& ) %+0.#($'strains relatively resistant to penicillin 0.25≤mic≤2 penicillin g 24...
TRANSCRIPT
�������&��)���%+0.#("$'��!
2018/11/06�12*3/���
������ ��� ,3-4
PGY-4 ���
1
�� �
August 28, 2018 N Engl J Med
��������Infective Endocarditis��� IE�
2
Introduction
IE9�37+���/&BA705:;��.H
• IE;�#$C�-82A<���"8��• �(:#9�37�� /���38-
→ %���C��6)�*��4@�'�/,@
+�;419%���/��3,
!�>?=%���/ �4@FGDE/,@.
BMC infectious Diseases 2014, 14:1403
Introduction
• ��<�)�=���7'2C.
• ���D(15�!<�+��<?8E90�$%D�,#��4C5A7-C.�+;BC��D �4C8,����0�":��><�0�@3..
• �6<���*7,#��0 &/=��.
Am Heart J 2007;154:1086-94
4
�����������������������
��� ���������.5
6
������
����
�� ��� ��
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
�� ��� ��
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
����
BMV Infectious disease 2014, 14: 140
IE�����������������������������systematic review�9����� �2��RCT�
9
����
10
����
� �� ��� �� �
(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
���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
���,/"
�� �� ��� �� ���
(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
��"57'
�� �� $�! �� ���
(3) Friedberg et alUSA
11� S. viridans=55%>E. fecalis=18%>
Culture negative=27%>
Aureomycin 5-8 weeks 36%
(4) Schein et alUSA
81� Streptococcus sp=94%>S. aureus=1%>
Enterococcus sp=1%>H. influenza=4%>
Sulfonamides10 days-14 weeks
10%
��6trimethroprim8&+;.ST�*��23/0):.
ST�6vancomycin5��2�%,0��1(/. =�>
8(9�# �2<-:2���46��+;3).
14
�!��
P ������ S.aureus�������101����
�� 65%, MRSA 47%!
I TMP-SMZ � 43�!
C Vancomycin � 58�!
O ��
TMP-SMZ � 37�/43�! vs Vancomycin � 57/58�!
Vancomycin ���� P<0.02 �����!
Ann Intern Med. 1992 Sep 1;117(5):390-8
15
� �0��
�� �� ��� �� ���
(5) Colli et alItaly
14� MRSA(60%)S. Viridans.30%/
Enterococcus sp.(10%)
iv vancomycin 5.3� 3.4 days→ oral linezolid 3 weeks
100%
(6) Dworkin et alUSA
13� S. Sureus.100%/ iv ciprofloxacin + oral rifampin 1 week
→ oral ciprofloxacin + rifampin3 weeks
77%
(7) Philips et alUK
13� S. Viridans.62%/Staphylococcus sp.(23%)
Other streptococci orEnterococcus sp.(15%)
Iv therapy < 2 weeks→ Oral penicillin V, ampicillin,
cloxacillin, flucloxacillin,erythromycin
100%
Linezolid&�%�$(���� ��!)(.β-*+,�%��&�'#"��.
16
� �-��
�� �� ��� �� ���
(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#� )����(*!�)�,���$��&�).
17
RCT
18
�� 9$�&
�� �� !�� �� ���
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%
$���)2+�.���#(1 pantient vs 13 patients) ���#(0 patient vs 10 patients)1��(%',+.β6345 1�����0�1" �/*-��.
19
� �<��
�� �� ��� �� ���
Heldman et alIsrael
85� MRSA:5%;MSSA(89%)CoNS(6%)
oral ciprofloxacin + rifampin 4 weeks vs
iv oxacillin or vancomycin(iv gentamicin first 5 days) 4 weeks
90%vs
91%
Stamboulian et alCanada
30� S. Viridans:50%;S.bovis:50%;
iv or im ceftriaxone first 2 weeks→ high dose oral amoxicillin 2 weeks
vsiv or im ceftriaxone 4 weeks
100%vs
100%
��&.(� ,+365-��(�0/.", 2978214"�%#,���%/'!*!$(*)
��+�"!$("�%/'!..
