The standard-of-care is to use intravenous antifungal agents for 2 weeks. The best antifungal drug is amphotericin B, which is highly potent, but also toxic and causes a multitude of side effects, some of which are serious.
The administration of amphotericin B for a prolonged period is infeasible in the health care settings where cryptococcal meningitis is most frequent. There are simply inadequate resources to enable this to be done safely. Thus, alternative approaches are required.
The Antimicrobial Pharmacodynamics and Therapeutics laboratory has been studying innovative ways that amphotericin B can be used in health care settings. We asked the question whether very short courses of therapy result in the same antifungal effect as standard daily therapy. We used well-characterised laboratory animal models of cryptococcal meningitis in mice and rabbits to test this idea.
We have studied two formulations of amphotericin B: amphotericin B deoxycholate and liposomal amphotericin B. For both agents, the results were strikingly similar. One-to-three dosages produced the same antifungal effect as daily therapy over a 2-week period. We published this work in leading peer-reviewed medical journals.
The findings from this experimental work are now being tested in patients from Africa with cryptococcal meningitis. The results from a clinical trial were presented at the CROI meeting in Seattle in 2017. Preliminary results from patients with cryptococcal meningitis receiving a single shot of amphotericin B appeared to be the same as patients receiving the standard daily therapy.
The results from this preliminary trial have been used to design the largest clinical trial on cryptococcal meningitis that has ever been performed with over 800 patients being enrolled. This trial has been funded by the EU and opened for enrollment in the latter part of 2017.
This case study is an exemplar of the use of laboratory animal models to provide the vital underpinning evidence for clinical trials. Without this evidence, the clinical trials are too risky to conduct and cannot proceed. Findings from both mice and rabbits predicted the response to patients and is a testament to the value of laboratory animal models for defining new treatments for lethal untreatable human infectious diseases.
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