Soil-transmitted helminthiases, one of 21 neglected tropical diseases, affects over a billion people worldwide. Noteworthy, soil-transmitted helminthiases encompasses the pathologies caused by one or more members of a group of parasitic worms colonizing the human gut. The soil-transmitted helminths (STHs) include a broad range of parasites, namely the roundworm Ascaris lumbricoides, the threadworm Strongyloides stercoralis, the whipworm Trichuris trichiura, and the two hookworms Ancylostoma duodenale and Necator americanus. Depending on the parasite species and severity of infection, symptoms differ. A heavy infection may include symptoms such as intestinal obstructions (A. lumbricoides), rectal prolapse (T. trichiura) and severe anemia (hookworms). Several commonalities legitimize the conflation under one umbrella-term. For instance, all STHs require a part of their development period in soil. Furthermore, STH infections mainly occur in the southern hemisphere and disproportionally affect people in resource-limited settings. Lastly, one commonality lies in the administered drugs to fight these parasite infections. While long-term disease prevention focuses on improving hygiene and sanitation, the short-term remedy lies in chemotherapy, and specifically mass drug administration (MDA) of albendazole and mebendazole.

MDA is a population-based approach in endemic regions, where people receive treatment without prior diagnosis. In the case of soil-transmitted helminthiases, MDA focuses primarily on children. There are multiple problems with this approach. Firstly, MDA currently relies on drug donations, which can be difficult to negotiate and pharmaceutical companies are considering an end to these donations. Secondly, untreated adults could might not only suffer from infections but also contribute to transmission and re-infection in endemic areas. Thirdly, species-level parasite epidemiology is heterogeneous, and, drug efficacies against the varying parasites differ. For instance, albendazole and mebendazole possess a low efficacy against T. trichiura, thus these drugs are not able to effectively reduce the burden and prevalence of T. trichiura infections. Lastly, repeated, population-based treatment without prior diagnosis could not only result in the development of drug resistance but also favor the occurrence of severe off-target effects, i.e. the unintended direct or indirect effects of a drug on a secondary target. A possible secondary target of anthelminthics could be gut bacteria, as they share their habitat in the human host’s intestine with the parasites. In contrast to the parasites, the majority of gut bacteria make up an indispensable part of our gastrointestinal tract aiding in digestion, providing protection against pathogens and stimulating immune responses. Therefore, we do not want to target those commensal helpers unintentionally.

Just like albendazole and mebendazole, ivermectin is used in MDA programs to reduce the burden of lymphatic filariasis and onchocerciasis, two additional neglected tropical diseases. In addition to this broad usage, ivermectin has been recommended as a partner-drug of albendazole, potentially finding its way into STH MDA programs to broaden treatment efficacy against T. trichiura. Moxidectin is registered for onchocerciasis and might be used in combination with albendazole for STH infections in the future. In our study, we found that ivermectin and moxidectin inhibit growth of a broad range of bacteria. These findings sound alarming, because they suggest that these drugs have the potential to disturb the balance in a healthy human gut. However, our findings originate from direct interaction tests, meaning that the bacteria and drugs were simply combined in a test tube. In humans, many more factors are at play. Diet, intake of other drugs, inflammation status, composition of the bacteria in the gut – just to name a few. Therefore, it would be premature, to sign this off as a confirmed off-target effect of these drugs in a real-world scenario.

1.5 years ago, during the defense of my master’s thesis, I was asked whether including ivermectin and moxidectin in MDA programs would be a worthwhile approach to fight STH infections. You can imagine that I was quite overwhelmed, given the complexity of the problem, the drawbacks of MDA campaigns and my data at hand. Fast forward 1.5 years and I can try to give you a short and a more extensive answer. The short answer is yes. The long answer starts with the fact that bacteria are simple biological entities, yet truly fascinating.

Bacteria are evolutionarily old. Very old. Over time, many bacterial species managed to make themselves at home in incredibly harsh habitats – imagine the bacterial communities that manage to survive in the depths of the Mariana Trench or bacteria overcoming the competitive and complex environment in the human gut. Simply put, bacteria are extremely adaptable. Let us assume this bacterial growth inhibition presented in the study actually takes place in the guts of humans, repeatedly treated with ivermectin and moxidectin in MDA campaigns. We can boldly assume that at some point bacteria should adapt to this selective pressure and develop mechanisms to conquer yet this challenge. Our second key finding suggests, that adaptation to ivermectin and moxidectin could actually take place. The next big question is “how”?

One possibility is to alter the biological machinery to allow for the degradation of the drug (e.g. ivermectin or moxidectin). Sadly, the adapted bacteria are not the sole beneficiaries of this evolutionary stunt. The parasite, the primary target of the drug, could thrive again with the drug neutralized. Simply put, such an adaptation could lower the treatment efficacy of ivermectin and moxidectin for STH infections, because we force bacteria to adapt to a drug that was not primarily targeted at them and they cope with this by degradation of the drug. Depending on the specificity of the employed adaptation mechanism, the biological consequences might have a wider range. For instance, resistance to one drug might infer cross-resistance to a structurally similar drug. In the case of ivermectin and moxidectin, supported by data presented in our study, this could include the antibiotic family called macrolides. Antibiotic resistance mechanisms are known to spread rapidly amongst bacteria, and, antibiotic resistant bacteria present one of the prime problems that public health is facing. It is therefore indispensable to also investigate and monitor this potential off-target effect closely.

I mentioned numerous drawbacks to MDA programs, but the control method is certainly not all bad. For one, MDA is cost-effective and targets the most vulnerable part of the population. A recent paper by Emerson P.M. et al. states a decline in infection burden and morbidity caused by STH infection between the years 2000 and 2019. According to the authors, this is attributable to the improvement of hygiene and sanitation, but also the efforts in regularly conducted MDA campaigns. However, the old, trusty workhorse might need some upgrades soon. With declining parasite prevalence, the focus of these campaigns needs to become more targeted to further advance towards disease elimination. Amongst other measures, this means increasing efforts in surveillance of disease epidemiology, and based on that, administering the right drugs targeted at the most prevalent parasite species in the corresponding region¹. This paradigm-shift will take time and until then MDA, with efforts towards a more targeted approach, is probably the best option in resource-limited settings. Towards elimination, there will therefore also be a demand for new or repurposed, efficacious drugs and drug combinations adequately targeting all STH species. This includes ivermectin and moxidectin. However, I would additionally propose to monitor potential off-target effects of these broadly used drugs closely. 

Sadly, there is no silver bullet to fight STH infections. Just as bacteria adapt to their environments, we need to adapt dynamically to the many issues we encounter. It requires a combination of efforts and strategies – and most of all – time. To a world without parasitic worms – I will keep you posted!

References

1. Emerson, P. M. et al. Need for a paradigm shift in soil-transmitted helminthiasis control: Targeting the right people, in the right place, and with the right drug(s). PLoS Negl. Trop. Dis. 18, e0012521, doi:10.1371/journal.pntd.0012521 (2024).

Photo Credit: Eveline Hürlimann