Singh Sanjay, Shrivastava Avneesh, Boorgula Gunavanthi D, Long Mary C, Robbins Brian, McShane Pamela J, Gumbo Tawanda, Srivastava Shashikant
bioRxiv. 2025 Aug 7:2025.08.05.668504. doi: 10.1101/2025.08.05.668504.
IDSA guideline-based therapy achieves sputum culture conversion rates in 20-34% of patients with (MAB) lung disease (LD). Double-β-lactam combinations have been proposed to improve cure, based on time-kill curves.
We performed minimum inhibitory concentrations (MICs) experiments followed by hollow fiber system model of MAB-LD (HFS-MAB) exposure-effect studies with sulbactam-durlobactam administered every 8h (q8h), q12h, and q24h, to identify target exposures. Next, the sulbactam-durlobactam target exposure plus ceftriaxone was administered in the HFS-MAB inoculated with three different MAB isolates, as was the sulbactam-durlobactam-ceftriaxone combination with epetraborole and omadacycline (SDCEO). -slopes (kill-speed) were calculated for all regimens. The minimal sulbactam-durlobactam clinical doses that achieved target exposure were identified using Monte Carlo experiments.
Ceftriaxone reduced sulbactam-durlobactam MICs by 8-tube dilutions. In the HFS-MAB, sulbactam-durlobactam microbial kill and antimicrobial resistance were linked to % time concentration persists above MIC (%T ), with target exposure of 50%. Sulbactam-durlobactam killed 3.85 log CFU/mL below day 0 burden ( ) with regrowth. Sulbactam-durlobactam plus ceftriaxone killed without regrowth and demonstrated Bliss' additivity. of bacterial population in >95% of virtual subjects were 2.28 (0.97-4.80) log CFU/mL/day for sulbactam-durlobactam-ceftriaxone and 2.91 (1.65-4.93) log CFU/mL/day for SDCEO. The optimal sulbactam-durlobactam dose co-administered with ceftriaxone was 2G q8h for creatinine clearance >90 mL/min, 2G q12h for 60-90 mL/min, 1G q12h for ≥30 to <60 mL/min, and 1G q24h for <30 mL/min.
Sulbactam-durlobactam-ceftriaxone achieved the highest microbial kill encountered so far in the HFS-MAB. Sulbactam-durlobactam-ceftriaxone should be tested as the backbone for novel treatment shortening regimens.
基于美国感染病学会（IDSA）指南的治疗方法使20%-34%的马耳他布鲁菌肺病（MAB-LD）患者实现痰培养转阴。基于时间杀菌曲线，已提出双β-内酰胺联合用药以提高治愈率。
我们进行了最低抑菌浓度（MIC）实验，随后进行了马耳他布鲁菌肺病中空纤维系统模型（HFS-MAB）暴露-效应研究，每8小时（q8h）、12小时（q12h）和24小时（q24h）给予舒巴坦-度洛巴坦，以确定目标暴露量。接下来，在接种了三种不同马耳他布鲁菌分离株的HFS-MAB中给予舒巴坦-度洛巴坦目标暴露量加头孢曲松，舒巴坦-度洛巴坦-头孢曲松联合依匹拉硼和奥玛环素（SDCEO）也是如此。计算所有治疗方案的杀菌斜率（杀菌速度）。使用蒙特卡洛实验确定达到目标暴露量的舒巴坦-度洛巴坦最低临床剂量。
头孢曲松使舒巴坦-度洛巴坦的MIC降低了8管稀释度。在HFS-MAB中，舒巴坦-度洛巴坦的微生物杀灭和抗菌耐药性与药物浓度持续高于MIC的时间百分比（%T>MIC）相关，目标暴露量为50%。舒巴坦-度洛巴坦在第0天负荷以下杀灭了3.85 log10 CFU/mL，但有细菌再生长。舒巴坦-度洛巴坦加头孢曲松杀灭细菌后无再生长，并显示出布利斯相加性。对于舒巴坦-度洛巴坦-头孢曲松，>95%虚拟受试者的细菌群体杀灭率为2.28（0.97-4.80）log10 CFU/mL/天，对于SDCEO为2.91（1.65-4.93）log10 CFU/mL/天。与头孢曲松联合使用的舒巴坦-度洛巴坦最佳剂量，肌酐清除率>90 mL/min时为2g q8h，60-90 mL/min时为2g q12h，≥30至<60 mL/min时为1g q12h，<30 mL/min时为1g q24h。
舒巴坦-度洛巴坦-头孢曲松在HFS-MAB中实现了迄今为止最高的微生物杀灭率。舒巴坦-度洛巴坦-头孢曲松应作为新型缩短治疗方案的基础进行测试。
