Rigorous, randomised controlled trial results from the PRINCIPLE Trial early on in the Pandemic contributed to antimicrobial stewardship world-wide
The antibiotics azithromycin and doxycycline were widely used early on in the pandemic to treat COVID-19 in the community because of their anti-inflammatory, antibacterial, and in-vitro antiviral activity, despite no clinical trial evidence that they worked. We showed that despite fewer consultations in HNS general practice in 2020, prescriptions of these drugs increased with the increasing incidence of COVID (BJGP Open 2021; DOI: 10.3399/BJGPO.2021.0087). Anticipating that many treatments for COVID-19 suitable for community use would require rapid evaluation, and that setting up a separate trial for each new drug would be inefficient, we designed, and against open competition, won funding for a platform, adaptive trial that could test a number of drugs at the same time and new treatments added. PRINCIPLE produced the first, robust RCT evidence from primary care from 2265 participants for azithromycin (Lancet March 4, 2021 https://doi.org/10.1016/ S0140-6736(21)00461-X ), and among 2689 participants for doxycycline (Lancet Respir Med July 27, 2021 https://doi.org/10.1016/ S2213-2600(21)00310-6) to prove that these drugs did not work for COVID-19. A Covid Clincial Alert from the CMO on 28 January 2021 was issued throughout the NHS to say that azithromycin should not be used either in hospital or primary care, and that “doxycycline should NOT be used in the management of confirmed or suspected COVID-19 infection within primary care, unless there are additional indications for which its use remains appropriate.” These findings from PRINCIPLE have influenced antibiotic stewardship world-wide ever since, and the world’s largest community COVID trial, PANORMAIC, which is determining who will, and will not, benefit from novel antiviral agents, is based on PRINCIPLE. Only 20% of clinical trials of COVID-19 therapeutics have been done in the community and most never recruited enough participants to produce useful findings.
1. A COVID-19 Therapeutic Alert (CEM/CMO/2021/0030 ) was issued on 28 January 2021 to General Practice, Community Pharmacies, ICS /STP and Clinical , commissioning Group Pharmacy Leads, NHS Trusts (NHS boards in Scotland and Wales) Regional Medical Directors, Regional Chief Pharmacists, Lead/Senior Pharmacists and Regional Procurement Pharmacy Leads, Trust/Hospital Medical Directors and Chief Pharmacists to circulate to medical, pharmacy and nursing staff managing COVID-19 patients, to “Ensure that the local primary care team is aware that antimicrobials should NOT be used in the primary management of COVID-19 infection…”.
2. WHO and NICE guidelines on the management of COVID-19 in the community state “Do not use azithromycin to treat Covid 19 in the community” This recommendation is based on three trials, the largest of which is PRINCIPLE. In addition, the NICE guidelines state, “Do not use doxycycline to treat COVID-19 in the community,” and the PRINCIPEL is the only reference (www.guidelines.co.uk/infection/nice-managing-covid-19-guideline/455939.article0). Evidence from PRINCIPEL similarly influences other guidelines worldwide.
3. The PRINCIPLE and the PANORAMIC TRIALs have informed research methods and priorities for the appropriate use of antimicrobials for COVID-19 worldwide: we are core members of WHO The COVID-19 Working Group on Outpatient Therapeutics Protocols that was established to promote rapid, fluid and efficient information sharing and promote collaboration, and we presented PRINCIPLE and PANORAMIC to the WHO R&D Development Summit, “COVID-19 Research and Innovation: powering the world’s pandemic response-no and in the future,” which has influenced the WHO COVID-19 R&D Blueprint (https://www.who.int/publications/m/item/covid-19-research-and-innovation—powering-the-world-s-pandemic-response-now-and-in-the-future.).
