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Page 1: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

�������&��)���%+0.#("$'��!

2018/11/06�12*3/���

������ ��� ,3-4

PGY-4 ���

1

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�� �

August 28, 2018 N Engl J Med

��������Infective Endocarditis��� IE�

2

Page 3: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Introduction

IE9�37+���/&BA705:;��.H

• IE;�#$C�-82A<���"8��• �(:#9�37�� /���38-

→ %���C��6)�*��4@�'�/,@

+�;419%���/��3,

!�>?=%���/ �4@FGDE/,@.

BMC infectious Diseases 2014, 14:1403

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Introduction

• ��<�)�=���7'2C.

• ���D(15�!<�+��<?8E90�$%D�,#��4C5A7-C.�+;BC��D �4C8,����0�":��><�0�@3..

• �6<���*7,#��0 &/=��.

Am Heart J 2007;154:1086-94

4

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��� ���������.5

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6

������

����

Page 7: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

�� ��� ��

Staphylococcus�MSSA��

Coagulase-negative staphylococcus

Native valves (Flu)cloxacillin 12g/dayor

Oxacillin 12g/day

4-6 Class�Level B

Class�Level B

Prosthetic valves (Flu)cloxacillin 12g/day or

Oxacillin 12g/day

with rifampin and gentamicin

≥6

≥6and 2

Class�Level B

Class�Level B

Class�Level B

Streptococcus spp. Strains penicillin susceptible

MIC≤0.125

Penicillin G 12-18 million U/dayor

Amoxicillin 100-200mg/kg/dayor

Ceftriaxone 2g/day

4

4

4

Class�Level B

Class�Level B

Class�Level B

7

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�� ��� ��

Strains relatively resistant to penicillin

0.25≤MIC≤2

Penicillin G 24 million U/dayor

Amoxicillin 200mg/kg/dayor

Ceftriaxone 2g/day combined with gentamicin

4

4

42

Class�Level B

Class�Level B

Class�Level B

Enterococcus spp. Beta-lactam andgentamicin-susceptible

Amoxicillin 200mg/kg/day With Gentamicin 3mg/kg/day

Ampicillin 200mg/kg/daywith Ceftriaxone 4g/day

Vancomycin 30mg/kg/daywith Gentamicin 3mg/kg/day

4-62-6

66

66

Class�Level B

Class�Level B

Class�Level C

8

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����

BMV Infectious disease 2014, 14: 140

IE�����������������������������systematic review�9����� �2��RCT�

9

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����

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����

� �� ��� �� �

(1) Chetty et alSouth Africa

15� Streptococcus sp�60%�Culture negative�40%�

Amoxycillin 6 weeks�47% probenecid�

87%

(2) Gray et alUK

13� S. viridans�62%�E. fecalis�1%�

Culture negative�37%�

Ampicillin or propicillin6 weeks��

probenecid�

92%

(3) Friedberg et alUSA

11� S. viridans�55%�E. fecalis�18%�

Culture negative�27%�

Aureomycin 5-8 weeks 36%

(4) Schein et alUSA

81� Streptococcus sp�94%�S. aureus�1%�

Enterococcus sp�1%�H. influenza�4%�

Sulfonamides10 days-14 weeks

10%

������������������11

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���24%

�� �� #�� �� ���

(1) Chetty et alSouth Africa

15� Streptococcus spA60%BCulture negativeA40%B

Amoxycillin 6 weeksA47% probenecidB

87%

(2) Gray et alUK

13� S. viridansA62%BE. fecalisA1%B

Culture negativeA37%B

Ampicillin or propicillin6 weeksA$

probenecidB

92%

*;82 ���2��.���)�+;:".30&. ,(,, Streptococcus)IE2#��240-60%<�5:*/7

���3�. 1�97-&*/(8�0:��)��+;:.��2*/)�2β-@=>?AampicillinB.6!':.

12

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���,/"

�� �� ��� �� ���

(3) Friedberg et al

USA

11� S. viridans755%8E. fecalis718%8

Culture negative727%8

Aureomycin 5-8 weeks 36%

(4) Schein et al

USA

81� Streptococcus sp794%8S. aureus71%8

Enterococcus sp71%8H. influenza74%8

Sulfonamides

10 days-14 weeks

10%

Aureomycin-�#tetracycline����(���(-

.)3*��%2+#.� -minocycline0doxycycline+*,

&#�����, ���!645(-��$�%2'#1.

13

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��"57'

�� �� $�! �� ���

(3) Friedberg et alUSA

11� S. viridans=55%>E. fecalis=18%>

Culture negative=27%>

Aureomycin 5-8 weeks 36%

(4) Schein et alUSA

81� Streptococcus sp=94%>S. aureus=1%>

Enterococcus sp=1%>H. influenza=4%>

Sulfonamides10 days-14 weeks

10%

��6trimethroprim8&+;.ST�*��23/0):.

