Treatment Of Invasive Mold Infections Research Articles

Duration of antifungal treatment in mold infection: when is enough?

Although invasive mold infections (IMI) are a major complication in high-risk populations, treatment duration has not yet been well defined. Guidelines suggest documenting clinical/radiological resolution and immunological recovery before stopping antifungal treatment, after a minimum duration of treatment of 3 months for invasive pulmonary aspergillosis, while longer (up to 6 months) duration is proposed for the treatment of invasive mucormycosis. However, data on and definitions of clinical/radiological resolution and immune recovery remain scarce. Limited real-life data suggest that often much longer courses of treatment are given, generally in the context of continuous immunosuppression, occasionally defined as secondary prophylaxis. However, clearcut definition and distinction of secondary prophylaxis from antifungal treatment remain to be defined. Decisions to stop antifungal treatment are based on poorly defined treatment responses and immune reconstitution and experts' opinions. More evidence is needed to determine the optimal duration of treatment of IMI. Well designed, easy to use, and realistic algorithms to help clinicians decide when to stop antifungal treatment are urgently needed.

483. Use of Terbinafine in Combination with Other Systemic Anti-fungal Agents As Treatment for Invasive Mold Infections. Experience from A National Cancer Institute Designated Cancer Center.

Abstract Background The severely Immunocompromised are at an increased risk of fatal infection caused by invasive molds. Amphotericin B and triazole agents with anti-mold activity are commonly used in treating invasive mold infections. There is some data from in-vitro experiments to suggest an enhanced killing of some molds when terbinafine is used in combination with certain azoles or amphotericin B. At our center, terbinafine is occasionally used in combination with other systemic anti-fungal agents in treating severely immunocompromised patients with invasive mold infections. Methods The study was a retrospective review of electronic medical records. Sixty-four patients treated for culture confirmed infection with mold isolates at the Moffitt Cancer Center from 1/1/2015 to 6/1/2021 were included in this study. There were 2 treatment groups: Group A comprised of those treated with a terbinafine containing regimen and Group B comprised of patients that were not treated with a terbinafine containing regimen. Results Treatment group A: Comprised of 14 patients. Twenty-nine percent (4/14) had skin/soft tissue infections, 21% (3/14) had rhinosinusitis, 21% (3/14) had pulmonary infections and 4 patients (29%) had disseminated infection. Thirty-six percent (5/14) were discharged with treatment response, 57% (8/14) did not respond to treatment or died due to the invasive mold infection and 7% (1/14) died as a result of malignancy. Treatment group B: Had 50 patients. thirty-eight percent (19/50) had pulmonary infections, 28% (14/50) with skin/soft tissue infections, 16% (8/50) had rhinosinusitis, 2% (1/50) were diagnosed with central nervous system infection, 2% (1/50) had gastrointestinal infection, 14% (7/50) had an unclear source of infection. Forty-eight percent (24/50) were discharged with treatment response, 42% (21/50) had treatment failure or died due to the invasive mold infection and 10% (5/50) died as a result of malignancy. Table 1Figure 1 Conclusion There was no statistically significant improvement in outcome observed in this study when terbinafine was used in addition to other systemic anti-fungal medications as treatment of invasive mold infections. There is a need for larger studies to determine if terbinafine has a role in the treatment of invasive mold infections. Disclosures All Authors: No reported disclosures.

2043. In Vitro Activity of Manogepix Against 2,810 Fungal Isolates from the SENTRY Surveillance Program (2020-2021) Stratified by Infection Type

