Candidiasis in Diabetes: Five-Year Retrospective on Glycaemic Control

Abstract

Background

Fungal infections are a significant global health burden, affecting over a billion individuals annually. Diabetes mellitus (DM) is a major risk factor, with over 7 million diabetic patients in Saudi Arabia. This study aimed to identify common fungal pathogens and associated risk factors in DM patients at King Fahad Hospital in Medina.

Methods

A retrospective-observational study analyzed electronic records of DM patients with positive fungal cultures from 2016 to 2021. Data included demographics, medical history, fungal isolates, resistance patterns, and biochemical parameters.

Results

A 54.5 fold increase in fungal infections was observed over five years, likely reflects the synergistic impact of the COVID-19 pandemic and enhanced diagnostic surveillance alongside the physiological vulnerability of a growing diabetic population struggling with poor glycemic and renal management. Male DM patients had a higher incidence of candidiasis. Candida parapsilosis was the most common species, followed by C. albicans. High fasting glucose, elevated HbA1c, and increased creatinine levels were significantly associated with higher infection rates. Bloodstream infections were most prevalent, followed by cutaneous and respiratory infections. Resistance was observed primarily in hospitalized patients, with C. krusei, C. dubliniensis, and C. parapsilosis demonstrating significant resistance.

Conclusions

This study highlights the significant burden of fungal infections in DM patients in Saudi Arabia. Candida species were the predominant isolates. Elevated glycemic control and renal function were major risk factors. The lack of a national fungal infection surveillance program hinders accurate assessment of the true burden of this disease. These findings emphasize the need for improved diagnostic strategies, targeted antifungal therapies, and enhanced surveillance programs to effectively manage fungal infections in DM patients.

Introduction

Diabetes is a global concern as 537 million population are suffering globally. This number will rise to 700 million by 2045 [1]. This chronic metabolic disorder affects 25% of the Saudi population. Diabetes significantly increases morbidity and mortality and serve as a major risk factor for fungus infections. By traumatic abrasive implantation, fungi can colonize pre-existing lesions, leading in a serious clinical condition [2]. Saudi Arabia has 7 million diabetic patients and 3 million prediabetic [3]. Diabetic individuals are more prone to experience complications such as secondary bacterial infections, foot ulcers, paronychias, cellulitis, osteomyelitis, gangrene, and lower-limb amputation compared to healthy individuals. Diabetes causes changes to the neurological system and impair circulation, which increases the risk of foot infections. The skin on the feet might become extremely dry and cracked as a result of the nerves controlling perspiration no longer working, and calluses tend to appear more often and accumulate more quickly [4]. These calluses can develop into open sores or ulcers if not routinely removed. If the feet are not frequently examined, diabetic nerve damage can result in loss of feeling (neuropathy), and an ulcer can get infected very fast [5]. Fungi are prevalent causing severe diseases, and secret mycotoxins under wide environmental conditions. Fungal infections have become a principal cause of disease and death in several risk groups of patients [6]. Diabetes mellitus (DM) is an important predisposing factor for fungal infections. These fungus infections can range in severity from asymptomatic, mild mucocutaneous infections to potentially fatal systemic infections [7]. DM patients with poor glycemic control have high blood sugar, low immunity (humeral and interleukin secretion), colonized pre-existing lesions, neuropathy, Corns and callus, poor circulation, and may develop, ischemia, foot ulcer and amputation. Studies have shown that DM patients have significantly higher rate of infections and especially nosocomial infections and more vulnerable to other infections such as pulmonary aspergillosis, cryptococcal meningitis aggravating HIV/AIDS, invasive candidiasis, and mucormycosis are the most prevalent fungal illnesses [8, 9]. Diabetic patients with fungal nail infection have a higher rate of foot ulceration and gangrene in comparison to people with diabetes without onychomycosis [10, 11]. Most occurring fungal pathogens depends on infection site, which may include, C. albicans, C. parapsilosis, C. famata, Pichia ohmeri, C. guilliermondii, Biopolaris hawaiiensis, Trichophyton schoenleinii, Aspergillus niger, Trichophyton rubrum, Fusarium oxysporum, and Penicilium marneffei. [12] This study aims to report the prevalence of fungal infections and associated risk factors in DM population in a major diabetic center in Medina, Saudi Arabia.

Methods

Study Design and Ethical Approval

This study utilized a non-interventional, single-center, retrospective observational design to evaluate the incidence and clinical outcomes of fungal infections in patients with Diabetes Mellitus (DM). The study was conducted at King Fahad Hospital in Madinah, Saudi Arabia. Ethical approval was granted by the Institutional Review Board (IRB) of the General Directorate of Health Affairs in Madinah (IRB-2021-206). In accordance with the retrospective nature of the electronic health record (EHR) review and the absence of direct patient interaction, the requirement for informed consent was waived. All data were anonymized to ensure patient confidentiality and used strictly for research purposes.

