Analysis | MDA and AMR symposium

By James Cross

Last week, LSHTM hosted the Mass Drug Administration (MDA) and Antimicrobial Resistance (AMR) Symposium. A large group of academics from a range of health topics and scientific disciplines joined us for a day of insights and debate regarding challenges and consequences around MDA and its link to AMR. Here are the overviews of the cases that were discussed at the event:
Azithromycin Case 
Dr Emma Harding-Esch began the case with informing us that, since the mid-1990s, a number of randomized controlled trials showed that single oral dose azithromycin was at least as effective in treating active trachoma as a prolonged course of topical tetracycline ointment. In 1996, as a result of this evidence, the WHO endorsed the use of azithromycin by trachoma control programs and has aimed to eliminate trachoma by 2020. Several research studies have now demonstrated the impact of MDA on decreasing trachoma prevalence. Prof Nicola Low went on to highlight the research around “off-target” effects of azithromycin. These are predictable results due to azithromycin’s broad-spectrum antimicrobial activity. This is supported by the fact that azithromycin MDA correlates with reduction in the prevalence of yaws, genital chlamydia, lower respiratory tract infections, and diarrhoea. However, detection of antimicrobial resistant strains of Streptococcus pneumoniaeStaphylococcus aureusEscherichia coli and Treponema pallidumsubspecies pertenue (causing yaws) might also be considered predictable. Interestingly, we heard about less predictable off target effects including observed reductions in all-cause child mortality in some studies of azithromycin MDA. Prof Daniel Chandramohan detailed findings on behalf of the SMCAZ trial group, presenting data on the effects of the addition of azithromycin (AZ) to monthly sulphadoxine-pyrimethamine plus amodiaquine (SPAQ), used for seasonal malaria chemoprevention in Burkina Faso and Mali. We heard that the incidence of death and malaria was similar in the two study groups, and that the incidence of gastrointestinal infections, upper respiratory tract infections and febrile illnesses not due to malaria, was lower among children who received azithromycin. At the same time, the percentage of pneumococcal isolates resistant to azithromycin in the AZ group increased from 3.1% to 18.9% in Burkina Faso and 0.9% to 28.4% in Mali. Dr Harry Pickering presented on the impact of azithromycin MDA on the gut microbiome and antimicrobial resistance, in relation to a sub-study in the MORDOR trial. A subset of children within the trial provided stool samples pre- and post- treatment with either azithromycin or placebo. Bacterial richness and diversity were equivalent between trial arms at baseline and 24 months. A trend of lower relative abundance of C. difficile was found in the azithromycin treatment arm at 24 months, conversely, E. coli abundance was marginally higher in the azithromycin treatment arm at 24 months. Mass distribution of azithromycin did not cause significant changes in the gut microbiome or prevalence of antimicrobial resistance in the examined district. It is plausible that, as seen with impacts on childhood mortality, impact of MDA may vary between communities. Lastly, we observed a presentation from Dr Jon Simon, who demystified the WHO guidelines development process and explained the multiple steps and processes undertaken to generate scientifically sound technical guidance based on independent assessment of the available scientific evidence.
Malaria Case
To begin, we heard from Prof Brian Greenwood talking about MDA for malaria control, and why this intervention has been neglected. We heard about the history of quinine MDA programs in Panama and Italy, and arguments around the MDA approach to malaria control from the WHO since the 1970s. One of the main reasons being that it could drive drug resistance. Prof Brian Greenwood detailed the effects of medicated salt (sub-therapeutic doses of anti-malarials) on the emergence of chloroquine and anti-folate resistance. Dr Jackie Cook then went on to detail modern applications of MDA for malaria infection, and whether they are likely to increase drug resistance. This was followed by Dr Colin Sutherland, describing the Access-SMC project in supporting the roll-out of seasonal malaria chemoprevention in children across 7 countries of the Sahel region of Africa. Dr Sutherland presented data from the largest ever program of molecular surveillance for malaria resistance genes, screening over 60,000 samples. Lastly, Dr Ian Hastings presented his groups findings using the malaria epidemiology simulation suite, OpenMalaria. We heard about the complex way MDA is investigated using this pharmacological model of drug treatment and resistance that allows variation on drug metabolization (pharmacokinetics) and parasite drug sensitivity (pharmacodynamics).
NTDs Case
The NTD section was a trio of talks by Dr Rachel Pullen, Dr Luc Coffeng, and Dr Bruno Levecke. This collection of presentations described how NTDs affect up to 2 billion people, with several of these conditions being helminth infections. MDA is the cornerstone strategy for helminthic NTD control and elimination and is annually used for deworming campaigns employing albendazole. Currently, there is no known drug resistance to human worms, but there is known drug resistance to benzimidazoles in animals. Future campaigns to control helminth diseases need to consider possible drug resistance in the human population due to constant exposure, alongside strategies for efficacy monitoring.   
Thematic Issues
This session began with a talk from Prof Marc Lipstich, who highlighted the importance of remembering that our interest when assessing consequences of MDA is not in drug sensitivity per se, but in an overall reduction of the mortality burden. Modeling is an important tool when estimating the number of treatment failures that would occur when drugs are used to treat infections, but when weighting effects against measured mortality benefits, we need to remember that any benefit will decrease as resistance arises. Dr Michael Millar then went on to detail the ethical considerations of MDA. Adding that mass use of antibiotics (population intervention) will help some but not all who are exposed to the intervention and will harm some in the present and potentially many more in the future. This deeply thought-provoking presentation then went on to ask if we should give future people a lower priority than present people because they owe their existence to those alive today (non-identity problem), or because technology advances and generally contributes more to the good as time goes on? Or are future people to be given equal respect to those alive today? In which case should we be prepared to sacrifice some today to save millions tomorrow? Does equal respect require equal access to effective antibiotics? The series of talks was then concluded by Dr Ellen Silbergeld, who gave a presentation on the unacknowledged literal and conceptual holes in our ways of thinking about sources and pathways of AMR that lead to inaccurate assessments and incomplete and potentially erroneous research and policies. Dr Silbegeld mentioned that AMR has long been focused on clinical aspects of drug use and emergence of AMR in clinically important pathogens. However, little attention has been paid to AM use and AMR in food animal production, of what we now recognize as the largest use of antimicrobials on an increasingly global scale. Concluding that, a lack of research in larger resistance reservoirs such as the overall environment and use of growth promoters in food production are currently leading us to build an incomplete picture of AMR.
Recordings of all the presentations can be found here and bios on all the speakers can be found here

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