Clinical experience with isavuconazole in healthy volunteers and patients with invasive aspergillosis in China, and the results from an exposure-response analysis.

BACKGROUND: Isavuconazole is a broad-spectrum triazole for the treatment of invasive fungal disease (IFD). OBJECTIVE: To investigate the clinical experience with isavuconazole in Chinese individuals. PATIENTS/METHODS: Participants were Chinese healthy volunteers from a Phase I pharmacokinetics (PK) and safety study of single/multiple doses of isavuconazole (n = 36) and Chinese patients from the global Phase III SECURE study that assessed safety and efficacy of isavuconazole vs voriconazole for IFD treatment (n = 26). RESULTS: No clinically relevant differences in PK were found between Chinese and Western participants, although exposure was increased in Chinese volunteers. Treatment-emergent adverse events (TEAEs) were reported in 75.0% of healthy volunteers, many of which were infusion-related. No serious AEs were reported. In SECURE, findings in Chinese patients (n = 26) were similar to the global population. For patients who received ≥1 dose of study drug, allcause mortality from first dose to Day 42 was 10.0% (1/10) with isavuconazole and 25.0% (4/16) with voriconazole (treatment difference [95% confidence interval, CI]: -15.0% [-43.2%, 13.2%]). Overall response at the end of treatment for patients with proven/probable IFD was 25.0% and 16.7% with isavuconazole and voriconazole, respectively (treatment difference [95% CI] -8.3% [-60.2%, 43.5%]). Isavuconazole was associated with lower incidence of hepatobiliary, eye, skin, subcutaneous tissue and psychiatric disorders compared with voriconazole and lower incidence of treatment-related TEAEs, serious TEAES or death overall. CONCLUSIONS: Although further research is required, this study demonstrated a favourable risk-benefit profile of isavuconazole in Chinese patients.

Dectin-1 rs3901533 and rs7309123 Polymorphisms Increase Susceptibility to Pulmonary Invasive Fungal Disease in Patients with Acute Myeloid Leukemia from a Chinese Han Population.

This study aimed to assess whether genetic variants of dendritic cell-associated C-type lectine-1 (Dectin-1), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) influence the susceptibility to pulmonary invasive fungal disease (IFD) in patients with acute myeloid leukemia (AML) from a Chinese Han population. Eight single nucleotide polymorphisms (SNPs) of Dectin-1 (rs16910526, rs3901533, and rs7309123), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) and MyD88 (rs4988453 and rs4988457) in the genomic DNA of 172 adult AML patients were genotyped. Pulmonary IFD was diagnosed as proven or probable according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus guidelines. SNPs that were significant in the univariate analysis were further analyzed using the multiple logistic regression analysis to determine their association with the occurrence of pulmonary IFD. The mRNA expression of Dectin-1 was detected according to the genotype by quantitative realtime PCR (qRT-PCR), and the correlation of this expression with the occurrence of pulmonary IFD in AML patients was analyzed. Two Dectin-1 intron SNPs (rs3901533 and rs7309123) were found to be significantly associated with the susceptibility to pulmonary IFD in AML patients in a Chinese Han population. Significant associations were noted between pulmonary IFD and Dectin-1 rs3901533 dominant model (G/T+G/G vs. T/T, OR: 2.158; 95% CI: 1.109-4.2, P=0.02), Dectin-1 rs3901533 G allele (OR: 2.201; 95% CI: 1.206-4.019, P=0.01), or Dectin-1 rs7309123 C allele (OR: 1.919; 95% CI: 1.047-3.518, P=0.03). There were no significant associations between pulmonary IFD and the remaining Dectin-1 SNPs (rs16910526), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) or MyD88 (rs4988453 and rs4988457). In conclusion, two Dectin-1 SNPs (rs3901533 and rs7309123) are associated with increased susceptibility to pulmonary IFD in AML patients in a Chinese Han population.

Invasive mycoses in patients with connective tissue disease from Southern China: clinical features and associated factors.

