paratek and Chair of the Antimicrobial Working Group).
  • [Registration link now posted] 24 Sep (online, 9-10.30a EST): webinar chaired by Dame Sally entitled “The global movement of microorganisms:  Tracking the spread of difficult-to-treat infections”, from a 4-part series sponsored by Wellcome Trust entitled “AMR in the Light of COVID-19 Webinar Series; From hypothetical to reality: How COVID-19 foretells a world without antibiotics.” Go here to register. Really unfortunate overlap with the next meeting, but both are being recorded … you’ll have to pick one to attend live and the other for replay!
  • 24 Sep 2020 (online, 15.30-17.30 CEST; 9.30-11.30a EST; 7-9p IST): Antibiotic Bootcamp Series webinar entitled “Moving from preclinical to clinical-stage: Challenges and opportunities.” Moderated by Erin Duffy (CARB-X), this webinar is jointly sponsored by GARDP, CARB-X, Novo REPAIR, JPIAMR, Wellcome Trust, ASM, and ESCMID. Since we can’t the ASM-ESCMID meeting, we’re still going to have the bootcamps! Go here to register.
  • 24 Sep 2020 (online, 17.15-18.15 CEST): ECCVID (ESCMID Conference on Coronavirus Disease) includes an AMR-focused symposium entitled “Antimicrobial resistance and COVID-19: learning policy lessons from one another” featuring Christine Ardal (Norway), Chantal Morel (Switzerland), and Kevin Outterson (US). You have to dig a bit in the online program to find this one, but it’s there! Go here to register.
  • 25 Sep 2020 (online, 9a-5p EST): FDA Workshop entitled “Addressing Challenges in Inhaled Antifungal Drug Development.” Go here to register.
  • 30 Sep 2020 (online, 2pm BST): Longitude Prize Sprint Workshop 2 entitled “Building Medtech Companies: Learn how to attract investment to fund product development and scale your company.” Details and registration are here.
  • 2 Oct 2020 (online meeting): 7th annual Boston Area Antimicrobial Research Network (BAARN) meeting. Go here for details.
  • 21-25 Oct 2020 (online meeting), IDWeek 2020. Go here for details.
  • 26-29 Oct 2020 (online meeting), Annual ESPID meeting (European Society for Pediatric ID, #38)
  • [NEW] 27 Oct 2020 (online, 9a-5p EST): FDA Workshop entitled “Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.” Go here to register.
  • 27 Oct 2020 (online meeting), BARDA Industry Day, a discussion of U.S. Government medical countermeasure priorities. Mark your calendar now and watch this website for details.
  • 9-12 Jul 2021 (Vienna): Annual ECCMID meeting (#31)
  • 18-21 May 2021 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
  • 20-24 June 2021 (Toronto): International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-12). Go here for details.
  • 3-7 Jun 2021 (Anaheim), ASM Microbe 2021. Go here for details.
  • 27 Jun-2 Jul 2021 (Ventura, CA): Gordon Research Conference entitled “Antimicrobial Peptides”. Go here for details, go here for the linked 26-27 Jun Gordon Research Seminar that precedes it.
  • 5-21 Aug 2021 (Marine Biology Laboratory, Woods Hole, MA): Residential course entitled “Molecular Mycology: Current Approaches to Fungal Pathogenesis.” This 2-week intensive training program has run annually for many years and gets outstanding reviews. Go here for details.
  • 8-11 Oct 2021 (Aberdeen, Scotland): 10th Trends in Medical Mycology. Go here for details.
  • 16-24 Oct 2021 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics, antibiotic resistance, and antibiotic R&D. The course is very intense, very detailed, and gets rave reviews. Registration is here and is limited to 40 students.
  • 6-11 Mar 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.
]]> Anti-Gram-negative beta-lactams in jeopardy: The rise of PBP3 mutations https://amr.solutions/2026/04/16/anti-gram-negative-beta-lactams-in-jeopardy-the-rise-of-pbp3-mutations/ Thu, 16 Apr 2026 08:47:42 +0000 https://amr.solutions/?p=25398

Dear All (and with thanks to Robert Bonomo and Patricia Bradford for guiding me on this newsletter; anything that’s correct is due to Patricia and Robert; all the mistakes are mine!),
 
This wonkish note has a short, simple version above my signature and then a longer version below by signature. The beta-lactam / beta-lactamase wizards will have to forgive the simplifications!
 
The basic plot for this note is that an emerging form of resistance in Gram-negative bacteria (PBP3 mutations) threatens our limited pool of BL-BLI (beta-lactam — beta-lactamase inhibitor) combinations that are active in the presence of metallo-beta-lactamases (MBLs). 
 
This problem was exemplified most recently in Fabrizio 2026 (and discussed further in Stellfox 2026). These papers discuss a clinical report of infection due to an E. coli strain which was carrying (i) serine-beta-lactamases, (ii) MBLs, (iii) a PBP3 mutation, and (iv) a mutation in the iron uptake system.
 
Here’s the short, simple version:

  1. A Gram-negative bacterium can become effectively resistant to (almost) all current BL-BLI combinations by carrying the triad of:
    1. Serine beta-lactamases
    2. Metallo beta-lactamases
    3. A mutation in PBP3 (the target of many of the beta-lactams)
  2. If you are both lucky and clever (as shown in Fabrizio 2026), it might be possible to design a drug combination that sidesteps the specific set of beta-lactamases and PBP mutations carried by a given organism.
  3. But, it would also be possible to envision situations in which all beta-lactams (and beta-lactam combinations) are rendered ineffective.

 
It’s the last point that is scary— if we see progressive emergence of PBP3 mutations in combination with MBLs, we’ll be increasingly in the land of DTR resistance (difficult to treat resistance, see the 25 Apr 2025 newsletter, “Evolving the idea of DTR to include antibiotic access”) and thus pushed into increased reliance on other, more difficult to use classes (e.g., the aminoglycosides).
 
Yow! The net action points for the community would be that (i) we should all be aware of this problem and (ii) we need to support programs advancing non-beta-lactam candidate antibiotics. We have so very few of these in the pipeline (see the 4 Oct 2025 newsletter, “WHO: Reviews of antibacterial therapeutics and diagnostics”) — we need more!
 
All best wishes, John, Patricia, and Robert
 
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.
 
Patricia Bradford, PhD | Antimicrobial Development Specialists, LLC |  pbradford@antimicrobialdev.com All opinions are my own.
 
Robert A. Bonomo, MD |Cleveland VA and Case Western Reserve University School of Medicine | Robert.Bonomo@va.gov | All opinions are my own.
 
