Antimicrobials Part 1: Basic Principles of Antimicrobial Therapy

Antimicrobials Part 1: Basic Principles of Antimicrobial Therapy Antimicrobials: Used to treat infectious diseases; 190 million doses of antibiotics are given in hospitals each day; Modern antimicrobials: 1930s and 1940s; Significantly reduced morbidity and mortality from infection Antibiotics: strictly speaking, a chemical produced by one microbe that can harm other microbes Antimicrobial agent: Any agent that can kill or suppress microorganisms Classification of Antimicrobial Drugs Classification By Susceptible Organism Narrow Spectrum ABX: active against a few species of bacteria or micro-organisms Broad Spectrum ABX: active against a wide varietyonly used when needed Classification By Mechanism Of Action: Drugs work on: Cell wall synthesis: activate enzymes that disrupt cell wall (PCN, cephalosporins) Cell membrane permeability: amphotericin B- increase membrane permeabilityleakage of material Protein synthesis (lethal): Aminoglycosides (gentamycin) Nonlethal inhibitors of protein synthesis: tetracyclines, slow growth but don’t kill bacteria Synthesis of nucleic acids: inhibit DNA/RNA by binding directly to nucleic acid or interact with enzymesRifampin, metronidazole, fluoroquinolones Antimetabolites: disrupt specific biochemical reactionsdecrease synthesis of constituentstrimethoprim or sulfonamides Viral enzyme inhibitors: suppress viral replication; inhibit specific enzymesDNA polymerase, transcriptase, integrase, neuramidinase *Bactericidal: Drugs are directly lethal to bacteria at clinically achievable concentrations *Bacteriostatic: Drugs can slow bacterial growth but do not cause cell death Acquired Resistance to Antimicrobial Drugs: acquired resistance can reder currently effective drugs totally uselessclinical crisis and constant need for new agentsOver time, organisms develop resistance; May have been highly responsive and then became less susceptible to one or more drugs Organisms with Microbial Drug Resistance: Enterococcus faecium, Staphylococcus aureus, Enterobacter species, Klebsiella species, Pseudomonas aeruginosa, Acinetobacter baumannii, Clostridium difficile Microbial Mechanisms of Drug Resistance: Four basic actions: 1) Decrease the concentration of a drug at its site of action: most drugs are intracellular 2) Inactivate a drug: Beta-lactam ring; drugs an reduce intracellular concentrationresist harm; Microbes can cease uptake of certain drugs (gent and tetra) OR microbes can increase active export of certain drugs (tetra, fluoroquinolones, macrolides) 3) Alter the structure of drug target molecules: structure of moleculealtered resistance 4) Produce a drug antagonist: RARE, microbes synthesize a compound that antagonizes a reaction Spontaneous mutation: Random changes in a microbe’s DNAgradual increase; Resistance to one drug Conjugation: Extrachromosomal DNA is transferred from one bacterium to anotherdonor organism must possess 2 unique DNA segmentsone codes for mechanisms of resistance and one for sexual apparatus or for DNA transferboth resistance factor; Gram-negative bacteria; Multiple drug resistance Antibiotic Use and Drug-Resistant Microbe Emergence How Antibiotic Use Promotes Resistance: Drugs make conditions favorable for overgrowth of microbes that have acquired mechanisms for resistancedrug resistant organism presentABX create selection pressure favoring its growth