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Background: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions., Methods: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged., Results: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA., Conclusions: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response.

Objectives: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD)., Patients and Methods: In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis., Results: The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI., Conclusions: In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury.

In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) published revised definitions for diagnosing invasive fungal disease. A previous prospective trial of liposomal amphotericin B for invasive mould disease (AmBiLoad) used modified EORTC/MSG 2002 criteria. We wished to re-evaluate the response and survival based on the revised definitions to compare the outcomes of early vs. late treatment. Patients who had received an allogeneic haematopoietic stem cell transplant or who were neutropaenic (absolute neutrophil count <500 μl(-1) within 14 days of study entry) had been recruited on the basis of a halo or air crescent sign on chest computerised tomography. Originally classified as probable invasive mould disease, they were categorised as possible invasive mould disease using 2008 criteria. Patients had received liposomal amphotericin B at either 3 or 10 mg kg(-1) QD for 14 days, followed by 3 mg kg(-1) QD. Response at end of treatment and the 12-week survival were re-calculated according to 2008 definitions. Six-week survival was estimated by Kaplan-Meier analysis. Of 201 patients with invasive mould disease, 118 (59%) had a diagnosis based on halo signs (possible cases). Mycological evidence was present in 83 (41%) cases (probable/proven cases). Survival rates at 12 weeks for possible vs. probable/proven cases in the 3 mg kg(-1) QD group were 82% vs. 58% (P = 0.006), and 65% vs. 50% (P = 0.15) in the 10 mg kg(-1) QD group. At 6 weeks, rates were 87% vs. 69% in the 3 mg kg(-1) QD group (P = 0.009), and 75% vs. 61% in the 10 mg kg(-1) QD group (P = 0.01). Patients with possible invasive mould disease based on EORTC/MSG 2008 criteria had improved survival rates compared with those treated for probable/proven invasive mould disease. As possible invasive mould disease probably reflects an early-stage of disease, a better outcome might be expected when treatment with liposomal amphotericin B is started preemptively., (© 2010 Blackwell Verlag GmbH.)

A rare case of oromandibular Rhizopus oryzae infection is described in a 55-year-old woman with acute myeloid leukaemia and decompensated diabetes mellitus. The infection developed during induction chemotherapy when the patient was neutropenic. She was treated with a combination of amphotericin B lipid formulation and caspofungin plus surgery. Debridement surgery included excision of the lower lip, chin, floor of the mouth, a portion of the tongue, as well as mandibular resection at the level of the horizontal branches. Eight weeks of combined antifungal therapy were followed by secondary prophylaxis with amphotericin B lipid formulation during consolidation chemotherapy after achieving complete response of both leukaemia and mucormycosis. Reconstructive surgery was carried out including insertion of a new biomaterial porous mandibular prosthesis, which showed excellent functionality after long-term follow-up, followed by several plastic surgery procedures once good tolerability and no adverse effects of the prosthesis were observed. This case shows that a well-coordinated multidisciplinary approach is critical to increase the chances of clinical success in this life-threatening infection., (Copyright © 2010 S. Karger AG, Basel.)

Background: Assessment of response to invasive aspergillosis (IA) therapy has been challenging in treatment trials., Methods: The causes of death over 12 weeks were categorized prospectively by a blinded data review committee using a priori defined criteria in participants in a randomized comparative trial of voriconazole versus amphotericin B as first-line therapy of proven or probable IA., Results: Death occurred in 98 of 277 patients during the 12-week course of study. Seventy-three of the 98 deaths (74%) occurred in the first 6 weeks; 25 deaths occurred during the second 6 weeks. Of the 73 deaths during the first 6 weeks, 50 (68%) were judged to be attributable to IA. Of the 25 deaths during the second 6 weeks, only 6 (24%) were judged to be attributable to IA. Fifty of the 56 deaths (89%) attributable to IA occurred during the first 6 weeks., Conclusions: These data suggest that most deaths due to IA occur during the first 6 weeks after the start of therapy and 6 weeks may be a better interval to judge the effectiveness of antifungal therapy because most deaths after 6 weeks are due to causes related to the underlying disease and its treatment rather than due to IA. Attributable mortality when assessed using a priori definitions and conducted in a blinded manner by a central data review committee can be useful in the assessment of IA therapy., ((c) 2008 American Cancer Society.)

