Ferro B E, Srivastava S, Gumbo T
Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia.
Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, TX, USA.
IJTLD Open. 2025 Sep 10;2(9):519-526. doi: 10.5588/ijtldopen.25.0173. eCollection 2025 Sep.
Guideline-based therapy (GBT) of (MAB) lung disease (LD) achieves a sputum culture conversion rate in ∼35% of patients. The β-lactam antibiotics, imipenem and cefoxitin, are the cornerstone of GBT. However, a 1-h half-life means multiple infusions per day, which is difficult for months-long therapy.
As an alternative, we tested ceftaroline-avibactam, with a 3-h half-life, in the hollow-fibre model system of MAB-LD (HFS-MAB). Eight ceftaroline-avibactam exposures were administered twice daily based on human intrapulmonary pharmacokinetics. Next, we compared GBT (cefoxitin-clarithromycin-amikacin) to standard-dose and to high-dose ceftaroline-avibactam-tigecycline-moxifloxacin regimens, in the HFS-MAB, mimicking the intrapulmonary pharmacokinetics of all drugs.
Ceftaroline-avibactam maximal microbial kill was 0.72 log colony-forming units (CFUs) per millilitre below day 0 burden (stasis). The ceftaroline pharmacokinetic-pharmacodynamic parameter linked to microbial kill and anti-microbial resistance was 0-24-h area under the concentration-time curve (AUC) to minimum inhibitory concentration. GBT killed 1.21 ± 0.25 log CFU/mL versus 0.45 ± 0.42 log CFU/mL below stasis for high-dose ceftaroline combination ( = 0.20). In combination regimens, proportion of the ceftaroline-resistant subpopulation was 41.22 ± 13.11 times lower than the cefoxitin-resistant subpopulation ( = 0.002).
Ceftaroline-avibactam administered twice a day would be an adequate replacement for the four-times-a-day cefoxitin treatments for MAB-LD.
基于指南的治疗（GBT）对非结核分枝杆菌（MAB）肺病（LD）的痰培养转化率约为35%的患者。β-内酰胺类抗生素亚胺培南和美洛西林是GBT的基石。然而，1小时的半衰期意味着每天需要多次输注，这对于长达数月的治疗来说很困难。
作为替代方案，我们在MAB-LD的中空纤维模型系统（HFS-MAB）中测试了半衰期为3小时的头孢洛林-阿维巴坦。根据人体肺内药代动力学，每天两次给予八次头孢洛林-阿维巴坦暴露。接下来，我们在HFS-MAB中，将GBT（美洛西林-克拉霉素-阿米卡星）与标准剂量和高剂量的头孢洛林-阿维巴坦-替加环素-莫西沙星方案进行比较，模拟所有药物的肺内药代动力学。
头孢洛林-阿维巴坦的最大微生物杀灭量比第0天的负荷（停滞）低0.72 log菌落形成单位（CFU）/毫升。与微生物杀灭和抗菌耐药性相关的头孢洛林药代动力学-药效学参数是浓度-时间曲线下0至24小时面积（AUC）与最低抑菌浓度之比。GBT杀灭1.21±0.25 log CFU/mL，而高剂量头孢洛林组合低于停滞状态时为0.45±0.42 log CFU/mL（P = 0.20）。在联合方案中，耐头孢洛林亚群的比例比耐美洛西林亚群低41.22±13.11倍（P = 0.002）。
每天两次给予头孢洛林-阿维巴坦将足以替代每天四次使用美洛西林治疗MAB-LD。
