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.     

Antifungal Therapy for Invasive Fungal Diseases in Allogeneic Stem Cell Transplant Recipients: An Update

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug–drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.     

Successful Treatment of Invasive Fungal Infection Due to Highly Resistant Aspergillus calidoustus in an Allogeneic Hematopoietic Cell Transplant Recipient

Invasive aspergillosis (IA) is the most common invasive fungal infection following a hematopoietic cell transplant, with emerging cryptic species exhibiting resistance to commonly used antifungals such as azoles. These species have been increasingly found after the introduction of anti-mold prophylaxis. We report a case of a 56-year-old female with primary myelofibrosis whose allogeneic hematopoietic cell transplant was complicated by disseminated fungal infection (skin, lung) due to Aspergillus calidoustus, a cryptic specie. Treatment of Aspergillus species remains challenging as these cryptic species are usually resistant to azoles including voriconazole which is the first line of treatment of IA. Infection was successfully treated with surgical excision and combination antifungal therapy based on in vitro susceptibility and synergy testing. Therapy included isavuconazole, a drug that has been shown to be non-inferior to voriconazole in the treatment of invasive mold infections.

     

Isavuconazole in a Successful Combination Treatment of Disseminated Mucormycosis in a Child with Acute Lymphoblastic Leukaemia and Generalized Haemochromatosis: A Case Report and Review of the Literature

Invasive mucormycosis in immunocompromised children is a life-threatening fungal infection. We report a case of a 7-year-old girl treated for acute lymphoblastic leukaemia complicated by disseminated mucormycosis during induction therapy. Microscopic examination of surgically removed lung tissue revealed wide, pauci-septate hyphae suggesting a Mucorales infection. This diagnosis was confirmed immunohistochemically and by PCR analysis followed by a final identification of Cunninghamella sp. The patient was treated successfully with surgical debridement and antifungal combination therapy with amphotericin B, caspofungin and isavuconazole. The use of isavuconazole in a child was not previously reported. Additionally, case reports concerning pulmonary mucormycoses in paediatric population published after 2010 were reviewed. Nineteen out of 26 identified patients suffered from haematological diseases. Reported mortality reached 38.5%. By the fact of rising morbidity, unsatisfactory results of treatment and remaining high mortality of mucormycoses in immunocompromised patients, new therapeutic options are warrant. Isavuconazole, with its broad-spectrum activity, good safety profile and favourable pharmacokinetics, is a promising drug. However, further studies are necessary to confirm positive impact of isavuconazole on mucormycosis treatment in children.

     

Kinetics of Anti-Mannan Antibodies Useful in Confirming Invasive Candidiasis in Immunocompromised Patients

In studying the anti-mannan antibodies longitudinally in serial serum samples of three immunocompromised patients, it was observed that anti-mannan antibodies started to increase shortly after the moment that cultures of deep-tissue sites became positive with Candida albicans. The mean anti-mannan antibody titers determined in a group of 36 immunocompromised patients with invasive candidiasis increased within two weeks after the probable onset of invasive candidiasis. In contrast, anti-mannan antibody levels in serial serum samples of 14 immunocompromised patients who were only colonized with C. albicans remained stable or decreased over time. The HA test measuring the anti-mannan antibodies was 64% sensitive and 89% specific in determining invasive candidiasis. In contrast, antibodies specific for candidal cytoplasmic antigens or enolase alone were of little value in confirming invasive candidiasis in these immunocompromised patients.     

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.     

Primary subcutaneous Nocardia asteroides infection in a renal allograft recipient

Nocardia asteroides is an important opportunistic pathogen in immunocompromised hosts. The primary infection is usually in the lungs and is followed by dissemination to other parts of the body. Primary subcutaneous infection with Nocardia asteroides has been reported rarely (three reports) and no such case has been reported in a renal transplant recipient. We describe here a case of renal transplant recipient who developed primary subcutaneous infection with Nocardia asteroides within one and half years of the transplantation. This revised version was published online in June 2006 with corrections to the Cover Date.     

Resistant Microascus cirrosus pneumonia can be treated with a combination of surgery, multiple anti-fungal agents and a growth factor

A 49-year old male with acute myelogenous leukemia relapsed eight years post allogeneic bone marrow transplantation. The patient received induction chemotherapy causing prolonged neutropenia. The patient developed pneumonia for which empirical antibacterial and antifungal therapy were started. The patient underwent a video-assisted thorocascopy with near complete resection of the lesion because of poor response to treatment. Microascus cirrosus was identified in the tissue. In vitro susceptibility test to different antifungal agents showed M. cirrosus was very resistant. The patient is undergoing second allogeneic transplant with improved pneumonia resulting from a combination of treatment for fungal infection, which included surgery, antifungal agents, and granulocyte-colony stimulating factor. The Microascus genus rarely causes invasive fungal infection in humans and can be very difficult to treat because of the resistance to available antifungal agents.     

