Therapy For Invasive Aspergillosis Research Articles

The cytochrome P450 reductase CprA is a rate-limiting factor for Cyp51A-mediated azole resistance in Aspergillus fumigatus.

Azole antifungals remain the "gold standard" therapy for invasive aspergillosis. The world-wide emergence of isolates resistant to this drug class, however, developed into a steadily increasing threat to human health over the past years. In Aspergillus fumigatus, major mechanisms of resistance involve increased expression of cyp51A encoding one of two isoenzymes targeted by azoles. Yet, the level of resistance caused by cyp51A upregulation, driven by either clinically relevant tandem repeat mutations within its promoter or the use of high expressing heterologous promoters, is limited. Cytochrome P450 enzymes such as Cyp51A rely on redox partners that provide electrons for their activity. A. fumigatus harbors several genes encoding putative candidate proteins including two paralogous cytochrome P450 reductases, CprA and CprB, and the cytochrome b 5 CybE. In this work, we investigated the contribution of each cprA, cprB, and cybE overexpression to cyp51A-mediated resistance to different medical and agricultural azoles. Using the bidirectional promoter PxylP, we conditionally expressed these genes in combination with cyp51A, revealing cprA as the main limiting factor. Similar to this approach, we overexpressed cprA in an azole-resistant background strain carrying a cyp51A allele with TR34 in its promoter, which led to a further increase in its resistance. Employing sterol measurements, we demonstrate an enhanced eburicol turnover during upregulation of either cprA or cyp51A, which was even more pronounced during their simultaneous overexpression. In summary, our work suggests that mutations leading to increased Cyp51A activity through increased electron supply could be key factors that elevate azole resistance.

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.

Quandaries of deciding when to change first-line therapy in invasive pulmonary aspergillosis.

We read the excellent viewpoint by Slavin et al. (J Antimicrob Chemother 2022; 77: 16-23) that draws upon the experience of an advisory board of notable experts to comprehensively address many of the clinical factors that drive the need for changes in antifungal therapy for invasive aspergillosis (IA). As noted by the authors, there remains a paucity of quality data to support many of the decisions faced by clinicians managing patients with IA. However, we would like to highlight several other important issues, not fully addressed in that viewpoint, that play an important role in deciding when to change antifungal therapy for IA.

Monoclonal Antibodies and Invasive Aspergillosis: Diagnostic and Therapeutic Perspectives.

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most patients are either diagnosed as “possible” or “probable” cases but not “proven”. Moreover, because of the lack of sensitive and specific tests, many high-risk patients receive an empirical therapy or a prolonged treatment of high-priced antifungal agents, leading to unnecessary adverse effects and a high risk of drug resistance. More precise diagnostic techniques alongside a targeted antifungal treatment are fundamental requirements for reducing the morbidity and mortality of IA. Monoclonal antibodies (mAbs) with high specificity in targeting the corresponding antigen(s) may have the potential to improve diagnostic tests and form the basis for novel IA treatments. This review summarizes the up-to-date application of mAb-based approaches in assisting IA diagnosis and therapy.

Combination of invasive aspergillosis and mucormycosis in children: a case report and the results of a multicenter study

