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.     

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.     

La micafungina en el tratamiento de la candidiasis invasiva en pacientes sometidos a trasplante de órgano sólido

BackgroundMicafungin is an echinocandin approved for the prevention of Candida spp. infection in hematopoietic stem cell transplantation and therapy of oesophageal candidiasis, disseminated candidiasis and candidemia in adults, children and neonates.AimsTo evaluate the role of micafungin for candidiasis therapy in solid organ transplant recipients.MethodsA medical literature review according to micafungin role for candidiasis therapy in transplant patients is performed.ResultsMicafungin has shown fungicide activity against Candida species, including strains resistant or poorly susceptible to fluconazole. No dose adjustment is required when micafungin is administered in combination with other drugs used in transplant patients, excluding sirolimus, nifedipine and itraconazol. With these drugs, a minimal dose reduction is recommended. The results observed in transplant patients included in clinical trials are favourable and similar to results obtained in other kind of patients.ConclusionsThe clinical results, its safety profile and the low grade of medical interactions permit micafungin to be considered for therapy in specific groups of transplant patients.     

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.     

Anidulafungin: experimental therapy of fungal infections in animal models

We have reviewed the existing data on the efficacy of anidulafungin, which is the most recent echinocandin in the experimental treatment of fungal infections. The scarce published data practically only refers to disseminated and pulmonary aspergillosis and to disseminated candidiasis. Anidulafungin shows fungistatic activity against Aspergillus fumigatus, and fungicidal activity against Candida albicans and Candida glabrata.     

Candidiasis, aspergillosis and other invasive mycoses in recipients of solid organ transplants

Invasive fungal diseases (IFD) are important causes of solid organ transplant-related morbidity and mortality. Modifications and improvements in the transplant surgical procedures, supportive care, and advances in the diagnosis and treatment of these IFD have produced notable changes in their epidemiology and outcome. Candida and other yeast genera continue to play an important etiological role, but Aspergillus and other filamentous fungi are the cause of most IFD in lung transplant recipients. This review is an update of the relevant findings in the literature related to the epidemiology, diagnosis and treatment of IFD in solid organ transplant recipients, with a main focus on invasive aspergillosis and candidiasis.     

In vitro activity of amphotericin B and anidulafungin against Candida spp. biofilms

Invasive infections caused by Candida spp. are increasing worldwide and are becoming an important cause of morbidity and mortality in immunocompromised patients. A large number of manifestations of candidiasis are associated with the formation of biofilms on inert or biological surfaces. Candida spp. biofilms are recalcitrant to treatment with conventional antifungal therapies. The aim of this study was dual 1) to determine the prevalence of biofilm producers among clinical isolates from catheter (16 C. albicans ) and blood culture (2 C. albicans and 30 C. tropicalis), and 2) to determine the activity of amphotericin B and anidulafungin against C. albicans and C. tropicalis biofilms of 24 and 48 hours of maturation. Biofilms were developed using a 96-well microtitre plate model and production and activity of antifungal agents against biofilms were determined by the tetrazolium (XTT) reduction assay. Of catheter and blood isolates, 62.5 and 56.25%, respectively, produced biofilms. By species, 68.42% of C. albicans and 53.33% of C. tropicalis were biofilm producers. C. albicans biofilms showed more resistance to amphotericin B and anidulafungin than their planktonic counterparts. Complete killing of biofilms was never achieved, even at the highest concentrations of the drugs tested. Anidulafungin displayed more activity than amphotericin B against C. albicans biofilms of 24 hours of maturation (GM MIC 0.354 vs. 0.686 microg/ml), but against C. tropicalis biofilms amphotericin B was more active (GM MIC 11.285 vs. 0.476 microg/ml). In contrast, against biofilms with 48 hours maturation, amphotericin B was more active against both species.     

