Summaries – AMR.Solutions

Chemicals vs. drugs (Part 3): XKCD has the final word

John Rex — Tue, 25 Feb 2020 21:21:47 +0000

This newsletter is part of a series — here are the links to Part 1, Part 2, (this one is Part 3), Part 4, and Part 5. You might also enjoy the discussion of AI-supported discovery in this May 2026 video from Nature.

Dear All,

As a coda to the two newsletters on Chemicals, Drugs, and Halicin (link and link), XKCD gets the final word:

Image reproduced with permission from https://xkcd.com/1217/. And, you might want to review XKCD on the importance of good apple stewardship (link).

With thanks to Natalie Ma for sharing this,

All best wishes, –jr

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

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.
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”. Go here for details.
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.

Chemical vs. drugs (Part 2): How do you discriminate? / More on halicin

John Rex — Mon, 24 Feb 2020 18:32:01 +0000

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.

Chemicals vs. drugs (Part 1): The end of bacitracin / the buzz around halicin

John Rex — Fri, 21 Feb 2020 19:49:50 +0000

This newsletter is the first of a series — here are the links to Part 2, Part 3, Part 4, and Part 5. You might also enjoy the discussion of AI-supported discovery in this May 2026 video from Nature.

Dear All,

Today’s theme is a 3-part journey that could be subtitled “Many are called, but few are chosen,” or “It’s easy to kill bacteria — steam, fire, and bleach are consistently effective — but those aren’t drugs!”

Our first stop is with a very old compound, bacitracin. Approved in 1948 because of its activity vs. S. aureus and thus long before the 1962 FDA amendment that standardized our approach to drug evaluation (link), it fell from regular usage due to its substantial toxicity. But, an IM (intramuscular) formulation of bacitracin remained on the list of FDA-approved drugs until it was withdrawn on 31 Jan 2020 (link). To learn more about the saga of IM bacitracin, I have previously written a 3-part series of newsletters discussing the FDA Advisory Committee held last year before finally retiring the IM formulation. Go here to find the first newsletter and follow the links to read parts 2 and 3 (or, click here and here).

So, is this a drug or just another toxic chemical? Well, it depends on your point of view. I think there was a time in the 1950s when the paucity of other choices and the rise of penicillin-resistant S. aureus would have made IM bacitracin better than nothing and hence, in context, it was a useful drug. But, today we have many other choices for this organism and hence bacitracin has been appropriately deleted from the systemic formulary. Its human use is now limited to topical application and it also has important veterinary uses.

Colistin (IV) is obviously a similar story. Despite its clear toxicities, we brought it back in to clinical use because other agents were failing. But, and as I’ve recently argued (link), it’s now time to put it back into the category of “not a drug.” It may still have inhaled uses, but IV use should come to a screeching halt!

Our second stop is with an article that just came out in Cell by Stokes et al. (link). Entitled A Deep Learning Approach to Antibiotic Discovery, the authors sought to use machine learning to identify antibacterial activity in compounds where such activity would not have otherwise been anticipated. You should read the paper yourself, but here’s the short version:

As a metric for possible antibacterial activity, the authors measured an E. coli MIC in 1,760 approved FDA drugs + several hundred additional natural products.
These data were used to build a predictive model that was then applied to 6,111 molecules in various stages of development as human drugs.
Hits were obtained and one of them, c-Jun N-terminal kinase inhibitor SU3327, was identified as having strong antibacterial activity.
Further work with SU3227 (renamed halicin by the authors, by inference an homage to HAL from 2001: A Space Odyssey, link) showed that SU3227 was active against a wide range of bacteria (Acinetobacter, Pseudomonas, and others) as well as against M. tuberculosis.
The authors showed that SU3227 had activity when applied topically in a murine wound infection model.
And finally, the authors report that their algorithm has found additional candidate antibiotics in a large compound library.

So, is this a drug or just another toxic chemical? Well, and with the caveat that I’d be happy to be proven wrong, my guess would be that SU3227/halicin is not a drug. At a very simple level, compounds that kill nearly everything often turn out to kill indiscriminately and hence are too toxic to use as systemic drugs. Consistent with this, c-Jun N-terminal kinases are involved in many critical biological pathways and work on inhibitors appears limited by the need to find highly selective variants (link). Perhaps SU3227/halicin could be developed for topical use, but that’s a space with very little unmet need.

Putting it all together, I think it is premature to call SU3227/halicin a drug or to think that this approach to discovery will dramatically shorten the overall development cycle for new antibiotics. The paper by Stokes et al. is truly fun to see and their insights might open up new chemical space for an antibiotic that will eventually get approved, but the work to be done from the point of showing in vitro activity is enormous: toxicology, manufacturing, formulation, in vivo pharmacology, and a lot more. It would be really cool if finding a new molecule could be reduced to something done in silico via a gadget from Star Trek but that is something for the distant future.

As related notes:

For those who want to dig more deeply into machine learning, I suggest the excellent blog by Derek Lowe in Science Translational Medicine (link).
The CO-ADD project (https://www.co-add.org/) offers a free in vitro screening service for compound collections and could be thought of as the bench-based version of the search conducted in the halicin paper. Compound libraries are screened at no cost against a key panel of susceptible and drug-resistant bacterial, and fungal pathogens. Check it out! 22 Jan 2020 addendum: 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.

In summary, antibacterial discovery is a tricky area and it makes you realize that the antibiotics we do have are true marvels! And while you’re thinking about drugs vs. chemicals, let me remind you of two prior newsletters that approach this topic:

The shorthand concept of Lipinski’s Rule of 5 (Ro5) is an interesting tool for making guesses about whether a molecule is likely to play well with biological systems and hence possibly become a drug (link).
Lynn Silver, one of the true masters of antibacterial discovery, has over time written a series of must-read articles on the perils and pitfalls of antibiotic discovery. Go here to get educated! 24 Feb 2020 update: And, go here to read her commentary on the paper by Stokes et al.

All best wishes, –jr

PS: This newsletter has a follow-up here and here.

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:

[NEW] 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!
20 Feb 2020 (London, UK): Westminster Health Forum conference entitled “Antimicrobial resistance – coordinating a global response and progress on the UK strategy.” Go here for details.
24 Feb 2020 (London, UK): One-day workshop hosted by Royal College of Nursing and the Longitude Prize entitled “Developing point-of-care diagnostics for urinary tract infections (UTIs): addressing clinical need in the UK.” Register here.
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.
[NEW] 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. Registration to follow; contact Lawson Ung (lawson_ung@meei.harvard.edu) for near-term 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.
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.

