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March 14, 2023

Despite great improvements in mortality for children under 5, sepsis remains a leading cause of death in young children. The highest incidence and mortality were seen in newborns, with the biggest impact seen in low- and middle-income countries in sub-Saharan Africa and Asia. This episode will highlight how the availability of guidelines, diagnostics, and therapeutics can make a difference in the smallest of patients. Content warning: this episode contains discussions of infant loss.


  • Kamala Thiagarajan - Freelance journalist, Global health and environmental sciences
  • Phoebe Williams - Pediatrician, Infectious Disease Physician, Faculty of Medicine,  University of Sydney
  • Seamus O’Brien - Director of Research and Development, Global Antibiotic Research and Development Program

Articles Mentioned in this Episode

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Superbugs Neonatal Sepsis Transcript

Marnie: Hello and welcome to Superbugs and You. True stories from scientists and patients around the world. This podcast series explores the threat of antimicrobial resistance, which occurs when bacteria, viruses, fungi, and parasites change over time and no longer respond to antibiotics and other medicines. In other words, they become superbugs. I am Doctor Marnie Peterson, and I've spent the last 25 years focused on this topic, both as an educator and researcher, and I will be your host.


Kamala Thiagarajan: Every day of our lives. We're waging a war. We're literally waging war with microbes.


Marnie: Despite great improvements in mortality for children under five years of age, sepsis remains a leading cause of death in young children. A Lancet study on the global burden of sepsis estimated there were 20.3 million sepsis cases worldwide in children under 5 in 2017, and an estimated 2.9 million deaths. The highest incidence and mortality were seen in newborns, with the biggest impact seen in low and middle income countries in sub-Saharan Africa and Asia. It is estimated that 1 in 5 people who died due to drug-resistant infections were children under five. Effective diagnosis and available appropriate therapy are critical for the treatment of sepsis. Improve guidelines on treatment are also critical. This episode will highlight how the availability of guidelines, diagnostics, and therapeutics can make a difference in the smallest of patients. Also, content warning this podcast, which is focused on neonatal sepsis, contains discussions of infant loss.


Kamala Thiagarajan: My name is Kamala Thiagarajan and I'm a freelance journalist. I report on global health and infectious diseases.


Marnie: Something I wanted to focus on to launch. Our discussion is an important article that you published in September 2022, titled in the BBC, titled Neonatal Sepsis The New Threat Posed by Superbugs. Now, neonatal sepsis is the focus of this podcast. Let's spend a little bit of time about the article, because there's a lot to dissect here and how you told the story and talked about some of the challenges. How did you get to the topic? Was it something you came up with? Recommended something a team did? Something you read? Well, one.


Kamala Thiagarajan: Of the reasons for my choosing the topic is also very personal. My own son had neonatal sepsis in 2011 when he was born, and today, thankfully, he's a healthy 13-year-old. But I think as writers we tend to ask ourselves, what if a lot? You know, what if, um, the medication hadn't worked? This is quite common and we don't really know about it. So I think from 2011 I've been speaking to mothers in my community, reaching out to health practitioners across India in trying to kind of figure out if neonatal sepsis is common. And I was shocked to find out that it was and it was kind of like really here underreported. I mean, we don't really hear too much about it. And so I feel like it was something that we needed to highlight and something that would help other parents.


Marnie: Can you speak to the prevalence and mortality of neonatal sepsis?


Kamala Thiagarajan: So I think 3 million babies worldwide are affected by neonatal sepsis. Some studies put that number down to 5 million. And I think 1 million of those babies are in India. So, um, a lot of our neonatal deaths are a result of sepsis. 20% of those 1 million babies, there's 200,000 babies every year die of neonatal sepsis. So it is something that requires urgent attention. And antibiotics are the cornerstone of this treatment. So we do use and what neonatal sepsis is, is actually it's chemicals released in your bloodstream as a result of a severe bacterial infection. And these chemicals can be quite toxic. They can shut down all the organs of the body. Um, and it's a very life-threatening disease. The baby can be affected with neonatal sepsis and then pass away in a matter of days. So it's something that needs to be treated urgently.


Marnie: So initially the patients becoming infected. What did you discover about how they became infected?


Kamala Thiagarajan: Well, neonatal sepsis is still quite a mystery, you know, even for medical practitioners, for researchers. No one really knows exactly where these infections are contracted. And but doctors suspect that babies become infected during the process of birth, you know, especially if the mother is infected with the bacteria that causes a premature delivery, like a premature rupture of membranes where the amniotic fluid just bursts. And, you know, we've we're seeing a lot of those infections in India right now. And I feel like whenever there is a premature birth, doctors are always wary about neonatal sepsis. But that's not the only way to contract it. The infection isn't always passed on from mother to baby. Sometimes babies contract neonatal sepsis, um, from their surroundings. For instance, in Bangladesh. Um, I spoke to doctors there, and one of the biggest challenges there is that, like 50% of the moms there still give birth at home and there's a lack of hygiene. So the baby could catch the infection from the environment, from the surroundings. And doctors I've spoken to this story have told me that, you know, babies catch infections from the neonatal intensive care units where they are taken to after birth, right from the equipment that they're hooked on to the life support equipment. If that isn't cleaned properly, you can catch neonatal sepsis from there as well. And these are like severe bacterial infections.


Marnie: What were some of the challenges that clinicians were facing with diagnosis and treatment?


Kamala Thiagarajan: Well, um, when I spoke to doctors, they told me that the diagnosis wasn't really a problem. They could diagnose neonatal sepsis pretty easily, but the challenge lay in the treatment, right? So they couldn't pinpoint the exact worm that was causing this, the exact bacterial infection. And they needed that kind of information to treat the baby effectively. And so a blood culture would take like about that would help pinpoint the worm in most cases, but it would take about 2 or 3 days. And that was the time that we didn't have. So it became important for doctors to kind of figure out how to treat it. And, um, increasingly, doctors were using more powerful antibiotics just as a precautionary measure because, the first and second-grade antibiotics didn't work.


