Anti-Microbials Module

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Antimicrobials
Anti-bacterials

* Need a drug selectively toxic to bacterial cells but won’t harm human cells * Many drugs that achieve this still have side effects as every drug is a poison

Bacterial Infections
* Immunocompromised especially vulnerable
* Opportunistic infection – Infection caused by pathogens that usually do not cause disease in a healthy immune system. A compromised immune system however presents ‘opportunity’ for pathogen to infect * Prophylaxis (procedure used to prevent disease) especially important here * Breakdown of barriers allows for disease transmission

1. International travel and immigration
2. Overpopulation leading to crowding
3. Nosocomial (hospital acquired) infections
* Hospitals known to have most resilient strains of microbes

Chemotherapy
* Use of drugs, selectively toxic to pathogenic organism (or cancer) but harmless or minimal effects on host * Infections organisms:
* Prokaryotes – cells without nuclei – bacteria
* Viruses – which utilise biochemical machinery of host * Cancer cells – eukaryotic cells similar to host cells

Bacteriostatic vs. Bacteriocidal
* Bacteriostatic – antibiotics that inhibit growth and reproduction of bacteria without killing them * Relies on immune system to destroy bacteria
* Bacteriocidal – antibiotic that kills bacteria
* CFU = colony forming units

Primary mechanism of Action of Antimicrobials
1. Inhibition of synthesis or damage to peptidoglycan cell wall * E.g. β-lactams e.g. penicillin
2. Inhibition of synthesis or damage to cytoplasmic membrane * Polymyxins and daptomycin
3. Modification in synthesis or metabolism of nucleic acids * Quinolones (inhibit DNA gyrase), Rifampin (inhibits RNA polymerase) 4. Inhibition or modification of protein synthesis
* Aminoglycosides, tetracyclines, etc. – Inhibit
5. Modification in energy metabolism
* Folate Antagonists – sulphonamides and trimethoprim * Many drugs have a high therapeutic index since they are – selectively toxic * Host immune system assists in clearance of infection * Therefore, use of antibiotics especially important in HIV/neutropenic patients *

Bacteria
* Need drugs selectively toxic to bacteria - Targets should be unique to bacteria therefore

Bacteria vs. Human Cells
* Cell Wall
* In prokaryotes has peptidoglycan
* Important for nutrient import and protection against osmotic shock * DNA and RNA synthesis
* Some biochemical process common to both eukaryotes and prokaryotes * Key differences required
* Cytoplasm
* Contains soluble enzymes and other proteins, ribosomes & small molecule biochemical intermediates * But bacteria do not have nuclei or mitochondria
* Outer membrane
* In bacteria, defines them taxonomically as Gram-negative or Gram-positive * May prevent penetration of antibacterial agents

Bacterial Resistance to Drugs
* Intrinsic resistance
* E.g. Pseudomonas aeruginosa – intrinsically resistant to many antibiotics because antibiotics unable to cross its outer membrane or bind to target sites * Acquired Resistance
* Mutation of existing genetic information or acquisition of new genes * Methods of Acquiring Resistance
* Conjugation – Two bacteria exchange genetic information * Usually from a plasmid that encodes an enzyme
* Most common – resistance conferring plasmids identified in virtually all bacteria * Transduction – a virus (bacteriophage) that exchanges DNA * Transformation – when bacteria pick up exogenous DNA from the environment * Least common

* Resistance Patways:
1. Altered Receptors for that drug
2. Enzymatic Degradation of drug
3. Bypassing – by using another metabolic pathway (resistant...
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