JCS 2017 Guideline on Prevention and Treatment of Infective Endocarditis

I. Introduction

1. Preface to Revision

In March 2018, the revised version of the guidelines regarding infective endocarditis (IE) was published in Japanese from the Japanese Society of Cardiology (the Guidelines for Prevention and Treatment of Infective Endocarditis (JCS2017)).^1,2 On the revision of the guidelines we reorganized the Guideline Writing Group. In addition to the Japanese Circulation Society, the Japanese Association for Thoracic Surgery, the Japanese Society of Pediatric Cardiology and Cardiac Surgery, and the Japanese College of Cardiology as previous members, new members, namely, the Japanese Society of Echocardiography, the Japanese Society for Cardiovascular Surgery, the Japanese Society for Adult Congenital Heart Disease, the Japan Stroke Society, the Japanese Association for Infectious Diseases, the Japanese Society of Chemotherapy, dentists specializing in IE, a visiting chief researcher of EBM Medical Information Division (Minds) of the Japan Council for Quality Health Care, joined the team. Furthermore, Japan Medical Library Association also joined to cooperate with the aim of developing clinical questions (CQs) of good quality and the responses to them.

Major points of updating from the previous revision are shown below.

1) Description of advancement of imaging techniques and bacteriological examination in the diagnosis of IE was added.

2) Indication of early surgery for IE, and the timing of surgery after the occurrence of neurological complications were discussed on the basis of accumulated evidence.

3) Many issues discussed about prevention of IE were reconsidered, and the opinions at the present time point were displayed.

4) New chapters were created to discuss device infection, right-sided IE, IE during pregnancy, non-bacterial thrombotic endocarditis (NBTE), and IE in elderly people.

This English version is a translated, abbreviated form of the Japanese version; the sections are selected based on importance, novelty, and difference from the existing guidelines. Thus, some parts were omitted from the English version.

We hope the guidelines will help not only cardiologists but also physicians in other fields and dentists lead to achievement of prevention of IE and treatment of good quality. Please remember that these guidelines intend to provide just one policy for helping diagnosis and decision of treatment strategy, and are not designed to deny the discretion of physicians.

2. About Recommendations

For the present guidelines, systematic review was conducted focusing on five CQs (Table 3). For each CQ, systemically collected articles were evaluated with respect to the ability to support recommendations, and the strength of recommendation was determined according to the rule of unanimity. To discriminate the recommendations based on systematic review and other recommendations, the former was presented using the method of Minds 2014 (strong recommendation, weak recommendation, and strength of body of evidence from A to D) to evaluate the body of evidence,³ and the latter was presented using the conventional method (Class I to III, level of evidence A to C).

Table 3. Clinical Questions Examined in Present Guidelines and Recommendations

		Evaluation by systematic review
		Strength of recommendation	Strength of body of evidence
CQ1	Is brain MRI useful for patients without neurological symptoms who have or are suspected to have IE? (In “Chapter V. 3. 2. Neurological Complications”, [Related section] “Chapter V. 3. 2. b. Methods of Diagnosis of Neurological Complications”, Table 14)
	It is proposed to obtain brain MRI (including DWI, FLAIR images, T2*WI, and MRA) at an early timing in the patients without neurological symptoms who have or are suspected to have IE	2 (weak)	C (weak)
CQ2	Should early surgery be conducted if a large vegetation is present? (In “Chapter VI. 2. Indications of Surgical Treatment and Timing of Operation”, [Related section] “Chapter VI. 2. a. General Remarks on Indications of Surgical Treatment”, Table 16)
	Surgery at the earliest timing possible is recommended for the patients with IE in the native valve (aortic valve or mitral valve) who have a vegetation of 10 mm or larger accompanying severe valve dysfunction	1 (strong)	B (moderate)
CQ3	Should surgery of IE be conducted at an early timing when neurological complications have occurred? (In “Chapter VI. 2. Indications of Surgical Treatment and Timing of Operation”, [Related section] “Chapter VI. 2. a. General Remarks on Indications of Surgical Treatment”, Table 16)
	(1) Surgery of IE is recommended not to be postponed if it is indicated, even when concurrent cerebral infarction is present* *Except for the cases with concurrent coma, herniation, or cerebral hemorrhage, as well as major central lesions	1 (strong)	B (moderate)
	(2) If new intracranial hemorrhage* is observed, it is proposed to wait 4 weeks to conduct open heart surgery if the hemodynamic condition is stable *Except for cerebral microbleeds	2 (weak)	C (weak)
CQ4	Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for the patients with high-risk heart diseases? (In “Chapter VIII 3. 2 Dental Diseases”, [Related section] “Chapter VIII. 1. General Remarks on Prevention of IE”, Table 17)
	(1) Antibiotic prophylaxis is recommended before dental procedures inducing bacteremia, such as tooth extraction, in adult highest-risk patients	1 (strong)	B (moderate)
	(2) Antibiotic prophylaxis is proposed before dental procedures inducing bacteremia, such as tooth extraction, in adult moderate-risk patients	2 (weak)	C (weak)
CQ5	Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for pediatric/congenital heart diseases? (In “Chapter IX 1. 5 Prevention”, [Related section] “Chapter IX. 1. 2 Risks According to Underlying Heart Disease”, Table 22)
	(1) Antibiotic prophylaxis is recommended before dental procedures inducing bacteremia, such as tooth extraction, in highest-risk patients with pediatric/adult congenital heart disease	1 (strong)	C (weak)
	(2) Antibiotic prophylaxis is proposed before dental procedures inducing bacteremia, such as tooth extraction, in moderate-risk patients with pediatric/adult congenital heart disease	2 (weak)	C (weak)

IE, infective endocarditis; MRI, magnetic resonance imaging; DWI, diffusion weighted image; FLAIR, fluid attenuated inversion recovery; MRA, magnetic resonance angiography; T2*WI, T2*-weighted image.

The strength of recommendation and the strength of body of evidence for 5 CQs are expressed as follows.³

■ Strength of Recommendation

“1”: Strongly recommended.

“2”: Weakly recommended (proposed).

■ Strength of Body of Evidence

A (strong): Strongly confident of the estimate of effect

B (moderate): Moderately confident of the estimate of effect

C (weak): Limited confidence of the estimate of effect

D (very weak): Very little confident of the estimate of effect

Class of recommendation and level of evidence for other parts are expressed in Table 1 and Table 2.

Table 1. Class of Recommendation

Class I	There is evidence and/or general agreement that a given procedure or treatment is effective and/or useful
Class II	There is no consistent evidence and/or general agreement that a given procedure or treatment is effective and/or useful
Class IIa	Weight of evidence and opinion is in favor of usefulness and/or effectiveness
Class IIb	Usefulness or effectiveness is not fully established by evidence or opinion
Class III	There is evidence and/or general agreement that the procedure or treatment is not effective and/or useful or may even be harmful

Table 2. Level of Evidence

Level A	Demonstrated with multiple randomized, controlled studies or meta-analyses
Level B	Demonstrated with a single randomized intervention clinical study or non- randomized, non-intervention studies
Level C	Only consensus opinion of experts and/or small-scale clinical studies (including retrospective studies and registration)

II. General Remarks

1. What Is IE?

IE is a systemic septic disease accompanying generation of vegetation containing bacterial aggregation on the valve, endocardium, and intima of large vessels, and showing various clinical symptoms such as bacteremia, vascular embolization, and cardiac disorders. Abnormal blood flow associated with valvular disease, congenital heart disease, or prosthetic valve replacement causes non-bacterial thrombotic endocarditis (NBTE) which is considered important precursors for IE. When transient bacteremia occurs in a patient with NBTE after dental or other procedures, bacteria adhere to the site of NBTE and grow to generate vegetation.

While IE often occurs in the patients with some underlying heart diseases, it may occur in the patients without a history of heart diseases. The predisposing event is unclear in many cases. It is important to keep the possibility of IE in mind when examining the patients with fever or embolism of unknown origin.

The diagnosis of IE is made on the basis of clinical symptoms associated with sepsis, identification of causative microorganisms in blood, and confirmation of destruction of the intracardiac structure associated with infection, including vegetation. Therefore, the major criteria in Duke criteria for diagnosis of IE are comprised of blood culture and echocardiography.^7,8 However, revision of the diagnostic criteria may become necessary in the future because identification of causative microorganisms by gene analysis, usefulness of computed tomography (CT) in evaluation of the intracardiac structure, and usefulness of positron emission tomography (PET), which visualizes inflammation itself, have come to be known.

2. Team Medicine

A team covering a wide range of areas (IE team) is required in the clinical management of IE presenting in various clinical aspects and necessitating advanced expertise.^4–6 It is not easy to constantly involve a group of specialists in actual clinical settings. However, at least close discussion with the specialists from the relevant areas should be continued.

3. Timing of Referral to Specialized Hospital

Not all IE patients visit a specialized hospital with an IE team. Therefore, when an institution finds it difficult to control a patient at their institution, they should consult another institution providing team medicine, or should refer the patient to such an institution for the purpose of transfer.

III. Diagnosis

1. Diagnostic Criteria for IE

Duke criteria (modified) are helpful for the diagnosis of IE (Table 4).^7,8 While the diagnostic sensitivity of Duke criteria is approximately 80%, the sensitivity in the early stage of disease is even lower. In particular, it becomes particularly low in cases with abscess formation, cases after prosthetic valve replacement, and cases after pacemaker implantation.^9,10 Recently, the usefulness of CT and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT in depicting annular abscess in cases of IE following prosthetic valve replacement has been reported. Since ¹⁸F-FDG PET/CT is useful in searching systemic inflammation, it has been reported to be useful in detecting the remote lesion causing IE. Table 5 and Figure 1 show the criteria of diagnosis according to the guidelines of the European Society of Cardiology (ESC).

Table 4. Diagnostic Criteria for IE (Modified Duke Criteria)⁸

Definite infective endocarditis
Pathologic criteria
(1) Microorganisms demonstrated by culture or histologic examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or
(2) Pathologic lesions; vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis
Clinical criteria
(1) 2 major criteria; or
(2) 1 major criterion and 3 minor criteria; or
(3) 5 minor criteria
Possible infective endocarditis
(1) 1 major criterion and 1 minor criterion; or
(2) 3 minor criteria
Rejected
(1) Firm alternate diagnosis explaining evidence of infective endocarditis; or
(2) Resolution of infective endocarditis syndrome with antibiotic therapy for ≤4 days; or
(3) No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for ≤4 days; or
(4) Does not meet criteria for possible infective endocarditis, as above
Definition of criteria
Major criteria
Blood culture positive for IE
Typical microorganisms consistent with IE from 2 separate blood cultures:
Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or
Community-acquired enterococci, in the absence of a primary focus; or
Microorganisms consistent with IE from persistently positive blood cultures, defined as follows:
At least 2 positive cultures of blood samples drawn >12 h apart; or
All of 3 or a majority of >4 separate cultures of blood (with first and last sample drawn at least 1 h apart)
Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer 11:800
Evidence of endocardial involvement
Echocardiogram positive for IE (TEE recommended in patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE [paravalvular abscess]; TTE as first test in other patients), defined as follows :
Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or
Abscess; or
New partial dehiscence of prosthetic valve
New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient)
Minor criteria
(1) Predisposition, predisposing heart condition or injection drug use
(2) Fever, temperature >38℃
(3) Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions
(4) Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor
(5) Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE

Table 5. New Imaging Diagnostic Criteria (ESC Guidelines 2015)⁴

Imaging positive for IE

a. Echocardiogram positive for IE:

• Vegetation;

• Abscess, pseudoaneurysm, intracardiac;

• Valvular perforation or aneurysm;

• New partial dehiscence of prosthetic valve

b. Abnormal activity around the site of prosthetic valve implantation detected by 18F-FDG PET/CT (only if the prosthesis was implanted for >3 months) or radiolabelled leukocytes SPECT/CT

c. Definite paravalvular lesions by cardiac CT

ESC guidelines incorporates these new imaging diagnostic criteria as major criteria in addition to modified Duke criteria (Table 4).

Figure 1.

Criteria for diagnosis of infective endocarditis incorporating new imaging diagnostic criteria (modified from Habib et al. 2015⁴). IE, infective endocarditis; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography.

2. Symptoms and Physical Findings

This section is omitted from the English version.

3. Microbiological Examination

3.1 Blood Culture

Blood culture is very important in the diagnosis of IE in the same way as sputum culture for pneumonia. IE may be suspected on the basis of positive results in blood cultures, and IE is observed in approximately 5 to 30% of the patients with bacteremia caused by Staphylococcus aureus.^11,12

Isolation of the causative microorganisms on blood culture will enable bacterial identification and sensitivity testing. The positive rate on blood culture becomes 90% or higher if blood specimens are collected before antibiotic treatments, but the positive rate on blood culture may decrease dramatically for some bacterial species if antibiotics have already been administered.^13,14 At least three sets of specimens should be submitted for blood culture. Submission of specimens for multiple times increases the volume of blood to be subjected to culture, and may increase detection sensitivity. The interval for collection of blood specimens has not been established, although there have been some recommendations such as collection of every 30 minutes, the interval of 1 hour between the first and last collection, or 6 hours or more.¹⁵ No difference in detection rate has been observed for arterial blood and venous blood, and it is unnecessary to collect blood specimens in the presence of high fever. Blood collection via catheters should be avoided in order to avoid contamination during blood collection. Even before the causative microorganisms determined, antibiotic treatment should be started in the emergency cases showing sepsis, and at least two sets of blood specimens should be collected within 1 hour.

Conversely, antibiotic treatment may be transiently suspended in cases with a subacute course. The appropriate duration of suspension is believed to be 2 or 3 days. However, antibiotics should not be discontinued in the patients with an unstable cardiorespiratory condition due to heart failure, patients with progressive infection foci (such as annular abscess), and patients who have embolism or are at high risk of embolism. Suspension of antibiotics must be avoided also in the IE patients with prosthetic valve.

For the patients with positive blood cultures, blood cultures should be repeated within several days after the start of treatment (approximately 3 days, or 48 to 72 hours after the start of treatment) to check the effect of the treatment.¹⁶ Although it is unnecessary to discontinue antibiotic treatment before collection of specimens, it is reasonable to collect specimens immediately before administration of antibiotics when the blood concentration of antibiotics is low. Blood culture should be repeated until negative results are obtained. Once the result has turned negative, additional blood culture is unnecessary unless changes in symptoms are observed.

3.2 Other Test Methods

a. Serologic Diagnosis and Polymerase Chain Reaction (PCR)

Microorganisms which are difficult to culture by usual blood culture, such as Bartonella and Coxiella burnetii, may cause IE. Concerning Bartonella, Bartonella quintana, which is known for trench fever, and Bartonella henselae, which is known as causative microorganism for cat scratch disease, may cause IE. Although the number is small, there have been case reports.^17,18 However, the percentage of Bartonella in the cases of IE is less than 1%, and routine antibody tests are unnecessary.

The positive rate on blood culture is also low in the cases of IE caused by fungi. Especially as to filamentous fungus such as Aspergillus, the positive rate is less than 10%. Although blood β-glucan and blood aspergillus antigen are useful, they are used for auxiliary diagnosis (even if the β-glucan level is high, differentiation of Candida and other fungi including Aspergillus is difficult, and cautions are required for non-specific reactions).

b. PCR for Extracted (Surgical) Specimens

The valve tissues obtained at the time of surgery can be subjected to culture and histological examination. While PCR and sequencing using 16S RNA amplification can be outsourced in Japan, they are not covered by insurance, and they are not conducted as routine tests in laboratories. The cases in which PCR is considered useful are the following: the cases with negative blood cultures, the cases in which blood culture is positive only once, and rare microorganism or normal bacterial flora on the skin are suspected to be causative microorganisms.¹⁹ However, contamination at the time of extraction of specimens may cause false positive results. Therefore, the clinical course and the results of blood cultures should also be taken into consideration when making judgement.²⁰ Detection by PCR becomes difficult after formalin fixation of specimens.

4. Echocardiography

Echocardiography plays the most important role in the diagnosis, treatment, follow-up and estimation of prognosis of IE. When IE is suspected, it should be performed in all cases, including the cases with negative blood cultures.^21,22

a. Positive Criteria

The major items related to echocardiographic findings on Duke criteria for diagnosis (Table 4) include (1) vegetation, (2) abscess or pseudoaneurysm, (3) new partial dehiscence of prosthetic valve, and (4) emergence of new valvular regurgitation (exacerbation of existing murmur alone is insufficient).

b. Significance of Vegetation

Vegetation is defined as periodically vibrating mass echo adhering to the endocardium mainly around the valve, or intracardiac device. When findings suggestive of vegetation are observed, the size, shape, adhesion site, and mobility should be monitored.

Examination of the changes in the size and mobility of vegetation after treatment is useful for evaluation of the effects of antibiotics. However, observation of the vegetation echo after treatment does not always mean recurrence.

c. Accuracy of Diagnosis

The sensitivity of transthoracic echocardiography (TTE) in detecting vegetation is approximately 70% for native valves, and approximately 50% for prosthetic valves. The sensitivity of transesophageal echocardiography (TEE) in detecting vegetation is 90% or more for both native valves and prosthetic valves. Both TTE and TEE show high specificity of approximately 90% in detecting vegetation. On the other hand, the sensitivity in detecting perivalvular abscess was low at 30 to 50% for TTE, and it varied from 50% to 90% among reports in TEE. Both TTE and TEE showed high specificity of 90% or more in detecting perivalvular abscess. The detection rate of positive findings for IE was low in cases with poor images, cases showing small vegetation (<3 mm), prosthetic valve, and valvular changes (including prolapse, thickening, and calcification), and cases with placement of devices such as pacemakers.

d. Indication of TTE and TEE (Table 6)

Table 6. Recommendations of Echocardiography in IE and Level of Evidence

	Class of recommendation	Level of evidence
TTE for all cases of suspected IE	I	B
TEE in the cases in which IE is suspected and adequate images cannot be obtained with TTE	I	B
TEE in the cases in which IE is suspected, and prosthetic valve or any other device has been placed	I	B
Re-examination after 3 to 7 days in the cases in which IE is clinically suspected in spite of the negative result on the first echocardiography	I	C
Echocardiography for the cases of staphylococcal bacteremia	IIa	B
TEE in the cases with positive result on TTE (except for the cases with IE only in the right cardiac valve)	IIa	C
Follow-up echocardiography after the onset of new complications	I	B
Follow-up echocardiography for evaluating therapeutic effects	I	C
Follow-up echocardiography for evaluating the onset of asymptomatic intracardiac complications	IIa	B
TTE at the end of treatment	I	C

IE, infective endocarditis; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography.