Abstract Background Manogepix is a new antifungal with a novel mechanism of action and potent in vitro activity against Candida (except C. krusei), Aspergillus, and rare mold isolates. The manogepix prodrug fosmanogepix is in Phase 2 development for the treatment of invasive mold infections caused by Aspergillus and rare molds (NCT04240886) and has completed Phase 2 studies for candidemia (NCT03604705) and C. auris (NCT04148287) infections. We evaluated the in vitro activity of manogepix and comparators against 2,810 geographically diverse fungal isolates collected in the SENTRY Surveillance Program during 2020-2021 and stratified them by infection type. Methods Antifungal susceptibility testing of manogepix and comparator agents was conducted according to CLSI M27 (2017) and M38 (2017) guidelines. Fungal surveillance isolates were collected from medical centers located in North America (30 sites; 37.9%), Europe (30 sites; 38.4%), Asia-Pacific (11 sites; 14.7%), and Latin America (6 sites; 9.0%). Infection sites included bloodstream infections (BSI; 48.3%), pneumonia in hospitalized patients (PIHP; 19.9%), skin and skin structure infections (SSSI; 7.8%), urinary tract infections (UTI; 3.1%), intra-abdominal infections (IAI; 1.6%), and other infection types (19.3%). Results Manogepix demonstrated potent in vitro activity against Candida spp. isolates (MIC50/90, 0.004-0.03/0.008-0.06 mg/L) regardless of infection type (Table). Similarly, manogepix was highly active against 534 Aspergillus spp. isolates (MEC50/90, 0.015/0.03 mg/L). Manogepix was active against 53 Cryptococcus neoformans var. grubii (MIC50/90, 0.25/1 mg/L), 19 Fusarium spp. (MEC50/90, 0.015/0.06 mg/L), 12 Lomentospora prolificans (MEC50/90, 0.03/0.06 mg/L), and 17 Scedosporium spp. isolates (MEC50/90, 0.06/0.12 mg/L). Conclusion Manogepix showed potent in vitro activity against Candida spp., Aspergillus spp., C. neoformans var. grubii, and rare molds, including Fusarium spp., L. prolificans, and Scedosporium spp. isolates. Notable activity was also demonstrated by manogepix against C. auris isolates. Further clinical development of fosmanogepix in difficult-to-treat, resistant fungal infections is warranted. Disclosures Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

595. Olorofim (OLO) for treatment of invasive mould infections in patients with limited or no treatment options: PK data from a Phase 2b open-label study (NCT03583164, Study 32)

Abstract Background OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. In preclinical PKPD studies, a plasma level ≥ 0.2 µg/mL was required for efficacy similar to mould-active azoles. Methods Patients in Study 32 (N=100) received OLO (30 mg tablets) guided either by therapeutic drug monitoring (TDM) based on baseline bodyweight and OLO pre-dose plasma levels (180 to 300 mg/day x 1 d to load then 120 to 240 mg/day, given BID or TID as appropriate) or a fixed dose (150 mg BID for 1d then 90 mg BID). For each subject, OLO PK profiles were determined over 1 or 2 dosing intervals, an additional 8 to 9 scheduled pre-dose samples were taken during the initial 84 days and every 1-3 months thereafter. Food intake was not constrained. Results Geometric mean steady-state OLO PK parameters in the 90 evaluable subjects were similar between the TDM and fixed dosing groups (Table). Mean OLO pre-dose concentrations were similar over time for all 100 patients regardless of group and regimen; drug concentration variability was slightly greater when TDM was not utilized (Figure). Pre-dose levels were greater than the Cmin observed over a dosing interval in most subjects (range of pre-dose: Cmin ratio of 1 to 15.8). which may be due to food-triggered release from a deep compartment such as the liver. Exposures exceeding the PD target (≥ 0.2 µg/mL) were consistently achieved. PK parameters predicted by population PK modelling of Phase II data were in reasonable agreement with observed data (Table). Table: OLO Systemic Exposure at Steady-State [median (5th – 95th percentiles)] 1 based on 90 mg BID Conclusion OLO is a novel mechanism oral antifungal with broad-spectrum mould activity. When administered as a fixed dose (90 mg BID), adequate exposure for efficacy against invasive mycoses is achieved, without the need to confirm by TDM Disclosures Karen Cornelissen, PhD, F2G: Employee James G. Wright, PhD, F2G: Advisor/Consultant Andrew Cristinacce, MSc by Research, F2G: Advisor/Consultant Roger Bruggemann, Pharm, PhD, Amplyx: Advisor/Consultant|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant|Mindipharma: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant.

870. Olorofim for the treatment of invasive mould infections in patients with limited or no treatment options: Comparison of interim results from a Phase 2B open-label study with outcomes in historical control populations (NCT03583164, FORMULA-OLS, Study 32)

