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I.
Pharmacological considerations
A. Why consider pharmacokinetics and pharmacodynamics?
1. Rational basis for antibiotic choice and dosing schedule
2. Relationship between drug, patient, and the antibiotic’s effect
3. Minimizes adverse effects and bacterial resistance
4. Improves likelihood of positive treatment outcome
B. PK and PD definitions
1. Pharmacokinetics (PK)
2. Pharmacodynamics (PD)
C. Pharmacokinetics
1. Absorption- bioavailability
2. Metabolism
a. Individual variability- factors to consider
3. Elimination
a. Individual variability- factors to consider
4. Ocular pharmacokinetics
D. Temporal characteristics of a drug’s effect
1. Pattern of temporal curve
2. Peak effect (cMax)
3. MEC and MIC
a. Minimal inhibitory concentration (MIC)
(1) Definition
(2) Limitations
4. Duration of action
5. Therapeutic window
6. Multiple dosing over time
E.
Relationship between prescribed drug dosage and final drug effect
1. Prescribed dose
2. Factors affecting the dose administered- patient variables
a. Patient compliance
b. Medication administration errors
3. Drug concentration at infection site
4. Intensity of the drug’s effect
5. Variables affecting both drug concentration and effect
a. Physiological and pathological factors
b. Patient’s age
c. Genetic factors
d. Interactions with other drug(s)
e. Development of tolerance
F.
Parameters controlling drug efficacy
1. Definition of efficacy
2. Concentration (cMax/MIC)
3. Time above the MIC (T>MIC)
4. AUC/MIC ratio
5. Post-antibiotic and other persistent effects
G. Limitations of pharmacodynamic application
1. In vitro vs. in vivo conditions
2. Variability among different microorganisms, or different strains of the same organism
3. Variability due to conditions at infection site
4. Variability among different drugs in the same class
5. Lack of consistent methods of analysis of in vitro pharmacodynamic studies
II.
Clinical considerations
A. How antibiotics work
1. Definition of an antibiotic
2. Drug receptors
3. Bacteriostatic and bactericidal definitions
4. Inhibit protein synthesis
a. Reversible (bacteriostatic)- macrolides; tetracyclines
b. Irreversible (bactericidal)- aminoglycosides
5. Inhibit cell wall synthesis (bactericidal)
a. B-lactams (penicillins, cephalosporins, carbapenems, monobactams);
bacitracin; glycopeptides (vancomycin)
6. Inhibit nucleic acid synthesis (bactericidal)
a. Quinolones, rifampin; nitofurantoin, metronidazole
7. Inhibit bacterial metabolism
a. Trimethoprim (bactericidal)
b. Sulfonamides (bacteriostatic)
8. Alter cell membrane permeability (bactericidal)
a. Polypeptides (polymyxin B; colistin)
B. Factors determining microorganism susceptibility or resistance
1. Drug concentration at infection site
2. Patient’s immune system status and defenses
a. Use of bactericidal vs. bacteriostatic antibiotics
3. Local conditions at infection site
4. Bacterial resistance to drug
a. Mechanisms of developing resistance
(1) Multidrug resistance
(2) MRSA and MRSE
5. Cell wall differences between Gram positive and Gram negative bacteria
C. 1st pattern of antimicrobial activity
1. Concentration-dependent killing and prolonged persistent effects
a. AUC/MIC and cMax/MIC parameters correlate with drug efficacy
2. Drugs showing this pattern
a. Quinolones, aminoglycosides
3. Goal of dosing regimen: maximize concentrations
D. 2nd pattern of antimicrobial activity
1. Time-dependent killing and minimal to moderate persistent effects
a. Time above MIC major parameter correlating with drug efficacy
2. Drugs showing this pattern
a. B-lactams, macrolides
3. Goal of dosing regimen: optimize duration of exposure
E.
3rd pattern of antimicrobial activity
1. Time-dependent killing and prolonged persistent effects (duration related to AUC)
a. AUC/MIC major parameter correlating with drug efficacy
2. Drugs showing this pattern
a. Vancomycin (glycopeptides), tetracyclines, azithromycin
3. Goal of dosing regimen: optimize amount of drug
F.
Choosing an antibiotic
1. Therapy goals
2. Empirical therapy considerations
3. When laboratory tests are helpful
a. Gram stain
b. Limitation of drug sensitivity results
4. Prophylactic vs. therapeutic treatment regimens
5. Pharmacokinetic considerations
a. Route of administration
III.
Antibiotics
A.
Aminoglycosides (tobramycin, gentamicin)
1. Antibacterial spectrum
2. Clinical guidelines
B.
Cephalosporins
1. 1st generation (cefazolin, cephalothin, cephalexin)
a. Antibacterial spectrum
b. Clinical guidelines
2. 2nd generation (cefamandole, cefoxitin, cefaclor, cefuroxime)
a. Antibacterial spectrum
b. Clinical guidelines
3. 3rd generation (ceftazidime, ceftriazxone)
a. Antibacterial spectrum
b. Clinical guidelines
4. 4th generation (cefepime)
a. Antibacterial spectrum
b. Clinical guidelines
C.
Macrolides (erythromycin and azithromycin)
1. Antibacterial spectrum
2. Clinical guidelines
D.
Penicillins
1. Antibacterial spectrum
2. Clinical guidelines
E.
Quinolones (ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, gatifloxacin, moxifloxacin)
1. Antibacterial spectrum
2. Clinical guidelines
F.
Tetracyclines
1. Antibacterial spectrum
2. Clinical guidelines
G. Trimethoprim and sulfonamides
1. Antibacterial spectrum
2. Clinical guidelines
H. Vancomycin
1. Antibacterial spectrum
2. Clinical guidelines
IV.
I.
Other antibiotics – polymyxin B and bacitracin
1. Antibacterial spectrum
2. Clinical guidelines
J.
Therapy with combined antibiotics
1. Indications for use
2. Advantages
3. Disadvantages
Summary
V.
References
1. Clinical Ocular Pharmacology by Bartlett, Jaanus and Blaho: Butterworth-Heinemann
Medical; 4th ed. 2001
2. Goodman & Gilman’s The Pharmacological Basis of Therapeutics; ed. Hardman and
Limbird; The McGraw-Hill Companies; 10th ed. 2001