Transcription:
Early Onset Sepsis: Evaluation and Management

Dr. Julie Weiner:  Hello, everyone. And welcome back to this edition of Neonatal Review: Isolette to Crib. Again, remember the purpose of this podcast is to review high-yield common topics in neonatology. While our focus is geared towards the perinatal and neonatal boards, anyone learning or studying neonatology will find this podcast helpful.

I will be one of the hosts for today's podcast. I'm Dr. Julie Weiner, one of the neonatologist and Medical Director for the NICU here at Children's Mercy Hospital in Kansas City, Missouri. We are located here in the Heartland where we have really good barbecue. So welcome and thank you for joining us.

To help prepare for boards, we have a collection of neonatologists to help us along the way. Today, we are going to be joined again by Dr. Joti Sharma, who will be the other host for this podcast. She is the Fellowship Program Director here at Children's Mercy hospital. Welcome back, Dr. Sharma, and tell everybody hi.

Dr. Jotishna Sharma: Hello. How's everyone doing?

Dr. Julie Weiner: Okay. So she is joining us today for take two of early-onset sepsis where last time we discussed the epidemiology and pathogenesis of early-onset neonatal sepsis. Today, we are going to talk about neonatal infections, early-onset sepsis, the evaluation and treatment. All right, Dr. Sharma. Tell us how do we manage these babies with early-onset neonatal sepsis.

Dr. Jotishna Sharma: Thank you, Dr. Weiner. Let's just dive right into it. And we will first talk about things to consider for evaluation of early-onset sepsis in the newborns. So when we are evaluating a newborn for early-onset sepsis, you need to consider three important aspects.

One is the perinatal risk factors. We discussed this in the previous podcast already, but some of this risk factors include chorioamnionitis, intrapartum maternal temperature of more than or equal to 38 degrees Celsius, maternal GBS colonization, prolonged rupture of membranes of more than or equal to 18 hours and prematurity.

The second aspect to consider in the evaluation is the clinical status of the newborn. It's interesting to note that about 60% to 90% of infants with EOS will become symptomatic in the first 24 to 48 hours of life. And lastly, the lab investigations.

Dr. Julie Weiner: So we know that considering the signs and symptoms for infection can be important in the evaluation. Can you discuss some of the signs and symptoms of neonatal sepsis?

Dr. Jotishna Sharma: Thanks, Dr. Weiner. Yes, the clinical signs and symptoms is an important aspect of evaluation of sepsis, especially early-onset neonatal sepsis. The signs and symptoms in the newborn vary by gestational age and severity of the infection. Such as a term infant may present with respiratory distress, including tachypnea, grunting due to pneumonia, which could be the presentation of EOS. The differential diagnosis that you need to consider in this situation is congenital heart disease and respiratory distress syndrome, while a premature infant may have increased apneic spells and be lethargic as opposed to respiratory distress.

Dr. Julie Weiner: How common is a fever with EOS?

Dr. Jotishna Sharma: Great question, because it is very common for us to think of fever when we think of infection. But when it comes to the newborns, it is rare for them to present with fever in EOS, unless they happen to be born to a febrile mother, then they may have fever immediately after delivery. It is actually more likely for an infant to have hypothermia as a sign of sepsis as opposed to fever.

Some of the other signs and symptoms that we need to consider, oxygen desaturations, bradycardia, poor perfusion, decreased capillary refill and, of course, hypotension. What is important to realize is that subtle changes in respiratory states of the newborn, temperature instability or feeding problems can be the first signs of a life-threatening infection.

Dr. Julie Weiner: Can you discuss more about the signs of infection for specifically preterm infants?

Dr. Jotishna Sharma: As I mentioned previously, in preterm infants, some of the signs and symptoms also depend on the gestational age. In a study of about 160 preterm infants, apnea, bradycardia and cyanosis was the first sign of infection in about two-thirds of the infants. It was the first sign in 50% of patients and increased respiratory effort in about 43% of patients. Other things to think about are feeding intolerance and abdominal distension, which can be a sign of septic ileus. It is also worthwhile to remember that signs and symptoms are more severe with Gram-negative and fungal infections as opposed to Gram-positive infections.

