SCCM Pod-460 CCE: Multiple PCR for Direct Detection of Bloodstream Infection After Pediatric Cardiac

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Nosocomial infections are a prevalent cause of death and complications in critically ill children. Conventional cultures are able to detect only up to 25% of bacteremias. Several studies have suggested that molecular tests could be a faster and effective tool for detection of bacterial infections. Marilyn N. Bulloch, PharmD, BCPS, FCCM, is joined by Sylvia Belda Hofheinz, MD, to discuss the article, “Multiple Polymerase Chain Reaction for Direct Detection of Bloodstream Infection After Cardiac Surgery in a PICU,” published in the June 2022 issue of Critical Care Explorations (Checa RMC, et al. Crit Care Explor. 2022;4:e0707). Dr. Hofheinz is a physician in the pediatric ICU at University Hospital 12 de Octubre in Madrid, Spain.

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Transcript:

Dr. Bulloch: Hello, and welcome to another edition of the Society of Critical Care Medicine’s podcast. I’m your host, Dr. Marilyn Bulloch. Today, I’ll be speaking with Dr. Sylvia Belda, and we will be talking about the article, “Multiple PCR for Direct Detection of Bloodstream Infection After Cardiac Surgery in a Pediatric Intensive Care Unit,” published in the June 2022 issue of Critical Care Explorations.

Dr. Belda has been a physician and associate faculty member in the pediatric intensive care unit at University Hospital 12 de Octubre in Madrid, Spain for over 20 years. She also serves as an associate professor of pediatrics at the Complutense University of Madrid and has been the director of the pediatric residency program at our hospital for 17 years. She developed the first National Primary Neonatal and Pediatric ECMO Transport Program in Spain. Her other interests lie in medical education and end-of-life care. Welcome, Dr. Belda. It sounds like you have a lot on your plate. Thank you so much for joining us. Before we start, do you have any disclosures to report?

Dr. Belda: I have no disclosures at all. I’m very happy to share this podcast with you.

Dr. Bulloch: We are happy that you’re here. Correlating cultures and rapid diagnostics is a really hot topic right now in infectious disease. In many ways, these rapid tests like PCR have been touted as a game changer. Your study specifically focuses on a niche. How did you and your group come up with the idea to study this topic in this particular patient population?

Dr. Belda: Our team has focused its research on infection in critically ill children. In our unit, we work with a large population of postoperative cardiac surgery patients of known complexity. There is concern about the sometimes late diagnosis of infections, especially catheter-associated and non-catheter-associated bacteremia in these patients caused by different, sometimes multiresistant germs, which often receive empirical nondirected antibiotics. The delay in diagnosis by conventional cultures and its consequences leads us to explore new diagnostic strategies. We consider that molecular techniques may be more cost-effective in this population than other alternatives. The possibility of having a result within a time window of minutes, which also allows us to make therapeutic decisions and to guide the treatment duration, makes molecular tests a fundamental field of research.

Dr. Bulloch: Dr. Belda, just from a practical standpoint, I’m at a large teaching community hospital in Alabama in the United States. It sounds like you’re at a large university hospital. Are these rapid diagnostics like PCR something that your institution and your team have been using for a while in practice or is this newer to your world?

Dr. Belda: It is pretty new in our hospital, but we were really keen to know if it has a clear indication and may help us better treat these patients.

Dr. Bulloch: Your study has an interesting design. Tell us how you came up with the methods used in the study and what they are.

Dr. Belda: Our idea was to assess the diagnostic accuracy of a molecular technique for the detection of bacterial DNA in a population of postoperative cardiac surgical patients in whom we suspected infection defined by clinical and laboratory criteria. So we thought we should select the population of consecutive cases and collect a whole blood sample and a parallel blood culture for comparison. But we also selected a sample of controls to compare and to assess false positives.

Dr. Bulloch: You said in your paper that your controls were randomly selected. I know a lot of times in case control studies we’ll match our controls with our case patients. Was that done here or were they just randomly evaluated?

