濫用抗生素之衝擊

衛生署 疾病管制局中區傳染病防治醫療網

王任賢 指揮官

濫用抗生素之定義

目前沒有人對此下過定義

但由抗生素使用的目的可見出端倪

抗生素使用之目的：將致病細菌殺死，並不對人體產生重大副作用及誘導出抗藥性菌株

濫用抗生素之定義：

抗生素之使用若無法有效將致病細菌殺死，但卻對人體產生重大副作用、或誘導出抗藥性菌株者稱為濫用抗生素

濫用抗生素之種類

一. 無法有效將致病細菌殺死1. 處方無效的抗生素

2. 處方有效的抗生素時沒有遵守藥物動力學之原理

二. 對人體產生重大副作用1. 處方抗生素時未依肝、腎或其他人體因素調整

2. 多種抗生素合併使用

三. 誘導出抗藥性菌株1. 抗生素使用期間過長

2. 固定處方少數抗生素

濫用抗生素之種類

一. 無法有效將致病細菌殺死1. 處方無效的抗生素

2. 處方有效的抗生素時沒有遵守藥物動力學之原理

二. 對人體產生重大副作用1. 處方抗生素時未依肝、腎或其他人體因素調整

2. 多種抗生素合併使用

三. 誘導出抗藥性菌株1. 抗生素使用期間過長

2. 固定處方少數抗生素

抗生素處方之模式

Empirical therapy De-escalation therapy：開始治療即處方有效抗生

素，病人變好後即停藥或換藥

Escalation therapy：開始治療先處方無效抗生素，待培養出來或病人變壞再換藥

Target therapy

Dudas StudyPredictors of Mortality: Multivariate Analysis

0.5 (0.2 to 1.6) 0.262nd/3rd generation CEPH or -lactam/ -lactamase inhibitor + macrolide (ICU)

0.4 (0.2 to 0.8)0.0092nd/3rd generation CEPH or -lactam/ -lactamase inhibitor + macrolide (non-ICU)

1.4 (1.1 to 1.9)0.02WBC 10K/mm3

1.9 (1.5 to 2.4)0.0001RR (10 Breaths/Min)1.2 (1.0 to 1.4)0.04SCr (1.0 mg/dl)1.5 (1.3 to 1.8)0.0001↑Age (Decades)2.6 (1.3 to 4.9)0.004>8 hr to administration of first antibiotic2.5 (1.4 to 4.7)0.003ICU admission3.3 (2.1 to 5.1)0.0001Change in initial antibiotics

Odds Ratio (95% CI)

p ValueVariable

Annals Pharmacotherapy 2000;34:446-452

Lower Mortality for Patients Who Received Initial Adequate Antimicrobial Therapy

Adapted with permission from Kollef MH et al. Chest 1999;115:462-474.

0

10

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60

All Causes0

10

20

30

40

50

60

Infection-Related

Hos

pita

l Mor

talit

y (%

)

Inadequate Therapy Adequate Therapy

p<0.001

p<0.001

In a prospective cohort study of ICU patients with infection (n=655), lower mortality was observed in patients who received initial adequate therapy

Mortality* Associated with Initial Inadequate Therapy in Critically Ill ICU Patients with HAP or Sepsis

0% 20% 40% 60% 80% 100%

Luna, 1997

Ibrahim, 2000***

Kollef, 1998

Harbarth, 2003***

Rello, 1997

Alvarez-Lerma, 1996** Initial adequatetherapy

Initial inadequatetherapy

*Mortality refers to crude or infection-related mortality. **Includes patients with HAP.***Patients had blood stream infections rather than pneumonia as in the other studies.Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.Luna CM et al. Chest 1997;111:676-685.Rello J et al. Am J Respir Crit Care Med 1997;156:196-200.Kollef MH et al. Chest 1998;113:412-420.Ibrahim EH at al. Chest 2000;118:146-155.Harbarth S et al. Am J Med 2003;115:529-535.Valles J et al. Chest 2003;123:1615-1624.