Marnie: As a writer focusing on global health. What are some of the differences in the issue of neonatal sepsis and Amr faced by people living in the Global South, or countries classified as low-income or developing?


Kamala Thiagarajan: There is definitely a difference in the way that antibiotic antimicrobial resistance works in the global North compared to the global South. We're finding that in the global South, there are far more gram-negative bacterial infections that are more virulent, that are more resistant to antibiotics. This is something that researchers have found recently, and this is something that they are trying to address. It's definitely a problem in Asia, and that's why we're seeing more infections here at countries that are also struggling with, um, establishing protocol, you know, in ICUs and ICUs, um, especially. And where there are clear guidelines for. In India, we do have clear guidelines as to, you know, how to secure an ICU, how to make it sterile. But sometimes we don't have trained staff. Sometimes those guidelines aren't always met. There are other challenges to the health system that crop up. So I think that that being aware of the systemic issues is important. And it's not really anyone's fault. It's just the way it is. And I think working together, I think it will really help.


Marnie: Did any of the clinicians you spoke with mention resource limitations related to laboratory testing and determining the bacteria responsible for the infection?


Kamala Thiagarajan: Some of our hospitals are in very rural areas and we don't have access to bigger labs. So that's always an issue. Um, and where you cannot even take a test, or if you do, it would take about a week for the results to get back to you. And that's quite useless to you. But it's also the nature of neonatal sepsis. It's a very complex infection. It's very hard to determine which bacteria it is that is infecting the babies. And you know how severe it is. So doctors don't want to like, you know, they just want to be safe. So if a mother has a premature delivery, if a mother has a premature delivery because of PROM, that is a premature rupture of membranes. What doctors tend to do is just treat them with antibiotics, treat the baby with antibiotics the minute the baby's born. But increasingly now, what we're finding is that when they start doing that, those antibiotics don't work, they aren't effective, and the babies are infected anyway with neonatal sepsis. And then you start using stronger antibiotics and stronger antibiotics to treat them. To our dismay, we're finding that even those last-degree antibiotics, the carbapenems, aren't working as well as they should. And so this is causing a lot of alarm.


Marnie: Were you able to speak to any of the families or individuals that lost babies to this infection, and how did that impact them?


Kamala Thiagarajan: I spoke to a lot of women who have lost their babies and the infection. I found that a lot of them are from lower-income backgrounds. A lot of them are giving birth in the hospital for the first time, and for them to lose a baby, it's quite a devastating loss. I think for anyone it is. But, you know, especially for these families, because it's particularly bewildering. They don't quite understand why they lost their baby in this way a few days after birth. And, um, it's quite tragic because they don't always have the resources to support themselves after that. You know, they don't have access to, um, say, if you have postnatal depression, they don't have access to the resources to get care. So I find that a lot of these women suffer a very silent, um, hidden burden. They carry it with them. And there's always this guilt associated with this because a lot of these women work right down to the last day of their pregnancies. So, um, I find that the thoughts that run through their heads is almost like, you know, um, did I do something wrong or did I do something to cause this to my baby? And there's a lot of guilt. There's a lot of guilt. So that's really sad. That's really a sad, hidden emotional burden to this disease. It's hard to lose a baby at any phase of your life, and hard to lose a child for parents at any phase of their lives, you know? But when you lose a baby, um, one week of holding the baby, of being able to bond with it or smelling the baby, and that's just sheer agony, you know, that's the kind of emotional pain that we're looking at with this.


Marnie: You mentioned the difficulty for mothers in handling this diagnosis and even the loss of their child. Do you know how this is affecting their family, like fathers or grandparents?


Kamala Thiagarajan: Um, I have spoken to some fathers and grandparents. Not as many as the women. But, you know, there is this cultural thing that comes into play, right? So in India, it's like, you know, if the baby doesn't survive, it's just something. And that isn't meant to be. And then you just move on with it. I think that the loss is felt more deeply by the woman. I mean, I don't know if I'm generalizing here, but I feel like the sense of failure and the sense of loss is felt very deeply by women. And of course, I'm sure fathers feel it too, but not to the same degree, or they don't relate to it in the same way. You know, life goes on. So it's hard. Especially the woman whose case I highlighted in the article, she had her baby after 11 years of trying to have a baby. Fertility treatments are really, really hard on your body and mind. To lose a baby at that phase, I think is really anguishing. It's torturous. It's hard on a woman because it's their bodies that are going through this.


Marnie: Can you tell us a little bit about your personal journey with this, and how that impacted you and how that made you feel?


Kamala Thiagarajan: Well, I gave birth in a fairly big corporate hospital in my city, and, um, we did have access to all the resources that we needed. But my baby was born pretty, um, you know, he was born at 34 weeks when he was taken to the neonatal intensive care unit. Um, I realized that the NICU was struggling for certain reasons, even though it was a big corporate hospital. There was a lack of trained nurses in the NICU. And looking back now, I feel like some of the guidelines weren't quite followed. For instance, um, there were more visitors in the NICU than there should have been. We have big families in India, and it's hard to say no to people who come and visit babies. And then the NICU nurses didn't always wear gloves and the hygiene wasn't always adequate. And my son caught sepsis not after birth, but just a whole week after birth. So this means he contracted the infection from the NICU. I feel like there are little breaches of protocol that, you know, could make all the difference between life and death, especially for babies hovering between that line and that, um, worldwide, that this is something that we need to look into and strengthen, especially in an ICU, especially when we're dealing with these kinds of virulent infections.


Marnie: Publishing this article in September, you've really brought more awareness to the issue. What more are you hoping to share about this topic?


