Increase In Invasive Fungal Infections Research Articles

Promising immunotherapeutic targets for treating candidiasis.

In the last twenty years, there has been a significant increase in invasive fungal infections, which has corresponded with the expanding population of individuals with compromised immune systems. As a result, the mortality rate linked to these infections remains unacceptably high. The currently available antifungal drugs, such as azoles, polyenes, and echinocandins, face limitations in terms of their diversity, the escalating resistance of fungi and the occurrence of significant adverse effects. Consequently, there is an urgent need to develop new antifungal medications. Vaccines and antibodies present a promising avenue for addressing fungal infections due to their targeted antifungal properties and ability to modulate the immune response. This review investigates the structure and function of cell wall proteins, secreted proteins, and functional proteins within C. albicans. Furthermore, it seeks to analyze the current advancements and challenges in macromolecular drugs to identify new targets for the effective management of candidiasis.

Effect of Star Topology Versus Linear Polymers on Antifungal Activity and Mammalian Cell Toxicity.

The global increase in invasive fungal infections and the emergence of drug-resistant strains demand the urgent development of novel antifungal drugs. In this context, synthetic polymers with diverse compositions, mimicking natural antimicrobial peptides, have shown promising potential for combating fungal infections. This study investigates how altering polymer end-groups and topology from linear to branched star-like structures affects their efficacy against Candida spp., including clinical isolates. Additionally, the polymers' biocompatibility is accessed with murine embryonic fibroblasts and red blood cells invitro. Notably, a low-molecular weight star polymer outperforms both its linear polymeric counterparts and amphotericin B (AmpB)in terms of an improved therapeutic index and reduced haemolytic activity, despite a higher minimum inhibitory concentration against Candida albicans (C. albicans) SC5314 (16-32µgmL-1 vs 1µgmL-1 for AmpB). These findings demonstrate the potential of synthetic polymers with diverse topologies as promising candidates for antifungal applications.

Trichoderma spp.-Related Pneumonia: A Case Report in Heart-Lung Transplantation Recipient and a Systematic Literature Review.

Opportunistic and hospital-acquired infections are common among recipients of solid organ transplantation. New pathogens are increasingly reported in the intensive care unit (ICU) population. We report a case of a patient who developed Trichoderma spp.-related pneumonia (TRP) after heart-lung transplantation. In the absence of antifungal susceptibility testing, TRP was confirmed by histological examination, and empirical therapy with voriconazole and caspofungin was swiftly initiated. Complete resolution of pneumonia was obtained after prolonged combination therapy. Given the lack of guidelines, we conducted a systematic review to elucidate the diagnostic and therapeutic strategies to apply during Trichoderma infection. After deduplication and selection of full texts, we found 42 articles eligible for the systematic review. Pneumonia seems to be the most common clinical manifestation (31.8%). The most used antifungal therapy was amphotericin B, while combination therapy was also reported (27.3%). All the patients were immunocompromised except for one case. Despite the rarity of Trichoderma spp. infection, the increase in invasive fungal infections is of growing importance in ICU, considering their impact on mortality and the emergence of antifungal resistance. In the absence of prospective and multicenter studies, a review can provide useful insight regarding the epidemiology, clinical manifestations, and management of these unexpected challenges.

Antifungal Drugs Shortage in India amidst Looming Increase in Invasive Fungal Infections among COVID-19 Patients: An Impending Crisis.

The widespread prevalence of fungal infections in the second wave of COVID-19 pandemic could be owed to ubiquitous and injudicious use of steroids and immunosuppressive nature of the virus. However, these fungal infections also meant increased use of antifungal drugs, hence endangering their supply. Amphotericin B is the first line drug for mucormycosis which was declared as an epidemic in India during the second wave. With the increasing demand of the drug, came challenges to manufacture and supply large quantities of the drug and exploitation by creating a black market and spread of false information and imprudent usage. It is of utmost importance to be prepared with adequate supply all over the nation and implementing safety regulations in manufacturing and supply of large quantities of drugs during the demanding times and make them accessible at a reasonable rate.

Evaluation of the in vitro Activity and in vivo Efficacy of Anidulafungin-Loaded Human Serum Albumin Nanoparticles Against Candida albicans.

