Five-year cross-sectional study to determine the burden of Candida spp. infections of the urinary tract system among patients attending tertiary hospital in Northwestern Tanzania

STRENGTHS AND LIMITATIONS OF THIS STUDY

  • Comprehensive 5-year retrospective dataset with over 20000 urine samples providing a robust foundation for the analysis of candiduria prevalence and associated factors.

  • Statistical rigour using binary logistic regression analysis enhances the study’s validity by identifying factors associated with candiduria while controlling for potential confounding variables.

  • Important clinical relevance particularly for tertiary hospitals that alert clinicians to consider urinary candidiasis as a potential diagnosis, especially in high-risk populations.

  • The study was single centre which might limit the generalizability of the findings to other healthcare settings or populations with different demographics and healthcare practices.

  • The study source of data is limited to microbiology laboratory which may not capture all relevant clinical information about the patients.

Background

Candiduria is a condition where a significant number of Candida spp. (>105 CFU/mL of urine) are present in the urine, along with clinical signs and symptoms.1 While Candida albicans has historically been the primary cause of urinary tract infections (UTIs), there is a noticeable shift towards non-albicans Candida spp. (NAC). Candida spp., being an opportunistic pathogen, mainly affects hospitalised and immunocompromised individuals.2 3 Globally, Candida-associated UTIs are reported to be escalating especially among immunocompromised patients and patients with chronic diseases or other predisposing conditions.4

Several risk factors contribute to Candida-associated UTIs, including female gender, chronic use of broad-spectrum antibiotics, diabetes mellitus, urinary indwelling catheters, urinary tract obstructions, urinary tract surgeries, major abdominal surgeries, immunosuppression drug use, malignancies and admission to intensive care units (ICUs).4–9 Female gender is susceptible due to the proximity of the urinary and vaginal systems, as well as the shorter female urethra, making it easier for Candida to spread, (table 1).

Table 1

Factors predisposing different risk groups to urinary tract infection due to Candida spp.

Chronic antibiotic use can disrupt normal microbiota, creating an environment where Candida spp. can thrive. A previous study documented increase of Candida spp. colonisation in the gastrointestinal tract from 30% to 100% during antibiotic therapy.10 Furthermore, patients with diabetes mellitus are also at higher risk due to factors like increased Candida colonisation in the vulval area, compromised immune status and elevated glucose levels. Other risk factors include urinary obstructions, nephrolithiasis and organ transplants (table 1). On the other hand, Candida spp. are reported to have ability of forming biofilm (embed in extracellular matrix11 and conferring significant resistance to antifungal therapy12 13) in both the biotic and abiotic surfaces which pose the patients with indwelling urinary catheter at greater risk of developing infection.14

The clinical presentation of Candida UTIs often mirrors that of bacterial UTIs, making it challenging for clinicians to suspect candiduria and subsequently initiate appropriate management. Common symptoms in symptomatic patients with suspected Candida UTIs include suprapubic pain, dysuria, increased urination frequency and urgency.1 While dysuria and abdominal pain are more frequently reported among patients with community-acquired Candida UTIs, healthcare-associated cases often present as asymptomatic.15 Notably, critically ill patients with candiduria exhibit higher mortality rates compared with those without candiduria.16 In Europe, candiduria ranks as the third most common infection among hospitalised individuals, although data in low-income and middle-income countries, including East Africa, remain limited despite higher rates of inappropriate antimicrobial use in this regions.17 18

C. albicans is known to be the major coloniser of the mucosal lining and predominant cause of mucosal lining infection including UTI (5). The high virulence capacity of C. albicans like ability to form biofilm,19 production of extracellular enzymes like proteases, phospholipase and haemolysis increases their ability to cause infections and spread.2 Studies have also documented the ability of NAC spp. causing UTI to produce these different virulence mechanisms.2 20 In recent decade, drastic changes have been documented in spectrum of Candida spp. and clinical severity of candiduria especially among hospitalised patients and people with chronic conditions like cancer, diabetic mellitus and patients undergoing major surgeries.6 21 22 The changes in severity and detrimental outcome of candiduria are highly associated with increased incidence of NAC spp. that have reduced susceptibility to common azole antifungal agents such as fluconazole like C. dubliniensis, C. norvegensis, C. tropicalis, C. krusei and C. glabrata.23 24 The overuse of azole agents in clinical care and increase in populations at high risk of fungal infections are among factors mentioned to influence the change.7 25

The observed shift in the aetiology of candiduria towards NAC species, which are less susceptible to fluconazole, further complicates the management of these patients, especially in resource-limited settings. Consequently, we conducted a review of laboratory data from patients who visited a tertiary university teaching hospital with a clinical diagnosis of UTIs over a 5-year period (2017–2021) to shed light on the burden of candiduria among patients seeking care for UTI complaints in a tertiary hospital setting.

