T2i: Steps to eradicate bacteria

a. Penetrate the organism

b. Avoid being pumped back out

c. Remain intact (avoid b-lactam hydrolysis)

2. Occupy an adequate number of binging sites (concentration dependant)

3. Remain at the binding site for long enough

2 major determinants of bacterial killing → TIME it remains at binding site

CONCENRTRATION

Time Dependant

All these a/b spend an extensive amount of time bound to the microorganism

Concentration Dependant

High concentrations at binding site eradicates organism

There are 3 major patterns of antimicrobial kill characteristics

Cmax = maximal or peak concentration
“concentration-dependent killing”
some antimicrobials depend on Cmax/MIC ratio as an important predictor of antimicrobial efficacy
higher the concentration, greater the rate and extent of microbial killing
aminoglycosides should ideally have Cmax/MIC ratio of at least 8-10 to prevent resistance

Time above MIC is duration that the antibiotic levels are above the MIC
“time dependent killing”
The ideal dosing regimen for certain antimicrobials is to maximise the duration pathogens are exposed to them
g. beta-lactams, clindamycin, erythromycin, linezolid
for beta-lactams and erythromycin, maximum killing is seen when the time above MIC is 70% of dosing interval

AUC above MIC is the area under the concentration-time curve that is above the MIC
some antimicrobials are dependent on this for maximal killing effect
24h AUC/MIC is a predictor of efficacy
eg. fluoroquinolones
— for gram negative bacteria, optimal 24h AUC/MIC ~ 125
— for gram positives bacteria, optimal 24h AUC/MIC ~ 40