Based on PRINCIPLE, we are now funded to deliver the PANORAMIC trial of novel anti-viral agents. PANORAMIC has the aim of determining whether early treatment of COVID-19 with novel antivirals reduces the need for hospital admission and improves recovery among those in higher risk. To our knowledge, PANORAMIC is the fastest recruiting trial of an antimicrobial ever done, with over 26,000 participants already randomised. We are now analysing the results for the drug molnupiravir which will guide care for this coming winter worldwide. Guided by antimicrobial stewardship concerns, as key aim is to determine who should be treated with novel antivirals, and who will not benefit. Targeting antimicrobials appropriately remains the key mission of this world-leading trial, which was only possible because of the lessons learned in PRINCIPLE.
Antifungal Stewardship in ventilated Covid-19 patients: the use of prophylactic nebulised liposomal amphotericin B to prevent Covid-19 Associated Pulmonary Aspergillosis
Early in the second pandemic wave of 2020 at Nottingham University Hospitals we observed an increase in possible or probable Covid-Associated Pulmonary Aspergillosis (CAPA) cases in ventilated Covid-19 patients in our Intensive Care Units (ICU), associated with a high mortality (75%). Managing these cases was challenging for a number of reasons; long turnaround times on respiratory and serum specimen Galactomannan testing at a referral laboratory, often leading to prolonged empirical antifungal therapy whilst awaiting results. This lead to associated drug toxicity (for example hepato-, cardio – and nephrotoxity) and significant drug-drug interactions in the intensive care setting. In addition, the national shortage of IV voriconazole led us to reconsider our whole management approach to CAPA locally. After multi-disciplinary discussions between microbiology, pharmacists and intensive care clinicians, we decided to move to an antifungal prophylaxis approach, rather than continuing our screening and empirical treatment approach. Prophylaxis with enteral mould-active antifungals was felt to be suboptimal due to the issues of variable absorption, proning affecting the availability of the enteral route, and the need for therapeutic drug monitoring with oral mould-active azoles. We therefore explored using prophylactic nebulised liposomal amphotericin (Ambisome®), using dosing and administration regimens extracted from the literature for other indications in haematological and lung transplant patients. After completing risk assessments and gaining approval from our local Drugs and Therapeutics Committee, we implemented twice-weekly nebulised AmBisome® in all ventilated Covid-19 patients in February 2021. Nursing action cards were created to support safe administration, and regular monitoring of any incidents was performed by the Antimicrobial Pharmacist team. We retrospectively and prospectively collected data on patients with a diagnosis of possible or probably CAPA, antifungal use in intensive care, and the number of respiratory and serum specimens referred for Galactomannan testing before and after introducing prophylaxis, to determine the impact of our intervention.
Prior to implementation of prophylaxis, there were 12 cases of possible or probable CAPA in 195 Covid-19 ICU patients (6.2%) in a nine-week period between December 2020 and January 2021, with a mortality of 75% (9/12). Following the implementation of twice-weekly nebulised AmBisome® prophylaxis, there was only 1 case in 81 ICU patients in a nine-week period between February and March 2021 that was diagnosed with probable CAPA (1.2%). On review this patient had in fact had required a break in the prophylaxis regime due to experiencing bronchospasm. On restarting prophylaxis, clinical deterioration led to a bronchoscopy which revealed white fungal plaques and lavage specimens subsequently grew Aspergillus fumigatus; the patient was treated with IV voriconazole for probable CAPA but unfortunately died within a week.
Antifungal usage in ICU areas fell dramatically post-implementation, with voriconazole usage falling from 136 vials/month in December 2020, to only 3 vials in February 2021, and no voriconazole used in March 2021. Total antifungal consumption in critical care areas fell post-implementation, even when accounting for the nebulised AmBisome® use, demonstrating that prophylactic nebulised AmBisome® was an effective antifungal stewardship intervention, leading to improved clinical outcomes and associated adverse drug effects. We saw no cases of either azole-resistant or amphotericin-resistant Aspergillus infections.
The numbers of respiratory and serum samples sent from ICU patients for Galactomannan testing reduced considerably, from 621 in the pre-intervention period to 209 in the post-intervention period, representing a 3-fold reduction in testing. At a cost of £62 per test, this represented a crude cost saving of £25k in testing costs alone during the nine-week post-implementation period.
