J Infect Chemother xxx (2018) 1e5

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Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Guideline

The 2016 JAID/JSC guidelines for clinical management of infectious

disease
Odontogenic infections
The Japanese Association for Infectious Disease/Japanese Society of Chemotherapy*, The
JAID/JSC Committee for Developing Treatment Guide and Guidelines for Clinical
Management of Infectious Disease, Odontogenic Infection Working Group

a r t i c l e i n f o

Article history: stewardship, a section on odontogenic infections was added in JAID/

Received 1 November 2016 JSC Guide 2014. In the present Guide to Clinical Management of In-
Received in revised form fectious Disease, the document was re-formatted by adding expla-
27 September 2017 nations between sentence lines to facilitate better understanding.
Accepted 27 September 2017
Available online xxx
We hope that the guidelines are widely adopted and used in the
treatment of odontogenic infections as well as for education in
Japan, and contribute to the health of people by improving the
quality of dental practice and preventing the increase in antibiotic
resistant microorganisms.
Contents In closing, we extend our deep gratitude to the members of the
1. Introduction committee and secretariat, who devoted tremendous time and
2. Odontogenic infections effort to the preparation of the guidelines.
References Supplementary notes:

1. The recommendation grades or strength of recommendation,

1. Preface and quality or evidence level of the literature were determined
according to the Outline for the Preparation of the Guidelines to
In 2011, the Japanese Association for Infectious Disease and Clinical Management of Infectious Disease (see below) established
Japanese Society of Chemotherapy published the JAID/JSC Guide to by the Japanese Association for Infectious Disease/Japanese
Clinical Management of Infectious Disease 2011. As there was no Society of Chemotherapy
section for odontogenic infections in the document, this section
was added in the revision (2014 JAID/JSC Guide to Clinical Manage- Recommendation grades
ment of Infectious Disease). A: Strongly recommended
The present healthcare environment is faced with the emer- B: General recommendation
gence of various antibiotic resistant microorganisms which has C: A clinical decision to be made by the attending physician
necessitated policy changes and the field of odontogenic infection based on a comprehensive consideration of factors
is no exception. In light of the spread of antibiotic resistant mi-
croorganisms, the inclusion of odontogenic infection in JAID/JSC Evidence level
Guide 2014 was necessary. Specifically, the Guide urged reconsid-
I: Randomized comparative study
eration of the use of the most widely used third-generation
II: Non-randomized comparative study
cephems in dental outpatient clinics. Prevotella, which is the lead-
III: Case report
ing cause of odontogenic infections, produce b-lactamase which
IV: Specialist's opinion
degrade penicillins and third-generation cephems, but this enzyme
activity is inhibited by b-lactamase inhibitors. As the use of peni-
2. Definition of first- and second-line drugs
cillin combined with b-lactamase inhibitors, as the first line anti-
biotic, for the treatment of odontogenic infections due to oral
The first- and second-line drugs were defined according to the
streptococci and anaerobic bacteria is consistent with antibiotic
General Outline for Preparing the Guidelines to Clinical Management
of Infectious Diseases by the Japanese Association for Infectious
* Corresponding author.
Diseases and Japanese Society of Chemotherapy.

