Invasive Mold Infections Research Articles

Regulated Cell Death as a Therapeutic Target for Novel Antifungal Peptides and Biologics.

The rise of microbial pathogens refractory to conventional antibiotics represents one of the most urgent and global public health concerns for the 21st century. Emergence of Candida auris isolates and the persistence of invasive mold infections that resist existing treatment and cause severe illness has underscored the threat of drug-resistant fungal infections. To meet these growing challenges, mechanistically novel agents and strategies are needed that surpass the conventional fungistatic or fungicidal drug actions. Host defense peptides have long been misunderstood as indiscriminant membrane detergents. However, evidence gathered over the past decade clearly points to their sophisticated and selective mechanisms of action, including exploiting regulated cell death pathways of their target pathogens. Such peptides perturb transmembrane potential and mitochondrial energetics, inducing phosphatidylserine accessibility and metacaspase activation in fungi. These mechanisms are often multimodal, affording target pathogens fewer resistance options as compared to traditional small molecule drugs. Here, recent advances in the field are examined regarding regulated cell death subroutines as potential therapeutic targets for innovative anti-infective peptides against pathogenic fungi. Furthering knowledge of protective host defense peptide interactions with target pathogens is key to advancing and applying novel prophylactic and therapeutic countermeasures to fungal resistance and pathogenesis.

Internal transcribed spacer based identification of Aspergillus fumigatus isolated from poultry feed samples

Among over 180 Aspergilli, Aspergillus fumigatus is the most common etiological agent causing invasive mold infection mostly in immunocompromised human and animal. Besides, the fungus is used for various useful purposes. However, for the utilization of A. fumigatus as a useful candidate, accurate identification is crucial. Here, the research work was aimed at identifying A. fumigatus from poultry feed samples using conventional and molecular techniques. Out of 23 feed samples, 2 (8.7%) were found to be positive for A. fumigatus. The internal transcribed spacer 1 (ITS 1) and ITS 2 regions and the 5.8S ribosomal DNA (rDNA) region of the fungus were amplified by polymerase chain reaction. The ITS regions are located between the 18S and 28S rRNA genes, and rRNA gene for 5.8S RNA separates these two ITS regions. The isolated gene has been sequenced and deposited in the GenBank (accession no. KC142152). The gene was 100% similar to other reference species of A. fumigatus, whereas in phylogenetic analysis, a clear distance was found in the cases of other Aspergilli. Based on the unique nature of the ITS1 and ITS2 regions and phylogenetic analysis of the genes, A. fumigatus was correctly identified. The isolated strain could be a good candidate for further studies especially for utilization in the field of biotechnology.Res. Agric. Livest. Fish.4(3): 165-171, December 2017

Retrospective review of immunocompromised children undergoing skin biopsy for suspected invasive infection: Analysis of factors predictive of invasive mold.

Cutaneous lesions are often the first marker of invasive mold infection, which can cause substantial morbidity in immunocompromised children. The purpose of this study was to describe the evaluation and outcomes of immunocompromised children who presented with findings requiring skin biopsy because of concern about invasive infection. In children who were biopsied, we sought to determine the factors predictive of invasive mold infection. A retrospective review was conducted at the Children's Hospital of Philadelphia. Patients included in the study were immunocompromised individuals younger than 26years old who underwent skin biopsy by the inpatient dermatology consultation team between January 1, 2003, and March 15, 2015, because of development of new cutaneous lesions that were suspected of being invasive infection. One hundred five encounters met the inclusion criteria. Fifty (47.6%) biopsied individuals had an infectious pathogen identified on histopathology or culture. Mold was the most common (36%) pathogen, followed by bacteria (32%) and yeast (26%). The presence of a single lesion (P=.001) and prior occlusion at the site of the lesion (P<.001) were associated with mold on biopsy. The combination of a single lesion, history of occlusion, and tissue necrosis on examination was highly predictive for invasive mold infection (86.3% [95% confidence interval 55.1-97.0%]). Of the 18 individuals with confirmed invasive mold infection, 13 (72%) underwent surgical resection, of whom 12 (92%) survived the 30-day follow-up period. Skin biopsy enabled the detection of a pathogen that informed directed therapeutic interventions in nearly half of participants. Institutions caring for immunocompromised children should ensure adequate staffing of clinical personnel approved to perform skin biopsies.

Real-Life Challenges to the Use of Antifungal Agents in Hematology Patients

One of the more serious complications of hematology and allogeneic hematopoietic stem cell transplant patients is the development of invasive fungal infections (IFIs). Due to the widespread use of prophylaxis active against Candida spp. in these populations, infections due to invasive molds, such as aspergillosis and mucormycosis, have become more predominant. Several real-life challenges complicate the optimal prophylaxis and management of patients who develop invasive mold infections. Selection of agents in this setting requires careful consideration to the strength of evidence, certainty of IFI diagnosis, side effect profile, drug interactions, and cost. In this review, we discuss the clinical evidence behind the optimal prophylaxis and treatment of IFIs in patients with hematological malignancies and review important practical considerations that should be taken in order to apply these data effectively to real-world patients.

Erratum: Epidemiology and clinical characteristics of invasive mould infections: A multicenter, retrospective analysis in five Asian countries.

Erratum: Epidemiology and clinical characteristics of invasive mould infections: A multicenter, retrospective analysis in five Asian countries.

Invasive Mold Infections (IMI) among Liver Transplant Recipients (LTR): Is It Time to Reconsider the Risk Factors that Determine Antifungal Prophylaxis?

Background IMI have high mortality among LTR. Prevention is critical. Data supporting guideline-recommended three-tiered approach to antifungal prophylaxis based on risk for IMI are lacking.Methods Retrospective study of 534 adult LTR at the Cleveland Clinic (CCF) August 2010–December 2014. We analyzed the association between IMI and risk factors: retransplantation, hemodialysis, reoperation, and fulminant hepatic failure. Model of end-stage liver disease (MELD) was evaluated as novel risk factor. We compared the incidence of IMI among three subgroups: no antifungal prophylaxis, prophylaxis against yeast alone, and prophylaxis against yeast and mold.ResultsMean age was 56 ± 11 years. 68% were male (n = 364). The most common underlying diseases were hepatitis C virus (32%), hepatocellular carcinoma (28%), alcoholic cirrhosis (19%), and nonalcoholic steatohepatitis (19%). The overall incidence of IMI was 0.9% (n = 5). The incidence of IMI among LTR with (n = 128) and without (n = 406) risk factors was 0.78 and 0.98%, respectively (see Figure). Table 1 details the risk factors and outcomes by subgroups. Only one patient with IMI had a risk factor for mold (reoperation). The other four had none. Incidence of IMI among LTR who did not receive antifungal prophylaxis was 1 and 0% in those who received yeast or mold prophylaxis. There was no association between MELD and IMI.Table 1.Risk factors and outcomes of 534 adult LTR at CCF, 2010–2014. No prophylaxis N = 410 (%) Prophylaxis against Candida N = 91 (%) Prophylaxis against mold N = 33 (%) Risk factorsRe-transplantation3 (0.7)8 (9)7 (21)Reoperation after transplant35 (9)24 (26)11 (33)Renal replacement therapy28 (7)26 (29)14 (42)Fulminant hepatic failure4 (1)2 (2)0 (0)Mean MELD (±SD)23 (6)29 (7)32 (8)MELD >22179 (44)73 (80)28 (85)MELD >2951 (12)38 (42)20 (61)OutcomesAny invasive fungal infection21 (5)4 (4)1 (3)Invasive mold5 (1)0 (0)0 (0)One-year all-cause mortality34 (8)12 (13)5 (15)Conclusion Risk factors and MELD did not predict IMI. Because risks are used to recommend mold-active prophylaxis, antifungal agent overuse may be a concern. Additional studies are needed to reconsider risk factors so that transplant providers may target antifungal agents appropriately, practice antifungal stewardship and improve outcomes.Disclosures All authors: No reported disclosures.

Invasive Mold Infections (IMIs) of the Central Nervous System (CNS) in Patients with Hematologic Cancer (HC) (2000–2016): Uncommon but Deadly

Background There is paucity of data regarding IMIs of the CNS in patients with HC or stem cell transplantation (SCT).Methods Review of the records of patients with HC and/or SCT recipients who were diagnosed with CNS IMIs at MD Anderson Cancer Center (1/1/2000–5/31/2016). IMIs were classified as proven or probable (EORTC/MSG criteria). We excluded patients with mixed CNS infections. Risk factors for survival at day 42 post diagnosis (dx) were assessed. A multivariate logistic regression analysis was performed to identify independent predictors of mortality.ResultsWe identified 40 patients (16 proven; 40%). Most patients were white (29; 73%) and male (33; 83%). Median age was 58 years. The most common HC was acute leukemia (23; 58%). Seventeen patients (43%) were SCT recipients; 13 (76%) had GVHD. Most patients had active HC and neutropenia at dx (38; 95% and 21; 53%, respectively). Twenty-seven patients (68%) were in the ICU at dx. Aspergillus sp. (13; 33%) and Mucorales (8; 20%) accounted for >50% of cases. CNS IMIs were deemed to be secondary to direct extension or hematogenous spread in 9 (23%) and 31 (77%) patients, respectively. In the latter group, 28/31 (90%) had fungal pneumonia. Of the 27 and 9 patients who had Aspergillus galactomannan antigen tested from serum and CSF, respectively, 18 had positivity in serum (66%) and 3 in CSF (33%). Most patients (30; 75%) had exposure to mold-active agents within 30d of dx. Most patients (34; 85%) received lipid AMB and were treated with combination therapy (33; 83%). Most CNS lesions presented as ring-enhancing abscesses radiographically (26; 65%). Absence of giant cells and granulomas in the pathologic examination of the brain lesions were associated with increased 42 days mortality (0% vs. 70%, P = 0.01 and 0% vs. 60% in those who survived, P = 0.03, respectively). In multivariate analysis, co-infection at the time of dx was associated with increased mortality (OR: 16.5, 95% CI: 1.4–198.3, P = 0.03) while steroid tapering was associated with decreased mortality (OR: 0.06, 95% CI: 0.01–0.53, P = 0.01). There was a trend towards protective role of surgical drainage (ORn = 0.18, 95% CI = 0.03–1.14, P = 0.07).Conclusion CNS IMIs occur in ill patients with active HC who are often pre-exposed to antifungals. Immune response in pathology, steroid tapering and possibly surgical drainage are associated with improved outcome.Disclosures D. P. Kontoyiannis, Pfizer: Research Contractor, Research support and Speaker honorarium. Astellas: Research Contractor, Research support and Speaker honorarium. Merck: Honorarium, Speaker honorarium. Cidara: Honorarium, Speaker honorarium. Amplyx: Honorarium, Speaker honorarium. F2G: Honorarium, Speaker honorarium

Pulmonary Mucormycosis Treated Successfully With Isavuconazonium and Surgical Therapy

SESSION TITLE: Fungal Infections 2 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Pulmonary mucormycosis is a rare but devastating fungal infection typically affecting immunocompromised hosts. Although mucorales can affect any organ, the lungs are the predominant site of infection in solid organ transplant patients.1 They pose a diagnostic and therapeutic challenge; therefore a high index of suspicion is required for early diagnosis and treatment. We report a case of pulmonary mucormycosis presenting as a cavitary lung lesion in a post renal transplant patient. CASE PRESENTATION: A 41 year old African American male with type I diabetes mellitus presented with fever, chills, night sweats, 20 lb weight loss, and dysphagia of one month duration. He had received a cadaveric right renal transplant four months earlier for end stage renal disease secondary to diabetic nephropathy and has been on immunosuppressive therapy. Laboratory tests were negative for Aspergillus Ab, Histoplasma Ab, HIV 1/2 Ab, Quantiferon gold, acid-fast bacilli (AFB) and urine legionella antigen. Glycohemoglobin 9.3%. A CT scan of the chest revealed a 4.8 cm X 4.2 cm dense, thick walled right lower lobe (RLL) cavitary lesion (Fig.1). Fiberoptic bronchoscopy revealed diffuse white plaques in the RLL. Bronchoalveolar lavage (BAL) cultures were negative for Pneumocystis jiroveci, AFB and malignant cells. EGD revealed extensive candida esophagitis. The patient was started on fluconazole for candida esophagitis and presumed candida cavitary pneumonia. Although the dysphagia improved, the shortness of breath worsened requiring readmission to the hospital two weeks later. The patient had a CT-guided fine needle biopsy of the cavitary lesion and histopathology revealed nonseptate hyphae. Cultures confirmed Mucor species. The patient underwent a right lower lobectomy and was placed on isavuconazonium therapy. DISCUSSION: In solid organ transplant recipients, immunosuppressive therapy is a major predisposing factor for mucormycosis. It can present as a focal consolidation, pleural effusion or cavitary lesion. Although BAL and sputum culture can aid diagnosis, definitive diagnosis requires histopathology. Fine needle aspiration cytology (FNAC) is an easy and reliable way of obtaining a diagnostic specimen. The cornerstone of treatment is amphotericin, however isavuconazonium has less nephrotoxicity and is better tolerated.2 CONCLUSIONS: In the diagnosis and management of mucormycosis in immunocompromised hosts, it is important to have a high index of suspicion, obtain a histopathologic specimen and be aware of newer treatment options with safer side effect profiles. Early diagnosis and combined medical and surgical management can be curative. Reference #1: Park BJ, Pappas PG, Wannemuehler KA, et al. Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001-2006. Emerging Infectious Diseases. 2011;17(10):1855-1864. Reference #2: Graves B, Morrissey CO, Wei A, et al. Isavuconazole as salvage therapy for mucormycosis. Medical Mycology Case Reprots. 2016;11:36-39. DISCLOSURE: The following authors have nothing to disclose: Tanveer Hassam No Product/Research Disclosure Information

Invasive mold infections of the central nervous system in patients with hematologic cancer or stem cell transplantation (2000–2016): Uncommon, with improved survival but still deadly often

Historically considered to have very poor outcome, there is paucity of recent data regarding invasive mold infections (IMIs) of the central nervous system (CNS) in patients with hematologic cancer (HC) or stem cell transplantation (SCT). We reviewed the records of HC patients and/or SCT recipients who were diagnosed with CNS IMIs (EORTC/MSG criteria) at MD Anderson Cancer Center (1/1/2000-6/31/2016). Risk factors for survival at day (d) 42 post diagnosis were assessed. We identified 40 such patients (16 with proven infection). The incidence density was 3.8 cases/100000 patient days and mortality remained stable throughout the study period. Most patients had active HC and neutropenia at diagnosis (95% and 53% respectively). Of the 25 patients with a microbiological diagnosis, Aspergillus spp and Mucorales accounted for 85% of cases. CNS IMIs were deemed to be secondary to hematogenous spread in 31 (77%), mostly (90%) fungal pneumonia. CNS lesions typically presented as solitary ring-enhancing abscesses in MRI (26; 65%). Most patients (34; 85%) received lipid AMB and were treated with combination therapy (33; 83%); Mortality 42d was 48%. In univariate analysis, lack of surgical drainage (p=0.01), absence of giant cells (p=0.01) and granulomas (p=0.03) were associated with increased 42d mortality. In multivariate analysis, co-infection was associated with increased (p=0.005), while steroid tapering was associated with decreased mortality (p = 0.01). Although less lethal, improved outcome in these uncommon infections was related only to immune response in histopathology, steroid tapering and possibly surgical drainage. In a contemporary 16-year cohort of 40 patients with hematologic cancer and mold infections of Central Nervous System, 42-day mortality was 48%. Improved survival was related to immune response in histopathology, absence of co-infections, corticosteroid tapering and possibly surgical drainage.

Volatile Organic Compounds: Upcoming Role in Diagnosis of Invasive Mould Infections

Purpose of Review Breath testing for fungal respiratory infections has great promise as samples can be obtained by non-invasive, repeatable techniques that can be done on a wide range of patients including children, the confused and from those in the intensive care unit (ICU). We have reviewed progress toward development of test applicable to clinical practice.

Molecular bases of antifungal resistance in filamentous fungi

Invasive mould infections due to Aspergillus spp., Fusarium spp., Scedosporium spp. and other filamentous fungi remain a significant cause of morbidity and mortality in immunocompromised patients. Antifungal therapy is required for successful patient management; however, limited antifungal drugs as well as the emergence of drug resistance pose a challenge to clinicians for effective management of these diseases. The evolution of multidrug-resistant strains owing to selective pressure as well as intrinsically-resistant pathogenic species are a major concern. Thus, it is necessary to gain a better insight into the antifungal resistance mechanisms and their clinical impact. So far, the resistance mechanisms responsible for acquired azole resistance include alteration of the drug target and its overexpression, biofilm formation and efflux pump upregulation. However, mechanisms responsible for polyene and echinocandin resistance are less understood in filamentous moulds, primarily due to incomplete correlation between in vitro susceptibility and clinical response to treatment. The present review gives an insight into the mechanisms implicated in resistance to different classes of antifungal agents both in human and plant pathogenic filamentous fungi. Furthermore, the spectrum of antifungal resistance in these filamentous fungi is highlighted.

Epidemiology and clinical characteristics of invasive mould infections: A multicenter, retrospective analysis in five Asian countries.

Formal, large-scale, multicenter studies of invasive mould infection (IMI) in Asia are rare. This 1-year, retrospective study was designed to assess the incidence and clinical determinants of IMI in centers in five countries (Thailand, Taiwan, Singapore, China, India). Patients treated in a single year (2012) were identified through discharge diagnoses, microbiology, and histopathology logs, and entered based on published definitions of IMI. A total of 155 cases were included (median age 54 years; 47.7% male). Of these, 47.7% had proven disease; the remainder had probable IMI. The most frequent host factors were prolonged steroid use (39.4%) and recent neutropenia (38.7%). Common underlying conditions included diabetes mellitus (DM; 30.9%), acute myeloid leukemia (19.4%), and rheumatologic conditions (11.6%). DM was more common in patients with no recent history of neutropenia or prolonged steroid use (P = .006). The lung was the most frequently involved site (78.7%), demonstrating a range of features on computed tomography (CT). Aspergillus was the most common mould cultured (71.6%), primarily A. fumigatus and A. flavus, although proportions varied in different centers. The most often used antifungal for empiric therapy was conventional amphotericin. Ninety-day mortality was 32.9%. This is the first multicenter Asian study of IMI not limited to specific patient groups or diagnostic methods. It suggests that DM and rheumatologic conditions be considered as risk factors for IMI and demonstrates that IMI should not be ruled out in patients whose chest features on CT do not fit the conventional criteria.

NK Cells and Their Role in Invasive Mold Infection.

There is growing evidence that Natural Killer (NK) cells exhibit in vitro activity against both Aspergillus and non-Aspergillus molds. Cytotoxic molecules such as NK cell-derived perforin seem to play an important role in the antifungal activity. In addition, NK cells release a number of cytokines upon stimulation by fungi, which modulate both innate and adaptive host immune responses. Whereas the in vitro data of the antifungal activity of NK cells are supported by animal studies, clinical data are scarce to date.

Early diagnosis of invasive mould infections and disease

Invasive mould infections (IMIs), such as invasive aspergillosis or mucormycosis, are a major cause of death in patients with haematological cancer and in patients receiving long-term immunosuppressive therapy. Early diagnosis and prompt initiation of antifungal therapy are crucial steps in the management of patients with IMI. The diagnosis of IMI remains a major challenge, with an increased spectrum of fungal pathogens and a diversity of clinical and radiological presentations within the expanding spectrum of immunocompromised hosts. Diagnosis is difficult to establish and is expressed on a scale of probability (proven, probable and possible). Imaging (CT scan), microbiological tools (direct examination, culture, PCR, fungal biomarkers) and histopathology are the pillars of the diagnostic work-up of IMI. None of the currently available diagnostic tests provides sufficient sensitivity and specificity alone, so the optimal approach relies on a combination of multiple diagnostic strategies, including imaging, fungal biomarkers (galactomannan and 1,3-β-d-glucan) and molecular tools. In recent years, the development of PCR for filamentous fungi (primarily Aspergillus or Mucorales) and the progress made in the standardization of fungal PCR technology, may lead to future advances in the field. The appropriate diagnostic approach for IMI should be individualized to each centre, taking into account the local epidemiology of IMI and the availability of diagnostic tests.

Invasive mould infections in the ICU setting: complexities and solutions

Infections caused by filamentous fungi represent a major burden in the ICU. Invasive aspergillosis is emerging in non-neutropenic individuals with predisposing conditions, e.g. corticosteroid treatment, chronic obstructive pulmonary disease, liver cirrhosis, solid organ cancer, HIV infection and transplantation. Diagnosis is challenging because the signs and symptoms are non-specific, and initiation of additional diagnostic examinations is often delayed because clinical suspicion is low. Isolation of an Aspergillus species from the respiratory tract in critically ill patients, and tests such as serum galactomannan, bronchoalveolar lavage 1-3-β-d-glucan and specific PCR should be interpreted with caution. ICU patients should start adequate antifungal therapy upon suspicion of invasive aspergillosis, without awaiting definitive proof. Voriconazole, and now isavuconazole, are the drugs of choice. Mucormycosis is a rare, but increasingly prevalent disease that occurs mainly in patients with uncontrolled diabetes mellitus, immunocompromised individuals or previously healthy patients with open wounds contaminated with Mucorales. A high proportion of cases are diagnosed in the ICU. Rapidly progressing necrotizing lesions in the rhino-sinusal area, the lungs or skin and soft tissues are the characteristic presentation. Confirmation of diagnosis is based on demonstration of tissue invasion by non-septate hyphae, and by new promising molecular techniques. Control of underlying predisposing conditions, rapid surgical resection and administration of liposomal amphotericin B are the main therapeutic actions, but new agents such as isavuconazole are a promising alternative. Patients with mucormycosis receive a substantial part of their care in ICUs and, despite advances in diagnosis and treatment, mortality remains very high.

Changes in the epidemiological landscape of invasive mould infections and disease.

Although a wide variety of pathogens are associated with invasive mould diseases, Aspergillus spp. have historically been one of the most common causative organisms. Most invasive mould infections are caused by members of the Aspergillus fumigatus species complex and an emerging issue is the occurrence of azole resistance in A. fumigatus, with resistance to amphotericin B documented in other Aspergillus spp. The epidemiology of invasive fungal disease has shifted in recent years as non-A. fumigatus Aspergillus spp. and other moulds have become progressively more important, although there are no consolidated data on the prevalence of less common species of moulds. The incidence of mucormycosis may have been underestimated, which is a potential concern since species belonging to the order Mucorales are more resistant to antifungal agents than Aspergillus spp. All species of Mucorales are unaffected by voriconazole and most show moderate resistance in vitro to echinocandins. Fusarium spp. may be the second most common nosocomial fungal pathogen after Aspergillus in some tertiary hospitals, and show a susceptibility profile marked by a higher level of resistance than that of Aspergillus spp. Recently, Scedosporium aurantiacum has been reported as an emerging opportunistic pathogen, against which voriconazole is the most active antifungal agent. Other mould species can infect humans, although invasive fungal disease occurs less frequently. Since uncommon mould species exhibit individual susceptibility profiles and require tailored clinical management, accurate classification at species level of the aetiological agent in any invasive fungal disease should be regarded as the standard of care.

Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations.

Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized.

Clinical considerations in the early treatment of invasive mould infections and disease.

Different therapeutic strategies for invasive fungal diseases have been explored, each with particular strengths and weaknesses. Broad-spectrum antifungal prophylaxis seems logical, but selective use is important due to its substantial disadvantages, including interference with diagnostic assays, selection for resistance, drug toxicity and drug-drug interactions. Antimould prophylaxis should be restricted to high-risk groups, such as patients undergoing intensive chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome, allogeneic HSCT patients with prior invasive fungal infection, graft-versus-host-disease or extended neutropenia, recipients of a solid organ transplant, or patients with a high-risk inherited immunodeficiency. An empirical approach, whereby mould-active therapy is started in neutropenic patients with fever unresponsive to broad-spectrum antibiotics, is widely applied but incurs the clinical and cost penalties associated with overtreatment. A benefit for all-cause mortality using empirical therapy has not been shown, but it is recommended for high-risk patients who remain febrile after 4-7 days of broad-spectrum antibiotics and in whom extended neutropenia is anticipated. There is growing interest in delaying antifungal treatment until an invasive fungal infection is confirmed ('pre-emptive' or 'diagnostics-driven' management), prompted by the development of more sensitive diagnostic techniques. Comparisons of empirical versus pre-emptive regimens are sparse, particularly with modern triazole agents, but treatment costs are lower with pre-emptive therapy and the available evidence has not indicated reduced efficacy. Pre-emptive treatment may be appropriate in neutropenic patients who remain febrile after administration of broad-spectrum antibiotics but who are clinically stable. Further work is required to define accurately the specific patient subgroups in which each management approach is optimal.

New pharmacological opportunities for the treatment of invasive mould diseases.

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.

Changing Epidemiology of Invasive Mold Infections in Patients Receiving Azole Prophylaxis

Breakthrough invasive mold infections (IMIs) that occur during posaconazole or voriconazole prophylaxis are rare complications for which epidemiological data are lacking. This retrospective analysis comparing 24 microbiologically documented breakthrough with 66 nonbreakthrough IMIs shows a shift towards non-Aspergillus molds with a significantly increased proportion of rare multidrug-resistant molds.