Abstract Background Olorofim is a novel antifungal agent active against Aspergillus spp (including azole-resistant strains), rare, resistant moulds (e.g., Lomentospora prolificans) and dimorphic moulds. Serial images of Lomentospora prolificans infection following breast enhancement surgery: progression of healing pre- and post-olorofim therapy. Post-surgical bone/ soft tissue Lomentospora prolificans infection of the chest wall in a healthy woman was uncontrolled with available agents (D -9 visible mould in wound base). At D42/84 overall response on olorofim monotherapy was stable; wound closure with complete resolution of IFI was achieved at D322 (case previously reported, ECCMID 2020 abstract #2585). Methods Patients with limited/no treatment options for proven invasive fungal infection (IFI) or probable pulmonary invasive aspergillosis (IA) using EORTC-MSGERC criteria1 received oral olorofim (150mg BID x1d loading dose then 90mg BID). Outcomes in the first 100 patients are compared with historical controls (HCs) as well as with expected outcomes in patients with baseline highly active, uncontrolled IFI (HAU-IFI). Results All-cause mortality in IA at month 3 (includes data to Day 100, the best-fit time point for IA HC data) was 17/53 (32%, 95 CI 20–46%) for olorofim vs. 40/46 (87%, 74–95%) in HCs given either no therapy or azole monotherapy for azole-resistant IA. Successful EORTC-MSGERC overall response2 (OR, complete or partial based on clinical + radiologic + mycologic improvement) was 47%/42% in IA (Day 42/D84, n = 53), 53%/53% (L. prolificans, n=17), 55%/36% (Scedosporium, n=11), and 50%/50% (other moulds, n=8). Stable response at D42/D84 predicted extended therapy responses, especially in HAU-IFI of brain and bone (Figure). For Coccidioides (n=11) OR was limited to stable due to very slow clearance of fungal serology but clinical response was rapid. Symptoms resolved completely in 18% (2/11) by D84 vs 3% (1/29) by D1523 in comparable HCs with poorly controlled extrapulmonary Coccidioides infection; similar trends were seen for other response measures. Conclusion Olorofim is a novel oral antifungal with activity against a wide range of mould infections which are difficult to treat. Compared with relevant HCs or expected outcomes for HAU-IFI, olorofim has a positive benefit-risk profile in a well-defined population of patients with limited/no treatment options. As noted previously3, considering stable in overall success if often appropriate when assessing responses in non-IA mould IFI.

Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections.

Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections.

Unmet needs and practical solutions in the management of invasive mould infections in Asia.

Management of invasive mould infections (IMIs) is challenging in Asia, as awareness among medical practitioners can be low and resources are limited. Timely diagnosis and appropriate treatment of IMIs can mitigate the impact on morbidity and mortality, but diagnostic methods, as well as access to preferred antifungal medications, may vary throughout the region. Knowledge of local epidemiology and accurate diagnosis and identification of causal pathogens would facilitate optimal treatment but data in Asia are lacking. To address these unmet needs in the management of IMIs, this paper is a call for urgent action in the following areas: improving awareness of the threat of IMIs; providing education to frontline clinicians across a broad range of specialties on 'red flags' for suspicion of IMIs; prioritizing cost-effective rapid diagnostic testing; improving access to preferred antifungal medications; and closing the gaps in local epidemiological data on IMIs to inform local treatment guidelines.

In vitro Activity of Isavuconazole and Comparators Against Clinical Isolates of Molds from a Multicenter Study in China.

PurposeMonitoring antifungal susceptibility patterns for new or established antifungals is imperative. Antifungal resistance is frequent in molds, frequently leading to invasive mold infections (IMIs) in immunocompromised patients with high morbidity and mortality. Limited availability of effective antifungals for treatment of IMIs in China is an enormous challenge. The purpose of this study was to monitor in vitro antifungal resistance profiles of mold isolates from China, with a particular focus on evaluating in vitro isavuconazole (ISA) activity against these isolates, contributing to the treatment guidance in clinics.MethodsWe evaluated the in vitro activity of ISA and its comparators (voriconazole [VOR] and amphotericin B [AMB]) against 131 clinical isolates of Aspergillus spp. (n = 105) and Mucorales order (n = 26) collected between 2017 and 2020 from China.ResultsISA and VOR exhibited similar in vitro activity against Aspergillus spp., with minimum inhibitory concentration (MIC)50 of 1 µg/mL and MIC90 of 2 µg/mL, respectively. Overall, AMB was less active than azoles against Aspergillus spp. (MIC50: 4 µg/mL, MIC90: 8 µg/mL). Against the Mucorales order, ISA demonstrated MIC50 of 0.5 µg/mL and MIC90 of 1 µg/mL; however, one strain each of Mucor circinelloides and Syncephalastrum racemosum were resistant to ISA (MICs: >8 µg/mL). VOR exhibited little or no activity (MIC50: 8 µg/mL, MIC90: >8 µg/mL) against the Mucorales order, whereas AMB had MIC50 and MIC90 of 1 µg/mL.ConclusionThis was the first multicenter, in vitro study conducted in China and demonstrated the excellent activities of ISA against most species of the Mucorales order. MIC indicated an advantage over currently available azole antifungals, positioning ISA as a potential alternative to VOR for clinical management of IMIs. As with other antimicrobials, clinicians should employ stewardship and best practices in relation to potential resistance to new azole antifungals.

