B Y T

TRNG I HC DC H NI

HONG TH ANH TH

TNG QUAN V C IM DC NG HC V DC LC HC

(PK/PD) CA KHNG SINH NHM BETA-LACTAM V TNH NG DNG

TRONG LM SNG

KHA LUN TT NGHIP DC S

H NI 2013

B Y T

TRNG I HC DC H NI

HONG TH ANH TH

TNG QUAN V C IM DC NG HC V DC LC HC

(PK/PD) CA KHNG SINH NHM BETA-LACTAM V TNH NG DNG TRONG

LM SNG

KHA LUN TT NGHIP DC S

Ngi hng dn:

1. Ths. Hong H Phng 2. Ths. Trnh Trung Hiu

Ni thc hin:

B mn Dc lm sng

H NI 2013

LI CM N

Vi tt c lng knh trng v s chn thnh, ti xin c by t nim bit n

su sc ti ThS. Hong H Phng v ThS. Trnh Trung Hiu nhng ngi

thy trc tip hng dn, ch bo tn tnh, gip v truyn t nhng kinh

nghim qu bu cho ti hon thnh kha lun ny.

Ti xin chn thnh cm n cc thy c gio b mn Dc lm sng

nhit tnh gip , to mi iu kin thun li cho ti trong thi gian c hc tp

b mn.

Ti cng xin gi ti ton th ging vin, cn b trng i hc Dc H Ni

li cm n chn thnh v s du dt, dy bo tn tnh trong sut nm nm ti hc tp

ti y.

Cui cng ti xin by t lng bit n su sc ti cha m knh yu, ngi

thn, bn b nhng ngi lun bn cnh ng vin, yu qu v gip ti

trong cuc sng!

H Ni, ngy 20 thng 5 nm 2013

Hong Th Anh Th

MC LC

CHNG 1: KIN THC CHUNG V DC NG HC/ DC LC

HC KHNG SINH ................................................................................................. 3 1.1. Dc ng hc khng sinh ...................................................................................... 3

1.2. Dc lc hc khng sinh ......................................................................................... 3

1.3. Mi quan h gia dc ng hc v dc lc hc khng sinh ............................... 3

1.4. Cc thng s dc ng hc/ dc lc hc khng sinh .......................................... 5

1.4.1. Cc thng s dc lc hc ............................................................................... 5

1.4.2. Cc thng s PK/PD ...................................................................................... 10

1.5. Phn loi khng sinh theo dc ng hc/ dc lc hc ...................................... 10

1.6. Nhng hn ch ca vic ng dng PK/PD vo thc hnh lm sng v cc gii

php tim nng ................................................................................................................. 15

1.6.1. Nhng hn ch ca vic ng dng PK/PD vo thc hnh lm sng ............. 15

1.6.2. Cc gii php tim nng ................................................................................. 16

1.7. ng dng dc ng hc/ dc lc hc khng sinh ............................................ 17

1.7.1 Thit lp phc ti u cho cc khng sinh mi v cc khng sinh ang c s

dng ............................................................................................................................. 17

1.7.2. Chng khng thuc ............................................................................................ 18

1.7.3. Thit lp im gy nhy cm (breakpoint) ........................................................ 22

1.7.4. Xy dng hng dn iu tr theo kinh nghim ................................................ 23

CHNG 2: DC NG HC DC LC HC CA KHNG SINH

NHM BETA - LACTAM ..................................................................................... 25 2.1. Gii thiu chung v nhm khng sinh beta lactam ................................................ 25

2.2. Dc ng hc ca cc khng sinh nhm beta lactam .......................................... 26

2.2.1. Mc hp thu .................................................................................................. 26

2.2.2. Mc phn b ................................................................................................. 27

2.2.3. Mc thi tr .................................................................................................. 27

2.3. Dc lc hc ca cc khng sinh nhm beta lactam ............................................. 28

2.3.1. Mc nhy cm ca cc vi khun vi khng sinh beta - lactam .................... 28

2.3.2. Tc dng hu khng sinh ca beta - lactam ....................................................... 30

2.4. Dc ng hc/ dc lc hc ca cc khng sinh nhm beta lactam ................... 32

2.4.1. Khng sinh dit khun ph thuc thi gian ....................................................... 32

2.4.2. Thng s PK/PD d bo hiu qu iu tr ca cc khng sinh beta - lactam l

%T>MIC ...................................................................................................................... 33

2.5. ng dng PK/PD khng sinh beta lactam trn lm sng ....................................... 35

2.5.1. Ti u ho hiu qu iu tr ............................................................................... 35

2.5.2. Gim khng thuc .............................................................................................. 54

DANH MC CC HNH

Hnh 1: Mi quan h gia dc ng hc v dc lc hc ........................................ 4

Hnh 2: Mi quan h gia dc ng hc dc lc hc v hiu qu iu tr ca

khng sinh. .................................................................................................................. 5

Hnh 3: Kt qu khng sinh theo phng php khuch tn a v phng php E-

test. .............................................................................................................................. 6

Hnh 4: S lng vi khun (a) v s lng vi khun khng (b) khi dng hai phc

garenoxacin khc nhau. ............................................................................................. 20

Hnh 5: ng cong dit khun ca khng sinh ticarcilin. ....................................... 33

Hnh 6: Gi tr %T>MIC ca 6 khng sinh nhm cephalosporin vi chng

Klebsiella pneumoniae chun. .................................................................................. 34

Hnh 7: So snh thi gian nng thuc trn MIC ca 3 phc : piperacilin 2g

truyn trong 30 pht, 4g truyn trong 30 pht v 2g truyn trong 4 gi .................. 36

Hnh 8: M t nng theo thi gian ca khng sinh beta-lactam khi tim tnh

mch gin on v truyn lin tc. ........................................................................... 38

Hnh 9: Nng trng thi n nh trong huyt tng v dch k cc m ca

meropenem khi iu tr trn nhng bnh nhn nhim khun nng khi tim tnh mch

gin on v truyn lin tc. ..................................................................................... 39

Hnh 10: M t thi gian nng thuc trn MIC khi truyn 500mg meropenem

nhanh trong 30 pht v 3 gi. ................................................................................... 47

Hnh 11: So snh thi gian nng thuc trong huyt tng trn MIC ca ba phc

s dng piperacilin l 2g truyn trong 30 pht, 4g truyn trong 30 pht v 2g

truyn trong 4 gi. ..................................................................................................... 48

Hnh 12: Kh nng t %T>MIC = 50% ca TZP ba phc .Error! Bookmark

not defined.

Hnh 13: Kh nng t %T>MIC mc tiu 5 phc s dng meropenem khc

nhau. .......................................................................................................................... 50

Hnh 14 (A) T l t vong sau 14 ngy v (B) s ngy nm vin ca bnh nhn

c iu tr bng phc truyn ko di trong 4 gi hoc truyn nhanh trong 0,5

gi ca TZP. .............................................................................................................. 52

DANH MC CC BNG

Bng 1: Phn loi cc khng sinh theo PK/PD. ........................................................ 14

Bng 2: Sinh kh dng ca mt s cephalosporin th h 1 v 2. .............................. 26

Bng 3: Sinh kh dng ca mt s cephalosporin th h 3. ..................................... 27

Bng 4: Thi gian bn thi ca mt s khng sinh nhm penicilin, cephalosporin,

carbapenem v monobactam ..................................................................................... 28

Bng 5: Cc gi tr im gy lm sng theo EUCAST ca 4 khng sinh nhm beta-

lactam: piperacilin - tazobactam, meropenem, doripenem v ceftazidin i vi 2

chng vi khun Enterobacteriaceae v Pseudomonas aeruginosa liu chun so vi

tng lng thuc nu dng theo ng truyn lin tc hoc ko di. ................. 42

Bng 6: Kh nng t %T>MIC = 50% ca piperacilin-tazobactam ba phc . . 49

DANH MC CC CH VIT TT

STT Ch vit

tt

Tn ting Anh y Tn ting Vit y

1 APACHE Acute Physiology and

Chronic Health Evaluation

Thang nh gi sc khe mn

tnh v tnh trng bnh l cp

tnh

2 AUC Area Under the Curve Din tch di ng cong

3 CFU Colony Forming Unit S n v hnh thnh khun lc

4 Cmax Maximum Concentration Nng ti a

5 Cpeak Peak Concentration Nng nh

6 ICU Intensive Care Unit Khoa hi sc tch cc

7 MIC Minimum Inhibitory

Concentration

Nng c ch ti thiu

8 MRSA Methicilin Resistant

Staphylococcus aureus

T cu vng khng Methicilin

9 PAE Postantibiotic Effect Tc dng hu khng sinh

10 PAE

SME

Postantibiotic Effect Sub -

MIC Effect

Tc dng hu khng sinh ph

nng di MIC

11 PALE Postantibiotic

Leukocytes Enhancement

Effect

Tc dng tng cng ca bch

cu hu khng sinh

12 PD Pharmacodynamics Dc lc hc

13 PK Pharmacokinetics Dc ng hc

14 PRSP Penicilin Resistant

Streptococus pneumoniae

Streptococus pneumonia khng

penicillin

15 TZP Piperacilin - tazobactam Piperacilin tazobactam

1

T VN

Hin tng khng khng sinh ang ngy cng tng cao v tr thnh mt vn

ng bo ng khng ch trn th gii m cn Vit Nam. T l nhim khun

trong bnh vin v trong cng ng do c vi khun khng thuc Gram dng v

Gram m ang khng ngng tng cao. Theo chng trnh gim st khng sinh ton

cu SENTRY, t cu vng khng methicilin l tc nhn gy bnh thng gp trong

bnh vin vi t l cao nht [11]. T l Streptococus pneumoniae khng penicillin

(PRSP) cng tng ln ng k c lin quan n vic s dng cc khng sinh nhm

beta-lactam M, Canada, Ty Ban Nha, Ai-x len [16]. Ti Vit Nam, kt qu t

mt nghin cu a trung tm cho thy t l Streptococus pneumoniae khng

penicillin (PRSP) l 80% v 89,7% chng vi khun Streptococus pneumoniae khng

vi t nht mt khng sinh nhm macrolid [17].

iu ny t ra nhu cu cp thit cn phi pht trin cc khng sinh mi v

ti u ho vic s dng cc khng sinh hin c. Cch tip cn thng qua dc ng

hc/ dc lc hc (PK/PD) c chng minh l mt cng c thit yu ti u

ho ch liu, va pht huy tc dng ti a, va gim tnh khng thuc [29].

Beta-lactam l nhm khng sinh c s dng ph bin nht trn lm sng

hin nay do thuc c phn b vo nhiu v tr khc nhau trn c th, c ph

khng khun rng nn c th iu tr c nhiu bnh nhim khun, t c tnh nn

c th tng liu iu tr c trn nhiu mc nhim khun [1, 15]. Mt hiu bit

ton din v cc c tnh dc ng hc/ dc lc hc ca nhm khng sinh ny s

gip nng cao hiu qu iu tr nhim khun trn lm sng. Chnh v l do trn

chng ti thc hin ti: Tng quan v c im dc ng hc/ dc lc hc

ca khng sinh nhm betalactam v tnh ng dng trong lm sng vi hai mc

tiu sau:

- Trnh by nhng kin thc chung lin quan n dc ng hc/ dc lc

hc ca khng sinh.

2

- Trnh by c im dc ng hc/ dc lc hc ca cc khng sinh

nhm betalactam v ng dng trong lm sng.

3

CHNG 1: KIN THC CHUNG V DC NG HC/ DC LC HC KHNG SINH

1.1. Dc ng hc khng sinh Dc ng hc (PK - pharmacokinetics) l mt mn khoa hc nghin cu v s

thay i ca nng thuc trong c th, c th l trong huyt thanh, huyt tng,

cc c quan hay m ch theo thi gian qua bn qu trnh hp thu, phn b, chuyn

ha, thi tr [43]. Vi khng sinh, dc ng hc nghin cu v s thay i nng

khng sinh trong c th theo thi gian, c bit l mi quan h gia phc liu

vi nng thuc trong huyt thanh v v tr nhim khun [18].

Cc thng s dc ng hc c xc nh da trn kt qu nh lng nng

khng sinh trong c th theo thi gian. C nhiu thng s dc ng hc, trong

cc thng s dc ng hc quan trng nht c s dng nh gi hiu qu ca

khng sinh l nng nh (Cpeak) , din tch di ng cong nng theo thi

gian (AUC) [43]. Trc y, phc liu khng sinh ch c xc nh da trn

cc thng s dc ng hc [4]. Tuy nhin, cc thng s dc ng hc khng th

m t c hiu qu khng khun ca khng sinh[43].

1.2. Dc lc hc khng sinh Dc lc hc (PD - pharmacodynamics) l mn khoa hc nghin cu mi quan

h gia nng thuc trong c th theo thi gian vi tc dng v c tnh ca thuc

[7, 10, 18, 32, 34]. Ni cch khc, dc lc hc miu t s tng tc gia thuc v

c th [10]. Vi khng sinh, dc lc hc m t mi quan h gia nng thuc vi

khun phi nhim nhng v tr nhim khun khc nhau vi tc dng dit khun

hoc km khun v c tnh ca khng sinh [10, 18, 32, 43].

S pht trin ca dc lc hc tng thm nhng kin thc v cch s dng

khng sinh iu tr nhim khun mt cch hiu qu nht vi t l vi khun khng

khng sinh thp nht [34].

1.3. Mi quan h gia dc ng hc v dc lc hc khng sinh Dc ng hc v dc lc hc c mi quan h mt thit vi nhau. Mi quan h

gia dc ng hc v dc lc hc (PK/PD) c minh ha trong hnh 1.