Criteria for Inclusion and Exclusion

This study focuses on identifying risk factors, outcomes, and resistance patterns associated with positive fungal culture infections in a specific high-risk population. Inclusion criteria were to include hospitalized adult patients from all departments (≥ 18 years old) with a documented diagnosis of Diabetes Mellitus (DM) and at least one positive fungal culture result identified during the hospitalization period within the defined study timeframe. Culture results and patient data available between October 10, 2016, and November 19, 2021. This specific time frame was chosen to allow for a five-year retrospective analysis with as complete data as possible. From an electronic search of the hospital database, information about patients with positive fungal cultures, associated demographics, antifungal therapy, comorbid conditions, species identification, and antifungal sensitivities were collected. Age, weight, height, body mass index (BMI), admission date, department, survival, laboratory tests, sample tested, organism identified, antibiotic, sensitivity, underlying diseases, discharge date, visitation date, and all episodes of diabetic and fungal-positive patients were included in the targeted population. Haematology profile, which includes platelet-count, WBCS, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, CRP, glucose-fasting, HBA1C, creatinine, HDL cholesterol, cholesterol, triglycerides, LDL cholesterol, alkaline phosphatase, antifungal therapy, and resistance profile of biochemical profiles. Any pathogenic fungus species isolated from at least one culture specimen from a patient exhibiting infection-related signs and symptoms was an episode of fungal infection. Patients were excluded from the study if they lacked a documented diagnosis of DM in their electronic health record (EHR). Furthermore, any culture results from specimens collected outside the defined study period were not considered for inclusion. Finally, patients with incomplete records precluding the reliable extraction of essential variables such as key laboratory results were also excluded from the final analysis to ensure data quality and integrity.

Laboratory Techniques

Fungal isolates were identified from a variety of samples by cultivating them on Sabouraud Dextrose Agar (SDA) and 5% sheep blood agar medium (MOH Saudi Prepared medium Laboratories). SDA plates were incubated for three weeks at 25–37 °C, while blood plates were incubated for 24 to 48 h at 37 °C (Forma Scientific Incubator, Germany).

Using the fully automated BacT/Alert VIRTUO Microbial Detection System (bioMérieux, Durham, NC, USA), blood samples were incubated both aerobically and anaerobically. Every blood culture bottle was incubated for a maximum of five days or until a signal-positive alarm was raised. Gram staining was used to further identify the positive blood culture bottles, and the department was verbally told that the sample came from a critical site. All results were recorded in the system. Following the manufacturer’s recommendations, sensitivity testing was carried out using the VITEK 2 system (bioMérieux, Marcy-L’Étoile, France) upon request. The new CLSI recommendations (resistance, sensitivity, and intermediate resistance) were used to interpret the antifungal susceptibility reporting requirements. For a maximum of five days or until a signal-positive alert was heard, all blood culture bottles were incubated. Bottles of positive blood cultures were processed for Gram staining for preliminary identification, and the department was verbally informed that the sample came from a critical site to expedite patient management. All preliminary and final results were recorded in the system.

Sensitivity testing was carried out using the VITEK 2 system (bioMérieux, Marcy-L’Étoile, France) as per standard clinical laboratory procedure. The Clinical and Laboratory Standards Institute (CLSI) M60 and M27/M38 recommendations in effect during the study period were used to interpret the antifungal susceptibility reporting requirements (Susceptible (S), Intermediate (I), and Resistant (R)). Testing was performed on isolates from sterile and non-sterile sites based on clinical relevance.

Biochemical Assays and Blood Glucose Measurement

Biochemical and haematological measurements were extracted from the EHR corresponding to the time of the positive fungal culture or the nearest preceding measurement. Blood sample results included the lipid profile in serum (total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG)) and blood glucose results (FBG and HbA1c), creatinine levels. Fasting Blood glucose (FBS), HbA1c, and lipid profiles were determined by chemoimmunoassay technology using the Cobas b 311 immunoassay analyser based on the manufacturer’s instructions (Roche Diagnostics, GmbH, Germany) at the Pathology & Laboratory Medicine in King Fahad Hospital Al Madinah Al Munawarrah.

Statistical Analysis

Data management and preliminary analysis were performed using Microsoft excel (version 362). Numerical data were reported as mean, mode, and ± standard deviation, while categorical data were reported using frequencies and percentages. Depending on the data distributions risk groups and comparative risk factors were tested using multivariate regression. The p value ≤ 0.05 were considered statistically significant. The annual prevalence of fungal infections was calculated by including patients with DM were counted as one case per year in the data analysis. Patients’ episodes were counted every time treatment was changed or new species were identified. Annual incidence rates were calculated for each year using the following formula: Incidence= Total population at risk during that year/Number of episodes in a given year x100. In this context the “number of total episodes” as presented in the data, acknowledging that recurrent infections in different years contribute to the total number of episodes. The Prevalence was calculated for each disease category by multiplying the annual incidence by the estimated duration of each disease. This approach was adopted to provide a more accurate representation of the burden of each disease, as the prevalence can significantly differ based on the chronic nature or typical duration of the specific condition. The formula used was:

Prevalence=Incidence × Duration of each disease. The specific “duration of each disease” for each category (Systemic 14 day, Subcutaneous 21 days, Superficial 7 days, Respiratory 150 days, and Urine 4 days) was estimated based on average number of days prescribed in previous literature. Mortality was defined as all-cause mortality within 30 days of the positive culture collection date. Mortality rate in resistant strains: For each specific bacterial species was calculated as = (Number of patients with infections caused by a resistant species who died / Total number of patients caused by that resistant species * 100). Mortality rate in susceptible strains: For each specific species, this rate was calculated as = (Number of patients with fungal infection caused by a susceptible species who died / Total number of patients with BSI caused by that susceptible bacterial species) * 100).