718. Posaconazole Versus Standard of Care for Treatment of Invasive Mold Infections

Abstract Background Invasive mold infections (IMIs) including Aspergillus spp. are a significant cause of morbidity and mortality in immunocompromised patients. Voriconazole is recommended as first line treatment for primary IA. Liposomal amphotericin B and isavuconazole are also recommended alternative therapies. Posaconazole has activity against mold species including those not covered by voriconazole, is available as an IV and oral formulation with a distinct adverse effect profile making it a potential effective alternative for treatment. This study investigated the clinical outcomes of treatment of invasive mold infections (IMIs) with posaconazole compared to standard of care (voriconazole, isavuconazole, liposomal amphotericin B). Methods A retrospective, single center, cohort study was completed to evaluate patients with IMIs treated with posaconazole versus those treated with standard of care therapy. Medication orders for posaconazole or standard of care therapy between January 2012 and December 2020 were identified from a clinical data repository. Only patients with antifungal orders with a listed indication for “treatment of fungal infection” were included. Data collected for each group included baseline demographics, underlying conditions, site of infection, type of mold, therapeutic drug monitoring and classification of IMI. Results A total of 120 patients met inclusion criteria, with 35 patients in the posaconazole group and 85 patients in the SOC group. Baseline characteristics were similar except for increased severe neutropenia in the posaconazole group (p< 0.0001), more probable IMIs in the SOC group (p=0.009) and more possible IMIs in the posaconazole group (p=0.043). In the posaconazole group 37.1% (13/35) of patients were treatment experienced vs. 29.4% (25/85) of patients in the SOC group. More patients achieved a complete/partial response in the SOC group compared to the posaconazole group (p=0.0001) and more patients experienced treatment failure in the posaconazole group (p=0.01). A higher proportion of patients experienced adverse effects in the SOC group compared to the posaconazole group (p=0.0001). Conclusion Posaconazole was not as effective as SOC in treating invasive mold infections but patients experienced comparatively fewer adverse events. Disclosures All Authors: No reported disclosures

Fungal infections in lung transplantation.

Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3–19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.

Predictors of Early and Late Mortality for Patients with Hematologic Malignancy and Invasive Mold Disease.

Background: Invasive mold infections (IMI) are leading infectious causes of mortality among patients with hematological malignancies. Objectives: To determine the relative contribution of host, disease, and treatment-related factors to patient survival. Methods: An observational, retrospective cohort study reviewing the medical records of patients with hematological malignancy and IMI (2006–2016). Causes of death were classified up to 90 days after diagnosis. Kaplan–Meier and Cox regression analyses were used to determine risk factors for early, late, and overall mortality. Results: Eighty-six patients with IMI were included; 29 (34%) and 41 (47%) died within 6 and 12 weeks of diagnosis, respectively. Death was attributed to IMI in 22 (53.6%) patients, all of whom died within 45 days of diagnosis. Risk factors for early mortality were elevated serum galactomannan, treatment with amphotericin B, IMI progression 3 weeks after diagnosis, and lymphoma undergoing HCT. Late mortality was associated with relapsed/refractory malignancy and elevated serum galactomannan. Conclusions: In this single-center study of patients with IMI, infections were the most frequent causes of death, and time-dependent risk factors for death were identified. These results may help direct risk-assessment and monitoring of patients undergoing treatment of IMI.

