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
抗生素使用之最新發展
• De-escalating therapy
• Pharmacokinetic & Pharmacodynamic
• Mutation prevention concentration
• Induction of β−lactamase
• Antibiotics interaction

2
Definition of De-Escalation Therapy

• Initial Appropriate Broad-Spectrum Therapy

Followed by a De-escalation of Antibiotic
Therapy

3
The Importance of Initial
Appropriate Therapy
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.
5
 Dudas Study
Predictors of Mortality: Multivariate Analysis
Odds Ratio
Variable p Value (95% Cl)
Change in Initial Antibiotic 0.0001 3.3 (2.1 to 5.1)
ICU Admission 0.003 2.5 (1.4 to 4.7)
>8 h to Administration 0.004 2.6 (1.3 to 4.9)
of First Antibiotic
↑ Age (Decades) 0.0001 1.5 (1.3 to 1.8)
SCr (1.0 mg/dL) 0.04 1.2 (1.0 to 1.4)
RR (10 Breaths/Min) 0.0001 1.9 (1.5 to 2.4)
WBC 10,000 Cells / mm3 0.02 1.4 (1.1 to 1.9)
2nd / 3rd Generation CEPH 0.009 0.4 (0.2 to 0.8)
or β-Lactam / β-Lactamase Inhibitor +
Macrolide (non-ICU)
2nd / 3rd Generation CEPH 0.26 0.5 (0.2 to 1.6)
or β-Lactam / β-Lactamase Inhibitor +
Macrolide (ICU)

Annals of Pharmacotherapy, 2000; 34:446-452

Lower Mortality for Patients Who Received
Initial Adequate Antimicrobial Therapy
In a prospective cohort study of ICU patients with infection (n=655), lower
mortality was observed in patients who received initial adequate therapy
60 60
p<0.001
Hospital Mortality (%)

50 50 p<0.001

40 40

30 30

20 20
10 10

0 0
All Causes Infection-Related
Inadequate Therapy Adequate Therapy

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

7
Mortality* Associated with Initial Inadequate Therapy
in Critically Ill ICU Patients with HAP or Sepsis
16.2%
Alvarez-Lerma, 1996** 24.7% Initial adequate
38% therapy
Luna, 1997 91%
Initial inadequate
15.6%
Rello, 1997 37%
therapy
33.3%
Kollef, 1998 60.8%

28.4%
Ibrahim, 2000*** 61.9%
24%
Harbarth, 2003*** 39%
31%
Valles, 2003*** 63%

Mortality
0% 20% 40% 60% 80% 100%
*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. 8
Valles J et al. Chest 2003;123:1615-1624.
 Treatment Can Affect Mortality in Patients With
Sepsis: Three Interventions
70 70 70

60 60 63% 60 63%
50 50 50
% Mortality

53%
40 40 40

30 30 30
31% 31%
20 25% 20 20

10 10 10

0 0 0
Activated C protein1 Hydrocortisone2 Adequate antibiotic
No Yes * therapy3

* “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.
9
Inadequate Therapy Closely Associated
with Presence of Antibiotic Resistance
• In several VAP studies, most resistant Gram-negative bacteria were
associated with the administration of inadequate antimicrobial treatment.

40
% Occurrence of Pathogen

35
30 % Inadequate
Treatment of VAP
25
20
15
10
5
0
Pathogen
r
us
sa

e
pp

he

ia
re
no

ot

on
au

er
gi

um
ct
ru

S.

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ae

to

.p
P.

ne

K
ci
A

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

10
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.
p<0.01
100
p=NS

80 91% Adequate ATB therapy

% Mortality

71% 70% Inadequate ATB therapy

60

40
38%
20

0
Pre-BAL (n=68) Post-BAL (n=65)

ATB = antibiotic; BAL = bronchoalveolar lavage

Adapted from Luna CM et al. Chest 1997;111:676-685.
11
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.
12
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.
13
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

14
Pathogens of nosocmial infection
• Pulmonary:
Enterobacterioceae, Pseudomonas,
Acinetobacter, MRSA
• Intraabdomen:
Enterobacterioceae, Pseudomonas, Anaerobes,
Enterococci, Candida
• CNS:
MRSA, Pseudomonas

15
Antimicrobial spectrum of penicillin G

• Streptococcus spp.
• Anaerobes
• Neisseria spp.

