Development Of Invasive Fungal Infections Research Articles

The evaluation of atorvastatin as an adjunct to fluconazole for the anti-fungal prophylaxis in acute myeloid leukemia: a multicenter, triple-blinded, randomized clinical trial.

The development of invasive fungal infections (IFIs) is a serious complication in acute myeloid leukemia (AML) patients who undergo an induction to remission chemotherapy. Given the increased mortality in AML patients with IFI despite prophylaxis, we need to address this problem. Statins have traditionally been employed in clinical settings as agents for reducing lipid levels. Nonetheless, recent investigations have brought to light their antifungal properties in animals, as well as in vitro studies. The objective of this study was to assess the effectiveness of atorvastatin when added to the routine IFI prophylaxis regimen in patients diagnosed with AML. A randomized, multicenter, triple-blind study was conducted on 76 AML patients aged 18-70, who received either placebo or atorvastatin in addition to fluconazole. Patients were followed for 30days in case of developing IFIs, patient survival, and atorvastatin- related adverse drug reactions. Data were analyzed with SPSS version 26.0. A level of significance of 0.05 was utilized as the threshold for all statistical tests. The data were analyzed by adjusting for the effect of age, regarding that there was a significant difference between the two groups, and showed that atorvastatin reduced the development of both probable and proven IFI (based on EORTC/MSGERC criteria) compared to placebo. IFI-free survival was also significantly better in the atorvastatin group. The incidence of developing aspergillosis did not differ between the two groups. No serious adverse events related to atorvastatin were observed. The present investigation has substantiated the antecedent in vitro and animal research on the fungicidal impact of statins and has suggested the need for additional research involving larger sample sizes and an extended duration of follow-up. Trial registration: This study was registered on the Iranian registry of clinical trials as IRCT20210503051166N1 (Date of confirmation 2021.05.03).

Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Treated with a Hypomethylating Agent and Venetoclax: A Real-World Experience in Pharmacovigilance

Background: The oral BCL2 inhibitor venetoclax, in combination with hypomethylating agents (HMA/Ven) improves overall survival in patients with acute myeloid leukemia (AML) either ≥ 75 years or medically unfit for intensive chemotherapy with a tolerable safety profile. It requires significant dose modification when used concomitantly with moderate-strong CYP3A inhibitors, typically azole antifungal agents. In the VIALE-A trial, over 60% of patients in the HMA/Ven arm received antifungal prophylaxis. However, there is no consensus of antifungal prophylaxis in AML patients treated with HMA/Ven given the incidence of invasive fungal infection is overall low and its impact on long-term outcomes remains not well-defined. Method: In the current study, we retrospectively reviewed the upfront treatment with HMA/Ven in newly diagnosed AML patients who were seen at Moffitt Cancer Center with detailed information of venetoclax dosing and concurrent antifungal use between 2018 and 2021, representing our first three years of real-world experience following accelerated approval of venetoclax by the FDA. Results: We identified 120 patients who received at least one cycle of HMA/Ven treatment. The median age at diagnosis was 76 years, and 62.5% being male. The baseline disease-related features are shown in Table. A prior history of myeloid malignancy was reported in 42 patients (35%), and 16 of them received HMA based therapy (13.3%). TP53 mutations were identified in 29 patients (24.8%), and 92 patients (76.7%) were classified as adverse risk based on ELN 2022 risk stratification. In terms of the HMA choice, 79 (65.8%) received azacitidine and rest were given decitabine. The median cycle of HMA/Ven treatment was 4, and HMA dose adjustment was rarely needed in the first 3 cycles (2.0-3.3%). In the first cycle, venetoclax dose was ramped up in 26.9%, and 34.4% received a target dose of 400 mg daily. Its dose required adjustment in about two-thirds of patients during the first three cycles (65.6-72.9%), with the primary reason being concurrent antifungal use (90.2-92.2%). Delays in treatment were found in nearly one fourth of patients (25.5%) during cycle 2 and 3, mainly attributed to poor count recovery and/or bacterial infections. In contrast, invasive fungal infection was uncommon during the first 3 cycles (cycle 1, 3.3%; cycle 2, 2.0%; cycle 3, 3.3%) with a cumulative incidence of 5% (6 patients with 5 possible and 1 proven fungal infections) despite most of them (83.3%) receiving antifungal prophylaxis before the development of invasive fungal infection. Eighty patients (66.7%) achieved complete remission or complete remission with incomplete hematologic recovery (CR/CRi) as the best response. In total, 19 patients (15.8%) ultimately underwent allogeneic stem cell transplant. The median overall survival was 10.8 months, and antifungal prophylaxis during the first three cycles was associated with a consistent trend of inferior overall survival (yes vs. no of antifungal use: cycle 1, 8.9 vs. 12.5 months, p = 0.296; cycle 2, 11.5 vs. 15.6 months, p = 0.206; cycle 3, 14.1 months vs. not reached, p = 0.063). In patients who were able to complete ≥ 3 cycles of HMA/Ven treatment, antifungal prophylaxis at any time was still associated with a trend of inferior overall survival (hazard ratio 1.79, 95% confidence interval 0.76-4.20, p = 0.183), after adjusting ELN 2022 risk status. Conclusion: The observed trend of inferior outcomes in newly diagnosed AML patients receiving HMA/Ven with concomitant antifungal prophylaxis might reflect poor count recovery due to underlying disease and/or treatment-related toxicity, which requires further prospective studies.

