Infective Endocarditis Trial Backs Less Intense Antibiotic Approach

Shorter antibiotic treatment worked better in clinically stabilized patients with infective endocarditis on the left side of the heart, even though the risk of infection relapse may be greater, according to the open-label randomized POET II trial.

After a minimum of 2-4 weeks to achieve clinical stability, those randomized to cease antibiotic treatment (tailored approach) had the edge over those receiving the typical standard of care regimen (4-6 weeks total duration) in terms of days alive within 6 months without antibiotic therapy for infective endocarditis or bacteremia (median 183 vs 169 days, P<0.001).

Patients in the tailored-approach group ended up taking antibiotics for 15 fewer days (median 26 vs 41 days, respectively), Henning Bundgaard, MD, of the University of Copenhagen in Denmark, reported at the European Society of Cardiology (ESC) Congress in Munich.

As for the primary safety endpoint, the strategy of tailored antibiotic treatment was associated with no excess all-cause death, unplanned cardiac surgery, or symptomatic embolic events within 6 months (8.2% vs 10.7%, P<0.001 for noninferiority), findings published simultaneously in the New England Journal of Medicine showed.

“We have challenged dogmas showing that less-intensive antibiotic therapy after stabilization is superior and safe, and we think that defining the stabilization point is a kind of personalized endocarditis treatment,” Bundgaard explained during a press briefing at ESC.

The 508 randomized participants had one of three pathogens responsible for about 70% of all infective endocarditis cases: Staphylococcus aureus, Enterococcus faecalis, or Streptococcus species.

A shorter antibiotic regimen is attractive for various reasons, including the potential for fewer side effects, less risk of antimicrobial resistance, better patient recovery, and lower costs. Nevertheless, study authors noted that 6 weeks of high-dose antibiotics is standard for infective endocarditis. This longer approach is based on expert opinion, given the lack of a biomarker that definitively shows when patients have reached bacterial clearance.

In the POET II trial, investigators used a combination of clinical, biochemical, and imaging criteria from the earlier POET trial to determine when patients were clinically stabilized. Their hypothesis was that this response-tailored treatment would result in 2 to 3 fewer weeks of IV or oral step-down antibiotic treatment.

In a key secondary analysis, standard therapy was linked with a significantly lower risk of relapse than tailored therapy, however. A return of bacteremia or infective endocarditis during 6-month follow-up happened in 5.1% of the tailored-therapy group and 1.6% of the standard-therapy group (P=0.04).

“Considering the potential benefits of a reduction in antibiotic exposure, an increase in the risk of relapse could be deemed acceptable if it is not associated with major clinical complications,” Bundgaard’s group argued. “The results of the sensitivity analysis in which relapse was included in the primary safety endpoint were reassuring for patients with infective endocarditis caused by streptococcus species or S. aureus, but more events appeared to occur among patients with infective endocarditis caused by E. faecalis in the tailored-therapy group.”

Even without accounting for relapses, tailored therapy held the advantage in the incidence of the composite safety endpoint when streptococcal and S. aureus infections were the causes: 3.6 percentage points lower with streptococcus species and 6.4 percentage points lower with S. aureus.

E. faecalis infections told a different story. Composite safety endpoint incidence rates were 6.8 percentage points lower among standard-therapy patients than tailored-therapy patients when E. faecalis was the causative pathogen. Relapse was also more common among E. faecalis patients (6.4%) than in the S. aureus (3.3%) or streptococcal (2.4%) patients.

The investigators cautioned that firm conclusions couldn’t be reached about E. faecalis, however, given that the study didn’t recruit its planned number of E. faecalis patients.

Another study limitation was the inclusion of just three pathogens, which may make study findings not generalizable for infections with rarer pathogens.

POET II was conducted in Denmark, Sweden, and the U.S. and included adults with infective endocarditis of prosthetic or native valves on the heart’s left side, a group that accounts for roughly half of all infective endocarditis cases. After clinical stabilization on 2-4 weeks of antibiotics therapy, patients were randomized 1:1 to either stop antibiotics or continue taking them for a full 4-6 weeks.

The cohort had a mean age of 70 years, and three-quarters were men. Streptococcus species were the most common pathogen, in 57.3% of patients, followed by S. aureus (24.2%), and E. faecalis (18.5%).

Nearly two-thirds of patients (63.2%) had affected aortic valves, while 26.4% had prosthetic valve infections. Before randomization, one in three people had undergone cardiac surgery.