Mortality

Valles, 2003***

24.7%

91%

37%

38%

15.6%

33.3%60.8%

28.4%61.9%

24%39%

63%31%

16.2%

Treatment Can Affect Mortality in Patients With Sepsis: Three Interventions

* “Yes” indicates that patients received the specified treatment, “No” indicates that they did not.1. Bernard GR et al. N Engl J Med 2001;344:699-709.2. Annane D et al. JAMA 2002;288:862-871. 3. Valles J et al. Chest 2003;123:1615-1624.

0

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70

% M

orta

lity

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Activated C protein1

Hydrocortisone2 Adequate antibiotic therapy3

No Yes

31%25%

63%

53%

63%

31%

*

0

20

40

60

80

100

Pre-BAL (n=68) Post-BAL (n=65)

Adequate ATB therapy

Inadequate ATB therapy

Delayed Therapy May Be Inadequate Therapy: Results from a Single-Center Study in VAP

Early appropriate therapy, before bacteriologic data are known, leads to an improved outcome.

ATB = antibiotic; BAL = bronchoalveolar lavageAdapted from Luna CM et al. Chest 1997;111:676-685.

% M

orta

lity

70%

91%

38%

71%

p<0.01

p=NS

Correct Timing of Antibiotic Administration May Improve Survival

In a prospective surveillance study of 107 patients with VAP:1 30.8% (33 of 107) had initially delayed appropriate antibiotic

therapy (IDAAT; therapy delayed for >24 hours after meeting diagnostic criteria for VAP).

Hospital mortality rate of 69.7% in patients with IDAAT versus 28.4% in patients without IDAAT.

In a retrospective cohort study of pneumonia in 14,069 Medicare patients:2 Administering antibiotics within 8 hours of hospital arrival and

collecting blood cultures within 24 hours was associated with improved survival

1. Iregui M et al. Chest 2002;122:262-268.2. Meehan TP et al. JAMA 1997;278:2080-2084.

Antibiotic Usage Linked to Bacterial Resistance: A Prospective Study

A greater percentage of VAP episodes was caused by potentially drug-resistant bacteria* in patients with prior antibiotic therapy.

0

10

20

30

40

50

60

70

With PriorAntibiotic Therapy

(n=96)

Without PriorAntibiotic Therapy

(n=39)

135 episodes of VAP

*Methicillin-resistant Staphylococcus aureus, P. aeruginosa, A. baumannii, S. maltophiliaTrouillet J-L. Am J Respir Crit Care Med 1998;157:531-539.

% V

AP e

piso

des*

處方有效的抗生素時沒有遵守藥物動力學之原理

PK/PD and Antimicrobial Efficacy 3 patterns of bacterial killing

Concentration dependent with prolonged persistent effect Aminoglycosides, quinolones Correlated with AUC/MIC , Peak/MIC

Time dependent with no persistent effect Betalactams Correlated with Time above MIC (T>MIC)

Time dependent with moderate to prolonged persistent effect Macrolides, azalides, clindamycin, tetracyclines,

glycopeptides, oxazolidinones Correlated with AUC/MIC

Craig, 4th ISAAR, Seoul 2003

Time-dependent killing

The relationship of time above MIC and the reduction in bacterial count in a neutropenicmouse model of Klebsiella pneumoniaefor cefotaxime. (Craig WA. Diagn Microbiol Infect Dis. 1995;22:89–96.)

