Editorial <\/p>\n\n\n\n
Staphylococcus aureus<\/em> bacteremia is a leading cause of infection-related death worldwide.1<\/a><\/sup> Roughly 30% of patients who develop S aureus<\/em> bacteremia will die within a year of index culture, yet relatively few randomized clinical trials have evaluated optimal antibiotic therapy.2<\/a><\/sup> Consequently, there is substantial variation in clinical practice and no clear global consensus on what constitutes the best standard of care.3<\/a><\/sup><\/a><\/p>\n\n\n\n In the US, treatment of S aureus<\/em> bacteremia typically involves 4 to 6 weeks of intravenous antibiotic therapy.1<\/a><\/sup>,4<\/a><\/sup>Studies to examine newer agents that might offer alternatives to this regimen are difficult to conduct, both because of intrinsic complexities of S aureus<\/em> bacteremia and the reluctance of clinicians to randomize patients to other regimens. Inclusion criteria of trials are often stringent, making it challenging to identify the Goldilocks candidate to inform new therapeutic approaches. Yet, there is a critical need to establish safe and effective treatment regimens that also offer convenience and other attributes important to patients and their families.<\/a><\/p>\n\n\n\n In the infectious diseases arena, the general shift to treating some serious infections (ie, endocarditis, osteomyelitis) with oral therapy rather than intravenous antibiotics is one such attempt.5<\/a><\/sup>,6<\/a><\/sup> These approaches offer several benefits, including reduced caregiver and nursing time, less frequent laboratory monitoring, and overall fewer health care resources. Oral agents also avoid central line\u2013associated complications (eg, infection, thrombosis), decrease the need for additional medications (eg, heparin to prevent or treat occlusion), and are environmentally friendly, requiring less plastic and resulting in fewer carbon emissions per dose compared with intravenous antibiotics.7<\/a><\/sup><\/a><\/p>\n\n\n\n Long-acting lipoglycopeptides, oritavancin and dalbavancin, are administered intravenously but dosed infrequently.8<\/a><\/sup>,9<\/a><\/sup> Initially studied and developed to avoid hospital admission for patients with acute bacterial skin and skin structure infections, off-label use of lipoglycopeptides for complex infections emerged amidst increasing administrative pressure to discharge patients and the intricacies of coordinating outpatient intravenous antibiotic therapy.8<\/a><\/sup> There is robust interest in leveraging these antibiotics, which have the potential to substantially decrease health care utilization and hospital length of stay, as step-down or consolidation therapy (ie, once the initial bacteremia has cleared) for S aureus<\/em> bacteremia.<\/a><\/p>\n\n\n\n In this issue of JAMA<\/em>, Turner and colleagues10<\/a><\/sup> report the results of the DOTS trial\u2014Dalbavancin as an Option for Treatment of Staphylococcus aureus<\/em> Bacteremia\u2014that compared dalbavancin with standard intravenous therapy for completion of treatment of complicated S aureus<\/em> bacteremia. This was an open-label, multicenter (US and Canada) trial that included hospitalized adult patients with complicated S aureus<\/em> bacteremia who achieved blood culture clearance following at least 72 hours, but not more than 10 days of initial antibacterial therapy. Patients were randomly assigned to receive either 2 doses of intravenous dalbavancin (1500 mg on days 1 and 8) or 4 to 8 total weeks of standard therapy (cefazolin or an antistaphylococcal penicillin if methicillin susceptible; vancomycin or daptomycin if methicillin resistant).<\/a><\/p>\n\n\n\n The primary outcome was superiority of dalbavancin by the desirability of outcome ranking at day 70, an end point that incorporated 5 components: clinical success, infectious complications, safety complications, mortality, and health-related quality of life. The authors report that the probability of a more desirable outcome at day 70 with dalbavancin compared with standard therapy was 47.7% (95% CI, 39.8% to 55.7%), concluding that dalbavancin was not superior to standard therapy.<\/a><\/p>\n\n\n\n The choice of desirability of outcome ranking as an end point aims to provide a more balanced measure of both the harms and benefits of each treatment in this trial.11<\/a><\/sup> Like bayesian-modeled trial end points, desirability of outcome ranking reflects the complexity of medical decision-making, presenting statistical end points more in line with the way humans think, trying to capture the reality that clinical care is not binary. It asks simply, what is the likelihood that one treatment will be superior to another? This also improves patient and caregiver understanding of the risks and benefits of treatments and moves toward holistic decision-making by clinicians.<\/a><\/p>\n\n\n\n The desirability of outcome ranking end point, however, is not without its limitations. For example, each step on the ordinal scale does not hold equal significance: transitioning from \u201calive with no failure\u201d to \u201calive with adverse event\u201d is 1 rank point, as is moving from \u201calive with failure, infectious complication, and adverse event\u201d to \u201cdeath,\u201d but the latter being of much greater consequence. While imperfect, the desirability of outcome ranking does better differentiating participants with more eventful courses from those with fewer eventful courses compared with other outcome measures.