Candida auris Urinary Tract Infections and Possible Treatment

Candida auris is a globally emerging pathogen that has been identified in urinary tract infections (UTIs) worldwide. The novel pathogen is characterized by common misidentification, difficult eradication, and multidrug resistance. To date, there is a paucity of data to guide the optimal management of C. auris UTIs. This review provides an overview of C. auris as an etiologic agent of UTIs, a comprehensive review of published data on C. auris UTIs, and a proposed treatment algorithm based on patient clinical status, the presence or absence of clinical infection, comorbidities, infection, and therapy history. Echinocandin and liposomal amphotericin B are recommended as first-line agents for most patients with C. auris isolated in the urine, with a focus on infection control measures and appropriate follow-up criteria. A variety of combination therapies, flucytosine, and amphotericin B bladder irrigations are offered as potential alternatives in the event of infection persistence or recurrence. The treatment approach centers on the aggressive treatment of C. auris in most patients, with the goal of preventing subsequent invasive spread, multi-drug resistance, and ultimate mortality. Published literature on C. auris urinary isolation and treatment is imperative for the future evolution of evidence-based treatment recommendations for this unique pathogen of concern.

risk of morbidity and mortality if infected with C. auris [7,9]. Patients with comorbidities such as diabetes, recent surgery, or prior systemic antimicrobial use are also at increased risk of infection with C. auris [7,9]. While the presence of C. auris in the urinary tract, as with other Candida species, does not automatically indicate a UTI and could rather represent colonization, there is no specific criteria to aid in differentiating colonization from infection [1]. Critical, clinical decision making must be utilized in these at risk patient populations to determine if the isolation of C. auris in the urine necessitates antifungal treatment and should be based on the potential risks of not treating.

Identification/Susceptibilities
C. auris frequently goes undetected or is misidentified by common yeast-identifying, biochemical-based systems [12,13]. It is often incorrectly identified as C. haemulonii, C. famata, C. sake, and C. parapsilosis [7,12,13]. Cases of misidentification have been documented with the following systems: VITEK 2 YST, API 20C, BD Phoenix yeast identification system, and MicroScan [7]. The utilization of updated software or 'libraries' for these systems, the application of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), and molecular-based systems, such as real-time PCR assays, have made it possible to correctly identify C.auris [7]. Additional information on these identification technologies can be found on the Centers for Diseases Control and Prevention (CDC) website under "Identification of Candida auris" [7]. If these methods are unavailable at an institution within the United States, the CDC recommends that the location coordinate with the State Public Health Department to have the purported C. haemulonii, C. famata, C. sake, and C. parapsilosis isolates tested at a CDC lab [7].
The true susceptibility breakpoints of C. auris isolates in the serum are not specifically defined [7]. Tentative MIC breakpoints are provided by the CDC based on data from similar Candida species: ≥4 µg/mL, ≥2 µg/mL, and ≥32 µg/mL for anidulafungin/micafungin, amphotericin B/caspofungin, and fluconazole, respectively [7]. These estimates are provided based on serum MIC data, and do not take into consideration the concentration of antifungal in the urinary tract [23]. Lack of data to support MIC breakpoints for C. auris, particularly urinary isolates, further complicates antifungal treatment decision making for this often multi-drug resistant pathogen.

