Mold-active Triazoles Research Articles

Invasive fusariosis in patients with leukaemia in the era of mould-active azoles: increasing incidence, frequent breakthrough infections and lack of improved outcomes.

Historically, patients with leukaemia and invasive fusariosis (IF) have experienced poor outcomes in the setting of persistent immunosuppression. Herein, we retrospectively reviewed the incidence, presentation and outcomes of IF that are scarcely studied in contemporary cohorts of leukaemia patients. We identified adult leukaemia patients with proven or probable IF at MD Anderson Cancer Center during 2009-21. Independent risk factors for 42 day mortality after IF diagnosis were determined using a multivariable logistic regression model. Combined with historical data, the annual IF incidence density over the past 23 years was estimated using Poisson regression analysis. Among 140 leukaemia patients with IF (114 proven), 118 patients (84%) had relapsed/refractory leukaemia and 124 (89%) had neutropenia at IF diagnosis. One hundred patients (71%) had pulmonary IF, 88 (63%) had disseminated IF and 48 (34%) had fungaemia. Coinfections were common (55%). Eighty-nine patients (64%) had breakthrough IF to mould-active triazoles. Most patients (84%) received combination antifungal therapy. Neutrophil recovery [adjusted OR (aOR), 0.04; 95% CI, 0.01-0.14; P < 0.0001], pulmonary IF (aOR, 3.28; 95% CI, 1.11-9.70; P = 0.032) and high SOFA score (aOR, 1.91 per 1-point increase; 95% CI, 1.47-2.50; P < 0.0001) were independent predictors of 42 day mortality outcomes. From 1998 to 2021, IF incidence density increased significantly at an annual ratio of 1.03 (95% CI, 1.01-1.06; P = 0.04). IF is predominantly seen in patients with relapsed/refractory leukaemia and increasingly seen as a breakthrough infection to mould-active triazoles. Despite frequent combination antifungal therapy, high mortality rates have persisted in patients with lasting neutropenia.

Real-world Use of Mold-Active Triazole Prophylaxis in the Prevention of Invasive Fungal Diseases: Results From a Subgroup Analysis of a Multicenter National Registry.

Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs. This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs). A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 voriconazole, and 252 multiple/sequenced MATs at/after index/enrollment) were included in the prophylaxis subgroup analysis. Patient characteristics were similar across MAT groups, but risk factors varied. Hematological malignancy predominated (76.5%) across all groups. Breakthrough IFDs occurred in 7.1% (73/1030) of patients with an investigator's assessment (5.0% [11/221] isavuconazole; 5.3% [20/374] posaconazole; 4.0% [9/226] voriconazole; and 15.8% [33/209] multiple/sequenced MATs). Aspergillus (29.5% [18/61]) and Candida (36.1% [22/61]) species were the most common breakthrough pathogens recovered. ADRs were reported in 14.1% of patients, and discontinuation of MATs due to ADRs was reported in 11.1% of patients (2.0% [5/245] isavuconazole; 8.2% [30/368] posaconazole; and 10.1% [27/267] voriconazole). Breakthrough IFDs were uncommon in patients who received MATs for prophylaxis. Candida and Aspergillus species were the most commonly reported breakthrough pathogens. The discontinuation of MATs due to ADRs was infrequent. These findings support prophylactic strategies with isavuconazole, posaconazole, and voriconazole in high-risk patients.

2114. Invasive fusariosis in the era of mold active azoles and molecular targeted chemotherapy: Increasing incidence and lack of improved outcomes