In Praise of Non-Inferiority

John Rex — Sat, 19 Sep 2020 17:00:13 +0000

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:

There are two types of trials: Superiority and non-inferiority (NI)
Infections can be lethal: Placebo is a bad idea!
Antibiotics are best developed before we need them!
NI trials are the public good that allows us to avoid COVID-19-like situations.
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.

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.

Categories of resistance: MDR, XDR, PDR, UDR, and (new!) DTR

John Rex — Sun, 13 Jan 2019 07:41:00 +0000

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 COMBACTE STAT-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 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

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)
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)
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)
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)
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)
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)
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)
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)
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.

Antibiotic supply chains: Challenges & Opportunities

John Rex — Thu, 05 May 2022 00:20:58 +0000

Dear All,

In a report entitled Understanding the Antibiotic Manufacturing Ecosystem: A view of global supply chains, pressure points, and implications for antimicrobial resistance response, the Boston Consulting Group and Wellcome Trust have examined at length the questions of (i) how the #FireExtinguishersOfMedicine are made and (ii) how they can be made with the least impact on the environment.

To see all this in context, there are are two parallel threads to consider. First, COVID has taught us about the fragile nature of supply chains in general. Antibiotics definitely have fragile supply chains and you can get a flavor of this by scanning this 2018 article in Forbes, this 2021 paper in BMJ Global Health, and FDA’s Drug Shortage webpage. Second, manufacturing discharges can themselves drive antibiotic resistance — ATMF’s 2021 review is a good summary of the problem. The need for responsible approaches to manufacturing was also clearly called out in proposals to establish environmental discharge from the AMR Industry Alliance. Notably, the AMR Industry Alliance (AMRIA) will publish an industry standard next month which, together with an independent certification scheme (expected in early 2023), could provide a mechanism to drive adoption of risk based, cost effective controls to minimize antibiotic emissions across the global supply chain and provide means by which manufacturers can give assurance of responsibly made antibiotics.

Addendum: the AMRIA published its Antibiotic Manufacturing Standard on 14 June 2022. See https://www.amrindustryalliance.org/shared-goals/common-antibiotic-manufacturing-framework/ for details, including research-based Predicted No-Effect Concentrations (PNECs). In collaboration with BSI (British Standards Institution), there is also an industry certification scheme. See also the 25 Sep 2023 newsletter for a further discussion of this scheme.

So, this new report analyzes the impact of possible environmental regulatory changes on antibiotic supply. The report starts from a very practical concern — it regulatory changes increase manufacturing costs, will manufacturing decline?

There are some excellent figures throughout the report but I wanted to share these two in particular. Production of antibiotics is not simple and, unfortunately, antibiotic discharge does happen. Note in particular (2nd figure) that most of the manufacturing happens in two of the most densely populated countries in the world:

In terms of the impact of environmental regulation to curb this issue, it really boils down to someone paying more and at what scale. If it is the developers, we all know how tough it is to just keep the lights on once you’ve made a new antibiotic. If it is the consumers, no one ever wants to pay more if they can help it. And, none of us will be happy if we break the supply chains for critical antibiotics! But how likely is this if new environmental regulation was introduced?

I encourage you to read the report yourself, but findings suggest environmental regulation can be compatible with strong antibiotic supply chains. However, policies should be developed in a supply chain-sensitive way and complimented with supportive measures for at-risk supply chains. The key being (no surprise!) to take a number of pragmatic steps in parallel. These include:

Evidence-based discharge limits
Standardized methods for monitoring discharge
Cost-efficient processes for meeting and monitoring compliance with the targets
Ambitious but feasible timelines for implementation
Consideration of the fragility of individual supply chains with an eye to ensuring that supply chains for critical antibiotics are not broken
International coordination on all the above, including actions by net-importers

The report suggests that the WHO and G7/G20 need to take the lead: global government action will be needed to change the way we develop and use antibiotics. Now is the time to include changing the way we manufacture them as part of this global effort!

Well done, BCG and Wellcome Trust! –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 (most current list is here):

JPIAMR’s 14th call is now open. Entitled “Disrupting drug resistance using innovative design”, the call seeks consortia that would seek to “improve the treatment of bacterial and fungal infections (including co-infection) and/or the prevention of the emergence/spread of resistance in humans, animals or plants through the improvement of the efficacy, specificity, delivery, combinations and/or repurposing of drugs and plant protection agents.” Bacteria, fungi, human health, animal health, and plant health are all in scope! Pre-proposals are due 8 Mar 2022; full proposals would be due 5 July 2022. Go here for details.
The AMR Action Fund is now open 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 a newly launched early-stage funding vehicle. Details are still coming into focus, but per comments on 25 Aug 2021 at the BIOCOM conference, their goal is to support ~4 companies per year with about $250k/company. Contact details are on their website (https://www.incate.net/).
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (more than 80 total awards, and counting, as they include contracting from prior rounds). New rounds from CARB-X will occur only after new funding is obtained in 2021.
It’s not a funder, but 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.
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).

