PK measures in space and time: Summary of high-resolution methods

Dear All: 

I recently sent around discussions of ways to measure/estimate drug concentrations both in living animals (aptamer-based probes, Kevin Plaxco’s group) and with sufficient spatial resolution to permit construction of 2d/3d drug concentration maps (MALDI-MSI, David Perlin’s group).

In the context of our efforts to learn to better apply PK-PD (e.g., the 14-15 June 2017 NIAID PK-PD workshop), these notes generated a lot of interest and in particular Ed Weinstein (FDA) made me aware of a book chapter in which he and his co-authors had looked at a range of such techniques.

Finding this intriguing, I worked with Kevin, David, and Ed to prepare a summary of the range of current techniques for doing something that you could loosely call PK in high resolution by time and/or space. Several ways of categorizing the methods are shown in the table below and you’ll find more details on each in this downloadable summary document. It’s fascinating to see them side-by-side and realize the wealth of opportunities that exist.

Each approach has strengths and weaknesses but I must say that MALDI-MSI and aptamer-based probes really standout as exciting new tools by offering strong spatial information (MALDI-MSI) or easily obtained continuous drug measures (aptamer-based probes) based in both cases on measurements of the unmodified analyte

Overview of techniques: Specialized probe and/or modified analyte vs. general approach to detection of unmodified analytes

Continuous, with
potential for in vivo
Single* time point
Offers
spatial
resolution
Fluorescent probeHyperpolarized NMR/MRIPET ImagingPhotoacoustic imagingLow energy (3H or 14C) radio-labeled analyte
with Whole-Body AutoradiographyMALDI-MSILaser-capture microdissection
Single*
site
Aptamers on a probeMicrodialysisGrind tissue & assay extract

*Of course, any single time point or single site method could be extended by doing serial sampling but there are practical limits to how much of this you can do.

Rough rank order of spatial imaging resolution methods:

  1. Higher resolution: MALDI-MSI, autoradiography
  2. Lower resolution: Fluorescent probe, Hyperpolarized NMR/MRI, PET Imaging, Photoacoustic imaging, Laser-capture microdissection

Absolute analyte concentration data: (1) Aptamers on a probe, (2) Microdialysis (with difficulty), (3) Laser-capture microdissection, and (4) Grind tissue & assay extract

If this intrigues, you may also want to look both at this book and PK-specific chapter within it:

  1. Book: Imaging Infections : From Bench to Bedside. S. K. Jain.: https://link.springer.com/book/10.1007%2F978-3-319-54592-9
  2. Chapter in said book Ordonez, A. A., L. E. Bambarger, S. K. Jain and E. A. Weinstein (2017). Biodistribution and Pharmacokinetics of Antimicrobials. Imaging Infections : From Bench to Bedside. S. K. Jain. Cham, Springer International Publishing: 209-222. :https://link.springer.com/chapter/10.1007/978-3-319-54592-9_10

And to round out this summary of PK-related ideas, you might also want to review the material from

MANY thanks to Ed, David, and Kevin for provoking this interesting exploration!

All best wishes, –jr

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

Upcoming meetings of interest to the AMR community:

Dear All,
 
The IDWeek 2024 program committee is again seeking programs on novel antimicrobial agents and novel diagnostics for presentation in pipeline sessions! Here’s what is sought:

  • “Industry partners are invited to submit antimicrobials that are in preclinical stages of development (Phase II and III preferred) or recently approved after January 2024.
  • “The pipeline sessions will include antibacterials, antifungals, and antivirals (excluding COVID-19 and HIV).
  • “The committee also invites companies developing novel diagnostic technologies with a minimum of some preliminary proof of concept data to submit.” 

This is a great opportunity to tell the story of your development project! The deadline to submit is Wednesday, June 26 via the application portal. Any questions should be directed to program@idsociety.org. Please share this email with anyone you think might be interested in applying!
 
In addition, I’ll also note that those with a more general story to tell should look at the BugHub Stage (and the Global BugHub stage). Both BugHub variants seek “presentations that touch on your experience of working in infectious diseases and presentations that ultimately lead to a greater understanding of our diverse field” via a TED Talk-esque speech about your work. The deadline for applications is 26 June, the same as for the pipeline sessions.

I look forward to seeing you there! 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.

John’s Top Recurring Meetings

Virtual meetings are easy to attend, but regular attendance at annual in-person events is the key to building your network and gaining deeper insight. My personal favorites for such in-person meetings are below. Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!

