醫(yī)學(xué)資料糖尿病潰瘍抗生素治療

1、糖尿病潰瘍抗生素治療的藥學(xué)監(jiān)護(hù)一、概述（）糖尿病潰瘍是糖尿病的一種常見的并發(fā)癥，以四肢常見，尤其是足部。而糖尿病潰瘍常常并發(fā)細(xì)菌感染。一方面糖尿病會(huì)使患者機(jī)體的抵抗力下降, 使得感染不易控制, 另一方面細(xì)菌感染又進(jìn)一步加快糖尿病潰瘍的發(fā)展, 形成互為因果的惡性循環(huán)，所以，糖尿病潰瘍的抗生素治療具有挑戰(zhàn)性和其自身的特點(diǎn)。臨床藥師在此過(guò)程中可以發(fā)揮積極的作用。結(jié)合臨床藥學(xué)實(shí)踐，對(duì)糖尿病潰瘍抗生素治療的藥學(xué)監(jiān)護(hù)做些交流。一、概述（2）一、概述（3）糖尿病患者:約50的住院日與潰瘍和感染有關(guān)1有潰瘍患者比沒(méi)有潰瘍患者的住院時(shí)間長(zhǎng)592僅治療感染潰瘍的直接費(fèi)用約需 $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、糖尿病感染的機(jī)理1. Armstrong DG et al. Diabetes Technol Ther. 2004;6:167177.2. Lipsky BA et al. Clin Infect Dis. 2004;39:885910.缺血愈合受損1血氧、營(yíng)養(yǎng)、抗

3、生素供給差1植物神經(jīng) 皮膚干燥、皸裂1感覺(jué)神經(jīng) 無(wú)法感知損傷1運(yùn)動(dòng)神經(jīng) 生物力學(xué)異常2中性粒細(xì)胞功能受損1,2糖尿病潰瘍感染神經(jīng)病變免疫病變血管病變?nèi)?、糖尿病潰瘍感染分?jí)（1）傷口無(wú)膿液或發(fā)炎癥狀（化膿、紅腫、疼痛、壓痛、發(fā)熱、或硬結(jié)）有兩項(xiàng)或兩項(xiàng)以上的感染癥狀，潰瘍周圍的紅腫范圍2 cm, 并且感染局限于皮膚或皮下淺表組織，沒(méi)有其他的局部或全身病變感染明顯但病人代謝穩(wěn)定、無(wú)全身性癥狀，并且至少有一項(xiàng)下列癥狀：蜂窩組織炎的范圍 2 cm, 淋巴管改變, 炎癥擴(kuò)散到皮下筋膜、深部組織膿腫, 壞疽, 以及涉及到肌肉、肌腱、關(guān)節(jié)或骨出現(xiàn)全身性的感染癥狀或代謝不穩(wěn)未感染 1輕度 2中度 3 重度 4

4、PEDIS 臨床感染表現(xiàn) 分級(jí)得分 PEDIS = perfusion, extent/size, depth/tissue loss, infection, and sensation.Lipsky BA et al. Clin Infect Dis. 2004;39:885910.三、糖尿病潰瘍感染分級(jí)（2）四、糖尿病潰瘍感染的治療目標(biāo)未發(fā)熱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 的影響Tentolouris N et al. Diabet Med. 1999;16:767-771.5.2感染病原

8、菌（6） 銅綠假單胞菌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）國(guó)內(nèi)報(bào)道六、糖尿病潰瘍感染抗生素選擇選擇原則（一）抗生素的經(jīng)驗(yàn)治療應(yīng)依據(jù)感染程度和可能的病原菌選擇抗生素(B-II). 對(duì)最近未使用過(guò)抗生素的輕中度感染患者，通常僅需要針對(duì)革蘭氏需氧球菌用藥 (A-II). 沒(méi)有必要常規(guī)地使用廣譜抗生素進(jìn)行經(jīng)驗(yàn)性治療，但對(duì)重度感染的患者，要依據(jù)培養(yǎng)結(jié)果和藥敏試驗(yàn)選擇使用廣譜抗生素 (B-III). 六

