Rethinking Carbapenems: A Pharmacokinetic Approach for Antimicrobial Selection in Infected Necrotizing Pancreatitis

Abstract

Objective: To provide an overview of pathophysiological changes to the pancreas during infected necrotizing pancreatitis (INP), optimal drug properties needed to penetrate the pancreas, human and animal studies supporting the use of antimicrobials, and carbapenem-sparing strategies in INP. Data Sources: A literature analysis of PubMed/MEDLINE was performed (from 1960 to September 2020) using the following key terms: infected necrotizing pancreatitis, necrotizing acute pancreatitis, and infected pancreatitis antimicrobial concentration. Individual antimicrobials were investigated with these search terms. Study Selection and Data Extraction: All relevant studies describing the management of INP, and human and animal pharmacokinetic (PK) data supporting antimicrobial use in the pancreas were reviewed for possible inclusion regardless of sample size or study design. Data Synthesis: Piperacillin/tazobactam and cefepime achieve adequate pancreatic tissue concentrations in INP studies. A majority of the literature supporting carbapenem use in INP involves imipenem, and meropenem Monte Carlo simulations suggest that standard dosing regimens of meropenem may not achieve PK targets to eradicate Pseudomonas aeruginosa. Relevance to Patient Care and Clinical Practice: Carbapenems are often utilized for INP treatment based on guideline recommendations. This review discusses PK data, the history of carbapenem use in INP, and the pathophysiology of pancreatitis to suggest carbapenem-sparing strategies and provides stewardship tactics such as when to start antimicrobials, which empirical antimicrobial to use, and when to discontinue antimicrobials in the INP setting. Conclusions: Noncarbapenem antipseudomonals, such as piperacillin/tazobactam and cefepime, are appropriate carbapenem-sparing options in INP, based on PK data, spectrum of activity, and risk of collateral damage.

Risk Factors for Mortality Among Critical Acute Pancreatitis Patients with Carbapenem-Resistant Organism Infections and Drug Resistance of Causative Pathogens

“…In our cohort, clinical microbiology laboratories use phenotypic tests based on actual growth inhibition, which can provide a full actual susceptibility picture. Moreover, our recommendations of antibiotic therapy, based on drug resistance profiles of the strains, need to be interpreted with caution, and doctors should select an appropriate antimicrobial regimen according to the specific clinical scenario which includes tissue penetration, plasma concentration, renal function and host response [ 33 ]. In this era of CRO, the next phase of fighting not only may focus on the development of novel antibiotics, such as imipenem–relebactam and cefiderocol, but may also investigate “new” therapeutic regimens from “old” antibiotics and prevent the occurrence of resistance.…”

Antibiotics in Necrotizing Soft Tissue Infections

“…Tissue penetration was also suggested to be dependent on the degree of necrosis, inflammation, and regional perfusion [109]. In a recent literature review, piperacillin-tazobactam or cefepime diffusion into pancreatic tissue seemed superior to that of meropenem, abounding for the use of carbapenem only when resistant pathogens are suspected [110]. Although similar profiles are expected in skin and soft tissue necrosis, studies to evaluate the impact of molecule choice and administration modalities on tissue diffusion and outcome are Suggested antibiotic treatment for necrotizing soft tissue infection (NSTI) and future perspectives.…”

Local Antibacterial Treatment in Patients With Infected Pancreatic Walled-Off Necrosis: A Systematic Review

“…Prophylactic antibiotics failed, however, to improve outcomes in patients with IPN [3]. Systemic antibiotics usually fail to reach therapeutic concentrations in necrotic areas due to impaired perfusion [4][5][6], being quinolones and carbapenems are those with the best penetration rates in necrotic areas [7,8] and, therefore, generally recommended for the systemic treatment of IPN [9].…”