https://doi.org/10.1016/j.jiac.2017.09.014
1341-321X/© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Kaneko A, et al., The 2016 JAID/JSC guidelines for clinical management of infectious disease
Odontogenic
infections, J Infect Chemother (2018), https://doi.org/10.1016/j.jiac.2017.09.014
2 The JAID/JSC Committee for Developing Treatment Guide and Guidelines for Clinical Management of Infectious Disease / J Infect Chemother xxx (2018) 1e5
First-line drugs: Recommended antimicrobial agents for initial
treatment
Second-line drugs: Alternative drugs when first-line drugs
cannot be used due to allergy, organ disorder, or local factors
3. Cautions
In this section, recommendations concerning the selection, route
of administration, and, in particularly, the dosage, is based on the
principle of achieving sufficient dosage. Therefore, dosage should be
adjusted appropriately taking into consideration each healthcare
institution's formulary as well as antibiogram, severity of illness,
underlying disease, age and presence or absence of organ disorders.
4. y indicates when treatment is not covered by the criteria
established by national healthcare insurance (indications for
usage, dosage, and bacterial agents in Japan).
5. A list of antimicrobial drug abbreviations is presented on the last
page.
2. Odontogenic infections
[Points to consider in antibacterial chemotherapy]
1. Since antibiotic tissue penetration into oral tissues such as the
infected jaw bone and abscess cavity is low resulting in low
antibiotic concentration at the site, it is important to perform
local procedures such as treatment of infected root canal, ab-
scess incision and drainage in parallel, Furthermore, anti-
inflammatory procedures such as incision and drainage is
extremely useful in reducing the bacterial load at the infected
site and resolving the anaerobic environment in the infected site
caused by anaerobic bacteria.
2. The selection of antibiotics with strong antibacterial activities
against oral streptococci and anaerobic bacteria, which are the
primary causes of odontogenic infections. The frequency of
involvement of obligate anaerobes increases with the severity of
the inflammation. For severe odontogenic infections, antimi-
crobials with strong antibacterial activities against anaerobic
bacteria that produce b-lactamase should be selected.
[Clinical classification of odontogenic infections]
Odontogenic infections are classified into groups 1 to 4 [1].
Group 1 [periodontitis]: Infectious sequelae of pulpitis including
apical periodontitis and marginal periodontitis which can lead to
other diseases such as gingival abscess, alveolar abscess, and palatal
abscess.
Group 2 [pericoronitis]: This condition is primarily associated
with an impacted wisdom tooth. Reddening, swelling, and pus
discharge are observed around the crown of the impacted wisdom
tooth. Abscess formation is rare. Pericoronitis may develop into jaw
inflammation and phlegmon. If the inflammation extends to the
space around the jaw bone, difficulty opening mouth and pain on
swallowing are observed.
Group 3 [jaw inflammation]: A condition including osteitis and
osteomyelitis that can develop from peroditis (Group 1) and peri-
coronitis (Group 2). This condition is more severe than Group 1 or 2
necessitating subperiosteal drainage and the use of antibiotics
administered by injection are often required. Osteomyelitis may be
acute, chronic, or sclerotic and occurs frequently in the mandible.
Group 4 [phlegmon of the jaw bone area]: A spreading inflam-
matory process developing from Groups 1e3. It includes space in-
fections such as infections of the sublingual, submandibular,
submental, pterygomandibular, lateral pharyngeal, and pharyngeal
Please cite this article in press as: Kaneko A, et al., The 2016 JAID/JSC guidelines for clinical management of infectious disease