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

8 Dec 2021: “The New Winds Pushing and Pulling Antibacterial Development.” This FABULOUS program featured talks from the UK team behind the NHS “Netflix” pilot, Kevin Outterson’s recently released report documenting the need for global Pull incentives to have a value of $2.2 – 4.8b, and speakers covering PASTEUR and work in the EU on pull incentives. The video is here — please make time to listen to this program!
The stunning 4 Feb 2022 webinar for the GRAM report (Global Research on Antimicrobial Resistance “1.27 million deaths per year are directly attributable to AMR”) is now available for replay. #AMRSOS!
[NEW] 13 May 2022 (Strasbourg, France): AC21 Workshop: “Pre-clinical development of antimicrobial peptides”, with contributions from the AC21 member universities in Stellenbosch, South Africa, Minneapolis, USA, Freiburg, Germany and Strasbourg, France as well as from other institutions. Participation is free and open to non-member institutions but registration is required. Supported by Academic Consortium 21. Go here for details.
16-18 June 2022 (Perth, Australia): Australasian Society for Infectious Diseases Annual Scientific Meeting is a hybrid event for adult and pediatric infectious disease and clinical microbiology specialists. Go here for details.
11-14 July 2022 (Sydney): Australian Society for Microbiology Annual National Meeting is a hybrid event that will feature a range of lectures and symposium sessions, as well as extensive opportunities for networking. Go here for details.
24-27 July 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.
28-31 July 2022 (Singapore): 10th International Congress of Asia Pacific Society of Infection Control is a hybrid event for professionals in the Asia Pacific region. Go here for details.
20-24 Sep 2022 (New Delhi): 21st Congress of the International Society for Human and Animal Mycology (ISHAM). Go here for details.
[NEW] 4-7 Oct 2022 (Dublin, Ireland): The 2022 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. This is an excellent meeting, especially for developers … and if you’ve missed it, the recordings from the 2021 meeting are online. Go here for details on the 2022 meeting.
19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
15-23 Oct 2022 (in person, residential, Les Pensières, Veyrier-du-Lac, France): The 6^th edition of Patrice Courvalin’s fabulous ICARe residential training course covering all things AMR is on for 2022! This is a soup-to-nuts training in AMR: it is very intense, very detailed, and always gets rave reviews from attendees. Registration is open 21 Mar 2022 to 21 June 2022 and is limited, so book your slot as soon as you can. Go here for more: https://www.icarecourse.org/
19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
27-30 Nov 2022 (Perth, Australia): 32nd International Congress of Antimicrobial Chemotherapy is the biennial congress of the International Society of Antimicrobial Chemotherapy (ISAC). Go here for details.

Non-traditional antibiotics: A pipeline review and an analysis of key development challenges

John Rex — Tue, 06 Aug 2019 11:10:19 +0000

Dear All,

Non-traditional alternatives to antibiotics have excited a lot of interest in the past few years but we’ve seen relatively few of these progress in a meaningful way (go here for Pew’s recent survey of the development landscape). Providing insights into the challenges of this area, two valuable and complementary articles on non-traditional antibiotics have recently been published.

Post-newsletter additions:

If you are interested in development issues for veterinary antibacterials, see this paper by Marilyn Martinez and Jeff Watts)
This 21 Nov 2017 newsletter summarizes the excellent R&D insights from Lynn Silver, many of which have applicability if you are thinking about non-traditional products.
Vaccines are (sort of) in the non-traditional category. Please see this 20 Dec 2018 newsletter and its internal updates for a discussion of just how hard novel vaccines can be to develop.
There was a GARDP REVIVE webinar on non-traditional products on 22 Aug 2024. Go here to stream the event recording.
13 Jan 2026: Neha Prasad and Sumati Nambiar wrote an instructive article on non-traditional product development that dives into the theme of development focused on community-level benefits: Prasad N, Nambiar S. Strategic Demonstration of the Clinical Utility of Nontraditional Antibacterials. ID Clin North Amer. 2025. https://doi.org/10.1016/j.idc.2025.11.006

First up, and authored by Ursula Theuretzbacher and Laura Piddock, is “Non-traditional Antibacterial Therapeutic Options and Challenges” (link). This paper is an in-depth review of the non-traditional pipeline and provides both tabular summaries of products in development as well as a by-category commentary on relevant issues. The paper’s key conclusion is that therapeutic non-traditional treatments will generally be used in combination with antibiotics and that “… these new strategies have additional and considerable hurdles before they can be shown safe and efficacious for patient use.”

So, what are those challenges? This brings us to #2 on your reading tour, “Designing development programs for non-traditional antibacterial agents” (link). Along with Holly Fernandez Lynch, Glenn Cohen, Jonathan Darrow & Kevin Outterson, I was a co-author on this one. This paper focuses in depth on development issues for non-traditional products by extending the thinking from Czaplewski et al. 2016 (link), a lecture I gave at ECCMID 2018 (link), and a joint talk with Kevin Outterson at the August 2018 FDA workshop on non-traditional products (link). The core messages here are that (a) the development pathways for non-traditional products are largely the same as for traditional small molecules, (b) the need to show superiority of the combination makes it very difficult to develop non-traditional products that seek to work in combination with an existing drug to augment, restore, or transform the existing drug’s effect, and (c) there may be a need for a broad discussion about products where most of the benefit accrues to the community as a whole rather than the individual.

Let me also note that this second paper is unusual in that its authors include lawyers & ethicists from Boston University, Harvard, and the University of Pennsylvania, together with a lone clinician (me). As a result, the discussion of trial design issues (and especially the deep logic of non-inferiority and superiority trials for antibiotics) is very detailed and exhaustive. If you’ve not previously studied this area in depth, this paper is a good place to start. I also recommend reviewing the 22 July 2019 newsletter that discussed the recent FDA LPAD workshop — wonkish point #4 and this related slide deck (link) are especially on point.

While I know that the messages in these papers will not be happy reading for those seeking to develop non-traditional alternatives to antibiotics, please also know that a personal level I’ve long been fascinated by the idea of non-traditional products and I would love to see some of them reach registration. Given how hard it is to find new traditional antibiotics, it is important that we vigorously pursue any plausible alternatives.

So, please read these papers with the attitude of “Tears today rather than tears tomorrow” and use them as a springboard from which to ensure that current programs anticipate and solve the issues that arise in late development.

All best wishes, –jr

Upcoming meetings of interest to the AMR community:

20 Aug 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Models for antimicrobial R&D: Computational modelling for population PK and PKPD.” Go here to register.
[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 main meeting on 4-6 Sep. Mark your calendar now and check back here for details.
6 Sep 2019 (Cambridge): CeBIL Annual Symposium 2019: Legal Innovation to Support the Development of Anti-Microbial Drugs. For more details and to register, go here.
6-8 Sep 2019 (Bilbao, Spain): 5th ESCMID conference on Vaccines. Check back here for details.
10 Sep 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Models for antimicrobial R&D: Advanced and complex in vivo models for infectious disease research.” Go here to register.
3 Oct 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Natural product antibiotics: from traditional screening to novel discovery approaches.” Go here to register.
2-6 Oct 2019 (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.
16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): 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.
12-13 Mar 2020 (Berlin?): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Final location is TBD, details will appear here, and you should mark your calendar now.
16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details.
18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)

