Maimoatanga I Therapeutics: Te Niwha Priority Research Area

Promoting equitable access to effective treatment for Staphylococcus aureus bacteraemia in Aotearoa New Zealand; Probenecid-boosted Oral antibiotic dosing in the SNAP trial (PR-O-SNAP). 

Staphylococcus aureus bacteraemia (SAB) is one of the most common serious bacterial infections seen in Aotearoa New Zealand. A conservative estimate for the incidence of SAB in the country is around 1100 people per year, which is amongst the highest reported in the developed world. SAB carries a 15-20% mortality, and patients with SAB typically have prolonged hospital stays. SAB disproportionately affects Māori and Pacific Peoples, babies, the elderly, and those living in socioeconomically deprived areas. Current SAB treatment involves prolonged courses (several weeks) of exclusively intravenous (IV) beta lactam antibiotics. 

Prolonged IV antibiotics are associated with increased risk of adverse effects and complications, inconvenience for the patient, and cost, compared with oral antibiotics. There is no evidence to demonstrate the superiority of IV administration in terms of clinical outcomes. There are also many areas of Aotearoa New Zealand that have limited access to home-based IV antibiotic therapy (OPAT), meaning patients in these areas with SAB need to travel long distances or remain in hospital for treatment. These areas are commonly more rural, have higher Māori populations and are more socioeconomically deprived.  

The publication of several high-quality studies of early transition to oral antibiotics after a short period of IV treatment (‘early oral switch’) in complicated and uncomplicated Staphylococcus aureus infection scenarios (not necessarily bloodstream infection) has prompted interest in investigating this strategy for SAB treatment. Pre-clinical evidence from work by researchers in Aotearoa New Zealand suggests co-administration of oral beta-lactams with probenecid (probenecid-beta-lactam combination therapy – PCT) significantly improves blood levels of the beta-lactam antibiotic (drug exposure), often to the extent where levels achieved via the oral route could be considered pharmacodynamically ‘equivalent’ to those achieved via IV administration. 

This evidence, suggesting PCT is a safe and effective alternative to weeks of IV antibiotic therapy, does not meet the high threshold required to change clinical practice, or be incorporated into SAB treatment guidelines.  

The aim of the proposed study is to produce robust pharmacological and clinical data demonstrating that PCT achieves drug exposure that is equivalent to what is achieved with IV therapy. This would provide evidence supporting the shortening and replacement of prolonged IV antibiotic courses for SAB with oral treatment.   

This project will leverage the existing infrastructure associated with the Staphylococcus aureus network adaptive platform trial (SNAP), which is an international study of SAB that is active in many locations in Aotearoa New Zealand already. Patients enrolled in SNAP who consent to enrolment into the PR-O-SNAP study would have blood samples collected at 2-3 different time points during their treatment to assess drug exposure whilst on IV therapy and PCT. Pharmacodynamic modelling will be used to compare the drug exposure achieved at the different time points. 

Summer Studentship 

As part of a ‘summer studentship’ project, we will also interview SAB survivors enrolled in PR-O-SNAP to ascertain their perspectives and experiences of IV and oral antibiotic treatment. Evidence generated from this qualitative patient-centred work will allow more nuanced discussions and enhance shared decision-making between clinicians and patients, and could contribute inform SAB treatment guidelines. 

Te Hiranga a Rangahau I Research Impact 

Based on existing evidence it is expected that PR-O-SNAP will demonstrate equivalent drug exposure with PCT compared to IV therapy. The data generated are expected to contribute to changes to evidence-based guidelines for SAB treatment in NZ and worldwide. This is expected to produce benefits both at the individual patient and at a healthcare system level:  

Patient level:   

Enable intravenous access devices to be removed earlier, reducing the risks and complications associated with these e.g. infection, thrombosis.  

Increase options regarding location of care delivery for SAB, including home-based care, with better access to whānau support, earlier return to work, and other activities of daily living. This will particularly be the case in areas with poor access to OPAT services, which tend to be more rural and socially deprived.  

Provide pharmacological data on the drug exposure achieved with beta-lactam antibiotic therapy in Māori and Pacific people. Dosing regimens for these common drugs are predominantly based on overseas populations, with minimal to no representation from Māori or Pacific People. Ethnic differences are known to occur with drug pharmacokinetics.   

