Candida species rarely cause UTIs in healthy individuals. However, glucosuria due to poorly controlled diabetes mellitus (DM) has long been assumed as a risk factor for acquiring UTIs and genital yeast infections [1]. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are antidiabetic drugs that were introduced to the European market in 2012. These drugs lower blood glucose levels by causing the kidneys to excrete glucose into the urine and they are often used in the management of type 2 DM (T2DM). However, several studies have reported side-effects of SGLT-2 inhibitors, including UTIs and genital yeast infections [2]. In 2015, the United States Food and Drug Administration (FDA) warned about a potential risk of UTIs and thereby increased awareness of SGLT-2 inhibitor usage. We present the case of a patient with diabetes who developed Candida parapsilosis fungaemia originating from the urinary tract, complicated by a fungus ball. This patient was previously treated with a SGLT-2 inhibitor. A 69-year-old man with T2DM and alcohol addiction was admitted to the department of urology due to UTI and urinary retention. His diabetes had been treated with metformin for 8 years, and from a year before admission he had also received linagliptin/empagliflozin (combined dipeptidyl peptidase 4 [DPP-4] inhibitor and SGLT-2 inhibitor) and repaglinide (a meglitinide). His prior medical history included a TURP. Subsequently he had an indwelling catheter, but this was successfully removed months before admission. He had suffered from Enterococcus faecalis UTI treated with oral pivampicillin 3 weeks before admission. The patient was admitted after falling at home feeling ill with muscle weakness and urinary retention. Upon hospital admission, he had a temperature of 34.2°C. Bloodwork showed creatinine 630 mmol/L, potassium 7.5 mmol/L, leucocytes 19.9 × 109/L and C-reactive protein 250 mg/L. Arterial puncture showed pH 7.22, HCO3 10.1 mmol/L and lactate 6.2 mmol/L. Ultrasound showed residual urine and an undefinable mass in the bladder thought to represent blood clots. A Foley catheter was placed, and 700 mL of pus was removed from the bladder. No blood was noted. A CT scan showed bilateral hydronephrosis due to infravesical obstruction, and confirmed the mass in the bladder, which measured 5.5 × 4.6 cm. The initial treatment included fluid therapy and intravenous administration of piperacillin/tazobactam and metronidazole. Throughout the hospital stay, oral antidiabetic medications were discontinued, and an attempt was made to manage the patient's blood glucose levels through insulin injections. On the following day, peripheral blood cultures revealed growth of yeast (Figs 1 and 2) identified as C. parapsilosis. Treatment commenced with an initial 200 mg loading dose of anidulafungin followed by 100 mg once daily. The isolate was later found to be susceptible to anidulafungin, fluconazole, voriconazole, amphotericin B, flucytosine and micafungin. The same yeast was found in the urine sample. Therefore, the treatment was changed to intravenous fluconazole 800 mg loading dose, followed by 400 mg once daily for 5 days, and then oral fluconazole 400 mg once daily. However, C. parapsilosis was again detected in blood cultures taken at 4 and 8 days after the initiation of antifungal treatments, prompting a return to intravenous anidulafungin. Despite regular flushing and multiple replacements of the Foley catheter, it continued to clot with white lumps. A CT scan performed 17 days after admission showed increasing hydronephrosis, pyelonephritis/pneumatic pyelitis, and an enlarging bladder mass, which measured 6.0 × 5.7 cm (Fig. 3). Another cystoscopy performed under general anaesthesia confirmed an amorphous lump in the bladder alongside multiple necrotic areas in the bladder wall (Fig. 4). The lump was surgically removed and histologically confirmed to contain numerous fungal hyphae. Subsequently treatment was switched to intravenous fluconazole combined with amphotericin B 50 mg/L, installed in the bladder once daily for 5 days. After >30 days of hospitalisation, the patient was discharged with an indwelling catheter and oral fluconazole. At discharge, his diabetes management was permanently altered to a regimen of metformin and insulin injections. A clinical follow-up with cystoscopy conducted 3 weeks later at the outpatient clinic showed white plaques on the bladder wall. However, a subsequent CT scan indicated decreasing signs of infection. At 6 weeks after discharge another cystoscopy showed no signs of fungal infection, and oral fluconazole was discontinued. Urodynamic investigation showed no BOO, and the patient has not had any fungal UTI since at 10 months of follow-up. Sodium-glucose