Beta-Lactams Dosing in Critically Ill Patients with Gram-Negative Bacterial Infections: A PK/PD Approach

Abstract

Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their efficacy depends on the percentage of dosing interval that the concentration remains above the minimum inhibitory concentration. The Gram-negative resistance rates of pathogens are increasing in the intensive care unit (ICU), and critically ill patients often possess physiology that makes dosing more challenging. The volume of distribution is usually increased, and drug clearance is variable. Augmented renal clearance and hypermetabolic states increase the clearance of beta-lactams, while acute kidney injury reduces the clearance. To overcome the factors affecting ICU patients and decreasing susceptibilities, dosing strategies involving higher doses, and extended or continuous infusions may be required. In this review, we specifically examined pharmacokinetic models in ICU patients, to determine the desired beta-lactam regimens for clinical breakpoints of Enterobacterales and Pseudomonas aeruginosa, as determined by the European Committee on Antimicrobial Susceptibility Testing. The beta-lactams evaluated included penicillins, cephalosporins, carbapenems, and monobactams. We found that when treating less-susceptible pathogens, especially P. aeruginosa, continuous infusions are frequently needed to achieve the desired pharmacokinetic/pharmacodynamic targets. More studies are needed to determine optimal dosing strategies in the novel beta-lactams.

Evaluation of pre-treated healthcare wastes during COVID-19 pandemic reveals pathogenic microbiota, antibiotics residues, and antibiotic resistance genes against beta-lactams

“…The UPLC-QTOF-MS metabolomic analysis uncovered the presence of antibiotic residues that had not been eliminated from microwave pre-treated HCW. Aminoglycosides, beta-lactams, and lincosamides antibiotics found in the HCW are commonly used to treat serious bacterial infections ( Germovsek et al, 2017 ; Maguigan et al, 2021 ; Spížek and Řezanka, 2017 ). In all circumstances, the presence of antibiotic compounds can influence the microbial community in HCW.…”

Pharmacokinetics, Pharmacodynamics, and Dosing Considerations of Novel β-Lactams and β-Lactam/β-Lactamase Inhibitors in Critically Ill Adult Patients: Focus on Obesity, Augmented Renal Clearance, Renal Replacement Therapies, and Extracorporeal Membrane Oxygenation

“…Such conclusion can be inferred from the pool of evidence pertaining to conventional β-lactams, where different antimicrobials were reported to be associated with altered PK when utilized among critically ill patients, and had suboptimal exposures when utilized at the usual manufacturer recommended dosing. Readers are encouraged to refer to the previous published literature for more in-depth information [ 17 , 25 , 91 , 92 ]…”

“…While standard dosing resulted in adequate attainment of a PD index of 40–60% of free drug concentration above MIC (%ƒT > MIC) for CAZ/AVI, C/T, and MEV, such dosing did not attain more aggressive targets (i.e., 100%ƒT > 1–4 × MIC). Although some reviews had recently described altered PK/PD for various NBLA during critical illness [ 14 , 15 ], sub-populations that warrant special considerations including obesity, augmented renal clearance (ARC), RRT modalities, and ECMO were commonly excluded or not comprehensively addressed [ 14 , 15 , 16 , 17 , 18 ]. Hence, this narrative review seeks to [ 1 ] summarize the evidence for the effects of common ICU circumstances (including ECMO, ARC, RRT, and obesity) on the PK of NBLA, and [ 2 ] evaluate whether the utilized dosing regimens were adequate in achieving the required PK/PD indices.…”

Challenging T > MIC Using Meropenem vs. Escherichia coli and Pseudomonas aeruginosa

“…Our TKC results could confirm that not solely the %T > MIC is decisive for an efficient bacterial eradication in vitro, but also the distribution of the selected %T > MIC. Our data indicate that three short periods of 13.3%T > MIC, which equals 3 × 3.2 h, above a concentration of at least 4×MIC of meropenem achieved best bacterial killing within 24 h compared to the continuous 40% T > MIC, which equals a period of 1 × 9.6 h. Previous studies have already shown that, for example, in critically ill patients the %T > MIC for beta-lactams might need to be adjusted from 40-70%T > MIC to 100%T > MIC to meet the target attainment (Maguigan et al, 2021). Moreover, Nielsen et al outlined in a predictive semi-mechanistic PK/PD model how changes in MIC of the target pathogen or alternating renal clearance rates of the patient could shift PK/PD indices of benzylpenicillin, cefuroxime, erythromycin, and other antibiotics (Nielsen et al, 2011).…”

“…In antimicrobial therapy the efficacy of antibiotics is not only dependent on the drug itself, but also on the patient's physiology including disease state, comorbidities or age, and the variety of the bacterial species (Maguigan et al, 2021).…”