ST�6vancomycin5��2�%,0��1(/. =�>

8(9�# �2<-:2���46��+;3).

14

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�!��

P ������ S.aureus�������101����

�� 65%, MRSA 47%!

I TMP-SMZ � 43�!

C Vancomycin � 58�!

O ��

TMP-SMZ � 37�/43�! vs Vancomycin � 57/58�!

Vancomycin ���� P<0.02 �����!

Ann Intern Med. 1992 Sep 1;117(5):390-8

15

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� �0��

�� �� ��� �� ���

(5) Colli et alItaly

14� MRSA(60%)S. Viridans.30%/

Enterococcus sp.(10%)

iv vancomycin 5.3� 3.4 days→ oral linezolid 3 weeks

100%

(6) Dworkin et alUSA

13� S. Sureus.100%/ iv ciprofloxacin + oral rifampin 1 week

→ oral ciprofloxacin + rifampin3 weeks

77%

(7) Philips et alUK

13� S. Viridans.62%/Staphylococcus sp.(23%)

Other streptococci orEnterococcus sp.(15%)

Iv therapy < 2 weeks→ Oral penicillin V, ampicillin,

cloxacillin, flucloxacillin,erythromycin

100%

Linezolid&�%�$(���� ��!)(.β-*+,�%��&�'#"��.

16

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� �-��

�� �� ��� �� ���

(5) Colli et alItaly

14� MRSA(60%)S. Viridans+30%,

Enterococcus sp.(10%)

iv vancomycin 5.3� 3.4 days→ oral linezolid 3 weeks

100%

(6) Dworkin et alUSA

13� S. Sureus+100%, iv ciprofloxacin + oral rifampin 1 week

→ oral ciprofloxacin + rifampin3 weeks

77%

(7) Philips et alUK

13� S. Viridans+62%,Staphylococcus sp.(23%)

Other streptococci orEnterococcus sp.(15%)

Iv therapy < 2 weeks→ Oral penicillin V, ampicillin,

cloxacillin, flucloxacillin,erythromycin

100%

Ciprofloxacin'rifampin%���"MSSA#� )����(*!�)�,���$��&�).

17

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RCT

18

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�� 9$�&

�� �� !�� �� ���

Heldman et alIsrael

85� MRSA75%8MSSA(89%)CoNS(6%)

oral ciprofloxacin + rifampin 4 weeks vs

iv oxacillin or vancomycin(iv gentamicin first 5 days) 4 weeks

90%vs

91%

Stamboulian et alCanada

30� S. Viridans750%8S.bovis750%8

iv or im ceftriaxone first 2 weeks→ high dose oral amoxicillin 2 weeks

vsiv or im ceftriaxone 4 weeks

100%vs

100%

$���)2+�.���#(1 pantient vs 13 patients) ���#(0 patient vs 10 patients)1��(%',+.β6345 1�����0�1" �/*-��.

19

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� �<��

�� �� ��� �� ���

Heldman et alIsrael

85� MRSA:5%;MSSA(89%)CoNS(6%)

oral ciprofloxacin + rifampin 4 weeks vs

iv oxacillin or vancomycin(iv gentamicin first 5 days) 4 weeks

90%vs

91%

Stamboulian et alCanada

30� S. Viridans:50%;S.bovis:50%;

iv or im ceftriaxone first 2 weeks→ high dose oral amoxicillin 2 weeks

vsiv or im ceftriaxone 4 weeks

100%vs

100%

��&.(� ,+365-��(�0/.", 2978214"�%#,���%/'!*!$(*)

��+�"!$("�%/'!..

20

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• ����,1β-@8:?�C�/><9AB�D0���#80-100%, 6&-#�'7*. %2,3����, 5, ��0��# �.

• Heldman4- Stamboulian40RCT1, ��,1β@8:?0��#,$.!0������, ��1��.�#�*7+"4),��/9=;(6��-1.4.!.

21

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������ ���

2000-2012�

Local protocols:≥7 days ivGeneral condition resolution of feverreduction CRPNegative blood culturesNormalization of lecocytosisNormalization of serum creatinineDisappearance or reduction of imagingabnormalities 22

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Streptococcus, enterococci<90D1Amoxicillin��8 &

(�

• Oral><���=�21�• �#����$;���:4• �"��C,�47��$;���:4

)

• ��8@7−10�'�<-!=�+60• ��, ��%�<.B�*=-!1A360• RCTC5B291�?4/

23

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(;7/3��

• IE4"�&���

• �.3���!="�/��+6'%4<%-.$1$

• �*,��/4 �%9����53� &��>

• ���/4����3���4�);.$:

• �3#$RCT41$

�3#$RCT/"�%9����5� *.8"���2�91$(0=�*,$

24

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�����

August 28, 2018 N Engl J Med

The Partial Oral Treatment of Endocarditis trial�POET�trial

25

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Method

26

Page 27: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Design and oversight

• 9A>B4+��'0(� , ����, $���, $� !&.