Although severe Covid-19 requiring ventilation is now thankfully more uncommon, nebulised AmBisome ® prophylaxis continues to be used in our ICU for these cases. We have shared our protocols with other centres who were experiencing a high frequency of CAPA cases. Given the similarities with Influenza-associated pulmonary aspergillosis (IAPA), we would consider this approach if there was a rise in severe influenza cases requiring intubation. In-house testing of respiratory and serum specimens for Aspergillus Galactomannan is being introduced to the microbiology laboratory in 2022, to further reduce turnaround times, improve clinical decision-making and timeliness of treatment in the diagnosis of CAPA or IAPA in ventilated ICU patients.
COVID vaccine allergy service – providing reassurance to encourage vaccination
On 9th December 2020, just three days into the national COVID vaccine programme, a warning was issued that anyone with a history of allergic reactions should not receive the Pfizer vaccine. This was widely publicised in the media and online as clinicians sought to identify the course in this novel product. For many vaccine recipients this message has remained a barrier to vaccination regardless of the allergen.
On 30th December 2020 the Commission on Human Medicines (CHM) narrowed this broad recommendation to restrict vaccine exclusion to only those with a previous history of allergic reaction to the ingredients of the vaccine, but those with any other allergies such as a food allergy can now have the vaccine. However the public and medical professionals still remain uncertain over proceeding with mRNA vaccines.
In January 2021 an allergist and anti-microbial pharmacist at University Hospital Southampton set up a review, advice and vaccination service for patients with concerns over having a COVID-19 vaccine due to allergy or reactions to first doses of COVID vaccine. The service accepted referrals from Hampshire, Isle of Wight, Dorset, Wiltshire and the Channel Islands, a population of 6million people. The service provided advice and reassurance to maximise vaccine administration close the patient’s home where possible.
Where a patient’s medication history did not provide reassurance of polyethylene glycol tolerance or their list of reactions raised concern over PEG allergy we offered skin testing to PEG, in the form of polyethylene glycol laxative solution, and the Pfizer BioNTech vaccine. This process provided reassurance before proceeding this vaccination.
Our preference is the Pfizer BioNTech product and we have found it to be tolerated even in those with chronic spontaneous urticaria when administered after an oral antihistamine premedication, as reflected in the Green Book 14a.
Our COVID vaccine allergy service has provided the opportunity for those with a history of allergy or reaction to first COVID vaccine doses to complete the course in a safe environment. The COVID-19 vaccination has been shown to reduce the severity and hospitalisation related to SARS CoV-2 infection and as such the COVID-19 vaccination programme is a national priority. Despite the viral cause of COVID-19 infection and availability of antiviral and monoclonal antibodies the use of antibiotics remains part of the treatment suspected or confirmed bacterial co-infection. Preventing severe infection thus avoiding this antibiotic use is a key stage in not adding to the AMR burden.
The Pfizer BioNTech (Comirnaty) and Moderna (Spikevax) products are based on novel mRNA technology with entirely new excipients compared with previous vaccine products. This has facilitated vaccination of those who have previously avoided all vaccination due to historical reactions, sometimes life threatening, to previous vaccines. We believe this mRNA technology will be utilised for other diseases and by giving those with previous reactions the confidence to receive this style of vaccine other infective conditions may be prevented. Our skin testing, using PEG and the Pfizer vaccine, has so far identified two people with confirmed PEG allergy who were offered alternative vaccine products.
This project supports the WHO Immunization Agenda 2030: A Global Strategy to Leave No One Behind which highlights the importance of vaccination in the battle against AMR. We have provided reassurance and safe administration of vaccination doses in place of vaccination exemption certificates.
We have submitted a request to become a Complex COVID Vaccination Centre – the view of NHSE is that these should be for administration of Nuvaxovid as an alternative to mRNA vaccines. Our view is that a significant number of patients continued to receive the AstraZeneca Vaxzevria product due to concerns over the mRNA vaccines and more people could be safely switched to this mode of vaccination.