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Outcomes of caspofungin use in the treatment of Candida-related urinary tract infections, a case series

Echinocandins are generally excluded in the treatment of Candida-related urinary tract infections due to their poor urinary concentration. In the presence of fluconazole resistant Candida species, such as C. Glabrata and C. auris, alternative therapies are needed. We herein report the use of caspofungin for the treatment of 10 patients with candiduria, including C. auris. Mycological cure was achieved in 6 of 7 patients and clinical cure was achieved in 8 of 10 patients. Larger studies are needed to confirm our findings.


Background
Cystitis caused by Candida is common in hospitalized patients [1]. The distinction between asymptomatic candiduria and Candida cystitis is not always straightforward, and when treatment is deemed appropriate, selecting the optimal antifungal therapy may be challenging. Oftentimes, candiduria represents colonization and requires no treatment. Diligence in assessing the likelihood of a true Candida cystitis should be practiced to avoid unnecessary treatment [1,2]. When the decision is made to treat a candiduria, drug selection is dependent on pharmacokinetics, fungal strain and anatomical site [1][2][3][4]. Fluconazole is typically the drug of choice for Candida cystitis on the basis of strong efficacy and favorable pharmacokinetics [2]. Of the Candida species, previous epidemiological data demonstrated a higher prevalence of C. albicans (40-65%), C. tropicalis and C. parapsilosis implicated in urinary tract infections [1,5] fluconazole traditionally offers adequate coverage for these Candida species. However, there has been an increasing prevalence of fluconazole-resistant albicans strains as well as a rise in non-albicans strains which are implicated in nosocomial infections [1,3,[5][6][7][8]. More recent distribution of Candida isolates in urinary tract infections depicts a higher prevalence of C. glabrata and C. krusei , which fluconazole offers little to no coverage of [5,8].
As such, there is a need to identify safe and effective alternative treatments for Candida cystitis/pyelonephritis in cases where fluconazole cannot be used. Although echinocandins achieve low urinary concentration, there are several case reports of successful clinical outcomes when used for the treatment of Candida urinary tract infections (UTIs) [3,[9][10][11]. The purpose of this study to identify the clinical and mycological cure rates of caspofungin for Candida-related urinary tract infections at our quaternary care institution.

Methods
We conducted a retrospective cohort study at a quaternary care hospital between January 2016 and October 2019. This retrospective review was conducted at the Cleveland Clinic in Abu Dhabi, United Arab Emirates. The study protocol was reviewed and approved by the institution's Research Ethic Board. Participants were included in the study based on the following criteria: age greater than 18 years, admitted to hospital and having a positive urine culture for any Candida species within 14 days of initiation of caspofungin. Exclusion criteria consisted of the following: the presence of an ileal conduit, kidney stones, pregnancy or recent urostomy (within 30 days). Baseline demographics and clinical data were obtained from the patients' electronic medical records. Pertinent baseline variables that were collected included the presence of indwelling catheters, duration of catheter insertion prior to * urine culture, presence of immunocompromising illness, urologic or prostate abnormalities, nephrolithiasis, congenital abnormalities of the urinary tract, critical care admission, prolonged hospitalization (greater than 7 days) and Candida species. Prevalence rates were reported using descriptive statistics for baseline demographics as well as for the primary and secondary outcomes. Cystitis was defined as Candida growth from a urinary culture and at least one of the following: dysuria, frequency or urgency. A complicated cystitis was defined as cystitis and at least one of the following risk factors: male, obstruction, immunocompromised, renal failure, renal transplant, neurogenic bladder, presence of an indwelling catheter or presence of renal calculi. A pyelonephritis was defined as Candida growth from a urinary culture and at least two of the following: fever, flank pain or costovertebral tenderness, leukocytosis, WBC casts in urine or symptoms of cystitis. Lastly, a catheter-associated urinary tract infection was defined as the presence of an indwelling urinary catheter with signs and symptoms of UTI, and or the presence of Candida growth in a single catheter urine specimen or midstream urine, despite removal of the catheter in the previous 48 h.
The primary outcome of mycological cure was defined as the eradication of Candida species on a repeat urine culture. Secondary outcomes included clinical cure (defined as defervescence, hemodynamic stability, resolution of urinary symptoms, if present, and normalization of WBCs within 72 h) and the recurrence of a positive Candida culture, of the same species, within up to 90 days.
Identification of Candida species in the laboratory was performed using Vitek2 and Vitek MS automated instruments (Biomerieux, France). Antifungal susceptibility testing was performed using Vitek 2 AST-YS08 susceptibility card. CLSI breakpoints were used for susceptibility interpretations for all Candida species except for Candida auris, where tentative CDC breakpoints were used.