Recent decades have seen a significant increase in invasive fungal infections, resulting in unacceptably high mortality rates. Anidulafungin (AN) is the newest echinocandin and appears to have several advantages over existing antifungals. However, its poor water solubility and burdensome route of administration (i.e., repeated, long-term intravenous infusions) have limited its practical use. The objective of this study was to develop anidulafungin-loaded Human Serum Albumin (HSA) nanoparticles (NP) so as to increase both its solubility and antifungal efficacy. HSA was reduced using SDS and DTT, allowing liberation of free thiols to form the intermolecular disulfide network and nanoassembly. Reduced HSA was then added to MES buffer (0.1 M, pH 4.8) and magnetically stirred at 350 rpm and 25°C with AN (m/m 50:1) for 2 h to form nanoparticles (AN NP). We next performed routine antifungal susceptibility testing of Candida strains (n = 31) using Clinical and Laboratory Standards Institute (CLSI) methodologies. Finally, the in vivo efficacy of both AN and AN NP was investigated in a murine model of invasive infection by one of the most common fungal species—C. albicans. The results indicated that our carrier formulations successfully improved the water solubility of AN and encapsulated AN, with the latter having a particle size of 29 ± 1.5 nm with Polymer dispersity index (PDI) equaling 0.173 ± 0.039. In vitro AN NP testing revealed a stronger effect against Candida species (n = 31), with Minimum Inhibitory Concentration (MIC) values 4- to 32-fold lower than AN alone. In mice infected with Candida and having invasive candidiasis, we found that AN NP prolonged survival time (P < 0.005) and reduced fungal burden in kidneys compared to equivalent concentrations of free drug (P < 0.0001). In conclusion, the anidulafungin nanoparticles developed here have the potential to improve drug administration and therapeutic outcomes for individuals suffering from fungal diseases.

1291. Safety of Isavuconazole Compared with Voriconazole as Primary Antifungal Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients

BackgroundVoriconazole (VCZ) is used as mold active primary antifungal prophylaxis (AFP) after allogenic hematopoietic cell transplant (HCT) but is frequently discontinued due to adverse events (AE), variable pharmacokinetics and drug-drug interactions. Limited data exists on the safety of Isavuconazole (ICZ) as AFP in HCT patients (pts). The study objectives were to compare 1) rates of AFP premature discontinuation (d/c), 2) changes in transaminases values from start to end of treatment (EOT) and 3) rates of invasive fungal infections (IFI) and all-cause mortality by Day (D) +180 post HCT between VCZ and ICZ AFP.MethodsThis is a matched cohort analysis of 95 pts enrolled in a clinical trial of ICZ AFP from 7/1/2017-10/31/2018 (ICZ-cohort) and 210 pts who received VCZ AFP standard of care between 9/1/2014-12/31/2015 at MSKCC (VCZ-cohort). The cohorts were matched using propensity scores (Table 1). AFP was administered for 75-100 days per institutional guidelines. Premature d/c of AFP was defined as d/c for IFI or AE by D +100 post HCT or interruption of >14 days for any reason. The cumulative incidence function and log rank test were used to compare groups. Mean transaminase values were compared using paired T-tests.Table 1. Baseline characteristics ResultsThe median (Interquartile range) duration of AFP was 94 (87-100) days and 76 (23-94) days in ICZ and VCZ cohorts respectively (p< 0.0001). Premature d/c occurred in 14/95 (14.7%) of ICZ and 92/210 (43.8%) of VCZ cohorts (p< 0.0001) (Figure 1). The most common cause for AFP d/c was hepatotoxicity: ICZ-cohort: 5/95 (5.26%) vs VCZ-cohort: 48/210 (22.8%). Transaminases at EOT and up to 14 days were increased in VCZ but not ICZ cohort (Figure 2). IFI occurred in 3.15% (3/95) in ICZ-cohort and 2.85% (6/210) in VCZ-cohort (p=0.88) (Figure 3). In ICZ-cohort IFI included 3 Candida bloodstream infections (BSI) occurring on ICZ AFP. In VCZ-cohort IFI included one Candida BSI after VCZ d/c, and 5 probable mold infections; 3/5 with serum galactomannan > 0.5 and 2 with beta-D-glucan > 80. IFI occurred on VCZ in 1 pt and after VCZ premature d/c in 5 pts. All-cause mortality was 6.31% (6/95) in ICZ-cohort and 2.85% (6/210) in VCZ-cohort (p=0.089).Figure 1. Cumulative incidence of premature discontinuation of AFP by D+100 Figure 2. Transaminases at baseline,end of treatment (EOT), EOT +7 days and EOT +14 days in ICZ- and VCZ cohorts Figure 3. Cumulative incidence of IFI by day +180 ConclusionThere was less premature discontinuation and hepatotoxicity with ICZ AFP, but no increase in IFI or death compared to VCZ AFP in allogeneic HCT pts.Disclosures Yeon Joo Lee, MD, MPH, Ansun BioPharma (Scientific Research Study Investigator)Astellas Pharma (Scientific Research Study Investigator) Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Dionysios Neofytos, MD, Basilea (Advisor or Review Panel member)Gilead (Advisor or Review Panel member)MSD (Advisor or Review Panel member, Research Grant or Support)Pfizer (Advisor or Review Panel member, Research Grant or Support) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)

