Épico project. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non-neutropenic critically ill adult patients

BackgroundAlthough there has been an improved management of invasive candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches.AimsWe sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with invasive candidiasis.MethodsA prospective Spanish survey reaching consensus by the DELPHI technique was made. It was anonymously conducted by electronic mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious diseases specialists, who answered to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations.ResultsIn the first term, 20 recommendations were preselected (Epidemiology 4, Scores 3, Diagnostic tools 4, Treatment 6 and De-escalation approaches 3). After the second round, the following 12 were validated: (1) Epidemiology (2 recommendations): think about candidiasis in your Intensive Care Unit (ICU) and do not forget that non-Candida albicans–Candida species also exist. (2) Diagnostic tools (4 recommendations): blood cultures should be performed under suspicion every 2–3 days and, if positive, every 3 days until obtaining the first negative result. Obtain sterile fluid and tissue, if possible (direct examination of the sample is important). Use non-culture based methods as microbiological tools, whenever possible. Determination of antifungal susceptibility is mandatory. (3) Scores (1 recommendation): as screening tool, use the Candida Score and determine multicolonization in high risk patients. (4) Treatment (4 recommendations): start early. Choose echinocandins. Withdraw any central venous catheter. Fundoscopy is needed. (5) De-escalation (1 recommendation): only applied when knowing susceptibility determinations and after 3 days of clinical stability. The higher rate of agreement was achieved in the optimization of microbiological tools and the withdrawal of the catheter, whereas the lower rate corresponded to de-escalation therapy and the use of scores.ConclusionsThe management of invasive candidiasis in ICU patients requires the application of a broad range of knowledge and skills that we summarize in our recommendations. These recommendations may help to identify the potential patients, standardize their global management and improve their outcomes, based on the DELPHI methodology.This article is also published in Spanish in this issue. It can be found in 10.1016/j.riam.2013.05.005     

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.     

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.     

白念珠菌耐药的分子机制研究进展

近年来,免疫受损人群不断增多,该人群念珠菌病发病率呈上升趋势。随着抗真菌药物的广泛应用,临床分离到的白念珠菌耐药株增多,有关白念珠菌对抗真菌药物的耐药机制的研究又有了进一步的进展。就白念珠菌对唑类、多烯类、5-氟胞嘧啶、棘白菌素类等抗真菌药物的耐药机制方面的研究进展,作了介绍。     

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.     

Enfermedades invasoras por hongos levaduriformes en pacientes neutropénicos

Invasive fungal diseases caused by yeasts still play an important role in the morbidity and mortality in neutropenic patients with haematological malignancies. Although the overall incidence of invasive candidiasis has decreased due to widespread use of antifungal prophylaxis, the incidence of non-Candida albicans Candida species is increasing compared with that of C. albicans, and mortality of invasive candidiasis continues to be high. In addition, there has been an increase in invasive infections caused by an array of uncommon yeasts, including species of the genus Malassezia, Rhodotorula, Trichosporon and Saprochaete, characterised by their resistance to echinocandins and poor prognosis.     

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.     

Is There Still a Place for Conventional Amphotericin B in the Treatment of Neonatal Fungal Infections?

Neonatal invasive fungal infections (IFIs) remain an increasing problem associated with high rates of morbidity and mortality, as well as late-onset neurodevelopmental implications. Invasive candidiasis remains the leading neonatal IFI. Candida albicans is the fungal species most often affecting this population, although a changing epidemiologic incidence to non-albicans Candida species is reported in some neonatal intensive care units. Many treatment recommendations are extrapolated from adult populations, emphasizing the need to establish the optimal antifungal agent, dosage, and duration of therapy in neonates. Historically, conventional amphotericin B has been considered an efficient and safe treatment approach for most neonatal IFIs. More recently, lipid formulations of amphotericin B have been studied, used alone or in combination with other antifungal agents such as azoles or echinocandins. The aim of this article is to review the published experience in the use of amphotericin B formulations to treat neonatal IFIs.     