16
Second generation penicillins
• Anti-Staphylococcus penicillins
Streptococcus, Staphylococcus
• Ampicillin and derivatives
Streptococcus, anaerobes, Neisseria, E.
coli, P. mirabilis, Salmonella, Shigella, H.
influenzae, Listeria monocytogenes
• Amoxicillin/clavulanic acid (augmentin)
Ampicillin/sulbactam (unasyn)

17
Third generation penicillins
• Lilacillin
• Ticarcillin
• Piperacillin
• Piperacillin/tazobactam
Ticarcillin/clavulanic acid

18
First generation cephalosporins

• Staphylococcus
• Streptococcus
• E. coli
• P. mirabilis
• K. pneumoniae

19
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
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

22
Imipenem/Meropenem coverage of
nosocmial pathogens
• Pulmonary:
Enterobacterioceae, Pseudomonas,
Acinetobacter, MRSA
• Intraabdomen:
Enterobacterioceae, Pseudomonas, Anaerobes,
Enterococci, Candida
• CNS:
MRSA, Pseudomonas

23
Candidate of empirical treatment
• Community acquired infection
Ampicillin/sulbactam,
Amoxicillin/clavulanic acid,
Ertapenem
• Nosocomial infection
Imipenem/cilastatin,
Meropenem,
Piperacillin/tazobactam

24
PK and PD
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)

26
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.)
27
Drug Penetration Issues: % tissue/serum
Tissue Vancomycin Teicoplanin Linezolid

Bone 7%–13%1 ~50%–60%8 60%12

CSF 0%–18%2,3 ~10%9 70%13

ELF 11%–17%4,5 450%13

Inflammatory
77%10 104%14
blister fluid
Muscle ~30%6 ~40%11 94%12
Peritoneal dialysis
~20%7 ~40%10 61%15
fluid

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.
28
Gendjar 2001.
Concentration of antimicrobial drugs in respiratory
fluids and tissues (Ratio sputum/serum %)

• Amikin 24 • Erythromycin 5
• Amoxicillin 3-6 • Gentamicin 27-40
• Ampicillin 3-10 • Isepamicin 80
• Cefaclor 8-10 • Minocin 28-60
• Cefotaxime 25 • Netilmicin 14-20
• Cefoxitin 20-25 • Ofloxacin 78-103
• Cefuroxime 18 • Piperacillin 4-15
• Doxycycline 20-35 • TMP/SMX >100/13-18
• Enoxacin 100
Eur Respir J 1990;3 :715-22
29
 Important PK/PD Parameters

Area under the curve

• AUC/MIC is the ratio over MIC

concentration
of the AUC to MIC

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

Time

30
 Important PK/PD Parameters
• Time above MIC : 8

Antibiotic concentration (ug/ml)

Proportion of the
dosing interval when 6 Drug A
the drug
concentration 4 Drug B
exceeds the MIC
2
B

0 A Time
Time above MIC

31
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

32
 Time dependent Killing
• Dosing regimen should 8
maximise the duration of
time above MIC 6 Drug A
• The unbound serum
concentration of the Drug B
4
antibiotic should be above
the MIC for at least 40%
to 50% of the dosing 2
interval B

0 A Time
Time above MIC

33
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.)

34
 Time-dependent Killing
Penicillins Cephalosporins
Mortality after 4 days of therapy (%)

100 Mortality of animals infected with

pneumococci was 100% when
80 T>MIC = or less than 20%
Survival was 90% - 100% when
60 T>MIC exceeded 40%-50%

40

20

0
0 20 40 60 80 100
Time above MIC (%)
Craig. Diagn Microbiol Infect Dis 1996; 25:213–217
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

36
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

37
 Concentration-dependent killing

Area under the curve • The 24 hour AUC/MIC ratio

should be
over MIC – =or >100 for severe
concentration
Antibiotic

PEAK infections and in

immunocompromised
hosts
– =or > 25 for less severe
infections and
immunocompetent
hosts
– =or>100 to prevent
emergence of resistant
mutants
Time

From : Jacobs MR. Int J Infectious Dis 2003( Suppl 1); 7: S13-20. 38
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.)
39
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)

40
Levofloxacin PK/PD correlations
134 hospitalized patients with respiratory tract, skin or complicated urinary tract
infections treated with 500 mg qd for 5-14 days

100
100
90 Bacteriologic outcome
No. of patients

80 Success
70 Failure
60
50
40
30 23
20
10 3 4 3 1
0
AUC:MIC <25 AUC:MIC 25-100 AUC:MIC >100
Bacteriologic Peak:MIC <3 Peak:MIC 3-12 Peak:MIC >12
failure rate 43% 11.5% 1%

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

 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 .)