Objective. To study risk factors, etiology, clinical signs and treatment outcomes of invasive aspergillosis (IA) and mucormycosis combination (IAM) in children. Materials and Methods. A retrospective review of Saint-Petersburg register (1998–2021) of patients with IA was done and children with IAM were included. EORTC/MSGERG 2019 criteria were used for diagnosing and treatment results evaluation of invasive mycosis. We presented a clinical case of IAM in a child with acute lymphoblastic leukemia relapse. Results. A total of 12 children with IAM were included. They accounted 8% of all pediatric patients with invasive aspergillosis (n = 152). IAM was diagnosed in children with hematological malignancies and solid tumors from 4 to 16 years (median age – 11.5 years), mostly in girls (83%). Main risk factors of IAM were prolonged lymphopenia (75%, median 22 days) and neutropenia (67%, median 30 days) due to chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. The predominant etiological agents of IA were Aspergillus niger (33%), A. nidulans (33%) and A. fumigatus (17%), of mucormycosis – Lichtheimia corymbifera (50%) and Rhizomucor spp. (50%). Based on EORTC/MSGERG 2019 criteria, «proven» mucormycosis was diagnosed in 83% of patients, «probable» – in 17%. «Probable» IA was found in 100% of patients. The most common clinical sites of IAM were the lungs (75%) and paranasal sinuses (43%), multifocal involvement was revealed in 33% of patients. Mucormycosis developed during antifungal therapy of IA in 83% of patients. Antifungal therapy of mucormycosis received 75% of patients (amphotericin B lipid complex – 89%, posaconazole – 78%, caspofungin – 33%), combined antifungal therapy – 33%, surgery – 50%; combination of surgical and antifungal treatment was used in 42% of patients. The overall 12-week survival was 77.8%. The use of combined surgical and antifungal treatment significantly improved the survival of children with IAM (p = 0.023). Conclusions. Mucormycosis was diagnosed in 8% of children with IA. IAM developed mostly in patients with hematological malignancies (83%), prolonged lymphopenia (75%) and neutropenia (67%) against the background of chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. In 83% of patients mucormycosis was diagnosed during antifungal therapy for IA. The development of IAM increased overall 12-week mortality (50%). The combination of antifungal therapy with surgical treatment significantly improved prognosis of IAM (p = 0.023).

Invasive Aspergillosis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Large Cohort Single-Center Study

Background. Invasive aspergillosis (IA) is dominant among invasive fungal infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The emergence of new immunosuppressive drugs, the expanding use of antifungal agents with activity against Aspergillus spp. on the one hand, and the improvement of the diagnostics and therapy on the other hand affect epidemiology of IA.Methods. We analyzed 663 patients who underwent allo-HSCT from 2016 to 2020 years in CIC 725. During the observation period, 43 patients with proven and probable IA were included into analysis. According to EORTC/MSG 2019 criteria, 2 proven and 41 probable cases were diagnosed in adults with hematological malignances and non-malignant hematological diseases during 1 year after allo-HSCT. We characterized the IA after allo-HSCT and conducted the comparative analysis of patients and transplant characteristics who developed IA after allo-HSCT and did not. The median follow up time was 13,9 months.Results. Cumulative incidence of IA during 1-year period after allo-HSCT was 8%. Among all cases of IA most common underlying diagnoses were acute leukemia - 32% and lymphomas - 30%. The main sites of infection were lungs 93%, sinuses - 2%, disseminated lesions - 5%. The IA was diagnosed by bronchoalveolar (BAL) or sinuses liquid culture in 54% cases, and the etiology were Aspergillus fumigatus - 8 (42%), Aspergillus niger - 5 (26%), Aspergillus flavus - 2 (11%), Aspergillus terreus - 1 (5%), Aspergillus spp. - 3 (16%). The median day of IA onset was day +59 (range, 2 to 282) after allo-HSCT. First line therapy of IA was predominantly with voriconazole (vori) monotherapy - 35 (81%), combination based on vori - 5 (12%). Salvage combination therapy were prescribed in two patients: vori + echinocandins (echino) and L amph B + echino. Overall survival at 12 weeks in patients with IA was 76%. Comparative analysis showed that in patients with IA statistically significant more frequent were patients with AML, HL, NHL, Ph(-) MPNs, second or more allo-HSCT, CMV-reactivation, aGVHD, aGVHD grade 3-4, severe chGVHD (Table 1). To identify the risk factors including primary antifungal prophylaxis planning to conduct the multivariate subgroup analysis. Patients with IA had lower level of lymphocytes on day +60 (p=0.006) and 100 (p=0.009) compared to patients without IA (pic.1).Conclusions. Incidence of IA after allo-HSCT was 8% with the median day +59. The main site of infection was lungs, etiology - Aspergillus fumigatus. Overall survival at 12 weeks in patients with IA was 76%. In the era of primary and secondary prophylaxis we identified risk groups for developing IA after allo-HSCT among the previously undescribed, worthy of further study: subsequent allo-HSCT, underlying disease: HL, NHL, Ph (-) MPNs. [Display omitted] DisclosuresKlimko: Gilead Sciences, MSD, Pfizer Pharmaceuticals, and Astellas Pharma: Speakers Bureau; Gilead Science, MSD, Pfizer: Membership on an entity's Board of Directors or advisory committees. Kulagin: Pfizer: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau.

