micro lecture 18

Question 1

what are the main things to consider in antimicrobial pharmacokinetics?

Answer 1

dosage and elimination

serum concentration varying over time: concentration in non-target tissues (toxic) and concentration in the site of infection (therapeutic)

Question 2

explain how pharmacokinetics is used to Evaluate antibiotic efficacy

Answer 2

Pharmacokinetics (PK):
Absorption, Distribution Metabolism, Elimination
these, along with the dosing regimen, determine
the time course of drug concentration in the
serum, various other tissues and body fluids

i.e. potency

Question 3

explain how Pharmacodynamics is used to Evaluate antibiotic efficacy

Answer 3

 Relationship between a drug’s concentrations
and its pharmacological and adverse effects

i.e. how it works best

Question 4

what are things to consider in pharmacokinetics with regards to absorption

Answer 4

How fast, how much, how dependable ?

 Can the infection affect this?
(vomiting, diarrhoea, shock, fluid shifting)

 Can we deliver direct to site ?
(bone, lung, skin, eye, brain, … )
we might be able to use drugs that normally
can’t reach

Question 5

what are things to consider in pharmacokinetics with regards to Distribution

Answer 5

Pharmacokinetics – Distribution
(NB measured levels are “always” from plasma)

 Access to difficult sites
(BBB, abscesses, “surfaces”)

 Tissue, intracellular concentrations

 Protein binding (mostly albumin)
~concentrations of free drug predict clinical
efficacy

Question 6

what are things to consider in pharmacokinetics with regards to Metabolism

Answer 6

Many antimicrobials are modified in
the body to form metabolites

 Activation of prodrug

 Less active metabolite

 Different toxicity patterns

Question 7

how are antimicrobials eliminated in the body (pharmacokinetics)

Answer 7

The kidneys via urine by glomerular filtration or
tubular secretion or both.
(many achieve high urinary levels)
 Tubular secretion important for beta-lactams
allowing rapid removal (see probenecid effect)
 Dose alterations when function is poor

The liver via bile and hence into the small intestine
(where they may sometimes be reabsorbed)
 Should be avoided or used cautiously in
patients with poor hepatic function

Question 8

why should elimination of antimicrobials through the liver be avoided or used cautiously in patients with liver problems?

Answer 8

they may be reabsorbed in the liver during elimination

Question 9

what are the different patterns of killing bacteria?

pharmacodynamics

Answer 9

Time-dependent killing with minimal
post-antibiotic effects

 Time-dependent killing with moderate-to-prolonged post-antibiotic effects

 Concentration-dependent killing with
prolonged post-antibiotic effects

Question 10

state facts about the Post-antibiotic effect (PAE)

Answer 10

 The persistent suppression of bacterial growth after
exposure to an antibacterial agent

 Observed for all antibacterials against Gram-positive
cocci, such as staphylococci. However, minimal in
vivo PAEs for β-lactams with streptococci

 Moderate to prolonged in vivo PAEs for inhibitors of
protein and nucleic acid synthesis
(aminoglycosides, quinolones, rifampin, macrolides
and tetracyclines) with Gram-negative bacilli

 Short or no in vivo PAEs for β-lactams with Gramnegative bacilli (only exception: carbapenems with
some strains of Pseudomonas aeruginosa)

Question 11

explain (the aim, the major parameter with efficacy, where is is seen and the time above MIC) of Time-dependent killing with minimal post-antibiotic effects as a pattern of bacteria killing

Answer 11

Goal of dosing regimen: to optimize duration of
antibacterial exposure at the site of infection

 Major parameter correlating with efficacy is the
percentage of the dosing interval for which the serum
concentration exceeds the MIC of the drug against the
pathogen, or ‘Time above MIC’

 Seen with all β-lactams, inc penicillins, cephalosporins

 For lactams, ‘Time above MIC’ target for efficacy is
> 40–70% of dosing interval (depending on bug and drug)

Question 12

explain (the aim, the major parameter with efficacy, where is is seen and the time above MIC) of Time-dependent killing with moderate-to-prolonged post-antibiotic effects as a pattern of bacteria killing

Answer 12

Goal of dosing regimen: to maximize drug
exposure (not concentration) at the site of infection

 Major parameter correlating with efficacy is
AUC/MIC

 Seen with:
macrolides
clindamycin
azalides
tetracyclines
oxazolidinones

Question 13

explain (the aim, the major parameter with efficacy, where is is seen and the time above MIC) of Concentration-dependent killing with
prolonged post-antibiotic effects as a pattern of bacteria killing

Answer 13

Goal of dosing regimen: to maximize either peak
concentration or exposure at the site of infection

Major parameters correlating with efficacy:
 AUC/MIC – the ratio of the 24-hour ‘area under the
curve’ (free serum drug concentration–time curve;
AUC) to the MIC
and/or
 Cmax/MIC – the ratio of the peak free serum drug
concentration (Cmax) to the MIC

 Seen with:
– aminoglycosides 
– daptomycin
– fluoroquinolones
 – amphotericin B
– ketolides
Concentration-dependent killing with
prolonged post-antibiotic effects
Andes et al. Cl

Question 14

you have to watch the lecture to understand the curves

Answer 14

you have to watch the lecture to understand the curves