56. High Frequencies of Adverse Drug Events with Intravenous vs Oral High-Dose Trimethoprim-Sulfamethoxazole: An Opportunity for Antibiotic Stewardship

Abstract Background Trimethoprim-sulfamethoxazole (TMP-SMX) is a high-bioavailability antibiotic associated with potentially serious adverse drug events (ADE). The objective of this study was to evaluate the safety of intravenous (IV) and oral (PO) high-dose TMP-SMX. Methods IRB-approved retrospective cohort of hospitalized patients from January 2016 to November 2020. Inclusion: ≥ 18 years old and > 72 hours of renally adjusted high-dose TMP-SMX defined as ≥ 5 mg/kg/day of TMP. Exclusion: prophylaxis. Endpoints during treatment: hyponatremia with sodium < 135 mmol/L, hyperkalemia with potassium > 5 mmol/L, serum creatinine increase of ≥ 0.3 mg/dL or 1.5-1.9 times from baseline, and fluid overload on physical exam. Descriptive and bivariate statistics were performed. Results Each group included 50 patients (Table 1). Intensive care unit patients comprised 82% IV TMP-SMX compared to 32% PO. Most common infection: respiratory tract 86% IV and 68.1% PO. Most common organisms were Stenotrophomonas maltophilia (52% IV and 18% PO) and Pneumocystis jiroveci (16.3% IV and 62% PO). Median (IQR) days of inpatient therapy: 6 (5-7.5) PO vs. 7.5 (6-11.3) IV. Median (IQR) days of total duration: 9 (6-21.5) PO vs. 12 (7.8-14) IV (p=0.93). IV group: 88% of patients received >1 liter of D5W daily. Median (IQR) liters of D5W daily was 1 (1-1.5). 56% had a diuretic added, and 38% had a diuretic dose increase. Majority of patients (78%) on IV were taking other oral medications. 100% patients experienced any adverse event with IV vs. 70% with PO (unAdjOR 2.43; 95% CI 1.89-3.13). Most common ADE in both groups: hyponatremia, hyperkalemia, and elevated creatinine. Hyponatremia: 92% with IV and 32% with PO (unAdjOR 24.44; 95% CI 7.50-79.68). Edema on physical exam, an ADE specific to IV TMP-SMX, was the third most common side effect in the IV group. Relative changes from baseline in sodium, potassium, and creatinine from those who experienced hyponatremia, hyperkalemia and elevated creatinine were listed in Table 2. Table 1. Baseline and Clinical Characteristics Table 2. Adverse Effects Conclusion Patients on IV TMP-SMX therapy were more likely to experience an ADE compared to PO, likely driven by the high volume of free water. Most patients on IV TMP-SMX were on other PO medications, suggesting a missed stewardship opportunity for IV to PO conversion to reduce patient harm. Disclosures Susan L. Davis, PharmD, Nothing to disclose Michael P. Veve, Pharm.D., Cumberland (Grant/Research Support)Paratek Pharmaceuticals (Research Grant or Support) Rachel Kenney, PharmD, Medtronic, Inc. (Other Financial or Material Support, spouse is an employee and shareholder)


High Frequencies of Adverse Drug Events with Intravenous vs Oral High-Dose
Background. Trimethoprim-sulfamethoxazole (TMP-SMX) is a high-bioavailability antibiotic associated with potentially serious adverse drug events (ADE). The objective of this study was to evaluate the safety of intravenous (IV) and oral (PO) high-dose TMP-SMX.
Methods. IRB-approved retrospective cohort of hospitalized patients from January 2016 to November 2020. Inclusion: ≥ 18 years old and > 72 hours of renally adjusted high-dose TMP-SMX defined as ≥ 5 mg/kg/day of TMP. Exclusion: prophylaxis. Endpoints during treatment: hyponatremia with sodium < 135 mmol/L, hyperkalemia with potassium > 5 mmol/L, serum creatinine increase of ≥ 0.3 mg/dL or 1.5-1.9 times from baseline, and fluid overload on physical exam. Descriptive and bivariate statistics were performed.
Results. Each group included 50 patients (Table 1). Intensive care unit patients comprised 82% IV TMP-SMX compared to 32% PO. Most common infection: respiratory tract 86% IV and 68.1% PO. Most common organisms were Stenotrophomonas maltophilia (52% IV and 18% PO) and Pneumocystis jiroveci (16.3% IV and 62% PO). Median (IQR) days of inpatient therapy: 6 (5-7.5) PO vs. 7.5 (6-11.3) IV. Median (IQR) days of total duration: 9 (6-21.5) PO vs. 12 (7.8-14) IV (p=0.93). IV group: 88% of patients received >1 liter of D5W daily. Median (IQR) liters of D5W daily was 1 (1-1.5). 56% had a diuretic added, and 38% had a diuretic dose increase. Majority of patients (78%) on IV were taking other oral medications. 100% patients experienced any adverse event with IV vs. 70% with PO (unAdjOR 2.43; 95% CI 1.89-3.13). Most common ADE in both groups: hyponatremia, hyperkalemia, and elevated creatinine. Hyponatremia: 92% with IV and 32% with PO (unAdjOR 24.44; 95% CI 7.50-79.68). Edema on physical exam, an ADE specific to IV TMP-SMX, was the third most common side effect in the IV group. Relative changes from baseline in sodium, potassium, and creatinine from those who experienced hyponatremia, hyperkalemia and elevated creatinine were listed in Table 2.  Background. A regional antibiotic stewardship program (ASP) within a large integrated healthcare system covering two, non-academic, tertiary care medical centers and an additional six community hospitals implemented multiple interventions to optimize antimicrobial therapy and reduce unnecessary hospital costs, such as transition to extended-infusion (EI) piperacillin/tazobactam (TZP), formulary restriction of antimicrobials, and antimicrobial stewardship clinical review. The purpose of this study was to evaluate the cost savings associated with these regional ASP initiatives.

Financial Impact of a Regional Antimicrobial Stewardship Cost Saving Initiative in a Large Integrated Healthcare System
Methods. This was a multicenter, retrospective, observational review of regional stewardship interventions across eight inpatient medical centers in Oregon. Data was collected from January 2019 to December of 2020. Cost savings associated with reduced TZP administrations was based on the duration of therapy for each encounter in adults who received TZP for >24 hours in 2020. The regional antimicrobial restriction policy was implemented in February 2020. Cost savings attributed to antimicrobial formulary restrictions and reduction in overall days of therapy/1000 patient days (DOT) were based on EPIC costs.
Results. The reduction in number of administrations with implementation of EI TZP resulted in $226,420 saved in 2020. $182,837 was saved due to decreased usage of restricted antimicrobial agents. An additional $433,341 was saved for overall antimicrobial costs due to 19,775 days reduction in overall DOT/1000 patient days.

Conclusion.
A community-based regional ASP has resulted in substantial financial impact and identified areas for future cost savings within the region.
Disclosures. All Authors: No reported disclosures