Biofilms and beyond: expanding echinocandin utility

Biofilms and beyond: expanding echinocandin utility Abstract Echinocandins have been in use for over 15 years, starting with the first approval in 2001. Current trends, such as increasing resistance to fluconazole and shifts toward non-albicans spp. of Candida, suggest a growing role for echinocandins, as reflected by recent (2016) updates to guidelines that recommend echinocandins as first-line treatment for candidaemia. The efficacy, tolerability, and safety of echinocandins and their target site of action (1,3-β-d-glucan synthesis) have prompted research into potential new uses, such as for treatment of biofilm infections, MDR Candida auris and dermatophytes. Moreover, new mycobiome discoveries linking inflammatory bowel disease (IBD; for instance Crohn’s disease) to fungi have led to preliminary but encouraging data regarding echinocandin therapy and treatment of IBD. In this article, we will review the available evidence and potential utility of echinocandins and 1,3-β-d-glucan synthesis inhibition in these areas of emerging interest. Overview and current use of echinocandins Echinocandins, one of the three major classes of antifungals (i.e. polyenes, azoles and echinocandins), are a relatively new player on the clinical stage when compared with the first reported use of amphotericin B in the 1950s.1 Caspofungin, the first echinocandin used for treatment of fungal infections, was approved by the FDA in 2001 for the treatment of invasive aspergillosis.2 In the following years, it was also approved for oesophageal candidiasis, invasive candidiasis and empirical therapy of suspected fungal infections in febrile neutropenic patients. Two other echinocandins, micafungin and anidulafungin, quickly followed suit and were approved in 2005 and 2006, respectively. Micafungin is currently administered for treatment of candidaemia, acute disseminated candidiasis, Candida peritonitis and abscesses, and oesophageal candidiasis, and prophylaxis of Candida infections, in patients undergoing haematopoietic stem cell transplantation.3 The last of these established echinocandins, anidulafungin, is used in treatment of candidaemia, other forms of Candida infections and oesophageal candidiasis.4 These echinocandins, however, have strictly been approved for daily intravenous (iv) administration as oral absorption has been shown to be poor and erratic.5 Echinocandins non-competitively inhibit the synthesis of 1,3-β-d-glucan, which is a major component of fungal cell walls but is absent in humans.6 This contributes to the low toxicity and well-tolerated characteristics of the echinocandins.7 While echinocandins are considered to have a favourable safety profile, some common adverse effects include rash, phlebitis and nausea.7 In contrast, use of azoles and polyenes is often complicated by side effects.2,8 Triazoles, such as voriconazole and itraconazole, can cause hepatotoxicity and have significant drug–drug interactions, while polyenes, such as amphotericin B, can cause nephrotoxicity.2,9 Both classes target fungal sterol pathways, with azoles inhibiting 14α-demethylation of lanosterol, a precursor of ergosterol, and amphotericin B binding directly to ergosterol, leading to leakage of cytoplasmic materials, cell lysis and death.10 Although ergosterol, the primary sterol found in fungal cell membranes, is not found in humans, polyenes can bind to cholesterol present in mammalian cell membranes, leading to their high toxicity. Echinocandins have a relatively broad spectrum of action, including fungicidal activity against yeasts, such as Candida spp., and moderate activity against moulds, such as Aspergillus spp.5,11 They have lower activity against Candida parapsilosis and Candida guilliermondii than other Candida spp., and are ineffective against Cryptococcus neoformans, Rhizopus spp., Fusarium spp. and Scedosporium spp.5 Development of resistance with increased use of echinocandins has been observed, and although resistance remains relatively rare, it is a growing concern.12 Current use of echinocandins is predominantly in the context of antifungal treatment; however, micafungin is also approved for use as prophylaxis. Antifungal prophylaxis is standard therapy for the prevention of fungal infections in immunosuppressed patients, such as haematopoietic stem cell transplant recipients.12–14 While fluconazole was once considered the antifungal drug of choice for this approach, increasing resistance development in various Candida spp., particularly C. glabrata, has limited its utility.12 Newer azoles, such as posaconazole and voriconazole, have largely replaced fluconazole in prophylaxis regimens, although similar concerns about resistance and drug–drug interactions with azoles remain. Consequently, efforts are now being made to develop antifungals that are effective against antifungal-resistant strains, in addition to evaluating combination therapy with the aim of identifying agents that are synergistically effective against such isolates.15–18 Given their pharmacokinetic profile, acceptable safety, minimal drug–drug interactions and potent antifungal activities against both azole-susceptible and -resistant Candida spp., echinocandins represent a suitable prophylactic alternative to azoles.12,16,18 The majority of evidence for antifungal prophylaxis with echinocandins is with micafungin, with fewer data available for caspofungin and anidulafungin.18–20 However, three large meta-analyses collectively revealed a reduced incidence of invasive fungal infections with echinocandin prophylaxis when compared with treatment with fluconazole or itraconazole.7,21–23 One of these recent meta-analyses, by Lee et al.,23 compared micafungin against azoles in treatment of invasive fungal infections in neutropenic patients. The study concluded that micafungin had higher rates of treatment success and lower rates of adverse events and safety-related issues when compared with azoles.23 Despite the evidence of echinocandin efficacy as antifungal prophylaxis, there are concerns that broadening patient exposure will lead to echinocandin resistance, particularly in C. glabrata,12,24 as was seen following the widespread use of fluconazole. Additionally, subtherapeutic drug levels achieved by current dosing regimens may further exacerbate the potential for resistance development. The ongoing challenge against anti-infective resistance underscores the importance of pharmacokinetic/pharmacodynamic (PK/PD)-optimized dosing, as well as appropriate treatment selection and antimicrobial stewardship.25–28 Although currently available echinocandins have improved our ability to manage patients with fungal infections, particularly against those caused by Candida, the utility of the class may not have been fully realized. There is a need for newer agents that can improve upon and address the limitations of currently established antifungals. These limitations include risk of resistance development, frequent dosing and oral availability. In the next section, we will review emerging research in novel therapeutics and understanding of fungal mechanisms, which may identify future areas of expanded utility for echinocandins and 1,3-β-glucan synthesis inhibition. Areas of research New agents Currently, there are two novel antifungals in development that target 1,3-β-glucan synthesis: rezafungin acetate (previously CD101, SP3025; Cidara Therapeutics, Inc., San Diego, CA, USA) and SCY-078 (MK-3118; Scynexis Inc., Jersey City, NJ, USA). Rezafungin is a long-acting, novel echinocandin that is being evaluated as a once-weekly iv infusion for the treatment of invasive candidiasis.29,30 It is biochemically stable in plasma, in aqueous solution and at high temperatures,31 properties that enable rezafungin to be formulated for other routes of administration (such as topical and subcutaneous).32–34 Rezafungin has a long half-life (≥130 h) and high plasma drug exposure, which favour front-loaded dosing as previously described with other concentration-dependent anti-infectives.28–30,35,36 Front-loading with a once-weekly iv infusion of rezafungin would maximize the drug effect at an earlier timepoint of the infection, when pathogen density is the greatest,29 thereby increasing the rate and success of eliminating the pathogen. The less frequent, once-weekly dosing of rezafungin compared with once-daily infusions of current echinocandins may also improve patient compliance and maintenance of treatment. In vitro studies by Pfaller et al.29,37 have shown that rezafungin activity against Candida is comparable to the activity of previously established echinocandins, such as anidulafungin and caspofungin. Its intrinsic potency and lack of cross-resistance with azoles and activity against resistant Candida strains have also been reported.12,26 Rezafungin has been shown to possess in vivo efficacy against infections caused by Candida, including as prophylaxis in mouse models of candidiasis, aspergillosis and Pneumocystis pneumonia.33,35,36 Phase I clinical