医学资料糖尿病溃疡抗生素治疗

1、糖尿病溃疡抗生素治疗的药学监护一、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用约需 $17,500 (1998，不包括截肢

2、者) 31.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. 2004;39:885910.缺血愈合受损1血氧、营养、抗

3、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

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 hoursWBC8000/mm3Poly Count60%Band Count1 Staphylococcus species In another multicenter trial in patients with diabetic foot

5、 infection, MRSA was isolated from 25/361 patients (7%)2MRSA is isolated in both inpatient and community settings3 MRSA isolation is associated with2:Previous antibiotic therapyWorse clinical outcomes1. Citron DM et al. Bacteriology of diabetic foot infections (DFI): 1640 isolates from 473 specimens

6、 abstract. IDSA; 2005.2. Lipsky BA et al. Clin Infect Dis. 2004;38:1724.3. Lipsky BA et al. Clin Infect Dis. 2004;39:885904.MSSA (n=18)*MRSA (n=12)* Patient Characteristics Age57.4 (4172) years56.8 (4075) years Duration of DM 10.4 (6.417.1) years11.2 (7.118) years Neuropathic ulcers50.0%58.3% Ulcer

7、area2.74 (0.257.2) cm22.64 (0.1610.5) cm2 Number of organisms0.8 (02)1.1 (03) HbA1c9.0% 0.5%8.9% 0.7% Creatinine165.4 42.1 mmol/L148.8 13.8 mmol/LCourse Time to healing17.8 (824) weeks35.4 (1964) weeks Amputations225.2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

8、菌（6） 铜绿假单胞菌P. aeruginosa may be an “environmental” pathogen1P. aeuruginosa has been associated with the following foot-infection syndromes2:Ulcer that is macerated because of soakingLong duration nonhealing wounds with prolonged, broad-spectrum antibiotic therapyIn 2 clinical trials in patients with

9、 diabetic foot infections:9% of 473 specimens were P. aeruginosa 3In the second study, Pseudomonas species were recovered from 7% (27/361) of patients41. 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 i

10、nfections (DFI): 1640 isolates from 473 specimens abstract. IDSA; 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

11、、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

12、、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. Clin 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)MildModerate Severe双氯西林yes克林霉素yes头孢氨苄yesTMP/SMX yes yes阿莫西林/克拉维酸yesyes左氧氟沙星yesyes头孢呋辛yes头孢曲松yes

13、六、糖尿病溃疡感染抗生素选择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 yesLipsky 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用药教育Severi

14、ty Route DurationLipsky BA et al. Clin Infect Dis. 2004;39:885910.7.1抗生素的用法用量（）Soft tissue onlyMild Topical or oral 12 weeks; up to 4 weeksif slow to resolveModerate Oral (or initial IV) 24 weeks Severe Initial IV then 24 weeks switch to oral Bone or jointNo residual infected tissue IV then consider

15、 oral25 daysResidual infected soft tissue IV then consider oral 24 weeksResidual infected (viable) bone IV then consider oral 46 weeksNo surgery, or residual dead bone IV then consider oral 3 monthsFor mild-to-moderate infections inpatients without gastrointestinal absorption problems and forwhom an

16、 oral agent with the appropriate spectrum is available,oral therapy is often appropriate, especially with highly bioavailableagents (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(300 mg q6h) - 哌拉西林/ 他唑巴坦 (3.

17、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 + 甲硝唑 (500 mg po or iv q 8 h)-A modi

18、fication 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

19、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Observational studyPopulationGlucose cutoffmmol/lRisksPomposelli et al 1998Post-opspot 12.2 on post-op Day 12.7x nosocomial infecti

20、onLatham et al 2001Cardiothoracic post-ophyperglycemia in first 48 hrs2x surgical site infectionCapes et al 2001ischemic stroke with no hx of DMadmission glucose 6.13x in-hospital or 30-day mortality and poor functional outcomeUmpierrez GE et al 2002newly diagnosed DM vs known DM vs normalFBS7.0 or

21、random11.1mortality16% vs 3% vs 1.7%Hyperglycaemia associated with Increased infection & Mortality Interventional StudyPopulationsTarget glucose level (mmol/l)OutcomesCommentsFurnary et al 1999Post cardiothoracic surgery8.3-11.1 24 hours post-opdeep sternal wound infection 0.8% vs 2.0%cost and LOSla

