Vineet Dubey, Nicola Farrington, Nicholas Harper, Adam Johnson, Iona Horner, Adam Stevenson, Annie Parkes, Lewis Hoare, Shampa Das, William Hope
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Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (<i>f</i>T > MIC). AB5075 and the AB5075<i>Δoxa-23</i> mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases <i>oxa-24/40</i> and <i>oxa-58</i> had an MIC of 64 mg/L. The metallo-β-lactamases <i>imp-1</i>, <i>vim-2</i>, and <i>ndm-1</i> had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed <i>in vivo</i> growth in the range of 0.75-1.4 log. The response to meropenem was consistent with the varying <i>f</i>T > MIC of the transformants and was readily described by an inhibitory sigmoid <i>E</i><sub>max</sub> relationship. Stasis was achieved with a <i>f</i>T > MIC of 0.36. These <i>A. baumannii</i> transformants are invaluable new tools for the assessment of anti-<i>Acinetobacter</i> compounds and provide a new pathway for AMR preparedness.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<i>Acinetobacter baumannii</i> transformants expressing oxacillinases and metallo-β-lactamases that confer resistance to meropenem: new tools for anti-<i>Acinetobacter</i> drug development and AMR preparedness.\",\"authors\":\"Vineet Dubey, Nicola Farrington, Nicholas Harper, Adam Johnson, Iona Horner, Adam Stevenson, Annie Parkes, Lewis Hoare, Shampa Das, William Hope\",\"doi\":\"10.1128/aac.00222-24\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Antimicrobial resistance (AMR) in <i>Acinetobacter baumannii</i> is an unmet medical need. Multiple drug-resistant/extremely drug-resistant strains of <i>A. baumannii</i> do not display growth well in <i>in vivo</i> models, and consequently, their response to antibacterial therapy is inconsistent. We addressed this issue by engineering carbapenem resistance motifs into the highly virulent genetic background of <i>A. baumannii</i> AB5075. This strain has a chromosomally encoded <i>oxa-23</i> that was deleted (<i>Δoxa-23</i>), then plasmids expressing <i>oxa-23</i>, <i>oxa-24/40</i>, <i>oxa-58</i>, <i>imp-1</i>, <i>vim-2</i>, and <i>ndm-1</i> were introduced to create the mutant strains. Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (<i>f</i>T > MIC). AB5075 and the AB5075<i>Δoxa-23</i> mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases <i>oxa-24/40</i> and <i>oxa-58</i> had an MIC of 64 mg/L. The metallo-β-lactamases <i>imp-1</i>, <i>vim-2</i>, and <i>ndm-1</i> had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed <i>in vivo</i> growth in the range of 0.75-1.4 log. The response to meropenem was consistent with the varying <i>f</i>T > MIC of the transformants and was readily described by an inhibitory sigmoid <i>E</i><sub>max</sub> relationship. Stasis was achieved with a <i>f</i>T > MIC of 0.36. 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引用次数: 0
摘要
鲍曼不动杆菌的抗菌药耐药性(AMR)是一项尚未满足的医疗需求。鲍曼不动杆菌的多重耐药/极端耐药菌株在体内模型中生长不良,因此它们对抗菌治疗的反应也不一致。为了解决这个问题,我们在鲍曼不动杆菌 AB5075 的高毒力遗传背景中加入了碳青霉烯耐药基因。该菌株染色体编码的oxa-23被删除(Δoxa-23),然后引入表达oxa-23、oxa-24/40、oxa-58、imp-1、vim-2和ndm-1的质粒来创建突变菌株。在嗜中性粒细胞小鼠大腿感染模型中,将每个转化株用作挑战株,评估其生长程度以及对每 6 小时皮下注射 200 毫克/千克(q6h)美罗培南的反应。药效学分析是通过将药物暴露量从剂量(毫克/千克)转化为给药间隔的分数来进行的;游离美罗培南浓度大于最低抑菌浓度(MIC)(fT > MIC)。AB5075 和 AB5075Δoxa-23 突变体的 MIC 分别为 32 毫克/升和 4 毫克/升。携带氧青霉素酶 oxa-24/40 和 oxa-58 的转化体的 MIC 为 64 毫克/升。金属-β-内酰胺酶 imp-1、vim-2 和 ndm-1 的 MIC 分别为 128、64 和 64 mg/L。所有经载体处理的转化株在体内的生长都在 0.75-1.4 log 的范围内。转化株对美罗培南的反应与转化株不同的 fT > MIC 值一致,并且很容易用抑制性的乙型曲线最大值关系来描述。当 fT > MIC 为 0.36 时,可达到抑制作用。这些鲍曼不动杆菌转化株是评估抗鲍曼不动杆菌化合物的宝贵新工具,并为防备 AMR 提供了一条新途径。
Acinetobacter baumannii transformants expressing oxacillinases and metallo-β-lactamases that confer resistance to meropenem: new tools for anti-Acinetobacter drug development and AMR preparedness.
Antimicrobial resistance (AMR) in Acinetobacter baumannii is an unmet medical need. Multiple drug-resistant/extremely drug-resistant strains of A. baumannii do not display growth well in in vivo models, and consequently, their response to antibacterial therapy is inconsistent. We addressed this issue by engineering carbapenem resistance motifs into the highly virulent genetic background of A. baumannii AB5075. This strain has a chromosomally encoded oxa-23 that was deleted (Δoxa-23), then plasmids expressing oxa-23, oxa-24/40, oxa-58, imp-1, vim-2, and ndm-1 were introduced to create the mutant strains. Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (fT > MIC). AB5075 and the AB5075Δoxa-23 mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases oxa-24/40 and oxa-58 had an MIC of 64 mg/L. The metallo-β-lactamases imp-1, vim-2, and ndm-1 had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed in vivo growth in the range of 0.75-1.4 log. The response to meropenem was consistent with the varying fT > MIC of the transformants and was readily described by an inhibitory sigmoid Emax relationship. Stasis was achieved with a fT > MIC of 0.36. These A. baumannii transformants are invaluable new tools for the assessment of anti-Acinetobacter compounds and provide a new pathway for AMR preparedness.
期刊介绍:
Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.