By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Completion of therapy of selected patients with infective endocarditis with orally administered antibiotics is feasible, safe, and effective.

SOURCE: Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2018; Aug 28. doi: 10.1056/NEJMoa1808312. [Epub ahead of print].

Iversen and colleagues reported the results of a randomized noninferiority trial examining a strategy of intravenous (IV) to oral conversion of antibiotic therapy carried out at multiple centers in Denmark. The study involved 400 adults with left-sided endocarditis due to one of the following organisms: Streptococcus, Enterococcus faecalis, Staphylococcus aureus, and coagulase-negative staphylococci. The entry criteria are listed in Table 1. Approximately half of the cases were caused by streptococci and one-fifth were caused by S. aureus (none were methicillin-resistant). Antibiotic therapy was initiated based on European guidelines as modified by the Danish Society of Cardiology with development of oral antibiotic choice guideline by the study investigators. The latter were based on pharmacokinetic/pharmacodynamic principles and always included two antibiotics from different classes and with different targets and pharmacokinetics. Rifampin often was included as one of the antibiotics.

Table 1: Entry Criteria

  • Age ≥ 18 years
  • Left-sided infective endocarditis
    • Fulfills modified Duke criteria
    • Native or prosthetic valve
  • Streptococcus, E. faecalis, S. aureus, or coagulase-negative staphylococcus
  • IV antibiotic for > 10 days and stable and ≥ 7 days after valve surgery (if performed)
  • No abscess or valve dysfunction requiring surgery (by transesophageal echo) at time of randomization

Table 2: Primary Composite Outcome

From time of randomization until six months after completion of antibiotic therapy:

  • All-cause mortality OR
  • Unplanned cardiac surgery OR
  • Embolic events OR
  • Relapse of bacteremia with the primary pathogen

Although 1,954 patients with possible endocarditis were referred to the participating centers, 400 (20%) were enrolled. The most frequent reason for nonenrollment was not meeting entry criteria and unwillingness or inability to provide informed consent. The mean age of the participants was 67 years, and approximately three-fourths were male; 38% had significant comorbidities. Only five patients were injection drug users. The aortic valve was involved most frequently, and 27% of patients had a preexisting prosthetic valve. During their treatment for endocarditis, 38% of patients had undergone valve surgery prior to randomization. Thirty-five patients had an implantable cardiac device; pacemakers were removed from 14 patients with infection of the device.

The median time from diagnosis to randomization was 17 days in each group. After randomization, treatment was continued for a median 19 days in those assigned to IV therapy alone and 17 days in those assigned to switch to oral therapy. The median length of hospital stay after randomization was 19 days in the IV group and only three days in the oral switch group; 80% of the oral therapy group were treated partially or completely as outpatients.

Therapeutic drug monitoring was performed, and seven patients were found to have below-target plasma concentrations of one of their two antibiotics (rifampin in three patients, moxifloxacin in two, and linezolid and dicloxacillin in one each). Although no change was made, none had an unfavorable outcome.

The composite primary outcome occurred in 24 (12.1%) IV-treated patients and 18 (9.0%) orally treated patients (between-group difference, 3.1 percentage points; 95% confidence interval, -3.4 to 9.6; P = 0.40), indicating noninferiority.

COMMENTARY

Every protocol for IV to oral antibiotic conversion that I have seen excludes patients with endocarditis, as well as several other serious infections. The following appear to be the only mentions of oral antibiotic therapy for endocarditis in the 2015 American Heart Association guidelines.1

  • “Absorption of orally administered antimicrobial agents may be unreliable and is generally not recommended for the treatment of endocarditis, especially during the initial phase of therapy.”
  • “In patients who will not comply with a course of parenteral antibiotic therapy, oral treatment may be an option. Two studies have evaluated the use of predominantly oral 4-week antibiotic regimens (ciprofloxacin plus rifampin) for the therapy of uncomplicated right-sided S. aureus endocarditis in IDUs. In each study, including one in which 70% of patients were HIV-seropositive, cure rates were 90%.”

Thus, except for right-sided endocarditis due to S. aureus, any oral therapy generally has been eschewed. However, this has not been the result of evidence that well-chosen orally administered antibiotics lead to failure of therapy, but a lack of any evidence. Iversen and colleagues now have provided strong evidence that follow-on oral therapy in stable patients after a period of IV antibiotic administration is effective in carefully selected patients. Although the published data are remarkably limited, an alternative consideration could be given to administration of lipoglycopeptides with very slow clearance, such as dalbavancin2 or oritavancin.

From a personal viewpoint, I have treated several patients with left-sided endocarditis in this way. However, the cases I selected were infected with one of two types of organisms: viridans streptococci with very low penicillin minimum inhibitory concentrations and HACEK organisms, which usually are exquisitely susceptible to fluoroquinolones. I remain a bit anxious in applying this approach to staphylococcal or enterococcal endocarditis or to cases of prosthetic valve infection, but I am willing to be convinced.

A final note: This paper deserves careful reading not only of the main paper but also of the accompanying 31-page supplemental appendix.

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. Tobudic S, Forstner C, Burgmann H, et al. Dalbavancin as primary and sequential treatment for Gram-positive infective endocarditis: 2-year experience at the General Hospital of Vienna. Clin Infect Dis 2018;67:795-798.