Antimicrobial pharmacokinetics and dosing in critically ill adults receiving prolonged intermittent renal replacement therapy: A systematic review.

Prolonged intermittent renal replacement therapy (PIRRT) is gaining popularity as a renal replacement modality in intensive care units, but there is a relative lack of guidance regarding antimicrobial clearance and dosing when compared with other modalities. The objectives of this systematic review were to: (1) identify and describe the pharmacokinetics (PK) of relevant antimicrobials used in critically ill adults receiving PIRRT, (2) evaluate the quality of evidence supporting these data, and (3) propose dosing recommendations based on the synthesis of these data. A search strategy for multiple databases was designed and executed to identify relevant published evidence describing the PK of antimicrobials used in critically ill adults receiving PIRRT. Quality assessment, evaluation of reporting, and relevant data extraction were conducted in duplicate. Synthesis of PK/pharmacodynamic (PD) outcomes, dosing recommendations from study authors, and physicochemical properties of included antibiotics were assessed by investigators in addition to the quality of evidence to develop dosing recommendations. Thirty-nine studies enrolling 452 patients met criteria for inclusion and provided PK and/or PD data for 20 antimicrobials in critically ill adults receiving PIRRT. Nineteen studies describe both PK and PD outcomes. Vancomycin (12 studies, 171 patients), meropenem (7 studies, 84 patients), and piperacillin/tazobactam (5 studies, 56 patients) were the most frequent antimicrobials encountered. The quality of evidence was deemed strong for 7/20 antimicrobials, and strong dosing recommendations were determined for 9/20 antimicrobials. This systematic review updates and addresses issues of quality in previous systematic reviews on this topic. Despite an overall low quality of evidence, strong recommendations were able to be made for almost half of the identified antimicrobials. Knowledge gaps persist for many antimicrobials, and higher quality studies (i.e., population PK studies with assessment of PD target attainment) are needed to address these gaps.

Drug-drug interactions with CFTR modulator therapy in cystic fibrosis: Focus on Trikafta®/Kaftrio®.

The combination of CFTR modulators ivacaftor, tezacaftor and elexacaftor (Trikafta®, Kaftrio®) significantly improve outcomes, including survival in a broad range of cystic fibrosis patients. These drugs have complicated metabolic profiles that make the potential for drug interactions an important consideration for prescribers, care providers and patients. Prolonged survival also increases risk of age-related disease and their associated pharmacotherapy, further increasing the risk of drug interactions and the need for increased vigilance amongst care providers. We systematically searched the literature for studies identifying and evaluating pharmacokinetic and pharmacodynamic drug interactions involving the components of Trikafta®/Kaftrio®. We also searched electronic databases of drugs for possible drug interactions based on metabolic profiles. We identified 86 potential drug interactions of which 13 were supported by 14 studies. There is a significant need for research to describe the likelihood, magnitude and clinical impact of the drug interactions proposed here.

Adverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews.

BACKGROUND: Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes. OBJECTIVE: The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers. METHODS: A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity. RESULTS: Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range [IQR] 15.0-28.0%), diarrhea (15.3%, IQR 9.7-29.2%) and rash (14.4%, IQR 10.3-19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2-6.0%), colitis (1.3%, IQR 0.6-6.1%) and neutropenia (1.2%, IQR 0.4-3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported. CONCLUSIONS: Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes. PROSPERO REGISTRATION: CRD42021231593.