Interpreting Dust Patterns – Antibiotic Matters
Dr Ian Ellul chats with Prof. Michael Borg on the nuts and bolts of MEETING PEOPLE antibiotic stewardship with all its subtle and not so subtle percolations.
Deciphering the science through the noise reminds me of the strife of Murphy Cooper to interpret the dust patterns in the science fiction movie Interstellar, directed in 2014 by Christopher Nolan. Contrary to the movie, science has no paranormal activity, yet, similar to the movie plot, passion, resilience
as well as serendipity play an important part in attaining achievements.
WHEN DID YOU REALISE THAT YOU WANTED TO BECOME A DOCTOR?
When I started University in 1981, there weren’t many choices for someone who was inclined for sciences. It was either teaching, pharmacy or medicine. I chose medicine. Truth be told, I was always inclined towards medicine. I remember at St. Aloysius’ College when we did a questionnaire on career options, as part of the subjects’ choice at the end of Form 2, my resulting preference was a tie between medicine and laboratory science. All these years later, I find myself precisely in those two paths.
WHY SPECIALIZE IN MICROBIOLOGY?
Microbiology was my preferred subject ever since I started listening to Prof. Paul Cuschieri in the lecture rooms during my 3rd undergraduate year. Thus, after graduating, when a call was issued for a senior registrar post in microbiology, I immediately applied for it. So in 1989 I travelled to London together with Dr Chris Barbara, who was also chosen from the same call. First we went to the London School of Hygiene and Tropical Medicine and then to University College Hospital. It was a period to remember for various reasons. It was the first time I lived abroad for such a long period. Also, it was an enriching experience since I had access to facilities which were unheard of locally at the time, including huge libraries and computers.
I also interacted with colleagues undergoing training who came from over fifteen different countries, ranging from Chad to Australia.
I ALWAYS ADMIRE YOUR SELF-CONFIDENCE. ALSO, THE MANNER IN WHICH YOU SPEAK SEEMS TO BETRAY A MORE CONVIVIAL DISPOSITION. DESCRIBE YOURSELF IN ONE SENTENCE.
A plainspoken person, hopefully with a bit of selfdepreciation and sense of humour.
ONE OF YOUR FIRST ARTICLES ON ANTIMICROBIAL RESISTANCE WAS OVER-THE-COUNTER ACQUISITION OF ANTIBIOTICS IN THE MALTESE GENERAL POPULATION PUBLISHED 20 YEARS AGO. WHERE DO WE STAND NOW?
This was one of my first research projects. I remember we participated in the Health Promotion stand at the Malta Trade Fair, choosing attendees randomly and asking them to compile a questionnaire on their antibiotic consumption. At the time there was little or no awareness about antibiotic resistance amongst the public and also, healthcare professionals. Even during my medical undergraduate course and microbiology specialisation abroad, this area was just given a fleeting mention. Today we are facing superbugs on a regular basis in tertiary care … MRSA, vancomycin-resistant enterococci (VRE), carbapenemresistant Enterobacteriaceae (CRE), extended spectrum β-lactamases (ESBL), etc. The establishment of the ECDC proved to be a watershed moment since it was the first time a pan-European entity relating to antimicrobial resistance (AMR) and appropriate use of antibiotics was established. Returning to your question, the use of OTC antibiotics has decreased drastically in Malta due to the awareness which has percolated through all societal strata, especially pharmacists.
IN 2015 I CONDUCTED A PROSPECTIVE PHARMACOEPIDEMIOLOGICAL REVIEW OF MEDICINES PRESCRIBED TO APPROX. 1000 CHILDREN BY COMMUNITY PAEDIATRICIANS AND GENERAL PRACTITIONERS IN MALTA. I FOUND THAT 23% OF PRESCRIPTIONS RELATED TO ANTI-INFECTIVES FOR SYSTEMIC USE. HOW DO WE COMPARE WITH OTHER COUNTRIES? ACCORDING TO A REPORT DRAWN IN 2019 BY THE OECD IN COLLABORATION WITH THE ECDC, IF AMR FOLLOW THE PROJECTED TRENDS, BY 2050, MALTA WILL POSSIBLY HAVE THE SECOND HIGHEST YEARLY EXPENDITURE IN EUROPE, I.E. €4.7 PER CAPITA. ITALY TOPS THE CHART AT APPROXIMATELY €4.8 PER CAPITA.
