Candidemia chronicles: Retrospective analysis of candidemia epidemiology, species distribution, and antifungal susceptibility patterns in Bahrain

Abstract

BACKGROUND

Invasive fungal infections, particularly candidemia, pose significant clinical challenges globally. Understanding local epidemiology, species distribution, and antifungal susceptibility patterns is crucial for effective management despite regional variations.

AIM

To investigate the epidemiology, species distribution, antifungal susceptibility patterns, and associated risk factors of candidemia among patients in Bahrain from 2021 to 2023.

METHODS

This retrospective study analyzed demographic data, Candida species distribution, antifungal susceptibility profiles, and risk factors among candidemia patients treated at a tertiary care hospital in Bahrain over three years. Data was collected from medical records and analyzed using descriptive statistics.

RESULTS

A total of 430 candidemia cases were identified. The mean age of patients was 65.7 years, with a mortality rate of 85.5%. Candida albicans (C. albicans) was the most common species, followed by Candida parapsilosis, Candida tropicalis (C. tropicalis), and emerging multidrug-resistant Candida auris (C. auris). Antifungal susceptibility varied across species, with declining susceptibility to azoles observed, particularly among C. albicans and C. tropicalis. Major risk factors included central venous catheters, broad-spectrum antibiotics, and surgical procedures.

CONCLUSION

This study highlights the substantial burden of candidemia among older adults in Bahrain, characterized by diverse Candida species. It also concerns levels of antifungal resistance, notably in C. auris. The findings underscore the importance of local epidemiological surveillance and tailored treatment strategies to improve outcomes and mitigate the spread of multidrug-resistant Candida species. Future research should focus on molecular resistance mechanisms and optimizing therapeutic approaches to address this growing public health concern.

Key Words: Candidemia; Fungal infections; Antifungal resistance; Epidemiology; Risk factors; Antifungal susceptibility; Bahrain

Core Tip: This study underscores the significant burden of candidemia in Bahrain, highlighting demographic trends, species distribution, antifungal susceptibility patterns, and critical risk factors over three years. The emergence of multidrug-resistant Candida species, particularly Candida auris, poses challenges to clinical management. High mortality rates underscore the critical need for early detection, prompt initiation of appropriate antifungal therapy guided by susceptibility testing, and rigorous infection control measures. Healthcare providers should prioritize antimicrobial stewardship, minimize invasive procedures when possible, and enhance surveillance efforts to mitigate the rising threat of antifungal resistance and improve patient outcomes in candidemia management.

INTRODUCTION

Candida is a type of yeast that naturally occurs in small amounts in the human body. It can be found ‎naturally in the gastrointestinal tract, mouth, and genital area. Candida typically lives in harmony with ‎other microorganisms and usually does not cause any harm. Nonetheless, specific circumstances, such as ‎a weakened immune system or an imbalance in the body's natural microbiota, can cause Candida to ‎overgrow and result in infections. The most typical form of Candida infection is candidiasis, which can ‎manifest in several ways, including oral thrush, vaginal yeast infection, cutaneous candidiasis, and ‎invasive candidiasis[1,2].‎ Human disease caused by Candida species is attributed to at least 15 distinct types. However, most invasive diseases, accounting for over 95%, can be traced back to the six most prevalent pathogens. These include Candida albicans (C. albicans), Candida auris (C. auris), Candida glabrata (C. glabrata), Candida krusei, Candida parapsilosis (C. parapsilosis), and Candida tropicalis (C. tropicalis) in certain regions[3].

Candidemia is a serious bloodstream infection caused by Candida species and is the most common form of invasive candidiasis. Its high morbidity and mortality rates pose a significant threat to healthcare facilities worldwide[4]. This infection is particularly dangerous for individuals with weakened immune systems and those hospitalized for an extended period. The early identification and management of this infection is often delayed, leading to severe clinical decline and fatalities that occur before the detection of Candida in blood cultures[5]. Understanding the incidence, predisposing factors, and antifungal susceptibility patterns of Candida isolates in specific regions is crucial for effectively preventing and managing this infection[6].

The prevalence of candidemia varies among different geographical regions and healthcare facilities. Factors like patient demographics, local prescribing practices, and infection control measures influence this prevalence[7]. Furthermore, understanding the risk factors associated with candidemia is vital for early identification and implementation of preventive measures. Several known risk factors, such as prolonged hospitalization, use of broad-spectrum antibiotics, and presence of central venous catheters (CVCs), have been implicated in candidemia[8]. Meanwhile, addressing the antifungal susceptibility patterns of Candida isolates is crucial to ensure proper treatment strategies. Resistance to commonly used antifungal agents, such as fluconazole and echinocandins, has been reported in various regions worldwide[9].

Investigating the antifungal susceptibility profiles of Candida isolates in Bahrain will aid in optimizing empirical therapy and formulating guidelines for antifungal use in clinical practice. Addressing the antifungal susceptibility patterns of Candida isolates is crucial to ensuring proper treatment strategies. Resistance to commonly used antifungal agents, such as fluconazole and echinocandins, has been reported in various regions globally. By examining the antifungal susceptibility profiles of Candida isolates in Bahrain, we can optimize empirical therapy and establish guidelines for antifungal use in clinical practice[10,11]. Like other parts of the world, the United Kingdom of Bahrain, a small island nation in the Arabian Gulf, has witnessed an increase in candidemia cases over the past decade[12]. However, no available comprehensive studies specifically focused on candidemia in Bahrain exist. There is no available data concerning the infection rate, the type of Candida species implicated in candidemia, and their antifungal susceptibility patterns.

