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“While the pandemic hit the world, the AMR crisis remained silent,” says Antonio Felici, VP Anti-Infectives of the drug discovery and development company Evotec. “Nevertheless, it is progressing and the emergency and spread of multidrug resistance is putting our existing antibiotic arsenal under increasing threat.”
In the battle against AMR, researchers are exploring innovative ways to get new drugs to the market. The in vitro Hollow Fibre Infection Model (HFIM) plays an important role in this process, helping both the characterization of new drugs and drug combinations, and the push to get them through clinical trials to approval.
The key to de-risking and expediting the development of new antimicrobial drugs is understanding the relationship between exposure to an antimicrobial compound (pharmacokinetics; PK), and the impact of that exposure on the target microbe (pharmacodynamics; PD). This understanding allows for optimized drug dosing to achieve efficacy and avoid resistance, which minimizes the risk of clinical trial failure.
Typically, this knowledge is gained in a series of in vivo models, mostly mice or rats. However, there are practical and ethical reasons to replace or refine these models with in vitro studies in the HFIM. This is particularly necessary when the nature of the micro-organism studied does not allow the establishment of in vivo models. It can also occur if the drug under investigation has tolerability issues in rodents, or if the PK of the investigational drug in rodents is very different from the expected PK in humans. An additional advantage of the HFIM over in vivo studies is that more compound combinations can be easily tested — an important aspect of the development of some antimicrobial dosing regimens.
“HFIM is the key to understanding the effect of drug treatment on the microbial population with any chosen PK profile,” says Pia Thommes, VP Anti-Infectives, Evotec. “Only with this understanding will we mitigate the risk of clinical trial failure and ultimately extend the clinical utility of the antimicrobials in the face of increasing AMR”.
Evotec has produced a white paper that describes the technical aspects of HFIM, and how it can be used in the development of antimicrobial therapies including multiple drug combinations. Advantages of the system include its ability to support the growth of organisms to high densities in continuous culture, and how it can also support long-duration experiments with multiple distinctive drug-infusion profiles. For example, studies using HFIM have found that a combination of levofloxacin and imipenem prevented the emergence of drug resistance in clinical isolates of Pseudomonas aeruginosa, even when subpopulations resistant to both drugs were present.1 Research also revealed that combinations of ampicillin, fosfomycin and ciprofloxacin delayed the emergence of antibiotic resistance in Escherichia coli.2
Evotec’s bespoke in vitro PK/PD capabilities using HFIM complement its in vivo expertise, and are tailored to individual antimicrobial development programmes including against Mycobacterium tuberculosis and fungi. New HFIMs can be established from strains in Evotec’s EVOstrAIn™. This collection of more than 8,000 reference and clinical isolates, possessing a wide range of antimicrobial profiles, mirror what may be encountered in a real-world setting and are relevant to required target product profiles.
“The HFIM is an important part of the advanced toolbox to enhance our understanding of the PK/PD relationship of novel antibiotics and de-risk their path into the clinic” says Thommes.