PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

While progress in reducing the rate of child mortality since the launch of the Millennium Development Goals in 1990 has been promising, improvements in reducing neonatal mortality have been far slower. Infections in the neonatal period are one of the major contributors to an ongoing high rate of neonatal morbidity and mortality worldwide. In an era of increasing antimicrobial resistance (AMR), the burden of infections caused by multidrug-resistant (MDR) bacteria resistant to the current WHO empirical therapeutic guidelines is resulting in a persistently unacceptably high rate of perinatal and infant mortality globally.

The burden of drug resistance in neonatal sepsis

In India alone, almost 60,000 neonates die each year due to infections with MDR pathogens¹. Recently, the NeoAMR network has also highlighted unexpectedly high rates of MDR Gram-negative bacterial (GNB) infections in infants across many continents². In neonatal units in South Africa and Bangladesh, two-thirds of GNB isolated from blood cultures were cephalosporin-resistant while 39% and 81%, respectively, were carbapenem-resistant². Single-unit studies have revealed similarly high rates of third-generation cephalosporin resistance among Klebsiella spp. in Nepal³ while in the major tertiary units in which we work in Sri Lanka and Indonesia, outbreaks due to ESBL-producing GNB and carbapenem-resistant Acinetobacter spp. have occurred frequently over the past decade.

Uncontrolled antimicrobial prescribing drives AMR in many healthcare settings. Almost 50% of neonatal units prescribe WHO ‘reserve’ antibiotics as empirical therapy for neonatal sepsis.

It is well documented that the burden of neonatal infections, and those that are antimicrobial-resistant, disproportionately affects low- and middle-income (LMIC) healthcare settings¹. This is often due to limited health budgets, particularly with regards to infection prevention and control resources. Late-onset, hospital-acquired infections with MDR organisms are therefore frequent occurrences and outbreaks in neonatal wards in these settings have the potential to cause very high mortality and morbidity rates^4,5.

While Gram-positive bacteria (particularly Streptococcus agalactiae, or Group B Streptococcus spp.) cause the greater burden of early-onset sepsis in infants in resource-rich settings, most invasive infections in infants in LMICs are due to GNB². This proposes reconsideration as to whether the definitions of ‘early-‘(implying vertically-acquired; mother-to-child transmission) and ‘late-‘ (implying horizontally-acquired; transmission from the environment or unrelated individuals) onset sepsis remain relevant. Infants in LMIC healthcare settings are most likely exposed to MDR GNB due to ward overcrowding and colonisation acquired from caregivers in the early perinatal period. Focussing on improving simple infection control strategies utilising affordable measures such as improved hand hygiene, exclusive breastfeeding and skin-to-skin mother-to-child care to prevent cross-infection may be a key intervention in resource-limited settings where labour and neonatal wards remain underfunded and overcrowded⁶.

Protecting available antibiotics to treat neonatal sepsis

Uncontrolled antimicrobial prescribing drives AMR in many healthcare settings. Almost 50% of neonatal units prescribe WHO ‘reserve’ antibiotics as empirical therapy for neonatal sepsis². In the South-East Asian health settings in which we work, this is often secondary to a lack of availability of narrower-spectrum agents, or quality control issues for in-country manufactured antibiotics. Clinicians in these settings tend to question the efficacy of narrow-spectrum agents and are more likely to prescribe broader-spectrum agents as the first-line of therapy, as well as being reluctant to de-escalate to suggested more targeted treatment approaches. Yet failing to limit access to, and prescribing of, the WHO’s ‘watch’ and ‘reserve’ antibiotics will diminish the currently available efficacious antibiotics and increase selection pressure of carbapenem-resistant Acinetobacter spp. and Enterobacterales.

In an era of increasing antimicrobial resistance (AMR), the burden of infections caused by multidrug-resistant (MDR) bacteria resistant to the current WHO empirical therapeutic guidelines is resulting in a persistently unacceptably high rate of perinatal and infant mortality globally.