Results

Patient Demographics and Incidence

Based on the data extracted from KFH and diabetic centre, the overall number of patients found positive for fungal infection was 219 patients, only 29 were diabetic patients (Table 1). These 29 diabetic patients had 811 episodes of fungal infections over five years (2016–2021). This represents a mean of 27.97 episodes per patient over the five-year study period, suggesting a pattern of chronic recurrence or persistent colonization in high-risk diabetic individuals rather than isolated acute events. Fungal infections were seen more in male (16 males with n = 559 episodes) compared to female (13 females with n = 252 episodes), mostly in adults age group (n = 578) verses seniors (n = 233). Samples were mostly requested for patients who were first diagnosed in new cases diabetic clinic (n = 435), followed by diabetes clinic(n = 214), endocrinology clinic (n = 152), Ophthalmology clinic (n = 6), and urology clinic (n = 4). Fungi were most isolated in aerobic blood samples (central n = 379, peripheral n = 211), other unspecified samples (n = 141), biopsy (n = 38), sputum (n = 24), wounds swabs, urine and anaerobic peripheral blood were six episodes each (n = 18). There was a 54.5 folds increase in fungal infections during the study period. This dramatic surge in fungal infections between 2016 and 2021 likely stems from a synergistic convergence of clinical, environmental, and systemic factors. Which involved COVID-19 pandemic, increased the vulnerability of immunocompromised diabetic patients to secondary opportunistic pathogens, alongside advancements in diagnostic infrastructure and electronic record-keeping that enhanced case detection. More fundamentally, the regional diabetes epidemic—defined by suboptimal glycemic management (elevated HbA1c and fasting glucose)—provides a metabolic environment highly conducive to fungal proliferation. When compounded by progressive renal dysfunction, as evidenced by rising creatinine levels, these physiological stressors significantly lower the immunological threshold for invasive bloodstream infections, transforming chronic metabolic disease into a high-risk gateway for systemic mycoses.

Table 1.

The Normal Reference range for biomarkers and Population groups

Parameters	Normal Reference Range
HbA1c (%)	4.3–6.0
FBG (mmol/L)	3.89–5.50
HDL-C (mmol/L)	1.04–1.55
LDL-C (mmol/L)	2.59–4.11
TC (mmol/L)	5.2–6.2
TAG (mmol/L)	1.7–2.2
Creatinine	0.7 to 1.3 mg/dL for adult males. 0.5 to 1.1 mg/dL for adult females.
BMI (Kg/m2)	18.5–24.9
Patient groups	No. of patients	No. of episodes	Ratio of Episodes per Patient
Total Diabetic cohort with positive microbial culture	28,397	107,966	3.8
↳Diabetic with Fungal infections	29	811	27.9
↳Diabetics without Fungal infections or not tested	28,368	107,155	3.77
Non-Diabetic with Fungal infections	190	768	4

*Values are obtained from references used by Madinah Hospital laboratories in Madinah region, Saudi Arabia

The incidence per 100 population of fungal infections within the study population over the five years were decreeing in 2016 incidence was 0.1756, 1.1838 in 2018, 0.3861 in 2019, 6.5995 in 2020, and 7.5959 in 2021 (Fig. 1). The most substantial year-on-year growth occurred between 2019 (0.38) and 2020 (6.59), coinciding with the peak of the global COVID-19 pandemic Table 2. The total prevalence couldn’t be determined as the duration of disease varied based on the type of infection. However, a Disease-Specific Prevalence was calculated based on the averge duration of each specific infection types.Respiratory infections demonstrated the highest calculated prevalence (Grand Total: 532.41), likely due to the longer clinical duration (150 days) associated with these episodes.In contrast, superficial and urine infections showed significantly lower prevalence rates (24.84 and 14.19, respectively), reflecting their shorter clinical courses (7 days and 4 days, respectively). Subcutaneous and systemic infections maintained moderate prevalence levels of 74.53 and 49.69, respectively Table 2.

Fig. 1.

Epidemiological Analysis of Candidiasis in Diabetic Inpatients: A- Temporal trend of candida species over five years with increase in non-Candida albicans (NAC) species compared to C.albicans. B- Species Distribution by Demographics, comparing causative agents in different categories such as age and gender, we observe dominance of NAC isolated in male adults. C- Infection site distribution, most Candidiasis were isolated from blood, biopsy and respiratory samples

Table 2.

Incidence and prevalence of fungal infections in diabetic populations with different diseases systemic, subcutaneous superficial, respiratory, and urine

incidence and prevalence				incidence	Prevalence =incidence *duration of each disease
years	number of patients	total episodes	Population at risk	incidence =episode/risk group (diabetics)*100	Systemic:14 days	subcutaneous:21 days	Superficial:7 days	Respiartory:150 days	Urine: 4 days
2016	1	7	3986	0.1756	2.4586	3.6879	1.2293	26.342	0.7025
2018	4	44	3717	1.1838	16.573	24.859	8.2863	177.56	4.735
2019	2	18	4662	0.3861	5.4054	8.1081	2.7027	57.915	1.5444
2020	14	360	5455	6.5995	92.392	138.59	46.196	989.92	26.398
2021	10	382	5029	7.5959	106.34	159.51	53.172	1139.4	30.384
Grand Total	31	811	22,849	3.5494	49.691	74.537	24.846	532.41	14.198

Analysis of Fungal Infection Risk Factors

Most patients had elevated hemoglobin A1C throughout the study period (79.7%, n = 21) with high fungal infections (n = 647). Only 4.8% (n = 2) had controlled HbA1C level with fungal infections (n = 39) and 15.4% had unknown levels (n = 6) with fungal infections (n = 125) (Table 3). In addition to diabetes other comorbidities were recorded as renal diseases of 40.8% (n = 331), respiratory of 15.2% (n = 124), Other (autoimmune) secondary injuries 11.7% (n = 95), Sepsis of 8.1% (n = 66), peripheral lower limb injuries of 8% (n = 65), head bleeding of 6.2% (n = 51), gastrointestinal tract diseases 6% (n = 49), Fever 2.2% (n = 18), and oncology of 1.4% (n = 12).

