Discussion

This study is one of the largest published cohorts to compare therapy-related outcomes among OPAT patients and provides additional data to inform selection of antimicrobial agents. Patients receiving vancomycin had higher rates of ADEs resulting in change or early discontinuation of treatment and higher rates of healthcare utilization when compared to daptomycin-treated patients (aOR, 3·71; 95% CI, 1·64–8·40). This association persisted throughout the duration of the OPAT treatment course, from week 1 to beyond week 8 of therapy. The incidence of ADEs leading to change or discontinuation of therapy in our cohort (16%) is similar to those reported in other published studies.Reference Ruh, Parameswaran, Wojciechowski and Mergenhagen ^{1 ,} Reference Suleyman, Kenney, Zervos and Weinmann ^{7 –} Reference Lee, Tam and Weigel ^{9 ,} Reference Shrestha, Mason and Gordon ¹²

The types and severity of ADEs in vancomycin- versus daptomycin-treated patients were substantively different (Fig. 2). The most common reason for therapy change in the daptomycin-treated patients was asymptomatic CK elevation, while hypersensitivity syndromes, organ dysfunction, and cytopenias were observed in the vancomycin group. Notably, 3 of 7 daptomycin patients who developed a skeletal muscle ADE were also taking a statin at the time of discharge. Some cases of skeletal muscle toxicity may have been reduced through a robust discharge medication reconciliation process. However, in some high-risk patients, discontinuing the statin may have outweighed any potential benefits. This high-risk population is also at increased risk of kidney injury, further complicating the clinical decision-making process.

The toxicity of intravenous antibiotics, particularly vancomycin, necessitates a careful review of the clinical indication for the expanded-spectrum gram-positive coverage. A significant number of patients in our cohort received vancomycin empirically without a confirmed microbiologic diagnosis of a resistant organism (23·4%). This treatment decision was driven in part by cases in which patients did not have a microbiologic culture obtained in the setting of an infectious process often caused by methicillin-resistant Staphylococcus aureus (MRSA) or coagulase-negative Staphylococci, such as skin and soft-tissue infections (5·8%), bone and joint infections (24·3%), and hardware-associated infections (37·8%). Careful consideration of MRSA risk is important before committing patients to a prolonged course of vancomycin. If microbiology results are not conclusive, alternative means of MRSA risk stratification, such as MRSA nasal screening, may be useful to tailor decision making. Negative nasal screening has a high negative predictive value and is useful in many instances for narrowing antimicrobial coverage.Reference Acuna-Villaorduna, Branch-Elliman, Strymish and Gupta ²⁹

The IDSA OPAT guidelines recommend weekly safety laboratory monitoring for patients receiving home infusions of vancomycin and daptomycin. These guidelines were last updated in 2004, however, and logistical challenges result in significant variation in real-world clinical practice.Reference Keller, Williams, Gavgani, Hirsch, Adamovich, Hohl, Gurses and Cosgrove ^{8 ,} Reference Keller, Ciuffetelli and Bilker ^{30 ,} Reference Lane, Marschall and Beekmann ³¹ Availability of OPAT laboratory testing is associated with a lower risk of hospital readmission and higher OPAT success.Reference Ruh, Parameswaran, Wojciechowski and Mergenhagen ^{1 ,} Reference Huck, Ginsberg, Gordon, Nowacki, Rehm and Shrestha ²⁸ We did not find a significant association between frequency of safety laboratory monitoring and reduced risk of adverse events; however, our study had limited power to detect a difference in this outcome between the 2 exposures groups.