While TTE is inferior to TEE in terms of sensitivity and specificity, it is noninvasive and can be performed repeatedly. Moreover, it is superior to TEE in evaluation of cardiac functions and hemodynamics using Doppler method. Therefore, it should be performed as soon as possible in all cases of suspected IE.^21,22

TEE should be performed when TTE cannot be used for diagnosis because of poor images, when IE is clinically suspected in spite of the negative result on TTE,^21,23–25 and when IE is suspected in the cases with prosthetic valve or the cases with insertion of other devices.^21,24,26

It is recommended to conduct TEE even in the cases with positive results on TTE for the purpose of evaluating the presence or absence of intracardiac complications.²⁷ Since TEE may fail to detect abnormalities in the early stage, the test should be performed again 3 to 7 days later if IE is clinically suspected.

Since IE is highly likely in the cases of staphylococcal bacteremia, TTE or TEE should proactively be performed in these cases.^11,28

e. Timing of Follow-up Echocardiography

Follow-up echocardiography should be conducted after 3 to 7 days when IE is clinically suspected even if the results on TTE and TEE are negative, or for the purpose of evaluating the effects of antibiotics or onset of intracardiac complications in the cases with the established diagnosis of IE. If staphylococci are the causative microorganism, follow-up should be conducted after an even shorter interval. Follow-up echocardiography should also be conducted if any changes have occurred in clinical findings.

f. Echocardiography at the End of Treatment

Echocardiography should always be conducted at the end of treatment to obtain follow-up basic data after completion of treatment. The shape of valves, condition of residual vegetation, and extent of regurgitation should be evaluated.

5. Other Imaging Diagnosis (Table 7)

Table 7. Recommendations of Imaging Diagnosis Other Than Echocardiography and Level of Evidence in Diagnosis of IE and Its Complications

	Class of recommendation	Level of evidence
It should be considered to conduct CT to detect vegetation or perivalvular abnormality, to diagnose coronary arterial disease, and to search systemic embolism in the patients who have or who are suspected to have IE in the native valve or IE in the prosthetic valve (it is preferred to use contrast, if possible)	IIa	C
It is recommended to conduct MRI to diagnose cerebrovascular diseases in the patients who have or who are suspected to have IE in the native valve or IE in the prosthetic valve	I (IIa*)	C
It may be considered to conduct MRI to diagnose systemic complications such as vegetation, perivalvular abscess, and osteomyelitis in the patients who have or who are suspected to have IE in the native valve or IE in the prosthetic valve	IIb	C
It may be considered to conduct gallium scintigraphy in the patients who are suspected to have IE if definite diagnosis cannot be made by other methods	IIb	C
In the patients who are suspected to have IE, especially the patients with implantation of a prosthetic valve or any devices, 18F-FDG PET/CT should be considered if definite diagnosis cannot be made by other methods (IE is not covered by insurance in Japan)	IIa	C
In the patients who are suspected to have IE, labeled leukocyte scintigraphy should be considered at a facility with the capability to conduct it, if definite diagnosis cannot be made by other methods	IIa	C

*If neurological symptoms are absent, class of recommendation is IIa. See “Chapter V. 3. 2. b. Methods of Diagnosis of Neurological Complications” and “CQ 1 Is brain MRI useful for patients without neurological symptoms who have or are suspected to have IE?”. IE, infective endocarditis; ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose.

Imaging diagnostic technology other than echocardiography has been used for the diagnosis of IE and its complications. See “Chapter III. 1. Diagnostic Criteria for IE” for the procedure of diagnosis of IE.

a. CT

Reduction of the scan time and improvement of temporal resolution can be achieved by increasing the number of detectors in multidetector-row CT (MDCT) and shortening the gantry rotation time, and it has become easier to obtain favorable images in the field of cardiology.

On contrast-enhanced CT, vegetation is visualized as a low-density nodule adhering to the valve or blood vessel. When the height is low, it is visualized as the thickening of the valve. Diagnosis is difficult when the movement of vegetation is fast or vegetation is small.^29,30

TEE is better for the diagnosis of vegetation, and addition of CT information does not improve the diagnostic ability. However, addition of CT improves the ability to diagnose perivalvular abnormality.³¹ The features of CT in diagnosis of IE include the following.^29–33

1) It is capable of visualizing vegetation, and the size shows good correlation with TEE, but diagnosis of small vegetation is difficult.

2) It shows good ability to detect perivalvular abnormalities such as abscess. If IE is suspected after prosthetic valve replacement, additional information can be expected.

3) If vegetation with a risk of embolism is observed in the aortic valve or the aortic wall, it can be used for preoperative examination of the coronary artery.

4) It can be used for the search of embolism in the whole body.

b. MRI

Magnetic resonance imaging (MRI) shows good ability in diagnosis of cerebrovascular diseases. It is recommended to conduct MRI, if possible, even in the patients without neurological symptoms (See “[CQ 1] Is brain MRI useful for patients without neurological symptoms who have or are suspected to have IE?”). It is also useful for diagnosis of osteomyelitis in the spine, etc. However, since it is inferior to CT in terms of spatial resolution and the scan time is longer, the situation in which it is used for the diagnosis of vegetation and perivalvular abscess is limited.²⁹

c. Gallium Scintigraphy/CT

Sensitivity of gallium scintigraphy for unidentified fever has been suggested to be 30% or lower. Gallium scintigraphy may be useful when definite diagnosis cannot be made by other methods. However, diagnostic accuracy for IE has not been established.^34,35

d. ¹⁸F-FDG PET/CT

Although insurance coverage of ¹⁸F-FDG PET and ¹⁸F-FDG PET/CT for heart diseases has been approved for viability assessment of the myocardium in patients with heart failure caused by ischemic heart disease, and diagnosis of inflammation sites in cardiac sarcoidosis, the use for IE and unidentified fever is not covered by Japanese medical insurance. However, improvement of diagnostic ability after addition of ¹⁸F-FDG PET/CT has been reported in patients with unidentified fever and patients with implantation of a prosthetic valve or devices.^36,37

e. Labeled Leukocyte Scintigraphy

It is not used very frequently in Japan because the labeling procedure is complicated. Concerning diagnostic ability of labeled leukocyte scintigraphy for IE, sensitivity of 90% and specificity of 100% have been reported.³⁸

6. Risk Evaluation at Admission

This section is omitted from the English version.

IV. Medical Treatment

1. Antimicrobial Treatment: Policy and General Principles

In the treatment of IE, the choice and treatment period of the antibiotics recommended in the existing guidelines and present guidelines are mainly based on the type of causative microorganisms, antibiotic susceptibility results, and the type of the valve (native valve or prosthetic valve). Isolation and identification of causative microorganisms is very important. Moreover, the factors related to the treatment results are the duration before diagnosis, immune status of hosts, causative microorganisms, severity of valvular regurgitation, progression of lesions (such as annular abscess), concurrent embolism, and organ dysfunction such as heart failure and renal failure, as well as surgical treatment and its timing. Multidisciplinary treatment provided through cooperation of not only cardiologists but also specialists from multiple fields (IE team) is required.

As to antimicrobial treatment, the roles of infectious disease specialists and pharmacists are important. In addition to the choice of antibiotics for bacteria with decreased susceptibility or multidrug-resistance and fungi, they should take pharmacokinetics (PK) and pharmacodynamics (PD) into consideration. They also play important roles in modifying and changing antibiotics against adverse reactions.

a. General Principles and PK/PD

When designing administration of antimicrobials, it is important to consider PK/PD parameters in order to avoid the emergence of resistant strain and to ensure efficacy. Administration design based on therapeutic drug monitoring (TDM) should be employed for vancomycin, teicoplanin, and aminoglycosides^15,39 (Table 8). It is necessary to administer over 1 hour for vancomycin and at least 30 minutes for teicoplanin (particular attention should be paid for the initial loading dose) in order to avoid red man syndrome (condition in which erythema and itching appear in the face and neck).

Table 8. Relationship Between Recommended Method of Use of Drugs for Therapeutic Drug Monitoring and Method of Use Approved in Japan

		Gentamicin	Vancomycin	Teicoplanin
Dosage regimen (when renal functions are normal)		3 mg/kg/day in 1–3 doses.	15–20 mg/kg per dose, twice	Day 1: 10 mg/kg, twice Day 2: 10 mg/kg, once or twice Day 3: 10 mg/kg, twice
Timing of blood sampling (when renal functions are normal)		Day 2 after the start of administration	Day 3 after the start of administration	(3) to 4 days after the start of administration
Timing of blood sampling	Peak concentration	1 hour after the start of drip infusion (30 minutes after completion of 30-minute administration)	Not determined in routine examination	Not determined
	Trough concentration	Within 30 minutes before administration
Target blood concentration	Peak concentration	3–5 μg/mL (when divided into 2 or 3 doses*)	–	–
	Trough concentration	Lower than 1 μg/mL	Adjusted to 15 to 20 μg/mL by TDM aiming at the initial concentration of 10 to 15 μg/mL	20–30 μg/mL
Dosage regimen in package insert		3 mg/kg/day in 1–3 doses	2 g/day in 2–4 doses	Day 1: 800 mg/day in 2 doses. Day 2, 3: 400 mg in one dose. Day 4~: dose adjusted according to renal functions.

*The recommended target level is not set for once daily administration. TDM, therapeutic drug monitoring.

b. Duration of Treatment

Duration of treatment should be the period recommended in the present guidelines. The necessary treatment period starts on the first day when negative blood cultures are obtained.

c. Relationship Between the Recommended Dose of Antibiotics and the Doses Approved in Japan

In IE treatment, antibiotics are often used at higher doses. Since aminoglycosides are used aiming at synergetic effect, they are used at stipulated doses.

d. New Antimicrobials (Daptomycin and Linezolid)

Daptomycin and linezolid are anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs. Non-inferiority of daptomycin to vancomycin in the treatment of IE has been reported in a comparative study, and daptomycin is positioned as a drug of the first choice.⁴⁰ Although linezolid has been revealed to be effective in the treatment of IE, it is not approved for IE treatment in Japan, and it is positioned as an alternative therapy.⁴¹ Attention should be paid to adverse reactions, such as thrombocytopenia in long-term administration.

e. Treatment of Infection Foci as Portal of Entry and Remote Site Infection

Treatment is necessary for the infection foci which has become the portal of entry of the causative microorganisms of IE, as well as the remote lesions developed from IE. The treatment method recommended as standard for each infection should be followed. Surgical approach should also be made as needed. The same applies to dental lesions.

2. Empirical Treatment

When antibiotic treatment is started before the blood culture results are obtained, the following points should be kept in mind in selecting antibiotics: (1) acute onset or subacute onset, (2) community-acquired infection or nosocomial or healthcare-associated infection, (3) severity (such as APACHE II score and presence/absence of septic shock), (4) native valve or prosthetic valve (or post-operative period), (5) clinical effects of antibiotics if they have already been administered, (6) coverage of most common causative microorganisms estimated based on age, patients’ medical background (such as dialysis), history of MRSA colonization, and so on. In particular, Staphylococcus aureus (especially those with methicillin resistance) is very important. When one considers to defer antibiotics for several days, the patients’ cardiopulmonary condition, presence or absence of annular abscess / intracardiac abscess, and embolism (size of vegetation ≥10 mm is a risk) should be checked.

a. Recent Trends in Causative Microorganisms (Table 9)

Table 9. Factors Associated With IE and Frequent Isolates

Associated area and item	Frequent isolate
Pediatric	Staphylococcus aureus, VGS, CNS, enterococci, and Streptococcus pneumoniae
Native valve	VGS, Staphylococcus aureus, CNS, enterococci, and other streptococci
Prosthetic valve	CNS, Staphylococcus aureus, VGS, enterococci, and Streptococcus gallolytics (bovis)
Congenital heart disease	VGS, Staphylococcus aureus, CNS, Streptococcus gallolytics (bovis), and enterococci
Healthcareassociated	Staphylococcus aureus, enterococci, VGS, CNS, and Streptococcus gallolytics (bovis)
Dialysis	Staphylococcus aureus, CNS, enterococci, VGS, and Pseudomonas aeruginosa
Drug injection	Staphylococcus aureus, VGS, CNS, enterococci, and Candida albicans

IE, infective endocarditis; VGS, viridans group streptococci; CNS, coagulase negative staphylococci.

The top three causative microorganisms are viridans group streptococci (VGS), staphylococci, and enterococci. While VGS is predominant in Japan,⁴² staphylococci have also been reported as predominant.^43,44 MRSA represents 7.5% of all cases of IE.⁴² Enterococci account for approximately 10%, and are common in elderly people (mean age of approximately 70 years).^45,46

b. Native Valve IE (Table 9 and Table 10)

Table 10. Recommendations of Empiric Treatment or Blood Culture* Negative IE

	Antibiotics	Dose	Class of recommendation	Level of evidence	Remarks
Native valve	Sulbactam/ampicillin	3 g, 3–4 times daily	IIb	C	When MRSA is unlikely When following a subacute clinical course
	+Ceftriaxone	2 g, once daily
	Daptomycin	8–10 mg/kg per dose, once daily	IIb	C	In the case of penicillin allergy
	+Ceftriaxone	+2 g, once daily
	Daptomycin	8–10 mg/kg/day, once daily	IIb	C	MRSA is considered
	+Sulbactam/ampicillin, or Panipenem/betamipron	3 g, 3–4 times daily 0.5 g, 3–4 times daily
	Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	IIb	C	In the case of penicillin allergy Enterococcus is also considered Precautions are required in the patients with decreased renal functions and elderly patients
	+Gentamicin	2 to 3 mg/kg, once daily
Prosthetic valve	Daptomycin	8–10 mg/kg, once daily	IIb	C	Ceftriaxone can be replaced with sulbactam/ampicillin
	+Ceftriaxone	2 g, once daily
	Daptomycin	8–10 mg/kg, once daily	IIb	C	MRSA is considered
	+Panipenem/betamipron	0.5 g, 3–4 times daily
	Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	IIb	C	Gentamicin can be administered at 1 mg/kg, 2 to 3 times daily Precautions are required in the patients with decreased renal functions and elderly patients
	+Gentamicin	2–3 mg/kg, once daily

*Targeted therapy should be conducted after the causative microorganisms has been identified. IE, infective endocarditis.

For community-acquired IE, VGS, staphylococci and enterococci should be covered. A choice of anti-MRSA drugs should be considered in cases of healthcare-associated onset or the cases with a history of MRSA colonization. When the date of onset is relatively clear, the clinical course is acute and the patient’s condition is rather severe, staphylococci and β-hemolytic streptococci are likely to be the causes, while VGS and enterococci can still be the causes.

c. Prosthetic Valve/Intracardiac Device IE (Table 9 and Table 10)

Staphylococci are causative microorganisms in 40% or more of the cases of prosthetic valve IE.⁴⁷ Early-onset IE within 2 months after valve surgery is attributable to staphylococci in a majority of cases. Coagulase negative staphylococci (CNS) are more predominant than Staphylococcus aureus. CNS in many of such cases are methicillin-resistant.^48,49 The causative microorganisms in the cases of onset more than 1 year after the operation are similar to those for IE in the native valve. Major causative microorganisms of IE associated with intracardiac devices are bacterial flora of the skin, and are staphylococci in 80% or more.⁵⁰ The choice of empiric antibiotics is similar to that for methicillin-resistant staphylococci.⁵¹

d. Culture-Negative IE

The following three reasons are plausible explanations for negative blood cultures. (1) The causative microorganisms are Coxiella, Bartonella, and other bacteria which are difficult to culture, (2) nutritionally variant streptococci, HACEK (Haemophilus aphrophilus, Haemophilus paraphrophilus Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), fungi and so on are likely to be the cause, and (3) antibiotics have been administered before blood culture.^14,52 In Japan, (3) is believed to be the main reason.²⁰

3. Targeted Therapy

3.1 Streptococci

a. Penicillin-Susceptible Streptococci (Table 11 and Table 12)

Table 11. Recommendations of Targeted Therapy for Native Valve IE

Antibiotics	Dosage	Period (weeks)	Class of recommendation	Level of evidence	Remarks
1) Penicillin G-susceptible (MIC ≤0.12 μg/mL) streptococci (VGS, Streptococcus gallolytics, and other streptococci)
Penicillin G	24 million unit/day* in 6 doses, or continuously	4	I	B
Ampicillin	8–12 g/day in 4–6 doses, or continuously	4	I	B
Ceftriaxone	2 g, once daily	4	I	B	Patients allergic to penicillin, elderly patients, and patients with decreased renal functions
Penicillin G	24 million unit/day* in 6 doses, or continuously	2	I	B	See the text for short-term treatment with Gentamicin
+Gentamicin	3 mg/kg, once daily	2
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	4	I	C	Patients allergic to β-lactams. See the text for dosage regimen and TDM
2) Streptococci non-susceptible to penicillin G (MIC ≥0.25 μg/mL)**
Penicillin G	24 million unit/day* in 6 doses, or continuously	4	I	B	Gentamicin can be administered at the dose of 1 mg/kg per dose, 2 to 3 times daily Not recommended in the cases of MIC >1.0 μg/mL for penicillin G
+Gentamicin	2–3 mg/kg, once daily	2
Ampicillin	8–12 g/day in 4–6 doses, or continuously	4–6**	I	B	Gentamicin can be administered at the dose of 1 mg/kg per dose, 2 to 3 times daily
+Gentamicin	2–3 mg/kg, once daily	2–6**
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	4	I	C	Patients allergic to penicillin
3) Enterococci
Ampicillin	8–12 g/day in 4–6 doses, or continuously	4–6	I	B	Gentamicin can be administered at the dose of 1 mg/kg per dose, 2 to 3 times daily. See the text for administration period of gentamicin
+Gentamicin	2–3 mg/kg, once daily	4 (2)–6
Ampicillin	8–12 g/day in 4–6 doses, or continuously	6	IIa	B	Should not be used for elderly patients, patients with decreased renal functions, and Enterococcus faecium
+Ceftriaxone	2 g, twice daily	6
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	4–6	I	B	Patients allergic to β-lactams. Not allowed for the strains highly resistant to gentamicin
+Gentamicin	2–3 mg/kg, once daily	4–6
4) Methicillin-susceptible staphylococci
Cefazolin	2 g, 3 times daily	4–6	I	B	Cefazolin can be replaced with sulbactam/ampicillin
Daptomycin± β-lactams, etc.	8–10 mg/kg, once daily	4–6	IIa	C	Patients allergic to β-lactams. See the text for doses and concomitant therapy
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	4–6	IIa	C	Patients allergic to β-lactams
5) Methicillin-resistant staphylococci
Daptomycin± β-lactams, etc.	8–10 mg/kg, once daily	4–6	I	B	See the text for doses and concomitant therapy
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	4–6	I	B	Adjusted to 15 to 20 μg/mL by TDM aiming at the initial concentration of 10 to 15 μg/mL Teicoplanin can be used (TDM is necessary)

*Doses should be adjusted according to the body weight and renal functions. 12–30 million unit/day, 30 million at maximum. **Infectious disease specialists should be consulted, including the administration with GM, in the cases non-susceptible to penicillin G, especially the cases with MIC >1.0 μg/mL. IE, infective endocarditis; VGS, viridans group streptococci; TDM, Therapeutic drug monitoring.