Review of Published Reports of Candia auris Isolates in Urine
Worldwide C. auris literature focuses largely on candidemia or other invasive infections, with very minimal data available on urinary isolation and other non-invasive sites and infections (respiratory tract, skin, etc.). However, brief reports on urine culture positivity rates as well as patient-specific culture data are found within this published information.
More generalized information on C. auris urinary culture positivity is available from a variety of countries, but epidemiology, pathology, susceptibility, and treatment are described for the entire study populations and are not provided based on urinary isolation subgroups. In a single center study conducted in Pakistan from 2014-2017, 193 C. auris strains were identified based on D1-D2 sequencing or by meeting pre-defined criteria [24]. Of the 193 strains, 83 were identified via urine cultures from indwelling catheters (73/83) or mid-stream samples (10/83) [24]. The 193 strains were collected from 92 individual patients, with 65 of those patients determined to have clinical infection and 19 diagnosed with a UTI without candidemia [24]. Antifungal therapy was deferred in 5/19 patients, 2 of these patients died within 24 h of the C. auris urine culture obtainment [24]. Two independent single-center European studies each reported urine culture positivity among C. auris infected populations [25,26]. There were 5 positive urine cultures isolated from 41 patients with candidemia in one study, with colonization preceding candidemia overall in 56% (23/41) of patients [25]. One potential urinary catheter infection (based on positive urine culture and signs and symptoms of infection requiring treatment) was identified among 50 infections in another study [26]. A report from Kuwait identified 314 C. auris isolates from 126 patients, of which 124 isolates were found in the urine [27]. Clinical C. auris infection was diagnosed in 49 patients in Russia from October 2016-December 2017 [28]. Positive culture sites included urine in 27 patients, urine/blood in 11 patients, blood/urine/tracheal aspirate in 5 patients, and urine/tracheal aspirate in 2 patients [28]. Reported cases of C. auris in New York were monitored from 2013-2017, with 51 clinical cases (defined based on intent of culture obtainment to diagnose or treat disease) identified with the initial site of culture positivity being the urine in 4 cases [29].
Persistence and mortality are frequently cited as factors associated with C. auris infections, and the data provided in the specific case reports of C. auris UTIs (Table 1) support these concerns. Patient 5 s cultures took 6 months to clear C. auris [31]. C. auris was isolated in Patient 10 s urine on day 7 and in the patient's blood on day 22 [34]. Similarly, candiduria was identified on day 0 in Patient 11 and candidemia was identified on day 27 [8]. Patient 11 s urine and blood cultures remained positive on days 95 and 97, respectively [8]. Patients 7 and 8 only survived 3-4 weeks and 2 weeks, respectively, from the time of isolation of a pan-resistant C. auris culture [32].  Broth Microdilution

Infection Control
Infection control measures are imperative in managing C. auris UTIs, as C. auris infections present risk of transmission similar to multi-drug resistant bacteria [7,35,36]. Proper use of personal protective equipment and handwashing or alcohol-based sanitizing is necessary to prevent patient-to-patient transmission by healthcare workers [7,35,36]. If possible, single patient rooms and designated equipment should be utilized in this patient population to prevent widespread transmission [7,35,36].
Appropriate cleaning practices are also key to the management of C. auris infection, as commonly utilized disinfectants are not guaranteed to be active against C. auris [7,[37][38][39]. Specifically, agents with only quaternary ammonia compounds are not effective against C. auris [7]. The Environmental Protection Agency (EPA) has a list of registered, hospital-grade disinfectants with activity against C. auris, including agents with the following active ingredients: hydrogen peroxide, sodium hypochlorite, hydrogen peroxide/peroxyacetic acid, quaternary ammonium monomer + ethanol + isopropanol, hydrogen peroxide/octanoic acid/peroxyacetic acid [7,40]. Additionally, the EPA has approved exemptions to this list based on CDC evaluation of appropriate extra agents, with equivalent active ingredients as listed above [7,40]. Of note, instructions provided by the manufacturer on the exempted agents do not include specific guidance for C. auris disinfection, and instructions provided by the CDC (available online) should be followed [7].

Infection Surveillance
Surveillance screening aids in the prevention of C. auris transmission and should be utilized when either colonized or infected patients are identified [7,9]. After isolation of C. auris in the urine, contacts of the patient should be screened one time for colonization and potential subsequent infection. Screening of the healthcare environment should also be conducted in order to prevent, identify, and manage the potential for an outbreak within the institution. Surveillance should occur weekly within the patient environment and at discharge. If surveillance screening is positive after discharge, repeat screening should be conducted after cleaning to ensure appropriate disinfection was achieved.

Source Control
As with all other infections, source control is imperative as a first step in the management of individual patients with C. auris urinary colonization or UTIs. When possible, all invasive lines must be removed in order to prevent the transition from colonization to infection or remove the nidus of infection. A single center study from Pakistan detailed 11 UTIs that were catheter associated, and the catheter was removed as part of therapy in 8/11 patients [24]. In the same study, 17 catheterized patients were determined to be asymptomatically colonized in the urine, and the catheter was only removed in 10/17 patients [24]. These examples of incomplete adherence to source control practices highlight the need to consider source control as an integral part of the management of C. auris UTIs.

Antifungal Therapy
There is a paucity of data regarding the optimal treatment regimen for C. auris UTIs [7]. Commonly utilized and well-tolerated antifungals may not be adequate for the treatment of C. auris due to both intrinsic and developed resistance mechanisms [8,[18][19][20][21]. Detailed here are specific considerations for each available class of antifungal agents, as well as a proposed treatment algorithm for C. auris UTIs.

