|Year : 2018 | Volume
| Issue : 1 | Page : 87-92
Echinocandins: Their role in the management of Candida biofilms
Subramanian Swaminathan1, Shweta Kamat2, Nalini Adele Pinto2
1 Department of Infectious Diseases, Gleneagles Global Hospital, Chennai, Tamil Nadu, India
2 Medical Affairs, Pfizer Ltd., Mumbai, Maharashtra, India
|Date of Web Publication||2-May-2018|
Dr. Shweta Kamat
206 La Vista, Rishivan, Kajupada Hills, Borivali (East), Mumbai - 400 066, Maharashtra
Source of Support: None, Conflict of Interest: None
The importance of antifungal agents and their clinical implications has received little attention in comparison to antibiotics, particularly in the health-care setting. However, apart from bacterial infections rising in hospitals, the incidences of fungal infections are growing with the development of resistance to conventional antifungal agents. Newer antifungal agents such as echinocandins (ECs) have been extensively studied over the past decade and are recognised as a superior treatment compared with prior antifungals as a first line of therapy in tertiary institutions. Caspofungin (CAS), micafungin (MICA) and anidulafungin (ANID) are the three most widely used EC antifungal agents. The treatment of biofilm-associated fungal infections affecting patients in tertiary health-care facilities has been identified as a challenge, particularly in Indian Intensive Care Unit (ICU) settings. With the rising number of critically ill patients requiring invasive devices such as central venous catheters for treatment, especially in ICUs, these devices serve as a potential source of nosocomial infections. Candida spp. colonisation is a major precursor of these infections and further complicates and prolongs treatment procedures, adding to increasing costs both for hospitals and the patient. Analysing studies involving the use of these agents can help in making critical decisions for antifungal therapy in the event of a fungal infection in the ICU. In addition, the development of resistance to antifungal agents is a crucial factor for assessing the appropriate antifungals that can be used for treatment. This review provides an overview of ANID in biofilms, along with CAS and MICA, in terms of clinical efficacy, resistance development and potency, primarily against Candida spp.
Keywords: Anidulafungin, biofilm, Candida, caspofungin, echinocandins, micafungin
|How to cite this article:|
Swaminathan S, Kamat S, Pinto NA. Echinocandins: Their role in the management of Candida biofilms. Indian J Med Microbiol 2018;36:87-92
|How to cite this URL:|
Swaminathan S, Kamat S, Pinto NA. Echinocandins: Their role in the management of Candida biofilms. Indian J Med Microbiol [serial online] 2018 [cited 2018 Jul 20];36:87-92. Available from: http://www.ijmm.org/text.asp?2018/36/1/87/231672
| ~ Introduction|| |
Fungal infections acquired as a result of hospitalisation play a major role in extending the duration of patient treatment. Therapy with appropriate and effective antifungals may help reduce this burden. The treatment of invasive fungal infections in adults and children heavily relied on the use of antifungal agents of the azole and polyene class. With the discovery and use of echinocandin (EC) agents in the last 15 years, fungal treatment with ECs as a result of nosocomial infections has been successfully carried out. Three currently available agents, namely, anidulafungin (ANID), caspofungin (CAS) and micafungin (MICA), are a class of antifungals that target 1 → 3β-D-glucan synthase, an enzyme involved in the synthesis of cell walls of fungi. In hospital settings, Candida species – both Candida albicans and C. non-albicans – the target of these antifungal agents, have been emerging as invasive pathogens in hospitalised patients. For instance, a systematic epidemiological study on 1400 Intensive Care Unit (ICU)-acquired candidaemia cases across 27 Indian centres indicated a prevalence of 6.51 cases/1000 ICU admissions. The severity of this infection, therefore, needs to be understood in terms of prevention and treatment options to decrease the burden of patient costs, treatment and poor outcomes.