Recent changes in candidemia trends in a tertiary hospital (2011–2018)

BackgroundThe epidemiology of candidemia has changed over the last decades and varies widely among geographic areas.AimsWe examined in children (aged 0–14) with candidemia the trends in the incidence rate of this infection, as well as the clinical characteristics of the patients, in order to optimize the prognosis and the control measures of this serious disease.MethodsA retrospective cohort study of candidemia in the period 2011–2018 in the neonatal intensive care unit (NICU), pediatric ICU (PICU) and pediatric wards of a tertiary hospital, was conducted. The clinical course, Candida species isolated, antifungal susceptibility, outcome and incidence rates were analyzed and compared.ResultsWe diagnosed 68 episodes of candidemia in 62 children, 48% occurred in the NICU, 31% in the PICU and 21% in pediatric wards. Candida albicans was the most frequent species isolated in NICU infants (53%), and Candida parapsilosis predominated among PICU patients (59%) and pediatric wards (50%). One third of NICU infants had invasive candidiasis (IC), most of them having extremely low birth weight (ELBW) (35%). All isolates were susceptible to the antifungal administered. Over time, the incidence of candidemia decreased in the PICU (from 2.2 to 0.3 episodes/1000 patient-days, OR = 0.6; 95%CI 0.5–0.8), whereas in the NICU and in the wards remained stable. Mortality occurred mostly in NICU patients (26%), predominated in ELBW infants and did not change over time.ConclusionsThe higher incidence and mortality of candidemia and IC observed in preterm infants requires a continuous evaluation of practices and diagnostic methods which will allow improving the prognosis of this most vulnerable population.     

Update on Antifungal Resistance and its Clinical Impact

Candida and Aspergillus species are important causes of opportunistic infection in an ever-growing number of vulnerable patients, and these infections are associated with high mortality. This has partly been attributed to the emerging resistance of pathogenic fungi to antifungal therapy, which potentially compromises the management of infected patients. Multi-azole resistance of Aspergillus fumigatus is a current health problem, as well as is the co-resistance of Candida glabrata to both azoles and echinocandins. In most cases, negative clinical consequences of reduced in vitro fungal susceptibility to azoles and/or echinocandins can be traced to acquisition of particular resistance mechanisms. While strategies using antifungal combinations or adjunctive agents that maximize the efficacy of existing antifungals may limit treatment failures, new therapeutic approaches, including antifungal agents with novel mechanisms of action, are urgent. In the meantime, more efforts should be devoted to close monitoring of antifungal resistance and its evolution in the clinical setting.     

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.     

Activity of Combined Antifungal Agents Against Multidrug-Resistant <Emphasis Type="Italic">Candida glabrata</Emphasis> Strains

In this study, we evaluated the in vitro activity of echinocandins, azoles, and amphotericin B alone and in combination against echinocandin/azole-sensitive and echinocandin/azole-resistant Candida glabrata isolates. Susceptibility tests were performed using the broth microdilution method in accordance with the Clinical and Laboratory Standards Institute document M27-A3. The checkerboard method was used to evaluate the fractional inhibitory concentration index of the interactions. Cross-resistance was observed among echinocandins; 15% of the isolates resistant to caspofungin were also resistant to anidulafungin and micafungin. Synergistic activity was observed in 70% of resistant C. glabrata when anidulafungin was combined with voriconazole or posaconazole. Higher (85%) synergism was found in the combination of caspofungin and voriconazole. The combinations of caspofungin with fluconazole, posaconazole and amphotericin B, micafungin with fluconazole, posaconazole and voriconazole, and anidulafungin with amphotericin B showed indifferent activities for the majority of the isolates. Anidulafungin combined with fluconazole showed the same percentage of synergism and indifference (45%). Antagonism was detected in 50% of isolates when micafungin was combined with amphotericin B. Combinations of echinocandins and antifungal azoles have great potential for in vivo assays which are required to evaluate the efficacy of these combinations against multidrug-resistant C. glabrata strains.     

