pkpd1_2.pdf

1PK/PD Applications inAntimicrobial Pharmacotherapy:

Dosing Regimen Consideration . .

. .

PK/PD PK/PD

Impact of Inappropriate Use of Antimicrobials

Appropriate Antimicrobial Pharmacotherapy

Absorption DistributionMetabolismElimination

(PD)

Pharmacokinetics Pharmacodynamics

DrugConcentration at infection site

Pathogen

BacterialKilling CURE

(PK)

Concentration-dependenceTime-dependence

Appropriate Antimicrobial Pharmacotherapy: Dosage Regimen Consideration

Dosage RegimenDoseDosing intervalRoute of administration Infusion timeDuration of therapy

????

1 20

1 azithromycin (250 mg) 2 1 3 2

2 : Azithromycin bioavailability (F) = 37-38%

Food-Drug Interaction

The presence of food in the gastrointestinal tract may reduce the bioavailability of azithromycinCAPSULES by 50%. Capsules should be taken at least 1 hour before or 2 hours after eating.

Micromedex

Take Home Message #1

Bioavailability

2 45 102 . 168 .

acute myeloid leukemia 1 2 ceftazidime vancomycin IV 5 pip/tazo IV 4.5 g q 8 hr gentamicin ? mg IV ODBUN=13 mg/dL, SCr=0.8 mg/dL

Gentamicin, OD-dosing =? : 102 . 168 .

Definition of Obesity

% IBW80 - 125 normal bodyweight

125 (130) - 190 obesity> 190 morbid obesity

3Gentamicin, OD-dosing =?

Male, IBW = 50 kg + [2.3 x (height - 60)] kgIBW = 50 kg + [2.3 x {(168-152.4)/2.54}] kg

= 64.1 kg %IBW = (102/64.1) x 100 = 159% Obesity

or BMI = 102/(1.68 x 1.68) = 36 kg/m2 class II Obesity

Obesity

Variable changes in drug disposition Volume of distribution (Vd) Total body clearance (CL)

Volume of distribution (Vd)

dose = 100 mg; conc. = 10 mg/L Vd = 10 L

Volume of distribution (Vd)Chemical properties of antibacterial e.g. pKapartition coefficient (lipid; water

solubility)protein binding

BODY WATER(easily accessible)

60% 40L

INTRACELLULAR40-45%, 25L

EXTRACELLULAR16-20%, 15L

INTERSTITIAL12-16%, 10L

INTRAVASCULAR(plasma)4%, 3L

BODY WATER(slowly accessible, e.g.

bone, tendon, cartilarge)6%

BoundFree Capillary endothelium

Cell membraneFAT

Water (20-40%)

Volume of distribution (Vd)

Vd L; L/kgVd of lipophilic drugs correlates better with

TBWVd of hydrophilic drugs relates better to ideal

bodyweight (IBW) (in general) or adjustedbodyweight (ABW) (in some drugs)

4Adjusted Bodyweight (ABW)

ABW = IBW + [C x (TBW - IBW)]C = correction factor = 0.2-0.4

ABW = 64.1 kg + [0.4 x (102 kg - 64.1 kg)]= 79.3 kg

Gentamicin, OD-dosing =?Which weight you will choose to calculate Vd? IBW = 64.1 kg orTBW = 102 kg (IBW + adipose tissue) orABW = 79.3 kg (IBW + water in adipose tissue)

Gentamicin

Highly polar basic compoundRelatively insoluble in lipidsPartial penetration into adipose tissueVolume of distribution = 0.25 L/kg

BODY WATER(easily accessible)

60% 40L

INTRACELLULAR40-45%, 25L

EXTRACELLULAR16-20%, 15L

INTERSTITIAL12-16%, 10L

INTRAVASCULAR(plasma)4%, 3L

BODY WATER(slowly accessible, e.g.

bone, tendon, cartilarge)6%

BoundFree Capillary endothelium

Cell membraneFAT

Water (20-40%)

Gentamicin, OD-dosing =?Which weight you will choose to calculate Vd? IBW = 64.1 kg orTBW = 102 kg (IBW + adipose tissue) orABW = 79.3 kg (IBW + water in adipose tissue)

Gentamicin, OD-dosing =?Vd in obesity (L) = Vd population (L/kg) x ABW (kg)