Dr. Belda: The controls were not matched because we found it was difficult to find exactly comparable patients in our heterogeneous population. But a comparative analysis of the baseline characteristics of the cases and controls was done. We included demographic and clinical variables like sex age, weight, the existence of comorbidities, or the surgical complexity and the cardiopulmonary bypass times, and we found no significant differences. So I think, even though we weren’t seeking for matched controls, they are pretty comparable.

Dr. Bulloch: I think you brought up a good point. In pediatrics in particular, it’s really difficult to get a group that looks exactly alike, much like you would expect in an adult population. So I can understand your approach there. Tell us about what you found in your study. What were your results?

Dr. Belda: Our main finding is a lack of accuracy in the molecular diagnostics used to detect bacteremia in the study patients. I think there are multiple explanations for this result, including that we made our analysis in whole blood samples and not in positive cultures. Maybe the sample preservation could play a role, the possible existence of false positives also in blood cultures and maybe also the use of a homemade PCR that was not a fully validated technique. But even so, I think these results force us to continue researching and modifying our methodology. As secondary results, I think they also are important. We found a significant prevalence of gram-negative bacteremia in these patients, and that may also help us to guide our antibiotics and our diagnostic and therapeutic options.

Dr. Bulloch: You mentioned using different types of analyses for your blood cultures and false positives. For your result purposes, did you require that a positive blood culture mean a positive set of blood cultures or did just one sample qualify as being categorized positive?

Dr. Belda: We included one sample, even though usually we get more than one. But with only one, we thought it was positive.

Dr. Bulloch: When we think about these, one of the things I’m always looking for is, How do I use this at the bedside with my patient? Practically, what does this mean? How do I use it in the real world? How do we take your findings and apply them to the bedside?

Dr. Belda: I think those are the most important questions of almost every research. That’s what we work for, for the patient and for the bedside. I think our outcomes are not very applicable at the moment given the poor results. But even so, the technique shows promise as a complement to blood culture, maybe under better conditions to shorten times and guide treatments. And we continue to work on it. I think knowing that nosocomial infection has such a tremendous impact on outcomes and that the gold standard for detecting bacteremia by blood cultures is very imperfect. Any potential adjuvant method deserves to be explored and researched. So even though our results were not the ones we expected, I think they help us to go on.

Dr. Bulloch: In your study, you saw there were cases where sometimes the blood culture would be positive but the PCR would be negative, sometimes the blood culture would be negative but the PCR would be positive. I think most of us can easily understand why that PCR test might be negative while the blood culture was positive. But outside the receipt of recent antibiotics, particularly, say the culture was drawn after antibiotics were given, what do you feel led to the negative blood culture but positive PCR tests that you saw?

Dr. Belda: These positive PCRs that we thought were false positives may be due to the collection of the whole blood sample, which maybe can be more easily contaminated. Maybe another reason and maybe a more probable reason could be that the detection of bacterial DNA is not necessarily synonymous with significant bacterial growth. I think that’s the main problem when you make PCR in whole blood samples. So we should be extremely cautious with these positives and looking at the results in light of the patient’s clinical and laboratory data, optimizing also the collection technique. But I think no test is valid without the patient.

Dr. Bulloch: That’s true. You’ve got to always look at the patient, know clinically what they’re looking like and how they’re responding. I think you just brought up a very good point—that we can’t use these tests isolated. They really do need to be used together. One of the things I noticed was that your study was open to pediatrics up to the age of 16 but the median age that was actually enrolled was quite young. How many older children and adolescents, maybe even teenagers, were included as cases? Or do you think that this is a study that really is more applicable to the younger patients?

Dr. Belda: Yes, it truly is. Although the original design aimed to include pediatric patients of all ages, our study population consisted mainly of infants under two years of age who most frequently underwent cardiac surgery, had more complex surgeries and therefore a higher incidence of suspected infection. So most of the cases were in this age span; this explains the limited age group in our sample, with only four teenagers and adolescents.

