B Y T TRNG I HC DC H NI KIU TIN THNH KHO ST TNH HNH S DNG VANCOMYCIN BNH VIN BCH MAI KHA LUN TT NGHIP DC S H NI - 2013 B Y T TRNG I HC DC H NI KIU TIN THNH KHO ST TNH HNH S DNG VANCOMYCIN BNH VIN BCH MAI KHA LUN TT NGHIP DC S Ngi hng dn: 1. TS. Nguyn Th Lin Hng 2. ThS. L Vn Anh Ni thc hin: 1. B mn Dc Lm Sng Trng i hc Dc H Ni 2. Bnh vin Bch Mai H NI - 2013 Li cm n Liu tin, ti xin chn thnh by t lng bitnsusc tihaingi thy: TS.Nguyn Th Lin Hng Trng b mn Dc Lm Sng trng i hc Dc H Ni v ThS. L Vn Anh KhoaDc Bnh vin BchMai,trc tipngvin,hng dn, ch bo ti trong sut qu trnh thc hin v hon thnh kho lun tt nghip ny. Ticngxinchnthnhcmnccthy c gio ca b mnDc Lm Sngtrngi hcDc H Ni nhngngi thy lun sn sng chia s nhng kh khn, vng mc ca ti trong qu trnh hc tp cng nh qu trnh lm kho lun. Ti xin trn trng gi li cm n n ton th cc bc s, dc s, cn b cng nhn vin ang cng tc ti khoa Dc, khoa Vi sinh, khoa Ho Sinh, cc khoa Lm sng, phng K hoch tng hp gip , to iu kin thun li nht cho ti trong sut qu trnh nghin cu. Cui cng, kho lun tt nghip ca ti s khng th hon thnh nu thiu s ng vin, gip ca gia nh, bn b. Ti xin gi li cm n n tt c nhng ngi bn c bit l nhngngi bntrongTND,gianhth 2 ca ti nhngngi bnlunstcnh,ng h v mt tinh thn trong sut qung ng hc i hc. Li cm n c bit v ngha nht, ti xin dnh cho M - ngisinhthnhvdng dcti, ticc nhng thnh cng ca ngy hm nay. Ti xin chn thnh cm n! H ni, ngy 19 thng 05 nm 2013 Sinh vin Kiu Tin Thnh MC LC T VN ....1 PHN 1. TNG QUAN3 1.1. I CNG V VANCOMYCIN ........................................................... 3 1.1.1. Lch s ra i v cu trc ha hc ............................................................. 3 1.1.2. c im dc ng hc ........................................................................... 4 1.1.3. c im dc lc hc .............................................................................. 6 1.1.4. Lin quan gia dc ng hc v dc lc hc (PK/PD) ...................... 10 1.2. CC KHUYN CO V S DNG VANCOMYCIN........................14 1.2.1.Chnh................................................................................................141.2.2. Chng ch nh v thn trng...............................................................151.2.3. Cch dng............................................................................................161.2.4. Liu dng.............................................................................................16 PHN 2.I TNG V PHNG PHP NGHIN CU......................18 2.1. GIAI ON TIN CU .......................................................................... 20 2.1.1. I TNG NGHIN CU ................................................................. 20 2.1.1.1. Bnh nhn ............................................................................................. 20 2.1.1.2 Vi khun................................................................................................. 20 2.1.2. PHNG PHP NGHIN CU............................................................ 21 2.1.2.1. Cch ly mu ........................................................................................ 