Transcript Pharmacodynamics of Antibiotics

Pharmacodynamics of
Antibiotics
Hail M. Al-Abdely, MD
Concepts
Pharmacokinetics
– describe how drugs behave in the human host
Pharmacodynamics
– the relationship between drug concentration
and antimicrobial effect. “Time course of
antimicrobial activity”
Concepts
Minimum 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-p
– Peak antibiotic concentration
Area under the curve (AUC)
– Amount of antibiotic delivered over a specific time.
Antimicrobial-micro-organism
interaction
Antibiotic 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
Control
CFU
Static
Cidal
Time
Questions
Can 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 help
– Concentrations have to be above the MIC.
How much above the MIC?
How long above the MIC?
Conc
MIC
Time
Patterns of Microbial Killing
Concentration dependent
– Higher concentration
greater killing
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.
Time-dependent killing
– Minimal concentration-dependent killing (4x
MIC)
– More exposure
more killing
Beta lactams, glycopeptides, clindamycin,
macrolides, tetracyclines, bactrim
Persistent Effects
Persistent 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 Effects
Post-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 Activity
Concentration dependent with moderate to
prolonged persistent effects
– Goal of dosing
Maximize concentrations
– PK parameter determining efficacy
Peak level and AUC
– Examples
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.
Patterns of Antimicrobial Activity
Time-dependent killing and minimal to
moderate persistent effects
– Goal of dosing
Maximize duration of exposure
– PK parameter determining efficacy
Time above the MIC
– Examples
Beta lactam, macrolides, clindamycin, flucytosine,
linezolid.
Patterns of Antimicrobial Activity
Time-dependent killing and prolonged
persistent effects
– Goal of dosing
Optimize amount of drug
– PK parameter determining efficacy
AUC
– Examples
Azithromycin, vancomycin, tetracyclines,
fluconazole.
PK/PD patterns
C-p
C-p
Concentration
MIC
AUC
AUC
Time
Tobramycin
9
8
Ticarcillin
7
6
9
5
8
4
Control
.25 MIC
1 MIC
4 MIC
16 MIC
64
Log 10 CFU/ml
7
3
2
0
2
4
6
9
6
5
4
3
8
2
7
0
2
4
Hours
6
5
Ciprofloxacin
4
3
2
0
2
4
6
6
Log 10 CFU/thigh
Ceftazidime effect on K. pneumoniae thigh infection in
neutropenic mice
10
100
1000
24hr AUC/MIC
1
10
100
Peak/MIC
1000
0
25
50
75
100
Time above MIC
Log 10 CFU/thigh
Temafloxacin effect on S. pneumoniae thigh infection in
neutropenic mice
10
100
1000
24hr AUC/MIC
1
10
100
Peak/MIC
1000
0
25
50
75
100
Time above MIC
Log 10 CFU/thigh
Ceftazidime
10
100
10001
100
Peak/MIC
10000
25
50
75
100
Time above MIC
Log 10 CFU/thigh
24hr AUC/MIC
10
Temafloxacin
10
100
10001
24hr AUC/MIC
10
100
Peak/MIC
10000
25
50
75
Time above MIC
100
Survival of Animals infected with S. pneumoniae
treated with cephalosporin and penicillin
100
Penicillin
Cephalosporins
80
Mortality%
60
40
20
0
0
20
40
60
Time above MIC%
80
100
Survival of Animals infected with GN bacilli treated
with Fluoroquinolones
100
80
Mortality%
60
40
20
0
1
10
24hr AUC/MIC
100
1000
Human Data
Percentage bacteriologic cure for ß-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.
Beta lactams
MIC
Time
Aminoglycosides
C-p
MIC
Time
Fluoroquinolones
C-p
AUC
MIC
Time
Glycopeptides
C-p
AUC
MIC
Time
Effects of PD on breakpoints Recommended for
many antibiotics for S. pneumoniae
Drug
Amoxicillin
Old NCCLS
Breakpoint
PD
(T>MIC>40%)
New NCCLS
Breakpoints
0.5
2
2
Cefaclor
-
0.5-1
1
Cefprozil
-
1-2
2
Cefpodoxime
-
0.5
0.5
0.5
1
1
Cefuroxime