Time-dependent Killing

0 20 40 60 80 1000

20

40

60

80

100

Time above MIC (%)

Penicillins Cephalosporins

Mor

talit

y af

ter 4

day

s of

ther

apy

(%)

Craig. Diagn Microbiol Infect Dis 1996; 25:213–217

Mortality of animals infected with pneumococci was 100% when T>MIC = or less than 20%Survival was 90% - 100% when T>MIC exceeded 40%-50%

Time-dependent killing

Clinical cure rates in otitismedia and sinusitis was higher than 80% when the T>MIC for betalactamantibiotics exceeded 40%of the dosing interval. (Dagan etal. J Antimicrob Chemother2001; 47:129-140)

Concentration-dependent killing

In a rat model of pneumococcalpneumonia, reliable killing by fluoroquinolones was achieved when the AUC/MIC > 25(Berry et al J Antimicrob Chemother2000; 45 [Suppl 1] : 87-93)

3 4

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No.

of

patie

nts

AUC:MIC <25 Peak:MIC <3

AUC:MIC 25-100 Peak:MIC 3-12

AUC:MIC >100 Peak:MIC >12

Success

Failure

Bacteriologicfailure rate 43% 11.5% 1%

Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5-14 days

Preston et al., JAMA 1998, 279:125-129

Bacteriologic outcome

Concentration-dependent killing

Probability graph for temperature normalization for Cmax/MIC ratio for aminoglycosides in 78 patients with culture-proven nosocomialgram-negative pneumonia. From Kashuba et al. Interscience Conference on Antimicrobial Agents and Chemotherapy, September 1996 Abstract A100 .

Thomas JK et al. Antimicrob Agents Chemother. 1998;42:521-527.

AUIC and ResistancePr

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ility

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emai

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ible

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ty o

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aini

ng s

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00

2525

7575

5050

100100

00 55 1010 1515 2020

Days from initiation of TherapyDays from initiation of Therapy

AUIC<100AUIC<100

AUIC>101AUIC>101

濫用抗生素之種類

一. 無法有效將致病細菌殺死1. 處方無效的抗生素

2. 處方有效的抗生素時沒有遵守藥物動力學之原理

二. 對人體產生重大副作用1. 處方抗生素時未依肝、腎或其他人體因素調整

2. 多種抗生素合併使用

三. 誘導出抗藥性菌株1. 抗生素使用期間過長

2. 固定處方少數抗生素

Myelosuppression of Linezolid(n=828)

60 (7.2)41 (4.9)16 (1.9)117 (14.1)All heme events

02 (0.2)02 (0.2)Pancytopenia

12 (1.5)5 (0.6)1 (0.12)18 (2.2)Leukopenia

24 (2.9)8 (1.0)3 (0.4)35 (4.2)Anemia

24 (2.9)26 (3.1)12 (1.4)62 (7.2)Thrombocytopenia

>28 days(n/%)

14–28 days(n/%)

<14 days(n/%)

Total(n/%)Adverse Event

• Patients treated > 28 days = 272; 14-28 = 301; < 14 days = 255

Important Safety Considerations (1) Myelosuppression (including anemia, leukopenia,

pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid

When linezolid was discontinued, the affected hematologic parameters rose toward pretreatment levels

If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is considered absolutely necessary to continue therapy

ZYVOX® [summary of product characteristics], New York, NY: Pfizer Inc; August 2005.

Important Safety Considerations (2) Close monitoring of blood counts is

recommended in patients who:1. Have pre-existing anemia, granulocytopenia, or

thrombocytopenia2. Are receiving concomitant medications that may

decrease hemoglobin levels, depress blood counts, or adversely affect platelet count or function

3. Have severe renal insufficiency4. Receive more than 10 to 14 days of therapy

Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression

ZYVOX® [summary of product characteristics], New York, NY: Pfizer Inc; August 2005.

Impact of Increasing VancomycinDosage Recommended vancomycin trough level 10 – 15 mg/L or 15 – 20 mg/L Achievable by 15 mg/kg ever 12 hour Need of a loading dose: 25 mg/kg

Baddour LM, et al. Circulation 2005;111:e394 – 434 Gemmell CG, et al. J Antimicrob Agent 2006;57:589 – 608

Wang JT, et al. J Antimicrob Agent 2001;47:246

Higher trough level? 20 – 25 mg/L: no outcome difference More renal toxicity

Wysocki M, et al. Antimicrob Agents Chemother 2001;45:2460 – 7

Voriconazole PK VariabilityTotal Daily Dose Trough, median

(range)Undetect. < 0.5 g/mL

200 mg 2.16 (0 - 3.07) 25% 25%

400 mg 1.09 (0 - 11.11) 15% 28%

500 mg 1.67 (0 - 5.9) 10% 20%

600 mg 1.57 (0 - 6.75) 17% 22%

800 mg 1.65 (0 - 12.5) 25% 38%

Relationship between dose per kg and trough weak (r = 0.26)

Trifilio et al. Cancer 2007; 109: 1532.Trifilio et al. Bone Marrow Trans 2005; 35: 509.