Background: Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds., Methods: Patients with proven or probable IA were randomized in a prospective, open pilot study to receive either a combination of liposomal amphotericin B (AmB) at the standard dose (3 mg/kg daily) and caspofungin at the standard dose or monotherapy with a high-dose AmB regimen (10 mg/kg daily)., Results: Thirty patients (21 men and 9 women) with hematologic malignancies were analyzed, and there were 15 patients in each arm. The median duration of treatment was 18 days for the combination group and 17 days for the high-dose monotherapy group. At the end of treatment, there were significantly more favorable overall responses (partial or complete responses; P = .028) in the combination group (10 of 15 patients; 67%) compared with the high-dose monotherapy group (4 of 15 patients; 27%). Survival rates at 12 weeks after inclusion were 100% and 80%, respectively. Infusion-related reactions occurred in 3 patients in the high-dose monotherapy group. A 2-fold increase in serum creatinine occurred in 4 of 17 patients (23%) who received high-dose monotherapy and 1 of 15 patient (7%) who received combination therapy; hypokalemia <3 mmol/L occurred in 3 patients and 2 patients, respectively., Conclusions: The combination of liposomal AmB and caspofungin was promising as therapy for IA compared with monotherapy. A trial that includes more patients will be required next to confirm the results of this pilot study., (2007 American Cancer Society)

Background: Treatment of invasive mold infection in immunocompromised patients remains challenging. Voriconazole has been shown to have efficacy and survival benefits over amphotericin B deoxycholate, but its utility is limited by drug interactions. Liposomal amphotericin B achieves maximum plasma levels at a dosage of 10 mg/kg per day, but clinical efficacy data for higher doses are lacking., Methods: In a double-blind trial, patients with proven or probable invasive mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for 14 days, followed by 3 mg/kg per day. The primary end point was favorable (i.e., complete or partial) response at the end of study drug treatment. Survival and safety outcomes were also evaluated., Results: Of 201 patients with confirmed invasive mold infection, 107 received the 3-mg/kg daily dose, and 94 received the 10-mg/kg daily dose. Invasive aspergillosis accounted for 97% of cases. Hematological malignancies were present in 93% of patients, and 73% of patients were neutropenic at baseline. A favorable response was achieved in 50% and 46% of patients in the 3- and 10-mg/kg groups, respectively (difference, 4%; 95% confidence interval, -10% to 18%; P>.05); the respective survival rates at 12 weeks were 72% and 59% (difference, 13%; 95% confidence interval, -0.2% to 26%; P>.05). Significantly higher rates of nephrotoxicity and hypokalemia were seen in the high-dose group., Conclusions: In highly immunocompromised patients, the effectiveness of 3 mg/kg of liposomal amphotericin B per day as first-line therapy for invasive aspergillosis is demonstrated, with a response rate of 50% and a 12-week survival rate of 72%. The regimen of 10 mg/kg per day demonstrated no additional benefit and higher rates of nephrotoxicity.

The use of antifungal combination therapy is a new clinical approach for combating fungal infections. Although few conclusive clinical studies have been performed to date, data exist that strongly suggest that combination therapy would benefit specific patient subgroups (e.g. stem-cell transplant recipients). This paper examines the evidence available from in vitro, experimental, and clinical studies, and seeks to discover viable clinical strategies for this promising new therapeutic approach.

Three lipid formulations of amphotericin B have been developed: amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B. These three compounds differ by their lipid composition and therefore by their physical characteristics, their pharmacokinetics, and their safety and efficacy profile. There is a consensus to accept reduced toxicity of these formulations, especially reduced, but not absence of, renal toxicity as compared to amphotericin B deoxycholate. Few well-designed studies have been conducted and none of them demonstrated convincingly superiority in term of efficacy of any of the lipid preparations over amphotericin B deoxycholate. Recently a double blind randomized study compared a standard dose of 3 mg/kg/d of liposomal amphotericin B and a loading dose (10 mg/kg/d for 14 days and then the standard dose) in primary therapy of invasive filamentous fungal infections, mainly aspergillosis. Response rate at end of randomized therapy as well as survival at 12 weeks was numerically superior in the standard dose arm but this difference was not statistically significant. Lack of benefit of high dose liposomal amphotericin B in aspergillosis cannot yet be extrapolated to other filamentous fungal infections. Nephrotoxicity was substantially higher in the loading dose arm and this contraindicates its use in clinical practice.

Background: In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis., Methods: Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed., Results: Fewer patients in the voriconazole group (52 [36%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P<.001)., Conclusions: This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis.

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.