Abstract Background Invasive fusariosis (IF) is an uncommon opportunistic mold infection primarily affecting patients (pts) with leukemia and allogeneic hematopoietic cell transplant (HSCT). Historically, IF had poor outcome when there is lack of recovery from immunosuppression. However, IF incidence and outcome in the in the era of new mold-active triazoles and leukemia regimens that incorporate molecularly targeted drugs is unknown. Methods We retrospectively studied the incidence, risk factors, clinical features, and outcome of microbiologically documented IF (revised EORTC/MSG criteria) in pts with leukemia at MD Anderson Cancer Center in the last 12 years (June 2009-October 2021). The independent risk factors for 42-day (d) mortality from IF diagnosis were assessed by a binary multivariable logistic regression model. Annual incidence density (1998-2021) was estimated using Poisson regression analysis. Results Among 140 IF pts (114 proven, 26 probable), 100 (71%) had pneumonia, 88 (63%) disseminated infection, and 32 (23%) sinusitis, with no apparent changes in relative frequency over the years. 124 pts (89%) had neutropenia (ANC &amp;lt; 500) at IF diagnosis, 118 (84%) had relapsed/refractory (R/R) leukemia, and 43 (31%) had prior HSCT. 19% (18/97 pts) of IF pts had positive serum galactomannan and 55% had coinfections. In the last 5 years of the study, 45/58 IF cases (78%) were breakthrough infections to mold active triazoles (12 voriconazole, 25 posaconazole, 8 isavuconazole). 74 (53%) out of the 140 IF pts died by d42. Only 6 pts (9%) had neutrophil recovery at time of death compared to 47 (64%) who survived until day 42 (P &amp;lt; 0.001). Neutrophil recovery (aOR 0.04, 95% CI 0.01-0.14), SOFA score (aOR 1.91 per point, 95% CI 1.47-2.50), and pneumonia (aOR 3.28, 95% CI 1.11-9.70) were independent predictors of 42-d mortality. Since 1998, the incidence density of IF continuously increased (P = 0.006) at an annual ratio of 1.05 (95% CI 1.02-1.07, Figure 1). Figure 1Incidence density of invasive fusariosis (per 100,000 patient-days) in leukemia patients between 1998 and 2021 Conclusion Over the past 23 years, IF incidence has been increasing. IF is predominantly seen in pts with R/R acute leukemia and increasingly seen as a breakthrough infection to mold-active triazoles. Even in contemporary pt cohorts, IF has high mortality in the setting of persistent myelosuppression. Disclosures Russell E. Lewis, PharmD, Air: Advisor/Consultant|Cidara: Advisor/Consultant|F2G: Advisor/Consultant|Gilead: Advisor/Consultant|Merck &amp; Co, Inc: Grant/Research Support|Synexis: Advisor/Consultant Dimiitrios P. Kontoyiannis, MD, ScD, PhD (hon), AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Advisor/Consultant.

868. In Vitro Activity of Isavuconazole and Other Mould-Active Triazoles Against Aspergillus fumigatus With and Without cyp51 Alterations

Abstract Background Azole resistance in Aspergillus fumigatus (AFM) is mainly associated with mutations in cyp51A and its promoter region or its homologue cyp51B. We evaluated the in vitro activity of isavuconazole (ISC), itraconazole (ITC), posaconazole (PSC), and voriconazole (VRC) against 660 AFM collected during 2017–2020. Methods Isolates from Europe (EU), North America (NA), Latin America (LA), and Asia-Pacific (APAC) were identified by MALDI-TOF and/or sequencing and tested by CLSI broth microdilution. CLSI epidemiological cut-off values (ECV) were applied. A PSC ECV of 0.5 mg/L was used. Non-wildtype (NWT) isolates to azoles were screened for alterations in the cyp51 genes using whole genome sequencing. Results Azoles had similar activities against 660 AFM isolates. Overall, AFM displayed WT MIC values to ISC (92.7%), ITC (92.9%), PSC (97.3%), and VRC (96.7%). Only 66 isolates (10.0%) were NWT to 1 or more of the azoles, and 32 harbored one or more alterations in the cyp51 genes. Of these AFM, 29/32 (90.1%) were NWT to ITC, 25/32 (78.1%) NWT to ISC, 17/32 (53.1%) NWT to VRC, and 11/32 (34.4%) NWT to PSC. The most frequent alteration was CYP51A TR34/L98H, carried by 14 EU isolates, all NWT to ISC and ITC. Four isolates from NA carried the alteration I242V in CYP51A (all NWT to ITC; all WT to ISC). One NA isolate carried the CYP51A alteration G448S (NWT to ISC, VRC, and ITC) and one carried A9T (NWT to ISC). A single isolate from APAC carried a CYP51A G138C alteration and was NWT to all 4 triazoles. Multiple alterations in CYP51A were detected in 5 isolates: 4/5 NWT to ISC or ITC, 1/5 NWT to VRC, all WT to PSC. Alterations in CYP51B were noted in 7 isolates; 6/7 carried Q42L, 3 from NA (all NWT to ITC and 2 NWT to ISC), 2 from APAC (all NWT to VRC or ISC), and 1 from EU (NWT to ISC, ITC, and PSC). Among 34 NWT isolates without cyp51 alterations, 32.4% were WT to ISC, 47.1% WT to ITC, 85.3% WT to VRC, and 82.4% WT to PSC. Conclusion The majority of AFM were WT to azoles. Ten different cyp51 alterations were detected in 32/66 NWT isolates. Only EU isolates harboured the environmental alteration TR34/L98H that was associated with a NWT phenotype to ISC and ITC. Alterations in AFM cyp51 can have variable effects on the in vitro activity of the azoles that are best delineated by testing all triazoles. Disclosures Michael A. Pfaller, MD, Pfizer: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), Cidara: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), Cidara: Grant/Research Support|Pfizer: Grant/Research Support.

