β-lactam antibiotic induced VCM-resistant MRSA

BIVR
定義：VCMとβ-lactam薬が拮抗するMRSA(β-lactam薬によってVCM耐性が誘導されるMRSA)

検出方法：VCM４μg/ml含有のBHIAに試験菌を塗抹し、β-lactam薬含有のpaper disc周辺に生育円を確認する。

Detection of BIVR by using Mu3 agar containing 4 μg/mL of VCM

CZX 0.1

CZX 1

CZX 10感受性MRSA

BIVR

耐性度の強いBIVR

疫学調査に使用

BIVRのマウス感染実験
VCM+CZX vs TEIC+CZXTherapeutic effects of vancomycin, and ceftizoxime alone andin combination against murine systemic infection in mice caused by BIVR.

100100

VCM 8 mg/Kg
8080

VCM + CZXSurvival (%)

VCM 4 mg/Kg
606040402020

VCM + CZXCZX 80 mg/Kg

CZX 80 mg/Kg

0001234days

5670

1234567days

波多野、横田、若井、武田Therapeutic effects of vancomycin, teicoplanin, and ceftizoxime alone andin combination against murine systemic infection in mice caused by BIVR.
100

100

TEIC + CZXSurvival (%)

80

80

VCM 4 mg/Kg
606040402020TEIC 8 mg/Kg
VCM + CZXCZX 80 mg/Kg

CZX 80 mg/Kg

0001234days

56701234567days

波多野、横田、若井、武田Induction of VCM-resistance of Mu3 strain by CZX
in condition of high concentration of inoculum size
107 CFU/ml
1.6OD 578nm

1.4
1.2
1
0.8
0.6
0.4
0.2
000.001

0.01

0. 1

1101001000(mConcentration of Ceftizoxime (mg/ml)

β-lactam antibiotic induced VCM-resistant MRSA (BIVR)
Aritaka N., Hanaki H. at al., AAC, 45(4):1292-4, 2001

Appropriate Induction Concentration of β-lactam antibiotic against various kinds BIVR1.6
BIVR-1
BIVR-2
BIVR-3
BIVR-4

1.4

OD 578nm

1.2
10.8
0.6
0.4
0.2
000.001

0.01

0.1

1101001000

Concentration of ceftizoxime ( µ g/ml)
Aritaka N., Hanaki H. at al., AAC, 45(4):1292-4, 2001

Appropriate Induction Concentration of β-lactam antibiotic against BIVR

A. Penicillins.

B. Methoxyimino-cephalosporins.

PCG
DMPPC
MPIPC
MCIPC
ABPC
PIPC

2CXM
CZX
CTRX
CFDN

10.5

100.001

0.01

0.1

11010001000

D. Cephamycins.

0.5

00.0010.01

0.111010001000

E. Monobactams.

CFX
CMZ
LMOX
FMOX
CMNX

0.1

110100

IPM
MEPM
PAPM
BIPM

1.5OD 578nm

OD 578nm
0.11101001000

1Concentration of ß-lactam antibiotics (µg/ml)

01000

2

10.5

0.5

0.01

0.01

F. Carbapenem.

1.5

0.5

0.001

0.001

AZT
CRMN

100

Concentration of ß-lactam antibiotics (µg/ml)

2

1.5

1Concentration of ß-lactam antibiotics (µg/ml)

2

OD 578nm

1.5

0.5

Concentration of ß-lactam antibiotics (µg/ml)

0CAZ
CFIX

OD 578nm

1.5

OD 578nm

OD 578nm

1.50C. Ceftazidime and cefixime.

