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p d!ng PK/PD trong l"a ch#n
khng sinh trong $i%u tr&
TS. !"ng Nguy#n !oan Trang
PK: Pharmacokinetics (d!"c #$ng h%c)
PD: Pharmacodynamics (d!"c l&c h%c)
C'N C( L)A CH*N KHNG SINH TRONG +I,U TR-
! Theo b'nh
! Theo tc nhn gy b'nh
! Theo tnh hnh #( khng KS
! Theo tnh tr)ng b'nh nhn (suy gan, suy th*n,+)
Phc
#,
BV
CC THNG S. GIP +NH GI VI/C S0 D1NG
KHNG SINH
Thng s2 d34c l"c (PD parameter):
MIC (Minimum inhibitory concentration) :
Cho bi-t hi'u l&c c.a khng sinh nh!ng kg cho bi-t
v( th/i gian tc d0ng c.a KS
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CC THNG S. GIP +NH GI VI/C S0 D1NG
KHNG SINH
Thng s2 d34c $5ng (PK parameter):
Cmax (N,ng #$ t1i #a c.a thu1c trong huy-t t!2ng)
Cmin (N,ng #$ thu1c ngay tr!3c khi dng li(u k- ti-p)
AUC (Di'n tch d!3i #!/ng cong n,ng #-th/i gian)
Cho bi-t th/i gian tc d0ng c.a KS nh!ng kg cho bi-t kh4
n5ng di't khu6n c.a KS
CC THNG S. GIP +NH GI VI/C S0 D1NG
KHNG SINH
Thng s2 d34c l"c/d34c $5ng (PD/PK parameter):
Peak/MIC (hay Cmax/MIC)
T/MIC
24h-AUC /MIC
PHN LO6I KHNG SINH THEO HI/U L)C DI/T KHU7N
- Hi8u l"c di8t khu9n ph! thu5c n:ng $5
- Hi8u l"c di8t khu9n ph! thu5c th;i gian
- Hi8u l"c di8t khu9n ko di
(PAE: post-antibiotic effect)
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Pattern of Activity Antibiotics Goal of Therapy
PK/PD
Parameter
Type I
Concentration-dependent
killing and
Prolonged persistent effects
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Maximize
concentrations
24h-AUC/MIC
Peak/MIC
Type II
Time-dependent killing and
Minimal persistent effects
Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins
Maximize duration of
exposure
T>MIC
Type III
Time-dependent killing and
Moderate to prolonged
persistent effects.
Azithromycin
Clindamycin
Oxazolidinones
Tetracyclines
Vancomycin
Maximize amount
of drug
24h-AUC/MIC
P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
- KS type 1:
Aminoglycosides: Peak/MIC 7 8-10 " trnh #( khng
Fluoroquinolones:
VK gram (-): 24h-AUC/MIC t1i !u 8 125
VK gram (+): 24h-AUC/MIC t1i !u 8 40
24h-AUC/MIC l9 t!:ng c.a cc FQ thay #;i ty theo t<ng KS
M=T S> K?T QU@ NGHIN CAU
Aminoglycoside Pharmacodynamics in Vivo
Initial serum
peak level
Died Survived
< 5mcg/ml 21% 79%
>= 5mcg/ml 2% 98%
Moore et al, J Infect Dis 149: 443, 1984
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Aminoglycoside Pharmacodynamics in Vivo
Moore et al, J Infect Dis 155: 93, 1987
P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
Aminoglycosides:
CBn tnh ton li(u dng #C #)t #Dnh (peak) mong mu1n
- Peak t2i thi<u = MIC * 8
- Li%u dng = Peak * Vd (th< tch phn b2)
P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
Aminoglycosides:
Vd: MIC = 1 mg/L " Li(u : 3mg/kg
MIC = 2 mg/L " Li(u : 6mg/kg (Li(u t1i #a c.a Genta., Tobra.)
MIC = 4 mg/L " Li(u : 15 mg/kg (Li(u t1i #a c.a Amikacin)
" Khng l&a ch%n Gentamicin, Tobramycin cho nhEng VK c MIC > 2
" Khng l&a ch%n Amikacin cho nhEng VK c MIC > 4
M=T S> K?T QU@ NGHIN CAU
Fluoroquinolone Pharmacodynamics vs S. pneumoniae
24h-AUC/MIC ratio
Microbiological
Response
< 33.7 (64%)
> 33.7 (100%)
Ambrose et al, Antimicrob Agents Chemo 10: 2793, 2001
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Cc ch.ng vi khu6n khc nhau cBn cc m0c
tiu PDI khc nhau #1i v3i fluoroquinolones
3 10 30 100 300 1000
24 hr AUC/MIC
0
20
40
60
80
100
P
e
r
c
e
n
t

m
o
r
t
a
li
t
y

P aeruginosa
Emax at
125 ...
5 10 25 50
24 Hr AUC/MIC
M
o
r
t
a
l
i
t
y

(
%
)
1 2.5 100
0
20
40
60
80
100
S. pneumoniae
Emax at
I
30 ...

P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
- KS type 2:
Beta lactam, Erythromycin : T/MIC nn 7 70% kho4ng li(u
(#1i v3i beta-lactam, T/MIC nn 7 50% kho4ng li(u)
Craig et al, Ped Infect Dis 15: 255, 1996
Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media
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P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
Beta-lactams:
- T5ng s1 lBn dng thu1c #C #)t T>MIC, tim truy(n ko di hay lin
t0c



- N,ng #$ #Dnh cao c thC kg cBn thi-t v gy ra #$c tnh
-N,ng #$ !-lactam trong mu nn 7 8 g/mL trn kho4ng 2/3
kho4ng li(u
(PK/PD breakpoint for !-lactams = 8 g/mL ) 10
20
30
40
50
60
70
80
90
100
0.001 0.01 0.1 1 10 100
MIC (mcg/mL)
T
a
r
g
e
t
A
t
t
a
in
m
e
n
t
(
%
)
500mg q8h 30min IV 500mg q6h 30min IV 1000mg q8h 30min IV
500mg q8h 3hr IV 500mg q6h 3hr IV 1000mg q8h 3hr IV
Tim truy%n meropenem 30 pht (gin $o=n) so v>i 3 gi;
(ko di), d? li8u t@ cc $o l3;ng d34c $5ng h#c
Lee et al, DMID Oct 2010
P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
- KS type 3:
Vancomycin : 24h-AUC/MIC nn 7 125 (1 s1 nghin
cFu #( nghG 7 400)
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Vancomycin Outcome vs 24h-AUC/MIC ratio
24h-AUC/MIC
ratio
Satisfactory Unsatisfactory
< 125 4 (50%) 4
> 125 71 (97%) 2
Hyatt et al, Clin Pharmacokinet 28: 143, 1995
P D1NG CC THNG S. PD/PK TRONG S0 D1NG
KHNG SINH
Xin chn thnh cm !n!!!