antimicrobial therapy

General concepts of antimicrobial therapy Antibiotics are substances produced by various species of microorganisms (bacteria, fungi, actinomycetes) that suppress the growth of other microorganisms. Common usage often extends the term antibiotics to include synthetic antimicrobial agents (sulfonamides and quinolone). Antibiotics differ in physical, chemical, and pharmacological properties, in antibacterial spectra, and in mechanism of action. Antibiotics act by interfering with life cycle of microorganisms. Antibiotics are classified on the basis of chemical structure and proposed mechanism of action, as follows: 1. Agents that inhibit synthesis of bacterial cell wall. E.g. penicillins and cephalosporins 2. Agents that act directly on the cell membrane of the microorganism. E.g. polymysin and nystatin 3. Agents that inhibit protein synthesis. E.g. chloramphenicol and tetracyclines. 4. Agents that alter protein synthesis. E.g. aminoglycosides. 5. Agents that affect bacterial nucleic acid metabolism. E.g. rifampin. 6. Antimetabolites. E.g. trimethoprim and sulfonamides. 7. Antiviral agents. E.g. acyclovir and zidovudine. Factors that determine the susceptibility and resistance of microorganisms to antimicrobial agents The concentration of antibiotic at the site of infection - Bacteriostatic agent (interfere with growth or replication of microorganism) – if host defence mechanism is intact - Bactericidal (killing bacteria) effect - if host defence mechanism is impaired The achievable concentration for an antibiotic in serum typically guides selection of the breakpoint for designating a microorganism as either susceptible or resistant. The concentration at the site of infection may be considerably lower than achievable serum concentration (vitreous fluid of the eye or cerebrospinal fluid). Bacterial resistance to antimicrobial agents For an antibiotic to be effective, - It must reach its target - It must bind to the target - It must interfere with the function of the target Bacterial resistance or an antimicrobial agent falls into three general categories: The drug does not reach its target The drug is not active The target is altered If a target is inside the cell, drug has to be transported inside the cell. Any factor that shuts down the transport mechanism confers resistance. E.g. respiratory enzymes are responsible for transporting gentamycin inside the cell. Mutation in the enzymes reduces the amount of gentamycin entering the cell, resulting into resistance. Bacterial resistance to  -lactam antibiotics is due to production of -lactamases. Alteration in the target result into reduced binding to drug or substitution of a new target that does not bind that drug for the native target. lactamases of gm –ve bacteria have spread widely to Escherichia coli, Neisseria gonorrhoeae and Haemophilus species. Selection of an Antimicrobial Agent Antibiotics are used in three general ways: Empirical therapy (initial therapy): the antibiotic must cover all of the likely pathogens although the infecting organism has not yet been defined. Combination or broad spectrum agent is applied. Definitive therapy: the pathogen is identified. A narrow spectrum, low toxicity regimen is given to complete the course of treatment. Prophylactic or preventive therapy: initiated as precaution or to prevent possible pathogens invading. Multiple antibiotics therapy: - for empirical therapy of an infection in which the cause is unknown - for treatment of polymicrobial infections - to enhance antimicrobial activity (i.e. synergism) for a specific infection - to prevent emergence of resistance Disadvantages of combination of antimicrobial agents - risk of toxicity from two or more agents - risk of toxicity from the selection of multiple drug resistant microorganisms