In addition, a characteristic of fungal species is the formation of biofilms, Candida spp. in particular being notorious. While biofilms are complex microbial aggregations that colonise abiotic or biotic surfaces, the invasiveness of fungi as part of a biofilm becomes profound due to an aggravated effect in an immunocompromised environment. For instance, colonising of medical devices such as central venous catheters (CVCs) or other mucosal-associated surfaces with these biofilms is primarily the cause a multitude of clinical-associated complications in health-care facilities, consequently affecting patients. As a result, the incidence of nosocomial infections such as catheter-related fungaemia increases in patients and leads to delays in surgeries or appropriate treatment that would facilitate recovery. The incidences of these hospital-acquired infections, therefore, have to be gradually brought under control and subsequently minimised. Effective treatment options to prevent and manage patients with biofilm-associated infections, therefore, require a detailed understanding of the action of EC agents and the adversities associated with drug cross-reactivity.
Echinocandins show comparatively significant in vivo and in vitro activity against Candida biofilms compared to antifungal agents such as azoles and polyenes. The focus of attention, therefore, needs to be in understanding the role of ECs and the problems that could potentially be associated with developing resistance against these agents. In this review, the issue of Candida spp-associated infections and the role of ECs are highlighted, with a focus on noteworthy studies related to understanding epidemiology, susceptibilities and clinical efficacy data of these drugs with respect to other antifungal treatment options. Biofilm-associated antifungal treatments are also indicated with ANID as a focus for a preferable treatment option.
Biofilms and Candida spp.
More than 50% of mucocutaneous and systemic yeast infections in hospitals worldwide are caused by C. albicans. The complex three-dimensional structures of biofilms form a favourable environment for micro niches of Candida species. The biofilm occurrence of these organisms contributing to numerous infections emphasises the importance of the studying these organisms in vitro. [Figure 1] depicts a schematic of typical Candida spp. colonisation and progression to a biofilm at different stages of formation. The ultrastructure and formation of these biofilms have been studied using scanning electron microscope, fluorescence time-lapse microscopy and confocal microscopy. Analysis clearly demonstrates that these biofilms show metabolically active cells with a maturity phase between 13 and 20 h forming a consolidated structure. When these biofilms rupture, they colonise other surfaces and subsequently lead to a rapid progression of the infection inside the patient.
|Figure 1: Phases of Candida spp. biofilm formation. Note: (1) Adhesion to the culture medium, (2) basal micro-colony layers, (3) additional hyphal layer formation and extracellular matrix formation (biofilm)|
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| ~ Echinocandins|| |
Emerging adverse reactions, such as allergies, side effects, drug interactions and resistance development in patients to antifungal triazoles and conventional deoxycholate amphotericin B treatment, led to the need to explore ECs as an alternative first line of therapy. The 1→3β-D-glucan synthase complex, which forms a crucial component unique to fungal cell wall biosynthesis, is targeted by EC agents. These semisynthetic cyclic lipopeptides have a favourable toxicity profile as they exhibit non-competitive inhibition against this complex, thereby hindering fungal growth. EC B, the parent compound of ANID, originated in 1947 followed by MK-991 (precursor of CAS) in 1989 and FK-463 (precursor of MICA) was identified in 1990. The US Food and Drug Administration (US FDA) eventually approved CAS (January 2001), MICA (March 2005) and ANID (February 2006) for the treatment of invasive fungal infections.
Mechanism of Action and Activity Spectrum
Synthetic modifications of lipopeptides from the fermentation broths of various fungi enable the formation of all EC molecules. In addition, all clinically relevant EC agents and those in development constitute (a) amphiphilic cyclic hexapeptides and (b) N-linked acyl lipid side-chain, with a molecular weight of approximately 1200. [Figure 2] shows a schematic structure of the three clinically available EC agents. The characteristic structure enables EC agents to exert an inhibitory activity by binding to 1→3β-D-glucan synthase which comprises two subunits: FKS1p (encoded by FKS1, FKS2 and FKS3 genes) responsible for cell wall remodelling and Rho1p (regulatory protein) driving or arresting cell wall synthesis. ANID, in particular, is differentiated from the other two ECs by its terphenyl side chain that provides the vital size and lipophilicity to enable optimisation of antifungal efficacy, with an extended activity spectrum (Candida and Aspergillus spp.). In contrast, CAS has an aliphatic side chain and MICA has an aromatic side chain with a phenyl-isoxazole-phenyl substitution, thereby making them water soluble unlike ANID.