testing has shown that rezafungin possesses an acceptable safety profile in humans,30 and a Phase II clinical trial of rezafungin iv as a treatment of candidaemia and invasive candidiasis is currently under way.38 STRIVE is a multicentre, randomized, double-blind study comparing the safety, tolerability and efficacy of once-weekly rezafungin iv with once-daily caspofungin iv followed by oral fluconazole step-down.38 SCY-078 is a semi-synthetic triterpene antifungal, structurally distinct from echinocandins but included in this discussion based on its common target of 1,3-β-d-glucan synthesis inhibition. SCY-078 by oral administration is in development for the treatment of invasive and mucocutaneous fungal infections caused by Candida and Aspergillus spp.39,40 As current echinocandins are only available for iv administration, SCY-078 oral bioavailability differentiates it and may enable its use in step-down approaches, which could drastically increase the number of patients that can be treated with 1,3-β-d-glucan synthesis inhibitors. In addition, it appears that there is some cross-resistance between echinocandins and SCY-078 for Candida strains but the binding sites seem to be non-identical.41 SCY-078 also holds promise due to its high anti-biofilm activity. This is supported by an in vitro study conducted on isolates obtained from candidaemia patients by Marcos-Zambrano et al.42 in which scanning electron microscopy analysis revealed that SCY-078 caused structural changes to the Candida biofilms with efficacy comparable to the most active anti-biofilm echinocandin, micafungin. SCY-078 has been tested clinically in Phase I trials, which demonstrated an acceptable safety profile, and a Phase II clinical trial with the oral formulation of SCY-078 as step-down treatment in invasive candidiasis was recently completed.39,40 In this prospective, multicentre, open-label, randomized, Phase II trial, patients were initially dosed with iv echinocandin therapy and then step-down therapy with either oral SCY-078 (n = 7; 1000 mg loading/500 mg daily or 1250 mg loading/750 mg daily) or standard of care (n = 7; oral fluconazole 800 mg loading dose followed by 400 mg daily or iv micafungin 100 mg daily) for up to 28 days. The daily oral doses of SCY-078 were safe, with comparable rates of adverse events between the SCY-078 and fluconazole groups, and the 1250 mg loading/750 mg daily dose was estimated to achieve the target exposure of ≥15.4 μM·h at steady state in ∼85% of the study population. There were no reports of mycological failure in the SCY-078 treatment group (n = 7), whereas fluconazole had two such reports (n = 7).39 Furthermore, evaluation of oral SCY-078 in a proof-of-concept Phase II clinical trial in patients with vulvovaginal candidiasis (VVC) was completed.39 Patients randomized to receive oral SCY-078 (n = 50) had a higher clinical cure rate as compared with the fluconazole treatment arm (n = 20) at both the test-of-cure visit (Day 24; 76% versus 65%, respectively) and at the end of observation (4 months; 88% versus 65%). Moreover, patients receiving SCY-078 had a lower recurrence rate of infection (4%) compared with those who received fluconazole (15%). Biofilms Biofilms, structured communities of microbes enclosed within a self-produced extracellular matrix, are found attached to both abiotic and biotic surfaces. Biofilms are of particular concern due to their ability to cause phenotypic resistance, thereby limiting treatment options. Candida species are a normal part of the microflora on human skin and mucosal surfaces. However, they are opportunistic, often linked to diabetes mellitus and intravascular catheter-associated infections, and the most common pathogenic fungi associated with biofilm formation.43,44 The most robust of the Candida biofilms are those formed by C. albicans, followed by C. parapsilosis. Often, infection and biofilm formation of Candida occurs in individuals with catheters, immunocompromised individuals or extremely ill patients. If the infection is catheter-associated, surgical removal is preferred whenever possible.45 In some cases, surgical manoeuvres may not be tolerated, and another course of action is required.43 As biofilms are one of the foremost causes of the continual presence of yeast in medical settings and given the deadly nature of biofilms, the need for effective treatments is great.43,46 A number of studies evaluated the activity of various antifungal agents against Candida biofilms. These studies showed that azoles (for example, fluconazole) and conventional amphotericin B are both ineffective in treating biofilms and that biofilms demonstrate intrinsic resistance against these antifungals.7,12,37,44,47 Studies by our group and others showed that the three clinically available echinocandins are efficacious against catheter infections both in vivo and in vitro.44,48–51 Similarly, lipid formulations of amphotericin B (liposomal and lipid complex) were shown to also possess potent antifungal activity, in preclinical studies as well as case reports.48,52–55 Owing to their safety and efficacy against biofilms, as well as their ability to target 1,3-β-d-glucan synthesis as a means of inhibiting excess production of extracellular matrix, echinocandins represent an attractive therapy against Candida biofilms. The most frequent opportunistic fungal infection in immunocompromised patients is mucosal candidiasis, which is an infection caused by biofilms forming on mucosal surfaces of the body (for instance, in the oral cavity, digestive tract and vagina).44 The composition of mucosal biofilm matrix is complex, though in general it is composed of polysaccharides (for example, glucans), proteins and extracellular DNA. This matrix provides a protective cover resulting in increased tolerance of antimicrobial agents by the microorganisms. Azoles were once considered to be the gold standard when treating vaginal candidiasis, but given the intrinsic resistance of biofilms to fluconazole and the emergence of azole-resistant strains, echinocandins are now being considered for the treatment of mucosal candidiasis (Table 1).45 A number of publications provide evidence in support of using echinocandins for the treatment of biofilm-associated fungal infections. For example, an oropharyngeal and oesophageal candidiasis rabbit model that evaluated the efficacy of anidulafungin to treat fluconazole resistance showed that this antifungal was efficacious in treating mucosal biofilms.44,49,In vitro and in vivo studies on catheter biofilms have shown success in treatment of infections with echinocandins. However, an oral mucosa study conducted by Nett et al.56 showed that systemic and topical echinocandin treatment modalities were relatively ineffective in treating denture C. albicans biofilms. Systemic administration of micafungin showed little improvement, possibly due to reduced drug aggregation in the oral mucosa.56 Yet an in vitro study conducted by Cateau et al.57 found that lock solutions of 2 and 5 mg/L, respectively, of caspofungin and micafungin used to treat biofilms forming on a silicone catheter led to a reduction of the metabolic activity of the biofilms, providing evidence that echinocandins can be effective in treating catheter biofilms. While further research is necessary, recent studies are corroborating that echinocandins are a promising therapy when considering treatment of mucosal and catheter biofilms. Table 1. Guidelines for treatment of Candida infections based on ESCMID and IDSA guidelines Candida infection  ESCMID   IDSA   treatment  recommendation strength and quality of evidencea  treatment  recommendation strength/quality of evidence  Mucosal candidiasis  azoles: FLC, POS and VRC  AII or AIII  not specified  NA  echinocandins or liposomal amphotericin B in severe cases  BII or BIII  VVC  oral FLC  AI  topical antifungals or oral FLC  strong/high  Intravascularb  surgery  AII or AIII  surgery; device replacement/removal  strong/low  LAmB  BII or BIII  LAmB, flucytosine or high-dose echinocandin  strong/low  CAS  BIII or CII  Catheter- associated candidaemia  removal of catheter  AII  removal of catheter  strong/moderate  echinocandins or LAmB  CII  Invasive candidaemia  echinocandins  AI  echinocandins  strong/high  Candida infection  ESCMID   IDSA   treatment  recommendation strength and quality of evidencea  treatment  recommendation strength/quality of evidence  Mucosal candidiasis  azoles: FLC, POS and VRC  AII or AIII  not specified  NA  echinocandins or liposomal amphotericin B in severe cases  BII or BIII  VVC  oral FLC  AI  topical antifungals or oral FLC  strong/high  Intravascularb  surgery  AII or AIII  surgery; device replacement/removal  strong/low  LAmB  BII or BIII  LAmB, flucytosine or high-dose echinocandin  strong/low  CAS  BIII or CII  Catheter- associated candidaemia  removal of catheter  AII  removal of catheter  strong/moderate  echinocandins or LAmB  CII  Invasive candidaemia  echinocandins  AI  echinocandins  strong/high  FLC, fluconazole; POS, posaconazole; VRC, voriconazole; LAmB, liposomal