• ���/9A>B4.�����,9B8�#��-�"'0, =@6A3��-�)(.

• �*.��/�%+1A<2B?;5A7A:'0(.

27

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Inclusion criteria• Duke criteria@�313���9IE� Adefined IEB• Streptococci, Enterococcus faecalis, Staphylococcus

aureus, Coagulase-negative staphylococci/(�#• 18���• 10���)�7�#$@+!��, ,>-: 9�&�87���)�7�#$@+!��@0?3

• 38℃��/2���• CRP/peak.=25%����2>.2mg/dL��8��, ,>-:WBC/15000/μl;5��2>

• ���948�*��8TTE6TEE/�%0?4->• "���@'<7-

28

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Exclusion criteria

• BMI>40

• ���&���� �$���� �'• ���%*51+630,5.5/ ��• ����"���&� ��#��!('��• ,524*)5-��

29

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Evaluation• ����%1-3 �$��TEE+���).

• ���%��"&��#�*'��, �2, 3�%�-,.0+��).

• ����&�����*' % $��.

• �!%��&�����(1��, 1, 3, 6/�$�-,.0+��).

30

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Choice of antibiotics

• ESCA?GM?P201574/+��!<(32.• ���!9�"#�&7OCLK.��0;2.

Q)$9Supplement p.17-18, 6�*%�R

• "#7��1:��'9H?@=J?MINE>, '����, MIC74-5��0;2.

• EUCAST8A?GM?P74/, �58 �6F>DB���68����.�(0;2.

31

Page 32: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Choice of antibiotics���� �, ��������2�����

���� . ���Supplement�������.

Penicillin and methicillin sensitive Staphylococcus aureus andcoaglase-negative staphylococci

• Amoxicillin 1g � 4 and fusidic acid 0.75g � 2• Amoxicillin 1g � 4 and rifampicin 0.6g � 2• Linezolid 0.6g � 2 and fusidic acid 0.75g � 2

��� dose Amoxicillin 1g � 4 , fusidic acid 0.75g � 2

Clindamycin 0.6g � 3, Dicloxacillin 1g � 4, Moxifloxacin 0.4g � 1

Rifampicin 0.6g � 2, Linezolid 0.6g � 2 32

Page 33: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Pharmacokinetics

• ��"/���'��(4,%3&5� *3+1, ���-0��#�&21, 5��, $��-01��.���/���/�'��(4+.

• ��� ���.�),, ���/"0!�(4+.

33

Page 34: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Trial procedures

• ������������� � ����"������111��!� #�.

• �����web+0&��%&),, *.($-/',�����#�.

34

Page 35: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Outcome

Primary outcome-�����!�&6,���.

• ����• �� #����• �(*+)• � �!�'��"%'���$��

35

Page 36: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Statistical analysis

• '��>A<@910B0,-.• ��297.5%2�(&9�7-5134002� +�#0�*68-.

• %���E� �0���� or ���0�����/!�,, Student’s t test or Mann Whitney U test9�).�$,-.

• :=;?��E���/!�,, chi-square test CYate’s"�9�4D9�).�$,-.

36

Page 37: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Statistical analysis

• 1<0>A=��'�!*.76�(��')?458,7/���+��.

• primary outcome(��')Cox���+��", ��:2A9�)3-A@;,A>9�%��"#.

• �$(��)intention-to-treat principle% �.

• P�)0.05�� ����'��&��#.

• ��)SPSS software version 22.0�IBM� , R software version 3.3.3+��

37

Page 38: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Results

38

Page 39: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Patients

• 20117�15� +20178�30�(IE!�.-&����0213*��#-%��1954�) �)�', modified Duke criteria/�%$%��)IE �400�420%5!��.

• 199�!����, 201�!���(�,�"+-%.

39

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40

Page 41: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

139���������

41

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���������

107������

A�� �����

152��������

����������

42

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Timing of randomization and length of stayin the hospital

����������

� � 17��13-23� vs ��� 17��12-24�

�����������

� �!19��14-25� vs ���!17��12-24�

�����������

� �! 19��14-25� vs ���! 3��1-10�

���160��80% �����

43

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Antibiotic treatment

• 4�,�)� �#/!��+��%1(.

21�-��, 1�-�,���, 2�-���3!��#/� �+��%1(�-*&.

• ��$��'0.)+!��,43�222%3), � �,24�212%3)�*0�",��+��%1(2���+��*� *&3

44

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45

�����������

���� ������

Page 46: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

46

Page 47: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

�������������� �. �����������.