Triazole Antifungals
Triazole antifungals inhibit the synthesis of ergosterol, which is a main membrane sterol of fungi [41]. These agents are preferable for treatment given the availability of oral formulations [41].
Fluconazole is the drug of choice for most Candida UTIs, but the resistance patterns of C. auris (as discussed previously) make the triazole an inappropriate choice for empiric therapy. However, clinical decision making becomes more difficult when attempting to optimize therapy based on susceptibility reports. Prior case reports suggest that C. auris infections may persist after fluconazole therapy despite reported fluconazole susceptible isolates [8,33].

Echinocandins
Echinocandin antifungals cause fungal cell lysis by inhibiting glucan synthesis [42]. These agents are extremely well tolerated compared to older antifungals such as amphotericin B and flucytosine, but are only available in intravenous formulations, which is less convenient compared to oral triazole options [42]. The significant resistance rates of C. auris strains to fluconazole, and presumptively the other triazoles, make echinocandins the first line agent for all C. auris infectious as they are predicted to be effective against 70% of C. auris isolates [7]. Although resistance rates of C. auris against the echinocandins are lower than those against the triazoles, resistance is still common and monotherapy may not be sufficient for the appropriate treatment of many UTIs [8,20,21].

Amphotericin B
Amphotericin B causes cell lysis by binding to ergosterol and creating pore channels that alter the permeability of the fungal cell membrane and allow for leakage of monovalent ions [43]. Unlike the triazoles, amphotericin B also binds to mammalian cells, which leads to increased toxicity for the patient [43]. Less toxic, liposomal formations of the medication are available; however, these formulations do not concentrate well in the urine and are not considered appropriate for the treatment of any Candida UTIs based the IDSA guidelines for the treatment of Candidiasis [43,44]. Despite significant intolerance and toxicity associated with this agent, amphotericin B deoxycholate should be considered in the treatment of C. auris given the high resistance rates associated with better tolerated agents such as the triazoles and echinocandins [7,8,[18][19][20][21]44].

Flucytosine
Flucytosine is an antimetabolite that acts as an antifungal via the inhibition of DNA and protein synthesis [45]. Flucytosine is an older agent that is not commonly utilized due to potential for hepatic and hematological toxicities [45]. However, as with amphotericin B, the potential for triazole, echinocandin, and polyene resistant C. auris strains, necessitates the consideration of alternative agents in the management of C. auris UTIs. Flucytosine is an attractive alternative to the commonly utilized antifungal agents, as it is primarily excreted into the urine in its active form, and initial C. auris resistance to flucytosine is uncommon based on current knowledge [22,45]. The utilization of flucytosine in multi-drug resistant strains of C. auris is consistent with current guideline recommendations for the treatment of another antifungal resistant Candida strain, C. glabrata [44]. Unfortunately, the development of candidal resistance to flucytosine during the course of therapy has been documented with other species, and it is reasonable to assume that this could also occur with C. auris, further highlighting the importance of repeat susceptibility testing throughout the course of drug therapy [44,46]. The potential for acquired resistance makes monotherapy with flucytosine an inappropriate treatment option for C. auris UTIs. An additional challenge encountered with flucytosine therapy is the lack of availability across the world. Per a 2016 estimate, flucytosine was not available in 78.3% of countries, but where available and accessible it should be considered for use in treating C. auris UTIs [47].
Among the specific cases with antifungal therapy reported in Table 1, 50% (4/8) of patients were treated with combination therapy [8,[30][31][32][33][34]. Based on the significant mortality and the antifungal resistance rates associated with C. auris infections, combination therapy may be a highly effective treatment strategy for persistent, recurrent, and resistant infections.