Invasive Aspergillosis in Chronic Lymphocytic Leukemia: Therapy and Outcomes

Background: Despite the introduction of novel non-cytotoxic therapies (such as ibrutinib, idelalisib and venetoclax) for the treatment of patients with CLL, opportunistic fungal infections such as Pneumocystis jiroveci and aspergillosis are reported in these patients (Ahn, Blood, 2016; Lionakis, Cancer Cell, 2017). The clinical characteristics and outcomes of chronic lymphocytic leukemia (CLL) patients (pts) who develop invasive aspergillosis (IA) are not well described in the literature.Methods: The Mayo Clinic CLL database was queried to identify CLL pts who had either a positive aspergillus culture or a positive galactomannan antigen test result between 1/1995-12/2016. We applied the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria to categorize pts to have either proven or probable IA. Patients who developed IA after an allogeneic stem cell transplant were excluded. The Mayo Clinic IRB approved this study.Results: 123 CLL pts met the inclusion criteria for this study with either a positive aspergillus culture or a positive galactomannan antigen test. Among these, 93 pts had asymptomatic antigenemia or colonization and were not included in the analysis. Thirty pts (34%) had a diagnosis of clinically significant aspergillosis, 14 pts with proven IA and 16 pts with probable IA. The baseline characteristics at the time of IA diagnosis are shown in Table 1. At the time of IA diagnosis, the median serum IgG was 332 mg/dL and median ANC was 1.5 x109/L.The median time from CLL diagnosis to IA diagnosis was 7.1 years (range: 0.15-17.59 years). The diagnosis of IA was made via both culture and antigen (Ag) in 7/30 pts (23%), culture alone in 18/30 pts (60%) and Ag alone in 6/30 pts (20%). Invasive pulmonary aspergillosis was the most frequent syndrome, seen in 28 pts (93%). In addition, there were 3 pts with invasive sinus aspergillosis, including one case with both pulmonary and sinus infection.Among those who received prior chemotherapy (N=23), the median time from last documented CLL directed therapy to diagnosis of IA was 3.5 months (range: 0.3-53.1 months). The most recent CLL treatment prior to IA diagnosis included: chemoimmunotherapy in 9 pts (39%), chemotherapy alone in 4 pts (17%), rituximab with high dose steroids in 3 pts (13%), alemtuzumab in 2 pts (9%), and ibrutinib in 5 pts (22%). Of the 5 patients diagnosed with IA while on Ibrutinib, 3 pts had proven IA and 2 pts had probable IA. The median duration between initiation of ibrutinib and diagnosis of IA was 2.5 months (0.03-21 months).No patient received antifungal prophylaxis prior to the diagnosis of IA. Therapy for IA consisted of voriconazole monotherapy in 16 pts (53%), 5 pts (17%) received voriconazole in combination with caspofungin, 4 pts (13%) voriconazole in combination with amphotericin, 2 pts (7%) amphotericin alone, and 3 pts (7%) died prior to receiving anti-fungal therapy. The median overall survival from IA diagnosis was 11.2 months. After a median follow-up of 9.3 months, 20 pts (67%) died: 9 pts (45%) died secondary to uncontrolled IA infection, 4 (20%) due to Pseudomonas aeruginosa bacteremia, 4 (20%) due to CLL progression, 2 (10%) due to concomitant fungal infections (Cryptococcus and Mucor), and 1 (6%) due to respiratory failure. None of the CLL specific prognostic markers were associated with OS.Conclusion: Invasive aspergillosis is a rare but devastating complication in CLL patients. In this large retrospective study, median overall survival following IA diagnosis is <1 year. Better tools at identifying potential risk factors and prophylaxis are important to prevent IA infection among CLL patients, to improve outcomes. [Display omitted] DisclosuresDing:Merck: Research Funding. Kay:Pharmacyclics: Research Funding; Gilead: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Tolero Corporation: Research Funding. Shanafelt:Genentech: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Hospira: Research Funding; Jannsen: Research Funding; Pharmacyclics: Research Funding. Parikh:Pharmacyclics: Research Funding; Pharmacyclics: Honoraria; AstraZeneca: Honoraria.

Prevalence of Azole-Resistant Aspergillus fumigatus is Highly Associated with Azole Fungicide Residues in the Fields.

