抗生素使用之最新發展

中國醫藥大學 附設醫院

感染科 王任賢主任

2

抗生素使用之最新發展

• De-escalating therapy

• Pharmacokinetic & Pharmacodynamic

• Mutation prevention concentration

• Induction of lactamase

• Antibiotics interaction

3

Definition of De-Escalation Therapy

• Initial Appropriate Broad-Spectrum Therapy Followed by a De-escalation of Antibiotic Therapy

The Importance of Initial Appropriate Therapy

5

Defining Appropriate Therapy

• Inadequate therapy – “. . .the microbiological documentation of infection…that was not effectively

treated at the time the causative microorganism and its antibiotic susceptibility were known…”1

• Other factors to consider in defining appropriate therapy:1,2

– Microbiologic data (including lack of consistently predicting outcome based on in vitro susceptibility)

– Monotherapy versus combination therapy– Dose and dosing frequency– Penetration– Timing– Toxicity– Risk of influencing resistance– Prior antibiotic use

1. Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.2. Kollef MH et al. Chest 1999;115:462-474.

Dudas StudyDudas Study

Change in Initial Antibiotic

ICU Admission

>8 h to Administration of First Antibiotic

Age (Decades)

SCr (1.0 mg/dL)

RR (10 Breaths/Min)

WBC 10,000 Cells / mm3

2nd / 3rd Generation CEPH 2nd / 3rd Generation CEPH or or -Lactam / -Lactam / -Lactamase Inhibitor + -Lactamase Inhibitor + Macrolide (non-ICU)Macrolide (non-ICU)

2nd / 3rd Generation CEPH 2nd / 3rd Generation CEPH or or -Lactam / -Lactam / -Lactamase Inhibitor + -Lactamase Inhibitor + Macrolide (ICU)Macrolide (ICU)

Change in Initial Antibiotic

ICU Admission

>8 h to Administration of First Antibiotic

Age (Decades)

SCr (1.0 mg/dL)

RR (10 Breaths/Min)

WBC 10,000 Cells / mm3

2nd / 3rd Generation CEPH 2nd / 3rd Generation CEPH or or -Lactam / -Lactam / -Lactamase Inhibitor + -Lactamase Inhibitor + Macrolide (non-ICU)Macrolide (non-ICU)

2nd / 3rd Generation CEPH 2nd / 3rd Generation CEPH or or -Lactam / -Lactam / -Lactamase Inhibitor + -Lactamase Inhibitor + Macrolide (ICU)Macrolide (ICU)

VariableVariableVariableVariable p Valuep Valuep Valuep ValueOdds RatioOdds Ratio

(95% Cl)(95% Cl)Odds RatioOdds Ratio

(95% Cl)(95% Cl)

Predictors of Mortality: Multivariate AnalysisPredictors of Mortality: Multivariate Analysis

0.0001

0.003

0.004

0.0001

0.04

0.0001

0.02

0.009

0.26

0.0001

0.003

0.004

0.0001

0.04

0.0001

0.02

0.009

0.26

3.3 (2.1 to 5.1)

2.5 (1.4 to 4.7)

2.6 (1.3 to 4.9)

1.5 (1.3 to 1.8)

1.2 (1.0 to 1.4)

1.9 (1.5 to 2.4)

1.4 (1.1 to 1.9)

0.4 (0.2 to 0.8)

0.5 (0.2 to 1.6)

3.3 (2.1 to 5.1)

2.5 (1.4 to 4.7)

2.6 (1.3 to 4.9)

1.5 (1.3 to 1.8)

1.2 (1.0 to 1.4)

1.9 (1.5 to 2.4)

1.4 (1.1 to 1.9)

0.4 (0.2 to 0.8)

0.5 (0.2 to 1.6)

Annals of Pharmacotherapy, 2000; 34:446-452Annals of Pharmacotherapy, 2000; 34:446-452Annals of Pharmacotherapy, 2000; 34:446-452Annals of Pharmacotherapy, 2000; 34:446-452

7

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

20

30

40

50

60

All Causes

0

10

20

30

40

50

60

Infection-Related

Ho

spit

al M

ort

alit

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

8

Mortality* Associated with Initial Inadequate Therapyin 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 adequate therapy

Initial inadequate therapy

*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%

9

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

10

20

30

40

50

60

70

% M

ort

alit

y

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%

*

10

Adapted from Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.

• In several VAP studies, most resistant Gram-negative bacteria were associated with the administration of inadequate antimicrobial treatment.

05

10152025303540

P. aer

ugin

osa

S. aur

eus

Acine

toba

cter

spp

other

K. pneu

mon

iae

% Inadequate Treatment of VAP

Inadequate Therapy Closely Associated with Presence of Antibiotic Resistance

% O

ccur

renc

e of

Pat

hoge

n

Pathogen

11

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

12

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.

