Is a Switch to Oral Antibiotics a Safe Option in Endocarditis?

Intravenous (IV) antibiotics have long been the mainstay for endocarditis treatment advocated across international guidelines.^1,2 This reflects the high mortality and complication rate associated with this severe infection. However, results from the Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) study published in New England Journal of Medicine, challenged this dogma and investigated whether a partial oral regimen may lead to equivalent outcomes.

In a cohort of 400 adults with left-sided endocarditis, researchers conducted a multicenter noninferiority randomized trial.³ After receiving at least 10 days of IV antibiotic therapy or at least one week of therapy following valve surgery, patients either received the standard of care —continuation of IV antibiotics — (n=199) or were switched to a microbiologically-appropriate oral regimen (n=201). The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the original organism.

Approximately half the isolated organisms in each group were streptococci species, followed by Enterococcus faecalis, Staphylococcus aureus, and coagulase negative staphylococci, in decreasing order of frequency. Prior to inclusion in the trial, roughly 27% of patients in both the oral and IV groups had prosthetic heart valves and 7.5% in the IV group and 10% in the oral group had pacemakers.³

Patients were included once they were determined to be clinically stable (defined as a temperature <38°C for >2 days, C-reactive protein ≤25% of peak level, white cell count <15 x 10⁹/L). Of note, this included a repeat transoesophageal echocardiogram within a 48-h-period of the switch to an oral regimen, primarily to exclude the development of an abscess.

Antibiotics following randomization were continued for a median of 19 days in the IV group and 17 days in the oral group. The primary outcome was reached in 24 patients (12.1%) in the IV group and 18 patients (9.0%) in the oral group at 6-month follow-up. The between-group difference of 3.1% (95% CI, −3.4 to 9.6; P =.40) met the pre-specified non-inferiority margin of −10%. There was no statistically significant difference between the two groups for any individual component of the composite end point. Further, researchers noted that 4 patients were switched from the oral treatment group to the IV group: 1 as a result of incident bacteremia with a different pathogen, 2 due to patient preference, and 1 because of nausea related to oral antibiotics.

Important caveats for this trial included the makeup of the patient population. As highlighted by the study authors and expert commentators, there were no patients with methicillin-resistant S aureus. Similarly,  there were very few IV drug users (1.5% in the IV group; 1.0% in the oral group) for whom this management approach would be particularly attractive.

The study highlighted the difficulties and costs arising from lengthy periods of IV therapy which often entail an extended hospital stay in regions in which outpatient parenteral treatment is not an option. Regardless of setting, attendant risks included catheter-site infections, bleeding, and thromboembolic disease. which can be avoided with oral treatment.

Infectious Disease Advisor spoke to Dr Kasper Iversen, clinical associate professor, Department of Cardiology, Herlev-Gentofte University Hospital, in Copenhage, Denmark, and first author of the NEJM article.

Infectious Disease Advisor: Very few randomly assigned individuals had IV drug use as a risk factor and there were no resistant organisms. Do you think the use of partial oral antibiotics can be considered safe in these groups?

Dr Iversen: We do. We consider the POET trial, and other similar trials examining oral antibiotics, as proof of concept. If oral therapy is available, we think it can also be used in IV drug users and for resistant organisms. Many antibiotics such as linezolid, moxifloxacin, rifampin, and fusidic acid would also be suitable for methicillin-resistant S aureus infections.

Infectious Disease Advisor: Given that the extensive exclusion criteria the application of these data in clinical settings in the United States will likely be limited, do you think a future randomized clinical trial can investigate noninferiority with less stringent conditions?

Dr Iversen: We do not consider the exclusion criteria strict. We think that more than half of patients with infective endocarditis could be included in a trial using the POET criteria. Considering the number of previous randomized controlled trials in endocarditis, we doubt that new randomized clinical trials with less stringent conditions will be conducted. More likely, we believe that data from POET will be extrapolated and observational data will confirm that the concept could be extended to other group patient groups.

Conclusion

The POET trial offers valuable new evidence indicating that in selected stable patients, the switch to oral antibiotics to complete a treatment course may be sufficient once the critical early period has been managed.

References

1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132: 1435-1486.
2. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology. Eur Heart J. 2015;36:3075-3128.3.
3. Iversen, K. et al. Partial oral versus intravenous antibiotic treatment of endocarditis.N Engl J Med. 2019;380:415-424. https://doi.org/10.1056/ NEJMoa1808312 (2018)