Risk Factors for Early Fungal Disease in Solid Organ Transplant Recipients: A Systematic Review and Meta-analysis.

Invasive fungal infections are associated with high morbidity in solid organ transplant recipients. Risk factor modification may help with preventative efforts. The objective of this study was to identify risk factors for the development of fungal infections within the first year following solid organ transplant. We searched for eligible articles through February 3, 2023. Studies published after January 1, 2001, that pertained to risk factors for development of invasive fungal infections in solid organ transplant were reviewed for inclusion. Of 3087 articles screened, 58 were included. Meta-analysis was conducted using a random-effects model to evaluate individual risk factors for the primary outcome of any invasive fungal infections and invasive candidiasis or invasive aspergillosis (when possible) within 1 y posttransplant. We found 3 variables with a high certainty of evidence and strong associations (relative effect estimate ≥ 2) to any early invasive fungal infections across all solid organ transplant groups: reoperation (odds ratio [OR], 2.92; confidence interval [CI], 1.79-4.75), posttransplant renal replacement therapy (OR, 2.91; CI, 1.87-4.51), and cytomegalovirus disease (OR, 2.97; CI, 1.78-4.94). Both posttransplant renal replacement therapy (OR, 3.36; CI, 1.78-6.34) and posttransplant cytomegalovirus disease (OR, 2.81; CI, 1.47-5.36) increased the odds of early posttransplant invasive aspergillosis. No individual variables could be pooled across groups for invasive candidiasis. Several common risk factors exist for the development of any invasive fungal infections in solid organ transplant recipients. Additional risk factors for invasive candidiasis and aspergillosis may be unique to the pathogen, transplanted organ, or both.

Bone Marrow Iron Stores Are Not Associated with Increased Risk for Invasive Fungal Infections in Patients with Newly Diagnosed Acute Leukemia or Myelodysplastic Syndrome in Transformation: Is There a Relationship?

Iron plays an important role in the pathogenesis of infections, including invasive fungal infections (IFIs). Studies suggested that iron overload might represent an additional risk factor for IFIs among patients with hematological malignancies. We conducted a prospective, multi-center study amongst adult patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in transformation to determine whether baseline iron overload as measured using the bone marrow iron store (BMIS) score is an independent risk factor for the development of IFIs. We also measured baseline serum iron and ferritin levels. A total of 98 patients were enrolled (76 with AML) and were followed for 12 months. Twenty-two patients developed IFI during the follow-up period (invasive aspergillosis n = 16, candidemia n = 5, mucormycosis n = 1). A baseline BMIS score ≥ 3 indicated that iron overload was relatively common (38/98 patients, 38%), and its frequency was comparable between patients with no IFIs (31/76, 40.7%) and in those with IFIs (8/22, 36.4%). Univariate analysis showed that only the presence of AML was associated with increased risk for IFIs [OR (95% CI) 7.40 (1.05-325.42)]. Both univariate and multivariate analyses showed that an increased BMIS score (≥3) at baseline was not an independent risk factor for IFIs. Similarly, there was no difference in serum iron and ferritin between the two groups that had similar demographic characteristics. Indices of iron overload were not independent risk factors for IFIs in our cohort of Greek patients with newly diagnosed AML/MDS in transformation.