Longer version (references are below):

  1. Beta-lactam antibiotics (collectively, the penicillins, cephalosporins, carbapenems, and monobactams) work by binding to PBPs (Penicillin-Binding Proteins)
    1. PBPs build and maintain the bacterial cell wall.
    2. By binding (and inhibiting) PBPs, the beta-lactams can kill bacteria.
  2. Resistance to beta-lactams has 4 main mechanisms:
    1. Beta-lactamase production: Enzymes that destroy beta-lactams
    2. Reduced permeability (entry) of beta-lactams into the bacteria
    3. Mutations in PBPs, the target of the beta-lactam (more on them below)
    4. Efflux: Various pumps such as MexAB-OprM (notorious in Pseudomonas aeruginosa) and AdeABC (in Acinetobacter spp.)
  3. Far and away the most important mechanism in Gram-negative bacteria is production of beta-lactamases (BLases)
    1. You can block BLases with a beta-lactamase inhibitor (BLI), thus protecting the BL.
    2. Adding a BLI to a BL has been an outstanding strategy for a very long time!
    3. We have LOTS of BL-BLI (beta-lactam + beta-lactamase-inhibitor) combinations … and many more are in the pipeline.
  4. There are two major groups of BLases: the serine BLases and MBLs
    1. These two groups differ greatly in the catalytic site of the enzyme, which results in difficulty in designing a single BLI molecule that would inhibit both types.
  5. About the serine-BLases:
    1. These are the most common and we have lots of BLIs for them.
    2. We had a big setback some years ago with the emergence of serine BLases (e.g., KPC) that could destroy the carbapenems (i.e., the carbapenemases) but that were not inhibited by the original series of BLIs that were based on the b-lactam structure (clavulanate, sulbactam, tazobactam).
    3. Helpfully, we had a substantial advance in serine BLI technology with the introduction of serine BLIs (avibactam, relebactam, vaborbactam, and their successors) that can block the carbapenemases.
  6. About the MBLs (e.g., NDM, VIM, IMP, and others):
    1. These are now seen with increasing frequency.
    2. We do not yet have any licensed BLIs for MBLs, however there are several in development.
  7. As an alternative to a BLI for MBLs, we’ve been relying on aztreonam, a monobactam)
    1. Monobactams are susceptible to serine-BLases (ESBLs) but are resistant to hydrolysis by the MBLs
    2. Aztreonam is the only widely available monobactam.
    3. Combined with a serine-active BLI to protect monobactam, you have a combination that works — and to fill this need, aztreonam-avibactam has now been developed and approved.
  8. But, we’re now seeing emergence of a mutation in PBP3 that creates monobactam and beta-lactam resistance
    1. Note that we’ve long seen PBP mutations in Gram-positive bacteria (e.g., Staphylococcus aureus becomes MRSA due to a PBP2a, a mutant form of PBP2) and N. gonorrhoeae.
    2. What’s new is that we’re now seeing an increase in PBP mutations in Gram-negative bacteria
  9. Each bacterial species has a number of PBPs (PBP1, PBP2, PBP3, etc.) that are designated based on size and differ in function. The key points for today are that:
    1. Cephalosporins and the “high-end” penicillins (those that act against Pseudomonas) act by binding to PBP1 and PBP3.
    2. The monobactams (aztreonam) act entirely by binding to PBP3.
    3. Mecillinam/amdinocillin binds exclusively to PBP2.
    4. Finally, the carbapenems are relatively omnivorous: they act by binding to PBP1, PBP2, and PBP3.
    5. And as you would guess, drugs that bind only 1 PBP are at risk for resistance to that target.
  10. Mutations in PBP3 have been associated with resistance to cefiderocol and newer BL-BLIs
    1. PBP3 is mutated by a four amino-acid insertion sequence that makes the binding site constricted so that it no longer permits beta-lactam entry except for the small carbapenems. This was first described in laboratory selected mutants during the development of aztreonam-avibactam (Alm 2015, see reference list).
    2. In the E. coli strain with the YRIN insertion described by Fabrizio 2026, molecular dynamic simulations suggested that the active site became more constricted allowing imipenem to “fit” but not ceftazidime or cefiderocol. The YRIN insertion also interacted with another region of the PBP (neighboring beta-strand) also narrowing/constraining the opening of the active site.
      1. As an aside, it is remarkable that molecular modeling done by Pymol (Alm 2015), SWISS-MODEL (Fabrizio 2026), and Discovery Studio (Fabrizio 2026 again) came to the same overall conclusion.
    3. Although cephalosporins bind both PBP1 and PBP3, the removal of activity against PBP3 greatly reduces the activity against that strain.
    4. This resistance mechanism has been increasing in frequency since the approval and widespread use of cefiderocol (Sadek 2025 and Fabrizio 2026, just to name a few of the papers on this topic).
  11. So, now you see the problem: Any single drug or BLI-BLI combination that is designed to overcome multiple resistance mechanisms may become ineffective when the resistance mechanisms combine forces. For example, in the case presented by Fabrizio et al:
    1. The isolate had two beta-lactamases: NDM-5 (MBL) and CMY-148 (serine AmpC-type), rendering it resistant to all beta-lactams except aztreonam and cefiderocol.
    2. The isolate had YIRN mutation in PBP-3, which blocked the activity of aztreonam.
    3. The isolate had a mutation in CirA (iron uptake system), which resulted in resistance to cefiderocol (and the PBP3 mutation may also contribute).
    4. Eeeek!

 
Repeating the conclusion from the short summary: The net action points for the community would be that (i) we should all be aware of this problem and (ii) we need to support programs advancing non-beta-lactam candidate antibiotics. We have so very few of these in the pipeline (see the 4 Oct 2025 newsletter, “WHO: Reviews of antibacterial therapeutics and diagnostics”) — we need more!
 
References

  1. Alm, RA, Johnstone MR, Lahiri SD: Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam/avibactam: role of a novel insertion in PBP3, J Antimicrob Chemother, 2015;70:1420–1428, https://doi.org/10.1093/jac/dku568
  2. Bush K, Bradford PA. β-Lactams and β-Lactamase Inhibitors: An Overview. Cold Spring Harbor Perspectives in Medicine. 2016;6(8):a025247. https://doi.org/10.1101/cshperspect.a025247
  3. Fabrizio C, Valzano F, Giuliano S, Morelli E, Serio D, Buccoliero GB, et al. Optimizing target inactivation to treat multidrug-resistant Escherichia coli with NDM and PBP3 mutations: “going the extra mile”. Antimicrobial Agents Chemotherapy. 2026:e0088725. https://doi.org/10.1128/aac.00887-25
  4. Mora-Ochomogo M, Lohans CT. β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates. RSC Med Chem. 2021;12(10):1623–39. https://doi.org/10.1039/D1MD00200G
  5. Pallotta R, Samuel L. Aitken PMPHB. NDM-Producing E coli Harboring PBP Insert Variants Emerges as New Threat. ContagionLive. 2024;09 (02).
  6. Sadek M, Duran JB, Chakraborty T, Poirel L, NARA Network; Nordmann P: Combined resistance mechanisms leading to high-level of cefiderocol resistance among NDM-like producing E. coli ST167 clinical isolates. Eur J Clin Microbiol Infect Dis. 2025; 44:2059-2066. https://doi.org/10.1007/s10096-025-05166-w.
  7. Sartori M, Toppo S, Lavezzo E. Molecular resistance mechanisms to newly approved antibiotics (2017-2025) in WHO priority pathogens. Frontiers in microbiology. 2025;16:1719798. https://doi.org/10.3389/fmicb.2025.1719798
  8. Stellfox ME, Doi Y. Case Commentary: When one target is not enough-PBP3 insertions and target redundancy in Escherichia coli. Antimicrob Agents Chemother. 2026:e0005326. https://doi.org/10.1128/aac.00053-26

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, the small meeting format of BEAM’s AMR Conference (March) and GAMRIC (September-October; formerly, the ESCMID-ASM conference series) creates excellent global networking. IDWeek (October) and ECCMID (April) are much larger meetings but also provide opportunities for networking with a substantial, focused audience via their Pipeline sessions. Hope to see you there!