Bahrain boasts a well-developed healthcare system that provides comprehensive medical services to its population. The country has a mix of public and private healthcare facilities, with the public sector being the primary provider of health services[13]. The Ministry of Health oversees public healthcare services, ensuring access to primary, secondary, and tertiary care. Bahrain's healthcare system is funded through government subsidies, employer contributions, and out-of-pocket payments[14]. Bahrain has a population of approximately 1.7 million people, with a significant expatriate community. The population growth rate is around 2%, driven by both natural increase and immigration[15]. The population includes a substantial proportion of young adults and working-age individuals, but there is also a growing elderly population due to increasing life expectancy. Bahrain's healthcare system is characterized by its accessibility, comprehensive services, and a blend of public and private healthcare facilities[16]. The government's commitment to providing free healthcare to citizens and the presence of a significant private sector cater to the diverse needs of the population.

This research article aims to bridge this knowledge gap by providing a detailed analysis of candidemia cases in Bahrain between 2021 and 2022. By examining candidemia within a central tertiary care hospital setting in Bahrain, this study seeks to shed light on the local burden of candidemia, providing valuable insights into the epidemiology of this infection, exploring the risk factors specific to the studied cohort, shedding light on the regional determinants contributing to candidemia incidence in the United Kingdom of Bahrain.

MATERIALS AND METHODS

Study design and setting

We retrospectively observed and analyzed the Candida profile of the patients admitted to the various departments of Salmanyia Medical Complex, United Kingdom of Bahrain, between January 2021 and December 2023, with positive blood culture of Candida species. Data were extracted and reviewed from the inpatients’ electronic health medical records from all government hospitals’ inpatients. The demographics, clinical data, microbiological profile, and included patient outcomes were extracted and tabulated using the Microsoft Excel database. We ensured that the data collection was systematic and consistent.

Definitions

Candidemia is defined by direct fungal detection in blood cultures. Despite blood culture being the gold standard to diagnose candidemia, it has many limitations, such as low sensitivity (between 21% and 71% in some studies) and the long time needed for the culture to yield results. It also cannot detect deep-seated infections after resolving candidemia. Other tests, such as anti-mannan antibodies, Candida mannan antigen, and B-d-glucan, can help to get rapid results but with high false positive results[17,18]. The study involved patients who had tested positive for Candida in their blood culture at least once. When a patient had multiple positive cultures, a new episode was only considered if the interval between it and the previous episode was more than two weeks[19]. Isolates were considered duplicates and ignored when identified from the same patient with the same Candida species and antifungal profile.

Laboratory technique

Clinical samples were ordered when fungal infection was clinically suspected or in high-risk patients. We incubated the blood culture bottles using BD Bactec (BioMérieux^®). We identified the fungal species using Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS, Bruker^®) and used broth microdilution method (Bruker^®) to identify the antifungal susceptibility following the manufacturer's instructions[20]. We tested fungal susceptibility to 5-fluorocytosine, amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole, and voriconazole[21]. We used the epidemiological cutoff values according to European Committee on Antimicrobial Susceptibility Testing recommendations. Phenotypic detection was done using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Bruker Daltonics, Germany). For C. auris, Food and Drug Administration Epidemiological cutoff values were used to interpret the minimal inhibitory concentrations[22].

Statistical analysis

For the statistical analysis, we utilized TexaSoft, WINKS Sialodacryoadenitis virus Software 2011 (Sixth Edition, Cedar Hill, Texas, United States) while collating all data on Excel 2017 (Microsoft, Redmond, WA, United States). We calculated the frequencies and percentages for different categorical variables and performed cross-tabulation between each two categorical variables. We conducted a χ² test to detect significant relationships between the variables and considered a P value of less than 0.05 statistically significant. A biomedical statistician conducted the statistical review of this study, and all data were anonymized.

Ethical approval

The Secondary Care Research Committee of Salmaniya Medical Complex, Ministry of Health, United Kingdom of Bahrain, has approved the study. However, ethical consideration was unnecessary as it was a non-interventional, retrospective study that did not expose patient data.

RESULTS

This retrospective study investigated the prevalence, risk factors, and antifungal susceptibility patterns of candidemia in patients admitted to Salmaniya Medical Complex, Bahrain, between January 2021 and December 2023. Table 1 displays the demographic data of patients diagnosed with candidemia during the study period. Over this period, 430 patients were identified with candidemia. The data reveals a slight decrease in cases yearly: 161 cases in 2021, 143 in 2022, and 126 in 2023. The mean age of the patients remained relatively stable, around 65.7 years ± 18.8 years, with a median age consistently around 70 years. The male-to-female ratio was nearly equal across the years. The gender distribution was nearly balanced, with a male-to-female ratio of approximately 1.1:1; males constituted 52.3% (225/430) and females 47.7% (205/430) of the cases. Bahraini nationals consistently comprised the majority of the patients. They represented 85% (365/430) of the patients, while non-Bahrainis comprised 15% (65/430). The overall mortality rate among these patients was 85.5% (368/430). The mortality rate among candidemia patients was alarmingly high, averaging 85.5% over the three years. This high mortality rate underscores the severity and impact of candidemia on the affected population.

Table 1 Demographic data of patients affected with fungemia over the three years of the study, n (%).