Primary outcome

47

Page 48: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Primary outcome�Kaplan-Meier plot���24��12.1%, ���18��9.0%

12.1%

9.0%

48

Page 49: & ) %+0.#($'Strains relatively resistant to penicillin 0.25≤MIC≤2 Penicillin G 24 million U/day or Amoxicillin 200mg/kg/day or Ceftriaxone 2g/day combined with gentamicin 4 4 4

Primary outcome

• ����69�-(528:146.

&+��*528:#��!'��,)%.

• Primary outcome,42�;10.5%< (�./'.

;���=24�;12.1%<, ���=18�;9.0%<<

37:6�+�,3.1% ;95% CI, -3.4 to 9.6; P=0.40<

→ �#�$/'.• ��".��*��%'4�0� %'per protocol

analysis+����→ �49

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��, ��, ������������� !� ������������

50

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���, � , ����, ��������� �"#!�������������

51

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Safety

• ���.71��.2��1�1������'���3. )-$/&,+'#4%1�1�1��2���0 )-$+. primary outcome2(651��.2�*/&,+.

• 221��.���1 <���12, ���10=7:98;<50%=, !"��<27%=, �����<14%=

52

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Discussion

53

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Discussion

• ����IE*, strptococcus, E. fecalis, S aureus, Coagulase-negative staphylococci !���*, ����-��$'�$' �*/, �� 3��-8:9$)2, ���+���*�4"+!�#5'.

• ��08:9%41*�17�6�$, ���*&.��*.:7;<!��+,('.

54

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Discussion

• AB@DEC��19��5��63'/.. �3<���19��1$;��-7)1$<.

• CNS�5primary outcome5��(#'/.(,+=6CNS��?�+-:&3��6��1���(�*, ��814 !(''/0,8/.+22" ,0%<2>=<.

55

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Discussion• ��J��K��4@%�0?NJ I��BPO?F>O@, ,.K%�0��"3@#�H�2Q�6IC, ?EZTUR\T_[`YS@�/�?N=�J4Q�:I8�BPD.

• ��4@4'��+I����`XV�!I, %�0��"3@��CD�;F&�@$*���I

HO`XV9AODL, ��aW^]K)HO2-<J�(G�517JMJQ�(CD.

56

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Discussion

• �-0,2B<$#!, +�!8*�98A. �:��6;�-0"2B<'�8DEJFKC�@B, HIJ��9%=517:�>/A.

• ����; �6:.���:��?,)�, � LIGM�(, ��:��, .&(�NC��34A.

57

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Limitation• ��$IIE�)ILF;N. ��$U��$I�,STQRI�=3L�)M��+�I�)J�����.

• !�I1�-�)IL��, DI�I%-M/��86�I25-30%I�)?'L3KOE<G<. 5�I. �")B> KOC, S aureusI���)?22%��.

• 9:F2�?�@, 5�G��#�I;N�)J��0H�4AOE<G<���, &�TQPR?(�H�7BE<N*�?;N.

58

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Limitation

• ���:%)�;� : �?"��:�6+C3=, ��6:���(.�8/$�>AD5,C�!�.+C.

• 34320%:&<D3��61-random�0D5,8,. *�:��E��2C7, ���:IE� :@B/:� 6, �':���(E��9FHG15#,:->1D8,.

59

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Conclusion

• ����IE

• Streptococcus, E. fecalis, S. aureus, Coagulase-negative staphylococci !���

• ����)����"�"&�-

��.�$# �'*, �� ,��)/10"&+����(��"���'�%$.

60

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�"

• ��./*8� ����IE)�($;<=4 �21��,+27&69/*8.

• ��!5Amoxicillin, fusidic acid, rifampicin, Linezolid, doxycycline, moxifloxacin42���.

Amoxicillin�5�'%�,����4#�+65�

��3��:�0-2*.

61

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%.

• ��+�F,�����<A!0/�O<A6MFG �#BGD6.

• ����IB3�), ��)F6=NF)BJ17�13�;NA8L,>F�19(�E�4O�H<?�*�95M.

• �$&G� FJF@9,'BGPICCO��<A�B3��"O-7:CJ5L, 3�P�2CGDKD6.

62

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�!

• ���2�0'>;G=AB8�.2��7+244�"1�-356)/3$*'.�MRSAL0�JMSSAL87�K, MRCNSL8�JCNSL15�K

• #���(����<9@E9G2017%���1���3��H ����1,'-�0C:FI8?D(� &

ESC 2015<9@E9G“follow-up should be performed during the first year ”

63

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��=�,

• ��!9�-6CIE�$9>+�=�%�, ���E��581C4:3�1. +��$9>��)B/�9� E *6C.

• �-"#3.;��90D?,��<GIH58��IFJK9A&12A5D;13, 7=�>�$@=(�:�+;IFJK3�':;C.

64