Antibacterial Concepts

Core Concepts:

1. Useful antibiotics should inhibit bacterial growth without causing harm to the human host.

• Examples: Neomycin is reserved for bladder irrigation & topical application due to its significant toxicity if absorbed systemically. Bacitracin, a topical antibiotic can cause renal failure if given i.m.
• Actinomycin D (Dactinomycin) is effective against gram-positive and gram-negative bacteria and some fungi, but its systemic (human) toxicity is so high that it is not used for this indication. It is used as an antineoplastic (e.g. for treatment of Wilms' tumor).

2. The drug needs to reach its site of action to be therapeutically effective.

• Examples: ciprofloxacin is a fluroquinolone useful in treating UTIs, because it is both effective against the common organisms causing UTIs, and undergoes renal clearance. However, gemifloxacin and moxifloxacin are fluoroquinolones that are not cleared by the kidney, and are therefore not approved for the treatment of UTIs. Aminoglycosides have poor penetration into the CNS.

3. Drugs that inhibit cell wall synthesis & DNA replication are bactericidal.
4. Most antimicrobial drugs that inhibit protein synthesis are bacteriostatic (exception: aminoglycosides).
5. Resistance of bacteria to antibiotics can result from mutation, gene transfer or adaptation.
6. Overuse of antibiotics promotes the development of resistant bacterial strains.
7. Combining an inhibitor of cell wall synthesis with a 2nd drug that acts intracellularly can produce a synergistic effect.
8. Combining two drugs that inhibit production of a key metabolic product can be synergistic.
9. Some antibiotics require the presence of oxygen to be effective and are therefore ineffective against anerobes.

• Examples: aminoglycosides are capable of inhibiting the ribosomes of anaerobic bacteria, but are cannot be taken up into anaerobic bacteria because their transport across bacterial cell membranes requires oxygen (Bryan et al, 1979).

10. Some antibiotics produce effects that are harmful in pregnancy & in pediatric patients.

• Examples: Tetracyclines (retardation of bone growth & tooth development); Fluoroquinolones (cartilage toxicity), Thalidomide (severe birth defects), chloramphenicol (gray baby syndrome), metronidazole (mutagenic).

11. Antibiotics with similar structure (penicillins & cephalosporins) can exhibit cross-hypersensitivity (incidence <3%).

Concept Maps:

Antibiotic Mechanisms

References:

1. Bryan LE, Kowand SK, VanDenElzen HM: Mechanism of Aminoglycoside Antibiotic Resistance in Anaerobic Bacteria: Clostridium perfringens and Bacteroides fragilis. Antimicrobial Agents & Chemotherapy. 15(1): 7-13, 1979.

Sample Case-based Questions:
Examples to come....