		2021	2022	2023	Total
Total number		161	143	126	430
Age (years)	mean ± SD	66.9 ± 26.7	68.6 ± 18.8	62.87 ± 19	65.7 ± 18.8
	Median	70	72	68	70
Sex	Male	84 (52.2)	79	62	225
	Female	77 (47.8)	64	64	205
	Male:female ratio	1.1:1	1.23:1	0.96:1	1.1:1
Nationality	Bahraini	131 (81.4)	123 (86)	111 (88)	365 (85)
	Non-Bahraini	30 (18.6 )	20 (14)	15 (12)	65 (15)
Prognosis	Live	23 (14.3)	26 (18.2)	13 (10)	62 (14.5)
	Deceased	138 (85.7)	117 (81.8)	113 (90)	368 (85.5)
Candida species	Candida albicans	48 (30)	22 (15.4)	33 (26.2)	103 (24)
	Candida tropicalis	30 (18.6)	29 (20.3)	23 (18.2)	82 (19)
	Candida parapsilosis	29 (18)	36 (25.2)	29 (23)	94 (22)
	Candida glabrata	19 (11.8)	7 (5)	10 (8)	36 (8)
	Candida auris	13 (8)	38 (26.5)	27 (23)	78 (18)
	Candida species	6 (3,7)	1 (0.7)	0	7 (1.6)
	Candida dubliniensis	4 (2.5)	1 (0.7)	1 (0.7)	6 (1.3)
	Candida lusitaniae	3 (1.9)	1 (0.7)	2 (1.4)	6 (1.3)
	Candida orthopsilosis	3 (1.9)	3 (2)	1 (0.7)	7 (1.6)
	Candida guilliermondii	2 (1.25)	0	0	2 (0.4)
	Candida metapsilosis	2 (1.25)	3 (2)	1 (0.7)	6 (1.3)
	Candida rugosa	2 (1.25)	0
	Candida krusei	0	2 (1.4)	1 (0.7)	3 (0.7)
	Candida Cyberlindnera fabianii	1 (0.65)	0	0	1 (0.2)
	Rhodotorula mucilaginosa var mucilaginos	1 (0.65)	0	0	1 (0.2)

The distribution of Candida species detected from patients with fungemia, also presented in Table 1, Figures 1, and 2, varied across the years. C. albicans was the most frequently isolated species, accounting for 24% (103/430) of the cases. C. parapsilosis was identified in 22% (94/430) of patients, C. tropicalis in 19% (82/430), C. auris in 18% (78/430), and C. glabrata in 8% (36/430). Examining the distribution of Candida species over the three years, C. albicans was consistently the most common species, though its prevalence fluctuated, being highest in 2021 (30%) and lowest in 2022 (15.4%). C. parapsilosis showed an increasing trend, rising from 18% in 2021 to 25.2% in 2022, then slightly decreasing to 23% in 2023. C. tropicalis maintained a relatively stable presence, around 18%-20% each year. The incidence of C. auris saw a significant rise, from 8% in 2021 to 26.5% in 2022, then slightly decreased to 23% in 2023. C. glabrata showed a decreasing trend, from 11.8% in 2021 to 5% in 2022 and 8% in 2023. Other less common Candida species, such as C. dubliniensis, C. lusitaniae, C. orthopsilosis, and others, remained relatively rare throughout the study period.

Figure 1 The percentage of candida species during the 3 years periods. C. albicans: Candida albicans; C. tropicalis: Candida tropicalis; C. parapsilosis: Candida parapsilosis; C. glabrata: Candida glabrata; C. auris: Candida auris.

Figure 2 The percentage of the different species throughout the study period. C. albicans: Candida albicans; C. tropicalis: Candida tropicalis; C. parapsilosis: Candida parapsilosis; C. glabrata: Candida glabrata; C. auris: Candida auris.

Table 2 summarizes the risk factors associated with invasive fungal infections. Several key risk factors were identified among patients with candidemia. The use of CVCs and other intravascular devices was particularly high, reported in 89.4% of patients in 2021, 92% in 2022, and 90% in 2023. Recent major surgery was noted in 18.5% of patients in 2021, 20% in 2022, and 15% in 2023. Vascular anastomosis was observed in 2%, 5%, and 3% of patients in 2021, 2022, and 2023, respectively. Necrotizing pancreatitis was reported in 0% of patients in 2021, 2% in 2022, and 4% in 2023. Candida colonization was present in 93.4% of patients in 2021, 87% in 2022, and 91% in 2023. Broad-spectrum antibiotic exposure was extremely common, observed in 98.7% of patients in 2021, 95% in 2022, and 96% in 2023. Dialysis was required in 17.2% of patients in 2021, 15% in 2022, and 19% in 2023. Parenteral nutrition was administered to 76.8% of patients in 2021, 81% in 2022, and 77% in 2023. Corticosteroid use was noted in 32.4% of patients in 2021, 42% in 2022, and 35% in 2023. Prior antifungal treatment was recorded in 47.7% of patients in 2021, 53% in 2022, and 49% in 2023.

Table 2 Risk factors associated with fungal infections.

Risk factors	2021 (n = 161)	2022 (n = 143)	2023 (n = 126)
Recent major surgery	18.5	20	15
Vascular 0 anastomosis	2	5	3
Necrotizing pancreatitis	0	2	4
Central venous catheters and other intravascular devices	89.4	92	90
Candida colonization	93.4	87	91
Exposure to broad spectrum antibiotics	98.7	95	96
Dialysis	17.2	15	19
Parenteral nutrition	76.8	81	77
Corticosteroids	32,4	42	35
Antifungal Rx	47.7	53	49

Table 3 provides the antifungal susceptibility profiles for the most common Candida species detected among the patients. C. albicans demonstrated 100% susceptibility to amphotericin B across all three years. However, susceptibility to fluconazole declined from 87.5% in 2021 to 52.3% in 2023. Voriconazole susceptibility also showed variability, with the highest rate in 2021 (79%) and the lowest in 2022 (63.6%). Susceptibility to posaconazole and itraconazole decreased over the years, with posaconazole dropping from 68.2% in 2021 to 36.4% in 2023, and itraconazole from 75% to 13.6%. Susceptibility to echinocandins (micafungin, anidulafungin, and caspofungin) remained at 100%.

