Invasive Mold Infections Research Articles

Study of Molds in Post COVID -19 Patients: An experience from Tertiary Care Centre

Introduction: Coronavirus disease 2019 (COVID-19) pandemic has emerged as a global health crisis in the century with a heavy toll on human life. The second wave of COVID-19 was lethal for the patients as they had to combat the virus along with the opportunistic fungal and bacterial infections triggered by it. Mucormycosis gained attention for its widespread existence during this period of the second wave of COVID-19. Material & Methods: Various clinical samples like biopsy tissues from paranasal sinuses, deep nasal swabs, bronchoalveolar lavage, sputum, etc. were studied for the presence of fungal elements by KOH examination and culture on Sabouraud’s dextrose agar. Identification of fungal isolate was done by growth characteristics, LPCB wet mount, and slide culture. Result: During the study period, a total of 214 samples were received of which 17 (7.9%) were positive for fungal growth. Rhizopus arrhizus was most frequently isolated. Diabetes mellitus and the use of steroid during COVID-19 hospitalization was observed to be common risk factors. Rhino-cerebral mucormycosis was found to be the commonest type. Conclusion: Invasive mould infections can lead to fatal outcomes, if not detected timely. Accurate identification of the fungus is important for the administration of appropriate antifungal therapy.

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.

When and how do we stop antifungal treatment for an invasive mould infection in allogeneic haematopoietic cell transplant recipients?

Limited data exist to describe end-of-treatment (EOT) parameters of antifungal therapy for invasive mould infections (IMI). In a 10-year cohort of consecutive adult allogeneic haematopoietic cell transplant recipients with proven/probable IMI, we describe treatment duration and patient profile at EOT. There were 61 patients with 66 proven/probable IMI identified: 47/66 (71%) invasive aspergillosis (IA), 11/66 (17%) mucormycosis, and 8/66 (12%) other-IMI. Excluding 5 (8%) patients lost to follow-up, treatment was prematurely discontinued due to death or palliative care in 29/56 (51.8%) patients. Antifungal treatment was completed in 27 (48.2%) patients, for a median duration of 280 days (IQR: 110, 809): 258 (IQR: 110, 1905) and 307.5 (99, 809) days in IA and non-IA IMI, respectively. Treatment was continued after 90 and 180 days in 43/56 (76.8%) and 30/56 (53.6%) patients, respectively. At EOT, most patients were not neutropenic (ANC: 2.12 G/L, IQR: 0.04, 5.3), with CD4+ counts at 99 cells/μl (IQR: 0, 759) and immunoglobulins at 5.6 g/L (IQR: 2.3, 10.6). Most patients (16/27, 59.3%) were not receiving steroids at EOT, while 14/27 (53.9%) were on another type of immunosuppression. Amongst 15 patients with imaging at EOT, 12 (80%) had complete/partial radiologic response. Any chart documentation or an infectious disease consultation on treatment discontinuation was observed in 12/56 (21%) and 11/56 (20%) patients, respectively. Long treatment courses are observed in patients with IMI, due to prolonged immunosuppression. Although immune reconstitution and radiological response were frequently observed at EOT, consistent documentation of treatment discontinuation based on well-defined parameters is lacking.

Keeping health care linens clean: Underrecognized hazards and critical control points to avoid contamination of laundered health care textiles

Outbreaks of health care-associated infections, particularly invasive mold infections, have been linked to environmental contamination of laundered health care textiles. Contamination may occur at the laundry or health care facility. This report highlights underrecognized hazards, control points, and actions that infection preventionists can take to help decrease the potential for patient exposure to contaminated health care textiles. Infection preventionists can use the checklists included in this report to assess laundry and health care facility management of laundered health care textiles.

