In vitro antifungal activity of anidulafungin

Anidulafungin is a new and very useful pharmacological tool for the treatment of invasive mycoses. The antifungal spectrum of anidulafungin reaches the most common pathogenic fungi. Anidulafungin is especially active against the genera Candida and Aspergillus. Its antifungal mechanism is based on the inhibition of the beta-1,3-D-glucan synthesis, an essential molecule for the cell wall architecture, with different consequences for Candida and Aspergillus, being anidulafungin fungicide for the former and fungistatic for the latter. This review describes the in vitro antifungal spectrum of anidulafungin based in the scientific and medical literature of recent years. We can underline that most than 99% of Candida isolates are susceptible to < or = 2 microg/ml of anidulafungin. MIC are very low (< or =0.125 microg/ml) for most clinical isolates of the species Candida albicans, Candida glabrata, Candida tropicalis and Candida krusei while Candida parapsilosis and Candida guilliermondii isolates are susceptible to anidulafungin concentrations < or = 2 microg/ml. An excellent activity of anidulafungin has been also described against Aspergillus, Pneumocystis and other fungi. However, its activity is very low against Cryptococcus and the Zygomycetes. The excellent activity of anidulafungin has made this antifungal a first line therapeutic indication for candidemia and invasive candidiasis in non-neutropenic patients.     

The role of anidulafungin therapy in solid organ transplant recipients

Anidulafungin is a new echinocandin recently approved for the treatment of esophageal candidiasis, candidemia and other forms of invasive candidiasis, such as peritonitis and intra-abdominal abscesses in non-neutropenic patients. It is fungicidal against Candida spp. and fungistatic against Aspergillus spp. It is active against Pneumocystis jirovecii. In contrast, anidulafungin does not have activity against Cryptococcus neoformans, Zygomycetes or molds, other than Aspergillus spp. The drug is well tolerated, even in patients with renal or hepatic impairment. In contrast to other echinocandins, it does not significantly interfere with the cytochrome P450 pathway and has a low drug-drug interaction profile, including calcineurinic agents and other drugs used in transplant recipients. So far, anidulafungin appears to have an excellent safety profile with few adverse events and it promises a special consideration in the management of fungal infections happening in transplant recipients.     

Anidulafungin: a new therapeutic approach in antifungal therapy. Pharmacology of anidulafungin

Anidulafungin is a new echinocandin antifungal agent which inhibits beta-1,3-D-glucan synthase and disrupts fungal cell-wall synthesis. It has marked antifungal activity against Candida spp. and Aspergillus spp., including amphotericin B and triazole resistant strains. Due to the limited oral availability, anidulafungin in clinical use is available for parenteral administration only. Elimination of anidulafungin takes place via slow non-enzymatic degradation to inactive metabolites. Less than 10% and 1% of the initially administered drug is excreted unchanged into feces and urine, respectively. It does not require dosage adjustment in subjects with hepatic or renal impairment established. Anidulafungin is generally well tolerated. Adverse events appear not to be dose or infusion related. The most common treatment related adverse events are phlebitis, headache, nausea, vomiting and pyrexia. The lack of interactions with tacrolimus, cyclosporine and corticosteroids and its limited toxicity profile places anidulafungin as an attractive new option for the treatment of invasive fungal infections especially in transplant patients.     

The fungal cell wall and the mechanism of action of anidulafungin

The fungal cell wall is a structure with a high plasticity that protects the cell from different types of environmental stresses including changes in osmotic pressure. In addition to that, the cell wall allows the fungal cell to interact with its environment, since some of its proteins are adhesins and receptors. Some of its components are highly immunogenic. The structure of the fungal cell wall is unique to the fungi, and it is composed of glucan, chitin and glycoproteins. Since humans lack the components present in the cell walls of fungi, this structure is an excellent target for the development of antifungal drugs. Anidulafungin, like the rest of echinocandins acts on beta-1,3-D-glucan synthase inhibiting the formation of beta-1,3-D-glucan and causing, depending on the type of fungus, a fungicidal or either a fungistatic effect.     

Peritonitis candidiásica en un paciente hemodinámicamente estable. Tratamiento antifúngico de elección… ¿fluconazol?

