Table of Content

Invasive Fungal Infections (IFIs)

  • Fungal infections are a global health issue, affecting millions of patients every year.  Among these, approximately 1.5 million are disseminated or invasive fungal infections (IFIs), requiring advanced treatment and hospitalization. 1
  • These high number of infections are also associated with high mortality rates, with some fungal infections reaching mortality rates between 90%–95%. 1
  • Fungi have emerged as both primary and opportunistic pathogens that possess the ability to cause infection both in immunocompetent and immunocompromised individuals respectively. Most of the fungal infections in human are undiagnosed and thus, less reported. 2
  • Those infections in which the fungi have invaded into the deep tissues and have established themselves resulting in prolonged illness are called as IFIs. 2
  • Fungal pathogens causing IFIs include yeasts (Candida spp, Cryptococcus spp) and moulds (Aspergillus spp, Fusarium spp, Scedosporium spp, Mucor, Rhizopus and Absidia). 2
  • IFIs are also caused by dimorphic fungi such as Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides spp, etc). 2
  • The initiation of antifungal treatment at an appropriate time is an important factor in the clinical outcomes of the patient. 3

Risk Factors for IFIs

  • The key risk factors for IFI include neutropenia <500 neutrophils/ml for more than 10 days, haematological malignancies, bone marrow transplantation, prolonged (>4 week) treatment with corticosteroids, prolonged (>7 days) stays in intensive care, chemotherapy, human immunodeficiency virus (HIV) infection, invasive medical procedures, and the newer immune suppressive agents. 3
  • Additional risk factors include malnutrition, solid organ transplantation, severe burns or prolonged stays in intensive care (>21 days), systemic corticosteroids for >7 days, and major surgery. 3
  • Also, there are reports of fungal infection in immunocompetent patients without signs or symptoms of conditions associated with immunocompromised status. 3

 

Invasive fungal infections affect millions of patients every year.  The major risk factors for IFI include:

  • Neutropenia <500 neutrophils/ml for more than 10 days
  • Haematological malignancies
  • Bone marrow transplantation
  • Prolonged (>4 week) treatment with corticosteroids
  • Prolonged (>7 days) stays in intensive care
  • Chemotherapy
  • Human immunodeficiency virus (HIV) infection
  • Invasive medical procedures
  • Newer immune suppressive agents

Antifungal Therapeutic Agents

The antifungal agents which have been approved as therapeutic options for fungal infections belong to different chemical classes such as polyenes, anti-metabolites, azoles, and echinocandins. 1, 4

Azoles

The agents in this class target the fungal plasma membrane through inhibition of the biosynthesis of ergosterol, a fungal plasma membrane component which is similar to cholesterol found in mammalian cell membranes. This occurs through the inhibition of the lanosterol 14α-demethylase (cytochrome P451 or CYP51), which catalyzes the final step in ergosterol biosynthesis. This leads to defects in fungal plasma membrane integrity and cellular integrity (Figure 1). 1

The most widely-used yeast-active azole is fluconazole. However, fluconazole resistance can present a significant clinical issue as some Candida species, such as C. krusei are intrinsically resistant to this drug, and Candida isolates such as Candida glabrata are often susceptible to this drug at high concentrations under which circumstances it is commonly associated with adverse reactions. 1, 5, 6

Itraconazole, voriconazole and posaconazole are mould-active azoles as these agents also inhibit many filamentous fungi in addition to retaining activity against Candida and Cryptococcus yeasts. 1

Itraconazole was the first accessible azole with substantial activity against moulds, such as Aspergillus fumigatus. But, bioavailability and toxicity issues with itraconazole limit its current use for IFIs. 1

Although voriconazole has demonstrated activity in vitro against fluconazole-resistant Candida spp., cross-resistance can occur. Voriconazole has also been associated with increased incidence of hepatotoxicity, transient visual disturbances (including abnormal vision, photophobia, color vision changes, or hallucinations), skin reactions, and mental confusion. 5

Posaconazole is a novel triazole being the first azole with extended activity against Zygomycetes. It is indicated for the prophylaxis of IFIs, especially in the setting of prolonged neutropenia after high dose cancer chemotherapy. Thus, most of studies with posaconazole so far have been for the prevention of invasive fungal disease in high risk patients, most notably allogeneic stem cell transplant recipients and neutropenic patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).  It also has the potential to interact with other medications due to the inhibition of hepatic CYP-450-dependent metabolism.  Absorption issues are a significant barrier to posaconazole oral suspension’s clinical use. 1, 5

The triazoles, as a class, have been associated with nausea, vomiting, diarrhea, hepatic toxicity and QTc prolongation. Also, in comparison to other antifungal classes, the triazoles appear to have the greatest potential for drug-drug interactions with selected antiretrovirals, anticonvulsants, chemotherapeutic agents, HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitors, immunosuppressants and amiodarone.  Amongst all the available triazoles, voriconazole is associated with the most drug-drug interactions, as it is both an inhibitor and substrate for all three CYP enzymes (2C19, 2C9, and 3A4). Of the triazoles, fluconazole and voriconazole have the highest central nervous system (CNS) penetration, while fluconazole is the only triazole that achieves reliable concentrations as active drug in the urine. 5

There is high prevalence of azole resistance among Candida species which is largely attributed to the cytostatic nature of these drugs. Also, Aspergillus and Cryptococcus strains have recently demonstrated azole resistance. 1

Additionally, cyclodextrin, a solubilizing agent used with some intravenous (IV) triazoles is associated with nephrotoxicity in patients with renal insufficiency. 1

Echinocandins

Three drugs from this class are currently approved for clinical usage: Caspofungin, micafungin and anidulafungin. Echinocandins affect cell wall biosynthesis through the non-competitive inhibition of β-1,3-glucan synthase enzyme which is involved in the biosynthesis of one of the most abundant fungal cell wall components (Figure 1). They are primarily used for the treatment of invasive candidiasis and as an alternative therapy for treatment of aspergillosis. They have low host toxicity and few drug interactions. However, they have no activity against Cryptococcus species. Also, due to their large molecular size, they are not orally bioavailable and so are only available in IV formulations. A few years ago, echinocandins were considered effective therapy for the most clinically-relevant Candida isolates. However, with increased use of these antifungal agents, echinocandin resistance in Candida species has also become more widespread. 1 This is being observed in the isolates of Candida parapsilosis and C. guilliermondii which are less susceptible to the echinocandins. 7

The concentration of echinocandins in organs, such as the heart and brain is much lower compared with plasma (0.3 and 0.06-fold, respectively). All echinocandins have been associated with infusion-like reactions including urticaria, rash, dyspnea and hypotension.  Since caspofungin is the oldest echinocandin, it has the most clinical data supporting its use. An important disadvantage of caspofungin is its drug interaction with cyclosporine and its need for adjustment with liver dysfunction. 5

Polyenes

Although both nystatin and amphotericin B are members of the polyene class, only amphotericin B is considered a treatment option for invasive fungal infections. 5

Conventional amphotericin B and its newer lipid formulations are broad spectrum polyene antifungals that target the fungal plasma membrane. They bind to and remove ergosterol from the plasma membrane thus reducing membrane integrity (Figure 1). They are indicated for the treatment of severe infections caused by fungi belonging to Candida species, Cryptococcus species, Zygomycetes division and as an alternative therapy for aspergillosis. They are also used to treat many life-threatening IFIs due to other fungi, such as Histoplasma, Coccidioides and Blastomyces. Amphotericin B is cytocidal for most fungi and only its IV formulations are used clinically. However, conventional amphotericin B can have severe side-effects, such as nephrotoxicity. Newer formulations of this drug, such as liposomal formulations, demonstrate more selective fungal targeting and less host toxicity. 1

