pk&pd susceptibility course 2010

8/8/2019 PK&PD Susceptibility Course 2010

1/44

11

Lim Tze PengSenior Pharmacist

Singapore General Hospital

PHARMACOKINETIC &PHARMACODYNAMICPRINCIPLES OF ANTIMICROBIAL USE


2/44

22

In order for an antimicrobial to be effective

it must firstreachthe active site of an

organism in a sufficient quantity and

remainthere for an adequate length of time

tointerruptnormal life functions of theorganism.


3/44

33

PHARMACOKINETICSPHARMACOKINETICS:

Describes the way that the body handles a drug.

PHARMACODYNAMICSPHARMACODYNAMICS:

Describes the characteristics of the interaction between

a xenobiotic, its active site, and pharmacologic action.


4/44

44

Pharmacokinetics Parameters

Absorption (F)Absorption (F)

DistributionDistribution

MetabolismMetabolism

EliminationElimination


5/44

55

Dose of drugadministered

Dose of drugAdministered

Drug concentrationIn systemic circulation

BIOAVALABILITY

Absorption


6/44

66

Distribution

Movement of drug from the bloodMovement of drug from the bloodinto the tissue and vice versainto the tissue and vice versa

Affected by nature of drugAffected by nature of drug

molecules, tissue or cellmolecules, tissue or cell

membrane, blood flowmembrane, blood flow

Affects the site of action andAffects the site of action and

intensity of actionintensity of action


7/44

77

Distribution


Drug in tissue

Of distribution


8/44

88

Metabolism

Transformation of the drug intoTransformation of the drug intoinactive or more activeinactive or more activemetabolites or metabolites withmetabolites or metabolites with

equal activitiesequal activities Affected byAffected by

metabolisingmetabolising organ (Liver, GIT,organ (Liver, GIT,

Kidney)Kidney)drug interactionsdrug interactions

AffectsAffects

halfhalf--lifelife


9/44

99

Elimination

Removal of drug from the bodyRemoval of drug from the body

Affected by the failure of clearingAffected by the failure of clearing

organs (kidney, liver, skin, lung etc)organs (kidney, liver, skin, lung etc)

Affects the removal of drug from theAffects the removal of drug from the

body and hence thebody and hence the drug dosingdrug dosing

Removal by other meansRemoval by other means


10/44

1010


Drug metabolized or excreted

Elimination


11/44

1111

Dosage Consideration

Patient FactorPatient Factor

AgeAge

WeightWeight

Organ FailureOrgan Failure

Disease statesDisease states Routes ofRoutes of

administrationadministration


12/44

1212

Why IV Injection and notoral?

Patient cannot take medication byPatient cannot take medication byother routesother routes

Medication is only available as IVMedication is only available as IV

injectioninjection

PatientPatients disease states disease state


13/44

1313

IVInjection

AdvantagesAdvantages Complete bioavailability ~ 100%Complete bioavailability ~ 100%

Fast onset of actionFast onset of action

Predictable blood concentrationPredictable blood concentration

DisadvantagesDisadvantages


14/44

1414

Concentration-time curve

Time

Concentration

Oral

IV


15/44

1515

Storage and Stability

LightLight TemperatureTemperature

MoistureMoisture

ConcentrationConcentration pHpH

Presence of oxygen, carbonPresence of oxygen, carbon

dioxidedioxide

Improper storage can lead toImproper storage can lead to

Reduced Potency and/orReduced Potency and/orIncreased Toxic EffectIncreased Toxic Effect


16/44

1616

Admixtures

Mixture of 2 or more drugs orMixture of 2 or more drugs orinfusion fluidsinfusion fluids

CompatibilityCompatibility

StabilityStability

Dosage changesDosage changes

Do not administer ifDo not administer if

unusualunusual colourcolour changechange

presence of particles or precipitatepresence of particles or precipitate


17/44

1717

Right drug+

Right dose


18/44

1818

Pharmacodynamics

Goal is to be able to predict the efficacy and toxicity of anGoal is to be able to predict the efficacy and toxicity of an

agent using pharmacokinetic data.agent using pharmacokinetic data.

These data would allow for the design of dosing regimensThese data would allow for the design of dosing regimensthat would optimize antimicrobial activity and minimizethat would optimize antimicrobial activity and minimize

patient toxicity.patient toxicity.


19/44

1919

Why Apply PK/PDPrinciples?

Improvedrates of cure

Minimizetoxicity

Enhanced rateof bacterial kill

Decreaseemergence of

resistance


20/44

2020

Beta-Lactams


21/44

2121

Beta-LactamsPenicillins Cephalosporins Others

Natural Pen V (oral)

Pen G (IV)

1st-Generation Cephalexin (oral)

Cephazolin (IV)

Monobactam Aztreonam (IV)

Aminopenicillins

Ampicillin (IV)

Amoxycillin (oral)

2nd-Generation

Cefuroxime

(oral & IV)

Carbepenem

Imipenem (IV)

Meropenem (IV) Doripenem (IV)

Beta-lactamase inhibitor

Clavulanic acid

Sulbactam

Tazobactam

3rdGeneration

Ceftriaxone (IV)

Ceftiazidime (IV)

Ceftibuten (oral)

