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The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Bundgaard at the Department of Car‑ diology B 2141, the Heart Center, Rig‑ shospitalet, Copenhagen University Hos‑ pital, Blegdamsvej 9, 2100 Copenhagen, Denmark, or at henning . bundgaard@ regionh . dk.

Drs. Iversen, Ihlemann, Høfsten, Fos‑ bøll, Køber, and Bundgaard are members of Copenhagen Health Science Partners.

This article was published on August 28, 2018, at NEJM.org.

BACKGROUND Patients with infective endocarditis on the left side of the heart are typically treated with intravenous antibiotic agents for up to 6 weeks. Whether a shift from intrave- nous to oral antibiotics once the patient is in stable condition would result in efficacy and safety similar to those with continued intravenous treatment is unknown.

METHODS In a randomized, noninferiority, multicenter trial, we assigned 400 adults in stable condition who had endocarditis on the left side of the heart caused by streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci and who were being treated with intravenous antibiotics to continue intravenous treatment (199 patients) or to switch to oral antibiotic treatment (201 patients). In all patients, antibiotic treatment was administered intravenously for at least 10 days. If feasible, patients in the orally treated group were discharged to outpatient treatment. The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed.

RESULTS After randomization, antibiotic treatment was completed after a median of 19 days (interquartile range, 14 to 25) in the intravenously treated group and 17 days (inter- quartile range, 14 to 25) in the orally treated group (P = 0.48). The primary composite outcome occurred in 24 patients (12.1%) in the intravenously treated group and in 18 (9.0%) in the orally treated group (between-group difference, 3.1 percentage points; 95% confidence interval, −3.4 to 9.6; P = 0.40), which met noninferiority criteria.

CONCLUSIONS In patients with endocarditis on the left side of the heart who were in stable con- dition, changing to oral antibiotic treatment was noninferior to continued intrave- nous antibiotic treatment. (Funded by the Danish Heart Foundation and others; POET ClinicalTrials.gov number, NCT01375257.)

A B S T R A C T

Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis

Kasper Iversen, M.D., D.M.Sc., Nikolaj Ihlemann, M.D., Ph.D., Sabine U. Gill, M.D., Ph.D., Trine Madsen, M.D., Ph.D., Hanne Elming, M.D., Ph.D.,

Kaare T. Jensen, M.D., Ph.D., Niels E. Bruun, M.D., D.M.Sc., Dan E. Høfsten, M.D., Ph.D., Kurt Fursted, M.D., D.M.Sc.,

Jens J. Christensen, M.D., D.M.Sc., Martin Schultz, M.D., Christine F. Klein, M.D., Emil L. Fosbøll, M.D., Ph.D., Flemming Rosenvinge, M.D.,

Henrik C. Schønheyder, M.D., D.M.Sc., Lars Køber, M.D., D.M.Sc., Christian Torp‑Pedersen, M.D., D.M.Sc., Jannik Helweg‑Larsen, M.D., D.M.Sc.,

Niels Tønder, M.D., D.M.Sc., Claus Moser, M.D., Ph.D., and Henning Bundgaard, M.D., D.M.Sc.

Original Article

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Patients with infective endocardi-tis on the left side of the heart are typically treated with intravenously administered anti- biotic agents for up to 6 weeks, according to guide- lines from the European Society of Cardiology and the American Heart Association.1,2 During the ini- tial phase after admission, intensive care and close monitoring are often needed. In-hospital mortality is reported to range from 15% to more than 45%, depending on the pathogen and on complicating factors, and half the patients undergo cardiac-valve surgery.3-5 The majority of complications, including death, are seen during the initial phase.6-8 For a large proportion of patients, the main reason for staying in the hospital after the initial phase is to complete intravenous antibiotic treatment. There- fore, if oral antibiotic treatment might be safe and efficient, part of the treatment period for patients in stable condition could take place outside hospi- tals, without the need for an intravenous catheter.