Due to its limited oral bioavailability (5 – 9%), amphotericin B is only available as an intravenous formulation. Amphotericin B distributes into the tissues of liver, spleen, lung, kidney; but nominally into the cerebrospinal fluid (CSF) achieving < 2.5% concentrations. The metabolic pathway of amphotericin B is still uncertain, with only 2.5 – 5% of active drug being excreted in urine and a trivial amount in bile. Although, the incidence of resistance to amphotericin B is rare among Candida spp., higher minimum inhibitory concentrations (MICs) have been reported with C. krusei and C. glabrata and intrinsic resistance towards amphotericin B has been reported with C. lusitaniae. 5

Anti-metabolites

Flucytosine is a fluoridated pyrimidine analog, which inhibits deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by incorporating into the growing nucleic acid chain and thus, preventing further extension. This damage of nucleic acids ultimately leads to cellular defects in protein biosynthesis and cell division (Figure 1). 1

Amphotericin B plus flucytosine is the first-line treatment for Cryptococcus central nervous system (CNS) infections.1 Flucytosine is also used primarily in combination with amphotericin B (AMB) for the treatment of invasive cryptococcal infections and some Candida spp. infections. 5 Oral bioavailability of flucytosine is reported as 78 – 89%, with peak serum concentrations occurring 2 hours after an oral dose in patients with normal renal function. Its protein binding is nominal (2.9 – 4%) and its tissue concentrations were found to be equivalent to serum levels in the spleen, heart, liver, kidney, and lung; 80% of serum levels were found in cerebrospinal fluid. Most of 5-FC (90%) is renally excreted as active drug, with a minor amount being metabolized hepatically. 5

Bone marrow toxicity occurs as adverse effect with flucytosine, especially in the presence of renal impairment. However, one of the truly limiting factors of this drug is its limited availability in countries with the highest incidence of cryptococcosis. 1

Figure 1: Mechanism of Action of Antifungal Agents 4

Unmet Needs in the Management of Critical IFIs

From the decade of 1960s, when antibiotic therapies were developed, an extreme rise in fungal infections was observed. This rising incidence of fungal infections is also due to the growing number of immune-deficient cases related to Acquired Immunodeficiency Syndrome (AIDS), cancer, old age, diabetes, cystic fibrosis, and organ transplants and other invasive surgical procedures. 8

Primary pathogens are naturally able to establish an infection in the healthy population while the opportunistic pathogens, among them commensal microorganisms of the healthy population, can develop infectious colonization of the human body when criteria, such as immunosuppression, are met. 8

Although extensive research has been done for the development of new therapeutic strategies, there are only a limited number of available drugs to fight against IFIs. 8

Candida albicans is still the most common causative agent of IFIs worldwide but recently, a shift toward non-albicans Candida species as causative agents of invasive candidiasis (IC) has been related to the increased use of fluconazole in prophylaxis or empiric therapy. 7

Fluconazole was the gold-standard treatment of fungal infections during the 1990s due to its good pharmacokinetic properties as well as its broad spectrum of activity. However, the over prescription of this drug by physicians for prophylaxis or treatment led to an increase in resistance to azole drugs. 8

Even though the new generation triazoles (posaconazole and voriconazole) were shown to be more effective against Candida and Aspergillus, compared to classical triazoles. However, their side effects and drug interactions are similar to those observed with fluconazole and itraconazole. 8

Polyenes are recommended as alternative therapy in cases of intolerance or limited availability of other antifungal agents. 9 They possess a lower but non-negligible affinity for cholesterol, the human counterpart of ergosterol. This slight affinity for cholesterol explains the high toxicity associated with antifungals and is responsible for several side effects. 8

Infusion-related reactions, which include fever, chills and shaking, are a serious concern with polyene therapy. These reactions have been reported both with conventional and lipid formulations of amphotericin B, although the incidence is significantly reduced with the latter9.

Although it has the broadest spectrum of any antifungal, amphotericin B (including lipid based formulations such as a lipid complex, a colloidal dispersion and a liposomal preparation) use has been limited in recent years due to concerns regarding toxicity. 5

Echinocandins are primarily used for the treatment of invasive candidiasis and as an alternative therapy for treatment of aspergillosis. They lack activity against Cryptococcus species. 1

Also, few case reports suggest that resistance to echinocandins may be seen in Candida spp., including C. albicans, C. glabrata, Candida krusei and C. parapsilosis. 9 The three echinocandins, i.e., caspofungin, micafungin, and anidulafungin, are large, amphipathic, cyclic peptides due to which they do not ordinarily penetrate the brain and CSF. They also show limited or low penetration into the aqueous and vitreous humors, pleural fluid. Even though all three echinocandins readily penetrate the kidney tissue, they exhibit low concentrations (<2% of the dose) of unchanged drug in human urine. 10 While the echinocandins achieve concentrations similar to plasma in small intestines, lung and spleen; other organs, such as the heart and brain have much lower concentrations compared with plasma (0.3 and 0.06-fold) respectively. 5

Thus, from the above evidences, we can conclude that treatment of IFIs is often complicated by low tolerability, narrow spectrum of activity, low distribution and penetration at various sites of infection, drug- or class-specific toxicities, have major drug interactions, or are not sufficiently active because fungi have become resistant.  4, 10

 

Fluconazole is a gold standard azole active against the yeast fungi while the newer azoles are active against the mould fungi also. However, all of them have limitations in terms of drug interactions and certain adverse effects like hepatotoxicity although the extent varies from agent to agent. Resistance towards azoles is also being observed to be increasing amongst the various Candida species.

Echinocandins are considered effective therapy for the most clinically-relevant Candida isolates. However, due to their large molecular size, are not orally bioavailable and they do not penetrate the brain and CSF. They also show low penetration into the aqueous and vitreous humors, pleural fluid and heart. Their low concentrations get excreted as unchanged drug in human urine. Also, echinocandin resistance is being reported in the isolates of Candida albicans, C. guilliermondii, C. parapsilosis, C. glabrata, C. krusei and C. parapsilosis species.

Although amphotericin B has the broadest spectrum amongst the antifungals and it is an alternative therapy for most refractory IFIs, there are concerns regarding its nephrotoxicity and infusion-related reactions.

These limitations of antifungal agents have supported achieving efficient clinical outcomes with combination therapy in the treatment and management of IFIs.

Flucytosine- An Essential Companion in IFI

In 1968, flucytosine was first used to treat human candidosis and cryptococcosis, and it remains one of the oldest antifungal agents still in use.The absorption of flucytosine is rapid in normal individuals, with bioavailability reported as 76%–89% after oral administration. It is a small, highly water soluble molecule that achieves good levels in vitreous fluids and urine. 16

Its tissue concentrations were found to be equivalent to serum levels in the spleen, heart, liver, kidney, and lung; 80% of serum levels were found in cerebrospinal fluid (CSF). The pharmacodynamic property that best correlates with efficacy appears to be time above the minimum inhibitory concentration (T > MIC, R 2 = 0.85). 5 Pharmacokinetic drug–drug interactions involving the cytochrome P450 system are a minor concern in flucytosine treatment. 17

Due to the substantial morbidity and mortality related to IFIs, treatment with a combination of antifungal agents is often considered. Overall, combination antifungal therapy approaches may be used to broaden the spectrum of activity, enhance the rate or extent of killing (eg, through synergy), minimize development of resistance, or reduce toxicities. Considerable concern has arisen regarding the use of common azoles in combination with amphotericin B, because these agents have the same target within the fungal cell membrane. Most in vitro studies of this combination have demonstrated mixed results of antagonism or indifference, whereas variable results for survival and tissue burden have been demonstrated in animal models of fungal infection. 18 For IFIs localized outside the bloodstream, target site kinetics of antifungals are a key issue in treatment. 17

Due to the dose-limiting nephrotoxicity of amphotericin B, the scarcity of readily available, effective antifungal compounds, and the improved therapeutic outcome in certain mycoses with combination antifungal therapy, interest in using flucytosine together with other antifungals (notably amphotericin B) to treat cryptococcal infections, selected infections caused by Candida spp., and chromoblastomycosis has increased. 5, 19

