Antifungal Considerations for Invasive Candidiasis in Pregnant Women

Invasive fungal disease due to the genus Candida can be life threatening.

This condition is most commonly implicated in patients receiving parenteral nutrition, broad-spectrum antibiotics, renal replacement therapies in the intensive care unit, implantable prosthetic devices, immunosuppressive medications, or those with neutropenia or central venous catheters.¹

Regardless of the disease, treatment in women of childbearing age should always include consideration of drug effects on the fetus when pregnant. This is particularly important in the case of invasive candidiasis, which has estimated mortality rates of up to 47%.¹

Systemic azole antifungal agents are classified as pregnancy category C, with the exceptions of voriconazole (Vfend) and high-dose fluconazole (>400mg/day), which are both category D.²

High-dose fluconazole, which is more typical in the treatment of invasive disease, has been reported to cause birth defects in infants born to mothers who took the drug during their first trimester.^3,4 Although low-dose fluconazole has not be associated with an increased risk of congenital malformations, it is typically used for vaginal candidiasis, rather than invasive disease such as candidemia.

The other azoles have been shown to be embryotoxic and teratogenic in animals.⁵

The recently approved isavuconazonium sulfate (Cresemba) is classified as pregnancy category C.² Adverse events have been seen in reproductive animal studies, and the drug’s manufacturer warns that isavuconazonium may cause fetal harm, specifically adverse developmental effects, when administered to pregnant women.⁶

Although there is no quality data on the use of echinocandins in pregnant women, the drugs in this class (anidulafungin, caspofungin, micafungin) are pregnancy category C because non-human studies have shown embryotoxic and teratogenic effects.² In rodents, the drugs have been shown to cross the placenta and be present in fetal plasma, as well as secreted in breast milk.⁵ Whether these effects occur in humans remains unknown.

Flucytosine (Ancobon) is classified as pregnancy category C and has been shown to be teratogenic in rats due to transformation to cytotoxic agent 5-fluorouracil in vivo.⁵

The polyene amphotericin B is pregnancy category B.² Although it is nephrotoxic, amphotericin B is considered to be the safest systemic antifungal agent for use in pregnancy.^2,5 The liposomal formulation is also considered safe, but other lipid formulations have not been adequately studied.⁷

All topical antifungals are considered to be safe for use in pregnancy because of minimal systemic absorption.⁵ These agents, however, are not used for invasive disease.

The Infectious Diseases Society of America recommends systemic amphotericin B as the treatment of choice for invasive Candida infections in pregnant women.¹ All other agents should be avoided in pregnancy, unless the benefits of treatment outweigh the risks to the fetus.

References

1. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-35.

2. Lexi-Comp Online Database. Hudson, OH: LexiComp, Inc. 2015.

3. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22(2):336-40.

4. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet. 1997;72(3):253-6.

5. Pilmis B, Jullien V, Sobel J, et al. Antifungal drugs during pregnancy: an updated review. J Antimicrob Chemother. 2015;70(1):14-22.

6. Cresemba (isavuconazonium) [prescribing information]. Northbrook, IL: Astellas Pharma US Inc; June 2015.

7. Mueller M, Balasegaram M, Koummuki Y, Ritmeijer K, Santana MR, Davidson R. A comparison of liposomal amphotericin B with sodium stibogluconate for the treatment of visceral leishmaniasis in pregnancy in Sudan. J Antimicrob Chemother. 2006;58(4):811-5.