Kamala Thiagarajan: I take heart in the fact that, you know, researchers worldwide are working on this right now, and there are promising advances. For instance, um, I read about bacteriophages that are viruses that are used to infect bacteria could be a potential alternative to antibiotics. So when antibiotics don't work, researchers are looking at how to train this army of bacteriophages to kind of work in their stead. And I think that's really exciting. So there is a lot of promise. There is a lot of hope. It's just that the bacteria for me, that is, you know, I often think of it like, if you're a Star Trek fan, I often think of it as the Borg. You know, it's they're the Borg is Captain Picard's worst enemy. It's it assimilates everyone. So every time we take antibiotics indiscriminately, I think we're creating something like the Borg, you know, at the super genome, because the antibiotics don't kill all of the bacteria. They kill most of it. Some of it escapes, and then it becomes stronger and it gets more virulent, and it gets stronger and it becomes this Borg-like figure, you know? Um, so I think that going forward, I think that we do need more awareness on how antibiotics are used and how we relate to antibiotics, how we would use them and how we relate to them in the future. I think that's very important to use it only when absolutely necessary to never self-medicate, to always understand that though, you're killing the germs, you're not killing all of it. You're creating a soup. It could be the soup kitchen for the superbug, you know, and that, you know, this could affect the most vulnerable babies in our society, could affect the most vulnerable people who have lung infections, who are going through other problems medically, you know, so it's something that I think that we should be more aware of.


Phoebe Williams: I'm Doctor Phoebe Williams, I'm a pediatrician and an infectious diseases physician, and I work at a couple of hospitals in Sydney as a clinician. But I also have an academic position at the University of Sydney, where I have a research focused on antimicrobial resistance, and in particular, neonatal sepsis. And I have a focus on resource-constrained settings. So I undertook my PhD in in rural Kenya with the Oxford Tropical Medicine Network. And subsequently, after I've moved back to Australia, I now focus most of my work in South East Asia and the Pacific.


Marnie: How did you first become interested in neonatal sepsis?


Phoebe Williams: Probably life experiences and also some amazing mentors have led me into the area that I'm working now. So, um, I am also the mother of four kids, and three of those children are triplets that were born prematurely, so they were born at just on 30 weeks after I got HELLP syndrome, and they had a really stormy time in intensive care themselves and a number of other families I watched endure the sort of the journey of their babies getting sepsis while I was a mum on the other side in intensive care, and I also had a family member who'd had triplets not many years before me, and one of her, um, or two of her sons ended up dying of neonatal sepsis. And so I had that sort of personal experience. And then when I was doing my PhD in Kilifi in Kenya, initially, my PhD started with a focus on antimicrobial resistance in children. Because obviously antimicrobial resistance is an increasingly important topic worldwide. And within my Ph.D., because I'd always had this global health interest, because before I did medicine, I did development economics. So I was always really interested in the social determinants of health and the huge health inequities worldwide. Um, and so when I was doing my PhD, it quickly became clear that the antimicrobial resistance burden is not equitable worldwide.


Phoebe Williams: And, um, I realized that resource-constrained setting had a far higher burden, not just of Amr, but also, um, less of a capacity to be able to treat patients that do have drug-resistant infections because they can't reach for the newest antibiotic agent off the shelf. And they're often not part of the big drug trials that are, um, exploring these newer agents. And so I realized within that journey that antimicrobial was a big issue, first of all, in children, and second of all, in poorer parts of the world. And then we quickly realized that the most at risk of the pediatric population were a few subpopulations of children. So in the first instance, um, children that have malnutrition, um, who my supervisor, Jay Barclay, has dedicated his research career to, to looking into are at very high risk of antimicrobial resistance, largely because they have many hospital admissions and are at high risk of infection. And then babies or neonates, which is a surname that refers to a baby in the first 28 days of their life. They are also a really high-risk group, probably the highest-risk group of children, um, for anti or for infections.


Phoebe Williams: And then in the context of increasing antimicrobial resistance for therefore having complications of Amr infections. And what we're starting to see worldwide is that because many mums are now delivering in health care facilities, which is a fantastic step forward for maternal child health in itself, but it hasn't necessarily come with the sustained scaling up of investment that we need to see for that to happen safely. So because we have gradually managed to encourage people to deliver their babies with healthcare facilities available so that if anything goes wrong, those emergencies can be acted on. We're subsequently now seeing quite stretched health systems that might not have basic infection prevention and control mechanisms in place that might not have access to a handwashing station at every bed, that might have very congested wards where 2 or 3 people are having to share a bed, particularly babies. And as soon as an antimicrobial-resistant bug gets into those settings, it spreads very, very quickly. And so that's why babies in particular, which are really just like many immunocompromised humans, are at very high risk of infection. And then once these bugs get into hospitals, they're at very high risk of acquiring these infections.


Marnie: Can you talk a little bit about the clinical course? And I know it can vary as you were just stating. It depends on the setting. Perhaps the economic resources. Are clinicians thinking about neonatal sepsis? Are they worried about AMR? When are they worried about Amr and what  does the mortality rate look like? I mean, you've already mentioned your own personal friends who had two babies die of this. So this is a very severe and life-threatening situation. So talk just a little bit about that in a highly-resourced country versus some of the other countries where your research comes from.


Phoebe Williams: Yeah. So it is really quite different in those two settings. So when I do an average work week here in Sydney in Australia, um, and we do our rounds in the neonatal intensive care unit, we're often chatting about babies who have been born as early as 23 weeks gestation. Um, and with our amazing, you know, health care facilities, we're able to keep babies alive and have really good outcomes that are born that early. But because they are born so vulnerable and so compromised at such a small size, and when so much of their so many body systems haven't developed, including their immune systems, all it takes is one bug to get into the intensive care unit. And those babies can get sick very, very quickly and can be very difficult to resuscitate. But often the types of bugs that we would see in a health care setting here in Australia, first of all, they vary from that intensive care setting from the premature babies. But we also see some babies come in from the community that might have picked up bugs at home because even a robust, healthy baby is still at a very high risk of infection in those first few weeks of life. And those babies tend to come in with what we call gram-positive organism infections.


