Invasive Candidiasis Due to Candida albicans and Its Treatment

Abstract

Invasive candidiasis secondary to Candida albicans should be highly suspected in patients exposed to the various risk factors that contribute to the affectation of this fungus, in order to provide early management of sepsis, through the use of antifungals in a timely manner, and to avoid the development of multiorgan failure. Diagnosis is fundamental and is based on laboratory studies, cultures, and risk scales; however, there are still limitations due to the fact that they do not have 100% sensitivity or specificity. Echinocandins remain the first line of treatment for patients with invasive candidiasis associated with C. albicans. Invasive candidiasis can affect any organ and increase mortality in adult and neonatal intensive care unit patients.

1. Introduction

The importance of the chapter is justified by the need to know the current perspective on the epidemiology, diagnosis, and treatment of invasive candidiasis, caused by Candida albicans, to be able to recognize and treat severe complications such as fungal sepsis, which represents a high mortality, mainly in immunocompromised patients.

Invasive candidiasis is a serious infection, most frequently caused by the genus Candida albicans, and can manifest as sepsis, with multiorgan dysfunction and septic shock. C. Albicans accounts for 50% of all causes of fungal sepsis in the intensive care unit, with a mortality rate of between 40 and 70%, so its diagnosis and treatment are relevant. C. albicans belongs to the eumycetes and is an opportunistic pathogen, which is characterized by having a unicellular body, being a pseudomycelium [1].

C. albicans infection is pathogenic when there is a deterioration in immunity, with previous colonization, changes in the normal flora, bacterial translocation, or other factors associated with the deterioration of cellular immunity. After invading the mucous membranes, Candida proliferates; adheres, forming plaques; and then spreads through the vascular system, causing candidemia, which is defined as the presence of Candida in the blood [2,3]. Candidemia causes T cell depletion and infects any organ, causing invasive candidiasis [4]. About 80% of C. albicans infections are associated with the formation of biofilms in different medical devices; the development of biofilms represents a greater systemic invasion and therefore a greater inflammatory response and resistance to antifungals [5].

C. albicans is the most frequently isolated germ in invasive candidiasis, associated with various risk factors, such as: the use of permanent medical devices, a prolonged hospital stay, and the use of antibiotics [6,7]. It is classified into invasive candidiasis with candidemia, invasive candidiasis without candidemia, and candidemia alone [8].

The main risk factors for invasive candidiasis by C. albicans are age, mainly in preterm infants; HIV infection with CD4 < 200; use of corticosteroids, total parenteral nutrition; deep candidiasis; septic shock with multiorgan failure; invasive fungal infection in newborns [9]; central venous catheter transfusions [10]; previous colonization [10]; hematologic malignancies, chemotherapy [11]; and hospital-acquired intravascular infections.

There are differences in the predominance of germs in both patients admitted to adult and pediatric critical care units, so much so that there is a growing predominance of C. no albicans in pediatric ICUs, such as C. parapsilosis (43%) [12].

Invasive candidiasis can affect any organ or system, due to exposure to various factors such as: alterations of the intestinal mucosa, virulence factors of the fungus, and predisposition to biofilm formation [13].

Cerebral candidiasis is common in patients with primary or secondary immunodeficiencies; it is observed in the form of C. albicans meningoencephalitis [14].

Respiratory candidiasis presents in the form of bronchopulmonary candidiasis, represents a rare cause of pneumonia, and is associated with states of severe immunosuppression; if this is suspected, a fibrobronchoscopy with bronchoalveolar lavage can be performed for its diagnosis [15].

Renal candidiasis, can cause kidney damage in kidney transplant recipients; in these cases, it is observed in the isolates: Candida no albicans, C. famata, C. tropicalis, C. parapsilosis, C. glabrata, and C. lusitaniae; however, Candida albicans continues to be the most frequent cause of renal candidiasis [16,17].

Severe urogenital candidiasis and vulvovaginal candidiasis can present in the form of abscesses, pelviperitonitis, emphysematous cystitis, emphysematous pyelonephritis in polymicrobial infections; are more frequent in patients with poorly controlled diabetes mellitus who are pregnant; and can transform into invasive candidiasis if adequate treatment is not carried out.

