Cyclopalladated Complexes With Functionalized Diphosphanes as Promising Antifungal Scaffolds.

The high mortality rate of invasive fungal infections and quick emergence of drug-resistant fungal pathogens urgently call for potent antifungal agents. Inspired by the cell penetrating peptide (CPP) octaarginine (R8), we elongated to 28 residues poly(d,l-homoarginine) to obtain potent toxicity against both fungi and mammalian cells. Further incorporation of glutamic acid residues shields positive charge density and introduces partial zwitterions in the obtained optimal peptide polymer that displays potent antifungal activity against drug-resistant fungi superior to antifungal drugs, excellent stability upon heating and UV exposure, negligible in vitro and in vivo toxicity, and strong therapeutic effects in treating invasive fungal infections. Moreover, the peptide polymer is insusceptible to antifungal resistance owing to the unique CPP-related antifungal mechanism of fungal membrane penetration followed by disruption of organelles within fungal cells. All these merits imply the effectiveness of our strategy to develop promising antifungal agents.

Cost-Effectiveness of Antifungal Strategies in High-Risk Neutropenic Patients

Cost-Effectiveness of Antifungal Strategies in High-Risk Neutropenic Patients.

BackgroundAllogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are exposed to an increased risk of invasive fungal infections (IFIs) due to neutropenia, immunosuppressive treatments, graft-versus-host disease (GvHD) and incomplete immune reconstitution. Although clinical benefit from antifungal prophylaxis has been demonstrated, IFIs remain a leading cause of morbidity and mortality in these patients. In the last decades, attention has also been focused on potential risk factors for IFI to tailor an antifungal prevention strategy based on risk stratification.Aim of the StudyThis retrospective single-center study aimed to assess the epidemiology and the prognostic factors of IFI in a large cohort of allo-HSCT patients.MethodsBetween January 2004 and December 2020, 563 patients with hematological malignancies received an allo-HSCT at the Stem Cell Transplant Unit in Turin: 191 patients (34%) received grafts from a matched sibling donor, 284 (50.5%) from a matched unrelated donor, and 87 (15.5%) from an haploidentical family member. The graft source was peripheral blood in 81.5% of the patients. Our policy for antifungal prophylaxis included fluconazole in matched related and unrelated donors, while micafungin was administered in patients receiving haploidentical transplant. According to this practice, fluconazole was administered in 441 patients (79.6%) and micafungin in 62 (11.2%), while only 9 patients received mold-active prophylaxis. Galactomannan testing was routinely performed twice a week; patients with persisting fever unresponsive to broad spectrum antibiotics were evaluated with lung high-resolution computed tomography (HRCT) scan. In case of imaging suggestive of IFI, bronchoalveolar lavage (BAL) was performed whenever feasible.Statistical AnalysisOnly probable/proven IFI (PP-IFI) occurring during the first 12 months after transplant have been evaluated. IFIs were classified as probable or proven according to the new revised European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) consensus criteria. Multivariate competing risk regression, binary logistic, and proportional hazard models were performed to identify risk factors for PP-IFI.ResultsA total of 58 PP-IFIs (n = 47 probable; n = 11 proven) occurred in our patients resulting in a cumulative incidence of 4.1%, 8.1%, and 9.6% at 30, 180, and 365 days, respectively. Molds were the predominant agents (n = 50 Aspergillus; n = 1 Mucor), followed by invasive candidemia (n = 5 non-albicans Candida; n = 1 Candida albicans; n = 1 Trichosporon). Lung was the most frequent site involved in patients with mold infections (47/51, 92.2%). Median time from HSCT to IFI was 98.44 days (0–365 days). Only 34.5% of patients with IFI were neutropenic at the time of infection. The presence of IFI had a significant impact on overall survival at 1 year (IFI, 32.8% vs. non-IFI, 54.6%; p < 0.001). IFI-related mortality rate was 20.7% in the overall population, 17% in patients with probable IFI, and 36% in patients with proven IFI. Multivariate competing risk regression revealed that donor type was the factor significantly associated to the risk of IFI [subdistribution hazard ratio (SDHR), 1.91, IC 1.13–3.20; p = 0.015]. BAL was informative in a consistent number of cases (36/57, 63.2%) leading to the identification of fungal (21), bacterial (4), viral (3), and polymicrobial (8) infections. Overall, 79 patients (14%) received a diagnostic-driven treatment, and 63 patients (11.2%) received a fever-driven treatment. Liposomal amphoteric B was the drug used in the majority of patients receiving diagnostic-driven therapy (30/79, 38%), while caspofungin was administered more frequently in patients who received a fever-driven strategy (27/63, 42.9%).ConclusionAccording to our experience, a non-mold active prophylaxis in patients undergoing allo-HSCT is feasible when combined with an intensive diagnostic work-up including CT scan and BAL. BAL performed at the onset of the disease may provide informative results in most patients. A diagnostic-driven treatment strategy may contribute to limit the use of costly antifungal therapies.