I just also want to briefly mention heart rate characteristics or HRC. More and more data is coming out in terms of changes in baseline variability as predictors of sepsis in the NICU, very low birth weight infants. And we will discuss more about this in the late-onset sepsis podcast.

Dr. Julie Weiner: Thank you, Dr Sharma, for mentioning that, because you are correct. The heart rate changes are becoming more and more recognized as an early predictor, early signs of sepsis. So can you talk about kind of that lab investigation regarding or relating to neonatal sepsis?

Dr. Jotishna Sharma: Yes, Dr. Weiner. So as clinicians, lab investigations are an important part of sepsis workup, but it is also important to perform evidence-based investigations. So we'll talk more about that. So the typical complete sepsis evaluation and workup in a neonate suspected of early-onset sepsis consists of obtaining a complete blood cell count with white cell and differential, a single blood culture, spinal tap for cell count and culture. Some may also consider culture and Gram stain of the tracheal aspirate in intubated neonates shortly after birth. The need for a chest x-ray is usually determined by the presence of respiratory symptoms.

Dr. Julie Weiner: How useful are the acute phase reactants such as CRP?

Dr. Jotishna Sharma: I'm glad you asked about acute phase reactants. So the two acute phase reactants that have become increasingly discussed and performed are the C-reactive proteins and the procalcitonin. And we will discuss more about this later in this podcast.

Dr. Julie Weiner: So white blood cell count is a common lab test done related to sepsis or when sepsis is suspected. How useful is this in the setting of early-onset sepsis?

Dr. Jotishna Sharma: Again, Dr. Weiner, you are correct. A complete blood cell count of which white blood cell count is a component is probably the most likely lab tests performed in a newborn. Total white cell count differential, absolute neutrophil count or ANC, and the ratio of immature to total neutrophils, otherwise known as I/T ratio, are all widely used as screening tests for neonatal sepsis.

Unfortunately, none of these tests have been particularly useful in identifying the majority of septic infants. The total white blood cell count actually has a poor positive predictive value for sepsis that is ruling in infection. Both high and low white cell count, except for leukopenia with regards to viral infection where it is useful, it is otherwise not useful for bacterial infection.

Dr. Julie Weiner: So what specifically about neutrophils? Are they helpful with early-onset sepsis prediction?

Dr. Jotishna Sharma: So neutropenia generally defined as ANC less than 1000 actually has a greater specificity for neonatal sepsis, so is more useful. But what is important to realize is that neutrophil counts are dependent on gestational age. It's usually higher in preterm infants compared to term infants, the delivery method and labor versus non-labor prior to delivery.

C-section with labor prior to delivery has higher neutrophil cell count compared to no labor with C-section at 12 hours of life. Infants have higher neutrophil counts in the first 18 hours of life. And altitude generally also affects the neutrophil count. Since our focus is early-onset sepsis, I just want us to note that the absolute immature neutrophil count peaks at about 12 hours of life to about 1500. Whereas at birth, it's about 1000.

Dr. Julie Weiner: So you did mention I/T ratios for sepsis evaluation, right? And I agree, we use those all the time. But can you comment how useful is it actually?

Dr. Jotishna Sharma: So I/T ratio is more useful in ruling out infection than ruling in infection. So a little bit more on the I/T ratio, a maximum normal I/T ratio of 0.16 occurs at birth and it reaches a nadir of 0.12 with increasing postnatal age. A single value of I/T ratio of more than 0.3 has a high negative predictive value of 99%, but a very poor positive predictive value of 25% for neonatal sepsis. Basically, which means that I/T ratio is useful for ruling out sepsis, but it does not correlate well with infants likely to have sepsis. Again, it is not very helpful in ruling in sepsis.

In a study of 1500 neonates, by Murphy and Weiner, they concluded that a combination of two serial normal I/T ratios and a negative blood culture at 24 hours of life in a neonate shortly after birth was accurate in ruling out early-onset sepsis. So basically, our standard is to wait for blood cultures at 48 hours. But they concluded that with two normal I/T ratios and a negative blood culture at 24 hours, you are safe to stop antibiotics.

