抗生素管制政策

中國醫藥大學 附設醫院
感染科主任 王任賢
 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
 健保現行之抗生素使用原則
• 病患發燒先使用第一線藥物
• 發燒三天不退可改用第二線藥物
• 發燒再三天不退可改用第三線藥物
 Dudas Study
Predictors of Mortality: Multivariate Analysis
Variable p Value Odds Ratio
(95% CI)
Change in initial antibiotics 0.0001 3.3 (2.1 to
ICU admission 0.003 5.1)
2.5 (1.4 to
>8 hr to administration of first antibiotic 0.004 4.7)
2.6 (1.3 to
↑Age (Decades) 0.0001 4.9)
1.5 (1.3 to
SCr (1.0 mg/dl) 0.04 1.8)
1.2 (1.0 to
RR (10 Breaths/Min) 0.0001 1.4)
1.9 (1.5 to
WBC 10K/mm3 0.02 2.4)
1.4 (1.1 to
2nd/3rd generation CEPH or β-lactam/ β- 0.009 1.9)
0.4 (0.2 to
lactamase inhibitor + macrolide (non-ICU) 0.8)
2nd/3rd generation CEPH or β-lactam/ β- 0.26 0.5 (0.2 to
lactamase inhibitor + macrolide (ICU) 1.6)
Annals Pharmacotherapy 2000;34:446-452
讓病患獲得最佳的抗生素治療
• Empirical therapy
訂定醫院內依症候群之抗生素使用原
則，並實施適當的管控
• Definite therapy
須兼顧治療效果及減少抗藥性之產生
 訂定依症候群之抗生素使用原則
• 蜂窩組織炎症候群
• 肺炎症候群
• 腦膜炎症候群
• 腹腔內感染症候群
• 骨關節感染症候群
• 泌尿道感染症候群
• --------
 Empirical therapy 之管控
• 必須要有相對應的電腦診斷碼及病歷記
載，才能開出處方
• 由藥局控管劑量、給藥間距、及治療時
間
 藥局之抗生素管控
• 控管抗生素之劑量、給藥間距、及治療
時間
• 管控抗生素之合併使用
• 管控抗生素之交互作用
• 管控抗生素之副作用
• 管控抗生素之過敏反應
• 不應以培養的有無來管控抗生素之使用
抗生素管制如何降低細菌產生
抗藥性？
 細菌如何產生抗藥性？
• 必須要個僅能將細菌殺個半死的藥物劑
量
• G(+) 細菌是以突變產生抗藥性
• G(-) 細菌主要是以產生 -lactamase 產
生抗藥性
 β-lactam antibiotics
• 與 penicillin binding protein (PBPs) 結
合 PBPs: transpeptidases
DD-carboxypeptidases
• 破壞細胞壁的合成
• 包括 penem, cephem, carbapenem,
monobactam, & sulbactam 五類
 β-lactamase 的多樣性
• 共有 190 種以上的 -lactamase
• 作用機轉：
serine ester hydrolysis
zinc attachment
• 基因來源：
chromosomal
plasmid-borne
β-lactam 抗藥性產生的機轉
∀ 產生 -lactamase
• 改變 PBPs
• 架空 PBPs
• 降低細胞壁的藥物通透性
• 將 -lactams 排出菌體外
Cell wall of Gram-positive bacteria
 Cell wall of
Gram(-) bacteria
 金黃色葡萄球菌的 -lactamase
• Plasmid-borne penicillinase
• 分泌到菌體外，很少能形成高濃度
• 對 benzylpenicillin, α-aminopenicillins,
ureidopenicillin, α-carboxypenicillin 有抗藥性
• 對 methicillin, cephalosporins 沒有抗藥性
• 均可為任一 -lactamase inhibitor 抑制
Ambler’s classification of β-lactamase
• Class A: “penicillinase”
plasmid-mediated, such as TEM and SHV
widely spread among GNB
• Class B: metalloenzymes (Zn2+ dependent)
• Class C: “cephalosporinase”
chromosome-mediated
widely spread among GNB
• Class D: “oxacillinase”
 Bush group 1 β-lactamase
• representive enzymes: AmpC
• cephalosporinase
• resistant to β-lactamase inhibitor
• chromosomally encoded
inducible: Enterobacter, C. freundii,
Serratia, P. aeruginosa
constitutive: E. coli
• plasmid mediated: E. coli, K. pneumoniae
• only susceptible to cefepime and imipenem
 Bush group 2 β-lactamase
• inhibited by β-lactamase inhibitor
• 2a: penicillinase (PC1 of S. aureus)
2b: broad-spectrum enzymes (TEM-1,2, SHV-1)
2be: ESBLs (TEM-3 to 28, SHV-2 to 6)
2br: broad-spectrum enzymes with reduced
binding to clavulanic acid (TEM-30-36, TRC-1)
2c: carbenicillinase (PSE-1, CARB-3)
2d: cloxacillinase (OXA-1, PSE-2)
2e: cephalosporinase (P. vulgaris)
2f: nonmetallo-carbapenemase (IMI-1,
NMC-A, Sme-1)
 Bush group 3 β-lactamase
• metallo-β-lactamase
• hydrolyze carbapenem
• found in Stenotrophomonas maltophilia
Aeromonas species
some strains of Bacteroides
some strains of P. aeruginosa
 Bush group 4 β-lactamase

