1. Anti-Viral Drugs
1.1. • AMR Conern • Innate and Acquired • 4 criteria have to be fulfilled • AMR Mechanism • Biofilm Formation • Suppersion and alteration of microflora [Microflora - Superinfection] • Prophylactic
1.1.1. • Treatment Failure • Increase mortality • Resistant bacteria may spread in the community and health care institutions . • Development of low-level resistance which compromises therapy and can go undetected. • Threats to go back to the pre-antibiotic era.
1.1.2. Innate: [insensetivity] • Since it occurs in organisms that have never been susceptible to that particular drug. • The properties of the bacterium are responsible for preventing the antibiotic action. • Always chromosomally mediated ----------------------------------------------- Acquired: [Genetic Method] • Bacteria which were previously become resistant after exposure to certain antibiotic. May occur by: Chromosomal method: [Mutation] Extrachromosomal method: [Plasmid]
1.1.2.1. Innate: 1] Obligate anaerobes resistant to all aminoglycosides since they lack the ETS. 2] Many G- including Pseudomonas resistant to macrolides and certain β-lactams. because the drugs are too hydrophobic to diffuse through the porin channels. 3] All G- bacteria are resistant to vancomycin. because of it is too large molecule. 4] The lack of a cell wall in Mycoplasma makes them resistant to β-lactams and target the cell wall.
1.1.2.2. Acquired: • Unlike intrinsic resistance, found only in some strains or subpopulations of each particular bacterial species. ----------------------------------------------- • Chromosomal method [Mutation]: • In genes involved in normal physiological processes and cellular structures Due to changes in the DNA sequence (point or frameshift). • Resistance against methicillin - Quinolones - Rifanpicin ----------------------------------------------- Extrachromosomal Method [Plasmid]: [Horizonal gene transfere] • Foreign resistance genes carried on plasmids or transposons by one of the processes such as [Transformation, Transduction or Conjugation] ----------------------------------------------- • Mutations take place at a regular but low frequency and it is of less clinical importance than the horizontal transfer of genes.
1.1.3. 4 Criteria have to be fulfilled: 1) A sufficient amount diffuse and accumulate in the cytoplasm. 2) Target for the antibacterial drug must exist in the cell. 3) The antibiotic must reach the target in sufficient quantity. 4) The antibiotic must not be inactivated or modified.
1.1.4. AMR mechanism of action: 1) Decreasing membrane permeability to the antibiotic. Due to alteration of membrane structure. 2) Prevention of drug accumulation in the bacterium. Due to presence of proteins functioning as Efflux pumps. 3) Production of enzymes that destroy or inactivate the antibiotic. 4) Alteration of target site which reduce the binding of antibiotics. 5) Using alternative pathways for metabolic requirements. N.B. More than one mechanism may be present in a resistant microorganism.
1.1.4.1. Preventing drug accumulation --------------------------------- • The receptor that transports the drug is altered so that the drug can't enter the cell. • Specialized membrane protiens are activated and pumb the drug out of the cell [Efflux]. --------------------------------------------------------- Tetracycline Resistance 3 mechanisms: 1] Efflux of the antibiotics. 2] Ribosome protection (target site alteration) 3] Modification of the antibiotic. --------------------------------------------------------- A new active form of tetracycline is 9 glycinyltetracyclines [Tigicycline] responsible for resistance by efflux and ribosomal protection.
1.1.4.2. Drug inactivation or modification ------------------------------------- Bacteria produce enzymes that either destroy the antimicrobial agent before it reaches its target or modify the drug so that it is no longer recognized by the target. ----------------------------------------------------------------- Examples: 1] [Staphylococi to pencillin]: Hydrolytic deactivation of the β-lactam ring in penicillins and cephalosporins by β-lactamase. Beta-lactam Resistance 3 mechanisms: 1] Inactivation of the antibiotic (β-Lactamases). 2] Target site alteration (MRSA). 3] Reduced permeability. N.B. β-Lactamases in G+ are produced extracellularly WHILE in G- in the periplasmic space so they have slower but stronger action on beta-lactams. 2] Acetylation of chloramphenicol (by chloramphenicol acetyl transferase). G- Enterobacteriaceae may produce an acetyl transferase that modifies chloramphenicol so that it is no longer active. 3] G- and G+ bacteria against aminoglycosides [They produce adenylating, phosphorylating or acetylating] that modify aminoglycosides to be inactive).
1.1.4.3. Alteration of target site Bacterial cells altered the target of the antimicrobial agent (which is typically a critical enzyme or ribosomal site)in a way that decreases its affinity for the antimicrobial agent. change in the structure of the target without affecting the normal function. ----------------------------------------------- Examples: 1] Alteration in penicillin-binding protein (PBPs) leading to reduced affinity of β-lactam antibiotics. e.g. MRSA 2] Alteration in vancomycin precursors reducing activity of vancomycin. e.g. VRSA and VRE 3] Alterations in subunits of DNA gyrase (Topoisomerase II) reducing activity of fluoroquinolones. e.g. many G- 4] Changes in RNA polymerase leading to reduced activity of rifampicin e.g. Mycobacterium tuberculosis.
1.1.4.4. Alteration of metabollic pathway Example: Many bacteria develop resistance against sulfonamide and trimethoprime through deviation from the usual pattern of folic acid synthesis . Sulphonamide resistance can be developed by overproduction of PABA
1.1.5. Prophylactic: 1] Pre treatment may prevent streptococcal infections in patients with a history of rheumatic heart disease. Patients may require years of treatment. 2] Pre treatment may prevent tuberculosis or meningitis among individuals who are in close contact with infected patients. 3] Pre treating of patients undergoing dental extractions or those having implanted prosthetic devices, such as artificial heart valves, to prevent contaminationof the prosthetic devices. 4] Treatment prior to most surgical procedures can decrease the incidence of infection afterwards.