4

Hnh 1: Mi quan h gia dc ng hc v dc lc hc [1]

Dc ng hc cho ta thy mt ch liu khng th thch hp trn mi

bnh nhn v dc lc hc cho ta thy mt nng ch cng khng th ph hp

vi mi bnh nhn [4]. Do , t c mc tiu iu tr, cn phi xc nh c

mi quan h gia nng v hiu qu ca thuc theo thi gian, hay cn phi c s

kt hp gia dc ng hc v dc lc hc [12].

i vi khng sinh PK/PD din t mi quan h gia mc phi nhim ca

thuc trong c th - hiu lc khng khun ca khng sinh in vitro (MIC) - tc dng

ca khng sinh trong c th (Hnh 2) [27]. Nhng thng s dc ng hc/dc lc

hc (PK/PD) tr nn c bit quan trng v cc thng s ny th hin mi lin h

gia nng thuc vi kh nng dit khun v kh nng chng khng thuc [7].

Mi lin h ny c s khc bit vi cc thuc khc v th th ca khng sinh l trn

vi khun ch khng phi trn t bo ca ngi [27]. Mt s lng ln cc nghin

cu th nghim in vitro v trn ng vt ch ra rng cc thng s PK/PD thch

hp cho tng nhm khng sinh c kh nng d on tt hiu qu iu tr [4, 13].

DC NG HC

Liu lng Nng thuc trong huyt thanh

Nng thuc ti cc m khc

Nng thuc ti v tr nhim khun

c tnh

Hiu qu iu tr

DC LC HC

5

Hnh 2: Mi quan h gia dc ng hc dc lc hc v hiu qu iu tr ca

khng sinh.

1.4. Cc thng s dc ng hc/ dc lc hc khng sinh 1.4.1. Cc thng s dc lc hc

a) Nng c ch ti thiu (MIC)

nh ngha

Nng c ch ti thiu (MIC - Minimum Inhibitory Concentration) l nng

khng sinh thp nht c ch hon ton s pht trin ca vi khun trong ng

nghim, quan st c bng mt thng sau thi gian khong 18-24 gi trong mt

mi trng tiu chun cha hn dch khong 105 106 CFU/ml [32, 40]. MIC50 v

MIC90 l nng khng sinh thp nht c th c ch c 50% v 90% s vi khun

[1].

MIC c xc nh bng hai phng php vi pha long v E-test. Vi pha

long c th c thc hin trong ng nghim hoc trn a thch. Mt lng vi

khun nht nh (105 106 CFU/ml) c nui cy trong mi trng thch hp, ri

cho mt lng khng sinh vi nhng nng khc nhau vo. nhit thch

hp, thng l 37oC, sau 18 24 gi, nng khng sinh thp nht m khng

cn nhn thy s pht trin ca vi khun chnh l nng c ch ti thiu (MIC)

[32].

Hiu lc khng khun ca khng

sinh in vitro (MIC)

Nng thuc phi nhim vi vi khun

in vivo (PK)

Phc liu

Tc dng khng khun ca khng sinh (hiu

qu trn vi sinh)

Hiu qu trn lm sng

6

E-test l mt thanh cha mt gradient nng bit ca mt khng sinh.

Cc thanh E-test c t ln b mt thch c mt lng vi khun nht nh (105

106 CFU/ml). Sau khi 37oC t 18 24 gi, kt qu l mt vng v khun hnh

elip ta trn bao quanh thanh E-test. Ti im m vng elip giao vi thanh E-test

chnh l nng c ch ti thiu ca khng sinh vi vi khun.

A B

Hnh 3: Kt qu khng sinh theo phng php khuch tn a (A) v phng

php E-test (B) [32].

ngha

MIC c th phn nh hiu lc ca khng sinh, xc nh vi khun l nhy

cm, trung gian hay khng vi khng sinh, d on c hiu qu ca khng sinh

[34, 40]. MIC l c s xc nh nng khng sinh cn t c ti v tr nhim

trng trong sut mt khong thi gian nht nh, t gip cc thy thuc la chn

v tnh ton liu khng sinh cho bnh nhn. Ngoi ra, MIC cn c dng gim

st dch t hc nhm nh gi v tnh hnh khng thuc ca vi khun qua s a

ra cc bin php nhm khng ch v ngn chn s ly lan ca vi khun khng thuc

trong bnh vin v cng ng [30].

Hn ch khi s dng MIC d on hiu qu ca khng sinh

MIC khng cung cp y nhng thng tin cn thit xy dng c ch

liu ti u do MIC c xc nh trong iu kin in vitro. Nhng iu kin khi

xc nh MIC khc bit vi iu kin nhim khun trn lm sng l nhc im khi

s dng thng s ny d on hiu qu ca khng sinh:

7

- Mi trng nui cy in vitro l cht lng khng c protein gn thuc trong

iu kin hiu khi pH 7,2. Trong khi iu kin ny v tr nhim khun l rt khc

bit: thng c tnh acid, k kh, v protein gn thuc vi 1 t l nht nh. Vi

khun c nui cy l cc chng tiu chun, vi nng c nh khong 105 106

CFU/ml , v ang giai on pht trin logarit, khc vi v tr nhim khun: mt

vi khun thng khong 108 ti 109 CFU/ml v hu nh khng pht trin v mt s

lng.

- MIC c xc nh 1 thi im c nh (18-24 gi sau khi ) v nng

thuc khng i trong sut thi gian nui cy, nhng thc t th nng thuc li

bin thin trong c th bnh nhn trong sut khong liu, v nng thuc trong

huyt tng khng phi lc no cng tng ng vi nng v tr nhim khun

[19].

- Vic xc nh ch s MIC gip m t hiu lc khng khun nng c

nh ti mt im duy nht trong 1 thi gian, khng m t c ht cc c im

dc ng hc ca khng sinh. Do , kh nng d on hiu qu iu tr da vo

MIC cn hn ch. C th, cc xt nghim xc nh MIC khng cho php xc nh

tc ng ca cc nng thuc khc nhau ln t l hoc mc dit khun, khng

xc nh xem tc dng c ch vi khun c bn vng v ko di sau khi tip xc vi

thuc khng sinh hay khng [18, 19, 34].

Do vy, MIC c th m t chnh xc tim nng ca s tng tc gia thuc

v vi sinh vt trong h thng th nghim in vitro, nhng chng khng th d on

mt cch tng i hiu qu iu tr [34]. V th, cn phi kt hp MIC v cc

thng s dc ng hc v dc lc hc khc.

Trc y, cc kt qu khng sinh thng t c s dng trong mi lin

h vi dc ng v dc lc ca khng sinh. Ngy nay i ph vi tnh trng vi

khun ngy cng khng vi nhiu khng sinh, cc nh y hc nhn thy s cn

thit phi s dng mi lin h ny. Chnh nh s dng tip cn PK/PD m cc bc

s iu tr c th chn la khng sinh g, liu lng nh th no c th thu c

hiu qu ti a khi iu tr trn bnh nhn.

8

b) Tc dng hu khng sinh (PAE)

Tc dng hu khng sinh (PAE)

Tc dng hu khng sinh (PAE - Postantibiotic effects) l thut ng dng

miu t s c ch lin tc s pht trin ca vi khun sau khi tip xc vi khng

sinh. PAE phn nh thi gian cn thit vi khun pht trin tr li sau khi tip xc

vi thuc [32].

Hin tng ny c quan st ln u tin vo nhng nm 1940 trong nhng

nghin cu v penicilin iu tr t cu v lin cu. T nhng nm 1970, nhiu

nghin cu m rng phm vi nghin cu vi cc khng sinh mi v trn vi

khun Gram m. PAE c chng minh trn in vitro bng ng hc tng trng ca

vi khun sau khi thuc b loi b [32].

PAE ph thuc vo cc yu t: nng khng sinh, thi gian vi khun tip

xc vi thuc, loi vi khun, loi khng sinh. Cc khng sinh c ch tng hp

protein hoc acid nucleic c PAE in vitro t trung bnh n di vi vi khun Gram

dng nhy cm nh t cu v lin cu v trc khun Gram m. Ngc li cc beta-

lactam li khng c hoc c PAE ngn trn trc khun Gram m, ch tr 1 ngoi l

duy nht c PAE trung bnh l carbapenem, ch yu trn Pseudomonas aeruginosa

[32].

PAE c nh hng n ch liu, vi nhng khng sinh c PAE di, s ln

a thuc s t hn so vi s ln a thuc c tnh da vo thi gian bn thi [32].

Tc dng hu khng sinh ph nng di MIC (PAE-SME)

Tc dng hu khng sinh ph nng di MIC (PAE-SME -

postantibiotic- effect sub-MIC effect) l tc dng b sung ca PAE ca khng sinh

xy ra cc nng thuc nh hn MIC trong nghin cu in vitro.V d: s tip

xc ca lin cu khun trong giai on PAE vi macrolid nng 1/10 v 3/10

MIC lm tng thi gian PAE tng ng l 50% v 100%, ng thi giai on ny

cng lm tng tnh nhy cm ca lin cu vi penicilin. Thi gian PAE-SME c

bo co trong cc y vn bao gm thi gian PAE cng vi thi gian c ch tng thm

9

do nng di MIC, nng di MIC ny cng c th gy ra bin i hnh thi

hc ca vi khun. Nh vy, PAE-SME phn nh iu kin in vivo mt cch gn gi

hn PAE, do s c ngha hn trong vic c tnh tc dng ko di ca khng

sinh trn lm sng [32].

Tc dng tng cng ca bch cu hu khng sinh (PALE)

Tc dng tng cng ca bch cu hu khng sinh (PALE - postantibiotic-

leukocytes enhancement effect) m t tc dng ca bch cu trong giai on hu

khng sinh. Cc nghin cu chng minh rng cc vi khun sau khi tip xc vi

khng sinh nhy cm vi tc dng thc bo ca bch cu hn cc vi khun khng

tip xc. Hin tng ny cng c th ko di thi gian PAE in vitro. Cc khng sinh

c PAE di nht c xu hng th hin tc dng hu khng sinh di nht khi c

tip xc vi bch cu.

PAE cng c chng minh in vivo trong rt nhiu cc m hnh nhim

khun khc nhau trn ng vt. Hin tng ny trn in vivo l s kt hp ca PAE

v PAE SME do nng thuc gim dn. Cc nghin cu trn ng vt c tin

hnh nhiu nht l m hnh gy nhim trng i chut mt bch cu trung tnh. Khi

th nghim trn chut khng gy mt bch cu trung tnh th PAE in vivo bao gm

c c PALE [32].

Mt s im khc quan trng gia PAE in vitro v in vivo

Thi gian ca PAE in vitro khng th tin lng c thi gian PAE in vivo.

Trong a s trng hp, PAE in vivo di hn PAE in vitro, do tc dng b sung ca

thuc nng nh hn MIC v tc dng ca bch cu. V d nh PAE in vivo ca

aminoglycosid v fluoroquinolon c ko di hn bi s c mt ca bch cu. Tuy

nhin cng c nhng trng hp PAE in vitro di hn so vi in vivo, nh PAE ko

di khi cho lin cu tip xc vi penicilin v cephalosporin ch quan st c trn in

vitro ch khng quan st c trn in vivo [32].

10

1.4.2. Cc thng s PK/PD Nh phn tch trn, MIC l thng s nh lng hiu lc khng khun

in vitro, nhng khi s dng nh gi hiu qu iu tr th cn nhiu hn ch. Do

cn kt hp MIC vi cc thng s dc ng hc. C ba thng s PK/PD d

on tt nht tc dng ca khng sinh. iu ny c chng minh trn cc m

hnh nhim khun trn ng vt v ngi. Ba thng s PK/PD l:

+ Cpeak/MIC (hay Cmax/MIC) c tnh bi nng nh hoc ti a chia

cho MIC. Trong , nng nh hoc ti a l nng thuc cao nht t c

hoc c tnh trong cc dch hoc m ca c th. n v tnh l mg/l hoc mg/ml

[1].

+ %T>MIC (t l thi gian T>MIC) l t l thi gian phi nhim ca vi

khun vi khng sinh c nng trn MIC so vi khong liu hay phn trm

khong cch liu trong nng thuc trong huyt tng cao hn MIC. n v

tnh % [1].

+ AUC/MIC l ch s c xc nh bi din tch di ng cong nng

theo thi gian so vi MIC ca vi khun gy bnh. Thng thng AUC c tnh

trong 24 gi, cho thng s tng ng l 24h-AUC/MIC [1].

1.5. Phn loi khng sinh theo dc ng hc/ dc lc hc Da vo nhng thng s PK/PD v tc dng hu khng sinh, cc khng sinh

c th c chia thnh ba nhm (Bng 1).

Nhm 1:

Nhm 1 l cc khng sinh dit khun ph thuc vo nng v c tc dng

hu khng sinh di, thng s PK/PD i din cho hiu qu iu tr l Cpeak/MIC

hoc AUC/MIC. Phc liu cn phi ti u ha nng . Nng cng cao, tc

dng dit khun cng nhanh v cng c m rng. Nhm ny bao gm cc khng

sinh aminoglycosid, daptomycin, fluoroquinolon, ketolid [4, 32, 34].

Vi cc khng sinh nhm aminoglycosid, Cpeak/MIC ti thiu phi bng 8-

10 ngn chn khng [4]. Nghin cu ca Moore v cng s chng minh c

mt mi quan h tuyn tnh gia Cpeak/MIC v t l p ng trn lm sng ca cc

11

khng sinh nhm aminoglycosid. Khi Cpeak/MIC 10, th t l ny 88% [2].