Triazole resistance in Aspergillus fumigatus is a growing public health concern. In addition to its emergence in the therapy of invasive aspergillosis by triazole medicines, it has been frequently detected in agricultural fields all over the world. Here, we explore the potential link between residues of azole fungicides with similar chemical structure to triazole medicines in soil and the emergence of resistant A. fumigatus (RAF) through 855 500 km2 monitoring survey in Eastern China covering 6 provinces. In total, 67.3%, 15.2%, 12.3%, 2.9%, 1.5%, 0.4%, and 0.3% of the soil samples contained these five fungicides (tebuconazole, difenoconazole, propiconazole, hexaconazole, and prochloraz) of 0-100, 100-200, 200-400, 400-600, 600-800, 800-1000, and >1000 ng/g, respectively. The fractions of samples containing RAF isolates were 2.4%, 5.2%, 6.4%, 7.7%, 7.4%, 14.3%, and 20.0% of the samples with total azole fungicide residues of 0-100, 100-200, 200-400, 400-600, 600-800, 800-1000, and >1000 ng/g, respectively. We find that the prevalence of RAFs is positively (P < 0.0001) correlated with residual levels of azole fungicides in soils. Our results suggest that the use of azole fungicides in agriculture should be minimized and the intervals between treatments expanded to reduce the selective pressure toward the development of resistance in A. fumigatus in agricultural fields.

Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis.

Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients.

Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated AST-IDCOP guidelines provide information on epidemiology, diagnosis, and management of Aspergillus after organ transplantation. Aspergillus is the most common invasive mold infection in solid-organ transplant (SOT) recipients, and it is the most common invasive fungal infection among lung transplant recipients. Time from transplant to diagnosis of invasive aspergillosis (IA) is variable, but most cases present within the first year post-transplant, with shortest time to onset among liver and heart transplant recipients. The overall 12-week mortality of IA in SOT exceeds 20%; prognosis is worse among those with central nervous system involvement or disseminated disease. Bronchoalveolar lavage galactomannan is preferred for the diagnosis of IA in lung and non-lung transplant recipients, in combination with other diagnostic modalities (eg, chest CT scan, culture). Voriconazole remains the drug of choice to treat IA, with isavuconazole and lipid formulations of amphotericin B regarded as alternative agents. The role of combination antifungals for primary therapy of IA remains controversial. Either universal prophylaxis or preemptive therapy is recommended in lung transplant recipients, whereas targeted prophylaxis is favored in liver and heart transplant recipients. In these guidelines, we also discuss newer antifungals and diagnostic tests, antifungal susceptibility testing, and special patient populations.

Correction: Combination Antifungal Therapy for Invasive Aspergillosis

Correction: Combination Antifungal Therapy for Invasive Aspergillosis

Treating invasive aspergillosis in patients with hematologic malignancy: diagnostic-driven approach versus empiric therapies

BackgroundEarly antifungal therapy for invasive aspergillosis (IA) has been associated with improved outcome. Traditionally, of empiric antifungal therapy has been used for clinically suspected IA. We compared outcomes of patients with hematologic malignancy and IA who were treated with voriconazole using the diagnostic driven DDA (DDA-Vori) that includes galactomannan testing vs. empiric therapy with a non-voriconazole-containing regimen (EMP-non-Vori) or empiric therapy with voriconazole (EMP-Vori).MethodsWe retrospectively reviewed the medical records of 342 hematologic malignancy patients diagnosed with proven, or probable IA between July 1993 and February 2016 at our medical center who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all-cause mortality, and IA-attributable mortality.ResultsBy multivariate analysis, factors predictive of a favorable response included localized/sinus IA vs. disseminated/pulmonary IA (p < 0.0001), not receiving white blood cell transfusion (p < 0.01), and DDA-Vori vs. EMP-non-Vori (p < 0.0001). In contrast, predictors of mortality within 6 weeks of initiating IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (p < 0.01), not undergoing stem cell transplantation within 1 year before IA (p = 0.01), and EMP-non-Vori vs. DDA-Vori (p < 0.001).ConclusionsDDA-Vori was associated with better outcome (response and survival) compared with EMP-non-Vori and with equivalent outcome to EMP-Vori in hematologic malignancy patients. These outcomes associated with the implementation of DDA could lead to a reduction in the unnecessary costs and adverse events associated with the widespread use of empiric therapy.

