Maher Joshua M, Huband Michael D, Lindley Jill M, Rhomberg Paul R, Aronin Steven I, Puttagunta Sailaja, Castanheira Mariana
Element Iowa City-JMI Laboratories, North Liberty, Iowa, USA.
Iterum Therapeutics, Old Saybrook, Connecticut, USA.
Microbiol Spectr. 2025 Mar 4;13(3):e0189824. doi: 10.1128/spectrum.01898-24. Epub 2025 Feb 5.
Sulopenem is an oral and intravenous penem antibiotic in clinical development for treatment of urinary tract and intra-abdominal infections caused by multidrug-resistant pathogens. This study evaluated antimicrobial activity of sulopenem by post-antibiotic effect (PAE), sub-inhibitory minimal inhibitory concentration PAE effect (PAE-SME), checkerboard testing, and time-kill testing. Testing sulopenem at 1×, 5×, or 10× the baseline MIC resulted in a PAE interval of 0.0-0.7 hours. When exposed to 0.5× the sulopenem MIC following 5× MIC, all isolate/agent combinations had PAE-SME values of >4.8 hours. Checkerboard testing revealed no instances of antagonism between sulopenem and comparator agents-indifference was observed in most sulopenem checkerboard combinations. Sulopenem demonstrated bactericidal activity (≥3 log [99.9%] reduction in viable organism counts) in all time-kill assays following 24 hours of incubation at 8× the baseline MIC (6/6), 5/6 displaying this activity within 8 hours. The present antimicrobial parameters seen at concentrations surrounding the MIC support optimization of sulopenem dosing and further development. The oral dosing regimen of sulopenem etzadroxil/probenecid 500 mg/500 mg administered every 12 hours was recently evaluated in two phase 3 clinical trials where sulopenem demonstrated efficacy against amoxicillin-clavulanate in uncomplicated urinary tract infection (uUTI) and against ciprofloxacin in fluoroquinolone-resistant uUTI.IMPORTANCESulopenem is an oral and intravenous penem antibiotic in clinical development for treatment of urinary tract and intra-abdominal infections caused by multidrug-resistant pathogens. This study evaluated sulopenem via broth microdilution susceptibility testing, PAE, sub-inhibitory MIC PAE effect, checkerboard testing, and time-kill testing. The results of this study-interpreted along with recent pharmacodynamic one-compartment and hollow-fiber infection model work-provide insight into the activity of sulopenem.
舒洛培南是一种口服和静脉注射的青霉烯类抗生素，目前正处于临床开发阶段，用于治疗由多重耐药病原体引起的尿路感染和腹腔内感染。本研究通过抗生素后效应（PAE）、亚抑菌最低抑菌浓度PAE效应（PAE-SME）、棋盘法试验和时间杀菌试验评估了舒洛培南的抗菌活性。以基线MIC的1倍、5倍或10倍测试舒洛培南，PAE间隔为0.0 - 0.7小时。在5倍MIC后暴露于0.5倍舒洛培南MIC时，所有分离株/药物组合的PAE-SME值均>4.8小时。棋盘法试验显示舒洛培南与对照药物之间无拮抗情况——在大多数舒洛培南棋盘法组合中观察到无差异。在以8倍基线MIC孵育24小时后的所有时间杀菌试验中，舒洛培南均表现出杀菌活性（活菌数减少≥3 log[99.9%]）（6/6），5/6在8小时内表现出该活性。在MIC周围浓度下观察到的当前抗菌参数支持舒洛培南给药方案的优化和进一步开发。舒洛培南乙酯/丙磺舒500 mg/500 mg每12小时一次的口服给药方案最近在两项3期临床试验中进行了评估，在这些试验中，舒洛培南在单纯性尿路感染（uUTI）中对阿莫西林-克拉维酸以及在氟喹诺酮耐药的uUTI中对环丙沙星均显示出疗效。重要性舒洛培南是一种口服和静脉注射的青霉烯类抗生素，目前正处于临床开发阶段，用于治疗由多重耐药病原体引起的尿路感染和腹腔内感染。本研究通过肉汤微量稀释药敏试验、PAE、亚抑菌MIC PAE效应、棋盘法试验和时间杀菌试验对舒洛培南进行了评估。本研究结果——结合近期的药效学单室和中空纤维感染模型研究进行解读——为了解舒洛培南的活性提供了依据。