Animal models and clinical studies have demonstrated improved outcomes with combination (FC with amphotericin B or fluconazole) therapy, as well as reduction in the development of resistance against flucytosine monotherapy.  Flucytosine alone is considered to have fungistatic activity against most fungal isolates, but when it is used with amphotericin B, the combination of these agents is fungicidal against most species and requires lower dosing of both agents.5 Another advantage of flucytosine is that the reported primary resistance to flucytosine monotherapy among Candida and Cryptococcus isolates remains very low (<2%).9

Role of Flucytosine in Invasive Candidal Infections

The leading cause of IFI is candidiasis, with 50% of cases occurring in intensive care unit (ICU) patients which can include a host of infections involving mucosal surfaces and the urinary tract, as well as more disseminated disease (e.g., sepsis, meningitis, endocarditis, intra-abdominal infections). 14

As described above, there is a shift in the epidemiology of invasive candidiasis towards non-albicans Candida species which has substantial consequences because they often have either reduced susceptibility or resistance to fluconazole which is commonly used preemptively to treat these infections. 14

Clinical experience indicates that candidiasis involving deep tissues, particularly in granulocytopenic patients, is best treated with a combination of amphotericin B and flucytosine. Therefore, in patients with invasive candidiasis, especially caused by non-albicans Candida species, addition of flucytosine to amphotericin B should be strongly considered as it has shown improved clinical outcomes. Improved survival or reduced tissue burden has been observed in animal models against Candida species, when flucytosine has been added azoles. 18, 19

Role of Flucytosine in Candidemia

Candida spp. are reported to be the fourth leading cause of blood stream infections (BSIs) overall and the third leading cause of these infections in ICU patients with mortality rates due to candidemia, ranging from 30 - 81%. 14, 15

Risk factors for candidemia include age, moderate-to-severe renal diseases, leukemia, lymphoma, gastrointestinal malignancies, metastatic solid tumors and chronic pulmonary diseases. 12

The findings of various studies conducted at several Indian hospitals report an incidence of 1 - 12 cases of candidemia per 1000 admissions. Although Candida albicans remains one of the most common species isolated, recent studies have shown an increase in the incidence of candidemia due to non‑albicans Candida, with the isolation rate ranging from 50 to 96% from tertiary care centers in India. Candida tropicalis and C. parapsilosis were found to be the predominant species causing candidemia in India. 15

In an Indian study, C. tropicalis (43%) was the predominant species isolated from the patients who died. Also, resistance to antifungal agents was observed in a few isolates. A total of 3.3% (6 C. glabrata, 1 C. rugosa) isolates were resistant to fluconazole and 2.8% were intermediately sensitive to fluconazole. A total of 3.3% (6 C. glabrata, 1 C. albicans) isolates were resistant to amphotericin B and 1.4% were intermediately sensitive to amphotericin B. Among the isolates of C. glabrata, 20% were resistant to both fluconazole and amphotericin B. However, no resistance was observed for flucytosine or voriconazole. Another Indian study reported resistance to amphotericin B in 15.4% C. albicans, 8.1% C. tropicalis, and 33.3% C. krusei strains. Thus, emergence of resistance to the azoles as well as even towards polyene group of antifungals is a matter of grave concern particularly in Indian scenario. 15

Flucytosine can be a good option as it has shown to be curative in 10 out of 11 non-granulocytopenic patients with persistent catheter-associated candidemia. 19

Also, flucytosine has also been used successfully in combination with the echinocandin, caspofungin or amphotericin B, or both to clear refractory cases of candidemia, as detailed in some published reports. 18

Role of Flucytosine in Candidal Infective Endocarditis

Fungi are an uncommon but emerging cause of infective endocarditis (IE), accounting for 1%-6% of total cases, and up to 10% of cases of prosthetic valve endocarditis (PVE). Candida species are the most frequent causes of fungal endocarditis. Due to Candida IE, overall mortality rate is more than 50%, despite treatment as compared to that in cases of IE due to other etiologies. Recent in vitro studies have shown reduced activity of amphotericin B against Candida biofilm, and poor penetration into vegetations and blood clots in experimental models of IE. 11

5-FC distributes widely in tissues and facilitates antifungal activity of amphotericin B in sites with poor penetration for amphotericin B, including the cardiac valves in addition to that in CSF and vitreous humor. In turn, the penetration of 5-FC to the cell interior is facilitated by the membrane-permeability increasing effects of amphotericin B. 20

For the management of fungal endocarditis, combined approach with both antifungal therapy and radical surgery offers survival advantage and is recommended. Amphotericin B is the drug of choice for treatment. The liposomal formulation is preferred because the lesser toxicity permits use of higher, potentially fungicidal doses (up to 5 mg/kg/day) and is often combined with 5-flucytosine for synergistic activity. 21

In an observational study, flucytosine was the most common concomitantly prescribed antifungal along with amphotericin B or an echinocandin. 22

Role of Flucytosine in Candidal Urinary Tract Infections

Generally, when the terms funguria or fungal urinary tract infection (UTI) are used, most physicians are referring to candiduria and urinary tract infections due to Candida species. This is due to the fact that other fungi, including yeasts, such as Cryptococcus neoformans and Trichosporon asahii, and molds, such as Aspergillus species and members of the Mucorales, can involve the kidney during the course of disseminated infection, but rarely cause symptoms referable to the urinary tract. Important risk factors predisposing to candiduria include older age, female sex, diabetes mellitus, antibiotic use, urinary tract obstruction, urinary tract surgery/instrumentation and urinary drainage device. Most infections are due to C. albicans; overall, this species accounts for 50% to 70% of isolates. C. glabrata is the second most common cause of urinary tract infections in most series, but Candida tropicalis is the second most common species in some centers. Candida parapsilosis, Candida krusei, and other unusual Candida species are less commonly found in urine. Patients with hematological malignancies and transplant recipients have a higher risk of developing C. glabrata urinary tract infection. Mortality with candiduria can be high in debilitated patients and those in advanced age. 23, 24

Most yeasts isolated from urine are only colonizers, which should not be treated. However, if a patient is thought to have a Candida urinary tract infection, knowledge of the species is crucial because many isolates of C. glabrata and all isolates of C. krusei are resistant to fluconazole, the standard treatment. 23, 24

Antifungal susceptibility studies should be performed if C. glabrata is isolated. In a minority of cases, the organism may be susceptible and fluconazole can be used; in many cases, however, the organism will be resistant, and other options will need to be explored. Most isolates of C. albicans, Candida parapsilosis, and Candida tropicalis are susceptible to fluconazole, but resistance has been reported, and susceptibility testing should be done for these species, as well as other unusual Candida species. 23, 24

There has been an increase in the incidence of candiduria caused by more resistant non- albicans Candida species. Candiduria may be the only indicator of a more serious invasive candidiasis, especially in immunocompromised patients. Since azoles other than fluconazole and all echinocandins are poorly excreted in urine they have been found to be less effective in candiduric patients. Although amphotericin B deoxycholate has generally been found to be efficacious in virtually all forms of invasive candidiasis, including UTI, less nephrotoxic lipid formulation of this agent are not recommended for treating renal candidiasis because of poor penetration in the renal parenchyma. With the proven efficacy of flucytosine in different forms of candidal UTI, excellent activity against non-albicans Candida and high concentrations in the urine; it may be considered as a useful option for patients who are intolerant to fluconazole and for whom fluconazole cannot be used. It may be combined with amphotericin B in order to avoid emergence of resistant strains. 25, 26

 

In patients with invasive candidiasis, especially caused by non-albicans Candida species, which often have either reduced susceptibility or resistance to fluconazole, addition of flucytosine to amphotericin B should be strongly considered as it has shown improved clinical outcomes. Limited data is also available against candidiasis for flucytosine in combination with azoles.

Flucytosine has been used successfully in combination with the echinocandin, caspofungin or amphotericin B, or both to clear refractory cases of candidemia.

5-FC distributes widely in tissues and facilitates antifungal activity of amphotericin B in sites with poor penetration for amphotericin B, including the cardiac valves in addition to that in CSF and vitreous humor. Therefore, the liposomal amphotericin B is often combined with 5-flucytosine for synergistic activity against Candida species causing fungal endocarditis.

