Distribution and Diagnostics of Invasive Candidiasis: Comparison
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Invasive candidiasis (IC) is a systemic life-threatening infection of immunocompromised humans, but remains a relatively neglected disease among public health authorities. Ongoing assessments of disease epidemiology are needed to identify and map trends of importance that may necessitate improvements in disease management and patient care. Well-established incidence increases, largely due to expanding populations of patients with pre-disposing risk factors, has led to increased clinical use and pressures on antifungal drugs. This has been exacerbated by a lack of fast, accurate diagnostics that have led treatment guidelines to often recommend preventative strategies in the absence of proven infection, resulting in unnecessary antifungal use in many instances. The consequences of this are multifactorial, but a contribution to emerging drug resistance is of primary concern, with high levels of antifungal use heavily implicated in global shifts to more resistant Candida strains.

  • Candida
  • invasive candidiasis
  • candidemia
  • epidemiology
  • antifungal
  • diagnostics

1. Introduction

Until relatively recently, fungi were a rare cause of life-threatening human disease. Since the early 1980s, invasive fungal diseases (IFDs) have been an increasing occurrence in healthcare environments due to an ever-expanding population susceptible to infection [1][2]. This has largely been driven by the advent of more aggressive interventions and treatments in modern healthcare, placing patients in prolonged states of severe immunosuppression [3][4].
Invasive candidiasis (IC), caused by yeast species in the fungal genus Candida, is one of the main systemic, opportunistic fungal diseases of immunocompromised patients. It is associated with significant global burden, with an estimated 750,000 cases occurring annually [5] and with unacceptably high mortality rates of up to 30% [6][7]. More than 15 Candida species have now been described as etiologic agents of IC, but >90% of cases are attributed to just five: C. albicans, C. glabrata, C. parapsilosis, C. tropicalis and C. krusei. Of these, C. albicans is predominant [1][8]. The term invasive candidiasis is used to describe two distinct disease entities: candidemia bloodstream infection (BSI) and deep-seated tissue candidiasis (Figure 1), which may occur independently or concomitantly [9].
Figure 1. Invasive candidiasis involves rapid dissemination of Candida yeast cells in the bloodstream (candidemia BSI) and/or tissue penetration by invasive hypha (deep-seated candidiasis). Hematogenous seeding of Candida yeast from blood-borne candidemia is often a key source of tissue candidiasis and vice versa [9]. Although hyphal extension is a well-described mechanism of C. albicans tissue invasion, its role is less clear for other clinically important Candida species such as C. glabrata where other mechanisms of invasion may be involved.
Despite being an increasing cause of morbidity and mortality in healthcare settings, IC is still a somewhat neglected topic among public health authorities. Consequently, improvements in disease management and patient care are urgently needed [1][5]. Of particular importance is a lack of fast, accurate diagnostics, with clinicians continuing to rely on suggestive clinical findings and the use of culture-based diagnostics with sub-optimal sensitivity to inform decision making [10]. It is suggested that up to 50% of disease episodes may go undiagnosed by these conventional methods, resulting in delayed treatment initiation and markedly worse patient outcomes [9][10][11]. To mitigate this, current treatment guidelines recommend that prophylactic or empirical preventative strategies be initiated in high-risk populations in the absence of proven infection [12][13]. Whilst some patients will benefit from these measures, non-specific implementation leads to unnecessary use of precious antifungals in many instances. This has led many to raise concerns about the risks of widespread drug resistance among Candida spp., particularly given the already limited availability of front-line antifungals [14][15].
Overall, IC represents a major global public health concern. A robust understanding of ongoing disease epidemiology is therefore of importance to identify concerning trends that may inform policy decisions and necessitate the need for improvements in disease management and patient care. In this research, a critical appraisal of the current IC epidemiologic landscape is made, focusing on prospective surveillance studies that assess patient pre-disposing risk factors, incidence, Candida spp. distribution and antifungal susceptibility patterns both spatially and temporally. Particular attention is given to the interplay between these factors. Antifungal treatment and diagnostics are outlined as two key components of IC management, with the influence of current practices on disease epidemiology considered. Realistic improvements in the implementation of these clinical activities are then proposed, offering the potential for a new era in disease management and patient care through improved antifungal stewardship and availability.