Results
A total of 10 patients were included in this chart review. Seven of them were admitted to the intensive care unit at the time of infection and 3 patients were admitted to an acute care unit. Eight patients had indwelling Foley catheters at the time of infection, which were exchanged or removed after starting caspofungin. Six patients had a catheter-associated Candida cystitis, 3 had a Candida pyelonephritis and 1 had asymptomatic candiduria. Of note, no patients had candidemia. The sample mean age was 66 ± 11 years, 5 of whom were female. Further, 8 patients were immunocompromised (6 of whom were receiving immunosuppressive therapy, one transplanted and one receiving chemotherapy) and all patients were diabetic. Three patients had benign prostatic hyperplasia and one patient had bilateral nephrostomy tubes in place at the time of the treatment. Candida species prevalence included the following: C. auris (caspofungin susceptible) in 5 patients, C. glabrata in 2 patients, C. lusitaniae in 1 patient, C. albicans in 1 patient and unspecified yeast in 1 patient.
Of the 10 patients, 6 had a fungal load greater than 100,000 CFU/ mL; pyuria was present in 7 patients. Caspofungin was administered as 70 mg intravenously once followed by 50 mg intravenously daily, with a mean treatment duration of 7 ± 2 days. Of the 7 subjects who had a repeat urine culture, the primary outcome of mycological cure was achieved in 6/7 patients (85%); the repeat culture was done within 7 ± 2 days after therapy initiation. Clinical cure was achieved in 8/10 patients (90%). Recurrence of cystitis within 90 days occurred in 4/8 patients (50%).

Discussion
Our findings describe the successful outcomes of utilizing caspofungin in the management of Candida-related urinary tract infections. Our sample encompassed a range of patients including those with catheter-related urinary tract infections, immunocompromised patients and patients with fever and hemodynamic instability. With increasing rates of resistance and the rise of non-albicans strains, alternative options are needed to treat urinary tract infections caused by resistant Candida species. Given the lack of robust data supporting the efficacy of echinocandins for the treatment of urinary tract infections, clinical practice guidelines have not advocated for their use for this particular indication [2].
To our knowledge, the largest study to date examining the use of caspofungin for UTIs, retrospectively included 6 patients whom were successfully treated (3 of which were secondary to hematogenous spread, and 3 were secondary to an ascending infection) [3]. Of the echinocandin class, there is presently more data supporting the use of micafungin for the treatment of Candida-related urinary tract infections. A study by Gabardi et al. retrospectively analyzed 33 patients using micafungin for the treatment of Candida UTI, demonstrating successful urinary sterilization for short and long term outcomes [11]. Similarly, Grau et al. described the successful use of micafungin for the treatment of Candida-related UTIs, of which 5 of the 6 were cystitis [10].
Urothelial infections (urethra and bladder) are usually superficial with a potential to invade the bladder wall while pyelonephritis is typically thought of as a renal parenchymal infection [12] As such, the treatment of cystitis and urethritis traditionally involves utilizing an antibiotic that is renally excreted to ensure eradication of the organism at the level of the surface mucosa.There is increasing evidence showing that high drug urinary excretion may not be required for the treatment of UTIs; pyelonephritis or otherwise [11]. It is thought that renal parenchymal and epithelial cells achieve adequate free drug concentrations through systemic absorption, which may be sufficient to treat urinary tract infections [12,13]. Our findings concur with other studies that demonstrate urinary fungal clearance when using echinocandins despite their low urinary excretion.
Free antimicrobials (unbound to protein) can move freely across different body fluid compartments including uroepithelial cells and intracellular and extracellular compartments, which may provide sufficient antimicrobial levels to treat superficial urotherlial infections and parenchymal kidney infections alike [13,14]. Serum-free drug concentration of antimicrobials can be used as an indicator and/or surrogate of tissue concentration when deciding on breakpoints of antimicrobials [13]. Our clinical and microbiologic cure rates suggest that therapeutic echinocandins' levels may have been achieved at the urothelial tissue level and could potentially be considered for the treatment of urinary tract infections despite their poor renal excretion. Echinocandins have a wider antifungal spectrum, are well tolerated and generally have fewer drug-drug interactions, making them an ideal alternative to manage resistant Candida, and particularly in immunocompromised patients.
The limitations of our study were inherent to its retrospective nature, small sample size and being a single-center study.

Conclusion
Caspofungin may achieve clinical and micrologic cure in the treatment of urinary tract infections caused by various Candida species. It may be a safe and effective alternative to azoles for the treatment of urinary infections in the case of resistant Candida strains, azole intolerance or where drug-drug interactions is of concern. Larger multicenter studies are needed before the widespread adoption of echinocandins for urinary infections can occur.

Sources of funding
This work received no funding from any source.

Ethical approval
Cleveland Clinic Abu Dhabi Ethics Research Committee approval was granted before initiating data collection. Consent was waived given the retrospective nature of the study.