1、糖尿病溃疡抗生素治疗的药学监护,四川大学华西医院药剂科刘春雨,一、概述（）,糖尿病溃疡是糖尿病的一种常见的并发症，以四肢常见，尤其是足部。而糖尿病溃疡常常并发细菌感染。一方面糖尿病会使患者机体的抵抗力下降, 使得感染不易控制, 另一方面细菌感染又进一步加快糖尿病溃疡的发展, 形成互为因果的恶性循环，所以，糖尿病溃疡的抗生素治疗具有挑战性和其自身的特点。临床药师在此过程中可以发挥积极的作用。结合临床药学实践，对糖尿病溃疡抗生素治疗的药学监护做些交流。,一、概述（2）,一、概述（3）,糖尿病患者: 约50的住院日与溃疡和感染有关1 有溃疡患者比没有溃疡患者的住院时间长592 仅治疗感染溃疡的直接费
2、用约需 $17,500 (1998，不包括截肢者) 3,1. Lipsky BA et al. Lancet. 2005;366:16951703. 2. Frykberg RG. Adv Wound Care. 1999;12:139141. 3. Tennvall GR et al. Clinical Infect Dis. 2004;39(suppl 2):S132S139.,二、糖尿病感染的机理,1. Armstrong DG et al. Diabetes Technol Ther. 2004;6:167177. 2. Lipsky BA et al. Clin Infect Dis
3、. 2004;39:885910.,缺血 愈合受损1 血氧、营养、抗生素供给差1,植物神经 皮肤干燥、皲裂1 感觉神经 无法感知损伤1 运动神经 生物力学异常2,中性粒细胞 功能受损1,2,糖尿病 溃疡感染,神经病变,免疫病变,血管病变,三、糖尿病溃疡感染分级（1）,伤口无脓液或发炎症状（化脓、红肿、疼痛、压痛、发热、或硬结） 有两项或两项以上的感染症状，溃疡周围的红肿范围2 cm, 并且感染局限于皮肤或皮下浅表组织，没有其他的局部或全身病变 感染明显但病人代谢稳定、无全身性症状，并且至少有一项下列症状：蜂窝组织炎的范围 2 cm, 淋巴管改变, 炎症扩散到皮下筋膜、深部组织脓肿, 坏疽, 以
4、及涉及到肌肉、肌腱、关节或骨 出现全身性的感染症状或代谢不稳,未感染 1轻度 2中度 3重度 4,PEDIS临床感染表现 分级 得分,PEDIS = perfusion, extent/size, depth/tissue loss, infection, and sensation. Lipsky BA et al. Clin Infect Dis. 2004;39:885910.,三、糖尿病溃疡感染分级（2）,四、糖尿病溃疡感染的治疗目标,未发热48 hours WBC8000/mm3 Poly Count60% Band Count3% 无发炎症状Neutrophil: A type o
5、f white blood cell, specifically a form of granulocyte, filled with neutrally-staining granules, tiny sacs of enzymes that help the cell to kill and digest microorganisms it has engulfed by phagocytosis. The mature neutrophil has a segmented nucleus (it is called a seg or poly) while the immature ne
6、utrophil has band-shape nucleus (it is called a band).,5.1 感染临床特点,提示感染: 局部发炎, 脓液流出, 窦管形成,软组织捻发音soft tissue crepitation 存在危及肢体感染的糖尿病患者中，不出现发热、寒战和白细胞增多者多达2/3 高血糖:存在危及肢体感染的常见症状 参IDSA Guidelines: Evaluating the Diabetic Patient Who has an Infected Foot,5.2 感染病原菌（1）,a Groups A, B, C, and G; b Often monom
7、icrobial; c Usually polymicrobial; d Antibiotic-resistant species (eg, methicillin-resistant S aureus, vancomycin-resistant enterococci, or extended-spectrum -lactamaseproducing gram-negative rods) are common.,5.2 感染病原菌（2）,一项多中心试验，共473 病人符合纳入标准 结果 分离出1,148 株需氧菌和492 株厌氧菌 50% 仅培养出需氧菌 42% 同时培养出需氧菌和厌氧菌
8、3% 仅培养出厌氧菌 平均分离株 (阳性培养基) 需氧菌: 2.8 (18) 厌氧菌: 2.1 (19),Citron DM et al. Bacteriology of diabetic foot infections (DFI): 1640 isolates from 473 specimens abstract. IDSA; 2005.,5.2 感染病原菌（3） 厌氧菌感染 (Foot),临床表现: 臭味溢出 组织内有气泡 坏死组织 革兰氏染色具多形性 培养或涂片阴性 常见厌氧菌: 脆弱拟杆菌 消化球菌 消化链球菌 核梭杆菌 产黑色素类杆菌,5.2 感染病原菌（4） MRSA,In a
9、large multicenter trial in patients with diabetic foot infection1: 11% of 473 specimens were MRSA 15% of patients grew 1 Staphylococcus species In another multicenter trial in patients with diabetic foot infection, MRSA was isolated from 25/361 patients (7%)2 MRSA is isolated in both inpatient and c
10、ommunity settings3 MRSA isolation is associated with2: Previous antibiotic therapy Worse clinical outcomes,1. Citron DM et al. Bacteriology of diabetic foot infections (DFI): 1640 isolates from 473 specimens abstract. IDSA; 2005. 2. Lipsky BA et al. Clin Infect Dis. 2004;38:1724. 3. Lipsky BA et al.
