Antibiotics, Pharmacology

1. Pharmacodynamics
of antibiotics
Capt. Htet Wai Moe
Resident Pharmacology

2. • The time course of drug concentration is
closely related to the antibiotic effect at the
site of infection and to any toxic effects
• Pharmacodynamic factors include pathogen
susceptibility testing, drug bactericidal versus
bacteriostatic activity, drug synergism,
antagonism and post-antibiotic effects
• Pharmacodynamic information is important
for selection of optimal antibiotic dosage
regimens

3. Pharmacodynamics
• “What the drug does to the body”
• Includes physiological and biochemical effects
of the drug & MOA
• Integrates : organism susceptibility + patient
pharmacokinetics

4. Antibiotic activity
• Bactericidal
– Kills the organism
– Examples : B lactams , Vancomycin,
Fluroquinolones, Aminoglycosides, Daptomycin,
metronidazole
• Bacteriostatic
– Inhibits the growth
– Requires aid of host defenses
– Relapses can occur after discontinuation of drug
– Examples: Macrolides, Clindamycin,
Sulfonamides, Linezolid, chloramphenicol

5. Bacteriostatic vs Bactericidal activity
• Bacteriostatic and bactericidal agents are
equivalent for treatment of most infectious
disease in immunocompetent hosts
• Bactericidal agents should be selected over
bacteriostatic ones in circumstances of
impaired local or systemic host defenses

6. Bactericidal agents
Concentration-dependent killing
• Killing action is concentration-dependent
• Rate and extent of killing increase with
increasing drug concentration
• E.g. Aminoglycosides, Fluroquinolones

7. Bactericidal agents
Time-dependent killing
• Bactericidal activity continues as long as serum
concentrations are greater than the MBC
• Minimal serum conc of free drug present for
40 - 50 % of dosing interval is called
pharmacodynamic breakpoint
• If MIC is below this breakpoint, then the drug is
clinically effective (sensitive)
• If MIC is above this breakpoint, the organism is
resistant
• E.g. β lactams, Vancomycin

8. Site and Mechanism of Action of
Antibiotics
1. Inhibition of cell wall synthesis
2. Alteration of cell membrane integrity
3. Inhibition of ribosomal protein synthesis
4. Suppression of DNA synthesis

10. Post-antibiotic effect
1. Bactericidal drugs
• Bacterial count reduces till conc above MBC
• When concentration falls below MBC, but
remains above MIC – bacterial count remains
stable or continues to decline
2. Bacteriostatic drugs
• Levels above MIC – bacterial counts decline
due to host factors ( immunity )
• Below MIC – persistent antibacterial effects
act

11. Post-antibiotic effect (PAE)
• A persistent antibacterial effect after a brief
antibiotic exposure that occurs even in the
absence of host defenses is termed PAE
• The organism may become more susceptible
to phagocytes – post antibiotic leucocyte
enhancement
• Concentration below MIC can alter bacterial
morphology, slows bacterial growth rate and
prolongs PAE

12. Mechanism of PAE
• Slow recovery after reversible nonlethal
damage to cell structures
• Persistence of the drug at a binding site or
within the periplasmic space
• The need to synthesize new enzymes before
growth can resume

13. PAE (cont.)
• Most antibiotic possess significant in vitro PAE
against susceptible gram-positive cocci
• Antibiotics with significant PAEs against
susceptible gram-negative bacilli are limited to
carbapenems and the agents that inhibit
protein or DNA synthesis

14. PAE (cont.)
• In vivo PAEs usually much longer than in vitro
PAEs
• Due to post-antibiotic leukocyte enhancement
(PALE) and exposure of bacteria to
subinhibitory antibiotic concentrations
• Efficacy of once-daily dosing regimens is in-
part due to PAE

15. Concepts of MIC & MBC
MIC (minimum inhibitory concentration)
• Defined as the minimal concentration of
antibiotic that prevents the clear suspension of
105 CFU/ ml from becoming turbid after
overnight incubation
• Turbidity signifies at least 10 times increase in
bacterial density
MBC (minimal bactericidal concentration)
• For Bactericidal drugs : same as MIC or upto 4
times MIC
• For Bacteriostatic drugs : many fold higher than
MIC

16. Pharmacokinetic principles
• The PK parameters define only the serum level
time course of an antibiotic
• They do not quantify the killing effect
• PK parameters :
– Cmax – the peak antibiotic concentration
– Cmin – the trough
– AUC – the area under serum concentration time
curve

17. • The PD parameters integrate organism
susceptibility (MIC) and PK parameters
• Define the killing effect
• PD parameters
– Cmax / MIC ratio
– T > MIC
– AUC 24 / MIC
– Post antibiotic effect
Pharmacodynamic principles