11、、糖尿病潰瘍感染抗生素選擇選擇原則（二）必須考慮患者最近使用過(guò)的抗生素和本地的抗生素藥敏報(bào)表，尤其需要考慮耐藥菌株的情況如 MRSA. 確切的抗生素治療必須建立在細(xì)菌培養(yǎng)結(jié)果、藥敏試驗(yàn)的基礎(chǔ)上，尤其是經(jīng)驗(yàn)治療的臨床反應(yīng)。 (C-III). 避免對(duì)未感染的潰瘍使用抗生素，現(xiàn)有的證據(jù)不支持對(duì)無(wú)臨床感染的潰瘍進(jìn)行抗生素治療 （破壞皮膚正常菌群、引起耐藥和條件致病菌的入侵）(D-III). 對(duì)清創(chuàng)后潰瘍組織菌落計(jì)數(shù) 106 CFU/g 或有-溶血鏈球菌，可以局部使用抗生素以降低潰瘍面的細(xì)菌水平. 一旦達(dá)到菌群平衡，要停止局部使用抗生素，減少抗生素可能的細(xì)胞毒性作用和耐藥菌株的發(fā)生 (Level I)六

12、、糖尿病潰瘍感染抗生素選擇影響因素影響糖尿病潰瘍感染抗生素治療的因素包括：Lipsky BA. Clin Infect Dis. 2004;39:S104S114.胃腸道吸收功能潛在的藥物毒性當(dāng)?shù)氐目股厮幟魣?bào)表社保及費(fèi)用病人意見臨床文獻(xiàn)感染臨床程度病原菌 (已知或可能的)最近使用過(guò)的抗生素感染部位的血管狀況抗生素的過(guò)敏情況肝腎功能六、糖尿病潰瘍感染抗生素選擇IDSA 推薦的抗生素方案（1）agent(s)MildModerate Severe雙氯西林yes克林霉素yes頭孢氨芐yesTMP/SMX yes yes阿莫西林/克拉維酸yesyes左氧氟沙星yesyes頭孢呋辛yes頭孢曲松yes

13、六、糖尿病潰瘍感染抗生素選擇IDSA 推薦的抗生素方案（2）agent(s) Mild Moderate Severe氨芐西林/舒巴坦 yes利奈唑酮 氨曲蘭 yes達(dá)托霉素氨曲蘭 yes頭孢呋辛 甲硝唑 yes替卡西林/克拉維酸 yes哌拉西林/他唑巴坦 yes yes左氧氟或環(huán)丙沙星克林霉素 yes yes亞胺培南/西司他丁 yes萬(wàn)古霉素頭孢他啶 甲硝唑 yesLipsky BA et al. Clin Infect Dis. 2004;39:885910.七、藥學(xué)服務(wù)7.1抗生素的用法用量7.2治療相關(guān)問(wèn)題7.3藥物相互作用7.4藥物動(dòng)力學(xué)作用7.5藥源性疾病7.6用藥教育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）- 頭孢氨芐 (500mg q6h)- 阿莫西林/克拉維酸 (500/125mg q8h)- 克林霉素 (300 mg q6h)- 環(huán)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) +環(huán)丙沙星 (400 mg ivq12h or 750 mg po q12 h)- 克林霉素 (600 mg q6h) + 3rd 頭孢 Life Threatening (Prolonged Intravenous)- 亞胺培蘭/cilastatin (500mg q6h)- 克林霉素(900mg tid) + 妥布霉素 (5.1mg/kg.ld) + 氨芐西林(50mg/kg. qid)- 美羅培蘭 1 g q8h- 萬(wàn)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治療相關(guān)問(wèn)題停藥：即使?jié)儧](méi)有愈合，當(dāng)感染癥狀和體征消除后，通常就可以停用抗生素。 換藥：如果代謝穩(wěn)定的病人在使用一個(gè)療程抗生素后臨床反應(yīng)不佳，可以考慮停用所有的抗生素，幾天后再送培養(yǎng)標(biāo)本。 (C-III).7.3藥物的相互作用影響血糖的抗生素：-有報(bào)道磺胺類使動(dòng)物產(chǎn)生低血糖。 -氟喹諾酮類引起血糖代謝障礙（加替沙星）。已報(bào)道氟喹諾酮類具有影響葡萄糖體內(nèi)穩(wěn)態(tài)的作用, 正在進(jìn)行

19、更深入的研究以確認(rèn)是否該類抗生素均有此作用。7.4藥物動(dòng)力學(xué)作用（）糖尿病腎病對(duì)藥物的影響（疾病影響藥物）7.4藥物動(dòng)力學(xué)作用（2）糖尿病血管病變對(duì)藥物的影響：在膿液、骨組織分布較高的抗生素7.5藥源性疾病影響腎功的抗生素（藥物不良反應(yīng)）氨基糖苷萬(wàn)古霉素兩性霉素磺胺類與部分頭孢類與肝藥酶抑制劑合用7.6用藥教育減負(fù)有氧與無(wú)氧鍛煉血糖控制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