BackgroundCandida peritonitis in postoperative patients is an independent predictor of mortality. Empirical early antifungal therapy should be started in these patients, since according to the results of studies in patients with candidemia, this has an impact on the prognosis. The treatment recommended by clinical practice guidelines in patients with haemodynamic instability are candins, but they do not make explicit recommendations for patients with dysfunction of other organs, or high lactate levels.Case reportA case of rescue treatment with anidulafungin in a patient with candidemia and Candida glabrata peritonitis postoperative haemodynamically stable, but with an acute renal failure and elevated plasma lactate, is reported. We discuss the antifungal treatment recommendations established by clinical practice guidelines.ConclusionsOne conclusion based on this case is that the haemodynamic instability as a marker of severe sepsis must be equated with dysfunction of any organ and/or a plasma lactate level ≥ 2.5 mmol/l in order to advocate candins as an antifungal treatment. In addition, it should be emphasised that anidulafungin was effective in a clinically difficult patient with candidemia and Candida peritonitis, even when used as late rescue antifungal treatment.     

EPICO 2.0 project. Development of educational therapeutic recommendations using the DELPHI technique on invasive candidiasis in critically ill adult patients in special situations

BackgroundAlthough there has been an improved management of invasive candidiasis in the last decade, still controversial issues remain, especially in different therapeutic critical care scenarios.AimsWe sought to identify the core clinical knowledge and to achieve high agreement recommendations required to care for critically ill adult patients with invasive candidiasis for antifungal treatment in special situations and different scenarios.MethodsSecond prospective Spanish survey reaching consensus by the DELPHI technique, conducted anonymously by electronic e-mail in the first phase to 23 national multidisciplinary experts in invasive fungal infections from five national scientific societies including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious disease specialists, answering 30 questions prepared by a coordination group after a strict review of literature in the last five years. The educational objectives spanned four categories, including peritoneal candidiasis, immunocompromised patients, special situations, and organ failures. The agreement among panelists in each item should be higher than 75% to be selected. In a second phase, after extracting recommendations from the selected items, a meeting was held with more than 60 specialists in a second round invited to validate the preselected recommendations.Measurements and main resultsIn the first phase, 15 recommendations were preselected (peritoneal candidiasis (3), immunocompromised patients (6), special situations (3), and organ failures (3)). After the second round the following 13 were validated: Peritoneal candidiasis (3): Source control and early adequate antifungal treatment is mandatory; empirical antifungal treatment is recommended in secondary nosocomial peritonitis with Candida spp. colonization risk factors and in tertiary peritonitis. Immunocompromised patients (5): consider hepatotoxicity and interactions before starting antifungal treatment with azoles in transplanted patients; treat candidemia in neutropenic adult patients with antifungal drugs at least 14 days after the first blood culture negative and until normalization of neutrophils is achieved. Caspofungin, if needed, is the echinocandin with most scientific evidence to treat candidemia in neutropenic adult patients; caspofungin is also the first choice drug to treat febrile candidemia; in neutropenic patients with candidemia remove catheter. Special situations (2): in moderate hepatocellular failure, patients with invasive candidiasis use echinocandins (preferably low doses of anidulafungin and caspofungin) and try to avoid azoles; in case of possible interactions review all the drugs involved and preferably use anidulafungin. Organ failures (3): echinocandins are the safest antifungal drugs; reconsider the use of azoles in patients under renal replacement therapy; all of the echinocandins to treat patients under continuous renal replacement therapy are accepted and do not require dosage adjustment.ConclusionsTreatment of invasive candidiasis in ICU patients requires a broad range of knowledge and skills as summarized in our recommendations. These recommendations may help to optimize the therapeutic management of these patients in special situations and different scenarios and improve their outcome based on the DELPHI methodology.     

Anidulafungin versus fluconazole in the treatment of Candida albicans chorioretinitis

BackgroundCandida albicans chorioretinitis is the most common cause of endogenous fungal endophthalmitis. Echinocandins are recommended as first-line therapy in the treatment of invasive candidiasis (IC), but in clinically stable patients with IC and endophthalmitis caused by Candida species susceptible to azole compounds these are the first-line treatment due to their better intraocular penetration.Case reportA 42-year-old woman admitted to hospital for duodenal perforation after gastrointestinal surgery and treated with broad-spectrum antibiotics developed C. albicans candidemia. According to protocol, an antifungal treatment with anidulafungin was given. The patient presented no visual symptoms but on routinary ophthalmoscopic examination multiple bilateral chorioretinal lesions were observed. Systemic therapy was changed to fluconazole, with good systemic and ocular results.ConclusionsAzole compounds are the first-line therapy for endophthalmitis associated with candidemia. However, clinical guidelines often propose echinocandins as the first option for IC. In some cases, C. albicans chorioretinitis will require a change in the systemic treatment to assure better intraocular penetration. According to the current evidence and our own experience, routine funduscopy is not necessary in all IC patients. However, we do recommend fundus examination in patients with visual symptoms or those unable to report them (paediatric patients and patients with an altered level of consciousness), and in those who are being treated with echinocandins in monotherapy.     