Dr. Julie Weiner: Just as a disclaimer, the Weiner associated with the study is of no relation to me. Okay. Moving on. How about platelet counts? Are they useful for sepsis evaluation?

Dr. Jotishna Sharma: Another great question. Since in clinical practice, we do focus on platelet count as a sign of sepsis, previous reports had suggested certain infections such as Gram-negative and fungal sepsis were associated with thrombocytopenia. But more recent larger cohort studies have not found this to be true. Actually, platelet counts are not very sensitive or specific for the diagnosis of neonatal sepsis and are not very helpful in monitoring the response to therapy if there is thrombocytopenia. So again, something that we in clinical practice depend on or think is important, it is not that useful.

Dr. Julie Weiner: So as we know, the blood culture is the gold standard lab investigation for sepsis. Can you comment on sufficient specimen to detect bacteria such as one versus two samples? samples

Dr. Jotishna Sharma: Yeah, it's interesting. You know, we order blood cultures, but we don't really think much about how much blood is taken or how much blood is needed. So in all neonates suspected of having sepsis, you should do a blood culture. And as you mentioned, traditionally, we did 0.5 mL, is considered the standard volume to adequately detect bacteremia in neonates. But some recent studies have shown that up to 25% of all neonates with sepsis have bacteremia with low colony counts.

Therefore, 0.5 mL volume of blood may not be sufficient. And some experts advocate for 1 mL of blood for blood culture, which doubles the likelihood of a positive yield. Now having said that, it would be nice to get 1 mL blood for blood culture, but that, as you know, is usually an issue when we have very low birth weight infants.

Dr. Julie Weiner: Yes, Dr. Sharma, I agree that blood volume becomes an issue with the little tiny baby. So let's move on and just talk a little bit more about the acute phase reactants since that also seems a common lab value we obtain.

Dr. Jotishna Sharma: Yes. And as I mentioned, the two that's commonly talked about is C-reactive protein and procalcitonin.

Dr. Julie Weiner: So, can you talk about the use of CRP for early-onset? I feel like this is probably more commonly what I see.

Dr. Jotishna Sharma: Yeah, correct. CRP is, I think, very commonly now used in NICUs. So C-reactive protein levels rise within six to eight hours of infection and they peak around 24 hours at onset of infection. Inflammation triggers the release of interleukin-6, which stimulates an increase in CRP. A value of less than or equal to 1 mg per dL or 10 mg per liter-- so you have to be aware of the units used by your lab-- is considered normal. CRP has its best predictive value if measured within 24 to 48 hours of onset of infection.

What is important to realize is that an increasing CRP level is a better predictor of infection than a single value. So if you decide to use CRP as a marker of infection, you need to do a follow-up CRP rather than base your clinical decision on just one level.

With regards to early-onset sepsis, two normal CRP determinations eight to 24 hours after birth and then 24 hours later have been shown to have a negative predictive value of 99%. That is ruling out infection. Basically, this means repeatedly normal CRP values are strong evidence against bacterial sepsis and can enable antibiotics to be safely discontinued.

Dr. Julie Weiner: Okay. Another acute phase reactant that has been more recently considered useful for our evaluation of suspected sepsis is procalcitonin. Can you talk about this and what you're seeing?

Dr. Jotishna Sharma: Yeah, Dr. Weiner. So procalcitonin is a propeptide of calcitonin and it's produced mainly by monocytes and hepatocytes and it's elevated during infections. The half-life of procalcitonin is 24 hours in peripheral blood and the normal level for neonates at 72 hours of age is 0.1 nanogram per mL.

Procalcitonin is more sensitive for earlier detection of sepsis than CRP. The procalcitonin level is more likely to be elevated during bacterial infections than during viral infections and declines rapidly with therapy. Again, it's important to note that while it is useful for evaluation of early onset sepsis, you will need to also realize that physiologic increases in procalcitonin occurs within the first 24 hours of birth and elevated levels in serum can occur under non-infectious conditions such as respiratory distress syndrome, hemodynamic instability, and infant of a diabetic mother. Again, another potential board question.

Currently, procalcitonin measurements have mainly been used in research and only recently have become available in clinical practice. But my guess is, in the future, it will be more readily used in clinical practice.