15% undetectable; 25%–62% may be “subtherapeutic”

Voriconazole - Neurotoxicity

Serious neurological adverse events in five patients Confusion, agitation, toxic

encephalopathy, myoclonies, hallucinations

Voriconazole trough concentrations correlated with neurotoxicity Odds ratio 284 (95% CI 0.96

- 84,407) for severe toxicity with 2-fold increase in voriconazole levels

Encephalopathy VRC trough < 5.5 (N=36)

VRC trough > 5.5 (N=16)

Incidence 0 5 (31%)

Interval after VRC start (Range)

NA 9 days (5 - 30)

*Association between neurologic adverse events and elevated voriconazole levels supported by other studies.

Pascual et al. Clin Infect Dis 2008; 46: 201.Imhof et al. Swiss Med Wkly 2006; 136: 739.Tan et al. J Clin Pharmacol 2006; 46: 235.

濫用抗生素之種類

一. 無法有效將致病細菌殺死1. 處方無效的抗生素

2. 處方有效的抗生素時沒有遵守藥物動力學之原理

二. 對人體產生重大副作用1. 處方抗生素時未依肝、腎或其他人體因素調整

2. 多種抗生素合併使用

三. 誘導出抗藥性菌株1. 抗生素使用期間過長

2. 固定處方少數抗生素

Results from a prospective study of 27 VAP patients in a single ICU. Initial empiric therapy was appropriate in all cases (even though Enterobacterand Pseudomonas were the cause of 67% of infections).

Major findings:• Clinical response to VAP therapy occurred within the first 6 days.• Acquired colonization, predominately with resistant pathogens

such as P. aeruginosa or Enterobacteriaceae, usually occurred in Week 2 and frequently preceded a recurrent episode.

• Persistence of endotracheal colonization with these Gram-negative bacteria was likely despite susceptibility to antibiotics.

Conclusion:• 7-day duration of treatment may be sufficient for patients

with VAP.

Lack of Microbiologic Benefit from Prolonged Antibiotic Therapy

Dennesen PJW et al. Am J Respir Crit Care Med 2001;163:1371-1375.

Resolution of VAPResults from a prospective study of 27 VAP patients in a single ICU

showed that parameters of infection improved over time.

Dennesen PJW et al. Am J Respir Crit Care Med 2001;163:1371-1375.

37.838.8

5 (3)

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45

Days

37.5

26.3

6 (2)

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45

DaysDay 0 Day 6 Mean days to resolution (median)

Leuk

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e co

unt

Tem

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2

12.914.2

8 (6)

0

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40

45

Days

Treatment of VAP with a Clinical Guideline with a Shorter Course of Therapy

Ibrahim EH et al. Crit Care Med 2001;29:1109-1115.

Results of a protocol, prospective study of patients (N=102) with clinical diagnosis of VAP with tracheal aspirate or bronchial cultures.• Before period: therapy as per treating physician (n=50). • After period: patients with VAP received antibiotic treatment according to

treatment guidelines; empiric treatment for P. aeruginosa; MRSA with vancomycin, imipenem/ciprofloxacin (selected based on local susceptibility data) (n=52).

• Modify therapy per culture after 24-48 hours; try to STOP therapy after 7 days unless clinically indicated otherwise.

After initiation of guideline:• Similar results in mortality, ICU or hospital length of stay.• Lower occurrence of secondary VAP (p=0.03).