Invasive Fungal Infections in Children With Acute Myeloid Leukemia: A Single-center Experience Over 19 Years.

Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality in children with acute myeloid leukemia (AML). This study aimed to evaluate the incidence, risk factors, etiology, and outcome of IFIs in children with AML and the effect of mold-active antifungal prophylaxis. We retrospectively reviewed pediatric patients treated for AML between January 2004 and December 2022. Proven, probable, or possible IFIs were defined using standardized definitions of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) classification published at 2008. A total of 298 febrile neutropenia episodes from 78 patients were evaluated. Proven, probable, and possible IFI rates were 3%, 2.6%, and 9.4%, respectively. Profound neutropenia was detected in 18 (58%) and prolonged neutropenia in 20 (64.5%) of the IFI episodes.. Invasive aspergillosis accounted for the majority of IFI episodes; however, non-albicans Candida spp. were the most isolated pathogens in the proven group. Patients with relapsed AML were particularly at risk for the development of IFI ( P =0.02). A significant decrease in IFI episodes was achieved with mold-active antifungal prophylaxis with voriconazole ( P =0.01, odds ratio: 0.288, %95 CI:0.104-0.797). The overall mortality was 35.8%, and the IFI-attributable mortality rate was 25%. In the multivariate analysis, relapsed disease was the most significant risk factor associated with mortality ( P =0.006, odds ratio:4.745; 95% CI: 1.573-14.316). Mold-active prophylaxis reduced the rate of IFIs in this cohort however IFI-related mortality was still high as 25% in pediatric AML patients. Relapsed AML was the most significant risk factor associated with mortality.

705 Evaluation of Invasive Fungal Infections in the Burn ICU

Abstract Introduction Fungal infections are increasingly associated with critical illness, especially in major burn injury. The risk factors of invasive fungal infections include central venous catheter (CVC) placement, mechanical ventilation, broad-spectrum antibiotics, renal replacement therapy (RRT), and total parental nutrition. Critically ill burn patients have additional risk factors including extensive wounds, impaired immune system, and repeated surgical intervention. Despite significant morbidity and mortality caused by invasive fungal infections, efforts to prevent them with antifungal prophylaxis have not improved outcomes. In patients who develop invasive fungal infection, appropriate empiric antifungal therapy is imperative to reduce morbidity and mortality especially in the setting of delayed culture and sensitivity data. The purpose of this study was to characterize risk factors associated with the development of invasive fungal infection, invasive fungal infection organisms and surgical and pharmacological management. Methods A retrospective chart review was completed of adult patients admitted to the burn ICU found to have an invasive fungal infection (defined as at least one positive blood or tissue fungal infection and receipt of systemic antifungal therapy). The primary outcome was to identify common fungal organisms. Secondary outcomes included susceptibility pattern of the organism, location of infection, surgical management including debridement and amputation, pharmacological management, median ICU and hospital length of stay, and in hospital mortality. Results A total of 10 patients of a goal of 100 patients with a median 54% TBSA burns were evaluated at this time. The most common yeast species included candida albicans; mold species included a variety of organisms such as fusarium, zygomycete and paecilomyces. Common risk factors among these patients included CVC access (57%), mechanical ventilation (43%), and RRT (43%). Yeast infections were primarily treated with anidulafungin and fluconazole, while mold infections were managed with systemic amphotericin as backbone in addition to voriconazole or isavuconazole. Patients underwent aggressive surgical debridement for source control. Median ICU stay was 53 days with a median hospital stay of 63 days, and 42% mortality. Conclusions Fungal infections among critically ill burn patients are associated with the high morbidity and mortality rates. Therefore, mitigation of modifiable risk factors is of utmost importance. This retrospective review of common fungal growth in our unit will inform future empiric antifungal management for patients with concern of invasive fungal infections. Applicability of Research to Practice Fungal infections present a clinical challenge for burn practitioners, especially in geographically moist areas. Prevention and informed surgical and pharmacological management are key to overcoming this infectious disease threat.