2. Species Distribution and Antifungal Susceptibilities

Globally, more than 15 Candida spp. are known etiologic agents of IC [16][17], but the majority (>90%) of infections are attributed to just five: C. albicans, C. glabrata, C. parapsilosis, C. tropicalis and C. krusei [2][6][18][19][20][21]. As such, they will be the focus here. Candida albicans has long been and remains the predominant species present as clinical isolates from infected patients [1], but an ongoing global shift towards non-albicans Candida (NAC) species that exhibit decreased antifungal susceptibility is well-established [2][22][23]. Emerging multi-drug-resistant species such as C. auris, first described in 2009, represent a serious public health threat and highlight further the concerning global divergence of Candida spp. implicated in IC to more resistant strains [24].
As with incidence, when assessing IC species distributions and antifungal susceptibilities, limitations in data must be considered. First is the sub-optimal sensitivity of blood culture, meaning data represent only the testing of isolates from disease events that were culture-positive [25], a partial spectrum of the total IC disease events. Furthermore, although undefined, inevitably not all culture positive cases will undergo species identification and antifungal susceptibility testing. However, as testing is common and even compulsory in some countries and healthcare settings [6][20], the volume of testing may be considered adequate and representative of the species distribution and antifungal susceptibility landscape. Comparisons are also challenged by factors that are not standardised across healthcare settings, with the use of different blood culture systems notable. For example, C. glabrata positivity rates have been shown to be higher where the BacT/Alert culture system is used [26][27]. Although this is clinically significant, quantification of differences between culture systems shows inconsistencies and will be impacted by other currently contested confounding factors [27][28]. As such, acceptable concordance will be assumed between blood culture systems in the isolation rates of Candida spp.
Here, an assessment of Candida spp. distribution and antifungal susceptibility will focus on spatial and temporal data shifts at the continental level. Additionally, specific consideration will be given to the role of patient pre-disposing risk factors in species distribution as well as the interaction between increased use of antifungals and shifts towards strains with less susceptibility [29].

2.1. Influence of Pre-Disposing Risk Factors

Pre-disposing risks for IC, both host and healthcare related factors, can influence the Candida spp. implicated in infection [6][29][30]. Increasing patient age, transplant procedures and prior fluconazole exposure are well-documented factors for increased isolation of C. glabrata [29][31][32][33][34]. The latter may point towards an applied selection pressure from fluconazole use, driving C. glabrata-implicated infection with greater drug resistance [35]. C. parapsilosis is renowned for its high prevalence among pre-term and low-birthweight infants [36][37][38][39]. This may be due to an elevated ability to form biofilms on indwelling devices, which are commonly used in this patient group [40][41]. Another key driver of C. parapsilosis infection is its ability for nosocomial spread, notably by hand carriage, leading to hospital outbreaks and persistence [39][42]. With the advent of at-home CVC management, C. parapsilosis may therefore also be responsible for the rise in community-acquired IC [8][43]. C. tropicalis and C. krusei have a heightened presence among severely neutropenic patients on oncology wards [44][45][46]. Oncology-specific C. tropicalis incidence now appears to be declining in certain settings, with widespread fluconazole prophylaxis and improved management of central venous catheters (CVCs) likely determinants in these observations [18][29]. Conversely, as with C. glabrata, fluconazole exposure is cited as a selection pressure that has acted in the emergence of resistant C. krusei, particularly among the oncology patient population [29]. However, reported increases in C. krusei prevalence pre-date widespread prophylaxis regimens [47], suggesting other factors have also influenced its emergence. These may include oncology-specific risk factors such as the long-term use of subcutaneous portacaths and CVCs as well as administration of certain chemotherapy agents [48].

2.2. Geographical Trends

Species distribution and antifungal susceptibility shows considerable geographical variation between individual countries, but trends can generally be elucidated at the continental level, such as the Americas and Europe (Figure 2). Across some continents (Asia, Africa and Oceania), few distinctive trends are observed and are not well-defined due to limited and contrasting data from mostly single-institution studies [49][50][51][52][53][54]. As a result, data from Asia will be assessed briefly and Africa and Oceania will be excluded from this research.
Figure 2. Distributions of Candida spp. as a percentage of total IC case counts across North America, South America, North Europe and South Europe [6][55][56][57][58]. In North America, C. albicans is the most prevalent Candida species, accounting for ~39% of IC episodes. The most common NAC species, representing just under 30% of cases, is C. glabrata with sequentially lower case contributions from C. parapsilosis, C. tropicalis and C. krusei. European IC species distribution shows two clear trends, split broadly between the north and south of the continent. Northern Europe typically exhibits a similar species distribution to North America, although a greater contribution from C. albicans is seen, accounting for 60% of cases. In contrast, the species landscape in southern Europe is more akin to that in South America, where C. parapsilosis is the most common NAC species. Across these four regions, <10% of total cases are attributed to species outside of the five described.