Lung and gut microbiomes in pulmonary aspergillosis: Exploring adjunctive therapies to combat the disease

Species within the Aspergillus spp. cause a wide range of infections in humans, including invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, and allergic bronchopulmonary aspergillosis, and are associated with high mortality rates. The incidence of pulmonary aspergillosis (PA) is on the rise, and the emergence of triazole-resistant Aspergillus spp. isolates, especially Aspergillus fumigatus, limits the efficacy of mold-active triazoles. Therefore, host-directed and novel adjunctive therapies are required to more effectively combat PA. In this review, we focus on PA from a microbiome perspective. We provide a general overview of the effects of the lung and gut microbiomes on the growth of Aspergillus spp. and host immunity. We highlight the potential of the microbiome as a therapeutic target for PA.

Multicenter Registry of Patients Receiving Systemic Mold-Active Triazoles for the Management of Invasive Fungal Infections.

Introduction‘Real-world’ data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs.MethodsData were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose.ResultsOverall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole).ConclusionsIn this ‘real-world’ study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00661-5.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

Comparison of Mold Active Triazoles as Primary Antifungal Prophylaxis in Patients With Newly Diagnosed Acute Myeloid Leukemia in the Era of Molecularly Targeted Therapies.

Multiple factors influence the choice of primary antifungal prophylaxis (PAP) in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) given the recent incorporation of targeted leukemia therapies into these regimens. We evaluated the incidence and characteristics of breakthrough invasive fungal infections (bIFI) in 277 adult patients with newly diagnosed AML undergoing RIC with high-intensity, or low-intensity venetoclax-containing therapy. Patients receiving posaconazole (PCZ), voriconazole (VCZ), or isavuconazole (ISA) for > 5 days as PAP during RIC were included. Echinocandin use prior to, but not concomitantly with, the PAP azole was allowed. IFI (modified EORTC/MSG criteria) occurring after > 5 days of continuous azole exposure or within 14 days of discontinuation were considered bIFI. Proven or probable bIFI were observed in 11 patients (4%). The incidence of bIFI was 2.9% for PCZ, 4.8% for VCZ, and 5.7% for ISA (P = .55). In total, 161 patients (58%) received echinocandin prophylaxis prior to azole initiation. Neither echinocandin exposure nor chemotherapy intensity impacted bIFI rate. Patients with bIFI had a lower rate of absolute neutrophil count recovery > 1000 cells/µL (64% vs 90%, P = .021) or complete remission (CR; 18% vs 66%, P = .002) after RIC. Thirty-eight patients (14%) discontinued PAP due to toxicity, most often hepatotoxicity. Discontinuation due to hepatotoxicity was similar among azoles (PCZ: 13%; VCZ: 15%; ISA: 13%). The rate of bIFI is low during RIC in patients with newly diagnosed AML receiving any of the mold-active triazoles as PAP. Neutrophil recovery and achievement of CR are important for bIFI risk.

