Subscribe
Share
Share
Embed
Communicable takes on hot topics in infectious diseases and clinical microbiology. Hosted by the editors of CMI Communications, the open-access journal of ESCMID, the European Society of Clinical Microbiology & Infectious Diseases.
Communicable E066: WAAW diagnostics
===
[00:00:00]
Thomas: Hi, and welcome back to Communicable, the podcast brought to you by CMI Communications, ESCMID's open access journal covering infectious diseases and clinical microbiology. My name is Thomas Tängden. I'm a professor and senior consultant on infectious diseases in Uppsala, Sweden, and an associate editor at CMI Comms.
I'm joined by my co-host, Annie Joseph, fellow editor at CMI Comms. Annie is a consultant medical microbiologist at NHS, specialist in women's health infection, diagnostics, and antimicrobial stewardship in Nottingham, England.
Hi, Thomas. It's, great to be back hosting. It's been a little while. so this episode is, in honor of World Antimicrobial Resistance Awareness Week, and we're excited to welcome two fantastic expert guests with us.
we're gonna be focusing on how diagnostics, in particular, can help to tackle AMR and be part of the solution to the global AMR [00:01:00] crisis. So our first guest today is Betsy Wonderly-Trainor. Betsy is an alliance director at CARB-X, a global nonprofit dedicated to addressing the threat of drug-resistant bacteria.
Annie: Throughout her career, betsy has focused on the development and commercialization of in vitro diagnostics for viral and bacterial detection. Prior to being at CARB-X, Betsy supported development at multiple innovative companies, in addition to leading product validation and implementation efforts at FIND and the WHO during the Ebola outbreak of twenty fourteen to fifteen.
She supported the development of target product profiles, global guidelines, and negotiated deals with donor organizations. Betsy has an amazing background in not only clinical research, but also in behavioral science and business. So we are very lucky to have her with us today on Communicable. Welcome, Betsy.
Thank you, Annie. Thank you, Thomas. It's a pleasure to be here with you today.
Thomas: Our second guest is Marc Mendelson, a professor of infectious diseases and the division head of infectious [00:02:00] diseases and HIV medicine at Groote Schuur Hospital, University of Cape Town.
Marc studied medicine at St Mary's Hospital, London, and specialized in infectious diseases at Addenbrooke's Hospital, Cambridge, where he attained his PhD. He then moved to the Rockefeller University, New York in 2001, subsequently to University of Cape Town to work on tuberculosis and innate immunity.
He's the co-founder of South African Antibiotic Stewardship Program and a member of scientific advisory committees of the WHO and other international organizations. Welcome, Mark.
Thanks very much, Thomas and to Annie, and it's great to join you today.
Annie: so as our listeners know, we usually start Communicule episodes with a get to know you question, and we make our host go first, so guests don't have to. So World Antimicrobial Awareness Week takes place every November, and it tends to be a pretty hectic week for anybody working in AMR and stewardship.
So if you could completely ignore your inbox and disappear somewhere else [00:03:00] in the world for a week in November, where would you go? so I'll go first. November is a time of year when it really starts to get very gray here in the middle of England, and then it just stays gray for about the next four months.
so definitely would have to be somewhere sunny and to get my vitamin D in before the winter. maybe somewhere with some history, too. So I'd probably head to the Greek Islands, get some sunshine, check out some of their ancient ruins, and escape World AMR Week for a change. how about you, Tuomas?
I'll bet it's gray in Sweden, isn't it?
it's dark. It's getting cold. I would probably go to a, a beach called Noosa. It's in Australia, Queensland, where I spent couple of weekends, in my life. it's a perfect place in November. It's springtime. It's beautiful, it's just about having fun and surfing.
Thomas: How about you, Betsy?
Betsy: Those sound lovely. I'm slightly biased. I'm in the midst of a really busy travel season, and autumn is actually my favorite season [00:04:00] here in, the US, and so I would really love to just kind of stay at home and hunker down with my family and watch the leaves change and enjoy the mists in the morning as the, temperature starts to drop, and just soak up all that is the autumn season in some quiet, quiet space.
But, that never seems to happen 'cause as you mentioned, this is just a really busy time of year, which is a wonderful thing 'cause we get to see each other in so many different, venues, and it's really great for connecting.
Fantastic. And you, Marc?
Oh, yeah. Cape Town in November is really perfect.
Marc: it's just before the winds begin, and, you get these wonderful clear days, so it's a great time to be here. But, actually, I have to admit that I am, going to be leaving Cape Town during World Antimicrobial Resistance Awareness Week, and, going for a couple of weeks to Japan to travel- Mm-hmm
um, and particularly 'cause of the autumn leaves, peak around then, so gonna be exploring a new country and a new, [00:05:00] culture.
Annie: It's very cool.
Thomas: Yeah. Sounds fantastic. Okay. So now let's get to the topic of today. why are diagnostics so important in the fight against AMR, and how much of the AMR problem is really a diagnostics problem?
Betsy, would you like to go first?
Betsy: Yeah, sure. , I think diagnostics in general, not just within AMR, are really the starting point for, clinicians in treating patients. And I think, with Ebola, the test is where you really start to stop transmission, especially when you don't have any therapeutics or vaccines available.
