Examination of Fluconazole-Induced Alopecia in an Animal Model and Human Cohort

Thompson, George R.; Krois, Charles R.; Affolter, Verena K.; Everett, Angela; Varjonen, Eeva; Sharon, Victoria R.; Singapuri, Anil; Dennis, Michael; Mchardy, Ian Howard; Yoo, Hong Sik; Fedor, Dawn M.; Wiederhold, Nathan P.; Aaron, Phylicia; Gelli, Angela C; Napoli, Joseph L.; White, Stephen D.

doi:10.1128/aac.01384-18

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…Of note, significant hair loss requiring treatment interruption was not observed in any of the patients in our study, despite its having been a feature in a number of patients previously on triazole therapy. Although the exact mechanism of azole-mediated hair loss is unclear, voriconazole and itraconazole have been found to inhibit CYP26A1-mediated hydroxylation of retinoic acid in vitro at concentrations of >1 µM [44], with alopecia reported due to itraconazole, voriconazole, and posaconazole. Resultant hair loss due to azoles can cause many patients to stop treatment due to the negative impact on self-esteem, mental health, and social interactions.…”

Section: Discussionmentioning

confidence: 99%

Experience of Isavuconazole as a Salvage Therapy in Chronic Pulmonary Fungal Disease

Nwankwo

Gilmartin

Matharu

et al. 2022

JoF

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Background: Instances of resistant fungal infection are rising in pulmonary disease, with limited therapeutic options. Therapeutic drug monitoring of azole antifungals has been necessary to ensure safety and efficacy but is considered unnecessary for the newest triazole isavuconazole. Aims: To characterise the prevalence of isavuconazole resistance and use in a tertiary respiratory centre. Methods: A retrospective observational analysis (2016–2021) of adult respiratory patients analysing fungal culture, therapeutic drug monitoring, and outcome post-isavuconazole therapy. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp. isolates. A total of 80.8% of A. fumigatus isolates had isavuconazole (MIC > 1 mg/L, and 73.0% > 2 mg/L) with a good correlation to voriconazole MIC (r = 0.7, p = 0.0002). A total of 54 patients underwent isavuconazole therapy during the study period (median duration 234 days (IQR: 24–499)). A total of 67% of patients tolerated isavuconazole, despite prior azole toxicity in 61.8%, with increased age (rpb = 0.31; p = 0.021) and male sex (φc = 0.30; p = 0.027) being associated with toxicity. A total of 132 isavuconazole levels were performed with 94.8% > 1 mg/L and 72% > 2 mg/L. Dose change from manufacturer’s recommendation was, however, required in 9.3% to achieve a concentration of >2 mg/L. Conclusion: We describe the use of isavuconazole as a salvage therapy in a chronic pulmonary fungal disease setting with a high prevalence of azole resistance. Therapeutic concentrations at standard dosing were high; however, results reinforce antifungal stewardship for optimization.

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Section: Discussionmentioning

confidence: 99%

Experience of Isavuconazole as a Salvage Therapy in Chronic Pulmonary Fungal Disease

Nwankwo

Gilmartin

Matharu

et al. 2022

JoF

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“…Of note, significant hair loss requiring treatment interruption was not observed in any of the patients in our study despite having been a feature in a number of patients previously on triazole therapy. Though the exact mechanism of azole mediated hair loss is unclear, voriconazole and itraconazole, have been found to inhibit CYP26A1 mediated hydroxylation of retinoic acid in vitro at concentrations of >1 μM [48], with alopecia reported due to itraconazole, voriconazole and posaconazole. Resultant hair loss due to azoles can cause many patients to stop treatment due to the negative impact on self-esteem, mental health and social interactions.…”

Section: Discussionmentioning

confidence: 99%

Experience of Isavuconazole as Salvage Therapy in Chronic Pulmonary Fungal Disease

Nwankwo¹,

Gilmartin²,

Matharu³

et al. 2022

Preprint

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Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical &amp; Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC &gt; 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% &gt;1mg/L and 72% &gt;2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.

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“…Although fluconazole adverse events are usually not life-threatening, hepatotoxicity and cardiac toxicity can occur. In addition, other side effects, such as alopecia, xerosis, and cheilitis have been frequently described [ 37 , 45 , 46 ]. In one study, Davis and colleagues described fluconazole long-term effects through retrospective evaluation of 124 adult patients with proven or probable coccidioidomycosis treated with fluconazole for a prolonged period.…”

Section: Effects On Antifungal Stewardship Practicementioning

confidence: 99%

Challenges Facing Antimicrobial Stewardship Programs in the Endemic Region for Coccidioidomycosis

Hayes,

Nix

2024

Open Forum Infectious Diseases

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Coccidioidomycosis poses a significant cost and morbidity burden in the United States. Additionally, coccidioidomycosis requires constant decision-making related to prevention, diagnosis, and management. Delays in diagnosis leads to significant consequences, including unnecessary diagnostic workup and antibacterial therapy. Antifungal stewardship considerations regarding empiric, prophylactic, and targeted management of coccidioidomycosis are also complex. In this review, the problems facing antimicrobial stewardship programs (ASPs) in the endemic region for coccidioidomycosis, consequences due to delayed or missed diagnoses of coccidioidomycosis on antibacterial prescribing, and excess antifungal prescribing for prevention and treatment of coccidioidomycosis are elucidated. Finally, our recommendations and research priorities for ASPs in the endemic region for coccidioidomycosis are outlined.

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Examination of Fluconazole-Induced Alopecia in an Animal Model and Human Cohort

Cited by 12 publications

References 25 publications

Experience of Isavuconazole as a Salvage Therapy in Chronic Pulmonary Fungal Disease

Experience of Isavuconazole as a Salvage Therapy in Chronic Pulmonary Fungal Disease

Experience of Isavuconazole as Salvage Therapy in Chronic Pulmonary Fungal Disease

Challenges Facing Antimicrobial Stewardship Programs in the Endemic Region for Coccidioidomycosis

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