抗生素使用與抗藥性細菌 - 802.mnd.gov.tw · donskey cj, cid;2006:43:s62-9. mice, animal...
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抗生素使用與抗藥性細菌
講師:王振泰
學習目標
學員於上完本門課程後應可以:
1. 瞭解抗生素的重要性與限制。
2. 說明抗生素的感染管制措施與細菌抗藥性監測。
3. 指出正確的抗生素使用方式與抗藥性細菌的產生。
4. 瞭解目前學界提出針對抗藥性細菌因應辦法,並應用這些方法於臨床診治工作中。
課程大綱
概況
防治措施與監測
正確的抗生素使用方式
抗藥性細菌產生
異質性抗生素
總結
概況
For patients presented with severe
infection
Timely effective antibiotics are important.
Using antibiotics too over is associated
with development of drug resistance.
是故進亦憂,退亦憂
抗生素使用之進退維谷
Concept of Collateral Damage
MRSA
VRE
MDR Klebsiella
MDR Enterobacter
MDR Pseudomonas
MDR Acinetobacter
CDI
Antibiotics Antibiotic-resistant
strain
防治措施與監測
Hospitalized Adults
12 Steps to Prevent Antimicrobial Resistance
Vaccinate
Get the catheters out
Target the pathogen
Access the experts
Practice antimicrobial control
Use local data
Treat infection, not contamination
Treat infection, not colonization
Know when to say “no” to vanco
Stop treatment when cured
Isolate the pathogen
Break the chain
1
2
3
4
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10
11
12 Prevent
Transmission
Use Antimicrobials
Wisely
Diagnose &
Treat Effectively
Prevent InfectionsVaccinate
Get the catheters out
Target the pathogen
Access the experts
Practice antimicrobial control
Use local data
Treat infection, not contamination
Treat infection, not colonization
Know when to say “no” to vanco
Stop treatment when cured
Isolate the pathogen
Break the chain
1
2
3
4
5
6
7
8
9
10
11
12
Vaccinate
Get the catheters out
Target the pathogen
Access the experts
Practice antimicrobial control
Use local data
Treat infection, not contamination
Treat infection, not colonization
Know when to say “no” to vanco
Stop treatment when cured
Isolate the pathogen
Break the chain
1
2
3
4
5
6
7
8
9
10
11
12 Prevent
Transmission
Use Antimicrobials
Wisely
Diagnose &
Treat Effectively
Prevent Infections
For disease X, three sufficient causes and component cause A is necessary.
Concept of Sufficient and Component
Causes
AB
CD
E
FA
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HI
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KA
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N
AB
CD
E
FA
B
CD
E
FA
G
HI
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KA
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HI
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KA
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A
L
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AB
CD
E
FA
G
HI
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KA
L
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N
AB
CD
E
FA
B
CD
E
FA
G
HI
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KA
G
HI
J
KA
L
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AB
CD
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FA
G
HI
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KA
L
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N
AB
CD
E
FA
B
CD
E
FA
G
HI
J
KA
G
HI
J
KA
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N
A
L
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N
A group of evidence-based
interventions
When implemented together, result
in better outcomes than when
implemented individually.
The Concept of Bundle Care
資料來源:5 Millions Lives Campaign. Getting Started Kit: Prevent Central Line infections How-to Guide.
Cambridge, MA: institute for Healthcare Improvements; 2008. www.ihi.org
Trap of Cause Inference
There exists different sufficient
causes
Even the true sufficient causes is
same, different study result may be
present.
AB
CD
E
FA
B
CD
E
FA
B
CD
E
FA
B
CD
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FA
B
CD
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CD
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B
CD
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FA
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CD
E
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CD
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CD
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CD
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CD
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F
Application of Bundle Care
應非照單全收其他醫院的Bundle care
要了解自己醫院的問題、長處
Sufficient cause的概念
Start small, go slow
杜摯:「利不百,不變法;功不十,不易器。」
Diffusion curve concept
現實成面絕非一蹴可幾
Supplemental Strategies to Consider
資料來源:Dellit TH, et al. Clin Infect Dis. 2007;44:159-177.
