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Coen van Hasselt

Antimicrobial resistance of bacterial infections is widely recognized as a serious public health risk. Developing novel antibiotics has proven to be highly challenging, so it is urgently required to find alternative strategies to combat resistant bacterial infections. According to Coen van Hasselt, further development of resistance can be prevented or delayed by redesigning dosing schedules for existing antibiotics.

Re-designing dosing schedules of antibiotics to prevent treatment resistance

‘When a bacterial infection is treated with antibiotics, there is always a risk that bacteria, which try to survive the attack, develop resistance’, Coen van Hasselt points out. ‘In various bacterial strains, that may cause severe infections, resistance against commonly used antibiotics is rapidly increasing.’ Infections with such multi-resistant strains become increasingly difficult or sometimes even impossible to treat, which may be fatal in patients. Van Hasselt: ‘Recently, a large study predicted that by 2050, more than ten million people worldwide may die from infections with such resistant pathogens. To date, the quest for new antibiotics to treat such infections has failed to yield enough really new agents.’

Still, the situation may be less hopeless than it seems. Van Hasselt states that much is to be gained by re-thinking how we use those antibiotics that are still effective. By optimising and individualising the dosage regimen for each patient, effectiveness of antibiotic treatments can be maintained while development of resistance can be slowed down or even avoided. In this way, the effectiveness of currently available antibiotics can be preserved for much longer.

‘So far, research on antibiotic dosing schedules has focused mainly on finding a dose regimen that kills most bacteria, but it has largely ignored whether and how fast these regimens induce development of resistance in micro-organisms. Often, only studies that investigate the effect of a 24 hour exposure to an antibiotic are considered. These experiments cannot show emergence of resistance that may occur during the treatment of infections in patients during a longer period.’

'We hope that by using our approach to find optimal dosing regimens, we can preserve the antibiotics for the effective treatment of future patients’

Van Hasselt proposes a more comprehensive approach in assessing dosage regimens. ‘We try to consider the actual concentration of antibiotics at the site of infection, and the role of the immune system. We also very carefully study what happens to populations of bacteria during antibiotic treatment schedules in patients. We develop mathematical models that capture these phenomena; they can be used to derive personalised treatments for individual patients. This model-based approach is powerful, because it allows integration of knowledge of fundamental pharmacological mechanisms with actual data from patients.’

After starting his group, Van Hasselt moved from performing purely computational research to also including ‘wet lab’ experiments. ‘We have designed our own experimental setup where we can cultivate pathogenic bacteria and simulate dosing schedules that are in use in patients. In this way, we aim to understand how resistant subpopulations of bacteria emerge or are suppressed during different dosing regimens, and also during treatments with combinations of antibiotics. Data gained from these experiments can be used to optimise mathematical model predictions for resistance.’

One recent study by his group focused on the antibiotic colistin, a last-resort antibiotic that is used to combat multi-drug-resistant pathogens. ‘In our models and experiments, we found that the standard dosing schedules of colistin rapidly lead to resistance in the clinically important pathogen Klebsiella pneumoniae. However, our results indicate that alternative dosage regimens can strongly suppress the emergence of resistance. We hope that by using our approach to find optimal dosing regimens, we can preserve the antibiotics for the effective treatment of future patients’, van Hasselt concludes.

Biography

After studying Bio-Pharmaceutical Sciences at Leiden University, pharmacologist Coen van Hasselt (1984) performed his PhD research at the Netherlands Cancer Institute in Amsterdam. He then worked at the Icahn School of Medicine at Mount Sinai in New York, supported by a Marie Curie postdoctoral fellowship. In 2018, he returned to Leiden as an assistant professor and started his own research group. Van Hasselt develops mathematical models that describe drug concentrations in the human body and their effects on disease, by combining biological knowledge of drug action with clinical data from patients.

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