0102030405060708090

100

Before(n=50)

After (n=52)

Optimizing De-escalation: Reducing Occurrence of Second Episode of VAP

0102030405060708090

100

Before(n=50)

After (n=52)

*p<0.001, **p=0.03, Mean APACHE II = 25.6, Mean CPIS = 6.7“Before” = before institution of guideline; “after” = after institution of guideline .Guideline included coverage for potentially resistance P. aeruginosa and MRSA.Adapted from Ibrahim EH et al. Crit Care Med 2001;29:1109-1115.

Results of a single-center, prospective clinical study in patients with VAP showed application of a clinical guideline requiring 7 days of treatment increased the administration of initial adequate antibiotic therapy and decreased overall duration of treatment.

Mortality

*

*No. occurrences

2nd VAP episode Adequate treatment

**

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Comparison of Shorter versus Longer Duration of Therapy for VAP*Results from a prospective, multicenter, randomized, double-blind study of 401 patients with VAP evaluating 8-day (n=197) vs. 15-day (n=204) course of antibiotics found:

• Among patients who had received appropriate initial empiric therapy, comparable clinical efficacy (mortality, recurrence, antibiotic free-days) was observed with 8- and 15-day treatment regimens.

• Multiresistant pathogens emerged more frequently in recurrences from patients treated for 15 days.

• The 8-day group had less antibiotic use (p<0.001).• In patients with infection due to nonfermenting Gram-negative

bacillus, there was a trend towards higher relapse rates with short-duration therapy.

*In non-immunocompromised patients.Chastre J et al. JAMA 2003;290:2588-2598.

Impact of Prolonged Surgical Prophylaxis

DESIGN: Prospective POPULATION: CABG patients (N=2641)

Group 1: pts who received < 48 hours of APGroup 2: pts who received > 48 hrs of AP

Impact of Prolonged Surgical AP OUTCOMES

• Incidence of SSI• Isolation of a resistant pathogen

RESULTS: 43% of patients received AP > 48 hrSSI Incidence• <48 hrs group: 8.7% (131/1502) vs• >48 hrs group: 8.8% (100/1139), p=1.0 Antimicrobial resistant pathogen • OR 1.6 (95% CI 1.1-2.6)

Duration of antibiotic therapy and

Microbiologist/Infectious diseases specialist input

254 ITUs, 34 countries

The greater the specialist input, the shorter the

duration of therapy (P < 0.0001)

Corona et al. JAC 52 (5): 849. (2003)

抗生素固定處方習慣與抗藥性

抗生素固定處方習慣之案例

一碰到發燒就處方cefa + GM 一碰到cellulitis就處方unasuyn/augmentin 一碰到MRSA就處方vancomycin 一碰到病人休克就處方Tienam

MRSA的治療用藥

Vancomycin/Teicoplanin Daptomycin Linezolid Tygacil Quinolone + rifampin Baktar + rifampin Fosfomycin

ESBL之治療選擇

Carbapenems (Tienam, meropenem, ertapenem)

2nd generation cephalosporins Tygacil

MDR-AB之治療選擇

Colistin Tygacil Carbapenem + aminoglycoside Rifampin + carbapenem, tobramycin, colistin

Cycling vs. Mixing and Selective Pressure on a Bacterial Clone

Bergstrom CT, et al. Proc Natl Acad Sci. 2004;101:13285-13290.

•• Cycling offers greater heterogeneity at the level of the ward

• Mixing offers greater heterogeneity at the level of the individual patient

固定某些抗生素之使用可誘導細菌對本身及其他抗生素產生抗藥性

Cephalosporins VRE ESBLs (thus MDR) Penicillins and combination inhibitor resistance Clostridium difficle

Metronidazole VRE All gram negative

Quinolones MRSA VRE ESBLs

Three studies found: In a single-center retrospective study, an increase in VRE

(54 cases/10,000 admissions) was associated with third-generation cephalosporins (p<0.001), metronidazole (p=0.008), and longer duration of quinolone use (p=0.03).1