Intravenous treatment during long hospital stays may be associated with an increased risk of complications, whereas a shorter length of hospi- tal stay has been associated with better outcomes in studies of other diseases.9-11 This forms the basis for recommendations in European and American guidelines for outpatient parenteral treatment of endocarditis in patients fulfilling certain criteria, a regimen commonly used in the United States.1,2,12,13 However, when outpatient parenteral treatment is given, logistic issues are critical, and education of the patients and staff is necessary to ensure that the patients adhere to the regimen, are ade- quately monitored for efficacy and adverse effects, and receive paramedic and social support, as well as easy access to medical advice. Oral antibiotic therapy may reduce these challenges and may be an appropriate alternative. However, the clinical evidence for the safety and efficacy of oral anti- biotic treatment of endocarditis is limited.14-18

In the current trial, we hypothesized that in patients in clinically stable condition who have endocarditis on the left side of the heart, a shift from intravenously to orally administered antibi- otic treatment would result in efficacy and safety that would be similar to those with continued in- travenous antibiotic treatment.

M e t h o d s

Trial Design and Oversight

The Partial Oral Treatment of Endocarditis (POET) trial was a nationwide investigator-initiated, multi-

center, randomized, unblinded, noninferiority tri- al performed at cardiac centers in Denmark. The trial design has been published previously.17 The trial was overseen by an independent data and safety monitoring board. The protocol is avail- able with the full text of this article at NEJM.org. The trial was approved by the regional scientific ethics committee for the Capital Region of Den- mark and by the Danish Data Protection Agency and was performed in accordance with the prin- ciples of the Declaration of Helsinki. All partici- pants provided written informed consent. All the authors vouch for the completeness and accuracy of the data and analyses presented and for the fidelity of the trial to the protocol.

Patients

Eligible patients were adults, 18 years of age or older, in stable condition who were receiving in- travenous antibiotic treatment for endocarditis on the left side of the heart (on native or prosthetic valves), who fulfilled the modified Duke criteria,19 and who had blood cultures that were positive for streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci. De- cisions about whether to offer surgery or to re- move a pacemaker or an implantable cardio- verter–defibrillator were made at multidisciplinary team meetings according to established guidelines and were not a part of the trial. Only patients in stable condition were enrolled (i.e., patients who had had satisfactory clinical responses to initial treatment, including antibiotic treatment admin- istered intravenously for at least 10 days and, among patients who had undergone valve sur- gery, for at least 7 days after the surgery). In ad- dition, transesophageal echocardiography per- formed before randomization had to show no signs of abscess formation or valve abnormali- ties that would require surgery (a full list of in- clusion and exclusion criteria is provided in Ta- ble S1 in the Supplementary Appendix, available at NEJM.org). At the time of randomization, at least 10 days of scheduled antibiotic treatment had to remain. Patients assigned to receive intra- venous treatment remained in the hospital until antibiotic treatment was completed. If feasible, patients assigned to receive oral treatment were treated in the outpatient clinics and were seen two to three times per week. Within 1 to 3 days before the completion of the assigned antibiotic treatment, transesophageal echocardiography was performed to confirm that the patient had a suf-

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ficient response to treatment. All patients were discharged from the hospital on the day the anti- biotic treatment was terminated (determined be- fore randomization); all patients were seen in the outpatient clinic at 1 week and at 1, 3, and 6 months after completion of antibiotic treatment. Enrollment and the assignment of treatment were performed by local investigators with a Web-based case-report-form system.

Choice of Antibiotics

Intravenous antibiotic treatment was administered in accordance with guidelines of the European Society of Cardiology, with modifications endorsed by the Danish Society of Cardiology.2,20 The trial investigators developed oral antibiotic treatment regimens as part of the trial (Table S2 in the Supplementary Appendix). Antibiotics for which published data showed moderate to high bio- availability were chosen. The oral regimens were based on pharmacokinetic calculations and ex- pected minimal inhibitory concentrations (MICs) for each bacterial species published by the Euro- pean Committee on Antimicrobial Susceptibility Testing (EUCAST).21 In all cases, susceptibility testing by means of disk diffusion was per- formed in accordance with EUCAST guidelines. MICs were determined with the use of Etest or VITEK2 (bioMérieux), and the choice of antibiot- ics for each patient was adjusted accordingly. In all cases, the oral regimens consisted of two antibiotics from different drug classes with dif- ferent antimicrobial mechanisms of action and different metabolization processes to reduce the risk of de facto monotherapy (e.g., in the case of reduced gastrointestinal uptake or fast metabo- lization of one drug).

