Neonatal Sepsis Treatment & Management

Historically, the treatment approach for suspected neonatal sepsis has included early aggressive initiation of antibiotics because of the neonate’s relative immunosuppression. Because early signs of sepsis in the newborn are nonspecific, diagnostic studies are often ordered and treatment initiated in neonates before the presence of sepsis has been proven. Moreover, because the American Academy of Pediatrics (AAP), ^{[22, 23]} the American College of Obstetricians and Gynecologists (ACOG), ^[24] and the Centers for Disease Control and Prevention (CDC) ^[25] all have recommended sepsis screening or treatment for various risk factors related to group B Streptococcus (GBS) infections, many asymptomatic neonates now undergo evaluation and are exposed to antibiotics.

This approach has been questioned in recent years as more evidence emerges on the deleterious impact of unnecessary antibiotic exposure, including interference with the establishment of breast feeding, alternations in gut microbiome, increased incidence of childhood obesity and development of antimicrobial resistance amongst others. ^[26]  Furthermore, amongst very low birth weight infants who were initially treated with antibiotics but subsequently proved to have negative cultures, there was an increased risk of mortality and stage 3 retinopathy of prematurity. ^[55]

A newer approach to this issue has used a multivariate predictive model which considers maternal GBS status, appropriateness of intrapartum GBS coverage, gestational age, duration of rupture of membranes, highest intrapartum maternal temperature, along with the neonate’s postpartum examination findings. This model, commonly referred to as the “Kaiser Sepsis Calculator” has allowed for a significant reduction in the use of empiric antibiotics (from 5.0% of all births before implementation to 2.8% of all births thereafter) and obtaining blood cultures (12.8% of all births before implementation to < 5% of all births thereafter), without an increase in the rate of morbidity or mortality or readmissions for early-onset sepsis. ^{[34, 35]}

Use of this approach should be limited to term and late preterm infants of 34 weeks’ gestation or later. Use of the sepsis calculator should be implemented at an institutional level, taking into account local resources and the incidence of early-onset sepsis. A standardized approach will lead to improved risk identification as well as needed buy-in from important stakeholders, such as obstetricians, nursing staff, and other care team members.

A neonate with sepsis may require treatment aimed at the overwhelming systemic effects of the disease. Cardiopulmonary support and intravenous (IV) nutrition may be required during the acute phase of the illness until the infant’s condition stabilizes. Monitoring of blood pressure, vital signs, hematocrit, platelet countss, and coagulation profile is vital. Not uncommonly, blood product transfusion, including packed red blood cells (PRBCs), platelets, and fresh frozen plasma (FFP), is indicated.

An infant with temperature instability needs thermoregulatory support with a radiant warmer or incubator. Once the infant is stable from a cardiopulmonary standpoint, parental contact is important.

Central line or peripherally inserted central catheter placement may be necessary in infants who require prolonged IV antimicrobial therapy for sepsis if peripheral IV access cannot be maintained. If an abscess is present, surgical drainage may be necessary as IV antibiotic therapy cannot adequately penetrate an abscess, and antibiotic treatment alone is often ineffective.

The infant may require transfer to a level III or IV perinatal center, especially if he or she requires cardiopulmonary support, parenteral nutrition, or prolonged IV access. The multidisciplinary services available at larger centers may be necessary if the neonate’s condition is acutely compromised.

Additional therapies have been investigated for the treatment of neonatal sepsis, including granulocyte transfusion, IV immune globulin (IVIg) infusion, exchange transfusion, plasmapheresis, and the use of recombinant cytokines. However, no substantial clinical trials have shown these treatments to be  beneficial.

In the United States and Canada, the current approach to the treatment of early-onset neonatal sepsis includes the administration of combined intravenous (IV) aminoglycoside and expanded-spectrum penicillin antibiotic therapy. This regimen provides coverage for gram-positive organisms, especially group B Streptococcus (GBS), and gram-negative bacteria, such as E coli. The specific antibiotics to be used are chosen on the basis of maternal history and prevalent trends of organism colonization and antibiotic susceptibility in individual hospitals.