Actividad antifúngica in vitro de la micafungina

BackgroundMicafungin is a new and very useful pharmacological tool for the treatment of invasive mycoses with a wide antifungal spectrum for the most common pathogenic fungi. Micafungin is especially active against the genera Candida and Aspergillus. Its antifungal mechanism is based on the inhibition of the β-1,3- D-glucan synthesis, an essential molecule for the cell wall architecture, with different con sequences for Candida and Aspergillus, being micafungin fungicide for the former and fungistatic for the latter.AimTo describe the in vitro antifungal spectrum of micafungin based in the scientific and medical lite rature of recent years.MethodsWe have done a bibliographic retrieval using the scientific terms, “micafungin”, “activity”, “Candida”, “Aspergillus”, “fungi”, “mycos*”, “susceptibility”, in PubMed/Medline from the National Library of Medicine de EE.UU. from 2005 to 2009.ResultsWe can underline that most than 99% of Candida isolates are susceptible to ≤ 2 μg/ml of micafungin. MIC are very low (≤ 0.125 μg/ml) for most clinical isolates of the species Candida albicans, Candida glabrata, Candida tropicalis and Candida krusei while Candida parapsilosis and Candida guilliermondii isolates are susceptible to anidulafungin concentrations ≤ 2 μg/ml. The activity of micafungin is excellent against those medical important species of Aspergillus. However, its activity is very low against Cryptococcus and the Zygomycetes.ConclusionsThe excellent activity of micafungin has made this antifungal a first line therapeutic indication for candidemia and invasive candidiasis in non-neutropenic patients.     

Current indications for voriconazole in onco-hematological patients

Invasive fungal infections (IFI) are the main cause of infectious death in cancer patients, especially in hematological malignancies and hematopoietic transplant recipients. Current epidemiology is characterized by a predominance of IFI caused by molds, mainly aspergillosis, along with a emergence of hard-to-treat fungi such are Zygomicetes, Fusarium and Scedosporium. Voriconazole is a broad spectrum antifungal agent with oral and intravenous formulations, approved by the EMEA for the treatment of invasive aspergillosis, candidemia in non-neutropenic patients, IFI caused by fluconazole-resistant species of Candida as well as Scedosporium and Fusarium infections. However, its use in clinical practice is broader, as empirical antifungal treatment and as secondary prophylaxis. It should be kept in mind the possibility of breakthrough IFI, particularly zygomycosis, in patients treated with voriconazole for long periods.     

Drug induced proteome changes in Candida albicans: comparison of the effect of beta(1,3) glucan synthase inhibitors and two triazoles,fluconazole and itraconazole

The dimorphic fungus Candida albicans is an opportunistic human pathogen. Candidiasis is usually treated with azole antifungal agents. However clinical treatments may fail due to the appearance of resistance to this class of antifungal agents in Candida. Echinocandin derivatives are an alternative for the treatment of these fungal infections and are active against azole resistant isolates of C. albicans. Azoles inhibit the lanosterol 14 alpha demethylase which is a key enzyme in the synthesis of ergosterol. In contrast, the echinocandin class of antibiotics inhibit noncompetitively beta-(1,3)-D-glucan synthesis in vitro. We have investigated the impact of mulundocandin on the proteome of C. albicans and compared it to those of a mulundocandin derivative, as well as to two azoles of different structure, fluconazole and itraconazole. The changes in gene expression underlying the antifungal responses were analyzed by comparative 2-D PAGE. Dose dependant responses were kinetically studied on C. albicans grown at 25 degrees C (yeast form) in synthetic dextrose medium. This study shows that antifungals with a common mechanism of action lead to comparable effects at the proteome level and that a proteomics approach can be used to distinguish different antifungals, with the promise to become a useful tool to study drugs of unknown mechanism of action.     

Candidemia in the Pediatric Intensive Care Unit: What’s Different from Candidemia in Adults?