Vaccines to turn back the tide of antimicrobial resistance

John Rex — Tue, 30 Mar 2021 02:16:37 +0000

See also

This related newsletter: 14 Jul 2022, entitled “WHO Vaccine Pipeline Review; CDC On Impact Of COVID On AMR.”
This 20 Oct 2024 report from WHO: “Estimating the impact of vaccines in reducing antimicrobial resistance and antibiotic use: technical report”
This 25 Apr 2024 paper in Lancet Global Health by Hausdorff and colleagues: “Facilitating the development of urgently required combination vaccines” DOI https://doi.org/10.1016/s2214-109x(24)00092-5

Dear All: As part of their Immunization Agenda 2030: A Global Strategy to Leave No One Behind, WHO have now published an AMR-focused action framework that summarizes ways we should seek to use vaccines both to reduce antibiotic use and to prevent the further emergence of antimicrobial resistance. Here are the links you need — I suggest you start with the first two, saving the others to explore as a deeper dive:

The AMR-focused Action Framework that we’ll be discussing
An overview paper on the Action Framework by Vekemans et al. in Clinical Infectious Diseases
A very detailed implementation plan for the overall 2030 Immunization Agenda (all vaccines, not just AMR-focused)
The website for Immunization Agenda 2030

The AMR-focused Action Framework has 3 core goals:

Expanding Use: In brief, we need to use the vaccines we have!
New Vaccines: In brief, a few new vaccines seem possible, but only a few
Expanding Knowledge of Vaccine Impact: In brief, driving policy change requires data!

Before we set off on our tour, please note that we are discussing the elements of the Immunization Agenda 2030 that are focused on vaccines for the standard bacteria. New vaccines for tuberculosis and vaccines for viral infections are also important but are out of scope (but as we will note, deploying antiviral vaccines can impact AMR, so there is some overlap). With that context noted, let’s take the tour!

This goal is broken into 3 objectives: (i) Expanding use, (ii) Updating guidance documents (and the data behind them), and (iii) Communication / Education.

In a way, this is both the easiest and most challenging goal! On the easy side, the point is that we already have a lot of great vaccines: the pneumococcus (S. pneumoniae, the cause of pneumonia across all ages), Haemophilus influenza type B (causes meningitis in children), rotavirus, measles, and influenza are well established and need to be used more widely. A newcomer on the scene is a conjugate vaccine for typhoid that also needs to rolled into the global distribution network.

Using these vaccines impacts AMR In two ways. For the actual bacterial infections (e.g., pneumococcal pneumonia), it’s obvious that a pneumonia that doesn’t occur is a pneumonia that doesn’t need treatment. But what about measles? Well, the point here would be that an episode of measles can set you up to need antibiotics for a secondary infection. Stated differently, staying healthy overall and not having symptomatic episodes of viral or bacterial infections is a great way to reduce use of antibiotics!

So, why do I say that this is also the most challenging goal? Well, the difficulties with both distribution and acceptance of vaccines are well documented … developing public trust takes sustained effort. This is hard work without any sort of single easy answer.

The objectives for this goal are what you’d expect: (i) ensure adequate funding for needed/plausible R&D and (ii) streamline regulatory and policy processes to the maximum extent possible.

The funding challenges and solutions here are similar to those for antibacterial agents. The R&D is slow and expensive and we need push-pull mechanisms such as subscription models.

The question of needed/plausible R&D is a very deep one. There are lots of bacterial infections that could use a vaccine, but not all vaccines are equally plausible. The 2018 Wellcome Trust-funded reported entitled Vaccines to tackle drug resistant infections: An evaluation of R&D opportunities tackles the question of need vs. plausibility and proposes that we think of possible new vaccines in 3 categories: (i) Bring to Market (i.e., get going and do it!), (ii) Advance Early R&D (i.e., looks possible, lets engage fully), and (iii) Collect Data and Explore Alternatives (Hmm — not obvious we can ever get there so keeping exploring while looking in parallel for non-vaccine approaches). When you consider the world of possible bacterial vaccines through this lens, here’s what you get:

Looking closely, we can see that the graphic adds the category Increase Uptake for established vaccines, thus reflecting back to Goal 1. The Bring to Market group focuses on vaccines for E. coli and Shigella as causes of gut (enteric) infections. The Advance R&D group is diverse and includes Staphylococcus aureus, Neisseria gonorrhoeae, E. coli (but now for UTI), and P. aeruginosa. All other bacteria fall into the Collect Data/Explore Alternatives bucket.

What’s instructive here is that this review found that vaccines are most likely for a limited number of additional bacteria. We should keep trying, but it would be good to hedge our bets for the other bacteria with parallel efforts to prevent infections both via general public health measures (clean food, clean water!) and via developing new antibiotics.

This goal has two objectives that really focus on public policy: (i) Collect more/better data on the impact of vaccines and (ii) Develop estimates of the value of vaccines.

These are the sorts of data that move public policy — legislative / political change only happens when we can clearly articulate the “What does it cost? What do get for our money?” side of things to political and financial leaders.

Such data are especially important as prevention involves paying for things to NOT happen. It’s so easy to see what you get when you pay for a new bridge (and you can even name it for somebody) but the equivalent for children who did NOT develop infection X is simply much less tangible. Thus, we have to measure it and prove its value over and over. If antibiotics are the fire extinguishers of medicine, then vaccines are the building codes that prevent cities from burning down! (Aside: the linked article on the history of building codes is fascinating … even Hammurabi had something to say on this topic during his reign in 1955-1913 BCE!).

—
Great stuff! As the paper by Vekemans et al. concludes:

“Health interventions and policies depend on public confidence.
“Advocacy and targeted communication can contribute to increased knowledge and catalyze the action needed to better protect everyone against infections and curb the threat that AMR poses to individuals, societies, and global health.”

In short, this community has a role to play as advocates for vaccines. By keeping us healthy, vaccines can delay / avert the rise of AMR. That noted, many of our fellow citizens do not understand how vaccines work and each one of us can be a source of needed insight!

All best wishes, –jr

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

Current funding opportunities (most current list is here):

Novo REPAIR Impact Fund will open its next global call on 1 April 2021. Go here for current details.
NIAID’s 2021 Broad Agency Announcement for product development is entitled “Development of Medical Countermeasures for Biothreat Agents, Antimicrobial-Resistant Infections an Emerging Infectious Diseases” and is now live with a 24 May 2021 deadline. Research areas include Vaccines, Therapeutics, and Sequencing-Based Diagnostics.
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (more than 80 total awards, and counting, as they include contracting from prior rounds). New rounds from CARB-X will occur only after new funding is obtained in 2021.
It’s not a funder, but 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.
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).