Low incidence of invasive fungal disease following CD19 chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma

AbstractCAR T-cell therapy has revolutionized the treatment of hematologic malignancies, although its use may be complicated by toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Invasive fungal disease (IFD) has been reported after CAR T-cell therapy, but the incidence in the absence of antifungal prophylaxis is unknown. Optimal prophylaxis strategies are widely debated. We performed a single-center retrospective study of 280 adults receiving CD19 CAR T-cell therapy for non-Hodgkin lymphoma (NHL) from December 2017 through September 2021. Patients did not receive routine antiyeast or antimold prophylaxis. IFD was identified between day of cell infusion and last follow-up. Cumulative incidence functions were calculated at 100 days and 18 months based on time to IFD, using dates of IFD-free death, initiation of salvage treatment, and hematopoietic cell transplantation as competing risks. Eight patients (2.9%) developed IFD, including 3 Pneumocystis jirovecii pneumonia, 3 invasive mold infections (IMIs), and 2 invasive yeast infections (IYIs). The 100-day cumulative incidence of IFD accounting for competing risks was 1.8% (95% confidence interval [CI], 0.8% to 4.4%). Among the 280 patients, early toxicities including CRS (85%) and ICANS (55%) and late toxicities after day 30 including grades 3 and 4 neutropenia (41%) and low CD4 T-cell count (20%) were common. IFD was rare among patients who received CD19 CAR T-cell therapy for NHL in the absence of routine antifungal prophylaxis, despite frequent toxicities. These results suggest that, in settings with low institutional rates of IFD, routine antifungal prophylaxis may not be indicated.

Extensive non-coding sequence divergence between the major human pathogen Aspergillus fumigatus and its relatives.

Invasive aspergillosis is a deadly fungal disease; more than 400,000 patients are infected worldwide each year and the mortality rate can be as high as 50-95%. Of the ~450 species in the genus Aspergillus only a few are known to be clinically relevant, with the major pathogen Aspergillus fumigatus being responsible for ~50% of all invasive mold infections. Genomic comparisons between A. fumigatus and other Aspergillus species have historically focused on protein-coding regions. However, most A. fumigatus genes, including those that modulate its virulence, are also present in other pathogenic and non-pathogenic closely related species. Our hypothesis is that differential gene regulation - mediated through the non-coding regions upstream of genes' first codon - contributes to A. fumigatus pathogenicity. To begin testing this, we compared non-coding regions upstream of the first codon of single-copy orthologous genes from the two A. fumigatus reference strains Af293 and A1163 and eight closely related Aspergillus section Fumigati species. We found that these non-coding regions showed extensive sequence variation and lack of homology across species. By examining the evolutionary rates of both protein-coding and non-coding regions in a subset of orthologous genes with highly conserved non-coding regions across the phylogeny, we identified 418 genes, including 25 genes known to modulate A. fumigatus virulence, whose non-coding regions exhibit a different rate of evolution in A. fumigatus. Examination of sequence alignments of these non-coding regions revealed numerous instances of insertions, deletions, and other types of mutations of at least a few nucleotides in A. fumigatus compared to its close relatives. These results show that closely related Aspergillus species that vary greatly in their pathogenicity exhibit extensive non-coding sequence variation and identify numerous changes in non-coding regions of A. fumigatus genes known to contribute to virulence.

Isavuconazole for COVID-19-Associated Invasive Mold Infections.

Isavuconazole is a broad-spectrum antifungal drug recently approved as a first-line treatment for invasive aspergillosis and as a first or alternative treatment for mucormycosis. The purpose of this review was to report and discuss the use of isavuconazole for the treatment of COVID-19-associated aspergillosis (CAPA), and COVID-19-associated mucormycosis (CAM). Among all studies which reported treatment of CAPA, approximately 10% of patients were reportedly treated with isavuconazole. Considering 14 identified studies that reported the use of isavuconazole for CAPA, isavuconazole was used in 40% of patients (95 of 235 treated patients), being first-line monotherapy in over half of them. We identified six studies that reported isavuconazole use in CAM, either alone or in combination therapy. Overall, isavuconazole was used as therapy in 13% of treated CAM patients, frequently as combination or sequential therapy. The use of isavuconazole in CAPA and CAM is complicated by the challenge of achieving adequate exposure in COVID-19 patients who are frequently obese and hospitalized in the ICU with concomitant renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO). The presence of data on high efficacy in the treatment of aspergillosis, lower potential for drug–drug interactions (DDIs) and for subtherapeutic levels, and no risk of QT prolongation compared to other mold-active azoles, better safety profile than voriconazole, and the possibility of using an intravenous formulation in the case of renal failure are the advantages of using isavuconazole in this setting.