Phoebe Williams: So historically, we all learn in med school about Group B strep or Streptococcus agalactiae being the number one cause of neonatal sepsis. And that is certainly something that holds very true for many healthcare settings worldwide, particularly in high-income settings. But what we've seen in the last ten years in, lower-income settings is that gram-negative pathogens. So your Enterobacterales in particular are becoming one of the most important causes of neonatal sepsis. And that includes both babies that present from the community in many of these settings, as well as babies that are in intensive care for a long time. And it's really making us start to think that perhaps it's time that we turned on our head this concept of, you know, early-onset sepsis, late-onset sepsis, and early onset comes from the mum. And, you know, historically that was the GBS sepsis that babies perhaps picked up during their vaginal delivery. And then late-onset sepsis was thought to be bugs that babies could come across when they went home from someone not washing their hands properly and factors like that. But what we've seen in many of these now really overburdened and under-resourced health care settings is that babies are getting multidrug resistant, gram-negative infections very, very early in their life course, and we're trying to work out if that's because they're born and then delivered into the hands of a midwife who's been working all night and had 22 deliveries and not had a chance to wash their hands between those deliveries, or are they born through a vaginal canal of a mum who's not had access to water and sanitation at home, and therefore has many multi-drug resistant pathogens that they're already colonized with? Or are they born and taken straight into a neonatal intensive care unit that has an outbreak of multi-drug resistant Acinetobacter baumannii in that NICU? So the epidemiology of neonatal sepsis is very, very different both within countries and between countries, depending on if you're looking at the community setting or the hospital setting, and even in hospital settings, it's very different for the baby that's just been born versus the 23-weeker that's been here for 8 or 12 weeks.


Phoebe Williams: And that's why babies are so at risk, because there's so many times in that first few weeks of their life that they can have the opportunity to be exposed to these pathogens, and combining that with that immune system that they have, that's really, really very compromised in those first few weeks of life.


Phoebe Williams: That's why they have such a high risk, of infection and mortality. So in in well-resourced healthcare settings, neonatal sepsis generally doesn't have a particularly high mortality rate if it's picked up very quickly and antibiotics are administered promptly. And I would say that most healthcare settings worldwide are quite good at doing that, because we all know that. You know, while sepsis is something that's usually can be well defined by looking at things like heart rate and, you know, a number of clinical features that would lead you down that diagnostic path. We're all very well aware that in babies they can do nothing, but sometimes just breathe out, breathe a little bit faster, or they can be lethargic or they can have a low-grade fever. And as healthcare workers worldwide, we've become very good at any baby that's having a wobble receiving some antibiotics, whether that means we're overprescribing antibiotics or not, we're still not sure we're still looking into that. But, um, I think that we're quite good at managing and treating that promptly. But what we're not good at is being able to have access to the antibiotics that we need for the multi-drug resistant infections, which are becoming more, more common.


Marnie: In mortality rate then will vary, obviously, and I am curious about your research will be interesting as you start to understand. And what is the source? It's probably multifactorial and the environment of which the mothers are living and their overall microbiome, whether that be their vaginal microbiome or their gut microbiome and things like this that are having that impact. So. I don't know if you have any ideas yet about that. Like if some of your research telling you some insight.


Phoebe Williams: Yeah, absolutely. So in terms of mortality rate, you know, in, in some of the health care settings that we're working in, in South East Asia, we're seeing case fatality rates of up to 70% of culture-positive babies. So three-quarters of babies that have a positive blood culture, um, will die in those, those health care settings. And that's because they are almost always due to multi-drug resistant pathogens. And there is just no access to antibiotics that work for those bugs. And then as part of that, we are therefore trying to break down understanding where that chain of transmission is occurring and seeing if there are spots that we can intervene along the way. And so there's a number of studies that have looked at sort of the rectal carriage and acquisition of babies in the neonatal intensive care unit. Um, we're about to start a study that will involve swabbing mums and babies at the time of delivery, and then every 48 hours while they're on a ward to try and pick up, you know, how quickly are babies colonized with these bugs? Because the first step before infection is colonization. And that will help us sort of delineate, you know, is it vertical transmission, is it horizontal transmission, is it horizontal transmission in a particular ward of the hospital? Um, and so you do have to do some real detective work to just go into each of these neonatal intensive care wards or postnatal wards and be able to break down, step by step, the potential chains of transmission to be able to have really cost-effective infection prevention and control mechanisms put in place that can try and intervene and prevent these infections.


Marnie: You mentioned that the babies dying, not having access to the antibiotics, or because some of these organisms are so resistant, there aren't antibiotics that they can have. I just want to clarify that for the listeners. And that gets at my other question, which is what microorganisms are you most concerned about?


Phoebe Williams: Yeah, no, that's a really good question. So I've actually just been part of a paper that has pulled together, um, many, many experts in neonatal sepsis globally from, you know, many health care settings across India, South Africa, the UK, Europe and Australia. And what we've done as part of that paper is, I don't know if you've heard before of the W.H.O. priority pathogens, but a few years ago, the World Health Organization established a list of pathogens that were the biggest risk for Amr worldwide in terms of lack of available effective therapies, both in the development pipeline and also in the access pipeline. Because, um, there's one thing having drugs that have been shown in studies to be efficacious against particular bugs, but if they're so expensive, um, and need to be stored or delivered, you know, over a prolonged infusion in places where nursing staff availability is limited, then they need more research in themselves. But what we've done is look at that Who priority pathogen list and create a neonatal priority pathogen list. Um, and you know, we've ranked sort of 10 to 12 pathogens there. But I think there's, you know, two key lessons. And one of them is that MBL-producing or metallo beta lactamase producing Enterobacterales, as well as carbapenem-resistant Acinetobacter baumannii, are really the two biggest worries globally for neonatal infections.


Phoebe Williams: And what we know is that there are a few, uh, a few drugs available to treat those sorts of infections, but there's not many, and they've really not been studied in children and particularly in neonates at all. And so the other thing that we look at in this paper is how can we make sure, in the context of many good observational studies in the last few years, showing us that, you know, MBL-producing Klebsiella pneumoniae and carbapenem-resistant Acinetobacter in particular, are two bugs that are causing the bulk of neonatal deaths globally. How can we try and really quickly get access globally for neonates to agents that are efficacious against them? So again, in that paper, we went through a process of looking what new agents are on the market and where they are at their various development phases, and what the scant research funding that is available should be investing their focus on. And within that paper we talk about durlobactam, solbactam and cefepime taniborbactam, and cefiderocol has really been three agents that offer a lot of promise for addressing the greatest burden of deaths from MDR organisms in neonates globally. And we talk about a strategy as to how we could really quickly try and get them through the rest of the development pipeline and available for children worldwide.


