Institute for Clinical Pharmacodynamics, Inc., Schenectady, NY, USA.
The Medicines Company, San Diego, CA, USA.
Curr Opin Pharmacol. 2017 Oct;36:86-93. doi: 10.1016/j.coph.2017.09.001. Epub 2017 Oct 27.
The world is awash in antibiotic-resistant bacteria. The usefulness of nearly every antibacterial agent available in our hospital pharmacies has been compromised. About half of the recently approved antimicrobial agents for gram-negative pathogens, those pending approval, and those entering clinical development are β-lactam-β-lactamase inhibitor combinations. Thus, we are betting heavily on the efficacy and durability of these agents. However, one needs to be cognizant that poor dose regimen design can result in suboptimal efficacy, on-therapy resistance development, and resistance selection that may harm the activity of all β-lactam-β-lactamase inhibitor combinations. Herein, we discuss three factors that developers and regulators need to consider when evaluating candidate β-lactam-β-lactamase inhibitor regimens: first, know the β-lactamase inhibitor pharmacokinetic-pharmacodynamic efficacy determinant; second, know the β-lactam-β-lactamase inhibitor exposures that prevent antibiotic-resistance amplification; and third, know that an optimized β-lactamase inhibitor dosage regimen won't save you from resistance if the partner β-lactam is suboptimal.
世界上充斥着抗生素耐药菌。我们医院药房中几乎所有可用的抗菌药物的功效都受到了影响。最近批准的用于革兰氏阴性病原体的抗菌药物中，大约有一半、正在等待批准的以及正在进入临床开发的都是β-内酰胺类-β-内酰胺酶抑制剂组合。因此，我们非常重视这些药物的疗效和持久性。然而，人们需要意识到，剂量方案设计不当可能导致疗效不佳、治疗过程中耐药性的产生以及耐药性的选择，从而可能损害所有β-内酰胺类-β-内酰胺酶抑制剂组合的活性。在此，我们讨论了开发者和监管机构在评估候选β-内酰胺类-β-内酰胺酶抑制剂方案时需要考虑的三个因素：首先，了解β-内酰胺酶抑制剂的药代动力学-药效学疗效决定因素；其次，了解防止抗生素耐药性扩增的β-内酰胺类-β-内酰胺酶抑制剂暴露量；最后，了解如果伴侣β-内酰胺不理想，优化的β-内酰胺酶抑制剂剂量方案也无法挽救耐药性。