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

20-22 April 2021 (online, 1-5p CET): JPIAMR-sponsored workshop entitled “Feeding the Antimicrobial Therapeutics Pipeline.” JPIAMR, the collaborative global effort of 28 countries (much of the EU and also Argentina, Canada, Egypt, Israel, Japan, Korea, South Africa, and Turkey), is organizing a mixture of keynote talks, abstract presentations, and discussion panels designed to encourage collaborative antibiotic R&D. Go here for more details and registration. Abstract deadline is March 17^th 2021; no previous JPIAMR funding required.
[NEW] 29 April 2021 (online, 5-6.30p CEST): GARDP-sponsored webinar entitled “AMR R&D efforts in the CMC and formulation arena: Do it right the first time!” Go here to register.
10-12 May 2021 (virtual): UK-focused Virtual AMR Innovation Mission sponsored by Innovate UK in collaboration with AMR Insights and Oxford innovation. This free 3-day virtual event seeks to connect AMR-focused start-ups, SMEs and Multinationals, Academia, Research Institutes, Regional Development Companies and other interested stakeholders in the UK, Europe and other parts of the world. It will be followed (COVID-willing!) by a face-to-face mission scheduled for 11-15 Oct 2021. Go here for more details.
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.
24-29 May 2021 (online and in Geneva): ESPID 2021, the 39th Annual Meeting of the European Society for Paediatric Infectious Diseases. 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.
20-24 Jun 2021 (virtual, various times): World Microbe Forum sponsored by the American Society for Microbiology (ASM) and the Federation of European Microbiological Societies (FEMS). Go here for more details and to register.
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.
9-12 Jul 2021 (virtual): Annual ECCMID meeting (#31)
[NEW] 26 Jul-30 Jul 2021 (online): Small World Initiative Instructor Training Workshop – training for undergraduate professors in the wet lab techniques, parallel curricula, & pedagogical instruction to engage students in the hunt to find new antibiotic-producing soil microbes. Go here to register.
14-29 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.
11-15 Oct 2021 (physical, somewhere in the UK): UK-focused Innovation Mission sponsored by Innovate UK in collaboration with AMR Insights and Oxford innovation. This free event seeks to connect AMR-focused start-ups, SMEs and Multinationals, Academia, Research Institutes, Regional Development Companies and other interested stakeholders in the UK, Europe and other parts of the world. Go here for more 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. Bonus feature: For obvious reasons, the course didn’t happen in 2020! But as a celebration of the course’s 5th year, a webinar version was held on 29 Oct 2020: go here to stream it.
25-28 Oct 2021 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
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.

Pull incentives for antibiotics: How much and why? — A review of STEDI and related literature

John Rex — Tue, 14 Apr 2020 13:59:55 +0000

Dear All (and with thanks to Kevin Outterson for co-authoring this newsletter),

The recent discussions of the NICE/NHS England pilot subscription model (detailed newsletter plus follow-up FAQ newsletter) and a new paper by Chantal Morel and colleagues on the idea of an Antibiotic Susceptibility Bonus (ASB, link) bring to the fore the question of how to value any given antibiotic for a pull incentive.

This is something that has been considered at some length but always in bits so we thought it might be useful to create a comprehensive summary of the key references on ways to value antibiotics. To that end, see the annotated references found just below the signature block.

We are sure we will have missed something – if you spot omissions, please let us know and we will update the posted version of this newsletter.

That caveat noted, it is instructive to see what we have generated. We have sorted the references into these 4 categories:

Scientific characteristics known at initial approval: Spectrum, mechanism, ease of use
1. The focus here has been on attributes that go beyond typical HTA features.
2. Antimicrobial spectrum relative to priority pathogen lists, mechanistic novelty, and medical attributes (e.g., oral administration) are of course fundamental.
3. In addition, several non-typical (at least for HTA) attributes become important. In recent work, the acronym STEDI is appearing as shorthand here (and here is a 10-minute YouTube video that talks through this):
  1. Spectrum: Benefits of being able to treat with a narrow-spectrum agent in some settings (note how this use of Spectrum has a very specific meaning).
  2. Transmission: Benefits from avoiding spread of infection
  3. Enablement: Benefits from making it safe to receive medical care
  4. Diversity: Using varied antibiotics reduces resistance pressure
  5. Insurance: Value of having an antibiotic to hand in case of sudden need
4. The public data on an approved drug should be sufficient to calculate all of these values, which is important for pull incentives.
5. Equally important, pull incentives based on such standards are clear targets for drug developers when selecting candidate preclinical molecules: you can predict the possible value of the compound before starting Phase 1.
Scientific characteristics that can only be studied over time: emergence of resistance
1. The recent paper by Morel that triggered this newsletter is in this category, as is a 2010 paper by Kesselheim & Outterson.
2. These papers discuss the idea of a reward for stewardship / lack of resistance.
3. This is a good idea but systematically collecting data on emergence of resistance takes a lot of effort – it is hard to really sample the globe! But alignment of all actors on this goal is still a good thing.
Top-down estimates: What is the value to society if you have an antibiotic (or the cost if you do not have one)?
1. Depending on spectrum and indication, a new antibiotic appears to offer a global value to society of $0.5 – $12b.
2. This wide estimate is being narrowed by more detailed modeling, but the key takeaway is that not every antibiotic deserves the same reward. The market certainly does not work that way and neither should a pull incentive.
Bottom-up estimates: What pull incentive is needed to cover the cost of creating an antibiotic?
1. A reward of $2b – $4b is needed to create an incentive that would be adequate to cover the cost of the R&D that leads to approval of a new antibiotic (including failed attempts).
2. Duties placed on the sponsor (post-approval studies, delinked supply commitments) reduce the net value to the sponsor

This is an impressive body of work. We like the convergence on both definable scientific attributes (spectrum relative to priority pathogen lists, ease of use, etc.) and an appropriate range of rewards (low single-digit $b range). As George Box said, “All models are wrong, some are useful” … and the steady refinement we’ve seen across these approaches suggests that we have found solid footing.

Taken with recent rumblings in the US Congress regarding a subscription model much larger than the UK model (more to follow on this), we are as hopeful as we have ever been that we will make progress in this space.