<\/a><\/p>\n\n\n\n Health-related quality of life served as a tiebreaker for patients with similar desirability of outcome rankings. Perhaps the most practical limitation of the DOTS trial is that the assessment surveys used to determine quality of life did not specifically address the outcomes most likely to result in superiority of dalbavancin, such as discharge to home instead of a skilled facility, discharge without central venous access, the absence of thrombosis (which occurred among 3 patients in the standard care group) and central line\u2013related infections, opinions on receiving daily medications, ability to store and receive intravenous drugs, or caregiver time. Given the clinical severity of S aureus<\/em> bacteremia and the lengthy associated recovery,12<\/a><\/sup> perhaps it is unsurprising that general quality-of-life measures were low and similar across both groups.<\/a><\/p>\n\n\n\n Secondary outcomes included clinical efficacy at day 70 (using a 20% noninferiority margin) and safety. Although the trial was open label, clinical outcomes were assessed by a review committee masked to treatment allocation. Clinical efficacy was demonstrated in 73 of 100 participants for dalbavancin and 72 of 100 for standard therapy (difference, 1.0% [95% CI, \u221211.5% to 13.5%]), meeting the prespecified 20% noninferiority margin.<\/a><\/p>\n\n\n\n The large noninferiority margin of 20% was based on clinician survey data and previous thresholds set in trials involving different patient populations.13<\/a><\/sup>,14<\/a><\/sup> At the greater than 70% clinical success rate observed in this trial (since patients were enrolled after blood culture clearance), a considerable increase in clinical failure in the dalbavancin group would still have been deemed noninferior, although most people would consider a large difference unacceptable. Overall, dalbavancin was noninferior compared with standard care, but perhaps a more pragmatic assessment of these data is that dalbavancin appeared similar to standard care for each component of the desirability of outcomes ranking and not superior overall.<\/a><\/p>\n\n\n\n Some other numbers are noteworthy. More patients in the standard care group experienced more than 4 days of bacteremia (10 vs 2), potentially indicating more severe infection. Although documentation of blood culture clearance was required for enrollment, the interval for blood culture draws was determined by local standards and the clinical care team, and daily blood cultures were not mandated. The median hospital length of stay after enrollment was 4 days (IQR, 2-8) in the standard therapy group vs 3 days (IQR, 2-7) in the dalbavancin group. Although these estimates overlap, even a single hospital day is clinically meaningful.<\/a><\/p>\n\n\n\n The ability to be discharged home vs a skilled nursing facility was not specifically addressed by Turner and colleagues; this metric is also deeply meaningful to patients and health systems, both socially and economically. The results of the DOTS trial help inform conversations between patients and clinicians on preferences for treatment (ie, daily intravenous medication at home or 2 doses of a lipoglycopeptide at an infusion center given 1 week apart) and should be justification for insurance providers to cover long-acting lipoglycopeptides as consolidation therapy for S aureus<\/em> bacteremia. Logistically, it is likely easier to coordinate a couple infusion appointments compared with facility placement or home health services at time of discharge, and clinicians should evaluate these data in the context of patient and institutional resources. Importantly, while not evaluated in this trial, concerns about a patient\u2019s ability to return in exactly 7 days for the second dose should be alleviated by robust pharmacokinetic modeling data suggesting adequate exposures of long-acting lipoglycopeptides up to 3 weeks after initial dosing, offering some flexibility in scheduling follow-up.15<\/a><\/sup><\/a><\/p>\n\n\n\n The DOTS trial has other limitations. The number of participants is relatively low at 200, although it is worth noting that as of 2024, the total number of patients randomized in published S aureus<\/em> bacteremia trials was only around 4000.1<\/a><\/sup> The trial excluded individuals with left-sided endocarditis or retained prosthetic material, populations that have a high rate of relapse and other complications. However, these exclusions also reflect the clinical reality that antibiotics are not a substitute for surgery or device removal.<\/a><\/p>\n\n\n\n The DOTS trial provides the best data available to date on the use of long-acting lipoglycopeptides as consolidation therapy for complicated S aureus<\/em> bacteremia. Recent publications demonstrate that even in the absence of high-quality data, clinicians and patients are willing to accept some uncertainty around efficacy as a reasonable tradeoff for the potential benefits of an operationally efficient and patient-centered treatment modality.8<\/a><\/sup> The work of Turner et al offers a practical roadmap for where dalbavancin should and should not be positioned clinically, connecting the dots and prompting a broader dialogue about novel approaches for treating S aureus<\/em> bacteremia.<\/p>\n","protected":false},"excerpt":{"rendered":" Editorial New Pathways to Treat\u00a0Staphylococcus au […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/28989"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=28989"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/28989\/revisions"}],"predecessor-version":[{"id":28990,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/28989\/revisions\/28990"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=28989"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=28989"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=28989"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}