21 2.1.2.2. Thit k nghin cu .............................................................................. 21 2.1.2.3. Ni dung nghin cu ............................................................................ 23 2.2. GIAI ON HI CU ............................................................................ 23 2.2.1. I TNG NGHIN CU.............................................................212.2.2. PHNG PHP NGHIN CU.......................................................22 2.3. PHNG PHP X L S LIU ........................................................ 25 PHN 3. THC NGHIM V KT QU..........................................................25 3.1. GIAI ON TIN CU .......................................................................... 26 3.1.1. nh gi kh nng t mc tiu AUC0-24/MIC 400 ca mu nghin cu. ............................................................................................................................ 26 3.1.2 nh gi kh nng dng Ctrough d onAUC0-24/MIC ...................... 30 3.2. GIAI ON HI CU ............................................................................ 34 3.2.1. c im ca mu nghin cu ................................................................ 34 3.2.2. c im s dng vancomycin trong mu nghin cu ........................... 37 PHN 4. BN LUN .............................................................................................. 51 4.1. GIAI ON TIN CU .......................................................................... 51 4.1.1. nh gi kh nng t mc tiu AUC0-24/MIC400 ca mu nghin cu .... 52 4.1.2. nh gi kh nng s dng Ctrough d on AUC0-24/MIC ........................ 54 4.2. GIAI ON HI CU .................................................................................. 54 4.2.1. c im mu nghin cu.............................................................................. 54 4.2.2. c im s dng vancomycin ...................................................................... 55 KT LUN V XUT 59 I. Kt lun ......................................................................................................... 57 II. xut ......................................................................................................... 58 DANH MC K HIU, CH VIT TT ADRAdverse drug reaction (Tc dng bt li ca thuc) ASHP AmericanSocietyofHealth-SystemPharmacists(Hi dc s M) AUC0-24 Areaunderthecurve24h(Dintchdingcong nng - thi gian trong 24h) ClcrClearance creatinine ( thanh thi creatinin) CpeakPeak concentration (Nng nh) CtroughTrough concentration (Nng y) FPIA Fluroescencepolarimmunoassay(Kthutmindch phn cc hunh quang) ICUIntensive Care Unit (Khoa iu tr tch cc) IDSA InfectionousdiseasessocietyofAmerica(Hiccbnh nhim khun M) MIC MinimalInhibitoryconcentration(Nngcchti thiu) NSAIDS Nonsteroidal anti-inflammatory drugs (Thuc khng vim khng steroid) PDPharmacodynamic (Dc lc hc) PKPharmacokinetic (Dc ng hc) S.aureusStaphylococcusaureus (T cu vng) SIDP SocietyofInfectiousDiseasesPharmacists(Hidcs cc bnh nhim khun M) T1/2Half