Stay safe in these unusual times … all best wishes, John & Kevin

Kevin Outterson, JD, Professor of Law, Boston University & Executive Director, CARB-X (these views are personal and do not necessarily reflect the views of CARB-X or any of its funders) @koutterson

Scientific characteristics known at initial approval: Spectrum, mechanism, ease of use
1. (link) STEDI: This is shorthand for the antibiotic values of Spectrum, Transmission, Enablement, Diversity, and Insurance (STEDI) was proposed by Outterson and Rex, Translat Res 2020 based on a list of attributes first proposed by Karlsberg 2017, below.
2. (link) Rex JH, Outterson K. Antibiotic Reimbursement in a Sales-Delinked Model: Context and a Benchmark-Based Global Approach. The Lancet Infectious Disease, 16:500-5, 2016.
  1. Proposes a point-based value based on spectrum, mechanistic novelty, medically relevant improvements, indications, pediatric data, and oral dosing.
  2. Metrics based on (lack of) emergence of resistance are not discussed.
3. (link) Simoens S, Spriet I. Guidance for Demonstrating the Societal Value of new Antibiotics. Frontiers in Pharmacology, 11(2327), 2021.
  1. (1 Feb 2021 addendum) Doesn’t use the shorthand STEDI, but does review those five attributes along with novelty.
4. (link) Karlsberg Schaffer S, West P, et al. Additional Elements of Value for Health Technology Assessment Decisions. Office of Health Economics Research Paper, 2017.
  1. Proposes adding the STEDI values to (i) Novel Mechanism and (ii) traditional HTA values of health gain, unmet need, cost offsets, and productivity benefits.
  2. Metrics based on (lack of) emergence of resistance are not discussed.
5. (link) Daniel GW, McClellan MB, et al. Value-Based Strategies for Encouraging New Development of Antimicrobial Drugs. Duke-Margolis Center for Health Policy white paper, 2017. Also described in a JAMA viewpoint (link).
  1. This paper proposes a Priority Antimicrobial Value and Entry (PAVE) Award with valuation based on spectrum, drug availability, support for sustainable use, and data collection on use and outcomes.
  2. Detailed metrics are not provided.
6. (link) Rothery C, Woods B, et al. Framework for Value Assessment of New Antimicrobials. Sheffield-York EEPRU white paper. 2018.
  1. This work is the economic foundation for the NHS England/NICE subscription pilot (see this newsletter).
  2. Proposes extending standard HTA frameworks by using the STEDI elements.
  3. Discusses the need to model predicted emergence of resistance as part of the baseline estimate of value.
7. (link) Neri M, Hampson G, et al. HTA and payment mechanisms for new drugs to tackle AMR. Office of Health Economics Research Paper, 2019.
  1. Provides an integrated review of Karlsberg Schaffer, Daniel, Rothery, and the in-progress manuscript by Morton et al.
8. (link) Morton A, Colson A, et al. Horses for courses: how should the value attributes of novel antibiotics be considered in reimbursement decision making? Manuscript in preparation, 2020.
  1. Considers STEDI-like attributes and also points to consideration of emergence of resistance.
Scientific characteristics that can only be studied over time: emergence of resistance
1. (link) Kesselheim AS, Outterson K. Improving antibiotic markets for long-term sustainability. Yale J Health Policy Law Ethics, 11:101-67, 2011.
  1. This early paper (2011) argues for an Antibiotic Conservation and Effectiveness (ACE) program that conditions payments on continued effectiveness. Effectiveness is never defined, but drug-bug susceptibility patterns and morbidity are both considered.
  2. Part of the goal of the ACE was to reward company behavior that promoted stewardship (continued effectiveness).
2. (link) Morel CM, Lindahl O, Harbarth S, de Kraker MEA, Edwards S, Hollis A. Industry incentives and antibiotic resistance: an introduction to the antibiotic susceptibility bonus. J Antibiot (Tokyo), 2020.
  1. Argues for the idea of an Antibiotic Susceptibility Bonus (ASB) as a performance measure component of a Market Entry Reward that is tied to “pathogen susceptibility to the product (the product’s ability to stave off resistance) at, for example, 5, 10, 15, and 20 years following market approval.”
Top-down estimates: What is the value to society if you have an antibiotic (or the cost if you do not have one)?
1. (link) Sertkaya A, Eyraud J, et al. Analytical framework for examining the value of antibacterial products. Eastern Research Group Report to US DHHS. United States Department of Health and Human Services, 2014.
  1. Using data from 2012 and before, the authors consider
    1. The Value of a Statistical Life Year (VSLY, an estimate of how much people are willing to pay to live a certain amount longer) and
    2. Estimates of reduced Quality-Adjusted Life Years (QALYs) based on both mortality (QALYs go to zero) and morbidity (QALY is reduced during illness).
  2. These ideas are used to estimate the value to society of a new drug as ranging from $0.5b to $12.2b:
    1. $0.5b for a new drug for acute bacterial otitis media (ABOM)
    2. $9.4b for a new drug for community-acquired bacterial pneumonia (CABP), and
    3. $12.2b for a new drug for hospital- or ventilator-associated bacterial pneumonia (HABP/VABP).
    4. If you look at this paper, be sure to also look at Kevin Outterson’s updated critiques and modeling presented during the 16 Jan 2020 Duke-Margolis payor meeting … see comments below in the bottom-up modeling section.
2. (link) Megiddo I, Drabik D, et al. Investing in antibiotics to alleviate future catastrophic outcomes: What is the value of having an effective antibiotic to mitigate pandemic influenza? Health Economics, 2019.
  1. Estimates the value of a new oral antibiotic based on societal value if the antibiotic is held in reserve (and hence no resistance develops) vs. value if it is used and resistance emerges.
  2. This is a complex UK-focused model but it aligns with the estimates from Sertkaya: see this newsletter for a discussion.
3. (link) NICE/NHS England Antibiotic Subscription Pilot, 2020.
  1. Implies a high-quality antibiotic has a global value of $4b.
  2. See newsletter at the link just above and be sure to read the FAQ closely.
Bottom-up estimates: What pull incentive is needed to cover the cost of creating an antibiotic?
1. (link) Sharma P and Towse A. New drugs to tackle antimicrobial resistance. 2011.
  1. The authors estimate that a reward of $1.4-1.8b is needed to produce an NPV return of $200m on an antibiotic discovery project (this paper works in Euros, we have converted to USD at the 2011 EUR/USD conversion rate of 1.3).
2. (link) Sertkaya A, Eyraud J, et al. 2014 (same paper as cited for the top-down section).
  1. The authors estimate that a reward of $1-1.2b is needed to produce an NPV return of $100m on an antibiotic discovery project.
3. (link) Securing New Drugs for Future Generations: The Pipeline of Antibiotics. UK Review on Antimicrobial Resistance, 2015 (May). The other reports from the UK AMR review are found here.
  1. Estimates a need to pay $1.6-3.7b on a global basis to provide the return needed to drive antibiotic innovation.
4. (link) Towse A, Hoyle CK, et al. Time for a Change in How New Antibiotics are Reimbursed: Development of an Insurance Framework for Funding New Antibiotics based on a Policy of Risk Mitigation. Health Policy, 121:1025-30, 2017.
  1. Estimates the eNPV of an antibiotic R&D program at -$0.5b to -$1.5b.
  2. Hence, the value of a global Pull reward needs to cover this negative NPV.
  3. Post-approval costs are estimated at $20-60m rather than the $300-400m that is known recognized as required (see similar comment for Ardal 2018 just below).
5. (link) Ardal C et al. DRIVE-AB Report: Revitalizing the antibiotic pipeline: stimulating innovation while driving sustainable use and global access. 2018.
  1. Used Monte Carlo agent-based simulations to demonstrate the impact of a pull incentive.
  2. Estimates a need to pay $1b per novel agent on a global basis to provide the return needed to drive innovation.
  3. Assumes post-approval costs of only $10m, a value that has recently been shown to be a significant underestimate (go to this newsletter for a detailed discussion of the superb 2019 ASM-ESCMID Bootcamp on this topic).
6. Outterson K. Unpublished manuscript in preparation that addresses critiques of the Sertkaya/ERG report with updated data. A recent presentation on this work in progress at the 16 Jan 2020 Duke Margolis meeting suggested that pull incentive values in $2-4B range are needed for a positive NPV, with continued high levels of support for push incentives. Go here for the materials from that meeting – jump to 4h 49m to hear Kevin’s presentation.