With the proven efficacy of flucytosine in different forms of candidal UTI, excellent activity against non-albicans Candida and high concentrations in the urine; it may be considered as a useful option for patients who are not suitable for fluconazole therapy as against the azoles (other than fluconazole) and echinocandins which are poorly excreted in urine and liposomal amphotericin B which poorly penetrates the renal parenchyma.

Role of Flucytosine in Cryptococcal Infections

Cryptococcosis is an important global infectious disease. The majority of cases are observed among patients with defective cell-mediated immunity. Human immunodeficiency virus (HIV) infection is the main risk factor, accounting for 95% of cases in middle- and low-income countries (MLICs).  The most common clinical presentation in HIV/AIDS patients is cryptococcal meningitis (CM), with over 1 million cases and 600,000 deaths per year. HIV-infected patients are mainly at risk of cryptococcosis when they become very immunosuppressed and their CD4 count drops below 100 cells/μL. A persistent elevation of the cryptococcal disease burden since the 1990s has been described from MLICs in Southeast Asia as shown below in Figure 2. 27

Figure 2: Global incidence and mortality from cryptococcal meningitis among United Nations global regions from 1997 to 2007. 27

Patients on immunosuppressive drugs (eg: transplant recipients) constitute most of the remaining caseload, although immunocompetent hosts are susceptible in some settings. Cryptococcosis disease occurs after 2.8%–8% of solid-organ transplants, and is the third-commonest invasive fungal infection in this setting, after Candida and Aspergillus. Kidney-transplant recipients were most often affected, fol­lowed by liver, heart, lung, and pancreas recipients as per a retrospective review of US data from 1996 to 2010. 27

Nonmeningeal (eg: pulmonary and cutaneous) clinical manifestations also occur, and bloodstream infection (cryptococcemia) may disseminate to multiple sites. These are proportionally more frequent in non-HIV-infected individuals. 27

In Cryptococcus species, the polysaccharide capsule protects the organism against the host immune system which is responsible for its pathogenicity.3

Cryptococcus neoformans and Cryptococcus gattii are the two principal human pathogens which are transmitted by inhala­tion. C. neoformans var. grubii (capsular serotype D) is the most common, and causes 82% of cryptococcal disease worldwide.  Cryptococcal infections due to another subtype, var. neoformans (capsular serotype A) is less common globally. C. gattii is mostly associated with illness in immunocompetent individuals from tropical and sub­tropical regions.  The actual burden of human disease due to C. gattii is probably underestimated, as many laboratories do not undertake detailed speciation of cryptococci. 27

The most commonly used combination of antifungal agents is that of 5FC with AmB or fluconazole, both against cryptococcosis. 4

Role of Flucytosine in Cryptococcal Meningitis in HIV and non-HIV Patients

In AIDS patients, monotherapy with either fluconazole or amphotericin B deoxycholate (AmB-d) to treat cryptococcal meningitis (CM) has resulted in poor clinical success rates, ranging from 34% with fluconazole to 40% with AmB-d. Combination therapy of 5-FC with amphotericin B has been shown to sterilize the cerebral spinal fluid (CSF) at a more rapid rate in comparison to monotherapy with AmB-d. 5

Therefore, flucytosine should accompany AmB during induction ther­apy at a dose of 100 mg/kg/day in HIV associated CM.  Omission of this agent has been associated with higher rates of mortality, treatment failure, and late relapse. 27

Patients developing CM after solid-organ transplant often take nephrotoxic immunosup­pressants (tacrolimus, cyclosporine or sirolimus) to prevent graft rejection, and 25% of transplant recipients have renal dysfunction at CM diagnosis. Therefore, kidney-friendly liposomal preparations of amphotericin B (eg: LAmB or ABLC) are recommended during induction therapy along with flucytosine. 27

There is no standard regimen for non-HIV, non-transplant patients with CM. Some authors advocate a longer (4–6 weeks) induction phase of amphotericin B/flucytosine while others favor a standard 2-week induction phase. Consolidation and maintenance therapy are identical to transplant recipients. 27

In non-HIV patients with cryptococcal meningitis, the combination of amphotericin B (0.3 mg/ kg/day) and 5-FC (150 mg/kg/day) administered for 6 weeks was superior in terms of clinical cure rate to amphotericin B alone (0.4 mg/kg/day) administered for 10 weeks.  Additional benefits such as fewer treatment failures or relapses, more rapid CSF sterilization (P<0.001) and less nephrotoxicity (P<0.05) were noted in the combination arm. 16, 28, 29

A similar trial evaluating the same combined regimen showed that treatment for 6 weeks rather than 4 weeks was required for most patients and that 4 weeks’ treatment may be used in non-immunocompromised patients with favourable prognostic signs, including a cerebrospinal fluid (CSF) cryptococcal antigen titre of <1:8 following treatment. 29

Role of Flucytosine in other Cryptococcal Infections

Fungaemia is an important clinical presentation of cryptococcosis and predicts a poorer prognosis. 30

Rarely, cryptococcaemia presents as ‘sepsis syndrome’ without obvious evidence of neurological involvement.  As suggested by some reports, the diagnosis of isolated cryptococcaemia is often delayed, resulting in high mortality. Therefore, a high index of clinical suspicion is needed; serum cryptococcal antigen assay, fungal blood culture should be performed and antifungal therapy within 48 hours should be considered as soon as the diagnosis is suspected. 30

The flucytosine with amphotericin B combination regimen has shown resolution of infection in patients with cancer treated for fungemia and empyema caused due to C. neoformans. 19

Also, non-AIDS patients with pulmonary cryptococcosis when administered with 5-flucytosine and amphotericin B recovered as confirmed by clinical symptomatology and radiograph. 31

As flucytosine demonstrates good susceptibility rates against Cryptococcus species, rapid absorption with higher bioavailability, higher concentrations in CSF as well as lungs, synergistic activity with amphotericin B, combination therapy of flucytosine with amphotericin B has been shown to improve clinical outcomes in cryptococcal meningitis associated with HIV and non-HIV patients and in patients with pulmonary and blood stream cryptococcal infections.

The combination therapy also allows lower dosing of both agents and hence, lower nephrotoxicity issues.

 

CYTORX

Composition

Each uncoated tablet contains:

Flucytosine IP……...…500 mg

Excipients……………...…...q.s.

Pharmacology

Pharmacodynamics

Mechanism of action

5-flucytosine is a prodrug which is converted to 5-fluorouracil its active form by cytosine deaminase inside the fungal cell. Cytosine permease localized in the fungal cell membrane is required for internalization of 5-flucytosine into the fungus. Therefore, a lack of cytosine permease or cytosine deaminase renders resistance to 5-flucytosine. 5-fluorouracil is converted into 5-fluorouridine monophosphate (FUMP), 5-fluorouridine diphosphate (FUDP) and finally into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into the fungal RNA instead of uridine triphosphate (UTP) causing inhibition of fungal protein synthesis. In addition, fluorodeoxyuridine monophosphate (FdUMP) formation is catalysed by the uridine monophosphate pyro-phosphorylase. FdUMP inhibits the fungal thymidylate synthase and thus, fungal DNA synthesis (Figure 2). 17

Through both of these mechanisms, 5-FC demonstrates its primarily fungistatic activity. 5

Figure 3: Intracellular pathway and mode of action of 5-fluorouracil (5-FU) 16

Mechanism of Resistance

Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug. Candida krusei should be considered to be resistant to flucytosine.

Pharmacokinetics (PK)

Absorption

When administered orally, this treatment is absorbed by the digestive tract at a rate of 90% and produces the same concentrations as those observed following short-term intravenous (IV) infusion with an identical dose. After single IV administration, peak serum concentrations are approximately equivalent, in micrograms/mL, to the dose administered in mg/kg.

Distribution

The volume of distribution is between 0.5 and 1 L/kg. This medicinal product is diffused throughout the body, including in the cerebrospinal fluid (CSF), as a result of very low binding (<5%) to plasma proteins. Urinary concentrations of this medicinal product are always higher than plasma concentrations in patients with normal renal function.