Table 12. Recommendations of Targeted Therapy for Prosthetic Valve IE

Antibiotics	Dosage	Period (weeks)	Class of recommendation	Level of evidence	Remarks
1) Streptococci (VGS, Streptococcus gallolytics, and other streptococci)
Penicillin G	24 million unit/day* in 6 doses, or continuously	6	IIa	B	Monotherapy is permitted for the cases susceptible to penicillin G (MIC ≤0.12 μg/mL) Gentamicin can be administered at the dose of 1 mg/kg, 2–3 times daily
±Gentamicin	2–3 mg/kg, once daily	2–6
Ampicillin	8–12 g/day in 4–6 doses, or continuously	6	IIa	B	Gentamicin can be administered at the dose of 1 mg/kg, 2–3 times daily
±Gentamicin	2–3 mg/kg, once daily	2–6
Ampicillin	8–12 g/day in 4–6 doses, or continuously	6	IIb	C	Elderly patients and patients with decreased renal functions
+Ceftriaxone	2 g, twice daily	6
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	6	IIa	C	Patients allergic to β-lactams
2) Enterococci
Ampicillin	8–12 g/day in 4–6 doses, or continuously	6	I	B	Not allowed for the strains highly resistant to gentamicin Gentamicin can be administered at the dose of 1 mg/kg, 2–3 times daily
+Gentamicin	2–3 mg/kg, once daily	6
Ampicillin	8–12 g/day in 4–6 doses, or continuously	6	IIa	C	Should not be used for Enterococcus faecium
+Ceftriaxone	2 g, twice daily	6
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	6	IIb	C	When the patient cannot tolerate β-lactams Not allowed for the strains highly resistant to gentamicin Gentamicin can be administered at the dose of 1 mg/kg, 2–3 times daily
+Gentamicin	2–3 mg/kg, once daily	6
3) Methicillin-sensitive staphylococci
Cefazolin	2 g, three times daily	6–8	I	C	Cefazolin can be replaced with sulbactam/ ampicillin Gentamicin can be administered at the dose of 1 mg/kg, 2–3 times daily See the text for the effects of rifampicin
+Gentamicin	2–3 mg/kg, once daily	2**
±Rifampicin	450–600 mg/day in 1–2 doses	6–8
Daptomycin± β-lactams, etc.	8–10 mg/kg, once daily	6–8	IIa	C	See the text for doses and combination therapy
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	6–8	IIa	C	Patients allergic to β-lactams Gentamicin can be administered at the dose of 1 mg/kg, 2–3 times daily
+Gentamicin	2–3 mg/kg, once daily	2**
±Rifampicin	450–600 mg/day in 1–2 doses	6–8
4) Methicillin-resistant staphylococci
Daptomycin+ β-lactams, etc.	8–10 mg/kg, once daily	6–8	I	C	See the text for doses and concomitant therapy
Vancomycin	1 g, twice daily, or 15 mg/kg, twice daily	6–8	I	C	Adjusted to 15 to 20 μg/mL by TDM aiming at the initial concentration of 10 to 15 μg/mL Teicoplanin can be used (TDM is necessary) See the text for aminoglycosides (including arbekacin) Gentamicin can be administered at the dose of 1 mg/kg per dose, 2 to 3 times daily
+Gentamicin	2–3 mg/kg, once daily	2**
±Rifampicin	450–600 mg/day in 1–2 doses	6–8

*Doses should be adjusted according to the body weight and renal functions. 12 million unit to 30 million unit/day at maximum. **Some opinion recommends concomitant administration of gentamicin for more than 2 weeks. IE, infective endocarditis; VGS, viridans group streptococci.

Among streptococci, VGS as an oral streptococcus is detected frequently, and is a main causative microorganism for the community-acquired IE in the native valve and IE in the prosthetic valve more than 1 year after an operation. For penicillin G, isolates with minimum inhibitory concentration (MIC) ≤0.12 μg/mL is considered susceptible. Most of VGS, Streptococcus gallolytics (Streptococcus bovis), and other streptococci show good susceptibility to penicillin G. Since penicillin G shows a short half-life in blood (30 minutes, when renal functions are normal), it is administered every 4 hours⁵³ or is administered continuously. Ampicillin can also be a choice of antibiotics. If the patient does not have immediate-type allergy to penicillin, cefazolin or ceftriaxone can be alternative of choice. If the patient cannot tolerate β-lactams including penicillin, vancomycin or teicoplanin should be selected. Some experts recommend addition of gentamicin for 2 weeks in the treatment regimen for prosthetic valve IE.¹⁵

b. Penicillin Non-Susceptible Streptococci (Table 11 and Table 12)

In evaluation of susceptibility to penicillin, VGS is regarded to be non-sensitive (moderate resistance or resistance) when MIC of penicillin G is ≥0.25 μg/mL and MIC of ampicillin is ≥0.5 μg/mL. Consultation with infectious disease specialists is recommended about the combined use of gentamicin and so on. For non-susceptible strains, penicillin G or ampicillin should be administered in combination with gentamicin for 2 to 4 weeks (4 to 6 weeks for prosthetic valve).⁵⁴ In the cases susceptible to ceftriaxone, gentamicin-including regimen is reasonable. In the cases non-susceptible to ceftriaxone, carbapenems can be selected.^55,56 If the patients are intolerant to β-lactams, combination of vancomycin or teicoplanin with gentamicin can be administered. Daptomycin has not been studied sufficiently. If administration of aminoglycosides is difficult in patients with renal dysfunction, monotherapy with vancomycin or teicoplanin with TDM, or combination of ampicillin and ceftriaxone can be considered.

c. Other Streptococci

Streptococcus pyogenes and Streptococcus agalactiae are highly pathogenic, and follow a relatively acute clinical course similar to that of staphylococci. Clinical symptoms are severe, and the mortality rate is also high (20% or higher).⁵⁷ Since susceptibility to penicillin is almost constantly good, penicillin G, ampicillin, or ceftriaxone is selected choice, while some experts recommend combination with gentamicin (Table 11).⁴

3.2 Enterococci (Table 11 and Table 12)

For enterococci, species identification and susceptibility tests should be performed. Enterococcus faecalis accounts for 90% or more of enterococci causing IE, and shows favorable susceptibility to penicillin. However, enterococci are resistant to many drugs including β-lactams, and long-term treatment is necessary. Since combination with gentamicin, which is used as the standard treatment, accompanies a problem of renal dysfunction, long-term administration of gentamicin is difficult, particularly in elderly patients.

In the treatment of enterococcal IE, ampicillin or vancomycin should be administered in combination with gentamicin (cases with MIC ≤500 μg/mL). For vancomycin, TDM should be conducted. The trough level should be 15 μg/mL according to that for MRSA (Table 8). The daily dose of gentamicin should be administered once daily or divided into 2 to 3 doses. The treatment results do not show differences even when gentamicin is administered once daily, and renal toxicity is less.^58,59

Concerning the duration of gentamicin administration, some reports suggest that the treatment results do not differ even when the duration is 2 weeks.^59,60 However, 2 weeks treatment should be avoided when IE is in the prosthetic valve, the vegetation size is large, and the patient is immunocompromised. The combination of ampicillin and ceftriaxone is also selected when renal dysfunction (creatinine clearance <50 mL/min) is present or when the strain shows high resistance to gentamicin (MIC >500 μg/mL).^61–63 Ampicillin and ceftriaxone combination should not be used for Enterococcus faecium.

Some researchers suggest that daptomycin does not exhibit sufficient efficacy as a monotherapy.⁶⁴ At present, its use is limited to the cases with vancomycin resistant enterococci (VRE) or salvage use in the same way as linezolid. For VRE, monotherapy with linezolid, or combination of daptomycin with ampicillin or gentamicin should be used.

3.3 Staphylococci

Staphylococci account for one-third of the cases of IE.⁴² The clinical course is acute, occasionally shows sudden changes, and is likely to become severe. Valve destruction and perivalvular progression are rapid, and remote lesions are frequent. Therefore, treatment with appropriate antibiotics and decision of operation without delay are required.

a. Staphylococcus Aureus (Table 11 and Table 12)

Staphylococcus aureus is associated with in-hospital mortality in IE. The mortality rate from IE caused by S. aureus is 20% or more,^65,66 and that in cases of IE in the prosthetic valve is even higher (47.5%).⁶⁷ MRSA accounts for 7.5% of all cases in which the pathogen is identified,⁴² and associated with age (elderly patients), and prosthesis-associated or healthcare-associated infection.^68,69 The mortality rate in the cases caused by MRSA has been reported to exceed 60%.^68,69

Cefazolin is the drug of first choice for methicillin-sensitive S. aureus (MSSA) in Japan. Daptomycin,⁷⁰ vancomycin, or teicoplanin should be used in cases intolerant of β-lactams because of allergy, etc. Addition of gentamicin is not recommended for staphylococcal native valve IE because of the nephrotoxity risk.⁷¹ The recommended duration of treatment is 4 to 6 weeks after negative conversion of blood culture. In cases accompanied by brain abscess or meningitis, other drugs rather than cefazolin should be selected, because delivery of cefazolin to the central nervous system is poor. Panipenem/betamipron, meropenem, or vancomycin should be considered as in the treatment of meningitis.⁷² Some experts recommend treatment with 3 drugs including gentamicin and rifampicin for IE in the prosthetic valve,^4,15,73 but the level of evidence is not sufficiently high.

For MRSA, daptomycin or vancomycin should be selected as the drug of first choice. While the indication of daptomycin in Japanese health insurance is limited to right-sided IE, it is also used for left-sided IE.⁷⁴ The duration of administration should be 4 to 6 weeks after negative conversion of blood culture. The duration should be 6 weeks or longer, approximately 8 weeks, for prosthetic valve IE. When daptomycin is selected, administration should be started at 8 to 10 mg/kg per dose, once daily. Better efficacy has been observed at higher doses (8 to 10 mg/kg) than once daily administration of 6 mg/kg per dose,⁷⁵ and some experts recommend a dose of ≥10 mg/kg.⁷⁰ The usefulness of administration of daptomycin in combination with β-lactams, aminoglycosides, rifampicin, fosfomycin, or sulfamethoxazole/trimethoprim has been suggested in some experimental and clinical studies.^76–80 Combination therapy should be considered under consultation with infectious disease specialists. In particular, combination therapy is recommended for prosthetic valve IE. The choices of additional antibiotics are the following: β-lactams such as panipenem/betamipron 2.0 to 3.0 g/day and sulbactam/ampicillin 9 g (or ampicillin 6 g)/day, gentamicin at 2 to 3 mg/kg/day, rifampicin at 450 to 600 mg/day, fosfomycin at 6.0 g/day, and sulfamethoxazole/trimethoprim such as trimethoprim at 5 to 8 mg/kg/day. As adverse reactions to daptomycin, attention should be paid to elevation of the blood creatine kinase (CK) level, eosinophilia, and eosinophilic pneumonia.

When vancomycin is selected, designing before administration and TDM should be conducted. The target blood trough level should be approximately 15 to 20 μg/mL³⁹ (Table 8).

The MIC of vancomycin ≤2 μg/mL means susceptible. However, if the MIC of vancomycin to the isolated MRSA is >1 μg/mL, the efficacy may be compromised even though target trough level is obtained. Therefore, efficacy evaluation should be conducted carefully for IE patients on the basis of confirmation of negative conversion of blood culture and the clinical course.

Combination of vancomycin and gentamicin is not recommended for native valve IE, because of the risk of renal toxicity. Three-drug combination therapy with vancomycin, gentamicin and rifampicin (6 weeks) is recommended as the standard therapy for staphylococcal prosthetic valve IE.^4,15,73 However, the addition of rifampicin is not based on sufficient evidence. Moreover, since rifampicin requires precautions for hepatic toxicity and drug interactions, and rifampicin resistance is easy to occur within a short period, consultation with pharmacists and infectious disease specialists is recommended.

Teicoplanin and linezolid are the drugs of second choice.^81–83 Teicoplanin is characterized by a quite long half-life in blood of approximately 50 hours, and loading dose is necessary for the blood concentration to reach a steady state at an early timing.³⁹ The target trough level should be 20 μg/mL or higher (not exceeding 30 μg/mL). Linezolid is not a drug approved for IE in Japan, and administration for a duration longer than 2 weeks is related to thrombocytopenia.⁴¹ However, efficacy in the treatment of IE has been observed in the case series with prosthetic valve, and strains with low susceptibility to vancomycin, cases intolerant of vancomycin, and cases of unsuccessful treatment.^83,84 Because linezolid shows favorable organ distribution, the cases accompanied by meningitis or brain abscess, and the cases accompanied by pneumonia are believed to be good indications. Infectious disease specialists should be consulted for combination therapy with other anti-MRSA drugs.

Concerning treatment with antibiotics other than anti-MRSA, combination therapy with imipenem/cilastatin and fosfomycin, which has been found to be useful in a multi-center study,⁸⁵ and combination of sulfamethoxazole/trimethoprim and clindamycin have been considered in some cases, although they were intended for salvage therapy.⁸⁶

b. Coagulase-Negative Staphylococci (CNS) (Table 11 and Table 12)

CNS accounts for approximately 10% of all cases of IE,⁴² and is frequently detected as a causative microorganism in the prosthetic valve IE at a relatively early timing after valve replacement surgery. Although it is often regarded as less virulent than S. aureus, the in-hospital mortality rate of IE caused by CNS is almost the same as that caused by S. aureus. In particular, the mortality rate in methicillin-resistant cases is high (40%).^48,49 The percentage of the cases that required surgical treatment was even higher than in the cases caused by S. aureus.

Antibiotic treatment of IE caused by CNS should be conducted in the same way as that for S. aureus. The combination therapy including rifampicin for IE in the prosthetic valve is based on a study of IE caused by CNS.

3.4 Gram-Negative Bacteria (Including HACEK)

HACEK is a group of gram-negative bacilli (Haemophilus aphrophilus, Haemophilus paraphrophilus, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) accounting for about 1% of IE.⁴² Although isolation from blood cultures is rare, their association with IE is strongly suspected. The mean age of the patients with IE caused by HACEK is approximately 10 years younger than that of all IE patients. Most cases are of community-acquired infection, and the prognosis is relatively good.

HACEK organisms show good susceptibility to the third-generation and fourth-generation cephems (Table 13). Most strains are susceptible to ampicillin,⁸⁷ but some are β-lactamase producing. Therefore, the susceptibility of isolated strains should be confirmed.⁸⁸ In cases intolerant with β-lactams, quinolones such as ciprofloxacin and levofloxacin also become choices⁸⁹ (Table 13).

Table 13. Recommendations of Antibiotics in IE Caused by HACEK and Level of Evidence

Antibiotics	Dosage	Period (weeks)	Class of recommendation	Level of evidence	Remarks
Ceftriaxone	2 g, once daily	4	IIa	B	Administration for 6 weeks for IE in the prosthetic valve (class of recommendation IIb and level of evidence C)
Sulbactam/ampicillin*	3 g, 3–4 times daily	4	IIb	B
Ciprofloxacin, or	300 mg, twice daily	4	IIb	C
Levofloxacin	500 mg, once daily

*Ampicillin can be administered in sensitive cases. IE, infective endocarditis.

IE caused by gram-negative bacteria other than HACEK is rare, accounting for only several percents.⁴² Among them, Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae account for a majority, while Pseudomonas aeruginosa is common next to Escherichia coli. Antibiotics should be selected from the third- and fourth-generation cephems, carbapenems, and quinolones according to the susceptibility results of isolates, and should be administered for up to approximately 6 weeks. Recommended treatment is combination of β-lactams and amikacin or gentamicin as the treatment of refractory gram-negative bacterial infection, but there has been no established treatment method, including the duration of aminoglycosides administration. Treatment is often difficult with antibiotics alone, and early surgery should be considered. However, the mortality rate exceeds 20% in spite of surgical treatment.⁹⁰

3.5 Fungi

The incidence of fungal IE is rare but refractory, and the mortality rate is extremely high (30 to 50%).⁹¹ Fungal IE is common in patients with prosthetic valve. Most cases of fungal IE are caused by Candida, and the cases caused by filamentous fungi such as Aspergillus are rare.

In the cases of fungal IE, it is difficult to control infection with medical treatment only, and some researchers recommend surgery within 1 week (native valve IE) or within several days (prosthetic valve IE).⁹² However, surgical treatment does not necessarily improve the survival rate,⁹³ and the cases of IE in the prosthetic valve that could be controlled with antifungal drugs have been reported.^94–96

As the drug of first choice for antifungal treatment, amphotericin-B lipid preparation, candins (micafungin and caspofungin), or voriconazole should be selected. However, combined administration of 2 drugs can be considered from the beginning of treatment⁹⁷ (for example, amphotericin-B+candin). Infectious disease specialists should be consulted.

After surgery, treatment with antifungal drugs should be added for 6 to 8 weeks.⁹³ The cases in which infection could be controlled with medical treatment alone should be treated for several months or more than 1 year (or lifelong) with oral azoles.⁹⁷

4. Efficacy Evaluation and Duration of Antibiotic Treatment

Efficacy should be evaluated at approximately 72 hours (48 to 72 hours) after the start of treatment with antibiotics under careful monitoring.¹⁶ Overall judgement should be made basically on the basis of vital signs, as well as subjective symptoms such as pyrexia, dyspnea, malaise, and anorexia, physical findings (changes in cardiac murmur, edema in limbs, and symptoms of embolus), test data, and imaging findings (echocardiography, chest radiography, head and body CT/MRI, etc.). Negative conversion on blood culture is mandatory in the cases with positive blood cultures before initiation of treatment. In cases caused by S. aureus and cases in an unstable condition such as heart failure, immediate judgement for surgery is necessary. Cooperation with several specialists and judgement for early surgery are required at any time after the start of treatment (See “Chapter II. 2. Team Medicine”).