Antimicrobial resistance is increasing in the general population worldwide, and infections are rising in neonatal units due to multidrug- and extensively multidrug-resistant bacteria, posing a significant treatment dilemma. ^[56]  Reserving broad-spectrum therapy for high-risk infants and quickly de-escalating once culture results are available is one strategy for improving neonatal outcomes. ^[57]

If an infection appears to be nosocomial, as is common in late-onset sepsis, antibiotic coverage should be directed at organisms implicated in hospital-acquired infections, including S aureus, S epidermidis, and Pseudomonas  species. Most strains of S aureus produce beta-lactamase, which makes them resistant to penicillin G, ampicillin, carbenicillin, and ticarcillin. Vancomycin has been favored for this coverage; however, concern exists that overuse of this drug may lead to vancomycin-resistant organisms, thereby eliminating the best response to penicillin-resistant organisms. For this reason, some clinicians prefer oxacillin or nafcillin therapy in this setting.

Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and their ability to reach adequate serum and cerebrospinal fluid (CSF) concentrations. However, their use has led to the rapid induction of antibiotic resistance in gram-negative organisms. Ceftriaxone displaces bilirubin from serum albumin and should be used with caution in infants with significant hyperbilirubinemia due to the risk of kernicterus or bilirubin encephalopathy. Selection of the most effective drug is based on resistance and sensitivities for the organism isolated from cultures. Studies linking early cefotaxime exposure to an increased risk of neonatal death support the practice of limiting cephalosporin use to case-specific, targeted circumstances, such as in infants with findings concerning for concomitant meningitis. ^[58]

Zaidi et al compared the failure rates of three clinic-based antibiotic regimens in 0- to 59-day-old infants with possible serious bacterial infections in Karachi, Pakistan. ^[59] In a randomized study, the researchers found that outpatient therapy with injectable antibiotics is an effective alternative when hospitalization is not possible. Procaine penicillin/gentamicin was superior to oral trimethoprim-sulfamethoxazole, whereas ceftriaxone was more expensive and less effective than penicillin/gentamicin. ^[59]

Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. Monitor serum drug levels during treatment to minimize the risk of these complications. The drug dosage or interval may have to be adjusted to achieve therapeutic drug serum levels. Infants who received aminoglycosides should undergo audiology and renal function screening before discharge to determine whether any short- or long-range toxic effects of these drugs have occurred.

If culture results are negative but the infant is at significant risk for or has clinical signs of sepsis, the clinician must decide whether to provide continued treatment. In most cases, 36-48 hours of negative culture results should allow the clinician to be confident that sepsis is absent; however, a small number of infants shown to have had sepsis by postmortem examination had negative culture results during their initial sepsis evaluation.

Although there remains concern that intrapartum maternal antibiotic administration may decrease the reliability of neonatal culture results, studies have failed to demonstrate a change in culture sensitivity or time to positive culture. ^{[40, 60]}  With this in mind, the need for continued therapy should be based not on a single test, but on a review of all diagnostic data, including the following:

• Culture results

• Maternal and intrapartum risk factors

• CSF results

• Complete blood cell (CBC) count and differential

• C-reactive protein (CRP) trends

• Radiographs

• Clinical progress

Infants with bacterial meningitis often require higher dosages of antibiotics and longer courses of treatment. In addition, these infants may require an antimicrobial that has better penetration of the blood-brain barrier, such as cephalosporins, so that therapeutic drug concentrations can be achieved in the cerebrospinal fluid (CSF).

To determine whether the CSF is sterile, a follow-up lumbar puncture is recommended within 24-36 hours after initiation of antibiotic therapy. If organisms are still present, modification of the drug type or dosage is required to adequately treat the meningitis. Continue antibiotic treatment for 2 weeks after sterilization of the CSF or for a minimum of 2 weeks with gram-positive meningitis and 3 weeks with gram-negative meningitis.  Consultation with an infectious disease specialist can be helpful in such situations.

Meningitis complicated by seizures or persistent positive cultures may require extended intravenous antimicrobial therapy. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Note that trimethoprim-sulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn.

Additional therapies that have been investigated for the treatment of neonatal sepsis include the following:

• Granulocyte transfusion

• Intravenous (IV) immunoglobulin (Ig) infusion

• Exchange transfusion

• Recombinant cytokine administration

Granulocyte transfusion

Granulocyte transfusion has been shown to be suitable for infants with significant depletion of the storage neutrophil pool; however, documentation of storage pool depletion requires bone marrow aspiration, and the granulocyte transfusion must be administered quickly if it is to be beneficial. The number of potential adverse effects (eg, graft-versus-host reaction, transmission of cytomegalovirus [CMV] or hepatitis B, and pulmonary leukocyte sequestration) is considerable. Consequently, this therapy remains experimental.

