Fluconazole-Associated Hypercalcemia in Patients with Coccidioidomycosis

Fluconazole, voriconazole, and itraconazole may potentiate the hypercalcemic effect of other medications, although to date, triazoles alone have not been linked to hypercalcemia. We describe a case of new-onset hypercalcemia in the setting of high-dose fluconazole that resolved after changing the antifungal regimen. We reviewed our institutional database to assess the frequency of moderate or severe hypercalcemia (serum calcium ≥12 mg/dL) among patients with coccidioidomycosis treated with a triazole. We identified 2,133 patients, seen from January 1, 2005, through December 20, 2012, with a diagnosis of coccidioidomycosis. Twenty-three patients (1%) had subsequent hypercalcemia; of these, 20 patients (87%) had moderate or severe hypercalcemia. Nine of the 20 patients (45%) with moderate or severe hypercalcemia were taking triazoles, and most had comorbid conditions that were risk factors for hypercalcemia (tertiary hyperparathyroidism, n=4; multiple myeloma, n=2; adrenal insufficiency, n=1). The effect of fluconazole on calcium metabolism possibly is small or not clinically significant until the dose is high. Fluconazole may also contribute to hypercalcemia in patients with underlying hyperparathyroidism because of the loss of calcium’s inhibitory effect on parathyroid hormone secretion. In summary, moderate or severe hypercalcemia is uncommon in coccidioidomycosis and rare in those treated with triazoles. High-dose fluconazole may be associated with symptomatic hypercalcemia, especially in patients with predisposing comorbid conditions.


Introduction
Triazoles are a class of commonly used antifungal agents that includes fluconazole, itraconazole, voriconazole, and posaconazole. Its mechanism of action is inhibition of fungal cytochrome P450 (CYP)dependent demethylation of lanosterol to ergosterol, which interferes with cytoplasmic membrane synthesis. Triazoles can function as both a substrate for and inhibitor of CYP enzymes, resulting in a wide range of drug-drug interactions with varying properties that are defined by the individual drugs involved [1,2]. Voriconazole and itraconazole are thought to potentiate the adverse effects of all-trans retinoic acid, specifically hypercalcemia, by inhibiting CYP, thereby increasing serum concentration of all-trans retinoic acid [3,4]. Fluconazole, a first-generation triazole, is generally well tolerated, with few clinically significant toxicities. It is commonly used in prophylaxis or treatment of various fungal infections, including candidiasis, cryptococcosis, and coccidioidomycosis [1,5].
In the non-English language literature, 1 report describes a patient with hypercalcemia associated with the use of fluconazole and all-trans retinoic acid and another describes a patient with hypercalcemia associated with fluconazole and rifampin [6,7]. Similar cases have not been reported in the English-language literature to date. Here, we describe a patient with new-onset hypercalcemia in the setting of highdose fluconazole. We searched our institution's records to identify additional patients with moderate or severe hypercalcemia while taking triazoles for treatment or suppression of coccidioidomycosis [8][9][10].

Case Report
The index case patient 9 in Tables 1 and 2 was a 28-year-old white man who was initially diagnosed with coccidioidal meningitis 6 years prior, while living in Arizona. He was treated with fluconazole (800 mg daily) and clinically improved. He continued the same fluconazole dose for 3 years. Subsequently, out of concern for the development of hepatotoxicity, his dose was gradually decreased over the next year to a nonstandard dose of 200 mg daily. Ataxia developed, and coccidioidomycosis exacerbation was diagnosed. The fluconazole dose was subsequently increased back to 800 mg daily and in the following year was decreased to 400 mg daily; while on the 400 mg dosage, hydrocephalus developed and the patient required ventriculoperitoneal shunting. Fluconazole dosage was subsequently increased back to 800 mg daily. Seven months later, abscesses of the brain stem and spinal column, reportedly due to coccidioidomycosis, developed and the patient required a surgical intervention. He was initially treated with amphotericin and then maintained on fluconazole 1,200 mg daily.
During the next 6 months, while continuing fluconazole at 1,200 mg daily, he underwent rehabilitation and began experiencing intermittent hypercalcemia requiring fluid resuscitation. He presented to the emergency department of our institution with symptomatic hypercalcemia (14.8 mg/dL). He was treated with intravenous fluid and furosemide, and hypercalcemia resolved by day 3. His parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D levels were suppressed, and PTH-related protein was negative (Table  1). A serum Coccidioides enzyme immunoassay and an immunodiffusion assay were positive for immunoglobulin G and negative for immunoglobulin M, and complement fixation was negative. His fluconazole was discontinued on day 2, and voriconazole 200 mg twice daily was initiated. He was discharged on day 3. On follow-up, the voriconazole level was shown to be subtherapeutic; the dose was increased to 400 mg, twice daily, to achieve a level within the therapeutic range (2.4 mcg/mL). Two months after initiating voriconazole treatment, he had no recurrence of hypercalcemia. He was subsequently lost to follow-up.