Theo mt nghin cu khc ca Kashuba v cng s, cho thy khi dng ngay t

ngy u tin cc khng sinh nhm aminoglycosid trn nhng bnh nhn vim phi

bnh vin, kh nng ht st v s lng bch cu tr v bnh thng vo ngy th 7

ca t iu tr t ti hn 90% khi Cpeak/MIC 10. iu ny c ngha rng nu

bnh nhn c iu tr vi mt liu hp l thu c mt Cpeak cao, th hiu

qu iu tr s c ti u ho. Nu bnh nhn dng liu thp v khng thng

xuyn, th ch c 60% c hi t hiu qu iu tr trong vng 7 ngy. Nhng d liu

ny cho thy dng thuc mt cch chnh xc v sm s cung cp mt c hi ti

a ha hiu qu khng khun [2].

Vi cc khng sinh nhm fluoroquinolon, AUC/MIC mc tiu c tc

dng ti u trn vi khun Gram m l khong 125, trn vi khun Gram dng l 40.

Tuy nhin, gi tr AUC/MIC mc tiu ca cc khng sinh fluoroquinolon l khc

nhau trn mt khong rt rng gia cc nghin cu [4]. Forrest v cng s

nghin cu vic s dng ciprofloxacin iu tr nhng bnh nhn vim phi bnh

vin, kt qu cho thy vi AUC/MIC 125, c hiu qu trn vi sinh v lm sng

u c ti a ha. Khi ti u ho hiu qu vi sinh th kh nng vi khun khng

thuc s c ti thiu ho, v vi khun b loi tr trc khi pht trin sc

khng. Cc vi khun khc nhau s c MIC vi cc khng sinh khc nhau. V d nh

cc nghin cu v AUC/MIC ca cc khng sinh nhm fluoroquinolon nh

ciprofloxacin, levofloxacin, gatifloxacin v moxifloxacin i vi Escherichia coli,

cho kt qu rt cao (t 400 n 1806). Nhng pht hin ny d on cc khng sinh

nhm fluoroquinolon c hiu qu iu tr cao i vi vi khun Escherichia coli.

Trong mt m phng Monte Carlo ca bn phc khc nhau ca levofloxacin v

ciprofloxacin i vi Pseudomonas aeruginosa (phn b MIC ca 671 chng), xc

sut ti a t AUC/MIC> 125 mc tiu l ch 71% (s dng ciprofloxacin 400 mg

tim tnh mch mi 8 gi). Pht hin ny cho thy vi nhim khun nng nghi ng

do Pseudomonas aeruginosa nn s dng cc khng sinh fluoroquinolon liu cho

hiu qu ti a hoc l s dng liu php phi hp.

12

Kt qu t cc nghin cu c tin hnh in vitro, trn ng vt v trn

ngi cho thy vi nhng nhim khun ng h hp di nhim Streptococcus

pneumoniae, cho thy vic duy tr AUC/MIC 40 ca cc khng sinh nhm

fluoroquinolon l ti u ho hiu qu dit khun. Con s ny thp hn so

vi cc nhim khun Gram m (l > 125) [2].

Nhm 2:

Nhm 2 bao gm cc khng sinh c tc dng dit khun t ph thuc vo

nng , ph thuc vo thi gian v c tc dng hu khng sinh ngn. Nng cao

khng c tc dng dit khun tt hn nng thp [32, 34]. %T>MIC l thng s

PK/PD quan trng nht d on hiu qu iu tr ca khng sinh. Vi nhng khng

sinh ny, tn s a thuc v liu l nhng yu t quyt nh quan trng tc dng

khng khun [34]. Nhm 2 bao gm cc khng sinh beta-lactam, erythromycin,

linezolid [4, 32, 34].

Mt nghin cu trn ng vt vim phi do Klebsiella pneumoniae c

iu tr bng khng sinh cefotaxime, cho thy mi tng quan gia s gim s

lng n v to khun lc v thi gian nng thuc trn MIC trong sut 24 gi

iu tr, khng ph thuc vo Cpeak/MIC hoc AUC/MIC. Tc dng dit khun ti

a t c khi T > MIC = 50%. Tng t nh vy, trong m hnh nhim khun i

chut do vi khun Streptococcus pneumoniae, khi iu tr bng khng sinh

cefprozil, c s gim s n v to khun lc v t l sng st u t ti a khi

T>MIC = 50%. iu ny cng c chng minh bng cc d liu lm sng.

Trong mt nghin cu nhng bnh nhn vim tai gia c iu tr bng cc khng

sinh ng ung vi liu m bo rng nng thuc lun ln hn MIC trong t

nht mt na thi gian gia cc khong liu, cho thy mi tng quan vi hiu

qu dit khun cao nht, c bit l vi cc khng sinh nhm beta-lactam [2].

Nhm 3:

Nhm 3 l cc khng sinh dit khun t ph thuc vo nng , ph thuc

vo thi gian v c tc dng hu khng sinh trung bnh, thng s d on tt nht

hiu qu iu tr l AUC/MIC [4, 32, 34]. Tn s a liu thng khng phi l yu

13

t quan trng quyt nh hiu qu [34]. Nhm ny gm c cc khng sinh macrolid,

clindamycin, oxazolidinon, tetracycline, vancomycin [4, 32, 34].

V d nh vancomycin, 24h-AUC/MIC cn thit t hiu qu iu tr t

nht l 125 [4]. Nghin cu ca Moise v cng s c tin hnh trn ngi, cho

thy t s AUC/MIC = 350 400 c th d bo iu tr thnh cng vi bnh nhn

nhim khun h hp do Streptococus aureus, trong cc bnh nhn t t s 24h-

AUC/MIC 400 s cho hiu qu dit khun nhanh hn nhm khng t 24h-

AUC/MIC = 400, l 10 so vi 30 ngy [14].

14

Bng 1: Phn loi cc khng sinh theo PK/PD [4], [32], [34].

Kiu tc dng Khng sinh Mc tiu iu tr Thng s PK/PD

Nhm 1

- Tc dng dit

khun ph thuc

vo nng .

- Tc dng hu

khng sinh di

Aminoglycosid

Daptomycin

Fluoroquinolon

Ketolid

- Ti u ha nng

bng liu cao.

- Khong cch

liu c th c

ko di v c tc

dng hu khng

sinh.

AUC/MIC

Cpeak/MIC

Nhm 2

- Tc dng dit

khun t ph

thuc vo nng

, ph thuc

vo thi gian.

- Tc dng hu

khng sinh ngn

Beta-lactam

Erythromycin

Linezolid

Ti u ha thi

gian phi nhim %T>MIC

Nhm 3

- Tc dng dit

khun t ph

thuc vo nng

, ph thuc

vo thi gian.

- Tc dng hu

khng sinh di

Macrolid

Clindamycin

Oxazolidinon

Tetracyclin

Vancomycin

Ti u ha lng

thuc a vo

AUC/MIC

15

1.6. Nhng hn ch ca vic ng dng PK/PD vo thc hnh lm sng v cc bin php khc phc

1.6.1. Nhng hn ch ca vic ng dng PK/PD vo thc hnh lm sng cc l thuyt PK/PD ng dng c vo thc hnh trn lm sng cng

gp kh nhiu kh khn. l s khc nhau gia cc c th v gi tr ca cc thng

s dc ng hc nh thanh thi, th tch phn b, dn n s khc bit v gi tr

ca cc thng s dc ng hc/dc lc hc nh Cpeak/MIC, AUC/MIC. Do ,

nng thuc trong huyt tng nn c nh lng trn tng c th bnh nhn.

Tuy nhin cc phng php nh lng nng thuc trong huyt tng s dng

trong nghin cu nh sc k lng hiu nng cao, sc k lng khi ph li khng

c s dng trn lm sng, v thit b c chi ph cao, thi gian quay vng di (phi

hiu chnh ct v xy dng ng chun), tr mt s h thng c thit lp th

nghim nhiu loi thuc cng mt lc. V vy, mi ln th nghim nn c tin

hnh trn hng lot mu. iu ny khng thun li khi nh lng nng thuc

cho cc bnh nhn hng ngy.

Thm vo , trong nhng nghin cu dc ng hc ca thuc, tnh nguyn

vin u l nhng ngi khe mnh, nn c th ly c nhiu mu mu trn mi

bnh nhn xc nh chnh xc cc thng s dc ng hc nh th tch phn b,

thanh thi, AUC. Vic ly mu thng xuyn trn bnh nhn c th lm gin

on qu trnh iu tr trn lm sng, khng thch hp vi cc nhm bnh nhn nht

nh nh nhng bnh nhn nng, bnh nhn c huyt ng khng n nh nh

ngi cao tui hoc tr em.

Trn thc t kh c th thu c mu v tr nhim khun. nh gi hot

tnh khng khun thng ch da trn nng thuc trong huyt thanh, song thc

cht nng thuc ti v tr nhim khun mi lin quan trc tip n hiu qu

khng khun v c s khc bit gia nng thuc ti v tr nhim khun v nng

thuc trong huyt thanh.

Phng th nghim vi sinh lm sng cung cp nhng thng tin v s nhy cm

hay khng ca vi khun vi khng sinh, c trng bng MIC ca vi khun. iu ny

16

ng vai tr v cng quan trng cho cc bc s trong vic a ra quyt nh nn s

dng khng sinh no v ch liu nh th no iu tr. Tuy nhin, khng phi

bnh nhn no vo vin cng c lm khng sinh v thi gian ly kt qu

khng sinh thng lu. Do vy ch yu iu tr nhim khun vn da trn kinh

nghim [20].

1.6.2. Cc gii php tim nng gii quyt nhng kh khn nu trn, cc phng php nh gi nng

thuc trong c th cn c khuyn khch pht trin vi thi gian quay vng nhanh

gp phn nh lng nhanh, ng nng thuc trong huyt tng ca mi bnh

nhn, c th iu tr trn c th bnh nhn.

Mt gii php khc l xy dng m hnh dc ng hc qun th thch hp

thu c nhng thng s dc ng hc/ dc lc hc, t s dng nh mt

hng dn iu tr ban u. Cc m hnh dc ng hc/ dc lc hc qun th gp

phn quan trng trong nghin cu mi quan h phi nhim v p ng v cung cp

nhng kin thc dc ng hc trn nhng nhm bnh nhn c th (v dn tc, di

truyn, gii tnh, chc nng thn,). Da trn nhng d liu thu c t cc m

hnh nghin cu ny, mt phc iu tr theo kinh nghim s c a ra mt

cch hp l trn tng nhm i tng bnh nhn.

Cc chng trnh ly mu cn c thit k ngu nhin ti u. Mt dy cc

nng trong huyt thanh l yu cu l tng c c mt c tnh chnh xc

s phi nhim thuc v gi tr ca cc thng s dc ng hc/dc lc hc trn

bnh nhn. Tuy nhin, vic ly nhiu mu trn nhng bnh nhn nhim khun nng

l phi thc t v thiu y c. Cc cng c m hnh ho v tnh ton thng s dc

ng hc c th gip vic ly mu tr nn n gin hn bng cch s dng thuyt

ly mu ti u, xc nh thi gian cho nhiu thng tin nht.

Cc d liu nh lng s nhy cm ca cc tc nhn gy bnh phi c c

sn hoc c th c kim tra nhanh c th cung cp ngay cho bc s lm sng,

bo m cc bc s k n nhng thuc thch hp nht vi liu ti u nht [20].

17

1.7. ng dng dc ng hc/ dc lc hc khng sinh Nhng kin thc v dc ng hc/ dc lc hc khng sinh gip ta thit lp

c phc liu ti u, pht trin thuc mi hay nhng cng thc mi, thit lp

im gy nhy cm v xy dng hng dn iu tr theo kinh nghim cc bnh

nhim khun [32].

1.7.1 Thit lp phc ti u cho cc khng sinh mi v cc khng sinh ang

c s dng

Xc nh cc thng s PK/PD v ln cn thit ca chng t hiu qu

iu tr rt hu dng cho vic chn la phc liu pha 3 th nghim lm sng

cho cc khng sinh mi, nh gi li phc ca cc khng sinh ang c s dng

hin gi, do s gim tnh nhy cm ca vi khun hay do cha c nghin cu c

th t trc [32].

Vi cc khng sinh c hiu qu ph thuc vo %T>MIC nh beta-lactam th

ti u ho iu tr phi ti u ho khong thi gian vi khun phi nhim vi

khng sinh nng trn MIC, bng cch a mt liu ln v thng xuyn,

thm ch l truyn lin tc [34]. Truyn lin tc c th gi nng thuc trong

huyt tng lun cao hn MIC trong sut 24 gi. c nhiu th nghim trn lm

sng chng minh truyn lin tc cho php tng liu thuc s dng hng ngy thp

hn so vi vic a thuc gin on v ci thin tc dng khng khun vi cc tc

nhn gy bnh t nhy cm. V d vi ceftazidime, t c hiu qu iu tr

tng ng, truyn lin tc ch cn 34 g/ngy, trong khi a thuc gin on cn

ti 6g/ngy. Truyn lin tc vi liu cao ampicilin c chng minh l thnh

cng khi iu tr nhng chng vi khun khng ampicilin (MIC = 3264 mg/L)

ca Enterococcus faecium khng vancomycin [32].

Vi cc khng sinh m hiu qu iu tr c d on bng thng s

Cpeak/MIC, nh cc khng sinh nhm aminoglycosid, th ti u ho iu tr,

phi a liu sao cho ln to ra mt Cpeak cao, m khng gy c tnh. C

th a liu khng thng xuyn hoc thm ch l mt ln mt ngy [34]. Liu

dng mt ln/ngy cn gim c tc dng ph trn thn v thnh gic ca cc

18

khng sinh aminoglycosid do vic hp thu thuc vo cc t bo ng thn v ni dch

tai gia nhiu hn khi nng thuc c duy tr trong mt khong thi gian di.