BACKGROUND: A retrospective study was performed to investigate the clinical features and associated factors of invasive mycoses (IM) in patients with connective tissue disease (CTD) from Southern China. METHODS: Demographic and clinical data were recorded. Associated factors were analyzed by logistic regression analysis. RESULTS: A total of 6911 patients with CTD were included. IM was diagnosed in 32 patients (incidence, 0.5%). IM was predominant in patients with ANCA-associated vasculitis (AAV) (incidence, 1.5%, 7/480). Lung was commonly involved (30/32, 93.8%). Aspergillus spp. (81.3%) were the leading strain. The positive rate of fungi detection in sputum culture was 69.0%. Serum galactomannan (GM) test was positive in bronchoalveolar lavage fluid (BALF) from seven (7/10, 70.0%) patients. Ten patients died (31.3%), including three with AAV (42.9%) and seven with SLE (36.8%). Penicillium marneffei was the most fatal (mortality, 100%). Non-survivors had higher prevalence of leukopenia (30.0% vs 4.5%, P = 0.04), lymphopenia (100.0% vs 59.1%, P = 0.02), elevated serum creatinine (70.0% vs 27.3%, P = 0.02), and co-infection (70.0% vs 18.2%, P = 0.004) than survivors. Multivariate logistic regression analysis showed that lymphopenia [odds ratio (OR) = 3.28, 95% confidence interval (CI) 1.29-8.38, P = 0.01] and median-to-high dose of glucocorticoid (GC) [OR = 3.40, 95% CI 1.04-11.13, P = 0.04] were associated with IM in patients with CTD. CONCLUSIONS: IM tended to develop in patients with AAV, resulting in high mortality. Sputum culture and GM test in BALF were effective methods to distinguish IM. Vigilance against lymphopenia, impaired kidney function, and co-infection improved the prognosis of IM.

Factors Associated to Invasive Fungal Infection in Hispanic Patients with Hematological Malignancies.

Fungal infections represent a serious complication for immunosuppressed patients resulting in an increased morbidity and mortality. A non-concurrent prospective study was performed to evaluate the factors associated to invasive fungal infection (IFI) in patients with hematological malignancies admitted to the University Hospital in San Juan, Puerto Rico from January 1st, 2011 through June 15th, 2014. The medical records of 84 patients were evaluated. Fifty-nine patients with IFI and twenty-five without IFI. The majority were men between 35 to 55 years old. The main hematological diagnosis was acute myelogenous leukemia (AML) followed by acute lymphoblastic leukemia (ALL). Seventy-percent developed IFI. The most common fungi were C. albicans followed by non-albicans species, Fusarium and, Aspergillus species, respectively. About 63% of the patients with AML and 81% without AML had IFI. Those who received steroids were more likely to develop IFI. After adjusting for AML and age, the odds of IFI among patients using steroids were 3.33 higher than those not using steroids. Patients who were exposed to different antifungal medication had 72% lower odds to develop IFI.

Economic evaluation of azoles as primary prophylaxis for the prevention of invasive fungal infections in Spanish patients undergoing allogeneic haematopoietic stem cell transplant.

Patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of developing invasive fungal infections (IFIs). Even with introduction of oral triazole antifungal agents (fluconazole, itraconazole, posaconazole and voriconazole) IFI-associated morbidity and mortality rates and economic burden remain high. Despite their proven efficacy, it is currently unknown which is the most cost-effective antifungal prophylaxis (AFP) agent. To determine the costs and outcomes associated with AFP, a decision-analytic model was used to simulate treatment in a hypothetical cohort of 1000 patients undergoing alloHSCT from the perspective of the Spanish National Health System. Generic itraconazole was the least costly AFP (€162) relative to fluconazole (€500), posaconazole oral suspension (€8628) or voriconazole (€6850). Compared with posaconazole, voriconazole was associated with the lowest number of breakthrough IFIs (36 vs 60); thus, the model predicted fewer deaths from breakthrough IFI for voriconazole (24) than posaconazole (33), and the lowest predicted costs associated with other licensed antifungal treatment and IFI treatment in a cohort of 1000. Voriconazole resulted in cost savings of €4707 per patient compared with posaconazole. Itraconazole demonstrated a high probability of being cost-effective. As primary AFP in alloHSCT patients 180 days posttransplant, voriconazole was more likely to be cost-effective than posaconazole regarding cost per additional IFI and additional death avoided.