20
• ����,1β-@8:?�C�/><9AB�D0���#80-100%, 6&-#�'7*. %2,3����, 5, ��0��# �.
• Heldman4- Stamboulian40RCT1, ��,1β@8:?0��#,$.!0������, ��1��.�#�*7+"4),��/9=;(6��-1.4.!.
21
������ ���
2000-2012�
Local protocols:≥7 days ivGeneral condition resolution of feverreduction CRPNegative blood culturesNormalization of lecocytosisNormalization of serum creatinineDisappearance or reduction of imagingabnormalities 22
Streptococcus, enterococci<90D1Amoxicillin��8 &
(�
• Oral><���=�21�• �#����$;���:4• �"��C,�47��$;���:4
)
• ��8@7−10�'�<-!=�+60• ��, ��%�<.B�*=-!1A360• RCTC5B291�?4/
23
(;7/3��
• IE4"�&���
• �.3���!="�/��+6'%4<%-.$1$
• �*,��/4 �%9����53� &��>
• ���/4����3���4�);.$:
• �3#$RCT41$
�3#$RCT/"�%9����5� *.8"���2�91$(0=�*,$
24
�����
August 28, 2018 N Engl J Med
The Partial Oral Treatment of Endocarditis trial�POET�trial
25
Method
26
Design and oversight
• 9A>B4+��'0(� , ����, $���, $� !&.
• ���/9A>B4.�����,9B8�#��-�"'0, =@6A3��-�)(.
• �*.��/�%+1A<2B?;5A7A:'0(.
27
Inclusion criteria• Duke criteria@�313���9IE� Adefined IEB• Streptococci, Enterococcus faecalis, Staphylococcus
aureus, Coagulase-negative staphylococci/(�#• 18���• 10���)�7�#$@+!��, ,>-: 9�&�87���)�7�#$@+!��@0?3
• 38℃��/2���• CRP/peak.=25%����2>.2mg/dL��8��, ,>-:WBC/15000/μl;5��2>
• ���948�*��8TTE6TEE/�%0?4->• "���@'<7-
28
Exclusion criteria
• BMI>40
• ���&���� �$���� �'• ���%*51+630,5.5/ ��• ����"���&� ��#��!('��• ,524*)5-��
29
Evaluation• ����%1-3 �$��TEE+���).
• ���%��"&��#�*'��, �2, 3�%�-,.0+��).
• ����&�����*' % $��.
• �!%��&�����(1��, 1, 3, 6/�$�-,.0+��).
30
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
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
Pharmacokinetics
• ��"/���'��(4,%3&5� *3+1, ���-0��#�&21, 5��, $��-01��.���/���/�'��(4+.
• ��� ���.�),, ���/"0!�(4+.
33
Trial procedures
• ������������� � ����"������111��!� #�.
• �����web+0&��%&),, *.($-/',�����#�.
34
Outcome
Primary outcome-�����!�&6,���.
• ����• �� #����• �(*+)• � �!�'��"%'���$��
35
Statistical analysis
• '��>A<@910B0,-.• ��297.5%2�(&9�7-5134002� +�#0�*68-.
• %���E� �0���� or ���0�����/!�,, Student’s t test or Mann Whitney U test9�).�$,-.
• :=;?��E���/!�,, chi-square test CYate’s"�9�4D9�).�$,-.
36
Statistical analysis
• 1<0>A=��'�!*.76�(��')?458,7/���+��.
• primary outcome(��')Cox���+��", ��:2A9�)3-A@;,A>9�%��"#.
• �$(��)intention-to-treat principle% �.
• P�)0.05�� ����'��&��#.
• ��)SPSS software version 22.0�IBM� , R software version 3.3.3+��
37
Results
38
Patients
• 20117�15� +20178�30�(IE!�.-&����0213*��#-%��1954�) �)�', modified Duke criteria/�%$%��)IE �400�420%5!��.
• 199�!����, 201�!���(�,�"+-%.