Healthcare system level:   

Intravenous treatment is considerably more expensive than oral antibiotic treatment, requires nursing time to administer, and requires administrative and district nursing support to enable delivery at home. It also takes time to arrange OPAT, which delays discharge from hospital, contributing to bed-block. This is highly relevant currently, with inpatient services in NZ under unprecedented strain, and nursing shortages at crisis levels.   

The ability to use oral antibiotics in place of IV would therefore have the potential to greatly reduce these costs and resource requirements. From a purely monetary perspective an extremely conservative estimate of 1 day length of stay reduction per patient with SAB, multiplied by $800/day to stay in hospital = 1100 patients/year x $800 = $880,000 per year saved by the NZ health system (based on inpatient bed costs at Te Whatu Ora - Counties Manukau).   

Furthermore, the results from this study would likely be translatable to other serious infections that are managed with prolonged IV beta-lactam therapy, such as infective endocarditis and complicated bone and joint infections, which would amplify the benefits cited above. 

Impact Case Study 

Whakarāpopoto Rangahau I Summary of Research 

Viral infections have posed a persistent threat to our health throughout history. The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted heavily on the world economy and health care systems, with millions of deaths recorded. 

To make matters worse, there are many other serious viral pathogens including influenza, which can be transmitted through similar mechanisms and have overlapping clinical features with SARS-CoV-2.  

Due to a number of complex factors including systemic barriers, viral pandemics such as influenza have disproportionately impacted Māori and Pacific Peoples with estimated mortality rates over seven times higher for Māori compared to non-Māori during the 1918 influenza pandemic.  

Currently, we have very few approved antivirals or vaccines available for the many viral pathogens that threaten our health. For the few viruses where we do have approved antivirals available, we are facing increasing drug-resistance and constant viral evolution continues to create new challenges to ensure our vaccines and antivirals remain effective. 

Therefore, it is essential to develop new safe and effective antiviral therapies. We need to use our scientific tools and local expertise to develop our own therapeutic strategies to actively protect our own people. Additionally, we need broad-spectrum antivirals in our toolkit to use as a first line of defence against any emerging novel viruses to give us time to develop and test vaccines for prevention.  

Our team has extensive experience and a long record of drug development from initial chemistry right through to human clinical trials. Therefore, this is a therapeutic innovation project that can build a platform to establish Aotearoa New Zealand-unique antiviral therapies against a wide range of viruses that can rapidly be clinically tested in humans. 

Our project has Māori co-leadership and co-design and aims to develop safe and effective broad-spectrum antivirals to combat significant viral pathogens with pandemic potential such as SARS-CoV-2, influenza and future novel or re-emerging viral threats. 

This will help to protect against excess morbidity and mortality from viral diseases that impact on all our populations including Māori and Pacific Peoples in Aotearoa New Zealand and beyond. The fact that it has potential efficacy against a wide range of viruses means it also gives this country a way to react quickly potential viral pandemics now and in the future. 

Viruses such as SARS-CoV-2, HSV, influenza and RSV are major health problems facing Aotearoa New Zealand. For some of these infections, vaccines can reduce the risk of getting sick, but many people will still become ill so there remains a need for antiviral drugs to treat affected people. 

Antivirals could also be a first line of defence against any new viruses that emerge to buy us time to develop vaccines and other antiviral tools to save lives. One type of antiviral drugs specifically targets the virus itself (e.g., Paxlovid and remdesivir for SARS-CoV-2, acyclovir for HSV and oseltamivir for influenza) but viruses can rapidly develop resistance to these. Another class of drugs targets the processes inside human cells that the virus needs to use when it infects us.  

This class of drug also has the potential to be effective against a wide range of viruses and targeting antivirals in this way offers the possibility of developing broad spectrum antivirals. More importantly, it is harder for viruses to develop resistance to these. Using both types of antiviral drugs in combination would potentially be even more effective, both in treating the infection and in preventing resistance from arising. In our previous work developing anti-cancer drugs we developed drugs targeting an enzyme called PI 3-kinase. 

