Neonatal sepsis: prevention and management

Neonatal infections are a significant cause of morbidity and mortality worldwide, especially in preterm and low-birth-weight infants^​1​. The prevalence and morbidity rates vary depending on factors such as gestational age, birth weight, healthcare settings and regional disparities^​2​. 

Long-term complications associated with neonatal sepsis, include: 

• Neurodevelopmental impairment: increased risk of cerebral palsy, cognitive delays and hearing/vision impairments^​3​;
• Bronchopulmonary dysplasia (BPD), particularly in preterm infants;
• Increased risk of necrotising enterocolitis (NEC), a life-threatening gastrointestinal condition. More information about NEC can be found in ‘Gastrointestinal complications associated with prematurity‘;
• Prolonged hospital stays, leading to increased healthcare costs and further complications^​4​.

Neonates (especially preterm and low-birthweight infants) are significantly more susceptible to infections owing to several physiological and immunological factors^​5​. Their underdeveloped immune system, limited physical barriers and exposure to pathogens during birth and hospital stays all contribute to this increased vulnerability^​6​.

Reasons for increased susceptibility can be seen in Figure 1^​6​.

Sepsis can be classified as either early-onset sepsis (EOS) or late-onset sepsis (LOS). This article will cover the recognition and management of both, as well as the pharmacist’s role in the prevention of these conditions.

Early-onset sepsis

Early-onset sepsis (EOS) occurs within the first 72 hours of life^​7​. It has an incidence of 0.5 to 1.0 per 1,000 live births in high-income countries^​8​. Rates of EOS are higher in very preterm infants (<32 weeks gestation), with rates of 13.5 per 1,000 live births^​9​.

When there is a strong clinical suspicion of sepsis, neonates must receive appropriate treatment promptly to reduce the mortality and morbidity associated with EOS. 

If any risk factors (see Box 1^​7​) or clinical indicators (see Table 1^​7​) for EOS are present, the following steps should be taken:

• A clinical assessment of the infant should be immediately performed;
• The maternal and neonatal history should be reviewed;
• The baby should be physically examined, including an assessment of vital signs^​7​.

This assessment should guide the clinical management of the baby.

In babies with any one red-flag risk factors or clinical indicators, or with two or more ‘non-red-flag’ risk factors or clinical indicators, further investigations (e.g. C-reactive protein levels, blood culture, lumbar puncture, eye swab for purulent eye discharge or skin swab for purulent umbilical discharge/periumbilical cellulitis) should be completed before starting antibiotics — antibiotics should be started immediately (i.e. not delayed until test results are available)^​7​.

In babies without red flags and with only one risk factor or one clinical indicator present, clinical judgement should be used to decide whether it is safe to withhold antibiotics and whether the baby’s vital signs and clinical condition need to be monitored. If monitoring is needed, it should be continued for at least 12 hours using a newborn early warning system, such as the Newborn Early Warning Trigger and Track 2 (NEWTT2) framework, which was published by British Association of Perinatal Medicine (BAPM) in 2023^​10​.

For more information on determining the need to start antibiotic treatment in babies with suspected EOS, please see the NICE guidance^​7​.

The Kaiser Permanente Sepsis Risk Calculator (KP-SRC) is an alternative assessment tool that uses the population’s background incidence of EOS, objective information at birth and the infant’s clinical presentation to evaluate risk of neonatal EOS in infants >34 weeks gestation^​11​. It has been shown to reduce the use of antibiotics and can be used to determine risk of neonatal sepsis for babies born after 34 weeks being cared for in a neonatal unit, transitional care unit or a postnatal ward. Studies have shown a 40–50% reduction in antibiotic use in some hospitals using the calculator^​12​. Reducing unnecessary antibiotics may help preserve the neonatal microbiome and lower risks of conditions such as NEC and antibiotic resistance.

After calculating the risk, neonates are categorised as:

• No evaluation needed (low risk);
• Clinical monitoring only (moderate risk);
• Empiric antibiotics recommended (high risk)^​11​.

Antibiotic prescribing 

The organisms that cause EOS in neonates are predominantly those that colonise the vagina or lower gastrointestinal tract in mothers; Group B strep and Escherichia coli (E coli) are the main organisms of concern^​13​. 

Intravenous benzylpenicillin and gentamicin are the drugs of choice for managing EOS^​7​. Benzylpenicillin has excellent activity against gram-positive organisms (such as Group B strep) and gentamicin has good cover against gram-negative organisms (such as E coli). Benzylpenicillin is administered at a dose of 25–50mg/kg at 8- or 12-hourly intervals, depending on age and the severity of the infection^​14​. 

To target gram-negative organisms in neonates aged under 7 days, gentamicin is usually administered as a 5mg/kg dose every 36 hours; however, the dose interval can be shortened to 24-hourly if the baby is severely unwell or increased to 48-hourly (or more) if the baby has renal issues and is struggling to eliminate gentamicin^​15​. Therapeutic drug monitoring is recommended because gentamicin has a narrow therapeutic range. Amikacin can be used as an alternative to gentamicin if there is a high incidence of gentamicin resistance locally.

In areas where therapeutic drug monitoring of aminoglycosides may be challenging (e.g. owing to a lack of medical staff or access to laboratory testing), a broad-spectrum third-generation cephalosporin, such as cefotaxime, can be used to treat early-onset sepsis, owing to its broad-spectrum antimicrobial activity, covering most of pathogens implicated in neonatal sepsis^​16​.