One of the clinical parameters for efficacy evaluation is body temperature. Among the patients who have received appropriate treatment with antibiotics, 70 to 75% of the patients get afebrile within 1 week, but it tends to take time when mucocutaneous findings (such as petechia and Janeway lesion) are present, the size of vegetation is large, embolism is present in large vessels, and diagnosis has taken many days. The number of days required for becoming afebrile is 2 to 4 days on average for VGS and enterococci, and approximately 7 to 10 days for S. aureus.^98,99

Pyrexia persists in spite of antibiotic treatment due to several reasons: progression of infection into the annular region, intracardiac abscess, formation of pulmonary embolism and other remote lesions, heart failure, and drug-induced fever. Uncontrolled infection is an important indication for early surgery, and may necessitate repeating blood culture and evaluation on echocardiography. If fever recurs, drug-induced fever is the most common cause (common around week 3 or week 4, and observed in approximately 30% of patients). Infection foci inside and outside of the heart still can be a cause for recurrent fever.⁹⁹ In addition, complications such as catheter-related bloodstream infection, urinary tract infection, and pneumonia should be considered. As laboratory test findings, the white blood cell count, C-reactive protein (CRP), and other inflammation markers can ancillary be referred to for prediction of prognosis or estimation of complications.¹⁰⁰

The duration of antibiotic treatment recommended in the present guidelines is not always based on sufficient comparative studies. While careful monitoring of the course is necessary even after completion of the scheduled treatment, routine blood culture is unnecessary if there are no findings suggestive of recurrence.

V. Evaluation and Management of Complications

1. Heart Failure

This section is omitted from the English version.

2. Uncontrolled Infection and Perivalvular Infection

This section is omitted from the English version.

3. Embolism

3.1 Evaluating the Risk of Embolism

This section is omitted from the English version.

3.2 Neurological Complications

a. Frequency and Types of Neurological Complications

Symptomatic neurological complications are observed in 10 to 35% of IE patients.^101–104 When asymptomatic cases are included, 65 to 80% of the patients show one or more neurological complications.^105–108 For the patients who are suspected to have IE, examination with brain MRI or contrast-enhanced CT is recommended even when obvious focal neurological symptoms are absent (see Table 14 and “[CQ 1] Is brain MRI useful for patients without neurological symptoms who have or are suspected to have IE?”).

Table 14. Recommendations for Diagnosis of Neurological Complications of Infective Endocarditis and Level of Evidence

	Class of recommendation	Level of evidence
When cerebral hemorrhage or subarachnoid hemorrhage is observed in a patient who is suspected to have IE, mycotic aneurysm should be searched by cerebrovascular imaging (cerebral angiography, CTA, or MRA)	I	C
For the patients who are suspected to have IE, precise examination of neurological complications using brain MRI should be considered, even when obvious focal neurological symptoms are not observed (see “CQ 1 Is brain MRI useful for the patients without neurological symptoms who have or are suspected to have IE?”)	IIa	C
When MRI cannot be obtained in the patients who are suspected to have IE or when the systemic condition of the patients is unstable, head plain CT may be considered, and three-dimensional CT angiography and head contrast-enhanced CT may be added, if necessary	IIb	C
As imaging methods of MRI, DWI, FLAIR images, T2*WI or SWI, and MRA may be considered	IIb	C

IE, infective endocarditis; CTA, computed tomography angiography; MRA, magnetic resonance angiography; DWI, diffusion weighted image; FLAIR, fluid attenuated inversion recovery; SWI, susceptibility-weighted imaging; T2*WI, T2*-weighted image.

The most common types of neurological complications are cerebral infarction and transient ischemic attack. Cerebral hemorrhage, subarachnoid hemorrhage, mycotic aneurysm, brain abscess, encephalomeningitis, toxic/metabolic encephalopathy, and epilepsy are also seen.^102,106,109 Cerebral infarction, including asymptomatic cases, is observed in approximately 50% of IE patients,^106,108 and cerebral hemorrhage and subarachnoid hemorrhage are observed in 5 to 10% of the patients.^106,108,110 In studies using brain MRI-T2*-weighted images (T2*WI), cerebral microbleeds have been observed in a large percentage of cases (approximately 60%), in addition to the above findings.^107,110,111 The percentage of the cases accompanied by mycotic aneurysm has been reported to be approximately 4 to 9%.^112,113 When cerebral hemorrhage or subarachnoid hemorrhage is observed, the percentage of the cases accompanied by mycotic aneurysm increases to 22%.¹¹² Mycotic aneurysm is often observed distal to the middle cerebral artery, and approximately 25% of the cases have multiple aneurysms.¹¹⁴ When cerebral hemorrhage or subarachnoid hemorrhage is observed in a patient who is suspected to have IE, it is strongly recommended to search mycotic aneurysm by cerebrovascular imaging (cerebral angiography, computed tomography angiography [CTA], or magnetic resonance angiography [MRA]) (Table 14).

b. Methods of Diagnosis of Neurological Complications (Table 14)

Brain MRI is most useful for the diagnosis of neurological complications accompanying IE. When MRI cannot be obtained, head plain CT should be obtained, and three-dimensional CT angiography and head contrast-enhanced CT should be added, if necessary (class of recommendation IIb, level of evidence C).

As imaging methods of MRI, diffusion weighted image (DWI), fluid attenuated inversion recovery (FLAIR) image, T2*WI or susceptibility-weighted image (SWI), and MRA are recommended (class of recommendation IIb, level of evidence C).

Since mycotic aneurysm often develops on the peripheral side of the middle cerebral artery, a larger field of view should be selected to include the entire middle cerebral artery (M3 or distal) when MRA is obtained. In the cases with cerebral hemorrhage or subarachnoid hemorrhage, cerebral angiography or three-dimensional CT angiography should be considered. In patients with IE, cerebral microbleeds are observed frequently on T2*WI and SWI, and association with mycotic aneurysm is suspected.^115,116 Brain abscess shows marked high signals on DWI of MRI, and is depicted as a low-density area on CT. Characteristic capsular ring-enhancing effect is observed on contrast MRI and contrast-enhanced CT.

When headache, disturbance of consciousness, or meningeal irritation symptoms are present and meningitis or subarachnoid hemorrhage is suspected, cerebrospinal fluid examination by lumbar puncture should be conducted.

CQ 1 Is brain MRI useful for patients without neurological symptoms who have or are suspected to have IE?

Answer:

It is proposed to obtain brain MRI (including DWI, FLAIR images, T2*WI, and MRA) at an early timing in the patients without neurological symptoms who have or are suspected to have IE.

Strength of recommendation 2: Weakly recommended (proposed)

Strength of body of evidence C (weak)

[Related section] “Chapter V. 2. b. Methods of Diagnosis of Neurological Complications”, Table 14

Commentary:

As described in detail in the previous section, various neurological complications are seen in patients with IE (See “Chapter V. 2. a. Frequency and Types of Neurological Complications”). Several studies have shown that, even in the IE patients without obvious neurological symptoms, screening tests using MRI show neurological complications in 40 to 80% of them.^{104,105,107,108,117–121} As compared with CT, MRI is able to detect small infarctions at a higher rate when DWI and FLAIR images are used. Moreover, when T2*WI or SWI is used, cerebral microbleeds can be detected.^117,122 Cerebral microbleeds have been used as an indicator for diseases of cerebral small vessels such as hypertensive cerebral small vessel disease and amyloid angiopathy, but cerebral microbleeds are also observed at a high rate in IE patients,¹¹¹ and its association with cerebral hemorrhage after open heart surgery^123,124 and mycotic aneurysm¹²⁰ is suspected. Magnetic resonance angiography is useful for identification of occluded vessels and mycotic aneurysm. Since mycotic aneurysm is often formed in the distal part of cerebral artery, an area including the distal part should be visualized on MRA, if possible (see “Chapter V. 2. b. Methods of Diagnosis of Neurological Complications”).

There has been no clear evidence regarding whether or not the patients’ prognosis is improved when brain MRI is obtained at an early timing in the patients without central nervous symptoms who have or are suspected to have IE.¹²² On the other hand, in a prospective observational study in which efficacy of obtaining brain MRI at an early timing in the patients who are suspected to have IE was examined, the accuracy of diagnosis of IE was improved in 32% of the patients when MRI was obtained at an early timing (improved from “possible” to “definite” in 26% and from “excluded” to “possible” in 6%), and the treatment strategy, including the timing of surgery and the antibiotics to be used, were changed on the basis of the results of MRI in 18% of the patients.^106,125 One paper suggests that cardiac surgery should be waited for at least 2 weeks because the risk of exacerbation of perioperative mortality and neurological symptoms is high in the patients with neurological complications.¹⁰³ However, recent observational studies have reported that cardiac surgery is conducted at earlier timings and perioperative mortality is low in patients with asymptomatic neurological complications,¹²⁶ that, among neurological complications, only cerebral hemorrhage and moderate to severe cerebral infarction are associated with poor prognosis,¹⁰¹ and that the incidence of postoperative hemorrhagic infarction is very low even if cerebral infarction is present as comorbidity.¹¹⁸ When asymptomatic neurological complications are observed, treatment strategy should be determined on the basis of overall judgement of the patient’s systemic condition, degree of cardiac functions and valvular destruction, status of infection control, risk of recurrence of neurological complications, and risk of perioperative complications.

There has been no study on the cost-effectiveness of brain MRI in the patients without neurological symptoms who have or are suspected to have IE. While MRI is more expensive than CT, latent costs for CT associated with adverse effects by radiation exposure or contrast medium need to be taken into consideration.

In addition to the above considerations, the prevalence of brain MRI in Japan and safety of brain MRI were also taken into consideration to generate the recommendation for this CQ. Thus, it is proposed to obtain brain MRI (including DWI, FLAIR images, T2*WI, and MRA) at the earliest timing in patients without neurological symptoms who have or are suspected to have IE.

c. Treatment of Neurological Complications (Figure 2 and Table 15)

Figure 2.

Treatment algorithm for mycotic cerebral aneurysm.

Table 15. Recommendations for Treatment of Neurological Complications of Infective Endocarditis and Level of Evidence

	Class of recommendation	Level of evidence
Antiplatelet therapy and anticoagulant therapy should be discontinued immediately if IE is accompanied by intracranial hemorrhage (except for cerebral microbleeds)	I	B
Surgical or endovascular treatment should be considered for ruptured mycotic aneurysm (see Figure 2)	I	C
It is not recommended to newly start antiplatelet therapy aiming at prevention of embolism in IE patients	III	B
Intravenous thrombolytic therapy is not recommended for acute cerebral infarction accompanying IE	III	B
It is not recommended to newly start anticoagulant therapy aiming at prevention of embolism in IE patients	III	C

IE, infective endocarditis.

The types of neurological complications include cerebral infarction, transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, brain abscess, and epileptic seizure. The most important treatment to prevent the onset and recurrence of neurological complications is believed to start appropriate antibiotic treatment at an early timing. Open heart surgery for the patients who have cerebral infarction or intracranial hemorrhage as comorbidity is stated separately (See “[CQ 3] Should surgery of IE be conducted at an early timing when neurological complications have occurred?”).

i. Antithrombotic Therapy for Neurological Complications

When intracranial hemorrhage (except for cerebral microbleeds) has occurred as comorbidity, antiplatelet therapy and anticoagulant therapy should be discontinued immediately (Table 15). On the other hand, consensus has not been established at present regarding whether or not anticoagulant therapy should be continued for the patients who have been receiving anticoagulant therapy when ischemic cerebrovascular disease occurs.⁴ Therefore, the decision whether anticoagulant therapy is continued or not should carefully be made considering risks of both the options.

On the other hand, it is not recommended to newly start antiplatelet therapy in IE patients because a possibility to increase the risk of hemorrhagic complications has been suggested¹²⁷ (Table 15). Although evidence regarding anticoagulant therapy is limited, it is not recommended to newly start anticoagulant therapy because it is also likely to increase the risk of hemorrhagic complications (Table 15).

ii. Acute Reperfusion Therapy for Neurological Complications

Intravenous thrombolytic therapy for acute cerebral infarction accompanying IE is not recommended because the incidence of intracranial hemorrhage after treatment is very high (approximately 20%)¹²⁸ (Table 15). For acute major artery occlusion by vegetation, endovascular thrombectomy is suggested to be safe and effective even in patients receiving anticoagulant therapy.¹²⁹

iii. Treatment for Intracerebral Hemorrhage and Hemorrhagic Infarction

When symptomatic intracerebral hemorrhage or hemorrhagic infarction exhibiting mass effect is observed, discontinuation or suspension of anticoagulant therapy should be considered. In some cases, craniotomy for removal of hematoma or decompressive craniectomy should be considered.¹³⁰

iv. Coil Embolization/Surgical Treatment for Mycotic Aneurysm (Figure 2 and Table 15)

Although evidence based on a randomized controlled trial is not available regarding treatment methods, Figure 2 summarizes treatment algorithm for mycotic aneurysm. While endovascular treatment has been conducted more often, surgical treatment may be preferred when intracerebral hemorrhage is present or revascularization is necessary.^131,132 In selection of treatment methods, judgement should be made on the basis of thorough examination of the systemic condition for each patient.

3.3 Other Embolism

This section is omitted from the English version.

4. Renal Dysfunction

This section is omitted from the English version.

5. Disseminated Intravascular Coagulation

This section is omitted from the English version.

VI. Surgical Treatment

1. Evaluation of Surgical Risk and Preoperative Assessment

a. Evaluation of Surgical Risk

Surgical risk can be evaluated using JapanSCORE,^133,134 STS score,¹³⁵ and EuroSCORE.¹³⁶ Operative mortality is high in patients requiring emergency surgery, cardiogenic/septic shock, infection by fungi or multidrug-resistant bacterium such as MRSA, prosthetic valve endocarditis, paravalvular abscess, neurological complications, renal failure, diabetes mellitus, and so forth.

b. Preoperative Assessment: Evaluation of Cerebral Vessels, Coronary Arteries, and Other Organs

Preoperative assessment of intracranial lesions is essential because IE accompanies neurological complications at high rates.^{4,73,101,103,118,123,124,137–142} The diagnosis of neurological complications is described in detail in “Chapter V. Evaluation and Management of Complications”. Patients with suspected myocardial ischemia require cardiac CT or coronary angiography.¹⁴³ Optimal modality should be selected based on patient’s clinical condition. Cardiac CT can simultaneously evaluate coronary arteries and aortic root infection.^{32,33,144,145} Coronary angiography precisely evaluates stenosis with calcification or with tachycardia, but it carries the risk of catheter manipulation-related embolism, especially in patients with aortic valve IE. Assessment of embolism and abscess in the spleen or kidneys is possible to be performed with minimal contrast medium by additional late-phase systemic CT following cardiac CT.

2. Indications of Surgical Treatment and Timing of Operation

a. General Remarks on Indications of Surgical Treatment

In the treatment of IE, surgical treatment should be always kept in mind as an option. Early surgical treatment should be considered when there are possibilities of progressing heart failure, destruction of intracardiac structure, refractory infection, and embolism. The team should discuss the treatment strategy for each patient because the appropriate timing of surgery and postoperative results are varied according to the type of causative microorganisms, comorbidities and so on. Early surgery can be classified as emergency surgery (within 24 hours), urgent surgery (within several days), and elective surgery (1 to 2 weeks after antibiotic treatment). Table 16 shows the indications of early surgery. In the cases not meeting the indications of early surgery, the indication and timing of surgery should be determined as usual valvular heart diseases. However, since the severity of valvular disease/bacteremia and possibility of embolism change from time to time in the cases of IE, careful monitoring is required to avoid missing the optimal timing of surgery.

Table 16. Recommendations of Early Surgery for IE and Level of Evidence

Situation	Indication/recommendation*1	Timing	Class of recommendation	Level of evidence
Heart failure	Refractory pulmonary edema and cardiogenic shock due to acute severe valve dysfunction or fistula formation	Emergency	I	B
	Heart failure due to severe valve dysfunction or rapidly worsening paravalvular leakage	Urgent	I	B
Uncontrolled infection	Annular abscess, pseudoaneurysm formation, fistula formation, increasing size of vegetation, and atrioventricular conduction disturbance	Urgent	I	B
	Persistent infection*2 exists despite no presence of other infection foci. Persistent infection includes (1) positive blood culture obtained at 2 to 3 days after appropriate antibiotic treatment or (2) sustained fever for 3 to 5 days or more after appropriate antibiotic treatment	Urgent	IIa	B
	Infection by fungi or highly multidrug-resistant bacteria	Urgent/elective	I	C
	Prosthetic valve endocarditis due to resistant staphylococci or non-HACEK Gram-negative bacteria	Urgent/elective	IIa	C
	Recurrent prosthetic valve endocarditis	Urgent/elective	IIa	C
Prevention of embolism	One or more embolisms after the initiation of appropriate antibiotic treatment and non-disappearing (size >10 mm) or growing vegetation	Urgent	I	B
	Native valve endocarditis with mobile vegetation exceeding 10 mm in size and severe valve dysfunction*3	Urgent	IIa	B
	Isolated huge vegetation exceeding 30 mm in size	Urgent	IIa	B
	Mobile vegetation exceeding 10 mm in size*4	Urgent	IIb	C
Timing of surgery in patients with neurological complications*5	Surgery should not be postponed in patients with non-hemorrhagic cerebral infarction when surgical treatment is appropriate Note: Except for cases with coma, brain herniation, or huge major central lesions	–	IIa	B
	Surgery should be postponed at least 4 weeks when new intracranial hemorrhage is detected. Note: Except for cases involving cerebral microbleeds	–	IIa	B

*1: Unless otherwise specified, the statements apply to both native valve endocarditis and prosthetic valve endocarditis.

*2: Infectious condition should be comprehensively evaluated on the basis of negative conversion of blood culture in addition to the degree of lowering of body temperature or inflammatory markers such as the white blood cell count and CRP value.

*3: Early surgery is recommended, especially when the risk of surgery is low (See “CQ 2 Should early surgery be conducted if a large vegetation is present?”).