Table 3.

comorbidities in diabetic patients with fungal positive culture

Row Labels	Candida albicans	NAC	Grand Total	P value
Gastrointestinal tract	43	6	49	0.0002
female	33	0	33
male	10	6	16
Head bleeding	0	51	51
male	0	51	51
Oncology	0	12	12
female	0	12	12
Respiratory	117	7	124
female	117	7	124
Renal	86	245	331	< 0.0001
female	30	0	30
male	56	245	301
Fever	6	12	18
male	6	12	18
Other (autoimmune) secondary injuries	60	35	95
male	60	35	95
Peripheral lower limb injuries	0	65	65
female	0	53	53
male	0	12	12
Sepsis		66	66
male	0	66	66
Grand Total	312	499	811

Comorbidities involving the gastrointestinal tract, renal system, and peripheral lower limb injuries were observed in both genders. However, certain comorbidities appeared to be gender specific. Fever, sepsis, head bleeding, and other (autoimmune) secondary injuries were only seen in male patients, whereas oncology and respiratory related comorbidities were observed only in female patients (Table 3).

Analysis of Fungal Infection Types and Outcomes

Candida species was the causative pathogen in this study (Table 4). The most isolated species was Candida parapsilosis (40.9%, n = 332), followed by Candida albicans (38.4%, n = 312), Candida glabrata (10.7%, n = 87), Candida tropicalis (2.9%, n = 24), other unidentified Candida species (2.5%, n = 21), Candida krusei (2.4%, n = 20), Candida dubliniensis (1.1%, n = 9), and Candida lusitaniae (0.7%, n = 6). Overall non-Candida albicans showed a consistent increase reaching 258 episodes by 2021 (n = 168, n = 124). Candida albicans was also increasing a with a slight drop (2020–2021) compared to certain species only appeared in specific years such as Candida Krusei only in 2020, Candida lusitaniae only in 2018, Candida dubliniensis only in 2021, Candida tropicalis 2018 and 2020, Candida glabrata between 2019 and 2020. Candidiasis was varied according to infection level and species identified.Most were detected in systemic (73% n = 596) and subcutaneous (22%n = 179). The main pathogens in systemic infections were mainly caused by Candida parapsilosis (52.6%, n = 314), followed by Candida albicans (29%, n = 174). In subcutaneous infections were mainly caused by Candida albicans (73%, n = 132), followed by Candida krusei (11%, n = 20), Candida parapsilosis (10%, n = 18). In respiratory infections Candida tropicalis was the main pathogen (50%, n = 12), followed by Candida dubliniensis and Candida albicans (25%, n = 6) each. In Urinary infections Candida tropicalis was the only pathogen isolated (n = 6). In superficial infections Candida lusitaniae was the only pathogen reported. In females C. albicans was seen more than NAC specially in adults (adults = 130: seniors = 50) while NAC was more prevalent in seniors (seniors = 50, adults = 22) (p value < 0.0001). In male NAC was dominant in adults (adults = 310, seniors = 17), C. albicans was also more reported in adults (adults = 116, seniors = 16). (Table 5)

Table 4.

Emergence of resistant isolates of Candida species and resistance rate for each species

Candida species	Intermediate	resistant	Sensitive	Unknown	Resistance rate%
Candida albicans	0	0	298	14	0
Candida dubliniensis	0	1	8	0	12.5%
Candida glabrata	6	0	81	0	7.4%
Candida krusei	4	4	12	0	57.1%
Candida lusitaniae	0	0	6	0	0
Candida parapsilosis	9	25	297	1	11.4%
Candida sp.	0	0	21	0	0
Candida tropicalis	0	0	24	0	0
Grand Total	19	30	747	15

Table 5.

The overall microbial mortality outcome and comparative mortality between fungal infection classification and in resistant and sensitive spacies in diabetic patients (p value of < 0.5 was considered significant shown in bold)

Type of infection	Survival	Death	Grand Total	Mortality %	Comparative Mortality between fungal Type of infection in diabetic patients
Respiratory	6	18	24	75	<0.0001
Superficial	0	6	6	100
Urine	6	0	6	0
Subcutaneous	167	12	179	6.70391061
Systemic	318	278	596	46.6442953
Grand Total	497	314	811	38.7176326
Microbial species	Survival	Deaths	Grand Total	Mortality %	Comparative Mortality between sensitive & resistant isolates p value
Candida albicans (S)	176	122	298	40.9	0.1336
NAC	306	192	498	38.6
Candida dubliniensis	3	6	9	66.7
R	1	0	1	0
S	2	6	8	75
Candida glabrata	12	75	87	86.2	0.3099
I	0	6	6	100
S	12	69	81	85.2
Candida krusei	20	0	20	0
R	8	0	8	0
S	12	0	12	0
Candida lusitaniae (S)	0	6	6	100
Candida parapsilosis	265	66	331	19.9	0.0040
R	34	0	34	0
S	231	66	297	22.2
Candida sp. (S)	0	21	21	100
Candida tropicalis (S)	6	18	24	75
Grand Total	482	314	796	39.4

C. albicans was not seen in patients with certain comorbidities such as head bleeding, oncology, peripheral lower limb injuries, or sepsis (Table 3).