Candida species bloodstream infections have been associated with high morbidity and mortality, especially in patients hospitalized in a pediatric intensive care unit (PICU). The incidence of such infections is rising because of malignancies, prolonged PICU stay, and the use of broad-spectrum antibiotics. Although Candida albicans remains the most frequently isolated species, non-albicans Candida species have shown an increased frequency. Treatment with fluconazole or an echinocandin should be considered in patients at high risk for candidemia or as initial treatment for non-neutropenic patients with candidemia, in addition to the removal of intravascular catheters. Treatment with a lipid formulation of amphotericin B or caspofungin is suggested for neutropenic patients. Early diagnosis, prompt therapy, and prevention are the cornerstones of controlling infection and improving outcome. Although there are some differences between children and adults with candidemia, especially in antifungal drug therapy and outcome, in general the incidence, risk factors, species variation, diagnostic methods, and management are similar.     

Echinocandins: production and applications

The first echinocandin-type antimycotic (echinocandin B) was discovered in the 1970s. It was followed by the isolation of more than 20 natural echinocandins. These cyclic lipo-hexapeptides are biosynthesized on non-ribosomal peptide synthase complexes by different ascomycota fungi. They have a unique mechanism of action; as non-competitive inhibitors of β-1,3-glucan synthase complex they target the fungal cell wall. Results of the structure–activity relationship experiments let us develop semisynthetic derivatives with improved properties. Three cyclic lipohiexapeptides (caspofungin, micafungin and anidulafungin) are currently approved for use in clinics. As they show good fungicidal (Candida spp.) or fungistatic (Aspergillus spp.) activity against the most important human pathogenic fungi including azole-resistant strains, they are an important addition to the antifungal armamentarium. Some evidence of acquired resistance against echinocandins has been detected among Candida glabrata strains in recent years, which enhanced the importance of data collected on the mechanism of acquired resistance developing against the echinocandins. In this review, we show the structural diversity of natural echinocandins, and we summarize the emerging data on their mode of action, biosynthesis and industrial production. Their clinical significance as well as the mechanism of natural and acquired resistance is also discussed.     

AmBisome,tres retos: infección por Candida auris,infección del sistema nervioso central e infección asociada a biopelículas

The treatment of invasive fungal infections remains a challenge, both for the diagnosis and for the need of providing the appropriate antifungal therapy. Candida auris is a pathogenic yeast that is responsible for hospital outbreaks, especially in intensive care units; it is characterized by a high resistance to the antifungal agents and can become multidrug-resistant. At present, the recommended antifungal agents for the invasive infections with this pathogen are echinocandins, always after carrying out an antifungal susceptibility testing. In case of no clinical response or persistent candidemia, the addition of liposomal amphotericin B or isavuconazole may be considered. Both fungal infection of the central nervous system and that associated with biomedical devices remain rare entities affecting mainly immunocompromised patients. However, an increase in their incidence in recent years, along with high morbidity and mortality, has been shown. The treatment of these infections is conditioned by the limited knowledge of the pharmacokinetic properties of antifungals. A better understanding of the pharmacokinetic and pharmacodynamic parameters of the different antifungals is essential to determine the efficacy of the antifungal agents in the treatment of these infections.     

Therapeutic efficacy of anidulafungin for the treatment of oesophageal candidiasis, candidemia and invasive candidiasis

Anidulafungin is a new echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It exhibits high in vitro and in vivo activities against Candida spp. and Aspergillus spp. In several clinical studies investigating Candida esophagitis; candidemia and invasive candidiasis, the clinical efficacy of this echinocandin was similar, or even superior, to that of established antifungals in candidemia. Antifungal activity against strains no longer susceptible to conventional antifungal agents, such as fluconazole and amphotericin B suggests that anidulafungin can be used as salvage therapy in life-threatening fungal infections. The limited toxicity profile, minimal drug-drug interactions and the fact that does not require dosage adjustment in subjects with hepatic or renal impairment, establishes this echinocandin as an attractive new option for the treatment of invasive fungal infections.     

Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.     

Puesta al día en la candidiasis invasora en el paciente crítico no neutropénico

Invasive candidiasis in non-neutropenic critically ill patients remains a challenge for clinicians due to its association with high morbidity and mortality rates, increased incidence, and health-care costs. It is well known that early diagnosis and treatment are associated with a better prognosis. For these reasons a thorough update has been performed in this setting focused on recent Spanish epidemiology, new predictive scores and microbiological tests such as mannan antigen, mannan antibodies, Candida albicans germ-tube antibodies or (1→3)-β-D-glucan detection, molecular techniques for the detection of fungal-specific DNA, advances in antifungal treatment and educational programs in Spain. An early diagnostic and therapeutic algorithm is proposed based on the combination of scores and microbiological test. The aim of this review is to provide physicians with the best information available in order to improve the prognosis of these patients.     