Dr. Julie Weiner: Thank you, Dr. Sharma. Let's discuss the usefulness of CSF for evaluation of early-onset sepsis. Do we always need to do an LP?

Dr. Jotishna Sharma: While an LP is important to rule out meningitis in infants with suspected sepsis, its routine use in neonates is controversial. So the risk of meningitis in high-risk neonates who appear healthy or those whose clinical signs appear to be due to non-infectious conditions such as RDS is very low.

Dr. Julie Weiner: What is the relationship between and meningitis and vice versa?

Dr. Jotishna Sharma: I'm glad you asked that question, because this is a question that we often ask in clinical practice. So I do have some data on that. So approximately 23% of neonates with bacteremia will also have meningitis and 38% of those with meningitis will have a negative blood culture. Therefore, LP should be a component of every neonatal sepsis evaluation.

So the gist is a very low threshold for performing LP in neonates who have a strong clinical picture suggestive of neonatal sepsis or have a positive blood culture. But at the same time, you also remember that while an LP needs to be done, it should not delay giving antibiotics, especially if the patient is hemodynamically unstable and very sick. The LP can be delayed and done later.

Dr. Julie Weiner: So before we move on to discussing treatment of early-onset sepsis, let's talk about how useful is the urine culture. Is that important to obtain?

Dr. Jotishna Sharma: Dr. Weiner, your questions keep coming. And again, this is another important one to think about. A routine urine culture need not be dutifully performed in the evaluation of early-onset neonatal sepsis. This is because a positive urine culture in the setting of early-onset neonatal sepsis is actually a reflection of high-grade bacteremia rather than an isolated UTI. So for this reason, it's not routine workup for EOS.

Dr. Julie Weiner: Thank you, Dr. Sharma. Now, that we've talked about kind of the management, let's move on to treatment.

Dr. Jotishna Sharma: Thanks, Dr. Weiner. Before we discuss the individual antibiotic choices, I do want to mention the broad group of anti-microbials that are used to treat neonatal sepsis. And these include three main groups. One is the beta-lactams that we all know about such as ampicillin and cefotaxime. The next is the extended spectrum beta-lactams, such as piperacillin-tazobactam and the carbapenems of which marapenem is the most commonly used. And the last group is the glycopeptides, which include vancomycin and aminoglycosides.

Dr. Julie Weiner: So, what is the choice for empiric antibiotic therapy in the setting of early-onset sepsis?

Dr. Jotishna Sharma: It is still the same as it's been for many years. The combination of ampicillin and gentamicin is still the most appropriate coverage for the most common organisms, which are GBS and E. coli.

Dr. Julie Weiner: Is there alternative empiric antibiotic therapy that can be considered?

Dr. Jotishna Sharma: So an alternative initial empiric treatment, which has been proposed, has been a combination of ampicillin and cefotaxime or another cephalosporin, such as ceftazidime since my understanding is cefotaxime is, I think, no longer available or is no longer being manufactured.

Dr. Julie Weiner: But isn't there some concerns for increased resistance for Gram-negative infections in neonatal populations with wide use of cefotaxime?

Dr. Jotishna Sharma: You are correct. There is some evidence that the combination of ampicillin and cefotaxime for early-onset neonatal sepsis leads to more resistant Gram-negative organisms being isolated in the neonatal units, and that there may be an increase in serious complications, such as NEC and death.

Some studies have noted an increase in the prevalence of invasive candidiasis in the NICUs where cefotaxime is used extensively as an initial empiric antimicrobial for EOS. So unless there are epidemiological concerns or concerns based on susceptibility to the organism isolated in the cultures, the recommended empirical treatment for neonatal sepsis remains ampicillin and gentamicin.

Dr. Julie Weiner: Okay. So once the blood culture is positive, what are the pathogen-directed therapy?

So Dr. Weiner, Dr. Jotishna Sharma: it's important that once we identify an organism that we modify the antibiotic treatment, and this helps to decrease the resistance. So with regards to a confirmed GBS infection, if you already started ampicillin and gentamicin empirically, then you can discontinue gentamicin once the cultures confirm GBS and treatment can be completed with ampicillin alone.

