Is there evidence to support the use of echinocandins for urinary tract infection?

Background

Fungal urinary tract infections (UTIs) are rare among healthy people, but may occur in up to 40% of patients who are hospitalized or have other comorbidities.¹ The most common fungal urinary pathogens are Candida species, particularly Candida albicans; it is estimated that 50 to 70% of Candida urinary tract infections are caused by C albicans, while 10 to 35% are caused by Candida glabrata and Candida tropicalis.^1-3 Other Candida species, such as Candida krusei and Candida parapsilosis, are less common in urine.

Candida species are normally found in the gastrointestinal tract and the female genital tract, as well as on the skin.^2,4 However, in some cases, these organisms may spread to the urinary tract and cause infection. Candiduria may develop via ascending or descending/hematogenous routes.^3,5 Fungi may migrate from the genital tract to the urinary tract and infect the bladder and/or kidney, causing cystitis or pyelonephritis. Alternatively, patients with candidemia may experience secondary infection of the kidney; these patients typically do not exhibit symptoms of UTI.  Risk factors for fungal UTI include advanced age, female sex, diabetes, presence of an indwelling urinary catheter, antibiotic therapy, and prior surgical procedures.⁵

Current Fungal UTI Treatment Recommendations

Patients with asymptomatic candiduria may not require treatment, as the presence of candiduria without symptoms likely signifies colonization, rather than true infection.⁵ Candiduria typically does not lead to candidemia, except among high-risk patient groups (neutropenic patients, very low-birth-weight infants, and patients undergoing urologic manipulation). In these patients, treatment of asymptomatic candiduria is recommended. Patients with candiduria and symptoms of UTI should also receive antifungal treatment.

Patients with indwelling urinary catheters and candiduria should have their catheters removed or changed as soon as possible; in many cases, catheter removal alone may be sufficient to clear candiduria in asymptomatic patients.¹ Fluconazole is the antifungal treatment of choice for Candida UTI; unlike other azole antifungals, this agent achieves high concentrations in the urine, and it is active against many Candida species, including C albicans.⁵ Unfortunately, many strains of C glabrata exhibit resistance to fluconazole, and fluconazole is not active against C krusei. In patients with fluconazole-resistant C glabrata, treatment with amphotericin B deoxycholate and/or flucytosine is recommended; flucytosine is inactive against C krusei, so for patients infected with this organism, amphotericin B deoxycholate is the treatment of choice. Both amphotericin B and flucytosine are associated with significant toxicities; flucytosine may cause bone marrow toxicity, while amphotericin B is often associated with nephrotoxicity.³ Although lipid formulations of amphotericin B carry a reduced risk of nephrotoxicity, these are not recommended for the treatment of UTI, because they do not achieve adequate concentrations in the urine.^3,5

What About Echinocandins?

Echinocandins (caspofungin, micafungin, and anidulafungin) are highly active against most Candida species, including C glabrata and C krusei.⁵ In addition to their broad-spectrum activity against Candida species, these agents have minimal adverse effects, making them common first-line choices for candidemia and invasive candidiasis. However, current guidelines do not recommend the use of echinocandins for Candida UTI, because these drugs do not achieve significant concentrations in urine. The urinary concentration of caspofungin is only 1.4% of the plasma concentration, and the urinary concentration of micafungin is even lower (0.7% of the plasma concentration).⁶ Anidulafungin urinary concentrations are <0.1% of plasma concentrations.  Despite these low urinary excretion rates, echinocandins have been used to treat candiduria successfully in some cases.⁵ The remainder of this article will explore the evidence for echinocandin use in UTI.

Literature Review

A number of case reports and case series have been published describing the use of echinocandins in fungal UTI (Table 1).^7-16 Micafungin has been most commonly used, although caspofungin use has also been reported. Most of the patients in these case reports were infected with C glabrata or C albicans. In the majority of cases, echinocandin treatment was successful in eradicating candiduria and resolving symptoms.

