Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.02476-20.
Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug-resistant breakthrough infections are common in some institutions despite the use of echinocandins as first-line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological properties and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in liver tissues in a clinically relevant IAC mouse model infected with Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however, robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multiday FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.
腹腔内念珠菌病 (IAC) 是最常见但未被充分认识的侵袭性念珠菌病形式之一。尽管使用棘白菌素作为一线药物，但 IAC 治疗困难，在一些机构中，治疗失败和耐药性突破感染很常见。福司莫格匹酯 (FMGX，前身为 APX001) 是一种首创的抗真菌前药，可静脉内和口服给药。FMGX 目前处于治疗危及生命的侵袭性真菌感染的 2 期临床开发阶段。为了探索 FMGX 治疗 IAC 的药理学特性和治疗潜力，我们评估了在感染有 Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) 的临床相关 IAC 小鼠模型中，活性物质马尼格匹酯 (MGX，前身为 APX001A) 的药物渗透和疗效。激光捕获显微切割 (LCM) 直接绝对药物定量用于评估药物渗透到肝脓肿病变的空间和定量。单次给药后，MGX 进入病变的分配过程缓慢；然而，重复给药 3 天后，在病变中实现了强大的积累。与这种药物渗透模式相关，接受多日 FMGX 方案治疗的小鼠观察到真菌负荷减少和肝脏清除。相比之下，给予米卡芬净治疗在 4 天治疗结束时仅使真菌负荷略有减少。这些结果表明，FMGX 是治疗 IAC 的有前途的候选药物。