Pharmacokinetics

To ensure that patients received sufficient doses of antibiotics, blood samples for the measure- ment of plasma levels of orally administered antibiotics were obtained on day 1 after the ad- ministration of a single dose (30 minutes and 1, 2, 4, and 6 hours after administration) and on day 5, after the administration of multiple doses (with the assumption that a steady state would have been achieved by this time). Samples were also obtained from patients in the intravenously treated group on day 1. Samples were analyzed with the use of high-pressure liquid chromatog- raphy. For safety considerations, the first dose and steady-state pharmacokinetics were evalu-

ated (Table S3 in the Supplementary Appendix). Antibiotic doses were adjusted according to phar- macokinetic findings, if necessary.

Trial Procedures

Participants were randomly assigned in a 1:1 ratio to continued intravenously administered antibiotic treatment or to a shift to orally administered anti- biotic treatment. Randomization was performed with the use of a Web-based system, in permuted blocks of 2 to 6, with stratification according to randomization site.

Outcomes

The primary outcome was a composite of all- cause mortality, unplanned cardiac surgery, clin- ically evident embolic events, or relapse of bac- teremia with the primary pathogen (detected in blood cultures obtained during follow-up or for clinical reasons) from randomization through 6 months after antibiotic treatment was complet- ed. A clinical-event adjudication committee, whose members were unaware of the treatment assign- ments, adjudicated the prespecified clinical out- comes. The committee consisted of experienced cardiologists and a specialist in infectious dis- eases.

Statistical Analysis

The trial was designed as a noninferiority trial; that is, it was designed to determine, with the use of a noninferiority margin, whether partial oral treatment was noninferior to conventional intra- venous treatment. We estimated event rates for the four components of the primary composite outcome from the literature17; we estimated the risk of all-cause mortality to be 2 to 5%, the risk of unplanned surgery to be 1 to 3%, the risk of embolic events to be 1 to 2%, and the risk of re- lapse of bacteremia to be 1 to 3%. Thus, the over- all risk of the primary outcome was 5 to 13%. A risk difference (i.e., a noninferiority margin) of 10 percentage points was chosen (see the Sup- plementary Appendix). Under the assumption of a 10% event rate and a 5% loss to follow-up, we determined that inclusion of 400 patients would be required to provide a power of 90% to confirm noninferiority, with a one-sided confidence inter- val of 97.5%. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate, and were com- pared with the use of Student’s t-test or the Mann– Whitney U test. Categorical variables are expressed

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as absolute numbers and frequencies and were compared with the chi-square test, including Yates’ correction for continuity. Logistic-regression analy- sis was used to calculate odds ratios for the pri- mary outcome in prespecified subgroups. Cox re- gression analysis was used to assess the components of the primary composite outcome to address competing risks (e.g., death). The proportional- hazard assumption was assessed with Schoenfeld residuals. All analyses were performed according

to the intention-to-treat principle. A per-protocol analysis is also presented for the primary out- come; in the per-protocol analysis, patients who crossed over from their assigned treatment to the other treatment were excluded. Cumulative inci- dences were calculated for events with competing risk (death) for the outcomes of unplanned cardiac surgery, embolic events, and relapse of bacteremia with the primary pathogen. Two-sided P values of less than 0.05 were considered to indicate statis- tical significance. Analyses were performed with the use of SPSS software, version 22.0 (IBM), and R software, version 3.3.3 (R Foundation for Statis- tical Computing).22-24

R e s u l t s

Patients

From July 15, 2011, to August 30, 2017, a total of 1954 patients who were referred to a cardiac cen- ter because of suspected endocarditis were screened for inclusion; 400 patients (20%) with endocarditis on the left side of the heart who fulfilled the modified Duke criteria for definite endocarditis were enrolled; 199 patients were randomly as- signed to continued conventional intravenous treatment, and 201 patients to a shift to oral treat- ment (Fig. 1). The most frequent reasons for ex- clusion were an unconfirmed diagnosis (22%), an unwillingness or inability to give informed con- sent (16%), or an infection that was caused by other bacteria (9%) (Table S4 in the Supplemen- tary Appendix). Generally, the two groups were well balanced with regard to baseline character- istics (Table 1). The majority of patients were men (77%), and the mean age was 67 years. A total of 139 patients (35%) had at least one major coex- isting medical condition. At the time of random- ization, the results of routine blood tests were similar in the groups, except that the C-reactive protein level was slightly higher in the intrave- nously treated group. The most frequently iden- tified pathogen was streptococcus, followed by S. aureus, E. faecalis, and coagulase-negative staphy- lococci (Table 1, and Table S5 in the Supplemen- tary Appendix).