Protecting the limited available agents that remain efficacious as treatment regimens is of utmost importance in the context of a dearth of new agents emerging in the antibiotic pipeline to combat the management of AMR infections⁷. Within a slow and inadequate global antibiotic development programme, neonatal healthcare professionals are particularly unable to access the few new agents that do reach the market due to the regulatory impediments inherent in licensing agents for children and neonates⁸. Furthermore, while many older antimicrobials show promise for treating AMR infections^9,10 their off-patent use remains widespread due to a multitude of hurdles in conducting clinical trials in this age group – risking poor efficacy and toxicity effects¹¹.

Addressing the knowledge gap in neonatal sepsis

While there is a gradual realisation of the importance of addressing AMR and neonatal sepsis to ensure gains can be made in neonatal morbidity and mortality on a global scale, there are gaps in understanding the current epidemiology of the bacteria causing neonatal sepsis in many LMIC settings, particularly within our geographic region. Robust global epidemiological data and antibiotic susceptibility profiles are necessary to ensure optimal empirical regimens are prescribed for the treatment of invasive neonatal infections, tailored to the local prevalence of AMR⁹. Through establishing a new regional collaboration to ascertain this data (NeoSEAP), clinician-researchers are collaborating to address this knowledge gap for Southeast Asia and The Pacific.

There are clear problems driving the burden of AMR and neonatal sepsis that disproportionately affect LMIC settings. By clearly defining the epidemiology of AMR in this vulnerable population and investing in simple infection prevention and control strategies as well as establishing antimicrobial prescribing practices in keeping with the WHO ‘access, watch and reserve’ categorisation, there is the potential to diminish the current burden of AMR in neonatal sepsis, to ensure the Sustainable Development Goals and Every Newborn Action Plan milestones can be achieved^12,13.

References

1. Laxminarayan R, Matsoso P, Pant S, Brower C, Rottingen J, Klugman K et. al. (2016) Access to effective antimicrobials: A worldwide challenge. Lancet 387: 168-75.
2. Li G, Bielicki JA, Ahmed ASMNU, Islam MS, Berezin EN, Gallacci CB et al. (2019) Towards understanding global patterns of antimicrobial use and resistance in neonatal sepsis: insights from the NeoAMR network. Archives of Disease in Childhood; 387(10014):168-75 
3. Yadav NS, Sharma S, Chaudhary DK, Panthi P, Pokhrel P, Shrestha A et al. (2018) Bacteriological profile of neonatal sepsis and antibiotic susceptibility pattern of isolates admitted at Kanti Children’s Hospital, Kathmandu, Nepal. BMC Research Notes; 11(1):301.
4. Folgori L, Bielicki J, Heath PT, Sharland M. (2017) Antimicrobial-resistant Gram-negative infections in neonates: burden of disease and challenges in treatment. Current Opinion in Infectious Diseases 30:281–8.
5. Johnson J, Robinson ML, Rajput UC, Valvi C, Kinikar A, Parikh TB et al. (2020) High Burden of Bloodstream Infections Associated With Antimicrobial Resistance and Mortality in the Neonatal Intensive Care Unit in Pune, India. Clinical Infectious Diseases ciaa554 
6. Conde-Agudelo A, Díaz-Rossello JL. (2016) Kangaroo mother care to reduce morbidity and mortality in low birthweight infants. Cochrane Database Systematic Reviews 
7. The Pew Charitable Trusts. (2020) Tracking the Global Pipeline of Antibiotics in Development.
8. Williams PCM, Bradley J, Roilides E, et al. (2021) Harmonising regulatory approval for antibiotics in children. The Lancet Child & Adolescent Health 5: 96–8.
9. Folgori L, Ellis SJ, Bielicki JA, Heath PT, Sharland M, Balasegaram M. (2017) Tackling antimicrobial resistance in neonatal sepsis. Lancet Global Health 2017; 5:e1066–8.
10. Williams PCM. Potential of fosfomycin in treating multidrug-resistant infections in children. (2020) Journal of Paediatrics and Child Health 56: 864–72.
11. Barker CIS, Standing JF, Kelly LE, et al. Pharmacokinetic studies in children: recommendations for practice and research. (2018) Archives of Disease in Childhood 103: 695 LP – 702.
12. Lawn J, Blencowe H, Oza S, You D, Lee A. (2014) Every Newborn: Progress, Priorities, and Potential beyond Survival. Lancet 384:189-205.
13. UNICEF. (2020) Ending Preventable Newborn Deaths and Stillbirths by 2030.