AMR may be compared to climate change; it has a multifactorial nature. Nonetheless the one factor which stands out is antibiotic use. If we look at statistics, when compared to the EU average, Malta is not an outlier in terms of total volume of antibiotics prescribed. However, 42% of local residents are prescribed at least one antibiotic a year; this is the second highest in the EU and more than twice that reported by Sweden and The Netherlands. We have two additional challenges. The first relates to the use of antibiotics where there is clinical uncertainty if the infection is bacterial or viral in origin. Use of antibiotics to treat sore throats in Malta is massively higher than Scandinavia. We also see this uncertainty in tertiary care in surgical prophylaxis. Although this practice is essential, there is no need to give such cover for several days, when one or two doses are equally effective. The second challenge relates to the type of antibiotics which are prescribed. We tend to steer towards broad spectrum antibiotics which are often unnecessary, especially in the community, and which disrupt our microbiome leading to resistance.
IN 2016 IN ONE OF MY EDITORIALS I DISCUSSED TEIXOBACTIN AS A POSSIBLE GAME-CHANGER FOR AMR. WHAT ARE YOUR VIEWS ON THIS DRUG AND SIMILAR ONES WHICH MAY BE IN THE PIPELINE.
Each conference which I have attended along the years invariably contained posters or oral presentations heralding a drug claimed to be a game changer in the fight against AMR; we are yet to see it. I remember one seminar which I attended at Cambridge University in the mid-nineties where carbapenems were trumpeted as the solution to the treatment of hospital infections. Fast forward by twenty years and we are seeing alarming levels of carbapenem-resistant and pan-resistant Klebsiella pneumoniae throughout the world. Obviously, such resistance is delayed by the judicious and focused use of antimicrobials. We also have the conundrum of antibiotic development. Developing a novel antimicrobial has been estimated to cost up to 1.5 billion dollars. And after that, what happens? People like me telling clinicians to use it sparingly to avoid resistance! You can understand why pharma would look towards investing research and development in other areas e.g rheumatology which would translate in on-demand use of the drug at higher volumes to make the investment worthwhile. Interestingly we are seeing a resurgence of old antibiotics. Tetracyclines, discovered in the 1940s, had fallen out of popularity by the end of the last century. Precisely because of this, they have been less affected by development of resistance and are now our flagship treatment against MRSA. They have got a very good activity spectrum against Maltese strains, meaning we can avoid using last resort agents such as vancomycin and teicoplanin in mild and moderate infections.
DOES MALTA HAVE ACCESS TO NOVEL ANTIBIOTICS?
We have some pockets of resistance in the community setting, especially for quinolones (most notably ciprofloxacin) as well as for macrolides and cephalosporins. But there are still good alternatives, even for the most serious infections such as those relating to Streptococcus pneumoniae. It is in tertiary care where access to novel antibiotics can be vital in specific cases. Thankfully our colleagues at the Central Procurement and Supplies Unit (CPSU) are great in crisis management and, more often than not, can source locally unavailable novel antibiotics in a timely manner on a named patient basis, if the need arises.
LAST DECEMBER YOU PUBLISHED AN ARTICLE ON THE PREVALENCE OF MRSA IN EUROPE, TOGETHER WITH PROF. LIBERATO CAMILLERI, AN OUTSTANDING STATISTICIAN WHOM I HAD THE PLEASURE TO COLLABORATE WITH. WHERE DOES MALTA STAND?
MRSA control is one of our greatest success stories. During the past 20 years, cases have dropped significantly. In 2002, MRSA constituted more than 60% of Staphylococcus aureus infections at Mater Dei; this is now less than 25%. There are various reasons for this but the main one is the screening programme which has been implemented since 2014 on all patients admitted to Mater Dei hospital. This means that any asymptomatic carriers are identified and decolonised immediately on admission. Otherwise, they would be a source of infection for other hospital patients. By severing this cycle, we have also improved antibiotic sensitivities of Staphylococcus aureus infections in ambulatory care, offsetting the increase in MRSA resistance within the community that we had experienced before the screening initiative.
DOES MALTA CARRY OUT GENOMIC SURVEILLANCE FOR HYPERVIRULENCE AND/OR MULTI-DRUG RESISTANCE?
Unfortunately, we do not have a local infrastructure to do this as routinely as we would like. Indeed, ECDC has recommended that we do regular molecular genetics for resistant strains. This is of particular value in outbreaks in order to identify transmission patterns. Although the antibiogram of different isolates of the same bacterial species may be identical, they could be different clones with no epidemiological linkage. You can only determine this through genomic typing. We do try to send isolates to laboratories abroad to carry out genomic surveillance as often as we can. This has shown, for example, that we have two main local strains of MRSA. These are the eMRSA-16, the classical UK strain, and a Malta clone which we first reported in 2010. This Maltese clone is a Staphylococcus aureus which is resistant only to methicillin and fusidic acid. It almost certainly originated from the abuse of fusidic acid topical creams and ointments which was locally widespread a decade or so ago.