This plays a crucial role in a process within human cells that we know viruses also need to successfully infect cells. This led the team to think these drugs might be useful as antiviral therapies. The team’s preliminary studies have shown it can indeed block the infection SARS-CoV-2, herpes simplex, influenza and other human viral pathogens. The current funding will allow the team to carry out the key follow-on studies to understand how these drugs achieve their antiviral effects and to see whether their efficacy can be improved by use in combination with the type of antivirals that target the virus itself.  

The results of these studies will guide which types of viral infection we would target in clinical trials. For the final plan we would hold consultation fono/hui within our Māori and Pacific communities and healthcare partners from within our networks to hear perspectives of users and to provide a platform for two-way dialogue before further clinical development (i.e., human trials) to ensure appropriate engagement, approach and uptake. We would also consult with infectious disease clinicians to discuss how these drugs could be used clinically. 

Antibiotics are underused in some patients in whom they would provide benefit and overused in others who could be harmed by unnecessary treatment. A core goal of antimicrobial stewardship (AMS) is to slow development of antibiotic resistance, which can also be thought of as antibiotic conservation – using antibiotics as well as we can to ensure these important medicines remain available and effective for our tamariki and mokopuna. 

The Problem 

At present there is no standard to both guide antibiotic prescribing and measure the appropriateness of treatment.  While we know there are marked inequities in the rates of infections for Māori and Pacific peoples in Aotearoa, very little is known about the inequities in infection treatment.  

Our Solution 

We plan to develop a national antibiotic guideline in Aotearoa that sets out the optimal treatment of infections.  

We will also develop innovative systems that automatically monitor antibiotic prescribing together with the reasons for prescribing antibiotics, and information about the populations for whom antibiotics were prescribed. 

Using our new guideline and monitoring system, we will then determine the appropriateness of antibiotic prescribing for important infectious diseases in Aotearoa (e.g. sore throats, skin infections, meningitis), with particular attention to prescribing for Māori, Pacific peoples and other population groups who bear a disproportionate burden of infectious disease in Aotearoa.  

Finally, we will work collaboratively with Māori health providers, and with hospital and community-based clinicians to determine how best to provide prescriber feedback about antibiotic prescribing and will assess the impact of feedback on prescribing practice. Our partnership with Te Niwha will provide the foundation for improving antibiotic use in Aotearoa. Improving antibiotic use via antimicrobial stewardship efforts in Aotearoa is critical to reducing the threat of antibiotic resistance, reducing harm, enhancing equitable care, and improving patient outcomes. 

Research locations: Auckland, Christchurch, Wellington, Dunedin. 

Te Hiranga a Rangahau I Research Impact 

Many public hospitals are not adequately resourced to provide AMS services, and AMS services are urgently needed in primary care. The outputs of our project will be available to all public hospitals and all primary care providers in Aotearoa and will make huge advances towards ensuring that all clinicians have access to appropriate AMS advice.  

The innovative outputs of the project will provide Aotearoa with the best AMS systems in the world. The impact of the project will be measured in the first instance by: (i) the frequency with which the new guidelines are viewed by prescribers in primary and secondary care, (ii) the magnitude of annual reductions in inappropriate antibiotic prescribing, and (iii) the magnitude of increases in guideline adherent antibiotic prescribing, all of which can be measured within the timescale of the project. 

In the longer term, the impact of the project will be measured by whether the quality of antibiotic prescribing demonstrates sustained improvement, the impact of infectious diseases on the people of Aotearoa declines, and the spread of antibiotic resistant bacteria is reduced. We are confident that the opportunity provided by this work with Te Niwha will not only improve the health of New Zealanders and also slow the development of antimicrobial resistance.  

An important impact of the project will be the creation of new collaborative relationships between people with varied roles and working in many different organisations, all of whom are determined to improve the care provided for people with infections in Aotearoa. We hope that these new relationships will be the base for ongoing research collaborations to further this work in the years ahead. 

Impact Case Study  

Whakarāpopoto Rangahau I Summary of Research

Traditional randomised clinical trials take too long for design, approval, and completion to be able to respond to pandemic infectious diseases threats. REMAP-CAP represents an innovation where an established learning healthcare platform trial, asking questions about respiratory tract infections between pandemics, can adapt quickly to respond to new respiratory infectious diseases.