amphotericin B; CAS, caspofungin; NA, not applicable. a Strength of recommendation is based on grade: A, strongly supported for use; B, moderately supported for use; and C, marginally supported for use. Quality of evidence is divided into levels: I, evidence from at least one randomized controlled trial; II, evidence from at least one non-randomized clinical trial, cohort or case-controlled analytical studies, multiple time series and/or dramatic results of uncontrolled experiments; and III, evidence from authorities in the field, clinical experience, descriptive case studies and/or reports from expert committees. b Treatment recommendation varies based on population group. Several Candida spp. also play a prominent role in the development of VVC. As is the case in many other mucosal fungal infections, C. albicans is by far the most frequent species causing VVC, being responsible for over 90% of cases, followed by C. glabrata as the most common non-albicans causative species.58 Increases in non-albicans Candida and azole resistance may be attributed in part to increased, indiscriminate use of over-the-counter antifungals (e.g. frequent use, incomplete courses of therapy).15 Host immune response relies heavily on vaginal epithelial cells. When VVC occurs, the interaction between Candida and vaginal epithelial cells leads to inflammation, which subsequently causes exacerbation of symptoms.15 The existence of biofilms on the vaginal mucosa was first demonstrated in a study conducted by Harriott et al.59 These authors reported success in both ex vivo and in vivo models and confirmed that C. albicans biofilms indeed develop on the vaginal mucosa. They postulated that increased fungal burden was correlated with biofilm formation in both models. Interestingly, the ex vivo model (developed via vaginal explants) was able to form biofilms in the absence of exogenous nutrients, thereby suggesting that biofilm formation may be the result of depleting the host nutrients. With regard to treatment of VVC, current standard treatment is 150 mg of oral fluconazole upon onset and is administered every 3–4 days while infection persists (Table 1).58,60,61 Unmet needs and issues with this treatment include the fungistatic activity of azoles against Candida spp., lower activity against non-albicans spp. and risk of further fluconazole resistance. Recurrent VVC, defined by at least three symptomatic episodes of VVC in the previous 12 months, is also a therapeutic challenge with current treatment.15,58 Owing to the clinical challenges posed by VVC, echinocandins and 1,3-β-d-glucan synthase inhibitors have several apparent advantages over azoles. They demonstrate fungicidal activity against a majority of Candida spp. (including azole-resistant isolates), have a lower occurrence of resistance themselves, and are overall safer to use with fewer drug–drug interactions.12 In terms of non-albicans Candida spp., in vitro studies by Sobel and Chaim24 revealed that C. glabrata and other non-albicans spp. typically have higher MICs of the available azole agents but are still susceptible to other available antifungals. Additionally, an in vitro study of echinocandin activity against Candida spp., including azole-resistant isolates, using topically applied rezafungin at the lower pH of the vaginal environment (pH 4), demonstrated potent activity against all isolates.62 The potential advantages of echinocandins and 1,3-β-d-glucan synthesis inhibition are compelling but not yet realized. Current echinocandins are administered iv, effectively precluding their use in VVC. Both topical rezafungin and oral SCY-078 have demonstrated proof of concept but require further development and clinical evaluation to establish utility in the treatment of VVC.63 However, successful advances in this area would offer the first novel class in decades for this indication. Candida spp. are also considered to be a leading cause of intravascular infections, including infectious fungal endocarditis and indwelling devices. Infectious fungal endocarditis is rare but serious, with reported mortality rates as high as 59% at 1 year.64 Current guidelines recommend treating fungal endocarditis with a combination of surgery and either an amphotericin B-based or echinocandin-based antifungal regimen (Table 1),16,61 even though the role of surgery and its invasive nature are increasingly called into question.16,40,44 Echinocandins may be clinically preferable based on the relative safety advantages and tolerability compared with polyene-based therapy for patients that are immunocompromised, unable to withstand surgery or at risk for drug–drug interactions.44 This notion is supported by a prospective cohort study of 70 cases of Candida endocarditis in which mortality was not impacted by choice of antifungal therapy (amphotericin B versus echinocandin) or by surgical intervention.64 In addition to safety and tolerability, echinocandins may also be of use in cases of resistance, which has been reported among isolates from confirmed fungal endocarditis.65 Similar recommendations for treatment are in place for Candida infections of vascular catheters, which are the most commonly infected implanted medical device and are another hotspot for Candida biofilms.44,66 Infections of ventricular assist devices (VADs) are less common but serious due to their high rates of mortality.67–70 In a recent retrospective review of 835 patients with VADs, the incidence of candidaemia was 6.2% and the mortality rate among these patients was between 50% (prior to discharge) and 76.3% (within 1 year).71 There is a strong correlation between biofilms and intravascular infections. Candida biofilms jeopardize the health of immunocompromised patients and candidaemia has been shown to be a significant contributor to mortality in these patients.43,44,72 The IDSA recommends removal of the indwelling device in suspected catheter-associated Candida infections. However, catheter or device removal is much easier said than done, especially in the paediatric population. Importantly, there are ample in vitro, in vivo and clinical case studies that demonstrate the efficacy of echinocandins in the treatment of biofilm-associated infections.7,22 Consequently, both the IDSA and the ESCMID recommended the use of echinocandins or lipid-based amphotericin B for treatment of vascular catheter-related infections (Table 1),45,61 as well as for treatment of VADs that cannot be removed. In addition, chronic suppressive therapy with fluconazole is recommended for susceptible isolates for as long as the VAD remains in place.16,40 The evolving distribution of Candida infections towards non-albicans spp. may ultimately require alternatives to fluconazole in order to avoid treatment failure. Mycobiome Recent studies characterizing the fungal and bacterial communities (mycobiome and bacteriome, respectively) reveal that bacteria and fungi co-exist in different body sites, interact, and have evolved cooperatively. This fungi–bacteria dynamic has demonstrated benefits for the microorganisms, sometimes at the expense of their hosts.73 We recently proposed that this inter-kingdom cooperation represents an evolutionary strategy adopted by microbes to protect themselves from the host immune system and antimicrobial insults.74 This emerging research has important implications regarding manipulation of the microbiota to improve or prevent certain pathological conditions. Backhed et al.75 have suggested several interventions targeting the intestinal microbiota, including the use of antibiotics, probiotics, prebiotics, faecal transplantation, immune modulators and phage therapy. The demonstrated dysbiosis involving fungi, in addition to bacteria, and the fungi–bacteria interactions shown by Hoarau et al.74 and Kalan et al.76 in the setting of Crohn’s disease and non-healing chronic wounds, respectively, suggest the potential of antifungal agents as a novel interventional approach. Samuel et al.77 conducted a retrospective database review that identified IBD patients (n = 6, with moderate to severe disease) on immunosuppressive (chronic infliximab) therapy who developed histoplasmosis. Treatment with itraconazole (median duration 6 months) and withdrawal of immunosuppression led to clinical and endoscopic remission at the end of therapy in 66% of patients. Other investigators provided further clinical evidence showing that fluconazole treatment improves ulcerative colitis.78 Since fungal and bacterial members of the microbiota form robust biofilms in the gut, any antifungal used to treat IBD must demonstrate efficacy against biofilms, such as echinocandins and other 1,3-β-d-glucan synthesis inhibitors, as described above. This nascent research on the role of the mycobiome in pathological conditions represents a truly novel potential for the future of echinocandins and antifungal therapy in general and should be considered. Candida auris C. auris, an emerging MDR Candida species identified in 2009,79 causes deadly, invasive infections