Invasive fungal infections following liver transplantation.

The review outlines the microbiology, presentation, prophylactic strategies, resistance patterns, and consequences of invasive fungal infections (IFIs) in orthotopic liver transplantation (OLT) recipients. There has been an increase in the proportion of non-albicans Candida causing IFIs. The biomarkers galactomannan and β-D-glucan should not be routinely used in the diagnosis of IFIs in OLT recipients due to their limited accuracy. Echinocandins have emerged as noninferior to fluconazole and other prophylactic regimens. Their broad spectrum of activity and side-effect profile are appealing; however, the development of echinocandin resistance, especially in Candida glabrata has been highlighted as one of their limitations. A significant decline in IFIs but an increase in IFIs caused by non-albicans Candida species has been observed in the model for end-stage liver disease era. Diagnostic tools remain limited. Studies continue to support antifungal prophylaxis individualized to recipient risk with echinocandins now established as an additional option for antifungal prophylaxis. The appropriate duration of antifungal prophylaxis remains ill-defined with some studies advocating targeted therapy based on clinical status and others more prolonged therapy beyond the historically common 4 weeks. However, prolonged therapy with echinocandins can result in resistance.

Fungal Biofilm – A Real Obstacle Against an Efficient Therapy: Lessons from Candida

The past decades have witnessed a dramatic increase in invasive fungal infections, especially caused by different species belonging to the Candida genus. Nowadays, even after many improvements in several medical procedures, Candida infections (candidiasis) still account for an unacceptable high rate of morbimortality in hospital settings. Corroborating this statement, fungal biofilms formed on both abiotic and living surfaces are responsible for an important medical and economic burden, since biofilm lifestyle confers numerous advantages to the pathogens, including high tolerance to environmental stresses such as antimicrobials and host immune responses. Aggravating this scenario, the currently used antifungal drugs have mostly been developed to target exponentially growing fungal cells and are poorly or not effective against biofilm structures. So, the challenges to inhibit biofilm formation (e.g., blocking the fungal adhesion and its fully development due to the changes of physicochemical properties of the inert substrates by covering or impregnating them with antimicrobial compounds, for example, silver nanoparticles) and/or to disarticulate mature biofilm architecture (e.g., by using compounds capable in destabilizing, weakening or destroying the extracellular matrix components, including inhibitors of quorum sensing signals, hydrolytic enzymes, surfactants, chelator agents and biocides) are stimulating researchers around the world to search novel strategies and new chemotherapeutic options to control fungal biofilm. In this context, the present review summarizes some promising approaches and/or strategies that could improve our ability to prevent or eradicate fungal biofilms in medical settings, focusing on the lessons learned with Candida model.

Fungal cell membrane-promising drug target for antifungal therapy.

Increase in invasive fungal infections over the past few years especially in immunocompromised patients prompted the search for new antifungal agents with improved efficacy. Current antifungal armoury includes very few effective drugs like Amphotericin B; new generation azoles, including voriconazole and posaconazole; echinocandins like caspofungin and micafungin to name a few. Azole class of antifungals which target the fungal cell membrane are the first choice of treatment for many years because of their effectiveness. As the fungal cell membrane is predominantly made up of sterols, glycerophospholipids and sphingolipids, the role of lipids in pathogenesis and target identification for improved therapeutics were largely pursued by researchers during the last few years. Present review focuses on cell membrane as an antifungal target with emphasis on membrane biogenesis, structure and function of cell membrane, cell membrane inhibitors, screening assays, recent advances and future prospects.