The Combination Treatment of Fosmanogepix and Liposomal Amphotericin B Is Superior to Monotherapy in Treating Experimental Invasive Mold Infections.

ABSTRACTInvasive pulmonary aspergillosis (IPA), invasive mucormycosis (IM), and invasive fusariosis (IF) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in clinical development with demonstrated broad-spectrum activity in animal models of infections. We sought to evaluate the benefit of combination therapy of FMGX plus liposomal amphotericin B (L-AMB) in severe delayed-treatment models of murine IPA, IM, and IF. While FMGX was equally as effective as L-AMB in prolonging the survival of mice infected with IPA, IM, or IF, combination therapy was superior to monotherapy in all three models. These findings were validated by greater reductions in the tissue fungal burdens (determined by quantitative PCR) of target organs in all three models versus the burdens in infected vehicle-treated (placebo) or monotherapy-treated mice. In general, histopathological examination of target organs corroborated the findings for fungal tissue burdens among all treatment arms. Our results show that treatment with the combination of FMGX plus L-AMB demonstrated high survival rates and fungal burden reductions in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These encouraging results warrant further investigation of the FMGX–plus–L-AMB combination treatment for severely ill patients with IPA, IM, and IF.

Invasive Mold Infections in Patients with Hematologic Malignities: The Effects of Environmental Factors

Invasive fungal infections (IFI) continue to be an important cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species constitute most of the IFI in these patients.. It has been reported that most of the invasive aspergillosis epidemics are related to the construction works in the hospital. In this study, we aimed to investigate the frequency of IFI in the old and the new hospital building after relocation in patients with hematological malignancies. Of 8042 patients who were hospitalized in the Department of Hematology, Ondokuz Mayıs University Faculty of Medicine between January 2015 and September 2019, 412 patients who were initiated antifungal therapy were included in the study. The patients in the hematology clinic, which were moved to the new oncology hospital building in January 2018, were grouped as prior and after relocation, and their demographical data, hematological diagnosis, chemotherapy regimens, mortality, IFI, focus of infection, presence of central venous catheter, antifungal prophylaxis and treatment, galactomannan level, fungal culture and computed tomography (CT) findings were evaluated retrospectively. It was determined that 55% of the patients were male and the median age was 58 (range:18-93). The rate of IFI development was 5.12% (n= 412) and the rate of invasive mold infection was 1.2% (n= 145). The most common hematological disease for which antifungal treatment initiated was acute myeloid leukemia (AML) with a rate of 50% (n= 206/412). Of patients, 73% received induction chemotherapy (42%, first induction, 31% reinduction), 13.4% received consolidation therapy. Invasive mold infection was diagnosed as 40% possible, 59% probable, 1% proven. While patients had similar characteristics such as age, gender, hematological disease, chemotherapy regimens and antifungal prophylaxis prior and after transportation, the rate of development of invasive mold infection was 2.1%, 2.06 / 1000 patient days, before transportation, 1.37% (p= 0.009), 1.15/1000 patient days (p<0.001) after transportation, and it was statistically significantly lower after transportation. The median value of galactomannan antigen was detected as 0.17 (0.02-5.9). Blood cultures revealed 10.3% fungal growth and the most common growth was Candida albicans with 54.8% and Mucor spp. as mold with 3.2%. Large-scale construction works such as renovation, extension and demolition works in old hospital buildings are a permanent condition in different units. Clinicians should be aware of that infections due to opportunistic fungi can be seen in immunosuppressive patients close to such construction sites, and even cause epidemics. It should be kept in mind that these infections, which can progress with serious morbidity and mortality are difficult to treat but can be prevented by infection control measures.

