Independent Association between Rate of Clearance of Infection and Clinical Outcome of HIV‐Associated Cryptococcal Meningitis: Analysis of a Combined Cohort of 262 Patients

Abstract

The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.

Poor long-term outcomes for cryptococcal meningitis in rural South Africa

“…5 High fungal burden is associated with mortality; our high rate of India ink positivity and reduced consciousness suggest advanced disease at presentation. 12 Sub-optimal induction therapy and management of CSF pressure might have contributed to high inpatient mortality, although we could not confirm this. Amphotericin B treatment was uncommon, mainly owing to drug supply problems, in accordance with national-level data showing that more than half of CM cases receive sub-optimal induction treatment.…”

Refractory and/or Relapsing Cryptococcosis Associated with Acquired Immune Deficiency Syndrome: Clinical Features, Genotype, and Virulence Factors of Cryptococcus spp. Isolates

“…2,27 It was observed in African and Asian patients that persistent infection is one of the factors related to death within 10 weeks of treatment. 28 Uncontrolled intracranial hypertension and secondary bacterial infection during antifungal treatment were the main causes of death of the 14 patients of the cohort studied (data not shown). The seriousness of refractory and/or relapsing cases also had an impact on the six patients who were cured, since 5/6 patients showed neurological sequelae.…”

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

“…Second, traditional growth assays are not useful for identifying molecules active against fungal biofilms, a medically important growth phase of these pathogens (Pierce et al 2008;LaFleur et al 2011;Srinivasan et al 2013). Third, traditional growth assays are unable to distinguish between molecules that inhibit growth and those that directly kill the organism, a feature that is particularly important for the treatment of some fungi (e.g., Cryptococcus) (Bicanic et al 2009). …”

“…In principle, fungicidal molecules would appear to be preferred over fungistatic agents because most patients with invasive fungal infections have compromised immunity and, thus, are more dependent on the antifungal agent to clear infections. In the setting of cryptococcal meningitis (Bicanic et al 2009), early fungicidal activity has been shown to correlate with clinical outcome, providing a mechanism for the superiority of fungicidal amphotericin B -based therapy when compared with treatment with fungistatic fluconazole. A second type of viability assay has been applied to the specific identification of fungicidal agents: the detection of extracellular adenylate kinase as a reporter of cell lysis (DiDone et al 2010).…”