RESUMO
BACKGROUND: Efficacy for prolonged infusion beta-lactam dosing schemes has been previously described, but there has been less focus on the safety of standard vs prolonged infusion protocols of beta-lactams. This study explored differences in adverse drug reactions (ADRs) reported for beta-lactams between each of these infusion protocols. METHODS: A systematic review of MEDLINE literature databases via PubMed was conducted and references were compiled. Articles were compiled and assessed with specific inclusion/exclusion criteria. We included randomized and nonrandomized, prospective, and retrospective cohort studies that reported adverse effects due to either standard (30-60 mins) or prolonged (≥3 hours) infusions of beta-lactam infusions. Total ADRs between strategies were analyzed by infusion methodology. The most consistently reported ADRs were subject to meta-analysis across studies. RESULTS: 12 studies met inclusion/exclusion criteria with data for 4163 patients. There was insufficient data to systematically analyze neurotoxicity or cytopenias. Seven studies reported on nephrotoxicity outcomes with no significant difference in event rates between standard (n=434/2258,19.2%) vs prolonged infusion (n=266/1271, 20.9%) of beta-lactams (OR=1.08, 95%CI [0.91, 1.29]). Six studies observed diarrhea in a total of 759 patients with no significant difference in patients of standard (n=18/399, 4.5%) vs prolonged (n=19/360, 5.3%) infusion of beta-lactams (OR=1.14, 95%CI [0.59,2.20]). CONCLUSION: Prolonged and standard infusion schemes for beta-lactams demonstrated similar adverse event rates. Future research should focus on improved standardization of adverse effect definitions and a priori aim to study neurotoxicity and cytopenias. Consistent recording of ADRs and standardized definitions of these reactions will be paramount to further study of this subject.
RESUMO
Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus-administration with allometric scaling is the most simple and commonly used strategy in pre-clinical kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched, bolus-administration with allometric scaling results in similar outcomes compared to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically-scaled, dose-matched, bolus-administration of vancomycin to an infusion-pump controlled, humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 h of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg·h/L [IQR 90.2-97.2] vs. 99.5 mg·h/L [IQR 95.1-104.0], P = 0.07). No significant differences in iohexol-measured kidney function nor meaningful differences in urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures. No differences in iohexol-measured GFR nor meaningful differences in urinary kidney injury biomarkers were observed among male Sprague-Dawley rats.