*4: Especially in cases with prosthetic valve endocarditis, anterior leaflet of mitral valve involvement, or the presence of other relative surgical indications.

*5: See “CQ 3 Should surgery of IE be conducted at an early timing when neurological complications have occurred?”

IE, infective endocarditis.

See “[CQ 3] Should surgery of IE be conducted at an early timing when neurological complications have occurred?” as well as Figure 3 and Table 16 for the timing of surgery in the cases in which neurological complications occur in the patients for whom early surgery is indicated.

Figure 3.

Treatment algorithm for neurological complications in infective endocarditis. IE, infective endocarditis; CT, computed tomography; MRI, magnetic resonance imaging; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography.

b. Congestive Heart Failure (Table 16)

Congestive heart failure is triggered by regurgitation mainly caused by valvular destruction, but it can also be caused by intracardiac shunt, and valvular obstruction caused by vegetation. Heart failure of NYHA III to IV can become an indication of emergency surgery.^146–149 Heart failure of NYHA II accompanied by severe valvular regurgitation also becomes an indication of early surgery if echocardiography suggests elevation of the left ventricular end-diastolic pressure and pulmonary hypertension.^148–152

Even the cases accompanying severe valvular regurgitation can be treated with conservative treatment with antibiotics and management of heart failure, if there are no apparent signs of heart failure and there are no other reasons for surgical indication, such as large vegetation. In such cases, surgical indication should be determined as usual valvular heart diseases.

c. Uncontrolled Infection (Table 16)

Uncontrolled infection is an indication for urgent surgery. Uncontrolled infection is defined as continuing positive blood culture and/or sustained infection findings such as fever, elevated white blood cell count, and high CRP level despite appropriate antibiotic treatment for a certain period (approximately 3 to 5 days).^16,99 Mortality is reported to be doubled if blood culture obtained at 48 to 72 hours after the initiation of antibiotics remains positive,¹⁶ and surgery should be performed without delay.

Patients with positive conversion of blood culture after confirming the absence of other infection foci are diagnosed as recurrent infection, and early surgery should be considered. Fungi, gram-negative bacteria,¹⁵³ or MRSA, which is less likely to respond to antibiotic treatment, often follows a clinical course of uncontrolled infection. Annular abscess, pseudoaneurysm formation, increasing size of vegetation, or heart block (complete atrioventricular block and left bundle branch block) are all characteristic of uncontrolled infection.^{27,150,152,154,155} The incidence of paravalvular abscess is higher in prosthetic valve endocarditis than in native valve endocarditis (55 to 78% vs. 10 to 32%).^156–161 In native valve endocarditis, aortic valve endocarditis is associated with a high rate of paravalvular abscess. In prosthetic valve endocarditis, the incidence of paravalvular abscess is high in endocarditis at the mitral position as well.

d. Infectious Embolism (Table 16)

Embolism, especially cerebral embolism, dramatically exacerbates the patients’ activities of daily living, even if it does not directly endanger life. Generally, the use of appropriate antibiotics will decrease the risk of embolism.¹⁰¹ However, it has been reported that the risk of embolism does not decrease even after antibiotic treatment in the cases of giant vegetation larger than 30 mm.¹⁰¹ If embolic events repeat even after the start of appropriate antibiotic treatment, the risk of subsequent embolic events should be high, and early surgery is reasonably indicated.⁴ Vegetation adhering to anterior mitral leaflet also accompanies a high risk of embolism.⁷³

CQ 2 Should early surgery be conducted if a large vegetation is present?

Answer:

Surgery at the earliest timing possible is recommended for the patients with IE in the native valve (aortic valve or mitral valve) who have a vegetation of 10 mm or larger accompanying severe valve dysfunction.

Strength of recommendation 1: Strongly recommended

Strength of body of evidence B (moderate)

[Related section] “Chapter VI. 2. a. General Remarks on Indications of Surgical Treatment”, Table 16

Commentary:

In the observational studies, early surgery of IE has been associated with better prognosis.^162–164 The usefulness of early surgery has been reported in Asian countries and Japan.^165,166 The indication of early surgery for IE cases accompanying heart failure, embolism which occurs repeatedly in spite of sufficient antibiotic treatment, uncontrollable local infection (abscess, pseudoaneurysm, and fistula), and drug-resistant causative microorganisms such as fungi has been generally established (see “Chapter VI. 2. a. General Remarks on Indications of Surgical Treatment”). On the other hand, implementation of early surgery in all cases of IE accompanies concerns about the risk of surgery-associated death and the risk of recurrence. Therefore, identification of the subgroup to be treated by early surgery has been needed.¹⁶⁵

In addition to mortality due to heart failure and other complications, IE may cause serious disabilities due to cerebral infarction caused by embolism of vegetation. A large vegetation of 10 mm or larger in size has been reported to be a risk factor of recurrent embolism.^27,167 The risk of embolism after the onset of IE is high in the early stage after onset, and appropriate antibiotic treatment is known to reduce the risks. However, it has been suggested that the risk of embolism does not decrease in cases with huge vegetation, as well as the cases in which vegetation grows in size during antibiotic treatment.¹⁰¹ Therefore, surgical indication has been discussed for prevention of embolism in cases with a large vegetation. In observational studies, the usefulness of early surgery for a large vegetation has been reported in Western countries and Japan,^149,168 while some reports have concerned that the incidences of early death, recurrence of IE, and valve dysfunction was high in early surgery.^169,170

In 2012, the only randomized study at present regarding surgical indication of IE was reported.¹⁷¹ Inclusion criteria were as follows: patients aged 18 years or older who have left-sided native valve IE accompanying a vegetation larger than 10 mm, who also have severe valve dysfunction (valvular regurgitation in most cases), and for whom emergency surgery is not indicated (moderate-to-severe heart failure, atrioventricular conduction block, abscess, destructive penetrating lesions, and IE caused by fungi). Patients aged 80 years or older, who had severe complications such as large cerebral infarction accompanying the risk of hemorrhagic changes and cancer were excluded. Patients with prosthetic valve IE and right-sided IE were also excluded. The patients were divided into the group to be surgically treated within 48 hours after randomization (37 patients) and the group receiving conventional treatment (39 patients). In both groups, appropriate antibiotics were administered. In the conventional treatment group, 30 patients (77%) were surgically treated (27 patients during the index hospitalization and 3 patients in the late phase), and 8 patients received semi-emergency surgery (6 to 10 days after randomization). Therefore, this study could be regarded to test the usefulness of urgent surgery for the patients with a large vegetation accompanying valve dysfunction.

Significant differences were observed in primary composite endpoints (in-hospital death, embolic events within 6 weeks after randomization) between the early surgery group and the conventional treatment group (hazard ratio 0.10 [95% confidence interval, 0.01–0.82, P=0.03]). While no difference was seen in the total number of deaths within 6 months (3% versus 5%, hazard ratio 0.51 [95% confidence interval 0.05–5.66, P=0.59]), differences were seen in the presence or absence of embolism observed within 6 weeks (0% versus 21%, P=0.005). In both groups, no patients were re-hospitalized because of embolic events and heart failure during the follow-up period. Moreover, there were few cases of recurrence of IE within 6 months: no significant differences were observed between the groups.

In the above report, randomization was conducted, but concealment of randomization was not performed. Blinding was not conducted, but systemic differences in other treatments are deemed to be unlikely. Embolic events were confirmed on images at the time of periodic visits to the hospital, and detection bias is thought to be small. Image inspection was conducted only when symptoms were present, and asymptomatic embolism was not evaluated. The necessary number of patients was calculated, and intention to treat analysis was conducted.

The frequencies of causative microorganisms were typical, with VGS accounting for 30% of the cases, other streptococci 30%, and Staphylococcus aureus 10%. The cases of cerebral infarction represented 30%. On the other hand, the patients were young (between 40 and 49 years), were relatively low risk, and were treated at the hospitals coping with a large number of surgical cases. A report suggested that the cases satisfying the conditions of this study was only 11.3% of the actual cases of left-sided native valve IE undermining validity of the results.¹⁷²

This cohort was followed up for 7 years. Although no difference was seen in total mortality, composite endpoints (total death, embolism, and recurrence of IE) were significantly better in the early surgery group (8.1%) than the conventional treatment group (30.8%).¹⁷³

On the basis of these results, the present guidelines recommend urgent surgery for the patients with IE in the native valve (aortic valve or mitral valve) who have a vegetation of 10 mm or larger accompanying severe valve dysfunction. However, the risk of surgery should be evaluated carefully. Moreover, prosthetic valve IE should not be included in the targets of this indication.

CQ 3 Should surgery of IE be conducted at an early timing when neurological complications have occurred?

Answer:

(1) Surgery of IE is recommended not to be postponed if it is indicated, even when concurrent cerebral infarction is present.*

*Except for the cases with concurrent coma, herniation, or cerebral hemorrhage, as well as major central lesions.

Strength of recommendation 1: Strongly recommended.

Strength of body of evidence B (moderate)

(2) If new intracranial hemorrhage* is observed, it is proposed to wait 4 weeks to conduct open heart surgery if the hemodynamic condition is stable.

*Except for cerebral microbleeds.

Strength of recommendation 2: Weakly recommended (proposed).

Strength of body of evidence C (weak)

[Related section] “Chapter VI. 2. a. General Remarks on Indications of Surgical Treatment”, Table 16

Commentary:

When neurological complications occur during the course of IE, it is often difficult to decide the timing of surgery. Because of the use of cardiopulmonary bypass, which may induce perioperative hypotension and necessitate the use of a large dose of heparin, there are risks of exacerbation of neurological complications such as cerebral ischemia and cerebral hemorrhage.^103,174 A multi-center retrospective study in Japan reported that, among the 181 patients who received surgery for IE, the rates of nosocomial death and exacerbation of neurological complications were high in the patients who underwent surgery in the early stage after the onset of neurological complications.¹⁰³ Therefore, it has been recommended to wait 4 weeks before surgery for IE accompanied by neurological complications. However, patients who show exacerbation of the condition while waiting for surgery are often observed. Furthermore, these early studies were retrospective observational studies, without risk stratification, and did not examine the impacts of the presence or absence of symptoms, the size of infarction lesion, and the size of vegetation.^103,174

In recent years, findings about early surgery in cases with neurological complications have been accumulated, and it has been revealed that the prognosis is not as bad as initially anticipated even if early surgery is conducted in cases accompanied by cerebral infarction.^{105,137–140,175–178} When risks were stratified in a prospective multi-center registration study, neither in-hospital mortality nor one-year mortality showed significant exacerbation when early surgery was conducted within 7 days after onset as compared with the cases in which surgery was conducted after that period.¹³⁹ Surgical mortality is high in the cases of cerebral infarction in the middle cerebral arterial region and cerebral infarction accompanied by cerebral hemorrhage, meningitis, and brain abscess; however, early cardiac surgery in the cases of cerebral infarction without these complications showed no significant differences in the incidences of perioperative neurological complications and mortality, as compared with the cases without cerebral infarction.¹³⁷ Several reports have showed that exacerbation of neurological complications after early surgery is rare and recovery is likely if any exacerbation occurs in the cases of cerebral infarction of 15 to 20 mm, in the cases without hemorrhage, and in the cases of asymptomatic or transient ischemic attack.^{105,140,175–178} Magnetic resonance imaging is effective for discovery of asymptomatic cerebral infarction, and its use is recommended.¹⁰⁴ According to a study in Japan, hemorrhagic changes were rare in the group of IE in which cerebral infarction was detected by MRI and early surgery was conducted.¹¹⁸

Only observational studies had been available regarding the usefulness of early surgery for IE, irrespective of the presence or absence of neurological complications. Kang et al. conducted prospective investigation of the usefulness of early surgery conducted within 48 hours for IE accompanied by a vegetation of 10 mm or larger and significant valve dysfunction. As a result, they reported that no significant differences were seen in the mortality, but the number of the cases of embolic events in particular was significantly small in the early surgery group.¹⁷¹ Since approximately 30% of these patients had cerebral infarction as comorbidity, these results seem to support the feasibility of early surgery in the cases of non-severe cerebral infarction.

Considering these results, we concluded that it is not appropriate to postpone surgery in the cases with neurological complications, unless neurological findings are severe (such as coma and brain herniation), if there are indications of early surgery such as heart failure, uncontrolled infection, abscess and huge vegetation accompanying high risks of embolism.

On the other hand, cerebral hemorrhage should be considered separately from cerebral embolism because it has a possibility of exacerbation irrespective of the timing of surgery after onset. Favorable surgical results without postoperative exacerbation of cerebral hemorrhage has been reported when the hemorrhagic focus is 20 to 30 mm or smaller in some reports,^140,179 but others reported early surgery within 7 days after onset was associated with exacerbation of neurological complications, such as enlargement of hemorrhagic focus.¹³⁸ Many reports recommend to wait approximately 4 weeks if cerebral hemorrhage accompanies,^{101,103,179,180} but preceding clipping or craniotomy may enable cardiac surgery to be performed earlier in cases of mycotic aneurysm¹⁸¹ (see “Chapter V. 3. 2. c. Treatment of Neurological Complications”). The risks and conditions of cardiac lesions and cerebral lesions in individual cases should be examined carefully before surgery is performed. Figure 3 shows the treatment algorithm for the cases with neurological complications.

e. Prosthetic Valve Endocarditis (Table 16)

Prosthetic valve endocarditis should be treated with the potential for surgery.^{148–150,182–189} Indication for surgery is considered on the basis of three conditions, i.e., heart failure, uncontrolled infection, and risk of embolism,^148,150,169 similar to native valve endocarditis. Heart failure due to rapidly worsening paravalvular regurgitation or prosthetic valve dysfunction is an indication for urgent surgery.^{147,148,150–152,154–156,160} Emergent or urgent surgery is required in patients with cardiogenic shock, fistula formation, or fluctuation of a prosthetic heart valve. Surgery for such patients improves their prognosis.^148,150

3. Surgical Treatment and Postoperative Management

The objective of surgery for IE is complete elimination of infection foci and tissue reconstruction.⁴ The infection recurrence rate after prosthetic valve replacement is comparable for mechanical valves and bioprosthetic valves.¹⁹⁰ When annular abscess is formed, small cavities can be closed after dissection of infected tissues, but large cavities necessitate drainage into the pericardium or blood flow.⁴

a. Mitral Valve IE

In cases of mitral valve IE, resection and reconstruction of infection foci can be achieved by mitral valve replacement if infection is confined to the valve or a part of subvalvular tissues. However, when durability of prosthetic mitral valves and complications are taken into consideration, mitral valvuloplasty is preferred in many cases. Patch repair with autologous pericardium or heterogeneous pericardium can be used for the lesion of valve perforation, and repair with artificial chordae tendineae can be performed for ruptured chordae tendineae. In the cases of more extensive valve destruction, it is important to judge feasibility of valve repair with residual tissues after dissection of infected tissues. On the other hand, valve replacement and reconstruction of the periannular region are necessary in severe cases in which infection reaches the periannular region to form abscess or the normal anatomic structure has been disrupted. The missing part should be reconstructed with autologous or heterogeneous pericardium after complete resection and dissection of infected tissues.

b. Aortic Valve IE

Replacement is effective when infection is confined to the valve.^191,192 When annular abscess is formed, patch formation after dissection can be conducted if the abscess cavity is small, but drainage into the pericardium should be performed if the abscess cavity is large. In such cases, replacement of the root becomes necessary. When extensive abscess accompanies, simultaneous replacement of the mitral valve can become an option. When the root replacement is performed, no significant differences are observed in the results in the cases using allografts, and the cases using prosthetic valves (bioprosthetic valve and mechanical valve) with Dacron grafts.¹⁹³ Favorable results of Ross surgery have been reported by facilities with good experience.^194,195

c. Postoperative Management

The differences from postoperative management for usual valvular heart disease are that exacerbation or new perioperative neurological complications can be observed, that the incidence of perivalvular regurgitation is high, and that infection as a cause of these complications may persist. The use of a bioprosthetic valve or valvuloplasty not needing anticoagulant therapy should be considered in the patients who have or who may have neurological complications.

VII. Follow-up After Discharge

This section is omitted from the English version.

VIII. Prevention

1. General Remarks on Prevention of IE

The incidence of IE in general population is reported to be 3 to 7/100,000 person-year.⁷³ It has become common to classify the patients with high risk of IE as the highest-risk group who is very likely to lead to serious outcome, including death, once developed IE, and as the moderate-risk group for others.^196–198

Western guidelines are less willing to recommend antibiotic prophylaxis before dental procedures because bacteremia can be induced by daily activities including tooth brushing, and the incidence of IE after dental procedures is extremely low. In particular, the guidelines released by the National Institute for Health and Care Excellence (NICE) in 2008 stated that antibiotic prophylaxis is unnecessary in all kinds of invasive dental procedures (however, the expression was modified in 2016 to that “it is not always unnecessary”).¹⁹⁹ The present guidelines recommend antibiotic prophylaxis for the high-risk patients with IE (both highest-risk and moderate-risk) (see Table 17 and “[CQ 4] Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for the patients with high-risk heart diseases?”). The appropriateness of these recommendations should be continuously verified in epidemiological studies.

Table 17. Risks of Infective Endocarditis in Adults According to Underlying Heart Disease, Recommendations of Antibiotic Prophylaxis During Dental and Oral Surgical Procedures, and Level of Evidence

Risk of IE	Class of recommendation	Level of evidence
1. Highest risk: high incidence, morbidity and mortality of infective endocarditis
• Patients after prosthetic valve replacement (bioprosthetic/mechanical valve), or patients with annular ring • Patients with a previous episode of IE • Patients with complex, cyanotic congenital heart disease (single ventricle, complete transposition of great arteries, tetralogy of Fallot) • Patients underwent shunting between systemic and pulmonary circulation	I	B
2. Moderate risk: lower morbidity and mortality despite high incidence of infective endocarditis
• Most of congenital heart diseases*1 • Acquired valvular heart diseases*2 • Hypertrophic cardiomyopathy with obstruction • Mitral valve prolapse with regurgitation	IIa	C
• Patients with intracardiac devices (pacemaker, implantable cardioverter defibrillator) • Patients with a long-term central venous catheter	IIb	C

See “CQ 4 Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for the patients with high-risk heart diseases?” for details about evaluation of evidence.

*1: Except for simple atrial septal defect (ostium secundum type).

*2: The risk of IE is low in mitral valve stenosis without regurgitation.