Relevant to Antibiotic Bundle
Surveillance:
Local epidemiology:
Causative pathogens and their drug
susceptibilities
Using antibiotics correctly
該治療才治療
正確的藥物種類、正確的劑量、正確的療程
避免collateral damage
教育、稽核與回饋
Etiology surveillance
Surveillance of drug resistance
SENTRY, EUCAST, TSAR
知己知彼,百戰不敗
More refined empirical therapy
More confident when culture results
being negative
Longitudinal Surveillance
正確的抗生素使用方式
取決於醫師的臨床能力
非細菌感染而投予抗生素
看的見非敵人,真正的敵人看不見
沒有理想的指標,可以明白的提供參考
Procalcitonin (PCT)?
C-reactive protein (CRP)?
該治療才治療:正確的診斷
Meta-analysis:with non-infection
New Marker of Bacterial Infections(1/2)
P < 0.05 P < 0.05
Sensitivity Specificity
Meta-analysis:with viral infection
New Marker of Bacterial Infections(2/2)
P < 0.05 P > 0.05
Sensitivity Specificity
Penetration
CNS, prostate (chronic), intracellular
Vegetation
Prosthesis – related
Microenvironment
Aminoglycosides:避免酸性、厭氧環境
Daptomycin:inactivated by surfactant
正確的種類(1/2)
Specific host factors:
Allergic history, renal, and liver function,
underlying diseases, concomitant
medication , etc.
正確的種類(2/2)
體重
體重過重時:
Ideal body weight versus true body weight
體重剛好或過輕時:true body weight
高劑量的時機
Immunocompromised host, CNS infection,
endocarditis, arthritis, osteomyelitis, etc.
PK/PD data之運用
Time –, concentration –, and AUC –
dependent
正確的劑量
Pharmacodynamics of antimicrobial agents
Relationship of AUIC & Resistance
Relationship of AUIC & Efficacy
資料來源: Madaras-Kelly KJ, et al. AAC 1996;627-32
Relationship of Cmax/MIC & efficacy
資料來源: Preston SL, et al. JAMA 1998;279:125-9
Clinical response:
levofloxacin
Clinical response:
levofloxacin
Microbial response:
levofloxacin
Microbial response:
levofloxacinClinical response:
levofloxacin
Clinical response:
levofloxacin
Microbial response:
levofloxacin
Microbial response:
levofloxacin
For the treatment for MRSA
Vancomycin:AUIC > 400 is needed
Not reachable when MIC ≥ 2 mg/L
Daptomycin:AUIC > 800 is needed
Increasing dosage to 8 mg/kg when
MIC=1mg/L
Other Important Examples
Depends on the risk of disease
relapse
Sites, species, speed of clinical response
Presence of abscess or foreign body
Examples :
Pneumonia:depend on clinical response
Meningitis 1 - 3 weeks
Endocarditis 4 - 6 weeks
Osteomyelitis > 6 weeks
正確的療程(1/3)
正確的療程(2/3)
資料來源: Boucher H, et al. Abstract L – 1204 in ICAAC 2006
Ventilator-associated pneumonia
NFGNB:15-day duration
Other pathogens:7-day duration
正確的療程(3/3)
資料來源:Chastre J et al. JAMA 2003;290:2588-2598.
Dennesen PJW et al. Am J Respir Crit Care Med 2001;163:1371-1375.
brahim EH et al. Crit Care Med 2001;29:1109-1115.