Clinical Considerations of Isavuconazole Administration in High-Risk Hematological Patients: A Single-Center 5-Year Experience

BackgroundThere are limited real-life data on isavuconazole prophylaxis and treatment of invasive mold infections (IMI) in hematological patients and allogeneic hematopoietic cell transplant (HCT) recipients.ObjectivesPrimary objective was to describe the indications of real-life isavuconazole administration at a university hospital. Secondary objectives included the description of liver function tests and QTc interval between baseline and end of treatment (EOT), clinical outcomes and breakthrough IMI by the EOT.Patients/MethodsThis was a 5-year single-center retrospective study of all adult patients with acute myeloid leukemia and/or allogeneic HCT recipients who received isavuconazole as prophylaxis and/or treatment between June 1, 2016, and July 31, 2020.ResultsAmong 30 identified patients, the indications for isavuconazole administration were adverse events associated with prior antifungal treatment (N: 18, 60%: hepatotoxicity, renal insufficiency, long QTc interval, neurotoxicity, and potential drug–drug interactions in 6, 4, 3, 1 and 4 patients, respectively), clinical efficacy (N: 5, 16.6%), and other reasons (N: 10, 33.3%; 5/10 patients treated with isavuconazole to facilitate hospital discharge with orally administered appropriate treatment). Alanine aminotransferase significantly decreased from baseline (mean: 129 IU/L, range: 73, 202) to a mean of 48 IU/L (range: 20, 80) by day 14 (P-value: 0.02), 23.5 IU/L (range: 20, 27) by day 28 (P-value: 0.03) and 16.5 IU/L (range: 16, 17) by day 42 (P-value: 0.009). The QTc interval decreased from baseline (mean: 456.8 ms, range: 390, 533) to EOT (mean: 433.8 ms, range: 400, 472; P-value: 0.03). The mean isavuconazole plasma concentration was 2.9 mg/L (range: 0.9, 6.7). There was no breakthrough IMI observed.ConclusionIsavuconazole is a safe and reliable antifungal agent in complex hematological patients, with relatively low hepatotoxicity and QTc interval shortening properties.

Self-Assembled Amphotericin B Pharmacosome-Like Vesicles Derived from Lipid-Based Microtubes: A Model Carrier to Further Explore

Background: Self-assembled drug delivery systems are of much interest since they can be produced by simple low cost and solvent-free procedures. Pharmacosomes are supramolecularstructured nanocarriers with benefits for drug stability and targeting delivery. Amphotericin B (AmB) still remains an important agent for the treatment of invasive mold infections, e.g invasive aspergillosis, although the challenge for new formulations is still prevailing due to high rates of toxicity. Objective: We have previously reported the incorporation of AmB into 12-hydroxystearic acid lipidbased microtubes (MTs) for topical use, herein we report the ability of AmB-MTs to self-assemble into vesicles upon dilution. Methods: AmB-MTs with different drug concentrations (1, 3, 5 mg/ml) were prepared, and size determination was carried out for different dilutions. Morphology was evaluated by microscopy. In vitro cytotoxicity was evaluated in Vero cells and in vitro activity against Aspergillus fumigatus and Aspergillus flavus was assessed. Results: AmB-MTs closed upon dilution to form vesicles ranging from 200 nm to 1μm. AmB MIC (Minimum inhibitory concentration) for both Aspergillus species was 0.0625 and 0.125 μg/ml for dispersion and reconstituted lyophilized, respectively. Conclusion: AmB pharmacosome-like vesicles are smaller structures than MTs may thus be favourable for other delivery routes. We assume that this kind of pharmacosomes-like carrier is a promising model for the obtention of new vesicular carriers based on lipid MTs.

Patient Characteristics and Risk Factors in Invasive Mold Infections: Comparison from a Systematic Review and Database Analysis.

IntroductionDiagnosis and treatment of invasive mold infections (IMI) can be challenging and IMI is a significant source of morbidity and mortality. Invasive aspergillosis (IA) and invasive mucormycosis (IM) are two of the most common mold infections. A better understanding of patient comorbidities and risk factors that predispose IMI may help clinicians to refine the difficult diagnostic and treatment process.MethodsA systematic literature review (SLR) was conducted (January 2008–October 2019) for studies reporting comorbidities/risk factors of patients with IA or IM (Phase I), followed by an analysis on the Optum® US EHR database of prominent risk factor cohorts based on SLR findings and expert opinion (Phase II). From the four identified patient cohorts: 1) patients undergoing solid organ transplant (SOT) and patients with 2) hematologic cancers, 3) diabetes, or 4) lung disease, rates of IA, IM, or concurrent IA and IM; patient comorbidities; and Charlson Comorbidity Index (CCI) scores were reported.ResultsThe SLR included 88 studies, and 46 were used to select comorbidities/risk factors cohorts in IA and IM patients. The most important comorbidities/risk factors in IA and IM patients were diabetes, lung disease, hematological malignances, and SOT. In the Optum database (N=101,340,454 patients), IA rates were highest in lung transplant (10.81%) patients and IM rates were highest in intestine transplant (0.83%) patients, lung transplant (0.43%), and hematopoietic stem cell transplant (0.49%). CCI scores were elevated in all mold infection groups compared to the total Optum cohort.ConclusionThe current study describes patient comorbidity and risk factors associated with IA and IM. These data can be used to refine clinical decision-making regarding when to suspect mold infections. Future research should focus on identifying whether patients respond differently to various antifungal treatments to determine if strategic recommendations should be made for certain patient groups.

