Estimating the value of new antibiotic treatment strategies in Zhejiang province, China: cost-effectiveness analysis based on a validated dynamic model.

OBJECTIVES: This analysis aims to better reflect the value of new antibiotic treatment strategies, thereby informing clinical antibiotic use, antimicrobial reimbursement and/or hospital formulary decision-making in China. DESIGN: We adapted a published and validated dynamic disease transmission and cost-effectiveness model to evaluate the clinical and economic outcomes of introducing a new antibiotic, ceftazidime/avibactam (CAZ-AVI) for treating resistant infections in Zhejiang province, China. Outcomes were assessed over a 10-year infectious period and an annual discount rate of 5%. Costs were extracted from the hospital's Health Information System (HIS) and obtained after data cleaning, aggregation and discounting. SETTING: The Chinese healthcare system perspective. PARTICIPANTS: 10 905 patients in a Chinese tier-3 hospital from 2018 to 2021 with any of the three common infections (complicated intra-abdominal infection (cIAI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) and infections with limited treatment options (LTO)) caused by three common resistant pathogens (Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa). INTERVENTIONS: (1) Current treatment strategy (piperacillin-tazobactam (pip/taz) and meropenem); (2) CAZ-AVI at the third line; (3) CAZ-AVI at the second line; (4) CAZ-AVI at the first line; (5) CAZ/AVI first line, two lines diversified (i.e., equal pip/taz and CAZ-AVI at the first line; meropenem at the last line) and (6) CAZ/AVI first line, all-lines diversified. PRIMARY OUTCOME MEASURES: Quality-adjusted life years (QALYs) lost, hospitalisation costs and incremental net monetary benefit (INMB) were used to assess cost-effectiveness. RESULTS: Over 10 years, the introduction of CAZ-AVI to the current treatment strategy led to lower hospitalisation costs and more QALYs across all five treatment strategies, with between 68 284 and 78 571 QALYs gained whilst saving up to US$236.37 for each additional QALY gained. The INMB of introducing CAZ-AVI is estimated up to US$3 550 811 878. CONCLUSIONS: Introducing CAZ-AVI had a positive impact on clinical and economic outcomes for treating antimicrobial resistance, and diversifying the antibiotics use early in the treatment might yield the best benefits.

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present in newly diagnosed acute myeloid leukemia (AML) patients with an incidence rate of approximately 30%. Recently, many FLT3 inhibitors have been developed and exhibit positive preclinical and clinical effects against AML. However, patients develop resistance soon after undergoing FLT3 inhibitor treatment, resulting in short durable responses and poor clinical effects. This review will discuss the main mechanisms of resistance to clinical FLT3 inhibitors and summarize the emerging strategies that are utilized to overcome drug resistance. Basically, medicinal chemistry efforts to develop new small-molecule FLT3 inhibitors offer a direct solution to this problem. Other potential strategies include the combination of FLT3 inhibitors with other therapies and the development of multitarget inhibitors. It is hoped that this review will provide inspiring insights into the discovery of new AML therapies that can eventually overcome the resistance to current FLT3 inhibitors.

Discovery of benzo[d]oxazole derivatives as the potent type-I FLT3-ITD inhibitors.

Fms-like tyrosine kinase 3 (FLT3) has been considered as a potential drug target for the treatment of acute myeloid leukemia (AML), because of its high and aberrant expression in AML patients, especially the patients with FLT3-ITD mutation. Initiating from a hit compound (IC50: 500 nM against FLT3-ITD), a series of compounds were designed and synthesized based on benzo[d]oxazole-2-amine scaffold to discover new potent FLT3-ITD inhibitors. During the medicinal chemistry works, flexible molecular docking was used to provide design rationale and study the binding modes of the target compounds. Through the mixed SAR exploration based on the enzymatic and cellular activities, compound T24 was identified with potent FLT3-ITD inhibitory (IC50: 0.41 nM) and anti-proliferative (IC50: 0.037 µM against MV4-11 cells) activities. And the binding mode of T24 with "DFG-in" FLT3 was simulated by a 20-ns molecular dynamics run, providing some insights into further medicinal chemistry efforts toward novel FLT3 inhibitors in AML therapy.