IVIg infusion

The rationale for IVIg infusion is that it could provide type-specific antibodies, thereby improving opsonization and phagocytosis of bacterial organisms and enhancing complement activation and chemotaxis of neonatal neutrophils. It has been studied as a possible therapy for neonatal sepsis, but at present, the data do not support its routine use for this purpose. The main difficulties with IVIg therapy are as follows:

• The effect has been transient.

• Clinically available IVIg solutions do not contain type-specific antibody.

• The adverse effects associated with the infusion of any blood product can occur.

In addition, dose-related problems with IVIg infusion limit its usefulness in neonatal populations. Research has demonstrated no improvement in outcomes for neonates with sepsis who receive IVIg therapy. ^[61]

Recombinant human cytokine administration

Administration of recombinant human cytokines to stimulate granulocyte progenitor cells has been studied as an adjunct to antibiotic therapy. It has shown promise in animal models, especially for group B Streptococcus (GBS) sepsis, but pretreatment or immediate treatment is required to demonstrate its efficacy. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) has been studied in clinical trials, but the use of these agents in clinical neonatology remains experimental.

The American College of Obstetrics and Gynecology (ACOG) ^[32] and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) ^[23] recommends that obstetric care include a strategy for managing early-onset group B streptoccocal (GBS) disease. Women with GBS bacteriuria should be treated during pregnancy when the condition is diagnosed and during the intrapartum period. It is also recommended that women who have previously given birth to an infant with invasive GBS disease receive antibiotic prophylaxis during labor and delivery.

Universal screening for GBS during pregnancy is now ubiquitous in the United States. The Centers for Disease Control and Prevention (CDC) created guidelines for the use of intrapartum antibiotic prophylaxis to prevent GBS infection in 1996, ^[62] which were subsequently updated in 2002, and 2010. ^{[3, 25]}

To minimize the risk of early-onset GBS disease, practitioners should obtain screening vaginal and rectal cultures at 35-37 weeks’ gestation in all pregnant women unless the patients have had GBS bacteriuria in the current pregnancy or have previously had a child with invasive GBS disease. Implementation of a screening protocol has led to a significant decrease in the incidence of neonatal GBS disease. ^{[2, 3, 4]} Recommendations have been formulated for antibiotic prophylaxis regimens. See the images below.

Neonatal sepsis. Indications and nonindications for intrapartum antibiotic prophylaxis to prevent early-onset group B streptococcal (GBS) disease. Table from Verani JR, McGee L, Schrag SJ, for the Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010 Nov 19. 59 (RR-10):1-36. Online at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm.

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Neonatal sepsis. Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal (GBS) disease. Diagram from Verani JR, McGee L, Schrag SJ, for the Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010 Nov 19. 59 (RR-10):1-36. Online at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm.

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An infectious disease consultation may be useful, especially if the infant is not responding to treatment, is infected with an unusual organism, or has had a complicated clinical course such as concomitant meningitis. In such cases, neurology consult may also be helpful in the presence of seizures, and to ensure outpatient follow-up of neurologic sequelae.

Consultation with a pharmacist may be helpful for obtaining advice on the most appropriate antibiotic or dosage to use if changes in the drug regimen prove necessary because of inadequate or toxic drug levels obtained with therapeutic monitoring.

A pediatric surgical consultation may be necessary if sepsis is complicated by abscess, if the differential diagnosis includes necrotizing enterocolitis (NEC), or if central line placement is required.

The primary care provider (PCP) should evaluate the infant with a history of neonatal sepsis within 1 week of discharge from the hospital. The infant can be assessed for superinfection and bacterial colonization associated with antibiotic therapy, especially if the therapy was prolonged. The PCP should evaluate the infant's growth and determine whether the feeding regimen and activity have returned to normal.

The Joint Commission on Infant Hearing of the American Academy of Pediatrics (AAP) ^[63]  and the American Academy of Audiology ^[64]  recommends that infants who received aminoglycosides should receive follow-up audiology testing, in addition to audiology screening before hospital discharge. Screen these infants between 3 and 6 months of discharge to determine whether damage has occurred.

If neonatal sepsis was associated with meningitis, prolonged hypoxia, extracorporeal membrane oxygenation therapy, or brain abscess formation, the infant should be observed for several years to assess his/her neurodevelopment. If problems are found, the child should receive appropriate early intervention services and therapies.