2189. Lefamulin 在 H1N1 流感病毒感染小鼠模型中的抗炎活性,Open Forum Infectious Diseases

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2189. Lefamulin 在 H1N1 流感病毒感染小鼠模型中的抗炎活性
Open Forum Infectious Diseases ( IF 3.8 ) Pub Date : 2022-12-15 , DOI: 10.1093/ofid/ofac492.1808
Wolfgang W Wicha ₁ , Sandy Kimber ₂ , Charlotte Cumper ₃ , Hon S Lam ₃ , Lorena S Ballesteros ₃ , Christopher Kirkham ₃ , Claire Richards ₃ , Steven P Gelone ₄ , Susanne Paukner ₄

Affiliation

背景 Lefamulin (LEF) 是美国 (US) FDA 批准用于治疗成人社区获得性细菌性肺炎的截短截短侧耳素抗生素。除了有效的抗菌活性外，LEF 还在 LPS 诱导的小鼠肺中性粒细胞增多症模型中表现出抗炎活性。我们研究了 lefamulin 在 H1N1 流感小鼠模型中与奥司他韦 (OTV) 和阿奇霉素 (AZM) 相比的抗炎活性。方法通过鼻内攻击 ~70 pfu 流感病毒 H1N1 A/PR/8/1934（第 0 天）对 BALB/c 小鼠进行感染。从第 -1 天开始使用临床相关剂量的药物治疗（LEF 70 mg/kg/天和 110/140 mg/kg/天，sc，AZM 30 mg/kg/天，i,p. 和 OTV 20 mg/kg /day po) 到第 6 天。在第 3 天和第 6 天，收集支气管肺泡灌洗液 (BALF) 以测量浸润的肺白细胞和细胞因子。感染后的肺免疫病理学在第 6 天通过终止时的大体病理学以及苏木精和伊红组织病理学进行评估。结果在未经治疗的载体对照动物中，流感感染如预期的那样进展，体重减轻，肺细胞浸润增加，TNF-α、IL-6 水平在第 3 天和第 6 天增加。LEF 治疗显着降低了总免疫细胞浸润到第 6 天，两种测试剂量均进入肺部（图左）。BALF 中的细胞因子水平在第 3 天病毒载量达到峰值时显着降低。此外，LEF 对肺大体病理学和存活率显示出积极影响。两种剂量的奥司他韦和 LEF，似乎能有效抑制流感引起的支气管间质性肺炎的发展，而阿奇霉素并未显示病理学降低（图右）。LEF、AZM 和 OTV 对感染 H1N1 流感病毒的 H1N1 感染小鼠 BALF 的抗炎作用。左图：第 0 天感染后肺部白细胞总浸润。条形代表平均值±SEM。右图：第 6 天肺部炎症和变性组织病理学评分。数据表示为平均组织病理学评分 + SEM (n=10)。对每个时间点运行单向方差分析，其中 Dunnett 与载体对照处理进行了多重比较。*表示p＜0.05的显着性水平。** 表示p＜0.01。结论 Lefamulin对急性流感病毒感染具有抗炎作用。流感感染后，LEF 能够显着降低肺部免疫病理学并改善小鼠的临床结果。该实验的结果与在 LPS 诱导的肺中性粒细胞增多症小鼠模型中观察到的结果一致。需要进一步的研究来评估 Lefamulin 的免疫调节潜力。Wolfgang W. Wicha，理学硕士，Nabriva Therapeutics：资助/研究支持|Nabriva Therapeutics：发明人|Nabriva Therapeutics：员工|Nabriva Therapeutics：股票/债券 Sandy Kimber，博士，Nabriva Therapeutics：资助/研究支持 Charlotte Cumper，理学士，Nabriva治疗学：资助/研究支持 Hon S. Lam，MSc，Nabriva Therapeutics：资助/研究支持 Lorena S. Ballesteros，理学硕士，Nabriva Therapeutics：资助/研究支持 Christopher Kirkham，博士，Nabriva Therapeutics：资助/研究支持 Claire Richards，

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2189. Anti-inflammatory Activity of Lefamulin in a Mouse Model of Influenza Virus H1N1 Infection

Background Lefamulin (LEF) is a pleuromutilin antibiotic approved by the United States (US) FDA for the treatment of community-acquired bacterial pneumonia in adults. In addition to the potent antibacterial activity, LEF has demonstrated anti-inflammatory activity in an LPS induced lung neutrophilia model in mice. We investigated the anti-inflammatory activity of lefamulin in the H1N1 influenza mouse model in comparison to oseltamivir (OTV) and azithromycin (AZM). Methods Infection was performed in BALB/c mice by intranasal challenge ∼70 pfu influenza virus H1N1 A/PR/8/1934 (Day 0). Treatment with drugs at clinically relevant doses started on Day -1 (LEF 70 mg/kg/day and 110/140 mg/kg/day, s.c., AZM 30 mg/kg/day, i,p. and OTV 20 mg/kg/day p.o.) to Day 6. On Days 3 and 6, bronchioalveolar lavage fluid (BALF) was collected to measure infiltrating lung leukocytes and cytokines. Lung immunopathology following infection was evaluated on Day 6 by gross pathology at termination together with hematoxylin and eosin histopathology. Results In untreated vehicle control animals, the influenza infection progressed as expected with bodyweight loss, increased cell infiltration into the lung and increased levels of TNF-α, IL-6 at day 3 and 6. Treatment with LEF significantly decreased the total immune cell infiltration into the lung by day 6 at both doses tested (Figure Left). Cytokine levels in the BALF were significantly reduced on day 3 when the viral load peaked. Furthermore, LEF showed positive effects on lung gross pathology and survival. Oseltamivir and LEF, at both doses, appeared efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin didn’t show reduced pathology (Figure Right). Anti-inflammatory effects of LEF, AZM and OTV in BALF of H1N1 infected mice infected with influenza virus H1N1. Left: Total lung leukocyte infiltrate following infection on day 0. Bars represent mean ± SEM. Right: Day 6 lung inflammation and degeneration histopathology score. Data are presented as mean histopathology score + SEM (n=10). One-way ANOVA, with Dunnett’s multiple comparisons against the vehicle control treatment was run for each timepoint. * represents significance level of p<0.05. ** indicates p<0.01. Conclusion Lefamulin showed anti-inflammatory treatment following acute influenza virus infection. Following influenza infection LEF was able to significantly reduce lung immunopathology and improve clinical outcome in mice. Results from this experiment were consistent with that observed in the LPS induced lung neutrophilia mouse model. Further studies are warranted to evaluate the immunomodulatory potential of Lefamulin. Disclosures Wolfgang W. Wicha, MSc, Nabriva Therapeutics: Grant/Research Support|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds Sandy Kimber, PhD, Nabriva Therapeutics: Grant/Research Support Charlotte Cumper, BSc, Nabriva Therapeutics: Grant/Research Support Hon S. Lam, MSc, Nabriva Therapeutics: Grant/Research Support Lorena S. Ballesteros, MSc, Nabriva Therapeutics: Grant/Research Support Christopher Kirkham, PhD, Nabriva Therapeutics: Grant/Research Support Claire Richards, PhD, Nabriva Therapeutics: Grant/Research Support Steven P. Gelone, PharmD, Nabriva Therapeutics: Board Member|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds|Nabriva Therapeutics: Stocks/Bonds Susanne Paukner, PhD, Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds.

更新日期：2022-12-15

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