For uncomplicated bacteremia, we usually treat for 10 days. While uncomplicated GBS meningitis, we usually treat for 14 days. However, some experts recommend a minimum of 21 days, especially for severely ill neonates. With regards to GBS meningitis, some experts do advocate for performing a repeat spinal tap at about 24 to 48 hours into treatment to document clearance as it may have some therapeutic and prognostic value.

Dr. Julie Weiner: Okay. I just want to put in a plug to say again, we will discuss GBS infection specifically in a future podcast in more detail. So once the blood culture is positive, what is the pathogen-directed therapy for E. Coli and other Gram-negative bacilli?

Dr. Jotishna Sharma: So for uncomplicated bacteremia due to ampicillin-sensitive E. coli, they should be treated for about 14 days from the first negative culture while meningitis should be treated for a minimum of 21 days.

In the US, while there's increased ampicillin and gentamicin resistance in E. coli isolates, this combination of antibiotic is still appropriate for empirical coverage for EOS. In these cases where there is concern for E. coli resistance, cefotaxime or cef-taz may be used. Gentamicin is usually discontinued until susceptibilities are obtained.

In the case of bacteremia with susceptible strain, monotherapy with ampicillin or cefotaxime is appropriate. In cases of E. coli meningitis, gentamicin maybe continued until CSF is sterile or for the first seven to 14 days out of a 21-day meningitis treatment. For other Gram-negative organisms, the duration is similar to that for E. coli. But the greater incidence of some complications of meningeal infections, such as brain abscess associated with citrobacter and enterobacter and Serratia species, you may need to treat longer than 21 days.

Dr. Julie Weiner: So a concern with deciding on antibiotics is the rise of ESBL producers with regard to Gram-negative infections. Can you kind of talk a little bit more about that?

Dr. Jotishna Sharma: Yeah. So Dr. Weiner, this is something that's kind of come up in the recent years. There has been some concern for increased prevalence of community extended-spectrum beta-lactamase or ESBL producers as etiologic agents for neonatal sepsis. So empirical antibiotic choice may need to be modified based on the epidemiological surveillance.

A recent report showed an increase in the prevalence of ESBL producers in the US with 36% of all E. coli infections in the study being caused by community-acquired ESBL producers. With regards to early-onset neonatal sepsis, there is a paucity of neonatal community-acquired ESBL epidemiological data in the US. Therefore, currently based on available reports, most neonatal infections secondary to E. coli in the US are community-acquired and remain sensitive to gentamicin.

Dr. Julie Weiner: What is the therapy for those organisms that are ESBL producers?

Dr. Jotishna Sharma: In those situations where you have confirmed ESBL-producing E. coli infections or you strongly suspect that the infection is an ESBL producer, meropenem has been used successfully in neonates.

Dr. Julie Weiner: Thank you, Dr. Sharma. So what about the pathogen-directed therapy for listeria, as I remembered that being a cause for early-onset sepsis?

Dr. Jotishna Sharma: Yes. Again, the good old combination of ampicillin and gentamicin is the optimal therapy for listeria. Important again to remember that cephalosporins are inactive against listeria and treatment failures have been reported with vancomycin. So for invasive infections with meningitis, the recommendation is 14 to 21 days.

Are there alternative adjunctive therapies to consider with early-onset sepsis?.

I think I know where you're going with this, Dr. Weiner. I think you are thinking about IVIg and G-CSF. So studies of IVIg therapy in suspected or proven neonatal sepsis did not demonstrate any improvement of patient outcome versus anti-microbial therapy alone and recombinant G-CSF given to neonates with neutropenia and sepsis showed no difference in severity of illness, morbidity and mortality, compared to the placebo. Therefore, in short, no adjuvantive therapy to antibiotics have been proven beneficial in the management of neonatal sepsis.

Dr. Julie Weiner: So now that we know how to treat and what antibiotic we should start the neonates on, are there any follow-up testing to be done?

Dr. Jotishna Sharma: So generally, most would recommend a repeat blood culture obtained usually within 24 hours of presumed effective therapy to document clearance. Persistent positive cultures can actually mean failure of the anti-microbial therapy or evidence of intravascular site infection. And therefore, antibiotic coverage and duration may need to be adjusted.