IE, infective endocarditis.

Since the level of risk may differ among the diseases classified as moderate-risk of IE, the IE risk of each disease is described for each section in “Chapter VIII. 2. What Types of Patients With Heart Disease Are Likely to Develop IE?” Antibiotic prophylaxis was examined mainly in relation to dental procedures. Other risks in treatment are also stated in “Chapter VIII. 3. Procedures, Treatment, and Background for Risks of IE and Prevention”. Concerning the route of entrance of causative microorganisms for IE, invasion via skin is known to be common.²⁰⁰ It is important to pay attention to the diseases causing decreases in the skin barrier functions, and to keep the skin clean during procedures. The conditions and the methods of prophylaxis are described in each section of “Chapter VIII. 3. Procedures, Treatment, and Background for Risks of IE and Prevention”.

2. What Types of Patients With Heart Disease Are Likely to Develop IE?

a. Patients With Prosthetic Valve or Previous IE

This section is omitted from the English version.

b. Adult Congenital Heart Disease

This section is omitted from the English version.

c. Aortic Valvular Disease

This section is omitted from the English version.

d. Mitral Valvular Disease / Mitral Valve Prolapse

This section is omitted from the English version.

e. Right-Sided Valvular Disease

This section is omitted from the English version.

f. Hypertrophic Cardiomyopathy

This section is omitted from the English version.

g. After Device Implantation

Infection associated with implantable cardiac devices tends to increase in recent years as treatment with devices, such as pacemaker, increases (see “Chapter IX. 2. IE on Cardiac Devices”). According to a cross-sectional study, the incidence of IE in patients with device implantation is estimated to be 40 events/100,000 person-year, which is higher than the incidence in the general population. In the present guidelines, patients after device implantation are classified as being at moderate risk of IE. However, antibiotic prophylaxis before dental procedures, and gastrointestinal and urogenital treatment in the patients with device implantation is not recommended in the guidelines of American Dental Society, American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC).^4,201–203

h. Others

This section is omitted from the English version.

3. Procedures, Treatment, and Background for Risks of IE and Prevention

3.1 Introduction

The procedures for which antibiotic prophylaxis is recommended include invasive dental procedures including scaling, tonsillectomy/adenoidectomy, and implantation of pacemaker and implantable cardioverter defibrillator (ICD).¹⁹⁶ Antibiotics should also be administered before invasive treatment of local infection.¹⁹⁶ Antibiotic prophylaxis is also recommended before surgical implantation of prosthetic valve and other cardiovascular prostheses, and transurethral resection of the prostate (TUR-P) in the patients with prosthetic valve.^204,205 However, it is not recommended for bronchoscopy/laryngoscopy, endotracheal intubation, tympanostomy tube insertion, TEE, gastrointestinal endoscopy, urethral catheterization, transurethral endoscopy, and central venous catheterization.¹⁹⁶ Antibiotic prophylaxis is recommended only in the cases with a history of IE for sclerotherapy for esophageal varices, dilatation of esophageal stenosis, colonoscopic test/treatment, biliary tract surgery, urethral dilatation, vaginal delivery and therapeutic abortion, cardiac catheterization, and skin incision.¹⁹⁶ These are summarized in Table 18.

Table 18. Recommendations of Antibiotic Prophylaxis for High-Risk Patients of Infective Endocarditis and Level of Evidence

Antibiotic prophylaxis	Situation	Class of recommendation	Level of evidence
Antibiotic prophylaxis is strongly recommended	• Dental and oral surgery: All invasive dental procedures causing bleeding and bacteremia (oral surgery such as tooth extraction, periodontal surgery, dental implant surgery, dental scaling, infected root canal treatment etc.) • Otolaryngologic field: Tonsillectomy and adenoidectomy • Cardiovascular field: Implantation of pacemaker and implantable cardioverter defibrillator	I	B
Antibiotic prophylaxis is preferable	• Invasive procedures for local infection foci: Abscess drainage and endoscopic examination and treatment for infection foci (including biliary obstruction) • Cardiovascular field: Implantation of prosthetic valve and other cardiovascular prostheses • Transurethral prostatectomy: Especially patients with prosthetic valve	IIa	C
Antibiotic prophylaxis can be performed. However, antibiotic prophylaxis is recommended for the patients with a history of IE	• Gastrointestinal field: Sclerotherapy for esophageal varices, dilatation of esophageal stenosis, mucosal biopsy or polypectomy by colonoscopy and proctoscopy, and biliary tract surgery • Urogenital/reproductive field: Urethral dilatation, vaginal delivery/vaginal hysterectomy, intrauterine curettage, therapeutic abortion/induced abortion, and insertion and removal of intrauterine devices • Cardiovascular field: Cardiac catheterization/percutaneous intravascular catheter intervention • Skin incision associated with surgery (especially in the patients with atopic dermatitis)	IIb	C
Antibiotic prophylaxis is not recommended	• Dental and oral surgery: Local anesthesia from uninfected site, orthodontic procedures, dental pulpectomy • Respiratory field: Bronchoscopy/ laryngoscopy, endotracheal intubation (transnasal/oral) • Otolaryngologic field: Tube insertion for tympanic perforation • Gastrointestinal field: Transesophageal echocardiography, gastrointestinal endoscopy (including biopsy) • Urogenital field: urethral catheterization and transurethral endoscopy (cystourethroscopy and pyeloureteroscopy) • Cardiovascular field: Central venous catheterization	III	B

IE, infective endocarditis.

3.2 Dental Diseases

a. Anatomy, Pathophysiology, and Situation in Japan

The two major dental diseases are dental caries and periodontal diseases, and are believed to be caused by respective causative oral bacterial species (Figures 4,5). Caries is known to be induced mainly by a type of Gram-positive facultative bacteria, Streptococcus mutans,²⁰⁶ and periodontal diseases are known to be induced by mixed infection with several Gram-negative obligatory anaerobes.²⁰⁷

Figure 4.

Progression of caries and onset of bacteremia.

Figure 5.

Progression of periodontal disease and onset of bacteremia.

Figure 4 schematically shows progression of caries (healthy, and C1 to C4). When dental plaque containing Streptococcus mutans adheres to the surface of the crown, caries begins to develop. When enamel and dentin decay along with progression of caries, tissues called pulp cavity, which are composed of dental pulp (nerves) and capillary vessels, are exposed. Under such a condition, oral bacteria can enter blood flow anytime, and dental pulp infection occurs.

Figure 5 schematically shows progression of periodontal diseases (healthy, gingivitis, and periodontitis). Periodontal disease can be divided mainly into gingivitis and periodontitis. When gingivitis progresses from a healthy state, hemorrhage is induced by stimulation with tooth brush, etc., and oral bacteria become able to enter blood flow. When inflammation progresses even more, ulcers are formed, and oral bacteria become able to enter blood flow easily anytime.

Tooth extraction, oral surgical treatment accompanying bleeding, dental implantation, and removal of dental calculous (scaling) are recognized as the dental procedures causing bacteremia.²⁰⁸ On the other hand, chewing and tooth brushing in daily life may cause bleeding, and bacteremia may be induced.²⁰⁹

When a state susceptible to bacteremia is generated, an environment for the IE-causing microorganisms present in the oral cavity to enter blood flow is established. Most of the causative microorganisms originating from the oral cavity are considered to be oral streptococci.^210,211 As major bacteria, mitis group streptococci, such as Streptococcus sanguinis, are known.²¹² However, it is extremely rare that major causative microorganisms for periodontal disease are isolated from blood of the patients with IE.²¹³

According to a questionnaire survey of general dental practitioners conducted in Japan, only a half of the responders answered that they used antibiotics for the purpose of preventing IE.²¹⁴ Only a half of them mentioned guidelines as the help to be referred to in deciding antibiotic prophylaxis. It is necessary to extensively distribute the guidelines among dentists in the future.²¹⁴

b. Doses of Antibiotics

It has long been suggested that IE can be induced by bacteremia resulting from dental procedures.²¹⁵ The incidence of bacteremia associated with dental procedures is almost 100% for tooth extraction, etc., and it is also high for scaling.²⁰⁸ It can also be induced by chewing and tooth brushing (Table 19).^{208,209,216–220}

Table 19. Incidence of Bacteremia Caused by Oral Procedures

Oral procedure	Incidence (%)
Tooth extraction	18–100
Wisdom tooth extraction	55
Dental scaling	8–79
Periodontal surgery	36–88
Infectious root canal treatment	42
Rubber dam insertion	29
Tooth brushing	23
Chewing	38

(Data summarized from Heimdahl A, et al. 1990,²⁰⁸ Roberts GI, et al. 1992,²⁰⁹ Lockhart PB, et al. 2008,²¹⁶ Hall G, et al. 1999,²¹⁷ Debelian GJ, et al. 1995,²¹⁸ Everett ED, et al. 1977,²¹⁹ and Guntheroth WG. 1984.²²⁰)

The incidence of bacteremia after tooth extraction is known to decrease by antibiotic prophylaxis.²¹⁶ On the other hand, in a model of IE induced by tooth extraction in rats, antibiotics had no impacts on bacteremia after tooth extraction but inhibited the onset of IE. The target of action of antibiotics is assumed to be not only suppression of the bacteremia but also inhibiting adhering ability of bacteria and bacterial growth after adhesion.²²¹

The MIC₉₀ of amoxicillin against oral streptococci isolated from dental infection²²² was 0.25 μg/mL in the anginosus group, and 0.5 μg/mL in the mitis group. On the other hand, the MIC₉₀ of clindamycin for oral streptococci isolated from dental infection was 64 μg/mL, but it was 0.125 μg/mL or lower for 80% of strains. The MIC₉₀ of a macrolide, azithromycin, was high (128 μg/mL). The cumulative curve of drug sensitivity was biphasic, and highly resistant strains were observed.

In antibiotic prophylaxis for oral streptococci, penicillins (amoxicillin, ampicillin, and penicillin V) are the drugs of first choice from antibiotic susceptibility. In cases of allergy to β-lactams (penicillins and cephems), macrolides (clarithromycin or azithromycin) or clindamycin are alternative.

Concerning the choice of antibiotics, AHA recommends single administration of oral medication in order to prescribe by dentists easier.¹⁹⁷ They recommend 2 g oral amoxicillin, because a blood concentration by oral route is comparable to that by intravenous injection and the effect can be maintained over a long period. In animal experiments, re-growth of the bacteria adhering to the vegetation occurs after 6 to 9 hours. Therefore, it is necessary to maintain the blood concentration of antibiotics for long period.²²³

In the present guidelines, single oral administration of amoxicillin 2 g within 1 hour before surgery is recommended (Table 20). Clindamycin, clarithromycin, and azithromycin are recommended in the cases of allergic to β-lactams, and ampicillin, cefazolin, ceftriaxone, and clindamycin are recommended if oral medication is unable to take (Table 20). If the dose of amoxicillin is reduced from 2 g for some reasons, additional administration of amoxicillin should be considered 5 to 6 hours after the first administration for a pharmacological reason to suppress growth of the bacteria adhered to the valve.

Table 20. Recommended Prophylactic Antibiotics Before Dental Procedures (Adults)

Route	Allergic to β-lactam antibiotics	Antibiotics	Dose	Frequency of administration	Remarks
Oral	Absent	Amoxicillin	2 g*1,*2	Single	1 hour before treatment
	Present	Clindamycin	600 mg	Single	1 hour before treatment
		Azithromycin	500 mg
		Clarithromycin	400 mg
Unable to take oral medication	Absent	Ampicillin	1–2 g	Single	Intravenous injection or intramuscular injection within 30 minutes after the start of surgery, or intravenous drip infusion over 30 minutes or more from the start of surgery
		Cefazolin	1 g
		Ceftriaxone	1 g		Intravenous injection within 30 minutes after the start of surgery, or intravenous drip infusion over 30 minutes or more from the start of surgery
	Present	Clindamycin	600 mg	Single	Intravenous injection within 30 minutes after the start of surgery, or intravenous drug infusion over 30 minutes or more from the start of surgery

*1: Or 30 mg/kg body weight.

*2: If the dose of amoxicillin is decreased from 2 g for some reasons, additional administration of 500 mg of amoxicillin should be considered 5 to 6 hours after first dose.

CQ 4 Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for the patients with high-risk heart diseases?

Answer:

(1) Antibiotic prophylaxis is recommended before dental procedures inducing bacteremia, such as tooth extraction, in adult highest-risk patients.*¹

Strength of recommendation 1: Strongly recommended

Strength of body of evidence (moderate)

(2) Antibiotic prophylaxis is proposed before dental procedures inducing bacteremia, such as tooth extraction, in adult moderate-risk patients.*²

Strength of recommendation 2: Weakly recommended (proposed).

Strength of body of evidence C (weak)

*¹Highest-risk group (patients susceptible to infection whose condition becomes severe easily) includes 1) the cases after prosthetic valve surgery, 2) history of IE, 3) unrepaired cyanosis type congenital heart disease including the cases using palliative anastomosis and artificial blood vessels, 4) within 6 months after the repair of congenital heart disease using artificial materials regardless of surgery or catheterization, 5) cases accompanying residual lesions at the repair site in spite of repair with patch or artificial materials, and 6) aortic coarctation.

*²Moderate-risk group (patients whose condition is not always serious but who are likely to show endocarditis) includes congenital heart diseases other than highest- and low-risk, hypertrophic obstructive cardiomyopathy, and mitral valve prolapse accompanying valvular regurgitation.

[Related section] “Chapter VIII. 1. General Remarks on Prevention of IE”, Table 18

Commentary:

Antibiotic prophylaxis for IE in dental procedures has been recommended in guidelines since 1950s,¹⁹⁷ but there is no definite evidence for efficacy of antibiotic prophylaxis. Cochrane Review in 2013 also concluded that no evidence was observed for efficacy of antibiotic prophylaxis.²²⁴ Concerns about the allergic reaction induced by antibiotic prophylaxis and emergence of resistant bacteria have also been mentioned. Reflecting these concerns, antibiotic prophylaxis in dental procedures has been reconsidered in the United States and Europe.^{197–199,225} As described in a different section, there are heart diseases with higher risk of IE than usual population. Among the patients with high risks of IE, it has been accepted to differentiate the patients who are likely to have a serious outcome, including death, after the onset of IE (highest-risk group) from other patients (moderate-risk group).^196–198 The guidelines issued in France in 2002,¹⁹⁸ in the United States in 2007,¹⁹⁷ and in Europe in 2009²²⁵ did not recommend antibiotic prophylaxis for the moderate-risk group but continuously recommended it for the highest-risk group. On the other hand, the recommendations by NICE in the United Kingdom in 2008 advised that antibiotic prophylaxis is not recommended for all patients including the highest-risk group.¹⁹⁹ Under such circumstances, the previous guidelines in Japan continued to recommend antibiotic prophylaxis.¹⁹⁶ In the present revision, a new recommendation has been generated on the basis of review of documents issued after revision of various guidelines in the 2000s.

The articles searched by systematic review and used for the present guidelines can be divided into three groups. The first is case control studies conducted before revision of the guidelines, which examined the presence or absence of antibiotic prophylaxis in the patients with and without IE.^226–228 The second group is reports on the changes in the incidence of IE in foreign countries before and after revision of the guidelines.^66,229–238 The third one is others, which includes a survey on the awareness of medical doctors and dentists about the guidelines,²³⁹ details about the cases in which IE occurred in spite of antibiotic prophylaxis,²⁴⁰ incidences of adverse reactions including allergy to antibiotics,²⁴¹ and estimated data on IE which is believed to have been prevented by antibiotic prophylaxis and their economic analyses.^242,243

Three articles are listed as case control studies.^226–228 Some reports found association between the onset of IE and antibiotic prophylaxis,²²⁷ while other reports did not find any association.^226,228 There are some limitations because of the method of subject registration or retrospective study design, and it is difficult to draw conclusions regarding antibiotic prophylaxis from these studies.

Articles of the second group, i.e., articles on the changes in the incidence of IE before and after changes of various guidelines, can be further divided into two subgroups. One is the studies conducted before and after discontinuation of antibiotic prophylaxis in all patients with heart diseases in the United Kingdom,^230,231 and the other is the studies conducted in the United States and Europe other than the United Kingdom, in which antibiotic prophylaxis was continued in the highest-risk group and was discontinued in the moderate-risk group.^{66,229,232–238} In the former type, the changes of the number of prescriptions of antibiotics before and after the guidelines were recorded because of the insurance system in which the advice from NICE is linked with payment of medical expenses. For the latter, no clear data are available regarding to which extent the changes in the guidelines were complied with.

After the changes of the guidelines, the number of cases of antibiotic prophylaxis decreased dramatically in the United Kingdom.^230,231 While no change was observed in the incidence of IE at first,²³¹ a slight, but statistically significant increase in the incidence of IE was observed as of 5 years after the changes of the guidelines.²³⁰ Because of the nature of observational studies, it is impossible to demonstrate the causal relationship between the decrease of antibiotic prophylaxis and the increase in the incidence of IE. Moreover, it needs to be kept in mind that spontaneous increases of IE over time regardless of the changes of the guidelines have been reported. However, temporal agreement was observed between the changes of the guidelines and the increase in the incidence of IE. Moreover, increases in the number of IE were observed not only in the highest-risk group but also in the groups with moderate or lower risk.²³⁰

The results from the United States and Europe other than the United Kingdom showed no consistent tendency in the increase or decrease in the incidence of IE before and after changes of the guidelines.^{66,229,232–238,244} For all of these results, the data regarding whether or not the amount of antibiotics prescribed decreased after revision of the guidelines are missing. Articles on the increase of IE before and after revision of the guidelines include reports on the increase of IE induced by oral streptococci, and a causal relationship with the presence or absence of antibiotic prophylaxis in dental procedures is suggested.²³² On the other hand, another article suggests that IE induced by streptococci has not increased or has rather decreased, and thus consensus has not been achieved.^235,244 The difference from the report from the United Kingdom may support the policy to continue antibiotic prophylaxis limited to the highest-risk group. However, it is also possible that the changes of the guidelines did not sufficiently modify the behaviors of physicians and dentists in the fields.²⁴⁵ In the United Kingdom, the awareness of the guidelines was high but the compliance rate was not as high as the awareness, and many physicians were thought to have continued antibiotic prophylaxis in spite of the new guidelines.²³⁹ This may be a reason why the increase of IE after the release of the guidelines remained small.