2.2.1. United States

Candida glabrata is of the highest concern in the US due to a combination of increasing incidence and high levels of resistance to front-line antifungals [6]. Up until the late 1990s, C. albicans accounted for ~50% of all Candida BSIs in the US [59], but its contribution has since decreased [6][18][60], with a concurrent increase in NAC incidence observed [1][6][18][59][60]. C. glabrata has emerged as the most frequent NAC species, making up 12% of isolates in 1999 [59] but now consistently accounting for just under 30% [6][18][60]. The significance of this trend is justified as C. glabrata exhibits high levels of triazole tolerance and emerging echinocandin resistance, albeit to a lesser extent [23][61]. Importantly, resistance shows considerable state variation perhaps due to differing patterns of population pre-disposing factors at a local level, outlining the importance of robust surveillance in local healthcare settings more widely. C. glabrata fluconazole resistance has been as high as 20% in selected US states (Georgia), but a gradual decline to ~10% has been observed since the 1990s [6][18]. Echinocandin resistance has increased simultaneously, with around 4% of C. glabrata isolates now displaying elevated MIC90 values (minimum concentration of antifungal required to inhibit growth of 90% of Candida cells) from susceptibility testing [6]. Decreasing clinical use of fluconazole in place of echinocandin as a first-choice treatment option is thought to be driving this shift, as selection pressures resulting from the use of these two drug classes change [60]. Candida echinocandin resistance remains low in most settings, but careful monitoring is required as clinical use inevitably increases [62]. Candida parapsilosis, C. tropicalis and C. krusei are much less frequently isolated, with events largely concentrated in specialist neonatal and oncology units. However, these NAC species also exhibit higher levels of antifungal resistance [35], suggesting the rapid emergence of C. glabrata in the US was mediated by several confounding risk factors in addition to selection for antifungal tolerant strains as the predominant factor [59]. It is noteworthy that C. krusei consistently exhibits fluconazole MIC90 values >64 μg/mL worldwide, rendering this antifungal of little use in C. krusei-implicated infections [59][60]. A more comprehensive national surveillance is required to track species-specific incidence and antifungal resistance trends.

2.2.2. Europe

Candida species distribution varies across the European continent. Northern Europe experiences a high contribution from C. albicans [55], whilst in central Europe, C. glabrata is of increasing prominence [63][64]. Regions of southern Europe consistently report C. parapsilosis as the most prevalent NAC strain [43][56][57].
Across northern Europe, C. albicans accounts for up to 70% of total IC cases, and C. glabrata is the most prevalent NAC species, contributing 10–20% of episodes [20][26][55][65][66][67][68][69]. However, an expected shift towards increasing isolation of more resistant NAC species with increased widespread antifungal use, as seen in the US, has not occurred [65]. A lower disease incidence in the overall population and thus reduced clinical use of antifungals to treat patients with IC may be responsible, limiting the selection pressure posed by such drugs [20]. In Denmark, observations differ and are more akin to the US, where continuing shifts to C. glabrata at the expense of C. albicans are seen [20][55][70][71]. Data from 2018 show that these species now account for 32.1% and 42.1% of culture confirmed cases, respectively [20]. Higher and combination use of numerous antifungals, notably fluconazole and itraconazole, in Danish healthcare may have driven the observed species disparity with other Nordic countries [55][70][71].
It might be expected that Danish Candida isolates would exhibit greater resistance resulting from higher antifungal use and associated selection pressures across Denmark (Figure 3). In fact, the opposite is observed whereby neighbouring countries (e.g., Norway) with lower antifungal use report Candida isolates with greater resistance levels, most notably for C. glabrata [55]. Explanations for this observation are not available, but it may be due to data contributing to these findings representing a small number of isolates (23 C. glabrata isolates from Norway compared to 165 from Denmark); hence, resistance rates calculated from susceptibility testing may not be nationally representative [55][72].
Figure 3. Defined daily dosage (DDD) of antifungal drugs for systemic use per 1000 inhabitants per day in 2011 in healthcare settings across Denmark, Finland, Sweden and Norway. The total use of systemic antifungal drugs is significantly higher across healthcare settings in Denmark than Norway, Sweden and Finland. In Denmark, the DDD per 1000 inhabitants per day was approximately 0.712 compared to 0.459, 0.26 and 0.2 for Finland, Sweden and Norway, respectively [55].
Across central and southern Europe, species and antifungal susceptibility data are comparatively scarce and rely on single/multi-centre studies rather than national programmes. Species distribution trends analogous to the US and Denmark have been reported from institutions across central Europe [63][64][73]. A multi-decade survey by the Fungal Infection Network of Switzerland emphasizes the role of antifungals in these observations, noting that increases in C. glabrata isolation and triazole use occurred concomitantly [64]. Studies by others in the region describe a potential reversal of epidemiologic trends, with a marked increase in C. albicans and simultaneous decrease in NAC species, driven mostly by reductions in C. parapsilosis and C. tropicalis prevalence [74][75]. Confirmatory data readouts are required, with important implications if these findings represent ongoing trends. Elsewhere, antifungal use has acted to increase incidence of more resistant NAC species, leading researchers to suggest that recent changes in antifungal practices that favour echinocandin use over triazoles may be implicated [76]. In southern Europe, C. parapsilosis is the most common NAC species [43][56][57], with fluconazole-resistant C. parapsilosis increasing in prevalence and responsible for a considerably higher neonatal candidemia incidence in the region [37][39][56]. Additionally, C. parapsilosis nosocomial transmission is common [42], and therefore outbreaks in an endemic situation cannot be ruled out and may contribute to its increasing isolation further [43]. Overall, given the increasing use of echinocandins in place of triazoles as first-line treatment for IC across Europe, potential changes in species distributions and associated echinocandin resistance should be monitored closely.