Enfermedades invasoras por hongos levaduriformes en el receptor de un trasplante de órgano sólido

Invasive yeast diseases are uncommon nowadays in solid organ transplant recipients. Invasive candidiasis (2%) usually presents during the first month after transplantation in patients with risk factors. Both common and transplant-specific risk factors have been identified, allowing very efficacious targeted prophylaxis strategies. The most common clinical presentations are fungaemia and local infections near the transplantation area. Cryptococcosis is usually a late infection. Its incidence remains stable and the specific risk factors have not been identified. When cryptococcosis is detected very early, transmission with the allograft should be considered. The most common clinical presentations include meningitis, pneumonia, and disseminated infection. Intracranial hypertension and immune reconstitution syndrome have to be considered.No therapeutic clinical trials have been conducted in solid organ transplant recipients, thus treatment recommendations are derived from data obtained from the general population. It is particularly important to consider the possibility of drug-drug interactions, mainly between azoles and calcineurin inhibitors. Both invasive candidiasis and cryptococcosis increase the mortality significantly in solid organ transplant recipients.     

Candidemia persistente en una paciente receptora de trasplante renopancreático

BackgroundIn recent decades, there has been an increase in the survival of recipients of solid organ trans-plants related to the improvement of the surgical technique, the introduction of protocols for immunosu-ppressive therapy, and the use of antimicrobial prophylaxis. Nonetheless, invasive fungal infection (IFI) is currently the major cause of morbidity and mortality in this group of patients. Invasive candidiasis is the most common IFI found after renal transplantation and is usually associated with total parenteral nutrition, broad-spectrum antibiotic therapy and abdominal surgery.Clinical caseWe report the case of a recent kidney-pancreas transplant recipient who developed a persis-tent catheter-related candidemia caused by Candida glabrata. The patient was treated with anidulafungin and had a good clinical course with no significant drug interactions.We discuss the possible causes and diagnostic and therapeutic alternatives of this kind of infection.     

Anidulafungin: a new echinocandin for the treatment of mycosis

The latest antifungal drugs introduced for clinical use are echinocandins; they possess a distinctive mechanism of action based on the inhibition of the beta-1,3-D-glucan sintesis, through the damage of the fungal cell wall without impairment of human cells because these do not contain beta-1,3-D-glucan. Among echinocandins, anidulafungin is the last that has received the FDA approval in the USA for the treatment of candidemia in non-neutropenic patients, intra-abdominal abscesses, peritonitis and esofagitis caused by Candida. In Europe, the EMEA has also approved its use for invasive candidiasis in non-neutropenic patients and for candidal esofagitis. The characteristics of anidulafungin are close to those of the ideal antifungal since it has a wide spectrum, is active at low minimal inhibitory concentrations and it is fungicidal for Candida. In addition, it is well tolerated, has few pharmacological interactions, is active intravenously, has a long half life and is auto-biodegradable. Finally, anidulafungin has shown a higher therapeutic efficiency when compared with the conventional treatment of candidemia, since although it is more expensive, the treatment with anidulafungin is highly cost effective.     

肝移植术后曲霉的气道定植与侵袭性曲霉病的关系

目的评价肝移植术后曲霉气道的定植及其发生侵袭性感染的风险。方法回顾2003—2004年南京八一医院和上海长征医院56例肝移植患者进行的连续组织学检查和曲霉培养结果。结果24例患者被分离出曲霉,2例发生侵袭性烟曲霉感染。这2例患者在移植后6个月内都有烟曲霉的定植,并且都死亡,占所有移植后死亡的29％。无曲霉定植者都未发生侵袭性曲霉感染。结论肝移植术后的侵袭性曲霉感染较为少见,但常致死,曲霉定植常见但为一过性,由于气管侵袭性曲霉感染只发生在有烟曲霉定植的移植后6个月内的患者,所以在此期间进行预防性的治疗能否有效降低侵袭性曲霉感染值得研究。     

In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature

The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.     

Probiotic bacteria for prophylaxis and therapy of candidiasis

A good deal of data support a role for probiotic intestinal bacteria in the prophylaxis and therapy of candidiasis. Candida spp. are highly infectious eukaryotes that can colonize and infect humans and other warm-blooded mammals, worldwide. Although most humans manifest antibody- and cell-mediated immune responses to Candida antigens a large percentage of the human population is colonized with Candida spp. in their alimentary and vaginal tracts. The bacterial flora plays a very important probiotic role in the prophylaxis of candidiasis by suppressing the growth of Candida spp. on mucosal and cutaneous surfaces; however, the specific bacteria and the mechanisms they use to inhibit Candida spp. and candidiasis are still poorly understood. The increased incidence of Candida infections, their increasing resistance to antifungal antibiotics and the fact that vaccines to protect against candidiasis are not yet available (and may not work in immunodeficient, Candida-susceptible, patients) provides a strong impetus for new research efforts to explore the use of probiotic, anti- Candida intestinal bacteria for the prophylaxis and therapy of candidiasis.     