and has become endemic in hospitals.80 Hospital-acquired transmissions have become so prolific that entire wards have been shut down.81 The pathogenicity and relatively rapid emergence of C. auris in recent years has generated heightened awareness and concerns about its transmission and treatment. Its full impact and implications for treatment remain to be seen, but preliminary research suggests a potential role for echinocandins and 1,3-β-d-glucan synthesis inhibition. Clinically speaking, C. auris appears to be linked to prolonged hospital stays, catheter use (including both iv and urinary catheters), surgery and underlying medical conditions, such as diabetes mellitus.82,C. auris acquisition in hospitals is on the rise, demonstrated through DNA sequence homogeneity in hospitals.82,83,C. auris is more reliably identified using DNA typing, as other methods, such as Vitek and API 20C, have misidentified C. auris as Candida haemulonii, Candida sake, Candida famata and/or Rhodotorula glutinus. MALDI-TOF will, also, accurately differentiate C. auris from similar yeast isolates if the reference database associated with the MALDI-TOF system contains the information necessary to make the identification.84 Fluconazole generally has extremely high MICs for C. auris, with other antifungals having varying MIC levels, limiting treatment options.85,86 Recent data show that 1,3-β-d-glucan synthesis inhibitors seem to be effective in inhibiting C. auris, although single C. auris strains have been identified with high MICs to antifungals in all three major classes.82,85,87 SCY-078 and rezafungin both seem to work well in vitro with demonstrated activity against C. auris biofilms, disruption of cell wall viability demonstrated with the use of scanning electron microscopy, and low MICs.85,87 Larkin et al.85 found that SCY-078 effectively disrupted the cell wall of C. auris, causing it to be unable to divide completely. In vivo testing with rezafungin is beginning to show usability against C. auris; Hagar et al.88 found that rezafungin showed significant reduction in kidney cfu and a higher rate of survival compared with fluconazole-, amphotericin B- and vehicle-treated groups in a disseminated candidiasis model. C. auris is the subject of highly active research across interests (epidemiology, microbiology, treatment, etc.) and further data are likely to be forthcoming. Therefore, as our understanding of C. auris grows, development of echinocandins for treatment is warranted as it may increase utility. Dermatophytes Superficial fungal infections are caused mainly by dermatophytes, including Trichophyton, Epidermophyton and Microsporum genera.89 Terbinafine, an allylamine, is the gold standard for treating such infections and shows potent antifungal activity both in vitro (with a low MIC of 0.001 mg/L) and in vivo.90–92 An in vitro study by Badali et al.93 revealed that, for 68 clinical strains of Trichophyton and Epidermophyton spp., terbinafine had the lowest MIC90 (0.063 mg/L) while fluconazole had the highest (>64 mg/L), confirming the potent nature of terbinafine against Trichophyton spp. (T. rubrum, T. mentagrophytes, T. verrucosum and T. schoenleinii) and Epidermophyton floccosum. A limited number of studies have investigated the efficacy of echinocandins against susceptible dermatophytes. In 2013, Bao et al.94 reported that caspofungin and micafungin facilitated morphological changes in hyphae at the microscopic level but did not fully inhibit the growth of dermatophytes in vitro. The relative lack of data in this area may be attributed to the impracticality of treating dermatophytes with once-daily iv infusions as indicated with current echinocandins. More recent data evaluating the anti-dermatophyte activity of echinocandins show promise, in part due to the feasibility of subcutaneous and intermittent dosing with rezafungin. Hager et al.95 evaluated rezafungin compared with terbinafine in the treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea-pig model. Infected guinea-pigs were randomized into the following groups, dosed on days 1 and 8: rezafungin 10 mg/kg; rezafungin 20 mg/kg; rezafungin 40 mg/kg; and terbinafine 10 mg/kg, as a positive control; and a vehicle control by subcutaneous injection. Two types of efficacy data were collected: mycological and clinical. Mycological efficacy was determined using a hair root invasion test and clinical efficacy was determined using a visual assessment scale as previously described by the research group.96 Mycological efficacy data showed that percentage improvements for groups treated with rezafungin 10, 20 and 40 mg/kg were 80.9%, 82.9% and 98.5%, respectively, and 54.2% for terbinafine 10 mg/kg on days 1 and 8. All treatment groups showed significant mycological efficacy compared with the vehicle control (P < 0.001; Figure 1). Clinical efficacy data showed that the percentage efficacies for groups treated with rezafungin 10, 20 and 40 mg/kg on days 1 and 8 were 90.5%, 94.2% and 98.4%, respectively, and 76.8% for terbinafine 10 mg/kg on days 1 and 8. Additionally, all treatment groups showed significant clinical improvement compared with the vehicle control (P < 0.001). Without further PK data, between-treatment comparisons or conclusions are limited due to the rapid clearance of terbinafine in these animal models. However, the finding that rezafungin dosed once weekly was efficacious in treating dermatophytosis in vivo is very encouraging. These mycological and clinical findings may lead to an alternative to daily dosing for extended treatment periods. Overall, these results warrant further clinical evaluation for potential utility in the treatment of dermatophytes. Figure 1. View largeDownload slide Clinical appearance of guinea pigs with T. mentagrophytes infection on day 12 after treatment on days 1 and 8. (a) Rezafungin 10 mg/kg. (b) Rezafungin 20 mg/kg. (c) Rezafungin 40 mg/kg. (d) Terbinafine 10 mg/kg. (e) Vehicle control by subcutaneous injection. Figure 1. View largeDownload slide Clinical appearance of guinea pigs with T. mentagrophytes infection on day 12 after treatment on days 1 and 8. (a) Rezafungin 10 mg/kg. (b) Rezafungin 20 mg/kg. (c) Rezafungin 40 mg/kg. (d) Terbinafine 10 mg/kg. (e) Vehicle control by subcutaneous injection. Future directions Echinocandins have been part of the antifungal armamentarium since 2001, and the intervening years have demonstrated the safety, tolerability and effectiveness of the class. Given these features, echinocandins are an attractive treatment modality, particularly when considering immunocompromised patients with advanced, systemic fungal infections. They are of especially keen interest in the treatment of Candida biofilms. The development of new agents that inhibit 1,3-β-d-glucan synthesis may expand the current utility of echinocandins. Future research should continue to investigate how biofilms and the mycobiome interact and help discover new approaches in the prevention and management of systemic diseases. Combinational therapies, such as antifungals and probiotics, have also shown promise in recent findings. Owing to the multitude of organisms involved in the microbiota and biofilms, such endeavours are inherently complicated but are nevertheless important areas of research that must be explored. Dynamic advances in sequencing and microscopy will enable better understanding of how the microbiota behaves in a biofilm on a microscopic level. We strongly advocate that such efforts should be and need to be undertaken as they may ultimately contribute to the development of effective therapies to overcome the challenges of biofilms and beyond. Acknowledgements The authors would like to thank Christopher L. Hager and Lisa Long for providing the dermatophyte figure. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara Therapeutics. Transparency declarations M. A. G. has received research contracts from Cidara Therapeutics, Inc. and Scynexis, Inc. and served as research contractor for both. All other authors: none to declare.  This article was co-developed and published based on all authors’ approval. The authors received no compensation for their contribution to this Supplement. References 1 Jambor WP, Steinberg BA, Suydam LO. Amphotericins A and B: two new antifungal antibiotics possessing high activity against deep-seated and superficial mycoses. Antibiot Annu  1955; 3: 574– 8. Google Scholar PubMed  2 Balkovec JM, Hughes DL, Masurekar PS et al.   Discovery and development of first in class antifungal caspofungin (CANCIDAS(R))–a case study. Nat Prod Rep  2013; 31: 15– 34. Google Scholar CrossRef Search ADS   3 Federal Label for Mycamine(micafungin). Drugs@FDA, 2016. 4 Federal Label for Eraxis(anidulafungin). Drugs@FDA, 2012. 5 Estes KE, Penzak SR, Calis KA et al.   Pharmacology and antifungal properties of anidulafungin, a new echinocandin. 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Biofilms and beyond: expanding echinocandin utility

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Oxford University Press