Metabolism

More than 90% of the flucytosine dose is recovered in unchanged form in the urine. Flucytosine is metabolized (probably by intestinal bacteria) to 5-fluorouracil (5-FU). The 5-FU/5-FC plasma concentration ratio is low.

Excretion

The plasma half-life is 3 to 6 hours. Elimination is rapid via the kidneys, mainly by glomerular filtration, in unchanged form. In patients with renal impairment, the plasma half-life is prolonged; the dosage must therefore be adjusted to creatinine clearance. Flucytosine is dialyzable.

Table 1: Overview on pharmacokinetics of flucytosine 17

 

Each tablet of Cytorx contains 500 mg of flucytosine. Flucytosine is a prodrug which is converted to 5-fluorouracil its active form by cytosine deaminase inside the fungal cell. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis or interfere with the biosynthesis of fungal DNA.

It is absorbed by the digestive tract at a rate of 90% and produces the same concentrations as those observed following short-term intravenous (IV) infusion with an identical dose.

It gets diffused throughout the body, including in the CSF due to its very low binding (<5%) to plasma proteins. Urinary concentrations of this medicinal product are always higher than plasma concentrations with more than 90% of the flucytosine dose being recovered in unchanged form in the urine.

It gets eliminated rapidly via the kidneys and has a plasma half-life is 3 to 6 hours. In patients with renal impairment, the plasma half-life is prolonged.

In vitro Activity

Flucytosine possesses a broad range of activity; mostly active against yeasts of Candida and Cryptococcus genera. 8, 29

Flucytosine also exhibits a post antifungal effect (PAFE) against Candida spp. and C. neoformans, which can persist for up to 7.4 or 5.4 hours, respectively. 5

Flucytosine has demonstrated favorable activity in vitro against several Candida spp. (except C. krusei), Cryptococcus spp., Torulopsis spp.  Rhodotorula spp., Saccharomyces cerevisiae, and certain causative pathogens of chromoblastomycosis (ex. Fonsecaea spp., Phialophora spp., Cladosporium spp.) 5, 29

Previous reports indicate that 99% of pretreatment isolates of C. neoformans and 88% of isolates of Candida species are susceptible to flucytosine.  Other fungi, including Aspergillus species, have shown variable susceptibility. 32

Flucytosine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

Candida albicans

Cryptococcus neoformans

Flucytosine exhibits in vitro minimum inhibitory concentrations (MIC values) of 4 mcg/mL, or less against most (≥90%) strains of the following microorganisms:

Candida dubliniensis

Candida glabrata

Candida guilliermondii

Candida lusitaniae

Candida parapsilosis

Candida tropicalis

Candida krusei should be considered to be resistant to flucytosine.

In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.

Strains initially susceptible to flucytosine may acquire resistance during treatment. It is therefore recommended that the sensitivity of these strains be evaluated before and also during treatment. Use of 5-FC discs is recommended.

For some pathogen species, synergy has been demonstrated in vitro and in vivo with a combination of flucytosine and amphotericin B, which is particularly pronounced in the case of organisms with reduced susceptibility to flucytosine.

Table 2: General patterns of susceptibility of Candida species amongst commonly used antifungal agents 33

I, intermediate; R, resistant; S, susceptible; S-DD, susceptible-dose dependent

 

Flucytosine has been shown to be active against most strains of the Candida albicans and Cryptococcus neoformans both in vitro and in clinical infections. It also demonstrates good susceptibility against non albicans Candida species such as Candida tropicalis, C. glabrata, C. parapsilosis, etc. Candida krusei is generally  considered to be resistant to flucytosine. However, the in vitro data suggests some susceptibility of flucytosine against C. krusei as well.

 

Indications

Flucytosine is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus.

Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine.

Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported.

Flucytosine should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to flucytosine.

Dosage and Administration

Dosages range from 50 to 150 mg/kg per day, depending on the nature of the infection, its site and sensitivity of the causative agent.

The daily dosage must be divided into three or four oral doses.

Combination with Other Antifungals

The flucytosine/amphotericin B combination is synergistic: in some cases, it allows a dose reduction and reduces the risk of the emergence of secondary resistance to flucytosine.

There does not seem to be antagonism with imidazole derivatives.

Special Populations

Renal Impairment

Doses must be administered at longer intervals, according to the following dosing regimen:

Table 3: Flucytosine Dosage Adjustment for Patients with Renal Impairment

Patients on Dialysis

Since flucytosine is dialysable, the dose of this medicinal product must be repeated after each blood-cleansing session.

Flucytosine is mainly indicated in the treatment of serious infections caused by susceptible strains such as:

1] Candidal infections: Septicemia, endocarditis and urinary system infections

2] Cryptococcal infections: Meningitis and pulmonary infections.

Dosages range from 50 to 150 mg/kg per day, depending on the nature of the infection, its site and sensitivity of the causative agent. The daily dosage must be divided into three or four oral doses.

In patients with renal impairment, dosage needs to be adjusted by administration at longer intervals. Since flucytosine is dialysable, the dose of this medicinal product must be repeated after each blood-cleansing session.

The flucytosine/amphotericin B combination is synergistic. In some cases, it allows a dose reduction and reduces the risk of the emergence of secondary resistance to flucytosine. There does not seem to be antagonism with imidazole derivatives.

 

Clinical Evidences for Flucytosine

A] In Cryptococcal Meningitis Associated with HIV/AIDS

Comparison of antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. 34

 Background/ Objective:

This study compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis.

Study Design/Methods:

Total 64 patients with a first episode of HIV-associated cryptococcal meningitis were randomized in equal numbers (16 in each group) to initial treatment with:

1] amphotericin B (0·7 mg/kg daily) or 2] amphotericin B plus flucytosine (100 mg/kg daily) or 3] amphotericin B plus fluconazole (400 mg daily) or 4] triple therapy with amphotericin B, flucytosine, and fluconazole.

Primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment.

Results:

An important prognostic factor was baseline CSF CFU counts. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0·0006), amphotericin B plus fluconazole (p=0·02), or triple therapy (p=0·02).

Conclusion:

Hence, at these doses, amphotericin B plus flucytosine was proven to be the most rapidly fungicidal regimen for HIV-associated cryptococcal meningitis. 

B] In Cryptococcal Meningitis Not Associated with HIV/AIDS

Comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis in non- HIV patients 28

Background/ Objective:

To compare amphotericin B monotherapy with a combination regimen containing both amphotericin B and flucytosine for cryptococcal meningitis.

Study Design/Methods:

Patients were included in the study only if Cryptococcus neoformans was documented in cultures of cerebrospinal fluid, brain or meninges. In 50 patients with 51 courses of therapy, 27 courses were administered with amphotericin B alone (10 week regimen- 0.4 mg/kg/day for 42 days, followed by 0.8 mg/kg every other day for 28 days) and 24 courses were administered with the combination (6 week regimen- amphotericin B, 0.3 mg/kg/day and flucytosine, 150 mg per kilogram per day divided in six hourly doses).

Table 4. Characteristics of the Cryptococcal Meningitis Patients Not Associated with HIV/AIDS Included in Study

Results:

Although the combination regimen was administered for only 6 weeks and amphotericin B for 10 weeks, the final results of all courses of therapy still favored the combination (76 % cured or improved) over amphotericin B alone (53 %) including courses that did not adhere. Also, combination therapy produced fewer failures or relapses (3 vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (5) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening.

Conclusion:

It was concluded that combined flucytosine-amphotericin B therapy is the regimen of choice in cryptococcal meningitis.

The combination of amphotericin B with flucytosine has shown improved clinical outcomes in various groups of patients with cryptococcal meningitis as follows:

1] In patients with HIV associated cryptococcal meningitis: It was proven to be the most rapidly fungicidal regimen as the clearance of cryptococci from the CSF was significantly faster.