BackgroundThe incidence of invasive fungal infections (IFI) and antifungal utilization is increasing in many healthcare settings. Little is known regarding antifungal stewardship strategies within broader antimicrobial stewardship programs (ASPs). This survey aimed to identify the use of antifungal stewardship at a diverse range of hospitals.MethodsA cross-sectional electronic survey of the SHEA Research Network (SRN) was completed August–September 2018 by a physician or pharmacist ASP leader. The SRN is a consortium of >100 hospitals participating in multicenter healthcare epidemiology research projects. Survey questions pertained to various aspects of antifungal stewardship, including audit and feedback, laboratory testing, and surveillance. Chi-square tested associations between ASP and hospital characteristics and use of antifungal stewardship strategies.Results45/111 (41%) facilities responded, including 10 international sites. Most facilities are academic medical centers (64.6%) and care for stem cell (73.3%) and solid-organ transplant (80.0%) patients. Most facilities have large, well established ASPs (60.0% > 5 members; 68.9% duration ≥6 years). 43 (95.6%) facilities use antifungal stewardship strategies in their ASP; most commonly prospective audit and feedback (33/43, 73.3%) performed by a pharmacist (23/33, 71.4%). Only half of ASPs (51.1%) create guidelines for IFI management. Most (71.1%) facilities offer rapid laboratory tests to diagnose IFI, but availability of PCR for fungal speciation and antifungal susceptibility testing varies (Figure 1). 29 ASPs (64.4%) perform surveillance of antifungal utilization, but only 9 (31.0%) report data to CDC’s National Healthcare Safety Network (NHSN). ASP size, ASP duration, and presence of transplant populations were not associated with a higher likelihood of using antifungal stewardship strategies (P > 0.05 for all).ConclusionUse of antifungal stewardship strategies is high at SRN hospitals, but mainly involves audit and feedback. ASPs should be encouraged to disseminate guidelines for IFI management, to promote access to laboratory-based tests for rapid and accurate IFI diagnosis, and to perform surveillance for antifungal utilization with data reporting to NHSN.DisclosuresAll authors: No reported disclosures.

A nonsymmetric phosphorus ylide and its palladium(II) complex have been synthesized as potential catalytically active compounds. The reaction of 1 equiv nonsymmetric phosphorus ylide, Ph2PCH2PPh2C(H)C(O)PhBr with [Pd(dppe)Cl2], followed by treatment with 2 equiv AgOTf led to [(dppe)Pd(Ph2PCH2PPh2C(H)C(O)PhBr)](OSO2CF3)2, which contains a five-membered P,P chelate ring on one side and a five-membered P,C chelate ring on the other side. The palladium complex was synthesized and investigated by fourier transform infrared spectroscopy (FT-IR), UV–visible, multinuclear (1H, 31P and 19F) nuclear magnetic resonance (NMR), and electrospray ionisation-mass spectroscopic techniques. FT-IR and 31P NMR studies revealed that the phosphorus ylide is coordinated to palladium via the terminal phosphorus (Pc) of the ylide and methene group (CH). Suzuki reactions for varying aryl halides using the cyclopalladated complex as an efficient catalyst were performed. Various aryl halides were coupled with arylboronic acids in DMF, under air, in the presence of 0.001 mol% of the homogeneous catalyst to afford the corresponding cross-coupled products in good to excellent yields.