And so the, value of the diagnostics is obvious when it's the only tool, cause it's the only way to triage patients and stop transmission. with antimicrobial resistance, it's not too different. we have a lot of, drug-resistant bacterial infections that are highly transmissible, and I think the sooner you can rapidly detect them and either isolate or just appropriately treat that patient, the sooner you can stop transmission.
You can, help that patient recover. You can also [00:06:00] really, have an impact by appropriately treating that patient through identifying what, pathogen is causing the infection and what medicines that infection will be susceptible to. You can really also preserve antibiotics that aren't needed in that patient and not put pressure on them, by overusing unnecessary antibiotics.
So I think diagnostics play a key role in general, but also very specifically within the AMR story and the fight against AMR. How much of AMR is really a diagnostics problem? I think, it's the beginning of the journey. and I think should be the beginning of the journey, but often isn't.
but I don't think it's because of the diagnostics. I think it's because of the, business, situation and the antibiotics being so readily available in many parts of the world, and so affordable. And so I think the challenge for us is more of a business problem versus a lack of tools problem
Thomas: Yeah, thanks. And we'll come [00:07:00] back to the business problems with diagnostics later on.
Annie: So where are the biggest gaps today then between what diagnostics can do and what clinicians actually need?
obviously the needs are different depending on the setting and the patient population. So let's start with hospitalized patients with severe infections in high income countries. Marc, what do you think about that?
Marc: Well, before I come to it, I just wanted to add to Betsy's great comments about, the importance of diagnostics and antimicrobial resistance.
I mean, from a clinician's point of view, so many of the prescribers, will tell you that the, the main driver for inappropriate use of antibiotics is probably diagnostic uncertainty. and so having access to reliable diagnostics which actually help in the management of the patient is critical.
Marc: Now, the question about whether, diagnostics are the central issue, in AMR, how much is diagnostics really a problem? I would say that it's a-- [00:08:00] the critical component, but it's not the major issue. You have to turn off the tap of infectious diseases and reduce burden, reduce people actually going to a prescriber or a, you know, doctor to actually get a diagnostic test in the first place, and then indeed an antibiotic.
So critical, but not the major issue. But i-in terms of gaps, and i-if we're thinking about high-income countries, severely ill patients, the biggest gaps I'm not sure are access related in terms of diagnostics per se, but the results of, available tests, they will often either arrive late.
they aren't only part of the conundrum, the prescribing, question, and they may fail to actually To change treatment at all. So we know that culture and, susceptibility testing takes days. That while nucleic acid tests commonly lack susceptibility information, thus not making a difference sometimes.[00:09:00]
Marc: We know that molecular panels for genotypic tests, the coverage there, may be problematic and they may not replace phenotypic testing. phenotypic tests are often nullified if you give antibiotics beforehand. and neither phenotypic nor genotypic tests really help with defining whether you've got infection versus colonization, or indeed contamination in many circumstances.
And I guess urinary tract, infections or bacteria in urine with asymptomatic bacteria versus symptomatic bacteria is a good example. So in a hospitalized severely ill patient where we lack a test with sufficient capability to differentiate either bacterial or viral infection, uncertainty will always favor broad empiric, treatment.
And results don't always translate into de-escalation or stopping antibiotics because , of entrenched prescribing habits and lack of [00:10:00] understanding and awareness and education around stewardship. So I think the, biggest gap probably is in incorporating rapid diagnostic tests into clinical care algorithms, for example, as part of clinical decision support systems.
If we could do that, I think that would fill an important gap, particularly for patients in this scenario of a severely ill patient in a high-income country hospital.
Thomas: Thank you, Marc, and, and we'll discuss a bit more later the implementation part and, maybe the lack of evidence on how the new diagnostics actually change practice and patient outcomes.
but before that, betsy, you recently co-authored a paper mapping the global landscape of diagnostics for bacterial pathogens driving AMR with a focus on low and middle-income countries. What were the main conclusions in this paper, and how is the situation different in these countries in terms of needs and challenges, do you think?
Betsy: Yeah, it's a great question, first, we have to ta-thank, Valeria [00:11:00] Gigante and Maureen Murtaugh for leading the WHO landscaping activities. I'm very grateful that they do that. The vast majority of products that are available today to detect, identify or perform resistance testing for bacterial priority pathogens are not suitable for use at all healthcare facility levels.
most systems do require, you know, sophisticated, well-equipped laboratories with well-trained laboratory staff, as Marc mentioned. and in LMICs, these, r-resources are less available more generally, and this effectively limits access to these tests to tertiary and high-level healthcare facilities.