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© The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
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10.1093/jac/dkx451
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Abstract

Abstract Echinocandins have been in use for over 15 years, starting with the first approval in 2001. Current trends, such as increasing resistance to fluconazole and shifts toward non-albicans spp. of Candida, suggest a growing role for echinocandins, as reflected by recent (2016) updates to guidelines that recommend echinocandins as first-line treatment for candidaemia. The efficacy, tolerability, and safety of echinocandins and their target site of action (1,3-β-d-glucan synthesis) have prompted research into potential new uses, such as for treatment of biofilm infections, MDR Candida auris and dermatophytes. Moreover, new mycobiome discoveries linking inflammatory bowel disease (IBD; for instance Crohn’s disease) to fungi have led to preliminary but encouraging data regarding echinocandin therapy and treatment of IBD. In this article, we will review the available evidence and potential utility of echinocandins and 1,3-β-d-glucan synthesis inhibition in these areas of emerging interest. Overview and current use of echinocandins Echinocandins, one of the three major classes of antifungals (i.e. polyenes, azoles and echinocandins), are a relatively new player on the clinical stage when compared with the first reported use of amphotericin B in the 1950s.1 Caspofungin, the first echinocandin used for treatment of fungal infections, was approved by the FDA in 2001 for the treatment of invasive aspergillosis.2 In the following years, it was also approved for oesophageal candidiasis, invasive candidiasis and empirical therapy of suspected fungal infections in febrile neutropenic patients. Two other echinocandins, micafungin and anidulafungin, quickly followed suit and were approved in 2005 and 2006, respectively. Micafungin is currently administered for treatment of candidaemia, acute disseminated candidiasis, Candida peritonitis and abscesses, and oesophageal candidiasis, and prophylaxis of Candida infections, in patients undergoing haematopoietic stem cell transplantation.3 The last of these established echinocandins, anidulafungin, is used in treatment of candidaemia, other forms of Candida infections and oesophageal candidiasis.4 These echinocandins, however, have strictly been approved for daily intravenous (iv) administration as oral absorption has been shown to be poor and erratic.5 Echinocandins non-competitively inhibit the synthesis of 1,3-β-d-glucan, which is a major component of fungal cell walls but is absent in humans.6 This contributes to the low toxicity and well-tolerated characteristics of the echinocandins.7 While echinocandins are considered to have a favourable safety profile, some common adverse effects include rash, phlebitis and nausea.7 In contrast, use of azoles and polyenes is often complicated by side effects.2,8 Triazoles, such as voriconazole and itraconazole, can cause hepatotoxicity and have significant drug–drug interactions, while polyenes, such as amphotericin B, can cause nephrotoxicity.2,9 Both classes target fungal sterol pathways, with azoles inhibiting 14α-demethylation of lanosterol, a precursor of ergosterol, and amphotericin B binding directly to ergosterol, leading to leakage of cytoplasmic materials, cell lysis and death.10 Although ergosterol, the primary sterol found in fungal cell membranes, is not found in humans, polyenes can bind to cholesterol present in mammalian cell membranes, leading to their high toxicity. Echinocandins have a relatively broad spectrum of action, including fungicidal activity against yeasts, such as Candida spp., and moderate activity against moulds, such as Aspergillus spp.5,11 They have lower activity against Candida parapsilosis and Candida guilliermondii than other Candida spp., and are ineffective against Cryptococcus neoformans, Rhizopus spp., Fusarium spp. and Scedosporium spp.5 Development of resistance with increased use of echinocandins has been observed, and although resistance remains relatively rare, it is a growing concern.12 Current use of echinocandins is predominantly in the context of antifungal treatment; however, micafungin is also approved for use as prophylaxis. Antifungal prophylaxis is standard therapy for the prevention of fungal infections in immunosuppressed patients, such as haematopoietic stem cell transplant recipients.12–14 While fluconazole was once considered the antifungal drug of choice for this approach, increasing resistance development in various Candida spp., particularly C. glabrata, has limited its utility.12 Newer azoles, such as posaconazole and voriconazole, have largely replaced fluconazole in prophylaxis regimens, although similar concerns about resistance and drug–drug interactions with azoles remain. Consequently, efforts are now being made to develop antifungals that are effective against antifungal-resistant strains, in addition to evaluating combination therapy with the aim of identifying agents that are synergistically effective against such isolates.15–18 Given their pharmacokinetic profile, acceptable safety, minimal drug–drug interactions and potent antifungal activities against both azole-susceptible and -resistant Candida spp., echinocandins represent a suitable prophylactic alternative to azoles.12,16,18 The majority of evidence for antifungal prophylaxis with echinocandins is with micafungin, with fewer data available for caspofungin and anidulafungin.18–20 However, three large meta-analyses collectively revealed a reduced incidence of invasive fungal infections with echinocandin prophylaxis when compared with treatment with fluconazole or itraconazole.7,21–23 One of these recent meta-analyses, by Lee et al.,23 compared micafungin against azoles in treatment of invasive fungal infections in neutropenic patients. The study concluded that micafungin had higher rates of treatment success and lower rates of adverse events and safety-related issues when compared with azoles.23 Despite the evidence of echinocandin efficacy as antifungal prophylaxis, there are concerns that broadening patient exposure will lead to echinocandin resistance, particularly in C. glabrata,12,24 as was seen following the widespread use of fluconazole. Additionally, subtherapeutic drug levels achieved by current dosing regimens may further exacerbate the potential for resistance development. The ongoing challenge against anti-infective resistance underscores the importance of pharmacokinetic/pharmacodynamic (PK/PD)-optimized dosing, as well as appropriate treatment selection and antimicrobial stewardship.25–28 Although currently available echinocandins have improved our ability to manage patients with fungal infections, particularly against those caused by Candida, the utility of the class may not have been fully realized. There is a need for newer agents that can improve upon and address the limitations of currently established antifungals. These limitations include risk of resistance development, frequent dosing and oral availability. In the next section, we will review emerging research in novel therapeutics and understanding of fungal mechanisms, which may identify future areas of expanded utility for echinocandins and 1,3-β-glucan synthesis inhibition. Areas of research New agents Currently, there are two novel antifungals in development that target 1,3-β-glucan synthesis: rezafungin acetate (previously CD101, SP3025; Cidara Therapeutics, Inc., San Diego, CA, USA) and SCY-078 (MK-3118; Scynexis Inc., Jersey City, NJ, USA). Rezafungin is a long-acting, novel echinocandin that is being evaluated as a once-weekly iv infusion for the treatment of invasive candidiasis.29,30 It is biochemically stable in plasma, in aqueous solution and at high temperatures,31 properties that enable rezafungin to be formulated for other routes of administration (such as topical and subcutaneous).32–34 Rezafungin has a long half-life (≥130 h) and high plasma drug exposure, which favour front-loaded dosing as previously described with other concentration-dependent anti-infectives.28–30,35,36 Front-loading with a once-weekly iv infusion of rezafungin would maximize the drug effect at an earlier timepoint of the infection, when pathogen density is the greatest,29 thereby increasing the rate and success of eliminating the pathogen. The less frequent, once-weekly dosing of rezafungin compared with once-daily infusions of current echinocandins may also improve patient compliance and maintenance of treatment. In vitro studies by Pfaller et al.29,37 have shown that rezafungin activity against Candida is comparable to the activity of previously established echinocandins, such as anidulafungin and caspofungin. Its intrinsic potency and lack of cross-resistance with azoles and activity against resistant Candida strains have also been reported.12,26 Rezafungin has been shown to possess in vivo efficacy against infections caused