  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details. 
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. Go here for the meeting’s general website. You can’t register (yet) for the 2024 event, but save the date!
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. Save the date! More details to come!
  • 25-26 February 2025 (Basel, Switzerland): The 9th AMR Conference 2025. Go here to register

Upcoming meetings of interest to the AMR community:

  • [NEW]  9 Apr 2024 (virtual, 830a-10a ET): GARDP’s next REVIVE webinar entitled “Progressing a discovery project – Criteria and challenges.” Register here.
  • [NEW] 9 Apr 2024 (virtual, 10a-1130a ET): CDC webinar “Impacts of Antimicrobial Resistance on Cancer Care.” Click here for details and to register.
  • 10-11 Apr 2024 (virtual): Sepsis Alliance AMR Conference, a 2-day conference focused on “Practical technologies to manage sepsis and counteract the expanding challenge of antimicrobial resistance.” Go here for details and to register.
  • 26 Apr 2024 (Barcelona, Spain): ESCMID workshop entitled “Using Data Science and Machine Learning for Infection Science: A Hands-on Introduction.” Click here to register or here for more details. 
  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 26-31 May 2024 (Montreal, Canada): EDAR7, the McGill AMR Centre’s 7th edition of their Environmental Dimension of Antimicrobial Resistance conference. Go here for details; final abstract deadline is 21 Dec 2023.
  • 28-29 May 2024 (in person, Uppsala, Sweden): Uppsala Antibiotic Days, a broad-ranging 2-day program hosted by the Uppsala Antibiotic Center. Go here for details and to register.
  • [NEW] 30-31 May 2024 (face-to-face in Rockville, Maryland as well as online, 8.30-5.30p ET on 30 May, 9-2.40p on 31 May): NIAID-sponsored workshop entitled “Towards realizing the promise of adjunctive immune therapy for invasive fungal infections”. The agenda covers host immunity to invasive fungal infections, immune modulators in the context of fungal infections; and strategies for testing immune modulators as adjunctive therapy. Go here for more details and to register.
  • 9-13 June 2024 (in person, Ascona, Switzerland): “New Approaches to Combat Antibiotic-Resistant Bacteria, 2nd Edition” is a Sunday-Thursday residential workshop focused on the deep biology of AMR. Sponsored by NCCR AntiResist (a Swiss National Science Foundation consortium), the scientific program has the feel of a Gordon Conference. Space is limited, so you are encouraged to apply promptly — go here for details.
  • 13-17 June 2024 (Atlanta, Georgia): ASM Microbe, the annual meeting of the American Society for Microbiology. You can’t register yet, but you can go here for general details.
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. See Recurring Meetings list, above.
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. See Recurring Meetings list, above. 
  • 19-27 Oct 2024 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance). Now in its 8th year, Patrice Courvalin directs the program with the support of an all-star scientific committee and faculty. The resulting soup-to-nuts training covers all aspects of antimicrobials, is very intense, and routinely gets rave reviews! Seating is limited, so mark your calendars now if you are interested. Applications open in March 2024 — go here for more details.
  • 4-5 Dec 2024 (in person, Washington, DC): “Fungal Dx 2024: Fungal Diagnostics in Clinical Practice” is a 2-day in-person workshop organized by ISHAM‘s Fungal Diagnostics Working Group. The program and registration links are available at https://fungaldx.com/; the agenda is comprehensive and features an all-star global list of speakers.

Share

48,015 → 0: Antibacterial discovery is hard. Really, really hard.

Dear All (and with thanks to Patricia Bradford for co-authoring this newsletter), When you are seeking novelty, antibacterial discovery is hard … really, really, REALLY hard. And it gets even harder if you want activity vs. Gram-negative bacteria. As the latest proof of this, a paper from GARDP’s Blasco et al. describing use of an

Call for Pull: Swiss Roundtable on Antibiotics

Dear All, To end the week, we have a really lovely paper from the Swiss Roundtable on Antibiotics (a multidisciplinary, non-profit Swiss association). Here are the links you need: The new (25 March 2024) paper entitled “Effective antibiotics for the Swiss health care system: today and in the future.” A prior (7 Feb 2023) paper

Help PASTEUR cross the finish line: Action Alert from IDSA!

Dear All, Today’s news is that the House PASTEUR sponsors (Drew Ferguson [R-GA-3], Scott Peters [D-CA-50], Jake LaTurner [RKS-2] and Mike Levin [D-CA-49]) are urging House leadership to authorize the PASTEUR Act without initially having funding attached. Although this may seem counterintuitive, initial passage as a $0 bill is a solid strategy — it is common

Scroll to Top