POET

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Iversen K, et al. "Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis". New England Journal of Medicine. 2018. 380:415-24.
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Clinical Question

In adult patients with left sided infective endocarditis (IE), is switching to oral antibiotics to complete therapy after at least 10 days IV safe and as effective as continued IV antibiotics?

Bottom Line

In patients with left-sided IE, partial oral antibiotic treatment after stabilization and clinical response to IV treatment is non-inferior to treatment with only IV antibiotics.

Major Points

Infective endocarditis (IE) is typically medically treated with up to six weeks of IV antibiotics, because of the need for a prolonged duration of high serum levels of bactericidal antibiotics for cure [1]. Patients presenting with heart failure, high-risk of embolism, and uncontrolled infection are indications for valvular surgery in current guidelines [2], [3]. Many patients remain hospitalized after stabilization to either complete IV antibiotic therapy, or until the insertion of a peripherally inserted central catheter so that IV treatment can be completed as an outpatient. Parenteral therapy as an outpatient reduces hospital length of stay, but is associated with logistic challenges related to adherence and monitoring. [4].

The Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) study was a non-inferiority trial that randomized 400 Danish patients between 2011 and 2017 with left-sided IE caused by typical organisms to complete treatment with either IV antibiotics, or switch to an oral antibiotic regimen after initial clinical stabilization with IV antibiotics and/or valvular surgery. To avoid subtherapeutic antibiotic serum levels, only patients with “clinically normal gastrointestinal uptake” were enrolled. Oral antibiotic regimens each contained 2 highly bioavailable antibiotics from different drug classes, with different antimicrobial mechanisms and metabolization. The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, clinically evident embolic events, or relapse of bacteria with primary pathogen. This primary outcome occurred in 9.0% of the orally treated group and 10.5% in the IV antibiotics (ABx), meeting non-inferiority margin of 10%. There were also fewer deaths and in the orally treated group, but not significantly so. Adverse effects, safety outcomes, and subgroup analysis were similar in both groups.

This trial has several important limitations. The generalizability may be limited as the Patients in the oral group treated as outpatients were seen frequently (2-3x a week), which may not reflect real-world monitoring, and only 5/400 patients were IV drug users. Included organisms represent about 70-75% of all IE and no MRSA was included. This was the first large clinical trial examining the efficacy of oral antibiotic treatment for left-sided IE and seems to confirm what had been suggested by previous literature[5][6][7]: that some patients with IE with working GI tracts capable of absorbing highly bioavailable antibiotics, can be partially treated with oral therapy.

Guidelines

As of February 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multicentre, 1:1 randomized allocation of intention, open-label non-inferiority trial
  • N=400 patients
    • Oral Therapy Arm = 201
    • IV Therapy Arm - 199
  • Setting: Danish patients referred to a cardiac center for suspected IE
  • Enrollment: 2011 to 2017
  • Mean follow-up: 6 months after ABx completed
  • Analysis: Intention-to-treat, Inferiority margin 10%
  • Primary outcome: A composite outcome of all-cause mortality, unplanned cardiac surgery, clinically evident embolic events, or relapse of bacteremia with the primary pathogen

Population

Inclusion Criteria

  • ≥ 18 years old
  • Left-sided endocarditis fulfilling the modified Duke criteria[8] (native or prosthetic valve)
  • Blood cultures positive with one of the following microorganisms:
    • Streptococcus
    • Enterococcus faecalis
    • Staphylococcus aureus
    • Coagulase-negative staphylococci (CoNS)
  • ≥ 10 days of appropriate IV antibiotic treatment overall, or ≥ 7 days of appropriate parenteral treatment after valve surgery
  • T< 38.0°C for > 2 days
  • A C-reactive protein (CRP) decrease to less than 25% of peak value OR < 20 mg/L, and white blood cell count < 15 x 10^9/L during antibiotic treatment
  • Transthoracic and transesophageal echocardiography performed within 48 hours of randomization 


Exclusion Criteria

  • Abscess formation demonstrated with transesophageal echocardiography
  • Body mass index > 40 kg/m2
  • Concomitant infection requiring intravenous antibiotic therapy
  • Inability to give informed consent to participation
  • Suspicion of reduced absorption of oral treatment due to abdominal disorder
  • Reduced compliance

Baseline Characteristics

Characteristics for Partial Oral Treatment (vs IV treatment in brackets where difference was significant).