Marnie: Uh, you spoke about infection prevention is one of the areas that you're looking at to reduce the risk of neonatal and sepsis. What are some of the other things that that you're focusing on to reduce this risk? I think you talked a little bit about nutrition, but I just want to highlight a. You. The other things that you're finding are important.


Phoebe Williams: So, you know, there's many risk factors you can't change, like how early a baby is born, what their birth weight is when they're born, um, how robust they are when they're born, even if they're born prematurely because they might have been compromised in the intrauterine environment and already be born, you know, on a back foot. We know in in many health care settings, particularly in, say, sub-Saharan Africa, babies might have been born with a placenta that has had a level of malaria parasitemia grumbling along in the background. And those babies are already born, you know, really on a back foot. So, you know, you could go, you can keep going back because then you're looking at, you know, what was the maternal nutritional status that, you know, enabled that pregnancy to proceed as well or not as otherwise. And then often if you look at a poor maternal nutrition status, you find that you're looking at a mum who's been married off very young and having babies very young. So the domino effect that leads to a vulnerable baby being born small and prematurely is often a very long, long setup of dominoes that's really difficult and sometimes overwhelming to try and think that you'll have any impact on. But there are a few things I think that we can definitely make a big impact on, and some of them is just optimizing the prescribing of antibiotics within neonatal intensive care units worldwide.


Phoebe Williams: So, you know, one thing we're doing is, is a point prevalence survey looking at antibiotic prescribing across many sites in South East Asia and the Pacific. And this is similar to a large one that was done by the new AMR network out of Saint George's University. And they found, you know, many places are using carbapenems, for example, as their first-line agents. And when you do that for many years in your NICU, you can imagine that carbapenem-resistant organisms therefore become ubiquitous. So trying to bring in good AMS and stewardship programs and then just trying to bring in really simple IPC measures that protect that neonate when they're born. So hand hygiene, we know that kangaroo care or skin-to-skin care is a much safer place for a baby to be than in a cot jammed next to three other babies. Exclusive breastfeeding to protect the microbiome. Some really simple early life course strategies can really help protect a baby and reduce their chance of getting colonized with these pathogens and subsequently infections with them.


Marnie: My question is twofold. Obviously, there's a tremendous impact of this, this infection on the family, um, some of which you've experienced yourself personally. And then also, what type of education are you giving to the family to help prevent this from happening in the first place? So I think it's probably twofold. You've seen it impact families. So therefore you probably have a very strong educational message for those families.


Phoebe Williams: Yeah. Look, but it's really hard. And a lot of those messages have to be delivered really carefully and cautiously and taking each healthcare system into account. And so when I, for example, was living and working in, in Kenya for a few years, I was quite amazed that kangaroo care just wasn't undertaken there in that, um, high dependency unit or postnatal wards at all. So again, I hope I'm not using a colloquial terms, and especially with my Australian accent, but kangaroo care's actually a WHO-preferred term that describes premature babies basically being cared for on the chest of their mum or their dad throughout their early neonatal weeks. Because we know that they therefore become often colonized with things that they might then subsequently get protection from within the breast milk. And we know that often being on mum or dad is just a much safer place than being in a cot that might be too hot, too cold, um, exposed to mosquitoes. Or, as I mentioned before, be a very congested cot where they'll become colonized with whatever the baby next to them has. I've worked in many healthcare settings where kangaroo care is used widely, and it's certainly advocated by the Who as a really important factor in optimizing the care of neonates. Certainly here in Australia, we try and use it as much as we can. The neonatal intensive care units, where I was both a parent and also where I work, have certain hours a day that it's restricted to, whereas I previously worked in Ethiopia, where those mums were expected to basically have the babies on their chest up to 24 hours a day. So the poor mums, they didn't get much of a life, but you know, they had really good outcomes for those babies on that ward in Ethiopia in Bahir Dar.


Phoebe Williams: But when I was in Kenya, no one was doing it and I couldn't quite believe this because the mortality rate was quite high for these babies. And I did establish a really good relationship with the head of the nursing, the nurse unit manager in that department. And she had also tried for many, many years, even as a Kenyan herself, to get kangaroo care on board. But she explained to me that in this really congested, tight ward where almost all the clinical officers and doctors were males and they would, you know, in, in their way that some. Medical professions do, they would sort of saunter in without notice and quickly want to examine a baby and saunter out. And, and these vulnerable mums, who are often quite young, that the last thing that they wanted to do in these shared clinical settings was to sit with their tops open and a baby on their chest. And so it's not quite so easy as going in and educating and putting up pamphlets and saying kangaroo care is best and you must all do it. You know, in some settings things will not be culturally appropriate. And we also can't go in as people that are lucky enough to be in well-resourced health care settings and say you must wash your hands when they don't necessarily have the funding to be able to buy Alco wash. So the education side of it and the rollout of those preventative sides is a lot more difficult than it sounds. And I think we have to make sure we have really strong collaborative partnerships and that things are sort of locally owned and grown as far as possible.


Marnie: As you mentioned previously, significant progress has been made to reduce mortality in children under five years of age. This podcast is specifically focused on neonates and their risk of infection or sepsis related to Amr. Have you seen the same progress in reducing infection and mortality in neonates, or is there still more work to be done?