Future challenges and chances in the diagnosis and management of invasive mould infections in cancer patients

Diagnosis, treatment, and management of invasive mould infections (IMI) are challenged by several risk factors, including local epidemiological characteristics, the emergence of fungal resistance and the innate resistance of emerging pathogens, the use of new immunosuppressants, as well as off-target effects of new oncological drugs. The presence of specific host genetic variants and the patient's immune system status may also influence the establishment of an IMI and the outcome of its therapy. Immunological components can thus be expected to play a pivotal role not only in the risk assessment and diagnosis, but also in the treatment of IMI. Cytokines could improve the reliability of an invasive aspergillosis diagnosis by serving as biomarkers as do serological and molecular assays, since they can be easily measured, and the turnaround time is short. The use of immunological markers in the assessment of treatment response could be helpful to reduce overtreatment in high risk patients and allow prompt escalation of antifungal treatment. Mould-active prophylaxis could be better targeted to individual host needs, leading to a targeted prophylaxis in patients with known immunological profiles associated with high susceptibility for IMI, in particular invasive aspergillosis. The alteration of cellular antifungal immune response through oncological drugs and immunosuppressants heavily influences the outcome and may be even more important than the choice of the antifungal treatment. There is a need for the development of new antifungal strategies, including individualized approaches for prevention and treatment of IMI that consider genetic traits of the patients.Lay Anticancer and immunosuppressive drugs may alter the ability of the immune system to fight invasive mould infections and may be more important than the choice of the antifungal treatment. Individualized approaches for prevention and treatment of invasive mold infections are needed.

Review of the Novel Investigational Antifungal Olorofim.

The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.

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

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

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

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

Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014.

Mould species represent the pathogens most commonly associated with invasive fungal disease in patients with haematological malignancies and patients of haemopoietic stem cell transplants. Invasive mould infections in these patient populations, particularly in the setting of neutropenia, are associated with high morbidity and mortality, and significantly increase the complexity of management. While Aspergillus species remain the most prevalent cause of invasive mould infections, Scedosporium and Fusarium species and the Mucormycetes continue to place a significant burden on the immunocompromised host. Evidence also suggests that infections caused by rare and emerging pathogens are increasing within the setting of broad-spectrum antifungal prophylaxis and improved survival times placing immunosuppressed patients at risk for longer. These guidelines present evidence-based recommendations for the antifungal management of common, rare and emerging mould infections in both adult and paediatric populations. Where relevant, the role of surgery, adjunctive therapy and immunotherapy is also discussed.

Posaconazole plasma concentrations and invasive mould infections in patients with haematological malignancies

Posaconazole (PCZ) is a triazole antifungal agent that has broad activity against pathogenic fungi and is increasingly used for prophylaxis and treatment of invasive mould infections (IMIs). PCZ is only available as an oral formulation, with varying absorption from the gastrointestinal tract. However, reports correlating PCZ plasma concentrations (PPCs) with breakthrough IMIs are rare. In this study, PPCs were analysed in a prospective, observational, single-centre study and the correlation of PPCs with breakthrough IMIs in patients with haematological malignancies was evaluated. Risk factors associated with low PPCs were further evaluated. A total of 109 PPCs were measured in 34 cases receiving PCZ prophylaxis (n=31) or treatment (n=3). Levels below the target of 0.5μg/mL were detected in 24 (71%) of the 34 cases; in 15 (63%) of these 24 cases concentrations were found to be <0.20μg/mL. Three patients receiving PCZ prophylaxis met the criteria of breakthrough infection. Notably, prior to development of IMI, PPCs were below the target in all three individuals. Associated risk factors for insufficient PPCs varied from previous reports. In conclusion, these data demonstrate that therapeutic drug monitoring of PCZ is mandatory in all patients with haematological malignancies as low PPCs are common and may be associated with development of IMIs.