• IMghien CIPU - Ky thugt
Du' bao hieu qua dieu tri va do an toan trong sir dung amikacin thong qua danh gia nong do thuoc trong mau
Ho&ng T h j K i m H u y e n , P h a m T h j T h u y Van Trudng Dgi hgc Duyc Hd Npi
D a t v a n d e
Amikacin id mdt khdng sinh nhdm aminoglycosid, cd ddc tinh didt k h u i n phu thudc n i n g dp vd n i n g dd t h u l c lidn quan chdt ehe v d i hipu qua vd tinh an todn. Cho d i n nay, y vdn da cdng nhdn nong d | dinh Cpaak e i n phdi dgt sao cho ty lp Cpeak/ MIC c i n a 8, ddc bidt vdi mdt sd vi k h u i n Gr(-) d l ddm bdo hidu qud d i l u trj; ndng dp ddy Ctrough c i n t h i p d u d i n g u d n g quy dinh d l ddm bdo tinh an todn eho bdnh nhdn. Hipn tgi chua ed mdt nghidn cdu nao d u p c t i l n hdnh vdi qui md ldn da trung tdm nhdm khao sdt thue trgng s u dyng amikacin thdng qua gidm sdt ndng dp t h u l c trong h u y l t thanh, cd so sanh vdi MIC cua khdng sinh vdi vi khuan d l dua ra mdt c h l dd lieu phii hpp trong d i l u tri tai Vipt Nam. O l cd t h i d l xuat d u p e bidn phap nhdm nang cao hipu qua vd dp an todn trong d i l u tri, chiing tdi xdc djnh ndng dp thudc trong mdu, t d dd tinh todn d l cd d u p e d y bdo hipu qud didu trj theo nong dd dinh vd Cpeak/MIC, dd an todn theo nong dp ddy.
D o i t u ' a n g v a p h u ' o n g p h a p n g h i e n CU'U
o d i t u y n g nghien c d u
Npi dung ndy d u p c t i l n hdnh trdn 2 d l l t u p n g nghien c u u : Bdnh nhdn co ehi djnh dung amikacin d l dieu trj nhiem k h u i n tgi 4 bpnh vipn TWQD 108, Bgch Mai, Thanh Nhdn yd Xanh Pdn va vi khuin gay bpnh friu thap d u p c tgi 4 benh vipn trdn.
Bdnh nhan Tieu ehuin lya chgn
Bpnh nhdn >16 tuoi, diing amikacin toi thieu 3 ngdy vd ed c h i n dodn nhiem k h u i n .
Tidu chuin lo^i trir
B0nh nhdn (BN) ed thay d i i t h i tich phan b l cOa t h u l c (phy n d cd thai, ede bdnh nhdn cd t i l n hdnh Ipe mdu, cdc BN bj m i t djch ngogi bdo n h i l u : bdng, ndn n h i l u , ia ehdy ngng, cac BN tw bdnh x o nang -cystic fibrosis, BN bi eo tmdng hodc phu), BN suy thgn ndng (dp thanh thai creatinin - CIcr <15ml/phut) hoge suy thgn khdng dn djnh, BN s d dyng amikacin vdi cdc dudng diing khdc ngodi d u d n g tiem. BN khdng dupc xdt nghidm creatinin vd dinh lup'ng ndng dp thulc trong mdu t r u d c theo d l cuong nghien cuu.
Vi khuan gay bgnh Tidu chuin lya chgn
Vi khuan (VK) dup'c phan Igp t u cac cae bdnh nhdn trong mau nghien c u u hoge vi khuin dupe phdn igp t u bpnh p h i m eung logi cua cdc t)pnh nhdn cd cung noi d i l u trj vd cung khodng thdi gian d i l u trj vdi cdc bdnh nhdn trong mdu nghien cdu.