Table 3 Antifungal susceptibility for the most common fungal strains detected from patients with fungaemia.

Candida species	Year	Number	Age (years)	Male:female	Death	Amphotericin B	5-fluorocytosine	Fluconazole	Voriconazole	Posaconazole	Itraconazole	Micafungin	Anidulafungin	Caspofungin
Candida albicans	2021	48	65.1 ± 18	0.7	89.5	100	N/A	87.5	79	68.2	75	13	21	100
	2022	24	71.6 ± 18.7	1.2:1	77.3	100	N/A	63.6	63.6	45.5	45.5	54.5	36.4	100
	2023	33	66.5 ± 15.6	1.5:1	80	100	N/A	52.3	71.4	66.6	36.4	13.6	13.6	100
	Total	103	66 ± 18.8	1:1	83	100	N/A	71	74.5	62.2	51	21.4	21	100
Candida tropicalis	2021	31	66.6± 14.7	1.9:1	89.6	100	N/A	15.7	10.5	5.5	10.5	N/A	0	0
	2022	29	65.6 ± 22	0.93	72	82	N/A	9	9	0	0	N/A	0	0
	2023	23	67.4 ± 19.4	1.1:1	92	100	N/A	0	0	0	0	0	0	0
	Total	83	67± 18.3	1.2:1	83	95.5	N/A	8.8	6.6	2.2	4.6	0	0	0
Candida parapsilosis	2021	27	61.2 ± 22.2	1.3:1	92	100	N/A	82	100	91	100	100	100	100
	2022	36	70.4 ± 14.9	1.1:1	87	100	N/A	68	95	95	95	100	100	100
	2023	29	61.7 ± 20.6	0.93:1	85.7	100	N/A	76.5	94	94	88.2	100	100	100
	Total	93	64.9 ± 196	1.1:1	88.5	100	N/A	75.7	95.6	93.7	93.2	100	100	100
Candida glabrata	2021	18	64.2 ± 13.7	2.2:1	94.7	100	N/A	0	N/A	N/A	N/A	100	54	54
	2022	7	70.6 ± 11.7	2.5:1	66.6	100	N/A	0	N/A	N/A	N/A	100	100	100
	2023	10	64.3	1:4	100	100	N/A	0	N/A	N/A	N/A	100	100	100
	Total	35	65.4 ± 15.4	1.25:1	88.8	100	N/A	0	N/A	N/A	N/A	100	64	64
Candida auris	2021	13	67.5 ± 21	1.2:1	100	100	N/A	0	N/A	N/A	N/A	87.5	87.5	87.5
	2022	38	72.4 ± 15.5	1.5:1	85.3	100	N/A	4	N/A	N/A	N/A	100	100	0
	2023	27	58.3 ± 18.9	0.93:1	100	100	N/A	0	N/A	N/A	N/A	100	100	4.5
	Total	78	66.6 ± 18.8	1.2:1	87.5	100	N/A	2	N/A	N/A	N/A	98	98	13.2

C. tropicalis displayed a high mortality rate, with susceptibility to amphotericin B slightly decreasing from 100% in 2021 to 95.5% overall. Susceptibility to fluconazole was very low, starting at 15.7% in 2021 and dropping to 0% by 2023. Voriconazole, posaconazole, and itraconazole also showed poor susceptibility rates, generally declining over the years. No susceptibility to echinocandins was recorded across the three years. C. parapsilosis maintained 100% susceptibility to amphotericin B, with fluconazole susceptibility remaining high but slightly fluctuating, from 82% in 2021 to 76.5% in 2023. Susceptibility to voriconazole, posaconazole, and itraconazole remained relatively stable and high across the years. Echinocandin susceptibility remained consistently at 100%.

C. glabrata showed complete susceptibility to amphotericin B throughout the study period. Fluconazole susceptibility was consistently 0%, and susceptibility to echinocandins varied, with micafungin, anidulafungin, and caspofungin showing better results in 2022 and 2023 compared to 2021. C. auris had a 100% susceptibility rate to amphotericin B across all years. Susceptibility to fluconazole was initially 0% in 2021, slightly increasing to 4% in 2022, and then returning to 0% in 2023. Echinocandin susceptibility was high in 2021 and 2022 but showed some resistance in 2023, particularly with caspofungin (4.5%).

While the most common Candida species (C. albicans, C. tropicalis, C. parapsilosis, C. glabrata, and C. auris) generally remained susceptible to amphotericin B (over 83% susceptible across all species and years) and flucytosine (over 95% susceptible), however, concerning trends in susceptibility were observed for other antifungal agents. For example, susceptibility to fluconazole declined significantly for C. tropicalis (15.7% in 2021 to 0% in 2023) and C. albicans (87.5% in 2021 to 52.3% in 2023). In addition, while all Candida species remained largely susceptible to caspofungin (over 88% susceptible), some isolates of C. glabrata showed intermediate susceptibility. Overall, the trend of antifungal susceptibility highlights the ongoing challenge of treating candidemia, with notable resistance patterns emerging in commonly used antifungal agents, particularly fluconazole and voriconazole, for certain Candida species. This emphasizes the need for continued monitoring and tailored treatment approaches to manage candidemia effectively.