Hu ht cc phn tch meta ca cc th nghim lm sng u chng minh rng ch

dng thuc mt ln/ngy c hiu qu lm sng cao hn v gim c tnh trn

thn ng k. Cc nghin cu cng chng minh cc c tnh trn thn din ra

chm vi ngy khi dng 1ln/ngy so vi khi dng nhiu ln/ngy [32].

c bit l vi cc khng sinh c c cp php trc khi cha c cc th

nghim lm sng, khng c sn cc thng tin v mi quan h phi nhim p ng

ca cc thuc ny ti u ho phc liu v nh gi xem phc liu hin ti

c ti u hay thm ch l c hiu qu khng. S thay i phc liu l mt vn

ng quan tm v nhng khng sinh c ang b khng cao, c bit l trn nhng vi

khun Gram m. Trong nhiu trng hp vi khun khng tt c nhng khng

sinh ang c s dng th cc khng sinh c li c s dng nh mt bin php

cui cng. V d nh vi cc chng sinh beta-lactamase ph rng th cc khng sinh

c nh colistin v fosfomycin c s dng m khng c mt s chc chn no v

phc ang c s dng. Vic nh gi li cc thuc ny l cp thit, bao gm

mi quan h PK/PD ti u ho liu [27].

1.7.2. Chng khng thuc

Vn khng thuc hin nay

Hin tng khng khng sinh ang ngy cng tng cao v tr thnh mt vn

ng bo ng. T l nhim khun trong bnh vin v trong cng ng do c vi

khun khng thuc Gram dng v Gram m ang khng ngng tng cao. Theo

chng trnh gim st khng sinh ton cu SENTRY, t cu vng khng methicilin

l tc nhn gy bnh thng xuyn c truyn trong bnh vin vi t l cao nht

trn th gii [11]. T l Streptococus pneumoniae khng penicilin (PRSP) cng tng

ln ng k c lin quan n vic s dng cc khng sinh nhm beta-lactam M,

Canada, Ty Ban Nha, Ai-x len [16]. Ti Vit Nam, kt qu t mt nghin cu a

trung tm cho thy t l PRSP l 80% v 89,7% chng vi khun khng vi t nht

mt khng sinh nhm macrolid [17].

19

Mi quan h PK/PD khng thuc

S tng cng l cn thit lm gim hin tng khng khng sinh. Cho

n nay, hu ht cc phc c ti u ha cho hiu qu, nhng cc gi tr cn

thit cho hiu qu c th khuch i tiu qun th khng. V vy, iu quan trng l

xc nh s phi nhim (v liu) va c tc dng dit khun tt va c ch c

hin tng khng khng sinh. C ba yu t nh hng n hin tng khng khng

sinh l s lng vi khun nhim khun, thi gian iu tr v hot ng ca h

min dch.

Nghin cu trn m hnh chut c bch cu ht nhim khun i do

Pseudomonas aeruginosa, v c iu tr bng levofloxacin nm 2003, Jumbe v

cng s chng minh c mt mi quan h gia AUC/MIC v kh nng dit khun

ti v tr nhim khun. Mi quan h ny b nh hng ng k bi kch thc vi

khun cy ban u [27].

Thi gian iu tr cng di th cng kh ngn chn s khuych i ca hin

tng khng thuc. Mt phc ch ko di 4-5 ngy c th cho mt tc dng dit

khun cao v gim thiu s khuych i qun th t bin khng thuc. Vic

m rng phc ln n 10 ngy c th lm cho vic iu tr gp tht bi do s

xut hin hin tng khng khng sinh nu tt c vi khun khng b tiu dit ht.

Mt nghin cu ca Tm v cng s nm 2007 kim tra nh hng ca thi gian

iu tr Staphylococcus aureus bng garenoxacin vi hai phc , mt cho

AUC/MIC = 100 v mt cho AUC/MIC = 280. C 2 phc cng cho mt t l

dit khun ti a trong 4-5 ngy [27].

20

Hnh 4: S lng vi khun (a) v s lng vi khun khng (b) khi dng hai phc

garenoxacin khc nhau [27].

Hnh 4 m t tc ng trn c qun th Staphylococcus aureus theo thi gian

ca 2 phc liu ca garenoxacin v tc ng trn qun th t nhy cm ca

Staphylococcus aureus theo thi gian ca 2 phc liu ca garenoxacin. C hai

phc c cng t l dit khun vo ngy th 5. Sau giai on ny, ch khng

mnh ht hiu lc. Trong hnh b, chng ta c th thy rng s tht bi ny l do

khuch i ca qun th khng. Nu iu tr kt thc vo ngy 4 hoc 5, khuch

Nhm chng

Nhm chng

(b) Thi gian (gi)

(a) Thi gian (gi)

21

i t bin t hoc khng xy ra. Vy mt phc mnh trong mt thi gian

ngn tiu dit ht khng sinh v ngn chn khng [27].

H min dch gp phn tiu dit vi khun. Drusano v cng s chng

minh rng, ty thuc vo vi khun, bch cu ht c th tiu dit vi khun khong

105 106 CFU/g. Vi Staphylococcus aureus v Pseudomonas aeruginosa, bch cu

ht c th tiu dit n 50 CFU/g mi ngy. Do , nu iu tr bng khng sinh,

khi s lng vi khun xung khong 102 -103 CFU c th dng iu tr, s vi khun

cn li ny s c loi tr bi h thng min dch [27].

Cch hn ch khng thuc

C th hn ch hin tng vi khun khng thuc bng cch gim thi gian

iu tr v d phng, gim thi gian vi khun phi nhim vi khng sinh. iu

ny c th lm c bng cch da vo nhng l thuyt PK/PD trn xc nh

mt phc iu tr ti u [27].

Mt phng php khc lm gim hin tng khng khng sinh kh ph bin

trn lm sng hin nay l phi hp khng sinh, c bit l trong cc trng hp

nhim khun nng hoc iu tr theo kinh nghim [27, 32].

Trn cc nhm bnh nhn c th, tnh u vit khi iu tr bng cch phi hp

khng sinh c chng minh. Cc nghin cu ca Lienhardt v Davies tin hnh

nm 2010 trn cc bnh nhn AIDS v lao, cho thy iu tr bng mt khng sinh

n c c coi l nguy him, nguy c xut hin khng khng sinh rt cao, phi

hp ng khng sinh gip tng hiu qu iu tr, gim hin tng khng khng sinh,

c bit vi cc vi khun tr nn khng trong khi iu tr, nh Pseudomonas

aeruginosa. Mt s nghin cu tin lm sng nh ca Mouton nm 1999, Louie v

cng s nm 2010, ch ra rng liu php kt hp trong mt s trng hp c th

ngn chn c s xut hin hin tng khng khng sinh [27].

t bin khng thuc thng xy ra tn s c nh (khong 10-9 n 10-10).

Tuy nhin, trong mt s trng hp, c bit l trong cc trng hp nhim trng

mn tnh nh vim phi tc nghn mn tnh, t bin khng thuc c th xut hin

tn s cao. Ngay c qun th c s lng vi khun thp cng cha cc vi khun c

22

gen tng t bin. Xc sut t bin tch lu trong gen cao s dn n s lng vi

khun khng cao. Khi iu tr bng liu php kt hp khng sinh c c ch tc dng

khc nhau th t l vi khun khng khng sinh s thp hn do vi khun kh t bin

chng li tt c cc c ch tc dng ca cc khng sinh phi hp.

Cc khng sinh c rt c quan tm khi dng liu php kt hp v chng

thng c s dng (hoc c khuyn khch s dng) bng cch kt hp vi cc

khng sinh khc. Tuy nhin, hiu qu ca cc khng sinh ny trong cc phc kt

hp cha c nghin cu c h thng v do n vn cha r liu vic kt hp

khng sinh c cung cp mt li ch r rng cho bnh nhn khng.

Tm li, nn s dng liu php kt hp cho bnh nhn nng hoc trong cc

trng hp c th (v d, nhim trng Pseudomonas) v phi tng cng nghin

cu a ra nhng li ch cho tng phc kt hp c th [27].

1.7.3. Thit lp im gy nhy cm (breakpoint)

la chn khng sinh, cc bc s lm sng da vo nhng d liu nhy

cm c bo co t phng th nghim vi sinh. Trong cc bo co ny, vi khun

c phn loi theo cc mc nhy cm (S susceptible) hay khng (R -

resistant) vi mt khng sinh nht nh, iu ny quyt nh t l iu tr thnh cng

hay tht bi tng ng trn lm sng [12, 32, 34]. Vi khun c phn loi l nhy

cm vi mt khng sinh, c ngha xc sut thnh cng khi iu tr khng sinh

cao, trong khi nu kt qu tr v l khng th t l tht bi khi iu tr vi khng

sinh cao hn. "Trung gian" (I intermediate) ch mt mc khng chc chn

trong p ng hoc ph thuc vo liu [12].

Trc y, vi khun c phn loi l nhy cm hay khng da trn s phn

b cc gi tr MIC ca vi khun vi khng sinh [32, 34]. Thng thng, phn b

MIC c hai nh, cc gi tr MIC ca cc chng hoang d hoc cc tiu qun th

nhy cm xung quanh mt gi tr, v cc gi tr MIC ca qun th khng xung

quanh mt gi tr khc. Thut ng "im gy nhy cm" ln u tin c s dng

trong bo co nghin cu kim tra tnh nhy cm ca vi khun vi khng sinh ca

23

Ericsson v Sherris nm 1971, l nng khng sinh ngn cch qun th hoang d

hoc nhy cm vi qun th khng [32].

Truc y, s phn b cc gi tr MIC ca cc vi khun nhy cm v khng

vi tng khng sinh nht nh l khc bit v thp hn nhiu so mc khng sinh

iu tr trn lm sng, lm cho quyt nh mt vi khun l nhy cm hay khng tr

nn n gin. Tuy nhin gn y, s phn b cc gi tr MIC ca vi khun nhy

cm v khng khng c s khc bit nhiu th dc lc hc ng mt vai tr quan

trng trong vic phn bit S, I v R, v mi quan h gia nng v hiu qu ngy

cng c chng minh r rng [27, 32, 34].

Do vy, PK/PD c s dng xc nh cc im gy nhy cm ca mi

khng sinh. u tin, mc tiu PK/PD c xc nh trong cc m hnh nhim

khun in vitro hoc trn ng vt. Sau m phng Monte Carlo c s dng

xem xt s thay i v nng thuc trong qun th, xc nh MIC m mt khng

sinh v phc nht nh c d kin s t cc mc tiu PK/PD cho phn ln

bnh nhn (v d, 90% n 95% t c mc tiu). Vi khun c gi l khng

khi c gi tr MIC trn im gy MIC theo PK/PD. V d, im gy MIC theo

PK/PD ca khng sinh beta-lactam l nng thuc sao cho t c trong 40-50%

khong thi gian dng thuc thu c hiu qu iu tr trn phn ln bnh nhn.

Nng thuc ny sau c xc nh nh l gii hn nhy cm PK/PD hoc

im gy. Trong iu tr, cc vi khun c gi tr MIC bng hoc thp hn nng

ny, xc xut thnh cng trong iu tr s cao hn [34].

1.7.4. Xy dng hng dn iu tr theo kinh nghim

V ln ca cc thng s PK/PD c xc nh trn m hnh nhim khun

ng vt nn c th d on hiu qu khng khun trn nhng nhim khun

ngi, iu l gii ti sao dc lc hc ngy cng c s dng nhiu thit

lp nhng hng dn iu tr theo kinh nghim. V d nh nhng hng dn iu

tr vim tai gia, vim phi mc phi ti cng ng s dng kh nng khng sinh

c th t c gi tr ca cc thng s PK/PD mc tiu cn thit trn c nhng tc

24

nhn gy bnh nhy cm v gim nhy cm xp hng hoc la chn khng sinh

khi iu tr [32].

25

CHNG 2: DC NG HC DC LC HC CA KHNG SINH NHM BETA-LACTAM

2.1. Gii thiu chung v nhm khng sinh beta-lactam Penicilin G l khng sinh beta-lactam u tin c Fleming tm ra vo nm

1928 v c s dng ln u tin nm 1941 cha cc nhim khun do t cu.

T n nay c nhiu khng sinh beta-lactam mi ra i t c hot tnh

khng khun mnh hn, ph rng hn, cc tnh cht dc ng hc, dc lc hc

tt hn v t b khng bi cc beta-lactamase. Do thn nc nn beta-lactam b thi

tr nhanh qua thn, trong khi chng l cc khng sinh dit khun c tc dng ph

thuc vo thi gian, thu c hiu qu dit khun, beta-lactam phi c thi gian

tip xc di vi vi khun nng trn MIC. Do cc khng sinh sau ny c

pht trin sao cho c th phn b chm vo mu sau khi tim bp, hp thu chm sau

khi ung hoc c th tim tnh mch trong mt thi gian di. V d nh procaine

penicilin G, benzathine penicilin G, penicilin V, phenethicilin, v propicilin. Tuy

nhin tc dng khng khun ca cc khng sinh ny b gii hn ch yu trn cc vi

khun Gram dng, v vy, cc khng sinh sau c nghin cu nhm m rng

ph sang c cc vi khun Gram m, nh ampicilin, hetacilin, ciclacilin, amoxicilin.

Ampicilin c gn thm gc ester lm tng hp thu khi dng ng ung.

Nhng khng sinh l dn cht ester ca ampicilin c th k tn ra nh bacampicilin,

talampicilin v pivampicilin. c th m rng ph sang Pseudomonas

aeruginosa, carbenicilin, ticarcilin v mezlocilin ln lt c tng hp.

Carbenicilin cng c gn thm gc ester c th dng c bng ng ung

[32].

