Effect of oral fluconazole 1200 mg/day on QT interval in African adults with HIV-associated cryptococcal meningitis

Molloy, Síle F.; Bradley, John; Karunaharan, Natasha; Mputu, Muhammad; Stone, Neil; Phulusa, Jacob; Chawinga, Chimwemwe; Gaskell, Katherine M; Segula, Dalitso; Ming, Damien; Peirse, Mary; Chanda, Duncan; Lakhi, Shabir; Loyse, Angela; Kanyama, Cecilia; Heyderman, Robert S.; Harrison, Thomas S.

doi:10.1097/qad.0000000000001961

Cited by 5 publications

(5 citation statements)

References 6 publications

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“…Notably, multiple organ dysfunction syndrome, cholestasis, liver injury, QT interval prolonged, aspergillus infection and renal impairment were the 6 PTs mentioned in the signal spectrum for all the TAD. The QT interval prolongation caused by TAD has been reported in the recent articles ( Molloy et al, 2018 ; Yu and Liao, 2022 ), and the results of our study are consistent with it.…”

Section: Resultssupporting

confidence: 93%

Pharmacovigilance of triazole antifungal agents: Analysis of the FDA adverse event reporting system (FAERS) database

Zhou

Wei

et al. 2022

Front. Pharmacol.

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Triazole antifungal drugs (TAD) are widely used to treat invasive fungal infections due to their broad antifungal spectrum and low toxicity. Despite their preference in the clinic, multiple Adverse Events (AE) are still reported each year. Objective: We aimed to characterize the distribution of Adverse Events associated with Triazole antifungal drugs in different systems and to identify Important Medical Events (IME) signals for Triazole antifungal drugs. Methods: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) was queried for Adverse Events related to Triazole antifungal drugs from 2012 to 2022. The Adverse Events caused by all other drugs and non-TAD antifungal drugs were analyzed as references. Reporting odds ratio and Bayesian confidence propagation neural network of information components were used to evaluate the association between Triazole antifungal drugs and Important Medical Events. Visual signal spectrum is mapped to identify potential adverse reaction signals. Results: Overall, 10,262 Adverse Events were reported to be associated with Triazole antifungal drugs, of which 5,563 cases were defined as Important Medical Events. Common adverse drug reactions (ADR) mentioned in the instructions such as delirium and hypokalemia were detected, as well as unlabeled ADRs such as rhabdomyolysis and hepatitis fulminant. Cholestasis, drug-induced liver injury, QT interval prolongation and renal impairment have notable signals in all Triazole antifungal drugs, with 50 percent of patients developing a severe clinical outcome. Isavuconazole had the lowest signal intensity and demonstrated a superior safety profile. Conclusion: Most results are generally consistent with previous studies and are documented in the prescribing instructions, but some IMEs are not included, such as hepatitis fulminant. Additional pharmaco-epidemiological or experimental studies are required to validate the small number of unlabeled ADRs. TAD-related Important Medical Eventshave a considerable potential to cause clinically serious outcomes. Clinical use of Triazole antifungal drugs requires more attention.

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Section: Resultssupporting

confidence: 93%

Pharmacovigilance of triazole antifungal agents: Analysis of the FDA adverse event reporting system (FAERS) database

Zhou

Wei

et al. 2022

Front. Pharmacol.

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“…Recognised side effects include thromboembolic disease and retinopathy (although the risk of these is low with short duration treatment) and QT prolongation of the cardiac cycle . QT prolongation might be expected to be a particular risk as doses are increased, especially when combined with fluconazole, which can also cause this conduction abnormality, and disordered serum electrolytes, frequently seen in cryptococcal disease as a consequence of amphotericin therapy and intracranial pathology . Any study would need to pay close attention to these risks, and a trial is underway in Vietnam (Clinicaltrials.gov NCT03112031).…”

Section: Discussionmentioning

confidence: 99%

The combination of tamoxifen with amphotericin B, but not with fluconazole, has synergistic activity against the majority of clinical isolates of Cryptococcus neoformans