In a multicenter, prospective study exposure to a -lactam antibiotic containing an oxyimino group (cefuroxime, cefotaxime, ceftriaxone, ceftazidime, aztreonam) was associated with ESBL production (RR 3.8, CI, 1.1 to 13.8).2

In a single-center retrospective study, emergence of broad-spectrum cephalosporin-resistant Enterobacter spp. in 10% (49/477) of patients with previously susceptible isolates, was explained by antibiotic use leading to resistance due to Type I -lactamase expression.3

Antibiotic Usage Impacts Bacterial Resistance

VRE = vancomycin-resistant Enterococcus1. Carmeli Y et al. Emerg Infect Dis 2002;8:802-807.2. Paterson D et al. Ann Intern Med 2004;140:26-32. 3. Kaye KS et al. Antimicrob Agents Chemother 2001;45:2628-30.

Relationship between the use of vancomycin and the development of VRE in U.S.A.

0

2

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UCL – Seminaire de Pathologie Infectieuse – 26 Oct 2000

12 %

Vancomycin and VRE: Stratified

42%44%3rd G cephalopsporin and/or metronidazole: Yes

21%21%3rd G cephalopsporin and metronidazole: No

24%36%No stratification

VancomycinRx Controls

VancomycinRx Cases

Association of Antecedent IV Antibiotic Treatment and VRE

.71.5.005211%21%Quinolones

.71.2.121.74.2%8.2%Imipenem

.81.1.917.9%8.6%Clindamycin

.81.0.071.515%21%Beta-inhibitors

.81.0.041.521%29%Penicillins

.0012.8.0012.65%30%3rd G Cephalosporins

.0082.1.0012.59%20%Metronidazole

.91.0.0161.719%29%Vancomycin

pORpORIV drug

AdjustedUnadjustedControlCase

Effect of duration of IV treatment and VRE

.031.04Quinolones

.31.033rd G Cephalosporins

.161.03Metronidazole

.61.0Vancomycin

pRRRegimen

OR.1 .5 1 5 10

Combined

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Tokars

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Peset

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Ostrowsky 1999

Morris (study 2)

Lucas

Loeb

Loeb

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Henning

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Morris (study 1)

Lucas

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Bhavnani

Meta-analysis on the effect of Anti-GNB agents on VRE

Harbarth S. AAC 2002

Cephalosporins Quinolones

3.6 2.3

Quinolone use and resistance

Dramatic increase in quinolone use Accompanied by increase in proportion of Quinolone-resistant gram negative MRSA C. difficle ESBL

Secular trends in quinolone resistant Enterobacteriaceae

Fluoroquinolones Resistance in USA

Neuhauser MM, JAMA 2003;289:885

PA (r=0.976; p<0.001)

GNB (r=0.891; p<0.001)

Differences Between Various Quinolones in Selecting QR-PA

22%14%36%*Levofloxacinexposure

7.5%8%9.5%Ciprofloxacin exposure

739255117N

ControlQS-PAQR-PAGroup

* OR 2.0, p=0.03 Kaye K. ICAAC 2004

Weber S. EID 2003

Quinolones and S. aureusMRSA vs. MSSA

MRSA

MSSA

Mechanisms of Resistance: Pseudomonas and Efflux Pumps

Adapted with permission from Livermore DM. Clin Infect Dis 2002;34:634-640.

Efflux System Pump (Mex B)

Imipenemand

meropenementer here

Meropenemis pumpedout whileimipenem

is notEfflux SystemExit Portal(OprM)

OuterMembrane

PeriplasmLinkerLipoprotein(Mex A)

CytoplasmicMembrane

Porin

抗生素管制之目的

讓病患獲得最適當的抗生素治療

減少細菌產生抗藥性

In 2002, out of 89 new drugs approved by U.S. FDA, no new antibiotics were approved.

Antibacterial Agents Approved by U.S. FDA, 1983-2004

02

468

101214

16

83-87 88-92 93-97 98-02 '02-04

Source: Speilberg et al. CID May 1, 2004

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