D-index as a Risk Factor for Invasive Fungal Infections in Patients With Acute Lymphoblastic Leukemia From a Reference Hematology Center in Bogota.

Introduction Patients with hematologic malignancies are susceptible hosts for the development of invasive fungal infection (IFI), one of the main life-threatening infectious complications faced by these patients. Currently, we have antifungal prophylaxis strategiesand antifungal treatment schemes and we recognize that the main risk factor involved is profound and prolonged neutropenia. D-index and cumulative D-index are quantitative parameters, which determine the magnitude of neutropenia, as a function of duration and depth and their value correlates with the occurrence of IFI. Materialand methods A case-control study in patients older than 18 years with acute lymphoblastic leukemia (ALL) was admitted between 2009 and 2019 at the National Cancer Institute for induction, consolidationand salvage chemotherapy. Results A total of 167 patients were included, who received 288 cycles of chemotherapy, the latter were considered the unit of analysis. A generalized estimating equations (GEE) model was designed to analyze correlated data; three quantitative and continuous variables of interest were included in this model: age (years), D-index and deep neutropenia (days). For the population D-index, an odds ratio (OR) = 1.000227 (95% CI 1.0002-1.0004); p < 0.001 was obtained. Conclusion D-index is associated with the development of IFI in patients with ALL, with an exponential increase in OR as the absolute value of the D-index increases.

Exposure-Response Relationship of Posaconazole Suspension in Theprophylaxis of Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

Antifungal prophylaxis with posaconazole has demonstrated a reduction in the risk of death due to Invasive fungal infections (IFI)in patients with acute myeloid leukemia (AML) during induction therapy. However, various factors affect the plasma levels of posaconazole and can potentially limit its efficacy. Therapeutic drug monitoring (TDM) can help optimize the dose, but literature is scant from centers with a high IFI burden. This study aimed to evaluate the proportion of de-novo AML patients on induction who could achieve the target level of 700ng/mL with posaconazole prophylaxis,factors that can influence the plasma levels, and the impact of plasma posaconazole levels on incidence of IFI. Patients with AML on induction therapy with no baseline IFI were enrolled at our tertiary cancer center which has high prevalence of IFI. These patients received posaconazole suspension as prophylaxis. Daily plasma levels were measured from Day 4 till Day 12 of posaconazole prophylaxis. All patients were monitored for the development of IFI. The data on adverse events, concomitant drugs, mucositis, vomiting, and diarrhea were recorded. A total of 411 samples from fifty patients were collected. Only 177 out of 411 samples had levels > 700 ng/mL. The median trough level was 610 ng/mL (range30-3000 ng/mL). The median time to achieve target trough concentration was four days (range 4-12 days) from the start of induction.Thirty-eight (76%) patients achieved target plasma levels by day 12 of induction.The median plasma level on day 12 was 690 ng/mL (range,30-1270) in patients who achieved target levels as compared to 340 (50-560) ng/mL in those who did not. Twenty-six (52%) patients had IFI in our study, and the median time to develop breakthrough IFI was 14 days (range 4-24 days). Median and range of plasma levels were 690 ng/ml (30-2410; n = 22) in those who developed IFI, while 590 ng/mL (50-2300 n = 24) in those who did not. The odds of developing IFI in patients who did not achieve the threshold trough concentration of 700 ng/mL was 7.14 (95% CI; 1.35-37.75, p = 0.0206). Occurrence of vomiting (p = 0.02), diarrhea (p = 0.0008), mucositis (p = 0.003) had adverse impact on achievement of target plasma posaconazole levels. A significant proportion of patients receiving posaconazole prophylaxis fail to achieve target plasma levels which can result in high risk of development of IFI. Occurrence of diarrhea, vomiting and mucositis can adversely affect the achievement target plasma levels.