Amphotericin B spectrum covers most of the fungal pathogens involved in human diseases. Its use is limited by infusion-related effects and nephrotoxicity. As a result of strong lipophilic properties, encapsulation in liposomes or binding to lipid complexes led to the development of lipid formulations in an attempt to increase both efficacy and safety. Three lipid formulations of amphotericin B are commercially available: a liposomal preparation, a lipid complex and a colloidal dispersion. They differ in their lipid composition, shape, pharmacokinetic behaviour and clinical effects. The nephrotoxicity of these formulations is significantly decreased compared to their parent compound. Infusion-related events are lowest with liposomal amphotericin B. Increased efficacy of the lipid formulations over conventional amphotericin B, however, still has to be demonstrated. These formulations are mainly indicated for the treatment of documented fungal infections in patients failing conventional amphotericin B or with renal impairment. Liposomal amphotericin B is also indicated for empirical therapy of suspected fungal infections in febrile neutropenic patients giving this compound an advantage over the two other formulations. Lipid formulations of amphotericin B are extremely expensive. Whether the increase in cost translates into a long-term benefit for the patient is still unknown.

Objective: A systematic review was performed to compare the effectiveness and tolerability of lipid-based amphotericin B (AmB) formulations and conventional AmB in the treatment of systemic fungal infections., Methods: The literature and unpublished studies were searched using MEDLINE, EMBASE, Biological Abstracts, AIDSLINE, CANCERLIT, CRD database, Cochrane Controlled Trials Register, and other databases. Search terms included: amphotericin, liposom*, lipid*, colloid*, antifungal agents, and mycoses. Studies were selected according to predetermined criteria. The outcome measures reviewed were efficacy, mortality, renal toxicity, and infusion-related reactions. Meta-analyses and number-needed-to-treat (NNT) analyses were performed., Results: Seven studies (8 publications) met the entry criteria. Meta-analysis showed that lipid-based formulations significantly reduced all-cause mortality risk by an estimated 28% compared with conventional AmB (odds ratio [OR], 0.72; 95% CI, 0.54 to 0.97). There was no significant difference in efficacy between the lipid-based formulations and conventional AmB (OR, 1.21; 95% CI, 0.98 to 1.49). AmB lipid complex (ABLC) and liposomal AmB (L-AmB) significantly reduced the risk of doubling serum creatinine by an estimated 58% (OR, 0.42; 95% CI, 0.33 to 0.54). There was no significant reduction in risk of infusion-related reactions with lipid-based formulations, although this was difficult to interpret given the lack of consistent control of confounding factors. Comparing the lipid-based formulations with conventional AmB, the overall NNT to prevent 1 death was 31. The NNT to prevent a doubling of serum creatinine for both ABLC and L-AmB compared with conventional AmB was 6., Conclusions: This study demonstrates advantages with lipid-based formulations over conventional AmB in terms of reduced risk of mortality and renal toxicity. Future trials in patients with proven fungal infection should control for factors such as premedication, infusion rates, fluid preloading, sodium/potassium supplementation, and concomitant medication.

Background: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis., Methods: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome., Results: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients)., Conclusions: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B., (Copyright 2002 Massachusetts Medical Society)

We report the first case of proven disseminated infection due to Fusarium dimerum associated with a favorable outcome in a patient with acute leukemia and prolonged neutropenia. The patient presented persistent fever, multiple necrotic skin lesions, and bilateral pneumopathy. F. dimerum was first isolated from three blood cultures and then from a skin biopsy and a mouth wash. Microscopy of positive blood cultures showed hyphae with phialides and few curved unicellular and some rare bicellular phialoconidia, permitting immediate presumptive identification of the genus FUSARIUM: The patient failed to respond to conventional amphotericin B but recovered after treatment was switched to amphotericin B-lipid complex and neutrophil recovery.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Invasive pulmonary aspergillosis is growing in incidence, as patients at risk are growing in diversity. Outside the classical context of neutropenia, new risk factors are emerging or newly identified, such as new anticancer drugs, viral pneumonias and hepatic dysfunctions. Clinical signs remain unspecific in these populations and the diagnostic work-up has considerably expanded. Computed tomography is key to assess the pulmonary lesions of aspergillosis, whose various features must be acknowledged. Positron-emission tomography can bring additional information for diagnosis and follow-up. The mycological argument for diagnosis is rarely fully conclusive, as biopsy from a sterile site is challenging in most clinical contexts. In patients with a risk and suggestive radiological findings, probable invasive aspergillosis is diagnosed through blood and bronchoalveolar lavage fluid samples by detecting galactomannan or DNA, or by direct microscopy and culture for the latter. Diagnosis is considered possible with mold infection in lack of mycological criterion. Nevertheless, the therapeutic decision should not be hindered by these research-oriented categories, that have been completed by better adapted ones in specific settings. Survival has been improved over the past decades with the development of relevant antifungals, including lipid formulations of amphotericin B and new azoles. New antifungals, including first-in-class molecules, are awaited. [ABSTRACT FROM AUTHOR]