ANTIBIOTIC STEWARDSHIP. YOUNG CLINICIANS ON ONE SIDE OF THE PITCH AND SEASONED CLINICIANS ON THE OTHER SIDE. WHO HAS THE BEST SCOREBOARD?
One cannot generalise but my anecdotal experience suggests that the younger cohort tend to have the best ethos relating to antibiotic stewardship. This probably stems from the fact, that contrary to my undergraduate years, today there is a much stronger focus on AMR in local medical curricula. Such focus is also mirrored in postgraduate specialisation training, including those relating to family medicine.
A STANFORD UNIVERSITY STUDY PUBLISHED IN 2020 ANALYSED DATA ARISING FROM SCIENTIFIC DISCIPLINES BETWEEN 1965 TO 2019 AND COVERING APPROXIMATELY 7 MILLION SCIENTISTS. THE RESEARCH ANALYSED THE NUMBER OF CITATIONS INCLUDING H -INDEX, AMONGST OTHER THINGS. THE RESEARCHERS HAVE ANALYSED THE CITATION IMPACT DURING THE SINGLE CALENDAR YEAR 2019 AND HAVE PLACED YOU AT NUMBER 92,783, MEANING THAT YOU FALL IN THE TOP 1.4% SCIENTISTS. HOW DID YOU HEAR OF THIS AND WHAT WERE YOUR INITIAL FEELINGS?
The news was communicated to me by the University of Malta’s Think magazine, which ran a feature on it. Needless to say, I was very pleased considering our limitations. Malta equates to a small European city in terms of research facilities and funding; so to rank on par with scientists from world-renowned centres of excellence was obviously extremely satisfying.
IN KEEPING WITH THE ABOVE, ACCORDING TO RESEARCHGATE YOU HAVE CLOCKED OVER 8,000 CITATIONS FOR YOUR 126 ARTICLES WHICH YOU PUBLISHED OVER A PERIOD OF 25 YEARS. I KNOW OTHER DOCTORS MAY HAVE PUBLISHED MUCH MORE THAN THAT, POSSIBLY OVER A SHORTER PERIOD, BUT WITH LESS CITATIONS. DO THESE 8,000 CITATIONS STEM FROM THE FACT THAT YOUR AREA HAS CLINICAL BUT ALSO ECONOMIC AND POLITICAL PERCOLATIONS?
You are right. In recent years, AMR has been discussed at the G7, G12, European Parliament and even the United Nations General Assembly. This effectively shows the significant impact that AMR has in areas other than medicine. Nonetheless, I believe that my citation track record may be pinned down to the fact that I always sought to avoid parochial publications and try to bridge knowledge gaps in my areas of interest. In 2003, my department was the first Maltese team to coordinate a multinational EU funded medical research project. ARMed involved 13 Euro-Mediterranean countries over 4 years and proved to be a pioneer in surveillance of antibiotic resistance and consumption in the south-eastern Mediterranean. It yielded 15 papers which are still being regularly cited today. Over the past decade, my research has focused on a previously unchartered aspect of antibiotic use and AMR … behavioural science and cultural anthropology. My publications have shown that you can explain a large degree of the heterogeneity of AMR (e.g. MRSA) within Europe simply from the country’s national culture. In particular, the cultural dimension of uncertainty avoidance explains most of the misuse of antibiotics in the Mediterranean, including prescribing antibiotics for predominantly viral conditions (such as colds, flu and sore throat) and the preference for broad spectrum formulations. This research appears to have been groundbreaking – at least judging from the invitations I have received to speak about it in international conferences.
IN NOVEMBER 2020, THE NEW COMMISSION IMPLEMENTING DECISION (EU) 2020/1729 ON THE MONITORING AND REPORTING OF ANTIMICROBIAL RESISTANCE IN ZOONOTIC AND COMMENSAL BACTERIA WAS PUBLISHED. HOW WILL THIS AFFECT MALTA?
The European Commission’s AMR Strategy focuses on a One Health European Joint Programme which also includes veterinary medicine relating to companion-animals as well as husbandry. Thus, when we speak about AMR we even need to factor in antibiotic resistance in plants, residues in sewage, etc which are all important drivers. Although we may not have the intensive farming of bigger countries like The Netherlands, zoonotic infections are also relevant for Malta. To give an example … if there is antibiotic resistance in poultry pathogens, any lack of hygiene during the cooking process could lead to the transfer of the resistance genes to bacteria in our intestines. Nonetheless our focus should mainly be on human medicine since it is antibiotic use in human, rather than veterinary medicine, that is likely driving resistance in our country.