13

De-Escalation Therapy

Stage 1 • Administering broad-spectrum antibiotic therapy to improve

outcomes (decrease mortality, prevent organ dysfunction, and decrease length of hospital stay)

Stage 2• Focusing on de-escalating as a means to minimize

resistance and improve cost-effectiveness

Note: In some patients, additional therapy to include pathogens not covered with the initial regimen may be necessary.

14

Pathogens of Community-acquired infection

• Pulmonary:S. pneumoniae, H. influenzae, M. catarrhalis

• Skin & soft tissue:Streptococci, Staphylococci,

Enterobacterioceae• Intraabdomen:

Enterobacterioceae, Anaerobes, Enterococci• CNS:

S. pneumoniae, H. influenzae, N. meningitidis

15

Pathogens of nosocmial infection

• Pulmonary: Enterobacterioceae, Pseudomonas, Acinetobacter, MRSA

• Intraabdomen:Enterobacterioceae, Pseudomonas,

Anaerobes, Enterococci, Candida• CNS:

MRSA, Pseudomonas

16

Antimicrobial spectrum of penicillin G

• Streptococcus spp.

• Anaerobes

• Neisseria spp.

17

Second generation penicillins

• Anti-Staphylococcus penicillinsStreptococcus, Staphylococcus

• Ampicillin and derivativesStreptococcus, anaerobes, Neisseria, E. coli, P. mirabilis, Salmonella, Shigella, H. influenzae, Listeria monocytogenes

• Amoxicillin/clavulanic acid (augmentin) Ampicillin/sulbactam (unasyn)

18

Third generation penicillins

• Lilacillin

• Ticarcillin

• Piperacillin

• Piperacillin/tazobactam Ticarcillin/clavulanic acid

19

First generation cephalosporins

• Staphylococcus

• Streptococcus

• E. coli

• P. mirabilis

• K. pneumoniae

第一代與第二代 cephalosporins的分野

Hemophilus influenzae

第二代與第三代 cephalosporins的分野

CNS penetration

22

Ertapenen coverage of community-acquired pathogens

• Pulmonary:S. pneumoniae, H. influenzae, M. catarrhalis

• Skin & soft tissue:Streptococci, Staphylococci,

Enterobacterioceae• Intraabdomen:

Enterobacterioceae, Anaerobes, Enterococci• CNS:

S. pneumoniae, H. influenzae, N. meningitidis

23

Imipenem/Meropenem coverage of nosocmial pathogens

• Pulmonary: Enterobacterioceae, Pseudomonas, Acinetobacter, MRSA

• Intraabdomen:Enterobacterioceae, Pseudomonas,

Anaerobes, Enterococci, Candida• CNS:

MRSA, Pseudomonas

24

Candidate of empirical treatment

• Community acquired infectionAmpicillin/sulbactam, Amoxicillin/clavulanic acid,Ertapenem

• Nosocomial infectionImipenem/cilastatin,

Meropenem,Piperacillin/tazobactam

PK and PD

26

What is PK and PD ?

• Pharmacokinetics (PK) is what the body does to a drug. This includes absorption, distribution, metabolism, and excretion

• Pharmacodynamics (PD) describes the biochemical and physiologic effects of the drug and its mechanism of action i.e. what the drug does to the body (or micro-organism in the case of antibiotics)

27

Relationship between PK and PD

From Craig WA. Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1–12.)

28

Drug Penetration Issues: % tissue/serum

61%15~40%10~20%7Peritoneal dialysis fluid

94%12~40%11~30%6Muscle

104%1477%10Inflammatory blister fluid

450%1311%–17%4,5ELF

70%13~10%90%–18%2,3CSF

60%12~50%–60%87%–13%1Bone

Linezolid Teicoplanin Vancomycin Tissue

1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Blevins 1984; 8. Wilson 2000; 9. Stahl 1987; 10. Wise 1986; 11. Frank 1997; 12. Lovering 2002; 13. SmPC; 14. Gee 2001; 15. Gendjar 2001.