by Candida, including as prophylaxis in mouse models of candidiasis, aspergillosis and Pneumocystis pneumonia.33,35,36 Phase I clinical testing has shown that rezafungin possesses an acceptable safety profile in humans,30 and a Phase II clinical trial of rezafungin iv as a treatment of candidaemia and invasive candidiasis is currently under way.38 STRIVE is a multicentre, randomized, double-blind study comparing the safety, tolerability and efficacy of once-weekly rezafungin iv with once-daily caspofungin iv followed by oral fluconazole step-down.38 SCY-078 is a semi-synthetic triterpene antifungal, structurally distinct from echinocandins but included in this discussion based on its common target of 1,3-β-d-glucan synthesis inhibition. SCY-078 by oral administration is in development for the treatment of invasive and mucocutaneous fungal infections caused by Candida and Aspergillus spp.39,40 As current echinocandins are only available for iv administration, SCY-078 oral bioavailability differentiates it and may enable its use in step-down approaches, which could drastically increase the number of patients that can be treated with 1,3-β-d-glucan synthesis inhibitors. In addition, it appears that there is some cross-resistance between echinocandins and SCY-078 for Candida strains but the binding sites seem to be non-identical.41 SCY-078 also holds promise due to its high anti-biofilm activity. This is supported by an in vitro study conducted on isolates obtained from candidaemia patients by Marcos-Zambrano et al.42 in which scanning electron microscopy analysis revealed that SCY-078 caused structural changes to the Candida biofilms with efficacy comparable to the most active anti-biofilm echinocandin, micafungin. SCY-078 has been tested clinically in Phase I trials, which demonstrated an acceptable safety profile, and a Phase II clinical trial with the oral formulation of SCY-078 as step-down treatment in invasive candidiasis was recently completed.39,40 In this prospective, multicentre, open-label, randomized, Phase II trial, patients were initially dosed with iv echinocandin therapy and then step-down therapy with either oral SCY-078 (n = 7; 1000 mg loading/500 mg daily or 1250 mg loading/750 mg daily) or standard of care (n = 7; oral fluconazole 800 mg loading dose followed by 400 mg daily or iv micafungin 100 mg daily) for up to 28 days. The daily oral doses of SCY-078 were safe, with comparable rates of adverse events between the SCY-078 and fluconazole groups, and the 1250 mg loading/750 mg daily dose was estimated to achieve the target exposure of ≥15.4 μM·h at steady state in ∼85% of the study population. There were no reports of mycological failure in the SCY-078 treatment group (n = 7), whereas fluconazole had two such reports (n = 7).39 Furthermore, evaluation of oral SCY-078 in a proof-of-concept Phase II clinical trial in patients with vulvovaginal candidiasis (VVC) was completed.39 Patients randomized to receive oral SCY-078 (n = 50) had a higher clinical cure rate as compared with the fluconazole treatment arm (n = 20) at both the test-of-cure visit (Day 24; 76% versus 65%, respectively) and at the end of observation (4 months; 88% versus 65%). Moreover, patients receiving SCY-078 had a lower recurrence rate of infection (4%) compared with those who received fluconazole (15%). Biofilms Biofilms, structured communities of microbes enclosed within a self-produced extracellular matrix, are found attached to both abiotic and biotic surfaces. Biofilms are of particular concern due to their ability to cause phenotypic resistance, thereby limiting treatment options. Candida species are a normal part of the microflora on human skin and mucosal surfaces. However, they are opportunistic, often linked to diabetes mellitus and intravascular catheter-associated infections, and the most common pathogenic fungi associated with biofilm formation.43,44 The most robust of the Candida biofilms are those formed by C. albicans, followed by C. parapsilosis. Often, infection and biofilm formation of Candida occurs in individuals with catheters, immunocompromised individuals or extremely ill patients. If the infection is catheter-associated, surgical removal is preferred whenever possible.45 In some cases, surgical manoeuvres may not be tolerated, and another course of action is required.43 As biofilms are one of the foremost causes of the continual presence of yeast in medical settings and given the deadly nature of biofilms, the need for effective treatments is great.43,46 A number of studies evaluated the activity of various antifungal agents against Candida biofilms. These studies showed that azoles (for example, fluconazole) and conventional amphotericin B are both ineffective in treating biofilms and that biofilms demonstrate intrinsic resistance against these antifungals.7,12,37,44,47 Studies by our group and others showed that the three clinically available echinocandins are efficacious against catheter infections both in vivo and in vitro.44,48–51 Similarly, lipid formulations of amphotericin B (liposomal and lipid complex) were shown to also possess potent antifungal activity, in preclinical studies as well as case reports.48,52–55 Owing to their safety and efficacy against biofilms, as well as their ability to target 1,3-β-d-glucan synthesis as a means of inhibiting excess production of extracellular matrix, echinocandins represent an attractive therapy against Candida biofilms. The most frequent opportunistic fungal infection in immunocompromised patients is mucosal candidiasis, which is an infection caused by biofilms forming on mucosal surfaces of the body (for instance, in the oral cavity, digestive tract and vagina).44 The composition of mucosal biofilm matrix is complex, though in general it is composed of polysaccharides (for example, glucans), proteins and extracellular DNA. This matrix provides a protective cover resulting in increased tolerance of antimicrobial agents by the microorganisms. Azoles were once considered to be the gold standard when treating vaginal candidiasis, but given the intrinsic resistance of biofilms to fluconazole and the emergence of azole-resistant strains, echinocandins are now being considered for the treatment of mucosal candidiasis (Table 1).45 A number of publications provide evidence in support of using echinocandins for the treatment of biofilm-associated fungal infections. For example, an oropharyngeal and oesophageal candidiasis rabbit model that evaluated the efficacy of anidulafungin to treat fluconazole resistance showed that this antifungal was efficacious in treating mucosal biofilms.44,49,In vitro and in vivo studies on catheter biofilms have shown success in treatment of infections with echinocandins. However, an oral mucosa study conducted by Nett et al.56 showed that systemic and topical echinocandin treatment modalities were relatively ineffective in treating denture C. albicans biofilms. Systemic administration of micafungin showed little improvement, possibly due to reduced drug aggregation in the oral mucosa.56 Yet an in vitro study conducted by Cateau et al.57 found that lock solutions of 2 and 5 mg/L, respectively, of caspofungin and micafungin used to treat biofilms forming on a silicone catheter led to a reduction of the metabolic activity of the biofilms, providing evidence that echinocandins can be effective in treating catheter biofilms. While further research is necessary, recent studies are corroborating that echinocandins are a promising therapy when considering treatment of mucosal and catheter biofilms. Table 1. Guidelines for treatment of Candida infections based on ESCMID and IDSA guidelines Candida infection  ESCMID   IDSA   treatment  recommendation strength and quality of evidencea  treatment  recommendation strength/quality of evidence  Mucosal candidiasis  azoles: FLC, POS and VRC  AII or AIII  not specified  NA  echinocandins or liposomal amphotericin B in severe cases  BII or BIII  VVC  oral FLC  AI  topical antifungals or oral FLC  strong/high  Intravascularb  surgery  AII or AIII  surgery; device replacement/removal  strong/low  LAmB  BII or BIII  LAmB, flucytosine or high-dose echinocandin  strong/low  CAS  BIII or CII  Catheter- associated candidaemia  removal of catheter  AII  removal of catheter  strong/moderate  echinocandins or LAmB  CII  Invasive candidaemia  echinocandins  AI  echinocandins  strong/high  Candida infection  ESCMID   IDSA   treatment  recommendation strength and quality of evidencea  treatment  recommendation strength/quality of evidence  Mucosal candidiasis  azoles: FLC, POS and VRC  AII or AIII  not specified  NA  echinocandins or liposomal amphotericin B in severe cases  BII or BIII  VVC  oral FLC  AI  topical antifungals or oral FLC  strong/high  Intravascularb  surgery  AII or AIII  surgery; device replacement/removal  strong/low  LAmB  BII or BIII  LAmB, flucytosine or high-dose echinocandin  strong/low  CAS  BIII or CII  Catheter- associated candidaemia  removal of catheter  AII  removal of catheter  strong/moderate  