Fungemia in patients with hematological malignancies, chemotherapy, and neutropenia are the important risk factors for high mortality.

Blood cultures play an important role in the first hour of sepsis, although the sensitivity and specificity proven ranges between 21 and 71%. Other supportive diagnostic methods are beta-D-glucan and procalcitonin biomarkers, with favorable results in the exclusion of invasive candidiasis with a sensitivity of 98% and negative predictive value of 95%. Since 50% of cultures for invasive candidiasis are negative, they have suggested diagnostic tests such as mannan/antimannan, germ tube antibody para-C. albicans, 1,3-β-d-glucan, polymerase chain reaction, and T2Candida panel, which aid early diagnosis before blood culture results and are of great importance. They should be performed on all patients with suspected invasive candidiasis due to C. albicans, as they improve treatment performance [18, 19].

Other recommended studies are the echocardiogram, when candidiasis of cardiac origin is suspected with the presence of vegetation in the valves or hemodialysis catheters; ophthalmoscopy can also be performed to visualize ocular infection in patients with invasive candidiasis.

Once the diagnosis has been made with a positive culture, it is necessary to follow the blood cultures until they are negative, and it is recommended to continue the treatment for 14 days after the negative result [20], another score used is the Candida Score due to multifocal colonization by Candida; admission to the ICU for surgery, sepsis, and parenteral nutrition allow a diagnostic approach to be made and a risk score assigned in patients with suspected invasive candidiasis, which can be started early according to high, medium, or low risk.

Echinocandins are the first-line antifungals for the treatment of invasive candidiasis [21]. In recent years, an increase in resistance to fluconazole and echinocandins by C. albicans has been observed, which has generated an epidemiological change to multidrug-resistant germs or other types of non-albicans Candida; the de-escalation from an echinocandin to fluconazole can be performed when the germ is susceptible [22,23].

Caspofungin is a fungicide against C. albicans, which belongs to the lipopeptides; its mechanism of action is inhibition of the synthesis of 1,3-beta-d-glucan of the cell wall; the loading dose is 70 mg followed by 50 mg daily or 70 mg each day. In patients with chronic kidney disease or hemodialysis, the same dose is considered; in patients with hepatic impairment, a decrease in its effect is observed.

Anidulafungin is an echinocandin used for the management of invasive candidiasis, with a loading dose of 200 mg and maintenance dose 100 mg daily; its effect is not affected by chronic kidney disease, and it is not necessary to adjust the dose in kidney disease, nor is it affected by liver failure; in the pediatric population, the dose (3 mg/kg on day 1, 1.5 mg/kg maintenance dose) has obtained good results, with success rates of 68.8% response to treatment in pediatric candidemia [24].

Micafungin is also effective for the management of invasive candidiasis at doses of 100 mg intravenously passed in 1 hour each day, with good penetration to the central nervous system for cerebral candidiasis [25,26].

Another management that we fear to take into consideration in the event of invasive candidiasis is to remove all medical devices such as catheters, central venous catheters, and hemodialysis catheters [27].

The main objective of the chapter is to determine the current therapeutics of invasive candidiasis caused by C. albicans.

2. Methodology

A search was carried out in databases and medical journals of high prestige such as PubMed, Mendeley, IntechOpen, LILACS, and Latindex; as a search pattern, the research question was used; clear, precise, and concise articles that addressed the topic, published in the last 5 years, were included.

3. Invasive candidiasis from different aspects

Observational studies, randomized trials, clinical cases, guidelines, systematic reviews, meta-analyses, and consensus documents on the epidemiology, risk factors, and diagnosis of invasive candidiasis due to Candida albicans and its current treatment were obtained.

C. albicans is a frequent cause of hospital infection at the level of adult and neonatal intensive care. Table 1 represents the types of locations such as esophageal and ophthalmic that can generate or be a consequence of candidemia or invasive candidiasis, risk factors for invasive candidiasis, and also as a frequent cause of sepsis and multiorgan failure. Table 2 discusses studies with the percentage of isolation for C. albicans in patients with invasive candidiasis according to the region of study, which presents different results due to different epidemiological aspects; Africa reported the lowest percentages of isolates, followed by Anhui in China, unlike Mexico and Spain with higher percentages of cultures for C. albicans. Figure 1 shows an infection by an invasive candidiasis of pulmonary origin with changes in the appearance of the tracheal mucosa; the mucosa is shown with a tendency to bleed and a white exophytic image with a result of pulmonary candidiasis, which proves that invasive candidiasis due to Candida can affect any organ or system when it occurs invasively. In some cases, invasive procedures are necessary for early diagnosis and treatment, and patients with risk factors must be highly suspicious.