= 0.25 L/kg x 79.3 kg= 19.83 L

5Gentamicin, OD-dosing =? (CLCR = 106; 131 mL/min)Initial dosing interval should be based on an

estimated renal functionCLCR (mL/min) Dosing interval

> 60 q 24 hr40-59 q 36 hr20-39 q 48 hr

Gentamicin, OD-dosingInfusion model:

Dose = k x Vd x Cmax x (1-e-k)t' (1-e-kt')

Dose = 0.231 hr-1 x 19.83 L x 20 mg/L x (1-e-0.231 x 24)1 hr (1-e-0.231 x 1)

= 442.35 mg

440 mg infused over 1 hr, OD

t1/2 = 3 hrk = 0.693/3 = 0.231 hr-1

Gentamicin, OD-dosing

Dose 102 . Vd 570 mg IBW 64.1 . Vd 360 mg ABW 79.3 . Vd 440mg

*Calculated by using infusion model


TBW, IBW ABW Vd IBW ABW

TBW

3 . 30 70 .

VP-shunt Acinetobacter baumannii cefoperazone/sulbactam, colistin, netilmycin imipenem, ceftazidime cefoperazone/sulbactam colistin

netilmycin 3

Vd (Volume of Distribution)

Vd (L/kg) %CNS PenetrationSulbactam 0.173 5.5% (non-inflammed)1

30% (inflammed)1Colistin 0.47-0.543 Poor (inflammed,

non-inflammed)425% (inflammed)2

Netilmycin 0.16-0.34 Poor (inflammed,non-inflammed)3

1Drugs 1987;33:577-609.,2Eur J Clin Microbiol Infect Dis (2002) 21:212214 (1 case, 14 yo), 3Micromedex, 4Neurosurgery (1980) 6:691714

6Loss of Drugs through VP-shunt Increased Dose

Max. Daily Dose ADRSulbactam 4 g HepatotoxicityColistin 5 mg/kg/day NephrotoxicityNetilmycin - Neprotoxicity,

Otoxicity

Intrathecal Administration

Intrathecal colistin 10 mg based q 12 hr(AJHP 2005;62:39-47)

Intrathecal Administration

Intrathecal netilmycin: 150 mg q 12 hr

J Infect. 2005 Dec;51(5):420-2.


Vd %penetration

4 30 Staphylococcal sepsis cloxacillin 1 IV 30 6 phlebitis 1 1

7Cloxacillin Normal doses provide therapeutic levels in PLEURAL, BILE,

and AMNIOTIC FLUIDSVolume of Distribution = 6.6 to 10.8 litersMetabolism: Liver, 30%-60%Excretion: Renal = 40%-70%; Renal Clearance = 113.7

mL/mintotal elimination rate constant in normal patients 1.21 hr -1ELIMINATION HALF-LIFE = 0.5 to 1 hour

Infusion model: CloxacillinDose 1 g in 0.5 hr q 6 hr

Cmax,ss = Dose x (1-e-kt')t'x k x Vd (1-e-k)

= 1 g x (1-e-1.21 x 0.5)0.5 hr x 1.21 hr-1 x 8 L (1-e-1.21 x 6)

= 94 mg/L

Infusion model: CloxacillinDose 1 g in 1 hr q 6 hr

Cmax,ss = Dose x (1-e-kt')t'x k x Vd (1-e-k)

= 1 g x (1-e-1.21 x 1)1 hr x 1.21 hr-1 x 8 L (1-e-1.21 x 6)

= 73 mg/L0

102030405060708090

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

(

/

.)

()

9473 Cloxacillin 1 g IV infuse 1 hr

Cloxacillin 1 g IV infuse 0.5 hr

0102030405060708090

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

(

/

.)

()



MIC E-test = 1 mcg/mL0

102030405060708090

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

(

/

.)

()



MIC E-test = 32 mcg/mL

8Azithromycin 500 mg IV OD, t1/2 = 68 hr

Cmax at steady stateBolus* 1.32 mg/LInfusion time 1 hr** 1.32 mg/LInfusion time 3 hrs ** 1.32 mg/L

Bolus model*Cmax,ss = Dose

Vd x (1-e-k)Cmax,ss = Dose x (1-e-kt')

t'x k x Vd (1-e-k)

Infusion model**


( ) MIC

5 65 70 kg 175 cm community-acquired pneumonia ampicillin 1 gm IV q 6 hr + gentamicin 350 mg IV infusion over 1 hr once daily STAT 3 16 2550 SCr 0.7 mg/dL, (. 7.00 ., 13.00 ., 19.00 . 1.00 . q 6 hr 7.00 . qd)

Scheduled Dose STAT Dose?