Summary: Background: The new Rasamsonia spp. complex can develop invasive infection in immunosuppression or chronic pulmonary disease. It has potential to be misidentified as other genera due to morphological similarities. Nowadays, there is a gap of knowledge on this fungi. Objectives: To provide knowledge base of risk factors and therapeutic decisions in invasive Rasamsonia spp. complex infection. Patients/Methods: Cases of invasive infection due to Rasamsonia spp. (formerly Geosmithia/Penicillium spp.) from FungiScope® registry and all reported cases from a literature were included. Results: We identified 23 invasive infections due to Rasamsonia spp., six (26.1%) in the FungiScope® registry. Main risk factors were chronic granulomatous disease (n = 12, 52.2%), immunosuppressive treatment (n = 10, 43.5%), haematopoietic stem cell transplantation (n = 7, 30.4%), graft‐versus‐host disease and major surgery (n = 4, 17.4%, each). Predominantly affected organs were the lungs (n = 21, 91.3%), disease disseminated in seven cases (30.4%). Fungal misidentification occurred in 47.8% (n = 11), and sequencing was used in 69.6% of the patients (n = 16) to diagnose. Breakthrough infection occurred in 13 patients (56.5%). All patients received antifungal treatment, mostly posaconazole (n = 11), caspofungin (n = 10) or voriconazole (n = 9). Combination therapy was administered in 13 patients (56.5%). Susceptibility testing showed high minimum inhibitory concentrations for azoles and amphotericin B, but not for echinocandins. No preferable treatment influencing favourable outcome was identified. Overall mortality was 39% (n = 9). Conclusion: Rasamsonia spp. are emerging fungi causing life‐threatening infections, especially in immunocompromised and critically ill patients. Mortality is high. Treatment is challenging and clinicians dealing with this patient population should become aware of this infection constituting a medical emergency. [ABSTRACT FROM AUTHOR]

Invasive pulmonary aspergillosis (IPA) remains difficult to diagnose and to treat. Most common risk factors are prolonged neutropenia, hematopoietic stem cell or solid organ transplantation, inherited or acquired immunodeficiency, administration of steroids or other immunosuppressive agents including monoclonal antibodies and new small molecules used for cancer therapy. Critically ill patients are also at high risk of IPA. Clinical signs are unspecific. Early computed tomography (CT)-scan identifies the two main aspects, angioinvasive and airway invasive aspergillosis. Although CT-scan findings are not fully specific they usually allow early initiation of therapy before mycological confirmation of the diagnosis. Role of 18F-fludeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) is discussed. Confirmation is based on microscopy and culture of respiratory samples, histopathology in case of biopsy, and importantly by detection of Aspergillus galactomannan using an immunoassay in serum and bronchoalveolar lavage fluid. Deoxyribonucleic acid detection by polymerase chain reaction is now standardized and increases the diagnosis yield. Two point of care tests detecting an Aspergillus glycoprotein using a lateral flow assay are also available. Mycological results allow classification into proven (irrespective of underlying condition), probable or possible (for cancer and severely immunosuppressed patients) or putative (for critically ill patients) IPA. New antifungal agents have been developed over the last 2 decades: new azoles (voriconazole, posaconazole, isavuconazole), lipid formulations of amphotericin B (liposomal amphotericin B, amphotericin B lipid complex), echinocandins (caspofungin, micafungin, anidulafungin). Results of main trials assessing these agents in monotherapy or in combination are presented as well as the recommendations for their use according to international guidelines. New agents are under development. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug-drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against Candida species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug-drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections. [ABSTRACT FROM AUTHOR]

Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA.Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model.Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3-5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (-1.39 [-2.21, -0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [-1.17, 1.53], 0.50 [-1.11, 2.13] and 0.32 [-0.19, 0.84], respectively) or overall response (-0.99 [-2.21, 0.29], -0.89 [-2.41, 0.65] and 0.06 [-0.43, 0.57], respectively).Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole. [ABSTRACT FROM AUTHOR]