Ertapenem (IV/IM)

Penicillinase-resistant

Cloxacillin (oral/IV)

4th-Generation

Cefepime (IV)

Extended-spectrum

Piperacillin (IV)5th-Generation

Ceftibiprole (IV)

Ceftaroline (IV)


22/44


23/44

2323

Commonly used in:Commonly used in:

CommunityCommunity--acquired pneumoniaacquired pneumonia

HospitalHospital--acquired pneumoniaacquired pneumonia Lower urinaryLower urinary--tract infectionstract infections

Throat/dental infectionsThroat/dental infections

Sinusitis, ear infections,Sinusitis, ear infections, Skin infectionsSkin infections

-lactams


24/44

2424

Ciprofloxacin

Fluoroquinolones


25/44

2525

Fluoroquinolones

Ciprofloxacin Levofloxacin Moxifloxacin

Doses:250-750mg BD (oral)200-400mg BD (IV)

Doses:750mg OM

Dose:400mg om (IV &oral)

Uses:

Gastro-intestinal infections, urinary-tract infections, as partof anti-TB drug regimen, respiratory infections, gonorrhoea,septicemia. Inhalational anthrax, bone/joint infections.


26/44

2626

Fluoroquinolones

LipophilicLipophilic

Distributes well into bones, tissues, CSF, ELFDistributes well into bones, tissues, CSF, ELF

Tissue concentrations sometimes exceed serumTissue concentrations sometimes exceed serum

levelslevels Intracellular actionIntracellular action

Various routes of eliminationVarious routes of elimination

VdVd less affected by patientsless affected by patientsvolume statusvolume status


27/44

2727

Gentamicin

Aminoglycosides


28/44

2828

AminoglycosidesGentamicin Amikacin Netilmycin Tobramycin

Dose:1-2.5mg/kg 8H4-7mg/kg od

Dose:

5-7.5 mg / kg /dose 8H15-20mg/kg od

Dose:1.5- 2mg / kg /dose 12H to 8H4-7mg/kg od

Dose:1-2 drops 4H to 1Hdep. on severity ofinfection.

(avail. as eyedrop)

Notes: No oral aminoglycosides are available because of poor absorption

from gut. See streptomycin under anti-TB class.

Uses: Bone, urinary-tract, respiratory-tract, skin & soft tissues, bloodinfections. It may be used topically as eyedrops or ointments for

superficial skin/eye infections


29/44


30/44

3030

Tetracyclines

Tetracycline Structure


31/44

3131

Tetracyclines

Tetracycline Doxycycline Minocycline

Dose:250-500mg q6H

Dose:100mg BD

Dose:200mg statthen 100mg BD

Uses:

Genital infections (Chlamydia)

Acne

Respiratory infections


32/44


33/44

3333

Macrolides - Structure

Erythromycin Structure

(Prototype)


34/44


35/44

3535

Macrolides

Uses:Uses:

CommunityCommunity--acquired pneumoniaacquired pneumonia

Atypical pneumoniaAtypical pneumonia Dental/throat infectionsDental/throat infections

SinusitisSinusitis

Skin infectionsSkin infections

Some genital infectionsSome genital infections


36/44

3636

Bactericidal VS Bacterostatic

Bactericidal activityBactericidal activity:

99.9% reduction in bacterial inoculum within a 24hperiod of exposure

BacterostaticBacterostatic activityactivity : inhibit growth and reproductionof bacteria by interfering with bacterial protein

production, DNA replication, or other aspects of bacterialcellular metabolism.


37/44

3737

An in-vitro phenomenem

Affected byAffected by MOAMOA

Growth conditionsGrowth conditions

Site of infectionSite of infection

Susceptibility of an organismSusceptibility of an organism


38/44

3838

Minimum InhibitoryConcentration

Lowest antimicrobial concentrationLowest antimicrobial concentrationthat prevents visiblethat prevents visible growtgrowt of anof an

organism after 24 hours of incubationorganism after 24 hours of incubation

at 35 degrees Celsiusat 35 degrees Celsius

Allow for a quantitative determinationAllow for a quantitative determinationofofin vitroin vitroantibacterial activityantibacterial activity


39/44

3939

Limitations of MIC

Do not account for the time course ofDo not account for the time course ofantimicrobial therapyantimicrobial therapy

Rate of bacterial killRate of bacterial kill

Dose kill response relationshipDose kill response relationship


40/44

4040

Intrinsic value of MIC

Site of infectionSite of infection Susceptibility breakpoints for:Susceptibility breakpoints for:

Different organisms (Different organisms (EnterobacteriaceaeEnterobacteriaceae

vsvs nonnon--fermentersfermenters)) Different site of infections (meningitisDifferent site of infections (meningitis vsvs

nonnon--meningitis)meningitis)

Different dosing regimens (1g over 0.5hDifferent dosing regimens (1g over 0.5hevery 8 hoursevery 8 hours vsvs 1g over 3h every 81g over 3h every 8hours)hours)


41/44

4141

Lim et alICAAC 2010


42/44

4242

Imhl et alIJAA 2009


43/44

4343Lim et alClin Therapeutics 2010


44/44

4444

THANK YOU!

pk&pd susceptibility course 2010

Documents