Nm 1945, Giuseppe Brotzu tm ra cephalosporin u tin. Sau hn 60 nm,

c hn 50 khng sinh nhm cephalosporin c pht trin c hot tnh dit

khun mnh hn v ph rng hn. Nu cc khng sinh cephalosporin th h mt c

hot tnh khng khun trn cc vi khun thng thng nh Staphylococcus spp.,

Streptococcus spp., Escherichia Coli v Klebsiella spp. Cc khng sinh

26

cephalosporin th h hai c ph tng t cc cephalosporin th h mt nhng c

hot tnh mnh hn trn mt s vi khun t gp. Cc khng sinh cephalosporin th

h ba c hot tnh mnh hn vi cc vi khun Gram m thng thng v cc tc

nhn gy bnh c hi, tuy nhin hot tnh trn vi khun Gram dng b gim i

[32]. n nay, beta-lactam c 4 nhm: penicilin, cephalosporin, carbapenem,

monobactam [15].

Beta-lactam l khng sinh c s dng ph bin nht trn lm sng hin

nay do beta-lactam c phn b vo nhiu v tr khc nhau trn c th, nn c th

iu tr c nhiu bnh nhim khun, t c tnh nn c th tng liu iu tr c

trn nhiu mc nhim khun [1, 15].

2.2. Dc ng hc ca cc khng sinh nhm beta-lactam 2.2.1. Mc hp thu

Phn ln cc beta-lactam t c hp thu qua ng tiu ho, tr mt s

khng sinh nh cc cephalosporin th h 1, 2 c hp thu khi dng ng ung

[6].

Cc cephalosporin th h 1, 2 (cephalexin, cefaclor, v cefprozil) hp thu tt

qua ng tiu ho, ch c cefuroxime axetil, t l hp thu qua ng tiu ho l 36

n 52% [33].

Bng 2: Sinh kh dng ca mt s cephalosporin th h 1 v 2.

Khng sinh Sinh kh dng (%)

Cephalexin 95

Cefatrizin 60

Cefaclor 90

Cefprozil 89

Cefuroxim axetil 36 52

Trong cc cephalosporin th h 3, ceftibuten l thuc c hp thu tt nht, c loi

tin thuc v cefixim, mc hp thu mi t 50%. Cefexim v ceftibuten c sinh

kh dng gim khi tng liu [33].

27

Bng 3: Sinh kh dng ca mt s cephalosporin th h 3.

Khng sinh Liu (mg) Sinh kh dng (%)

Cefixim 200 50

400 40

Ceftibuten 200 95

400 80

Cefetamet pivoxil 500 45 50

Cefpodoxim proxetil 200 50

2.2.2. Mc phn b

Th tch phn b ca cc beta-lactam cao 0,15-0,24 L /kg [32] nn cc khng

sinh beta-lactam phn b vo hu ht cc dch trong c th (tr mt v tuyn tin

lit ch c aztreonam thm nhp c) nn c th c s dng cho nhiu bnh

nhim trng [15, 32]. Do c bn cht l cc acid yu, thn nc, khng thn lipid

nn cc khng sinh beta-lactam khng phn b c vo trong cc t bo nn khng

dng iu tr cc bnh nhim khun do cc vi khun ni bo nh Mycoplasma

hoc Chlamydia [8, 32].

2.2.3. Mc thi tr

Cc beta-lactam c thi gian bn thi ngn, thng l t 1-3 gi, tr mt s

t cc khng sinh nhm cephalosporin nh ceftriaxon, c thi gian bn thi ln n

7-8 gi. C th cc khng sinh nhm penicilin c thi gian bn thi t 0,8-1,2 gi,

carbapenem l khong 1 gi [25, 28, 32]. Cc cephalosporin c thi gian bn thi t

1,4 - 8 gi. Cc khng sinh cephalosporin th h 1 v 2 c thi gian bn thi di 2

gi, cn cc khng sinh th h ba di hn, di 3 gi, tr ceftriaxon c thi gian

bn thi di ln ti 8 gi [15, 33].

28

Bng 4: Thi gian bn thi ca mt s khng sinh nhm penicilin,

cephalosporin, carbapenem v monobactam [33, 44]

Penicilin T1/2

(gi)

Cephalosporin T1/2

(gi)

Carbapenem T1/2

(gi)

Monobactam T1/2

(gi)

Penicilin G 0,5 Cephalexin 0,9 Imipenem 1,0 Aztreonam 1,8

Nafcilin 0,5 Cefatrizine 1,7 Meropenem 1,0

Oxacilin 0,5 Cefaclor 0,77

- 1,0

Ertapenem 3,8

Ampicilin 1,0 Cefprozil 1,3 Doripenem 0,93

Carbenicilin 1,1 Cefuroxim

axetil

1,3 -

1,8

Panipenem 1,2

Ticarcilin 1,2 Cefixim 3,4

3,8

Biapenem 1,0

Ceftibuten 2,5

2,9

Cefetamet

pivoxil

2,3

Cefpodoxim

proxetil

2,7

2.3. Dc lc hc ca cc khng sinh nhm beta-lactam 2.3.1. Mc nhy cm ca cc vi khun vi khng sinh beta-lactam

Mc nhy cm ca vi khun vi cc khng sinh c biu th qua nng

c ch ti thiu (MIC). Gi tr ca MIC thay i ph thuc vo khng sinh, vi

khun, v tr nhim khun, ng dng thuc, s kt hp cc khng sinh vi nhau

v tng tiu ch.

29

Cc nghin cu cho thy MIC ca vi khun thay i theo cc khng sinh

beta-lactam nh trn vi khun Gram m, tc v t l dit khun ca cc khng

sinh penicilin, cephalosporin v carbapenem l khc nhau, trong nhm

cacbapenem l mnh nht v nhm penicilin l yu nht [23]. S khc nhau cng

c ghi nhn gia cc khng sinh trong cng mt nhm, nh trong nhm

carbapenem, doripenem c tc dng yu nht trn cc chng vi khun sinh beta-

latctamase ph rng, vi MIC90 ln hn 2 - 4 ln so vi meropenem v imipenem

[5].

Gi tr ca MIC cn thay i theo vi khun, v d nh vi

piperacilin/tazobactam, theo Vin lm sng v th nghim chun (CLSI - Clinical

and Laboratory Standards Institute), gii hn MIC c cho l nhy cm vi

Enterobacteriaceae v Acinetobacter l 16 mg/L, cn vi Pseudomonas aeruginosa

l 64/4 mg/L [21].

cc v tr nhim khun khc nhau, gi tr MIC cng khc nhau. V d nh

MIC ca Streptococcus pneumoniae vi penicilin, nu nhim khun mng no, vi

khun c coi l nhy vi MIC 0,06mg/mL, khng l 0,12mg/mL, vi cc

nhim khun cc v tr khc, vi khun c coi l nhy vi MIC 2 mg/mL, trung

gian l 4 mg/mL v khng l 8 mg/mL [41].

Mc nhy cm ca vi khun cn thay i ph thuc vo ng a thuc.

Vi cc hi chng vim khng phi mng no, khi dng thuc qua ng tnh

mch, gi tr MIC nhy cm ca Streptococcus pneumoniae vi penicilin l

2g/mL, cn qua ng ung l 0.06g/mL [41].

Khi kt hp khng sinh, nhy cm ca vi khun c tng ln. V d nh

trong mt th nghim in vitro, khi kt hp vi mt aminoglycosid, Pseudomonas

aeruginosa tr nn t khng doripenem hn [5].

Gi tr MIC cng thay i theo tng tiu ch khc nhau nh mc nhy

cm ca doripenem trn vi khun Pseudomonas aeruginosa, theo EUCAST, gi tr

MIC m ti vi khun c cho l nhy cm vi khng sinh l 1 mg/L v khng

l 4 mg/L, cn i vi Cc qun l dc Hoa K l 2 mg/L v 8mg/L [5].

30

2.3.2. Tc dng hu khng sinh ca beta-lactam

Nhng nghin cu tin lm sng cho thy cc khng sinh nhm penicilin,

cephalosporin, monobactam v carbapenem c tc dng hu khng sinh vi hu ht

cc vi khun Gram dng nh Staphylococcus aureus, Streptococcus pyogenes v

Streptococcus pneumoniae. Trn vi khun Gram m nh Escherichia coli,

Klebsiella spp, Proteus spp v Pseudomonas aeruginosa, cc khng sinh penicilin

v cephalosporin dng nh khng c hoc ch c rt t, ch c carbapenem mi c

tc dng hu khng sinh [3, 15, 23].

Tc dng hu khng sinh ca nhm beta-lactam thng rt ngn. Trong mt

m hnh nhim khun i trn chut gim bch cu, PAE ca cc beta-lactam vi

Staphylococcus aureus l t 1,2 n 4,5 gi. Penicilin v cephalosporin c PAE vi

cc vi khun Gram dng l t 1 n 3 gi. V d nh cc khng sinh Penicilin:

PAE ca benzylpenicilin (penicilin G), ampicilin, cloxacilin, dicloxacilin, nafcilin

v methicilin bng 1,5 n 1,9 gi trong cc th nghim in vitro nng 4-5 ln

MIC sau 2 gi tip xc trn cc t cu v lin cu [28, 32]. PAE ca cc khng sinh

carbapenem vi Pseudomonas aeruginosa l nh hn 2 gi ph thuc vo chng vi

khun [32].

Tc dng hu khng sinh ph thuc vo nng , thi gian phi nhim, v

thay i theo khng sinh, vi khun, khi kt hp khng sinh.

Khi nng tng, PAE cng tng. Theo cc nghin cu in vitro v in vivo

trn c vi khun Gram m v Gram dng, cc cephalosporin c PAE tng khi nng

tng, bt k ng dng l ung hay tim [24, 33]. Hoc vi cc carbapenem, khi

tng nng ca imipenem v meropenem, PAE vi cc vi khun Staphylococcus

aureus, Pseudomonas aeruginosa v Escherichia coli cng tng ln [24].

Tng t nh vy, PAE cng tng khi thi gian vi khun phi nhim vi

khng sinh tng. Khi cc penicilin tip xc vi cc t cu v lin cu nh

benzylpenicilin v Staphylococcus aureus hay ampicilin v Streptococcus

pneumoniae trong 2 gi nng 4-5 ln MIC, PAE ch bng 1,5 1,9 gi, khi thi

gian phi nhim tng ln 4 gi, PAE tng ln n 4 gi [28].

31

Tc dng hu khng sinh thay i theo tng khng sinh. V d nh trn cng

t cu Gram dng Staphylococcus aureus, theo mt nghin cu trn m hnh chut

nhim khun i gim bch cu, PAE ca benzylpenicilin v nafcilin l 1,4 v 3,0

gi, [28]. Cng trn chng t cu vng Staphylococcus aureus, sau 2 gi tip xc

vi nng 10MIC, PAE ca ertapenem v imipenem tng ng l1,5 v 1,3 gi

[44]. Hay trong mt th nghim in vitro khc, PAE ca Escherichia coli v

Pseudomonas aeruginosa khi tip xc vi nng bng 4MIC ca imipenem l 2

v 4 gi, cn vi meropenem l 5 v 4 gi [28].

Mt khng sinh cng c tc dng hu khng sinh trn nhng vi khun khc

nhau l khc nhau. V d nh penicilin ch c tc dng hu khng sinh trn cc vi

khun Gram dng, khng c trn cc vi khun Gram m, dn n thi gian nng

thuc trn MIC cn thit ca penicilin trn cc vi khun Gram m di hn so vi

cc vi khun Gram dng, nn khong cch a liu khi iu tr nhim khun Gram

dng c ko di hn so vi Gram m. Tng t nh vy, cc cephalosporin ch

c tc dng hu khng sinh trn nhng vi khun Gram dng nh t cu v lin

cu, ch khng c trn cc vi khun Gram m nh h vi khun ng rut v trc

khun m xanh. Trong mt th nghim in vivo trn chut nhim khun i gim

bch cu, cefazolin v cefoperazon u c tc dng hu khng sinh t 2,1 n 5,6

gi trn Staphylococcus aureus, nhng khng c trn Escherichia coli, Klebsiella

pneumoniae v Pseudomonas aeruginosa. Mt th nghim khc vi cc khng sinh

nhm cephalosporin, nh cefotaxim, cefoperazon v ceftazidim, sau 2 gi tip xc

nng 4-5MIC, cc khng sinh ny c PAE t 0,9 n 1,5 gi trn

Staphylococcus aureus, nhng khng c PAE trn Pseudomonas aeruginosa v

Escherichia coli [24].

S phi hp cc khng sinh cng lm thay i PAE ca cc khng sinh n

l. S dng m hnh nhim khun i chut do Staphylococcus aureus nh gi

hiu qu ca vic kt hp khng sinh, cc nh nghin cu ch ra rng khi kt hp

aminoglycosid v mt beta-lactam s to ra mt PAE di hn so vi PAE ca tng

thnh phn [32].

32

Nhn chung, PAE quan st thy trn in vivo ln hn in vitro, do tc dng hu

khng sinh di MIC v tc dng ca bch cu. V d, PAE ca benzylpenicilin l

2,4 h vi Streptococus pyogenes. Khi phi nhim vi nng di MIC ca

penicilin (0,3 MIC), PAE vi Streptococus pyogenes tng ln n 22 gi [32].

Hoc trong mt th nghim trn chut gim bch cu b nhim khun i, cc beta-

lactam vi cc liu khc nhau, to ra mt PAE t 1,5 n 3 gi, cn trn chut

thng, PAE ko di hn t 3 5 gi [9].