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.     

Treatment options in emerging mold infections

Although Zygomycetes, Fusarium spp, and Scedosporium spp are far less frequent causes of invasive fungal disease than Aspergillus and Candida, they are emerging. These types of infections in severely immunocompromised patients have a common feature: a poor clinical response to antifungal therapy. Infection is usually airborne, although local infections in cases of skin trauma are also possible. These fungi are resistant to some common antifungal agents; therefore, surgical debridement of the necrotic tissue, when possible, should be combined with specific systemic antifungal treatment in immunocompromised patients. In the absence of randomized clinical trials, most experience in the treatment of these infections is with amphotericin B. Experience with new antifungal agents is still limited, and recovery from neutropenia remains the main predictor of a favorable outcome.     

Candidiasis invasora en el paciente crítico quemado

BackgroundThe advances in burn care therapy have extended considerably the survival of seriously burned patients, exposing them to infectious complications, notably fungal infections. Due to the difficulty in the diagnosis of invasive mycoses and their high associated mortality rates, approaches to prophylactic or pre-emptive antifungal therapy in high-risk burned patients have been proposed, although these guidelines remain controversial. On the other hand, the management of these conditions is a serious problem, especially in critically ill patients with multiorgan failure, including severely ill burn patients due to the shortage of available antifungal agents. However, in the last several years, the range of antifungal agents has been significantly extended, which have led to an improvement in the treatment of invasive fungal infection in this population.Clinical caseWe report a case of invasive candidiasis in a severelly ill burns patient successfully treated with an echinocandin. In this case report, current treatment options are discussed, and a review of the literature of previously published cases is made.ConclusionsThere are still significant gaps in our knowledge of the optimal diagnostic and management approach for invasive candidiasis in burn patients. Prospective studies are needed in this population to optimise management and improve outcomes in this state of high morbidity and mortality.     

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.     

Invasive Rhinosinusitis Caused by <Emphasis Type="Italic">Lasiodiplodia theobromae</Emphasis> in an Allogeneic Hematopoietic Cell Transplant Recipient Case Report and Review of Literature

Lasiodiplodia theobromae is a known plant pathogen in tropical and subtropical areas. Few cases have been reported in humans (usually keratitis and endophthalmitis) with only two cases of fungal sinusitis in immunocompromised and immunocompetent patients published to date. We report a case of invasive sinusitis secondary to L. theobromae in an allogeneic hematopoietic cell transplant recipient successfully treated with surgical debridement and triazole antifungals with a review of available literature.     

Successful Surgical Intervention for the Management of Endocarditis due to Multidrug Resistant <Emphasis Type="Italic">Candida parapsilosis</Emphasis>: Case Report and Literature Review

Candida parapsilosis is an uncommon cause of invasive endocarditis. This pathogen induces severe complications and carries a high mortality rate. We describe a case of C. parapsilosis endocarditis in a 54-year-old man with a history of HIV and Hepatitis C infection who previously underwent prosthetic valve replacement due to bacterial endocarditis. The patient presented with prolonged febrile episodes and fungemia with repeat blood cultures positive for C. parapsilosis. The patient failed multiple regimens of antifungal therapy and the C. parapsilosis isolate progressively acquired resistance to a number of drugs. Due to the multidrug resistant nature of the isolate, replacement of the infected valve was required to resolve his fungemia, and the patient remained asymptomatic for two years. This case is unusual due to the multidrug resistant nature of the isolate requiring both combined medical and surgical intervention. A review of published reports indicates that endocarditis due to C. parapsilosis responds well to a combination of medical and surgical interventions; the latter is particularly suitable for immunocompromised hosts.     