Tidu chuin logi trir
Cdc m i u phdn Igp cd k i t qud xet nghidm muc dd nhgy cdm bang phuong phdp khoanh g i i y Id trung gian v d khdng vdi amikacin theo tidu ehi bidn gidi kdt qud cua Vidn c h u i n thuc Idm sang v d xdt nghidm Hoa Ky (Clinical and Laboratory Standards Institute - CLSI)
P h u o n g p h d p n g h i e n c i n i
- Nghien c u u md td tien c u u khdng can thiep.
- Vide djnh lup'ng amikadn d u o e thyc hipn tgi Khoa Hda sinh - Bdnh vipn Bach IVlai, sd dyng ky thudt m i l n djch ddng nhit (Homogeneous immunoassay) tren he mdy Cobas 5 0 1 , thudc t h u s u dyng Kit No.04791959 cua hang R o c h e - Hitachi, Thyy Sy.
Cdc vi k h u i n dup'c xac dinh MIC vdi amikacin bdng p h u o n g phap E - test cue hang BioMerieux Clinical Diagnostics.
TAP C H i DlTQIC H Q C - 07/2012 ( S 6 435 NAM 52)
» Nghien cu'u - Ky thuat
Tidu c h u i n ddnh gid: Trong nghien cdu nay, ddnh gid hipu qua s d dung theo che dp l i l u 1 lan/ngdy (ODD) vdi quy dinh nhu sau:
+ Theo ndng dp dinh Cpaa^ (meg/ml): t i i u u :
>56 - 75, gdn tdi u u : 45 - 56 va khdng dat: <45 + Theo Cpeak/MIC- toi u u 510, g i n t i i u u : 8 -
<10, khdng dgt: <8.
- Ddnh gid an todn qua nong dp ddy Crougw (mcg/mi): dgt: < 1, khdng dgt' > 1 .
X u ly k i t q u a nghien c i r u
Cae du lipu thu dupe t d bdnh nhdn nghien cdu dupc nhap vd x u ly bang p h i n m I m SPSS 18.0.
S6 lieu thu dupc v l MIC cua vi khuan se dupc tfnh MlCgo cua tung logi vi khuan va ciia q u i n t h i vi khuan bdng phan m I m WHONET 5.0.
K e t q u a n g h i e n cCfu
Sd luong bdnh nhan s u dung amikacin tgi 4 benh vien dupe dua vdo trong nghidn c d u t i l n cdu t i n g sd la 160 bdnh nhan, vdi sd lupng bdnh nhan tdng bpnh vien nhu sau:
- Benh vidn Bgch Mai (BVBM): 60 benh nhan; bdnh vipn TLCQD 108 (BV108): 30 bdnh nhan , bpnh vien Thanh Nhan (BVTN). 30 benh nhan, benh vidn Xanh Pdn (BVSP): 40 benh nhan; trong do ed 140 bpnh nhdn dung l i l u 1
lan/ngdy, 20 benh nhan dung l i l u 2 lln/ngdy.
Dgc diem benh nhan cua mau nghien c d u tien c u u
Bang 1 : Ddc diem mdu nghidn cwu tiin ciru Chi tieu nghien cwu
Tuoi TB (nam) Thdi gian dung amikacin (ngdy)
TB±SD TB±SD Chwc nang thSn cua BN
tfnh theo CIcr Binh thudng Suy thdn nh?
Suy thdn trung binh
Clcr>80 BOCIcra 50 50>Clcr2 10 Tong
61,8 ±16,7 11,4 ±6,8
binh nhan 22 13,8 75 46,9 63 39,4 160 100,0 Nhieu bdnh nhan trong mau nghidn edu cd suy giam chuc nang than (>85% n l u tinh theo dd thanh thai creatinin), la nhung d l l tupng e i n hipu ehinh l i l u diing va theo ddi ddc tinh.