Odontogenic
infections, J Infect Chemother (2018), https://doi.org/10.1016/j.jiac.2017.09.014
spaces. Drainage of these cavities is important. Antibiotics admin-
istered by injection are used in many patients.
[Major causative bacteria of odontogenic infections and fre-
quency of detection]
During the period 2005e2009, of the 3112 isolates of major
causative bacteria recovered from oral closed abscesses, 73%
were Streptococcus, 48% were Prevotella, and 47% were Peptos-
treptococcus. P. intermedia was the most frequently isolated
Prevotella sp. and Parvimonas micra (P. micros) was the most
frequently isolated Peptostreptococcus (includes those genera
listed within the Peptostreptococcus genus under previous tax-
onomy and currently re-classified as Peptostreptococcus, Parvi-
monas, Finegoldia, Peptoniphilus, etc.). The isolation frequency of
Fusobacterium and Porphyromonas were about 9 and 6%,
respectively [2]. Within the Streptococcus genus, S. constellatus
and S. intermedus were most frequently isolated, followed by
S. mitis and S. oralis.
No marked difference was observed in the isolation frequency of
major causative bacteria for odontogenic infections Groups 1e4,
but anaerobic bacteria tended to be more frequently isolated in
phlegmon (Group 4), which was severe in many patients.
Excluding pericoronitis and odontogenic maxillary sinusitis
within odontogenic infection Group 2, species within the
Streptococcus anginosus group (S. anginosus, S. intermedius, and
S. constellatus) were detected more frequently than other
streptococcal species [2].
[Antimicrobial susceptibility profile of the major causative
bacteria associated with odontogenic infections (Table 1 and 2)]
Among Gram negative rods, antimicrobial susceptibility testing
of isolates recovered from closed oral abscesses during
2008e2009 showed high MIC values against Prevotella to ABPC
(ampicillin), CFDN (cefdinir), and CTRX (ceftriaxone) with a MIC90
of 16 mg/mL or above due to the high frequency of b-lactamase-
producing strains. The MIC90 of SBT/ABPC (sulbactam/ampicillin),
a penicillin combined with a b-lactamase inhibitor, was 2 mg/mL.
The MIC90 of AZM (azithromycin) and CLDM (clindamycin) was
high at 16 mg/mL or above, but the MIC50 of CLDM was 0.015 mg/mL
or below. The MIC90 of MNZ (metronidazole), which is the first-
line antibiotic for anaerobic bacterial infection in Western coun-
tries and added to indications and usage for anaerobic bacterial
infection in Japan, was 4 mg/mL. As there are few b-lactamase-
producing Porphyromonas sp, few strains resistant to penicillins
and cephems were found as evidenced by a MIC90 of 0.12 mg/mL.
The AZM MIC90 against Fusobacterium was high because of the
presence of strains intrinsically resistant to macrolides, but the
MIC90 for other antibiotics were low [3].
For the Gram-positive cocci, the MIC90 of b-lactam antibiotics
against Peptostreptococcus and Streptococcus anginosus group
was generally low. AZM and CLDM showed a two-peak distri-
bution of MIC values with a low MIC50 and a high MIC90 against
viridans group Streptococcus [3].
During the clinical trials for STFX (sitafloxacin), the MIC90 was
0.1 mg/mL or lower with antibacterial activity 8e256 times
stronger than those of existing fluoroquinolone antibiotics [4].
For the Prevotella genus, which is the most frequently isolated
anaerobic bacteria, many of the isolates produced b-lactamase.
In general, b-lactamase is classified into Molecular Classes A-D,
which are the penicillinases, carbapenemases, cephalospor-
inases, and oxacillinases, respectively. The genus Prevotella,
which produces b-lactamase belonging to subclass A2e, shows
 The JAID/JSC Committee for Developing Treatment Guide and Guidelines for Clinical Management of Infectious Disease / J Infect Chemother xxx (2018) 1e5 3