The aortic valve was affected in the majority of cases, and in 27% (107 patients), a previously in- serted prosthetic valve was affected (details are provided in Table S6 in the Supplementary Appen- dix). Before randomization, 152 of the 400 enrolled patients (38%) had undergone valve surgery (Ta-

Figure 1. Enrollment and Randomization of Patients.

Inclusion and exclusion criteria are listed in Table S1, and additional details on reasons for exclusion are provided in Table S4, in the Supplementary Appendix. Signs of abscess formation were identified by transesophageal echocardiography (TEE) immediately before randomization. No patients were lost to follow‑up. The body‑mass index (BMI) is the weight in kilo‑ grams divided by the square of the height in meters.

400 Underwent randomization

1954 Patients were assessed for eligibility

1554 Were excluded 428 Did not fulfill modified Duke

criteria 174 Had endocarditis caused

by other bacteria 3 Were febrile (temperature

≥38.0°C) 132 Had high level of C-reactive

protein, white cells, or both 130 Had signs of abscess

formation 13 Had no TEE available <48 hr 3 Were severely obese

(BMI >40) 64 Had other infection requiring

intravenous treatment 22 Were not expected to adhere

to the assigned regimen 14 Had suspected reduced

gastrointestinal uptake 303 Were not willing or able

to give consent 18 Had heart-valve surgery

planned 25 Had impaired immune

response 4 Had had endocarditis within

the previous yr 150 Met other exclusion criteria 71 Died

199 Were assigned to intravenous antibiotic treatment

201 Were assigned to a shift to oral antibiotic treatment

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bles S7 and S8 in the Supplementary Appendix), including 22 patients with prosthetic-valve endo- carditis (12 patients in the intravenously treated group and 10 in the orally treated group). A total of 35 patients had an implanted cardiac device; 14 patients with pacemaker endocarditis had their pacemaker removed during the current en- docarditis disease course (Table S9 in the Supple- mentary Appendix). There were no significant dif- ferences between the two groups regarding the frequency of involvement of the aortic valve, mitral valve, or combined aortic and mitral valve; re- garding involvement of the native valve as com- pared with the prosthetic valve; or regarding the number of patients who underwent valve surgery before randomization (Table 1).

Timing of Randomization and Length of Stay in the Hospital

The median time from the diagnosis of endocar- ditis of the left side of the heart to randomiza- tion was 17 days (interquartile range, 13 to 23) in the intravenously treated group and 17 days (interquartile range, 12 to 24) in the orally treated group. After randomization, patients were treated according to the assigned regimen for a median of 19 days (interquartile range, 14 to 25) in the intravenously treated group and 17 days (interquar- tile range, 14 to 25) in the orally treated group. In the orally treated group, 160 patients (80%) were partially or completely treated as outpatients. Af- ter randomization, the median length of stay in the hospital (not a prespecified outcome) was 19 days (interquartile range, 14 to 25) in the intrave- nously treated group and 3 days (interquartile range, 1 to 10) in the orally treated group (P<0.001).

Antibiotic Treatment

Antibiotic treatment regimens for the 201 pa- tients in the orally treated group who had mono- microbial infections at randomization are listed in Table S10 in the Supplementary Appendix (MICs and breakpoints are provided in Fig. S1, and susceptibility to penicillin and methicillin in Table S11, in the Supplementary Appendix). Four patients crossed over from the orally treated group to the intravenously treated group (1 be- cause of nausea, 1 because of a new incident of bacteremia with a different pathogen, and 2 be- cause of patient preference). No patients crossed over from the intravenously treated group to the orally treated group. From the time of random- ization until antibiotic therapy was completed,

Characteristic

Intravenous Treatment (N = 199)

Oral Treatment (N = 201)

Mean age — yr 67.3±12.0 67.6±12.6

Female sex — no. (%) 50 (25.1) 42 (20.9)

Body temperature — °C 36.9±0.45 37.0±0.44

Coexisting condition or risk factor — no. (%)

Diabetes 36 (18.1) 31 (15.4)

Renal failure 25 (12.6) 21 (10.4)

Dialysis 13 (6.5) 15 (7.5)

COPD 17 (8.5) 9 (4.5)