3am 7am 11am 3pm 7pm 11pm 3am 7am 11am 3pm 7pm 11pm 3pm

Blood

Conce

ntrati

on Therapeutic LevelToxic Level

4 hrs

Gentamicin 350 mg IV Once Daily

Blood

Conce

ntrati

on (m

g/L)

20

10

5


16 17 MIC1

< 2 mg/L


Blood

Conce

ntrati

on (m

g/L) 4 hrs

20

10

5

06.5 mg/dL

3am 7am 11am 3pm 7pm 11pm 3am 7am 11am 3pm 7pm 11pm 3pm16 17

< 2 mg/L

9Gentamicin 350 mg IV Once Daily

Blood

Conce

ntrati

on (m

g/L)

10 hrs

20

10

5

0

10 STAT( dose 2 10 3)


2 mg/dL


Blood

Conce

ntrati

on (m

g/L)

10 hrs

20

10

5

0

10 STAT( dose 2 10 3)


2 mg/dL


Blood

Conce

ntrati

on (m

g/L)

14 hrs 14 hrs

20

10

5

0

7.00 . dose 3 ( 28 dose dose 2 dose dose 3 14 dose


0.69 mg/dL 0.69 mg/dL

16 17

Gentamicin 350 mg IV Once DailyBlo

od Co

ncentr

ation

(mg/L

)

14 hrs

20

10

5

0

dose 2 STAT

dosing interval 12 3PM 5PM (14 STAT) 0.69 mg/dL 2 mg/dL

0.69 mg/dL


2 mg/dL

STAT Dose/ STAT

2*Aminoglycosides# 5mg/kg IV 1 hr Once Daily 10 Aminoglycosides# 1.5mg/kg IV 0.5 hr q 8 hr 6 Amikacin 15 mg/kg IV 1 hr Once daily 10 Amikacin 5 mg/kg IV 0.5 hr q 8 hr 6 Kapseal 300 mg/day PO after LD 18 LDInfatab 100 mg PO q 8 hr after LD 24 LDPhenytoin 100 mg IV q 8 hr after LD 24 LD Vancomycin 1 g IV 1 hr q 12 hr 9 *#Gentamicin, netilmicin, tobramycin

STAT Schedule maximum dose/ recommended dose/ 1-2 ()

10


STAT Schedule STAT dose dose high-alert drug

d

6 75 IBW = 72 kg febrile neutropenia chemotherapy 3 7 cefepime 2 g IV q 8 hr. 2 : SCr 2.0 mg/dL,

WBC 800 /..

Cefepime

Adults:Most infections: IV 1-2 g q 12 hrs for 7-10 days;

higher doses or more frequent administration may be required in pseudomonal infectionsMonotherapy for febrile neutropenia: IV 2 g q 8 hrs

for 7 days or until the neutropenia resolvesRenal impairment: adjust dosing regimen

Cefepime

Recommended dose: 2 g q 8 hr. No maximum daily dose is suggested.Dosing in renal insufficiency:

CLcr (mL/min) Dose30-60 2 g q 12 hr11-29 2 g q 24 hr

11

Other DrugsAmpicillin; Adults: oral, IV, IM: 250-500 mg q 6 hr = 1-2 g/daySepsis/meningitis: IM,IV 150-250 mg/kg/24 hrs

divided q 3-4 hr (range 6-12 g/day)Cefazolin: Adults:

250 mg to 2 g q 6-12 hrs, depending on severity of infection; maximum dose : 12 g/day

0.01 0.1 1.0 10 100Drug Concentration (mg/L)

Perc

ent M

axim

al E

ffect

100

80

60

40

20

0

Emax

Ampicillin: 12 g/day

Cefepime: 6 g/day

Ampicillin: 2 g/day


max. daily dose normal recommended dose max. daily dose max. daily dose normal

recommended dose

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pkpd1_2.pdf