Table 1  CLDM 150 mg given every 6 h [B I [7,8]]

Antimicrobial activities against clinical isolates of Prevotella species and Porphyr-  AZM 500 mg given once a day for 3 days (not indicated for
omonas spescies (MIC:mg/mL).
children in dentistry) [B I [9,10]]
Organism (strains) Drug MIC range MIC50 MIC90  AZM 2 g given once a day (not indicated for children in
Prevotella (252) ABPC &0.015e＞16 0.12 ＞16 dentistry) [C Ⅳ]
ABPC/SBT &0.015e8 0.12 2  CAM (clarithromycin) 200 mg, given 2 times/day (for children:
CFDN &0.015e＞16 0.12 16 7.5 mg/kg given 2 times/dayy*) [B II [11]]
CTRX &0.015e＞16 0.25 16
CLDM &0.015e＞16 &0.015 ＞16
AZM &0.015e＞16 0.5 ＞16 * According to information from the Social Insurance Medical
MNZ &0.015e＞16 1 4 Fee Payment Claims and Reimbursement Services in Japan, CAM is
Porphyromonas (41) ABPC &0.015e＞16 &0.015 0.12 approved in children, if upon review, it has been prescribed for
ABPC/SBT &0.015e2 &0.015 0.12 “periodontitis, osteitis”.
CFDN &0.015e＞16 &0.015 0.03
CTRX &0.015e＞16 &0.015 0.12
CLDM &0.015e＞16 &0.015 ＞16 (2) Group 3 or 4 (severe infections)
AZM 0.25e＞16 2 ＞16
MNZ &0.015e1 0.06 0.25 In severe odontogenic infections such as phlegmon of the jaw
ampicillin (ABPC), sulbactam/ampicillin (ABPC/SBT), cefdinir (CFDN), ceftriaxone bone area and cervical abscesses, there is a need to take into
(CTRX), clindamycin (CLDM), azithromycin (AZM), metronidazole (MNZ). consideration b-lactamase-producing anaerobic bacteria.
In patients for whom the prognosis is exacerbation of jaw bone
resistance to penicillin and cephems including the third gener- inflammation,
ation cephalosporins, but enzyme activity is inhibited by b-
lactamase inhibitors such as sulbactam and tazobactam. Of the  SBTPC (sultamicillin) y* 375 mg given 2e3 times/day (not indi-
681 Prevotella tested, 240 (35%) were b-lactamase-producing cated for dentistry in children) [C Ⅳ]
strains; the resistant rate according to CLSI criteria was 37% for
ABPC, 13% for CTRX, and 10% for CLDM [5]. * According to information from the Social Insurance Medical
Fee Payment Claims and Reimbursement Services, the use of SBTPC
[Recommended antimicrobial therapy] is approved, if upon review, it has been prescribed for osteitis, and
phlegmon of the jaw bone area and other secondary infections
As a general rule, the effectiveness of antibiotics in treating following surgery.
odontogenic infections should be assessed within 3 days. If the
condition worsens, the addition of a surgical anti-inflammatory  CVA/AMPC (clavulanic acid/amoxicillin) y 250 mg given 4 times/
procedure and a change to another antibiotic should be consid- day (not indicated for children in dentistry) [C Ⅳ]
ered. According to the American Academy of Periodontology, the  AMPC oncey 500 mg given3 times/day (children: 15 mg/kg given
duration of antibiotic treatment using a particular antimicrobial 3 times/day) [C Ⅳ]
agent for odontogenic infections should be about 8 days [6].
If there is penicillin allergy,
1. First-line oral drugs
 CLDM:150 mg given every 6 h [C I [12]]
(1) Group 1 or 2 (mild to moderate symptoms)  CCI (cefaclor) 250 mg given 3 times/day (children: 15 mg/kg/, 3
times/day) [B]
In patients with abscesses, anti-inflammatory treatment such as
an incision should be administered, Caution should be exercised as about 15% of children with
penicillin allergy also have allergy to cephem antibiotics.
 AMPC (amoxicillin) 250 mg given 3e4 times/day (10e15 mg/kg,
3 times/day in children) [A IV [1]]  STFX (sitafloxacin) 100 mg given 2 times/day (not indicated for
children in dentistry) [CIII [4]]
If there is penicillin allergy,
2. Second-line oral drugs
Table 2
When no response to penicillin or cephem antibiotics are
Antimicrobial activities against clinical isolates of Peptostreptococcus species and
Viridans Streptococcus (MIC:mg/mL).
observed in the advanced stages of inflammation, the presence of
b-lactamase-producing organisms should be considered dictating
Organism (strains) Drug MIC range MIC50 MIC90
the need for administration of the following antibiotics:
Peptostreptococcus (258) ABPC &0.015e>16 <0.015 0.12
ABPC/SBT &0.015e8 <0.015 0.12  STFX 100 mg given 2 times/day (not indicated for children) [C III
CFDN &0.015e>16 0.03 0.12
CTRX &0.015e>16 0.06 0.5
[4]]
CLDM &0.015e>16 0.06 0.25  FRPM (faropenem) 150e200 mg 3 times/day (children: 5 mg/kg
AZM &0.015e>16 2 8 given 3 times/day) [C]
MNZ &0.015e>16 2 16
Viridans Streptococcus (194) ABPC &0.015e>16 0.06 1
2. Antibiotics administered by the injection route
CFDN &0.015e16 0.25 2
CTRX &0.015e>16 0.12 1 Medical treatment while hospitalized is recommended for those
CLDM &0.015e>16 &0.015 16 patients with severe osteitis accompanied by difficulties in opening
AZM &0.015e>16 0.03 >16 the mouth and swallowing (Group 3) or phlegmon (Group 4)
MNZ >16e>16 >16 >16 showing severe symptoms of acute inflammation. Many patients
ampicillin (ABPC), sulbactam/ampicillin (ABPC/SBT), cefdinir (CFDN), ceftriaxone will require pus drainage by incision. In particular, for phlegmon,
(CTRX), clindamycin (CLDM), azithromycin (AZM), metronidazole (MNZ). incision of the cavity or place of phlegmonous process is necessary.