echinocandins or LAmB  CII  Invasive candidaemia  echinocandins  AI  echinocandins  strong/high  FLC, fluconazole; POS, posaconazole; VRC, voriconazole; LAmB, liposomal amphotericin B; CAS, caspofungin; NA, not applicable. a Strength of recommendation is based on grade: A, strongly supported for use; B, moderately supported for use; and C, marginally supported for use. Quality of evidence is divided into levels: I, evidence from at least one randomized controlled trial; II, evidence from at least one non-randomized clinical trial, cohort or case-controlled analytical studies, multiple time series and/or dramatic results of uncontrolled experiments; and III, evidence from authorities in the field, clinical experience, descriptive case studies and/or reports from expert committees. b Treatment recommendation varies based on population group. Several Candida spp. also play a prominent role in the development of VVC. As is the case in many other mucosal fungal infections, C. albicans is by far the most frequent species causing VVC, being responsible for over 90% of cases, followed by C. glabrata as the most common non-albicans causative species.58 Increases in non-albicans Candida and azole resistance may be attributed in part to increased, indiscriminate use of over-the-counter antifungals (e.g. frequent use, incomplete courses of therapy).15 Host immune response relies heavily on vaginal epithelial cells. When VVC occurs, the interaction between Candida and vaginal epithelial cells leads to inflammation, which subsequently causes exacerbation of symptoms.15 The existence of biofilms on the vaginal mucosa was first demonstrated in a study conducted by Harriott et al.59 These authors reported success in both ex vivo and in vivo models and confirmed that C. albicans biofilms indeed develop on the vaginal mucosa. They postulated that increased fungal burden was correlated with biofilm formation in both models. Interestingly, the ex vivo model (developed via vaginal explants) was able to form biofilms in the absence of exogenous nutrients, thereby suggesting that biofilm formation may be the result of depleting the host nutrients. With regard to treatment of VVC, current standard treatment is 150 mg of oral fluconazole upon onset and is administered every 3–4 days while infection persists (Table 1).58,60,61 Unmet needs and issues with this treatment include the fungistatic activity of azoles against Candida spp., lower activity against non-albicans spp. and risk of further fluconazole resistance. Recurrent VVC, defined by at least three symptomatic episodes of VVC in the previous 12 months, is also a therapeutic challenge with current treatment.15,58 Owing to the clinical challenges posed by VVC, echinocandins and 1,3-β-d-glucan synthase inhibitors have several apparent advantages over azoles. They demonstrate fungicidal activity against a majority of Candida spp. (including azole-resistant isolates), have a lower occurrence of resistance themselves, and are overall safer to use with fewer drug–drug interactions.12 In terms of non-albicans Candida spp., in vitro studies by Sobel and Chaim24 revealed that C. glabrata and other non-albicans spp. typically have higher MICs of the available azole agents but are still susceptible to other available antifungals. Additionally, an in vitro study of echinocandin activity against Candida spp., including azole-resistant isolates, using topically applied rezafungin at the lower pH of the vaginal environment (pH 4), demonstrated potent activity against all isolates.62 The potential advantages of echinocandins and 1,3-β-d-glucan synthesis inhibition are compelling but not yet realized. Current echinocandins are administered iv, effectively precluding their use in VVC. Both topical rezafungin and oral SCY-078 have demonstrated proof of concept but require further development and clinical evaluation to establish utility in the treatment of VVC.63 However, successful advances in this area would offer the first novel class in decades for this indication. Candida spp. are also considered to be a leading cause of intravascular infections, including infectious fungal endocarditis and indwelling devices. Infectious fungal endocarditis is rare but serious, with reported mortality rates as high as 59% at 1 year.64 Current guidelines recommend treating fungal endocarditis with a combination of surgery and either an amphotericin B-based or echinocandin-based antifungal regimen (Table 1),16,61 even though the role of surgery and its invasive nature are increasingly called into question.16,40,44 Echinocandins may be clinically preferable based on the relative safety advantages and tolerability compared with polyene-based therapy for patients that are immunocompromised, unable to withstand surgery or at risk for drug–drug interactions.44 This notion is supported by a prospective cohort study of 70 cases of Candida endocarditis in which mortality was not impacted by choice of antifungal therapy (amphotericin B versus echinocandin) or by surgical intervention.64 In addition to safety and tolerability, echinocandins may also be of use in cases of resistance, which has been reported among isolates from confirmed fungal endocarditis.65 Similar recommendations for treatment are in place for Candida infections of vascular catheters, which are the most commonly infected implanted medical device and are another hotspot for Candida biofilms.44,66 Infections of ventricular assist devices (VADs) are less common but serious due to their high rates of mortality.67–70 In a recent retrospective review of 835 patients with VADs, the incidence of candidaemia was 6.2% and the mortality rate among these patients was between 50% (prior to discharge) and 76.3% (within 1 year).71 There is a strong correlation between biofilms and intravascular infections. Candida biofilms jeopardize the health of immunocompromised patients and candidaemia has been shown to be a significant contributor to mortality in these patients.43,44,72 The IDSA recommends removal of the indwelling device in suspected catheter-associated Candida infections. However, catheter or device removal is much easier said than done, especially in the paediatric population. Importantly, there are ample in vitro, in vivo and clinical case studies that demonstrate the efficacy of echinocandins in the treatment of biofilm-associated infections.7,22 Consequently, both the IDSA and the ESCMID recommended the use of echinocandins or lipid-based amphotericin B for treatment of vascular catheter-related infections (Table 1),45,61 as well as for treatment of VADs that cannot be removed. In addition, chronic suppressive therapy with fluconazole is recommended for susceptible isolates for as long as the VAD remains in place.16,40 The evolving distribution of Candida infections towards non-albicans spp. may ultimately require alternatives to fluconazole in order to avoid treatment failure. Mycobiome Recent studies characterizing the fungal and bacterial communities (mycobiome and bacteriome, respectively) reveal that bacteria and fungi co-exist in different body sites, interact, and have evolved cooperatively. This fungi–bacteria dynamic has demonstrated benefits for the microorganisms, sometimes at the expense of their hosts.73 We recently proposed that this inter-kingdom cooperation represents an evolutionary strategy adopted by microbes to protect themselves from the host immune system and antimicrobial insults.74 This emerging research has important implications regarding manipulation of the microbiota to improve or prevent certain pathological conditions. Backhed et al.75 have suggested several interventions targeting the intestinal microbiota, including the use of antibiotics, probiotics, prebiotics, faecal transplantation, immune modulators and phage therapy. The demonstrated dysbiosis involving fungi, in addition to bacteria, and the fungi–bacteria interactions shown by Hoarau et al.74 and Kalan et al.76 in the setting of Crohn’s disease and non-healing chronic wounds, respectively, suggest the potential of antifungal agents as a novel interventional approach. Samuel et al.77 conducted a retrospective database review that identified IBD patients (n = 6, with moderate to severe disease) on immunosuppressive (chronic infliximab) therapy who developed histoplasmosis. Treatment with itraconazole (median duration 6 months) and withdrawal of immunosuppression led to clinical and endoscopic remission at the end of therapy in 66% of patients. Other investigators provided further clinical evidence showing that fluconazole treatment improves ulcerative colitis.78 Since fungal and bacterial members of the microbiota form robust biofilms in the gut, any antifungal used to treat IBD must demonstrate efficacy against biofilms, such as echinocandins and other 1,3-β-d-glucan synthesis inhibitors, as described above. This nascent research on the role of the mycobiome in pathological conditions represents a truly novel potential for the future of echinocandins and antifungal therapy in general