CRP can suggest that babies are not infected, when you already know!

I wrote a blog post about 3 years ago about a study examining procalcitonin use in neonatal early-onset sepsis. You can see from my post that the authors didn’t, to my mind, show any utility of procalcitonin (PCT) either alone or in addition to the CRP for diagnosis of EOS. They have just published a secondary analysis of the trial (Stocker M, et al. C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study. Clin Infect Dis. 2020) which shows the following:

Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours

Which is all well and good, but not much use. Blood cultures are almost always positive by 36 hours, so by the time the PCT and CRP are useful you already know if the baby has sepsis or not! The actual time to positive cultures has just been reviewed, (Marks L, et al. Time to positive blood culture in early-onset neonatal sepsis: A retrospective clinical study and review of the literature. J Paediatr Child Health. 2020;56(9):1371-5). Using the Bactec system they found that 98% of positive blood cultures in babies with EOS were positive at less than 24 hours, and the only one that was positive later was taken after antibiotics had been started. In their review of the literature, blood cultures for EOS were positive by 24 hours in 92% to 100%. In my practice, we now stop antibiotics if cultures are negative at 36 hours, the idea being that in the rare case of a culture being positive between 36 and 48 hours we can restart the antibiotics without actually missing a dose, but the dose which would normally have been given at 48 hours is avoided if the cultures are negative. Given this new publication, we can probably stop even earlier, at least for EOS, and limit antibiotic courses to one or two doses for the majority of babies who are screened but do not have EOS.

The Bactec system and other similar systems are extremely sensitive to even very low bacterial counts as long as 1 mL of blood is used, they screen the culture medium continuously and an alarm bell rings in the lab if they become positive, bringing a laboratory technician scurrying over to get the result and phone it to the NICU. I actually don’t know how it all works, but that is the image I have in my mind. We have a very efficient lab that always telephones when a blood culture is positive, but just as a backup we ensure that someone checks with the laboratory directly before stopping antibiotics. Reducing unnecessary antibiotic use is an important goal, this most recent publication again fails to show that CRP or procalctinon measurements, single or repeated, assist in achieving that goal.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged . Bookmark the permalink.

2 Responses to CRP can suggest that babies are not infected, when you already know!

  1. Martin Stocker says:

    Hi Keith,

    Thanks for your comment on our study. I’m always happy if you choose our studies to give a feedback! Of course you are right: Blood cultures are almost always positive by 36 hours and with the knowledge that most culture-negative sepsis cases are truly not infected, you don’t need any biomarker to stop antibiotics for suspected EOS. Unfortunately, that is still not the standard management in many NICUs all over the world: Fear of missed culture-negative sepsis in neonates with persistence of clinical signs is still a massive driver of a prolonged treatment. Recently, we had a baby with pneumonia due to pseudomonas (proven by post-mortem autopsy) and negative blood cultures, but positive pseudomonas-PCR in the blood. So, culture-negative sepsis happens, but probably rarely. Nevertheless, cases like this nurture the fear of such an event.

    Therefore, I agree that biomarkers are not a must have, they are just a potential help if the fear overcomes the mind of physicians caring for babies. Not a big step, but hopefully a little one helping to reduce antibiotic overtreatment. And I agree with you, that we can probably stop antibiotics even earlier for most cases of suspected EOS.

    Thanks again for your feedback, Martin

    • Thanks for the comment Martin, I think this was an important study, and well performed, and this new analysis helps to put the results in perspective. It is clear that there are babies with localized infections who do not have positive blood cultures, it happens at every other age, so why would newborns be exempt? Most of our therapy is for potential septicemia, and when babies have no clinical signs of pulmonary or CNS infection, and negative blood cultures then stopping antibiotics at 24 hours can be the standard, only to be broken for good reasons. Many of us try and find reasons to continue antibiotics, I think we should be looking for reasons to stop them.

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