Antibiotic prophylaxis may not be able to prevent IE in some cases.²⁴⁰ Moreover, an estimation shows that antibiotic prophylaxis can prevent IE in only a very small number of cases.²⁴² However, since IE causes a serious outcome once it has occurred, the effect on the patients’ life and economic impact are great even if the number of cases of successful prevention is very small.²⁴³ On the other hand, adverse events caused by antibiotic prophylaxis for IE have been extremely rare.²⁴¹

On the basis of the above considerations, the present guidelines recommend antibiotic prophylaxis for the highest-risk group. Moreover, considering the results showing that IE increased also in the patients at moderate or lower risk after discontinuation of antibiotic prophylaxis in the United Kingdom, and that IE induced by streptococci, which is resident bacterial flora in the oral cavity, increased in the United States and Europe other than the United Kingdom, the present guidelines also suggest antibiotic prophylaxis for the moderate-risk group. The number of patients with heart diseases classified into the moderate-risk group is huge, and cost-effectiveness of conducting antibiotic prophylaxis in all patients has not been established. However, once IE occurs, it may lead to hospitalization, surgery, cerebral infarction or death, and the impact on individual patients is tremendous. Although the possibility of leading to a serious outcome after the onset of IE is not very large in the moderate-risk group, it is advisable to decide to prescribe antibiotic prophylaxis for each patient on the basis of thorough discussion with the patient. Adequate measures for preventing IE other than antibiotic prophylaxis, including maintenance of oral hygiene, and education for early detection are also important. We hope that this recommendation further improves the awareness of patients and health professionals about IE and its prevention.

3.3 Skin Disease

This section is omitted from the English version.

3.4 Steroid Usage

This section is omitted from the English version.

3.5 Pneumonia and Other Remote Site Infection

This section is omitted from the English version.

3.6 Chronic Central Venous Catheter

This section is omitted from the English version.

3.7 Catheterization and Intracardiac Device Implantation

This section is omitted from the English version.

3.8 Prevention Before Respiratory, Esophageal, Gastrointestinal, Genitourinary Procedures

This section is omitted from the English version.

3.9 Cardiac Surgery

This section is omitted from the English version.

3.10 Education on IE in High-Risk Patients and Education on Measures for Coping With Pyrexia

Moderate-risk or highest-risk patients should be instructed to voluntarily report to medical personnel that they have a risk of IE. Attending physicians need to notify to the patients the name of the underlying heart disease, presence or absence of intracardiac prostheses or pacemaker, and necessity of antibiotic prophylaxis. It is recommended to distribute a document like the one shown in Table 21 to patients.

Table 21. Example of Document to be Distributed to High-Risk Patients for IE

You have a heart disease which is prone to infective endocarditis (a condition in which bacteria growth on the valves and inner membranes inside the heart, and induce high fever, heart failure, brain stroke, and so on)

Therefore,

1. Appropriate prevention is necessary when you have your tooth extracted or pyorrhea incision. Be sure to notify it to your dentist and ask for appropriate prophylactic treatment 2. If you leave pyorrhea or dental caries reaching the tooth root untreated, you easily get infective endocarditis. You should consult dentists for regular check-up of your oral condition 3. Keep your mouth clean by regular tooth brushing and care of the gums, and receive appropriate guidance from dentists 4. Some procedures and surgery may cause infective endocarditis. Before the procedure or surgery, please inform your physician that you are prone to infective endocarditis 5. Do not take oral antibiotic drugs carelessly when you have high fever, when you cannot identify the cause of the fever, or when the fever cannot be resolved immediately. Consult with your cardiologist in such cases

IE, infective endocarditis.

Moderate-risk or highest-risk patients should be instructed to consult a medical institution if pyrexia persists for 4 days or longer. The usefulness of oral antibiotics in the case of pyrexia is unclear, and it may lower the detection rate on blood culture.

Daily oral and skin hygiene control is important for prevention of infection. It is also necessary to encourage them to visit dentists so that they can receive information regarding appropriate oral hygiene control. Since IE in the patients with atopic dermatitis becomes severe,²⁴⁶ consultation with dermatologists should also be considered.

IX. Management of Specific Situations

1. Congenital Heart Disease and Pediatric IE

1.1 General Remarks on Congenital Heart Disease and Pediatric IE

While the incidence of IE in general pediatric population is 0.34 to 0.64 per 100,000 person-year, which is lower than that in adults. However, the incidence becomes higher, 41 per 100,000 person-year, in the population with congenital heart disease. The percentage of the patients with congenital heart disease in the entire pediatric patients with IE is 30 to 80%.^247–249

The risks of IE in pediatric patients are (1) presence of congenital heart disease, (2) abnormal hemodynamics sustained after the surgical repair of congenital heart disease, and the presence of prostheses used in surgery, such as prosthetic valve and patch, (3) catheter placement in surgery, (4) decreased immune defense mechanism, and (5) susceptibility to infection with Staphylococcus aureus.^197,250

The reasons for high risks of IE in patients with congenital heart disease are that they are susceptible to intimal damage caused by disturbed blood flow and jet lesion, and that bacteria are likely to adhere to the surface of prostheses used in surgical operation. Among disease groups, the higher incidence of IE is found in cases with heterotaxy syndrome especially in asplenia (right isomelism) which is prone to Streptococcus pneumoniae infection.^{248,249,251–255}

The most common causative microorganisms in pediatric cases is Staphylococcus aureus, followed by VGS and CNS in this order. Beyond that Staphylococcus aureus infection is common, the condition tends to become severe in pediatric age. Infection of placed catheter and nosocomial infection may also be caused by gram-negative bacteria and fungi.^4,197,256

1.2 Risks According to Underlying Heart Disease

In the AHA Guidelines,¹⁹⁷ the group in which complications are likely to occur and the mortality rate is high is defined as the highest risk, and antibiotic prophylaxis is recommended only for this group. On the other hand, “Management and Prevention of Infective Endocarditis in Congenital Heart Disease and Pediatric Cardiac Disease” issued by the Japanese Society of Pediatric Cardiology and Cardiac Surgery²⁵⁰ classified the risks for each underlying heart disease into three groups, highest-risk, moderate-risk, and low-risk. Highest-risk is a group in which the condition is likely to occur and is likely to become severe, moderate-risk is a group in which the condition is likely to occur but the risk of becoming severe is low, and low-risk is a group in which the risk is almost the same as in the cases without the disease. Thus, antibiotic prophylaxis is recommended in the highest-risk and moderate-risk groups.²⁵⁰ This is because many of the patients with IE occurred after dental procedures were in the moderate-risk group according to the national survey in Japan.

In this revision, the risk classification of the Japanese Society of Pediatric Cardiology and Cardiac Surgery was followed, and antibiotic prophylaxis in dental procedures was strongly recommended for the highest-risk group, and weakly recommended for the moderate-risk group (Table 22) (Also see “[CQ 5] Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for pediatric/congenital heart diseases?”). Bicuspid aortic valve theoretically has a risk of IE if mild eccentric regurgitation is present even if stenosis is absent.

Table 22. Risks of Infective Endocarditis in Pediatric/Congenital Heart Disease According to Underlying Heart Disease, Recommendations of Antibiotic Prophylaxis During Dental and Oral Surgical Procedures, and Level of Evidence

Risk of infective endocarditis	Class of recommendation	Level of evidence
1. Highest risk: high incidence, morbidity and mortality of infective endocarditis
• After prosthetic valve surgery • History of IE • Unrepaired cyanosis type congenital heart disease including palliative anastomosis and use of artificial blood vessels • Within 6 months after the repair of congenital heart disease using artificial materials regardless of surgery or catheterization • Cases accompanying residual lesions at the repair site in spite of repair with patch or artificial materials • Aortic coarctation	I	B
2. Moderate risk: lower morbidity and mortality despite high incidence of infective endocarditis
• Congenital heart diseases except for those in the highest-risk group and the low-risk group (including bicuspid aortic valve) • Hypertrophic cardiomyopathy with obstruction • Mitral valve prolapse with regurgitation	IIa	C
3. Low risk: No particular risk of infection, and almost the same risk of infection as ordinary people
• Isolated atrial septal defect of ostium secundum type • Repaired ventricular septal defect or patent ductus arteriosus 6 months after surgery and without residual shunt • After coronary artery bypass surgery • Mitral valve prolapse without valvular regurgitation • Physiological, functional or innocent cardiac murmur • History of Kawasaki disease without valve dysfunction	III	C

See “CQ 5 Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for pediatric/congenital heart diseases?” for details about evaluation of evidence. IE, infective endocarditis.

In the national survey of the Japanese Society of Pediatric Cardiology and Cardiac Surgery, 170 pediatric patients with IE included 23 patients who did not show underlying heart disease (14%).^250,251 Therefore, IE should be considered in differential diagnosis in the cases of pyrexia of unknown causes even if underlying heart disease is absent.

1.3 Diagnosis

a. General Remarks on Diagnosis of Congenital Heart Disease and Pediatric IE

The modified Duke criteria for diagnosis (Table 4) is widely used in clinical settings because the sensitivity of diagnosis exceeds 70% even in pediatric cases although the early diagnostic accuracy is low.^250,257 In imaging for diagnosis, not only TEE but also MRI, CT, and PET should be considered as useful modalities for pediatric cases.^4,257,258 It is also a key to improve the accuracy and the detection rate of blood culture in pediatric cases, by setting the proper timing, method, frequency, number of specimens of blood sampling as well as the storing method during sample transportation until conduct of the culture test.

b. Symptoms

This section is omitted from the English version.

c. Blood Culture

This section is omitted from the English version.

d. Echocardiography

This section is omitted from the English version.

e. Other Imaging Diagnosis

This section is omitted from the English version.

f. Evaluation of Complications (Heart Failure, Perivalvular Abscess, Embolism and Intracranial Complications)

This section is omitted from the English version.

1.4 Treatment

a. Medical Treatment

The recommendations for adults should be basically followed in the choice of antibiotics in pediatric cases. Recommendations of antibiotic treatment in pediatric cases are shown in Table 23.

Table 23. Recommendations of Antibiotics in Pediatric Infective Endocarditis and Level of Evidence

Causative microorganisms	Antibiotics	In the case of allergy to penicillin	Administration period (weeks)	Class of recommendation	Level of evidence
Viridans group streptococci, Streptococcus bovis, enterococci (if sensitive)	PenicillinG±Gentamicin	Vancomycin	PenicillinG: 4–6 Gentamicin: 2 Vancomycin: 4–6	I	B
	Ampicillin±Gentamicin	Vancomycin	Ampicillin: 4 Vancomycin: 4–6	I	C
Staphylococcus aureus (methicillin-sensitive)	Cefazolin±Gentamicin	Vancomycin	Cefazolin: 6–8 Gentamicin: 2 Vancomycin: 6–8	IIa	C
Staphylococcus aureus (methicillin-resistant)	Vancomycin (or Teicoplanin)± Gentamicin		Vancomycin: 6–8 Gentamicin: 2 Teicoplanin: 6–8	I	B
	Daptomycin		Daptomycin: 6–8	IIb	C
Gram-negative bacteria, Enterobacteriaceae	Broad-spectrum cephems (cefepime, cefotaxime, ceftazidime, ceftriaxone) +gentamicin		Broad-spectrum cephems: ≥6	IIb	C
Haemophilus (HACEK)	Ceftriaxone		Ceftriaxone: 4–6	I	C
	Ampicillin+gentamicin		Ampicillin: 4–6 Gentamicin: 2	I	C
Blood culture negative (postoperative cases)	Vancomycin±gentamicin		Vancomycin: 6–8 Gentamicin: 2	IIb	C
Blood culture negative (non-postoperative cases)	Cefazolin+gentamicin ±penicillin G		Cefazolin: 6–8 Gentamicin: 2 Penicillin G: 6–8	IIb	C
Fungi	Lipoid amphotericin B		Lipoid amphotericin B: 8	I	C

Daily dose for children with normal renal functions

Ampicillin: 50 mg/kg per dose, 4 to 6 times daily

Gentamicin*: 1 to 2.5 mg/kg per dose, 3 times daily

Sulbactam/ampicillin: 50 mg/kg per dose, 4 to 6 times daily

Cefazolin: 25 mg/kg per dose, 4 times daily

Cefepime: 50 mg/kg per dose, 3 times daily

Cefotaxime: 50 mg/kg per dose, 4 times daily

Ceftazidime: 50 mg/kg per dose, 3 times daily

Ceftriaxone: 50 mg/kg per dose, twice daily

Daptomycin: 6 mg/kg per dose, once daily (in the case of MRSA, 6 to 10/kg per dose, once daily)

Teicoplanin**: 10 mg/kg is administered three times at 12-hour intervals, followed by intravenous drip infusion of 10 mg/kg, once daily, over 30 minutes or more. Neonates are treated with intravenous drip infusion at the dose of 16 mg/kg only at the first dose, followed by drip infusion at the dose of 8 mg/kg/ over 30 minutes or more.

Vancomycin*: 15 to 20 mg/kg per dose, 4 times daily (younger than 13 years), intravenous drip infusion over 1 hour

Penicillin G: 50,000 unit/kg per dose, 4 to 6 times daily

Rifampicin: 8 to 10 mg/kg per dose, twice daily

Lipoid amphotericin B: 2.5 to 5 mg/kg per dose, once daily

*Blood concentrations should be determined periodically for gentamicin and vancomycin (TDM: Therapeutic drug monitoring), and the doses and administration should be planned.

**Since the half-life of teicoplanin is long (approximately 50 hours), TDM should aim at the peak of approximately 40 μg/mL and the trough of approximately 20 μg/mL (25 μg/mL, if possible).

IE, infective endocarditis.

For IE caused by streptococci, the guidelines of the Japanese Society of Pediatric Cardiology and Cardiac Surgery²⁵⁰ recommends concomitant administration of penicillin G and aminoglycoside if the strain is non-sensitive to penicillin G (benzylpenicillin). The statement of AHA²⁵⁷ recommends administration of penicillin G alone or ceftriaxone alone to avoid adverse reactions to aminoglycosides in the cases sensitive to penicillin.

Although IE caused by enterococci is not common in pediatric patients, concomitant administration of penicillin and gentamicin is recommended in the case of strains sensitive to penicillin.²⁵⁷ Involvement of specialists of infection is desired in cases of resistant strains.

As antibiotic treatment for staphylococci, the AHA Statement recommends penicillin G for the strains sensitive to penicillin G, penicillinase-resistant penicillin (oxacillin and cloxacillin) for resistant strains, vancomycin for methicillin-resistant strains (so-called MRSA), and daptomycin for vancomycin-resistant strains. The guidelines of the Japanese Society of Pediatric Cardiology and Cardiac Surgery recommends cefazolin for methicillin-sensitive strains, and vancomycin for methicillin-resistant strains. Among the cases of MRSA infection, concomitant administration of anti-MRSA drug and other antibiotics such as rifampicin should be considered for IE in the prosthetic valve and the cases refractory to early treatment.⁴¹

For antibiotic treatment in the cases negative on blood culture, the recommendations of the Japanese Society of Pediatric Cardiology and Cardiac Surgery should be followed. The AHA Statement recommends concomitant administration of sulbactam/ampicillin and gentamicin instead of cefazolin for non-postoperative cases of IE negative on blood culture.

b. Surgical Treatment

This section is omitted from the English version.

1.5 Prevention

a. Treatment Necessitating Prophylactic Measures and Current Status

The dental procedures necessitating prophylactic measures in the field of pediatrics are basically the same as the dental procedures for adults, although there are some unique points.²⁵⁰ Generally, the dental procedure which is most likely to induce bacteremia is tooth extraction. However, extraction of a primary tooth, which accompanies absorption of the root of the tooth, is not so invasive as extraction of a permanent tooth. Moreover, although bleeding may be observed when a primary tooth falls off, bacteremia is not considered in usual cases.²⁵⁹

In March 2017, a questionnaire survey was conducted among all members with cooperation of the Japanese Society of Pediatric Dentistry.²⁶⁰ The results suggested that the dental procedure which may become a risk of IE is recognized on the basis of the degree of bacteremia, which is assumed to be induced by each treatment.

b. Recommended Prophylactic Measures and Recurrent Status

Table 24 shows the type and dose of antibiotics used in antibiotic prophylaxis for pediatric patients.^259,261 The guidelines state that amoxicillin should be selected for the cases in which oral administration is possible, and that the drug should be orally taken at the dose of 50 mg per kg body weight (2 g at maximum) 1 hour before the procedure. How the antibiotics are used is discussed in detail in the section for adults.

Table 24. Recommended Antibiotic Prophylaxis Before Dental Procedures (Children)

Route	Allergy to β-lactam antibiotics	Antibiotics	Dose	Frequency of administration	Remarks
Oral administration is possible	Absent	Amoxicillin	50 mg/kg (2 g at maximum)	Single	1 hour before treatment
	Present	Clindamycin	20 mg/kg (600 mg at maximum)	Single	1 hour before treatment
		Azithromycin	15 mg/kg (500 mg at maximum)
		Clarithromycin	15 mg/kg (400 mg at maximum)
Oral administration is impossible	Absent	Ampicillin	50 mg/kg (2 g at maximum)	Single	Intravenous injection or intramuscular injection within 30 minutes after the start of surgery, or intravenous drug infusion over 30 minutes or more from the start of surgery
		Cefazolin	50 mg/kg (1 g at maximum)
		Ceftriaxone	50 mg/kg (1 g at maximum)		Intravenous injection within 30 minutes after the start of surgery, or intravenous drug infusion over 30 minutes or more from the start of surgery
	Present	Clindamycin	20 mg/kg (600 mg at maximum)	Single	Intravenous injection within 30 minutes after the start of surgery, or intravenous drug infusion over 30 minutes or more from the start of surgery

The prevalence of neonatal heart diseases in Japan is reported to be approximately 1 out of 100 patients,²⁶² and general dental practitioners have many chances to encounter pediatric patients with a risk of IE. Further educational activities about the guidelines are important in order to enable all pediatric patients with a risk of IE to receive dental procedures with appropriate prevention of IE.

CQ 5 Is antibiotic prophylaxis necessary for prevention of IE in dental procedures for pediatric/congenital heart diseases?

Answer:

(1) Antibiotic prophylaxis is recommended before dental procedures inducing bacteremia, such as tooth extraction, in highest-risk patients with pediatric/adult congenital heart disease.*¹

Strength of recommendation 1: Strongly recommended

Strength of body of evidence C (weak)

(2) Antibiotic prophylaxis is proposed before dental procedures inducing bacteremia, such as tooth extraction, in moderate-risk patients with pediatric/adult congenital heart disease.*²

Strength of recommendation 2: Weakly recommended (proposed).