Liver disease 7 (3.5) 6 (3.0)

Cancer 14 (7.0) 18 (9.0)

Intravenous drug use 3 (1.5) 2 (1.0)

Pathogen — no. (%)†

Streptococcus 104 (52.3) 92 (45.8)

Enterococcus faecalis 46 (23.1) 51 (25.4)

Staphylococcus aureus‡ 40 (20.1) 47 (23.4)

Coagulase‑negative staphylococci 10 (5.0) 13 (6.5)

Laboratory results at randomization

Hemoglobin — mmol/liter 6.3±1.1 6.5±1.0

Leukocytes — ×10−9/liter 7.6±3.6 7.2±2.6

C‑reactive protein — mg/liter 24.3±18.4 19.9±16.7

Creatinine — μmol/liter 124±112 141±164

Preexisting prosthesis, implant, or cardiac disease — no. (%)

Prosthetic heart valve 53 (26.6) 54 (26.9)

Pacemaker 15 (7.5) 20 (10.0)

Other known valve disease 82 (41.2) 90 (44.8)

Cardiac involvement at randomization — no. (%)§

Mitral‑valve endocarditis 65 (32.7) 72 (35.8)

Aortic‑valve endocarditis 109 (54.8) 109 (54.2)

Mitral‑valve and aortic‑valve endocarditis

23 (11.6) 20 (10.0)

Endocarditis in other locations§ 2 (1.0) 0

Pacemaker endocarditis 6 (3.0) 8 (4.0)

Vegetation size >9 mm 7 (3.5) 11 (5.5)

Moderate or severe valve regurgitation 19 (9.5) 23 (11.4)

Valve surgery during current disease course

75 (37.7) 77 (38.3)

* Plus–minus values are means ±SD. To convert the values for creatinine to milligrams per deciliter, divide by 88.4. There were no significant differences between the groups except for the C‑reactive protein level, which was slightly higher in the intravenously treated group. COPD denotes chronic obstructive pulmonary disease.

† Patients could have had an infection with more than one pathogen. ‡ No patients had an infection with a methicillin‑resistant strain of S. aureus. § One patient had an infected ventricular septal defect, and one patient had an

infected myxoma in the left atrium.

Table 1. Characteristics of the Patients at Baseline.*

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43 patients (22%) in the intravenously treated group were switched to a different intravenous antibiotic regimen, and 24 (12%) in the orally treated group were switched to a different oral regimen (P<0.01).

Primary Outcome

All enrolled patients were followed for 6 months after the antibiotic treatment was completed or until death. No patients were lost to follow-up. The primary composite outcome occurred in a total of 42 patients (10.5%) — in 24 patients (12.1%) in the intravenously treated group and in 18 (9.0%) in the orally treated group (odds ratio, 0.72; 95% confidence interval [CI], 0.37 to 1.36). The between-group difference was 3.1 percent- age points (95% CI, –3.4 to 9.6; P = 0.40) in favor of oral treatment, and the criterion for noninfe- riority was therefore met. In the per-protocol analysis, the primary composite outcome oc- curred in 24 of 199 patients (12.1%) in the intra- venously treated group and in 18 of 197 (9.1%) in the orally treated group (between-group dif- ference, 3.0 percentage points; 95% CI, –3.2 to 9.2). In a sensitivity analysis in which the 4 pa- tients who were switched from oral to intrave- nous therapy were considered to have had treat- ment failure, the criterion for noninferiority was still met. In this analysis, the primary outcome occurred in 24 of 199 patients in the intrave- nously treated group and in 22 of 201 patients in the orally treated group (between-group differ- ence, 1.2 percentage points; 95% CI, –5.6 to 7.5).

The number of events for each component of the primary composite outcome is provided in Table 2 (with additional details in Table S12 in

the Supplementary Appendix). The incidences of embolic episodes, unplanned cardiac surgery, and relapse of bacteremia with the primary pathogen were similar in the two groups. There were fewer deaths in the orally treated group than in the in- travenously treated group. Cumulative incidence plots for the primary composite outcome and its four components are shown in Figure 2, and in Figure S2 in the Supplementary Appendix. A breakdown of the bacterial species for each com- ponent of the primary outcome is provided in Table S13 in the Supplementary Appendix.