So I think we really saw a need for, more deployable systems that can be used out-outside of the healthcare settings. that doesn't limit them to only being used outside of the healthcare settings. It just makes that now a feasible, area for testing to be practiced. And, . We know from the Lancet Commission that, about half the population has limited access to diagnostics, and I think that's even greater if you look at the lower levels of the health system in LMICs. and so I think we're [00:12:00] looking at Gaps where, you can essentially go direct from specimen, so diagnostic approaches that don't require culture but can allow you to go direct from specimen, whether that's urine, blood, alternative less invasive sample types for, diagnosing respiratory tract infections and others.
and just in general, simpler products, products that can be used by a larger cater of, healthcare workers that can expand testing so that we can really diagnose before patients go into hospital, diagnose a urinary tract infection before it becomes sepsis, and really start to move, the needle on addressing the, AMR problem at the community level
Thanks, Betsy. , We'll put a link in the show notes, to that paper as well so listeners can, find out more about that one. you've both already touched actually on, phenotypic versus genotypic testing and I think for a lot of people, the traditional sort of culture-based phenotypic susceptibility testing [00:13:00] probably still is the first thing that comes to mind when thinking about AMR.
Annie: but the challenge really of implementing, genetic tests still feels like we're not quite there even in high income countries. Marc, do you want to kind of do a bit of a deeper dive on that? what really are the pros and cons of genotypic tests, and why have we not had that wider scale adoption yet?
it's a great question. So I guess, , pros and cons. the pros of genetic testing, really come down in part to speed, quicker turnaround times, which might then, I say might support, targeted treatment and de-escalation if that genotypic test has the ability to you know, give you the right answer.
the ability to detect the organism when antibiotics, I mentioned,, antibiotics often given prior to a diagnostic test, and phenotypic testing clearly suffers from, you know, having an antibiotic around. So, even if growth is suppressed, the genotypic test may [00:14:00] give you the answer.
Marc: and then for particular organisms and particular resistance genes, there's very high specificity and sensitivity of many of these tests. So, those are really the pros. If you think about the cons of a genotypic tests, the test will only test obviously for what it is designed to test for.
. Now, as we go forward, we may be able to pack in far more, targets and organisms into our rapid diagnostic test, but that is one of the cons. a negative resistance test, genotypically doesn't reliably rule out resistance if the, test isn't comprehensively looking at all the potential resistance mutations.
so that again is a potential, con. the other point about it is that even if a gene is detected, we don't, know automatically whether that's being expressed. So just because the gene's there doesn't automatically mean that there's going to be resistance.
where, phenotypic testing comes to the fore. And then largely, you know, the costs [00:15:00] are generally higher than for phenotypic tests. they may require dedicated hardware, dedicated reagents, and that, , many staff or many laboratories in the low, middle-income countries in particular, like in my settings, will not be able to afford.
So while they're very powerful tools, they don't automatically give the answer that you want. And probably the ideal , is a mix between genotypic and phenotypic testing.
Annie: Marc, you've just made me think there about the potential for sort of diagnostic escape mutants. I mean, the bacteria and viruses, they're so clever, and then we're never gonna defeat them.
And it's just made me think about, you know, if you've got a panel that's gonna pick up organisms that carry CTXM, KPC, et cetera, when something new comes along, you could be completely in the dark and have a massive problem on your hands relying only on genotypic testing.
Marc: Absolutely. No, I totally agree.
phenotypic testing and surveillance, whole genome [00:16:00] sequencing, and all these things that, will allow us to hopefully recognize or predict, potentially predict, what resistance mutations are going to be playing important role is critical to keep on top of
Thomas: Okay. I'm gonna turn to Betsy again. we hear a lot about promising new rapid diagnostics, but most of them never make it to routine care. It's something we hear about and read about. What prevents promising technologies from reaching routine clinical practice? What incentives would encourage more investment in diagnostics for AMR you think?
Betsy: Well, here we go. This is the tough nut to crack. as mentioned before, I think a big challenge here is, behavior change, and, I think behavior change is often not because of a lack of will. I think a lot of clinicians would prefer to use a rapid diagnostic test that can very clearly tell them what the pathogen is and what, treatment is likely most effective.
but I think they're not necessarily incentivized to follow that action or follow [00:17:00] that desire to, provide the best care to the patient, and often it's actually disincentivized, because it's a bundled payment and you make more money or you save more money if you actually, can cut costs in the patient journey and, and this is how definitely in the US the reimbursement system is set up today is very much disincentivizing testing or at least incentivizing the lowest cost testing.
and I think until we move away from that, until we move towards more of a value-based, care payment method I think we'll continue to see this disincentive to performing testing to guide therapeutic decision-making. in the community it's a little bit different. I think the lack of existing financing structures in general at the community level make testing prior to prescribing or just, seeking empiric antibiotics, It makes that an even more complicated system, right?
there aren't many, community-based reimbursement [00:18:00] systems that have been effective in the AMR space. And so I think we actually have to build from the ground up there to really support community-based testing and diagnosing these infections early before they, progress and have to lead to hospital stays.
a-again, I don't think it's lack of will. I think we have many tools. There's still a lot of direct from specimen tools are still in the pipeline and, coming, and I'm very excited for the day when they reach the market. But even a lot of the tools we do have, I think it's not a lack of desire to use them, it's just a lack of a supportive structure that encourages and reimburses for appropriate use of them.
Thomas: Yeah, and, Marc, you, touched on this a little bit before, like how we use the new tests and how they should probably not be evaluated like standalone tools, but be implemented in some algorithm or, management strategy, like on how to take care of the patients, like combining different tests, combining it with maybe clinical parameters or other decision support tools.
have we [00:19:00] failed in this process, like in the evaluation of, of new diagnostic tools, do you think?