DISCUSSION

This is the first study to estimate the burden of invasive fungal infection in the United Kingdom of Bahrain without previous epidemiological or clinical studies. The findings from this study highlight several critical aspects of candidemia among patients from 2021 to 2023, underscoring the evolving nature of fungal infections and the associated challenges in clinical management in the United Kingdom. The demographic data reveal that candidemia predominantly affects older adults, with a mean age of 65.7 years and a high mortality rate of 85.5%. The gender distribution was nearly balanced, with a slight male predominance. Bahraini nationals constituted most cases, reflecting the local demographic distribution and healthcare access patterns. Studies from neighboring Gulf countries such as Saudi Arabia and the United Arab Emirates (UAE) have reported similar demographic profiles among candidemia patients, with a predominance of elderly individuals and a slight male preponderance[23,24]. Many studies showed that older age is associated with a high mortality rate and a trend of higher resistance rate to multiple antifungal drugs[25], partially explaining the high mortality rate observed in the current study. Older age is usually associated with high rates of comorbid conditions, aging-related pathophysiological changes, Candida l colonization, and polypharmacy[26,27]. The high mortality rates observed in our study (85.5%) align closely with findings from these regions[28-31], indicating a consistent challenge in managing invasive fungal infections despite advances in medical care. Bahrain's high mortality rate from candidemia is influenced by factors such as uneven access to healthcare facilities, variability in care standards due to a diverse healthcare workforce, and suboptimal infection control practices. The patient population, particularly older adults with multiple comorbidities like diabetes and cardiovascular diseases, is highly vulnerable. High usage of CVCs and broad-spectrum antibiotics further increases infection risks. In comparison, high-income countries with robust healthcare infrastructure, advanced infection control, and comprehensive chronic disease management see lower mortality rates. In contrast, low-income and middle-income countries often face higher mortality due to resource constraints and limited healthcare access. To improve outcomes, Bahrain could enhance infection control, implement antimicrobial stewardship, expand healthcare access, invest in healthcare worker training, manage chronic diseases more effectively, and conduct ongoing research and surveillance.

Species distribution and trends

The distribution of Candida species varied over the three years, with C. albicans being the most frequently isolated species, followed by C. parapsilosis, C. tropicalis, and C. auris. Notably, C. auris, known for its multidrug-resistant properties, represented a significant proportion of the isolates (18%). The emergence of C. auris as a major pathogen is particularly concerning due to its ability to cause outbreaks and its high resistance to multiple antifungal agents[32]. C. auris has a profound impact on patient outcomes and healthcare practices due to its multidrug-resistant nature, which complicates treatment and leads to higher mortality rates. Its persistence in healthcare environments and resistance to standard antifungal treatments pose significant challenges for outbreak management, necessitating enhanced infection control measures and improved diagnostic capabilities. In Bahrain, the emergence of C. auris is influenced by several healthcare practices and environmental factors. High utilization of CVCs and broad-spectrum antibiotics increases the risk of candidemia by providing pathways for C. auris to enter the bloodstream and promoting fungal resistance. Inadequate antifungal stewardship further exacerbates the problem. Environmental factors also play a role; the warm and humid climate of Bahrain creates an ideal environment for fungal growth, while insufficient cleaning and disinfection practices in healthcare settings facilitate the persistence and spread of C. auris. Additionally, the aging population and rising number of individuals with chronic conditions heighten the risk of invasive fungal infections. Addressing these issues requires enhanced infection control practices, improved environmental hygiene, and effective antifungal stewardship.

The fluctuating prevalence of other Candida species can be attributed to factors such as the use of broad-spectrum antifungals and antibiotics, healthcare practices like central venous catheterization, environmental conditions, and regional differences. While C. albicans remains a predominant species across the Gulf[23,33], the emergence of C. auris as a significant pathogen observed in our study has also been noted in Saudi Arabia and the UAE[34]. This multidrug-resistant species poses a formidable clinical challenge due to its ability to cause outbreaks and its intrinsic resistance to many antifungal agents[35]. Globally, candidemia epidemiology shows considerable variability influenced by regional healthcare practices, antimicrobial stewardship, and patient demographics[36]. Studies from Europe, China, and North America often highlight C. glabrata and C. parapsilosis as prominent species with varying levels of antifungal resistance[37-40]. As observed in our study, the trend of increasing resistance to azole antifungals, particularly among C. tropicalis and C. glabrata, mirrors findings from diverse geographic regions[41,42]. This underscores the global concern regarding the emergence of multidrug-resistant Candida species and the implications for clinical management.

Risk factors analysis

Several risk factors were consistently associated with candidemia, including using old age, CVCs, exposure to broad-spectrum antibiotics, and parenteral nutrition. These factors are well-known predisposing conditions for invasive fungal infections, as they disrupt normal host defenses and create environments conducive to fungal growth[8,43]. Identifying and understanding risk factors associated with candidemia are crucial for effective management and prevention strategies[44]. Our study identifies several significant risk factors consistent with previous literature and highlights regional variations that warrant attention.