2] In non-HIV associated cryptococcal meningitis which included solid organ transplant patients: It resulted in fewer failures or relapses, more rapid sterilization of the cerebrospinal fluid and less nephrotoxicity than did amphotericin B alone.

 

C] In immunocompromised patients with Cryptococcal and Candidal Pulmonary and Blood Stream Infections

Evaluation of Safety and Pharmacokinetics of Flucytosine in Immunocompromised Patients19

Background/ Objective:

The possibly dose-limiting, hematologic, gastrointestinal, and hepatic toxicities of flucytosine has led to a reluctance in its use in myelosuppressed patients. Thus, its use in patients with cancer or aplastic anemia during a 2.5-year period was evaluated in terms of safety and tolerability.

Study Design/Methods:

17 patients (9 males and 8 females) on amphotericin B plus flucytosine were finally included out of which nine had lymphoma, including the lymphoblastic type, three had solid tumors, three had leukemia, and one had aplastic anemia. Candida albicans was the infecting organism in four patients, producing a fasciitis, fungemia, hepatosplenic candidiasis, and combined fungemia and hepatosplenic candidiasis in one patient each.  

An unidentified Candida species was responsible in four cases-three of hepatosplenic candidiasis and one of fungemia. Torulopsis glabrata and Candida guilliermondii were each responsible for one episode of fungemia. Candida tropicalis was found in two cases of fungemia and in one case of hepatosplenic candidiasis. Cryptococcus neoformans was found in two patients, one with a progressive solitary lung nodule and the other with a pleural effusion and cryptococcemia. Aspergillus species were responsible for two cases of pneumonia.

Serial serum levels of flucytosine measured by a creatinine iminohydrolase assay permitted reliable dosage adjustment.

Results:

The combination of amphotericin B plus flucytosine eradicated the mycosis in 12 (71%) of 17 patients, whereas 3 (18%) of 17 died of progressive fungal infection. During therapy, only 2 (12%) of 17 patients had elevated mean serum levels of flucytosine (>100 mcg/mL) and 3 (18%) other patients had transiently elevated levels. Paired serum samples (n = 45) obtained at steady state during therapy with orally administered flucytosine showed similar peak and trough levels. Adverse effects of flucytosine therapy included one case each of reversible nausea, diarrhea, elevated transaminase levels, and thrombocytopenia. No cases of bone marrow aplasia, enterocolitis, hepatitis, or death due to flucytosine toxicity were encountered.

Conclusion:

It was concluded that flucytosine in combination with amphotericin B is well tolerated in myelosuppressed patients when serum flucytosine levels are serially monitored.

 

The combination of amphotericin B with flucytosine has shown improved clinical outcomes in various immunocompromised patients with cryptococcal and candidal pulmonary and blood stream infections in terms of:

1] Eradication of the mycosis in 71% of patients

2] Safety, as it was well tolerated in these myelosuppressed patients when serum flucytosine levels are serially monitored.

 

 

D] In Candiduria

Assessment of Clinical Outcomes with Flucytosine in Candidal Urinary tract Infections35

Background/ Objective:

To reports clinical experience with flucytosine in the treatment of patients with urinary candidiasis.

Study Design/Methods:

The 30 patients (19 female and 11 male with 18 to 81 years age) selected to evaluate flucytosine were hospital patients admitted for other reasons such as:

Nine patients had diabetes mellitus whose hospital admissions were prompted for treatment of bacterial infections, peripheral vascular disease, or stabilization of the diabetic condition, namely, marked ketosis and coma. 

In 8 patients with arteriosclerosis problems developed related to congestive heart failure, cerebral vascular disease, peripheral vascular disease, and pneumonia. Seven patients with neoplasms had either surgical treatment or chemotherapy. Six patients had been admitted for a variety of causes, which included neurologic disorders, gastrointestinal bleeding, chronic renal disease, or multiple trauma. Criteria for treatment with flucytosine included Candida counts greater than 10,000 colonies per milliliter; elevated serum antibody titers against Candida antigen, and lack of response to local antifungal therapy.

Flucytosine was given at a dosage of 100 mg/kg per day in four divided doses. Daily dosage for the group ranged from 4 to 10 gm.

Treatment was given for four to six weeks, during which time cultures were obtained from the urine and other sites at weekly intervals.

Results:

Twenty-three of 30 patients (77 per cent) responded to treatment. Side effects were few and limited to reversible changes in liver function and bone marrow. Intravenous amphotericin B was administered to 2 patients who failed to respond to treatment with flucytosine since Candida continued to be cultured from these patients which resulted in subsequent resolution of candiduria and drop in antibody titers. In 4 other non-responders, serum antibody titers did not change, but clinically the patients appeared better and they subsequently left the hospital. The seventh patient who suffered a treatment failure, died of myocardial infarction.

Conclusion:

 Flucytosine given orally provides the physician with an alternative treatment for significant Candida infections.

Flucytosine has shown 77 % clinical response in treatment of patients with urinary candidiasis. Side effects were few and limited to reversible changes in liver function and bone marrow. Thus, oral flucytosine provides the physician with an alternative treatment for significant Candidal urinary tract infections.

 

E] In Fungal Endocarditis

Table 5: Case Reports on Use of Flucytosine in Fungal Endocarditis 36, 37

Sr. No

Case History

Causative pathogen

of Endocarditis

Intervention

Clinical

Outcomes

Conclusion

1

77-year-old

man underwent

valve

replacement

for calcific

aortic stenosis;

Clinical signs

of endocarditis

were absent;

Transesophageal echocardiography

(TEE)

identified

a mobile

vegetation

within the

leaflets of the

prosthetic valve

Blood cultures

were positive

for Candida albicans.

Amphotericin B and

flucytosine were

given for two weeks.

The prosthetic

valve was removed,

and an aortic-valve

homograft was

implanted to

reconstruct the

heart.

Postoperatively,

the patient received

liposomal

amphotericin

B and flucytosine

followed by oral

fluconazole .

The sepsis

cleared.

Flucytosine

successfully

cleared

sepsis due

to PVE. 36

2.

36-year-old male was

found to have

isolated

pulmonary

valve

endocarditis;

presented

three

weeks of low

grade fever,

generalized

rash and fatigue.

Candida

parapsilosis was

found in blood.

TEE demonstrated

A 4.5 cm vegetation

on the pulmonary

valve, without

involvement of other

valves. The patient

was deemed not to

be a surgical candidate

and was subsequently

started on intravenous

liposomal

amphotericinB

and 5-flucytosine.

Excellent

clinical

outcomes

were

observed.

In selective

cases and

if there are

no known

complications,

fungal

endocarditis

can be

managed

successfully

using

anti-fungal

agents. 37

 

 

 

 

 

 

 

 

 

 

 

Clinical Study on Use of Amphotericin B with Flucytosine in Fungal Endocarditis 38

Background/ Objective:

Following homograft valve replacement, occurrence of fungal endocarditis remains an important cause of mortality and morbidity. The purpose of this study was to attempt to define the clinical course and results of different methods of treatment.

Study Design/Methods:

In a clinical study conducted between 1969 and 1978, 27 patients developed fungal endocarditis, an overall incidence of 2-2% for the 1207 patients in whom the homograft valves were inserted.

Candida spp. were the most common isolates (85%) and C. albicans the most frequent (70%); others being Candida parakrusei, Candida stellatoidea, Candida tropicalis. Three of the non-Candida fungi were Aspergillus spp. and there was one isolate of Petriellidium boydii.

Six of the patients died within 3 days of diagnosis of endocarditis before any effective chemotherapy could be initiated. The remaining 21 patients were treated with intensive chemotherapy of amphotericin B in combination with flucytosine. Flucytosine was not used in 2 cases in which the organism was known to be resistant to the drug. Amphotericin B IV was given in increasing doses up to 100 mg/day usually for 6 weeks. Flucytosine was given orally at doses of up to 12 g/day, usually for 3 months; one patient received flucytosine for more than 6 months without adverse effect.