  • 17-21 April 2026 (Munich, Germany): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. You can go here to register and view the program.The meeting schedule will again includes a Science Policy Forum on Friday afternoon (all who are interested in Pull incentives should be there!) and an innovation-focused Pipeline Monday.
  • 22-24 Sep 2026 (Lisbon, Portugal): The 2nd GAMRIC, the Global AMR Innovators Conference (London, UK). Formerly the ESCMID-ASM (or ASM-ESCMID depending on location) Joint Conference on Drug Development for AMR, 2026 will be the 11th year for this series that is now under the joint sponsorship of CARB-X, ESCMID, BEAM Alliance, GARDP, LifeArc, Boston University, and AMR.Solutions. The ongoing series employs the successful format of prior meetings with a single-track meeting and substantial networking time. The 2025 meeting was a sell-out success! A written summary of the 2025 meeting is here and the videos from the sessions are now available here. Registration for the 2026 meeting is now open and you can view the preliminary program here. Abstract submissions are open through Fri 10 Apr at noon CET; note as well that travel grants are available for attendees with accepted abstracts. A late-breaker window be announced for July.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026, the annual meeting of the Infectious Diseases Society of America. Details are not yet available but I would expect the program to continue to provide a substantial opportunity to present a product to a large audience (see also adjacent note about ESCMID) as well as opportunities to present at an IDWeek Pipeline Session.
  • 23-24 Mar 2027 (Basel, Switzerland): The 10th AMR Conference (3-4 Mar 2026) is now over and offered a rich program that included a 10-year retrospective (we’ve done a lot!), regulatory updates, discussions of how to pursue development in China, and much more … in addition to being a superb opportunity for networking! I am told the session videos will soon be available on the conference website. Mark your calendars for next year’s 11th AMR Conference!

  Upcoming meetings of interest to the AMR community:

  • 17-21 April 2026 (Munich, Germany): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 28 Apr 2026 (9:30-11:00 CET, virtual): REVIVE (GARDP)-sponsored webinar: “Natural product-inspired antibiotics: Successes and future prospects.” Go here for details and to register.
  • 4-8 June 2026 (Washington, DC): ASM Microbe, the annual meeting of the American Society for Microbiology. The meeting format is evolving and next year will combine 3 meetings (ASM Health, ASM Applied and Environmental Microbiology, and ASM Mechanism Discovery) into one event. Go here for details.
  • 11-12 Jun 2026 (Washington, DC): The Second Annual Unite for Sepsis Symposium, presented by the Sepsis Alliance. The event seeks to accelerate progress in sepsis research and care. Go here for details and to register.
  • 22-24 Sep 2026 GAMRIC (Lisbon, Portugal), the Global AMR Innovators Conference (London, UK; formerly the ESCMID-ASM Joint Conference on Drug Development for AMR). See list of Top Recurring meetings, above..
  • 10-18 Oct 2026 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2026 will be the 10th year for this program. Patrice Courvalin orchestrates content 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! Registration for 2026 will be during March 16–July 3, 2026. You can go here for more details and you should put a reminder in your calendar register on / after 16 March.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026. See list of Top Recurring meetings, above.
  • 10-13 November 2026 (Madrid, Spain): The International Society for Infectious Diseases (ISID) has announced its 21st International Congress on Infectious Diseases (ICID). Register and view the preliminary program here (Early bird closes 30 July 2026); abstract deadline is 28 April 2026.
  • 23-24 Mar 2027 (Basel, Switzerland): The 11th AMR Conference sponsored by the BEAM Alliance. See list of Top Recurring meetings, above.
  • ??? Mar 2028 (yes, that’s 2028, with location TBD): The 2028 Gordon Research Conference (GRC, https://www.grc.org/) entitled “Antibacterials of Tomorrow to Combat the Global Threat of Antimicrobial Resistance” and its related Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers will be sometime in March 2028. The organizers hope to coordinate dates and location with the 2028 BEAM-AMR meeting. Details to follow — mark your calendar!

Self-paced courses, online training materials, and other reference materials:

Current funding opportunities

  • CARB-X have announced a funding round that will be open 8-22 April 2026 (there will also be a round during 4Q 2026). There are 4 funding themes as below. Informational webinars have been announced for 9 and 10 April 2026.
    • Direct-acting therapeutics for infections caused by Gram-negative bacteria
    • Novel Chemistry for AMR Challenge – target-based therapeutics.
    • Non-vaccine approaches to prevent neonatal sepsis
    • Diagnostics for neonatal sepsis
  • The Horizon Europe Work Programme 2026-2027 includes at least 3 calls of interest within its Cluster 1 — see the list below.  The application window starts 10 Feb 2026 and closes on 16 Apr 2026. See also the 12 Dec 2025 newsletter about the call. Note as well that there calls for agents to prevent and/or treat viral infections.
    • HORIZON-HLTH-2027-01-DISEASE-08: Development of innovative antimicrobials against pathogens resistant to antimicrobials
    • HORIZON-HLTH-2027-02-IND-02: Portable point-of-care diagnostics
    • HORIZON-HLTH-2026-01-DISEASE-03:Advancing research on the prevention, diagnosis, and management of post-infection long-term conditions. 
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • 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.
  • 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
    • 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. See also the 7 Feb 2026 newsletter (“The global funding pipeline, 2017-2023: A review”) about an excellent deep dive by the Hub team into patterns of funding over time.
    • Antimicrobial Resistance Research and Innovation in Australia is an actively updated summary that covers Australia’s AMR research and patent landscape. It is provided via collaboration between The Lens (an ambitious project seeking to discover, analyse, and map global innovation knowledge) and CSIRO (Commonwealth Scientific and Industrial Research Organisation, an Australian Government agency responsible for scientific research). Lots to explore here!
    • 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).
]]> Categories of resistance: MDR, XDR, PDR, UDR, and (new!) DTR https://amr.solutions/2019/01/13/categories-of-resistance-mdr-xdr-pdr-udr-and-new-dtr/ https://amr.solutions/2019/01/13/categories-of-resistance-mdr-xdr-pdr-udr-and-new-dtr/#respond Sun, 13 Jan 2019 07:41:00 +0000 https://13.43.35.2/?p=84

Note: See also these related newsletters: 20 Feb 2020 (link) on DTR as part of the language of resistance and 7 June 2020 (link) on using DTR to estimate antibiotic value. There is also a 5-minute DTR explainer on YouTube that you might find useful.

Dear All:

When thinking about studies of resistant pathogens, issues of case-finding and statistical design are frequent topics of debate. As an example, the recent De Kraker et al. (CID 2018) paper by the COMBACTESTAT-Net group gives a great survey of ideas for optimizing design and analysis of these trials. (Note that full titles and cites of all papers mentioned in this note are given below my signature.)

A less-discussed area of late (at least to my ear) has been the implications of the categories of resistance. Based on expert consensus, CDC and ECDC gave us a widely used set of ideas in Magiorakos et al. (CMI 2012):

  • MDR (Multi-Drug Resistance) was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories.
  • XDR (eXtensive Drug Resistance) was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories).
  • PDR (Pan Drug Resistance) was defined as non-susceptibility to all agents in all antimicrobial categories.

McDonnell et al. (disclaimer: I am an author on both papers mentioned in this paragraph) added to this list by proposing (CID 2016) the idea of UDR (Usual Drug Resistance) to describe isolates that aren’t fully susceptible wild-type strains but that can nonetheless be readily treated with standard therapies. UDR is useful shorthand for the setting in which a novel agent is tested against an existing standard-of-care agent in a non-inferiority trial (for more on this, see the expanded discussion in CID 2017).