  • Demographics:
    • Mean Age: 67.6 years
    • Female Sex: 20.9%
  • Comorbidities:
    • Diabetes: 15.4%
    • Renal failure: 10.4%
    • Dialysis: 7.5%
    • COPD: 4.5% (vs. 8.5%
    • IV drug use: 1.0% (vs. 1.5%)
  • Lab results at randomization:
    • WBC: 7.2
    • C-reactive Protein: 19.9 (vs. 24.3) mg/L
    • Creatinine: 141 micromol/L
  • Pathogen:
    • Streptococcus: 45.8%
    • E. Faecalis: 25.4%
    • Methicillin-Sensitive S. Aureus (MSSA): 23.4%
    • CoNS: 6.5%
    • Methicillin-Resistant S. Aureus (MRSA): 0%
  • Prosthesis/Implants:
    • Prothetic heart valve: 26.9%
    • Pacemaker 10%
    • Pacemaker endocarditis: 4.0%
  • Pattern of IE (valves involved):
    • Mitral-valve endocarditis: 35.8%
    • Aortic-valve endocarditis: 54.2%
    • Mitral + aortic-valve endocarditis: 10.0%
  • Valve surgery during current disease course: 38.3%

Interventions

  • Partial Oral Treatment (intervention arm)
    • Completion of antibiotic therapy with a regimen of 2 antibiotics of different classes, based on sensitivities and MIC’s of cultured organisms. Serum levels of antibiotics in this arm were checked at Day 1 and 5 of therapy.
      • Most common regimens: Dicloxacillin and Rifampicin (RIF), Amoxicillin (AMX) and Moxifloxacin, AMX + RIF, AMX + Linezolid.
      • At patients' preference and with attending physician's discretion, patients in the oral group were discharged to follow-up in outpatient clinics 2-3 times a week until completion of therapy.
  • Full IV Treatment (control arm)
    • Completion of antibiotic therapy with continued IV antibiotics.

Transesophageal echocardiogram (TEE) was done in all patients 1 week prior to completion of treatment. After completion of therapy, all patients were seen in clinic follow-up at 1 week, 1, 3, and 6-months.

Outcomes

Comparisons are partial oral vs full intravenous treatment

Primary Outcomes

All-cause mortality, unplanned cardiac surgery, clinically evident embolism, and relapse of bacteremia
9.0% vs 12.1% (OR 0.72, 95% CI, 0.37 to 1.36)
3.1% difference (95% CI, -3.4 to 9.6, P = 0.40).

Component Analysis

All cause mortality
3.5% vs 6.5% (HR 0.53, 95% CI 0.21 to 1.32)
Unplanned cardiac surgery
3% vs 3% (HR 0.99, 95% CI 0.32 to 3.07)
Embolic event
1.5% vs 1.5% (HR 0.97, 95% CI 0.20 to 4.82)
Relapse of positive blood culture
2.5% vs 2.5% (HR 0.97, 95%CI 0.29 to 3.33)

Subgroup Analysis

Median length of stay in hospital after randomization
3 days vs. 19 days, P < 0.001

There were no significant differences for the pre-specified subgroups of: sex, diabetes, renal disease, species of bacteria, patients who underwent surgical treatment, type of valve (prosthetic vs native), and type of diseased valve (aortic vs. mitral valves).

Adverse Events

Adverse effects from antibiotic therapy
5% vs 6%, P = 0.66

Criticisms

  • Only patients with left-sided IE were enrolled.
  • 25-30% of patients with IE caused by bacteria other than the ones listed in the inclusion criteria were excluded.
  • Few patients with IV drug use were enrolled (n=5/400)
  • Patients were referred into the study by other physicians (therefore potentially creating referral bias).
  • Patients in the oral group treated as outpatients were seen frequently (2-3x a week), which may not reflect real-world monitoring.
  • No patients with methicillin-resistant Staphylococcus Aureus (MRSA) IE were enrolled in this study
  • only 20% of the screened population was randomized

Funding

Trial was funded with grants from the Danish Heart Foundation, the Capital Regions Research Council, the Hartmann’s Foundation, Svend Aage Andersens Foundation, and the Novo Nordisk Foundation (grant).

Further Reading

  1. Hoen B & Duval X Clinical practice. Infective endocarditis. N. Engl. J. Med. 2013. 368:1425-33.
  2. Habib G 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 (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur. Heart J. 2015. 36:3075-3128.
  3. Baddour LM 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. 132:1435-86.
  4. Andrews MM & von Reyn CF Patient selection criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Clin. Infect. Dis. 2001. 33:203-9.
  5. Al-Omari A et al. Oral antibiotic therapy for the treatment of infective endocarditis: a systematic review. BMC Infect. Dis. 2014. 14:140.
  6. Heldman AW et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am. J. Med. 1996. 101:68-76.
  7. Dworkin RJ et al. Treatment of right-sided Staphylococcus aureus endocarditis in intravenous drug users with ciprofloxacin and rifampicin. Lancet 1989. 2:1071-3.
  8. Li JS et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin. Infect. Dis. 2000. 30:633-8.