Congenital cutaneous candidiasis associated with maternal peripartum candidemia

BackgroundCutaneous congenital candidiasis (CCC) is a rare condition consisting of invasive fungal infection of the epidermis and dermis that mostly affects preterm infants. Maternal vaginal candidiasis is present in half of the cases, although the occurrence of invasive candidiasis during pregnancy or peripartum period is exceptional.Case reportWe present the case of a full-term infant that was born by vacuum-assisted vaginal delivery to an apparently healthy 33 year-old woman with no history of intravenous drug use or vaginal candidiasis during pregnancy. The newborn showed a diffuse maculopapular rash with respiratory distress and bilateral interstitial lung infiltrates, requiring nasal continuous positive airway pressure support. Blood cultures obtained from the mother due to intrapartum fever yielded Candida albicans. Cultures of vaginal discharge and neonate skin also yielded C. albicans with the same in vitro susceptibly pattern. No alternative source for candidemia was identified. The clinical course after starting a systemic antifungal therapy was favorable in both the mother and the neonate, with clearance of candidemia and resolution of the skin lesions.ConclusionsCCC must be considered in full-term newborns with maculopapular rash at birth or during the first days of life. The absence of alternative sources for bloodstream infection in the present case suggests a potential etiopathogenic relationship between CCC and maternal candidemia. It is reasonable to rule out postpartum candidemia when CCC is suspected.     

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.     

Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit

Invasive Candida infections are a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). Extremely preterm and very low birth weight infants are at the highest risk of infection. There are currently no antifungal agents that have FDA-labeling for the treatment of invasive candidiasis in the neonatal population. Based on the current IDSA guidelines, amphotericin and fluconazole are considered first-line options for neonatal candidiasis. The newer antifungal agents (i.e., echinocandins and voriconazole) are currently considered second-line or salvage therapy; however, evidence supporting their use is emerging. This review focuses on the supporting evidence for the selection of antifungal agents for treatment of invasive Candida infections in the NICU.     

A Fatal Case of <Emphasis Type="Italic">Candida auris</Emphasis> and <Emphasis Type="Italic">Candida tropicalis</Emphasis> Candidemia in Neutropenic Patient

We report a fatal case of Candida auris that was involved in mixed candidemia with Candida tropicalis, isolated from the blood of a neutropenic patient. Identification of both isolates was confirmed by amplification and sequencing of internal transcribed spacer and D1/D2 domain of large subunit in rRNA gene. Antifungal susceptibility test by E-test method revealed that C. auris was resistant to amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole and voriconazole. On the other hand, C. tropicalis was sensitive to all antifungal tested. The use of chromogenic agar as isolation media is vital in detecting mixed candidemia.     

High rate of Candida deep-seated infection in patients under chronic hemodialysis with extended central venous catheter use

BackgroundHemodialysis has been described as an important risk factor for the development of candidemia in patients suffering from chronic renal failure.AimsThe aim of this study was to evaluate the epidemiology of candidemia in outpatients with renal replacement therapy (RRT) by hemodialysis where the fungemia clearly represents a healthcare-associated infection.MethodsWe retrospectively collected clinical and laboratory data from patients undergoing at least 3 months of RRT by hemodialysis who developed candidemia within 48 h of hospital admission.ResultsWe identified 14 patients with candidemia with central venous catheters (CVC) in place for 11–277 days before developing fungemia. Deep-seated infection was documented in 6 out of 14 candidiasis cases (43%), including 5 cases of endocarditis (36%).ConclusionsCVC in patients under RRT should be promptly replaced by fistulas and grafts to avoid bloodstream infections. Facing a case of candidemia, adequate source control and prompt initiation of antifungal therapy are mandatory to avoid morbidity and mortality.     

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.