Carbapenem-Resistant Infections: How Do Genetic Elements Affect Transmission?

The World Health Organization and the CDC have declared Carbapenem-resistant Enterobacterales infections are an urgent public health threat. The infections are not easy to treat and have a high mortality rate. However, all of these infections are different. How does having the Carbapenemase gene affect the mortality of patients with carbapenem-resistant Enterobacterales infections?

Medical background, Enterobacterales bacterium including salmonella, E. coli, plague bacillus, proteobacteria, gram-negative, 3d rendering.

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Lucy Witt, MD, MPH, a third-year infectious disease Fellow at Emory University in Atlanta, presented a poster this year at SHEA held in Seattle, Washington, April 11-14, 2023, titled Carbapenemase Genes and Mortality in Patients with Carbapenem-resistant Enterobacterales in Atlanta, Georgia, from 2011 to 2020. She spoke with Infection Control Today^® (ICT^®) about her presentation. She spoke with ICT last year as well.

ICT: Please explain your study and why the information is important.

Lucy Witt, MD, MPH: This poster details a study that we completed last year here in Atlanta that was looking at all patients in the Atlanta, Georgia, metropolitan area with carbapenem-resistant Enterobacterales infections, as you and your listeners probably know; these are urgent public health threats as stated by both the World Health Organization and the CDC. And one of the big reasons people worry about carbapenem-resistant Enterobacterales infections is that they're hard to treat. Carbapenem antibiotics are already broad-spectrum antibiotics reserved for very severe and drug-resistant infections. But then specifically, the mechanism for resistance that confers this resistance to carbapenems can sometimes be found on these mobile transmissible genetic elements called plasmids. So that's an infection control problem. That's what people worry about because these mobile elements can spread between bacteria within the same patient. Then, of course, very concerningly from one patient to the next. So it's both a concern for the patient's overall well-being and mortality because it does have high mortality when you get this type of infection, but also for infection control. The question we want to answer with our study was, first, how many of these carbapenem-resistant Enterobacteriaceae infections have those carbapenemase genes, those potentially transmissible genetic elements? Because we know from other studies that not all of them do.

There are many challenges for health care epidemiologists in the current environment; the biggest could be burnout. And that encompasses many issues we're seeing, health care workers, you know, from nurses to physicians to environmental services to obviously, Infection Preventionists are fatigued. It's been a long couple of years with COVID-19. And both long hours and having other health care workers with the public questioning what they're doing, questioning the decision-making, questioning the science we use to guide our decisions, and constantly defending our choices. That's created much burnout.

Then also, is there a mortality difference between the patients with these potentially transmissible genetic elements, these carbapenemase genes, and those without, because there are other ways to become resistant to carbapenem antibiotics? So we took data on all the carbapenem-resistant Enterobacteriaceae infections in the Atlanta metropolitan area between 2011 and 2020. We gathered this information about these infections through the Georgia Emerging Infections program. That is an active population and laboratory-based surveillance program that collects isolates of infections from laboratories in the Atlanta metropolitan area and then uses chart abstraction to get detailed information about the patients affected by these infections.

We collected data on 284 isolates that underwent whole genome sequencing by our investigational laboratory at Emory [University] or the CDC because the CDC helps fund the Georgia Emerging Infections program. This included infections from sterile sites like blood and nonsterile sites like urine. We found that about 60% of the bacteria that cause these infections did have a carbapenemase gene. And Klebsiella pneumonia was prominently featured in terms of having a carbapenemase gene. Over 84% of Klebsiella pneumoniae isolates had these genes. So that's the bacteria most likely to have one of these genes, and the most common carbapenemase type was a KPC-3. That are consistent with what we know is normal or has been previously described in the United States.

So KPC-3 [K pneumoniae carbapenemases, KPC ] is the most common carbapenemase gene in the United States. We did not find that there was a mortality difference between patients who had a carbapenemase gene or had carbapenem resistance through other mechanisms, which I was not that surprised that, as I mentioned before, if you have a carbapenem-resistant Enterobacterales infection, you had limited treatment options regardless of the mechanism of resistance, especially before the era of the novel beta-lactam beta-lactamase inhibitors which were FDA approved around 2015, right in the middle of our study period. We also found that within the infections with carbapenemase genes, there was a high number of extended-spectrum beta-lactamase genes—another resistance mechanism. But then, in the patients who were carbapenem-resistant but did not have a carbapenemase gene, we saw many AMP C genes, another resistant mechanism gene.