Marc: I think we have. I mean, I think we also have to, in many respects, hold our hands up and say we failed patients, because to me, clinicians are their own rapid diagnostic tools. You know, we are meant to be able to take a history and examine a patient and the whole issue around, , viral versus bacterial infection, everyone is gasping for a test that will, help to tell the difference.
But I would put to you that in a very large percentage of patients, a history and examination will go very far towards making that decision for you as well. And so I think we do have to evaluate rapid diagnostic tests within the clinical, algorithm, the way we think. But I think that clinicians are too quick to, grasp for a diagnostic test, when they actually haven't done the groundwork first, which actually might negate that test being [00:20:00] used in the first place.
I guess I'm conflating a couple of issues there, but it does occur to me more and more and what I see, is that we don't use the diagnostics in terms of history and examination that actually are important part of the entire, investigation structure
Thomas: Yeah, and it goes , in both ways, right? if you made your assessment, the clinical assessment, maybe you don't trust the diagnostic tool if, the result doesn't fit with what you suspect or if you get the result and it's negative, you feel like maybe there are some other bacteria somewhere that we haven't detected.
You need to trust the test. You need to act on the result, otherwise it won't make a, a difference anyway.
Marc: yes. And the pretest, you gotta take in the pretest probability. , Where I sit TB, you know, we're in TB central, so many times the answer will be TB. And when we see patients, we are immediately thinking about that when we're using diagnostic tests.
Whereas in another setting , , for example, perhaps Thomas in your settings, although you see TB, it's completely different. So the pretest [00:21:00] probabilities of any test, will be important in terms of how we interpret them.
Betsy, when you were talking, it reminded me of something about 10 years ago. I was talking to, some of our primary care providers locally about, point of care CRP for respiratory tract presentations in the community and sort of sharing some of the data around how that might reduce upfront prescribing for amoxicillin, and they said, "Okay, okay, okay.
Annie: Yeah, this all sounds very good, but how much does the amoxicillin cost?" And I was like, "It was e- 18 pence." And, "How much does the the point of care CRP cost?" And I was like, "80 pounds." And they just laughed. That was the end of the conversation for quite a long while. Did eventually get there, but that was the initial, you know
the antibiotics are still way cheaper, so, what are we really expecting, healthcare providers to do? along that line, thinking about incentivization, there's been a lot of attention and some early successes in implementing delinkage [00:22:00] schemes for new antimicrobial drugs, which is where financial reimbursement is not linked to volume of usage, at least for an initial period of time.
do you think there's any potential for this kind of model to work for new diagnostics? And could this maybe improve access and overcome some of those initial financial hurdles? Betsy, do you want to go first?
Betsy: So, there is an active effort to answer this question. I hope the answer to your question is yes, there is a pathway forward to really think through some of these larger societal values that diagnostics, enable.
the Office of Health Economics has been working on a new framework called the STRIDES Framework, and it's essentially taking the steady values which were identified for antibiotics to support the valuation of antibiotics and applying that to diagnostics. And so, it's spectrum, transmission, research, insurance, diversity, enablement, and surveillance, STRIDES.
there was a, working group that came together [00:23:00] to really try to, leverage the learnings from the antibiotic use of study to think through how we could do something similar, for diagnostics. And I, really do think this is a strong framework, and now-- the Office of Health Economics is moving forward with, working through use cases to try to start to quantify some of these metrics across some of the different syndromic areas.
And so we actually just heard from them last week, about some of the work they're doing on bloodstream infections and, some of the other priority syndromic areas that CARB-X is, interested in. I am heartened by this approach where we're, we're not looking at just length of stay and just the patient-specific measures of value, but really starting to think about, well, what's the value of decreasing transmission more quickly versus seeing increased transmission throughout the hospital setting?
What's the value of, the role of diagnostics playing preserving last line antimicrobials? with Neisseria gonorrhea, we've been on last line antimicrobials for many years now, and we now have these novel therapies [00:24:00] coming, and how will we use them? how will we be thinking about this responsibly, and what should the role of, of diagnostics be?
I'm very excited about the STRIDES Framework. it's still early days, but I am hopeful it will at least encourage us to start thinking differently about how we measure the value of diagnostics, 'cause just looking at patient impact is really missing the big picture, which is decreasing antimicrobial resistance over time at the population level.
Thomas: Yeah, I think that's a really good point, And it illustrates how hard it is to really properly, understand all the pos-positive effects of a new diagnostics or potential positive effects.
I think we are, so used to prescribing empirical therapy broadly and then deescalate that we are, having a really hard time understanding how a rapid test could, essentially shift, the curves or, probabilities from, let's say you have thirty percent risk of resistance, that means you have twenty percent chance of susceptibility in that [00:25:00] pathogen and how that could potentially save us from a lot of broad-spectrum antibiotic use.
But it's, gonna be hard to show that, Mark? Do you have any thoughts on, on this?