Our study's high prevalence of CVCs and other intravascular devices among candidemia patients (89.4% in 2021, 92% in 2022, and 90% in 2023) underscores their role as major risk factors. These devices provide a conduit for Candida species to enter the bloodstream, leading to invasive infections[45]. Similar findings have been reported globally and in other Gulf region studies, emphasizing the importance of strict adherence to infection control measures and catheter care protocols to mitigate these risks[46,47]. Another significant risk factor observed in our study is the widespread use of broad-spectrum antibiotics, reported in 98.7% of patients in 2021, 95% in 2022, and 96% in 2023. Antibiotic therapy disrupts the normal flora, creating an environment conducive to Candida overgrowth and subsequent infection[48]. This association has been well-established in the literature and underscores the critical need for antimicrobial stewardship programs to optimize antibiotic use and reduce the incidence of secondary fungal infections[49].

Our findings indicate variable prevalence rates for recent major surgery (18.5% to 20%) and vascular anastomosis (2% to 5%) across the study years. These surgical procedures can compromise host defenses and predispose patients to candidemia, consistent with findings from other studies globally[50,51]. High rates of Candida colonization (93.4% to 91%) and dialysis (17.2% to 19%) further highlight their role as predisposing factors. Colonization serves as a reservoir for subsequent bloodstream infections[52], while dialysis procedures increase the risk of catheter-related infections and systemic fungal spread[53]. Our cohort's use of parenteral nutrition (76.8% to 81%) and corticosteroids (32.4% to 42%) underscores their immunosuppressive effects, which can impair host defenses against Candida species. These findings align with previous studies highlighting their association with increased candidemia risk[54,55].

Our findings align with previous studies from the Gulf region and globally, confirming the universal nature of these risk factors in predisposing patients to candidemia. Studies from Saudi Arabia and the UAE report similar risk factor profiles, emphasizing the consistent challenges posed by invasive fungal infections across the region[56]. Studies globally have also identified CVCs, broad-spectrum antibiotics, and surgical interventions as predominant risk factors for candidemia[24,57,58]. The prevalence of specific risk factors across regions varies, influenced by local healthcare practices, patient demographics, and antimicrobial use policies[59].

Understanding the epidemiology and risk factors associated with candidemia is essential for guiding clinical practice and implementing targeted prevention strategies[60]. It is the healthcare professionals who play a crucial role in implementing these strategies. Multifaceted approaches, including infection control measures, antimicrobial stewardship, and early detection strategies, are critical in reducing the incidence and improving outcomes of candidemia. Future research should focus on tailored interventions to mitigate specific risk factors identified in different healthcare settings, ultimately enhancing patient care and safety[61].

Antifungal susceptibility trends

Antifungal susceptibility patterns among Candida species are crucial for guiding empirical therapy and optimizing treatment outcomes in candidemia[62]. Our study provides valuable insights into the susceptibility profiles of commonly isolated Candida species over three years, highlighting trends and implications for clinical practice. Our findings indicate variable susceptibility profiles among Candida species to different antifungal agents. C. albicans, the predominant species in our study, demonstrated consistent susceptibility to amphotericin B and 5-fluorocytosine across the years, with varying susceptibility to azoles and echinocandins. While susceptibility to echinocandins remained relatively stable, C. albicans showed declining susceptibility to fluconazole and voriconazole over the years, with fluconazole susceptibility dropping from 87.5% in 2021 to 52.3% in 2023. This trend indicates a growing resistance to azole antifungals, commonly used in clinical practice. However, echinocandin susceptibility (micafungin, anidulafungin, and caspofungin) remained at 100%, suggesting that these agents are still effective for treating C. albicans infections.

Comparatively, studies from other regions also report similar resistance patterns. Research from Europe and North America indicates increasing resistance to azoles, particularly fluconazole, among C. albicans isolates[63,64]. This global trend underscores the need for continuous monitoring and the potential necessity of adjusting empirical treatment protocols to incorporate agents with sustained efficacy, such as echinocandins or rifapentine[65]. Region-specific studies, such as those from the Gulf region, further corroborate our findings. For instance, recent reports highlight a growing prevalence of azole-resistant C. albicans strains, echoing our observed decline in susceptibility[66-68]. These comparative insights emphasize the universal nature of antifungal resistance trends and the importance of local epidemiological data in guiding treatment decisions.

C. tropicalis species exhibited high susceptibility to amphotericin B but decreased susceptibility to fluconazole (starting at 15.7% in 2021 and reaching 0% by 2023). This species also showed poor susceptibility to other azoles, highlighting the necessity for alternative antifungal strategies. Echinocandin susceptibility remained variable but generally lower than that of other agents. The consistent susceptibility to amphotericin B offers a viable treatment option for infections caused by C. tropicalis. The increasing resistance of C. tropicalis to antifungal agents, particularly azoles like fluconazole, is a significant concern. Overuse and misuse of antifungal medications, environmental factors, hospital settings, genetic mutations, and the global spread of resistant strains all contribute to this issue[69,70]. Comparative studies from other regions reflect similar resistance patterns. For example, research from Asia and Europe has also documented declining fluconazole susceptibility among C. tropicalis isolates. A study in China reported fluconazole resistance rates rising from 16.7% in 2010 to 87.5%–100% after 2014[71], paralleling our findings of complete resistance by 2023. Similarly, European surveillance data highlight increasing resistance to azoles among C. tropicalis, corroborating our observations[24]. Arastehfar et al[72] showed an increase in the prevalence of fluconazole-non-susceptible C. tropicalis blood isolates in Turkey reaching. In the Gulf region, studies have different patterns in azole resistance among C. tropicalis isolates. Reports from Saudi Arabia showed 95% susceptibility to azole antifungals[31], while studies from Kuwait have shown a susceptibility rate of up to 100%, indicating the effects of different factors on antifungal susceptibility[27]. These findings across different geographical locations emphasize the global nature of this resistance issue. Echinocandin susceptibility among C. tropicalis remains a topic of concern, as variability in efficacy has been noted in several studies[73]. For instance, Swedish research indicates fluctuating susceptibility rates, aligning with the variable echinocandin susceptibility observed in our study[74]. This variability necessitates careful consideration of local susceptibility data when choosing echinocandin therapy.