If there are any indicators of Listeria infection (e.g. dark-coloured, foul-smelling amniotic fluid), benzylpenicillin can be changed to amoxicillin 50–100mg/kg 8 or 12-hourly (depending on age). Listeria is an uncommon but serious cause of neonatal sepsis and meningitis^​17​. 

Complications and mortality

Complications from EOS depend on the causative organism, gestational age, and how quickly treatment is initiated. While many term babies recover well with prompt antibiotic treatment, preterm and critically ill neonates have a higher risk of severe complications.

The overall mortality from EOS is around 2–3% in term neonates and around 15–30% in preterm neonates (<32 weeks gestation)^​18​. Gram-negative sepsis (e.g. E coli) has a higher mortality rate of around 20-30%, especially in preterm neonates^​19​. The mortality rate of Listeria is similar to this, but rare.

Late onset sepsis

Late onset sepsis (LOS) occurs after 72 hours of life and is typically acquired from the hospital (nosocomial) or community^​20​. Incidence in term infants is 1.6% of live births^​21​. It is more common in preterm neonates owing to prolonged hospital stays, invasive procedures and immature immune systems. In preterm neonates, particularly very low birth weight (<1,500g) infants, LOS can occur in 12–50% of cases^​21​. Mortality rates are 10–20%, but can be as high as 35% in extremely low birth weight (<1,000g) neonates^​21,22​.

Gram-positive bacteria (e.g. Coagulase negative staphylococcus (CoNS), Staphylococcus aureus, Enterococcus) are the most common causes of LOS, especially in neonatal intensive care units (NICUs)^​23,24​. Gram-negative bacteria (e.g. E. coli, Klebsiella, Pseudomonas) are more aggressive and associated with higher mortality^​25​. Fungal infections (Candida) can occur in very preterm neonates with prolonged antibiotic use and/or central lines^​26​. Risk factors, such as central lines, ventilation and NEC, influence the causative organisms^​27​.

Signs and symptoms

The clinical signs and symptoms of late-onset sepsis are wide-ranging, as outlined in Table 2^​7​.

LOS in neonates can progress rapidly, meaning that early recognition and treatment are critical. Even one red-flag symptom or multiple mild symptoms should prompt urgent evaluation and empirical antibiotic therapy^​7​. If any red-flag symptoms are present, sepsis should be assumed until proven otherwise.

Red-flag symptoms of LOS can be seen in Figure 2^​7​.

If any red-flag symptoms are present, the baby should receive a sepsis screen and antibiotics should be started within one hour; waiting for test results should not delay starting treatment^​7​. 

Empirical treatment 

For babies with suspected late-onset neonatal infection, a combination of narrow-spectrum antibiotics (such as IV flucloxacillin plus gentamicin) are usually given as first-line treatment^​7​. Flucloxacillin can be replaced with vancomycin or teicoplanin when there are additional concerns about gram positive organisms; for example, when infants have indwelling plastic lines, such as central venous catheters at risk of infections with CoNS, which is common in preterm infants^​28​.

If NEC is suspected, an antibiotic that is active against anaerobic bacteria (such as metronidazole) should be added^​7​. If first-line treatments are ineffective, switching to an alternative agent such as meropenem should be considered, as this has good cover against gram-negative bacteria, such as Klebsiella and Pseudomonas^​29​.

Treatment should be guided and adjusted based on blood culture results^​30​. If Candida species are suspected, fluconazole or liposomal amphotericin B should be added^​31​.

Duration of treatment depends on the causative organism and severity of infection, for example:

• Bacteraemia (without meningitis): 7–10 days;
• Meningitis: 14–21 days^​21​;
• Fungal sepsis: 4–6 weeks^​32​.

NICE management recommendations for neonates with suspected late-onset sepsis are outlined in Figure 3^​7​.

The Pharmaceutical Journal (adapted from NICE)

NICE guidelines recommend giving prophylactic oral nystatin to prevent fungal infections in babies treated with antibiotics for suspected late-onset neonatal infection, if they weigh under 1,500g or were born at less than 30 weeks gestation^​7​. If it is not possible to administer oral nystatin, IV fluconazole can be used instead — this is an off-label use of fluconazole, so caution must be exercised when deciding what dose to give.

The South East London Paediatric Formulary recommends 3mg/kg every 72 hours for the first 2 weeks of life, then 3mg/kg every 48 hours for the following 2 weeks, then 3mg/kg every 24 hours for 2 weeks (until central IV line and endotracheal tubes have been removed)^​33​. This changing dose interval reflects how preterm neonates are able to clear the drug faster as their liver enzymes mature^​34​.

Prevention

Preventing infections in premature or unwell neonates is critical to reducing morbidity and mortality^​35​. NICUs implement strict infection control measures, including maternal screening, antimicrobial prophylaxis and hygiene protocols^​35​. These strategies are summarised in the Box 2.

Conclusion

Neonatal sepsis remains a leading cause of morbidity and mortality, particularly in preterm and critically ill infants^​57​. Early recognition, timely antibiotic administration and appropriate antimicrobial stewardship are essential for optimal outcomes^​58​. Pharmacists play a crucial role in ensuring correct antibiotic selection, dosing and monitoring to balance effective treatment with minimising resistance risks.