Strength of body of evidence C (weak)

*¹The highest-risk group (patients susceptible to infection whose condition becomes severe easily) includes the patients who have received bioprosthetic valve, prosthetic valve replacement including bioprosthetic valve and allogeneic valve, patients with a history of IE, complex, cyanotic congenital heart disease, and patients created shunts between systemic and pulmonary circulation.

*²Moderate-risk group (patients whose condition is not always serious but who are likely to show endocarditis) includes most congenital heart diseases, acquired valvular diseases, hypertrophic obstructive cardiomyopathy, and mitral valve prolapse accompanying valvular regurgitation

[Related section] “Chapter IX. 1. 2 Risks According to Underlying Heart Disease”, Table 22

Commentary:

There have been no randomized studies to conclude this question. Moreover, it is difficult to expect that a meaningful randomized study is conducted in the future because the incidence of the condition is low. After revision of the AHA Guidelines in 2007, antibiotic prophylaxis for IE was completely discontinued or was changed to the policy to administer the drugs only to highest-risk patients.^197,199 Recently, the late-phase outcomes in adults after revision of the AHA Guidelines in 2007 have been reported. As described in the section for adults, the number of cases of IE increased in the United Kingdom after revision of the guidelines.²³⁰ On the other hand, the risk of serious adverse reactions caused by a single dose of antibiotic prophylaxis is extremely low.²⁴¹ Considering these results, the present guidelines recommend antibiotic prophylaxis in dental procedures for adult highest-risk patients, and weakly recommends it to moderate-risk patients.

Concerning the changes of the incidence of IE after modification of the guidelines, the present systematic review found only two reports each from the United States and Canada regarding the study focused on pediatric/congenital heart disease.^237,263 Moreover, the results did not demonstrate increases of IE after modification of the guidelines. However, these are not considered to demonstrate the uselessness of antibiotic prophylaxis for pediatric/congenital heart disease. According to a study using the database of the Canadian Institute for Health Information, inpatients with IE of the age younger than 18 years accounts for only 2.4% of all inpatients with IE, and there have been no reports of statistical analysis focused on the changes in the number of inpatients with IE aged younger than 18 years.²³⁷ A study from the pediatric database in the United States incorporated only the data until the third year after modification of the guidelines, and it is considered to be too early to draw any conclusions.²⁶³ Even after the modification of the AHA Guidelines, changes in the behaviors for antibiotic prophylaxis in actual clinical settings were not marked.²⁶⁴

Because congenital heart disease is common among pediatric patients with IE and is likely to become serious, prophylaxis is believed to be more important than in adults.²⁶⁵ Moreover, considering the reports that antibiotic prophylaxis in pediatric patients reduces bacteremia in tooth extraction,^266–271 it has been decided to continue recommendation of antibiotic prophylaxis for the pediatric patients except for those in the low-risk group. It is strongly recommended for the highest-risk group, and weakly recommended for the moderate-risk group.

2. IE on Cardiac Devices

Along with the development of various cardiac implantable electronic devices (CIEDs) and the increasing number of patients with CIED, infection of CIED continues to increase every year.^272,273 Since CIED infection can often become serious and fatal,²⁷⁴ early diagnosis and appropriate decision of the treatment strategy are important.

a. Definition

Device-related infection can be classified into local device infection and cardiac device-related IE (CDRIE).⁴ Local device infection is the infection localized to the pocket of the cardiac device, and local clinical findings of inflammation are present at the device implantation site.²⁷⁵ On the other hand, CDRIE is a condition in which infection reaches the leads or endocardium including the cardiac valve leaflets.

b. Pathophysiology

The main route of CIED infection is the pocket infection during the process of implantation surgery, or percutaneous infection via the part where the device or the electrodes are exposed to skin surface. When inflammation reaches the cardiac chamber from the pocket infection via the intravascular portion of the electrode, IE occurs. The pocket infection or infection in the intravascular portion of the electrode can also occur in a secondary manner as a result of the bacteremia from the distant infected foci. Vegetation induced by IE can occur at any sites in the superior vena cava, tricuspid valve, right atrial wall, and right ventricular wall from the insertion vein. Septic pulmonary embolism is a frequent complication in association with the formation of vegetation.^276,277 but it is often asymptomatic.²⁷⁸ The most common causative microorganisms is staphylococci in CDRIE.^279,280 Polymicrobial infection is also sometimes identified as causative microorganisms.^280–282

c. Diagnosis

The most important thing is to suspect CIED infection first and perform necessary examinations when unexplained fever is observed in the patients with CIED. On the other hand, fever is often blunted in CDRIE, particularly in elderly patients. Thus, attention should also be paid to laboratory tests including the white blood cell count and increases of CRP. It should be noted that CDRIE may develop with respiratory symptoms or chest pain induced by septic pulmonary embolism.

Similarly to other cases of IE, diagnosis of CDRIE is based mainly on blood culture and echocardiography. Echocardiography is useful for evaluation of vegetation adhered to the electrodes and in the cardiac chambers. While TEE is considered to be superior to TTE in diagnosing CDRIE,^282–285 better images may be obtained by TTE in some cases. Therefore, it is recommended to combine TTE and TEE for evaluation of vegetation. On the other hand, in some cases, vegetation may not be detected because of artifacts even if these two methods are used, or vegetation may not be evaluated adequately because it is located along the lead course.^286–288 Intracardiac echocardiography is effective in such cases. If vegetation cannot be ruled out by these echocardiographic tests, labeled leukocyte scintigraphy²⁸⁹ and ¹⁸F-FDG PET/CT are reported to be useful for the diagnosis in CDRIE suspected cases.^37,289,290 Positive culture of intravascular electrode may support the diagnosis of CDRIE; however, the possibility of a pseudo-positive culture result cannot be ruled out, due to contamination from the skin or the wound site during the removal procedure of the lead. Using aforementioned imaging modalities enables evaluation of the location of inflammation in the lead, cardiac chamber or septic pulmonary embolism.^37,290,291

d. Treatment Strategy

The essential treatment strategy in CDRIE is continuous antibiotic therapy and complete removal of CIED including the leads. Antibiotic therapy should be started after blood culture and before removal of the device, and should be continued for at least 2 weeks, or for 4 to 6 weeks, if necessary, after removal of the device.⁴

Table 25 shows the indication of CIED removal. Complete removal of CIED including the leads is recommended for all patients diagnosed as CDRIE (class of recommendation I). Medical treatment alone in CDRIE without removal of CIED is associated with high risk of recurrent IE and poor prognosis.^292–294 On the other hand, removal of CIED by open heart surgery involves a high risk of perioperative mortality.²⁸¹ Thus, percutaneous lead extraction with limited risks is recommended in the removal of infected CIED^295–297 (Table 26). In cases more than 1 year after device implantation, percutaneous lead extraction by simple manual traction may be difficult because of strong adhesion of the lead to veins or myocardium or adhesion of multiple leads. In such cases, percutaneous extraction using excimer laser may be effective.^298–300 Since percutaneous extraction of CIED may induce complications such as postoperative cardiac tamponade, it should be performed at experienced centers where sufficient surgical back-up is available in the cases of emergency²⁹⁵ (Table 26).

Table 25. Recommendations for Device Removal in CIEDs Infection

	Class of recommendation	Level of evidence
Complete removal of the device is recommended in patients diagnosed as definite CDRIE	I	C
Complete removal of the device is recommended in patients diagnosed as device local infection	I	C
Complete removal of the device should be considered in patients in whom CIEDs infection is strongly suspected and without other apparent sources of infection	IIa	C
Complete removal of the device may be considered in patients in whom IE infection of native valve or prosthetic valve was diagnosed but CEIDs infection is not definitive	IIb	C

CIEDs, cardiac implantable electronic devices; CDRIE, cardiac device-associated IE.

Table 26. Recommendations for Method of Device Removal for CIEDs Infection and Level of Evidence

	Class of recommendation	Level of evidence
Percutaneous extraction of the device including the lead is recommended in patients diagnosed as CDRIE (including the cases with vegetation of 10 mm or larger)	I	B
Percutaneous extraction of the device including the lead is recommended in patients diagnosed as device local infection	I	C
Percutaneous extraction of the device should be performed at experienced centers where sufficient surgical back-up is available	I	B
Surgical removal of the device should be considered in patients diagnosed as CDRIE if percutaneous extraction of the device is expected to be difficult or impossible	IIa	C
Surgical removal of the device should be considered in patients diagnosed as CDRIE if concomitant surgical repair is required for destruction of valves or cardiac chambers	IIa	C
Surgical removal of the device may be considered in patients diagnosed as CDRIE with large vegetation of 20 mm or larger one	IIb	C

CIEDs, cardiac implantable electronic devices; CDRIE, cardiac device-associated IE.

Surgical removal of CIED should be considered if percutaneous extraction is expected to be difficult or impossible. It also should be considered if concomitant surgical repair is required for destruction of valves or cardiac chambers. Since the patients having large vegetation are at a high risk of pulmonary embolism at percutaneous extraction,^276,301 surgical resection of vegetation may be considered at the same time with surgical removal of CIED. On the other hand, septic pulmonary embolism is clinically asymptomatic in many cases,²⁷⁸ and clinical evidence is limited regarding the specific size of vegetation requiring surgery. Therefore, the present guidelines recommend surgical removal as Class IIb in the cases with a vegetation of 20 mm or larger and recommended percutaneous extraction as Class I in the cases with a vegetation of smaller than 20 mm according to the guidelines of ESC.⁴ However, surgical risk greatly depends on the individual condition of patients. It is essential to determine the method of device removal considering the procedural risks in each case.

e. Timing of Re-Implantation of Device

Past history of CIED infection is associated with a high risk of recurrent device infection after re-implantation of the device. Therefore, clinical indication of CIED re-implantation should be carefully evaluated after removal of the device^275,296 (Table 27). Re-implantation should be performed at a timing when adequate infection control is obtained by antibiotic therapy. The device should be re-implanted on the contralateral side of the site of device infection. Surgical device implantation using the epicardial lead may be useful for preventing recurrence of infection. Leadless pacemaker is one of the options in the cases in which the risk of recurrence of pocket infection is high and VVI mode is indicated.^301,302 Temporal pacing can become a risk factor for subsequent infection of re-implanted device³⁰³ and should be avoided if possible.

Table 27. Recommendations for Re-Placement of CIEDs After Device Removal and Level of Evidence

	Class of recommendation	Level of evidence
Clinical indication of the device implantation should be carefully re-evaluated after removal of the device	I	C
If re-implantation of the device is considered to be necessary, antibiotic therapy should be continued and device implantation should be conducted after confirming that blood culture is negative and findings of inflammation have subsided	IIa	C
In patients requiring re-implantation of the pacemaker, the temporal pacing on the contralateral side may be considered until re-implantation	IIb	C
Routine temporal pacing is not recommended after removal of the infected device	III	C

CIEDs, cardiac implantable electronic devices.

3. Right-Sided IE

This section is omitted from the English version.

4. IE in Pregnancy

While IE associated with pregnancy is extremely rare, the mortality rate of pregnant women and fetuses is very high.⁴ The risk factors for IE in pregnancy are maternal congenital heart disease and rheumatic heart disease. In Western countries, intravenous drug user is listed as a risk factor.³⁰⁴

Guidelines in Japan and abroad recommend antibiotic prophylaxis before delivery for pregnant women at high risk for IE.^305,306 See “Guidelines for Indication and Management of Pregnancy and Delivery in Women with Heat Disease”³⁰⁶ of The Japanese Circulation Society for specific prophylactic methods.

5. Non-Bacterial Thrombotic Endocarditis

This section is omitted from the English version.

6. IE in Elderly Patients

IE in elderly patients tends to increase.³⁰⁷ It is slightly more dominant in men, and infection with Staphylococcus aureus and healthcare-associated IE are common.³⁰⁷ The intestinal and urinary tract infections are likely to become the portal of entry of causative microorganisms.^308,309 Since symptoms are atypical, the thresholds for blood culture and echocardiography could be set low. Vegetation is often small, and concurrent embolism is less frequent.³¹⁰ The lesion is often difficult to visualize on echocardiography because of calcification of the valve. Since it has been reported that vegetation is small in IE in elderly patients and abscess is likely to occur concomitantly, TEE may be more useful than TTE.³⁰⁸ Contrast CT is often difficult because of poor renal functions, and abdominal ultrasonography and brain MRI may be needed instead.³¹⁰

The incidence of adverse reactions to antibiotics is high because of renal dysfunction.³¹¹ Renal dysfunction and cognitive impairment may occur concomitantly, and surgery is not conducted in many cases in spite of surgical indication. The in-hospital prognosis is comparable in elderly patients and non-elderly patients, but the prognosis after discharge from the hospital is worse in elderly patients because complications are more common.^308,309,311

Acknowledgments

We would like to thank the members of the Independent Assessment Committee, Professors Makoto Akaishi (Department of Cardiology, Tokai University Tokyo Hospital), Takashi Akasaka (Department of Cardiovascular Medicine, Wakayama Medical University), Yutaka Otsuji (Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine), Takeshi Kimura (Department of Cardiovascular Medicine, Kyoto University), Junjiro Kobayashi (Department of Cardiac Surgery, National Cerebral and Cardiovascular Center), and Kazuo Tanemoto (Department of Cardiovascular Surgery, Kawasaki Medical School).

Appendix 1 JCS Joint Working Group

Chair:

• Satoshi Nakatani, Division of Health Sciences, Osaka University Graduate School of Medicine

Members:

• Kyomi Ashihara, Department of Cardiology, Tokyo Women’s Medical University

• Masao Daimon, Department of Clinical Laboratory/Cardiology, the University of Tokyo

• Kiyoyuki Eishi, Division of Cardiovascular Surgery, Nagasaki University Graduate School of Biomedical Sciences

• Masahiro Higashi, Department of Radiology, National Hospital Organization, Osaka National Hospital

• Shiro Iwanaga, Department of Cardiology, Saitama Medical University International Medical Center

• Chisato Izumi, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center

• Toshimi Kimura, Department of Pharmacy, Tokyo Women’s Medical University Hospital

• Kotaro Mitsutake, Department of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center

• Tomoaki Murakami, Department of Cardiology, Chiba Children’s Hospital

• Kazuhiko Nakano, Division of Oral Infection and Disease Control, Osaka University Graduate School of Dentistry

• Hiroyuki Nakase, Department of Neurosurgery, Nara Medical University

• Takahiro Ohara, Division of Community Medicine, Tohoku Medical and Pharmaceutical University

• Yutaka Okita, Cardio-Aortic Center, Takatsuki General Hospital

• Kazunori Toyoda, Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center

• Satoshi Yasukochi, Heart Center, Nagano Children’s Hospital

Collaborators:

• Katsuhito Fujiu, Department of Cardiovascular Medicine, the University of Tokyo

• Takashi Miura, Division of Cardiovascular Surgery, Nagasaki University Graduate School of Biomedical Sciences

• Toshio Morizane, Japan Council for Quality Health Care

• Ichiro Nakagawa, Department of Neurosurgery, Nara Medical University

• Ryota Nomura, Division of Oral Infection and Disease Control, Osaka University Graduate School of Dentistry

• Shuhei Okazaki, Department of Neurology, National Cerebral and Cardiovascular Center

• Haruo Sakamoto, Department of Oral and Maxicillofacial Surgery, Tokai University Hachioji Hospital

• Hiroshi Tanaka, Department of Surgery, Division of Cardiovascular Surgery, Kobe University

Independent Assessment Committee:

• Makoto Akaishi, Department of Cardiology, Tokai University Tokyo Hospital

• Takashi Akasaka, Department of Cardiovascular Medicine, Wakayama Medical University

• Takeshi Kimura, Department of Cardiovascular Medicine, Kyoto University

• Junjiro Kobayashi, Department of Cardiac Surgery, National Cerebral and Cardiovascular Center

• Yutaka Otsuji, Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine

• Kazuo Tanemoto, Department of Cardiovascular Surgery, Kawasaki Medical School

(The affiliations of the members are as of January, 2019)

Appendix 2 Disclosure of Potential Conflicts of Interest (COI): JCS 2017 Guideline on Prevention and Treatment of Infective Endocarditis in Japan

Author	Employment or leading position (Private company)	Shareholder	Royalty of patent right	Remuneration	Payment for a manuscript	Provision of research fund	Scholarship donation / Endowed Chair	Other rewards	Declaration regarding spouse, relative in the first degree, or other persons sharing income/property
Team leader: Satoshi Nakatani				Edwards 　Lifesciences
Team member: Yutaka Okita	JMS Edwards 　Lifesciences TERUMO 　CORPORATION Medtronic Japan Japan Lifeline			St. Jude Medical			Century Medical, Inc. CSL Behring Senko 　Medical Instrument
Team member: Toshimi Kimura				Meiji Seika 　Pharma
Team member: Kazunori Toyoda				Daiichi Sankyo Bayer Yakuhin Bristol-Myers 　Squibb Boehringer 　Ingelheim Takeda 　Pharmaceutical 　Company
Team member: Kotaro Mitsutake				MSD
Team member: Satoshi Yasukochi				Actelion 　Pharmaceuticals 　Japan
Cooperator: Katsuhito Fujiu				Daiichi Sankyo Medtronic Japan			Medtronic Japan Abbott Japan Boston Scientific 　Japan Japan Lifeline BIOTRONIK Japan NTT Docomo

Notation of corporation is omitted. Nothing special to be mentioned for team members and cooperators other than those mentioned above.

Team member: Kyomi Ashihara, Absent

Team member: Chisato Izumi, Absent

Team member: Shiro Iwanaga, Absent

Team member: Kiyoyuki Eishi, Absent

Team member: Takahiro Ohara, Absent

Team member: Masao Daimon, Absent

Team member: Hiroyuki Nakase, Absent

Team member: Kazuhiko Nakano, Absent

Team member: Masahiro Higashi, Absent

Team member: Tomoaki Murakami, Absent

Cooperator: Shuhei Okazaki, Absent

Cooperator: Haruo Sakamoto, Absent

Cooperator: Hiroshi Tanaka, Absent

Cooperator: Ichiro Nakagawa, Absent

Cooperator: Ryota Nomura, Absent

Cooperator: Takashi Miura, Absent

Cooperator: Toshio Morizane, Absent

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