Marc: Yeah. I think the other example, in terms of trying to develop pull incentives for diagnostics, , there's something called Neotest, which is led by, I think the technical lead is Akhil Bansal, and it's a partnership between the Center for Global Development and, Market Shaping Accelerator, which have pretty much launched or trying to launch an advance market commitment for rapid diagnostic tests.
this one is based and focused on neonatal sepsis in low- and middle-income countries. Similar to some of the pull incentives for antibiotics. it would mean, funders committing in advance, , to make top-up payments when healthcare providers procure and, and use, those diagnostic tests that qualify, and it enables, [00:26:00] sufficient market return, on investment and therefore, incentive for companies to develop, diagnostics.
So I think that's a really good example of what I hope will come to fruition, in which I think this could really become a- an important pull incentive.
Thomas: And that also moved the decision to invest in a diagnostic tool from the healthcare provider to a higher level political decision in the end.
Betsy: Yeah. And just on Neotest on, on pull incentives, you know, CARB-X's funding call this year is actually focused on a neonatal sepsis rapid triage test, to align with the Neotest pull incentive because we really do see a need for aligning push incentives, right, R&D funding focused on AMR with pull incentives.
We're in year 10 now at CARB-X of funding research and development of new diagnostics, therapeutics and vaccines, and the diagnostics are moving quickly and, and we really need to be doing more on market shaping and getting the markets ready for these products, [00:27:00] which are great products.
We exist for a reason. We exist because there was no organic market to really spur innovation in this space because the revenue opportunity is so limited or or at least, fragmented. And so we need to do more here, and we really are excited to be partnering with CGD on the Neotest, to really team up, push and pull incentives to start to make some real progress in this space of demonstrating how we can work most effectively in AMR.
Thomas: So we already discussed how diagnostics can help not only for the individual patient to shorten time to effective treatment, but how it can reduce unnecessary antibiotic use. So, Marc, how should we think about the economics of diagnostics when the benefits appear elsewhere in the healthcare system or benefit society at large, rather than the individual patient?
If appropriate antibiotic use is the main goal, what diagnostic would make the most difference?
Marc: Yeah. Sadly, I think that, Economic analyses are very rarely altruistic. So [00:28:00] although everything we really think about around antimicrobial resistance with, effective antibiotics being global common goods and everything that ties into achieving, the appropriate use of antibiotics, which includes the diagnostics, of course, should be within an ec-economic analysis.
But it's quite a privilege to be able to think about broader economic use and benefits of tests when you think that for so many, in the world's population, diagnostics, as we've, mentioned, Annie and Bets were discussing earlier, are often out of pocket or even the providers, you know, if you've got an antibiotic that costs a hundredth of the cost of the, diagnostic test, then that diagnostic test isn't gonna be used.
So a discussion around the economics of it is really, a bit of a moot point. But if we are thinking about the state, diagnostics that are provided by the state, then yes, , you need to bring in broader calculations of economics, including everything from how that might [00:29:00] affect the actual cost of antibiotic use, the length of stays in hospitals, the healthcare facilities, readmissions, et cetera.
the whole gamut. I think i-in terms of which diagnostic tests would make the most difference to appropriate use, the major issue around appropriate use, again, in the c-community setting really is this issue between virus and bacteria. And one thing to point out is that, Annie was talking about in some of the analyses she had been involved in previously, th-this issue around CRP.
Marc: Okay, so, so C-reactive protein we all know as a nonspecific marker, an acute phase reactant. But it has been shown not only in high-income countries in Europe, UK, and elsewhere to actually be able to reduce unnecessary antibiotic prescribing in certain infection presentations, and particularly in, lower respiratory tract infection.
And indeed at the community level, point-of-care CRP has been shown, to reduce, unnecessary antibiotic prescribing [00:30:00] safely in Vietnam, in primary care for adults and children, in, Kyr-Kyrgyzstan, in, children, and even in Nigeria being used , for non-prescription dispensing in Private community pharmacies.
So we, have got a tool, but we don't use it. So the big question is why don't we use it? There's also been health economic analyses of these studies which have all shown benefit. So you know what? We've got a tool, we don't use it, but we want another tool which we think we're going to use. And, you either follow the evidence or you don't.
And I would say that we need to think much more carefully about the use of point-of-care CRP. And I think it could really be part of a toolkit for informal prescribers to make them part of the solution rather than part of the problem, which could also open up a whole new channel of, access to antibiotics in low middle-income countries, potentially safely.
, in the hospital setting, , the same diagnostic would still be important. I mean, how often do I see [00:31:00] patients clearly don't need an antibiotic presenting with undifferentiated fever and cough, getting an antibiotic and, C-reactive protein isn't even thought about.
but I guess, in a hospital setting, particularly in high-income countries, as we said in the first discussion, it's around etiology and resistance patterns, which would be of great value if you could increase or decrease the turnaround time and ensure that, you know, you're not only optimizing antibiotic use when it's needed but removing it when it's not
Thomas: Yeah. the discussion about CRP is very interesting. So I've been working with the Swedish Antimicrobial Stewardship Program for many years. And in Sweden, we believe CRP is driving antibiotic use, unnecessary antibiotic use in primary care because when you take it and it's just slightly elevated, people tend to prescribe antibiotics.
