What is the management of refractory neonatal sepsis (Neonatal Sepsis)?

From the Guidelines

Management of refractory neonatal sepsis requires aggressive intervention with broad-spectrum antibiotics, supportive care, and adjunctive therapies, prioritizing the use of meropenem and vancomycin due to high resistance rates to traditional antibiotics such as gentamicin and ampicillin in low- and lower-middle-income countries, as highlighted in recent studies 1.

Key Considerations

• Initial treatment should include a combination of broad-spectrum antibiotics, with consideration of local antimicrobial resistance patterns.
• Supportive measures are crucial and include maintaining adequate perfusion with fluid resuscitation, vasopressors if needed, respiratory support, and correction of metabolic derangements.
• The use of meropenem (20-40 mg/kg/dose every 8 hours) plus vancomycin (10-15 mg/kg/dose every 6-12 hours) may be necessary to cover resistant gram-negative and gram-positive organisms including MRSA, given the high levels of resistance to gentamicin and ceftriaxone reported in recent studies 1.
• Consider adding antifungal therapy with amphotericin B (1 mg/kg/day) or fluconazole (12 mg/kg loading, then 6 mg/kg/day) if fungal infection is suspected.
• Intravenous immunoglobulin (IVIG) at 500-1000 mg/kg may be considered in severe cases to boost the immune response.

Monitoring and Adjustment

• Continuous monitoring of vital signs, blood gases, electrolytes, and organ function is essential, with frequent reassessment of antibiotic therapy based on culture results and clinical response.
• The underlying pathophysiology involves overwhelming infection triggering systemic inflammatory response, which can lead to multi-organ dysfunction, making early aggressive intervention critical to prevent irreversible damage and improve survival rates, as emphasized by the Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children 1.

Clinical Practice

• Clinicians should be aware of the local epidemiology of antimicrobial resistance and adjust empirical antibiotic regimens accordingly, considering the findings of recent systematic reviews and meta-analyses 1.
• The development of region- or country-specific empirical antibiotic regimens for neonatal sepsis is indicated, highlighting the need for structured AMR surveillance and reporting in low- and lower-middle-income countries.

From the FDA Drug Label

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. Clinical studies have shown gentamicin injection to be effective in bacterial neonatal sepsis; In the neonate with suspected bacterial sepsis or staphylococcal pneumonia, a penicillin-type drug is also usually indicated as concomitant therapy with gentamicin.

The management of refractory neonatal sepsis may involve the use of gentamicin in combination with a penicillin-type drug as concomitant therapy.

• Gentamicin has been shown to be effective in bacterial neonatal sepsis.
• The decision to continue therapy with gentamicin should be based on the results of susceptibility tests, the severity of the infection, and other important considerations 2.

From the Research

Management of Refractory Neonatal Sepsis

• Neonatal sepsis is a diagnosis made in infants less than 28 days of life, consisting of a clinical syndrome that may include systemic signs of infection, circulatory shock, and multisystem organ failure 3.
• Commonly involved bacteria include Staphylococcus aureus and Escherichia coli, with risk factors including central venous catheter use and prolonged hospitalization 3.
• Blood culture remains the gold standard for diagnosis, and immediate treatment with antibiotics is imperative 3.

Antibiotic Regimens

• The benefits and harms of different antibiotic regimens for early-onset neonatal sepsis remain unclear due to the lack of well-powered trials and the high risk of systematic errors 4.
• Current evidence is insufficient to support any antibiotic regimen being superior to another, with a need for large RCTs assessing different antibiotic regimens in early-onset neonatal sepsis with low risk of bias 4.
• Ampicillin plus gentamicin remains the recommended antibiotic regimen for early onset neonatal sepsis, but potential limitations of this regimen have been identified based on clinical and pathogen characteristics 5.

Alternative Antibiotic Regimens

• Five antibiotics have been identified as potential alternatives for the treatment of neonatal sepsis caused by multidrug-resistant bacteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime 6.
• These agents have the potential to be used in novel combination empiric regimens for neonatal sepsis, but data gaps need to be addressed by pharmacokinetic trials and pharmacodynamic characterization 6.
• Antimicrobial susceptibility profiles among neonatal early-onset sepsis pathogens have been studied, with the vast majority of contemporary EOS pathogens susceptible to the combination of ampicillin and gentamicin 7.

Considerations for Treatment

• Clinicians may consider the addition of broader-spectrum therapy among newborns at highest risk of EOS, but caution is needed as neither the substitution nor the addition of 1 single antimicrobial agent is likely to provide adequate empiric therapy in all cases 7.
• The estimated 8% of EOS cases caused by isolates nonsusceptible to both ampicillin and gentamicin are most likely to occur among preterm, very-low birth weight infants 7.