1. Introduction

The outcomes in patients with invasive candidiasis are generally dependent on mycological cure, the severity of the underlying conditions, and the time frame of therapy. The delay in the introduction of antifungal treatment for each 12–24 h may result in increases in mortality rate of up to 100% [49].

There are three major points that affect the outcome and duration of invasive candidiasis. First is the early diagnosis of infection. This requires the analysis of risk factors and clinical manifestations and the prompt use of all available approved cultural and non-cultural diagnostic methods [27,146]. Second is the search for the possible source of infection and its removal. It is very important to eliminate all blood and urine catheters. often encountered as sources of infection. as well as prosthetic devices where possible. All catheters and devices should be cultured upon removal. The surgical debridement of the site of infection has to be performed or, alternatively, the drainage of abscesses or infected peritoneal or pleural fluids should be performed [21,27,69,126,147]. Third, early effective systemic antifungal therapy has to be administered [69,126]. The delay in the administration of antifungal therapy, inappropriate formulations, and inadequate dosages result in higher mortality rates [148,149,150]. It is important to consider both the susceptibility of the yeast and drug–drug interactions along with the PK/PD data which have a high impact on certain loci of infections (e.g., in Candida endocarditis, Candida endophthalmitis, the central nervous system, or bone tissue involvement) [27].

The deficiency in reliable and sensitive methods for the diagnosis of invasive candidiasis and the long time (2–4 days) necessary for the isolation of fungus and susceptibility testing makes the early treatment that is crucial for a positive outcome challenging. The major aim is to start therapy as early as possible and use the effective regiment, but this is not easily feasible. There are several regularly updated detailed guidelines for the treatment of invasive candidiasis that can be helpful to healthcare professionals [150,151].

Systemic antifungals are used in the treatment of invasive candidiasis. There are four classes of preparations that differ in their mechanisms of action. One of the earliest systemic antifungal preparations introduced to clinical practice in 1959 was polyene amphotericin B [152]. It has been successfully used in the treatment of different invasive fungal infections, including candidiasis, since that time. Polyenes bind to ergosterol, the major component of the fungal cell membrane, creating pores and subsequent cell death [153,154]. These agents have a broad spectrum and a potent fungicidal effect. Most Candida species retain susceptibility to systemic polyenes. However, resistance is frequently detected in C. lusitaniae [155]. Amphotericin B and its lipid formulations are the only systemic polyenes available with lipid formulations less toxic and better tolerated by patients [156]. The use of conventional amphotericin B is limited by often-encountered individual intolerance and nephrotoxicity [157,158,159].

5-fluorocytosine (flucytosine) was developed as an antimetabolite in 1957. It inhibits fungal protein synthesis after being converted to 5-fluorouracil by cytosine deaminase and incorporated into fungal RNA, replacing uridylic acid. It is also a potent inhibitor of fungal DNA synthesis through the inhibition of thymidylate synthetase [160,161]. The drug is effective against a wide range of Candida spp., is well tolerated, and has a synergistic effect with amphotericin B. Flucytosine is used in combination with amphotericin B in invasive candidiasis in neonates with Candida meningitis due to its superb penetration into the cerebrospinal fluid. The use of flucytosine monotherapy is limited due to easily emerging resistance [162,163,164,165]. Hematologic and hepatic toxicities are associated with flucytosine administration. The careful monitoring of blood cell count is recommended. The adjustment of dose is advocated in patients with renal disfunction: serum concentration monitoring is helpful [164].

Systemic azoles and currently widely used triasoles have several antifungal formulations, including fluconazole, itraconazole, voriconazole, posaconazole, ravuconazole, and isavuconazole. Azoles inhibit lanosterol 14α demethylase, a key enzyme of ergosterol biosynthesis. Azoles generally demonstrate fungistatic activity against Candida spp. Most of them are active against fungi, causing invasive candidiasis with some agents demonstrating decreased activity against certain species. Resistance to fluconazole is most common in C. auris, C. glabrata, and C. parapsilosis; C. krusei has intrinsic resistance to fluconazole. Resistance to other azoles is rarely encountered, though increasing in frequency [166,167,168,169].

Echinocandins (micafungin, anidulafungin, caspofungin) present the newest class of antifungals and feature a fungicidal effect in Candida species. Their mechanism of action is the inhibition of β-D-glucan synthase, the important enzyme in cell wall synthesis. All echinocandins have high efficiency in invasive infections and an exceptional safety profile. A novel echinocandin rezafungin with once-weekly dosing and activity against Candida spp., including subsets of echinocandin-resistant Candida auris, has been recently developed and is currently in phase III trials [170,171,172,173,174,175,176]. Echinocandins demonstrate wide distribution in different organs and tissues, except the brain and eyes [52,177].