Elderly versus nonelderly patients with invasive fungal infections: species distribution and antifungal resistance, SENTRY antifungal surveillance program 2017-2019

We utilized the SENTRY surveillance database from 2017 through 2019 to address pathogen frequency and antifungal resistance among 4,497 clinical isolates of fungi from patients who were either ≥ 65 years (2,170 isolates) or between 18 and 64 years of age (2,327 isolates). The younger population was more frequently infected with non-Candida yeasts and non-Aspergillus moulds. Candida glabrata was more common in the older age group (P value = 0.02). Resistance to the triazole and echinocandin classes was less common in the elderly population (4.3% and 2.7%, respectively) compared to the younger age group (11.4% and 4.4%, respectively). Resistance to fluconazole in C. parapsilosis (11.4%) was elevated in the older patient group. Decreased susceptibility to the mould-active triazoles among A. fumigatus isolates was greater in the younger age group (7.8%) than the older age group (4.4%). These data emphasize the importance of species identification and antifungal susceptibility testing to guide the treatment of individual patients.

Interaction in vitro of pulmonary surfactant with antifungal agents used for treatment and prevention of invasive aspergillosis.

Optimizing antifungal therapy is important to improve outcomes in severely immunocompromised patients. We analysed the in vitro interaction between pulmonary surfactant and antifungal agents used for management of invasive pulmonary aspergillosis. Amphotericin B formulations, mould-active triazoles and echinocandins were tested in vitro against 24 clinical isolates of different Aspergillus spp. with and without the addition of a commercial porcine surfactant (Curosurf®; Poractant alfa, Nycomed, Austria). The data are presented as MIC or minimum effective concentration (MEC) ranges, as MIC or MEC values that inhibited 90% of the isolates (MIC90 or MEC90) and as geometric mean (GM) MIC or MEC values. For amphotericin B products, addition of surfactant to a final concentration of 10% led to a statistically significant reduction of the GM MIC for all Aspergillus isolates tested after 24 h (0.765 versus 0.552 mg/L; P < 0.05). For the mould-active triazoles, addition of 10% surfactant resulted in a significantly higher GM MIC at 48 h (0.625 versus 0.898 mg/L; P < 0.05). For the echinocandins, the addition of 10% surfactant led to a significantly higher GM MEC after both 24 h (0.409 versus 0.6532 mg/L; P < 0.01) and 48 h (0.527 versus 0.9378 mg/L; P < 0.01). There were no meaningful differences between individual members of the three existing classes of antifungal agents or between the different Aspergillus spp. tested. Using EUCAST methodology, addition of porcine surfactant up to a concentration of 10% had a minor, and presumably non-relevant, impact on the in vitro activity of antifungal agents used in prophylaxis and treatment of invasive pulmonary aspergillosis.

Trends of the Epidemiology of Candidemia in Switzerland: A 15-Year FUNGINOS Survey.

BackgroundThe increasing incidence of candidemia and emergence of drug-resistant Candida species are major concerns worldwide. Long-term surveillance studies are needed.MethodsThe Fungal Infection Network of Switzerland (FUNGINOS) conducted a 15-year (2004–2018), nationwide, epidemiological study of candidemia. Hospital-based incidence of candidemia, Candida species distribution, antifungal susceptibility, and consumption were stratified in 3 periods (2004–2008, 2009–2013, 2014–2018). Population-based incidence over the period 2009–2018 derived from the Swiss Antibiotic Resistance Surveillance System (ANRESIS).ResultsA total of 2273 Candida blood isolates were studied. Population and hospital-based annual incidence of candidemia increased from 2.96 to 4.20/100 000 inhabitants (P = .022) and 0.86 to 0.99/10 000 patient-days (P = .124), respectively. The proportion of Candida albicans decreased significantly from 60% to 53% (P = .0023), whereas Candida glabrata increased from 18% to 27% (P < .0001). Other non-albicans Candida species remained stable. Candida glabrata bloodstream infections occurred predominantly in the age group 18–40 and above 65 years. A higher proportional increase of C glabrata was recorded in wards (18% to 29%, P < .0001) versus intensive care units (19% to 24%, P = .22). According to Clinical and Laboratory Standards Institute, nonsusceptibility to fluconazole in C albicans was observed in 1% of isolates, and anidulafungin and micafungin nonsusceptibility was observed in 2% of C albicans and C glabrata. Fluconazole consumption, the most frequently used antifungal, remained stable, whereas use of mold-active triazoles and echinocandins increased significantly in the last decade (P < .0001).ConclusionsOver the 15-year period, the incidence of candidemia increased. A species shift toward C glabrata was recently observed, concurring with increased consumption of mold-active triazoles.