Phoebe Williams: You know, we've made great progress in reducing child mortality rates globally, but there's still such a divergence in your risk of dying before you turn 16 based on the country that you happen to be born in. And I think that really we have the tools within our generation to try and see that inequity reduce. And we have, you know, we know what can reduce child mortality globally. But most importantly, while we have made some progress in reducing child mortality over the last 20 or 30 years since the Millennium Development Goals were launched in the 1990s, we've really just not made progress in neonatal mortality at all. And every, every step that we have forward in neonatal health care. Um, so, for example, I mentioned in the podcast the, um, you know, progress in encouraging safe births in health care facilities. For every step we make forward, we then have another step backwards, because we're not always giving those strategies with long term, sustainable solutions. And that's where we're now seeing overcrowding and Amr and the spread of these bugs. So I think that we just have so much that we can achieve in reducing some of these inequities within our lifetime. And I think that sometimes it's really easy. You know, I can do a few weeks on call here in Sydney and completely forget how different the clinical picture is, and then I jump on a plane and go and do a ward round in Indonesia. And I think, God, I can't believe I thought I was busy last week in Sydney. You know, the way these clinicians are working that are based in these health care settings, doing 16-hour days and just up against insurmountable challenges, um, I think that we all have a role to play to, to make sure that some of those inequities reduce in our lifetime.


Seamus O'Brien: I am Seamus O'Brien. I'm the research and development director for GARDP, which is the Global Antibiotic Research and Development Partnership. Before that, I've worked in industry and the majority of that time has been in the development of of antibiotics.


Marnie: You mentioned that you currently work with GARDP. Could you describe to our listeners what your organization does and your role in research and development?


Seamus O'Brien: GARDP is a not-for-profit foundation, and we are focused on working in partnership with others to address and accelerate the development and delivery of antibiotics as treatments for priority drug resistant infections. And one of my key roles as R&D director is to develop a portfolio of treatment options which address the key drug resistant infections, which have been prioritized by a number of different mechanisms. And I'll come to that short shortly. But these are really I need to develop these to a point where they can be delivered and implemented in countries. And this portfolio of treatment options is being developed to address those infections where there is the greatest unmet need and the unmet need is due to a burden of disease due to antibiotic resistance. Because we're for these infections, we have very limited or no treatment options. We have two main disease areas sepsis and the related hospital acquired and community acquired serious bacterial infections, which can lead to sepsis and also sexually transmitted infections. We work with partners on the R&D and the particularly the development side, but also we work with them to ensure sustainable access to those, to antibiotics as treatments, promoting the responsible use and trying to to deliver them and make them available in countries, in an affordable way as well. What we're really, um, focusing on is to develop this portfolio for both adults and children. So we, we look to partner with companies who have got antibiotics, which we think are priority antibiotics. And we look to see whether we can partner with them to, develop them, for children of all ages and then particularly for sepsis within, for neonates. So neonatal sepsis because that's a population which is particularly impacted by Amr through this infection syndrome.


Marnie: So we're talking about the specific research and drug development for neonates. What are some of the key things that are important here? The key considerations as you are working on some of these programs?


Seamus O'Brien: Firstly, the reason we're gap and others need to really focus on neonatal sepsis is because it's an infection syndrome with a significant, significant mortality burden. And that's driven by an increasing resistance to current recommended treatment. And then there's also an unacceptable delay in new antibiotics being developed for this vulnerable population. So I think that's the reason. That's a reason that, you know, the main reason that we and others are focusing on that, and I think in terms of, you know, the next steps and what we need to do and what's required is that we do have a sort of greater understanding of generally in adults and in children, which, which syndromes, uh, caused by which resistant bacteria are responsible for the, for the greatest burden of disease. And that came out of the um, the GRAM study, the Global Burden of Disease estimate study and also a study that we conducted called NeoOBS, Neonatal Observation and the Barnard study, which, demonstrated the level of mortality that you see in neonatal sepsis, the range of antibiotics used to treat the neonatal sepsis, which suggests that you need lots of antibiotics because there is a concern about emerging resistance due to the WHO-recommended regimens. When we got involved in this program and started putting this forward in as a core part of our disease area strategy, it was really clear that we needed to focus on two main areas. One area was, the fact that there was increasing resistance to who recommended regimens, and we needed to do something quite quickly. We needed to look at something, whether there are existing antibiotics which were not being used, which could possibly be potential have potential value and use in neonatal sepsis.


Seamus O'Brien: So we identified antibiotics to do that. And we looked to see if we could develop them as treatment options for um, what's called the empiric treatment for neonatal sepsis. The other main area is that unfortunately, we're seeing more and more babies who are thought to be infected by pathogens, for which there are very limited treatment options. These definitely required new antibiotics to be developed to target treatment for those babies. And that's these are infections which are due to bacteria which were, uh, multidrug-resistant to a range of different antibiotics. We are sort of committed to building a coalition of partners to ensure that the community understands and the key stakeholders, stakeholders understand that we need to prioritize the. Of antibiotics for neonates as a population. So be that developing treatment options with current antibiotics, but also developing new antibiotics for those pathogens such as um, carbapenem-resistant Enterobacterales and Acinetobacter, making sure we accelerate the development of those through pediatric programs, development programs, and ensuring that we demonstrate the evidence for their use in neonates. Uh, the publication that we just, um, published paper we just published was really to call out a need to understand, obviously, the pathophysiology of neonatal sepsis, but to address the antibiotic development pathway, to make sure we, we, um, try to accelerate the evaluation of these antibiotics in neonates, understand which bacteria were really the key priority, bacteria for bacterial pathogens for neonatal sepsis, and which antibiotics were in late-stage development or recently approved, which we could focus for, for attention to be accelerated, to be used in neonates.


Marnie: Can you talk just a little bit about some of the challenges of completing clinical trials for neonatal sepsis?


Seamus O'Brien: So to get to the point of evaluating the utility of an antibiotic as a treatment in neonates, you have to go through, particularly if it's a new chemical entity, you have to go through a pediatric development plan, which is agreed with the main regulatory authorities FDA in the US and EMA in Europe. The problem is that, um, the challenges from a study perspective really come from the studies that are mandated by those respective regulatory, um, authorities. So the challenge is to ensure that we have greater harmonization between both agencies. So, um, we ensure that we're not duplicating the research in babies, basically duplicating it because we're asking for the same studies from each agency and ensuring that, um, that we get consistency in terms of what type of data is required and what level of studies and what type of studies are needed to be done. So at the moment, there has been some movement and more flexibility and more harmonization across the two agencies. And for the indication studies that were asked to do, children always don't manifest and present for those indications from a clinical perspective in the same way as adults do. And, um, this can also lead to recruitment challenges and families who are looking to, you know, support research and to give consent to, to their children being randomized in these in clinical trials for, for antibiotics and other and other areas.