Current funding opportunities:

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.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes funders and projects by geography, stage, and more.

Upcoming meetings of interest to the AMR community:

28 Apr 2020 (online, 17:00-18:30 CEST): GARDP REVIVE webinar. Title: “Inhaled antimicrobials: Do we get the drug to the bug?” Speaker: Harm A. W. M. Tiddens. Go here to register.
9 Jul 2020 (online, 09:00-10:30 CEST): GARDP REVIVE webinar. Title: “The challenges and opportunities for antimicrobial R&D in low- and middle-income countries – India case study.” Speaker: Anand Anandkumar. Go here to register.
17 Jul-2 Aug 2020 (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.
29 Jul-2 Aug 2020 (Philadelphia, PA): Small World Initiative Instructor Training Workshop – training for undergraduate professors and high school teachers in wet lab techniques, parallel curricula, pedagogical instruction to engage students in the hunt to find new antibiotics in soil. Go here to register.
4 Aug 2020 (Silver Spring): FDA workshop entitled “Development Considerations of Antifungal Drugs to Address Unmet Medical Need.” Go here to register.
5 Aug 2020 (Silver Spring): FDA workshop entitled “Developing Antifungal Drugs for the Treatment of Coccidioidomycosis (Valley Fever) Infection.” Go here to register.
24-25 Aug 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.
September 2020. 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 runs annually from September and covers microbiology, clinical practice and policy. The course webpage is here.
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. Registration is here and is limited to 40 students.
26-29 Oct 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)
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.

All-in cost of a new antibiotic from discovery to 10 years on market

John Rex — Sat, 09 Jan 2021 20:25:33 +0000

Dear All (and with thanks to Kevin Krause for co-authoring this newsletter),

The elements that contribute to the all-in cost of an antibiotic have been reviewed in two prior newsletters:

6 Mar 2020 (focused on cost of R&D to approval): What does an antibiotic cost to develop? What is it worth? How to afford it?
7 Jan 2020 (focused on post-approval costs): “Melinta, Part 2 / Bankruptcy Is Not The End / Post-Approval Costs For An Antibiotic”

As a further review of these ideas, Kevin Krause and I had an opportunity last week to present an integrated summary via a pair of back-to-back talks on the first day of the 5-8 Jan 2021 meeting of the NASEM committee convened for the project entitled “Examining the Long-term Health and Economic Effects of Antimicrobial Resistance in the United States.”

Krause: “The Post-Approval Challenges of Antimicrobial Development” (.pdf) (.pptx) (YouTube)
Rex: “Pricing of Antibiotics & Proposals to Strengthen the Pipeline” (.pdf) (.pptx) (YouTube)

Here are the key ideas as we see them (and please read or listen to the talks for more detail!):

The process is slow: Expect it take take 10-20 years for a true novel class to go from first molecule to approved product.
Integrating all R&D costs (the failures and the final success), a realistic average cost to first approval is ~$1.3b.
- 13 Oct 2024 addendum: Useful references here are and DiMasi 2016 J Health Econ, Wouters 2020 JAMA, and Outterson 2021 Health Affairs.
Keeping the product on the market (supply chain, pharmacovigilance, etc.) requires a total of ~$350m for the first 10 years after approval
- This is the cost for each successful molecule: There aren’t a lot of synergies in bringing several molecules into one portfolio.
- From a cash flow perspective, costs are highest in the first few years after approval and the $ figures in Kevin’s talk focus on the first five years. The resulting squeeze on the innovator’s bottom line will have a predictably negative effect!
The total of ~$1.7b is for the absolutely required costs that would be incurred by any group
- This cost includes the cost of failures along the way to (i) first approval in one indication and (ii) the required post-approval activities for the compound.
- This cost covers salaries, a pediatric program, supply chain, surveillance studies to monitor for development of resistance, and medical support.
- This cost does not include marketing efforts beyond required medical education (e.g., answering questions from prescribers).
- The costs are the same for large companies vs. small, for-profit vs. not-for-profit, etc.
Recognizing these true costs of new molecules helps frame the discussion of the size of global pull incentives such as the UK Antibiotic Subscription Pilot (18 Dec 2020 newsletter) and the PASTEUR Act in the US (9 Dec 2020 newsletter).