PAE l mt thng s dc lc hc quan trng xc nh thi gian trn MIC

cn thit, t xy dng mt phc dng thuc ti u cho cc beta-lactam. S tn

ti ca PAE ng rng thi gian trn MIC c th t hn 100% khong thi gian

dng thuc, do c th dng thuc gin on [32].

2.4. Dc ng hc/ dc lc hc ca cc khng sinh nhm beta-lactam 2.4.1. Khng sinh dit khun ph thuc thi gian

Eagle l ngi u tin xut khi nim khng sinh dit khun ph thuc

thi gian cho beta-lactam t cui nhng nm 1940. Eagle chng minh trn in

vivo, nng penicilin ko di l cn thit cho hiu qu iu tr v gim tng lng

thuc hng ngy. Eagle cng chng minh in vivo trn m hnh chut v th

mt bch cu, thi gian nng penicilin trn MIC ca vi khun c lin quan n

hiu qu ca thuc [32].

Cho n nay c nhiu nghin cu chng minh rng khi tng nng t 0

n 4 - 5 ln MIC, tc dng ca beta-lactam tng. Tc dng ti a ca beta-lactam

t c khi nng thuc t do trong huyt thanh duy tr mc 4 5 ln MIC [8,

23, 26, 35, 36]. Khi tng nng hn na th hiu qu dit khun (tc v mc

dit khun) thu c tng khng ng k, thm ch l khng tng [3, 8, 23, 36]. V

d nh mt nghin cu ca Craig v Andes trn in vitro vi khng sinh ticarcilin

chng minh beta-lactam l khng sinh c lp vo nng v ph thuc thi gian.

T l v mc dit khun gia 4MIC so vi 16MIC v 64MIC l tng t,

iu ny cho thy a thuc t nng vt qu MIC gp bn ln l khng cn

thit [32].

33

Thi gian (gi)

Hnh 5: ng cong dit khun ca khng sinh ticarcilin [32].

2.4.2. Thng s PK/PD d bo hiu qu iu tr ca cc khng sinh beta-

lactam l %T>MIC

Theo cc nghin cu in vitro, in vivo, beta-lactam l khng sinh ph thuc

vo thi gian, thng s PKPD d on chnh xc nht tc dng ca beta-lactam l

%T>MIC [23, 32, 34, 36, 38]. Theo cc nghin cu in vitro, trn ng vt, cng

nh trn lm sng, t hiu qu iu tr th %T>MIC phi t 40-50% [22, 34,

44]. Khi %T>MIC t 40-50%, t l sch khun ln ti 85% - 100% [9, 43].

Trong mt nghin cu dng beta-lactam cho cc bnh nhn vim tai gia nhim

Streptococcus pneumoniae v Haemophilus influenza, mc dit khun t t

80% - 85% khi %T>MIC 40% - 50%. Mt nghin cu khc trn nhng bnh nhn

nhp vin do vim phi mc phi ti cng ng, hiu qu lm sng khng c s

khc bit khi dng cefuroxim 1500mg /ngy truyn lin tc (T>MIC=100%) vi

750 mg3 ln/ngy truyn gin on (T>MIC= 50% - 60%) [34]. iu ny cho thy

rng %T>MIC khong 50% l t hiu qu iu tr cn thit [34, 44]. Tuy

nhin, cn lu rng %T>MIC mc tiu cng thay i theo tng khng sinh, vi

khun, v tr nhim khun v i tng bnh nhn.

Nhm chng Log10 CFU/ml

4 MIC

16 MIC

64 MIC

0,25 MIC 1 MIC

34

Theo nh nhiu ti liu th %T>MIC cn phi t c c tc dng km

khun vi cc khng sinh nhm penicilin l 30%, cephalosporin l 35-40%, vi

carbapenem l 20%, cn c tc dng dit sch vi khun th l 50% vi penicilin,

60-70% vi cephalosporin v vi carbapenem l 40% [3, 21, 22, 30, 31, 37, 44].

%T>MIC ca carbapenem thp nht trong nhm beta-lactam do PAE in vivo ca

cc khng sinh nhm ny cao nht [5]. Trong cng mt nhm %T>MIC mc tiu

ca cc khng sinh vi mt vi khun nht nh c khc nhau, nhng khng ng k.

V d nh %T>MIC ca 6 khng sinh nhm cephalosporin di y vi chng

Klebsiella pneumoniae chun [9].

Hnh 6: Gi tr %T>MIC ca 6 khng sinh nhm cephalosporin vi chng

Klebsiella pneumoniae chun.

Hnh 6 cho thy gi tr %T>MIC tnh theo nng thuc t do trong huyt

tng ca 6 khng sinh nhm cephalosporin: ceftazidim, cefepim, cefpirom,

cefotaxim, ceftriaxon v cefonicid l xp x nhau. Tuy nhin do t l lin kt vi

protein khc nhau nn gi %T>MIC tnh theo nng thuc ton phn c s khc

bit [9].

Gi tr %T>MIC cng thay i theo tng i tng bnh nhn. Nhng nghin

cu trn i tng bnh nhn nhim cc chng a khng c MIC cao cho thy

%T>MIC cn phi cao hn so vi nhng i tng bnh thng [3, 43]. Vi nhng

bnh nhn bnh thng %T>MIC cn thit ch bng khong 40-70%, nhng i vi

35

nhng bnh nhn nng %T>MIC cn phi t ti 100% m bo hiu qu iu

tr c kt qu [37].

Cc vi khun khc nhau cng t ra nhng %T>MIC khc nhau. V d nh vi

cc vi khun Gram dng, %T>MIC ca beta-lactam cn t c ca m bo

sch khun nhn chung l 30-40%, cn vi vi khun Gram m l 60-70% [39].

C th vi cc khng sinh nhm cephalosporin, %T>MIC cn t c ti u

ho hiu qu iu tr, l khong 6070% vi Enterobacteriaceae v 4050% vi

Staphylococcus aureus [37]. Hay to ra cng mt hiu qu dit khun, cefazolin

cn tip xc vi Escherichia coli lu hn Staphylococcus aureus (%T>MIC > 60%

so vi 20%). S khc bit ny l do cefazolin c tc dng hu khng sinh trn

Staphylococcus aureus m khng c tc dng hu khng sinh trn Escherichia coli

[32]. Mt nghin cu trn m hnh chut nhim khun i v vim phi, iu tr

bng ba khng sinh nhm carbapenem cng ch ra rng, vi nhng vi khun khc

nhau, %T>MIC mc tiu khc nhau. %T>MIC mc tiu ca ba khng sinh

imipenem, meropenem, biapenem khng c s khc bit ng k, nhn chung l vi

Escherichia coli, %T>MIC mc tiu bng 30%, vi Klebsiella pneumoniae hoc

Pseudomonas aeruginosa l 20% [28].

2.5. ng dng PK/PD khng sinh beta-lactam trn lm sng 2.5.1. Ti u ho hiu qu iu tr

Beta-lactam l khng sinh dit khun ph thuc thi gian. Thng s PK/PD

quan trng nht d on c kt qu iu tr ca cc khng sinh beta-lactam l

%T>MIC. ti u ho hiu qu iu tr cc bnh nhim khun hay t c

%T>MIC mc tiu vi khng sinh beta-lactam, cc bin php sau y thng c

xut: tng liu, tng tn sut a thuc, dng cc thuc c dc ng hc c

ci thin nh dng cc khng sinh c thi gian bn thi di hn hoc tng thi gian

tim truyn [21, 22, 26, 31, 32, 38]. C th tng thi gian tim truyn bng cch

truyn gin on, mi ln t 0,5-1 gi, truyn di hn t 3-4 gi, hoc truyn lin

tc trong 24 gi vi mt tc truyn xc nh v thng c bt u bng mt

liu ln tim tnh mch [23].

36

a) Tng liu Mt nghin cu m phng bng phng php Monte Carlo vi TZP

(Piperacilin-tazobactam) cho thy khi tng liu TZP t 3,375g ln 4,5g mi 6 gi,

khng lm thay i ng k hiu qu iu tr. tng T >MIC ln mt t1/2, liu cn

phi tng hai ln. V hu ht cc khng sinh nhm beta-lactam c t1/2 = 30 pht 1

gi nn tng gp i liu cng ch tng thm 30 pht 1 gi nng thuc trong

huyt tng trn MIC, iu ny khng c nhiu ngha trn lm sng, trong khi

tng liu dn n tng chi ph iu tr v c tnh [21]. Mt th nghim in vivo vi

khng sinh piperacilin cho thy khi tng liu ln gp i t 2g ln 4g truyn trong

30 pht, th thi gian nng thuc trong huyt tng trn MIC cng ch tng c

mt t1/2 l 1,5 gi [22].

Hnh 7: So snh thi gian nng thuc trn MIC ca 3 phc : piperacilin 2g

truyn trong 30 pht, 4g truyn trong 30 pht v 2g truyn trong 4 gi [22]

b) Tng tn sut a thuc

MIC = 10mg/L

2g truyn 4 gi

4g truyn 30 pht

2g truyn 30 pht

Nng (mg/L)

Thi gian (gi)

37

Tng tn sut a thuc s lm tng chi ph mua thuc v cc nguy c xut

hin c tnh ca thuc do dng mt lng thuc ln, ng thi cn lm tng cng

y t chun b v tim thuc [21, 22].

c) Ko di thi gian truyn C th ko di thi gian truyn bng cch truyn lin tc trong 24 gi hoc

ko di gin on [21].

Truyn lin tc

Truyn lin tc m bo mt nng cao trn MIC v duy tr c nng

trong mt khong thi gian di trong sut 24 gi [3, 30, 32]. 17 th nghim

ngu nhin so snh truyn lin tc v tim tnh mch gin on, kt qu l nng

nh ca thuc khi tim tnh mch gin on bng 5,5 ln so vi nng thuc

trng thi n nh khi truyn lin tc, ngc li nng y khi tim tnh mch

gin on thp hn n 5,8 ln nng thuc trng thi n nh khi truyn tnh

mch lin tc [23]. V beta-lactam l khng sinh dit khun ph thuc vo thi gian,

khng ph thuc vo nng , nn tim tnh mch gin on to ra mt Cpeak cao

khng cn thit v v nng khng sinh di MIC trong phn ln khong thi

gian a thuc, dn n %T>MIC khi tim tnh mch gin on thp hn nhiu so

vi truyn lin tc vi cng mt liu (Hnh 8) [3, 23].

38

Hnh 8: M t nng theo thi gian ca khng sinh beta-lactam khi tim tnh

mch gin on (nt lin) v truyn lin tc (nt t).

Mt nghin cu in vivo khc vi khng sinh meropenem, cng cho thy khi

tim tnh mch, nng nh trong huyt tng ca thuc cao gp 10 ln nng

thuc trong huyt tng khi truyn gin on, tuy nhin kh nng thuc xm nhp

vo dch k cng nh hn n 10 ln. Nng y ca thuc khi tim tnh mch

cng c chng minh nh hn rt nhiu ln so vi nng thuc khi truyn lin

tc (Hnh 9).

Thi gian (gi)

Nng ca khng sinh beta lactam (mg/L)

39

Hnh 9: Nng trng thi n nh trong huyt tng v dch k cc m ca

meropenem khi iu tr trn nhng bnh nhn nhim khun nng khi tim tnh

mch gin on v truyn lin tc [3].

Nhng u im ca truyn tnh mch lin tc so vi tim tnh mch

Truyn tnh mch lin tc t hiu qu iu tr cao hn so vi truyn tnh mch nhanh gin on

Truyn tnh mch lin tc c chng minh in vitro, trn lm sng c th

lm tng tc p ng v ci thin ng k hiu qu iu tr vi mt chi ph thp

hn so vi ch tim truyn tnh mch nhanh, vi thi gian cn h st v hi

phc s lng t bo bch cu ngn hn [21, 30]. In vivo, c mt nghin cu

thc hin trn m hnh th vim ni tm mc nhim Enterococcus faecalis (MIC =

1 mg/L), iu tr bng ampicilin theo hai cch l truyn lin tc v tim tnh mch 3

ln/ngy vi cng mt liu l 450 mg/kg/ngy, kt qu cho thy t l sng st khi

truyn lin tc cao hn l 84% so vi tim tnh mch l 61% [24]. Cc nghin cu

trn lm sng cng cho kt qu tng t. Mt nghin cu dng

piperacilin/tazobactam iu tr nhim khun cho thy khi truyn lin tc c t l

khi trn lm sng v vi sinh tng ng l 94% v 91%, cao hn khi tim truyn

Nng thuc trong huyt tng khi tim tnh mch

Nng thuc trong dch k khi truyn tnh mch

Nng thuc trong dch k khi tim tnh mch

Nng thuc trong huyt tng khi truyn tnh mch

40

nhanh l 82% v 75% [21]. Hay mt nghin cu khc ca Lodise v cng s ch

ra rng thi gian nm vin trung bnh khi truyn lin tc hoc ko di thp hn so

vi tim tnh mch gin on (l 21 ngy so vi 38 ngy, P = 0,02) [36]. c bit

mt nghin cu lm sng trn 98 bnh nhn vi nhiu loi nhim khun khc nhau

nh nhim khun da v cu trc da, nhim khun h hp, nhim khun bng c

iu tr bng piperacilin-tazobactam, cho thy vic truyn lin tc cho hiu qu

thnh cng trn vi sinh cao hn, bnh nhn gim st nhanh hn khi truyn gin

on [23].