2200.001

0.010.1

1101001000

Concentration of ß-lactam antibiotics (µg/ml)

000.0010.010.1

1101001000

Concentration of ß-lactam antibiotics (µg/ml)

Aritaka N., Hanaki H. at al., AAC, 45(4):1292-4, 2001

Detection of BIVR by using commercialized paper discs
containing various kinds β-lactam antibiotics
Antibiotics (µ g/ml)

Benzylpenicillin (10)Oxacillin (1)Ampicillin (10)Amoxicillin (25)
Mezlocillin (75)
Piperacillin (100)Ticarcillin (75)
Carbenicillin (100)Sulbenicillin (30)
Ampicillin /Sulbactam (20)
Amoxicillin/Clavulanic acid (30)
Ticarcillin/Clavulanic acid (85)

Cefoxitine (30)
Cefmatazole (30)
Cefotetan (30)
Cefminox (30)
Cefbuperazone (75)
Latamoxef (30)
Flomoxef (30)
Carumonam (30)Imipenem (10)Panipenem (10)Meropenem (10)µ g/ml)

24 hr

48 hr

Antibiotics (－＋＋＋－－－－＋＋＋－＋＋＋＋＋＋－＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋

Cefaclor (30)Cefixime (5)Cefteram (10)
Cefpodoxime (10)Ceftibuten (30)
Ceftamet (10)Cefdinir (5)Cephalothin (30)
Cefsulodin (30)
Cefamandole (30)
Cefotiam (30)
Cefuroxime (30)
Cefotaxime (30)
Ceftizoxime (30)
Cefmenoxime (30)
Ceftriaxone (30)
Cefodizime (30)
Cefoperazone (75)
Ceftazidime (30)
Cefepime (30)
Cefpirome (30)
Cefpiramide (75)
Cefoperazone/Sulbactam (75/30)

24 hr

48 hr＋＋＋＋＋＋＋－－－－＋＋＋＋＋＋－＋＋＋－－＋＋＋＋＋＋＋－－＋－＋＋＋＋＋＋－＋＋＋－－－：濃度を変えることによって全て＋として検出されている
Hanaki H, Inaba Y, et al, Jpn . J. Antibiot., 51 : 521-530, 1998.

BIVRの疫学調査

検体別BIVR検出率（％） 24施設
検出部位

検体数

BIVR数 BIVR検出率（％）

血液髄液
血液カテ
呼吸器
尿便
皮膚・創部
膿

143
12911551039681275

190354431913.2
010.3
4.7
3.9
3.1
1.2
3.3

その他

8622.3

検体総数1969954.8 (4.2)(P<0.001)

Comparison of BIVR detection rate between
blood- and non-blood-isolated MRSA
Numberof BIVRDetection Rateof BIVR(%)

SampleNumberof strains

Blood

749

13417.8

Non-blood3539

1684.8(1999-2002)

4298

302

P＜0.001

Annual transition of BIVR detection rate (%)
from blood

18Detection rate (%)

161412

VCM

1086
420

1/45

1/45

3/50

5/49

134/749

78-84

85-89

90-94

95-99

99-02

Chronological classification
Yamaguchi N, Hanaki H, J.J.A.Inf.D, Vo77, p661‐666 2003

BIVR感染症の症例報告

temperature
41

Burn patient

3937
35Days 1
1910CRP 0.5
25.6
GM 0.83g/kg
PIPC 0.2g/kg
every 24h
every 8hAntibiotics
CPR 0.16g/kg
every 24h

1242735

VCM 20.8mg/kg
every 12h
IPM/CS 62.5mg/kg
every 12h51448.1
ABK 4.2mg/kg ABK 2.5mg/kg
every 24h
every 12h
SBT/ABPC 62.5mg/kg
every 12h

Fu6

Fu10

Fu18

FDA209P

Mu3

Mu50

3
Disk
placement**1. 1:10 μg/ml ; 2:1 μg/ml; 3: 0.1 μg/ml; 4: 0.01 μg/ml, imipenem respectively.

(Haraga、Hanaki、Nagayama et al. Int J Infect Dis Vol.6 No.4 302-8. 2002)

VCM単剤とVCM単剤とβ単剤とβ－ラクタム薬併用における臨床効果
10088.9％9080

臨床効果70

年間数万人

60

p = 0.004 χ245.8％

50n = 42403020100
VCM単剤

VCM ＋β-ラクタム薬：70％以上が併用

第51回日本化学療法学会 演題No.67 賀来先生、谷川先生、相川先生、清水先生