K i t qua xdc djnh MIC cua cae vl khuin nhgy cam trong ede bdnh vien nghien cuu
Cdc vi khuan nhgy cam vdi amikacin thu d u p c t u cac bdnh pham cua bdnh nhan ed ehan dodn tuong t u vdi m i u nghidn edu t i l n cdu d u p c xac djnh MIC (bang 2):
Bang 2: Kdt qua xac dinh MIC vl khudn phdn igp dwoc tai cdc benh vien Loai vi khuan
P.aeruginosa K. pneumoniae Aanetobactersp M catan-halis
E.coli Entaobactersp
Proteus sp.
Citrobacter sp.
Serratia marcescens S. aureus
Tong
n 5 9 6 5
25 Bvioa
MlCtn 3 4 12
•
2
-
8 n 6 23 3 7 10
49 BVBM
UICK, 12 3 3
8 3
8 n 5 9 1 8 1 1
4 3 32
BVSP MICm
4 3 3 4 3 3 4 3 4
n 7 6 1
9 3 2 2
10 41
BVTN MICu
4 2 1 2 1,5
3 2
4 3 - MlCgo CLJa q u i n t h i chung nhgy cam khde
biet giua cac bdnh vien, trong dd 2 bdnh vien tuyln trung u o n g ed MICgo cOa qudn t h i cao lion so vdi 2 bdnh vidn t u y l n thdnh phd.
Du bdo hieu qua d i l u trj va do an toan thong flMa danh gia nong d d amikacin trong mau
Xdc djnh nong do dinh (Cp^t) theo cdc m d c liiu tren benh nhan
Do bpnh nhdn d u p c diing theo Ip t h u l c ndn trong bang danh gia, ndng dp dinh se tuong dng vdi moi mde l i l u tfnh theo s l mg md khdng phdi mg/kg nhu quy djnh.Trong nghidn edu nay Chung tdl chi tfnh cdch dua thuoc 1 lln/ngdy.
TAP CHf DirpC HQC - 07/2012 (S6 435 NAM 52)
• Nghien CLPU - Ky thuat
B a n g 3: Ndng dd dinh tmng binh theo cic muc lieu vi chd dd lidu
Ning d^ dinh Chi dd Iliu
SOOmg X 1 lln/ngdy 750mg x 1 lln/ngdy lOOOmgx 1 lln/ngdy
dao d^ng 24.8 ±7,0 12.9-38.7 39,3±12.5- 12,5-68,6 0,00 44,7 ±10,6- 14,8-58,4
- N6ng dp dinh dao dOng idn giOa cSc c^c th4 trong ciing mi>c ii^u.
- N6ng do dinh trung binh khac bipt c6 y nghTa th6ng ki giOa c4c c h l dd iliu, n6ng dO dinh trung binh ciia nhbm li^u lOOOmg/l^n cao nh^t.
Dinh gii ty /$ d^t nong dd dinh theo quy djnh
B i n g i-.Tyli bjnh nhin dat ndng dd dinh theo chd dd Iliu 1 lin /ngiy Iliu dimg (mg/lin) -n (%) Dinh gia hiiu qua theo Cp,., ——
7S0mg lOOOmg
Ting n(%) Khong dgt {Cpea* <45) 12 (100,0) 31 (73,8) 34 (39,5) 77 (55,0)
G4n l6i u'u (45S CpBok <56) 7 (16,7) 50 (35,7)
T6I U'U (56S Cp„k S75)
TAng 12 (100,0)
4 (9,5) 42(100,0)
9 (10,5) 86(100,0)
13 (9,3) 140 (100,0) - Glua cdc m u e l i l u trong c h l dd l i l u 1 khi diing l i l u SOOmg vd t h i p n h i t d muc lilu lln/ngdy, ty id khdng dgt n i n g dd dfnh cao n h i t lOOOmg.