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.

Donor and Peri-Transplant Hospitalization Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients

<h3>Purpose</h3> Invasive fungal infections (IFIs) remain a frequent complication in the lung transplant (LTx) population even in the current era of antifungal prophylaxis. The organ donor and peri-transplant period risk factors for IFI remain ill-defined. Our study goal is to identify novel risk factors for IFI, focusing on the organ donor and the recipient's transplant hospitalization. <h3>Methods</h3> We performed a single-center, case-control study. The source cohort included all adults who underwent LTx between 1/1/12-3/31/17. The primary outcome was a Probable or Proven IFI within 6 months of transplantation, as defined by EORTC/MSG criteria. Multivariable logistic regression and Cox proportional hazard regression analyses were used to identify independent risk factors for IFI. <h3>Results</h3> Of 329 LTx recipients, 45 (14%) developed IFI. The median time to IFI was 50 days (IQR: 25-110) after transplantation. Independent risk factors for IFI included: donor steroid pre-conditioning (aOR 2.24, 95%CI: 1.05-4.77, p=0.04); cardiopulmonary bypass (aOR 3.07, 95%CI: 1.06-8.87, p=0.04); ICU length of stay >30 days (aOR 3.34, 95%CI: 1.48-75, p<0.01); and bronchial anastomotic dehiscence (aOR 14.06, 95%CI: 1.99-99.34, p=0.01). Mold isolated on donor respiratory culture increased the hazard of IFI in LTx recipients (Table 1). Peri-transplant hospitalization complications that increased the hazard of IFI included: multiple positive fungal cultures, airway ischemia, and prolonged ICU stay (Table 1). Fungal treatment for ≥90 days after transplant was protective against development of IFI (Table 1). <h3>Conclusion</h3> IFI was common in our LTx cohort. Certain donor characteristics and peri-transplant complications increased the likelihood of IFI. Interventional studies, targeting the modifiable risk factors identified in this study, are needed to reduce IFI risk in LTx recipients.

Retrospective Evaluation of Risk Factors for the Development of Invasive Fungal Infections in Immunosuppressed Patients

Retrospective Evaluation of Risk Factors for the Development of Invasive Fungal Infections in Immunosuppressed Patients

Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies.

The use of targeted biologic therapies for hematological malignancies has greatly expanded in recent years. These agents act upon specific molecular pathways in order to target malignant cells but frequently have broader effects involving both innate and adaptive immunity. Patients with hematological malignancies have unique risk factors for infection, including immune dysregulation related to their underlying disease and sequelae of prior treatment regimens. Determining the individual risk of infection related to any novel agent is challenging in this setting. Invasive fungal infections (IFIs) represent one of the most morbid infectious complications observed in hematological malignancy. In recent years, growing evidence suggests that certain small molecule inhibitors, such as BTK inhibitors and PI3K inhibitors, may cause an increased risk of IFI in certain patients. It is imperative to better understand the impact that novel targeted therapies might have on the development of IFIs in this high-risk patient population.

Invasive Fungal Infections After Liver Transplantation: A Retrospective Matched Controlled Risk Analysis.