Now adding to this conversation, Kadri et al. (CID 2018) propose the idea of DTR: Difficult-to-Treat Resistance. Their point of departure is the idea that the MDR-XDR-PDR definitions make no distinction between strengths and weaknesses of the individual antibiotics: agents with higher efficacy and lower toxicity are counted in the same way as agents with lower efficacy and higher toxicity.

To address this, Kadri et al. define DTR as resistance to all of the typical first-line, lower toxicity agents, defined by Kadri et al. as the beta-lactams (including carbapenems and beta-lactamase inhibitor combinations) and the fluoroquinolones. In this setting, agents with toxicity or pharmacology limitations (e.g., the nephrotoxic aminoglycosides) must be used.

9 Apr 2026 addendum: Visually, Kadri 2018 includes this graphic showing the idea of DTR … note how DTR include all of PDR but only portions of MDR and XDR:

Kadri 2018 - Graphical view of UDR-MDR-XDR-PDR-DTR

 

Kadri et al. argue that discriminating among the qualities of the agents that must be used as resistance increases may help explain why Lye et al. (CMI 2012) found that “multidrug resistance per se is not associated with higher mortality when effective antibiotics are used for definitive therapy.” As another example, this might help explain in part the high and similar mortality with both colistin monotherapy and colistin-based combination therapies in the prospective study reported by Paul et al. (LancetID 2018, see also the related editorial by Perez and Bonomo, and a helpful secondary analysis by Zak-Doron and colleagues).

And, their thinking proved correct. Based on data from the Premier Healthcare Database from 173 US institutions on 46,521 Gram-Negative Blood Stream Infection (GNBSI) isolates from the period 2009-2013, about 1.5% of isolates were DTR. Critically, patients with DTR GNBSI isolates had a 40% higher adjusted mortality risk than those with non-DTR GNBSI. These findings were consistent in a variety of sensitivity analyses including by-species analyses.

This is a fascinating and helpful result and it is worth the effort to work carefully through the entire Kadri paper as well as the related papers mentioned above. As a simple but very meaningful concept that can be readily applied at the bedside, I think we’re going to see DTR used repeatedly as we go forward.

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/

Full titles and cites of papers

  1. de Kraker, M. E. A., H. Sommer, F. de Velde, I. Gravestock, E. Weiss, A. McAleenan, S. Nikolakopoulos, O. Amit, T. Ashton, J. Beyersmann, L. Held, A. M. Lovering, A. P. MacGowan, J. W. Mouton, J. F. Timsit, D. Wilson, M. Wolkewitz, E. Bettiol, A. Dane, S. Harbarth and C.-N. Consortium (2018). “Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE’s STAT-Net.” Clin Infect Dis 67(12): 1922-1931. (link)
  2. Kadri, S. S., J. Adjemian, Y. L. Lai, A. B. Spaulding, E. Ricotta, D. R. Prevots, T. N. Palmore, C. Rhee, M. Klompas, J. P. Dekker, J. H. Powers, 3rd, A. F. Suffredini, D. C. Hooper, S. Fridkin, R. L. Danner and I. National Institutes of Health Antimicrobial Resistance Outcomes Research (2018). “Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents.” Clin Infect Dis 67(12): 1803-1814. (link)
  3. Lye, D. C., A. Earnest, M. L. Ling, T. E. Lee, H. C. Yong, D. A. Fisher, P. Krishnan and L. Y. Hsu (2012). “The impact of multidrug resistance in healthcare-associated and nosocomial Gram-negative bacteraemia on mortality and length of stay: cohort study.” Clin Microbiol Infect 18(5): 502-508. (link)
  4. Magiorakos, A. P., A. Srinivasan, R. B. Carey, Y. Carmeli, M. E. Falagas, C. G. Giske, S. Harbarth, J. F. Hindler, G. Kahlmeter, B. Olsson-Liljequist, D. L. Paterson, L. B. Rice, J. Stelling, M. J. Struelens, A. Vatopoulos, J. T. Weber and D. L. Monnet (2012). “Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.” Clin Microbiol Infect 18(3): 268-281. (link)
  5. McDonnell, A. M., J. H. Rex, H. Goossens, M. Bonten, V. G. Fowler and A. Dane (2016). “Efficient Delivery of Investigational Antibacterial Agents via Sustainable Clinical Trial Networks.” Clinical Infectious Diseases 63 (Suppl. 2): S57-S59. (link)
  6. Paul, M., G. L. Daikos, E. Durante-Mangoni, D. Yahav, Y. Carmeli, Y. D. Benattar, A. Skiada, R. Andini, N. Eliakim-Raz, A. Nutman, O. Zusman, A. Antoniadou, P. C. Pafundi, A. Adler, Y. Dickstein, I. Pavleas, R. Zampino, V. Daitch, R. Bitterman, H. Zayyad, F. Koppel, I. Levi, T. Babich, L. E. Friberg, J. W. Mouton, U. Theuretzbacher and L. Leibovici (2018). “Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial.” Lancet Infect Dis 18(4): 391-400. (link)
  7. Perez, F. and R. A. Bonomo (2018). “Evidence to improve the treatment of infections caused by carbapenem-resistant Gram-negative bacteria.” Lancet Infect Dis 18(4): 358-360. (link)
  8. Rex, J. H., G. H. Talbot, M. J. Goldberger, B. I. Eisenstein, R. M. Echols, J. F. Tomayko, M. N. Dudley and A. Dane (2017). “Progress in the fight against multidrug-resistant bacteria 2005-2016: Modern non-inferiority trial designs enable antibiotic development in advance of epidemic bacterial resistance.” Clinical Infectious Diseases 65: 141-146. (link)
  9. Zak-Doron, Y., Y. Dishon Benattar, I. Pfeffer, G. L. Daikos, A. Skiada, A. Antoniadou, E. Durante-Mangoni, R. Andini, G. Cavezza, L. Leibovici, D. Yahav, N. Eliakim-Raz, Y. Carmeli, A. Nutman, M. Paul and A. S. Group (2018). “The Association Between Empirical Antibiotic Treatment and Mortality in Severe Infections Caused by Carbapenem-resistant Gram-negative Bacteria: A Prospective Study.” Clin Infect Dis 67(12): 1815-1823. (link)

Upcoming meetings of interest to the AMR community:

 