968. Managing Invasive Aspergillosis in the Era of Diagnostic PCR and Increasing Triazole Resistance: A Modeling Study of Different Strategies

BackgroundTriazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of invasive Aspergillosis (IA) worldwide. New polymerase chain reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole resistance on a genetic level, which opened up new possibilities for targeted therapy. In the absence of clinical trials, a modeling study delivers estimates of the added value of resistance detection with PCR and which empiric therapy would be optimal when local resistance rates are known.MethodsWe performed a decision-analytic modeling study based on epidemiological data of IA, extended with estimated dynamics of resistance rates and treatment effectiveness. We compared 6 clinical strategies that differ in the use of PCR diagnostics (A: not used, B: used) and in empiric therapeutic choice in case of unknown triazole susceptibility: Voriconazole (1, VOR), Liposomal Amphotericin B (2, LAmB), or both (3). Outcome measures were proportion of correct treatment, survival, and serious adverse events.ResultsImplementing Aspergillus PCR tests was projected to result in residual treatment susceptibility mismatches of <5% for a triazole resistance rate up to 20% (using VOR). Empiric LAmB outperformed VOR at resistance rates higher than 5–20%, depending on PCR use and estimated survival benefits of VOR over LAmB (Figure 1). Combination therapy of VOR and LAmB performed best at all resistance rates but the advantage over the other strategies should be weighed against the expected increased number of drug-related serious adverse events (Figure 2). The advantage of combination therapy over LAmB monotherapy became smaller at higher triazole-resistance rates.ConclusionIntroduction of current Aspergillus PCR tests on BAL-fluid is an effective way to increase the proportion of patients that receive targeted therapy for IA. The results indicate that close monitoring of background resistance rates and of adverse drug events are important to attain the potential benefits of LAmB. The choice of strategy ultimately depends on the probability of triazole resistance, the availability of PCR, and individual patient characteristics. Disclosures All authors: No reported disclosures.

Managing invasive aspergillosis in haematological patients in the era of resistance polymerase chain reaction and increasing triazole resistance: A modelling study of different strategies

Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of invasive aspergillosis (IA) worldwide. New polymerase chain reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole resistance at a genetic level, which has opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR, and which empiric therapy would be optimal when local resistance rates are known. A decision-analytic modelling study was performed based on epidemiological data of IA, extended with estimated dynamics of resistance rates and treatment effectiveness. Six clinical strategies were compared that differ in use of PCR diagnostics (used vs not used) and in empiric therapeutic choice in case of unknown triazole susceptibility: voriconazole, liposomal amphotericin B (LAmB) or both. Outcome measures were proportion of correct treatment, survival and serious adverse events. Implementing aspergillus PCR tests was projected to result in residual treatment-susceptibility mismatches of <5% for a triazole resistance rate up to 20% (using voriconazole). Empiric LAmB outperformed voriconazole at resistance rates >5-20%, depending on PCR use and estimated survival benefits of voriconazole over LAmB. Combination therapy of voriconazole and LAmB performed best at all resistance rates, but the advantage over the other strategies should be weighed against the expected increased number of drug-related serious adverse events. The advantage of combination therapy over LAmB monotherapy became smaller at higher triazole resistance rates. Introduction of current aspergillus PCR tests on BAL fluid is an effective way to increase the proportion of patients that receive targeted therapy for IA. The results indicate that close monitoring of background resistance rates and adverse drug events are important to attain the potential benefits of LAmB. The choice of strategy ultimately depends on the probability of triazole resistance, the availability of PCR and individual patient characteristics.