BackgroundInvasive fungal infections (IFI) are major risks for mortality after liver transplantation (LT). The aim of this study was to evaluate possible risk factors for the development of IFI after LT.Material/MethodsAll adult patients with IFI after LT between January 2012 and December 2016 at Essen University were identified. Pre-, intra-, and postoperative data were reviewed. These were compared to a 1-to-3 matched control group. Multinominal univariate and multivariate regression analyses were performed.ResultsOut of the 579 adults who underwent LT, 33 (5.6%) developed postoperative IFI. Fourteen had invasive aspergillosis with 7 (50%) mortality, and 19 had Candida sepsis with 7 (37%) mortality. The overall mortality due to invasive fungal infections was 42%. Perfusion fluid contamination with yeast was detected in 5 patients (15%). Multivariate regression analyses showed that preoperative dialysis (OR=1.163; CI: 1.038–1.302), Eurotransplant donor risk index (OR=0.04; CI=0.003–0.519), length of hospital stay (OR=25.074; CI: 23.99–26.208), and yeast contamination of the preservation fluid (OR=47.8; CI: 4.77–478, 96) were associated with IFI in the Candida group, whereas duration of surgery (OR=1.013; CI: 1.005–1.022), ventilation hours (OR=0.993; CI=0.986–0.999), and days of postoperative dialysis (OR=1.195; CI: 1.048–1,362) were associated with IFI in the aspergillosis group.ConclusionsPost-LT IFI had 42% mortality in our cohort. Prophylactic antifungal therapy should be expanded to broader risk groups as defined above.

Invasive Fungal Diseases in Children with Acute Leukemia and Severe Aplastic Anemia.

Although the outcomes of childhood leukemia and severe aplastic anemia (SAA) have improved, infectious complications are still the major concern. Particularly worrisome are invasive fungal diseases (IFDs), one of the most common causes of infectious-related deaths in patients with prolonged neutropenia. A retrospective study was conducted of IFDs in pediatric patients with newly diagnosed or relapsed acute leukemia, or with SAA, at Siriraj Hospital, Mahidol University, Thailand. There were 241 patients: 150 with acute lymphoblastic leukemia (ALL), 35 with acute myeloid leukemia (AML), 31 with relapsed leukemia, and 25 with SAA. Their median age was 5.4 years (range, 0.3–16.0 years). The overall IFD prevalence was 10.7%, with a breakdown in the ALL, AML, relapsed leukemia, and SAA patients of 8%, 11.4%, 19.3%, and 16%, respectively. Pulmonary IFD caused by invasive aspergillosis was the most common, accounting for 38.5% of all infection sites. Candidemia was present in 34.6% of the IFD patients; Candida tropicalis was the most common organism. The overall case-fatality rate was 38.5%, with the highest rate found in relapsed leukemia (75%). The incidences of IFDs in patients with relapsed leukemia and SAA who received fungal prophylaxis were significantly lower than in those who did not (P = N/A and 0.04, respectively). IFDs in Thai children with hematological diseases appeared to be prevalent, with a high fatality rate. The usage of antifungal prophylaxes should be considered for patients with SAA to prevent IFDs.

Enteral Delivery of Posaconazole or Izavuconazole in Patients with Inability to Swallow Tablets Can Achieve Therapeutic Drug Levels: A Single Center Pilot Study

<h3>Purpose</h3> One of the most common challenges facing the transplant population are invasive fungal infections including aspergillosis, mucormycosis, and those due to endemic fungi. Fungal prophylaxis is becoming standard of practice to limit development of invasive fungal infections. Isavuconazole and posaconazole are commonly used antifungal medications as both prophylaxis and treatment. These drugs are approved for oral and intravenous (IV) administration however, use via alternative enteric routes have not been well studied. <h3>Methods</h3> A retrospective chart review was conducted of transplant patients receiving triazole therapy for prophylaxis or treatment over a seven month period. Patients with an inability to swallow oral medications switched during their course of care from IV therapy to non-oral enteric administration of isavuconazole or posaconazole via nasogastric, orogastric, percutaneous endoscopic gastrostomy (PEG), or percutaneous endoscopic gastrojejunostomy (PEG-J) tubes were included in the study. <h3>Results</h3> We identified 17 patients administered isavuconazole or posaconazole via non-oral enteric routes (Table 1). The indication for therapy was primarily for prophylaxis after single or double lung transplantation. The majority (83%) of cases were therapeutic at the time of their first drug level assessment, with a mean level of 2.47 +/- 0.71 for isavuconazole and 0.84 +/- 1.03 for posaconazole. All patients not therapeutic at initial assessment had doses increased and subsequently achieved therapeutic levels. <h3>Conclusion</h3> Our case series shows isavuconazole and posaconazole can be administered via non-oral enteric routes with therapeutic drug monitoring to achieve acceptable serum drug concentrations and avoid prolonged IV therapy in a transplant population. Given the increasing complexity and age of transplant recipients, continued studies are needed to address alternative antifungal dosing regimens.