  • 15 Jan 2018 (London): BSAC’s Antimicrobial Chemotherapy Conference 2019: “An ABC for everyone involved in developing new antimicrobials.” Details here.
  • 29 Jan 2018 (REVIVE webinar): “Clinical development for non-developers Part 3: Antibacterial Drug Enhancer Combinations and Non-traditional Products.” Register here.
  • 4-5 Feb 2019 (London): Hamied Foundation UK-India Antimicrobial Resistance Meeting 2019. This is a 2-day meeting focused on building research links between the UK and India with the specific aim of jointly addressing the challenge of AMR. Register here.
  • 14-15 Mar 2019 (Berlin): BEAM-, CARB-X-, Novo REPAIR-, DZIF-, ND4BB-ENABLE-sponsored (among a long list!) Berlin Conference on Novel Antimicrobials and AMR Diagnostics. Details here. Poster submissions are being accepted through 9 Jan (details here).
  • 21-22 Mar 2019 (Birmingham, UK): BSAC Spring Conference.
  • 26 Mar 2019 (London, UK): Sponsored by The Economist, a 1-day symposium entitled “Antimicrobial Resistance: Preventing an antibiotic apocalypse.” Register here.
  • 13-16 Apr 2019 (Amsterdam): Annual ECCMID meeting
  • 16-18 Apr 2019 (Utrecht): ICOHAR, International Conference on One Health Antimicrobial Resistance. Organized by the ESCMID Study Group for Veterinary Microbiology (ESGVM).
  • 24-26 Apr 2019 (Boston): Annual SHEA (Soc. for Hospital Epidemiology of America) Spring meeting
  • 6-11 May 2019 (Ljubljana, Slovenia): 37th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Details here.
  • 3-6 Jun 2019 (Philadelphia): Annual BIO meeting
  • [NEW] 10-11 June 2019 (Research Triangle Park, NC): AMR Action Summit on R&D and Commercialization. Sponsors include the British-American Business Council, the UK Gov’t, CARB-X, the NC Biotechnology Center, and others. Details here.
  • 20-24 June 2019 (San Francisco): Annual ASM Microbe meeting.
  • [Mark your calendar now!] 3-6 Sep 2019 (Boston). Annual ASM-ESCMID Conference on Antibiotic Development. The Bootcamp series will continue on 3 Sep with the main meeting on 4-6 Sep. Mark your calendar now and check back here for details.
  • 6-8 Sep 2019 (Bilbao, Spain): 5th ESCMID conference on Vaccines. Check back here for details.
  • 2-6 Oct 2018 (Washington, DC): IDSA’s annual IDWeek meeting.
  • 19-27 Oct 2019 (Annecy, France): International Course on Antibiotics and Resistance (ICARe) – A soup-to-nuts intensive residential training program on all things AMR, especially R&D for new antibiotics. See this link for details.
]]> https://amr.solutions/2019/01/13/categories-of-resistance-mdr-xdr-pdr-udr-and-new-dtr/feed/ 0 Two new oral drugs for gonorrhea! https://amr.solutions/2026/01/13/two-new-oral-drugs-for-gonorrhea/ Tue, 13 Jan 2026 20:26:12 +0000 https://amr.solutions/?p=19212

Dear All (wonkish … but worth it … get ready to follow the links!),

Greetings in the new year! As a marvelous way to end the last year, the US FDA announced on 12 Dec 2025 its approval of two new oral therapies for gonorrhea, thus addressing the priority pathogen lists of both WHO (High priority) and CDC (Urgent) due to the rise in resistant infections. Achieving this has been a huge lift for reasons we’ll discuss below. To get you started, here are the main links you need:


So, what are the key messages from these materials? Well, let’s start with the usual points that (i) developing new antibiotics is really, really hard (4 April 2025 newsletter), (ii) the trials are slow and expensive (30 June 2020 newsletter summarizing FDA’s 40-year experience), (iii) the patients with greatest unmet need are hard to enroll, and (iv) the return on investment is generally negative.

And although it is not obvious given the reasonably high frequency of sexually transmitted infections, gonorrhea (hereinafter abbreviated as NG for Neisseria gonorrhea) poses several additional hurdles to developers. To get us started on these further issues, Sue Cammarata’s discussion of two drugs that failed in Phase 3 provides this summary:

Sue Cammarat's summary of the challenges in developing drugs for gonorrhea


What are the challenges that led to the failure of those two drugs in Phase 3? With the aid of the comments from Hook 2020, let’s walk through the ideas in the slide above:

First (and just about the only bit of good news in this list of challenges), NG itself is readily tested in the laboratory. It can be cultured and MICs can be generated. But, it turns out that it also readily mutates to become resistant. Unemo and Shafer gave us a vivid graphical illustration of the problem in their 2014 paper (Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev. 2014;27(3):587–613, https://doi.org/10.1128/cmr.00010-14):

Note that the x-axis of the figure above is time (1930-2020) and the y-axis is the accumulation of resistance determinants. As the funnel of available drugs gets smaller and smaller, we have the ongoing evolution of highly resistant infections.

Second, preclinical animal models of NG have been hard to create because humans are the only natural hosts for NG. As summarized in the presentation by Ann Jerse, creating faithful mimics of human infection has only recently become possible. Third, those models do not fully encompass important body site differences (e.g., genital infection vs. upper reproductive tract infections). Collectively, these are challenges for reliable PK-PD predictions and hence for reliable dose selection.

Fourth (and fifth), Phase 1 studies are of course possible, but assessing PK at the diverse relevant body sites is problematic. GC is most often symptomatic in the male urethra where as women can be entirely asymptomatic. Infection can also be endometrial, in the ovarian ducts, or the pharynx … and all of these sites may have different PK properties.

Sixth and seventh, Phase 2 and Phase 3 studies encounter further issues that tend to reduce enrollment of women and children (and thus limit the quantity/quality of data available for these groups):

  • The differences in presentation (symptomatic in men, [often] asymptomatic in women) mean that it’s hard to enroll enough women in trials.
  • It can be harder to culture NG from women during certain points in the menstrual cycle.
  • Women must also be screened for pregnancy and (generally) not enrolled (although the thinking on this is evolving towards a much more nuanced benefit-risk consideration — see the summary by Sewell et al. of an excellent 2021 Duke-Margolis workshop on this topic).
  • Likewise, limitations on enrolling children generally mean that sexually active adolescents are excluded.
  • For statistical reasons driven by the high cure rate of a good comparator in patients with susceptible infections (as well as the expectation of a 10% non-inferiority margin), the required studies (at least for Phase 3) tend to be relatively large. 

 
Finally, and even though it doesn’t cause failure of trial programs, I’ll add an eighth challenge: return on investment (ROI). As you’ve probably realized by now, part of the reason that therapies for chronic diseases are well reimbursed as that the drugs are needed for extended periods (if not for life). In the case of gonorrhea, however, the focus on developing single-dose therapies really works against adequate ROI … it’s difficult enough with 2-week therapies … but cure via a single dose really takes this challenge to its logical limit.

—
Whew! My hat is off to the teams that brought these products to initial approval! Well done! And now comes the equally large challenge of making these agents available globally. It will be interesting to see how this evolves: 

  • GARDP have published a case study of their work to develop zoliflodacin in which they note that they seek to use sub-licensing agreements to make zoliflodacin available soon in Thailand and South Africa (two countries that participated in their Phase 3 study). 
  • Per a personal communication with the GSK development team, I can also say that GSK is currently exploring potential pathways to make gepotidacin available in other countries where there is a medical unmet while preserving gepotidacin’s long-term effectiveness with robust surveillance and strong antimicrobial stewardship. To this end, I would make the guess that GSK will be leveraging their 20+ years of collaborations on neglected tropical diseases (NTDs) in support of access to antimicrobials in general. As an example, GSK has a collaboration with AMREF Health Africa to build generalized frameworks supporting responsible and equitable antibiotic access (along with appropriate use) in regions with unmet need.
  • The work planned by both groups is consistent with the ideas from the 2021 Stewardship and Access guidance (22 Mar 2021 newsletter) that was jointly developed by CARB-X, Wellcome, BARDA, GARDP, and others.