Results
We identified 2,133 patients with a diagnosis of coccidioidomycosis. The diagnosis preceded development of hypercalcemia for 23 patients. Twenty (87%) had moderate or severe hypercalcemia; of these, 9 (45%) had been taking triazoles before hypercalcemia developed. Specifically, 8 patients were taking fluconazole and 1 was taking voriconazole. Six patients were men. Seven patients had comorbid conditions that were risk factors for hypercalcemia (Table 1). Patient 8 was the only case with a high Coccidioides titer (1:256); the remaining patients had negative or low titer or no clinical evidence of dissemination. Table 2 shows interventions and outcomes for each patient. Concurrent with hypercalcemia management, the antifungal regimen was changed from fluconazole to voriconazole for patients 8 and 9, with no recurrence of hypercalcemia at last follow-up (19 and 2 months, respectively). Both were taking high-dose fluconazole (800 and 1,200 mg daily, respectively) before the development of hypercalcemia. Hypercalcemia did not improve rapidly for patient 3, even after reducing the fluconazole dose by half. Patient 4 discontinued fluconazole after transplant kidney nephrectomy and cessation of immunosuppressive medications. Patient 6 discontinued fluconazole within 30 days of the hypercalcemia episode. Hypercalcemia resolved in the patients 1, 5, and 7 without any changes to fluconazole. Patient 2 was taking voriconazole when hypercalcemia developed. She had multiple myeloma and changes were made to her chemotherapy regimen. Hypercalcemia resolved without any changes to voriconazole.

Discussion
Coccidioidomycosis is rarely linked with hypercalcemia, despite its association with a granulomatous immune response [11][12][13][14][15][16]. In our large cohort of patients with coccidioidomycosis, approximately 1% of patients had subsequent hypercalcemia. In the English-language literature, 22 cases of hypercalcemia attributed to coccidioidomycosis have been reported. All were complicated by dissemination, with calcium levels as high as 15.6 mg/dL [11][12][13][14][15][16]. In our 9 patients, 6 had complement fixation titers available, and only patient 8 had a high titer (1:256) with no clinical evidence of dissemination. Patients 3 and 9, the cases with central nervous system involvement, were receiving longterm fluconazole therapy with negative titer and no clinical evidence of relapse. In patients 2, 5, and 7, coccidioidomycosis did not appear to be a contributing factor to hypercalcemia. Because coccidioidomycosis is an uncommon cause of hypercalcemia, other causes such as medications should be considered. For the index patient, medication changes (from fluconazole to voriconazole) had a temporal relationship with resolution of hypercalcemia. His Coccidioides titer was negative at the time of hypercalcemia, he had no comorbid conditions that were thought to cause hypercalcemia, and his medications other than fluconazole were not known to cause hypercalcemia. Fluconazole, voriconazole, and itraconazole are all potent inhibitors of CYP enzymes, with CYP3A4 and CYP2C9 being inhibited mainly by voriconazole but also by fluconazole [17]. All-trans retinoic acid, the active metabolite of vitamin A, is catabolized by CYP enzymes, including CYP3A4 and CYP2C9 [18]. Inhibition of these enzymes by high-dose triazoles and subsequent reduction in the rate of all-trans retinoic acid catabolism has been reported to potentiate the hypercalcemic effects [3,4]. The effect of fluconazole on calcium metabolism might be small or it might not become clinically significant until the dose is high (eg, the 1,200 mg daily dose in our index patient). A high dose might have contributed to the most severe case of hypercalcemia in this series: patient 8 (calcium level, 17.2 mg/dL) was taking 800 mg of fluconazole daily in the setting of marked renal insufficiency. Indeed, dosedependent effects have been reported in fluconazole-associated drug interactions and toxicities [19][20][21][22][23].
Another possible mechanism for the development of hypercalcemia with fluconazole treatment may be an underlying alteration in calcium homeostasis. In healthy subjects, non-parathyroid-induced increase in serum calcium inhibits PTH secretion, thereby maintaining normal serum calcium levels. However, for patients with primary and tertiary hyperparathyroidism, parathyroid function is autonomous and this compensatory mechanism is lost, leading to overt hypercalcemia [24]. Hydrochlorothiazide might exacerbate PTH-mediated hypercalcemia because of the loss of calcium's inhibitory effect on PTH secretion [24][25][26]. Fluconazole possibly contributed to PTH-mediated hypercalcemia in this fashion in patients 1, 3, 4, and 5, all of whom had tertiary hyperparathyroidism attributable to end-stage renal disease after kidney transplantation. When the underlying PTH-mediated hypercalcemia was addressed by cinacalcet (patients 4 and 5), parathyroidectomy (patient3), or eventual involution of hyperplastic parathyroid glands (patient 1), the calcium level normalized through restoration of calcium homeostasis, despite continuing fluconazole treatment.
Our study has several limitations. As a retrospective study, we did not have measurements of PTH and complement fixation titer on all patients, and the adjustment of triazoles, if any, was not standardized. Serum albumin levels were not available in some cases, and therefore we were unable to correct the calcium measurements. Patients may have had laboratory testing outside our facility, and results were not available for review. We excluded patients with mild hypercalcemia because it is often asymptomatic [10]. Seven of the 9 patients had comorbid conditions that are known risk factors for hypercalcemia, making it difficult to isolate the effect of triazoles on serum calcium levels. In addition, as a renal transplant center, our patient population likely has a higher prevalence of tertiary hyperparathyroidism, which can cause hypercalcemia. Finally, our study was conducted at a tertiary referral center; therefore, the results may not be broadly generalizable.
In summary, moderate or severe hypercalcemia is uncommon in coccidioidomycosis and is rare in those treated with triazoles. Highdose fluconazole may be associated with symptomatic hypercalcemia, especially in patients with predisposing comorbid conditions.