And so interesting genetic abnormalities in the 2 different groups appear to be different, depending on whether you have a carbapenemase gene. These data were very similar to what's been noted in national cohorts. So, for instance, Crackle-2 was a national investigation of carbapenemase genes; they found similar rates of carbapenemase genes and carbapenem-resistant Enterobacterales and also did not find that there was a mortality difference if you had a carbapenemase gene versus if you didn't, there had been other studies that may be suggested a mortality risk with carbapenemase genes, but that is not what we found. And I do. So there was debate. This adds more data to the concept that it doesn't matter why you're carbapenem-resistant; you need to be careful and ensure you're getting treated correctly, regardless of the mechanism of action. I do think that the newer drugs, as I mentioned, the newer beta-lactam, beta-lactamase inhibitors, cefiderocol, the new cephalosporin, and eravacycline, have changed the game a little bit with carbapenemase carbapenem-resistant Enterobacterales, and have given more treatment options for these infections and have helped us create very nuanced treatment options.

The Infectious Diseases Society for America came out with guidance documents on how to treat these, and they have specific recommendations that align the treatment with the resistance mechanism. Going forward, we may see a difference in mortality benefit, depending on the mechanism of resistance, because now we know, you know, if you have a KPC, you probably should be using 1 drug versus if you don't, another drug might be fine. This data will likely change as we go forward. From an infection prevention and infection control standpoint, as we can more quickly and effectively identify the patients with carbapenemase genes, we'll be able to research to see if the spread to other patients, mostly from patients who have carbapenemase genes. Is it those patients we should be isolating and making sure of contact precautions? Or is it all patients with carbapenem-resistant Enterobacterales, because regardless of the mechanism, they risk spreading those bacteria to other patients? As the technology changes and becomes more available and more clinical microbiology labs, the implications of this carbapenemase gene, acquisition, and presence will become clearer.

ICT: What results surprised you?

LW: What surprised me that is probably unique to our data is that we found an association between patients of lower age and patients of the male sex; this is all charts identified with carbapenemase genes. And that was a head-scratcher. I, you know, at first, I couldn't figure out why we saw that. But when we looked at the data, we noticed that most of our patients on chronic dialysis were of a lower age. We're a majority male, and carbapenemase genes are usually health care-associated. And so the explanation for that is that dialysis is a health care interaction. And so, these younger male patients are more likely to interact with the health care system and thus at a higher risk for acquiring the carbapenemase genes. So I think in our study, this associated association between lower age and male sex is probably just a marker for chronic dialysis.

ICT: Taking a step back, what is health care epidemiologists' biggest challenge? And how can it be overcome?

LW: There are many challenges for health care epidemiologists in the current environment; the biggest could be burnout. And that encompasses many issues we're seeing, health care workers, you know, from nurses to physicians to environmental services to obviously, Infection Preventionists are fatigued. It's been a long couple of years with COVID-19. And both long hours and having other health care workers with the public questioning what they're doing, questioning the decision-making, questioning the science we use to guide our decisions, and constantly defending our choices. That's created much burnout. And the health care workers are sick of constantly changing requirements; many facilities are starting to change their mask requirements, and it's causing some confusion, although my understanding is that it's overall been well received, the change in the masking policies. And we still have more work to do to continue to instill confidence because, especially after the summer, we're probably going to see an uptick in respiratory viruses come the fall and may have to change our tune again. And that'll be another challenge. But it's impossible to predict. And we're going to have to follow the science. The way we can overcome that is, as I mentioned, following the science but also making sure we involve all of our stakeholders, our health care workers, our patients, and our families in all our decisions and make sure that we're open in our decision-making process and that we hear the concerns and the thoughts of everyone who gets affected by infection prevention and infection control changes, and, and try to, you know, make the best decision with the information we have.

ICT: What are you most excited about this year's SHEA meeting?

LW: I am pleased to be in person after not attending conferences for a few years. It's been great to see people in person. I will be completing the hospital epidemiology track, and they have many interesting presentations focused on health care epidemiology. I'm excited to learn and be on that track with others interested in health care epidemiology.

ICT: You won a scholarship.

LW: I was lucky to be selected for the Jonathan Freeman Scholarship. My mentor, Jesse Jacob, had one, and prior his prime mentees had one, to allow me to attend the conference and participate in the health care epidemiology track. I'm fortunate to have been selected, and I'm very thankful to SHEA for giving me the opportunity and just excited to attend.

ICT: Is there anything else you'd like to add?

LW: There are many challenges going forward. C auris is on everybody's mind right now. And I'm hopeful that between COVID-19 and Cauris and monkeypox, infection control and infection prevention are going to become the well esteemed and well-known parts of health care and that people will continue to have an interest in what we're doing and continue to support the efforts of infection preventionists and health care epidemiologists in their local hospitals.

This transcript has been edited for length and clarity.