life (Thi gian bn thi) TDKMMTc dng khng mong mun TDM Therapeutic Drug Monitoring (Gim stthuc trong iu tr) TGTherapeutic guidelines (Hng dn iu tr ca Australia) VdVolume of distribution (Th tch phn b) DANH MC BNG STTK hiuTn bng 1Bng 1.1Liu dng ng tim ca vancomycin theo AHFS da theo tui 2Bng 1.2 Liudngngtimcavancomycintheotnhtrngnhim khun 3Bng 1.3Liudngvancomycinngtimivingilnvtrem trn12tuidatrnchcnngthntheoTherapeuticguidelines 2010 4Bng 1.4Liudngvancomycinngtimchotremdi12tuitheo Therapeutic guidelines 2010 5Bng 2.1Phn loi nng creatinin huyt thanh theo gii hn in trn phiu xt nghim ha sinh. 6Bng 3.1Gi tr AUC0-24 ca mu nghin cu 7Bng 3.2Phn b gi tr MIC ca mu nghin cu 8Bng 3.3Kt qu tnh ton gi tr AUC0-24/MIC ca qun th bnh nhn 9Bng 3.4KhnngtchtiuAUC0-24/MIC400trntngphnnhm bnh nhn da theo MIC 10Bng 3.5Kh nng t ch tiu AUC0-24/MIC trn tng ch liu dng 11Bng 3.6Kh nng t ch tiu AUC0-24/MIC trn nhm bnh nhn s dng liu theo v khng theo khuyn co ca Therapeutic guidelines 12Bng 3.7T l t gi tr AUC0-24/MIC i vi cc khong Ctrough khuyn co v cc gi tr MIC gi nh. 13Bng 3.8Mt s c im chung ca mu nghin cu 14Bng 3.9Phnbbnhnhntheonngcreatininhuytthanhvhs thanh thi creatinin 15Bng 3.10C cu cc bnh nhim khun trong mu nghin cu 16Bng 3.11T l cc bnh mc km 17Bng 3.12SlngbnhnhnphnlpcMRSAvMSSAtrongcc bnhnhnsdngvancomycintheophcbanuvphc thay th 18Bng 3.13Phn b cc bnh nhim khun trong nhm cc bnh nhn s dng vancomycin theo phc ban u v phc thay th 19Bng 3.14Cckhngsinhphihpvivancomycintrongphcbanu v phc thay th 20Bng 3.15Ch liu dng vancomycin c s dng trong mu nghin cu 21Bng 3.16Ch liu dng cho cc bnh nhn khng xc nh c CLCR 22Bng 3.17Kt qu so snh ch liu dng ca mu nghin cu vi ch liu dng trong Therapeutic guidelines 23Bng 3.18Phn b bnh nhn theo cch dng vancomycin 24Bng 3.19Phn b bnh nhn theo thi gian s dng vancomycin 25Bng 3.20T l phi hp cc thuc c tng tc bt li vi vancomycin 26Bng 3.21T l bnh nhn c tc dng khng mong mun trn thn 27Bng 3.22Hiu qu iu tr tng th trn mu nghin cu 28Bng 3.23Mt s ch tiu nh gi hiu qu iu tr thu thp c trong mu nghin cu DANH MC HNH V, S STTK hiuTn hnh 1Hnh 1.1Cu trc ha hc ca vancomycin 2Hnh 1.2M hnh dc ng hc ca vancomycin 3Hnh 1.3C ch tc dng ca vancomycin 4Hnh 1.4C ch khng vancomycin 5Hnh 1.5 ChsPK/PDctrngchoccloikhngsinhkhc nhau 6Hnh 1.6Cch tnh AUC0-24 theo phng php thc nghim 7Hnh 1.7Tnh AUC0-24 theo hnh thang thng v hnh thang cong 8Hnh 3.1Gi tr AUC0-24 trn 30 bnh nhn nghin cu 9Hnh 3.2 Tng quan gia AUC0-24/MIC v Ctrough khi qun th c MIC=1g/ml 10Hnh 3.3 Tng quan gia AUC0-24/MIC v Ctrough khi qun th c MIC=1,5g/ml 11Hnh 3.4 Tng quan gia AUC0-24/MIC v Ctrough khi qun th c MIC=2g/ml 12Hnh 3.5 Hsthanhthicreatinincaccbnhnhntrongmi ch liu dng 13S 2.1S thit k nghin cu 1 Vancomycinlmtkhngsinhpolypeptidlnuctmthyvonm1952, datrnmthotchtphnlpctchngvikhunStreptomyces orientalis[23]. Thuc c tc dng tt trn cc vi khunGram (+) a kh v k kh, c bit l t cu vng, k c cc chng khng methicillin (MRSA). Ngay t khi c a vo s dng, c tnh trn tai v thn ca vancomycin l mt vn c quantmhngu[33].Ngoira,trongnhngnmtrliy,tnhhnhkhng