抗生素使用與抗藥性細菌 - 802.mnd.gov.tw · donskey cj, cid;2006:43:s62-9. mice, animal...

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

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12 Prevent

Transmission

Use Antimicrobials

Wisely

Diagnose &

Treat Effectively

Prevent InfectionsVaccinate


Target the pathogen

Access the experts


Use local data






Break the chain

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12

Vaccinate


Target the pathogen

Access the experts


Use local data






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

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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

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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)


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


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


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.


資料來源：Bergstrom CT, et al., PNAS USA 2004;32:53-60.

Overall colonization rate


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


Months 1 – 10

Patient-specific

Months 11 – 22

Prioritization

Months 23 – 34

Restriction

Months 35 – 44

Diversity



•Multiple choice

•Length of stay


Changed in


following a pre-


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


Months 1 – 10

Patient-specific

Months 11 – 22

Prioritization

Months 23 – 34

Restriction

Months 35 – 44

Diversity



•Multiple choice

•Length of stay


Changed in


following a pre-


APCarbCipClin+

APCephPip/tazo


Months 1 – 10

Patient-specific

Months 11 – 22

Prioritization

Months 23 – 34

Restriction

Months 35 – 44

Diversity



•Multiple choice

•Length of stay


Changed in


following a pre-


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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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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