Seamus O'Brien: It does can cause impacts for the family supporting the trial in terms of quality of life and consenting, and then moving on to neonates. Consenting for a newborn baby to enter into a clinical trial is a is a major decision, and you need to understand the value of that trial for your baby so that it's difficult to have a conversation with a parent to address. And I have not had that because I'm not a clinician. But, um, I it's difficult to address consent here in neonates from a, from a societal benefit. You really have to demonstrate the study has got some value for their for the baby with neonates. So the key thing which both agencies agree with is that they are willing to support extrapolating from efficacy from an efficacy perspective. But we do need to demonstrate that PK, in children across all age ranges and in neonates within different age ranges, within neonates, just.


Marnie: So people that are listening like PK is, is the pharmacokinetics. Yes, of an antibiotic. And you're really trying to understand if you give a particular dose, how high is the concentration of the drug and how long does it stay at a particular concentration to have its effectiveness, and how quickly is it eliminated via whatever route it's metabolized or, or, renally eliminated.


Seamus O'Brien: And that's important to be sure that you're getting the right exposure in the different organs too, to ensure that you get, um, the exposure to cover the potential pathogens that you may see. So you get a match, the PK, PD predictions that you see in adults, in children based on the PK that you're that you, that you that you're seeing from from children when you conduct the pediatric studies. So those studies are still important to do PK studies in children and babies. And they also have challenges because what's called a single-dose PK study you give the first dose. They are usually given on a background of existing therapy. So it's difficult to explain to parents why are you giving this additional drug to the baby? Um, but that's the current, approach to doing a single-dose PK. What we'd like to see in terms of addressing those challenges is trying to see whether we can close the gap between regulatory studies and studies, which demonstrate the utility of antibiotics as treatments for neonates. So maybe embedding some of the PK regulatory requirements into a study, which also demonstrates that this antibiotic may be in a regimen with other antibiotics, can. The neonatal sepsis that your baby has, rather than just saying, this study is going to demonstrate the PK of these antibiotics in your baby. So I think that's what we're trying to do more of. And those studies are much more relevant for where the impact of AMR is really hitting. And that's in, you know, in babies in certain resource-constrained countries, the people.


Marnie: That are on the front line trying to make this happen for you are clinicians that are engaging with researchers. How do you promote that collaboration with your clinical trial teams and, you know, your overall research R&D strategy? Because there are different parts of the of the world as well, that these things are being carried out.


Seamus O'Brien: What we do and what we plan to do is, um, is to build a sort of coalition of partners and have a sort of platform approach to pediatric antibiotic development and neonatal sepsis. We have, um, a network of sites and centers which are interested and are involved in in the regulatory pediatric studies and are looking to ensure that those studies are particularly undertaken in babies who have a burden of neonatal sepsis. As we just discussed, you can demonstrate the value of the regulatory studies to their babies and then maybe have a follow-up into a study which is particularly focusing on the use of that antibiotic, which is being, um, which is an investigational product, into a future evaluation to treat neonatal sepsis. So that sort of platform approach, used using studies which can be adapted to maybe address some regulatory requirements, but also to address from a PK pharmacokinetic and pharmacodynamic perspective, but also then to use that platform to, undertake a more broader utility studies is the way forward. We have just um, for example, becoming part of a consortium-based approach with um, European and African partners. A new consortium called Snip Africa, which has been supported by the European Developing Countries Clinical Trials Partnership. I always get that wrong. EDCCTP which is a consortium and part of that will be a large interventional study, a sort of public health-focused study in neonatal sepsis. There will be other work packages focusing on dosing in neonates or PK studies, uh, some microbiology surveillance and then another sort of work packages looking at building capability within sites, uh, to undertake both pharmacokinetic studies and also um efficacy and safety studies, so that I think there's 12 to 13 partners and I think seven of those are in Africa.


Seamus O'Brien: From a group perspective, it's really important that that we demonstrate our commitment to, to make these drugs available where possible. So, um, if it's a new drug which is in development, which is, which has been co-developed with a partner, we, we look for, um, licensing rights for, for countries where we think the drug is most, um, most needed both in adults and in children. So access for children is a key focus for GARDP. We would look then to have licensing agreements, uh, in those countries to make the drug available. Obviously, we then would have to follow the right regulatory route to make sure they're approved, in the individual countries for existing antibiotics. That's a challenge because some of those, some of these are sort of old antibiotics which have not been evaluated in neonates. And we are currently working with some companies who make these drugs available from a generic basis. And we're looking to partner with them hopefully to support the availability of these drugs in new treatment regimens for, neonatal sepsis. It's a pathway which doesn't exist. And we're trying to build this pathway with our partners. So it's hard work but it's needed. Um, and it involves trying to, um, gain commitment for what is actually a low volume of use initially. So it may need some other public health funding approaches to support the, um, you know, the sort of sublicensing and the approaches to make the drug available.


Marnie: In your role as the Director of Research and Development for GARDP, what other focus areas do you have that you're excited about, or some of the areas that you're considering?


Seamus O'Brien: Our study called Neo one, which we're running in partnership with, um, Saint George's in London, MRC Clinical Trials Unit and Penta, and a whole host of partners in Africa and hopefully Asia and Latin America. We're just about to start the stage one, phase one of that, where we're evaluating three new treatments regimens based on existing antibiotics. We've gone through a whole process of working out how these drugs in combination can kill the main pathogens in in the test tube. I won't go into details about different sort of models where you can look at demonstrating synergy between those drugs and reducing the emergence of resistance. And we've now gone to do a preparing. A run in part one study to ensure that these new combinations are safe. And look at the PK in neonates. And then we're going to rank them against a number of treatments which are currently used to treat neonatal sepsis in a number of countries. And Africa will be the first continent where we would start the study. So we're really excited about that. It's a novel design for this study, um, designed by Professor Sarah Walker in the MRC Clinical Trials Unit in London, which I think is going to be the template for future studies looking at randomized treatments and sort of personalized approach for the infection type and the type of, um, how should I say the clinical background for the for the baby that's being that's being randomized in the study. So, yeah, that's an exciting time for us the next the first few months of this year to get that study up and going.