The results of the prespecified subgroup anal- yses of the primary outcome are shown in Fig- ure 3. Homogeneity was seen for all subgroups, and all interactions were nonsignificant.

Safety

In seven patients in the orally treated group, the plasma concentration of one of the two admin- istered antibiotics was not at the most effective level, as assessed by peak levels and time above the MIC (rifampicin in the case of three patients, moxifloxacin in two patients, linezolid in one patient, and dicloxacillin in one patient) (Fig. S3 in the Supplementary Appendix). In all seven patients, the plasma concentration of the other simultaneously administered antibiotic was ap- propriate. The primary outcome did not occur in any of these patients. No antibiotic regimens were changed on the basis of pharmacokinetic findings.

Adverse effects from antibiotics were report- ed in 22 patients (6%) after randomization — in 12 patients (6%) in the intravenously treated group and in 10 (5%) in the orally treated group (P = 0.66). The most frequently reported adverse

Component

Intravenous Treatment (N = 199)

Oral Treatment (N = 201) Difference

Hazard Ratio (95% CI)

number (percent) percentage points

(95% CI)

All‑cause mortality 13 (6.5) 7 (3.5) 3.0 (−1.4 to 7.7) 0.53 (0.21 to 1.32)

Unplanned cardiac surgery 6 (3.0) 6 (3.0) 0 (−3.3 to 3.4) 0.99 (0.32 to 3.07)

Embolic event 3 (1.5) 3 (1.5) 0 (−2.4 to 2.4) 0.97 (0.20 to 4.82)

Relapse of the positive blood culture† 5 (2.5) 5 (2.5) 0 (−3.1 to 3.1) 0.97 (0.28 to 3.33)

* Six patients, three in each group, had two outcomes. † For details about relapse of the positive blood culture, see the Supplementary Appendix.

Table 2. Distribution of the Four Components of the Primary Composite Outcome.*

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effects were allergy (50%), bone marrow suppres- sion (27%), and gastrointestinal effects (14%), with no significant differences between groups (Ta- ble S14 in the Supplementary Appendix).

D i s c u s s i o n

In patients with endocarditis on the left side of the heart caused by streptococcus, E. faecalis, S. aureus, or coagulase-negative staphylococci, who were in clinically stable condition and who had had an adequate response to initial treatment, a shift from initial intravenous to oral antibiotic treat- ment was noninferior to continued intravenous antibiotic treatment. The patients in the orally treated group were shifted from intravenous to oral treatment on about day 17, the midpoint of the treatment period. Thus, during half the treat- ment period, the patients in the orally treated group were eligible for partial or complete outpa- tient treatment.

The results seemed consistent across prespeci- fied subgroups, including the subgroups defined according to type of valve affected (native valve or prosthetic valve) and according to type of treat- ment (surgery during the disease course or con- servative treatment). It should also be noted that the primary outcome seemed similar across the four different bacterial types. However, the trial was not powered to assess the primary outcome in any of the prespecified subgroups. The high rate of the primary outcome in patients with co- agulase-negative staphylococci probably reflects diagnostic delays combined with the fact that it often occurred in older and more frail patients who had serious coexisting conditions.

The rationale for this trial was that in pa- tients with normal gastrointestinal function, the uptake of orally administered antibiotics may allow sufficient plasma concentrations of antibi- otics to achieve bacterial killing.10 As part of the trial, oral regimens were developed, and specific combinations of oral antibiotics were chosen for each regimen (Table S2 in the Supplementary Appendix). The main concern related to the ad- ministration of oral antibiotics as compared with intravenous administration is whether the gas- trointestinal uptake is sufficient. In this trial, only patients considered to have clinically nor- mal gastrointestinal uptake were enrolled. The regimens that were developed for the trial in- cluded antibiotics generally known to have mod-

erate to high bioavailability, and the antibiotics were carefully selected for each patient (Table S10 in the Supplementary Appendix). To address the risk of subtherapeutic antibiotic levels related to potentially reduced gastrointestinal uptake, as well as the risk of variations in pharmacokinet- ics of the orally administered antibiotics, all oral regimens included two antibiotics from different drug classes and with different antibacterial ef- fects and different metabolization processes. In addition, pharmacokinetic measurements were performed. It was not necessary to change anti- biotic therapy in any of the patients on the basis of pharmacokinetic findings. Therefore, we do not consider pharmacokinetics to be a factor when of- fering oral antibiotic therapy if the currently ap- plied randomization criteria are met and two antibiotics with good bioavailability are pre- scribed (both carefully selected on the basis of bacterial identification and antimicrobial sus- ceptibility testing) and the patient’s gastrointes- tinal uptake is considered to be normal.