2.2.3. South America

In South America, Candida species distribution is characterised by high proportions of C. parapsilosis, C. tropicalis and C. albicans, contributing >80% of the total IC caseload [58]. C. parapsilosis is the predominant NAC species and accounts for ~26.5% of cases across the continent, comparable to observations from southern Europe [56][57][58]. In addition, data from certain countries (Colombia and Venezuela) suggest that C. parapsilosis might now be the most common species implicated in infection, surpassing C. albicans as the primary causative agent [58]. This may be explained as C. parapsilosis is isolated across all age strata whilst on other continents its frequency is heavily concentrated in infant candidiasis.
C. glabrata, of major concern in the US and Europe, accounts for just 6% of IC cases across the South American continent. Additionally, low levels of overall antifungal resistance are seen, and it is thought that lower antifungal use might be implicated in both these trends [58][77][78]. C. glabrata is of greater prominence in Brazil, increasing in prevalence and currently accounting for 10% of disease events. Interestingly, differences in antifungal (particularly fluconazole) use were found to be negligible in this increase, with defined daily doses (DDD) consistent with those in neighbouring countries. Therefore, it is suggested that an ageing Brazilian population might be the cause, with increasing age a pre-disposing risk for C. glabrata infection specifically [58]. This has important implications, because as other South American countries develop an ageing population in the future, they may expect to see increasing C. glabrata isolation with inherent resistance. In fact, more recent data from Peru support these claims with C. glabrata now approaching 10% of cases there also [77]. Of note, C. guilliermondii was found to have a higher incidence than both C. glabrata and C. krusei, driven by an exceptionally high prevalence in Honduras, accounting for 28% of candidemia cases. High prevalence of C. parapsilosis overall and C. guilliermondii in specific regions warrants important considerations for antifungal stewardship in South America, as these species contain naturally occurring polymorphisms that increase the likelihood of emerging echinocandin resistance [79][80].
At present, triazoles are still recommended as the first-line therapy for IC. With potential for future increasing isolation of C. glabrata and associated triazole resistance, as seen in Brazil, this may change. If this trend continues, treatment guidelines may increasingly recommend echinocandin use over triazoles. In this scenario, additional surveillance will be required to promptly identify trends that may arise in C. parapsilosis and C. guilliermondii echinocandin resistance specifically.

2.2.4. Asia

Across the Asian continent, few distinctive trends in current species distribution and antifungal susceptibility can be concluded due to limited, contrasting data from mostly single-institution retrospective surveillance studies. Generally, C. tropicalis might be the primary etiologic agent of IC across west Asia (e.g., Pakistan, India) whilst in east Asia (e.g., China), C. albicans remains the most prevalent species with widely varied contributions from NAC species [49][50][51][52][53][54]. This is unsurprising given that China covers a land area of 9.38 million km2 and has a population of nearly 1.5 billion, which will inevitably show regional variations in pre-disposing population dynamics and risk factors that influence species distribution.

