Treatment of Cryptococcal Meningitis: How Have We Got Here and Where are We Going?

Abstract

Cryptococcal meningitis is a devastating brain infection cause by encapsulated yeasts of the Cryptococcus genus. Exposure, through inhalation, is likely universal by adulthood, but symptomatic infection only occurs in a minority, in most cases, months or years after exposure. Disease has been described in almost all tissues, but it is the organism's tropism for the central nervous system that results in the most devastating illness. While invasive disease can occur in the immunocompetent, the greatest burden by far is in immunocompromised individuals, particularly people living with human immunodeficiency virus (HIV), organ transplant recipients and those on glucocorticoid therapy or other immunosuppressive drugs. Clinical presentation is variable, but diagnosis is usually straightforward, with cerebrospinal fluid microscopy, culture, and antigen testing proving significantly more sensitive than diagnostic tests for other brain infections. Although disease incidence has reduced since the advent of effective HIV therapy, mortality when disease occurs remains extremely high, and has changed little in recent decades. This Therapy in Practice review is an update of a talk first given by JND at the European Congress on Clinical Microbiology and Infectious Diseases in 2019 in the Netherlands. The review contextualizes the most recently published World Health Organization (WHO) guidelines for the treatment of HIV-associated cryptococcal meningitis in terms of the data from large, randomized, controlled trials published between 1997 and 2022. We discuss the rationale for induction and maintenance therapy and the efficacy and undesirable effects of the current therapeutic armamentarium of amphotericin, flucytosine and fluconazole. We address recent research into repurposed drugs such as sertraline and tamoxifen, and potential future treatment options, including the novel antifungals fosmanogepix, efungumab and oteseconazole, and non-pharmaceutical solutions such as neurapheresis cerebrospinal fluid filtration.

Fig. 1

India ink stain of Cryptococcus neoformans cells showing extensive capsule development and characteristic budding of daughter cells. Cell diameters excluding capsule are 5–10 um across

Fig. 2

Key clinical trials in the management of cryptococcal meningitis. AmB amphotericin B, 5FC flucytosine, CM cryptococcal meningitis, CSF cerebrospinal fluid, 14d 14 days

Fig. 3

Treatment arms of the ACTA trial. Principle comparisons were between arm 1 versus arms 4 and 5 (the oral vs intravenous induction treatment strategy), and arms 2 and 3 versus arms 4 and 5 (1 week vs 2 weeks of amphotericin strategy). After induction therapy (the first 2 weeks), all patients received fluconazole 800 mg/day consolidation therapy until 10 weeks after randomization

Fig. 4

Strategies to improve treatment of cryptococcal meningitis. AmB amphotericin, CSF cerebrospinal fluid, HSP90 heat shock protein 90