So we're actually discouraging people from using it and try to, make people use an algorithm where they make the clinical assessment first, and then if the patient fulfills some certain criteria, then you take the [00:32:00] test. And this is the same for tonsillitis. So you shouldn't just take a rapid test for streptococci.
If you do that, you will prescribe antibiotics to a lot of people who don't actually need it. But you first make your clinical examination, and then if you fulfill some pre-specified criteria, then you take the test, and then you make a decision based on the result.
Marc: Yeah. I totally agree with you, and I think this is why over testing in general is so dangerous, and particularly out of the context of the patient in front of you because, you're going to get tests which may be slightly positive, but in the full clinical assessment doesn't warrant the action that you're describing.
So again, it's also about evaluating rapid diagnostic tests within a clinical rather than as a standalone, test to which you make a decision. So it's very interesting what you're saying the anatomy of the decisions is important.
looking at those pathways, looking at how people make these decisions.
Before we shift, I just [00:33:00] wanted to make one comment about the, delinkage between, the economics of diagnostics when the benefits appear elsewhere in the healthcare system. we've had a few companies launch out of the CARB-X portfolio, and we've seen this delinkage really be one of the biggest barriers to market uptake.
Betsy: And so for hospital-based systems, the clinical microbiology lab has to procure the product. If it's an instrumented pro-product, the instrument and the consumables. And there are many, , innovative incentive programs to help support those costs, like the Novel Technology Add-on Payment or the NTAP in the US.
But they only support it at a, fraction of the price of these products, and that reimbursement actually goes to the hospital. So it goes to a completely different budget, and it rarely comes back to the clinical microbiology lab that made the purchase, that fronted the money for the investment in the new technology.
And so, , when this happened the first time, I think it was frustrating, but now we're quite a few years [00:34:00] into this cycle, this broken cycle of how we operationalize the uptake of new diagnostics in healthcare systems. And we're seeing this break between the clin micro budget having to pay, the hospital being reimbursed, and never making the clin micro budget whole.
And so I think you have your multiple end users for these products, but the one that is actually paying for it is really disincentivized to bring it in because they have to carve that out from their existing budget versus relying on the reimbursement mechanism that's currently set up. And so I think we need some innovation in terms of how we reimburse diagnostics in the hospital care setting.
they're also currently bundled in many disease areas, into the DRG. And so again, there's a disincentive to use any of the newer rapid diagnostic tests that might cost more than culture or other existing, technologies that are available at lower costs. but I just think this delinkage is really important for us to think about and be aware of in our different settings across the world, how are payment decisions being [00:35:00] made, and how are they being operationalized, and what kind of barriers to uptake exist there?
Marc: if I can just add to that, per experience here in South Africa, the medical insurance companies, the medical aids here will not reimburse for a point of care test in the doctor's office. So even if we, , want to try and push C-reactive protein point of care, for example, or PCT or whatever, then that's, the problem.
the whole economics of it and getting the policymakers and health systems people involved is critical
Thomas: so with rising AMR rates, diagnostics become increasingly important, but as we just discussed, the needs will be different depending on the setting and the clinical scenario, and there are several types of diagnostics that can be considered.
Who needs to be involved in designing new diagnostics so that they meet the most important clinical needs, and in the end are affordable and possible to implement in clinical practice on local, national, and global levels? That's [00:36:00] a big question for you, Betsy.
Betsy: it's a timely one. you know, CARB-X is investing in novel diagnostics and platform expansion of existing diagnostics for other disease areas or sample types, and we're actually in the midst of our strategic review. We sit down every three years and revisit what the unmet medical needs are, what the diagnostic gaps are, the pipeline, and really try to prioritize our, funding for the next three years.
And we invite a lot of people into these discussions, and I think this is our largest group yet this year. Mark very kindly participated in those discussions and, , we try to, include all not all, but many of the most important voices in those discussions. it's, patients, it's clinicians, it's laboratorians, public health experts, payers as we were just discussing.
You know, the payer's perspective really matters at the end of the day, both from an education perspective, but also from a decision-making and, taking initiative to make change perspective. I think, the developer's perspective is important, , what's technically feasible [00:37:00] within a meaningful timeframe.
and then, , just, wise individuals across all of those spaces who have seen different approaches come and go over the years, who have seen innovation and can really kind of help us hone in on lessons learned over the many years of, doing this, not necessarily in the AMR space, but across, other disease areas.
And so we really try to take a holistic look at this and then aggregate all of those inputs into something meaningful to help us really prioritize what we're asking the innovators either in the space or outside of the space that we're trying to attract into the space, to develop so that it really does someday, in the not so distant future, reach patients and make an impact, both at the patient level and at the public health level
Thomas: Yeah. And again, because we work in very different settings, the response to what diagnostics we need will be different also. how do you deal with that? How can you, objectively assess the value of diagnostics globally? it's a great question.
Betsy: [00:38:00] Yeah. And we, revisit this question every time we do one of these strategic reviews, and we've had separate calls with different geographic regions. We've had group calls with, just a, spattering of, humans across different parts of the world. And I think at the end of the day, you realize there are differences, right?