11、 Clin Infect Dis. 2004;39:885904.,MSSA (n=18)* MRSA (n=12)* Patient Characteristics Age 57.4 (4172) years 56.8 (4075) yearsDuration of DM 10.4 (6.417.1) years 11.2 (7.118) yearsNeuropathic ulcers 50.0% 58.3% Ulcer area 2.74 (0.257.2) cm2 2.64 (0.1610.5) cm2Number of organisms 0.8 (02) 1.1 (03) HbA1c
12、 9.0% 0.5% 8.9% 0.7%Creatinine 165.4 42.1 mmol/L 148.8 13.8 mmol/L Course Time to healing 17.8 (824) weeks 35.4 (1964) weeksAmputations 2 2,5.2 感染病原菌（5） MRSA and MSSA 的影响,Tentolouris N et al. Diabet Med. 1999;16:767-771.,5.2 感染病原菌（6） 铜绿假单胞菌,P. aeruginosa may be an “environmental” pathogen1 P. aeurug
13、inosa has been associated with the following foot-infection syndromes2: Ulcer that is macerated because of soaking Long duration nonhealing wounds with prolonged, broad-spectrum antibiotic therapy In 2 clinical trials in patients with diabetic foot infections: 9% of 473 specimens were P. aeruginosa
14、3 In the second study, Pseudomonas species were recovered from 7% (27/361) of patients4,1. Lipsky BA et al. Lancet. 2005;366:16951703. 2. Lipsky BA et al. Clin Infect Dis. 2004;39:885904. 3. Citron DM et al. Bacteriology of diabetic foot infections (DFI): 1640 isolates from 473 specimens abstract. I
15、DSA; 2005. 4. Lipsky BA et al. Clin Infect Dis. 2004;38:1724.,5.2 感染病原菌（7） 国内报道,六、糖尿病溃疡感染抗生素选择 选择原则（一）,抗生素的经验治疗应依据感染程度和可能的病原菌选择抗生素(B-II). 对最近未使用过抗生素的轻中度感染患者，通常仅需要针对革兰氏需氧球菌用药 (A-II). 没有必要常规地使用广谱抗生素进行经验性治疗，但对重度感染的患者，要依据培养结果和药敏试验选择使用广谱抗生素 (B-III).,六、糖尿病溃疡感染抗生素选择 选择原则（二）,必须考虑患者最近使用过的抗生素和本地的抗生素药敏报表，尤其需要考
16、虑耐药菌株的情况如 MRSA.确切的抗生素治疗必须建立在细菌培养结果、药敏试验的基础上，尤其是经验治疗的临床反应。 (C-III). 避免对未感染的溃疡使用抗生素，现有的证据不支持对无临床感染的溃疡进行抗生素治疗 （破坏皮肤正常菌群、引起耐药和条件致病菌的入侵）(D-III). 对清创后溃疡组织菌落计数 106 CFU/g 或有-溶血链球菌，可以局部使用抗生素以降低溃疡面的细菌水平. 一旦达到菌群平衡，要停止局部使用抗生素，减少抗生素可能的细胞毒性作用和耐药菌株的发生 (Level I),六、糖尿病溃疡感染抗生素选择 影响因素,影响糖尿病溃疡感染抗生素治疗的因素包括：,Lipsky BA. C
17、lin Infect Dis. 2004;39:S104S114.,胃肠道吸收功能 潜在的药物毒性 当地的抗生素药敏报表 社保及费用 病人意见 临床文献,感染临床程度 病原菌 (已知或可能的) 最近使用过的抗生素 感染部位的血管状况 抗生素的过敏情况 肝肾功能,六、糖尿病溃疡感染抗生素选择 IDSA 推荐的抗生素方案（1）,agent(s) Mild Moderate Severe双氯西林 yes 克林霉素 yes 头孢氨苄 yes TMP/SMX yes yes 阿莫西林/克拉维酸 yes yes 左氧氟沙星 yes yes 头孢呋辛 yes 头孢曲松 yes,六、糖尿病溃疡感染抗生素选择
18、IDSA 推荐的抗生素方案（2）,agent(s) Mild Moderate Severe氨苄西林/舒巴坦 yes 利奈唑酮 氨曲兰 yes 达托霉素氨曲兰 yes 头孢呋辛 甲硝唑 yes 替卡西林/克拉维酸 yes 哌拉西林/他唑巴坦 yes yes 左氧氟或环丙沙星克林霉素 yes yes 亚胺培南/西司他丁 yes 万古霉素头孢他啶 甲硝唑 yes,Lipsky BA et al. Clin Infect Dis. 2004;39:885910.,七、药学服务,7.1 抗生素的用法用量 7.2 治疗相关问题 7.3 药物相互作用 7.4 药物动力学作用 7.5 药源性疾病 7.6 用
19、药教育,Severity Route Duration,Lipsky BA et al. Clin Infect Dis. 2004;39:885910.,7.1 抗生素的用法用量（）,Soft tissue only Mild Topical or oral 12 weeks; up to 4 weeks if slow to resolve Moderate Oral (or initial IV) 24 weeksSevere Initial IV then 24 weeksswitch to oral Bone or joint No residual infected tissue
20、IV then consider oral 25 days Residual infected soft tissue IV then consider oral 24 weeks Residual infected (viable) bone IV then consider oral 46 weeks No surgery, or residualdead bone IV then consider oral 3 monthsFor mild-to-moderate infections inpatients without gastrointestinal absorption prob
