A 67-year-old woman with acute myeloid leukemia experienced refractory hypokalemia while taking low-dose posaconazole. After her initial cycle of decitabine, she was started on an antimicrobial prophylactic regimen including 300-mg posaconazole tablets daily. Lab work showed a posaconazole level of 3,970 ng/ml, over five times the minimum recommended value of 700 ng/ml, and her posaconazole dose was reduced to 200 mg daily. Following two additional cycles of decitabine and venetoclax, the patient presented for neutropenic fever and diarrhea. On admission, she was normotensive but hypokalemic, with a serum potassium level of 2.8 meq/liter. The diarrhea resolved, yet she remained hypokalemic, with a serum potassium nadir of 1.7 meq/liter despite repletion of up to 200 meq of potassium a day. Her repeat posaconazole level was 3,270 ng/ml, and her dose was further reduced to 100 mg daily. Following her dose reduction, labs were consistent with a syndrome of apparent mineralocorticoid excess. Her fractional excretion of potassium of 59% and a transtubular potassium gradient of 14.2 indicated urinary potassium wasting. Her plasma renin activity of Ͻ0.6 ng/ml/h and an aldosterone level of Ͻ4.0 ng/dl indicated no hyperaldosterone state. Five days after her dose reduction (allowing for Ͼ4 half-lives), she was found to have a persistently elevated posaconazole level of 2,380 ng/ml. Her 11-deoxycortisol level was markedly elevated at 519 ng/dl, and her serum cortisol/cortisone ratio was 16.1, indicating a derangement in her steroid synthesis pathways. Her serum potassium stabilized to 3.2 to 4.4 mmol/liter on the final days of her admission, and she was discharged on 100 mg spironolactone, with 40 meq potassium twice daily, and 100 mg posaconazole. Posaconazole is a broad-spectrum triazole antifungal that interferes with fungal steroid synthesis by inhibiting lanosterol 14␣-demethylase (1). It is used as antifungal prophylaxis, and it has a more favorable adverse-effect profile than other triazole antifungals (2). While studies show that 49 to 79% of neutropenic patients reach desired serum concentrations at a dose of 200 mg daily (3, 4), the standard prophylactic dose is 300 mg daily. Higher serum concentrations have been associated with more favorable clinical responses (5), but higher serum concentrations might also confer an increased risk of off-target interactions. While the drug labeling indicated that 28% of patients receiving 300 mg injected posaconazole daily experienced hypokalemia (6), the extent of hypokalemia was not reported, and given that 39% of patients experienced diarrhea, those data do not strongly suggest metabolic impacts of posaconazole. Recently, two case reports have described hypokalemia and hypertension associated with elevated posaconazole levels, with a proposed mechanism being inhibition of the 11-hydroxysteroid dehydrogenase enzyme type 2 (11-HSD2) isoform, leading to mineralocorticoid excess (7, 8). In these cases, the hypokalemia resolved with reduction of the dose of posaconazole.
ImportancePhysician parents, particularly women, are more likely to experience burnout, poor family-career balance, adverse maternal and fetal outcomes, and stigmatization compared with nonparent colleagues. Because many physicians delay child-rearing due to the rigorous demands of medical training, favorable parental leave policies for faculty physicians are crucial to prevent physician workforce attrition.ObjectiveTo evaluate paid and unpaid parental leave policies at medical schools ranked by US News & World Report in 2020 and identify factors associated with leave policies.Design, Setting, and ParticipantsThis cross-sectional national study was performed at US medical schools reviewed from December 1, 2019, through May 31, 2020, and February 1 through March 31, 2021, due to the COVID-19 pandemic. All medical schools ranked by US News & World Report in 2020 were included.Main Outcomes and MeasuresThe primary outcome was the number of weeks of paid and unpaid leave for birth, nonbirth, adoption, and foster care physician parents. Institutional policies for the number of weeks of leave and requirements to use vacation, sick, or disability leave were characterized. Institutional factors were evaluated for association with the duration of paid parental leave using χ2 tests.ResultsAmong the 90 ranked medical schools, 87 had available data. Sixty-three medical schools (72.4%) had some paid leave for birth mothers, but only 13 (14.9%) offered 12 weeks of fully paid leave. While 11 medical schools (12.6%) offered 12 weeks of full paid leave for nonbirth parents, 38 (43.7%) had no paid leave for nonbirth parents. Adoptive and foster parents had no paid leave in 35 (40.2%) and 65 (74.7%) medical schools, respectively. Median paid parental leave was 4 (IQR, 0-8) weeks for birth parents, 4 (IQR, 0-6) weeks for adoptive parents, 3 (IQR, 0-6) weeks for nonbirth parents, and 0 (IQR, 0-1) weeks for foster parents. About one-third of medical schools required birth mothers to use vacation (29 [33.3%]), sick leave (31 [35.6%]), or short-term disability (9 [10.3%]). Among institutional characteristics, higher ranking (top vs bottom quartile: 30.4% vs 4.0%; P = .03) and private designation (private vs public, 23.5% vs 9.4%; P < .001) was associated with a higher rate of 12 weeks of paid leave for birth mothers.Conclusions and RelevanceIn this cross-sectional national study of medical schools ranked by US News & World Report in 2020, many physician faculty receive no or very limited paid parental leave. The lack of paid parental leave was associated with higher rates of physician burnout and work-life integration dissatisfaction and may further perpetuate sex, racial and ethnic, and socioeconomic disparities in academic medicine.
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