Looking to the long-term, having two new drugs is marvelous … but resistance will doubtless develop over time to both. We’ll need further agents and we need a vaccine! It’s been interesting to see data emerge (Abara 2025 JID, https://doi.org/10.1093/infdis/jiae383 is a good review) showing that the vaccine for Neisseria meningitidis provides at least some protection vs. Neisseria gonorrhea. This would seem to bode well for further work!

With thanks to the many, many colleagues who have worked for years to bring this drugs to this point and with best wishes for 2026, –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.

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, the small meeting format of BEAM’s AMR Conference (March) and GAMRIC (September-October; formerly, the ESCMID-ASM conference series) creates excellent global networking. IDWeek (October) and ECCMID (April) are much larger meetings but also provide opportunities for networking with a substantial, focused audience via their Pipeline sessions. Hope to see you there!

  • 3-4 Mar 2026 (Basel, Switzerland): The 10th AMR Conference. Sponsored by the BEAM Alliance, the 9th AMR Conference was an excellent meeting! A draft program has been posted and registration is now open. Please plan to attend! 
  • 17-21 April 2026 (Munich, Germany): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. You can go here to register and view the preliminary program; the abstract submission window for 2026 will run 15 October to 26 Nov 2025. For those who would like a substantial opportunity to present a product to a large audience (see also adjacent note about IDWeek), I know that the meeting schedule will again include Pipeline Monday.
  • 22-24 Sep 2026 (Lisbon, Portugal): The 2nd GAMRIC, the Global AMR Innovators Conference (London, UK). Formerly the ESCMID-ASM (or ASM-ESCMID depending on location) Joint Conference on Drug Development for AMR, 2026 will be the 11th year for this series that is now under the joint sponsorship of CARB-X, ESCMID, BEAM Alliance, GARDP, LifeArc, Boston University, and AMR.Solutions. The ongoing series employs the successful format of prior meetings with a single-track meeting and substantial networking time. The 2025 meeting was a sell-out success! A written summary of the meeting is here and the video from the sessions is now available here. Registration will open March 2026; the abstract submission window will be 10-31 March 2026.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026, the annual meeting of the Infectious Diseases Society of America. Details are not yet available but I would expect the program to continue to provide a substantial opportunity to present a product to a large audience (see also adjacent note about ESCMID) as well as opportunities to present at an IDWeek Pipeline Session.

 

  Upcoming meetings of interest to the AMR community:

  • [NEW] 21 Jan 2026 (virtual, 18.30-19.45 CET): The World Economic Forum’s annual meeting in Davos will include the broadcast of an Open Forum event entitled “The Fragile Future of Antibiotics.” Go here for most current details on the program; the link to the livestream should become visible at that same link. A recording will be available after the event.
  • 21 Jan to 15 April 2026 (every Wednesday, 11a-12.30p MST / 1p-2.30p EST / 6-7.30p GMT / 7-8.30p CET): CAN-AMR-Net (Canadian Antimicrobial Resistance Network) is running a 12-lecture in-depth training course entitled “Antibiotic Drug Discovery: From AI-Enabled Discovery to Successful Commercialization Comprehensive Training.”
    • The course will span the entirety of antibiotic development from early discovery to clinical, regulatory, and marketing stages. Go here for more details on the planned lectures and to register.
    • To best enable interaction, seating is limited – please register promptly if you are interested. The course fee ranges from $100 to $500 CAD based on geography and background.
    • CAN-AMR-Net is a Health Research Training Platform (HRTP) funded by the Canadian Institutes of Health Research (CIHR) from 2024 to 2030 and this course is part of their goal to train the next generation of researchers, practitioners, and leaders in the application of transdisciplinary methodologies and communication skills across One Health sectors to tackle the problem of AMR. For questions or suggestions on the course contents, contact Sameeh Salama at: ssalama@fedorapharma.com
  • 28-30 Jan 2026 (Las Vegas, NV, USA): IDSA and ASM have announced a new US-based meeting series entitled IMARI (Interdisciplinary Meeting on Antimicrobial Resistance and Innovation) that is described as a “forum for collaboration and exploration around the latest advances in antimicrobial drug discovery and development.” Go here for details and to register.
  • 4-5 Feb 2026 (virtual, 8a-noon GMT on both days): Antimicrobial Chemotherapy Conference 2026, sponsored by BSAC and GARDP. Registration here: acc-conference.com. Abstracts are welcomed and can be submitted here; abstract deadline is Friday, 14 November 2025, 17:00 GMT.
  • 5 Feb 2026 (in person, Alderley Park, UK): BioInfect, the annual AMR-focused networking conference delivered by BioNow. Go here for details and to register.
  • 5-6 Feb 2026 (virtual or in person [FDA White Oak campus, 1.30-5p ET on 5 Feb; 8.30-4p ET on 6 Feb): FDA hosted public workshop #10 in their series entitled Advancing the Development of Pediatric Therapeutics (ADEPT). The goal is to discuss challenges seen in neonatal and rare disease product development and to identify ways to leverage rare disease product development tools and regulatory frameworks. Go here for more details and here to register. The challenges of pediatric development run deep … and we need to find ways to protect children by including them in research rather than excluding them. On this theme, you might enjoy reviewing the related 7 Apr 2021 newsletter (“Developing antibiotics for children: There are no easy answers”) and the 27 May 2022 newsletter (“Antibacterial guidance (including pediatrics): Parallel EMA+FDA updates”).
  • 18-20 Feb 2026 (Sydney, Australia, in person): The “AMR 2026 Summit”, hosted by the Fleming Initiative and Australia’s Science Agency, CSIRO. This event (website) will spotlight evidence-informed One Health approaches, practical solutions to implementation barriers, and strategies for public engagement, education, and advocacy. Space is limited, so (and sort of like applying to attend a Gordon Conference), please register your interest to attend here.
  • 3-4 Mar 2026 (Basel, Switzerland): The 10th AMR Conference sponsored by the BEAM Alliance. See list of Top Recurring meetings, above.
  • 8-13 Mar 2026 (Renaissance Tuscany Il Ciocco, Italy): 2026 Gordon Research Conference (GRC) entitled “Antibacterials of Tomorrow to Combat the Global Threat of Antimicrobial Resistance.” A Gordon Research Seminar (GRS) will be held the weekend before (7-8 Mar) for young doctoral and post-doctoral researchers. Space for the GRS and the GRC is limited; for details and to apply, go here for the GRC and here for the GRS.
  • 17-21 April 2026 (Munich, Germany): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 4-8 June 2026 (Washington, DC): ASM Microbe, the annual meeting of the American Society for Microbiology. The meeting format is evolving and next year will combine 3 meetings (ASM Health, ASM Applied and Environmental Microbiology, and ASM Mechanism Discovery) into one event. Go here for details.
  • 22-24 Sep 2026 GAMRIC (Lisbon, Portugal), the Global AMR Innovators Conference (London, UK; formerly the ESCMID-ASM Joint Conference on Drug Development for AMR). See list of Top Recurring meetings, above..
  • 10-18 Oct 2026 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2026 will be the 10th year for this program. Patrice Courvalin orchestrates content 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! Registration for 2026 will not open for some time; go here for more details and put a reminder in your calendar to check back in the Spring if you are interested.
  • 21-24 Oct 2026 (Washington, DC, USA): IDWeek 2026. See list of Top Recurring meetings, above.
  • [NEW] 10-13 November 2026 (Madrid, Spain): The International Society for Infectious Diseases (ISID) has announced its 21st International Congress on Infectious Diseases (ICID). Register and view the preliminary program here. Note as well that the organizers have an open call for topic proposals with a 20 Jan 2026 deadline. 