|Figure 2: Chemical structures of echinocandin agents. Note: (a) Caspofungin – fatty acid side chain, (b) micafungin – 3.5-diphenyl-substituted isoxazole ring side chain, (c) anidulafungin – pentyloxy terphenyl side chain|
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The potency of these antifungals is largely determined by their geometry and lipophilicity, and although they have a similar core structure, the different corresponding side chains have been observed to essentially confer improved inhibitory activity against different fungi and reduced toxicity as compared to azoles and polyenes. [Figure 3] depicts some of the organisms against which these EC agents exert an inhibitory effect. Consequently, targeting of fungal species needs to be carefully understood as the disparity of the glucan comprised in cell walls, and other structural variations of different fungi may result in EC agents causing different clinical effects, i.e., profound growth changes., EC agents exert maximum activity against Candida spp. and are therefore considered highly potent against these organisms, especially in hospital settings where a majority of infections are caused due to Candida spp. colonisation.
|Figure 3: Range of echinocandin activity. Note: Highly active corresponding to very low minimum inhibitory concentration, and good in vivo activity; very active implying low minimum inhibitory concentration, mostly without fungicidal activity; some activity implying detectible activity with therapeutic potential; and inactive corresponding to no intrinsic activity|
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The success of a therapy depends greatly on in vitro susceptibility tests of the organism to the antimicrobial agent and would show a significant effect in vivo. Two reference methods have been specified by the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing for broth microdilution and antifungal susceptibility testing with respect to ECs against Candida spp. Although the inoculation and minimum inhibitory concentration (MIC) endpoint criterion outlined by both organisations are concurrent, differences in species-specific breakpoints continue to evolve with respect to EC and other antifungal agents among regions as well. For instance, Candida-specific clinical breakpoints were revised by the CLSI in 2011, taking into account the variable activity of EC agents across species. However, invasive candidiasis treatment variations have been noted amongst EC agents. For example, a CAS-related paradoxical growth effect (PGE) was observed against Candida spp. biofilms as opposed to MICA, in terms of a reduced effect at increasing concentrations., As a result, EC activity variations have further brought into question the effectiveness of these treatments in terms of resistance development among Candida spp. Although fairly minimal, studies directed towards the mechanism of Candida spp. resistance would additionally depend on structural attributes of the biofilm phases and micro-niches within them.
Caspofungin was the first EC agent to be approved by the US FDA in January 2001. As opposed to prior azole and polyene antifungal formulations, CAS displayed a new targeting approach, i.e., inhibition of cell wall synthesis rather than targeting cell membrane entities, which proved to be a significant breakthrough in fungal treatments. In an attempt to understand the advantages of CAS over fluconazole, a sequential drug therapy regimen was carried out to study the effect of EC activity in C. albicans biofilms and revealed a higher resistance development to CAS treatment with prior fluconazole treatment. The phenomenon of decreased potency of CAS against biofilms indicates a possible interaction of antifungal agents. Hence, ensuring accuracy in prescribing effective drugs in the first line of treatment forms a crucial factor in decreasing the incidence of developing EC resistance and maintaining drug potency.
In addition, CAS being a compound that was studied extensively, substantial data on safety and efficacy profiles against Candida spp. have been reported, suggesting it as a better substitute to other antifungal agents. For instance, a study conducted in 2004 revealed CAS as a preferable alternative to liposomal amphotericin B for the prevention of Candida- related infections in patients with persistent fever and neutropenia. Concurrent findings revealed a good activity of CAS to treat Candida- associated infections; however, further studies over the past decade have highlighted that the drug has shown an increased incidence of cross-reactivity when administered with other drugs in clinical settings. Investigations to address this treatment hurdle led to a number of clinical safety and efficacy studies of other EC compounds to be carried out.