A Salmonella typhi rapid diagnostic test isn't necessarily n-needed in, London. But a low-cost, highly accurate, test that can rapidly detect a pathogen with, limited interaction by a layperson, that type of design thinking can benefit tests that can be used anywhere in the world, whether it's rural Kentucky or it's rural Kenya.
And I think, we do see more similarities when it comes to design thinking than differences. I think where the real differences are, are in the pathogens and the syndromic areas, that we see, , leading to the highest disease burden in different parts of the world
Thomas: Yeah. And it's a very [00:39:00] important task and work that you're doing. I hear sometimes from people representing companies developing new diagnostics that they feel a lot of responsibility to show the benefit and the value of their products, while they're originally maybe more focused on the performance of the test, the sensitivity and specificity.
Betsy: Hmm.
Thomas: is there another way of doing this in the future, you think? who should do these analysis?
Betsy: Yeah, you know, we bucket these into clinical utility studies. They've become, I'd say, equally important to the FDA or stringent regulatory authority, approvals, which, the regulatory approvals are the ones that really focus in on sensitivity, specificity, reproducibility, et cetera.
And so I think that's what the manufacturer can control, and so that's what the manufacturers historically have really focused on. It was also historically, the bigger bar to get over. I think we're moving into a world, especially in AMR and bacterial infections, where, demonstrating the clinical utility, [00:40:00] to all of your different end users, to the patient, to the clinician, to the lab, to the payer, to the hospital system, right?
How is this going to save me money versus cost me money over time or in the near, term, to civil society who have been affected by these, different syndromic areas over time. We're not starting from scratch. there's a great publication by Melissa Miller, quite a few years ago now, that has, the different end users for clinical utility studies pretty well articulated.
And I know there's a group in Europe that's working on a framework for this as well, just to start to try to get some consensus. 'Cause I think the manufacturers feel like they have to please everybody, and those are really expensive studies if you want evidence to back up all of those endpoints that all of the different end users wanna see.
And none of these companies have those resources to be able to do that, in a statist-statistically meaningful way. And so I do think we, as the end users of the products, whether you're a patient, clinician, payer, lab director, whoever, need to be thoughtful about what we're [00:41:00] asking the companies to demonstrate and, realize that, there has to be a balance, right?
Otherwise, no one will ever be able to deliver meaningful endpoints to clinical utility studies
So looking ahead, how do you think diagnostics for bacterial infections will change in the next 10 years, and what can we do differently? Let's start with, researchers and clinicians. What can they do differently? Marc, do you want to go first?
Marc: Right. Yeah, in the coming ten years I would guess we're gonna see faster direct sample to answer tests at point of care with, for broader pathogens, I hope, and broader resistance profiling. I'm sure that whole genome sequencing as it continues to become cheaper and perhaps using AI, we can try and understand better, relationships between genotype and phenotype.
I think that's, definitely a, possibility. I really hope, as we've sort of talked a bit about already in this podcast, that point-of-care diagnostics become [00:42:00] part of clinical decision support sys-systems in a broader sense, and that these tests are, as CARB-X, has also committed to, which is wonderful, to really, support these tests at community level, thinking about community level in low, middle-income countries.
in terms of the hospitalized patients, I think we're likely to see, new directions in monitoring biomarkers, in patients with sepsis, for example, diag-diagnostics, monitoring lactate through interstitial fluid, monitoring patches in real time, and maybe even, a-again, antibiotic levels, using that sort of methodology.
I guess the pipe dream for me is, equitable access to diagnostics in low and middle-income countries, as high income countries. we've talked about for the clinicians using clinical skills as much as diagnostic tests, returning to the basics of medicine management, and clinicians can use diagnostic tests better for stewardship.
In terms of re-researchers, We talked about [00:43:00] pull incentives and we touched a little bit about push incentives, but we actually do need, to think much more carefully and, how we are funding, push incentives for diagnostics. I mean, if you look at the R&D, the G20, hub dashboard for in terms of investment in R&D since 2017, so there's been over twenty billion invested and vast majority is in, of course in therapeutics and basic research rather than diagnostics or vaccines, which actually get very little.
So I think we need to think very carefully about how we're apportioning, funds so the researchers need to be supported. and really we haven't even talked about fungal, diagnostics, Candida auris and others coming through at a horrible pace So yeah, those are sort of areas that clinicians and researchers should play a role.
Annie: A lot of food for thought there. and what about policymakers? Betsy, what do policymakers need to do differently?
Betsy: I think in general, antibiotics has had the limelight over the [00:44:00] last ten years, which is great. we need new antibiotics. we're churning through our existing, toolkit pretty quickly here. I think we also need to be really thoughtful about how we use the existing antibiotics and how we use these new ones as they come to market.
resistance testing and using diagnostics to preserve effective therapies and appropriately implement novel therapies should be a key focus over the next t-ten years. And I think policymakers will have a, major role in that in terms of, incentives and, disincentives, to really encourage appropriate behavior.
that big spend in antibiotics will only go so far if we just churn through them as they come to market. But I realize it's a balance. You want them to be accessible, but we also just really need to be thoughtful about the long-term, impact of, near-term decisions as we think about the package.
what is the appropriate diagnostic? What is the appropriate antibiotic or, variety of antibiotics for a syndromic area? how do vaccines play into this and preventatives? And really be [00:45:00] thoughtful from a holistic perspective. And then policy should be aligned with that.