21、lems and for whom an oral agent with the appropriate spectrum is available,oral therapy is often appropriate, especially with highly bioavailable agents (A-II).,7.1 抗生素的用法用量（2）,- 头孢氨苄 (500mg q6h) - 阿莫西林/克拉维酸 (500/125mg q8h) - 克林霉素 (300 mg q6h) - 环丙沙星 (500 mg or 750 mg bid) - TMP/SMX(1ds bid) + 克林霉素(
22、300 mg q6h) - 哌拉西林/ 他唑巴坦 (3.375g q6h) - 克林霉素 (600 mg q8h) +环丙沙星 (400 mg ivq12h or 750 mg po q12 h) - 克林霉素 (600 mg q6h) + 3rd 头孢 Life Threatening (Prolonged Intravenous) - 亚胺培兰/cilastatin (500mg q6h) - 克林霉素(900mg tid) + 妥布霉素 (5.1mg/kg.ld) + 氨苄西林(50mg/kg. qid) - 美罗培兰 1 g q8h - 万古霉素 (1g q12h) + 氨基糖苷 +
23、甲硝唑 (500 mg po or iv q 8 h) -A modification must be made for renal impairment/hemodialysis, hepatic impairment and allergies in certain cases.,7.2 治疗相关问题,停药：即使溃疡没有愈合，当感染症状和体征消除后，通常就可以停用抗生素。 换药：如果代谢稳定的病人在使用一个疗程抗生素后临床反应不佳，可以考虑停用所有的抗生素，几天后再送培养标本。 (C-III).,7.3 药物的相互作用,影响血糖的抗生素：-有报道磺胺类使动物产生低血糖。-氟喹诺酮类引起血糖
24、代谢障碍（加替沙星）。已报道氟喹诺酮类具有影响葡萄糖体内稳态的作用, 正在进行更深入的研究以确认是否该类抗生素均有此作用。,7.4 药物动力学作用（）,糖尿病肾病对药物的影响（疾病影响药物）,7.4 药物动力学作用（2）,糖尿病血管病变对药物的影响：在脓液、骨组织分布较高的抗生素,7.5 药源性疾病,影响肾功的抗生素（药物不良反应）氨基糖苷万古霉素两性霉素磺胺类与部分头孢类与肝药酶抑制剂合用,7.6 用药教育,减负 有氧与无氧锻炼 血糖控制,Hyperglycaemia associated with Increased infection & Mortality,Good Glycaemic
25、 Control Decreased Wound Infection Rate,Case Study 1: Patient Seen in Podiatrists Office*,45-year-old male accountant with type 2 diabetes Personal history Recurrent plantar callus on left foot; monitored bimonthly for past 2 years Good glycemic control (HbA1c = 7.5%) Good vascular status: palpable
26、pedal pulses Sensory loss (10 g monofilament test),Case Study 1: Patient Seen in Podiatrists Office (cont),Recent history Increased time spent golfing; new golf shoes Acute findings Swelling, no pain for 1 week Redness, “blister” in last 24 hours No fever Large bulla under fourth metatarsal head sit
27、e of previous plantar keratoma Erythema around site, extending 2 cm proximally and medially into the plantar arch,Case Study 1: Patient Seen in Podiatrists Office (cont),Treatment Deroofing of bulla 2 cc brownish-red, nonpurulent fluid expressed and cultured Skin debrided to reveal: Central crater-l
28、ike area Healthy granulation tissue at the base Peripheral to crater: more superficial desquamation extending proximally and distally associated with trapped fluid Sterile dressing with silver sulfadiazine cream Empiric oral antibiotic prescription for gram-positive cocci Cultures reveal methicillin
29、-sensitive S. aureus (MSSA),Case Study 1: Patient Seen in Podiatrists Office (cont),IDSA Classification “Mild” diabetic foot infectionFollow-up After 3 days Erythema mostly resolved Undermined areas healing Only central ulcer remaining,Case Study 3: Patient Seen by ED Physician*,47-year-old female l
30、awyer with type 2 diabetesPersonal history Chronic hypertension Recent history New boots caused a large blister around big toe joint 3 days prior No pain initially; some fluid secretion Home treatment: Epsom salt soaking, adhesive bandages Past 24 hours: increased redness and swelling of forefoot,Ca