Amphotericin B Bladder Irrigations
The utilization of conventional amphotericin B bladder irrigations dates back to the 1960s and is theoretically useful for the treatment of lower UTIs [49][50][51]. The practice is controversial due to limited efficacy data and the availability of well-tolerated systemic antifungal agents, as the initial impetus to use amphotericin B bladder irrigations was to avoid the toxicity associated with older systemic antifungals [49]. However, the potential inactivity of antifungal agents against C. auris may necessitate the use of alternative treatment options. If a C. auris infection is persistent despite the exhaustion of systemic options, direct installation of amphotericin B may be an alternative option to control the infection. While this method will not be utilized for treatment in the majority of C. auris UTI patients, it should be considered within the treatment algorithm for persistent, recurrent, and resistant infections. Figure 1 details a proposed treatment algorithm for C. auris UTIs. The algorithm is based on patient clinical status, the presence or absence of clinical infection, comorbidities, infection, and therapy history. Appropriate infection and source control measures, as delineated above, should be utilized in all patients with C. auris identified on culture. The CDC recommends against the antifungal treatment of C. auris isolated from non-invasive sites such as the urine [7]. In the proposed guidance, we recommend against treatment only if the patient meets specific criteria, as is detailed in Treatment Pathway A. In Treatment Pathway C, monotherapy with an echinocandin is the first line treatment for patients meeting clinical, microbiological, and treatment history criteria, which is consistent with CDC recommendations for invasive C. auris infections [7]. Treatment Pathway B provides decision making support for more difficult infections, and echinocandin monotherapy is not considered appropriate for patients meeting criteria for this treatment pathway. Treatment decisions should be based on prior therapy, and prior and current culture susceptibility results (if available), as detailed in the algorithm. Therapy alterations in response to persistent and recurrent infections should be based on prior therapy, repeat culture susceptibility data, and clinical status of the patient. Repeat cultures throughout therapy are recommended due to concern over the development of resistance during active antifungal therapy. Bladder irrigation in addition to systemic antifungal therapy should be considered if the infection persists despite combination systemic therapy. Even in patients with concomitant candidemia, bladder irrigation should still be considered given the potential for the urinary infection to be the source of the candidemia.

Eradication Screening
Repeated screening of infected or colonized patients during and after therapy should be utilized in order to ensure the efficacy of therapy and prevent the spread of C. auris [7,9]. While end of treatment cultures are not common with most infections, C. auris is an unfamiliar pathogen that is associated with persistent infection and significant mortality. Test of eradication is the most effective method to identifying treatment failures and persistent infection in order to guide if continued therapy is necessary and to prevent the spread of infection. Cultures should be obtained weekly from previously positive sites as well as the blood until criteria for discontinuation of infection control measure are met, as detailed below. Antifungal therapy may be discontinued when culture negativity is documented on two consecutive weekly screenings, as long as all clinical signs and symptoms of infection have resolved. Antifungal therapy should be continued for a minimum of 14 days after first negative culture, as is recommended by Infectious Diseases Society of America (IDSA) for the treatment of candidemia [44]. Adherence to this guidance by the IDSA was chosen based on the mortality associated with C. auris infections and a lack of data to guide duration of therapy specifically for C. auris infections. Additional screening of the axilla and groin can be considered if an institution feels that it would be of clinical utility, this practice is currently supported by the CDC [7]. Once antifungal therapy is discontinued, weekly cultures should be continued to guide the discontinuation of infection control measures. Two negative cultures, one week apart, are adequate to consider the discontinuation of infection control measures. However, it is important to consider the potential for C. auris to remain undetected even if present, and the impact that may have on false negative screening of previously colonized or infected patients. Patients previously colonized or infected with C. auris may have repeated, negative cultures, and then subsequent positive cultures. While this could potentially represent new infection with C. auris, given the commonality of this pathogen going undetected, and lack of truly effective treatment regimens, it is also possible that this could indicate persistent infection. The official discontinuation of infection control precautions should be determined on a case-by-case basis, with the awareness that colonization or infection may still be present. Patient follow-up should be conducted one month after the discontinuation of infection control measures, including repeat cultures.

Discussion
Candida auris is a novel, unfamiliar pathogen that has quickly become of worldwide concern since its discovery in Japan in 2009 [10]. Multiple factors play a role in making C. auris a pathogen of concern, starting with the need for updated identification systems and software (MALDI-TOF, PCR assays, etc.) to prevent the misidentification of C. auris as other Candida species, such as C. haemulonii, C. famata, C. sake, and C. parapsilosis [8,[10][11][12][13]. After proper identification, enhanced source control measures are required to stop the spread of C. auris, as it persists on surfaces and in the environment

