Pharmacokinetics of Non-β-Lactam β-Lactamase Inhibitors

Abstract

The growing emergence of drug-resistant bacterial strains is an issue to treat severe infections, and many efforts have identified new pharmacological agents. The inhibitors of β-lactamases (BLI) have gained a prominent role in the safeguard of beta-lactams. In the last years, new β-lactam–BLI combinations have been registered or are still under clinical evaluation, demonstrating their effectiveness to treat complicated infections. It is also noteworthy that the pharmacokinetics of BLIs partly matches that of β-lactams companions, meaning that some clinical situations, as well as renal impairment and renal replacement therapies, may alter the disposition of both drugs. Common pharmacokinetic characteristics, linear pharmacokinetics across a wide range of doses, and known pharmacokinetic/pharmacodynamic parameters may guide modifications of dosing regimens for both β-lactams and BLIs. However, comorbidities (i.e., burns, diabetes, cancer) and severe changes in individual pathological conditions (i.e., acute renal impairment, sepsis) could make dose adaptation difficult, because the impact of those factors on BLI pharmacokinetics is partly known. Therapeutic drug monitoring protocols may overcome those issues and offer strategies to personalize drug doses in the intensive care setting. Further prospective clinical trials are warranted to improve the use of BLIs and their β-lactam companions in severe and complicated infections.

Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review—Part I

“…Despite the scarcity of data, new beta-lactamase inhibitors can diffuse into the ELF [ 92 , 93 ], and this feature is important for their use in combination with beta-lactams [ 148 ].…”

β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

“…In many instances, it has been noticed that β-lactam-BLI combinations require a high concentration of either of the components for the desired activity in in-vivo studies, which can lead to toxicity or undesirable pharmacological outcomes (Papp-Wallace, 2019). Additionally, many BLIs exhibit low oral absorption, especially in their native form, and demand chemical modifications to stabilize them and exhibit better oral absorption (Luci et al, 2021). For instance, sulbactam in its native form was identified to have poor oral absorption as compared to pivaloyloxymethyl ester of sulbactam (Campoli-Richards and Brogden, 1987).…”

Sulbactam‐durlobactam: A novel β‐lactam‐β‐lactamase inhibitor combination targeting carbapenem‐resistant Acinetobacter baumannii infections

“…or unbound AUC/MIC (fAUC/MIC). [14][15][16][17] Another DBO-BLI, avibactam, has slow but reversible binding making time above the critical concentration (T > C T ), the index that most closely explains its activity. 18 Comparatively, irreversible inhibitors such as vaborbactam and relebactam rely on concentration and time exposure for target attainment where fAUC/MIC is a more accurate index.…”

“…Consistent with previous phase I studies, SUL-DUR was largely well-tolerated among the subjects with no clinically meaningful differences in safety data. [14][15][16]39 Another phase I study evaluated patients with mild, moderate, and severe RI who were treated with SUL-DUR. It was found that RI did not increase the risk of having an AE.…”