The susceptibility of various fungal species to the antifungal medication tested was evaluated (Table 4). The overall resistance of candidiasis was 6% (n = 49) of total tested Candida isolates. The highest was seen in 5-Fluorocytosine 2.6% (n = 21), Fluconazole 1.5% (n = 12), Caspofungin 1.3% (n = 10), Amphotericin B and Micafungin each accounting for 0.4% (n = 3). All these isolates were found in bloodstream infections only, which emerged during 2020 (n = 25) to 2021(n = 24). Resistant indicates the fungus may not respond to the treatment entirely. “Intermediate” resistance indicates the fungus may require higher doses of the medication or may not respond to treatment entirely. “Unknown” susceptibility indicates that the specific antifungal medication’s effectiveness against that isolate was not determined in this study.

A total of 811 fungal infection episodes caused by Candida species were analyzed for antifungal susceptibility. Of these, 747 episodes (92.1%) involved sensitive isolates, 30 (3.7%) involved resistant isolates, and 19 (2.3%) were classified as intermediate. Antifungal susceptibility data were unavailable for 15 episodes (1.8%). Resistance rates varied notably by species. C. krusei exhibited the highest resistance rate (57.1%), followed by C. dubliniensis (12.5%) and C. parapsilosis (11.4%). In contrast, C. albicans, C. tropicalis, C. lusitaniae, and Candida sp. showed no resistance.

The overall mortality rate was (n = 314/811, 38.7%). Mortality varied significantly by infection type (p < 0.000, Chi-square test). The highest mortality rate was observed in superficial infections (n = 6/6, 100%), followed by respiratory infections (n = 18/24, 75%) and systemic infections (n = 278/596, 46.6%). The mortality of superficial infections were likely associated with the patients’ underlying metabolic state rather than the superficial infection itself. Subcutaneous infections had a markedly lower mortality rate (n = 12/179, 6.7%), while no deaths were reported in urinary fungal infections (n = 0/6, 0%).

Mortality varied across species, and between resistant and sensitive isolates. The highest mortality was observed with C. lusitaniae, Candida sp., and C. glabrata (100%, 100%, and 86.2%, respectively), followed by C. tropicalis (75%) and C. dubliniensis (66.7%). No mortality was recorded in patients infected with C. krusei (0%). A statistically significant difference in mortality between resistant and sensitive isolates was observed only in C. parapsilosis: mortality was 0% (n = 34; 0/34) in patients with resistant isolates, compared to 22.2% (n = 297; 66/297) in those with sensitive isolates (P = 0.004, Chi-square test). For other species, including C. glabrata (P = 0.3099) and C. dubliniensis (P = 0.1336), the difference between resistant and sensitive isolates was not statistically significant.

Results for Glucose, Lipids and Biochemical Assays

Diabetic patients, particularly males and those with poor blood sugar control (high fasting glucose and HbA1c levels) are at a higher risk of fungal infections (Table 6). The most common fungal agents were Candida parapsilosis (n = 332, 41%) and Candida albicans (n = 312, 39%), together accounting for approximately 80% of the total 811 fungal isolates (Table 6). High fasting glucose levels are associated with the majority of fungal infections (n = 633, 78%). However, normal glucose levels (n = 94, 12%) and low glucose levels (n = 84, 10%) have fewer cases. High HbA1c levels (indicative of poor blood sugar control) are correlated with a high prevalence of candidiasis (n = 647, 80%). Whereas normal HbA1c levels show a very low presence of infections (n = 39, 5%).

Table 6.

Demographics, Complete blood count, blood glucose blood profiles for fungal infection episodes in 29 T2DM patents with nationality 25 Saudi, 4 non-Saudi patients)

	C.albicans	C.dubliniensis	C. glabrata	C.krusei	C.lusitaniae	C.parapsilosis	Candida sp.	C.tropicalis	Total	%	P value
Nationality	312	9	87	20	6	332	21	24	811	-	< 0.0001
NON-SAUDI	25	-	12	-	-	7	-	6	50	6.1
SAUDI	287	9	75	20	6	325	21	18	761	93.8
Gender	312	9	87	20	6	332	21	24	811	-	< 0.0001
female	180	-	15	20	6	25	-	6	252	31.1
male	132	9	72	-	-	307	21	18	559	68.9
Age	312	9	87	20	6	332	21	24	811		< 0.0001
Adults (< 60)	246	-	15		-	296	21	-	578	71.3
Seniors (> 60)	66	9	72	20	6	36	-	24	233	28.7
RBCs	312	9	87	20	6	332	21	24	811	-	< 0.0001
Low	155	9	72	20	6	325	21	18	626	77.2
Normal	157	-	15	-	-	7	-	6	185	22.8
WBS	312	9	87	20	6	332	21	24	811	-	< 0.0001
High	122	3	15	-	6	138	-	6	290	35.7
Low	70	-	12	-	-	65	-	12	159	19.6
Normal	120	6	60	20	-	129	21	6	362	44.6
Hemoglobin	312	9	87	20	6	332	21	24	811	-	< 0.0001
Normal	66	-	15	20	-	-	-	6	107	13.2
Low	246	9	72	-	6	332	21	18	704	86.8
HCT	312	9	87	20	6	332	21	24	811	-	< 0.0001
Low	180	9	72		6	332	21	18	638	78.6
Normal	132	-	15	20	-	-	-	6	173	21.3
Platelet	312	9	87	20	6	332	21	24	811	-	< 0.0001
High	31	3	-	-	-	18	-	-	52	6.4
Low	143	6	75		6	25	21	12	288	35.5
Normal	138	-	12	20	-	289	-	12	471	58.1
BMI	312	9	87	20	6	332	21	24	811	-	< 0.0001
Underweight	33	-	-	-	-	-	-	6	39	4.8
Normal	72	-	-	20	6	266	21	12	397	48.9
Overweight	60	9	27	-	-	66		6	168	20.7
obese	147	-	60	-	-	-	-	-	207	25.5
Fasting glucose	312	9	87	20	6	332	21	24	811	-	< 0.0001
High	180	9	75	20	6	325		18	633	78.1
Low	56	-	-	-	-	7	21	-	84	10.3
Normal	76	-	12	-	-	-	-	6	94	11.6
HBA1C	312	9	87	20	6	332	21	24	811	-	< 0.0001
Unknown	40	-	60	-	-	25	-	-	125	15.4
Normal	33	-	-	-	6	-	-	-	39	4.8
female	33	-	-	-	6	-	-	-	39	-
High	239	9	27	20		307	21	24	647	-
female	117	-	15	20	-	-	-	6	158	-
male	122	9	12	-	-	307	21	18	489	79.8