22、ck of randomizationused historical controlsDIGAMI 1Malmberg et al 1995AMI7.0-10.9; mean glucose 9.6 vs 11.7mortality 29% at 1 yr 28% at 3.4 yrsNNT=9? in-pt or both in-pt and out-pt glycemic control accountableDIGAMI 2Malmberg et al 2005AMI7.0-10.0No sig difference in mortalityNo sig diff in glucose

23、levels among three groups (end A1c 6.8%) Underpowered study Good Glycaemic Control Decreased Wound Infection RateCase Study 1: Patient Seen in Podiatrists Office*45-year-old male accountant with type 2 diabetes Personal historyRecurrent plantar callus on left foot; monitored bimonthly for past 2 yea

24、rsGood glycemic control (HbA1c = 7.5%)Good vascular status: palpable pedal pulsesSensory loss (10 g monofilament test)Case Study 1: Patient Seen in Podiatrists Office (cont)Recent historyIncreased time spent golfing; new golf shoesAcute findingsSwelling, no pain for 1 weekRedness, “blister” in last

25、24 hoursNo feverLarge bulla under fourth metatarsal head site of previous plantar keratomaErythema around site, extending 2 cm proximally and medially into the plantar archCase Study 1: Patient Seen in Podiatrists Office (cont)TreatmentDeroofing of bulla2 cc brownish-red, nonpurulent fluid expressed

26、 and culturedSkin debrided to reveal: Central crater-like areaHealthy granulation tissue at the basePeripheral to crater: more superficial desquamation extending proximally and distally associated with trapped fluidSterile dressing with silver sulfadiazine creamEmpiric oral antibiotic prescription f

27、or gram-positive cocciCultures reveal methicillin-sensitive S. aureus (MSSA)Case Study 1: Patient Seen in Podiatrists Office (cont)IDSA Classification “Mild” diabetic foot infectionFollow-upAfter 3 daysErythema mostly resolvedUndermined areas healingOnly central ulcer remaining Case Study 3: Patient

28、 Seen by ED Physician*47-year-old female lawyer with type 2 diabetesPersonal historyChronic hypertension Recent historyNew boots caused a large blister around big toe joint 3 days priorNo pain initially; some fluid secretionHome treatment: Epsom salt soaking, adhesive bandagesPast 24 hours: increase

29、d redness and swelling of forefootCase Study 3: Patient Seen by ED Physician (cont)Acute findingsNo feverLarge flaccid bulla over medial aspect of first metatarsal-phalangeal joint with central opening draining serous fluidErythema over entire medial forefoot but not more extensiveAbsent protective

30、sensation (10 g monofilament)WBC = 13.0 109 cells/LGlucose = 165 mg/dL (HbA1c = 8%)BUN and creatinine slightly elevatedPalpable pedal pulses; equivalent bilaterallyCase Study 3: Patient Seen by ED Physician (cont)TreatmentDeroofing of bulla by emergency department physicianSuperficial lesion with he

31、althy red tissue underneathSingle dose of IV antibioticCase Study 3: Patient Seen by ED Physician (cont)IDSA Classification “Moderate” diabetic foot infectionFollow-upED physician advises admission to hospital, infectious disease consultation, continued IV antibiotic; but patient refuses hospital ad

32、missionPatient understands possible consequences but still refuses to be admittedArrangement made for visiting nurse to provide home IV antibiotic infusionDischarged against medical adviceCase Study 5: Patient Seen by Hospitalist*55-year-old male bus driver with type 1 diabetesPersonal historyDiabet

33、es uncontrolledMalignant hypertensionLong-standing callus on bottom of footOccasional care of local podiatristHabit of “picking” at callus after showeringNever felt pain in footCase Study 5: Patient Seen by Hospitalist (cont)Recent history“Picked” at foot 1 week earlierAcute findingsSmall, deep-appearing plantar ulcer under third metatarsal headNo pus; minimal serous drainagePatchy dorsal erythema, forefoot and midfoot around third metatarsal phalangeal joints; less second and fourthPulses palpable but no protective sensationCas