Evaluation of targeted versus universal prophylaxis for the prevention of invasive fungal infections following lung transplantation.

Antifungal prophylaxis to prevent invasive fungal infections (IFI) is widely used following lung transplantation, but the optimal strategy remains unclear. We compared universal with targeted antifungal prophylaxis for effectiveness in preventing IFI. Adult patients who underwent lung transplantation at the University of Michigan from /1 July 2014-31 December 2017 were studied for 18months post-transplant. Universal prophylaxis consisted of itraconazole with or without inhaled liposomal amphotericin B. Using specific criteria, targeted prophylaxis was given with voriconazole for patients at risk for invasive pulmonary aspergillosis (IPA) and with fluconazole or micafungin for patients at risk for invasive candidiasis. Risk factors, occurrence of proven/probable IFI, and mortality were analyzed for the two prophylaxis cohorts. Of 105 lung transplant recipients, 84 (80%) received a double lung transplant, and 38 (36%) of patients underwent transplant for pulmonary fibrosis. Fifty-nine (56%) patients received universal antifungal prophylaxis, and 46 (44%), targeted antifungal prophylaxis. Among 20 proven/probable IFI, there were 14 IPA, 4 invasive candidiasis, 1 cryptococcosis, and 1 deep sternal mold infection. Six (10%) IFI occurred in the universal prophylaxis cohort and 14 (30%) in the targeted prophylaxis cohort. Five of 6 (83%) IFI in the universal prophylaxis cohort, compared with 9/14 (64%) in the targeted prophylaxis cohort, were IPA Candida infections occurred only in the targeted prophylaxis cohort. The development of IFI was more likely in the targeted prophylaxis cohort than the universal prophylaxis cohort, HR=4.32 (1.51-12.38), P=.0064. Universal antifungal prophylaxis appears to be more effective than targeted antifungal prophylaxis for prevention of IFI after lung transplant.

Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents

AbstractThe combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy.

Invasive Fungal Infections With Good Survival Following Liver Transplant: A Single-Center Experience From a Developing Country

Invasive fungal infection following liver transplant is considered as one of the important factors influencing morbidity and mortality among liver transplant recipients. The aim of the present study was to describe the prevalence of invasive fungal infections and their predisposing factors in a singlecenter cohort of patients who received liver transplant. For this study, 250 adult patients undergoing orthotopic liver transplant between March 2010 and March 2015 were enrolled. All patients were followed prospectively for infections. The diagnosis of invasive fungal infection was made in 15 patients (6%). One patient had 2 episodes of fungal infection, and reoperation was performed for 3 patients. Invasive aspergillosis developed in 8 patients (53.3%),followed by Candida species infection in 3 patients (20%) and cryptococcosis in 2 patients (13.3%).The main predisposing factors were renal failure (12/15) and positive history of rejection (11/15). Other risk factors for development of invasive fungal infections were choledochojejunostomy in 3 patients (20%), bile leaks in 3 patients (20%), and pretransplant steroid use in 2 patients (11.8%). Two patients (13.3%) died due to invasive fungal infections. In this single-center series of liver transplant recipients, the incidence of invasive fungal infections was relatively low, probably due to the universal prophylaxis with fluconazole and limited use of the broad-spectrum antibiotics. Early diagnosis and treatment of invasive fungal infections could lead to a better prognosis for liver transplant recipients with invasive fungal infections.