Hai

Van

Ngan

et al. 2019

Mycoses

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Summary Background Cryptococcal meningitis has fatality rates of 40%‐70%, resulting in 200 000 deaths each year. The best outcomes are achieved with amphotericin combined with flucytosine but flucytosine is expensive and unavailable where most disease occurs. More effective and affordable treatments are needed. Tamoxifen, a selective oestrogen receptor modulator frequently indicated for breast cancer, has been found to have synergistic activity against the Cryptococcus neoformans type strain when combined with amphotericin or fluconazole. It is cheap, off‐licence, widely available and well‐tolerated, and thus a pragmatic potential treatment for cryptococcal disease. Objectives We wanted to determine the susceptibility of clinical isolates of C. neoformans to tamoxifen alone and in combination with other antifungals, to determine whether there is sufficient evidence of activity to justify a clinical trial. Methods We used the CLSI broth microdilution protocol to test the susceptibility of 30 randomly selected clinical isolates of C. neoformans to tamoxifen, in dual combination with amphotericin, fluconazole or flucytosine, and in triple combination with amphotericin and fluconazole. Evidence of drug interactions was assessed using the fractional inhibitory concentration index. Results The MIC50 and MIC90 of tamoxifen were 4 and 16 mg/L, respectively. The combination of tamoxifen and amphotericin suggested a synergistic interaction in 20 of 30 (67%) isolates. There was no interaction between tamoxifen and either fluconazole or flucytosine. Synergy was maintained in 3‐Dimensional chequerboard testing. There was no evidence of antagonism. Conclusions Tamoxifen may be a useful addition to treatment with amphotericin and fluconazole for cryptococcal meningitis; a trial is justified.

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“…It is worth highlight that azithromycin, among others antimicrobials, show electrophysiological effects similar to class III antiarrhythmic drugs (MARTINS et al, 2015) and fluconazole may prolong the QT interval, either directly or by inhibiting the hepatic metabolism of other agents that have direct action under this signal, such as atazanavir an antiretroviral drug involved in treatment of HIV infections (Molloy, et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Intrabases divergences in the mHealth era: a drug interaction investigation in an infectious-diseases hospital setting

Souza

Silva

Cascão

et al. 2021

RSD

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Introduction: Information on potential drug interactions (PDI) are obtained from databases available on the web or through mobile healthcare applications (mHealth), and can prevent unfavorable clinical outcomes for patients. This study compared PDI information available in Micromedex® drug interaction checker, its web version and its mHealth app. Method: A cross-sectional study realized based on a retrospective review of drug prescriptions in a reference hospital in infectology in the Midwest Region of Brazil, 2018. We selected all prescriptions containing two or more drugs. Drugs were classified according to the first level of the Anatomical Therapeutic Chemical (ATC) classification, according to the route of administration and the number of drugs prescribed. PDIs were classified according to the severity system and four-level evidence classification system. Results: This study selected 72 patients, predominantly male, median age of 38 years, average length of stay of 15.8 days, and most diagnosed with HIV/AIDS. The most frequently prescribed anatomical groups according to ATC were digestive system and metabolism (22.1%) and general anti-infectives for systemic use (21.6%). The average number of drugs per prescription was 10.8 (SD±6.7). The Micromedex® mHealth app found 381 PDIs while its web version detected 502 PDIs, with an average of 5.3 and 7.0 and frequency of 61.1% and 72.2%, respectively. According to the severity classification in mHealth and web versions, the following stood out, respectively: 221 and 321 severe; 139 and 149 moderate. The majority (>65%) of identified PDIs had their documentation classified as reasonable. Conclusion: Digital tools although they aid decision-making, are not unanimous and consistent in detecting such interactions.

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Effect of oral fluconazole 1200 mg/day on QT interval in African adults with HIV-associated cryptococcal meningitis

Cited by 5 publications

References 6 publications

Pharmacovigilance of triazole antifungal agents: Analysis of the FDA adverse event reporting system (FAERS) database

Pharmacovigilance of triazole antifungal agents: Analysis of the FDA adverse event reporting system (FAERS) database

The combination of tamoxifen with amphotericin B, but not with fluconazole, has synergistic activity against the majority of clinical isolates of Cryptococcus neoformans

Intrabases divergences in the mHealth era: a drug interaction investigation in an infectious-diseases hospital setting

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