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

Abstract

Objective: Dose optimization of novel β-lactam antibiotics (NBLA) has become necessary given the increased prevalence of multidrug-resistant infections in intensive care units coupled with the limited number of available treatment options. Unfortunately, recommended dose regimens of NBLA based on PK/PD indices are not well-defined for critically ill patients presenting with special situations (i.e., obesity, extracorporeal membrane oxygenation (ECMO), augmented renal clearance (ARC), and renal replacement therapies (RRT)). This review aimed to discuss and summarize the available literature on the PK/PD attained indices of NBLA among critically ill patients with special circumstances. Data Sources: PubMed, MEDLINE, Scopus, Google Scholar, and Embase databases were searched for studies published between January 2011 and May 2022. Study selection and data extraction: Articles relevant to NBLA (i.e., ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, ceftobiprole, imipenem/relebactam, and meropenem/vaborbactam) were selected. The MeSH terms of “obesity”, “augmented renal clearance”, “renal replacement therapy”, “extracorporeal membrane oxygenation”, “pharmacokinetic”, “pharmacodynamic” “critically ill”, and “intensive care” were used for identification of articles. The search was limited to adult humans’ studies that were published in English. A narrative synthesis of included studies was then conducted accordingly. Data synthesis: Available evidence surrounding the use of NBLA among critically ill patients presenting with special situations was limited by the small sample size of the included studies coupled with high heterogeneity. The PK/PD target attainments of NBLA were reported to be minimally affected by obesity and/or ECMO, whereas the effect of renal functionality (in the form of either ARC or RRT) was more substantial. Conclusion: Critically ill patients presenting with special circumstances might be at risk of altered NBLA pharmacokinetics, particularly in the settings of ARC and RRT. More robust, well-designed trials are still required to define effective dose regimens able to attain therapeutic PK/PD indices of NBLA when utilized in those special scenarios, and thus aid in improving the patients’ outcomes.

Antimicrobial Exposure in Critically Ill Patients with Sepsis-Associated Multi-Organ Dysfunction Requiring Extracorporeal Organ Support: A Narrative Review

“…Recently, Backdach et al [ 51 ] systematically reviewed the results of 27 articles on PK/PD characteristics of novel β-lactams and β-lactams/β-lactamase inhibitors in critically ill patients receiving ECOS. Specifically, they found that increasing doses of Cefiderocol (standard dose: 2 g Q8h) might be necessary to attain PK/PD indexes in relationship with residual renal function, highly resistant pathogen and CRRT intensity (from 1.5 g Q12h for effluent flow rate ≤ 2 L/h to 2 g Q8h for effluent flow rate ≥ 4 L/h), while the maintenance dose of Ceftolozane/Tazobactam should be lowered (from 1.5–3 g Q8h to 0.75 Q8h) during CRRT.…”

“…Specifically, they found that increasing doses of Cefiderocol (standard dose: 2 g Q8h) might be necessary to attain PK/PD indexes in relationship with residual renal function, highly resistant pathogen and CRRT intensity (from 1.5 g Q12h for effluent flow rate ≤ 2 L/h to 2 g Q8h for effluent flow rate ≥ 4 L/h), while the maintenance dose of Ceftolozane/Tazobactam should be lowered (from 1.5–3 g Q8h to 0.75 Q8h) during CRRT. In contrast, no evidence was available for other antimicrobials such as Caftazidime/Avibactam, Imipenem/Relabatam and Meropenem/Vaborbactam [ 51 ].…”

“…Currently, TDM has not been widely used in daily clinical practice and significant variation among hospitals was reported in terms of use, antimicrobial selection, sampling time points, assays, PK/PD targets and dose adjustment algorithms [ 98 , 99 ]. Moreover, critically ill septic patients receiving ECOS represent a subpopulation of patients that is commonly excluded from clinical investigations [ 51 ]. However, this tool may enable real-time antimicrobial PK measurements at the bedside, thus allowing clinicians to adjust the antimicrobial dose to the evolving patient’s clinical condition and pathogen susceptibility.…”

Novel Antimicrobial Agents for Gram-Negative Pathogens

“…Dose reduction for all, for example, following the commencement of renal replacement therapy, may result in suboptimal therapeutic levels for many patients [ 22 ]. On the contrary, total daily dosing must increase whenever there is augmented renal clearance of the administered antimicrobials [ 23 , 24 , 25 ]. All the drugs covered in this review, except for eravacycline and omadacycline, are hydrophilic, present a low volume of distribution and protein binding, and are renally cleared [ 26 ].…”

Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study

“…However, the process of choosing a PD metric for PTA analysis may lead to drastically different dosing conclusions based on the chosen target [ 7 ]. Furthermore, there are other less commonly used metrics, such as a cumulative fraction of response (CFR), which aid in the decision of which population subgroups to simulate, and other factors such as protein binding, which may also play a significant role in how dosing decisions are made [ 8 , 12 ]. The technical aspects of how the Monte Carlo simulations were performed may also have an impact on PTA [ 13 ].…”