Author	Type of Candidiasis	C. albicans	Risk factor for Candida Albicans
Robertson, et al. 2023	Esophageal candidiasis	88% of esophagitis are secondary to C. albicans	Age, HIV infection, and corticosteroid use correlate with candidal esophagitis.
Phongkhun, et al. 2023	Ocular Candidiasis and Candida Endophthalmitis in candidemia Patients	The presence of C. albicans was associated with Candida endophthalmitis	Total parenteral nutrition has been associated with C. albicans candidiasis and causes ocular candidiasis
McCarty, et al. 2023	Candidemia and invasive candidiasis	85% of cases presented with candidemia and 15% presented without candidemia	Hospital-acquired bloodstream infections in patients admitted to critical care units
Gonzalez-Lara, et al. 2020.	Invasive candidiasis	The most common causative agent is C. albicans	Profound candidiasis and septic shock with multiorgan failure.
Ferrando, et al. 2023	Neonatal invasive candidiasis	Candida albicans is the most common cause of invasive fungal disease in preterm and/or low-birth weight infants	Invasive fungal infection in newborns

Table 1.

Risk factors for invasive candidiasis caused by C. albicans.

Author: Javier Aquiles, Hidalgo Acosta.

Author	Invasive candidiasis by study region	Diagnosis
Okoye, et al. 2022	Invasive candidiasis in Africa	C. albicans 32.6% of cases
Wang, et al. 2022	Invasive candidiasis in critically ill patients in Anhui, China	C. albicans 41.49% of reports
Franco, 2021	Invasive candidiasis in Mexico and Spain	In the Spanish pediatrics population C. albicans 36%, Mexican pediatric patients C. albicans infections predominate (64%). In Spanish adult patients C. albicans (40–75%). In Mexican adult patients, C. albicans 62%.

Table 2.

Invasive candidiasis due to C. albicans according to the study region and the percentage of C. albicans diagnoses.

Author: Javier Aquiles, Hidalgo Acosta.

Figure 1.

Image of the tracheal lumen observed during a flexible diagnostic fibrobronchoscopy in a patient with invasive candidiasis of pulmonary focus; an exophytic white image inside the bronchus with a whitish tracheal mucosa with a tendency to bleed can be evidenced. Source: Dr. Javier Aquiles Hidalgo Acosta.

Table 3 shows the current therapeutics from randomized trials on the treatment of invasive candidiasis. Echinocandins (caspofungin, anidulafungin, rezafungin, micafungin) are the most widely used first-line treatment with better results. New drugs (Fosmanogepix, ibrexafungerp) improve the possibility of administering oral doses, and other drugs already used such as amphotericin have also demonstrated their efficacy. As therapeutic options for the management of invasive candidiasis, new molecules have emerged for the treatment of this fungal sepsis [28, 29, 30, 31, 32, 33].

