Pharmacodynamics of AntibioticsHail M. Al-Abdely, MD

ConceptsPharmacokineticsdescribe how drugs behave in the human host

Pharmacodynamicsthe relationship between drug concentration and antimicrobial effect. Time course of antimicrobial activity

ConceptsMinimum Inhibitory Concentration (MIC)The lowest concentration of an antibiotic that inhibits bacterial growth after 16-20 hrs incubation.Minimum Bacteriocidal Concentrations.The lowest concentration of an antibiotic required to kill 99.9% bacterial growth after 16-20 hrs exposure.C-pPeak antibiotic concentrationArea under the curve (AUC)Amount of antibiotic delivered over a specific time.

Antimicrobial-micro-organism interactionAntibiotic must reach the binding site of the microbe to interfere with the life cycle.Antibiotic must occupy sufficient number of active sites.Antibiotic must reside on the active site for sufficient time. Antibiotics are not contact poisons.

Static versus Cidal

QuestionsCan this antibiotic inhibit/kill these bacteria?Can this antibiotic reach the site of bacterial replication?What concentration of this antibiotic is needed to inhibit/kill bacteria?Will the antibiotic kill better or faster if we increase its concentration?Do we need to keep the antibiotic concentration always high throughout the day?

Can this antibiotic inhibit/kill these bacteria?In vitro susceptibility testing

Mixing bacteria with antibiotic at different concentrations and observing for bacterial growth.

What concentration of this antibiotic is needed to inhibit/kill bacteria?In vitro offers some helpConcentrations have to be above the MIC.How much above the MIC?How long above the MIC?

Patterns of Microbial KillingConcentration dependentHigher concentration greater killing Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B.Time-dependent killingMinimal concentration-dependent killing (4x MIC)More exposure more killingBeta lactams, glycopeptides, clindamycin, macrolides, tetracyclines, bactrim

Persistent EffectsPersistent suppression of bacterial growth following antimicrobial exposure.Moderate to prolonged against all GM positives (In vitro)Moderate to prolonged against GM negatives for protein and nucleic acid synthesis inhibitors.Minimal or non against GM negatives for beta lactams (except carabapenems against P. aeruginosa)

Persistent EffectsPost-antibiotic sub-MIC effect.Prolonged drug level at sub-MIC augment the post-antibiotic effect.Post-antibiotic leukocyte killing enhancement.Augmentation of intracellular killing by leukocytes.The longest PAE with antibiotics exhibiting this characteristic.

Patterns of Antimicrobial ActivityConcentration dependent with moderate to prolonged persistent effectsGoal of dosingMaximize concentrationsPK parameter determining efficacyPeak level and AUCExamplesAminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B.

Patterns of Antimicrobial ActivityTime-dependent killing and minimal to moderate persistent effectsGoal of dosingMaximize duration of exposurePK parameter determining efficacyTime above the MICExamplesBeta lactam, macrolides, clindamycin, flucytosine, linezolid.

Patterns of Antimicrobial ActivityTime-dependent killing and prolonged persistent effectsGoal of dosingOptimize amount of drugPK parameter determining efficacyAUCExamplesAzithromycin, vancomycin, tetracyclines, fluconazole.

PK/PD patterns

Ceftazidime effect on K. pneumoniae thigh infection in neutropenic mice

Temafloxacin effect on S. pneumoniae thigh infection in neutropenic mice

CeftazidimeTemafloxacin

Survival of Animals infected with S. pneumoniae treated with cephalosporin and penicillin

Survival of Animals infected with GN bacilli treated with Fluoroquinolones

Percentage bacteriologic cure for -lactam agents against Streptococcus pneumoniae (black circle) and Haemophilus influenzae (white circle) in children with acute otitis media Craig WA, Andes W.. Pediatr Infect Dis J 1996;15:255-9. Human Data

Beta lactams

Aminoglycosides

FluoroquinolonesAUC

AUCGlycopeptides

Effects of PD on breakpoints Recommended for many antibiotics for S. pneumoniae