YOU HAVE OBVIOUSLY BEEN AN ACTOR ON THE COVID-19 STAGE. DO YOU THINK THAT POLITICS AND PUBLIC HEALTH TALLY WITH EACH OTHER?
Politics and public health can be strange bed fellows. We have seen how the US politicized the use of face masks. Or the stand of the UK to achieve herd immunity, at the expense of widespread testing, during the initial stages of the pandemic. Obviously, these may stem from the fact that lockdowns have such major repercussions, including on the economy. It is clear however that the countries that tackled COVID-19 most effectively were those which achieved harmony between these two vital areas.
MIXED MESSAGES HAVE BEEN AN ACHILLES HEEL OF PUBLIC HEALTH DURING THIS PANDEMIC. RECOMMENDATIONS PROPOSED BY INTERNATIONAL PUBLIC HEALTH INSTITUTIONS, AND THEN RELAYED TO US, HAVE BEEN RIDDLED WITH INCONGRUENCIES. I GIVE SOME EXAMPLES … NO FACE MASKS ARE NEEDED FOR USE BY THE GENERAL PUBLIC … VISORS ARE AS EFFECTIVE AS MASKS … CLOTH MASKS ARE FIT FOR PURPOSE [WITHOUT SPECIFYING THAT THEY SHOULD BE THREE-LAYERED] … WHAT IS YOUR OPINION ON THIS EVOLUTION?
Evidence-based medicine has often been the casualty of this pandemic. Tackling a pandemic, especially in the initial stages, was challenging since there were too many unknowns. I agree with you that there may have been mixed messages. Even today, we still have wide variations between countries relating to wearing of masks in outdoor spaces. The initial reluctance to advocate widespread use of masks by the public stemmed from the Chinese lockdown which severed the supply of PPEs to the rest of the world. There were even anecdotes of aeroplanes full of PPEs being “hijacked” by another country which offered more money, even as the plane was on the airport tarmac awaiting clearance to fly to the original buyer. In this background, WHO could not deliver a message saying that the public should use masks widely since the limited stock had to be prioritised for where it definitely made a difference i.e. for healthcare professionals providing patient care. Amidst this backdrop with rising cases and deaths, I guess it was easy to make knee jerk reactions in lieu of evidence-based decisions.
HOW WILL MALTA EXPERIENCE COVID-22?
Coronaviruses exhibit one of the greatest mutation rates among viruses. Yet we know that, to date, all vaccines available in Malta are extremely effective at reducing the morbidity and mortality caused by all currently identified variants. To a slightly lesser extent, vaccines are also effective at reducing the transmissibility. I suspect that SARS-CoV-2 will remain as part of our microbial background for years to come, similar to what happened with the swine flu. We have had a sterling vaccination campaign banking on our strengths i.e. small country, close team of decision makers, and the resilience shown time and time again by our nation in the face of a crises. We may well need booster doses on a yearly basis. This, together with more effective antivirals, should hopefully ensure that COVID-19 remains under control and allow us to return to some degree of normality.
HOW DO YOU ENVISAGE YOURSELF IN TEN YEARS’ TIME ON THE DOORSILL OF RETIREMENT?
I would love to continue teaching since contact with students is so fulfilling. However, I wish to spend a large part of my time travelling the world. I am an avid traveller, even relishing the hours which I spend in mid-air. My academic work has taken me to more than 50 countries in 4 continents but my bucket list is nowhere complete. I especially wish to go to China and Australia as well as do more safaris in sub-Saharan Africa. WHAT DO YOU THINK OF CME.30, OUR ONLINE CONTINUING MEDICAL EDUCATION PORTAL? CME30.eu is the future. Since 2020 we have used CME30. eu as an effective portal to convey our messages, ranging from the European Antibiotic Awareness Day to COVID-19 training. We managed to reach out to significantly more doctors and pharmacists than previous years when we used to hold seminars at Mater Dei Hospital. Organising these seminars used to entail massive headaches related to sourcing funding, organising the logistics, etc… and then attendance was often underwhelming. On the other hand, our CME30.eu sessions managed to attract hundreds of healthcare professionals, who are not our usual crowd. I guess it is easier for someone to arrive home after a clinic and simply log in to your portal, rather than to have to drive to Mater Dei, or to a hotel, and then return so late back home. Our message can be delivered more efficiently online, with reduced costs and less administrative hassle. This is probably one of the most useful legacies of COVID-19.