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Lim Tze PengSenior Pharmacist
Singapore General Hospital
PHARMACOKINETIC &PHARMACODYNAMICPRINCIPLES OF ANTIMICROBIAL USE
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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.
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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.
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Pharmacokinetics Parameters
Absorption (F)Absorption (F)
DistributionDistribution
MetabolismMetabolism
EliminationElimination
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Dose of drugadministered
Dose of drugAdministered
Drug concentrationIn systemic circulation
BIOAVALABILITY
Absorption
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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
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Distribution
Drug concentrationIn systemic circulation
Drug in tissue
Of distribution
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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
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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
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Drug concentrationIn systemic circulation
Drug metabolized or excreted
Elimination
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Dosage Consideration
Patient FactorPatient Factor
AgeAge
WeightWeight
Organ FailureOrgan Failure
Disease statesDisease states Routes ofRoutes of
administrationadministration
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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
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IVInjection
AdvantagesAdvantages Complete bioavailability ~ 100%Complete bioavailability ~ 100%
Fast onset of actionFast onset of action
Predictable blood concentrationPredictable blood concentration
DisadvantagesDisadvantages
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Concentration-time curve
Time
Concentration
Oral
IV
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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
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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
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Right drug+
Right dose
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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.
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Why Apply PK/PDPrinciples?
Improvedrates of cure
Minimizetoxicity
Enhanced rateof bacterial kill
Decreaseemergence of
resistance
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Beta-Lactams
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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)
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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
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Ciprofloxacin
Fluoroquinolones
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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.
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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
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Gentamicin
Aminoglycosides
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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
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Tetracyclines
Tetracycline Structure
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Tetracyclines
Tetracycline Doxycycline Minocycline
Dose:250-500mg q6H
Dose:100mg BD
Dose:200mg statthen 100mg BD
Uses:
Genital infections (Chlamydia)
Acne
Respiratory infections
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Macrolides - Structure
Erythromycin Structure
(Prototype)
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Macrolides
Uses:Uses:
CommunityCommunity--acquired pneumoniaacquired pneumonia
Atypical pneumoniaAtypical pneumonia Dental/throat infectionsDental/throat infections
SinusitisSinusitis
Skin infectionsSkin infections
Some genital infectionsSome genital infections
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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.
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An in-vitro phenomenem
Affected byAffected by MOAMOA
Growth conditionsGrowth conditions
Site of infectionSite of infection
Susceptibility of an organismSusceptibility of an organism
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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
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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
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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)
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Lim et alICAAC 2010
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Imhl et alIJAA 2009
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THANK YOU!