It is still unclear how echinocandins may successfully treat UTI despite their poor urinary excretion rates. In the candidiasis treatment guidelines, it is noted that echinocandins may be useful for infection that is localized to the kidneys (ie, infection acquired through hematogenous spread), because they are able to attain good concentrations in renal tissue.⁵ Authors of one report suggest that, although micafungin has a low urinary excretion rate, it may still be effective in UTI because it achieves plasma concentrations that are high enough to generate therapeutic urinary concentrations.¹⁰ These authors measured urinary concentrations of micafungin in 6 patients with fungal UTI and tried to correlate the urinary maximum concentration (C_max)/minimum inhibitory concentration (MIC) ratio to clinical efficacy. Plasma C_max/MIC ratios ≥4 have been previously correlated with clinical efficacy of micafungin; in this study, the urine C_max/MIC ratio was ≥4 for all but 1 patient. All patients who attained a urine C_max/MIC ratio ≥4 had success with micafungin treatment, while the single patient who did not achieve this target experienced therapeutic failure.

Although the majority of patients presented in case reports had success with echinocandin treatment, the overall number of patients studied remains low, and it is possible that negative findings were less likely to be reported and published than positive findings. The preliminary results from these case reports are promising, but further studies are required to establish echinocandins as effective, reliable treatment options for fungal UTI.

Table 1. Summary of reports describing echinocandin use for fungal UTI.

Conclusion

Echinocandins are typically not recommended for the treatment of UTI, because they are not well-excreted in the urine.⁵ However, in some cases, echinocandin therapy may be effective for patients with UTI caused by Candida species. Further studies are required to confirm the preliminary successes seen in case reports: however, echinocandins may be considered as alternative treatment options for patients who are unable to receive recommended therapies for fungal UTI. Out of the available echinocandins, micafungin seems to have the most promising data. Optimal dose and length of therapy for echinocandins in UTI remains to be determined.

 References

1. Thomas L, Tracy CR. Treatment of fungal urinary tract infection. Urol Clin North Am. 2015;42(4):473-483.
2. Alfouzan WA, Dhar R. Candiduria: Evidence-based approach to management, are we there yet? J Mycol Med. 2017;27(3):293-302.
3. Kauffman CA. Diagnosis and management of fungal urinary tract infection. Infect Dis Clin North Am. 2014;28(1):61-74.
4. Carver PL. Invasive fungal infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: a pathophysiologic approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146073167. Accessed July 11. 2019.
5. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.
6. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362(9390):1142-1151.
7. Multani A, Subramanian AK, Liu AY. Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: case report and review of the literature. Transpl Infect Dis. 2019:e13118.
8. Rezai MS, Vaezi A, Fakhim H, et al. Successful treatment with caspofungin of candiduria in a child with Wilms tumor; review of literature. J Mycol Med. 2017;27(2):261-265.
9. Gabardi S, Martin S, Sura M, Mohammed A, Golan Y. Micafungin treatment and eradication of candiduria among hospitalized patients. Int Urol Nephrol. 2016;48(11):1881-1885.
10. Grau S, Luque S, Echeverria-Esnal D, et al. Urinary micafungin levels are sufficient to treat urinary tract infections caused by Candida spp. Int J Antimicrob Agents. 2016;48(2):212-214.
11. Kane LE, Muzevich KM. Micafungin in the treatment of candiduria: A case series. Med Mycol Case Rep. 2016;11:5-8.
12. Pieralli F, Bazzini C, Vannucchi V, Mancini A, Nozzoli C. A case of Candida glabrata severe urinary sepsis successfully treated with micafungin. Med Mycol Case Rep. 2014;5:1-3.
13. Malani AN. Failure of caspofungin for treatment of Candida glabrata candiduria: case report and review of the literature. Infect Dis Clin Pract. 2010;18(4):271-272.
14. Lagrotteria D, Rotstein C, Lee CH. Treatment of candiduria with micafungin: A case series. Can J Infect Dis Med Microbiol. 2007;18(2):149-150.
15. Sobel JD, Bradshaw SK, Lipka CJ, Kartsonis NA. Caspofungin in the treatment of symptomatic candiduria. Clin Infect Dis. 2007;44(5):e46-49.
16. Schelenz S, Ross CN. Limitations of caspofungin in the treatment of obstructive pyonephrosis due to Candida glabrata infection. BMC Infect Dis. 2006;6:126.

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2019

The information presented is current as of July 8, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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