Other followup testings may include monitoring the trends in CRP and I/T ratios to assess the response to therapy. And some would consider repeat spinal tap in some situations to assess the improvement in cell count.

Dr. Julie Weiner: Okay, Dr. Sharma. Thank you so much for walking us through evaluation and treatment. kind of summarize what we've been talking about during this podcast. podcast.

Dr. Jotishna Sharma: So to summarize this podcast, we talked about the evaluation and treatment of EOS. The evaluation for EOS should consider perinatal risk factors, clinical status of the newborn with respect to signs and symptoms and lab investigations.

The typical complete sepsis evaluation or workup in a neonate suspected of EOS consists of obtaining a complete white blood cell count with differential, a single blood culture, a spinal tap with cell count and culture, tracheal aspirate if the patient is intubated shortly after birth, CRP and, if possible, procalcitonin.

In terms of empiric antibiotic therapy, combination of ampicillin and gentamicin provide coverage for the most common organisms, GBS and E. coli. Once infection is confirmed with positive cultures, pathogen-driven therapy includes for uncomplicated GBS bacteremia, treatment for 10 days while uncomplicated GBS meningitis is initially treated for 14 days. For severely ill neonates with GBS, some may treat for 21 days. With regards to pathogen-driven therapy for E. coli, uncomplicated bacteremia due to ampicillin-sensitive E. coli, treatment for 14 days from the first negative culture. While for meningitis, a minimum of 21 days.

In ESBL-producing E. coli infections, meropenem has been successfully used. For listeria infections, the combination of ampicillin and gentamicin is the optimal therapy. For uncomplicated bacteremia, we treat for 10 to 14 days. For invasive infection with meningitis, treat for 14 to 21 days.

Dr. Julie Weiner: Thank you, Dr. Sharma, for that summary. Okay. Do you have questions that we're going to go over?

Dr. Jotishna Sharma: Yes, I do have two questions in this section. The first question is a 38-week gestation infant develops severe respiratory distress approximately three hours after birth. The maternal rupture of membranes was about 26 hours with maternal GBS unknown and no exposure to intrapartum antibiotics. Infant required intubation and mechanical ventilation. Once he's stabilized on mechanical ventilation, you proceed with a sepsis workup. Sepsis workup will likely include all of the following except, A, a complete white blood cell count with differential; B, a chest x-ray; C, tracheal aspirate with Gram stain and culture; D, urine culture; E, CRP.

Dr. Julie Weiner: Okay. Dr. Sharma. So if I remember what we just talked about not too long ago, answer is D. Do you want to explain why? you want to explain why.

Dr. Jotishna Sharma: Yes, Dr. Weiner, you are correct. You will not do a urine culture. All the others, the white cell count, the chest x-ray, the tracheal aspirate and the CRP are all part of the workup for early-onset neonatal sepsis, except urine culture.

Dr. Julie Weiner: Okay. Are we ready for the next question?

Dr. Jotishna Sharma: The next question is the following are correct for treatment for early-onset sepsis, except... so which of these is incorrect. A, duration of treatment for uncomplicated GBS bacteremia is 10 days; B, studies of IVIg therapy in neonatal sepsis has shown improvement of patient outcome versus anti-microbial therapy alone; C, ESBL-producing E. coli infections can be treated with meropenem; D, the duration of treatment for uncomplicated listeria bacteremia is 10 to 14 days with ampicillin and gentamicin. So which of these is incorrect?

Dr. Julie Weiner: I think the answer is B. Dr. Sharma, do you want to explain.

Dr. Jotishna Sharma: Yes. Dr. Weiner, you are correct. All the others are correct except B. Actually, as I have covered earlier, IVIg has not shown to help in early-onset neonatal infection.

Dr. Julie Weiner: Thank you, Dr. Sharma. Hopefully, this information will give you all a better understanding  of the management and treatment of early-onset sepsis. This is Neonatology Review: Isolette to Crib. And again, I'm Dr. Julie Weiner. Thank you for listening and please join us for the next podcast.