Discussion
Candida auris is a novel, unfamiliar pathogen that has quickly become of worldwide concern since its discovery in Japan in 2009 [10]. Multiple factors play a role in making C. auris a pathogen of concern, starting with the need for updated identification systems and software (MALDI-TOF, PCR assays, etc.) to prevent the misidentification of C. auris as other Candida species, such as C. haemulonii, C. famata, C. sake, and C. parapsilosis [8,[10][11][12][13]. After proper identification, enhanced source control measures are required to stop the spread of C. auris, as it persists on surfaces and in the environment in a fashion similar to MDR bacteria [7]. C. auris infections are also often prolonged, presenting challenges in both determining durations of therapy as well as deciphering colonization from persistent infection, and further, from recurrent infection [7,8,17]. Perhaps the ultimate challenge that C. auris presents is the significant resistance patterns the isolates commonly express, limiting the availability of efficacious antifungal treatment options [7,[18][19][20][21].
Candida species are frequently isolated in the urine, however details of C. auris in the urinary tract are not well documented in the literature that is published on the pathogen. What is apparent throughout the available literature, however, is that urine isolates comprise a significant portion of C. auris cultures found within surveillance study populations, and that there is a vast uncertainty of how to properly manage C. auris urinary tract infections once diagnosed [8,[24][25][26][27][28][29][30][31][32][33][34]. In one study, C. auris was isolated in the urine in 92% of patients reviewed, demonstrating that the urine is likely a key site in C. auris infections [28]. The treatment of patients with C. auris in the urine has historically been highly variable and ranged from no treatment to combination antifungal therapy for prolonged durations. Even source control, a quintessential component of all infection management, was not conducted in 36% of patients with C. auris isolated in the urine in a published report [24]. Among the 11 specific case reports we identified (Table 1), concomitant candidemia was reported in 60% of patients, highlighting the potential for C. auris urinary isolation to serve as early indication of invasive infection and the importance of obtaining blood cultures at the time of urinary isolation [8,[30][31][32][33][34]. Two patient cases reporting the isolation of a pan-resistant C. auris culture documented a time to patient death of 2-4 weeks, which supports the notion that these infections should be identified early and managed aggressively [32].
The current body of literature does not provide any consistent evidence for a preferred management strategy for patients with C. auris UTIs. Although the CDC recommends against treating non-invasive C. auris infections, we believe that the risk for persistent, pan-resistant infection and potential for morbidity and mortality that is apparent throughout published reports necessitates treatment of most C. auris infections, regardless of isolation site [7]. Deferring treatment at the time of urinary isolation may put the patient at increased risk of invasive infection, at which point C. auris is incredibly difficult to treat effectively. Despite lack of evidence to guide the optimal utilization of antifungal agent(s) for C. auris infections, we recommend a systematic approach (Figure 1) to therapy selection based on currently known resistance data. Echinocandins and amphotericin B deoxycholate present the most promising data for efficacy against C. auris isolates [7,8,[20][21][22]. For this reason, our treatment pathways begin with monotherapy with either of these agents, or, more often, combination therapy. However, current data suggests that echinocandin and polyene resistance is common among C. auris isolates, and treatment failure remains a concern [7,8,[20][21][22]. Therefore, it is imperative for the treatment algorithm to include additional antifungal agent considerations, such as flucytosine and amphotericin B deoxycholate bladder irrigations.
Triazole antifungals were left out of the proposed treatment algorithm. Based on available literature, C. auris resistance rates to fluconazole approach 100%, and there is a lack of data regarding resistance rates to the other triazole agents [7,8,18,19,[30][31][32]34]. Until more data on the utilization of these agents becomes available, we are not comfortable recommending these agents for the treatment of C. auris, with a preference to use agents that have a higher likelihood of being effective, such as echinocandins and amphotericin B.

Conclusions
Robust data to support any therapy recommendations for the treatment of C. auris UTIs is not available. However, these infections are growing in prevalence and represent a large burden to both the healthcare system and patients. The treatment algorithm proposed here is a culmination of the currently available data. The approach focuses on the aggressive treatment of C. auris in most patients to hopefully prevent subsequent invasive spread, multi-drug resistance, and ultimately mortality. Moving forward, it is imperative that information regarding C. auris urinary isolation, concomitantly positive sites, treatment management, including both infection control measures and antifungal agent selection, and duration of therapy is collected and disseminated in order to design evidence based, effective treatment regimens for patients infected with this unique Candida species. The treatment approach to these infections will continue to evolve as more data becomes available.

Conflicts of Interest:
The authors declare no conflict of interest.