Micafungin was approved by the US FDA in 2005 for oesophageal candidiasis, invasive candidiasis and prophylaxis of Candida infections in patients undergoing haematopoietic stem cell transplantation., Compared to prior treatment of fluconazole, the success rate of MICA revealed a comparatively better outcome, suggesting the use of this EC agent for invasive candidaemia and aspergillosis., Moreover, Candida tropicalis-associated fungal biofilm infections have been better treated with MICA as opposed to liposomal amphotericin B, although both showed potent in vitro activity against C. albicans. The study, among others, indicates a difference in species coverage of antifungal agents, with EC agents showing potent activity across a wider range of Candida spp. as compared to prior antifungals.
The bioavailability of MICA is similar to CAS, but adverse effects need to be taken into consideration as differences in drug reactions with its concomitant use have been observed. Although these are fairly minimal as compared to CAS, the frequencies of histamine-related injection-site reactions have been reported with the use of MICA, as with most drug administration route effects. Nevertheless, a study indicating adverse drug–drug interaction caused by mild-azole formulations versus high dosage MICA for prophylaxis, after allogeneic stem cell transplantation, revealed MICA as a better alternative with no liver- or renal-associated abnormalities.
An additional attribute of this EC agent is its association with the treatment of specific fungal strains, which unlike ANID and CAS are strain independent. In addition, observations from time-kill plots of CAS, MICA and ANID revealed strain as well as concentration dependency for MICA to achieve fungicidal. Fungicidal activity, therefore, depends on effective MICs of the desired EC agent as well as duration of exposure to kill Candida spp.
The US FDA approved ANID for Candida-associated infections in 2006. The clinical efficacy of this drug has been found to show similarity to fluconazole with respect to treatment of patients with candidaemia or invasive candidaemia, with a further advantage of efficacy against fluconazole-resistant mucosal candidiasis. ANID treatment was successful in 75.6% of candidaemia patient cases with a comparatively lower mortality rate (23%), while fluconazole was 60.1% successful with a higher mortality rate (31%). This study suggests a non-inferiority treatment of ANID to fluconazole which supports its use in the first line of antifungal therapy.
Apart from low bioavailability, a minimal drug interaction was observed as ANID does not interfere with the cytochrome P450 system, suggesting no significant interactions with other drug concomitants. However, being relatively well tolerated, incidences of histamine-related adverse effects suggest precautionary measures of minimising infusion rates need to be formalised.
To further understand the activity of ANID, C. albicans has been chosen for ANID resistance studies due to strongest evidence against these organisms as they are responsible for a number of nosocomial infections. The effectiveness of ANID against Candida spp. biofilms was analysed using a clinically relevant in vitro microbiological model, where the outcome indicated ANID being highly effective in terms of inhibiting planktonic cell growth and biofilm formation. Another study against four Candida spp. strains was demonstrated by Maiolo et al. (2014)which indicated the best fungicidal activity using ANID, compared to other EC agents in a MIC and micro-calorimetry assay. [Table 1] shows antifungal susceptibilities of different Candida strains. The MICs of ANID ranging from 0.125 to 2 μg/ml and minimum heat inhibitory concentration value of ≤32 μg/ml against Candida spp. biofilms indicates its excellent inhibitory effect compared to other antifungals. However, further comparative studies need to be conducted to standardise treatment to achieve effective potency against other Candida spp. For instance, Rosato et al.(2013) demonstrated susceptibility of C. albicans and C. tropicalis biofilms to ANID, but which was refractory to Candida parapsilosis unlike other antifungals. In addition, a PGE was observed with some biofilm strains of the former two species that require further experimental evidence to establish the significance of this finding.