Dir bdo hj#u qua dieu trj t h o n g qua d d n h gid t y s l Cpa,k/MiC Bang 5: Ty Id bdnh nhdn dgt ty so Cp^ai/MIC trong nhdm dung 1 lin/ngdy Danh gii hiiu qua theo
ly s6 Cp^i^imiC Ktiong dgt Gan to! U'U
To! U'U Tong
SftOmg n(%) 1 (50,0)
1 (50,0) 2 (100,0)
750 mg n(%) 1 (12,5)
0 7 (87,5) 8 (100,0)
lOQOmg n (%) 4 (17,4) 2 (8,7) 17 (73,9) 23 (100,0)
Tong n(%) 6 (18,2)
2(6,1) 25 (75,7) 33(100,0) - Cd 75,7% bpnh nhdn dgt muc Cpeak/MIC tdi u u ; t j id khdng dgt kha cao (18,2%).
D u bao t i n h an t o a n khi s d d u n g amilcacin t h d n g qua xdc d j n h n d n g d p ddy Bdng 6: Ty id benh nhan dgt ndng dd ddy theo ehi dd liiu 1 lin /ngdy
Dinh gii an toan theo Cimugh Dd thanh thil creatinin (ml/phut) - n (%) Ting n(%) Khdng dat ( C ^ >1) 27 (54,0) 36 (52,9) 6 (27,3) 69 (49,3)
Ogt (Quo 23 (46.0) 32 (47,1) 16(72,7) 71 (50,7)
Tong 50 (100,0) 68 (100,0) 22 (100,0) 140 (100,0)
Trong m i u nghidn cdu, ty id bdnh nhdn khdng dgt ndng dd ddy r i t cao (49,3%) vd ed xu h u d n g tdng ldn khi bdnh nhan ed chuc nang thdn binh thudng.
B a n l u $ n
Cdc dgc d i l m eua m i u nghidn c d u nhu tuoi trung binh cao (61 tuoi); thdi gian s u dyng amikacin trung binh Id 11 ngdy (>7 ngdy); >80%
benh nhan cd giam chdc nang thgn eho t h i y cdc bdnh nhdn nay la nhung doi t u p n g e i n luu y gidm sdt trong d i l u tri do ddy Id ede yeu to
nguy eo ciia ddc tfnh trdn th§n vd tai. Cdc ddc d i l m ndy cung t u o n g dong vdi cae bdnh nhdn trong cdc nghidn edu t i l n hdnh trudc ddy tgi bpnh vipn Bgch Mai'^. Trong nghien c d u ndy, 71 chung vi k h u i n dup'c phan Igp, trong do 70%
chung nhgy cdm vdi amikacin vdi ty lp vi khuin Gr(-) c h i l m da s l . MICgo cua quan t h i cdc Chung nhay cdm kha cao (8 ^g/ml). D i l u c i n luu y Id n i n g dp dinh can dat cua amikacin trong cae taj li$u h u d n g d i n giam sat d i l u trj Id khodng 45-75 f i g / m l ^ ^ l dat chi s l PK/PD t i i u'u vdi eac MIC t u 4-8 jig/ml. Cdc ehung vi khuin
T.^P CHI DlTQIC H Q C - 07/2012 (SO 435 NAM 52)
• Nghien ctpu - Ky thuat
CO MIC>8|ig/ml, ed kha ndng t h I t bgi d i l u trj cao hon do rat khd dat d u p c chf sd PK/PD tdi u u vdi che dp l i l u thdng t h u d n g . Cdc chung tryc khuan mu xanh, M. catarrhalis phdn ldp d u p e ed MIC Id 12 jig/mi, dii kdt qua khdng sinh dd Id nhgy cam, v i n ed kha nang dap ung dieu trj trdn ldm sdng kdm k l ea khi da diing dii l i l u amikacin. Vdi muc lieu dung 750 mg va lOOOmg, tuong dng vdi khoang 15 vd 20 mg/kg can ngng, khi dung d u d n g tmh mgch, nong dp dinh trung binh eua nhdm bpnh nhan trong nghien euu nay lan l u p t Id 39,3 ± 12,5 vd 44,7 ± 10,6 pg/ml. K i t qud nay cd khdc biet vdi k i t qua cOa mdt s l nghidn edu khde, theo dd khi diing lieu 15 vd 20 mg/kg theo c h l dd ODD tren bpnh nhdn nhidm k h u i n ngng thi Cpeak chi dgt 33,5±14,8 pg/ml vd 33,8±4,7pg/ml - mdt n i n g dp khd dam bao hipu qua d i l u trj neu vi k h u i n gdy bdnh nghi ngd la cdc tryc k h u i n Gr(-) ed MIC cao nhu tryc khuan mu xanh vd A.