To characterize antifungal stewardship among antimicrobial stewardship programs (ASPs) at a diverse range of hospitals and to correlate antifungal stewardship with hospital characteristics. Cross-sectional survey. ASP physician and/or pharmacist members at Society for Healthcare Epidemiology of America (SHEA) Research Network (SRN) hospitals. An electronic survey administered August-September 2018 via the SRN to 111 hospitals. The χ2 test was used to test associations between ASP and hospital characteristics and use of antifungal stewardship strategies. Of 111 hospitals, 45 (41%) responded; most were academic medical centers (65%) caring for stem-cell patients (73.3%) and solid-organ transplant patients (80.0%). Most hospitals have large, well-established ASPs: 60% had >5 team members and 68.9% had a duration ≥6 years. In 43 hospitals (95.6%), ASPs used antifungal stewardship strategies, most commonly prospective audit and feedback (73.3%) by a pharmacist (71.4%). Half of ASPs (51.1%) created guidelines for invasive fungal infection (IFI) management. Most hospitals (71.1%) offered rapid laboratory tests to diagnose IFI, but polymerase chain reaction (PCR) testing and antifungal susceptibility testing varied. Also, 29 ASPs (64.4%) perform surveillance of antifungal utilization, but only 9 (31%) reported to the CDC National Healthcare Safety Network. ASP size, duration, and presence of transplant populations were not associated with a higher likelihood of using antifungal stewardship strategies (P > .05 for all). The use of antifungal stewardship strategies was high at SRN hospitals, but they mainly involved audit and feedback. ASPs should be encouraged (1) to disseminate guidelines for IFI management, (2) to promote access to laboratory tests for rapid and accurate IFI diagnosis, and (3) to perform surveillance for antifungal utilization with reporting to the CDC.

The practice of hematopoietic stem cell transplantation (HSCT) has undergone many changes that affect the likelihood that a given patient would develop an invasive fungal infection (IFI). The risks for IFI and the types of IFI that may occur are not continuous over the time course after transplantation. IFIs vary with the events that occur during the pre-engraftment neutropenic period, the early post-engraftment period until approximately day 100 post-transplant, and those in the late post-engraftment period after day 100. A number of well-recognized transplant recipient-, transplant procedure-, and transplant complication-related factors play a role in the likelihood of IFI. Important recipient-related factors include age, state of the underlying disease for which the HSCT is being done, and treatment-related history. Transplant procedure-related factors include the type of transplant (autologous or allogeneic), the use of and timing of anti-fungal prevention strategies including whether or not the transplant was conducted in a protected environment to minimize environmental exposure to mould conidia, the choice of conditioning (myeloablative or non-myeloablative), human leucocyte antigen-relatedness [autologous, matched related, mismatched related (including haploidentical pairings), unrelated (matched or mismatched)], stem cell source (bone marrow, peripheral, or cord blood), stem cell dosing, and stem cell product processing (red cell, plasma, or T-lymphocyte depletions, or CD34 selections). Transplant-related complications include duration of pre-engraftment period of neutropenia, graft failure or rejection, the degree of cytotoxic conditioning therapy-related intestinal mucosal damage, acute and chronic graft-versus-host disease (GvHD), the use of corticosteroids for the prevention or management of GvHD, the presence of cytomegalovirus infection and disease. The interaction of these factors over a given patient's journey through HSCT conspires to promote or reduce the overall IFI risk and set the conditions for the development of any given IFI. The following discussion attempts to look at this from the perspective of the transplant physician struggling to account for these interactions and their attendant risks for IFI.

Patients with hematological malignancies are severely immunocompromised and are at high risk of invasive fungal infection (IFI), particularly those undergoing remission-induction chemotherapy for acute myeloid leukemia (AML). IFIs are a major cause of morbidity and mortality in such patients. We planned to study the incidence of IFI in patients with AML undergoing intensive chemotherapy and receiving antifungal prophylaxis. We retrospectively reviewed consecutive 46 patients with non-M3 AML, who received induction chemotherapy and systemic antifungal prophylaxis. None of the patients had IFI at the time of initiation of the chemotherapy. Patients were monitored for the occurrence of IFI using high-resolution computerized tomography of the chest or para-nasal sinus and test for galactomannan antigen on serum or broncho-alveolar lavage and were followed up for 90days. Of the 46 patients on intensive chemotherapies, 41, 4 and 1 patients were started on posaconazole, amphotericin B and voriconazole prophylaxis, respectively. The occurrence of possible and probable IFI was observed in 16 and 4 patients respectively, in which 19 patients were on posaconazole and 1 patient was on amphotericin-B prophylaxis. Overall mortality in the study population was 11 (23.9%). Four out of 20 patients died with IFI but none of the death was attributable to IFI. IFI still remains a significant cause of morbidity and mortality in patients with AML despite universal use of antifungal prophylaxis. With effective pharmacotherapy, the mortality due to IFI is preventable. Appropriate antifungal prophylaxis strategy still needs to be developed through larger and prospective studies.