| ~ Echinocandins and Relevance in Biofilms|| |
The shift towards using ECs over azoles and polyenes for indications, such as oesophageal candidiasis, invasive candidiasis and candidaemia, invasive aspergillosis and prophylaxis of invasive fungal infections, has been a major step since their clinical development and demonstration of better comparative efficacy. An open-label study to understand the efficacy of ANID in Asian patients with candidaemia showed a success rate of 58.8% for patients >65 years and 81% for those with CVCs. This finding, moreover, was consistent with previous studies in Western populations. Furthermore, comparative data of ANID versus other antifungals in critical-care settings have been increasingly studied in the light of developing resistance. For instance, a randomised double-blind trial conducted in 200 high-risk liver transplantation patients who received either ANID or fluconazole showed comparable efficacy for antifungal prophylaxis, with ANID likely to show a benefit in those patients with an increased Aspergillus infection risk. Moreover, the safety and efficacy of intravitreal ANID versus amphotericin B and voriconazole were assessed in an experimental Candida endophthalmitis model that revealed non-inferior clinical, microbiological and histopathological scores. Pivotal clinical efficacy studies comparing the effects of CAS, MICA and ANID against comparator antifungals showed superiority in terms of shorter duration of dosage. This has gradually resulted in prescription of these antifungals for empirical treatment therapies in ICUs and other health-care settings over older antifungals.
Candida spp. biofilm formation is recognised as a clinical problem in transplant, oncology and intensive care medicine, with prevention and management posing a challenge due to limitations in effective therapeutic options., Although the possibility of biofilms acquiring antifungal resistance is relatively slow against ECs, the converse has been observed to occur towards triazoles and amphotericin treatments. For instance, as compared to CAS and amphotericin B treatment, a time-kill study compared with fluconazole treatment indicated better eradication of Candida biofilms over 48 h. Moreover, a study on in vitro growth of sessile yeast indicated biofilm formation despite being subjected to 1024 mg/L of fluconazole concentration. This study among several others is suggestive of a developing resistance pattern to azoles , and the shift towards employing ECs for the treatment and prevention of biofilm formation.
The advances in understanding the structural aspect of biofilms and their formations have significantly improved over the past decade with emerging sophisticated microscopy and imaging technology. Medical challenges have persisted, however, due to unavailability of standardised biofilm susceptibility reference data, regulatory guidelines to test new antibiofilm agents and manage biofilm-associated infections in clinical settings. The European Society of Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of America have charted candidiasis management guidelines along with treatment for biofilm infections., Antifungal lock therapy with systemic antifungal therapy has been suggested in patients where CVC-related candidaemia biofilm management becomes difficult. Lack of sufficient data for ANID as compared to CAS has resulted in dependence on in vitro studies, to understand clinical efficacy profiles to establish procedures for treatment recommendations, such as those provided by the Infectious Diseases Working Party of the German Society of Haematology and Oncology. For instance, a retrospective study demonstrating the efficacy of antifungal drugs against Candida spp. indicated that CVC removal did not benefit patients, particularly those who were neutropenic, but warrants CVC removal in cancer patients with candidaemia.
| ~ Conclusion|| |
Fungal infections as a result of colonisation of medical devices, most frequently by Candida spp., remain a major difficulty for hospitals to combat, with resistance to antifungal agents on the rise. While azole antifungals and amphotericin B formulations target different cell components than ECs, mechanisms of biofilm-associated resistance such as increased efflux pump activity and stress response induction have been profoundly increasing in either case. While CAS and MICA have been explored with respect to other antifungals, ANID, being a relatively new EC in the market, still requires additional studies using biofilm models to establish its safety and efficacy in critical care settings. Anti-biofilm strategies such as using a high-dose therapy and anti-infective lock therapy may be explored as interesting options to overcome resistance and achieve desired fungal suppression with minimal or no toxicity.
Combinatorial therapy treatments have been gaining importance where resistance possibilities are on the rise. For instance, a synergistic drug effect of ANID with non-steroidal anti-inflammatory drugs has shown a significant inhibitory response towards C. albicans biofilm, suggesting a scope for improving EC agent potency. However, fungal molecular mechanisms have to be further studied to avoid unfavourable effects of inducing biofilm formations as opposed to fungal clearance.
Financial support and sponsorship
Pfizer Ltd., India.
Conflicts of interest
Dr. S. Swaminathan has been a speaker at Pfizer forums and has received advisory board and consultant honoraria from Pfizer Ltd., India. S. Kamat is a full-time employee of Pfizer Ltd., India and N.A. Pinto is working as a Consultant with Pfizer Ltd., India at the time of publication.
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[Figure 1], [Figure 2], [Figure 3]