Methodology

This was a 5-year chart review using a cross-sectional study design that involved microbiology laboratory patients’ records of Bugando Medical Centre (BMC). The records were retrieved from the laboratory information management system, that is, the electronic health management system of BMC. The extracted data included demographic characteristics, hospital status and culture results of patients whose urine were cultured at BMC microbiology laboratory from January 2017 to December 2021.

Study settings

BMC is a consultant and university teaching hospital of the Catholic University of Health and Allied Sciences (CUHAS) for the lake zone of the United Republic of Tanzania. It is situated along the shores of Lake Victoria in Mwanza City, Northwestern Tanzania. It has an estimate of 1000 bed capacity and serves a catchment’s population of approximately 13 million people. The hospital microbiology laboratory is accredited according to International Standard Organization 15189 by Southern African Development Community Accreditation Service (SADCAS) with accreditation number MD002.

Inclusion and exclusion criteria

The study included all patients with UTI diagnosis who attended at BMC outpatient department and those who were admitted in the wards. The study excluded all patients with incomplete data on key variables such as age, gender, hospital status and attended clinic.

Sampling, data collection and laboratory procedure

Data of the patients who submitted urine (either clean catch midstream or catheter urine) samples to microbiology department for culture and sensitivity from the year 2017 to year March 2022 were retrieved and analysed. All urine samples in microbiology laboratory were processed based on laboratory standard operating procedures. For detection of Candida spp. causing UTI, urine sample was inoculated to the Sabouraud’s dextrose agar (SDA) using 1 µL or 10 µL standardised disposable sterile plastic loop. The inoculated SDA plate was incubated aerobically at 37°C for 18–24 hours. Candiduria was defined as yeast growth of >105 CFU per millilitre of urine reported in the microbiology laboratory information system of BMC. The identification was done based on colony morphology, gram stain reaction and formation of germ tube on human or sheep serum detected by wet preparation after 3 hours of incubation at 37°C.

Data management and analysis

All social demographic, clinical and microbiological data were extracted from the DISA computer system of BMC to excel sheet for cleaning and coding before being imported to STATA V.15 for analysis. Categorical data were summarised using proportions while continuous data were summarised using median and IQR. Logistic regression analysis was used to determine factors associated with Candida spp. infections of the urinary tract system. Furthermore, we did logistic regression analysis to determine factors associated with NAC spp. A p value <0.05 at 95% CI was considered statistically significant for all analyses.

Ethical clearance

The protocol of this study was approved by the joint CUHAS/BMC research ethics and review committee with certificate number 2281/2022. Permission to use the laboratory data granted by the Director General of the BMC. Since the study used secondary data and patients were not there to consent, the CUHAS/BMC research ethics and review committee waived the individual consent.

Patient and public involvement

No patient involved.

Results

A total of 62335 biological samples were brought for microbiological analysis in microbiology laboratory at BMC over the 5-year period (2017–2022). Urine sample brought for culture and sensitivity contribute to 33.3% (20755) of all biological samples submitted in microbiology laboratory. Of the urine sample submitted for culture and sensitivity, 867 (4.2%) missed data on age of the patient, 19 (0.09%) missed both age and sex and 836 (3.9%) missed detail on patient ward or clinic attended and therefore excluded from the final analysis (figure 1).

Figure 1
Figure 1

Flowchart for urine sample brought in microbiology lab for urinalysis in 2017–2022.

Characteristics of study participants

The median age of the patients with urine sample brought in microbiology laboratory for culture and sensitivity was 19 (4–46) years with age range of 0–101 years. Distribution of patients according to gender were similar in all years with overall more than half of patients (52.8%, 10051) being female. With exception of the year 2017 where more than half of patients were inpatients, in the rest of the years, majority of patients were outpatients with overall two-thirds (67.5%, 12843) coming from outpatient departments. The number of urine sample collected per year seems to have increased with years and majority of them collected in 2021 (28.8%; see table 2).

