Empiric therapy for neonatal sepsis

Key points

Most early-onset infections in high-resource settings are caused by group B Streptococcus and Escherichia coli.
Ampicillin + gentamicin is an appropriate empirical antibiotic regimen for early-onset sepsis in most settings.
Most late-onset infections are caused by Gram-positive organisms.
Nafcillin + gentamicin balances the need for a narrow spectrum with the risks of potentially providing inadequate empirical treatment in most cases.
Empirical antimicrobials targeting methicillin-resistant Staphylococcus aureus , Pseudomonas , yeast, and viruses should be considered if risk factors are present but are unnecessary in most cases.

Neonatal sepsis refers to the onset of systemic symptoms triggered by a pathogen during the first month of age and is associated with significant morbidity and mortality. Although neonatal sepsis can be due to bacteria, viruses, fungi, and parasites, bacterial infections account for the vast majority of cases, and the term “neonatal sepsis” is often used to refer to bacterial infections specifically. There is not currently a consensus definition for neonatal sepsis. Neonatal infections are differentiated into early onset and late onset based on the age of the infant when symptoms develop.

Clinical signs of neonatal sepsis are often nonspecific and can include lethargy, poor feeding, irritability, and temperature instability. Blood culture and antibiotic susceptibility testing results are often not available for 48 to 72 hours after collection, prolonging the amount of time before an infection can be proven and targeted treatment initiated. Delaying treatment for infants with bacterial infections may increase their risk of morbidity and mortality. For this reason, empiric treatment is often started while awaiting culture results. Changes in the epidemiology of neonatal sepsis, as well as the growing number of cases due to antibiotic-resistant pathogens, have made the optimal antibiotic combination for empiric treatment in the modern era uncertain. ^, Pathogens causing neonatal sepsis in low- and middle-income countries are often quite different from those seen in higher-income settings. Local and regional pathogen distributions and antibiotic susceptibility patterns should be used to inform empirical antibiotic selection. This review will discuss the relative risks and benefits of antibiotics currently used for the empiric treatment of neonatal sepsis in higher-income settings.

Early-onset sepsis

Pathogens responsible for early-onset infections are typically acquired from the mother’s genital tract during delivery and cause symptoms within the first 3 days of life. Prolonged membrane rupture, chorioamnionitis, and prematurity increase the risk of early-onset sepsis (EOS). Approximately 65% of EOS cases are due to Streptococcus agalactiae (group B Streptococcus [GBS]) or Escherichia coli ( Table 2.1 ). Other bacteria that cause EOS include viridans group streptococci, Enterococcus species, enteric Gram-negative bacilli, and Listeria monocytogenes . Mortality due to EOS varies by gestational age but can be as high as 29%. For this reason, antibiotics are started empirically while awaiting culture results.

TABLE 2.1

Organisms Causing ≥5% of Neonatal EOS Cases

Organism	% of Cases
≥37 weeks’ gestational age
Streptococcus agalactiae	51
Escherichia coli	15
Enterococcus spp.	9
Streptococcus pyogenes	6
<37 weeks’ gestational age
Escherichia coli	51
Streptococcus agalactiae	13
Haemophilus spp.	5
Klebsiella spp.	5

Ampicillin and gentamicin

The American Academy of Pediatrics and the World Health Organization recommend empiric treatment with ampicillin or penicillin in combination with gentamicin for infants with suspected EOS. ^, ^, Ampicillin provides coverage against many Gram-positive infections, including GBS, Enterococcus species, and L. monocytogenes , as well as some Gram-negative pathogens. The addition of gentamicin allows for coverage of a greater number of Gram-negative bacteria, including ampicillin-resistant E. coli . Other advantages include relatively low cost and extensive experience with this specific combination.

Ampicillin

Penicillins, such as ampicillin, are relatively safe and inexpensive to use in infants. Rare side effects include allergic reactions, neutropenia, and, with high exposures, seizures. Furthermore, GBS remains a leading cause of EOS, despite widespread implementation of intrapartum antibiotic prophylaxis (IAP) for pregnant women colonized with GBS. Multiple studies conducted over the past 2 decades confirm that GBS isolates remain fully susceptible to beta-lactams, including penicillin and ampicillin. ^, ^,

Ampicillin is additionally the drug of choice for susceptible infections due to Enterococcus species and L. monocytogenes . L. monocytogenes is a well-known but uncommon cause of maternal and neonatal infection. ^, EOS develops in the infant when transplacental transmission of listeriosis occurs following maternal infection or through acquisition of maternal gastrointestinal and vaginal flora during the birth process. Despite its rarity, EOS due to L. monocytogenes is associated with a high mortality and significant sequelae in survivors. ^, Although no study has demonstrated the benefits of early effective therapy for this particular condition, given the available evidence it seems prudent to provide optimal empiric therapy for this organism until it has been ruled out.

Gentamicin

Aminoglycosides, such as gentamicin, provide excellent activity against Gram-negative bacilli and also provide synergy with penicillins to increase activity against GBS, S. aureus , enterococci, and L. monocytogenes . ^, Additional advantages of gentamicin treatment include infrequent resistance and low cost compared to many newer antibiotics. Although infections due to ampicillin-resistant E. coli have increased, gentamicin-resistant E. coli infections are rare. Recent studies in the United States, England, and Germany have found that, although ampicillin resistance in E. coli is common, >90% remain susceptible to gentamicin. ^, ^, These studies suggest that the specific combination of ampicillin and gentamicin remains an appropriate empiric therapy for EOS in most centers.

Limitations of ampicillin and gentamicin

Although ampicillin plus gentamicin is the most common antibiotic combination used for EOS, the continued appropriateness of this antibiotic strategy has been questioned by several investigators who argue that other agents may be more advantageous.

Ampicillin concerns

A commonly noted problem with using ampicillin as empirical treatment for EOS is the trend of increasing ampicillin resistance among EOS cases due to E. coli . ^, ^, Since widespread IAP with ampicillin was recommended in 1996, the proportion of EOS E. coli infections resistant to ampicillin has increased, especially among premature and very-low-birth-weight infants. ^, As many as 78% to 85% of early-onset E. coli infections are due to ampicillin-resistant strains.

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