and should be considered. Candida auris C. auris, an emerging MDR Candida species identified in 2009,79 causes deadly, invasive infections and has become endemic in hospitals.80 Hospital-acquired transmissions have become so prolific that entire wards have been shut down.81 The pathogenicity and relatively rapid emergence of C. auris in recent years has generated heightened awareness and concerns about its transmission and treatment. Its full impact and implications for treatment remain to be seen, but preliminary research suggests a potential role for echinocandins and 1,3-β-d-glucan synthesis inhibition. Clinically speaking, C. auris appears to be linked to prolonged hospital stays, catheter use (including both iv and urinary catheters), surgery and underlying medical conditions, such as diabetes mellitus.82,C. auris acquisition in hospitals is on the rise, demonstrated through DNA sequence homogeneity in hospitals.82,83,C. auris is more reliably identified using DNA typing, as other methods, such as Vitek and API 20C, have misidentified C. auris as Candida haemulonii, Candida sake, Candida famata and/or Rhodotorula glutinus. MALDI-TOF will, also, accurately differentiate C. auris from similar yeast isolates if the reference database associated with the MALDI-TOF system contains the information necessary to make the identification.84 Fluconazole generally has extremely high MICs for C. auris, with other antifungals having varying MIC levels, limiting treatment options.85,86 Recent data show that 1,3-β-d-glucan synthesis inhibitors seem to be effective in inhibiting C. auris, although single C. auris strains have been identified with high MICs to antifungals in all three major classes.82,85,87 SCY-078 and rezafungin both seem to work well in vitro with demonstrated activity against C. auris biofilms, disruption of cell wall viability demonstrated with the use of scanning electron microscopy, and low MICs.85,87 Larkin et al.85 found that SCY-078 effectively disrupted the cell wall of C. auris, causing it to be unable to divide completely. In vivo testing with rezafungin is beginning to show usability against C. auris; Hagar et al.88 found that rezafungin showed significant reduction in kidney cfu and a higher rate of survival compared with fluconazole-, amphotericin B- and vehicle-treated groups in a disseminated candidiasis model. C. auris is the subject of highly active research across interests (epidemiology, microbiology, treatment, etc.) and further data are likely to be forthcoming. Therefore, as our understanding of C. auris grows, development of echinocandins for treatment is warranted as it may increase utility. Dermatophytes Superficial fungal infections are caused mainly by dermatophytes, including Trichophyton, Epidermophyton and Microsporum genera.89 Terbinafine, an allylamine, is the gold standard for treating such infections and shows potent antifungal activity both in vitro (with a low MIC of 0.001 mg/L) and in vivo.90–92 An in vitro study by Badali et al.93 revealed that, for 68 clinical strains of Trichophyton and Epidermophyton spp., terbinafine had the lowest MIC90 (0.063 mg/L) while fluconazole had the highest (>64 mg/L), confirming the potent nature of terbinafine against Trichophyton spp. (T. rubrum, T. mentagrophytes, T. verrucosum and T. schoenleinii) and Epidermophyton floccosum. A limited number of studies have investigated the efficacy of echinocandins against susceptible dermatophytes. In 2013, Bao et al.94 reported that caspofungin and micafungin facilitated morphological changes in hyphae at the microscopic level but did not fully inhibit the growth of dermatophytes in vitro. The relative lack of data in this area may be attributed to the impracticality of treating dermatophytes with once-daily iv infusions as indicated with current echinocandins. More recent data evaluating the anti-dermatophyte activity of echinocandins show promise, in part due to the feasibility of subcutaneous and intermittent dosing with rezafungin. Hager et al.95 evaluated rezafungin compared with terbinafine in the treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea-pig model. Infected guinea-pigs were randomized into the following groups, dosed on days 1 and 8: rezafungin 10 mg/kg; rezafungin 20 mg/kg; rezafungin 40 mg/kg; and terbinafine 10 mg/kg, as a positive control; and a vehicle control by subcutaneous injection. Two types of efficacy data were collected: mycological and clinical. Mycological efficacy was determined using a hair root invasion test and clinical efficacy was determined using a visual assessment scale as previously described by the research group.96 Mycological efficacy data showed that percentage improvements for groups treated with rezafungin 10, 20 and 40 mg/kg were 80.9%, 82.9% and 98.5%, respectively, and 54.2% for terbinafine 10 mg/kg on days 1 and 8. All treatment groups showed significant mycological efficacy compared with the vehicle control (P < 0.001; Figure 1). Clinical efficacy data showed that the percentage efficacies for groups treated with rezafungin 10, 20 and 40 mg/kg on days 1 and 8 were 90.5%, 94.2% and 98.4%, respectively, and 76.8% for terbinafine 10 mg/kg on days 1 and 8. Additionally, all treatment groups showed significant clinical improvement compared with the vehicle control (P < 0.001). Without further PK data, between-treatment comparisons or conclusions are limited due to the rapid clearance of terbinafine in these animal models. However, the finding that rezafungin dosed once weekly was efficacious in treating dermatophytosis in vivo is very encouraging. These mycological and clinical findings may lead to an alternative to daily dosing for extended treatment periods. Overall, these results warrant further clinical evaluation for potential utility in the treatment of dermatophytes. Figure 1. View largeDownload slide Clinical appearance of guinea pigs with T. mentagrophytes infection on day 12 after treatment on days 1 and 8. (a) Rezafungin 10 mg/kg. (b) Rezafungin 20 mg/kg. (c) Rezafungin 40 mg/kg. (d) Terbinafine 10 mg/kg. (e) Vehicle control by subcutaneous injection. Figure 1. View largeDownload slide Clinical appearance of guinea pigs with T. mentagrophytes infection on day 12 after treatment on days 1 and 8. (a) Rezafungin 10 mg/kg. (b) Rezafungin 20 mg/kg. (c) Rezafungin 40 mg/kg. (d) Terbinafine 10 mg/kg. (e) Vehicle control by subcutaneous injection. Future directions Echinocandins have been part of the antifungal armamentarium since 2001, and the intervening years have demonstrated the safety, tolerability and effectiveness of the class. Given these features, echinocandins are an attractive treatment modality, particularly when considering immunocompromised patients with advanced, systemic fungal infections. They are of especially keen interest in the treatment of Candida biofilms. The development of new agents that inhibit 1,3-β-d-glucan synthesis may expand the current utility of echinocandins. Future research should continue to investigate how biofilms and the mycobiome interact and help discover new approaches in the prevention and management of systemic diseases. Combinational therapies, such as antifungals and probiotics, have also shown promise in recent findings. Owing to the multitude of organisms involved in the microbiota and biofilms, such endeavours are inherently complicated but are nevertheless important areas of research that must be explored. Dynamic advances in sequencing and microscopy will enable better understanding of how the microbiota behaves in a biofilm on a microscopic level. We strongly advocate that such efforts should be and need to be undertaken as they may ultimately contribute to the development of effective therapies to overcome the challenges of biofilms and beyond. Acknowledgements The authors would like to thank Christopher L. Hager and Lisa Long for providing the dermatophyte figure. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara Therapeutics. Transparency declarations M. A. G. has received research contracts from Cidara Therapeutics, Inc. and Scynexis, Inc. and served as research contractor for both. All other authors: none to declare.  This article was co-developed and published based on all authors’ approval. The authors received no compensation for their contribution to this Supplement. References 1 Jambor WP, Steinberg BA, Suydam LO. Amphotericins A and B: two new antifungal antibiotics possessing high activity against deep-seated and superficial mycoses. Antibiot Annu  1955; 3: 574– 8. Google Scholar PubMed  2 Balkovec JM, Hughes DL, Masurekar PS et al.   Discovery and development of first in class antifungal caspofungin (CANCIDAS(R))–a case study. Nat Prod Rep  2013; 31: 15– 34. Google Scholar CrossRef Search ADS   3 Federal Label for Mycamine(micafungin). Drugs@FDA, 2016. 4 Federal Label for Eraxis(anidulafungin). Drugs@FDA, 2012. 5 Estes KE, Penzak SR, Calis KA et al.   Pharmacology and antifungal properties of anidulafungin, a new echinocandin. 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