Antifungal susceptibilities of opportunistic filamentous fungal pathogens from the Asia and Western Pacific Region: data from the SENTRY Antifungal Surveillance Program (2011\u20132019)

Antifungal surveillance is an important tool to monitor the prevalence of uncommon fungal species and increasing antifungal resistance throughout the world, but data comparing results across several different Asian countries are scarce. In this study, 372 invasive molds collected in the Asia-Western Pacific region in 2011–2019 were susceptibility tested for mold-active triazoles (isavuconazole, posaconazole, voriconazole, and itraconazole). The collection includes 318 Aspergillus spp. isolates and 53 non-Aspergillus molds. The MIC values using CLSI methods for isavuconazole versus Aspergillus fumigatus ranged from 0.25 to 2 mg l−1. Isavuconazole, itraconazole, posaconazole, and voriconazole acted similarly against A. fumigatus. The mold-active triazoles exhibited a wildtype phenotype to most of the Aspergillus spp. isolates tested (>94%), but poor activity against Fusarium solani species complex and Lomentospora prolificans. Voriconazole was most active against the Scedosporium spp. and posaconazole was most active against the Mucorales. In summary, isavuconazole displayed excellent activity against most species of Aspergillus and was comparable to other mold-active triazoles against non-Aspergillus molds.

A Collaborative Tale of Diagnosing and Treating Chronic Pulmonary Aspergillosis, from the Perspectives of Clinical Microbiologists, Surgical Pathologists, and Infectious Disease Clinicians.

Chronic pulmonary aspergillosis (CPA) refers to a spectrum of Aspergillus-mediated disease that is associated with high morbidity and mortality, with its true prevalence vastly underestimated. The diagnosis of CPA includes characteristic radiographical findings in conjunction with persistent and systemic symptoms present for at least three months, and evidence of Aspergillus infection. Traditionally, Aspergillus infection has been confirmed through histopathology and microbiological studies, including fungal culture and serology, but these methodologies have limitations that are discussed in this review. The treatment of CPA requires an individualized approach and consideration of both medical and surgical options. Most Aspergillus species are considered susceptible to mold-active triazoles, echinocandins, and amphotericin B; however, antifungal resistance is emerging and well documented, demonstrating the need for novel therapies and antifungal susceptibility testing that correlates with clinical response. Here, we describe the clinical presentation, diagnosis, and treatment of CPA, with an emphasis on the strengths and pitfalls of diagnostic and treatment approaches, as well as future directions, including whole genome sequencing and metagenomic sequencing. The advancement of molecular technology enables rapid and precise species level identification, and the determination of molecular mechanisms of resistance, bridging the clinical infectious disease, anatomical pathology, microbiology, and molecular biology disciplines.

Pulmonary infections in the hematopoietic cell transplant patient.

Despite progress in the management of pulmonary infections in the hematopoietic cell transplant (HCT) population, substantial diagnostic, and therapeutic uncertainty remains. A growing HCT population reflects more transplants and improved long-term survival. We continue to learn about the epidemiologic and prognostic significance of posttransplant pulmonary infections. Mold-active triazoles have removed invasive fungal pneumonia as a barrier to transplant eligibility. Ibrutinib and respiratory viruses are newly recognized risk factors for invasive fungal disease. Prophylaxis has elevated concerns of resistance in invasive fungal species and late onset Cytomegalovirus. The impact of human herpesviruses, community-associated respiratory viruses, and the microbiome is increasingly appreciated. Multiple antiviral therapies are currently in clinical trials and novel molecular diagnostics may improve the performance of bronchoscopy for infectious causes. Fungal and viral pneumonias remain an important cause of morbidity and mortality in the HCT population. Despite our increased understanding of the epidemiology and outcomes of species-specific diagnoses, the utility of invasive diagnostic testing continues to be debated and effective therapies for many clinically relevant pathogens remain limited. Pulmonary infections are a priority for research efforts in this immunocompromised population.