Dr. Bulloch: Only four. That’s interesting. I know it’s hard to really draw a complete correlation with just having four of them, but when people think of pediatrics, particularly those who aren’t in the area of pediatrics, there’s this tendency to generalize them all as the same. But we know there’s a lot of diversity within ages of this population, particularly with pharmacokinetics, pharmacodynamics, and just pathophysiology in general. Some of the adult studies that you mentioned in your article did find a correlation between blood culture and PCR. Again, I realize it’s probably difficult to draw any sort of definitive conclusions. But, at first look, did you notice any discrepancies in results based on age?

Dr. Belda: I think this is a very interesting question and it is possible that a greater discrepancy between culture and PCR is observed in children than in adults, as fewer and smaller blood samples are collected in little children, although the technique should have a similar efficacy. We did not observe differences by age in a sample. But again, maybe the number of adolescents included is too little to draw any conclusions.

Dr. Bulloch: Is that age range that you’re talking about you were including, is that pretty in alignment with the people who are receiving this type of surgery?

Dr. Belda: Yes, because we saw most of the infections in the children who stayed for longer periods and had more times of central lines and so on. These were mostly the little ones with the more complex surgeries.

Dr. Bulloch: One of the things that I noticed when I was reading your study was that it revealed that patients were primarily infected with gram-negative pathogens. You had said that this could be because pediatric cardiac surgery patients have risk factors for gram-negative organisms. For those of us who don’t work with pediatrics primarily, can you tell us what these specific risk factors are for the little kids?

Dr. Belda: Yes. Young age and neonatal age specifically are known to be risk factors for gram-negative infections, as well as the presence of devices like central lines or urinary catheters for sometimes prolonged periods of times, as is the mere stay in a pediatric intensive care unit environment. Also, previous surgeries, cardiopulmonary bypass, the use of mechanical ventilation or parental nutrition or gastrointestinal alterations, and low cardiac output state also increase the risk of gram-negative bacteremia. All of these risk factors are prevalent in cardiac postoperative patients, especially those who have undergone complex surgeries in the first months of life.

Dr. Bulloch: Is there anything specific about the age? I know you mentioned being neonatal and their bodies that increases their risk. Is it related to just how well or not well developed their immune system is?

Dr. Belda: I also think there are barriers, they suffer more sometimes, gram-negatives especially. The gastrointestinal tract of neonates is very susceptible to any low-cardiac output state, so they are really vulnerable.

Dr. Bulloch: You mentioned in the article that prophylactic antibiotics given postoperatively cover for gram-positive organisms, and that could account for one of the reasons you found a predominance of gram-negative bacteria, but you also mentioned that another study found that PCR did not perform as well in detecting gram-positive organisms. I found this fascinating because, in my world, I particularly think about gram-positives being a prominent source of infection. But when choosing these panels for PCR, should we continue to include as many gram-positive organisms as we currently are including? Or do you think it might be better to narrow the panels down?

Dr. Belda: This is a very good question. From our sample of 57 cases, 26 of the patients were receiving antibiotics when the samples for blood culture and multiple PCR were collected. Nine of each had a positive blood culture or a positive PCR. In other studies, this is used as an explanation for the low diagnostic yield of the blood cultures. In our unit, we use cefazolin during 24 hours of the prophylactic antibiotic, mainly covering for gram-positive bacteria as most of us do. I think the study you are referring to is the study by Pilarczyk, which is a study about adult patients after cardiac surgery. The detection rate of gram-positive bacteria was significantly higher with blood cultures compared to SeptiFast PCR. But I think this data cannot be generalized to date since multiple PCR panels, the samples we use, the clinical conditions of the patients vary widely and require further studies. So although prophylaxis generally may decrease gram-positive infections, it cannot be ruled out. The speed and ease of PCR allows us to detect multiple germs without increasing the diagnostic effort. So they should definitely continue to be sought and included in our studies.

Dr. Bulloch: We talked earlier about how we apply this to the bedside. I always think, Well, how did the patients do? What were their actual clinical outcomes? Did you see any differences in clinical outcomes between patients who had those concordant results between multiple PCR and blood cultures versus those who didn’t have matching results?