Fungal fatal attraction: a mechanistic review on targeting liposomal amphotericin B (AmBisome®) to the fungal membrane

Abstract

Liposomal amphotericin B (AmBisome^®) is a lipid-based nanotherapeutic that is used successfully worldwide to treat a broad range of life-threatening invasive fungal infections. In subtropical regions, AmBisome is emerging as the treatment of choice for human parasitic protozoan pathogens such as those from the genus Leishmania. The key to the remarkable efficacy of AmBisome is attributed to its liposome based formulation to deliver a potent drug at high dosage with significantly reduced toxicity in patients with immunocompromised systems. In spite of the rising frequency of AmBisome usage globally, the mechanisms underlying its ability to target to the sites of infection remain largely unknown. This review provides an overview of the current mechanistic understanding of AmBisome, discusses potential challenges and opportunities for the development of clinically effective, refractory resistant antifungal agents.     

Farmacoeconomía del tratamiento de las candidiasis invasoras

BackgroundInvasive candidiasis episodes have increased during last years and they have been related with high rates of crude mortality. Invasive candidiasis-related deaths have not diminished significantly with the introduction of antifungals in the past decade. Finantial managers are worried about extra costs from acquisition of new antifungal agents.AimThis review includes the main studies age-stratified to assess different variables related to the economic burden of invasive candidiasis.MethodsSystematic review of biomedic databases including Medline, PubMed and EMBASE.ResultsThe studies show hospital stay as the main variable related with higher impact in the increase of invasive candidiasis costs. Acquisition costs of antifungals have a very low impact in the invasive candidiasis costs.ConclusionsPharmacoeconomics applied in candidiasis invasive therapy must avoid assessing acquisition costs of antifungals exclusively, needing to include both direct and indirect costs associated with this fungal infection. The cost of antifungal acquisition represents a low impact in the overall economic burden of this fungal infection. Further pharmacoeconomics evaluations should be performed including similar definitions to decrease the possible bias in results interpretation.     

Chemokine Receptor Ccr1 Drives Neutrophil-Mediated Kidney Immunopathology and Mortality in Invasive Candidiasis

Invasive candidiasis is the 4^th leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1^lo to Ccr1^high at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1^+/+ and Ccr1^−/− donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1^+/+ recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1^+/+ cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.     

The continuous changes in the aetiology and epidemiology of invasive candidiasis: from familiar <Emphasis Type="Italic">Candida albicans</Emphasis> to multiresistant <Emphasis Type="Italic">Candida auris</Emphasis>

Recent changes in the aetiology and epidemiology of invasive candidiasis have serious implications for current and future diagnosis, treatment and prognosis. The aim of the current review was to discuss the epidemiology of invasive candidiasis, the distribution of Candida species in different regions of the world, the medical concerns of the changing aetiology and the emergence of antifungal resistance. Overall burden of invasive candidiasis remains high, especially in vulnerable persons, such as the elderly, immunosuppressed or debilitated patients. Moreover, there is a progressive shift in the aetiology of invasive candidiasis from Candida albicans to other species of Candida, probably related to the increased use of azole drugs with a clear trend towards increased antifungal resistance. Finally, the emergence and rise of multiresistant species, such as Candida auris or Candida glabrata, is a major threat making necessary invasive candidiasis worldwide surveillances. These changes have serious implications for the diagnosis, treatment and prognosis of invasive candidiasis. Updated knowledge of the current local epidemiology of invasive candidiasis is critical for the clinical management.     

A Mucormycosis Case in a Cirrhotic Patient Successfully Treated with Posaconazole and Review of Published Literature

Mucormycosis is an invasive fungal infection associated with a high mortality rate, especially in immunocompromised hosts. Mucormycosis rarely occurs in cirrhotic patients. Here, we report a case of mucormycosis with underlying liver cirrhosis and diabetes mellitus. The patient suffered from maxillary sinusitis and osteomyelitis, and the infection was successfully treated with antifungal agents, surgical debridement, and hyperbaric oxygen therapy. The antifungal treatments used were liposomal amphotericin B, itraconazole, and posaconazole. Although our patient had liver cirrhosis (Child-Pugh classification B), no hepatic decompensation was developed during the treatment course of posaconazole. This is the first report of the safe and effective use of posaconazole for the treatment of mucormycosis in a cirrhotic patient.     

Breakthrough Hormographiella aspergillata Infection in a Patient with Acute Myeloid Leukemia Receiving Posaconazole Prophylaxis: A Case Report and Review

Breakthrough invasive infections occur in immunosuppressed patients while they are receiving antifungal agents for both prophylaxis and therapy. Under such conditions, unusual fungal infections emerge. Hormographiella aspergillata is considered an uncommon human pathogen and causes devastating infections. Here, we present a case report of necrotizing pneumonia caused by H. aspergillata as a breakthrough infection in a neutropenic patient and review all previous cases of H. aspergillata infection reported in the literature.