Early diagnosis and early efficient initial therapy play a crucial role in the outcome of infection: a 24 h delay in obtaining positive blood cultures is associated with an almost two-fold increase in mortality in cancer patients [178]. Echinocandins are considered the drugs of choice for initial therapy in most cases of invasive candidiasis [179,180,181], though it depends on the severity of infection, data on the effectiveness of the antifungal treatment in previous episodes and intolerance to antifungals, the involvement of organs that demand specific permeability, and the tissue distribution of the agent (central nervous system, valves, bones, articular tissues, etc). Data on the dominant pathogen and its antifungal susceptibility in certain hospital settings, such as wards and departments, especially in non-neutropenic patients when an exogenous source of infection is suspected, are also important (Table 2).

Echinocandins were effective as initial treatment in 70–75% of patients with invasive candidiasis, according to randomized clinical trials [27,180]. Lower than expected survival rate might be due to the insusceptibility of the fungus to the agent used, or other circumstances (severe underlying condition or infection, delay in diagnosis or the initiation of therapy, non-performed debridement, or poor permeability of the drug into the infected site) [182,183,184,185,186]. An analysis of seven randomized clinical trials in roughly 2000 patients with invasive candidiasis showed that choice of an echinocandin as the initial treatment was associated with a significantly lower 30-day mortality rate compared with azoles or amphotericin B [150]. Worse outcomes were associated with C. tropicalis infections, higher APACHE II score, and older age [150]. C. parapsilosis usually demonstrates higher MIC to echinocandins than other Candida spp. Nevertheless, data from several clinical trials have shown that initial therapy with any echinocandin is appropriate for patients with C. parapsilosis infection, contrary to infections caused by other Candida spp. with acquired resistance to echinocandins [187,188,189]. Two randomized trials compared an echinocandin with an azole as a first-line therapy of candidaemia. One of them demonstrated that overall response rates were lower with fluconazole (60%) examined against anidulafungin (76%); another provided similar data for isavuconazole (60%) compared with caspofungin (71%) [182].

De-escalation or step-down therapy with changes from echinocandins to azoles provides favorable results in invasive candidiasis with different organ involvement (Table 2). The step-down therapy is normally started after 3–7 days of initial treatment and is administered in accordance with the results of susceptibility testing. Fluconazole could be the perfect choice for infections caused by susceptible strains with high efficiency, well-tolerability, and oral formulations with absorption from the gastrointestinal tract above 90% (Table 2). Several clinical trials did not reveal any differences in the 30-day survival or mycological cure rates of patients who received echinocandin therapy and those who were transferred to de-escalation therapy with oral azoles, according to susceptibility testing after 5 days of treatment with echinocandin [184,190]. Another option for step-down therapy with azoles in invasive candidiasis is voriconazole active against C. guilliermondii, C. glabrata and C. krusei with reduced susceptibility or resistance to fluconazole. De-escalation therapy significantly decreases the financial burden of invasive candidiasis for healthcare systems, with reduced hospital costs and shortened stay, as azoles, unlike echinocandins, can be successfully administered as oral formulations.

Azoles have some advantages compared to echinocandins as a first-line therapy treatment for the involvement of certain organs. Contrary to echinocandins, azoles easily cross the blood–brain barrier, making them the drug of choice for initial treatment in cases with central nervous system involvement. Fluconazole is widely used in low-income countries with a low prevalence of azole resistance as the first therapeutic choice in all types of invasive Candida infections. Patients with invasive candidiasis and no previous exposure to azoles may receive azoles as initial therapy if they are stable hemodynamically and do not have an increased risk of C. glabrata infection. The group of patients at high risk of C. glabrata includes patients with cancer or diabetes mellitus, and the elderly [69]. There are trials of newer azoles (posaconazole, ravuconazole, isavuconazole) demonstrating excellent in vitro activity against C. krusei, C. guilliermondii and C. glabrata. They might be alternatives to echinocandins as a first-line therapy [27,191].

Amphotericin B deoxycholate or, preferably, lipid formulations may be considered in infections refractory to other systemic antifungals in Candida endocarditis or Candida endophthalmitis. Intolerance of other classes of antifungals in individuals may also favor the use of amphotericin B lipid formulations. Multidrug-resistant strains with resistance to azoles and echinocandins are encountered with increasing frequency in C. glabrata and C. auris, with amphotericin B lipid formulations successfully used in these cases. Pan-drug-resistant strains of C. auris with no available treatment options have already been reported [192].

The recommended duration of systemic antifungal therapy for candidemia is at least 14 days after the eradication of Candida spp. from the blood and the resolution of all symptoms and signs of infection [69,151]. In deep-seated invasive candidiasis, e.g., chronic hepatosplenic candidiasis or intra-abdominal candidiasis, the duration of treatment normally differs from several weeks to 6–12 months and is individually adjusted. It is guided by the rate of lesion resolution, physicians’ personal experience, and scarce and typically non-randomized studies [27].