Severe infections and antimicrobial resistance

In an era when increasing levels of antibiotic resistance threaten the ability to prevent and treat severe infections, which can be life threatening for children and especially newborns, research on how to efficiently and conservatively use antimicrobials in various populations is urgently needed.

Penta has been involved in several European and global initiatives aimed at better characterizing the use of antimicrobials among children and neonates, as well as the scale of resistance in this population and investigating optimal treatment regimens for common neonatal infections.

How are severe infections and antimicrobial resistance impacting children’s health?

In 2018, 5.3 million children under the age of five died (IGME), with newborn deaths accounting for 47% of these deaths.

Infant mortality rate is an important marker of the overall health of a society, which is used as a key international indicator by the United Nations Sustainable Development Goals, and in UNICEF international comparisons.

Despite advances in fighting diseases in children, infections cause nearly a quarter (23%) of all neonatal deaths.

Neonatal sepsis, a systemic infection occurring in the first 28 days of life, encompasses bloodstream infections, meningitis, and pneumonia. It is the third most common cause of deaths among neonates, accounting for 225,000 deaths globally each year. South Asia and sub-Saharan Africa have the highest burden of neonatal sepsis in the world. Poverty, low coverage of effective interventions, including facility births, and gross inequities in delivery of healthcare contribute to this situation.

Children running towards body of water
Photo by Orhan Kaya

Alongside the problem of infections in babies and children, there is growing concern in relation to drug resistance, and the burden of antimicrobial-resistant microorganisms. Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi.

Antimicrobial resistance has worsened over the last decade: approx. 50-70% of common pathogens, particularly those acquired in hospitals, exhibit a high degree of resistance to first and second- line treatments, recommended by the WHO.  Multidrug-resistant pathogens account for 30% of all global neonatal sepsis mortality (Lancet 2016).

Given the already limited treatment options we have for babies and children – this is a serious threat.  Several classes of antibiotics that we have historically used to combat severe diseases in children, such as diarrhoea, pneumonia and neonatal sepsis, are now no longer effective. Children, especially babies and young infants, are always the last in line to benefit from any new drug development and often require treatments that are adapted to their specific needs. Few data are available to support optimal treatment of multidrug-resistant infections, even in adults. The number of robust clinical studies assessing old or new antibiotics involving neonates is very small.

Neonates should be more highly prioritised in research and development globally. Research into the development of enhanced diagnostics that are practical for use in low-income and middle-income countries is required, along with provision of novel evidence-based treatment options that can be made readily available worldwide.

Video on antimicrobial resistance as a threat for children's health

Hospital-acquired infections and infections resistant to antibiotics are a disproportionate burden in Africa  and Asia. Without an audacious effort, we will not have the solutions we need to save the lives of babies worldwide.

Why don’t we have better antibiotic treatment options for babies and children?

It is widely recognized that the antibiotics market is broken (WHO) and that insufficient market incentives have slowed research and development in this area and many pharmaceutical and biotechnology companies have abandoned the field altogether. It can take more than 10 years before we know if an antibiotic is safe and effective to use in adults – with many antibiotics being used in children off-label (OECD). The profound lack of drugs in development gives us huge cause for concern. Drug development for antivirals (HIV, Hepatitis, arbo and corona virus) and anti-tuberculosis is, likewise, lagging behind for treatment (and prevention) options to be used in children. Drug development for anti-infectives is about 25% of global Research & Development. However, children are very rarely included in early R&D for a variety of reasons, principally related to the complexity and cost of the research required, as well as, the market share remaining small.

Recent regulatory incentives have been undertaken to ensure the studies being undertaken include children. Still, children – babies especially – will fall further behind in treatment access without a more concerted and deliberate investment.

beabywearing
Photo by Barbara Alcada

Where is this burden most felt and why?