Vi nhng bnh nhn nhim khun nh, s khc bit v hiu qu iu tr

gia phc truyn lin tc v tim tnh mch gin on khng c nhn thy r

nt do t l t vong ca cc bnh nhn ny rt thp [3]. S khc bit v hiu qu

iu tr gia ch truyn lin tc v tim tnh mch gin on ch c nhn thy

r rt trn nhng bnh nhn nng v nhng bnh nhn ny mi c s thay i v

sinh l bnh nghim trng, lm gim nng khng sinh hiu dng [3, 22, 23]. Hn

na, nhng bnh nhn ny thng b nhim cc tc nhn gy bnh t nhy cm. Do

hai yu t ny m mc tiu PK/PD rt kh t c nhng bnh nhn b bnh

nng [3].

c nhng th nghim lm sng chng minh c hiu qu vt tri ca

ch truyn lin tc so vi ch tim tnh mch gin on trn nhng bnh nhn

nng, hay c s suy gim min dch. Trn lm sng, vi khng sinh nhm penicilin

nh piperacilin/tazobactam, cng c nghin cu trn cc bnh nhn ung th cho

thy truyn lin tc gip ci thin hiu qu iu tr, lm gim st, c bit vi

nhng bnh nhn b gim bch cu vi t l khi ln ti 65% so vi ch tim

truyn nhanh l 21% [21]. Mt nghin cu khc c thc hin vi mt khng sinh

nhm cephalosporin l cefamandol ca Bodey v cng s, so snh hiu qu ca

cefamandol kt hp vi carbenicilin gia truyn lin tc v gin on. Kt qu cho

thy khng c s khc bit ng k v hiu qu iu tr gia hai phc nhng

bnh nhn nh, tuy nhin vi nhng bnh nhn bch cu b gim nghim trng,

truyn lin tc cho mt kt qu lm sng tt hn (65% so vi 21%, p = 0.03) [32].

41

Vi cc khng sinh nhm carbapenem, c nhiu nghin cu chng minh hiu

qu u vit khi dng phc truyn lin tc trn nhng bnh nhn nng v nhng

bnh nhn nhim cc tc nhn gy bnh t nhy cm. Trong mt nghin cu tin

cu cho nh trn nhng bnh nhn nng cho thy cc thng s dc ng hc ca

meropenem gia hai ch truyn lin tc v gin on c s khc bit ng k.

Mc d sau khi truyn lin tc, din tch di ng cong nng theo thi gian

thp hn ng k nhng nng ti trng thi n nh vn trn MIC ca nhng

chng vi khun ph bin trong ton b thi gian truyn. Mt nghin cu hi cu

trn bnh nhn vim phi th my cho thy t l khi trn lm sng sau khi truyn

lin tc meropenem cao hn ng k so vi khi truyn gin on (l 90,5% so vi

59,6%, p MIC = 62% trong khi truyn lin tc t %T>MIC = 100%, c bit khi MIC

cao gp i (32 mg/L) th truyn lin tc vn c T>MIC vt tri so vi tim tnh

mch l 65% so vi 39%. T , ta c th nhn thy truyn lin tc khng nhng c

th dit c cc vi khun t nhy cm m thm ch cn vi liu thp hn (Bng 5)

[36].

42

Bng 5: Cc gi tr im gy lm sng theo EUCAST ca 4 khng sinh nhm

beta-lactam: piperacilin - tazobactam, meropenem, doripenem v ceftazidin i

vi 2 chng vi khun Enterobacteriaceae v Pseudomonas aeruginosa liu

chun so vi tng lng thuc nu dng theo ng truyn lin tc hoc ko

di [23].

Khng sinh im gy lm sng (mg/L) im gy khi

truyn lin tc

hoc ko di

(mg/L)

Enterobacteriaceae Pseudomonas

aeruginosa

Piperacilin -

tazobactam

8 16 16

Meropenem 2 2 8

Doripenem 1 1 4

Ceftazidin 1 8 16

Theo piperacilin - tazobactam truyn lin tc hoc ko di c th c li

vi nhng bnh nhn nhim cc chng vi khun c MIC = 816 mg/L [23].

Trong mt nghin cu khc cng s dng piperacilin-tazobactam iu tr nhng

bnh nhn vim phi th my do cc vi khun Gram m (ch yu l

Enterobacteriaceae hoc Pseudomonas aeruginosa) cho thy truyn lin tc mang

li t l khi bnh trn lm sng cao hn so vi truyn gin on, c bit khi MIC

cng cao th t l ny cng tng [23].

Vi cc khng sinh nhm carbapenem, mt nghin cu hi cu khc cng

c thc hin trn nhng bnh nhn vim phi th my, gy ra bi cc vi khun

Gram m c iu tr bng meropenem, truyn lin tc cng cho thy mt t l

khi bnh cao hn truyn gin on (90,5% v 59,6%) [23].

Cc d liu trn cho ta thy c t s khc bit v hiu qu iu tr nhng vi

khun cn nhy cm vi thuc khi truyn lin tc hoc gin on. Tuy nhin, khi vi

khun tr nn t nhy cm hn trong k nguyn khng thuc ngy nay, th truyn

lin tc c kh nng m bo t l iu tr thnh cng cao hn so vi truyn gin

43

on [3]. Mt khc, vi nhng vi khun vn cn nhy, c MIC thp, khi truyn lin

tc hoc ko di thi gian truyn c th gim liu cho bnh nhn [30]. Vi nhng

bnh nhn nng nhim cc chng vi khun gim nhy cm, c MIC cao th vic

truyn lin tc hoc ko di thi gian truyn cc khng sinh nhm beta-lactam l

cn thit [21].

Gim tng lng thuc trong mt ngy cho bnh nhn Truyn lin tc l mt cch thit thc duy tr 100% thi gian trn MIC

ca cc khng sinh beta-lactam vi liu thp hn so vi truyn gin on (v d,

liu ca ceftazidime khi truyn lin tc trong 24 gi l 3g so vi khi dng gin on

l 1-2 g mi 8 gi) [22, 28]. Hay ni mt cch khc, vi nhng vi khun cn nhy

cm, vic truyn lin tc cc khng sinh beta-lactam c th em li hiu qu tng

ng vi tng liu hng ngy thp hn phc truyn gin on [3, 22, 28, 32].

iu ny c bit quan trng khi chn phc iu tr cho cc nhim khun m

cha r v tnh nhy cm vi khng sinh [22]. c nhiu bng chng c trong in

vitro, in vivo v trn lm sng chng minh vi cng mt hiu qu iu tr, phc

truyn lin tc yu cu mt liu thp hn so vi truyn gin on. Nh mt nghin

cu trn chut nhim khun Klebsiella pneumoniae ch ra liu ca ceftazidime

cn thit m bo t l sng 50% l 0,36 mg/kg/ngy khi truyn lin tc v 1,42

mg/kg/ngy khi dng ch tim tnh mch [24]. Mt th nghim khc trn lm

sng s dng cefotaxime iu tr trn nhng bnh nhn tc nghn phi mn tnh,

cho thy truyn lin tc vi liu 2g mt ngy cho mt hiu qu vi sinh v lm sng

tng t nh khi dng liu 1g mi 8 gi [30]. Theo mt nghin cu trn lm sng

khc, iu tr cc nhim khun nhim Pseudomonas aeruginosa, imipenem v

meropenem cn mt liu l 1 g truyn lin tc trong 24 gi so vi truyn gin on

l 1g mi 8 gi [28].

Gim chi ph iu tr Nh phn tch trn, truyn lin tc cc khng sinh beta-lactam iu

tr nhng bnh nhn nhim khun nh c th dng vi liu thp hn truyn gin

on, nn chi ph thuc men cho bnh nhn c gim i, ngoi ra do truyn lin

44

tc ch cn a thuc mt ngy mt ln nn gim bt cc chi ph c lin quan

n vic a thuc nh chi ph iu dng, dng c truyn. Mt khc, bnh nhn

cn mau chng hi phc, thi gian nm vin s ngn hn, v vy m tng chi ph

iu tr s t hn truyn gin on [21, 30].

Ti bnh vin Hartford, c hai nghin cu lm sng v vic truyn lin tc

cc khng sinh nhm beta-lactam. Nghin cu th nht so snh cefuroxim truyn

lin tc 1500 mg hoc dng gin on 750mg mi 8 h (mi nhm c n = 25)

iu tr vim phi mc phi ti cng ng. Kt qu cho thy t l khi trn lm sng

khng c s khc bit, nhng nhm bnh nhn c iu tr bng phc truyn

lin tc c thi gian iu tr ngn hn, tng liu cefuroxim thp hn, do m tng

chi ph cng thp hn. Lng thuc trung bnh cefuroxim tim tnh mch cho mt

bnh nhn gim ng k (P = 0,04) t 8,0 3,4 g cho dng gin on n 5,9 3,2

g cho truyn lin tc. Chi ph trung bnh hng ngy (bao gm c thuc khng sinh,

cng iu dng, vt dng y t) cng gim ng k. Nghin cu th hai l mt th

nghim tin cu ngu nhin so snh v tnh hiu qu v kinh t ca ceftazidim gia

ch truyn lin tc (3g/ngy) v truyn gin on (2g mi 8h) kt hp vi

tobramycin mt ln mi ngy iu tr vim phi bnh vin ICU trn 35 bnh

nhn, 17 bnh nhn c truyn lin tc v 18 bnh nhn c truyn gin on.

Nhm truyn lin tc t t l thnh cng trn lm sng cao hn nhm truyn gin

on l 94% so vi 83%, trong phc truyn lin tc ch s dng mt na s

liu so vi phc tim tnh mch gin on. Cc chi ph (bao gm c chi ph mua

thuc, chun b v a thuc) ca nhm truyn lin tc thp hn ng k (p =

0,001) so vi nhm truyn gin on [32]. Mt nghin cu khc trn nhng bnh

nhn nhim khun, ch yu l vim phi cng cho thy khi iu tr bng cch

truyn lin tc cefuroxim, liu cn thit s t i, thi gian nm vin cng c rt

ngn hn nn c th tit kim c nhiu chi ph hn so vi ch tim tnh mch

[23].

Nhng nhc im ca ch truyn lin tc trong 24 gi

45

Truyn lin tc yu cu mt ng tnh mch ring trong sut 24 gi, iu

ny rt kh thc hin c trn lm sng, c bit vi nhng bnh nhn nng,

nhng bnh nhn khng dng ng ung c m phi truyn nhiu loi thuc

khc nhau [21, 22, 32].

Th hai, l tnh n nh ca cc khng sinh, c bt l nhm khng sinh

carbapenem. Cc khng sinh piperacilin/tazobactam, temocilin, cefepime,

ceftazidime c th n nh nhit phng trong t nht 24 gi [39]. Tuy nhin cc

khng sinh nhm carbapenem nh doripenem, imipenem, v meropenem ch n

nh nhit phng trong khong 4 - 16 gi ty dung dch dng pha long

[36], ch tr doripenem c th n nh trong khong 12 - 24 gi 25 C [5]. Cc

khng sinh nhanh chng b phn hu khi nhit cng cao, v d nh doripenem

bn trong 24 gi nhit 25oC, khi nhit ln ti 37 C doripenem ch cn n

nh trong 12 gi v khi nhit ln ti 40 C th thi gian doripenem n nh li

c rt ngn cn 6 gi. Tng t nh doripenem, imipenem cng n nh c

trong khong 4-10 gi nhit phng, 6 gi 30 C, khi nhit ln ti 35 C th

ch cn 4 gi v khi nhit ln ti 40 C th imipenem ch cn n nh trong 3 gi.

Meropenem cng ch n nh c trong khong 4 -12 gi nhit phng v

nhanh chng b mt hot tnh khi nhit ln 37 C [26, 28, 39]. iu ny l mt

lu rt quan trng khi s dng meropenem cc nc nhit i [26]. Meropenem

ch gi c hot tnh trong 24 gi khi c gi nhit < 4 C [30, 39], nhit

cng thp th thi gian meropenem c th n nh cng di. V vy, meropenem

c th truyn lin tc trong 12 gi, hoc thm ch l 24 gi nu c gi trong mt

thit b lm mt hoc trong cc ti lnh 4oC, nu khng th c th thay thuc

thng xuyn [5, 26, 28].

Truyn lin tc yu cu phi chn mt ng truyn thuc v nu khng th

rt kh c th duy tr mt m ca tnh mch v tr a thuc trong sut khong

thi gian truyn, iu ny gy thm mt nguy c nhim khun bnh vin na cho

bnh nhn [21, 22]. Mt khc, lng ph thuc do tng lng thuc hng ngy s

c pha khi chun b dch truyn trong 24 gi, khi ngng s dng sm, lng

46

thuc ny khng th c ti s dng v phi b i. Tuy nhin, chi ph ny l rt

nh nu so vi hiu qu bnh nhn nhn c khi truyn lin tc nh phn tch

[36]. Ngoi ra, truyn lin tc cn lm hn ch s di chuyn ca bnh nhn [21, 22].

Ni tm li, truyn ko di hay truyn lin tc cc khng sinh beta-lactam

khng phi l liu php thch hp vi mi bnh nhn, nhng n c ngha c bit

quan trng vi nhng bnh nhn mc bnh nng vi tc nhn gy bnh c MIC cao

[21].

Truyn ko di gin on

Truyn ko di gin on va c nhng li ch ca vic dng thuc gin on, va

c nhng u th v dc ng hc ca truyn lin tc [21].

Ko di %T>MIC Phn trc cho thy %T>MIC cn thit ti u ho hiu qu iu tr

khng cn t 100%, do vy ta c th dng phc truyn ko di gin on lm

gim nhng nhc im ca vic dng phc truyn lin tc [21, 22, 42]. Vic ko

di thi gian truyn s lm tng T>MIC ca khng sinh so vi truyn tnh mch

nhanh trong 30 pht. Mt nghin cu cho thy khi truyn meropenem liu 500mg

trong 3 gi, thi gian nng thuc trn MIC l 6 gi, cn khi truyn nhanh trong

vng 30 pht, thi gian nng thuc trn MIC ch t 4 gi (Hnh 10) [30].