Table 2

Demographic characteristics of patients with urine samples over 5 years (2017–2021)

Urine culture results and Candida spp. distribution

After quantitative culture of urine samples, 946 (4.8%), 13701 (70.1%) and 4916 (25.1%) had contaminant growth and requested to repeat urine collection, non-significant growth of pathogen and significant growth of pathogen, respectively. The prevalence of significant Candida spp. growth was 1.2% (221, n=19003). Of patients with significant growth of pathogens, 4.6% (221, n=4772) had significant growth of Candida spp. Slightly higher prevalence of candiduria was observed among urine samples from female patients compared with male patients (5.4% vs 3.6%, p value=0.006). The trends across different years show low prevalence of candiduria-associated UTI with exception of 2017 (prevalence of 8.1%) and 2021 (prevalence of 5.4%). The overall prevalence of UTI associated with candiduria was higher among inpatients compared with outpatients (9.4%, n=1882 vs 1.6%, n=2890) with p value=0.000. Similarly, higher burden of candiduria among inpatients is displayed across all 5 years (table 3).

Table 3

Distribution of growth associated with UTI across years, sex and department

Of 221 significant Candida spp. growth, two-thirds (145, 65.6%) were NAC spp. In table 4, the NAC spp. dominated from 2017 to 2020, whereas C. albicans were pronounced in 2021. The proportion of male patients with candiduria due to NAC spp. was significantly higher than that of female patients (81.1% (60, n=74) vs 57.8% (85, n=147), p=0.0003). In addition, the NAC spp. remained prevalent among inpatients and outpatients and across different age groups with the highest pick be at 0–9 years (80%) and 30–39 years (81.2%; table 3).

Table 4

Factors associated with significant Candida infection of urinary tract system

Factors associated with candiduria and NAC spp.

Increase in age of a patient, being female and being admitted were found to associate with candiduria causing UTI in the univariate analysis. But, only sex and hospital department remained statistically significant at multivariate analysis. Female patients had almost twice odds of having candiduria growth compared with male patients (OR=1.71, 95% CI: 1.27 to 2.28, p value <0.001), and being admitted (OR=6.55, 95% CI 4.66 to 9.19, p value <0.001) was significantly associated with increase odds of having significant growth of Candida spp. in urine (table 4).

At the univariate analysis, we found that increase in age of a patient and admitted to the ward were significantly associated with NAC causing UTI. However, at multivariate analysis, only hospital department that patients received healthcare services remained statistically significant, whereas age and sex of the patients did not matter. Those admitted patients had seven times more odds of having NAC causing UTI compared with those attended at outpatient department with similar complaints (OR=4.472, 95%CI: 4.86 to 11.48, p value <0.001; table 4).

Discussion

Candiduria is documented as the early maker of disseminated Candida infection in critically ill patients that seeded in the kidney through haematogenous spread.26 27 The presence of Candida spp. in urine is associated with increased mortality especially among immunocompromised patients with number of comorbidities. The presence of pyuria and budding yeast or yeast with pseudohyphae under the microscopy is one of the indicators for candiduria; however, in patient with indwelling catheter, the sensitivity and specificity is low.28 The increase in population of patients with chronic conditions like diabetic mellitus, chronic kidney diseases, organ transplants, bed-ridden patients and patients with indwelling urinary catheter has increased the risk of opportunistic infection like candiduria both for outpatients and hospitalised patients. This study has reviewed the prevalence of candiduria among outpatients and inpatients at tertiary hospital over 5 years and documented the associated risk factors.

Candiduria was observed in approximately 5% of patients with confirmed UTIs, with a higher incidence noted among hospitalised individuals. The increased detection of candiduria in inpatients underscores the opportunistic nature of Candida spp. This trend was further substantiated in the present study revealing that admitted patients had 8.22 times the odds of experiencing candiduria compared with those attending outpatient departments. Notably, within the subset of patients with UTIs, the prevalence of significant candiduria was greater in the year 2017 compared with other years. Contrary to our expectations, during the years 2019–2021 when the COVID-19 pandemic was at its peak and there was heightened use of antibiotics,29 30 potentially predisposing individuals to Candida infections, this study found a lower prevalence in those specific years. This discrepancy can be attributed to the commonly widespread use of antibiotics in the study settings even before pandemic.31