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.

The unresolved issues in the management of mucormycosis

Mucormycosis represents the second most frequent invasive mold infection after invasive aspergillosis and its incidence tends to increase around the world [1]. The disease not only affects patients with severe immune defects (e.g. hematologic cancer patients, transplant recipients), but also apparently immunocompetent individuals, such as those with uncontrolled diabetes, sequela of tuberculosis, chronic kidney disease or following severe trauma [1,2]. For these reasons, the burden of mucormycosis is particularly high in low- and middle-income countries with limited access to healthcare structures.

Inhaled Antifungal Agents for Treatment and Prophylaxis of Bronchopulmonary Invasive Mold Infections.

Pulmonary mold infections are life-threatening diseases with high morbi-mortalities. Treatment is based on systemic antifungal agents belonging to the families of polyenes (amphotericin B) and triazoles. Despite this treatment, mortality remains high and the doses of systemic antifungals cannot be increased as they often lead to toxicity. The pulmonary aerosolization of antifungal agents can theoretically increase their concentration at the infectious site, which could improve their efficacy while limiting their systemic exposure and toxicity. However, clinical experience is poor and thus inhaled agent utilization remains unclear in term of indications, drugs, and devices. This comprehensive literature review aims to describe the pharmacokinetic behavior and the efficacy of inhaled antifungal drugs as prophylaxes and curative treatments both in animal models and humans.

Invasive mould infections in patients from floodwater-damaged areas after hurricane Harvey – a closer look at an immunocompromised cancer patient population

ObjectivesExtensive floodwater damage following hurricane Harvey raised concerns of increase in invasive mould infections (IMIs), especially in immunocompromised patients. To more comprehensively characterize the IMI landscape pre- and post-Harvey, we used a modified, less restrictive clinical IMI (mcIMI) definition by incorporating therapeutic-intent antifungal drug prescriptions combined with an expanded list of host and clinical features. MethodsWe reviewed 103 patients at MD Anderson Cancer Center (Houston, Texas), who lived in Harvey-affected counties and had mould-positive cultures within 12 months pre-/post-Harvey (36 and 67 patients, respectively). Cases were classified as proven or probable IMI (EORTC/MSG criteria), mcIMI, or colonization/contamination. We also compared in-hospital mortality and 42- day survival outcomes of patients with mcIMI pre-/post-Harvey. ResultsThe number of patients with mould- positive cultures from Harvey-affected counties almost doubled from 36 pre- Harvey to 67 post- Harvey (p < 0.01). In contrast, no significant changes in (mc)IMI incidence post-Harvey nor changes in the aetiological mould genera were noted. However, patients with mcIMIs from flood affected areas had significantly higher in-hospital mortality (p = 0.01). ConclusionsWe observed increased colonization but no excess cases of (mc)IMIs in immunosuppressed cancer patients from affected areas following a large flooding event such as hurricane Harvey.

Conventional Antifungals for Invasive Infections Delivered by Unconventional Methods; Aerosols, Irrigants, Directed Injections and Impregnated Cement.

The administration of approved antifungals via unapproved formulations or administration routes (such as aerosol, direct injection, irrigation, topical formulation and antifungal-impregnated orthopedic beads or cement) may be resorted to in an attempt to optimize drug exposure while minimizing toxicities and/or drug interactions associated with conventional (systemic) administrations. Existing data regarding such administrations are mostly restricted to uncontrolled case reports of patients with diseases refractory to conventional therapies. Attribution of efficacy and tolerability is most often problematic. This review updates prior published summaries, reflecting the most recent data and its application by available prevention and treatment guidelines for invasive fungal infections. Of the various dosage forms and antifungals, perhaps none is more widely reported than the application of amphotericin B-containing aerosols for the prevention of invasive mold infections (notably Aspergillus spp.).