vancomycin ca cc chng vi khun ngy cng nghim trng. Cc nghin cu trn ngvtvmtstnghincutrnngichrarngtcdngditkhunca vancomycinkhngphthucnng,vAUC/MIClchsdcnghcc thdngdonhiuqucathuc.Datrnccktqunghincu,tl AUC/MIC400ccoilmctiutchiuqulmsngivi vancomycin[17],[31].Tuynhintrnthct,cthxcnhchnhxctl AUC/MICcabnhnhn,cnphitinhnhlynhiumumu,iunykhin choquytrnhTDMtrnnphctpvtnkm.Mtkhc,trnthgii,cc chuyn gia u khuyn co s dng nng y (Ctrough) nh mt ch s chnh xc vcnghathchnhnhtgimstnngvancomycintronghuyt thanh [31]. Theo di iu tr (TDM Therapeutic Drug Monitoring) l mt quy trnh c s dng gim st cc thuc c khong iu tr hp, cc thuc c th gy ra c tnh, t ti u ho liu dng, cch s dng ca thuc trn mi c th bnh nhn [20]. Chnh v vy, vic thit k mt quy trnh TDM hp l a vo thc t iu tr l mt yu cu cp thit. Hin nay, bnh vin Bch Mai l mt bnh vin tuyn cui c quy m ln nht min Bc. y l ni tp trung cc bnh nhn nhim khun nng vi bnh cnh rt a dng, ng thi l mt trong s t cc bnh vin p dng cc k thut, quy trnh tin tin trong chn on, theo di v iu tr, c bit l cc cngtcDclmsng.Tuynhinbnhvinvnchaxydngcmtquy trnh TDM chun cho vancomycin, iu ny lm vic theo di iu tr tr nn kh khn. Thc t c cc nghin cu v nng y ca vancomycin, tuy nhin ch T VN 2 s AUC/MIC vn cha c nh gi mt cch c th. Ngoi ra, quy trnh theo di s dng vancomycin c lin quan mt thit n cc tiu ch nh ch nh, liu dng, cch dng, thi gian s dng, c tnhVi thc trng , chng ti tin hnh thc hin ti Kho st tnh hnh s dng vancomycin bnh vin Bch Mai vi 3 mc tiu c th nh sau: 1.KhostkhnngtmctiuAUC0-24/MICcaccbnhnhnang c s dng vancomycin bnh vin Bch Mai. 2.nh gi tng quan gia ch s Ctrough v AUC0-24/MIC, t nh gi kh nng s dng ch s Ctrough d on AUC0-24/MIC 3.Kho st tnh hnh s dng vancomycin ti bnh vin Bch Mai trn cc tiu ch: ch nh, liu dng, cch dng, phi hp khng sinh, thi gian s dng, tng tc thuc, theo di tc dng khng mong mun v hiu qu iu tr. Txutnhng binphpnhmnngcaotnhhiuqu,antoncavics dngvancomycin,aracnhnggichovicxydngquytrnhtheodi iu tr i vi thuc. 3 PHN 1.TNG QUAN 1.1. I CNG V VANCOMYCIN 1.1.1. Lch s ra i v cu trc ha hc a. Lch s ra i Nhngnm1950,thiimchcmtvilachnkhngsinhiutrbnh nhimkhuntcukhngpenicillin,EliLillyandCompanytinhnhmt chng trnh vi mc tiu tm ra mt loi khng sinh c tc dng i vi cc chng t cu ni trn. Vonm1952,mtmcsBorneogimtmuchthohccho bn ca mnh l Tin s E.C.Kornield, mt nh ho hc hu c ti Eli Lilly. Mt t chc sng c phn lp t mu (Streptomycesorientalis)snxut ramt loi cht c t tn l 05865 c kh nng chng li hu ht cc vi khun Gr(+), bao gm c t cu khng penicillin. Mt vi vi khun k kh, bao gm c Clostridia cng nhycmvi05865.Ccthnghiminvitroctinhnhxcnhxem hotlcca05865ccbotntrongcciukingyrakhngthuc khng. Cc th nghim trn ng vt sau a ra kt qu cht 05865 an ton v hiuqutrnngi.Saukhiccitinvcutrchohc,ngitathuc vancomycin dng cho cc th nghim lm sng [23],[26]. b. Cu trc ha hc Hnh 1.1: Cu trc ho hc ca vancomycin 4 Vancomycin l mt glycopeptid ba vng c phn t lng khong 1500 dalton, bao gm mt chui 7 lin kt peptid. Do cu trc ho hc c nhiu lin kt peptid nn vancomycin l mt khng sinh c kh nng tan tt trong nc, phn b rng ri vo cc m v dch ngoi bo trong c th [28]. 