Recommendations for the duration of antibi- otic therapy and for in-hospital intravenous ad- ministration in patients with endocarditis are based mainly on observational studies.25,26 Lon-

Figure 2. Kaplan–Meier Plot of the Probability of the Primary Composite Outcome.

The primary composite outcome was all‑cause mortality, unplanned cardi‑ ac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from randomization until 6 months after antibiotic treatment was completed. The oral treatment group shifted from intravenously ad‑ ministered antibiotics to orally administered antibiotics at a median of 17 days after the start of treatment. The inset shows the same data on an enlarged y axis.

P ro

b ab

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o f

P ri

m ar

y O

u tc

o m

1.0

0.8

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0.0 0 30 60 180 210 240

Days since Randomization

No. at Risk Intravenous treatment Oral treatment

199 201

192 197

186 196

174 183

150

176 184

120

181 188

183 191

28 36

0 0

Intravenous treatment

Oral treatment

0.15

0.05

0.10

0.00 0 30 60 180 210 24015012090

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ger hospital stays may be a psychological and a physical burden,27-30 whereas shortened stays have been associated with better outcomes in studies of other diseases9-11 and may reduce costs. Oral antibiotic therapy may also minimize the chal- lenges associated with outpatient parenteral treat- ment,1,2,12,13 including logistics, monitoring, and risks of complications associated with intrave- nous catheters (e.g., bleeding, local and systemic infections, and venous thrombosis).

Several observational studies16-18 and a system- atic review by Al-Omari et al.14 have addressed the safety and efficacy of a shift from intravenous to oral therapy in the treatment of endocarditis. Generally, it has been shown that partial oral treatment has an acceptable cure rate in selected cases of endocarditis on the right side of the heart, whereas the literature on oral treatment for endocarditis on the left side of the heart is

sparse. In a small study involving patients with endocarditis on the left side of the heart (12 pa- tients with a median age of 66 years, of whom 75% were men), we reported that a shift to oral therapy was efficient and safe.17

Our trial has several limitations. Only patients with endocarditis on the left side of the heart were enrolled; however, it should be noted that patients with simultaneous infection of a cardio- vascular implantable electronic device or endo- carditis on the right side of the heart were not excluded. Only patients with endocarditis caused by certain bacterial species were eligible, and the results may not apply to the remaining 25 to 30% of patients who have endocarditis caused by other bacteria or to patients with culture-negative endo- carditis. In addition, only five intravenous drug users were enrolled, only 22% of the enrolled patients had S. aureus, and, although it was not a

Figure 3. Rates of the Primary Outcome in Prespecified Subgroups.

1.0 2.0 6.05.04.03.0

Intravenous Treatment BetterOral Treatment Better

All patients

Age

≤65.5 yr

>65.5 yr

Sex

Female

Male

Diabetes

Yes

Renal disease

Yes

Bacteria

Streptococci

Enterococcus faecalis

Staphylococcus aureus

Coagulase-negative staphylococci

Surgical treatment

Yes

Type of valve

Prosthetic heart valve

Native heart valve

Involved valve

Aortic valve

Mitral valve

Intravenous Treatment Odds Ratio (95% CI)

Oral TreatmentSubgroup

P Value for Interaction

24/199 (12.1)

9/83 (10.8)

15/116 (12.9)

5/50 (10.0)

19/149 (12.8)

8/36 (22.2)

16/163 (9.8)

5/25 (20.0)

19/174 (10.9)

10/104 (9.6)

7/46 (15.2)

3/40 (7.5)

4/10 (40.0)

6/75 (8.0)

18/124 (14.5)

11/53 (20.8)

13/146 (8.9)

16/109 (14.7)

6/65 (9.2)

18/201 (9.0)

7/91 (7.7)

11/110 (10.0)

6/42 (14.3)

12/159 (7.5)

4/32 (12.5)

14/169 (8.3)

5/21 (23.8)

13/180 (7.2)

8/92 (8.7)

4/51 (7.8)

3/47 (6.4)

3/13 (23.1)

3/77 (3.9)