Invasive mold infection of the gastrointestinal tract: A case series of 22 immunocompromised patients from a single academic center.

Invasive mold infection (IMI) of the gastrointestinal (GI) tract is a rare complication in immunocompromised patients that carries a high mortality rate. It is most often described in the setting of disseminated disease. Early diagnosis and treatment are critical in its management, but this is rarely obtained, leading to delayed therapy. To describe the clinical characteristics, treatment and outcomes of this infection, we reviewed all the cases of adult patients with histopathological findings from autopsy or surgical specimens that demonstrated fungal invasion into the GI tract at Stanford Hospital & Clinics from January 1997 to August 2020. Twenty-two patients that met criteria were identified and they were all immunocompromised, either due to their underlying medical conditions or the treatments that they received. The most common underlying disease was hematological malignancies (63.6%) and the most common symptoms were abdominal pain, GI bleeding and diarrhea. A majority of patients (72.7%) had disseminated invasive mold infection, while the rest had isolated GI tract involvement. In 2/3 of our cases, the fungal genus or species was confirmed based on culture or PCR results. Given the very high mortality associated with GI mold infection, this diagnosis should be considered when evaluating immunocompromised patients with concerning GI signs and symptoms. A timely recognition of the infection, prompt initiation of appropriate antifungal therapy as well as surgical intervention if feasible, are key to improve survival from this devastating infection.Lay summaryPatients with a weakened immune system can suffer from mold infections in the bowel, which are difficult to diagnose and have very high death rate. We examined such cases in our institution in order to learn about their clinical and microbiological features. This study can further improve our understanding of these infections in order to improve patient outcome.

Voriconazole-Induced Hepatotoxicity Concise up-to-date review

Voriconazole is a wide spectrum antifungal used primarily for invasive aspergillosis, an invasive mold infection occurs mostly in immunocompromised patients. Hepatotoxicity is the most common voriconazole-related adverse reaction that leads to treatment discontinuation. Even though reported incidence of hepatic adverse reactions during phase 2 and 3 clinical trials were less than 10%, observational studies in post marketing phase revealed much higher incidence reaching up to 69%. Therefore, the burden caused by hepatotoxicity and interruption of antifungal therapy put immunocompromised patients at serious risk.&#x0D; Currently, there is no biomarker in routine clinical use that can clearly predict susceptibility to voriconazole-induced hepatotoxicity. In effort to identify a predictor, plasma concentrations of voriconazole and cytochrome (CYP) 2C19 genotype/phenotype, which is responsible from substantial inter-individual changes in voriconazole pharmacokinetics, are the most studied subjects. Hepatotoxicity tends to occur at higher concentrations (&gt;4 mg/L), but so far, no significant association has identified in this matter. Although CYP2C19 genotype is strongly associated with voriconazole plasma concentration, current data is insufficient to define a causal relationship between CYP2C19 genotype and voriconazole-induced hepatotoxicity.&#x0D; This article reviews the epidemiology, mechanism, laboratory features of voriconazole-induced hepatotoxicity and current literature investigating the influence of voriconazole plasma concentration and CYP2C19 genetics on voriconazole-induced hepatotoxicity.

Frequency and causes of antifungal treatment changes in allogeneic haematopoïetic cell transplant recipients with invasive mould infections.