47

Hnh 10: M t thi gian nng thuc trn MIC khi truyn 500mg meropenem

nhanh trong 30 pht v 3 gi [30].

Mt v d khc khi truyn nhanh 2g piperacilin trong 30 pht, thi gian nng

thuc trn MIC ch t 4,5 gi, so vi truyn trong vng 4 gi l 6,5 gi. thu

c thi gian nng thuc trn MIC bng 6,5 gi, liu ca piperacilin phi tng

gp i ln 4g (Hnh 11) [22].

Nng (g/mL)

Thi gian (gi)

Truyn tnh mch ko di (3 gi)

Truyn tnh mch nhanh (30 pht)

48

Hnh 11: So snh thi gian nng thuc trong huyt tng trn MIC ca ba

phc s dng piperacilin l 2g truyn trong 30 pht, 4g truyn trong 30 pht

v 2g truyn trong 4 gi [22].

Truyn ko di c hiu qu trn nhng vi khun t nhy cm c MIC cao

Mt nghin cu m phng Monte Carlo trn nhng ngi tnh nguyn khe

mnh, so snh kh nng t c %T>MIC = 50% ca piperacilin-tazobactam ba

phc l 3,375 g truyn ko di 4 gi mi 8 gi vi liu 3,375 g truyn trong 30

pht mi 4 hoc 6 gi. Vi kh nng t c %T>MIC mc tiu cho 3 phc

nh trong bng 6.

Nng (mg/L)

Thi gian (gi)

MIC = 10mg/L

2g truyn 4 gi

4g truyn 30 pht

2g truyn 30 pht

49

Bng 6: Kh nng t %T>MIC = 50% ca piperacilin-tazobactam ba phc

[22].

Phc

Kh nng t

c

%T>MIC

mc tiu khi

MIC 1mg/L

Kh nng t

c

%T>MIC

mc tiu khi

MIC 8 mg/L

Kh nng t

c

%T>MIC mc

tiu khi 8mg/L

MIC

16mg/L

Kh nng

t c

%T>MIC

mc tiu khi

MIC

16mg/L

3,375 g truyn

ko di 4 gi

mi 8 gi

100% 100% 100% - 92% 90%

50

Kh nng t c %T>MIC = 40%

Vy, khi truyn ko di s c kh nng thu c %T>MIC cn thit cao hn

vi liu thp hn, ngay c vi nhng vi khun c MIC cao. Cn vi nhng vi khun

c MIC cao hn 16mg/L th khng phc no cn tc dng (do khng c phc

no t c %T>MIC 50%) [22].

Mt nghin cu tng t cng c thc hin trn mt khng sinh khc ca

nhm beta-lactam l meropenem cng cho kt qu tng t [22].

Hnh 13: Kh nng t %T>MIC mc tiu 5 phc s dng meropenem khc

nhau.

Hay theo mt nghin cu trn m hnh dc ng hc khc, khi ko di thi

gian truyn cc khng sinh nhm carbapenem nh doripenem v meropenem s cho

hiu qu vi sinh cao hn truyn gin on vi cc vi khun c MIC cao. C th,

doripenem truyn ko di trong 4 gi c kt qu vi sinh tng t truyn gin on

trn nhng chng Pseudomonas aeruginosa c MIC 2 mg/L, cn khi MIC ln ti

4 mg/L th ch c truyn ko di mi cho hiu qu u vit hn. Khng sinh

0,5g truyn 3gi mi 8gi

1g truyn 0,5 gi mi 8gi

0,5g truyn 0.5gi mi 6gi

1g truyn 3gi mi 8gi

0,5g truyn 1gi mi 8gi

51

Meropenem khi dng vi liu cao, thi gian truyn di (2g, 3gi truyn) cng cho

thy mt t l sch khun Pseudomonas aeruginosa c MIC 816 mg/L [23].

Truyn ko di gin on th hin hiu qu vt tri trn nhng bnh nhn nng

Li ch ca vic truyn ko di cc khng sinh beta-lactam trn nhng bnh

nhn nng c nhn mnh bng mt nghin cu thc hin ti bnh vin trung tm

y t Albany. Da trn m phng Monte Carlo, TZP truyn ko di (3,375g truyn

trong 4 gi mi 8 gi) c thay th cho TZP truyn nhanh gin on (3,375g

truyn trong 30 pht mi 4 hoc 6 gi) v c coi nh l phc chun ca TZP

t thng 2 nm 2002.

Trc thng 2 nm 2002, tt c bnh nhn c iu tr bng phc c ca

TZP, sau thng 2 nm 2002, tt c bnh nhn c iu tr bng phc TZP

truyn ko di gin on.

nh gi tc ng ca vic thay i ch liu ny, c mt nghin

cu ca Lodise v cng s so snh t l t vong sau 14 ngy v thi gian nm vin

nhng bnh nhn truyn nhanh gin on v nhng bnh nhn truyn ko di khi

iu tr cc bnh nhim khun vi chng Pseudomonas aeruginosa nhy cm vi

thuc t nm 2000 n nm 2004. Kt qu ca nghin cu ch ra rng nhng

bnh nhn c xc nh l c nguy c t vong cao nht sau 14 ngy (im

APACHE II 17, APACHE - Acute Physiology and Chronic Health Evaluation),

nguy c t vong v thi gian nm vin ca nhm nhng bnh nhn dng phc

truyn ko di t hn so vi nhng bnh nhn dng phc truyn nhanh.

52

Hnh 14 (A) T l t vong sau 14 ngy v (B) s ngy nm vin ca bnh nhn

c iu tr bng phc truyn ko di trong 4 gi hoc truyn nhanh trong

0,5 gi ca TZP [21, 36].

Vi nhng bnh nhn nh (n=115, c APACHE < 17), t l t vong v thi

gian nm vin l nh nhau, nhng vi nhng bnh nhn nng (n=79, c APACHE >

Truyn tnh mch qung ngn

Truyn ko di

Truyn ko di

Truyn tnh mch qung ngn

T l t vong sau 14 ngy (%)

S ngy nm vin trung bnh (ngy)

53

17) th vic ko di thi gian truyn ln n 4 gi lm gim t l t vong v thi

gian nm vin hn nhng bnh nhn dng phc tim truyn tnh mch ngn [23].

Gim tng liu thuc trong mt ngy, gim chi ph cho bnh nhn v x hi

Truyn ko di gin on m bo %T>MIC cn thit dit khun, ci

thin tnh trng nhim khun ca bnh nhn, vi liu thp hn phc tim tnh

mch gin on. C th, truyn ko di cho php t c %T>MIC mc tiu vi

tng lng thuc hng ngy thp hn 25-50% so vi phc liu chun ca cc

khng sinh beta-lactam [21]. V vy, phng php ny rt thch hp lm gim

chi ph thuc men cho bnh nhn [21, 30]. Mt v d nh khi dng

piperacilin/tazobactam 3,375 g truyn trong 4 gi mi 8 ting v 3,375 g truyn

trong 30 pht mi 4 hoc 6 ting trn nhng bnh nhn nhim khun nng vi vi

khun Pseudomonas aeruginosa. Vi nhng bnh nhn c nguy c t vong cao,

phc truyn ko di lm gim ng k t l t vong sau 14 ngy so vi phc

truyn ngn (l 12,2% so vi 31,6%) v thi gian nm vin trung bnh (21 ngy so

vi 38 ngy) vi liu thp hn 25-50% tng liu hng ngy, gim ng k chi ph

thuc men cho bnh nhn [30].

Gim nhc im ca ch truyn lin tc Th nht, truyn tnh mch ko di gin on khng yu cu mt ng

truyn tnh mch ring, nn c th s dng trn nhiu bnh nhn, c bit l cc

bnh nhn nng, cn phi truyn nhiu thuc ng thi. Th hai, truyn tnh mch

ko di gin on s lm gim n mc thp nht s lng ph thuc, v cc khng

sinh ch c chun b cho tng t truyn mt, khng cn thit phi chun b

khng sinh trong 24 gi. Th ba, truyn tnh mch ko di gin on cho php bnh

nhn c th i li c, khng cn nm im ti ging [21].

Tuy nhin, vic truyn tnh mch gin on ny lm tng cng vic cho y t iu

dng, dng c chun b v a thuc [21].

54

2.5.2. Gim khng thuc

Tnh nhy cm ca vi khun vi khng sinh l khng ng nht gia cc vi

khun trong qun th. Nu liu qu thp, khng sinh khng t c nng dit

khun th kh nng xut hin khng thuc s tng ln. Vi khun khng beta-lactam

qua 3 c ch:

1. Bt hot khng sinh beta-lactam bi beta-lactamase. Gen sn xut beta-

lactamase nm trong nhim sc th v/hoc plasmid. Gen beta-lactamase

thng c thc hin trn plasmid. Cc plasmid c chuyn t mt t bo

vi khun sng cc t bo khc qua cc th h.

2. Thay i mc tiu tc dng lm gim mi quan h gia thuc v murein

transpeptidase - protein gn penicilin.

3. Thay i tnh thm ca mng lm gim s xm nhp ca thuc.

Mt vi khun c th c mt hoc nhiu c ch khng thuc [32].

trnh hin tng khng thuc, c th s dng phng php ti u ho

liu iu tr nh phn tch trn hoc kt hp cc khng sinh beta-lactam vi

cht c ch beta-lactamase.

Hin nay, t l nhim cc vi khun Gram m v Gram dng khng thuc

bng cch sn xut ra beta-lactamase ngy cng cao. Beta-lactamase l mt h cc

enzym thy phn vng penicilin v cephalosporin ca beta-lactam, dn n vic tm

kim cc loi khng sinh mi hoc kt hp mt beta-lactam vi mt cht c ch

beta-lactamase. Ngy nay trn th trng c ba cht c ch beta-lactamase

(clavulanat, sulbactam v tazobactam) c s dng kt hp vi mt khng sinh

beta-lactam. Mc tiu ca s kt hp ny l m rng phm vi ca cc beta-

lactam trn cc vi khun Gram dng v Gram m khng thuc [32].

Theo mt nghin cu in vitro, tazobactam c a sau piperacilin khng

lm tng cng hiu qu dit khun ca piperacilin. Tng t nh vy, mt nghin

cu in vivo trn chut nhim khun huyt do Escherichia coli, hiu qu ca

ampicilin-sulbactam khng ph thuc vo vic sulbactam c a sau hay ng

thi vi ampicilin [32].

55

Xc nh %T>MIC ti u cho s kt hp beta-lactam v cht c ch beta-

lactamase l kh phc tp v c enzyme v cht c ch u nh hng n tin trnh

thoi ha ca beta-lactamase. S lng v loi enzyme sn xut bi cc vi khun c

nh hng ng k n hot tnh ca cc cht c ch. Phc liu hin ti c nng

cht c ch vt qu im gy nhy cm in vitro ch trong 2-3 gi, khng phi l

ton b thi gian dng thuc. V vy, dc lc hc c o ca betalactam - beta-

lactamase r rng l yu t quyt nh. Gii thch cho hiu qu iu tr ca cc

thuc ny c th l do hiu qu c ch hu beta-lactamase. Mt m hnh c s

dng xc nh hiu qu hu khng sinh, tc dng ca tazobactam c nh gi

trn chng beta-lactamase ca vi khun Escherichia coli. S tip xc ca vi khun

vi tazobactam v piperacilin trong ln nhim khun trc dn n vic piperacilin

vn cn c hiu qu dit khun trong t phi nhim th hai khi piperacilin c

dng mt mnh. Vi khun ban u khng tip xc vi tazobactam khng cht bi

piperacilin trong tip xc th hai. Tng t nh vy, cc nh nghin cu khc

bo co mt hiu qu c ch hu beta-lactamase trong s pht trin li ca

nhng vi khun khng amoxicilin c ngn chn bi mt mnh amoxicilin sau khi

tip xc v loi b amoxicilin v clavulanat [32].

Trong mt nghin cu in vitro ca piperacilin so vi piperacilin/ tazobactam,

vic b sung tazobactam khng lm thay i tc dng dit khun ca piperacilin

trn chng Escherichia coli nhy cm vi piperacilin. Bng cch thm tazobactam,

hiu qu dit khun ca piperacilin trn Escherichia coli khng piperacilin tng

ng vi hiu qu dit khun trn cc chng nhy cm, mc d sau 3 gi nng

tazobactam gim xung di 4 mg/L (nng s dng trong th nghim tnh nhy

cm). V vy, khong thi gian dng thuc ca betalactam beta-lactamase c th

c m rng cho mt s thi gian hu hn ca thi gian b hn ch bi vic ti

tch t beta-lactamase ca vi khun. Trn c s ca s t cc nghin cu in vitro

ny, c v nh liu piperacilin-tazobactam mi 8 gi thay v mi 6 gi l mt phc

hp l [32].

56

KT LUN

Dc ng hc/ dc lc hc khng sinh m t mi quan h gia mc

phi nhim ca khng sinh trong c th v hiu lc khng khun ca khng sinh in

vitro vi hiu qu trn lm sng. iu ny gip d on chnh xc hn hiu qu

iu tr ca thuc. C ba thng s dc ng hc/ dc lc hc quan trng l

AUC/MIC, Cpeak/MIC v %T>MIC. Da trn nhng c im dc ng hc/

dc lc hc v tc dng hu khng sinh, cc khng sinh c chia thnh ba nhm:

tc dng dit khun ph thuc vo nng v tc dng hu khng sinh di, tc

dng dit khun ph thuc vo thi gian v tc dng hu khng sinh ngn, tc dng

dit khun ph thuc vo thi gian v tc dng hu khng sinh di. T y, phc

s dng ti u