1.1.2. c im dc ng hc a.Hp thu Vancomycin t c hp thu qua ng tiu ho (sinh kh dng ng ung 80 -Da trn phngphp Cockcroft- Gault[2], tnh h s thanh thi creatinin ti thiimbtuiutrbngvancomycin.Phnloihsthanhthicreatinin theo Hng dn iu tr ca Australia ( Therapeutic guidelines 2010)[15] Trn 90 ml/pht T 60 n 90 ml/pht T 20 n 60 ml/pht Di 20 ml/pht +c im bnh l ca bnh nhn: -Bnh nhim khun do S.aureus. -Bnh l mc km. b. c im s dng vancomycin ca mu nghin cu +Ch nh iu tr. +Phc iu tr: 25 -V tr ca vancomycin trong phc iu tr. -S phi hp vancomycin trong cc phc iu tr. +Ch liu dng vancomycin. -Kho st cc ch liu thc dng -Sosnhchliudngvancomycintrongmunghincuvichliu dngtrongHngdniutrcaAustralia(Therapeuticguidelines 2010)[15]. +Cch dng: -Dung mi pha truyn. -Nng dung dch vancomycin pha truyn. -Thi gian truyn. +Tng tc thuc: trong qu trnh thu thp thng tin bnh nhn, chng ti ch ly thng tin nhng thuc c trong danh mc km theo (ph lc 2). +Tc dng khng mong mun: -c tnh trn thn: cn c vo tng nng creatinin huyt thanh. Bnh nhn c coi l c gim chc nng thn dothuc khi trscreatininhuyt thanhtng0,5mg/dl(tngng45mol/l),hoctng50%sovinng creatinin huyt thanh ban u, trong t nht 2 ln o k t khi bt u iu tr n 3 ngy sau khi kt thc liu trnh iu tr [9],[25],[33]. -Tc dng khng mong mun khc. + Hiu qu iu tr tng th: -Hiuquiutrcghitrnbnhn:gmcccmckhi,,khng thay i, nng, t vong - Hiu qu da trn cc din bin lm sng v cc ch s cn lm sng: ci thin cctriuchnglmsng,htstsau48hiutr,chsbchcu,CRP, procalcitonin, cy khun. 2.3. PHNG PHP X L S LIU Kt qu nghin cu c x l bng phn mm Microsoft Excel 2010. 26 PHN 3. THC NGHIM V KT QU 3.1. GIAI ON TIN CU 3.1.1. nh gi kh nng t mc tiu AUC0-24/MIC 400 ca mu nghin cu a. Kho st gi tr AUC0-24 trn cc bnh nhn trong mu nghin cu Thng tin v bnh nhn v cc gi tr Cpeak, Ctrough, MIC ca mu nghin cu c trnh by bng ph lc 3 TccgitrCpeak,Ctrough,vthigiantruynvancomycincabnhnhn,cth tnhcAUC0-24tngngchotngtrnghpavophngphpca Deryke [14]. Cc gi tr AUC0-24 ca tng bnh nhn c trnh by trong hnh 3.1. Hnh 3.1. Gi tr AUC0-24 trn 30 bnh nhn nghin cu T cc gi tr AUC0-24 ca tng bnh nhn, chng ti thu c kt qu gi tr AUC0-24 ca mu nghin cu c trnh by trong bng 3.1. Bng 3.1. Gi tr AUC0-24 ca mu nghin cu Gi tr Trung bnh(g.h/ml)687,33 lch chun(g.h/ml)246,96 Khong phn b201,81 - 1345,95 27 Nhn xt:Gi tr AUC0-24 ca mu nghin cu c khong dao ng ln, t 201,81 n 1345,95vi gi tr trung bnh l 687,33246,96g.h/ml. b. Kho st phn b gi tr MI C trong mu nghin cu Kt qu MIC ca mu nghin cu c trnh by trong bng 3.2. Bng 3.2. Phn b gi tr MIC ca mu nghin cu Gi tr MI CS lng bnh nhnT l % 1g/ml413,33 1,5g/ml2066,67 2g/ml620 Tng30100 Nhn xt: Trong mu nghin cu, gi tr MIC thu c ch yu l 1,5g/ml, chim t l 66,67%. c. Kho st gi tr AUC0-24/MI C TccgitrAUC0-24vMICtngngcatngbnhnhn,chngtitnh ton c ch s AUC0-24/MIC ca tng bnh nhn trong mu nghin cu. Kt qu c trnh by bng 3.3. Bng 3.3. Kt qu tnh ton gi tr AUC0-24/MIC ca qun th bnh nhn Gi tr Trung bnh458,68 lch chun185,68 Khong phn b134,54 897,29 S lng bnh nhn c AUC0-24/MIC 400: 19/30 (t l 63,33%) S lng bnh nhn c AUC0-24/MI C