Optimizing Outcomes in Immunocompromised Hosts: Understanding the Role of Immunotherapy in Invasive Fungal Diseases.

A major global concern is the emergence and spread of systemic life-threatening fungal infections in critically ill patients. The increase in invasive fungal infections, caused most commonly by Candida and Aspergillus species, occurs in patients with impaired defenses due to a number of reasons such as underlying disease, the use of chemotherapeutic and immunosuppressive agents, broad-spectrum antibiotics, prosthetic devices and grafts, burns, neutropenia and HIV infection. The high morbidity and mortality associated with these infections is compounded by the limited therapeutic options and the emergence of drug resistant fungi. Hence, creative approaches to bridge the significant gap in antifungal drug development needs to be explored. Here, we review the potential anti-fungal targets for patient-centered therapies and immune-enhancing strategies for the prevention and treatment of invasive fungal diseases.

Combination of fluconazole with non-antifungal agents: A promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery

The past decades have witnessed a dramatic increase in invasive fungal infections, especially candidiasis. Despite the development of more effective new antifungal agents, fluconazole (FLC) is still widely used in the clinic because of its efficacy and low toxicity. However, as the number of patients treated with FLC has increased, FLC-resistant Candida albicans isolates emerge more frequently. In addition, biofilm-associated infections are commonly encountered and their resistance poses a great challenge to antifungal treatment. Various approaches have been proposed to increase the susceptibility of C. albicans to FLC in order to cope with treatment failures, among which is the combination of FLC with different classes of non-antifungal agents such as antibacterials, calcineurin inhibitors, heat shock protein 90 inhibitors, calcium homeostasis regulators and traditional Chinese medicine drugs. Interestingly, many of these combinations showed synergistic effects against C. albicans, especially resistant strains. The main mechanisms of these synergistic effects appear to be increasing the permeability of the membrane, reducing the efflux of antifungal drugs, interfering with intracellular ion homeostasis, inhibiting the activity of proteins and enzymes required for fungal survival, and inhibiting biofilm formation. These modes of action and the antifungal mechanisms of various compounds referenced in this paper highlight the idea that the reversal of fungal resistance can be achieved through various mechanisms. Studies examining drug interactions will hopefully provide new approaches against antifungal drug resistance as well as insight into antifungal agent discovery.

Evaluation of antifungal susceptibility testing in Candida isolates by Candifast and disk-diffusion method.

With the increase in invasive fungal infections due to Candida species and resistance to antifungal therapy, in vitro antifungal susceptibility testing is becoming an important part of clinical microbiology laboratories. Along with broth microdilution and disk diffusion method, various commercial methods are being increasingly used for antifungal susceptibility testing, especially in the developed world. In our study, we compared the antifungal susceptibility patterns of 39 isolates of Candida to three antifungal drugs (fluconazole, amphotericin B, ketoconazole) by Candifast and disk diffusion method. The following resistance pattern was found by Candifast: Fluconazole (30.8%), ketoconazole (12.8%), amphotericin B (0%). The results obtained by disk diffusion method were in complete agreement with Candifast results.

Role of enteric supplementation of probiotics on late-onset sepsis by candida species in preterm low birth weight neonates: A randomized, double blind, placebo-controlled trial

Background:The increase in invasive fungal infections (IFIs) in neonatal intensive care unit (NICU) is jeopardizing the survival of preterm neonates. Probiotics modulating the intestinal microflora of preterm neonates may minimize enteral fungal colonization.Aims:This study was to examine whether probiotic supplementation in neonates reduced fungal septicemia.Materials and Methods:This prospective, randomized, double blind trial investigating the supplementation of preterm infants with a probiotic was done from May 2012 to April 2013, with 112 subjects randomized into two groups. Primary outcome: Decreased fungal colonization in gastrointestinal tract. Others: Incidence of late onset septicemia; duration of the primary hospital admission; number of days until full enteral feeds established.Results:Full feed establishment was earlier in probiotics group compared to placebo group (P = 0.016). The duration of hospitalization was less in the probiotic group (P = 0.002). Stool fungal colonization, an important outcome parameter was 3.03 ± 2.33 × 105 colony formation units (CFU) in the probiotics group compared to 3 ± 1.5 × 105 CFU in the placebo group (P = 0.03). Fungal infection is less in the study group (P = 0.001).Conclusion:The key features of our study were reduced enteral fungal colonization, reduce invasive fungal sepsis, earlier establishment of full enteral feeds, and reduced duration of hospital stay in the probiotics group.