In the current study, proportion of patients with candiduria due to NAC spp. were higher than those due to C. albicans. Candiduria due to NAC spp. have been reported to rise in recent decades,32 33 especially for NAC spp. with reduced susceptibility to fluconazole like C. glabrata and C. krusei.2 The NAC spp. infections are currently documented as emergency threat due to the associated treatment failure.34 The increased episodes of NAC spp. causing infections like candiduria and candidaemia have been associated with increased prevalence of severe immunosuppression illness, prematurity, empirical use of antimycotic agents like fluconazole and overuse of broad-spectrum antibiotic.35–37 In the current study, NAC spp. were most prevalent among inpatients, while among outpatients, C. albicans were most prevalent. This can be explained by the possibility that significantly high proportion of inpatients might had history of broad-spectrum antibiotic use, azole antifungal use including fluconazole and severe illness that predispose them to NAC spp. infections. These data were not captured in the current analysis.

Due to limited diagnosis of mycological conditions in the routine clinical microbiology laboratory in the study setting as in other centres in the low-income and middle-income countries 2 38 the burden of fungi infection are under estimated. The NAC spp. detected from the studied patients were not further identified to species level, and antifungal susceptibility testing was not conducted. Studies elsewhere have reported C. glabrata and C. tropicalis to be the leading NAC spp. causing candiduria.32 36 Due to the fact that Candida infections of the urinary tract are highly associated with disseminated candidiasis like candidaemia and deep-seated candidiasis,9 39 40 the management of patient with candiduria is advised to be in according to the susceptibility profile of the involved pathogen. Missing antifungal susceptibility profile of the responsible pathogen that can guide patient management is of great health concern. In the study settings, fluconazole is the routine antifungal treatment used for management of different fungi infections2 41 including urinary candidiasis due to its high urinary concentration.40 However, some research evidence elsewhere suggest the management of candiduria to most rely on the treatment of the primary course like removal of urinary catheter, ureters obstructing fungal balls42 prior to administration of the antifungal agents like oral or intravenous fluconazole, irrigation of the bladder with amphotericin B, intravenous amphotericin B or oral flucytosine.43

In the current study, female patients had 2.15 higher odds of getting candiduria than male patients. The increased risk of urinary candidiasis among female patients than their counterpart has been associated with the fact that Candida are normal flora in vaginal and gastrointestinal tract that has close proximity with the urinary system simplify the possibility of ascending and causing UTI when the environmental conditions allows.44 Furthermore, just like in bacterial infection of the urinary tract the short urethra, hygienic practices and hormonal changes (during pregnancy) propagate the infections. Other studies elsewhere have also reported the predominance of Candida urinary infections among female patients.8 45

NAC spp. have mainly been documented to cause healthcare-associated infections than community-acquired infection.37 46 This has further been observed in the current study whereby admitted patients had seven odds of having infection due to NAC spp. The risk increased among admitted patients due to their reduced susceptibility to azole antifungal agents which are mainly used in treatment of fungi infections in hospital settings.

Study limitation

Given the substantial importance of the documented findings regarding the prevalence of Candida infections within the urinary tract system over a 5-year span at a tertiary hospital in sub-Saharan Africa, it is imperative to acknowledge that the absence of specific data on NAC species responsible for candiduria, along with their antifungal susceptibility profiles, restricts its broader public health implications, particularly concerning the optimal management of affected patients. Moreover, the retrospective nature of the study and the partial integration of the electronic health management system (spanning laboratory, clinical and pharmacy domains) influenced the scope of collectable data, precluding the comprehensive reporting of the treatments administered to these patients, information that holds significant public health relevance. It is paramount that this study is published in its current form to ensure critical contributions of data from lower-resource settings to the field.

Conclusion

Urinary candidiasis affects 5 in every 100 patients with UTI. The infection is most common among female and admitted patients. NAC species are the predominant cause of urinary candidiasis among hospital-admitted patients. Clinicians at tertiary hospitals should consider urinary candidiasis among patients in risk group who present with UTI-like symptoms. Further study to explore treatment outcome of these patients is highly recommended.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data have been included in the manuscript.

Ethics statements

Patient consent for publication

Acknowledgments

We would like to thank quality office of central pathology laboratory BMC for support during data extraction.

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