Breaking colonization resistance
創造契機
Selective pressure
永續經營
Collateral Effect of Abx on Bacteria
抗藥性細菌產生
抗藥性細菌產生
人體內可供細菌移生總容量 具抗藥性細菌
具感受性細菌 Antibiotics breaks
colonization resistance
MDR bacteria in pool
具抗藥性細菌
臨床之感染與問題
Antibiotics
Selective pressure
Cross transmission via
various vectors
人體內可供細菌移生總容量 具抗藥性細菌
具感受性細菌 Antibiotics breaks
colonization resistance
MDR bacteria in pool
具抗藥性細菌
臨床之感染與問題
Antibiotics
Selective pressure
Cross transmission via
various vectors
Colonization Resistance (1/2)
資料來源:Hoyen CK et al., AAC;2003:47:3610-2.
Stiefel U et al., ICHE;2004;25:373-9.
Pultz NJ, et al., AAC;2005:49:3513-6.
Donskey CJ, CID;2006:43:S62-9.
Mice, animal
models
Mice, animal
models
Colonization Resistance (2/2)
資料來源: Donskey CJ, CID;2006:43:S62-9
Healthy volunteer
Indigenous E. coli Ciprofloxacin-resistant GNB
Healthy volunteer
Indigenous E. coli Ciprofloxacin-resistant GNB
減少對colonization resistance的破壞
人體的indigenous flora以anaerobes為大宗
不隨便使用具有anti-anaerobes效果之抗生素
Strategies on Antibiotics(1/2)
資料來源: Donskey CJ, CID;2006:43:S62-9
減少selective pressure
Under epidemic settings
減少特定的抗生素:antibiotic replacement
Under endemic settings
Antibiotic heterogeneity
Short course treatment and de-escalating
regimen
Strategies on Antibiotics(2/2)
Antibiotics Replacement
Oral vancomycin for C. difficile
VRE增加,改用metronidazole
Rocephin / Fortum
ESBL-producing strain增多,改用Tazocin
或Maxipime
不勝枚舉的例子
資料來源:Pena C, et al., AAC 1998;42:53-8.
Patterson JE, et al., ICHE 2000;21:455-8.
Landman D, et al., CID 1999;28:1062-6.
資料來源: HICPAC. MMWR 1995;44:1-13
Fluoroquinolones
FQ-resistant P. aeruginosa增多,改用其他抗生素
不勝枚舉的例子
資料來源:Paramythiotou E, et al. CID 2004;38:670-7.
Tacconelli E, et al., EID 2002;8:220-1.
ICU patients, matched case-control
Multivariate analysis
Variable other than antibiotics:
Only the duration of previous ICU stay
remaining a significant factor
Variable of antibiotics:
Imipenem
Meropenem
Ceftazidime
台灣之光(?):P(X)DRAB(1/2)
資料來源: Tsai HT, et al., DMID, 2008
台灣之光(?):P(X)DRAB(2/2)
資料來源: Tsai HT, DMID;2008
異質性抗生素
Antibiotic cycling
minimize the emergence of resistance
because selection pressure for bacteria to
develop resistance to a specific antibiotic
would be reduced as organisms become
exposed to continually varying
antimicrobials.
Heterogeneity of Antibiotics(1/3)
資料來源: Niederman MS. AJRCCM 1997;156:1029-31
Antibiotic cycling
The problem is
Bacterial population: mixing present, not
symmetrically introduced as happened in so
called cycling.
Heterogeneity of Antibiotics(2/3)
資料來源:Bergstrom CT, et al., PNAS USA 2004;32:53-60.
Overall colonization rate
Heterogeneity of Antibiotics(3/3)
資料來源:Bergstrom CT, et al., PNAS USA 2004;32:53-60.
