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 StudyPredictors of Mortality: Multivariate Analysis

Variable p Value Odds Ratio (95% CI)

Change in initial antibiotics 0.0001 3.3 (2.1 to 5.1)

ICU admission 0.003 2.5 (1.4 to 4.7)

>8 hr to administration of first antibiotic 0.004 2.6 (1.3 to 4.9)

↑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 10K/mm3 0.02 1.4 (1.1 to 1.9)

2nd/3rd generation CEPH or -lactam/ -lactamase inhibitor + macrolide (non-ICU)

0.009 0.4 (0.2 to 0.8)

2nd/3rd generation CEPH or -lactam/ -lactamase inhibitor + macrolide (ICU)

0.26 0.5 (0.2 to 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

-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, m

onobactam, & sulbactam 五類

-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

-lactam 抗藥性產生的機轉

1. 產產 -lactamase

2. 改變 PBPs

3. 架空 PBPs

4. 降低細胞壁的藥物通透性5. 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, -aminopenicillins, ureid

openicillin, -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 -lactamase

• Class A: “penicillinase” plasmid-mediated, such as TEM a

nd SHV widely spread among GNB

• Class B: metalloenzymes (Zn2+ dependent)• Class C: “cephalosporinase”

chromosome-mediatedwidely spread among GNB

• Class D: “oxacillinase”

Bush group 1 -lactamase• representive enzymes: AmpC• cephalosporinase• resistant to -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 -lactamase• inhibited by -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. vulgari

s) 2f: nonmetallo-carbapenemase (IMI-1, NMC-A, Sme-1)

Bush group 3 -lactamase• metallo--lactamase

• hydrolyze carbapenem

• found in Stenotrophomonas maltophiliaAeromonas species

some strains of Bacteroides some strains of P. aeruginosa

Bush group 4 -lactamase

• penicillinase not inhibited by clavulanic acid

• found in P. cepacia

格蘭氏陰性菌的 -lactamase: I

• 低濃度 AmpCchromosomal, inducibleR to ampicillin, augmentin, cephalothin, cef

oxitin• 高濃度 AmpC

chromosomal, hyperproducerplasmid-borneR to all antibiotics except cefepime, imipene

m

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-borneR to ampicillin, augmentin, ticarcillin, piperacillin, timentin, cephalothin, cefoperazone

• ESBLs (TEM/SHV 的衍生物 ): plasmid-borne R to all antibiotics except imipenem, cephamycins,

產-lactam/-lactamase inhibitor combination

All -lactam antibiotics & -lactamase inhibitors are

-lactamase inducer

Inducible AmpC -lactamase

• 可因抗生素的使用而誘發出來，可見於：Enterobacter speciesSerratia marcescensHafnia alvei Citrobacter freundii

indole-positive Proteus Providencia speciesMorganella morganiiPseudomonas aeruginosa

-lactamase inhibitors

• Oxacillin

• Clavams: clavulanic acid

• Penicillanic acid sulphones: sulbactam

tazobactam

-lactam & -lactamase inhibitor combinations

• Unasyn: ampicillin/sulbactam

• Augmentin: amoxicillin/clavulanic acid

• Timentin: ticarcillin/clavulanic acid

• Tazocin: piperacillin/tazobactam

IC50 values for inhibition of various -lactamase by -lactamase inhibitor

Enzyme IC50 (M) 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-100.005 0.94 0.09 SHV-10.012 12 0.15

Class C P99>100 5.6 0.008

Class D OXA-11.8 4.7 1.4

Induction potential at concentrations below the organisms MIC

Induction potential Rank order

Highest Carbapenems and cephamycinsAminopenicillins

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

-lactamase inducibility: I• Ampicillin/sulbactam am

picillin: labile, strong inducer sulbactam: resistant, weak inducer

• Amoxicillin/clavulanic acid amoxicillin: labile, strong inducer clavulanic acid: resistant, strong inducer

-lactamase inducibility: II

• Piperacillin/tazobactampiperacillin: moderate R, weak ind

ucer tazobactam: resistant, weak inducer

• Ticarcillin/clavulanic acidticarcillin: moderate R, weak inducer

clavulanic acid: resistant, strong inducer

Paradoxically induce increasing production of-lactamase

Clavulanic acid > Sulbactam > Tazobactam

Classification of antibiotics• Labile, strong -lactamase inducer

1st & 2nd generation -lactams• Labile, weak -lactamase inducer

3rd generation cephalosporins ureidopenicillins

• Stable, weak -lactamase inducer4th generation cephalosporins

• Stable, strong -lactamase inducercarbapenems

Blood culture: E. coliAmpicillin R

Cefazolin S

Gentamicin R

Ampicillin/sulbactam S

Cefuroxime S

Cefoxitin S

Amikin S

Cefotaxime S

Ceftazidime S

Ciprofloxacin S

Tetracycline R

TMP/SMX R

Tienam S

Cefepime S

Antibiotics control policy

• By generation: a cost control policy1st, 2nd, & 3rd generation

• For empirical therapyby clinical syndrome

• For definite therapyby 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 -lactam antibiotics• Penicillin-resistant, oxacillin-susceptible resistan

t to -lactamase-labile penicillins susceptible to -lactamase-stable penicillins, cephems, carbapenems, -lactamase inhibitor combinations

• Oxacillin-resistantonly susceptible to vancomycin & teicoplanin

Enterobacterioceae 的紙錠法藥敏試驗• Intestinal isolates of Salmonella & Shigella

ampicillina quinolone

TMP/SMX• Extraintestinal isolate of Salmonella

plus chloramphenicol a third generation cep

halosporin

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