Introduction to Evidence for Global Management of Serious Bacterial Infections in Young Infants Aged 0–59 Days

Every year, about 3.5 million children die in the first 59 days of life, with 98% of these deaths occurring in low- and middle-income countries (LMICs).^1,2 Serious bacterial infections (SBI) (defined in this publication as sepsis, pneumonia and meningitis, see Table 1) are estimated to cause >556 000 deaths each year.^2,3 Survivors of SBI are at risk for long-term disability,⁴ and SBI account for about 3% of all disability-adjusted life years in global burden of disease estimates.^1,2 

To reduce both morbidity and mortality in LMICs, the World Health Organization (WHO) and United Nations Children’s Fund (UNICEF) guidelines are first and foremost to refer infants with SBI urgently to hospital for antibiotic treatment.^5–8 Hospitals and health facilities are defined by WHO and UNICEF according to “level” (primary, secondary, tertiary) (Table 2).⁹ 

However, WHO and UNICEF must also provide guidance for challenging situations where referral to health facilities is difficult or not possible. These settings include humanitarian and fragile states with high levels of conflict, remote areas with difficult access, and settings where families may be unable to seek care because of concerns about child care (such as financial constraints or other settings where mothers are not allowed to leave the home). In these settings, health care providers may provide home visiting from community health workers, mobile health clinics, and primary health care clinics, as well as doctors and pediatricians managing infants in district hospitals.^5–8 

Blood culture is the current gold standard for the diagnosis of neonatal sepsis. However, blood cultures miss many causative pathogens, especially fastidious organisms and those that cause rapidly progressive and fulminating disease.^10–12 Causative organisms may differ in low compared with high resource settings.^11,13–15 Although there is no unified diagnostic approach, there is general consensus that the diagnosis of sepsis must include signs of systemic system involvement such as shock, hypovolemia, hypotension, and inflammation.^6,8,16–19 Many factors complicate the diagnosis of sepsis in young infants. For example, it is common for blood cultures and laboratory tests to be negative because of inadequate specimens, poor laboratory capacity, or pretreatment with antibiotics. Additionally, bloodwork is often difficult to obtain in young infants, and blood culture equipment is commonly not available in many LMICs. Severe viral illness and cardiac failure are also well known to mimic the signs of bacterial sepsis in newborns. Clinical signs often advance rapidly, and recognition of illness by an infant’s primary caregiver can occur late.^6,15,16,20 Assessment by health care workers is also challenging. The detection of clinical signs of sepsis in young infants is well known to be difficult.^15,21–23 False positives and false negatives are common even when infants are examined by highly trained health personnel.^21,22 Poor specificity of clinical syndromes is also a problem in clinical studies. Studies that recruit participants on the basis of clinical syndromes often have poor negative predictive value for serious bacterial infections (ie, some participants may not truly have serious bacterial infection).^24–26 Overall, because of high mortality from serious bacterial infection in infants aged 0 to 59 days, many clinicians consider it is important to prioritize clinical signs with higher sensitivity over specificity.

To assist with these problems, WHO, UNICEF, and other organizations have proposed a number of case definitions and clinical algorithms for SBI on the basis of integrated management of childhood illness (IMCI).^{6,15,17,19,23,27} IMCI is a joint WHO/UNICEF initiative introduced in 1995 aiming to reduce child mortality and morbidity in resource-limited settings. Recognizing the limited resources in community/first-level health facility settings, IMCI adopted a syndromic approach, enabling classification of illness severity in children based only on clinical signs. Over time, IMCI guidelines have evolved and adapted to local epidemiologic policy, health system, and community contexts, and have split into guidelines for infants aged 0 to 59 days and 2 months to 5 years. In 2014, the “7 sign IMCI algorithm” was developed, which was further refined in 2019 and is the IMCI in current use (Table 1).⁷ Also in 2019, WHO designated 3 separate risk groups: “Critical illness” with highest mortality risk, “clinical severe infection” with moderate mortality risk, and fast breathing (Table 1).^7,28,29 In addition, in 2013, the WHO Hospital Pocket Book for Children⁸ described additional signs that can be used for the identification of an infant with danger signs in hospital (Table 1).

Antimicrobial resistance to common bacterial pathogens in young infants is also of increasing concern. Multidrug-resistant strains such as those producing extended spectrum β-lactamase and carbapenemases are becoming more common in all settings.^5,19,30–32 However, antimicrobial resistance data are limited and most current studies are from tertiary hospital settings that do not reflect district hospital- and community-level resistance patterns.^1,5,19 To assist with treatment standardization and antibiotic stewardship, WHO has developed the WHO Aware, Access, Watch, Reserve (AWaRe) classification⁵ and the WHO AWaRe antibiotic book.¹⁹ The AWaRe classification gives guidance on first- and second-choice antibiotics for common infections in high-income countries and LMICs, and has classified antibiotics into 4 groups: Access, Watch, Reserve, and Not Recommended (Table 3). Access antibiotics are generally considered to have a narrow spectrum of activity, lower cost, a good safety profile, and low resistance potential. They are often recommended as empirical first- or second-choice treatment options for common infections. Watch antibiotics are broader-spectrum antibiotics, generally with higher costs, and are recommended only as first-choice options for patients with more severe clinical presentations or for infections where the causative pathogens are more likely to be resistant to Access antibiotics. Reserve antibiotics are last-choice antibiotics used to treat multidrug-resistant infection.^5,19,32