15/124 (12.1)

6/54 (11.1)

12/146 (8.2)

11/109 (10.1)

5/72 (6.9)

0.0

0.72 (0.37–1.36)

0.68 (0.23–1.93)

0.75 (0.32–1.70)

1.50 (0.42–5.59)

0.56 (0.26–1.18)

0.50 (0.12–1.78)

0.83 (0.39–1.76)

1.25 (0.31–5.24)

0.64 (0.30–1.32)

0.90 (0.33–2.37)

0.47 (0.12–1.69)

0.84 (0.15–4.78)

0.45 (0.07–2.72)

0.47 (0.10–1.84)

0.81 (0.39–1.69)

0.48 (0.15–1.37)

0.92 (0.40–2.09)

0.65 (0.28–1.47)

0.73 (0.20–2.56)

0.34

0.19

0.51

0.40

0.94

0.50

0.35

0.56

no. of events/total no. (%)

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n engl j med nejm.org 9

A n tibio tic Tr e atmen t of End oc a r ditis

criterion for exclusion, no patients with methi- cillin-resistant S. aureus or other antibiotic-resis- tant phenotypes were enrolled. Referral bias may have affected our findings, because some patients — most likely elderly patients who are fragile and have serious coexisting conditions — may not have been referred to one of the participating centers. The criteria for inclusion in the trial were strict, and clinicians should use these cri- teria in the decision to shift a patient from intra- venous to oral therapy (see Fig. S4 in the Supple- mentary Appendix). In geographic areas with higher rates of antibiotic resistance, these criteria would also be applicable, since they are based on antibiotic treatment guided by state-of-the-art sus- ceptibility testing. However, the smaller number of effective antibiotics that can be used in areas with a higher degree of antibacterial resistance may represent a limitation.

An additional limitation is that the discharge of patients who were receiving oral treatment to outpatient treatment was not mandatory and was decided according to the patient’s prefer-

ence and the discretion of the treating physician. Therefore, the duration of outpatient treatment may have been underestimated. Only 20% of the screened population underwent randomization. Considering the reasons for exclusion (Fig. 1), it seems likely that a larger fraction of patients with endocarditis on the left side of the heart may be candidates for partial oral therapy.

In conclusion, in patients who had endocar- ditis on the left side of the heart caused by streptococcus, E. faecalis, S. aureus, or coagulase- negative staphylococci and who were in stable condition, a shift from intravenously adminis- tered to orally administered antibiotic treatment was noninferior to continued intravenous antibi- otic treatment.

Supported by unrestricted grants from the Danish Heart Foundation, the Capital Regions Research Council, the Hart- mann’s Foundation, Svend Aage Andersens Foundation, and the Novo Nordisk Foundation (Borregaard Clinical Scientist Fellow- ship in translational research; grant no. NNF17OC0025074).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Appendix The authors’ affiliations are as follows: the Department of Cardiology, Herlev-Gentofte University Hospital (K.I., M.S., C.F.K.), Department of Cardiology, the Heart Center, Rigshospitalet, Copenhagen University Hospital (N.I., D.E.H., E.L.F., L.K., H.B.), the Departments of Infectious Diseases (J.H.-L.) and Clinical Microbiology (C.M.), Rigshospitalet, the Department of Cardiology, Hill- erød Hospital (N.T.), and the Department of Clinical Microbiology, Slagelse Hospital and Institute of Clinical Medicine (J.J.C.), University of Copenhagen, Copenhagen, the Departments of Cardiology (S.U.G.) and Clinical Microbiology (F.R.), Odense Univer- sity Hospital, Odense, the Departments of Cardiology (T.M.) and Cardiology and Epidemiology and Biostatistics (C.T.-P.), Aalborg University Hospital, the Department of Clinical Microbiology, Aalborg University Hospital, Aalborg University (H.C.S.), and the Department of Health Science and Technology, Aalborg University (C.T.-P.), Aalborg, the Department of Cardiology, Zealand Uni- versity Hospital, Roskilde (H.E.), the Department of Cardiology, Aarhus University Hospital, Aarhus (K.T.J.), the Department of Cardi- ology, University Hospital of Copenhagen, Gentofte (N.E.B.), and the Department of Bacteria, Parasites and Fungi, Statens Serum In- stitut, Copenhagen (K.F.) — all in Denmark.

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