Please cite this article in press as: Kaneko A, et al., The 2016 JAID/JSC guidelines for clinical management of infectious disease
Odontogenic
infections, J Infect Chemother (2018), https://doi.org/10.1016/j.jiac.2017.09.014
4 The JAID/JSC Committee for Developing Treatment Guide and Guidelines for Clinical Management of Infectious Disease / J Infect Chemother xxx (2018) 1e5
Table 3
Prophylactic use of antibiotics in dentistry and oral surgery procedures and treatment in children [19].
Patients Antibiotics
Can be administered orally AMPC
Not orally administrable ABPC
Patients with penicillin allergy CLDM
CEX
AZM
CAM
CLDM
CEZ
It is necessary to perform needle aspiration, collect samples, and
perform a Gram stain to determine the likely causative agent fol-
lowed by bacterial identification and drug susceptibility testing.
Patients with severe phlegmon of the oral floor or deep neck ab-
scess must be diagnosed by imaging using CT [A Ⅳ].
(1) Moderate infections
 SBT/ABPC (sulbactam/ampicillin)y* administered by IV injection
or drip infusion at 3 g divided into 2e4 doses (children: 75 mg/
kg given 3 times/day by IV injection or drip infusion) [C]
*Though not approved for this indication, the Social Insurance
Medical Fee Payment Claims and Reimbursement Services will
approve the use of SBT/ABPC, if upon review, the regimen has been
prescribed for phlegmon around the jaw bone or peritonsillar
abscess.
 CTRX 1e2 g given 1e2 times/day (children: 25e60 mg/kg
given1-2 times/day by IV injection or drip infusion <50e60 mg/
kg/day>) [B]
(2) Severe infections
 MEPM (meropenem) 0.5e1 g given3 times/day by IV drip infu-
sion over 30 min or longer (children: 20 mg/kg given 3 times/
day by IV drip infusion, the dose may be increased to 120 mg/kg/
day for severe or refractory infection) [CIII [13]]
 DRPM (doripenem) 0.25e1 g given 3 times/day, IV drip infusion
over 30 min or longer (children: 20 mg/kg given 3 times/day by
IV drip infusion; the dose may be increased to 40 mg/kg/time or
severe or refractory infections up to a maximum of 1 g/time)
[CIII [14]]
(3) Severest infections such as necrotizing fasciitis
 Combination of carbapenem and CLDM* [C]
*According to the Social Insurance Medical Fee Payment Claims
and Reimbursement Services, the use of CLDM for injection is
approved, if upon review, the drug has been administered intra-
venously for necrotizing fasciitis or toxic shock syndrome.
4. Prevention of infective endocarditis
According to the guidelines of the 2008 American Heart Asso-
ciation (AHA) [15] and 2009 European guidelines [16], prophylactic
administration of antibiotics during dental treatments should be
limited to those patients following an artificial valve replacement,
those with a history of infective endocarditis (IE), and those with
congenital heart disease (unrepaired cyanotic congenital heart
disease, within 6 months after surgery). In 2008, the English Na-
tional Institute for Health and Clinical Excellence (NICE) declared
prophylactic administration of antibiotics and gargling with
chlorhexidine before dental treatment to be unnecessary for the
Please cite this article in press as: Kaneko A, et al., The 2016 JAID/JSC guidelines for clinical management of infectious disease
Odontogenic
infections, J Infect Chemother (2018), https://doi.org/10.1016/j.jiac.2017.09.014
Administration method
Orally administered at 50 mg/kg 1 hour before treatment
Administered by IV injection or drip infusion at 50 mg/kg within 30 minutes before treatment
Orally administered at 20 mg/kg 1 hour before treatment
Orally administered at 50 mg/kg 1 hour before treatment
Orally administered at 15 mg/kg 1 hour before treatment
Orally administered at 15 mg/kgy 1 hour before treatment
Administered by iv injection at 20 mg/kg within 30 minutes before treatment
Administered by iv injection or drip infusion at 50 mg/kg within 30 minutes before treatment
prevention of IE [17]. After NICE recommendation decided to cease
antibiotics prophylaxis for prevention of IE, Dayer et al. pointed that
incidence of IE in UK has increased because of decreased AMPC
prescription by dentists [18]. With some serious discussions, NICE
declared that antibiotic prophylaxis against IE is not recommended
routinely for people undergoing dental procedures in 2016 [19].
The Japanese Guidelines for the Prevention and Treatment of IE
recommends prophylactic administration of antibiotics in patients
at high risk of developing IE including those with congenital dis-
eases and valve disease [20,21]. These Guidelines recommend
prophylactic oral administration of the following antibiotics 1 h
before treatment.
First-line drugs
 AMPC 2 g 1 h before treatment (can be reduced to 30 mg/kg
depending on the body weight) [AIV1 [5,16,20,21]]
If there is penicillin allergy
 CLDM 600 mg (2 g in the European guidelines) [BIV [20,21]]
 AZM 500 mg [BIV [20,21]]
 CAM500 mgy [BIV [20,21]]
 CEX (cephalexin) or CDX (cefadroxil) 2 g [BIV [20,21]]
For prophylaxis in children, see the following (Table 3) [20,21].
Self-reporting of conflicts of interest
The author, Naoki Tsumura, has received lecture fees from MSD
KK.
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Odontogenic
infections, J Infect Chemother (2018), https://doi.org/10.1016/j.jiac.2017.09.014
5
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