Comorbid conditions such as high cholesterol, elevated triglycerides, high LDL levels, and obesity further increase the risk of fungal infections. A significant proportion of patients with high cholesterol levels also have fungal infections (Table 7). High triglyceride levels are prevalent among patients with fungal infections. Also, elevated LDL cholesterol levels are observed in many patients suffering from fungal infections. Impaired kidney function, as indicated by elevated creatinine levels, also correlates with a higher frequency of fungal infections in diabetic patients. High creatinine levels, indicative of impaired kidney function, are associated with a higher incidence of fungal infections (n = 559, 69%). In details, Candida dubliniensis comprises 1% (n = 9), Candida krusei comprises 2.5% (n = 20), and Candida lusitaniae comprises 0.7% (n = 6).

Table 7.

Lipid profiles and CRP fungal infection episodes in 29 T2DM patients

Parmeter /Organisms	C.albicans	C.dubliniensis	C.glabrata	C.krusei	C.lusitaniae	C.parapsilosis	Candida sp.	C.tropicalis	Total	%	P value
Creatinine	312	9	87	20	6	332	21	24	811		< 0.0001
High	122	-	60	-	-	332	21	24	559	68.9
Low	33	-	-	20	-	-	-	-	53	6.5
Normal	157	9	27	-	6	-	-	-	199	24.5	Normal
HDL	312	9	87	20	6	332	21	24	811		< 0.0001
Unknown	77	-	-	-	-	18	-	-	95	11.7
Low	16	-	15	-	6	51	-	18	106	13.1
Normal	219	9	72	20	-	263	21	6	610	75.2
Cholesterol	312	9	87	20	6	332	21	24	811		< 0.0001
High	-	-	12	-	-	-	-	-	12	1.5
Low	33	9	-	-	-	-	-	-	42	5.2
Normal	279	-	75	20	6	332	21	24	757	93.3
Triglyceride	312	9	87	20	6	332	21	24	811		< 0.0001
unknown	-	-	60	-	-	-	-	-	60	7.4
Normal	275	9	27	20	6	260	21	24	642	79.2
High	37	-	-	-	-	72	-	-	109	13.4
LDL	312	9	87	20	6	332	21	24	811		< 0.0001
unknown	234	9	12	-	6	43	21	18	343	42.3
Low	12	-	60	-	-	289	-	6	367	45.3
Normal	66	-	15	20	-	-	-	-	101	12.4
Alkaline-phosphates	312	9	87	20	6	332	21	24	811		< 0.0001
High	96		75			188	21	18	398	49.1
Low		-	-	-	6	-	-	-	6	0.7
Normal	216	9	12	20		144		6	407	50.1
CRP	312	9	87	20	6	332	21	24	811		< 0.0001
Unknown	195	-	27	20	6	44	-	6	298	36.7
High	78	9	60	-	-	288	21	12	468	57.7
Normal	39	-	-	-	-	-	-	6	45	5.5

Discussion

This study investigated fungal infections in a diabetic population over a five-year period. We report the high prevalence of fungal infections in diabetic patients with poor glycemic control. Most of the study subjects and episodes belong to Saudi population (94%), thus representing local demographics. Diabetic patients had a significantly higher number of fungal infection episodes compared to non-diabetic patients, despite being a smaller group. Similar to previously published data most Diabetic patients with fungal infections were from new clinic [13]. Thus, indicate patients with diabetes had higher blood sugar levels prior to being diagnosed, and the majority of them were uncontrollable as a result, the prevalence of fungal infections was higher in this group. Almost 80% of diabetic patients with fungal infections had uncontrolled HbA1c levels, indicating poor blood sugar management [14]. The findings from the study highlight the significant burden of fungal infections among type 2 diabetic patients, emphasizing the importance of stringent blood glucose control and regular monitoring of potential infection markers. The high prevalence of Candida species as causative agents aligns with the global trend of Candida infections being common in immunocompromised individuals, including diabetics. According to Pfaller and Diekema study, Candida species are the leading cause of fungal infections in immunocompromised patients, including those with diabetes, due to their ability to colonize and infect various body sites under conditions of impaired immunity [14]. Hyperglycemia has been shown to impair neutrophil function, reduce cytokine production, and promote fungal growth, increasing infection susceptibility in diabetic patients [15]. Dyslipidemia, common in diabetic patients, has been linked to increased infection rates due to its impact on immune cell function and overall metabolic health [16]. Chronic kidney disease in diabetic patients is associated with increased infection risk due to reduced immune surveillance and the presence of uremic toxins that impair immune function [17].

