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Lancet Infect Dis. Author manuscript; available in PMC 2017 October 01. Published in final edited form as: Lancet Infect Dis. 2016 October ; 16(10): 1111–1112. doi:10.1016/S1473-3099(16)30340-1.

Authors reply: Fluconazole Pharmacokinetics in Human Cryptococcal Meningitis Joshua Rhein1,2, Kirsten Nielsen1, David R. Boulware1, and David B Meya2 1University

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of Minnesota, Minneapolis, MN, USA 2Infectious Disease Institute, Makerere University, Kampala, Uganda We agree with Veringa and colleagues regarding the importance of pharmacologic analyses in assessing antifungal efficacy for cryptococcal meningitis. Yet, we caution in translating single drug pharmacologic analysis to combination therapy. Fluconazole 800 mg/day monotherapy for induction cryptococcal meningitis therapy has poor outcomes as fluconazole’s area under the curve (AUC) exposure is suboptimal with respect to the Cryptococcus minimum inhibitory concentration (MIC).1 This concern is certainly justified in our setting, where we have observed decreasing fluconazole susceptibility. In our recent analysis that included the first 95 of the 128 Cryptococcus isolates reported in our trial,2 only 25% had MICs below ≤ 2μg/mL breakpoint, 47% ≤4μg/mL, and 78% ≤8μg/mL.3

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Our sertraline study, however, examined the use of combination induction therapy with amphotericin B, fluconazole, and sertraline. We did measure plasma samples (n=99) between day 7 and 28 while receiving fluconazole 800mg/day (Figure). The median plasma level was 37 μg/mL (IQR, 24 to 51, 95th percentile 72) at steady state equating to median AUC of 990 μg*hr/mL (IQR, 720 to 1260). Day 14 fluconazole CSF concentrations (n=39) were similar to plasma; median 39 μg/mL (IQR, 28 to 53, 95th percentile 69) with CSF being a median 90% (IQR, 68% to 115%) of steady state plasma levels (n=24). Among 69 participants, the median fluconazole AUC/MIC ratio was 178 (IQR, 91 to 410) with only 26% (18/69) of participants having AUC/MIC ratio >389. Consistent with previous reports of additive interactions between fluconazole and sertraline,4 checkerboard synergy testing of nine isolates showed bi-directional reduction of MICs for fluconazole and sertraline. With fluconazole, sertraline MICs decreased 2-fold (range 1–5). Similarly, with adjunctive sertraline, we observed a 2-fold (range 1–8) reduction in fluconazole MIC, theoretically doubling the AUC/MIC ratio to a median of 356 with 43% (30/69) having >389 ratio. Assuming linear pharmacokinetics,1 with 1200mg/day fluconazole and 2-fold MIC reduction with adjunctive sertraline, only 64% (44/69) would reach fluconazole AUC/MIC ratio >389. Fluconazole AUC/MIC ratio was not associated with survival (P=0.57). Antifungal pharmacologic models have focused on drug exposure and MICs during induction therapy, and the predictive value in other stages of cryptococcal infection/disease

Corresponding Author: Joshua Rhein, Division of Infectious Diseases & International Medicine, Department of Medicine, University of Minnesota, MMC 250, 420 Delaware St SE, Minneapolis, MN 55455 USA. [email protected]. We declare no competing interests.

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are unknown. Possibly, the adjunctive sertraline benefit is most consequential during consolidation fluconazole monotherapy. An all oral regimen for cryptococcosis would offer tremendous advantages, particularly for asymptomatic antigenemia preemptive treatment where fluconazole monotherapy is inadequate.5 Randomized trials utilizing new, all-oral treatment regimens for cryptococcosis are urgently needed as are nested pharmacokinetic analyses.

References

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1. Sudan A, Livermore J, Howard SJ, et al. Pharmacokinetics and pharmacodynamics of fluconazole for cryptococcal meningoencephalitis: implications for antifungal therapy and in vitro susceptibility breakpoints. Antimicrobial agents and chemotherapy. 2013; 57(6):2793–800. [PubMed: 23571544] 2. Rhein J, Morawski BM, Hullsiek KH, et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. The Lancet infectious diseases. 2016; 16(7):809–18. [PubMed: 26971081] 3. Smith KD, Achan B, Hullsiek KH, et al. Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda. Antimicrobial agents and chemotherapy. 2015; 59(12): 7197–204. [PubMed: 26324276] 4. Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrobial agents and chemotherapy. 2012; 56(7):3758–66. [PubMed: 22508310] 5. Morawski, BM., Boulware, DR., Nalintya, E., et al. Pre-ART Cryptococcal Antigen Titer Associated With Preemptive Fluconazole Failure. Conference on Retroviruses and Opportunistic Infections (CROI); Boston, MA. 2016.

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luconazole plasma concentrations over 28 days when receiving fluconazole 800 mg/day for cryptococcal meningitis in Uganda. Fluconazole mean (±SD) levels increased from 30 (±14) μg/mL at 7 days to 41 (±14) μg/mL at 14 days to 52 (±19) μg/mL at 28 days, reflecting further accumulation due to a long halflife.

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Sertraline for HIV-associated cryptococcal meningitis - Authors' reply.

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