These findings are limited in several ways. First, there is potential for residual confounding present in all observational designs. This may explain our finding that receipt of therapy at a long-term acute-care or skilled nursing facility was associated with a lower risk of medication change due to ADE. A higher burden of comorbidities was noted among patients at facilities (Supplementary Table 1). In a sensitivity analysis including patients who died, the association between receipt of therapy at a long-term acute-care or skilled nursing facility and the primary outcome did not persist (P=·12), suggesting that unmeasured confounding may be driving this finding. Second, as a single-center analysis, this cohort and the clinical practices in our center may not be reflective of those in other OPAT clinics. In addition, anticipated OPAT duration of at least 14 days was a qualification for enrollment; shorter courses that are at lower risk of ADEs were not included. To ensure that only clinically significant ADEs were reflected in our results, we limited our primary outcome to ADEs that resulted in a therapy change or discontinuation. We also did not consider common adverse events, such as red man syndrome, that may negatively impact a patient’s quality of life without resulting in a change in therapy. There was a high rate of hospital readmission in this cohort as compared to other studies, potentially reflecting a sicker patient population, although a long follow up period—extended 30 days beyond the completion of OPAT therapy—may also have impacted this result.Reference Suleyman, Kenney, Zervos and Weinmann ^{7 ,} Reference Keller, Williams, Gavgani, Hirsch, Adamovich, Hohl, Gurses and Cosgrove ^{8 ,} Reference Means, Bleasdale, Sikka and Gross ^{10 ,} Reference Shrestha, Mason and Gordon ^{12 ,} Reference Schmidt, Hearn, Gabriel, Spencer and McCurdy ^{14 ,} Reference Madaline, Nori and Mowrey ²⁰

Our study is one of the few published analyses comparing adverse events and healthcare utilization associated with 2 of the most commonly prescribed gram-positive agents in the OPAT setting, daptomycin and vancomycin. Other strengths include the size of the cohort included, the breadth of infectious diagnoses considered, and the completeness of the data with minimal missing covariates or outcomes. With an organized OPAT program involving physicians, nurses, and administrative staff, pertinent clinical and demographic data for each patient was documented at the time of enrollment and clinical follow up, optimizing data capture.

Pre-enrollment evaluation of patients with an infectious disease consultation and sufficient clinical support to ensure a complete care transition reduces adverse events and overall OPAT costs.Reference Conant, Erdman and Osterholzer ^{17 ,} Reference Muldoon, Snydman, Penland and Allison ^{19 ,} Reference Madaline, Nori and Mowrey ²⁰ Careful consideration is necessary when selecting an antibiotic agent for long-term therapy, including the risk of selection for antibiotic resistance, costs, ease of administration, need for monitoring, and the known risk of complications, including ADEs. By defining the primary outcome as ADEs that required a change or discontinuation of therapy, the results of this study are more directly related to the choice of antimicrobial agent used for treatment, a programmatic decision for an OPAT clinic, rather than outcomes related to healthcare delivery, nursing care, or patient preferences. Our study informs inpatient clinicians and infectious disease OPAT providers regarding the risks of ADEs among recipients of vancomycin versus daptomycin.

The perceived drawbacks of daptomycin—primarily cost and broader spectrum of activity—must be weighed against the apparent challenges of long-term vancomycin: high rates of clinically significant ADEs and utilization of OPAT clinic resources. While our study did not include an economic analysis, our results suggest that vancomycin, although less expensive on a per-dose basis, is associated with complications that may render it more expensive when used for prolonged therapy in the outpatient setting. Notably, Medicare recipients (42·4% of this study’s cohort) without supplemental insurance are often restricted in their long-term antibiotic options with regard to type of antimicrobial agent and site of therapy. As our analysis demonstrates, daptomycin is a safer alternative to vancomycin for gram-positive therapy in OPAT. Therefore, a Medicare recipient with a low burden of comorbidities and the ability to self-administer a once-daily medication may be better served receiving daptomycin home infusions. In addition to the direct medical costs associated with complications, vancomycin is also associated with other societal costs attributable to lost time and work productivity. For example, vancomycin infusions last for 1–2 hours, typically multiple times per day, compared to <30 minutes once daily for daptomycin. Prospective analysis to compare the rates of clinical success and ADEs would alleviate some of the confounding challenges present in this study, and further cost-effectiveness analyses of these 2 medications would greatly inform the decisions of health systems beyond the wholesale price of the medication.