265. Clinical Epidemiology of Invasive Fungal Infection with Aspergillus and Mucor Species in a Tertiary Children’s Hospital

BackgroundPatients undergoing hematopoietic stem cell transplantation and patients with hematologic malignancies are at increased risk for acquiring invasive fungal infection (IFI) due to immune system impairment from chemotherapy. Affected patients require prolonged antifungal therapy with the risk of associated toxicity and extended hospitalization due to delay of accurate diagnosis. There is a lack of effective serologic biomarkers and hesitancy to proceed with tissue diagnosis due to thrombocytopenia or other associated risks. Mortality in oncology patients with invasive mycoses is high, with pediatric mortality rates of 30–40% at 12 weeks following diagnosis.MethodsAll patients that were admitted to Lurie Children’s Hospital between January 2014 and December 2018 and received voriconazole, ambisome, posaconazole and isavuconazole were identified. The following data were retrospectively collected: CT chest and sinus, (1,3)-β-d-Glucan and Aspergillus galactomannan, ANC and ALC at diagnosis, blood next-generation sequencing, tissue 18s rRNA, fungal culture, duration of neutropenia and lymphopenia, site of infection, time between underlying diagnosis and development of IFI, surgical intervention and associated mortality.ResultsA total of 94 unique patients that received voriconazole were identified. There were 8 proven cases of invasive Aspergillus infection the past 5 years, 50% male, mean age 14 years. Only 25% of patients had positive serum Aspergillus galactomannan and 37.5% had positive β-d-Glucan. Seven cases were due to Aspergillus fumigatus and one case was due to Aspergillus flavus. There were 9 patients with mucormycosis and all but one were culture positive. Three patients with Mucor had mold identification in blood next-generation sequencing prior to surgery. Mucor associated mortality was 22.2%.ConclusionThe majority of pediatric patients with invasive aspergillosis did not have characteristic chest CT imaging findings and serum Aspergillus galactomannan was usually negative.The was no associated mortality in invasive Aspergillus cases, whereas the mortality rate of invasive mucormycosis was 22.2%. Although we have a small sample size, this is significantly lower compared with published literature.Disclosures All authors: No reported disclosures.

1735. Epidemiology of Invasive Fungal Infections During Induction Chemotherapy in Adults With Newly Diagnosed Acute Myeloid Leukemia Without Antifungal Prophylaxis: A Retrospective Cohort Study

BackgroundWhile invasive fungal infections (IFIs) are common in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy, little current data exist on the epidemiology of IFIs in this patient population given widespread use of antifungal prophylaxis. Because our institution does not administer antifungal prophylaxis, we are in a unique position to study the natural history of IFIs in these patients.MethodsWe evaluated the incidence of IFIs using established definitions in adults with AML undergoing induction chemotherapy at Stanford Health Care from 2012 to 2017. We also analyzed incidence of antifungal treatment, impact of IFI diagnosis on survival, and risk factors for IFI development. Patients were followed for up to 12 weeks after beginning induction chemotherapy.ResultsOf 488 patients analyzed, 243 were eligible for inclusion. The median age was 57 (interquartile range 45–65). Men composed 134 (55%) of the patients and 157 (65%) where white. Fifty-four (22%) had antecedent myelodysplastic syndrome; most received a “7 + 3” regimen involving cytarabine and an anthracycline. Thirty-one (13%) developed a proven or probable IFI; 104 (43%) developed a proven, probable, or possible IFI. Most IFIs were due to lower respiratory tract disease. Eighteen identified organisms were Candida, including six C. albicans. Eight organisms were mold, including four Aspergillus isolates (all but one A. fumigatus) and one isolate each of Fusarium solani, Rhizomucor, Rhizopus, and Scedosporium apiospermum/Pseudallescheria boydii. One hundred ninety patients (78%) received antifungals during their initial admission and 99 (46%) of patients surviving their initial admission were discharged on antifungals. Only 66.7% of patients with a proven or probable IFI survived through 12 weeks, compared with 92.2% of those without (P = 0.007). Baseline absolute neutrophil count ≤500 cells/μL and longer duration of neutropenia were significantly associated with development of proven or probable IFIs.ConclusionAmong patients receiving induction chemotherapy for AML, IFIs due to Candida and mold remain frequent absent antifungal prophylaxis and are associated with worse survival. Our findings support the use of antifungal prophylaxis in this patient population.Disclosures All authors: No reported disclosures.