42
AUIC and Resistance
Thomas JK et al. Antimicrob Agents Chemother. 1998;42:521-527.
Probability of remaining susceptible

100

75
AUIC>101

50

25 AUIC<100

0
0 5 10 15 20
Days from initiation of Therapy
Mutation prevention
concentration
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

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

Selective Amplification of Resistant Mutants

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

MIC Compromised
immune system

Spread
Healthy
Immune
system
Clearance
Wild-type cells Outbreak
of infection
Resistant mutants
Selective Amplification of Resistant Mutants
Help from
Immune
system Clearance
of infection
MPC

Clearance
Wild-type cells
of infection
Resistant mutants
 Mutant Selection Window (MSW)
Serum or tissue drug concentration

MPC

MSW

MIC

Time post-administration
Serum or tissue drug concentration
Mutant Prevention Window
Cmax
toxic
Maximal Safe Concentration
(MSC)
No
mutant
MPC

MSW

MIC

Time post-administration

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

S. pneumoniae MPC of Fluoroquinolones

Cmax MIC90 MPC

Gatifloxacin 4.2 µg/mL 0.5 µg/mL 4 µg/mL

400mg qd
Levofloxacin 5.7 µg/mL 1 µg/mL 8 µg/mL
500mg qd
Moxifloxacin 4.5 µg/mL 0.25 µg/mL 2 µg/mL
400mg qd

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

Induction of AmpC β-lactamase
細胞壁 peptidoglycan 之建構單元
tripeptide

M -D-ala-D-ala
pentapeptide
G

M: N-acetylmuramic acid (MurNAc)

G: N-acetylglucosamine (GlcNAc)
Tripeptide: L-Ala-D-Glu-m-A2-pm
D-ala: D-alanine
52
細胞壁的合成過程
Transglycosylation G M G M
G M

G M G M
Transpeptidation

G M

53
AmpC β-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

54
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

55
ampR and ampC

ampR AmpR binding site ampC

promote
AmpR
：

AmpC
AmpR

56
細胞壁建構原料之取得方式
 自行合成 (Biosynthesis)
 資源回收 (Recycling)
細胞壁原料之取得 : 自行合成
L
GM
UDP L
M
UDP UDP
M ML L GM

UDP
G
AmpR repressor
L GM

L : lipid transporter
細胞質 , cytosol 細胞膜 Periplasmic space
58
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 G
 M
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

59
 AmpD 的作用
Gmase
G M M G M M
AmpD
或 + +

AmpD=N-acetyl-anhydromuramyl-L-alanine amidase
M = 1, 6-anhydro-N-acetylmuramic acid

為很強的 AmpR inducer ，因此可促進 AmpC 的合成

60
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

61
當細菌 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

62
Inducible AmpC β-lactamase

 可因抗生素的使用而誘發出來，可見於：
Enterobacter species
Serratia marcescens
Hafnia alvei
Citrobacter freundii
Indole-positive Proteus
Providencia species
Morganella morganii
Pseudomonas aeruginosa

63
Induction potential at concentrations below
the organisms MIC

Induction potential Rank order

Highest Carbapenems and cephamycins
Aminopenicillins
Carbenicillin, ticarcillin
Ureidopenicillins
第 1,2,3 代 cephalosporins
Clavulanic acid
Cefpirome, cefepime
Sulfone inhibitors
Lowest Aztreonam

Diagn Microbiolo Infect Dis 1998;31:461-6 64

Antibiotics interaction
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.
70
135 episodes of VAP
60
% VAP episodes*

50
40
30
20
10
0
With Prior Without Prior
Antibiotic Therapy Antibiotic Therapy
(n=96) (n=39)
*Methicillin-resistant Staphylococcus aureus, P. aeruginosa, A. baumannii, S. maltophilia
Trouillet J-L. Am J Respir Crit Care Med 1998;157:531-539.
66
Antibiotic Usage Impacts Bacterial
Resistance
• 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 β-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 β-lactamase expression.3
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.
67
Mechanisms of Resistance:
Pseudomonas and Efflux Pumps
Meropenem Imipenem
is pumped and
out while meropenem
imipenem enter here
Efflux System is not
Exit Portal
(OprM)
Outer
Membrane

Porin

Periplasm
Linker
Lipoprotein
(Mex A)
Cytoplasmic
Membrane

Efflux System Pump (Mex B)

Adapted with permission from Livermore DM. Clin Infect Dis 2002;34:634-640.
68
Mechanism of Cross-Resistance
Between 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.

69
懇 請 賜 教