In the current study, C. parapsilosis maintained high susceptibility to fluconazole and other azoles and echinocandins, which were observed consistently across the study years, making it more manageable than other species. This highlights a favorable susceptibility profile that aligns with previous reports. The high susceptibility of C. parapsilosis to fluconazole, other azoles, and echinocandins observed in our study can be attributed to several factors[75]. One primary reason is the inherent genetic makeup of C. parapsilosis, which appears less prone to developing resistance mutations than other Candida species, such as C. glabrata and C. auris[76]. Additionally, C. parapsilosis is less commonly exposed to selective pressure from antifungal treatments in clinical settings, reducing the likelihood of resistance development[77]. Moreover, C. parapsilosis is known to have lower intrinsic resistance mechanisms, such as reduced efflux pump activity and less frequent mutations in key genes like ERG11 and FKS1, which are commonly associated with azole and echinocandin resistance, respectively[78]. The lower usage of antifungal agents against C. parapsilosis infections, possibly due to its lower virulence and pathogenicity than other Candida species, also contributes to its sustained susceptibility profile[79]. However, the emergence of resistance in even a small proportion of isolates necessitates ongoing surveillance.

C. glabrata, known for its intrinsic resistance, showed complete resistance to fluconazole with a consistent 0% susceptibility rate and variable susceptibility to echinocandins across the study period. Recent evidence indicates that most invasive candidiasis caused by C. glabrata is associated with biofilm growth. C. glabrata biofilms exhibit antifungal resistance due to their compact, dense structure of yeast cells nested in an extracellular matrix rich in proteins and carbohydrates, particularly β-1,3 glucan. Many genes are linked to biofilm formation in C. glabrata, such as EPA6, which encodes adhesin controlled by multiple factors, including the CgYak1p kinase, chromatin remodeling Swi/Snf complex components, subtelomeric silencing, and the transcription factor CgCst6[80-82]. This resistance pattern underscores the challenges in treating infections caused by this species. The variable resistance to Echinocandin emphasizes the need for susceptibility testing to guide therapy for C. glabrata infections[83].

Since it was identified in 2009 by a Japanese scientist, C. auris has been reported worldwide[84]. Emerging as a global concern due to multidrug resistance, C. auris in our study exhibited high resistance to fluconazole but variable susceptibility to echinocandins (particularly caspofungin, which showed some resistance in 2023) and amphotericin B. Our findings confirm the worldwide concern about this emerging multidrug-resistant fungus that is rapidly spreading throughout the world as being reported from more than 30 countries with the shift from multi-drug resistant to pan-drug resistant[85]. Lockhart et al[86] reported a simultaneous rise of multidrug-resistant C. auris on three continents, using whole-genome sequencing, suggesting closely simultaneous and new independent emergence of various clonal populations on three continents. Therefore, infection with C. auris is expected to be associated with high mortality rates due to its resistance to multiple classes of antifungal drugs[87]. The observed resistance trends underscore the need for vigilance and rapid detection methods to ensure appropriate and effective treatment when managing infections caused by this elusive pathogen.

Rising antifungal resistance rates pose significant challenges in managing invasive fungal infections. Increased resistance to common antifungals, such as fluconazole, reduces the effectiveness of standard treatments, leading to more severe and prolonged infections. This situation often necessitates the use of stronger, more toxic, and costly antifungal agents, which can increase patient morbidity and healthcare expenses. To combat this issue, early and accurate diagnostics are crucial for selecting appropriate therapies based on resistance profiles. Antifungal stewardship programs play a vital role by optimizing antifungal use, curbing unnecessary prescriptions, and monitoring resistance patterns. These programs should also focus on adjusting treatment protocols as resistance trends evolve. Enhanced infection control practices, including stringent hygiene and isolation measures, are necessary to prevent the spread of resistant strains. Additionally, educating healthcare professionals about resistance trends and investing in research for new antifungal agents are essential. Collaborative efforts among healthcare institutions, public health agencies, and research organizations are key to effective surveillance and resistance management.

Clinical implications

The high mortality rate associated with candidemia, coupled with the increasing resistance to commonly used antifungals, underscores the importance of susceptibility testing and individualized treatment approaches in managing candidemia[88]. Rapid identification of Candida species and their susceptibility profiles is essential to guide timely and appropriate antifungal therapy[89]. Additionally, preventive measures, such as reducing broad-spectrum antibiotic use and minimizing the duration of central venous catheter use, are crucial in mitigating the risk of candidemia[90]. Clinicians should consider local epidemiological data and susceptibility profiles when selecting empirical therapy, especially in critically ill patients at high risk for invasive fungal infections[91]. Future research should focus on molecular mechanisms of resistance, novel antifungal agents, and strategies to optimize antifungal therapy efficacy while minimizing the development of resistance. Collaborative efforts are essential to combatting the rising threat of multidrug-resistant Candida species and improving patient outcomes in candidemia management. To mitigate the risks associated with candidemia, healthcare providers should implement several practical strategies. First, they should adhere to strict infection control practices, such as proper hand hygiene, sterilization of medical equipment, and isolation protocols for infected patients, to prevent the spread of infection[92]. Second, the judicious use of antibiotics should be prioritized to avoid unnecessary use of broad-spectrum antibiotics, which can disrupt normal flora and promote fungal growth. Third, healthcare providers should monitor and promptly remove CVCs when they are no longer necessary to reduce the risk of catheter-related infections[93]. Fourth, early diagnostic methods, such as molecular assays and rapid fungal cultures, should be employed to quickly identify the causative pathogens and their resistance profiles, allowing for targeted therapy. Fifth, antifungal stewardship programs should be established to optimize the use of antifungal agents, ensuring appropriate prescribing practices and reducing the development of resistance[94]. Finally, continuous education and training programs for healthcare professionals on the latest guidelines and best practices in infection control and antifungal management are essential to keep them updated and enhance patient care[95].