Results:

Candida infections were the most common and the Aspergillus infections were generally fatal. Nine (33%) patients who have not shown any sign of recurrence between 17 and 87 months after treatment of fungal endocarditis were considered as examples of successful chemotherapy. The deaths of 11 (41 %) of the patients within 2 weeks of the diagnosis of fungal endocarditis probably represents uncontrolled fulminating infection. The effectiveness of this policy is supported by the fact that 9 (69%) of the 16 patients who received intensive initial chemotherapy for more than 2 weeks have a long-term survival of 17-87 months.

Conclusion:

Thus, intensive initial chemotherapy, to control the infection, can permit the patient to recover from the acute symptoms of endocarditis. The cardiac status of the patient may then be assessed and a decision made about the eventual replacement of the affected valve.

 

Intensive chemotherapy of amphotericin B in combination with flucytosine was shown to be effective in improving the acute symptoms of candidal endocarditis caused by both Candida albicans and non albicans Candida species such as C. tropicalis, C. prapsilosis and C. parakrusei.

 

 

 

Guidelines/Recommendations on Flucytosine

A] For Patients with Cryptococcal Meningitis and CNS infections

Clinical practice guide­lines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America 39

Cerebral cyptococcomas 39

1] Induction therapy with AmBd (0.7–1 mg/kg per day IV), liposomal AmB (3–4 mg/kg per day IV), or ABLC (5 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for at least 6 weeks (B-III).

2] Consolidation and maintenance therapy with fluconazole (400–800 mg per day orally) for 6–18 months (B-III).

B] For Patients with Other Cryptococcal Infections

Clinical practice guide­lines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America 39

Treatment Strategies for Patients with Nonmeningeal Cryptococcosis

Cryptococcosis in a resource-limited health care environment

With CNS and/or disseminated disease when polyene is not available but flucytosine is available, induction therapy is fluconazole (≥800 mg per day orally; 1200 mg per day is favored) plus flucytosine (100 mg/kg per day orally) for 2–10 weeks, followed by maintenance therapy with fluconazole (200–400 mg per day orally) (B-II).

C. gattii Infection

1] For CNS and disseminated disease due to C. gattii, induction, consolidation, and suppressive treatment are the same as for C. neoformans (A-II).

2] More diagnostic focus by radiology and follow-up examinations are needed for cryptococcomas/hydrocephalus due to C. gattii than that due to C. neoformans, but the management principles are the same (B-II).

3] Pulmonary cryptococcosis (same as C. neoformans): single, small cryptococcoma suggests fluconazole (400 mg per day orally); for very large and multiple cryptococcomas, consider a combination of AmBd and flucytosine therapy for 4–6 weeks, followed by fluconazole for 6–18 months, depending on whether surgery was performed (B-III).

C] For Patients with Candidal Infections

Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America 40

Treatment for Candida Intravascular Infections, Including Endocarditis and Infections of Implantable Cardiac Devices

For native valve endocarditis, lipid formulation AmB, 3–5 mg/kg daily, with or without flucytosine, 25 mg/kg 4 times daily, OR high-dose echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) is recommended for initial therapy (strong recommendation; low-quality evidence).

Treatment for Candida Chorioretinitis Without Vitritis

For fluconazole-/voriconazole-resistant isolates, liposomal AmB, 3–5 mg/kg intravenous daily, with or without oral flucytosine, 25 mg/kg 4 times daily is recommended (strong recommendation; low-quality evidence).

Treatment for Central Nervous System Candidiasis

For initial treatment, liposomal AmB, 5 mg/kg daily, with or without oral flucytosine, 25 mg/kg 4 times daily is recommended (strong recommendation; low-quality evidence).

Treatment for Symptomatic Candida Cystitis

For fluconazole-resistant C. glabrata, AmB deoxycholate, 0.3–0.6 mg/kg daily for 1–7 days OR oral flucytosine, 25 mg/kg 4 times daily for 7–10 days is recommended (strong recommendation; low-quality evidence).

Treatment for Symptomatic Ascending Candida Pyelonephritis

1] For fluconazole-resistant C. glabrata, AmB deoxycholate, 0.3–0.6 mg/kg daily for 1–7 days with or without oral flucytosine, 25 mg/kg 4 times daily, is recommended (strong recommendation; low-quality evidence).

2] For fluconazole-resistant C. glabrata, monotherapy with oral flucytosine, 25 mg/kg 4 times daily for 2 weeks, could be considered (weak recommendation; low-quality evidence).

Suggested Algorithms for the management of Candiduria 25

Since it is difficult to differentiate if candiduria in a patient is because of the fungal colonization of urinary tract or true UTI it poses a dilemma for the physician to decide whether to initiate antifungal therapy or not. In a recent study, it has been suggested that a classification scheme might be followed for systematic management of candiduria (Figs. 4 and 5). In order to do so, it is proposed that the patients be grouped as those with:

•      Asymptomatic candiduria (previously healthy patients);

•      Asymptomatic candiduria (predisposed outpatients);

•      Asymptomatic candiduria (predisposed inpatients);

•      Symptomatic candiduria (cystitis, pyelonephritis, prostatitis, epididymo-orchitis, or urinary tract fungus balls);

•      Clinically unstable condition with candiduria

Figure 4: Algorithm for the management of asymptomatic candiduria. 25

Figure 5: Algorithm for the management of symptomatic candiduria 25

IDSA Guideline Recommendations for use of Flucytosine:

1] For the treatment of cryptococcal meningitis in HIV patients, the combination of amphotericin B deoxycholate or liposomal amphotericin B (in patients with renal function concerns) and flucytosine is recommended for 2 weeks as induction therapy.

2] For the treatment of cryptococcal meningitis in Transplant patients, the combination of liposomal amphotericin B and flucytosine is recommended for 2 weeks as induction therapy.

3] For the treatment of cryptococcal meningitis in non -HIV and non-Transplant patients, the combination of amphotericin B deoxycholate or liposomal amphotericin B and flucytosine is recommended for ≥4 weeks as induction therapy.

4] For the treatment of nonmeningeal cryptococcosis, such as in immunosuppressed and immunocompetent patients with severe pulmonary cryptococccosis and in patients with cryptococcemia, combination of amphotericin B and flucytosine is recommended to be used as initial antifungal regimen (same as CNS disease) for 12 months.

5] For the treatment of native valve endocarditis, lipid formulation AmB with or without flucytosine, or high-dose echinocandin is recommended for initial therapy.

6] For the treatment of symptomatic Candida cystitis caused by fluconazole-resistant C. glabrata, amphotericin B deoxycholate for 1–7 days or oral flucytosine for 7–10 days is recommended.

7] For the treatment for symptomatic ascending Candida pyelonephritis caused by fluconazole-resistant C. glabrata, amphotericin B deoxycholate for 1–7 days with or without oral flucytosine, is recommended; monotherapy with oral flucytosine for 2 weeks, can be considered too.

Safety Profile of Cytorx

Contraindications

Flucytosine is contraindicated in the following:

• In patients with known hypersensitivity to flucytosine or to any of the excipients.

• In combination with certain antiviral nucleosides such as brivudine, sorivudine and their analogs .

• In breastfeeding women.

Warnings and Precautions

General

Treatment with this medicinal product should be administered after identification of the strain and an assessment with regard to flucytosine susceptibility, due to possible primary resistance. It should be maintained under regular medical surveillance.

Flucytosine must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they 1) have a hematologic disease; 2) are being treated with radiation or drugs that depress bone marrow; or, 3) have a history of treatment with such drugs or radiation.

Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.

Before therapy with flucytosine is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined. Close monitoring of the patient during therapy is essential.

Drug Interactions

Combinations Requiring Precautions for Use

Zidovudine

Increased hematological toxicity (additive myelotoxic effects). More frequent monitoring of blood counts is recommended.

Drugs with Bone Marrow or Renal Toxicity

In combination with a medicinal product with bone marrow or renal toxicity, more frequent monitoring of blood counts is recommended throughout the entire treatment, in view of the increased risk of hematological disorders.

Cytosine Arabinoside

Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity of flucytosine by competitive inhibition.