Author	Intervention	Population	Dose	Results	Conclusions
Thompson, et al. 2023	Rezafungin versus caspofungin for the treatment of candidemia and invasive (ReSTORE)	≥18 years with systemic signs and mycological confirmation of candidemia or invasive candidiasis	Weekly intravenous rezafungin (400 mg at week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (loading dose of 70 mg on day 1). followed by 50 mg daily) for no more than 4 weeks.	(59%) of patients in the rezafungin group and (61%) of patients in the caspofungin group had an overall cure on day 14. Mortality (24%) in the rezafungin group and (21%) in caspofungin patients	Rezafungin was not inferior to caspofungin for overall cure at day 14 and all-cause mortality at 30 days.
Roilides, et al. 2019	Safety, Tolerability, and Efficacy of Anidulafungin in the Treatment of Invasive Candidiasis	Children 2 to <18 years of age	3 mg/kg on day 1, 1.5 mg/kg daily	All-cause mortality ranged from 8.2% to 14.3%	Anidulafungin as a treatment option for invasive candidiasis in children aged 2 to <18 years
Kim, et al. 2020	Caspofungin versus amphotericin B deoxycholate in the treatment of invasive candidiasis in neonates	Neonates and infants under 3 months of age	2 mg/kg caspofungin intravenously once daily or 1 mg/kg amphotericin B deoxycholate	The survival rate at 2 weeks after treatment was 71.0% in the caspofungin group and 68.8% in the amphotericin group	Amphotericin had more adverse effects with similar mortality
Auriti, et al. 2021	High-dose micafungin in neonates and young infants with invasive candidiasis	neonates and young infants with invasive candidiasis	micafungin at doses of 8 mg/kg	Resolution of infection was achieved in 86.7% of treated patients	Micafungin at a dose of 8 mg/kg daily is effective and well tolerated in neonates and young infants
Kullberg, et al. 2019	Isavuconazole versus caspofungin in the treatment of candidemia and other invasive Candida infections	Adult patients with candidemia or invasive candidiasis.	Isavuconazole (200 mg intravenously [IV] three times daily for 2 days, followed by 200 mg IV once daily or caspofungin 70 mg IV on day 1, followed by 50 mg IV [70 mg in patients >80 kg])	A successful overall response was observed in 60.3% of patients in the isavuconazole group and 71.1% in the caspofungin group	Caspofungin was superior as an initial empirical treatment
Spec, et al. 2019	Oral Ibrexafungerp After Initial Echinocandin-Based Therapy	Non-neutropenic patients with invasive candidiasis	Ibrexafungerp 750 mg versus standard of care	Similar favorable response rates across all ibrexafungerp groups: 86%	The estimated oral dose of ibrexafungerp to reach target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a similar favorable overall response rate
Pappas, et al. 2023	Fosmanogepix, for the treatment of candidemia	Non-neutropenic adults. Participants with candidemia, defined as a positive blood culture for Candida spp.	1000 mg IV twice daily on day 1, followed by 600 mg IV maintenance once daily and optional switch to 700 mg orally once daily starting on day 4	Treatment success was 80% and survival at day 30 was 85%	Fosmanogepix may be a safe, well-tolerated, and effective treatment for non-neutropenic patients with candidemia

Table 3.

A current treatment of invasive candidiasis from randomized phase 2 and 3 clinical studies on the safety and efficacy of the different treatments.

Author: Javier Aquiles, Hidalgo Acosta.

4. Conclusions

Blood cultures do not have a specificity and sensitivity of 100% to predict the decision to start or withdraw antifungal treatment in the face of suspected invasive fungal infection, worse if it is an immunosuppressed patient whose clinical debut is atypical, so it is necessary to take advantage of the golden hour and use more effective diagnostic tests and the appropriate time, hand in hand, with the analysis of the risk and epidemiological factors corresponding to Candida albicans.

Previous colonization is one of the most important factors found for invasive candidiasis; among others, HIV, parenteral nutrition, bloodstream infections, sepsis, septic shock, multiorgan failure, and neonatal infection are very important factors to initiate empirical antifungal therapy and thus improve survival in patients with invasive candidiasis caused by C. albicans.

Obtaining blood culture samples in the golden 1st hour of sepsis in patients with risk factors for invasive candidiasis will allow early treatment to be initiated in populations with increased risk of invasive candidiasis. It is necessary to investigate the reason for the marked epidemiological changes that may be associated with various factors. Mexico presented the highest percentages of C. albicans followed by Spain, China, and Africa in patients with invasive candidiasis.

Acknowledgments

A special thanks to my mother, teacher Mrs. Juana Narcisa Acosta Alcívar, an example to follow in education in Ecuador, Abigucho, Claris, Lucciana, Gladys, This is done with full funding from the authors.

Conflict of interest

The authors declare no conflict of interest.

Appendices and nomenclature

C	Candida
HIV	human immunodeficiency virus
CD4	CD4 T lymphocytes
ICU	intensive care unit
EQUAL	quality of clinical candidemia management
IV	intravenous