39
40
139���������
41
���������
107������
A�� �����
152��������
����������
42
Timing of randomization and length of stayin the hospital
����������
� � 17��13-23� vs ��� 17��12-24�
�����������
� �!19��14-25� vs ���!17��12-24�
�����������
� �! 19��14-25� vs ���! 3��1-10�
���160��80% �����
43
Antibiotic treatment
• 4�,�)� �#/!��+��%1(.
21�-��, 1�-�,���, 2�-���3!��#/� �+��%1(�-*&.
• ��$��'0.)+!��,43�222%3), � �,24�212%3)�*0�",��+��%1(2���+��*� *&3
44
45
�����������
���� ������
46
�������������� �. �����������.
Primary outcome
47
Primary outcome�Kaplan-Meier plot���24��12.1%, ���18��9.0%
12.1%
9.0%
48
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<
→ �#�$/'.• ��".��*��%'4�0� %'per protocol
analysis+����→ �49
��, ��, ������������� !� ������������
50
���, � , ����, ��������� �"#!�������������
51
Safety
• ���.71��.2��1�1������'���3. )-$/&,+'#4%1�1�1��2���0 )-$+. primary outcome2(651��.2�*/&,+.
• 221��.���1 <���12, ���10=7:98;<50%=, !"��<27%=, �����<14%=
52
Discussion
53
Discussion
• ����IE*, strptococcus, E. fecalis, S aureus, Coagulase-negative staphylococci !���*, ����-��$'�$' �*/, �� 3��-8:9$)2, ���+���*�4"+!�#5'.
• ��08:9%41*�17�6�$, ���*&.��*.:7;<!��+,('.
54
Discussion
• AB@DEC��19��5��63'/.. �3<���19��1$;��-7)1$<.
• CNS�5primary outcome5��(#'/.(,+=6CNS��?�+-:&3��6��1���(�*, ��814 !(''/0,8/.+22" ,0%<2>=<.
55
Discussion• ��J��K��4@%�0?NJ I��BPO?F>O@, ,.K%�0��"3@#�H�2Q�6IC, ?EZTUR\T_[`YS@�/�?N=�J4Q�:I8�BPD.
• ��4@4'��+I����`XV�!I, %�0��"3@��CD�;F&�@$*���I
HO`XV9AODL, ��aW^]K)HO2-<J�(G�517JMJQ�(CD.
56
Discussion
• �-0,2B<$#!, +�!8*�98A. �:��6;�-0"2B<'�8DEJFKC�@B, HIJ��9%=517:�>/A.
• ����; �6:.���:��?,)�, � LIGM�(, ��:��, .&(�NC��34A.
57
Limitation• ��$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
Limitation
• ���:%)�;� : �?"��:�6+C3=, ��6:���(.�8/$�>AD5,C�!�.+C.
• 34320%:&<D3��61-random�0D5,8,. *�:��E��2C7, ���:IE� :@B/:� 6, �':���(E��9FHG15#,:->1D8,.
59
Conclusion
• ����IE
• Streptococcus, E. fecalis, S. aureus, Coagulase-negative staphylococci !���
• ����)����"�"&�-
��.�$# �'*, �� ,��)/10"&+����(��"���'�%$.
60
�"
• ��./*8� ����IE)�($;<=4 �21��,+27&69/*8.
• ��!5Amoxicillin, fusidic acid, rifampicin, Linezolid, doxycycline, moxifloxacin42���.
Amoxicillin�5�'%�,����4#�+65�
��3��:�0-2*.
61
%.
• ��+�F,�����<A!0/�O<A6MFG �#BGD6.
• ����IB3�), ��)F6=NF)BJ17�13�;NA8L,>F�19(�E�4O�H<?�*�95M.
• �$&G� FJF@9,'BGPICCO��<A�B3��"O-7:CJ5L, 3�P�2CGDKD6.
62
�!
• ���2�0'>;G=AB8�.2��7+244�"1�-356)/3$*'.�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
��=�,
• ��!9�-6CIE�$9>+�=�%�, ���E��581C4:3�1. +��$9>��)B/�9� E *6C.
• �-"#3.;��90D?,��<GIH58��IFJK9A&12A5D;13, 7=�>�$@=(�:�+;IFJK3�':;C.
64