baumaniP' ^'. Theo mdt nghidn cdu da trung tdm tren 74 bpnh nhan, khi md phdng sang c h l dp lieu 15mg/kg amikacin, ehi cd 9% bdnh nhan dat nong dp ydu cau"^. Trong mpt nghien cdu cd can thipp l i l u dimg amikacin, ty Id bpnh nhan khdng dgt ndng dd dinh (£45pg/ml) t u o n g dng la 90,0%'^'. Nhu vdy, nghien c d u nay cd ndng flfl dinh trung binh khd eao so vdi mdt so nghien CLPU khdc nhung ty Id bpnh nhan dgt d u p e ndng do dilu tri vdn cdn thap. De dam bdo hieu qua dieu trj, Cpeak/MIC can dat tdt nhat Id >10 va ft nhit la 8-10'^. Ty Id bpnh nhan khdng dgt ty so Cpeak/MIC tdi uu vd gan t i i u u la 18,2%. Nhu vay, tren cdc bdnh nhan ed k i t qud xdt nghidm vi khuin Id nhgy cdm vdi amikacin ed den g i n 1/5 sd bdnh nhan ed t h i cd ddp ung lam sdng kem. Trong nghidn c u u ndy, khi khdng ed can thiep v l lieu diing, 49,3%. bpnh nhan ed ndng dd day amikadn eao hon so vdi k h u y l n eao. Tham khao mdt nghien euu can thipp lieu trdn bpnh nhan h i i sdc tich cue, trong do l i l u ban d i u dupc tinh d y a vao do thanh thdi creatinin theo hudng d i n eua Sanford, 23,3% bdnh nhan ed Cirough >1 pg/ml^^. Do vay, vide tinh l i l u ban d i u theo cdn ngng vd chuc ndng thgn cd cdi thien doan toan khi s u dung amikacin.
Kit luan
Ve di^ bao liifu qua cua vipc s d dgng amikacin
- Theo n i n g dp dinh; vdi c h l dp l i l u 1 lln/ngdy, t f Id bdnh nhdn dgt nong dd dinh toi uu Id 9,3%. g i n t i i u u Id 35,7% va khdng t i i u u la 55,0%. Ty lp nay khde bipt gida cdc l i l u dung.
TAP CHf mfrtC HOC - 07/2012 (SO 435 NAM 52)
- Theo Cpeak/MIC: Tren cdc trudng hpp ed xet nghipm vi khudn nhgy vdi amikacin cd 75,7% trudng hpp dgt ehi so tdi u u , 6 , 1 % dgt mde gan toi uu va 18,2% bdnh nhan cd chf so khdng dgt vd ed t h i cd ddp dng lam sang khdng phii hpp vdi xdt nghidm vi k h u i n .
Ve d y bdo tinh an toan khi s d dung amikacin theo n i n g dp day
51,7% bdnh nhan cd n i n g dp ddy dgt, 49,3%
ed nong dd ddy khdng dgt.
D l x u i t
Cdc bdnh vipn ndn tang cudng xet nghiem vi khuan gdy bpnh, vd n l u cd the, xdc djnh MIC cua amikacin, trdn eo s d dd xdy dyng dich ndng dp dinh vd l i l u diing cua amikacin phu hpp;
Tdng b u d c t i l n hanh gidm sat nong dd thuoc trong mdu khi dieu trj amikacin d l ddm bdo hieu qud va an todn d i l u tri.