31、se Study 3: Patient Seen by ED Physician (cont),Acute findings No fever Large flaccid bulla over medial aspect of first metatarsal-phalangeal joint with central opening draining serous fluid Erythema over entire medial forefoot but not more extensive Absent protective sensation (10 g monofilament) W
32、BC = 13.0 109 cells/L Glucose = 165 mg/dL (HbA1c = 8%) BUN and creatinine slightly elevated Palpable pedal pulses; equivalent bilaterally,Case Study 3: Patient Seen by ED Physician (cont),Treatment Deroofing of bulla by emergency department physician Superficial lesion with healthy red tissue undern
33、eath Single dose of IV antibiotic,Case Study 3: Patient Seen by ED Physician (cont),IDSA Classification “Moderate” diabetic foot infection Follow-up ED physician advises admission to hospital, infectious disease consultation, continued IV antibiotic; but patient refuses hospital admission Patient un
34、derstands possible consequences but still refuses to be admitted Arrangement made for visiting nurse to provide home IV antibiotic infusion Discharged against medical advice,Case Study 5: Patient Seen by Hospitalist*,55-year-old male bus driver with type 1 diabetesPersonal history Diabetes uncontrol
35、led Malignant hypertension Long-standing callus on bottom of foot Occasional care of local podiatrist Habit of “picking” at callus after showering Never felt pain in foot,Case Study 5: Patient Seen by Hospitalist (cont),Recent history “Picked” at foot 1 week earlier Acute findings Small, deep-appear
36、ing plantar ulcer under third metatarsal head No pus; minimal serous drainage Patchy dorsal erythema, forefoot and midfoot around third metatarsal phalangeal joints; less second and fourth Pulses palpable but no protective sensation,Case Study 5: Patient Seen by Hospitalist (cont),Acute findings (co
37、nt) Structural foot deformities secondary to earlier surgeries No fever Sterile probe revealed clear sinus tract to third metatarsal head; soft, yielding bone Cellulitis; possible osteomyelitis WBC normal (9.9) ESR = 45 mm/hr (elevated) Glucose = 600 mg/dL (HbA1c = 13.4%),Case Study 5: Patient Seen
38、by Hospitalist (cont),Treatment IV antibiotic initiated After stabilization, x-rays revealed lysis of Head of third metatarsal Base of proximal phalanx of third toe MRI Confirmed x-ray findings Revealed marrow edema from head of metatarsal to bone midshaft; similar changes and dorsal cellulitis of p
39、roximal phalanx Ray resection removed third toe, distal half of third metatarsal Wound left open for proper packing Bone biopsy, culture confirmed osteomyelitis,Case Study 5: Patient Seen by Hospitalist (cont),IDSA Classification “Severe” diabetic foot infection due to metabolic instability at presentationFollow-up Bone biopsy, culture confirmed osteomyelitis of both third metatarsal and third toe Methicillin-susceptible Staphylococcus aureus cultured 6-week course of IV antibiotics,
