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p d! ng PK/PD trong l " a ch #nkhng 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 D1 NGKHNG SINH

Thng s 2 d34 c l" c (PD parameter):

MIC (Minimum inhibitory concentration) :

Cho bi- t hi' u l&c c. a khng sinh nh! ng kg cho bi- tv( th/ i gian tc d0ng c. a KS

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CC THNG S. GIP +NH GI VI/ C S0 D1 NG

KHNG SINH

Thng s 2 d34 c $5ng (PK parameter):

Cmax (N, ng #$ t1i #a c. a thu1c trong huy- t t!2 ng)

Cmin (N, ng #$ thu1c ngay tr !3 c khi dng li( u k- ti- p)

AUC (Di' n tch d!3 i #!/ 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 D1 NG

KHNG SINH

Thng s 2 d34 c l" c/d34 c $5ng (PD/PK parameter):

Peak/MIC (hay Cmax/MIC)

T/MIC

24h-AUC /MIC

PHN LO6 I KHNG SINH THEO HI/ U L) C DI/ T KHU7 N

- Hi8u l" c di8t khu9n ph ! thu5c n : ng $5

- Hi8u l" c di8t khu9n ph ! thu5c th ; i gian

- Hi8u l" c di8t khu 9n ko di

(PAE: post-antibiotic effect)

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Pattern of Activity Antibiotics Goal of Therapy PK/PDParameter

Type I Concentration-dependentkilling andProlonged persistent effects

AminoglycosidesDaptomycinFluoroquinolonesKetolides

Maximizeconcentrations

24h-AUC/MICPeak/MIC

Type II Time-dependent killing andMinimal persistent effects

CarbapenemsCephalosporinsErythromycinLinezolidPenicillins

Maximize duration ofexposure T>MIC

Type III Time-dependent killing andModerate to prolongedpersistent effects.

AzithromycinClindamycinOxazolidinonesTetracyclinesVancomycin

Maximize amountof drug 24h-AUC/MIC

P D1 NG CC THNG S. PD/PK TRONG S0 D1 NGKHNG SINH

- KS type 1:

Aminoglycosides: Peak/MIC7 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 K? T QU @ NGHIN CAU

Aminoglycoside Pharmacodynamics in Vivo

Initial serumpeak 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 D1 NG CC THNG S. PD/PK TRONG S0 D1 NG

KHNG SINH

P D1 NG CC THNG S. PD/PK TRONG S0 D1 NG

KHNG SINH

Aminoglycosides:

CBn tnh ton li( u dng #C #) t #D nh (peak) mong mu1n

- Peak t 2i thi 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 MicrobiologicalResponse

< 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 c Bn cc m0ctiu PDI khc nhau #1i v3i fluoroquinolones

3 10 30 100 3 00 1000

24 hr AUC/MIC

0

20

40

60

80

100

P e r c e n

t m o r t a

l i t y

P aeruginosa

Emax at125 ...

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 D1 NG CC THNG S. PD/PK TRONG S0 D1 NGKHNG SINH

- KS type 2:

Beta lactam, Erythromycin : T/MIC nn7 70% kho4ng li( u

(#1i v3i beta-lactam, T/MIC nn7 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 D1 NG CC THNG S. PD/PK TRONG S0 D1 NG

KHNG SINH

Beta-lactams:

- T5ng s1 lBn dng thu1c #C #) t T>MIC, tim truy( n ko di hay lint0c

- N, ng #$ #D nh cao c thC kg cBn thi- t v gy ra #$c tnh

- N, ng #$ ! -lactam trong mu nn 7 8 g/mL trn kho4ng 2/3kho4ng li( u

(PK/PD breakpoint for ! -lactams = 8 g/mL ) 1020

30

40

50

60

70

80

90

100

0.001 0.01 0.1 1 10 100MIC (mcg/mL)

T a r g e t

A t t a

i n m e n

t ( % )

5 00 mg q 8h 3 0m in I V 5 00 mg q 6h 30 mi n I V 10 00 mg q 8h 3 0m in I V

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 d34 c $5ng h#c

Lee et al, DMID Oct 2010

P D1 NG CC THNG S. PD/PK TRONG S0 D1 NGKHNG SINH

- KS type 3:

Vancomycin : 24h-AUC/MIC nn7 125 (1 s1 nghincFu #( nghG 7 400)

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Vancomycin Outcome vs 24h-AUC/MIC ratio

24h-AUC/MICratio Satisfactory Unsatisfactory

< 125 4 (50%) 4

> 125 71 (97%) 2

Hyatt et al, Clin Pharmacokinet 28: 143, 1995

P D1 NG CC THNG S. PD/PK TRONG S0 D1 NG

KHNG SINH

Xin chn thnh cm ! n!!!