2252. Patient Preferences for Triazole Antifungals in the Treatment of Invasive Mold Infection: A Discrete Choice Experiment

BackgroundInvasive mold infections (IMIs) are an increasing cause of morbidity and mortality worldwide.1 Pharmacological differences among the currently available mold-active triazoles make treatment selection complex.1 To the best of our knowledge, this is the first study to assess patient preferences for mold-active triazoles in IMI treatment.MethodsPatients were included if they were aged ≥ 18 years with investigator-confirmed invasive aspergillosis or invasive mucormycosis; had received voriconazole, isavuconazonium sulfate or posaconazole within ≤ 1 week previously; and were outpatients for ≥ 3 weeks. Participants were presented with 14 choice cards, each with two hypothetical treatments with varying levels of attributes, and asked to select their preferred treatment. Preference weights for attribute levels were analyzed using conditional logit regression and used to calculate the impact of changes in attribute levels on patient choices; relative attribute importance (RAI); and patient willingness to pay (WTP; monthly out-of-pocket cost) for an attribute improvement.ResultsOf 50 participants, 52% were female and the mean age was 47.3 years; 40%, 40%, and 28% had used posaconazole, voriconazole and isavuconazonium sulfate, respectively (Figure 1). Route of administration (27% RAI), treatment duration (22% RAI), and chance of symptom relief after treatment (20% RAI) were the most important attributes for patients (Figure 2). The odds ratios for patients choosing oral suspension or tablets/capsules over IV infusion were 5.6 and 4.5, respectively (P < 0.001) (Figure 3); patients were willing to pay an additional $205/month or $180/month out of pocket for these respective routes of administration over IV (Figure 4). The odds ratio for patients choosing a 30-day over a 90-day treatment were 4.1 (P < 0.001) (Figure 3); this decrease in duration was valued by patients at $168/month (Figure 4). For a 50% vs. 30% chance of symptom relief, the odds ratio was 3.5 (P < 0.001) (Figure 3) and WTP was $147.89/month (Figure 4).ConclusionPatients considered route of administration, treatment duration and chance of symptom relief to be the most important IMI treatment attributes among mold-active triazoles. 1Jenks JD et al. (2019) Med Mycol 57:S168–S178 Disclosures All authors: No reported disclosures.

In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017.

Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hard-to-treat molds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC50, 0.008 μg/ml; MIC90, 0.06 μg/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, APX001A (MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC50], 0.015 μg/ml; MEC90, 0.03 μg/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 μg/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

Broad spectrum triazoles for invasive mould infections in adults: Which drug and when?

Invasive mould infections are an increasing cause of morbidity and mortality globally, mainly due to increasing numbers of immunocompromised individuals at risk for fungal infections. The introduction of broad spectrum triazoles, which are much better tolerated compared to conventional amphotericin B formulations, has increased survival, particularly in invasive mould infection. However, early initiation of appropriate antifungal treatment remains a major predictor of outcome in invasive mould infection, but despite significant advances in diagnosis of these diseases, early diagnosis remains a challenge. As a result, prophylaxis with mould-active triazoles is widely used for those patients at highest risk for invasive mould infection, including patients with prolonged neutropenia after induction chemotherapy for acute myeloid leukemia and patients with graft-versus-host-disease. Posaconazole is the recommended drug of choice for antimould prophylaxis in these high-risk patients. Voriconazole has its primary role in treatment of invasive aspergillosis but not in prophylaxis. Recently, isavuconazole has been introduced as an excellent alternative to voriconazole for primary treatment of invasive aspergillosis in patients with hematological malignancies. Compared to voriconazole, isavuconazole and posaconazole have broader activity against moulds and are therefore also an option for treatment of mucormycosis in the presence of intolerance or contraindications against liposomal amphotericin B.

Emerging threat of triazole-resistant Aspergillus fumigatus.

Invasive aspergillosis is a leading cause of morbidity and mortality among immunocompromised populations and is predicted to cause more than 200 000 life-threatening infections each year. Aspergillus fumigatus is the most prevalent pathogen isolated from patients with invasive aspergillosis, accounting for more than 60% of all cases. Currently, the only antifungal agents available with consistent activity against A. fumigatus are the mould-active triazoles and amphotericin B, of which the triazoles commonly represent both front-line and salvage therapeutic options. Unfortunately, the treatment of infections caused by A. fumigatus has recently been further complicated by the global emergence of triazole resistance among both clinical and environmental isolates. Mutations in the A. fumigatus sterol-demethylase gene cyp51A, overexpression of cyp51A and overexpression of efflux pump genes are all known to contribute to resistance, yet much of the triazole resistance among A. fumigatus still remains unexplained. Also lacking is clinical experience with therapeutic options for the treatment of triazole-resistant A. fumigatus infections and mortality associated with these infections remains unacceptably high. Thus, further research is greatly needed to both better understand the emerging threat of triazole-resistant A. fumigatus and to develop novel therapeutic strategies to combat these resistant infections.