—
One way to summarize would be to say that “Luck is not a strategy!” If we really want new molecules, we have to plan for real costs and real timelines. Importantly, the costs are independent of the underlying business model.

All models (large pharma, small pharma, for-profit, non-profit, public benefit) will confront similar costs.
Large pharma do have some advantages for creation of a global distribution network, but supply chain costs, trial costs, and regulatory requirements are largely independent of the underlying business model.
Corporate models (especially small biotech) are already very lean and incorporate every possible cost reduction strategy: even nonprofits must earn positive margins in order to be sustainable.
For more on this, see Outterson K, Rex JH. Evaluating for-profit public benefit corporations as an additional structure for antibiotic development and commercialization. Translational Research, 2020, https://doi.org/10.1016/j.trsl.2020.02.006.

So, that’s a lot of bad news: new antibiotics are expensive and take a long time to create! The good news is that although it takes a lot of money and time to get there, we see strong signs that the needed ecosystem is coming into existence:

The more than 90 pre-clinical to Phase 1 projects funded to date by CARB-X and the Novo REPAIR Impact Fund are proof of the interest by many in this area.
The recently created $1b AMR Action Fund will provide support for Phase 2-3 for the most promising molecules (9 Jul 2020 newsletter) and has the intent of bringing 2-4 molecules to approval by 2030. Aside: Don’t forget that this fund will require Pull incentives to be self-sustaining — without such Pull awards, both it and any molecules reaching approval will likely go bankrupt.
Finally, the high-level discussions of strong Pull models now include
- The UK and US (as noted above)
- The recently announced EU Pharmaceutical Strategy (28 Nov 2020 newsletter)
  - A pilot will be announced this year, per the Commission
  - Encouragingly, an EU-JAMRAI-sponsored survey (link to 11 Dec 2020 white paper) of policymakers in 13 countries (10 from EU plus Canada, South Africa, and Japan) found support for incentives in most countries, including interest in a multinational incentive
- Activity in Japan (11 Jan 2020 newsletter)
- And other early signs of interest (the 9 Dec 2020 newsletter provides a global survey of novel antibiotic reimbursement models)

Wow! It is indeed amazing to reflect on how far we’ve come in this area in the last 10 years. There is still more to do, but this momentum is so very encouraging!

All best wishes, John and Kevin

Kevin Krause, BSc, MBA | V.P. Clinical Sciences and Development Operations, AN2 Therapeutics. All opinions are my own.

Current funding opportunities (most current list is here):

CDC has released a Broad Agency Announcement with that includes multiple opportunities for AMR-related work. See this newsletter for details. The deadline is 13 Jan 2021.
FDA have released RFPs for work on breakpoint updates, impact of extended duration infusion beta-lactam therapy, and development of PROs for NTM, ABPA, and coccidioidomycosis. All have 28 Jan 2021 deadlines for an initial Quad Chart and White Paper. See this newsletter for more details.
The US Department of Defense is funding pre-clinical research on small molecules vs. P. aeruginosa. See this newsletter for details. The deadline is 18 Feb 2021.
FDA have announced two fellowship opportunities (one for research on ordinal endpoints, one for research on endpoints in cUTI), both with a 26 Feb 2021 deadline. See this newsletter for more details.
CDC has released an RFP entitled “Safe Healthcare, Epidemiology, and Prevention Research Development (SHEPheRD)” that seeks support for a broad range of healthcare epidemiology projects. See this newsletter for details. The deadline is 3 Mar 2021.
The National Institute of Allergy and Infectious Diseases (NIAID) Applicant Assistance Program (AAP) provides no cost support for companies planning to apply for a Phase II, Fast Track, or Direct-to-Phase II SBIR or STTR Award. Go here for details.
Novo REPAIR Impact Fund closed its most recent round on 31 Jul 2020. Go here for current details.
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (75 total awards, and counting and they conclude contracting on prior rounds), including future options on those awards. New rounds from CARB-X will occur only after new funding is obtained in 2021.
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.
Finally, 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):

14 Jan 2021 (online, 5-6.30p CET): GARDP-sponsored webinar entitled “Manipulating the host response to treat infections,” moderated by Neeloffer Mookherjee. Go here to register.
18-20 Jan 2021 (online, 10.00a EST to ???): A pair of virtual Keystone Symposia entitled “Harnessing the Microbiome for Disease Prevention and Therapy” and “The Microbiome: From Mother to Child”. Not a lot specifically on infection, but the deep biology typical of Keystone’s programs looks fascinating. Go here and here to register.
25 Jan 2021 (online, 4-6 UK): Update webinar by the NHS England and NHS Improvement team who are running the UK Antibiotic Subscription pilot. Please mark your calendar now; the link for the webinar will be posted to https://amr.solutions/meetings/ when I have it.
26-28 Jan 2021 (online, runs ~7.30a-5.00p Central each day): 4th Annual Texas Medical Center Antimicrobial Resistance and Stewardship Conference. Sponsored by McGovern Medical School, ARLG, and the Gulf Coast Consortia, the agenda includes both poster sessions and keynotes. The call for abstracts closes 18 Dec 2020. Go here for more details.
2-3 Feb 2021 (online, 1-5p GMT): Antimicrobial Chemotherapy Conference 2021 sponsored by BSAC and GARDP in collaboration with the Helmholtz Institute for Pharmaceutical Sciences (HIPS), the German Center for Infection Research (DZIF) and the International Research Alliance for Antibiotic Discovery and Development (IRAADD, a JPIAMR-funded network). Go here for details and to register.
10-11 Feb 2021 (online, 10a-4p EST): Virtual public meeting of PACCARB (US Presidential Advisory Council on Combatting Antimicrobial Resistant Bacteria). Go here for details.
[TITLE AMENDED] 25 Feb 2021 (online, 5-6.30p CET): GARDP-sponsored webinar entitled “From discovery to the pre-clinical antimicrobial candidate,” moderated by Michael Mourez. Go here to register.
10-12 Mar 2021 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register; abstract deadline is 15 Nov 2020.
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.
24-29 May 2021 (online and in Geneva): ESPID 2021, the 39th Annual Meeting of the European Society for Paediatric Infectious Diseases. 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. Bonus feature: For obvious reasons, the course didn’t happen in 2020! But as a celebration of the course’s 5th year, a webinar version was held on 29 Oct 2020: go here to stream it.
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.