Major criteria

• Positive blood cultures for infective endocarditis

In the absence of a primary focus, positive cultures from two separate blood cultures of one of the following typical organisms.

• • Streptococci viridans.

  • Streptococcus bovis.

  • HACEK group (Haemophilus species, Actinobacillus actinomycetes comitants, Cardiobacterium hominis, Eikenlla species, Kingella kingae).

  • Community‐acquired S. aureus or Staphylococcus enterococci.

OR

• • Persistently positive blood cultures of a micro‐organism consistent with infective endocarditis.

OR

• • Single blood culture for Coxiella burnetii or antiphase I immunoglobulin (Ig)G antibody titre greater than 1:800.

• Evidence of endocardial involvement.

• • New valvular regurgitation.

OR

• • Positive echocardiogram (oscillating intracardiac mass in the absence of an alternative anatomic explanation OR abscess OR new partial dehiscence of prosthetic valve).

Minor criteria

• Predisposing heart condition OR intravenous drug use.

• Fever (at least 38.0 °C).

• Vascular phenomena (arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhage, Janeway lesions).

• Immunological phenomena (glomerulonephritis, Osler's nodes, Roth spots, positive rheumatoid factor).

• Microbiological evidence of positive blood culture not meeting major criterion but excluding single positive culture for coagulase negative Staphylococci and organisms that do not cause endocarditis OR serological evidence of active infection with organism consistent with infective endocarditis.

We excluded people with possible infective endocarditis (e.g. with one major and one minor criteria or three minor criteria).

We excluded pregnant women with endocarditis because drugs such as tetracyclines and chloramphenicol have well‐described fetal or neonatal adverse effects and should be avoided. In general, however, human studies on the safety of many antimicrobial agents in pregnancy and lactation are limited, and antimicrobial agents should be prescribed with caution (Leekha 2011).

Primary outcomes

• All‐cause mortality during hospital stay and all‐cause mortality at one year.

• Cure, defined as: disappearance of fever, sterilisation of blood cultures and normalisation of inflammatory markers during treatment and in the subsequent four weeks (Baddour 2005; Hoen 2006).

• Adverse events including treatment‐related adverse events (TRAE) (Ioannidis 2004). TRAE was defined as: "a response to a drug which is noxious and uninitiated and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic functions" (Nebeker 2004). We extracted the number of participants with at least one TRAE out of the total randomised in each study arm.

Secondary outcomes

• Incidence of septic embolism (number of participants out of the total randomised).

• Incidence of congestive heart failure (number of participants out of the total randomised).

• Quality of life (as measured by a validated scale).

• Need for cardiac surgical interventions (valve reconstruction or valve replacement (Mesana 2006)) (number of participants who undergo surgery of the total randomised).

  • Indication for cardiac surgical intervention:

    • Haemodynamic compromise.

    • Persistent or uncontrolled infection (or both) despite aggressive medical therapy.

    • Embolisation.

• Uncontrolled infection (persisting infection, perivalvular extension).

• Relapse of endocarditis (new onset of fever, chills, or other evidence of systemic toxicity caused by the same species within six months of the initial episode).

Generation of allocation sequence (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.   

Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

• low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

• unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.

Blinding or masking (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We judged studies at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

• low risk, high risk or unclear risk for participants;

• low risk, high risk or unclear risk for personnel;

• low risk, high risk or unclear risk for outcome assessors.

Incomplete outcome data (checking for possible attrition bias through withdrawals, drop‐outs, protocol deviations)

• Low risk (any one of the following): no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data were imputed using appropriate methods.

• High risk (any one of the following): reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; 'as‐treated' analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

• Unclear risk (any one of the following): insufficient reporting of attrition/exclusions to permit judgement of 'low risk' or 'high risk' (e.g. number randomised not stated, no reasons for missing data provided); the study did not address this outcome.

Selective reporting bias (reporting bias due to selective outcome reporting)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

• low risk (any one of the following): the study protocol was available and all of the study's pre‐specified (primary and secondary) outcomes that were of interest in the review were reported in the pre‐specified way, or the study protocol was not available but it was clear that the published reports included all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon);

• high risk (any one of the following): not all of the study's pre‐specified primary outcomes were reported; one or more primary outcomes was reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes was not pre‐specified (unless clear justification for their reporting was provided, such as an unexpected adverse effect); one or more outcomes of interest in the review were reported incompletely so that they could not be entered in a meta‐analysis; the study report did not include results for a key outcome that would be expected to have been reported for such a study;

• Unclear risk: insufficient information to permit judgement of 'low risk' or 'high risk'.

Free of other bias (bias due to problems not covered elsewhere)

We described for each included study any important concerns we had about other possible sources of bias (sponsorship bias, confirmation bias, bias of the presentation data, etc.).

• Low risk, the trial appears to be free of other components that could put it at risk of bias.

• High risk, there are other factors in the trial that could put it at risk of bias (e.g. no sample size calculation made).

• Unclear risk, the trial may or may not be free of other components that could put it at risk of bias.

Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses ‐ see Sensitivity analysis. 

'Summary of findings' tables

We used the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with all main outcomes (all‐cause mortality during hospital stay and all‐cause mortality at one year, cure, adverse events, TRAE, incidence of congestive heart failure, incidence of septic embolism, need for cardiac surgical intervention) and we constructed 'Summary of findings' tables using the GRADE profiler software (GRADEpro 2008). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the quality of a body of evidence considers within study risk of bias, the directness of the evidence, heterogeneity in the data, precision of effect estimates and risk of publication bias (Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h).

We constructed four tables: summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4.