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      Posaconazole-Induced Hypertension and Hypokalemia: Mechanistic Evaluation

      , MD 1 , , MD 2 , , PharmD 3 , , PhD 4 , , MD 5

      Open Forum Infectious Diseases

      Oxford University Press

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          Abstract

          Background

          Recent studies have shown the new posaconazole delayed-release tablets have superior bioavailability compared with the liquid suspension formulation. As higher serum posaconazole concentrations have been associated with improved clinical responses, this formulation has been a welcome addition to available treatment options. However, higher serum and tissue levels are likely to reveal previously undescribed toxicity as adverse events attributed to “off-target” effects are observed.

          Methods

          We prospectively identified two patients with new onset hypertension, hypokalemia, and alkalosis after starting posaconazole tablets. Patient vital signs and laboratory values were within normal limits prior to starting posaconazole; however, following over 30 days of therapy both patients became newly hypertensive (mean systolic BP increase 59 mmHg). Serum posaconazole levels were 4.3–4.6 μg/ml. Complete suppression of renin and aldosterone, with increased 11-deoxycortisol, estradiol levels, and cortisol/cortisone ratios were observed in both patients. The TTKG in both patients was inappropriately elevated.

          Results

          Posaconazole-induced disruption of the steroid biosynthesis pathway in patients has not previously been described, but has been suggested by in vitro studies. Our patients’ laboratory results show clinically significant inhibition of 11β-hydroxysteroid dehydrogenase enzyme type 2 isoform (11β-HSD2) as evidenced by: the elevated 11-deoxycortisol (with subsequent suppression of renin and aldosterone), the highly elevated cortisol/cortisone ratio, and the inappropriately elevated TTKG in the setting of hypokalemia. The normal deoxycorticosterone confirms normal function of 11β-hydroxylase and the observed effects in our patients are thus downstream from this enzyme.

          Conclusion

          Our findings support in vitro predictions and highlight the clinical sequelae of posaconazole-mediated inhibition of 11β-HSD2. Additional studies are necessary to determine the frequency of posaconazole induced apparent mineralocorticoid excess syndrome and whether other azole antifungals can be associated with this phenomenon.

          Disclosures

          All authors: No reported disclosures.

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          Author and article information

          Journal
          Open Forum Infect Dis
          Open Forum Infect Dis
          ofid
          Open Forum Infectious Diseases
          Oxford University Press (US )
          2328-8957
          Fall 2017
          04 October 2017
          04 October 2017
          : 4
          : Suppl 1 , ID Week 2017 Abstracts
          : S76
          Affiliations
          [1 ] Internal Medicine, University of California Davis Medical Center , Sacramento, California
          [2 ] Internal Medicine, UC Davis , Sacramento, California
          [3 ] Pharmacy, University of California, Davis Medical Center , Sacramento, California
          [4 ] UC-Davis , Davis, California
          [5 ] Internal Medicine, UC-Davis , Sacramento, California
          Author notes

          Session: 44. Clinical Mycology

          Thursday, October 5, 2017: 12:30 PM

          Article
          ofx163.012
          10.1093/ofid/ofx163.012
          5631889
          © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

          Page count
          Pages: 1
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