Dr. Belda: We didn’t find any differences, although it is possible that they would exist in a larger sample of patients. But it’s very important to know that, among the 19 microorganisms identified by PCR, we only had five, that’s 26% that were concordant to the blood culture results. So I think this is really too little number to draw any conclusions.

Dr. Bulloch: Right. And it’s probably hard to draw any conclusions about any impact on antimicrobial stewardship or something along those lines as well.

Dr. Belda: Totally. I think it’s hard to get the line between the research and the patients, but I think it goes step by step. So this was just the first step and we really plan to go on.

Dr. Bulloch: You plan to go on. What’s your next step?

Dr. Belda: Well, we believe in molecular techniques as a complement more than an alternative to culture diagnosis of infections, especially in critically ill children and mainly because of their speed and the information that it can provide and the impact they may have on the antibiotics we give. We are now working on molecular PCR techniques as a complement to positive blood cultures to gain rapid information and use with other clinical and laboratory data, as we were saying maybe with procalcitonin levels or with the clinical status. Altogether, that may improve the use of antibiotics, maybe allowing their use for fewer days or with a narrow spectrum. I think in our time where antibiotic resistance and multiresistant infections are a tremendously serious problem and burden, this may be an important advantage.

Dr. Bulloch: That would be fantastic. I think all of us are looking at ways to be better antibiotic stewards and protect the antimicrobial arsenal that we have for our patients. Anything that we find that could help that, I know would be really welcome and fascinating, so I wish you luck there. But let’s get back to this study. Your group enrolled 57 patients, your sample size calculation estimated that you needed around 108 patients with suspected infection. Do you feel like your study was underpowered or do you feel like a difference in sample size calculation versus how many cases you actually enrolled may have impacted your results?

Dr. Belda: I think this was due to the differences between what you plan and real life. The collection of the samples turned out to be more complex than we expected, and it took a lot longer than planned. In light of the poor results in terms of PCR and blood culture concordance and the time consumed for the sample collection, we decided not to extend the study any further. Also, summing cases and controls, we nearly reached the estimate, even though some of the cases were excluded because in the analysis they did not meet the initially established criteria. So it’s sometimes difficult to go with your plan. But we do not believe that the results would have improved, which was the main reason for not continuing. Still, we believe that the data described are relevant and deserve close attention in order to focus our research efforts correctly in further studies. I think it’s very important to share also the results that we are not expecting and that we are not so happy with, because maybe another group may focus their research better in light of what we found, and I think that’s very important too.

Dr. Bulloch: You bring up a good point. Sometimes these studies that don’t show a benefit still bring about positive change in our clinical practices. This has been fascinating for me. Is there any last bit of wisdom you want to share with us about this topic?

Dr. Belda: I was very happy to share this podcast with you. It was a pleasure. I think it is really necessary to continue research in this line and to seek better results, maybe trying to have better samples, maybe with the positive blood cultures and maybe also establishing which multiple PCR test is the best in which environment. I’m always focusing the things to the patient, because I think no research makes any sense without the patient. So I think that’s very important for me. I’m sure that better results can be achieved, especially because the gold standard, that is the blood culture for detecting bacteremia, is far from perfect. I think we have a really good starting point to improve what we are doing now.

Dr. Bulloch: You’re absolutely right. Like everybody else, we look forward to seeing what happens and how we’re going to be diagnosing our patients in the future. I want to thank you again for joining us. This concludes another edition of the Society of Critical care Medicine’s podcast. I want to thank you so much for being here today and talking with us, and thank you to everyone for joining us.

Marilyn N. Bulloch, PharmD, BCPS, FCCM, is an associate clinical professor and director of strategic operations at Auburn University Harrison School of Pharmacy. She is also an adjunct associate professor in the Department of Family, Internal and Rural Medicine at the University of Alabama in Tuscaloosa, Alabama USA, and the University of Alabama Birmingham School of Medicine.

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