Marnie: You described in your introduction that you have previous experience working in the pharmaceutical industry. What are some of the differences you've experienced working in industry versus GARDP, a not for profit R&D organization?


Seamus O'Brien: What I would say my experience in industry has been with Big Pharma. I've not worked in biotech. I think people who work in those units and those groups are as committed as my colleagues in GARDP. I would say that very committed. But there's obviously a challenge with trying to get air time for a smaller volume, which has very small returns and investment if you're in comparison to oncology, for example, if I answer your comment, your question in the context of pediatric development and neonate antibiotic development, what I would say is that it's very challenging for industry and pharma in particular, but particularly biotechs, we do most of the antibiotic development at the moment. It's particularly difficult for them to focus on pediatric development because it's a significant. And I'm going I'm talking about economics now rather than R&D, but it's a significant cost to develop your antibiotics, just to get to the first indication in adults, the pediatric development programs. Actually, in reference to some of the comments I made about the lack of harmonization, complete harmonization across the agencies are complex studies and are becoming more expensive because you ask the question about difficulties in recruiting. Some of the pediatric regulatory studies, uh, remain open as an open protocol for years because we can't finish companies can't finish recruitment on them. So it's so costly to keep those studies open. So the cost of and I know some very learned colleagues I that I collaborate with on, on, on in this area have published papers to say that pediatric programs cost as much, if not more, than some of the adult development. So I don't see industry able to focus on pediatric development as an unmet public health need because it's such a significant burden for them.


Seamus O'Brien: And use the word burden in a different way here. Financial burden when you're trying to justify the investment in a development program. And that's a real challenge. So without a way of reimbursing antibiotics, which recognizes their value to treat infections in adults and children, we run the risk of antibiotics either not being available at all or only completing their adult development. And the gap between approval in adults to children in neonates is just going to get longer and longer. So we're in a situation globally here now where resources are constrained across the board for many things and particularly for antibiotic development. So I do think we have and this is one of my sort of buzz phrases. We have to prioritize. We really have to focus on those those infection syndromes in those populations, including children and neonates, where we are seeing the greatest of burden of disease and come up with a plan to address those, and a public health plan and a regulatory plan is critical as well. And then talk to the originator companies who are developing these assets and say, look, we know this is a challenge for you. We're going to partner with you and look to get, you know, funding to really accelerate those public health pathways, including pediatric development, which they may not be able to address. So we're sort of doing that in a, in some development, joint development that we have with some companies. But I think it needs to be a broader coalition of partners to do that and someone to help with the prioritization. I think that's key. I'm glad you are willing to take a lead on that. But we need to work with WHO and others to, to focus in on that.


Marnie: Those listening. They want to know what actions can we take to reduce the risk of drug resistant infections.


Kamala Thiagarajan: We can limit our intake of antibiotics. Don't take them unless they're absolutely required. Never self-medicate. And also I would say if you have an opportunity, if you have an opportunity to create awareness about antibiotic use among your family, among, you know, your kids, I think that's important because a lot of people who self-medicate are in the teenage age group. But there was another study that found that, and they don't quite understand that antibiotics don't work against viruses. And so we don't actually need them. So refer a common cold or for a sore throat. So, you know, if you can create and pass along that awareness I think every bit counts. Right.


Seamus O'Brien: Think about personal health and make sure you support your immune system. Get vaccinated from a personal perspective to reduce viral infections, to reduce and obviously for bacterial infections, but from a viral perspective to reduce the possibility of secondary infections, which could lead to treatment of antibiotics, which could lead to resistance. So I try not to be too political but support locally the your funding of your local health services and um, maybe the introduction of targets to address hospital-acquired infections. Ask your politicians to support incentives to support the development of access to new interventions such as antibiotics. And, um, go back to the point we made earlier in economic and support and economic and reimbursement model that addresses the value of antibiotics globally and nationally, nationally. I focus a lot there on antibiotics, but there are lots of other interventions which will have a major factor, such as infection prevention control globally and the need for sanitation globally.


Phoebe Williams: I think globally, the most important thing that all of us can do as clinicians or as members of the general public is use antibiotics wisely, having that understanding of a viral infection versus a bacterial infection, and that we don't we shouldn't be using antibiotics just in case to cover viral infections. And, you know, in many health care settings, there's a real expectation from the consumer. If they go to their doctor, they want a script. And so I think as the general public understanding and trusting in your clinician when they say, look, I think this is actually viral, why don't we see how you go? And as you know, people working in healthcare trying to refrain from the overuse of antibiotics, and then once we gradually have a few new agents come through this pipeline that is actually very dry and not keeping up with the rate of antimicrobial resistance at all. Um, we just need to make sure we use those agents appropriately and don't overuse them as we have with so many agents over the last 100 years since antibiotics were discovered. And at the same time, we have to make sure that people who need antibiotics have access to them, and particularly people with these multi-drug resistant infections in many of these resource-constrained health care settings.


Marnie: You've been listening to Superbugs and You, a podcast series focused on true stories from scientists and patients around the world on the threat of antimicrobial resistance. This series is co-created by the Center for Infectious Disease Research and Policy and the Antimicrobial Resistance Fighter Coalition. The podcast is produced by Elise Holmes, Diane Flayhart, and Natalie Vestin. For more news and information on antimicrobial resistance and stewardship, check out our websites cidrap.umn.edu ASP and Antimicrobial Resistance Fighters. Org. You can also find us on Twitter @CIDRAP_ASP and @AMresistance.


This podcast is co-created by CIDRAP-ASP and the Antimicrobial Resistance Fighter Coalition (ARFC).

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