Principles of Antibiotic Use (Walworth) - 4/25/16 Flashcards
Define selective toxicity.
Unique targets:
- Bacterial cell wall
- Biosynthetic pathways unique to microorganisms (i.e. bacteria make their own folate… don’t need it from diet like us)
- Unique fungal plasma membrane components (i.e. cell wall)
Preferential targets:
- Bacterial ribosome
- Dihydrofolate reductase (common to both bacterial and human cells)
Distinguish: prophylactic therapy, empiric (experimental) therapy, and definitive therapy.
Prophylatic therapy: patient does not have infection…
- Example: immunosuppressed patients - targeted therapy
- Example: rifampin to prevent meningococcal meningitis in people in close contact to a case
- Example; Prevent wound infections after surgical procedures (most extensive and best-studied use)
Empiric therapy: after on-set of symptoms
- Simple, rapid lab techniques used (strep test, Gram’s stain)
- Cultures of site of infection and blood should be taken BEFORE institution of therapy
Definitive: knowing exactly what the pathogen is and what agent you want to use to target that pathogen
- Specific and narrow-spectrum agent
Describe why susceptibility testing is important and the concepts of bacteriostatic vs bactericidal.
Success depends on achieving concentration AT THE SITE OF INFECTION that is sufficient to inhibit growth.
Host defenses may influence whether an agent is BACTERIOSTATIC or BACTERICIDAL.
Bacteriostatic:
- Agent does not kill bacteria but inhibits their growth (i.e. protein synthesis inhibitors)
- If MIC (minimal inhibitory concentration) is within therapeutic range of drug, but MBC (minimal bactericidal concentration) is not
Bactericidal:
- Cell wall-active agents that reduce number of cells in population –> kills (i.e. rifampin and quinolones)
- If MBC is within therapeutic range of drug
- NOTE: Limitations
- Drug may be ‘static in one growth medium but ‘cidal in another
- Drug may be ‘static against one organism and ‘cidal against another
Resistance occurs when concentration of drug required to kill or inhibit microbe is greater than concentration that can be safely achieved.
What factors influence susceptibility?
- Site of infection
- Achievable serum concentration vs concentration at infection site (i.e., if patient has meningitis, the concentration that can be achieved in plasma is one thing but how much of the drug can get across blood brain barrier to site of infection and limit growth of bacteria in that setting is what’s important)
- Serum concentration relative to concentration in urine (may be higher in urine, so “resistant” organism at plasma concentration may be susceptible at urine concentration) - Local factors (low pH, high protein concentration, anaerobic conditions)
List reasons for drug combinations.
- An exception, not a rule
- Empirical therapy of severe infection when causative organism unknown
- Treatment of polymicrobial infections
- Enhance antimicrobial activity for specific infection
- Prevent emergence of resistance
- Reduce toxicity to host
Example:
Frequency of resistance to any one drug: 1 in 10^6 cells
Frequency of resistance to two drugs: 1 in 10^12 cells
Of particular importance in TB therapy, especially multi-drug resistant TB (generally use agents that differ in their mechanism of action)
Combination Therapy terms:
- Synergistic
- Additive
- Indifferent
- Antagonistics
Synergistic: one drug affects bug such that it is more sensitive to inhibitory action of another drug
Additive: drugs work independently of one another
*Bactericidal drugs in combination tend to be additive or synergistic - cell wall synthesis inhibitor + aminoglycoside
Indifferent: combination no different than individuals
Antagonistic: combination less effective than individuals
*Bacteriostatic antibiotics frequently antagonize action of bactericidal ones (i.e. tetracyclines antagnoze beta-lactams)
What are antibiotics?
Natural products produced by various species of microorganisms that suppress the growth of other microorganisms and eventually may destroy them
