Predictors of Therapy Outcomes for Cryptococcal Meningitis: Failure of In Vitro Susceptibility Testing, Success of Early Fungicidal Activity
By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
Dr. Deresinski reports no financial relationships relevant to this field of study.
SYNOPSIS: Although in vitro susceptibility testing failed to have value in predicting therapeutic outcome in patients with cryptococcal meningitis, detection of a rapid decline in fungal density in cerebrospinal fluid was associated with improved outcomes in a separate study.
SOURCES: O’Connor L, Van Anh D, Chau TTH, et al. Antifungal susceptibility does not correlate with fungal clearance or survival in AIDS-associated cryptococcal meningitis. Clin Infect Dis 2020; Oct. 14:ciaa1544. doi: 10.1093/cid/ciaa1544. [Online ahead of print.]
Pullen MF, Hullsiek KH, Rhein J, et al. Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in clinical trials. Clin Infect Dis 2020;71:e45-e49.
O’Connor and colleagues examined the ability of in vitro susceptibility testing to predict the outcome of treatment of cryptococcal meningitis using data from a previously reported open-label, randomized clinical trial.1 In that trial, patients with acquired immunodeficiency syndrome (AIDS) were randomized to initially receive amphotericin B alone for four weeks, amphotericin B plus flucytosine for two weeks, or amphotericin B plus fluconazole for two weeks — each followed by fluconazole alone to complete 10 weeks of therapy. The combination of amphotericin B and flucytosine was associated with a survival benefit relative to the other regimens, and fluconazole did not significantly add to that seen with amphotericin B alone. The amphotericin B plus flucytosine combination also was associated with more rapid cryptococcal clearance from cerebrospinal fluid (CSF).
Two hundred sixty-nine patients were included in the study. The Sensititre YeastOne minimum inhibitory concentration (MIC) breakpoints used for the analysis were: amphotericin B, ≤ 0.512 mcg/mL; flucytosine, ≤ 4 mcg/mL; fluconazole, ≤ 8 mcg/mL. An examination of the hazard ratios found no consistent trend of individual MICs in relation to 70-day survival. Similarly, there was no apparent relationship between mortality and categorization of isolates as either susceptible or non-susceptible. This was true even when limiting the evaluation to patients with high baseline fungal loads: > 6 × 106 colony forming units/mL of CSF. There also was no association between MICs and a reduction in fungal CSF load after 14 days of therapy.
Separately, Pullen and colleagues examined data from three Phase II clinical trials of treatment of 738 AIDS patients with cryptococcal meningitis, all of whom received induction therapy with amphotericin B plus fluconazole. Their purpose was to examine the predictive value of early fungicidal activity (EFA) with regard to mortality. EFA was determined by serial examination of CSF with determination of the reduction in cryptococcal density over the first 10 days of therapy. In vitro susceptibility testing was not reported. Patients with a decrease in CSF of < 0.20 log10 CFU/ day had an 18-week mortality rate of 50% compared to 37% in those with greater decreases in CFU density. The hazard ratio for mortality associated with an EFA < 0.20 was 1.60 (95% confidence interval [CI], 1.25-2.04; P = 0.002). However, this group had confounding factors with lower CD4 counts and lesser CSF pleocytosis.
The question of the ability of in vitro susceptibility results to predict the response to chemotherapy of cryptococcal meningitis has been addressed previously, but no definitive answer has been forthcoming. One likely reason for this failure has been the use of a variety of non-standard susceptibility testing methods. Both Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommend broth microdilution as the standard method for testing Cryptococcus spp., but the results obtained with Sensititre YeastOne, which was used by O’Connor et al, correlates well with the standard method and was used in this study.
The lack of predictive value of in vitro susceptibility testing may be the result of a variety of factors, such as the complexity of the host response and complications of meningitis such as CSF obstruction that may be more the result of the inflammatory response than to organism replication. In addition, the potent activity and limited MIC range of amphotericin B, which was received by all the patients, may have primarily dictated the outcomes.
In contrast, Pullen et al found that EFA, a measure that could be considered an in vivo susceptibility test, had predictive value regarding the therapeutic outcome and also validated the use of EFA as a surrogate marker in clinical trials, although host factors may have affected the outcomes. It should be noted that O’Connor and colleagues had failed to find a correlation between MIC and EFA, a finding, which taken together with the results of Pullen and colleagues, further indicates the lack of value of MIC determinations in cryptococcal meningitis.
- Day JN, Chau TTH, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013;368:1291-1302.
Although in vitro susceptibility testing failed to have value in predicting therapeutic outcome in patients with cryptococcal meningitis, detection of a rapid decline in fungal density in cerebrospinal fluid was associated with improved outcomes in a separate study.
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