Recently, several randomized studies have been published that will shape treatment decisions in the prevention and management of invasive mould infections. Liposomal amphotericin B is an option for empirical or targeted treatment of invasive aspergillosis or mucormycosis, but for prophylaxis therapy, the triazole class now predominates. The triazole voriconazole is currently regarded as a drug of choice for the treatment of proven or probable invasive aspergillosis, and has shown significantly higher response rates than amphotericin B deoxycholate in this setting, with fewer severe drug-related adverse events. Isavuconazole, the newest triazole agent, offers the advantages of once-daily dosing, a wider spectrum of antifungal activity than voriconazole, predictable pharmacokinetics and fewer CYP enzyme-mediated drug interactions. A recent large randomized clinical trial showed mortality to be similar under isavuconazole or voriconazole in patients with invasive mould disease, with fewer drug-related adverse events in isavuconazole-treated patients. Another study has indicated that isavuconazole is also effective in mucormycosis infections but patient numbers were small and confirmation is awaited. Experimental studies combining different drug classes with antimould activity have been promising, but the clinical database is limited. A large randomized trial of combination therapy compared voriconazole plus the echinocandin anidulafungin versus voriconazole monotherapy in patients with invasive aspergillosis. Results showed the overall response rate to be similar, but combination therapy improved survival for the subpopulation of patients in whom the diagnosis was confirmed by serum and/or bronchoalveolar lavage fluid galactomannan positivity. This active field of research is likely to continue evolving rapidly in the coming years. [ABSTRACT FROM AUTHOR]

The article focuses on the guidelines of the Infectious Diseases Society of America to treat the life-threatening infection aspergillosis. There are three major forms of aspergillosis including invasive aspergillosis, chronic forms of aspergillosis and allergic forms of aspergillosis. Based on the randomized controlled trials, voriconazole is considered the primary treatment for invasive aspergillosis. In addition, the liposomal amphotericin B (L-AMB) is considered an effective alternative primary therapy to some patients.

Background. Conventional amphotericin B-based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a >70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species. Methods. In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy. Results. Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia. Conclusion. These results suggest that posaconazole is useful for the treatment of invasive fusariosis. [ABSTRACT FROM AUTHOR]

It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P = 0.09); P = 0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P = 0.05 and P = 0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P = 0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P < 0.001). The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety. [ABSTRACT FROM AUTHOR]

A reply by O. A. Cornely and colleagues to a letter to the editor about their article "Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing" in the 2007 issue is presented.

Randomized controlled trials (RCTs) provide the most reliable estimates of the effects of treatments. However, not all treatments are compared in available RCTs, making comparison of treatments problematic. Mixed treatment comparisons (MTCs) can provide estimates of the comparative effects of treatments across a range of available therapeutic options. MTCs use networks of available direct comparisons to estimate differences in treatments that have not been estimated in trials via a common comparator. We conducted a systematic review and MTCs of comparative RCTs in haematological patients of anti-mould active agents used for the empirical treatment of febrile neutropenia (Analysis 1), and pre-emptive therapy (Analysis 2) of invasive mould diseases. In addition, we summarized the evidence available associated with the use of directed treatment strategies (Analysis 3). For empirical therapy, caspofungin proved superior to amphotericin B, liposomal amphotericin B, amphotericin B lipid complex and voriconazole in the outcome of survival, but no agents showed superiority for treatment response. There was no evidence of a difference between pre-emptive and empirical strategies on mortality outcomes. For directed therapy, voriconazole was superior to amphotericin B for overall survival, and both voriconazole and liposomal amphotericin B were superior to amphotericin B and amphotericin B colloidal dispersion on the outcome of response. While limited to some degree by the availability of RCTs, the MTCs reported here provide the best available evidence of relative therapeutic success for different available treatment strategies. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the paper by Pachl and colleagues which provide the results of a double-blind study comparing Mycograb with a placebo plus a lipid-assocated formulation of amphotericin B for the treatment of invasie candidiasis.

A response by R. Herbrecht, D.W. Denning, and T.F. Patterson to several letters to the editor about their article "Voriconazole Versus Amphotericin B for Primary Therapy of Invasive Aspergillosis," in the August 8, 2002 issue.

• Similar mortality for Scedosporium and Lomentospora -related infections in children. • Median time to death for children with Lomentospora -infections was less than a week. • Infection of the brain and blood were associated with high mortality. • Voriconazole administration and surgery for antifungal treatment improve survival. Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections. Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected. Fifty-five children (median age 9 years [IQR: 5–14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment. Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3–28] versus 61 days [IQR: 16–148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35–51.40] and HR 6.12 [95% CI 1.52–24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11–0.99] and HR 0.09 [95% CI 0.02–0.40], respectively). Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome. [ABSTRACT FROM AUTHOR]