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

Log 10 CFU/ml

Ticarcillin

Hours

Ciprofloxacin

Log 10 CFU/thigh

Ceftazidime effect on K. pneumoniae thigh infection in

neutropenic mice

10

100

1000

24hr AUC/MIC

10

100

Peak/MIC

1000

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

10

100

Peak/MIC

1000

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

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

10

24hr AUC/MIC

100

1000

Human Data

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.

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

Cefaclor

0.5-1

Cefprozil

1-2

Cefpodoxime

0.5

0.5

0.5

Cefuroxime