The majority of healthy children are able to fight minor infection with their body’s immune defenses. However, there are some factors that can compromise a child’s immune system, putting a child at a higher risk of severe infections. Being born too early or too small puts babies at high risk for getting serious infections at or around birth – and contribute to developing newborn sepsis. A child’s immune system may be weakened by malnutrition or undernourishment, or by pre-existing illnesses, such as HIV infection.

Our ability to treat serious infections requires prevention through immunization, good hygiene and sanitation, equitable access and appropriate use of existing and new antimicrobial medicines. Children who live in low-resource settings face a greater risk of infection, due to poor sanitary conditions, the lack of resources for optimal hygiene practices and inadequate infection prevention. Vaccination against many previously fatal diseases has led to dramatic reductions in deaths due to infection, but most infectious diseases do not have effective vaccinations available, particularly gram-negative bacteria. Children in low-resource countries, generally, do not have access to well-functioning, adequately resourced and affordable health services that can treat such infection as they arise.

Some of the most severe childhood diseases in low-resources countries – malaria, pneumonia, other respiratory infections and dysentery – can no longer be easily cured with the existing antibiotics or medicines. In these countries, effective and accessible antibiotics are crucial for saving the lives of children who have those diseases.

Further complicating this situation is the limited amount of research and data available on how to prevent the impact of antimicrobial resistance on children. It is crucial that children are not left behind in the global antimicrobial resistance response, which must explicitly address the specific needs and vulnerabilities of children.

Video on problem of infections and antimicrobial resistance in Africa
Ramesh Agarwal video

Prevention, prompt diagnosis and appropriate treatment are crucially important in reducing neonatal and child mortality – and the areas of focus for Penta.

What are we doing to tackle this problem? 

Improving newborn health is critical to achieving the United Nations Sustainable Development Goals. We know that by continuing our work to improve the evidence base for optimal choice of the right Drug, Dose, Duration and Delivery, we can support the global effort to improve health outcomes in newborns and children.

A top priority for the Penta network is to ensure we deliver new and improved treatment and prevention options for severe infections in babies and children.

We seek to improve the evidence base for optimal choice of the right Drug, Dose, Duration and Delivery in severe infections and infections caused by antimicrobial-resistant microorganisms.

In collaboration with our global collaborators (GARDPSGULMRC CTU and CUAMM), we are committed to tackling antimicrobial resistance in children and to bring this issue to the attention of governments, researchers and industry. Together, we are working to create a platform of connected researchers, scientists, clinicians and implementation partners that will enable us to develop and deliver innovative real world research that will be used to bring new and improved treatment and prevention options that are affordable and available, as fast as possible.

This collaborative platform operates through a network of experienced paediatric and neonatal units from high, low and middle-income settings, coordinated by Penta and working closely with GARDP.

Video "Bringing antibiotics back to routine clinical care"

Our global reach

This partnership allows us to maximize our expertise in the fields of paediatric treatments and antimicrobial resistance. The knowledge we are creating together can help public health and industry partners to speed-up access to antibiotics and facilitate the dissemination and routine implementation of global treatment guidelines (cit. C. Giaquinto)

The Penta network offers a cross learning platform to ensure sharing of expertise between the high-income countries and low- and middle-resource settings. The Network connects researchers and collaborators to enable them to undertake studies, introduce best practice, undergo training and carry out clinical activities. One product of the network is to develop streamlined paediatric development plans: these are important documents that aim at ensuring that the necessary data are obtained through studies in children, to support the authorisation of a medicine for children. The work of the network can accelerate regulatory approval of treatments by ensuring children’s trials are started as early as possible; and to incorporate innovative designs to maximise the information that can be gained from each trial.

Video "our studies in collaboration with GARDP"

We have an ambitious plan and pipeline of priority studies planned and needing to be conducted in high and low -income countries.  These will be critical to ensure we develop the evidence base to support new and improved treatment options, and effective methods for preventing antimicrobial resistance.

Penta takes to heart both mothers and children: we work on the prevention of mother-to-child transmission but also on the identification of optimal treatment for babies who get infected, using old and new antibiotics and testing new combinations of antibiotics (cit. M. Sharland)

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