Utilidad clínica de la micafungina en el tratamiento de las candidiasis invasoras en el paciente oncohematológico

BackgroundInvasive candidiasis is a severe infection among onco-hematological patients, with an attributable mortality around 40%. Micafungin has shown efficacy in antifungal prophylaxis among hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis.AimsTo assess the role of micafungin in the treatment of invasive candidiasis among onco-hematological patients.MethodsLiterature review.ResultsIn a study on 126 patients with candidemia treated with micafungin, an overall response rate of 83% was reported. A double-blind study of 531 patients with invasive candidiasis comparing micafungin (100 mg/day) versus liposomal amphotericin B (3 mg/kg/day) reported success in 90% of patients in both arms, with a more favorable safety profile with micafungin. Other double blind randomized, phase III study compared two doses of micafungin (100 mg/day and 150 mg/day) with standard doses of caspofungin (70 mg loading dose, then 50 mg/day) in adults with invasive candidiasis. Overall success rate was 74% for micafungin 100 mg/day, 70% for micafungin 150 mg/day, and 71% for caspofungin. A double blind randomized study compared micafungin (2 mg/kg/day) to liposomal amphotericin B (3 mg/kg/day) in the treatment of invasive candidiasis in children with a predominance of infections with non-albicans Candida spp. Overall success rate was similar (73% for micafungin and 76% for liposomal amphotericin B).ConclusionsComparative phase III studies have demonstrated non-inferiority of micafungin compared to standard antifungal agents for invasive candidiasis. Micafungin is safe and effective in the treatment of children and adults with invasive candidiasis. Effectivity in invasive infections caused by non-albicans Candida spp is especially relevant in onco-hematological patients receiving fluconazole prophylaxis.     

Epidemiología de las candidiasis invasoras en población pediátrica y adulta

BackgroundInvasive candidiasis (IC) is the most frequent fungal disease in children and adults.AimsTo critically review and update the current epidemiology of Candida spp. disease in neonates, children and adults (critically ill patients and in oncohematologic patients and in solid organ transplant recipients).MethodsWe searched the PubMed/Medline, discussing the current data.Results and conclusionsIC is associated with high attributable morbimortality and increased healthcare costs. In the last decades the incidence of invasive Candida spp. disease has increased in critically ill patients, has decreased in oncohematologic patients, although currently the involvement of non-albicans Candida species in the etiology of this disease is increasing steadily.     

Micafungina en el tratamiento de la infección fúngica en modelos animales

BackgroundMicafungin is an echinocandin antifungal drug recently approved for the treatment of candidiasis. The possibility of its clinical use against other invasive mycoses, has aroused the interest of numerous investigators in evaluating its efficacy in different animal models.ObjectivesTo critically review the current data on the use of micafungin in the treatment of invasive mycoses in animal models.MethodsWe searched the PubMed/Medline data base (National Library of Medicine) from 2005 to 2008, both inclusive, on the use of micafungin in the experimental treatment of the fungal infection.Results and conclusionsSeven, of a total of 18 articles reviewed, were done in animal models of candidiasis and six in animal models of pulmonary or SNC aspergillosis. Similarly to the other echinocandins, caspofungin and anidulafungin, micafungin seems to exert a fungicidal activity against Candida albicans and Candida glabrata and a fungistatic activity against Aspergillus fumigatus. The paradoxical effect observed in lung tissue the experimental caspofungin treatment of aspergillosis has not been seen in the case of micafungin. The available data demonstrate a higher efficacy of micafungin versus fluconazole in the experimental treatment of C. albicans infections caused by strains susceptible in vitro to both drugs. To improve the efficacy of micafungin in the treatment of C. glabrata and A. fumigatus infections, several authors have tested different combined therapies, the combination of micafungin with amphotericin B being that showed the best results.     