Limitations

This study has several limitations that warrant consideration. Firstly, it was conducted at a single center, which may restrict the generalizability of findings to other healthcare settings within Bahrain or regions with different healthcare practices and patient demographics. Variability in local healthcare practices, infrastructure, and patient populations means that the findings might not be applicable to different settings or larger geographic areas, potentially affecting the broader applicability of the conclusions drawn from the study. Secondly, retrospective data collection can introduce several biases that may affect the validity of study findings. For instance, incomplete or inconsistent medical records can lead to missing data on key variables, such as patient demographics or clinical outcomes, skewing the results. Recall bias may occur if data are dependent on historical records that are not uniformly detailed. Moreover, the sample size for certain Candida species and specific years might be relatively small, affecting the precision of the observed prevalence estimates and resistance patterns. Variability in antifungal susceptibility testing methods across the study period could also influence the accuracy and comparability of susceptibility data reported. Furthermore, differences in species identification methods or techniques over the study period might impact the reported distribution of Candida species and their resistance profiles. The reliance on documented risk factors from medical records may not capture all relevant clinical variables or potential confounders influencing candidemia risk. Additionally, the study population included diverse patient groups with varying underlying conditions and comorbidities, introducing heterogeneity that could affect the interpretation of results and their generalizability. While the study spanned three years, longer-term trends and potential fluctuations in candidemia incidence, species distribution, and resistance patterns over a broader timeframe were not fully explored. Moreover, specific aspects of clinical management (e.g., treatment protocols and adherence to guidelines) were not extensively addressed, which could impact outcomes and observed resistance patterns. Lastly, the findings may not fully reflect broader regional or global epidemiological trends in candidemia due to local healthcare practices, antimicrobial use policies, and unique demographic characteristics specific to Bahrain. Addressing these limitations in future research can enhance the robustness and applicability of studies on candidemia in Bahrain and similar settings, providing more comprehensive insights into invasive fungal infections and guiding effective clinical management strategies.

Recommendations

Enhanced surveillance and ongoing epidemiological studies are crucial to monitor candidemia trends, species distribution, and antifungal resistance patterns. This proactive approach will enable early detection of multidrug-resistant strains like C. auris and inform timely public health responses. Implementing robust antifungal stewardship programs is essential to optimize antifungal use, promote judicious prescribing of azoles, and prioritize effective agents based on local susceptibility data. Strengthening infection prevention and control measures, particularly focusing on reducing central venous catheter-related infections, is paramount. This includes strict adherence to catheter care protocols, vigilant monitoring, and timely removal of unnecessary catheters. Continuous education and training for healthcare providers on candidemia recognition, diagnosis, and management are critical, emphasizing early initiation of appropriate antifungal therapy tailored to local resistance profiles and patient-specific risks. Supporting research into molecular mechanisms of antifungal resistance and fostering the development of novel antifungal agents and diagnostics will enhance treatment options. Multidisciplinary collaboration among clinical microbiologists, infectious disease specialists, pharmacists, and infection control teams is essential for comprehensive candidemia management strategies. Lastly, increasing public awareness about candidemia risk factors and infection prevention practices will empower patients and caregivers to advocate for safer healthcare practices. Implementing these recommendations will be pivotal in addressing candidemia challenges in Bahrain, improving patient outcomes, and reducing the impact of invasive fungal infections in healthcare settings.

CONCLUSION

In conclusion, this study provides valuable insights into the epidemiology, species distribution, antifungal susceptibility patterns, and associated risk factors of candidemia among patients in Bahrain from 2021 to 2023. The findings underscore the significant burden of invasive fungal infections, particularly among older adults, with a notable mortality rate and a diverse spectrum of Candida species. The emergence of multidrug-resistant species, including C. auris, presents ongoing challenges in clinical management and highlights the importance of surveillance and timely intervention strategies. Antifungal susceptibility trends reveal varying degrees of resistance among different Candida species, emphasizing the need for tailored treatment approaches guided by local susceptibility data. Common risk factors such as CVCs, broad-spectrum antibiotics, and surgical interventions underscore the importance of infection control measures and antimicrobial stewardship to mitigate candidemia risk. Despite its limitations, including single-center retrospective design and potential biases inherent to observational studies, this research contributes to understanding candidemia in Bahrain's healthcare landscape. Future studies should focus on longitudinal surveillance, molecular mechanisms of resistance, and optimizing therapeutic strategies to improve patient outcomes and mitigate the rising threat of multidrug-resistant Candida species. Overall, this study provides a foundation for targeted interventions and policy development aimed at reducing the incidence and improving the management of candidemia in Bahrain and similar healthcare settings globally.