Nirmatrelvir/ritonavir was recently granted emergency use authorization for mild-moderate coronavirus disease 2019. Drug-drug interactions between ritonavir and tacrolimus are under-appreciated by non-transplant providers. We describe two solid organ transplant recipients prescribed nirmatrelvir/ritonavir for outpatient use that developed tacrolimus toxicity requiring hospitalization and were managed with rifampin for toxicity reversal.

Introduction: Fluid stewardship targets optimal fluid management to improve patient outcomes. Intravenous (IV) medications, flushes, and blood products, collectively referred to as hidden fluids, contribute to fluid intake in the intensive care unit (ICU). The impact of specific IV medications on fluid intake is unknown. Objective: Characterize IV medication classes based on contribution to ICU fluid intake by frequency of administration and total volume infused to identify targets for fluid stewardship. Methods: This multi-center, retrospective nested cohort study included patients admitted to a medical or surgical ICU between January 2017 and December 2018. The primary outcome was to identify the volume contribution of specific IV medication classes administered over the first 3 ICU days. Secondary outcomes were the administration frequency of these medications and their proportion of total daily volume intake over the first 3 ICU days. Results: The study included 210 patients. The largest mean administration volumes over the course of the first 3 ICU days were attributed to antibacterials (968 ± 846 mL), vitamins/minerals/electrolytes (416 ± 935 mL), pain/agitation/delirium agents (310 ± 512 mL), and vasoactive agents (282 ± 744 mL). The highest frequencies over the course of the first 3 ICU days were attributed to antibacterials (n = 180; 86%), pain/agitation/delirium agents (n = 143; 68%), vitamins/minerals/electrolytes (n = 123; 59%), and vasoactive agents (n = 96; 46%). IV medications contributed 2601 ± 2573 mL of fluid volume per patient over the first 3 ICU days, accounting for 42% ± 29% of overall volume. Conclusion: IV medications contribute over 40% of total fluid intake within the first 3 days of ICU admission, with antibacterials as top contributors by administration volume and frequency. Future research implementing fluid stewardship to ICU fluid sources, such as concentrating IV medications, switching IV medications to oral formulations, de-escalation of antibacterials, and reduction of maintenance fluids, should be performed to minimize hidden fluids from IV medications.

Background The treatment of extended-spectrum beta-lactamase (ESBL)-producing urinary tract infections (UTI) may include either intravenous (IV) or oral (PO) antibiotics, according to the Infectious Diseases Society of America guidelines for resistant gram negative infections. The purpose of this study is to evaluate if PO step-down antibiotics, the switch group, compared to continued IV therapy in these UTIs affects clinical outcomes. Methods This multicenter retrospective cohort study was conducted in hospitalized patients with an ESBL-producing UTI between July 2016 and March 2020. The control group received a complete antibiotic course with a carbapenem. The switch group was transitioned to an oral agent within five days from initiation of a carbapenem. The primary endpoint was a composite all-cause clinical failure, which was defined as readmission or hospital mortality within 30 days of hospital discharge or a change in antibiotic during hospital admission. The secondary endpoints included individual components of the primary outcome, readmission indication, inpatient length of stay, direct antibiotic costs, and adverse events. Results The study included 153 patients: 95 and 58 patients in the control and switch groups, respectively. Demographics between the two groups were similar (Table 1). The mean ± SD duration of therapy was 8.7 ± 3.1 and 7.1 ± 3.3 days, respectively. Four oral agents were used for step-down therapy (Figure 1). The primary outcome occurred in 28% in both groups (27 vs 16 patients, p=0.91). The individual components of the primary outcome and readmission indication were also similar: readmission (93% vs 94%, p=0.95), readmission due to a recurrent UTI (33% vs 25%, p=0.73), hospital mortality (7% vs 6%, p=1.0), and change in antibiotic (0% vs 2%, p=0.38). The median (IQR) length of stay and direct antibiotic cost in the control and switch groups were 8 (6) vs 5 (2) days (p< 0.01) and &278 (&244) vs &180 (&104) (p< 0.01), respectively. Adverse events were similar in both groups except for diarrhea (15% vs 2%, p=0.01). Table 1. Baseline Demographics. SD: standard deviation, ICU: intensive care unit, qSOFA: quick Sequential Organ Failure Assessment, ESBL: extended spectrum beta-lactamase, UTI: urinary tract infection Figure 1. Oral Antibiotics. QD: once daily, BID: twice daily, Q2D: every 2 days, Q3D: every 3 days, DS tab: double strength tablet Conclusion There was no difference in clinical failure, readmission rate, mortality rate, or change in antibiotic between the control and switch groups; however, the switch group was associated with reduced hospital length of stay and direct antibiotic cost. Disclosures All Authors: No reported disclosures

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is a powerful tool for making connections in both organic reactions and biological systems. However, the use of this ligation process in living cells is limited by the toxicity associated with unbound copper ions. As an initial attempt to create peptide-based accelerating ligands capable of cellular expression, we performed synthesis and selection for such species on solid-phase synthesis beads bearing both candidate ligand and alkyne substrate. A simple histidine-containing motif (HXXH) was identified, and found after solution-phase optimization to produce single-turnover systems showing moderate rate acceleration over the ligand-free reaction. CuAAC reaction rates and yields for different alkynes were found to respond to the peptide ligands, demonstrating a substrate scope beyond what was used for the selection steps, but also illustrating the potential difficulty in evolving a general CuAAC catalyst.