Neonatal Sepsis Treatment & Management

When neonatal sepsis is suspected, treatment should be initiated immediately because of the neonate’s relative immunosuppression. Begin antibiotics as soon as diagnostic tests are performed.

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, platelets, and coagulation studies 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.

Surgical consultation for central line 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; IV antibiotic therapy cannot adequately penetrate an abscess, and antibiotic treatment alone is ineffective.

The infant may require transfer to a level III 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, and the use of recombinant cytokines. However, no substantial clinical trials have shown that these treatments are beneficial.

In the United States and Canada, the current approach to the treatment of early-onset neonatal sepsis includes combined IV aminoglycoside and expanded-spectrum penicillin antibiotic therapy. This provides coverage for gram-positive organisms, especially group B Streptococcus (GBS), and gram-negative bacteria, such as Escherichia 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 nurseries.

If an infection appears to be nosocomial (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 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 resistance in gram-negative organisms. Ceftriaxone displaces bilirubin from serum albumin and should be used with caution in infants with significant hyperbilirubinemia. Resistance and sensitivities for the organism isolated from cultures are used to select the most effective drug.

Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. The serum drug level is assessed around the third dose or at 48 hours after the start of treatment to determine whether levels are within the therapeutic range. The drug dosage or interval may have to be adjusted to optimize the drug serum levels. Infants who received aminoglycosides should undergo audiology screening before discharge.

If the infant’s clinical condition has not improved, a serum level may also be warranted to ensure that a therapeutic level has been reached. In addition, renal function and hearing screening should be considered after completion of the therapeutic course 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, 2-3 days 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.

Management is further complicated if the mother received antibiotic therapy before delivery, especially if she received the therapy within several hours of delivery. This may result in negative culture results in an infant who actually has bacteremia or sepsis. 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

Treatment for 7-10 days may be appropriate, even if culture results remain negative at 48-72 hours.

Infants with bacterial meningitis often require different 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 so that therapeutic drug concentrations can be achieved in the 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 treat the meningitis adequately. 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.

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

Ventriculoperitoneal shunting for hydrocephalus

If hydrocephalus is associated with neonatal meningitis and if there is progressive accumulation of CSF, a ventriculoperitoneal (VP) shunt may be necessary to drain off the excess fluid. The immediate complications of shunt placement are overdrainage, equipment failure, disconnection, migration of catheter, and shunt infection. Abdominal obstruction, omental cysts, and perforation of the bladder, gallbladder, or bowel are uncommon.

The VP shunt may cause long-term neurologic complications, including slit-ventricle syndrome, seizures, neuro-ophthalmologic problems, and craniosynostosis. Nevertheless, the outcome for children with VP shunt placement is generally good with careful follow-up.

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

• Granulocyte transfusion
• IVIg 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.^[24]

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 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.

Because of gastrointestinal (GI) symptoms, feeding intolerance, or poor feeding, it may be necessary to give the neonate nothing by mouth (nil per os; NPO) during the first days of treatment. Consider parenteral nutrition to ensure that the patient’s intake of calories, protein, minerals, and electrolytes is adequate during this period.

For the infant whose condition is seriously compromised, feeding may be restarted via a nasogastric tube For most infants, breast milk is the enteral diet recommended by the American Academy of Pediatrics (AAP).

The Committee on Infectious Diseases of the AAP recommends that obstetric care include a strategy for managing early-onset GBS disease. Women with GBS bacteriuria should be treated during pregnancy when the condition is diagnosed and during the intrapartum period. The committee also recommends that women who have previously given birth to an infant with invasive GBS disease receive antibiotic prophylaxis during labor and delivery.

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 (see the first image below). Recommendations have been formulated for antibiotic prophylaxis regimens (see the second image below).

Other methods of preventing late-onset sepsis, particularly in the preterm neonate, are under investigation. Administration of lactoferrin, the major whey protein in mammalian milk, is thought to have properties that contribute to innate immune host defenses.^[25]

An infectious disease consultation is useful, especially if the infant is not responding to treatment, is infected with an unusual organism, or has had a complicated clinical course. If neonatal meningitis is identified, consultation with a pediatric neurologist may be necessary for assistance with outpatient follow-up of neurologic sequelae. Inpatient consultation may be necessary if meningitis is complicated by seizures.

Consultation with a pediatric pharmacologist 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 neonatal sepsis within 1 week of discharge from the hospital. The infant can be evaluated for superinfection and bacterial colonization associated with antibiotic therapy, especially if the therapy was prolonged. The PCP should evaluate growth and determine whether the feeding regimen and activity have returned to normal.

The Joint Commission on Infant Hearing of the AAP recommends that infants who received aminoglycosides should receive follow-up audiology testing, in addition to audiology screening before hospital discharge. Screen these infants at 3 months—but no later than 6 months—after 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 neurodevelopment. If problems are found, the child should receive appropriate early intervention services and therapies.