Self-paced courses, online training materials, and other reference materials:

Current funding opportunities

  • EU OHAMR (One Health AMR) has opened its first call with a request for consortia to propose projects on (i) combination therapies, (ii) ways to improve adherence to protocols, and (iii) ways to assess/inform regarding the impact of antimicrobials used in veterinary medicine and food agriculture. The window for pre-proposals runs 18 Nov 2025 to 2 Feb 2026. See also the 22 Oct 2025 newsletter about the call.
  • The Horizon Europe Work Programme 2026-2027 includes at least 3 calls of interest within its Cluster 1 — see the list below.  The application window starts 10 Feb 2026 and closes on 16 Apr 2026. See also the 12 Dec 2025 newsletter about the call. Note as well that there calls for agents to prevent and/or treat viral infections.
    • HORIZON-HLTH-2027-01-DISEASE-08: Development of innovative antimicrobials against pathogens resistant to antimicrobials
    • HORIZON-HLTH-2027-02-IND-02: Portable point-of-care diagnostics
    • HORIZON-HLTH-2026-01-DISEASE-03:Advancing research on the prevention, diagnosis, and management of post-infection long-term conditions. 
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • 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.
  • 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/).
  • CARB-X had an open call (its 2nd call for 2025) that ran 1-12 Dec 2025. I am sure there will be calls in 2026 and I’ll announce them when they are published.
  • These things aren’t sources of funds but would help you develop funding applications
    • 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.
    • Antimicrobial Resistance Research and Innovation in Australia is an actively updated summary that covers Australia’s AMR research and patent landscape. It is provided via collaboration between The Lens (an ambitious project seeking to discover, analyse, and map global innovation knowledge) and CSIRO (Commonwealth Scientific and Industrial Research Organisation, an Australian Government agency responsible for scientific research). Lots to explore here!
    • 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).
]]> The 37,000-year view: Infections in Eurasia https://amr.solutions/2025/09/17/the-37000-year-view-infections-in-eurasia/ Wed, 17 Sep 2025 12:28:50 +0000 https://amr.solutions/?p=18675

Dear All (prepare for something that is delightfully different and marvelously wonkish AND with thanks to Lance Price for co-authoring this newsletter),

Continuing with the theme in the 15 Aug 2025 newsletter (“Global livestock resistome: Antibiotic resistance is widespread!”) of ways to use sequencing of samples from the environment, we have today an amazing paper in Nature which shows that infections have been plaguing mankind for a long, long time:

Sikora, M., Canteri, E., Fernandez-Guerra, A. et al. The spatiotemporal distribution of human pathogens in ancient Eurasia. Nature 643, 1011–1019 (2025). https://doi.org/10.1038/s41586-025-09192-8.

In brief, the authors analyzed ancient human DNA for evidence of infectious diseases, creating a global infection map spanning spanning 37,000 years. At a more technical level, the process is well summarized by the opening lines of the abstract (line breaks added):

  • “To create an archaeogenetic-based spatiotemporal map of human pathogens,
    • we screened shotgun-sequencing data from 1,313 ancient humans
    • covering 37,000 years of Eurasian history.
  • “We demonstrate the widespread presence of ancient bacterial, viral and parasite DNA, identifying 5,486 individual hits against 492 species from 136 genera.”

You’ll want to spend some time with paper yourself, but let us intrigue you with the data on Yersinia pestis (aka, “the plague”) and Borrelia recurrentis (louse-borne relapsing fever). First up, these figures on Y. pestis:

Geospatial map of cases of plague over the period 10,000 to 0 BP
Timeline of cases of plague over the period 10,000 to 0 BP

Look closely … there are 5 boxed figures and some x-axes stacked up here! They require careful study!

  • The upper pair of figures (the map and the boxed figure below it) with the timeline x-axis running from 10,000 BP to 0 BP show the distribution across Eurasia of samples showing DNA for the plague.
    • The authors do have data going back to 37,000 BP, but this analysis focuses on the most recent 10,000 years.
      • Background BP = Before Present based on radiocarbon dating.
      • By definition, 0 BP = 1950 AD.
      • To convert to BC/AD (or BCE/CE), it helps to round a bit by envisioning the scale as running from -10,000 to 0 and then adding 2,000 … 10,000 to 0 BP is thus ~8000 BC/BCE to ~2,000 AD/CE.
    • The light grey dots are the estimated date of the samples from the entire dataset of 1,313 individuals. The colored dots correspond to the dates of the plague-positive DNA samples.
  • Moving down, we have a trio of boxed figures that, importantly, share the same 10,000 BP to present (~8,000 BC to ~2,000 AD) timeline.
    • Just above the first boxed figure of this trio, note the thin grey line with grey and blue dots. The authors are here combining their cases of plague (blue dots) with other published cases (grey dots).
    • Then, the first boxed figure of the trio gives a grand roll up (blue line with y-axis labeled Detection Rate) of their best estimate of the timing of cases and hence timing of waves of cases.
    • The two final boxed figures are the statistical analyses that underpin the Detection Rate estimate.


Impressive! The plague has come and gone over thousands of years! But interestingly, note that it didn’t become common until about 6,000 BP. And then please note the relatively low rates of plague in the periods 2,800-2,000 BP and then again 1,600-600 BP. 

With those dates in mind, let’s now look at the same figures for louse-borne relapsing fever (LBRF). It may be less familiar than the plague, but it is also a deadly disease. Here we go:

Geospatial map of cases of louse-borne relapsing fever over the period 10,000 to 0 BP
Timeline of cases of louse-borne relapsing fever over the period 10,000 to 0 BP

First, just absorb the general pattern for LBRF: As with the plague, there were no cases until ~6,000 to 5,000 BP then waves of cases thereafter. This timing is instructive … as the paper states, “A striking feature shared in the temporal dynamics of plague and LBRF was the absence of detectable cases before roughly 6,000 bp, coinciding with a transition of individuals in predominantly hunter-gatherer contexts to those in farming or pastoralist cultural contexts.”

Next, look at the two periods when plague was relatively quiescent (2,800-2,000, then 1,600-600 BP). Combined with evidence of steady rates of detection environmental pathogens (Fig. 5 in the ms if you want to follow along), this contrast of low rates of plague with the steady rates of LBRF cases is evidence that failure to observe cases of plague was not due to inadequate sampling but rather that the plague really did have have periods of relative quiescence. 

—
Fascinating stuff, especially how closely the emergence of zoonotic diseases aligns with paleological estimates of livestock domestication. There’s more to explore in this paper (e.g., hints about leprosy, syphilis, and hepatitis B; cases of diphtheria from 11,000 BP; and more) and we’ll leave you to it. As you read, you might also enjoy the summary that includes some quotes from the authors in the 9 July 2025 New York Times.

And finally, this paper is evidence of the power of antibiotics and the many ways that their absence until about 80 years ago so often changed history. As the authors observe in their introduction:

  • “Until around 1850, at least a quarter of all children died before the age of one, and around another quarter before turning 15.
  • “Infectious diseases are estimated to have been responsible for more than half of these deaths.”


Please keep working on those new drugs! All best wishes, John & Lance

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.