S u m m a r y
Introduction:Therapeutic drug monitoring (TDM) of amikacin is popular in developed countries but unconventional in Vietnam. Beside this. MIC of amikacin for isolates varied from hospital to hospital, so that there were a chance for ineffectiveness of amikacin in the patients.
Objectives.The aim of this study was to predict the efficacy and the safety of amikacin usage in patients based on amikacin plasma concentrations and PK/PD indice. Patients and methods: This is a prospective obseivational study included 160 adult patients admitted 4 general hospitals. The patients were treated with amikacin and blood samples were taken to determine Cpeak and Ctrough of amikacin at steady state. In the same time, MICgo of amikacin for strains which were isolated from patients and susceptible with amikacin, were determined. Prediction the efficacy was based on Cpeaks and Cpeak/MIC. the safety was based on Ctroughs in 140 patients with ODD regime. Results: The MIC90 of amikacin for isolates from hospitals 108. Bach Mai. Saint Paul's and Thanh Nhan was 8. 8, 4 and 3 pg/ml, respectively. The rates of patients had achieved Cpeak. Cpeak/MIC and Ctrough in the recommended ranges were 45%, 81.8%; and SI.7%; recpectively. Conclusion: Our results suggested that the usage of amikacin in patients was not really effective and safe. Therefore, TDM of amikacin should be applied regulariy. Further studies with the aims to identify the varies of MICgo of isolates and phanvacxykinetic parameters of
57
• Nghien CCFU - Ky thuat
patients in a larger number will provide valuable infonvation for TDM amikacin in patients.
Keywords: Amikacin. PK/PD indices, concentration.
Tdi lieu tham khao 1. Beaucaire G., et al. (1991), "Clinical and bacteriological efficacy, and practical aspects of amikacin given once daily for severe infections", J.
Antimicrob Chemother. 27 Suppl C, p. 91-103.
2. Betts R. F„ et al, (2003), Reese and Betl's: A practice approach to infection. 5th ed., Lippincott Williams S Wilkins, p. 1065-1076
3. Cunha B. A. (2011), Antibiotic essentials, lO'"
ed,, Jones and Bartlett Learning.
4. Gilbert D. N , etal. (2010), The sanford guide to antimicrobial therapy, 40 ed., Antimicrobial therapy.
5. Mcevoy G. K., et al. (2004), AHFS drug Information. American Society of Health-System Pharmacist.
6. Nguyen T. V., et al. (2007), Evaluation amikacin use by monitoring plasma drug concentration in patients at intensive care unit - Bach mai hospital, in Indochina Conference on Pharmaceutical Science, 5'^ Bangkok, Thailand.
7. Taccone F S , et al. (2010), "Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock", Crit Care. 14(2), p. 53
Dinh chinh
Do sa suit trong qud trlnh in I n . Tgp chi Dupc hpc s6 434, thdng 6/2012 cd mdt s l sai sdt tgi trang 38, cOt 1, Hinh 1; Ciu true hod hoc cua chit sd 1; trang 51, So d l 1: Ouy trlnh ting hgp; trang 52, Hinh 1: Ciu tnic cua phdn tw cua phyllanthin.
Nay xin dupc dinh chfnh nhu sau:
Hinh 1 : Cau (rue hda hgc cua chit sd 1 (myricitrin) Hinh 1 : Ciu tnJc cua phdn tir cua phyllanthin
X X H -" - ?' L 1
(6) R=H. X=H (18%) (7) R=OC2H5 X=H (94%) (B) R= H X=N (81%)
HaCO-
HgCO'
:xo
X=H (43%) X=H (30%) X=N(43%)
(/) dung cy Dean-Stark, toluen, reflux 18-24h (//) methanol, NaBH4, nhiSl dO phdng
{110 LDA/THF -7SOC/5h, sau d6 a6 dnhi^tdO phbng H (53%) H (77%) :=N (98%)
So* do 1 : Quy trlnh tdng hgp Rat mong dupc cdc tdc gid vd ban dpc thdng cam.
TAP CHi DirpC HQC - 07/2012 (S6 435 NAM 52)