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POET: Oral antibiotics viable residual treatment for left-sided endocarditis
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MUNICH — Patients with left-sided infective endocarditis who after stabilization received treatment with oral antibiotics had similar outcomes to those who remained on IV antibiotics and a shorter hospital stay, according to the POET trial presented at the European Society of Cardiology Congress.
This patient population often remains hospitalized for 6 weeks because of prolonged treatment with IV antibiotics, and it was not known if shifting to oral antibiotics once a patient is stabilized would lead to similar outcomes, Henning Bundgaard, MD, DMSc, from the department of cardiology, the Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, said in a press conference.
“We know that there is a high in-hospital complication and mortality rate in the early critical phase of the disease,” he said. “After stabilization, the main reason for staying in the hospital for the majority of patients is just to receive IV antibiotics.”
For the POET noninferiority study, Bundgaard and colleagues randomly assigned 400 patients in stable condition with left-sided infective endocarditis caused by streptococcus, Enterococcus faecalis, Staphylococcus aureus or coagulase-negative staphylococci and who were on IV antibiotics for at least 10 days to continued treatment with IV antibiotics or a shift to oral antibiotics. Oral treatment included two antibiotics in all cases, chosen according to careful susceptibility testing.
Patients in the oral antibiotics group were discharged to outpatient treatment if feasible.
The primary outcome was a composite of all-caused mortality, unplanned cardiac surgery, embolic events or relapse of bacteremia with the primary pathogen. Patients were followed for 6 months after their antibiotic treatment was completed. The findings were simultaneously published in The New England Journal of Medicine.
IV antibiotics were administered in accordance with ESC guidelines, with modifications from the Danish Society of Cardiology. The oral antibiotic treatment regimens were developed by the researchers and were based on pharmacokinetic calculations and expected minimal inhibitory concentrations for each biological species as determined by the European Committee on Antimicrobial Susceptibility Testing.
Patients were randomly assigned to oral or continued IV antibiotic treatment after a median of 17 days on an initial IV antibiotic regimen. Following randomization, antibiotic treatment was completed after a median of 19 days in the IV group (interquartile range [IQR], 14-25) and a median of 17 days in the oral group (IQR, 14-25; P = .48), according to the researchers.
Noninferiority criteria were met, Bundgaard said. The primary outcome occurred in 12.1% of the IV group and 9% of the oral group (between-group difference, 3.1 percentage points; 95% CI, –3.4 to 9.6; P = .4; OR = 0.72; 95% CI, 0.37-1.36) in an intention-to-treat analysis. The per-protocol analysis and a sensitivity analysis had similar results.
There were no significant differences between the groups in any of the individual components of the primary outcome, but mortality was numerically higher in the IV group, according to the researchers.
“The efficacy and safety of changing to oral antibiotic treatment was noninferior to continued intravenous antibiotic treatment in stabilized patients with left-sided endocarditis,” Bundgaard said during the press conference. “We saw similar results across a number of comorbidities, including whether the patient had a native or prosthetic valve and whether the patient had surgery during the disease course or was conservatively treated. Oral antibiotics can be safely administered for as much as half the recommended treatment period, which is 6 weeks in most patients, and that could potentially be as outpatient treatment. Most important, more than 50% of patients with infective endocarditis may be candidates for oral antibiotic treatment.” – by Erik Swain
References:
Bundgaard H, et al. Hot Line Session 5. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.
Iversen K, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1808312.
Disclosure: The study was funded in part by the Novo Nordisk Foundation. Bundgaard reports no relevant financial disclosures. Please see the study for a list of the other authors’ relevant financial disclosures.
Perspective
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Frederick A. Masoudi, MD, MSPH
This is an important trial for a number of reasons. Endocarditis is fairly common and has a substantial impact on patients. The treatment that is usually recommended for left-sided endocarditis is a fairly long period of treatment with IV antibiotics, much of which is provided in the inpatient setting. But even if it’s possible to treat patients in the outpatient setting, it’s logistically challenging to set that up, and requires a fair amount of resources. So the idea of determining whether or not it might be possible to use an oral regimen to in part treat left-sided endocarditis is important.
The researchers found no evidence of inferiority, so they met the primary endpoint with respect to the oral vs. IV regimens. Even though this patient group was relatively carefully selected, ie, they had all received at least 10 days of IV antibiotics, they were all clinically stable, they were afebrile, they had no evidence of marked inflammation via the inflammatory markers and they all had a transesophageal echocardiogram, about a quarter of them had prior valve surgery or a prosthetic valve, so this was not an entirely low-risk population.
The findings are interesting and stimulating. It should make clinicians think about starting to use oral regimens, at least in the patients like those enrolled in this trial, keeping in mind that none of the organisms responsible for the infections were antibiotic-resistant. There may be an option for an oral regimen in selected patients that we think will be able to adhere to a two-drug oral regimen for part of their treatment. In this trial, the median time for the oral treatment was 17 days, and patients in the oral-treatment group still had a fair amount of treatment with IV antibiotics first (a median of 17 days).
It appears that a little more than 2 weeks in the hospital were saved due to the orally treated regimen. This may be more convenient for patients and may be more cost-effective when applied appropriately.
The patients in the oral-treatment group were seen two or three times per week during the course of their residual therapy and they had TEEs shortly prior to cessation of antibiotics, so they were followed fairly closely. I am curious to see how this will be implemented in practice. My guess is that given the high stakes of failure in the treatment of endocarditis, clinicians will be cautious in applying this approach in practice, particularly for patients with prosthetic valves. Randomized trials in infective endocarditis have been very difficult to perform. This is therefore a remarkable study because it is a rigorous randomized trial in endocarditis that enhances our understanding of the best therapy for these patients.
Professor of Medicine
Division of Cardiology
Department of Medicine
University of Colorado School of Medicine
Anschutz Medical Campus
Chief Science Advisor
American College of Cardiology’s National Cardiovascular Data Registry
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