Clinical efficacy of new antifungal agents

Several new options are now available for treating serious fungal infections. All three echinocandin agents currently available have been shown in randomized, blinded clinical trials to be efficacious in treating candidemia and invasive candidiasis. By contrast, the demonstrated efficacy of the echinocandins for the treatment of invasive aspergillosis has been based on historically controlled salvage treatment trials in patients failing or intolerant of other therapies. The new triazole agents, voriconazole and posaconazole, have a broad spectrum of antifungal activity. Voriconazole has become the agent of choice for invasive aspergillosis. On the basis of compassionate treatment data, posaconazole appears to be effective for treatment of zygomycosis. These agents have also been shown to be effective in the treatment of non-Aspergillus mould infections, several of the endemic mycoses and serious Candida infections.     

Activity of anidulafungin against Candida biofilms

Currently, no standardized method to study the in vitro activity of antifungal agents on biofilms is available, thus, the comparison among different authors is difficult. The studies discussed in this review use the XTT reduction to measure the activity of antifungals on biofilms of 24 h of maturation. To date, biofilm anidulafungin MICs of 47 isolates of Candida spp. (25 Candida albicans, 16 Candida tropicalis, 5 Candida dubliniensis and 1 Candida parapsilosis) have been published. The geometric mean MIC of anidulafungin on biofilms of Candida spp. is of 1.18 microg/ml. Against isolates of species with great capacity of biofilm formation, the geometric mean MIC is 0.325 (C. albicans), 2 (C. parapsilosis) and 0.5 microg/ml (C. dubliniensis). No echinocandin has activity on C. tropicalis biofilms. In addition, anidulafungin can be used for lock therapy of catheters since it is the echinocandin with the least in vitro paradoxical effect.     

The patient with candidemia: Treatment choices and algorithms

Candidemia and other forms of invasive candidiasis have become increasingly important health care-associated infections. Risk factors are easily identified in patients with this disease, and about one half are residents of an ICU. In recent years, the treatment of candidemia and invasive candidiasis has significantly evolved from amphotericin B-based regimens to the echinocandins and fluconazole. A strategy of “step-down” therapy from an echinocandin to fluconazole in selected non-neutropenic patients with candidemia has been commonly practiced but not well studied. The approach to candidemia in the neutropenic patient is similar, but a lipid formulation of amphotericin B or voriconazole is often preferred because of the risk of concomitant mold infection. The biggest therapeutic challenge remaining to clinicians is the intensive care unit patient with multiple risk factors and a clinical suspicion of invasive candidiasis. Because optimal therapy in these patients is unknown, well-designed clinical trials and the continued development of non-culture-based diagnostic assays are crucial.     

Particularidades clínicas del paciente crítico con infección fúngica invasora

BackgroundInvasive fungal infection (IFI) is an entity that encompasses different types of infections caused by different types of those fungi pathogenic for humans. In the setting of critically ill patients with multiple and oftenconcurrent risk factors and comorbidities the most common are those caused by the Candida and Aspergillus species. Among the characteristics of IFI in critically ill patients, three aspects can be highlighted: those related to the host (e.g.: risk factors, clinical severity), those related with the pathogen (sensitivity, virulence), or those concerning antifungal treatment (spectrum, features PK / PD, safety, interactions). The fungus that most often causes an IFI in critically ill patients is Candida; the most common type infections are candidemia, Candida peritonitis and catheter-related infections. In recent years new antifungal treatments have expanded the therapeutic options, with echinocandins as a clear choice, often the first in the latest guidelines in critically ill patients with IFI.Case reportWe report the case of a critically ill patient having the most common risk factors, multiple organ dysfunction and development of an IFI. The complexity of establishing an antifungal treatment from the moment of its inception, its setting, and the considerations of the different therapeutic possibilities according to organ dysfunction of the patient are discussed. The antifungal treatment options mentioned in the current guidelines and recommendations are also evaluated.ConclusionsThe most common fungal infection in critically ill patients is invasive candidiasis, with candidemia or candida peritonitis being the most frequent clinical presentations. Candins have brought new possibilities for treating these complex patients due to their good safety profile and clinical efficacy.