The incidence of fungal infections in the diabetic population showed considerable fluctuation over the five-year study period, rising from 0.1756 per 100 population in 2016 to 7.5959 in 2021. The highest rise occurred between 2019 (0.3861) and 2020 (6.5995). This can be linked to the recent enhancement in clinical awareness and fungal diagnostics in developing countries [18]. Another contributing factor to the increased incidence of fungal diseases in 2020 is the emergence of COVID-19 and its associated clinical practices, including steroid use, broad spectrum antibiotics, and extended hospitalizations. A retrospective study conducted at King Fahd Hospital of the University in Saudi Arabia between March 2020 and September 2021 revealed a notable rise in secondary fungal infections among critically ill COVID-19 patients. Of the 314 ICU patients included in the study, 25.2% developed secondary fungal infections, predominantly caused by Candida species, with C. albicans, C. tropicalis, and C. parapsilosis being the most common. These infections were significantly associated with invasive mechanical ventilation [19]. This trend is consistent with global findings that reported a rise in Candida infections among COVID-19 patients, particularly those with diabetes. The rise in Candida infections has been attributed to the fact that critically ill COVID-19 patients often require ICU admission and mechanical ventilation, which increase the risk of acquiring nosocomial fungal infections. Additional contributing factors include immune dysfunction, prolonged hospitalization, and the use of broad-spectrum antibiotics [20–22].

The Diabetic population has seen a significant global increase in recent decades thus increasing the number of patients susceptible to fungal infections. Global estimates for the prevalence of diabetes across all age categories rose from 2.8% in 2000 to 4.4% in 2030 [23]. It is anticipated that by 2030, there will be 366 million diabetics worldwide, up from 171 million in 2000 [23]. The rise in the percentage of adults over 65 was the most significant demographic shift affecting the prevalence of diabetes worldwide [23]. The older population frequently suffer from deteriorating immune system, especially those who have diabetes. Other factors that increase with age and may further weaken the immune system and increase vulnerability in diabetics, such as the use of chemotherapy, immunosuppressive medications to treat autoimmune disorders, avoid transplant rejection, or antibiotics use which creates a microbial imbalance allowing opportunistic fungi to invade [24]. A notable limitation of this study is the relatively small number of individual diabetic patients (n = 29) who yielded positive fungal cultures compared to the non-diabetic cohort. However, this small subset generated a disproportionately high volume of clinical episodes (n = 811), resulting in a mean of 28.0 episodes per patient. This high frequency suggests that in the Medina region, a specific phenotype of poorly controlled diabetic patients may experience chronic, recalcitrant fungal colonization rather than isolated acute infections. While the small n-size limits the generalizability of the findings to all diabetic patients, it highlights a critical ‘high-utilizer’ group that significantly drives the 54-fold increase in hospital fungal burden over the study period.

This study also highlighted the growing threat of fungal infections concerning diabetes in healthcare settings. Candida species, particularly C. parapsilosis and C. albicans, were the most common fungal pathogens identified. There was a concerning rise in non- Candida albicans (NAC) species, known for their potential resistance to antifungal medications. Fungal infections were most prevalent in the bloodstream and subcutaneous tissues. C. parapsilosis was the leading cause in systemic infections, while C. albicans dominated in subcutaneous infections. These results align with the global statistics of predominance of C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei [25–28].

C. albicans was more common in females, especially adults, while NAC species were more prevalent in senior males (p value < 0.0001). This suggests potential gender-based differences in susceptibility factors. While this study observed a predominantly male population among patients with fungal infections, further investigation is needed to determine the cause of this disparity. Factors beyond HbA1c control, such as hormonal, occupational exposures, or underlying health conditions, may also play a role. Research have shown the influence of estrogen, on the susceptibility of females to C. albicans infections [29]. Estrogen promotes the virulence of C. albicans by upregulation of the GPD2 gene, reducing immune recognition and enhancing its ability to evade the host’s immune [29]. There’s a notable exception in certain occupational settings, especially in Saudi Arabia. In the past, males were more involved in outdoor professions, including construction, agriculture, and oil and gas industries. These occupations often expose individuals to dusty and damp environments, which are ideal breeding grounds for various fungal species [30]. Thus, protective gear usage is necessary yet, adherence to the proper usage may vary. Males might be less likely to consistently wear masks, gloves, and protective clothing, especially in hot and humid conditions. Males might be less likely to seek medical attention for early symptoms, leading to delayed diagnosis and treatment [31]. Diabetic patients with fungal infections often had additional health complications, including renal issues, respiratory problems, and peripheral limb injuries [32, 33]. Certain comorbidities, like oncology and respiratory problems, were more frequent in females, while others like sepsis were seen only in males. Research on the impact of specific comorbidities on fungal infections in diabetics is needed as the sample size was limited.