BackgroundAntifungal treatment duration and changes for invasive mould infections (IMI) have been poorly described.MethodsWe performed a 10‐year cohort study of adult (≥18‐year‐old) allogeneic haematopoietic cell transplant recipients with proven/probable IMI to describe the duration and changes of antifungal treatment. All‐cause‐12‐week mortality was described.ResultsSixty‐one patients with 66 IMI were identified. Overall treatment duration was 157 days (IQR: 14–675) and 213 (IQR: 90–675) days for patients still alive by Day 84 post‐IMI diagnosis. There was at least one treatment change in 57/66 (86.4%) cases: median 2, (IQR: 0–6, range:0–8). There were 179 antifungal treatment changes due to 193 reasons: clinical efficacy (104/193, 53.9%), toxicity (55/193, 28.5%), toxicity or drug interactions resolution (15/193, 7.8%) and logistical reasons (11/193, 5.7%) and 15/193 (7.8%) changes due to unknown reasons. Clinical efficacy reasons included lack of improvement (34/104, 32.7%), targeted treatment (30/104, 28.8%), subtherapeutic drug levels (14/104, 13.5%) and other (26/104, 25%). Toxicity reasons included hepatotoxicity, nephrotoxicity, drug interactions, neurotoxicity and other in 24 (43.6%), 12 (21.8%), 12 (21.8%), 4 (7.4%) and 3 (5.5%) cases respectively. All‐cause 12‐week mortality was 31% (19/61), higher in patients whose antifungal treatment (logrank 0.04) or appropriate antifungal treatment (logrank 0.01) was started >7 days post‐IMI diagnosis. All‐cause 1‐year mortality was higher in patients with ≥2 changes of treatment during the first 6 weeks post‐IMI diagnosis (logrank 0.008) with an OR: 4.00 (p = .04).ConclusionsPatients with IMI require long treatment courses with multiple changes for variable reasons and potential effects on clinical outcomes, demonstrating the need more effective and safer treatment options. Early initiation of appropriate antifungal treatment is associated with improved outcomes.

Three Cases of Gastrointestinal Mucor Colonization in Patients With Prolonged Neutropenia

Abstract Mucor is a well-known opportunistic organism; however, it rarely infects the gastrointestinal (GI) tract. Although known to transiently colonize healthy immunocompetent individuals, the incidence of mucormycosis is increasing in patients with hematologic malignancies, which can have serious consequences in an immunocompromised host. This abstract presents 3 patients from a single institution with Mucor colonization of their stool. Each patient had a hematologic malignancy and was neutropenic when diagnosed with Mucor colonization of the stool. The duration of neutropenia ranged from 1 to 76 days with median of 31 days at the time of diagnosis. Patients were observed for symptoms of GI tract invasion, and they received antimold prophylaxis while neutropenic. Despite GI shedding, no mold sinusitis or pneumonia or gastroenteritis was noted. Gastrointestinal mucormycosis was never noted during their hospital course. This case series emphasizes the importance of not dismissing mold colonization of the stool in a patient with prolonged neutropenia who is at high risk of invasive GI tract mucormycosis. When stool cultures grow Mucor in patients with prolonged neutropenia, anti-Mucor therapy is indicated and may prevent invasive mold infection during the period of risk.

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&amp;lt; 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

Invasive Mold Infections in Allogeneic Hematopoietic Cell Transplant Recipients in 2020: Have We Made Enough Progress?

BackgroundDespite progress in diagnostic, prevention, and treatment strategies, invasive mold infections (IMIs) remain the leading cause of mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients.MethodsWe describe the incidence, risk factors, and mortality of allo-HCT recipients with proven/probable IMI in a retrospective single-center 10-year (01/01/2010–01/01/2020) cohort study.ResultsAmong 515 allo-HCT recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%), and other molds (8/51, 15%). Overall, 35/51 (68.6%) breakthrough IMIs (bIMIs) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31–180, and >180 days post-HCT, respectively. Risk factors for IMI included prior allo-HCT (sub hazard ratio [SHR], 4.06; P = .004) and grade ≥2 acute graft-vs-host disease (aGvHD; SHR, 3.52; P < .001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (P = .02). Mortality predictors included disease relapse (hazard ratio [HR], 7.47; P < .001), aGvHD (HR, 1.51; P = .001), CMV serology–positive recipients (HR, 1.47; P = .03), and IMI (HR, 3.94; P < .001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (log-rank P = .47). At 1 year post–IMI diagnosis, 70.8% (34/48) of the patients were dead.ConclusionsIA mortality has remained relatively unchanged during the last 2 decades. More than two-thirds of allo-HCT recipients with IMI die by 1 year post–IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.