Invasive fungal infection in immunocompromised patients

At present, the concept of immunocompromised patient cannot be applied exclusively to the classic groups of cancer, HIV-infected or transplanted patients. The cytotoxic treatment of patients with much more common conditions such as asthma, inflammatory bowel disease or rheumatoid arthritis has produced an exponential increase in the universe of patients with different degrees of immunological commitment. The generalization of transplantation procedures, even in advanced ages of life, the prolonged survival of patients with cancer and the decrease of the viral load in HIV-infected patients have resulted in long-term immunosupresions. The prevalence of invasive fungal infections (IFIs) is increasing in immunocompromised patients but each group of immunocompromised patients present peculiarities that must be recognized to be addressed appropriately. Despite the recent advances in the diagnosis and treatment of IFIs, they still present unacceptable morbility and mortality rates. Although IFIs are commonly caused by Candida spp. or Aspergillus spp., a variety of fungi are emerging as agents of IFIs. These emerging fungi require an individualized basic and clinical study. The aim of this work is to review the IFIs caused by common and emerging fungi in the three more numerous groups of immunocompromised patients: HIV-infected patients, solid organ transplant recipients and cancer patients, especially those with hematological malignancies or hematopoietic stem-cell transplantation.     

Splenic hyalohyphomycosis. Case report

Invasive aspergillosis is an important cause of morbidity and mortality in severely immunocompromised patients, especially those who are neutropenic or who have undergone bone marrow or solid-organ transplant. We report a case of hyalohyphomycosis morphologically suggestive of an Aspergillus spp. in a 22-year-old patient with aplastic anaemia, treated with multiple transfusions and broad spectrum antibiotics.     

Tratamiento con equinocandinas en un paciente crítico sometido a técnica continua de reemplazo renal

BackgroundCritically ill patients with invasive candidiasis (IC) often suffer renal failure, which sometimes requires continuous renal replacement techniques (CRRT). Echinocandins are the first line treatment for IC in critically ill patients with mild or severe illness. Their elimination during CRRT should be negligible due to their pharmacokinetic and pharmacodynamic (PK/PD) profile, and dose adjustment are not needed, as suggested by the few reported clinical studies.Clinical caseThis is the case of a 66 year old male who underwent surgery due to peritonitis secondary to intestinal suture dehiscence. The patient was admitted to ICU with septic shock symptoms and multiple organ dysfunction syndrome (MODS), and CRRT was started. Anidulafungin was prescribed at the usual dosage due to the IC risk factors present, and the observation of yeasts in the peritoneal fluid. Anidulafungin was selected due to the hepatic failure suffered by the patient. An isolate of Candida albicans susceptible to fluconazole was cultured from peritoneal fluid and rectal exudates. However, anidulafungin was maintained due to the MODS and observing the clearance of fluconazole during CRRT. The patient's condition improved favourably, being moved to the surgical ward 20 days after the surgery.ConclusionsEchinocandins, due to their PK/PD profile, could be safely given at usual doses to critically ill patients undergoing CRRT. However, new studies are required to strengthen this recommendation. Its extrahepatic metabolism makes anidulafungin a more attractive option among echinocandins and other antifungals when used in patients with different degrees of hepatic failure     

Immunological biomarkers of tolerance in human kidney transplantation: An updated literature review

The half-life of transplanted kidneys is <10 years. Acute or chronic rejections have a negative impact on transplant outcome. Therefore, achieving to allograft tolerance for improving long-term transplant outcome is a desirable goal of transplantation field. In contrast, there are evidence that distinct immunological characteristics lead to tolerance in some transplant recipients. In contrast, the main reason for allograft loss is immunological responses. Various immune cells including T cells, B cells, dendritic cells, macrophages, natural killer, and myeloid-derived suppressor cells damage graft tissue and, thereby, graft loss happens. Therefore, being armed with the comprehensive knowledge about either preimmunological or postimmunological characteristics of renal transplant patients may help us to achieve an operational tolerance. In the present study, we are going to review and discuss immunological characteristics of renal transplant recipients with rejection and compare them with tolerant subjects.