Comparing Diagnostic-Driven Approaches to Empiric Therapy in the Treatment of Invasive Aspergillosis in Patients with Hematologic Malignancy

Background Early antifungal therapy of invasive aspergillosis (IA) has been shown to be associated with improved outcome. Given the difficulty to establish the diagnosis of IA based on conventional methods, early initiation of empiric antifungal therapy has been used in patients with clinically suspected IA. Diagnostic-driven approach (DDA) relies on using novel diagnostic methods (e.g., early galactomannan testing). In this current study, we compared the outcomes of hematological malignancy (HM) patients with IA who were treated with Voriconazole using the DDA (DDA-Vori) vs. empiric therapy with a non-Voriconazole containing regimen (EMP-non-Vori) or empiric therapy with Voriconazole (EMP-Vori).Methods We retrospectively reviewed the medical records of 604 HM patients with documented, proven or probable IA (according to EORTC/MSG criteria) diagnosed between July, 1993 and February, 2016 at our center. We included 346 patients with underlying host factors, a suggestive CT findings of IA, and positive biopsy, fungal culture or galactomannan indicative of IA, and who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all causing mortality and IA attributable mortality.ResultsThe patients’ median age was 54 years and 59% were males. By multivariate analysis, factors that were predictive of a favorable response included: localized/sinus IA vs. disseminated/pulmonary IA (P < 0.0001), not receiving WBC transfusion (P < 0.01), and DDA-VORI vs. EMP-non-Vori (P < 0.0001). On the other hand, predictors of mortality within 6 weeks of initiation of IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (P < 0.01), not having stem-cell transplant within 1 year prior of IA (P = 0.01) and EMP-non-Vori vs. DDA-Vori (P < 0.001).Conclusion DDA-Vori is associated with a better outcome (response and survival) when compared with EMP-non-Vori and equivalent outcome to EMP-Vori. The superior to equivalent outcome associated with the DDA approach could also reduce unnecessary costs and adverse events associated with widespread use of empiric therapy.Disclosures I. Raad, Merck: Grant Investigator, Research grant. Allergan: Grant Investigator, Research grant. Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty

Orphan drugs for the treatment of aspergillosis: focus on isavuconazole

Orphan drugs for the treatment of aspergillosis: focus on isavuconazole Samantha E Jacobs,1 Vidmantas Petraitis,1 Catherine B Small,1 Thomas J Walsh1–3 1Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, 2Department of Pediatrics, 3Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA Abstract: Invasive aspergillosis (IA) is a particularly devastating manifestation of Aspergillus infection affecting profoundly immunocompromised patients. Voriconazole has been approved as first-line therapy for IA since 2003; however, nonlinear pharmacokinetics, adverse effects, and drug–drug interactions at time hinder its use. Isavuconazole is a new broad-spectrum triazole with potent activity against Aspergillus species. In animal models and clinical trials in humans, isavuconazole has shown comparable efficacy to that of voriconazole in the treatment of IA. Advantages of isavuconazole include a more favorable pharmacokinetic profile and fewer adverse events. This review summarizes the pharmacologic characteristics, in vitro activity, and clinical data supporting the use of isavuconazole as an emerging alternative therapy for IA. Keywords: isavuconazole, invasive aspergillosis, antifungal therapy, fungal infection

FunResDB-A web resource for genotypic susceptibility testing of Aspergillus fumigatus.

Therapy of invasive aspergillosis is becoming more difficult due to the emergence of azole resistance in Aspergillus fumigatus. A majority of resistant strains carries mutations in the CYP51A gene. Due to a lack of sensitivity of culture-based methods, molecular detection of A. fumigatus has become an important diagnostic tool. We set up the database FunResDB (www.nrz-myk.de/funresdb) to gather all available information about CYP51A-dependent azole resistance from published literature. In summary, the screening resulted in 79 CYP51A variants, which are linked to 59 nonsynonymous mutations. A tailor-made online sequence analysis tool allows for genotypic susceptibility testing of A. fumigatus.

Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain

ObjectiveAccording to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System.MethodsAn economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables.ResultsAccording to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763–16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively.ConclusionAccording to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan-positive patients in Spain who have hematologic disease or hematopoietic stem cell transplant, compared with VOR monotherapy.

Combination Antifungal Therapy for Invasive Aspergillosis Among Patients with Hematopoietic Cell Transplantation and Positive Galactomannan

Combination Antifungal Therapy for Invasive Aspergillosis Among Patients with Hematopoietic Cell Transplantation and Positive Galactomannan

Voriconazole Therapeutic Drug Monitoring Among Lung Transplant Recipients Receiving Targeted Therapy for Invasive Aspergillosis

Voriconazole Therapeutic Drug Monitoring Among Lung Transplant Recipients Receiving Targeted Therapy for Invasive Aspergillosis