And industry will, follow
Thomas: Yeah, I think that's a very good point about the new drugs, how they should probably be accompanied by stewardship, but that also takes diagnostics. Like how can you otherwise ensure their use when they're needed and not just empirically? I mean, cost is a factor, but, I think there's a lot of, work to be done there, to save the few new antibiotics we get.
Betsy: Yeah. Just one last thing. I think we across all of clinicians, researchers, policymakers, funders, industry, et cetera, we need to align in the diagnostic space. You know, I think the antibiotic space has done a really nice job of aligning their messaging, aligning their energy, really picking their priorities and making that a clear message to policymakers to move the needle there.
There's still quite a distance to go, but the diagnostics industry is much more fragmented and, I'd say immature in this space. And so I think what I'd like to see over the next ten years is we really [00:46:00] change that, and we start to, take a lot of the lessons learned in these convenings we've been having over the last two years, where we're actually acknowledging all these challenges and confronting them and being really uncomfortable with the economic challenges, and really start to harness, some alignment in this space, harness our energy and focus and move together, forward so that we can really move the needle for the diagnostics industry and field as a whole.
Marc: can I, just add one thing to that? When one reviews, potential new diagnostics, one of the thing that comes out relatively often i-is that, there is a need to support across industry interoperable platforms. Betsy, ple-please correct me if I'm wrong, but , I think that would actually help, because it might reduce costs and, you know, make it more broadly available and, really focus on reliable supply as well, is important
Betsy: Yeah. the only thing I'll add is I think, expanding platform technologies that are already being used for other disease [00:47:00] areas like HIV, TB, or other chronic diseases, I think is a more efficient pathway because you already have that existing install base. The supply chain, as Mark mentioned, can be a real hindrance.
so where we can leverage existing infrastructure, efficiently to address bacterial infections, I think we will go farther faster. but there are a lot of areas that might be difficult, and so I think there is still a play for novel innovation But yeah, collaboration will be key to really moving forward in this space
Thomas: Thank you. that's a lot to think about for the future. And it's almost time to wrap up this episode. But before we do, there's one more question for both of you. If you could have one new diagnostic tool available tomorrow to tackle the AMR problem, what would that be? Betsy, you can only pick one.
Betsy: Yeah. You might be surprised I'm asked this question often. there's no silver bullet. I don't think there's a one-size-fits-all test that's gonna really, like, transform AMR. We've seen programs try this, and [00:48:00] none have been successful to date. but I think the most impactful tool to really move the needle to tackle the AMR problem, really, would be a financial incentive to support appropriate use of diagnostics that we do have and those innovative technologies coming to market, so that we are supporting clinicians who wanna do better and use these as part of their clinical care algorithm and approach to be able to afford to practice and prescribe more effectively.
I think without addressing the economic problem here, we're gonna continue to hit our heads against a wall in trying to see impact from these really, innovative tests and some that are already existing and really sturdy supports for the diagnostic ecosystem.
Thomas: Yeah. What about you, Marc?
Marc: I agree with Betsy. I, don't think there's a silver bullet. There are lots of great candidates. thinking about a really good rapid point of care test for gonorrhea and resistance profile, I think would go a long way. An important test in, [00:49:00] sub-Saharan Africa, particularly in the edge in terms of trying to ensure that we don't increase, HIV transmission as we lose gonorrhea treatments.
if I could have one wish, it would be that we use what we've got better, particularly CRP. I think a C-reactive protein test that applies an electric shock every time you prescribe an antibiotic without thinking once you've used it.
Marc: So if I'm allowed that, I'm sure there's a way using microfluidics and, and a few leads connected to certain parts of people's bodies, it could be very useful.
Betsy: Someone's in the Halloween spirit. Frankenstein-y.
Thomas: That's quite aggressive antimicrobial stewardship practice.
Marc: Yeah, well, you know- Great
Thomas: idea
Marc: the, the, the softly, softly gentle approach hasn't worked. I mean, how are we doing with that then?
Betsy: Time to be aggressive.
Marc: When I last looked, I think AMR was worsening each day. But anyway,
Thomas: It's a perfect ending of this episode.
Thank you so much again [00:50:00] to our guests, Betsy Wunderlee-Treanor from Carb-X and Marc Mendelson at the University of Cape Town, and thank you for listening to Communicable, the CMI Comms podcast.
This episode was hosted by Annie Joseph in Nottingham, England, and Tuomas Tängdén in Uppsala, Sweden, associate editors at CMI Comms, ESMID's open access journal. It was edited by Angela Huttner, executive producer at Communicable.
Theme music was composed and conducted by Joseph McDade. Any literature we've discussed today can be found in the show notes. You can subscribe to Communicable wherever you get your podcasts, or you can find it on ESMID's website for the CMI Comms journal. Thank you for listening and helping CMI Comms and ESMID move the conversation in ID and clinical microbiology further along.