• penicillinase not inhibited by clavulanic

acid
• found in P. cepacia
 格蘭氏陰性菌的 -
lactamase: I
• 低濃度 AmpC
chromosomal, inducible R to
ampicillin, augmentin, cephalothin, cefoxitin
• 高濃度 AmpC
chromosomal, hyperproducer
plasmid-borne R to
all antibiotics except cefepime, imipenem
 格蘭氏陰性菌的 -lactamase:
II
• 低濃度 TEM/SHV: chromosomal
R to ampicillin, ticarcillin
• 高濃度 TEM/SHV: plasmid-borne
R to ampicillin, augmentin, ticarcillin, piperacillin,
timentin, cephalothin, cefoperazone
• ESBLs (TEM/SHV 的衍生物 ): plasmid-borne
R to all antibiotics except imipenem, cephamycins, β-
lactam/β-lactamase inhibitor combination
 All β-lactam antibiotics &
β-lactamase inhibitors are
β-lactamase inducer
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
 β-lactamase inhibitors
• Oxacillin
• Clavams: clavulanic acid
• Penicillanic acid sulphones:
sulbactam
tazobactam
 β-lactam & β-lactamase inhibitor
combinations
• Unasyn: ampicillin/sulbactam
• Augmentin: amoxicillin/clavulanic acid
• Timentin: ticarcillin/clavulanic acid
• Tazocin: piperacillin/tazobactam
IC50 values for inhibition of various β-lactamase
by β-lactamase inhibitor
Enzyme IC50 (µM)
Clavulanic acid Sulbactam Tazobactam
Class A
S. aureus PC1 0.03 0.08 0.03
TEM-1 0.09 0.9 0.1
TEM-2 0.02 2.4
0.02 TEM-9 0.009 0.27
0.08 TEM-10 0.005 0.94
0.09 SHV-1 0.012 12
0.15
Class C
P99 >100 5.6
0.008
Class D
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
 β-lactamase inducibility: I
• Ampicillin/sulbactam
ampicillin: labile, strong inducer sulbactam:
resistant, weak inducer
• Amoxicillin/clavulanic acid
amoxicillin: labile, strong inducer clavulanic
acid: resistant, strong inducer
 β-lactamase inducibility: II
• Piperacillin/tazobactam
piperacillin: moderate R, weak inducer
tazobactam: resistant, weak inducer
• Ticarcillin/clavulanic acid
ticarcillin: moderate R, weak inducer
clavulanic acid: resistant, strong inducer
 Paradoxically induce
increasing production of β-
lactamase
Clavulanic acid > Sulbactam >
Tazobactam
 Classification of antibiotics
• Labile, strong β-lactamase inducer
1st & 2nd generation β-lactams
• Labile, weak β-lactamase inducer
3rd generation cephalosporins
ureidopenicillins
• Stable, weak β-lactamase inducer
4th generation cephalosporins
• Stable, strong β-lactamase inducer
carbapenems
 Blood culture: E. coli
Ampicillin R Cefotaxime S
Cefazolin S Ceftazidime S
Gentamicin R Ciprofloxacin S
Ampicillin/sulbactam S Tetracycline R
Cefuroxime S TMP/SMX R
Cefoxitin S Tienam S
Amikin S Cefepime S
 Antibiotics control policy
• By generation: a cost control policy
1st, 2nd, & 3rd generation
• For empirical therapy
by clinical syndrome
• For definite therapy
by reduce resistance
 實驗室之抗生素管制政策
• 提供所有可供治療藥物之敏感性試驗結
果
• 不提供不可作為治療依據之檢驗結果
Staphylococcus spp. 的紙錠法判讀準則
• Penicillin-susceptible
susceptible to all β-lactam antibiotics
• Penicillin-resistant, oxacillin-susceptible
resistant to β-lactamase-labile penicillins
susceptible to β-lactamase-stable penicillins,
cephems, carbapenems, β-lactamase inhibitor
combinations
• Oxacillin-resistant
only susceptible to vancomycin & teicoplanin
Enterobacterioceae 的紙錠法藥敏試驗
• Intestinal isolates of Salmonella & Shigella
ampicillin
a quinolone
TMP/SMX
• Extraintestinal isolate of Salmonella
plus chloramphenicol
a third generation cephalosporin
懇 請 賜 教