Invasive fungal infections (IFIs) pose significant challenges in clinical settings, particularly due to their high morbidity and mortality rates. The rising incidence of these infections, coupled with increasing antifungal resistance, underscores the urgent need for novel therapeutic strategies. Current antifungal drugs target the fungal cell membrane, cell wall, or intracellular components, but resistance mechanisms such as altered drug-target interactions, enhanced efflux, and adaptive cellular responses have diminished their efficacy. Recent research has highlighted the potential of dual inhibitors that simultaneously target multiple pathways or enzymes involved in fungal growth and survival. Combining pharmacophores, such as lanosterol 14α-demethylase (CYP51), heat shock protein 90 (HSP90), histone deacetylase (HDAC), and squalene epoxidase (SE) inhibitors, has led to the development of compounds with enhanced antifungal activity and reduced resistance. This dual-target approach, along with novel chemical scaffolds, not only represents a promising strategy for combating antifungal resistance but is also being utilized in the development of anticancer agents. This review explores the development of new antifungal agents that employ mono-, dual-, or multi-target strategies to combat IFIs. We discuss emerging antifungal targets, resistance mechanisms, and innovative therapeutic approaches that offer hope in managing these challenging infections.

6579 Background: The epidemiology and outcomes of invasive fungal infections (IFI) in patients with acute myelogenous leukemia (AML) have been poorly described. Methods: We performed a single center, retrospective analysis of the epidemiology, risk factors and clinical outcomes of IFIs in newly-diagnosed AML patients undergoing intensive, multi-agent induction timed sequential therapy (TST). Patients did not receive antifungal prophylaxis. IFIs were defined using EORTC/MSG criteria. Results: Of 97 consecutive patients (58% male; median age 53, range 22-72) admitted in 2007 and 2008, 27 (28%) had IFI, of which 7 (26%) were proven, 1 (4%) probable, and 17 (68%) possible with lung CT findings characteristic of fungal (mold) pneumonia. Of 8 proven/probable cases, 4 were due to molds and 4 were due to yeasts. Of 91 (94%) receiving antifungal therapy beginning median day 7 (range day -14 through day 25) of AML treatment; 41 (42%) received monotherapy (66% liposomal amphotericin B, 34% voriconazole) and the rest received multiple antifungals. Using univariate analysis, we identified risk factors for IFIs (Table 1). Occurrence of IFI was associated with lower complete remission rate (52% vs. 70% -IFI, p=0.06) and a decrease in 6 month survival (58% vs. 85% -IFI, p=0.01). Conclusions: AML patients with IFIs are more likely to die within 6 months of beginning intensive induction TST. Through this analysis, we are able to identify risk factors that may be associated with development of IFIs. Such identification may help to develop effective preventive antifungal strategies for high risk AML patients. Risk factors for + IFI cohort (overall), and for IFIs due to yeasts and molds No IFI (N=70) IFI (N=27) P- value IFI- yeasts (N=4) P-value IFI-moulds (N=23) P-value Age > 50 years (%) 49 70 0.07 75 NS 70 0.09 Presenting blast count > 10,000 (%) 26 44 0.09 50 NS 43 0.12 Time to ANC < 100 cells/mm3* 7 5 0.08 4 0.16 5 0.16 Time to recovery of ANC >100 cells/mm3* 22.5 26 0.07 25 NS 27 0.12 Onset of mucositis** 14 11.5 0.03 8.5 0.14 12 0.06 Duration of parenteral nutrition* 10 15 0.04 15 NS 14.5 0.07 NS: Non significant, ANC: Absolute neutrophil count. * Median Days of AML therapy (begins on Day 1) No significant financial relationships to disclose.

Invasive fungal infections cause over 3.7 million deaths worldwide annually, underscoring the critical need for new antifungal agents. Developing selective antifungal agents is challenging due to the shared eukaryotic nature of both fungal and mammalian cells. Toward addressing this, synthetic polymers designed to mimic host defense peptides are promising new candidates for combating fungal infections. This study investigates well-defined multiblock terpolymers with specific arrangements of cationic, hydrophobic, and hydrophilic groups, as potential antifungal agents. The block sequence in these copolymers significantly impacts their minimum inhibition concentration (MIC) against Candida albicans and biocompatibility. Furthermore, compared to their statistical counterparts, these block polymers exhibit lower MIC values in certain instances. Notably, triblock terpolymers containing a central hydrophobic block present an enhanced antifungal efficacy and biocompatibility. These findings highlight the potential of block sequence-controlled polymers as a versatile platform for developing customized and targeted antifungal therapies.

Immunotherapy for Invasive Fungal Infections in Transplant Patients: Back to the Future?

Invasive Fungal Infections in Adults with Newly Diagnosed AML Undergoing Intensive Chemotherapy: Characterization, Risk Factors, and Outcomes in a Single Institution

PIN55 - Economic Analysis of Empiric Versus Diagnostic-Driven Strategies for Immunocompromised Patients With Suspected Aspergillus Invasive Fungal Infections In China