The use of echinocandins in hospitalized children in the United States.

Echinocandins are used for treatment of invasive candidiasis, but data on their use in children are limited. We sought to describe the epidemiology of echinocandin use in hospitalized children in the United States.We performed a retrospective cohort study of children <18 years of age hospitalized between January 2005 and December 2015 and exposed to ≥1 day of a systemic antifungal agent using the Pediatric Health Information System (PHIS) database. Univariate analyses compared recipients of two echinocandin agents, caspofungin and micafungin. Crude prescribing rates of each antifungal group were calculated across hospitals and per year. The rate of antifungal agent prescribing over time was assessed using two-level mixed-effects negative binomial regression, accounting for variability in prescribing by hospital over time. From 2005 to 2015, fluconazole was prescribed most often (n = 148,859, 74.3%), followed by mould-active triazoles (n = 36,131, 18.0%), amphotericin products (n = 29,008, 14.5%), and echinocandins (n = 28,371, 14.2%). The crude rate of systemic antifungal prescribing decreased across all PHIS hospitals from 36.3 to 33.8 per 1000 admissions during the study period, but echinocandin prescribing increased from 2.2 to 7.2 per 1000 admissions. A mixed effects regression model revealed that echinocandin prescribing increased by 15.1% per year (95% CI 11.2-19.2). Echinocandin administration increased from 6.1% to 21.0% of admissions during which a systemic antifungal agent was given. In conclusion, echinocandin use has increased significantly over time, accounting for an increasing proportion of systemic antifungal prescribing in children.

Implementation of Isavuconazole in a Fluorescence-Based High-Performance Liquid Chromatography Kit Allowing Simultaneous Detection of All Four Currently Licensed Mold-Active Triazoles.

Isavuconazole (ISZ) is a newly available broad-spectrum triazole agent recently approved for the treatment of both invasive aspergillosis and mucormycosis. The aim of this study was to develop a simple and reliable method for therapeutic drug monitoring (TDM) of ISZ in human plasma samples. The method involves using a kit from ChromSystems intended for TDM of itraconazole (ITZ), posaconazole (PSZ), and voriconazole (VRZ) in serum/plasma for sample preparation and high-performance liquid chromatography, using fluorescence detection with emission and excitation wavelengths set to 261 and 366nm, respectively. The assay was linear over the ISZ concentration range of 0.2 to 20.0mg/liter, using a 0.1-ml sample volume. The inter- and intraday coefficients of variation were all below 3.7%, whereas the accuracies ranged from 95.0 to 106.2% and the mean extraction recovery was 91.9%. In addition, the method worked well using four different Vacutainer types, with six different healthy volunteers and under a number of relevant storage conditions. Finally, the ISZ detection could be seamlessly implemented in the TDM kit for VRZ, PSZ, and ITZ, enabling simultaneous detection of all four triazoles. This method proved to be simple, accurate, precise, and well suited for routine analysis work. It has been implemented in our laboratory for the simultaneous quantitative analysis of ISZ, VRZ, PSZ, and ITZ for TDM and pharmacokinetic research. IMPORTANCE Isavuconazole is a new broad-spectrum triazole agent recently approved for the treatment of both invasive aspergillosis and mucormycosis. Currently, there is no consensus regarding the potential need for TDM of isavuconazole, and no therapeutic window has been defined. However, at the ECIL-6 meeting in 2015, it was advised that TDM is indicated in a number of different settings. In this study, we describe a rapid and validated isocratic HPLC method for fluorescence-based detection and quantification of isavuconazole in human plasma/serum samples. The method is simple and efficient with good accuracy and precision and importantly only requires a small volume of patient plasma/serum. Furthermore, this method is highly sensitive and selective and can be detected simultaneously with the three other triazoles, itraconazole, voriconazole, and posaconazole, without the need for expensive mass spectrometry equipment.