A small but significant percentage of Candida isolates exhibited resistance to antifungal medications (6%), particularly bloodstream infections. This aligns with a study comparing susceptibility of 207 Candida sp. isolates from Iranian patients to caspofungin, 9.7% of the isolates exhibited resistance to caspofungin [34]. These non-sensitive isolates were mainly found in patients with cancer, diabetes mellitus and AIDS [34]. Other studies reported higher – lower percentage of resistances ranging from 3% to 37% depending on the region, disease and antifungal used [35, 36]. In this study, C. krusei demonstrated the highest resistance rate (57.1%). This finding is consistent with global reports that C. krusei is intrinsically resistant to fluconazole and shows reduced susceptibility to several antifungal agents [37, 38]. This alignment highlights the importance of implementing routine susceptibility testing, particularly in clinical settings where C. krusei is isolated. However, our data also showed that C. parapsilosis accounted for the highest number of resistant isolates (n = 34), despite its lower resistance rate (11.4%). This high number reflects its clinical relevance and widespread occurrence in our setting. A significant rise in fluconazole-resistant C. parapsilosis isolates was observed in Kuwait between 2012 and 2015, as reported by Asadzadeh et al. [39]. They found that 15 out of 442 C. parapsilosis isolates (3.4%) were resistant to fluconazole, and resistance was linked to mutations in the ERG11 gene and efflux pump overexpression, highlighting the need for continued antifungal susceptibility monitoring in the region. Furthermore, a global systematic review and meta-analysis of 79 studies estimated pooled resistance rates of C. parapsilosis to 3 of the most important antifungal drugs: fluconazole, amphotericin B, and voriconazole at 15.2%, 1.3%, and 4.7%, respectively, emphasizing its emerging resistance profile [40].

C. parapsilosis could form biofilm and the synthesis of phospholipase and aspartyl protease seem to be linked to virulence in particular to catheter-related candidemia [41]. Candida dubliniensis had only one resistant isolate while Candida krusei displayed four resistant isolates. Overall, Candida albicans, Candida lusitaniae, and Candida tropicalis showed complete susceptibility to the antifungal medication tested in this study. Candida glabrata and Candida parapsilosis also showed a notable percentage of isolates with intermediate resistance. Previous studies reported paradoxical growth (low to intermediate susceptibility) in C.tropicalis, C. parapsilosis, C. albicans, C. dubliniensis, and C. krusei [42]. This has been connected to the activation of temporary compensatory processes that cause cells faced with a high drug concentration to accumulate chitin and decrease their β [1, 3]-glucan content. It is important to note that susceptibility testing was not performed on a portion of the isolates for several Candida species which may explain some of the recurrent infections and failed treatment in the study population. This highlights the need for continued monitoring of antifungal resistance patterns.

The variation in mortality across fungal infection types and species in our study highlights the multifactorial nature of fungal infections outcomes. The highest mortality rate was observed in infections caused by C. lusitaniae, Candida sp., and C. glabrata (100%, 100%, and 86.2%, respectively), as well as in superficial (100%), respiratory (75%), and systemic infections (46.6%). These findings are in line with previous studies reporting higher mortality in non-albicans Candida infections, particularly those caused by C. glabrata [43]. Furthermore, A review on C. glabrata invasive candidiasis reported that mortality frequently ranges from 40% to 60%, primarily due to its inherent reduced susceptibility to the most commonly used azoles and increased virulence [44]. The high mortality observed in our study in respiratory and systemic fungal infections is consistent with evidence demonstrating the severity of invasive and respiratory candidiasis. Globally, the mortality associated with candidemia and disseminated Candida infections is estimated to be around 30% [45]. Additionally, a study has shown that Candida colonization in respiratory tract is linked to higher hospital mortality, especially in patients on mechanical ventilation [46].

The study doesn’t determine the prevalence of fungal infections due to the varying durations of different infections. No reports of mould infections were found which might be due to diagnostic testing biased that we are selecting for yeast. Respiratory infections, which are typically caused by viruses or bacteria, weren’t a primary area of investigation in this analysis. The use of conventional detection methods which included culture-based techniques and microscopy may not detect all fungal species compared to molecular techniques. The study focused on diagnosed fungal infections, not fungal colonization or co-infections. The colonization of the fungal isolates was unique to each participant since it was found that none of the patients had numerous fungal growths. Further research is needed to understand the rise in fungal infections and the gender disparities need further investigation. Developing strategies to improve glycemic control, reduce polypharmacy and prevent fungal infections in diabetic populations is crucial. Analyzing if specific medications are used to manage diabetes, or antibiotics, corticosteroids are associated with fungal infection risk [47]. It is necessary to consider the risk of drug interactions as well as the burden of pills, which is already quite high [48].

Conclusions

The study highlights the significant burden of fungal infections among type 2 diabetic patients, particularly those with poor glycemic control. Emphasizing the importance of stringent blood glucose control and regular monitoring of potential infection markers. The high prevalence of Candida species as causative agents aligns with the global trend of Candida infections being common in immunocompromised individuals, including diabetics. dominance of NAC species, and emergence of antifungal resistance pose serious challenges. The study underscores the complex interplay between diabetes, poor glycemic control, dyslipidemia, renal dysfunction, and the heightened risk of fungal infections. Therefore, implementing comprehensive management strategies for diabetic patients, including regular screening for infections and maintaining optimal metabolic control, is crucial to reducing the incidence and severity of these infections.

Author Contributions

Conceptualization, methodology, formal analysis, AK, HS; investigation, resources, WS, ZA, AK; data curation, AK, AB.; writing—original draft preparation, AK; writing—review and editing, WS, ZA, HS visualization, AK.; supervision, AK, WS; project administration, AK. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethical Standards

This study was conducted in accordance with the ethical standards of AL Madinah Health Cluster, Saudi Arabia. Ethical approval for this study was obtained from (IRB: 2021-206).

Clinical Trial Number

Not Applicable.

Informed Consent

Patient consent was waived due to the nature of the study being retrospective.

Competing of Interest

The authors declare no competing interests.