18. AUC
• The area under concentration – time curve at
a steady state over 24 hr period
• It is used as a reference value, if not stated,
assumed to be of 24 hours
T > MIC
• The cumulative percentage of a 24 hr. period
that the drug concentration exceeds the MIC
at a steady state

19. Patterns of antibiotic action
Pattern of
activity
PK/PD
parameter
Goal of therapy Examples
Type I Concentration
dependent
prolonged PAE
AUC/MIC
Cmax/MIC
Maximize
concentration
Aminoglycoside
Fluroquinolones
Daptomycin
Ketolides
Type II Time dependent
minimal PAE
T>MIC Maximize duration
of exposure
Penicillins
Carbapenems
Cephalosporins
Linezolids
E.mycin
Type III Time dependent
prolonged PAE
AUC/MIC Maximize amount
of drug
Azithromycin
Clindamycin
Tetracycline
Vancomycin

20. Antimicrobial drug combinations
Rationale for combination antibiotic therapy
• To provide broad-spectrum empiric therapy in
seriously ill patients
• To treat polymicrobial infections
• To decrease the emergence of resistant strains
• To decrease dose-related toxicity
• To obtain enhanced inhibition or killing

21. Synergism and Antagonism
Synergism
• > A + B
• Greater bactericidal activity with the
combination than activity of either agents
alone

22. Mechanism of Synergistic Action
• Blockade of sequential steps in a metabolic
sequences
– E.g. Trimethoprim-sulfamethoxazole
• Inhibition of enzymatic inactivation
– E.g. β lactamase inhibitor drugs (Sulbactam)
• Enhancement of antimicrobial agent uptake
– E.g. Penicillin can increase the uptake of
aminoglycosides by a number of bacteria

23. Mechanism of Antagonistic Action
• Inhibition of cidal activity by static agents
• Bacteriostatic agents can antagonize the action of
bactericidal cell wall-active agents as cell wall-active
agents require that the bacteria be actively growing
and dividing
• Induction of enzymatic inactivation
– Some gram-negative bacilli possess inducible β
lactamase
– β lactam antibiotics are potent inducers of β
lactamase production
– If an inducing agent is combined with an intrinsically
active but hydrolysable β lactam such as piperacillin,
antagonism may result

24. Inoculum effect
• Significant increase in the MIC of an antibiotic
when the number of organisms inoculated is
increased
• Occurs with beta-lactam antibiotics in relation
to beta-lactamase-producing bacteria
• Although certain antibiotics exhibit an IE, they
are still capable of eradicating infections when
administered appropriately
• Thus, the clinical significance of this laboratory
phenomenon has yet to be elucidated

25. Pharmacodynamic differences in
Antibiotic classes
Penicillin & Beta lactams
• Primarily time dependent killing
• T > MIC is the most important determinant for
beta lactam killing effect
• Longer exposure resulted in better killing
effect as seen in E. coli

26. Aminoglycosides
• Concentration dependent killing effect
• Peak/MIC of > 8:1 is associated with treatment
success
• They demonstrate 2-10 hr, cocentration
dependent PAE for many GN organisms
Pharmacodynamics differences in
Antibiotic classes

27. Fluroquinolones
• Concentration dependent killing
• Both peak/MIC & AUC/MIC : linked to efficacy
• Estimated AUC/MIC of 350-450 – linked with
maximal killing for ciprofloxacin
• AUC/MIC of 125 -250 demonstrated optimal
killing
• levofloxacin in UTI, demonstrated optimal
efficacy with peak/MIC of 12.2
Pharmacodynamics differences in
Antibiotic classes

28. Miscellaneous nomenclature
Pharmacodynamic indices and related
AUBC
• Area under bactericidal curve
• Calculated over 24 hrs at steady state
AUIC
• Area under inhibitory curve
• Reserved for those cases where actual
inhibitory titers have been measured

29. Post Exposure Effects
In vitro PAE
• Period of suppression of bacterial growth after short
exposure of organisms to antibiotic
Sub MIC effect
• Any effect of antibiotic with concentration below MIC
Post antibiotic sub-MIC effect
• Effect of sub MIC drug concentration on bacterial
growth following serial exposure to drug concentration
exceeding MIC
Post MIC effect
• The difference in time for number of antibiotic exposed
bacteria vs controls to increase 1 log values after drug
concentration falls below the MIC

30. Terms under consideration
Mutation prevention concentration
• Concentration preventing growth at a high
inoculum (>109) using agar dilution technology
• Due to higher inoculum, higher chances of
selecting mutants
Mutant selection window
• Difference between MIC and MPC for a given
organism
Mutant prevention index
• Ration between MPC and MIC

31. THANK YOU!