Drugs that impair glomerular filtration may prolong the biological half-life of flucytosine.

Laboratory Tests

Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leukocyte and thrombocyte count) and liver function (alkaline phosphatase, serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase ) should be determined at frequent intervals during treatment as indicated. It is recommended that blood counts and liver function tests be performed (alanine aminotransferase , aspartate aminotransferase , alkaline phosphatases) along with regular monitoring, especially at the start of treatment.

Drug/Laboratory Test Interactions

Measurement of serum creatinine levels should be determined by the Jaffé reaction, since flucytosine does not interfere with the determination of creatinine values by this method. Most automated equipment for measurement of creatinine makes use of the Jaffé reaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Flucytosine has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of S. typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes.

Flucytosine was non-mutagenic in three different repair assay systems (i.e., rec, uvr and pol). There have been no adequate trials in animals on the effects of flucytosine on fertility or reproductive performance. The fertility and reproductive performance of the offspring (F generation) of mice treated with 100 mg/kg/day (345 mg/m2/day or 0.059 times the human dose), 200 mg/kg/day (690 mg/m2/day or 0.118 times the human dose) or 400 mg/kg/day (1,380 mg/m2/day or 0.236 times the human dose) of flucytosine on days 7 to 13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring.

Influence on Diagnostic Tests

Flucytosine may interfere in the enzymatic (2-step) creatinine assay by causing an artificial elevation of the values observed.

Contraception in Men and Women

Flucytosine is partially metabolized to 5-fluorouracil, which is genotoxic and considered to be potentially teratogenic in humans.

Women of childbearing potential have to use effective contraception during treatment and up to 1 month after discontinuation of treatment.

Male patients (or their female partners of childbearing potential) have to use effective contraception during treatment and up to 3 months after discontinuation of treatment.

Renal Impairment

Flucytosine must be given with extreme caution to patients with impaired renal function. Since flucytosine is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Flucytosine serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.

As elimination of this medicinal product is exclusively renal, creatinine clearance must be regularly monitored in patients with renal impairment or in combination with a nephrotoxic agent likely to alter renal function, and the dosage must be adjusted according to this clearance.

Almost 65 to 75% of flucytosine present in the body is removed by hemodialysis. Therefore, in patients on dialysis, administration of this medicinal product must be repeated after each dialysis or blood-cleansing session.

Pregnancy

Studies in animals have shown reproductive toxicity for flucytosine and one of its metabolites (5-fluorouracil) (teratogenicity and embryotoxicity). In humans, flucytosine crosses the placenta.

There are very limited data from the use of flucytosine in pregnant women. Embryonic or foetal toxicity cannot be excluded, especially in the event of exposure during the first trimester. Therefore, flucytosine must not be used during pregnancy and in women of childbearing potential without effective contraception, unless absolutely necessary in case of life-threatening infections and in the absence of an effective therapeutic alternative.

If flucytosine is administered during pregnancy, the patient must be advised of the teratogenic risk with flucytosine and careful prenatal and postnatal monitoring must be performed. Furthermore, if administered up until delivery and in view of the safety profile of flucytosine, neonatal surveillance (hematological and hepatic) must be performed.

Lactation

There are no data on the excretion of flucytosine in human milk. Breastfeeding is contraindicated during treatment with flucytosine.

Pediatric Use

Flucytosine tablets are not suitable for children under 6 years of age, who often have difficulty swallowing them due to their size. In this case, the tablets can be crushed to facilitate administration.

Undesirable Effects

·         Gastrointestinal disorders such as nausea, diarrhea and, more rarely, vomiting.

·         Hematological disorders: (leukopenia, thrombocytopenia), mainly moderate and transient and more common in patients with renal impairment or when serum flucytosine levels exceed 100 μg/mL. More severe disorders (aplasia, agranulocytosis), potentially irreversible and possibly fatal in exception cases, have sometimes been observed; mainly, however, in patients undergoing treatment with bone marrow toxicity.

Hepatic disorders: elevated transaminase levels (ASAT, ALAT), alkaline phosphatases, resolving upon discontinuation of treatment, as well as rare acute cases of hepatitis, have sometimes been observed.

Cardiac disorders in exceptional cases, usually ischemic in nature.

Allergic manifestations: rare cases of skin rash and exceptional cases of Lyell’s syndrome.

Given below are the adverse reactions that have occurred during treatment with flucytosine capsules and are grouped according to the organ system affected:

Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction.

Respiratory: Respiratory arrest, chest pain, dyspnea.

Dermatologic: Rash, pruritus, urticaria, photosensitivity.

Gastrointestinal: Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury, including hepatic necrosis with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, enterocolitis, bilirubin elevation, increased hepatic enzymes.

Genitourinary: Azotemia, creatinine and blood urea nitrogen (BUN) elevation, crystalluria, renal failure.

Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.

Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.

Psychiatric: Confusion, hallucinations, psychosis.

• Miscellaneous: Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell’s syndrome.

The most common adverse effects reported with flucytosine therapy are gastrointestinal (6 %) and can include nausea, vomiting, diarrhea, and abdominal discomfort. 5

Hepatotoxicity (reported with a range of 0 – 41%) has also been associated with the use of flucytosine, and typically presents with elevated transaminases and alkaline phosphatase. 5

The most severe toxicity associated with 5-FC treatment is bone-marrow depression manifested as serious or life-threatening leucocytopenia, thrombocytopenia and/or pancytopenia. A study showed that bone-marrow depression occurred in 60% of patients with 5-FC concentrations >100 mg/L, and in 12% of patients with 5-FC concentrations <100 mg/L. 29

Flucytosine must be given with extreme caution to patients with bone marrow depression.

Blood concentrations and kidney function should be monitored during flucytosine therapy.

Flucytosine should not be used in pregnant and breast feeding women.

 

 

Storage and Handling Instructions

Store below 25°C, excursion permitted between 15°C to 30°C. Protect from light.

Keep all medicines out of reach of children.

Place in Therapy

Flucytosine is a small, highly water soluble, pyrimidine analogue that has rapid oral absorption and achieves good levels in heart, lung, liver, spleen, kidney tissues, including the cerebrospinal fluid, vitreous fluids and urine.

It shows synergistic action with amphotericin B and thus can be used in the following indications in combination therapy:

1] For induction therapy of cryptococcal meningitis in HIV, solid organ transplant as well as non-HIV and non- solid organ transplant patients- as it results in more rapid sterilization of the cerebrospinal fluid than did amphotericin B alone; also recommended by IDSA guidelines as first line therapy.

2] For other non-meningeal cryptococcal infections such as severe pulmonary cryptococcosis, non pulmonary cryptococcosis and cryptococcemia in immunosuppressed and immunocompetent patients and it is recommended by IDSA guidelines.

3] For candidal endocarditis, candidemia or sepsis, endopthalmitis and candiduria- as it demonstrates excellent activity against fluconazole resistant non-albicans Candida species and penetration into eye, heart, CSF, urine as against echinocandins and amphotericin B which do not penetrate well into these tissues.

It can also be used in combination with fluconazole and echinocandins for the treatment of candidal infections which are caused due to isolates resistant to first line antifungals.

Flucytosine is a small, highly water soluble molecule that has rapid oral absorption and achieves good levels in heart, lung, liver, spleen, kidney, eye tissues, including the cerebrospinal fluid and urine.

It exhibits good susceptibility against Cryptococcus species, Candida albicans and non albicans Candida species.

It is a good option to be used in combination with amphotericin B in following infections:

•      Cryptococcal meningitis in HIV, solid organ transplant as well as non-HIV and non- solid organ transplant patients

•      Non-meningeal cryptococcal infections such as severe pulmonary cryptococcosis, non pulmonary cryptococcosis and cryptococcemia in immunosuppressed and immunocompetent patients

•      Candidal endocarditis, candidemia and candiduria.

It can also be used in combination with fluconazole and echinocandins for the treatment of candidal infections which are caused due to isolates resistant to first line antifungals.

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