Lance B. Price, PhD | Co-director, Antibiotic Resistance Action Center | Professor, Milken Institute School of Public Health, George Washington University. E: lprice@gwu.edu; Twitter @battlesuperbugs. All opinions are my own.

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, the small meeting format of BEAM’s AMR Conference (March) and GAMRIC (September-October; formerly, the ESCMID-ASM conference series) creates excellent global networking. IDWeek (October) and ECCMID (April) are much larger meetings but also provide opportunities for networking with a substantial, focused audience via their Pipeline sessions. Hope to see you there!

  • 1-3 Oct 2025 GAMRIC, the Global AMR Innovators Conference (London, UK). Formerly the ESCMID-ASM Joint Conference on Drug Development for AMR, this meeting series is now in its 10th year and is being continued under the joint sponsorship of CARB-X, ESCMID, BEAM Alliance, GARDP, LifeArc, Boston University, and AMR.Solutions. The ongoing series will continue the successful format of prior meetings with a single-track meeting and substantial networking time (go here to see details of the outstanding 2024 meeting).
    • Registration is now open and the preliminary agenda can be found at that same link (https://www.gamric.org/). The meeting will be limited to approximately 300 attendees, so please be sure to register promptly to avoid disappointment!
  • 19-22 Oct 2025 (Georgia, USA): IDWeek 2025, the annual meeting of the Infectious Diseases Society of America. Go here to register. For those who would like a substantial opportunity to present a product to a large audience (see also adjacent note about ESCMID), note the call for applications to present at an IDWeek Pipeline Session; go here to submit an application for your compound or diagnostic.
  • 3-4 Mar 2026 (Basel, Switzerland): The 10th AMR Conference. Sponsored by the BEAM Alliance, the 9th AMR Conference has just concluded and it’s again been an excellent meeting! Please mark your calendar for next year. You can’t register yet, but details will appear here! 
  • 17-21 April 2026 (Munich, Germany): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. You can’t register yet, but you can go here for details on the outstanding 2025 meeting. For those who would like a substantial opportunity to present a product to a large audience (see also adjacent note about IDWeek), I know that the meeting schedule will again include Pipeline Monday; go here to see details from 2025.

  Upcoming meetings of interest to the AMR community:

  • 15-19 Sep 2025 (virtual): US CDC-sponsored the 9th Annual Fungal Disease Awareness Week (FDAW). Daily themed events include “Think Fungus” on 15 Sep, “Fungi are everywhere” on 16 Sep, and “Fungal diseases and drug resistance (19 Sep). Signup for the Mycotic Diseases Branch newsletter to stay updated.
  • 1-3 Oct 2025 GAMRIC, the Global AMR Innovators Conference (London, UK; formerly the ESCMID-ASM Joint Conference on Drug Development for AMR). See list of Top Recurring meetings, above..
  • 11-19 Oct 2025 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance) … and 2025 will be the 9th year for this program. Patrice Courvalin orchestrates content 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 are being accepted from 20 Mar to 21 Jun 2025 — go here for more details.
  • 17-20 Sep 2025 (Porto, PT): 14th International Meeting on Microbial Epidemiological Markers (IMMEM XIV). Go here for details.
  • 9-13 Nov 2025 (Portland, OR, USA): ASM Conference on Biofilms. Go here for details and to register.
  • 18-24 Nov 2025 (global, multiple locations): World Antibiotic Awareness Week (WAAW) is convened annually on 18-24 Nov by WHO with national events (e.g., CDC’s US Antibiotic Awareness Week (USAAW); ECDC’s 18 Nov European Antibiotic Awareness Day) occurring around the globe. Details will follow as events become visible.
  • 19-22 Oct 2025 (Georgia, USA): IDWeek 2025. See list of Top Recurring meetings, above.
  • 29-31 Oct 2025 (Bengalaru, India): ASM Global Research Symposium on the One Health Approach to Antimicrobial Resistance (AMR), hosted in partnership with the Centre for Infectious Disease Research (CIDR) at the Indian Institute of Science (IISc). Go here for details and to register.
  • 28-30 Jan 2026 (Las Vegas, NV, USA): IDSA and ASM have announced a new US-based meeting series entitled IAMRI (Interdisciplinary Meeting on Antimicrobial Resistance and Innovation) and described as a “forum for collaboration and exploration around the latest advances in antimicrobial drug discovery and development.” You can’t register yet (the website says registration will open September 2025) but you go here for the program and to submit an abstract (deadline for abstracts is 1 Oct 2025).
  • [NEW] 4-5 Feb 2026 (virtual, 8a-noon GMT on both days): Antimicrobial Chemotherapy Conference 2026, sponsored by BSAC and GARDP. Registration here: acc-conference.com. Abstracts are welcomed and can be submitted here; abstract deadline is Friday, 14 November 2025, 17:00 GMT.
  • 3-4 Mar 2026 (Basel, Switzerland): The 10th AMR Conference sponsored by the BEAM Alliance. See list of Top Recurring meetings, above.
  • 8-13 Mar 2026 (Renaissance Tuscany Il Ciocco, Italy): 2026 Gordon Research Conference (GRC) entitled “Antibacterials of Tomorrow to Combat the Global Threat of Antimicrobial Resistance.” A Gordon Research Seminar (GRS) will be held the weekend before (7-8 Mar) for young doctoral and post-doctoral researchers. Space for the GRS and the GRC is limited; for details and to apply, go here for the GRC and here for the GRS.
  • 17-21 April 2026 (Munich, Germany): ESCMID Global 2026, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 4-8 June 2026 (Washington, DC): ASM Microbe, the annual meeting of the American Society for Microbiology. The meeting format is evolving and next year will combine 3 meetings (ASM Health, ASM Applied and Environmental Microbiology, and ASM Mechanism Discovery) into one event. Go here for details.

Self-paced courses, online training materials, and other reference materials:

Current funding opportunities

  • NNF (Novo Nordisk Foundation) have announced their “Challenge Programme 2026 – Unravelling the Pathways of Human Invasive Fungal Diseases. The call seeks applications from EU-centered consortia (global partners are possible) for research in 4 areas: (i) fungal virulence factors, (ii) host-pathogen interactions, (iii) mechanisms of anti-fungal resistance, and (iv) fungal disease markers. Applications are due by 8 Oct 2025. Go here for details. 
  • ENABLE-2 has continuously open calls for both its Hit-to-Lead program as well as its Hit Identification/Validation incubator. Applicants must be academics and non-profits in Europe due to restrictions from the funders. Applications are evaluated in cycles … see the website for details on current timing for reviews. 
  • CARB-X will have two calls during 2025 that span two areas: (i) Small molecules for Gram-negatives (the focus is on Pseudomonas aeruginosa) and (ii) Diagnostics for typhoid (the focus is diagnosis of acute infections in 60 minutes or less). See this 26 Feb 2025 newsletter for a discussion of the call and go here for the CARB-X webpage on the call. The first cycle is now closed (it ran16-30 April 2025); the 2nd round will be open 1-12 Dec 2025.
  • 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.
  • 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
    • 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.
    • Antimicrobial Resistance Research and Innovation in Australia is an actively updated summary that covers Australia’s AMR research and patent landscape. It is provided via collaboration between The Lens (an ambitious project seeking to discover, analyse, and map global innovation knowledge) and CSIRO (Commonwealth Scientific and Industrial Research Organisation, an Australian Government agency responsible for scientific research). Lots to explore here!
    • 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).
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