29

Concentration of antimicrobial drugs in respiratory fluids and tissues (Ratio sputum/serum %)

• Amikin 24• Amoxicillin 3-6• Ampicillin 3-10• Cefaclor 8-10• Cefotaxime 25• Cefoxitin 20-25• Cefuroxime 18• Doxycycline 20-35• Enoxacin 100

• Erythromycin 5• Gentamicin 27-40• Isepamicin 80• Minocin 28-60• Netilmicin 14-20• Ofloxacin 78-103• Piperacillin 4-15• TMP/SMX >100/13-18

Eur Respir J 1990;3 :715-22

30

Important PK/PD Parameters

• AUC/MIC is the ratio of the AUC to MIC

• Peak/MIC is the ratio of the peak concentration to MIC

An

tib

ioti

c co

nce

ntr

atio

nMIC

Time

Area under the curve over MIC

PEAK

31

Important PK/PD Parameters

• Time above MIC : Proportion of the dosing interval when the drug concentration exceeds the MIC

Time above MICTime

An

tib

ioti

c co

nce

ntr

atio

n (

ug

/ml)

2

Drug A

Drug B

A

B

4

6

8

0

32

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

33

Time dependent Killing

• Dosing regimen should maximise the duration of time above MIC

• The unbound serum concentration of the antibiotic should be above the MIC for at least 40% to 50% of the dosing interval

Time above MICTime

2

Drug A

Drug B

A

B

4

6

8

0

34

Time-dependent killing

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

Time-dependent Killing

0 20 40 60 80 100

0

20

40

60

80

100

Time above MIC (%)

Penicillins Cephalosporins

Mo

rtal

ity

afte

r 4

day

s o

f th

erap

y (%

)

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%

36

Time-dependent killing

• Clinical cure rates in otitis media and sinusitis was higher than 80% when the T>MIC for betalactam antibiotics exceeded 40% of the dosing interval. (Dagan etal. J Antimicrob Chemother 2001; 47:129-140

37

Concentration-dependent killing

• Dosing regimen should aim to maximise the area under the curve (AUC) or the peak concentration

• Both AUC/MIC and Peak/MIC are predictors of bacterial eradication

• AUC/MIC and Cmax/MIC are covariates; when AUC/MIC increases the Cmax/MIC also increases

38

Concentration-dependent killing

• The 24 hour AUC/MIC ratio should be– =or >100 for severe

infections and in immunocompromised hosts

– =or > 25 for less severe infections and immunocompetent hosts

– =or>100 to prevent emergence of resistant mutants

From : Jacobs MR. Int J Infectious Dis 2003( Suppl 1); 7: S13-20.

An

tib

ioti

c co

nce

ntr

atio

n

Time

Area under the curve over MIC

PEAK

39

Concentration-dependent killing

• Time kill curves for Pseudomonas aeruginosa ATCC 27853 with exposure to tobramycin, ciprofloxacin, and ticarcillin at concentrations from one fourth to 64 times the minimum inhibitory concentration. (From Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro: A review. Scand J Infect Dis. 1991;74:63–70.)

40

Concentration-dependent killing

• In a rat model of pneumococcal pneumonia, reliable killing by fluoroquinolones was achieved when the AUC/MIC > 25 (Berry et al J Antimicrob Chemother 2000; 45 [Suppl 1] : 87-93)

3 4

23

3

100

10

10

20

30

40

50

60

70

80

90

100

No

. o

f p

ati

en

ts

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

42

Concentration-dependent killing

• Probability graph for temperature normalization for Cmax/MIC ratio for aminoglycosides in 78 patients with culture-proven nosocomial gram-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 ResistanceP

rob

abil

ity

of

rem

ain

ing

su

scep

tib

leP

rob

abil

ity

of

rem

ain

ing

su

scep

tib

le

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

Mutation prevention concentration

Dong Y et al. 1999. Antimicrob Agents and Chemother. 43:1-3

Mutation prevention concentration• Antibiotics differ in their:

– bactericidal activity [MIC for 104]– ability to prevent the selection of resistant mutants [MPC]

• MPC = minimal antibiotic concentration that prevents the selection of first-step resistant mutants in the presence of large numbers of cells (1010)

• Low MICs do not necessarily predict low MPCs• Antibiotics with low MPCs prevent the selection and

spread of resistant bacterial strains

2 in 1 billion 200 in 1 million 20 in 200 million

Selective Amplification of Resistant Mutants

Wild-type cells

Resistant mutants

Compromised immune system

Healthy Immune system Clearance

of infection

Spread

Outbreak

MIC

Selective Amplification of Resistant Mutants

Wild-type cells

Resistant mutants

Help from Immune system

Clearance of infection

X

Clearance of infection

MPC

Time post-administration

MIC

MPC

Se

rum

or

tissu

e d

rug

co

nce

ntr

atio

nMutant Selection Window (MSW)

MSW

Seru

m o

r ti

ssu

e d

rug

con

cen

trati

on

Time post-administration

Zhao & Drlica J Infect Dis 2002;185:in press

Maximal Safe Concentration (MSC)

MPC

MIC

Cmax

toxic

No mutant

MSW

Mutant Prevention Window

S. pneumoniae MPC of Fluoroquinolones

Emerging Infectious Diseases 2003;9(1):1-9Emerging Infectious Diseases 2003;9(1):1-9