Fungal Infections in the Elderly

Fungi are increasingly recognised as major pathogens in critically ill patients. Several reasons have been proposed for the increase in invasive fungal infections, including the use of antineoplastic and immunosuppressive agents, broad-spectrum antibiotics, and prosthetic devices and grafts, and more aggressive surgery. Patients with burns, neutropenia, HIV infection and pancreatitis are also predisposed to fungal infection Candidiasis is caused by infection with species of the genus Candida, predominantly with Candida albicans. Candida species are ubiquitous fungi that represent the most common fungal pathogens that affect humans. The growing problem of mucosal and systemic candidiasis reflects the enormous increase in the number of patients at risk and the increased opportunity that exists for Candida species to invade tissues normally resistant to invasion.

Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant‐Associated Infection Surveillance Network (TRANSNET)

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Impact of antifungal resistance in Australia

The last two to three decades have seen a major increase in invasive fungal infections (IFIs), a small, but increasing proportion of which are caused by pathogens with partial or complete resistance to antifungal drugs. The increase in IFIs has largely been associated with the increase in immunocompromised and critically ill patients. Opportunistic infections with relatively drug-resistant environmental fungi account for much of the resistance. In addition, amongst the only fungal species to colonise humans, Candida, two species that are resistant (C. krusei) or relatively resistant (C. glabrata) to fluconazole have emerged. In part this is explained by the selection pressure exerted by widespread use of fluconazole. Together with the introduction of new antifungal drugs with selective and/or variable antifungal activity, these changes have stimulated interest in understanding mechanisms and origins of resistance, the identification of resistance in the laboratory and its relationship to clinical outcomes, and in surveillance of clinical isolates and populations at risk of IFIs.

Invasive fungal infections: a review of epidemiology and management options

Fungi are increasingly recognised as major pathogens in critically ill patients. Candida spp. and Cryptococcus spp. are the yeasts most frequently isolated in clinical practice. The most frequent filamentous fungi (moulds) isolated are Aspergillus spp., but Fusarium spp., Scedosporium spp., Penicillium spp., and Zygomycetes are increasingly seen. Several reasons have been proposed for the increase in invasive fungal infections, including the use of antineoplastic and immunosuppressive agents, broad-spectrum antibiotics, and prosthetic devices and grafts, and more aggressive surgery. Patients with burns, neutropenia, HIV infection and pancreatitis are also predisposed to fungal infection. The epidemiology and clinical features of fungal infections are reviewed, together with antifungal agents currently or soon to be available.

Laboratory Diagnosis and Therapy of Invasive Fungal Infections

Diagnosing fungal infections remains a problem, particularly in the immunocompromised patient. Symptoms are mostly non-specific and colonization is difficult to distinguish from invasive disease. Existing diagnostic tools often lack sensitivity. Thus, the combination of various diagnostic tools is mandatory to allow earlier diagnosis of systemic fungal infections. Microscopy, culture based methods, antigen detection, and PCR may help to facilitate and accelerate the diagnosis. Galactomannan and glucan are two promising antigens that may be useful for early detection of the infection, but also for therapeutic monitoring. Sensitive and specific PCR assays to detect fungal DNA are an important part of the diagnostic approach. But extensive validation and standardization is strongly needed, before PCR assays can be used in a routine laboratory. The tremendous increase in invasive fungal infections has led to an increased interest in new antifungal agents and the field of antifungal chemotherapy evolved even more rapidly than diagnostic assays. The development of less toxic formulations of amphotericin B, the introduction of improved azoles and the availability of the echinocandins are opening new opportunities for the treatment of fungal infections. However, continuing efforts in the laboratory and well-designed clinical trials are still needed.

New antifungal agents.

With the relentless increase in invasive fungal infections, particularly in critically ill and immunocompromised patients, it is good to know that there are new additions to the antifungal armamentarium. These include not only new formulations of existing drugs and the development of new triazole agents, but also the introduction of a new class of antifungal drug.