3. Diagnostics

Invasive candidiasis encompasses two distinct disease entities, candidemia BSI and deep-seated tissue candidiasis, with their distinction having important implications for diagnosis [9]. Blood culture representing the primary diagnostic choice to inform clinicians when IC infection is suspected [81][82]. Increasing development, availability and use of non-culture biomarker tests will likely complement rather than replace culture methods in the future, with combined use promising a new paradigm in patient care and disease management [10][82][83][84][85][86].

3.1. Culture-Based Diagnostics

Culture-based diagnostics, involving the detection and growth of viable Candida cells, typically from blood, has been the primary diagnostic tool for decades [81][82]. Culture accurately diagnoses the majority of active candidemia BSI cases, with non-culture diagnostics unlikely to offer significantly lower thresholds of detection [87]. However, ~50% of total IC infection episodes are thought to go undiagnosed by blood culture, reflecting insufficient or absent viable Candida cells in circulation for detection [10][25]. These missed diagnoses are largely due to low detection rates and false-negative results for deep-seated tissue candidiasis [9][85][88], resulting from intermittent release of cells from infected tissue sites into circulation or deep-seated candidiasis that is independent of blood-borne candidemia [9][10][85][89]. Sensitivity is also influenced by Candida spp., mode of infection and antifungal drugs with C. glabrata-implicated candidemia, infection stemming from extravascular sources and use of antifungals at the time of blood draw associated with lower burdens of the pathogen and decreased likelihood of positive culture [25][90][91]. In addition to sub-optimal sensitivity for deep-seated infection and non-active candidemia, blood cultures are associated with highly variable and slow turnaround times, taking up to 8 days until positive culture [25][89]. Sub-optimal sensitivity and slow turnaround times mean that blood culture has limited utility as a definitive diagnostic, with clinicians usually utilising culture for confirmatory purposes and often taking account of multiple suggestive clinical findings to inform clinical decision making instead.

3.2. CHROMagar for Species Identification

Widely used mediums for the isolation and growth of Candida, such as Sabouraud dextrose agar (SDA) and potato dextrose agar (PDA), are unable to differentiate between Candida spp. commonly implicated in IC [92][93]. CHROMagar Candida offers a solution, a selective and differential chromogenic isolation medium allowing for presumptive identification of some Candida strains of clinical importance through observations of contrasting colony morphology and colour [93][94][95][96]. Contrasting colony colours result from reactions of species-specific enzymes with a proprietary chromogenic substrate [93]. Studies indicate that C. albicans, C. tropicalis, C. krusei [94][97] and sometimes C. glabrata [94][98] can be differentiated based on these characteristics when grown on this chromogenic medium. Of note, C. parapsilosis, due to a wide range of colony colours and morphologies, cannot be distinguished using CHROMagar [99].
The use of CHROMagar medium to identify Candida strains implicated in infection, particularly NAC species, can assist clinicians in selecting appropriate antifungal drugs that will be effective and thus may yield significant patient benefit. However, in settings where C. parapsilosis is the predominant NAC species, such as in South America and Southern Europe, the utility of CHROMagar will be more limited.

3.3. Disease Management and Patient Care Impacts

Culture-based diagnostics have important implications for the patient care and management of IC in healthcare settings, resulting from their poor sensitivity and slow turnaround times that lead to limited clinical utility and gaps in people's understanding of the clinical disease spectrum [9][10][81]. Resulting delayed or missed diagnosis of these infections are therefore common and may negatively influence patient prognosis by hindering the initiation of treatment [11]. To mitigate this, current treatment guidelines recommend that early empirical and prophylactic therapy be initiated in high-risk individuals in the absence of an active infection or prior to culture diagnosis [12][13]. Although some individuals will benefit from this practice, its implementation across whole populations of high-risk patients leads to unnecessary use of precious antifungals in many instances, with important implications [12][100]. Of primary concern are the risks of emerging antifungal-resistant strains, as outlined previously, resulting from the high selection pressures caused by widespread high levels of antifungal use. This may decrease drug efficacy in an already limited number of licensed antifungal agents for IC treatment. Furthermore, the significant healthcare costs implicated in high antifungal use as well as severe side effects endured by recipients are also important [15][29][35]. Antifungal toxicities have both direct and indirect effects on patient health [15]. Indirect impacts may relate to patients’ underlying conditions, with waning compliance to oral medication regimens due to antifungal-induced nausea and vomiting of particular concern among paediatrics [101].
Poor sensitivity of culture-based diagnostics for IC and slow turnaround times have ultimately meant that clinicians must balance the benefits of early empirical or prophylactic therapy in selected high-risk individuals with the risks posed by an increased propensity for emerging antifungal resistance, severe side effects and substantial healthcare costs.

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