Cmax MIC90 MPC

Gatifloxacin

400mg qd

4.2 µg/mL 0.5 µg/mL 4 µg/mL

Levofloxacin

500mg qd

5.7 µg/mL 1 µg/mL 8 µg/mL

Moxifloxacin

400mg qd

4.5 µg/mL 0.25 µg/mL 2 µg/mL

Induction of AmpC -lactamase

52

細胞壁 peptidoglycan 之建構單元

-D-ala-D-ala

G

M

pentapeptide

M: N-acetylmuramic acid (MurNAc)G: N-acetylglucosamine (GlcNAc)Tripeptide: L-Ala-D-Glu-m-A2-pmD-ala: D-alanine

tripeptide

53

細胞壁的合成過程

G M G M

G GM M

G M

G M

Transglycosylation

Transpeptidation

54

AmpC -lactamase

AmpC b-lactamase 為細菌染色體上 ampC 基因的產物

存在於 Salmonella 以外的任何腸內菌及 Pseudomonas aeruginosa 中

為一個 cephalosporinase

55

ampR and ampC

ampR 基因位於 ampC 基因的上游位置，二者間隔著 38 bp 的間距

ampR 的基因產物為 AmpR 蛋白，其為一DNA binding protein

AmpR 的 receptor 即為 ampR/ampC 之間距，二者結合可促進 ampC 產生 AmpC b-lactamase

56

ampR and ampC

ampR ampC AmpR binding site

AmpR

AmpR

AmpC

promote：

細胞壁建構原料之取得方式自行合成 (Biosynthesis)資源回收 (Recycling)

58

細胞壁原料之取得 : 自行合成

細胞膜細胞質 , cytosol Periplasmic space

M UDP

M UDP

M UDP

L

G UDP

L GM

L

L

L GM

GM

L : lipid transporter

AmpR repressor

59

細胞壁原料之取得 : 資源回收 大部分 peptidoglycan 的分解產物均會穿越細胞膜回收再利用

主要分解產物為 ，經由細胞膜上的 AmpG (permease) 而再吸收

但只有 可再利用來合成細胞壁，故再利用前要先行分解，這項分解任務由 AmpD 來執行

MG

60

AmpD 的作用

G M G MM M

或 + +AmpD

AmpD=N-acetyl-anhydromuramyl-L-alanine amidase

M = 1, 6-anhydro-N-acetylmuramic acid

A

A 為很強的 AmpR inducer ，因此可促進 AmpC 的合成

Gmase

61

當細菌正常生長時 細胞質內 UDP-MurNAc-pentapeptide 為主要細胞壁合成的中間產物，其可有效的抑制 AmpR 的活性，因此抑制了 AmpC 的產生

除非 -----ampD 突變，失去了功能細菌碰到抗生素了

62

當細菌碰到 b-lactam 抗生素時 Periplasmic space 出現大量 peptidoglycan 分解產物，其中大部分會進入細胞質內

分解產物中 anhMurNAc-tripeptide 為很強的 AmpR inducer ，當 AmpD 沒法處理時可造成 AmpC 大量生成

AmpC 的產生是很快的，一旦產生大量只對 cefepime 及 carbapenem 有效

63

Inducible AmpC -lactamase

可因抗生素的使用而誘發出來，可見於：Enterobacter species

Serratia marcescensHafnia alvei

Citrobacter freundiiIndole-positive ProteusProvidencia speciesMorganella morganii

Pseudomonas aeruginosa

64

Induction potential at concentrations below the organisms MIC

Induction potential Rank orderHighest Carbapenems and cephamycins

AminopenicillinsCarbenicillin, ticarcillinUreidopenicillins第 1,2,3 代 cephalosporinsClavulanic acidCefpirome, cefepimeSulfone inhibitors

Lowest Aztreonam

Diagn Microbiolo Infect Dis 1998;31:461-6

Antibiotics interaction

66

Antibiotic Usage Linked to Bacterial Antibiotic Usage Linked to Bacterial Resistance: A Prospective StudyResistance: 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 Prior Antibiotic 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

ep

iso

des

*

67

• 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 Antibiotic Usage Impacts Bacterial ResistanceResistance

VRE = vancomycin-resistant Enterococcus 1. 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.

68

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

69

Mechanism of Cross-Resistance Mechanism of Cross-Resistance Between Quinolones and CarbapenemsBetween Quinolones and Carbapenems

• Published data have shown:– Selection by fluoroquinolones (but not by carbapenems) of nfxc

(mexT) mutant strains of Pseudomonas aeruginosa with:

(1) up-regulated MexEF-OprN pump (efflux), and

(2) down-regulated OprD (decreased permeability)

• Fluoroquinolone use can decrease susceptibility to both fluoroquinolones and carbapenems.

Livermore DM. Clin Infect Dis 2002;34:634-640.

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