I have now posted quite a few times about ways to reduce antibiotic use in the NICU, and in the term baby nursery.
One thing that would help to reduce unnecessary usage is to abandon the idea that culture-negative sepsis is an entity that needs to be treated with antibiotics. I well remember a pair of mono-chorionic twins from several years ago that had identical presentations of early-onset sepsis with shock in the first few hours of life. One had a blood culture positive for E. Coli, the other had negative cultures. Presumably the cytokine/inflammatory response in the bacteremic twin had been shared with his brother through anastomotic channels. Treating such an inflammatory response syndrome with antibiotics is unlikely to improve outcome.
A great perspectives article recently published on-line in Pediatrics (Cantey JB, Baird SD. Ending the Culture of Culture-Negative Sepsis in the Neonatal ICU. Pediatrics. 2017) reviews the reasoning many people use to continue antibiotics in the face of negative cultures. They note the following:
1. if a culture of at least 1 mL is obtained before starting antibiotics, the sensitivity of detecting organisms down to a bacterial density of 4 CFU/mL is close to 100%, and is probably even better with the newest culture techniques.
2. Infants with negative cultures at 36 to 48 hours who have their antibiotics stopped virtually never need further treatment.
3. Infants who have negative cultures after maternal antibiotic therapy were either not infected or have been adequately treated. This is not a reason for continuing antibiotics.
4. Ancillary tests (CRP, procalcitonin, and the like) are of no use for deciding if a baby is septic, they have poor positive predictive value, and are non-specific.
5. Our clinical opinion as to the likelihood of sepsis is very poorly predictive of true sepsis.
“Culture negative sepsis” may indeed exist, the example I gave above is one situation which you could call by that name, viral infections, leading to an inflammatory response, are another. Neither situation is likely to benefit from prolonged antibiotic therapy.
The authors conclude that we need to learn to trust our blood cultures
Put simply, if the bacteria cannot grow in the blood culture bottle (an ideal medium at an ideal temperature, free of antibiotics, complement, or phagocytes), then why would they grow effectively in the infant’s bloodstream? As we learn more about the adverse effects of antibiotic exposure on short- and long-term neonatal outcomes, it becomes increasingly clear that prolonged antibiotic therapy for suspected sepsis is a luxury our infants cannot afford.
If you have access, I urge you to read this well-reasoned and well-written piece, and take its message to heart. Prolonged antibiotic therapy in the face of negative cultures increases the risk of later sepsis, and of necrotizing enterocolitis. Killing probiotic organisms in the gut with antibiotics allows the overgrowth of pathogens which can then wreak havoc.
I think we should have a rule that antibiotics are always stopped after 36 hours. Continuing them would then need a definitive decision, which would be easy if the cultures are positive, and should almost always be a decision to not restart in the face of negative blood cultures.
Neonatal Research 
I agree, this is an important topic. Our research group recently published a paper entitled « Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis ».
https://www.ncbi.nlm.nih.gov/pubmed/28369594
Antibiotics, not used with a good indication, are clearly associated with potentially severe side effects.
Kind regards
Claus Klingenberg, Tromsø, Norway
I think this, along with other of your entries in this blog, have perfectly summed up how we should approach this clinical entity (culture negative sepsis), which has always served as an excuse to continue the use of antibiotics.
When we face a newborn with a suspicion of sepsis and try so hard to convince ourselves that everything is due to an infection, despite the evidence against him, I feel like a researcher who, despite concluding an experiment and to verify that his hypothesis was incorrect, refuses to accept the null hypothesis.
I believe that this small but substantial article will help us to better deal with these cases, so frequent in the NICU.
Thanks
Here in England, we treat all neonates with five days of anti-microbial therapy if they have had an abnormal CRP (>10mg/l) despite no growth in blood culture at 36 hours. I think the reasoning behind this is the presumption that something significant – possibly infective – must have caused the rise in CRP and therefore require treatment with anti-microbial therapy for an arbitrary length of time. I don’t think there is any evidence to back this up so maybe it is dogmatic?.. May I ask what the practice is in Canada?
I would agree that this is non-evidence based dogma. The CRP is very non-specific, has very poor predictive value, and there is no reliable information that prolonging antibiotics because of a raised CRP is beneficial for the baby. Canadian practice is very variable. I have only asked for a CRP 2 or 3 times in my entire career! Babies with negative cultures can have antibiotics stopped safely even when the CRP is elevated. It is actually easier to do this if you don’t measure the CRP.
Keith, I would strongly endorse the points that you make in your commentary. But I think that you omitted one of the primary reasons for the inappropriate continuation of antibiotics in “culture-negative sepsis,” namely reduction of physician stress levels. Being a NICU attending is very difficult, and every day is filled with complex decisions, often life and death. If one has an infant who did not appear well at birth, but has adequate blood cultures drawn that are negative at 36-48 hours, if one stops antibiotics, one then needs to pay continuing very close attention to that child, adding to the daily NICU worries and stress. If antibiotics are continued, however, that requirement and it’s attendant stress are (incorrectly) reduced in the mind of the physician, especially if one can then subsequently pawn off the antibiotic decision to whoever might be covering for the weekend or a rotation change, etc. I have long felt that a number of NICU decisions are not necessarily made for the infant’s benefit, but for the reduction of internal stress among the NICU staff. I fully realize that this way of thinking is a harsh criticism of my colleagues in Neonatology, but I think it is the reality of many circumstances in which we all become a bit intellectually lazy simply to make ourselves feel more at ease. And I would be totally dishonest if I did not point out my own complicity in such decisions at various times in my own career. But the risks of poor antibiotic stewardship are very serious, and the potential downstream breeding of resistant microorganisms as well as the increased risks for that individual infant (NEC, fungal sepsis, etc.), should never be forgotten when confronted with the decision to stop antibiotics with negative blood cultures. Thanks for another excellent commentary.
In a baby with continued signs of illness after negative cultures, for instance poor feeding, continued O2 requirement, would it be unnecessary to continue antibiotics?
I share the concerns expressed about the use of antibiotics to treat culture negative sepsis. However, sepsis can be present in body cavities without entering the blood stream such as ventilator associated pneumonia, or abdominal sepsis. Would these not be an arguement to continue treatment with antibiotics in the face of a negative blood culture?