co-transporter 2 inhibitors are commonly used in the treatment of T2DM. Their use has been associated with an increased incidence of genital fungal infections [2], but their association with UTIs and severe systemic fungal infections is still unclear. Previous studies present conflicting results regarding the risk of UTIs [2], but the literature often does not distinguish between bacterial and fungal UTIs, leading to a limited understanding of the risk specifically associated with fungal UTIs. In our case, the patient was on a treatment with a combination of DPP-4 and SGLT-2 inhibitors; however, we suspect that his fungal infection was a side-effect of empagliflozin. In phase III trials, empagliflozin was associated with a higher rate of UTIs, especially in individuals with a history of chronic or recurrent UTIs [3]. According to Yang et al. [4], the use of SGLT-2 inhibitors in patients with T2DM on metformin was associated with an increased risk of genital infections and UTIs compared to DPP-4 inhibitor. Previous studies have shown that the risk of UTI or genital infections was not increased with linagliptin [5]. Additionally post-marketing reports have indicated serious UTIs, such as urosepsis and pyelonephritis requiring hospitalisation, in patients taking SGLT-2 inhibitors like empagliflozin (https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious). Hazique et al. [6] in 2023 reported a case of 39-year-old woman with T2DM of 15 years who experienced recurrent UTIs after starting empagliflozin. Her condition improved after discontinuing empagliflozin. When treating symptomatic Candida sp. UTIs, multiple factors need to be considered. Initially, echinocandins (such as anidulafungin) are recommended for treating documented invasive candidiasis before identifying the species and its sensitivities. However, they are not advised as the first-line treatment for UTIs due to their poor urine penetration. For fluconazole-susceptible organisms such as C. albicans, C. tropicalis and C. parapsilosis fluconazole is the preferred choice due to its safety profile, efficacy, and high concentration in urine. In retrospect, using intravenous anidulafungin in our case was suboptimal, given the UTI focus. However, the main reason for the initial treatment is likely to be the lack of adequately addressing the infection source, which is vital for successful outcomes. Fungus balls, a rare challenging complication of Candida sp. UTIs in adults, are primarily described through case reports. The available treatment options of fungus balls are limited and often require surgical removal, followed by local antifungal irrigation [1]. Previous case reports highlight the importance of early surgical intervention. Woloshuk et al. [7] described a case of a female patient with T2DM with a C. glabrata fungus ball with subsequent candidaemia. This occurred 11 months after initiating SGLT-2 inhibitor (empagliflozin) treatment. The patient was successfully treated with intravenous amphotericin B and micafungin, followed by antegrade amphotericin B irrigations through nephrostomy tubes and ureteroscopic extraction of the ureteric obstruction. In our case, earlier removal of the obstruction would likely have reduced the duration of hospitalisation, as significant clinical improvement was observed after cystoscopy. At Copenhagen University Hospital, Herlev and Gentofte, we have observed an increase in patients with diabetes treated with SGLT-2 inhibitors who develop symptomatic Candida sp. UTIs and fungaemia originating from the urinary tract. There are no clear guidelines on continuing SGLT-2 inhibitors in patients with recurrent UTIs. A consensus from Asia-Pacific advises using SGLT-2 inhibitors only after a UTI-free year. For those with complex UTI histories, SGLT-2 inhibitors may be an option if severe UTI risks are resolved [8]. In conclusion, our case shows a possible link between SGLT-2 inhibitors and severe fungal infection in patients with diabetes. Probably the incidence of fungal UTIs in patients treated with SGLT-2 inhibitors is underestimated due to lack of attention and limited evidence in the literature. Further investigation is needed to explore the correlation between fungal UTIs and the use of SGLT-2 inhibitors in patients with diabetes. Furthermore, our case underscores the importance of early surgical intervention in the effective treatment of fungus balls. None declared. Written informed consent was obtained from the patient for the publication of any images or data included in this report. A copy of the informed consent form is available on request.
No takes yet. Share an insight, caveat, or question.
Mathiasen et al. (2024) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: