Invasive fungal disease in the immunocompromised host: changing epidemiology, new antifungal therapies, and management challenges.

BACKGROUND: Invasive fungal disease (IFD) causes morbidity and mortality in immunocompromised hosts (ICHs). Based on increasing recognition of the impact of IFD on human disease, a recent WHO priority list identified key areas of need. OBJECTIVES: This review examines changes in the epidemiology of IFD, in particular the emergence of antifungal-resistant pathogens and the current availability of rapid diagnostic tests and antifungal treatment options. SOURCES: Literature between 2000 and January 2024 regarding fungal epidemiology, diagnostic tests, antifungal resistance, emerging fungal pathogens, and novel antifungal agents in both adult and paediatric ICH were reviewed. CONTENT: We describe the changing epidemiology and continued burden and mortality of IFD in ICH. Furthermore, we discuss the emergence of antifungal-resistant organisms driven by new immunosuppressed populations, climate change, and antifungal exposure in the individual and environment. We highlight novel antifungal agents and how they will address current unmet needs. IMPLICATIONS: The changing epidemiology and increased population at risk for IFD, lack of recognition or quantification of risks for IFD with new therapies, current gaps in the availability of rapid diagnostic tests, and the imminent availability of novel antifungals with distinct spectra of activity argue for improved availability of and access to rapid diagnostics, antifungal stewardship programmes, and global access to antifungal agents.

Epidemiology of Invasive Fungal Diseases: A 10-Year Experience in a Tertiary Pediatric Hematology-Oncology Department in Greece.

Although advances in the management of pediatric neoplasms have profoundly improved infectious disease outcomes, invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in children and adolescents with high-risk hematological malignancies. A retrospective study was conducted in the Pediatric Hematology-Oncology Department of the University General Hospital of Heraklion for 2013-2022 to estimate the prevalence and describe the clinical and epidemiological characteristics of IFDs for pediatric and adolescent patients with neoplasia. Demographic, clinical, and laboratory parameters were analyzed to identify risk factors for the development of IFD. The overall prevalence of IFDs was estimated to be 7.8% (12/154 patients) throughout the study. The mean age at IFD diagnosis was 9.8 years (SD 6.4 years). The most common IFD was possible/probable invasive pulmonary aspergillosis (IPA; in ≈50%), followed by candidemia/invasive candidiasis (in 44%). Candida parapsilosis was the most prevalent Candida species (4/6 events). Of interest, the majority (75%) of IFDs were breakthrough infections. Patients with increased risk for IFDs were those who were colonized by fungi in sites other than the oral cavity, hospitalized in the intensive care unit for >7 days, received >7 different antimicrobials in the last 3 months, or had severe neutropenia for >44 days. Two children out of a total of 12 with IFD died due to refractory disease or relapse (16.7%). More detailed and prospective epidemiological studies on fungal infections in pediatric patients with hematological or solid neoplasms can contribute to the optimization of prevention and treatment.

Optimizing Antifungal Treatment Strategies to Prevent Invasive Pulmonary Aspergillosis Infection-Related Deaths in Intensive Care Unit Patients: The Need for Standardization of Research Definitions.

The clinical spectrum of invasive pulmonary aspergillosis (IPA) has expanded in recent decades. A large group of patients admitted to intensive care units (ICU) is indeed susceptible to the development of IPA. Although timely diagnosis and antifungal therapy of IPA in this expanding population is crucial to prevent IPA-related deaths, the magnitude of the favorable prognostic impact of antifungal therapy is difficult to measure precisely. In our opinion, the development of standardized research definitions could have favorable implications for further improving our ability both to measure the favorable effect of antifungal treatment and to prevent IPA-related death in ICU patients.

Isobavachalcone Exhibits Potent Antifungal Efficacy by Inhibiting Enolase Activity and Glycolysis in Candida albicans.

Invasive fungal diseases (IFDs) are becoming increasingly acknowledged as a significant concern linked to heightened rates of morbidity and mortality. Regrettably, the available antifungal therapies for managing IFDs are constrained. Emerging evidence indicates that enolase holds promise as a potential target protein for combating IFDs; however, there is currently a deficiency in antifungal medications specifically targeting enolase. This study establishes that isobavachalcone (IBC) exhibits noteworthy antifungal efficacy both in vitro and in vivo. Moreover, our study has demonstrated that IBC effectively targets Eno1 in Candida albicans (CaEno1), resulting in the suppression of the glycolytic pathway. Additionally, our research has indicated that IBC exhibits a higher affinity for CaEno1 compared to human Eno1 (hEno1), with the presence of isoprenoid in the side chain of IBC playing a crucial role in its ability to inhibit enolase activity. These findings contribute to the comprehension of antifungal approaches that target Eno1, identifying IBC as a potential inhibitor of Eno1 in human pathogenic fungi.

Meeting the Therapeutic Challenges of Emergent and Rare Invasive Fungal Diseases Through Novel Clinical Trial Designs.

Treatments for emerging and rare invasive fungal diseases (IFDs) represent a critical unmet medical need. For IFDs that occur less frequently than invasive aspergillosis, such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis, randomized controlled clinical trials are impractical and unlikely to meet urgent public health needs. Understanding regulatory approaches for approval of drugs for rare cancers and rare metabolic diseases could help meet the challenges of studying drugs for rare IFDs. A single-arm, controlled clinical trial with a high-quality external control(s), with confirmatory evidence from nonclinical studies, including pharmacokinetic/pharmacodynamic data in predictive animal models of the disease may support findings of effectiveness of new drugs and biologics. Control populations may include historical controls from published literature, patient registries, and/or contemporaneous external control groups. Continuous engagement among clinicians, industrial sponsors, and regulatory agencies to develop consensus on trial design and innovative development pathways for emergent and rare invasive fungal diseases is important.

Cerebral Infectious Opportunistic Lesions in a Patient with Acute Myeloid Leukaemia: The Challenge of Diagnosis and Clinical Management.

Central nervous system (CNS) lesions, especially invasive fungal diseases (IFDs), in immunocompromised patients pose a great challenge in diagnosis and treatment. We report the case of a 48-year-old man with acute myeloid leukaemia and probable pulmonary aspergillosis, who developed hyposthenia of the left upper limb, after achieving leukaemia remission and while on voriconazole. Magnetic resonance imaging (MRI) showed oedematous CNS lesions with a haemorrhagic component in the right hemisphere with lepto-meningitis. After 2 weeks of antibiotics and amphotericin-B, brain biopsy revealed chronic inflammation with abscess and necrosis, while cultures were negative. Clinical recovery was attained, he was discharged on isavuconazole and allogeneic transplant was postponed, introducing azacitidine as a maintenance therapy. After initial improvement, MRI worsened; brain biopsy was repeated, showing similar histology; and 16S metagenomics sequencing analysis was positive (Veilonella, Pseudomonas). Despite 1 month of meropenem, MRI did not improve. The computer tomography and PET scan excluded extra-cranial infectious-inflammatory sites, and auto-immune genesis (sarcoidosis, histiocytosis, CNS vasculitis) was deemed unlikely due to the histological findings and unilateral lesions. We hypothesised possible IFD with peri-lesion inflammation and methyl-prednisolone was successfully introduced. Steroid tapering is ongoing and isavuconazole discontinuation is planned with close follow-up. In conclusion, the management of CNS complications in immunocompromised patients needs an interdisciplinary approach.

Marine-Derived Metabolites Act as Promising Antifungal Agents.

The incidence of invasive fungal diseases (IFDs) is on the rise globally, particularly among immunocompromised patients, leading to significant morbidity and mortality. Current clinical antifungal agents, such as polyenes, azoles, and echinocandins, face increasing resistance from pathogenic fungi. Therefore, there is a pressing need for the development of novel antifungal drugs. Marine-derived secondary metabolites represent valuable resources that are characterized by varied chemical structures and pharmacological activities. While numerous compounds exhibiting promising antifungal activity have been identified, a comprehensive review elucidating their specific underlying mechanisms remains lacking. In this review, we have compiled a summary of antifungal compounds derived from marine organisms, highlighting their diverse mechanisms of action targeting various fungal cellular components, including the cell wall, cell membrane, mitochondria, chromosomes, drug efflux pumps, and several biological processes, including vesicular trafficking and the growth of hyphae and biofilms. This review is helpful for the subsequent development of antifungal drugs due to its summary of the antifungal mechanisms of secondary metabolites from marine organisms.

Pharmacokinetics, safety, and tolerability of fosmanogepix IV to oral switch and multiple IV doses in healthy participants.

Fosmanogepix [FMGX, APX001; active form: manogepix (MGX), APX001A] is a first-in-class, intravenous (IV)/oral antifungal currently being evaluated for invasive fungal disease treatment. Data from two phase 1, placebo-controlled studies [IV-oral switch (study 1) and multiple IV doses (study 2)] evaluating FMGX tolerability, and pharmacokinetics (PK) are presented. Healthy adults (study 1: 18-65 years; study 2: 18-55 years) were eligible (randomized 3:1 to FMGX: placebo). Eleven participants completed study 1. In study 2, 51 participants (48 planned + 3 replacement) were enrolled in six cohorts (8 participants each; 34 completed the study). In study 1, overall MGX systemic exposures were comparable from day 1 to day 42 of dosing; steady-state plasma concentrations were achieved in ≤24 h following two IV loading doses (1,000 mg) and exposures maintained after switching [IV (600 mg) to daily oral doses (800 mg)]. FMGX was safe and well-tolerated. In study 2, FMGX IV doses (loading doses twice daily/maintenance doses once daily; 3-h infusion) of 1,500/900 mg (cohort A), 900/900 mg (cohort B), and 1,000/900 mg (cohort C: with ondansetron) were not well-tolerated; most participants reported nausea and infrequent vomiting. FMGX IV doses of 1,000/750 mg (cohort D), 1,000/850 mg (cohort E), and 1,000/900 mg (cohort F: ondansetron prn) were relatively better tolerated. Steady-state systemic exposures were achieved between days 2 and 4. All cohorts had similar geometric mean (GM) concentrations during maintenance dosing and similar GM PK parameters. Dosing regimen evaluated in study 1 was safe, well-tolerated, and may be used for future clinical evaluations.

Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM.

PURPOSE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.

Incidence of invasive fungal diseases in inflammatory bowel disease patients: A nationwide study in South Korea.

BACKGROUND: Limited reports exist regarding invasive fungal diseases (IFDs) in inflammatory bowel disease (IBD) patients. OBJECTIVES: This study aims to investigate the incidence and risk factors of IFDs, specifically invasive candidiasis, aspergillosis and pneumocystosis, in IBD patients in South Korea using nationwide data. PATIENTS/METHODS: A population-based retrospective cohort of 42,913 IBD patients between January 2010 and December 2018 was evaluated using the Health Insurance Review and Assessment database. The primary outcome was the incidence of IFDs, including invasive candidiasis, aspergillosis and pneumocystosis, while the secondary outcome involved analysing the risk factors associated with each specific infection. RESULTS: The study included a total of 42,913 IBD patients, with 29,909 (69.7%) diagnosed with ulcerative colitis (UC) and 13,004 (30.3%) diagnosed with Crohn's disease (CD). IFDs occurred in 166 IBD patients (0.4%), with 93 cases in UC patients and 73 cases in CD patients. The incidence rates of invasive candidiasis, aspergillosis and pneumocystosis in IBD patients were 0.71 per 1000 person-years (PYs), 0.15 per 1000 PYs and 0.12 per 1000 PYs, respectively. The cumulative incidence of invasive candidiasis (adjusted p-value <.001) and Pneumocystosis (adjusted p-value = .012) was found to be higher in CD patients than in UC patients. Each IFD had different risk factors, including IBD subtypes, age at diagnosis, anti-tumour necrotic factor agents or the Charlson comorbidity index. CONCLUSION: Based on nationwide data in South Korea, this study shows that IFDs occur consistently in patients with IBD, albeit with a low frequency.

High-Risk Neutropenic Fever and Invasive Fungal Diseases in Patients with Hematological Malignancies.

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug-drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs' risk stratification), and new antifungals and their features (rezafungin and olorofim).

Fungal infections in pediatric patients with acute myeloid leukemia in a tertiary hospital.

Introduction: Acute leukemia accounts for more than 30% of all pediatric cancer cases, and of these, 15-20% are acute myeloid leukemia (AML). Children who super from AML are more likely to develop infections due to the humoral and cellular immune deficits generated by the disease and its treatment. The incidence of fungal infections is underestimated; reports show that up to 75% of fungal infections go undiagnosed until autopsy. In only 30 years, the incidence of invasive candidiasis has increased by 40-fold. Thus, the high morbidity and mortality associated with fungal infections in hematological patients make it necessary to adopt preventive measures. Methods: This work aimed to retrospectively identify pediatric patients with acute myeloid leukemia and invasive fungal diseases (IFDs) in a Latin American tertiary care hospital. A retrospective analysis of 36 clinical records of pediatric patients diagnosed with AML from 2007 to 2017 was carried out. Results: One hundred and twenty-nine hospitalizations were associated with infectious events. Thirteen patients in our study presented 15 infectious events associated with IFDs (11.6%). Two patients died because of complications related to IFDs (15.3%). The most frequent IFD type was aspergillosis, which was observed in 7 cases, followed by Candidemia, which was observed in 4 cases. The most frequent clinical manifestations were fever and respiratory distress. Discussion: Mortality due to IFD can be prevented with effective pharmacotherapy. An appropriate antifungal prophylaxis strategy still needs to be developed through larger prospective studies in Latin America.

A Functional Polymorphism in IL-1B Is Associated With Immune Reconstitution Inflammatory Syndrome of Chronic Disseminated Candidiasis.

We investigated single nucleotide polymorphisms (SNPs) possibly involved in immune reconstitution inflammatory syndrome of chronic disseminated candidiasis (IRIS-CDC) through a candidate gene approach and a prospective matched-control study. We found that an SNP located in interleukin-1B at rs1143627 was significantly associated with the risk of developing IRIS-CDC.

What's New in Prevention of Invasive Fungal Diseases during Hospital Construction and Renovation Work: An Overview.

The goal of the overview was to give insight into the recent data of invasive fungal diseases (IFDs) associated with construction and renovation in healthcare settings as well as the recent evidence about available prevention and infection control measures. The number of studies describing IFD outbreaks associated with construction or renovation is on the rise again. Applying adequate prevention measures is still a challenge not just for healthcare workers but also for architects and construction workers as well. The role of multidisciplinary teams in the planning and monitoring of prevention measures cannot be overemphasized. Dust control is an inevitable part of every prevention plan. HEPA filters are helpful in the prevention of fungal outbreaks in hematologic patients, but further studies are needed to clarify the extent in which they contribute as specific control measures. The cut-off value for a "threating" level of fungal spore contamination still remains to be defined. The value of antifungal prophylaxis is difficult to assess because other preventive measures are simultaneously applied. Recommendations are still based on few meta-analyses, a large number of descriptive reports, and the opinion of respective authorities. Outbreak reports in the literature are a valuable resource and should be used for education as well as for preparing outbreak investigations.

Health economic analysis of patients treated with isavuconazole in a German comprehensive cancer centre.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening and demand timely and appropriate treatment. Research showed that isavuconazole treatment positively affects clinical outcome and length of hospital stay (LOS). OBJECTIVES: The aim of this study was to assess the hospital costs of patients diagnosed with IFD and treated with isavuconazole using real-world data from a German cancer centre. PATIENTS/METHODS: Data and LOS collected from Jan-2016 to Jun-2021 at Department I of Internal Medicine, University Hospital Cologne were retrieved. Case-related resources consumed during the hospital stay across isavuconazole routes of administration (oral, parenteral, and mixed administration) were identified, quantified, valued and compared via a cost analysis that adopted the healthcare payer perspective. RESULTS: In total, 101 cases with isavuconazole treatment were identified (oral: n = 22, 21.8%; parenteral: n = 59, 58.4%; mixed: n = 20, 19.8%). Median total LOS was greater in the mixed group (46.5 days; p = .009). Median ICU LOS and ventilation duration were both longest in the parenteral-only group (16 days, p = .008; 224 h, p = .003). Invasive aspergillosis was the most frequent isavuconazole indication (n = 86, 85.2%). Average hospital costs were highest in the mixed group (€ 101,226). The median overall costs of cases treated with isavuconazole was € 52,050. CONCLUSIONS: Treating IFD is resource intensive, often requires intensive care and implies high rates of in-hospital mortality. Our study emphasises the high hospital treatment costs and thus the need for reimbursement systems to enable live-saving costly treatments.

Interpretation of 2022 World Health Organization fungal priority pathogens list / 中华实用儿科临床杂志

The global morbidity of invasive fungal diseases (IFD) tends to increase, especially in immunocompromised people.Due to the atypical symptoms, unclear etiological mechanism, and emerging antifungal resistance, IFD challenge current clinical diagnosis and treatment.The World Health Organization (WHO) developed the first WHO fungal priority pathogens list in 2022.The most concerning fungal pathogens were listed and summarized to promote further understanding of the epidemiology of IFD and antifungal drug resistance.It is hoped to provide a basis for the prevention and interventions of IFD.

Invasive Fungal Diseases in Africa: A Critical Literature Review.

Invasive fungal diseases (IFDs) are of huge concern in resource-limited settings, particularly in Africa, due to the unavailability of diagnostic armamentarium for IFDs, thus making definitive diagnosis challenging. IFDs have non-specific systemic manifestations overlapping with more frequent illnesses, such as tuberculosis, HIV, and HIV-related opportunistic infections and malignancies. Consequently, IFDs are often undiagnosed or misdiagnosed. We critically reviewed the available literature on IFDs in Africa to provide a better understanding of their epidemiology, disease burden to guide future research and interventions. Cryptococcosis is the most encountered IFD in Africa, accounting for most of the HIV-related deaths in sub-Saharan Africa. Invasive aspergillosis, though somewhat underdiagnosed and/or misdiagnosed as tuberculosis, is increasingly being reported with a similar predilection towards people living with HIV. More cases of histoplasmosis are also being reported with recent epidemiological studies, particularly from Western Africa, showing high prevalence rates amongst presumptive tuberculosis patients and patients living with HIV. The burden of pneumocystis pneumonia has reduced significantly probably due to increased uptake of anti-retroviral therapy among people living with HIV both in Africa, and globally. Mucormycosis, talaromycosis, emergomycosis, blastomycosis, and coccidiomycosis have also been reported but with very few studies from the literature. The emergence of resistance to most of the available antifungal drugs in Africa is yet of huge concern as reported in other regions. IFDs in Africa is much more common than it appears and contributes significantly to morbidity and mortality. Huge investment is needed to drive awareness and fungi related research especially in diagnostics and antifungal therapy.

Clinical research advances of isavuconazole in the treatment of invasive fungal diseases.

Purpose: Invasive fungal diseases (IFD) are a major global public health concern. The incidence of IFD has increased the demand for antifungal agents. Isavuconazole (ISA) is a new triazole antifungal agent that has shown promising efficacy in the prophylaxis and treatment of invasive fungal diseases. The aim of this review is to summarize the recent real-world experiences of using ISA for the treatment and prevention of IFD. Methods: We performed a comprehensive literature search of the MEDLINE, PubMed, Embase, and Cochrane databases for clinical applications of ISA in the real world. Tables and reference lists are presented for this systematic review. Results: IFD poses a major threat to public health and causes high mortality rates. ISA may provide a good treatment. For example, the efficacy of ISA in the treatment of invasive aspergillosis (IA) is comparable to that of voriconazole, and its efficacy in the treatment of invasive mucormycosis (IM) is similar to that of liposomal amphotericin B (L-AmB); therefore, ISA is recommended as the first-line treatment for IA and IM. ISA can also achieve good efficacy in the treatment of invasive candidiasis (IC) and can be used as an alternative to de-escalation therapy after first-line drug therapy. In addition, most studies have shown the efficacy and safety of ISA for the prophylaxis of IFD. Conclusion: Taken together, ISA are expected to become a new choice for the treatment and prevention of IFD because of their good tolerability, high bioavailability, and few drug interactions.

Molecular identification, antifungal susceptibility, and resistance mechanisms of pathogenic yeasts from the China antifungal resistance surveillance trial (CARST-fungi) study.

To have a comprehensive understanding of epidemiology and antifungal susceptibilities in pathogenic yeasts, the China Antifungal Resistance Surveillance Trial (CARST-fungi) study was conducted. All yeast isolates were identified by ribosomal DNA sequencing. Antifungal susceptibilities were performed using CLSI M27-A4 broth microdilution method. Sequence and expression level of resistant-related genes in resistant/non-wide-type (NWT) Candida isolates were analyzed. Totally 269 nonduplicate yeast isolates from 261 patients were collected. About half of the yeast isolates (127, 47.2%) were recovered from blood, followed by ascetic fluid (46, 17.1%). C. albicans remained the most prevalent (120, 44.6%), followed by C. parapsilosis complex (50, 18.6%), C. tropicalis (40, 14.9%), and C. glabrata (36, 13.4%). Fourteen (11.7%) C. albicans isolates and 1 (2.0%) C. parapsilosis isolate were resistant/NWT to triazoles. Only 42.5% (17/40) C. tropicalis were susceptible/WT to all the triazoles, with 19 (47.5%) isolates NWT to posaconazole and 8 (20%) cross-resistant to triazoles. Among C. glabrata, 20 (55.6%) and 8 (22.2%) isolates were resistant/NWT to voriconazole and posaconazole, respectively, and 4 (10.3%) isolates were cross-resistant to triazoles. Isavuconazole was the most active triazole against common Candida isolates. Except for 2 isolates of C. glabrata cross-resistant to echinocandins which were also NWT to POS and defined as multidrug-resistant, echinocandins exhibit good activity against common Candida species. All isolates were WT to AMB. For less common species, Rhodotorula mucilaginosa exhibited high MICs to echinocandins and FLC, and 1 isolate of Trichosporon asahii showed high MICs to all the antifungals except AMB. Among triazole-resistant Candida isolates, ERG11 mutations were detected in 10/14 C. albicans and 6/23 C. tropicalis, while 21/23 C. tropicalis showed MDR1 overexpression. Overexpression of CDR1, CDR2, and SNQ2 exhibited in 14, 13, and 8 of 25 triazole-resistant C. glabrata isolates, with 5 isolates harboring PDR1 mutations and 2 echinocandins-resistant isolates harboring S663P mutation in FKS2. Overall, the CARST-fungi study demonstrated that although C. albicans remain the most predominant species, non-C. albicans species accounted for a high proportion. Triazole-resistance is notable among C. tropicalis and C. glabrata. Multidrug-resistant isolates of C. glabrata and less common yeast have been emerging.

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas.

The aim of this review is to highlight mechanisms of immunosuppression for each agent, along with pooled analyses of infectious complications from the available medical literature. Rituximab confers no increase in grade ≥3 infectious risks, except in the case of patients with advanced-stage non-Hodgkin lymphoma. Gemtuzumab ozogamicin links with high rates of grade ≥3 infections which, however, are comparable with historical cohorts. Pembrolizumab exhibits a favorable safety profile in terms of severe infections. Despite high rates of hypogammaglobulinemia (HGG) with blinatumomab, low-grade ≥3 infection rates were observed, especially in the post-reinduction therapy of relapsed B-acute lymphoblastic leukemia. Imatinib and nilotinib are generally devoid of severe infectious complications, but dasatinib may slightly increase the risk of opportunistic infections. Data on crizotinib and pan-Trk inhibitors entrectinib and larotrectinib are limited. CAR T-cell therapy with tisagenlecleucel is associated with grade ≥3 infections in children and is linked with HGG and the emergence of immune-related adverse events. Off-label therapies inotuzumab ozogamicin, brentuximab vedotin, and venetoclax demonstrate low rates of treatment-related grade ≥3 infections, while the addition of bortezomib to standard chemotherapy in T-cell malignancies seems to decrease the infection risk during induction. Prophylaxis, immune reconstitution, and vaccinations for each targeted agent are discussed, along with comparisons to adult studies.