Mar. 2000 – Oct. 2003
14-bed ICU
Cycling v.s. Diversity: a case study
資料來源: Sandiumenge A, et al. J Antimicrob Agents 2006;57:1197 – 1204
Length and periods of usage
Months 1 – 10
Patient-specific
Months 11 – 22
Prioritization
Months 23 – 34
Restriction
Months 35 – 44
Diversity
Therapy determined by a
patient-specific strategy
•Multiple choice
•Length of stay
•Prior antibiotic exposure
Changed in
consecutive patients
following a pre-
established schedule
APCarbCipClin+
APCephPip/tazo
Length and periods of usage
Months 1 – 10
Patient-specific
Months 11 – 22
Prioritization
Months 23 – 34
Restriction
Months 35 – 44
Diversity
Therapy determined by a
patient-specific strategy
•Multiple choice
•Length of stay
•Prior antibiotic exposure
Changed in
consecutive patients
following a pre-
established schedule
APCarbCipClin+
APCephPip/tazo
Ca
rba
pe
ne
m
Ce
ph
alo
sp
orin
Pip
/ t
azo
No
Pip
/ t
azo
Ce
ph
alo
sp
orin
Ca
rba
pe
ne
m
Months 1 - 10
Patient-specificMonths 11 - 22
Prioritization
Months 23 - 34
Restriction
Months 35 -44
Diversity
Length and periods of usage
Months 1 – 10
Patient-specific
Months 11 – 22
Prioritization
Months 23 – 34
Restriction
Months 35 – 44
Diversity
Therapy determined by a
patient-specific strategy
•Multiple choice
•Length of stay
•Prior antibiotic exposure
Changed in
consecutive patients
following a pre-
established schedule
APCarbCipClin+
APCephPip/tazo
Length and periods of usage
Months 1 – 10
Patient-specific
Months 11 – 22
Prioritization
Months 23 – 34
Restriction
Months 35 – 44
Diversity
Therapy determined by a
patient-specific strategy
•Multiple choice
•Length of stay
•Prior antibiotic exposure
Changed in
consecutive patients
following a pre-
established schedule
APCarbCipClin+
APCephPip/tazo
Ca
rba
pe
ne
m
Ce
ph
alo
sp
orin
Pip
/ t
azo
No
Pip
/ t
azo
Ce
ph
alo
sp
orin
Ca
rba
pe
ne
m
Months 1 - 10
Patient-specificMonths 11 - 22
Prioritization
Months 23 - 34
Restriction
Months 35 -44
Diversity
Antimicrobial Homogeneity Index
Evaluation of Heterogeneity
資料來源: Sandiumenge A, et al. J Antimicrob Agents 2006;57:1197 – 1204
Results(1/2)
Low antibiotic heterogeneity is
associated with increased antibiotic
resistance
RR=15, CRAB
RR=5, ESBL-producing
Enterobacteriaceae
Results(2/2)
Offers more mixing than cycling
Reduce the overall selective pressure
Should be considered rather than
cycling
Heterogeneity of Antibiotics
資料來源:Bonhoeffer S, et al. PNAC USA.1997;94:12106-12111.
Bonten MJM, et al. CID.2001;33:1739-1746.
Fridkin SK. CID. 2003;36:1438-1444.
Bergstrom CT, et al. PNAS USA.2004;101:13285-13290.
Sandiumenge A, et al. JAC.2006;57:1197-1204
Kollef MH, et al. CID. 2006;43:S82-8.
Stage 1
Administering broad-spectrum antibiotic
therapy to improve outcomes (decrease
mortality, prevent organ dysfunction, and
decrease length fstay)
Stage 2
Focusing on de-escalating as a means to
minimize resistance and improve cost-
effectiveness
DE-ESCALATION THERAPY
資料來源:Kollef MH. CID 2005:40:S85-8
Malacarne P, et al. JAC 2004;54:221-4
教育、稽核與回饋
適當的獎勵:
需要比較高的獎勵
正向增強
適當的處罰:
負向增強
通常只要一點處罰就會有效
總結
終曲
Lack of agents with novel action will
continue well into the future
Need to initiate an effective and
comprehensive infection control
program
Need to develop and implement an
antibiotic optimization program
Evaluate all current therapies for
potential “collateral damage” impact
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