Antibacterial and Antiviral Drug Resistance

EPID 8500 College of Public Health University of Georgia

History of Antimicrobial Agents

Paul Ehrlich
Discovered treatment for syphilis Magic Bullet
Based on selective nature of histologic staining If a compound could be made that selectively targeted the diseasecausing organism, a toxin could be delivered with the compound selectively.

History of Antimicrobial Agents

Accidental discovery, 1928
No growth of bacterial around mold, Penicillium notatum, on agar plate Named it penicillin Determined antimicrobial properties Published in 1929, little attention to discovery Fleming struggled to isolate and purify the antibiotic agent Concluded it would not be useful clinically

History of Antimicrobial Agents

Chain and Florey
Revisited Flemings discovery from 10 years earlier Isolated and concentrated penicillin Discovered penicillins therapeutic action and chemical composition Theorized structure that was confirmed by X-ray crytallography

Treated man with facial cellulitis and showed immediate improvement Developed mass production of penicillim

Definitions
Antibiotic
Chemical produced by a microorganism that kills or inhibits the growth of another microorganism

Antimicrobial agent
Chemical that kills or inhibits the growth of another microorganism

Definitions
Disinfectant: Antimicrobial agent used only on inanimate objects
Pasteurization: destruction of all diseaseproducing microorganisms in a food product Sterilization: Killing or removal of all living organisms and viruses

Definition
Chemotherapeutic agent: Antimicrobial agent that can be used internally
Bactericidal
Minimum bactericidal concentration (MBC)
Lowest concentration that kills 99.9% of a bacterial population

Bacteriostatic
Minimum bacteriostatic concentration (MIC)
Lowest concentration that inhibits the growth of a bacterial population

Definition
Antimicrobial Resistance
Relative or complete lack of effect of antimicrobial agent against a previously susceptible microbe

Sources of Antibiotics
Microorganism Gram-Positive Rod Bacillus subtilis Bacillus polymyxa Actinomycetes Streptomyces nodosus Streptomyces venezuelae Streptomyces aureofaciens Streptomyces erythraeus Streptomyces fradiae Streptomyces griseus Micromonospora purpureae Fungi Antibiotic Bacitracin Polymyxin Amphotericin B Chloramphenicol Tetracycline Erythromycin Neomycin Streptomycin Gentamicin

Cephalosprium spp. Penicillium griseofulvum Penicillium notatum

Cephalothin Griseofulvin Penicillin

Drug Susceptibility Testing

Inoculate an agar plate with specimen Place antibiotic discs on plate Incubate Measure radius of zone of inhibition Standardized reporting

Minimum Inhibitory Concentration

Minimum Bactericidal Concentration

Selection of Drug Resistant Organisms

Factors Promoting Antimicrobial Resistant Bacteria and Viruses

Inappropriate use of antibiotics
Worldwide overuse Incomplete or incorrect therapeutic regimens Availability of antibiotics without prescription

Failure of hospital infection control practices Widespread use of antibiotics as a growth enhancer in agriculture Clonal dissemination of antibiotic resistant bacteria

Penicillin Use and Penicillin Resistant S. pneumoniae

Consequences of Antimicrobial Resistance

Reduced effectiveness of current antibiotics Increased morbidity and mortality Increased number and length of hospitalizations More expensive therapeutic alternatives Need for continual research and development in the area

Mechanisms of Antimicrobial Resistance

Enzymatic Modification Decreased concentration of antibiotic Alteration of drug target

Mechanisms of Antimicrobial Resistance

Enzymatic Modification
Antimicobial Beta-lactams Penicillin Cephalosporins Mechanism of Action Blocks cell wall synthesis Resistance Mechanism Inactivation Mutation

Mechanisms of Resistance
Antimicrobial Glycopeptides (vancomycin) Aminoglycoside Mechanism of Action Block cell wall synthesis Block protein synthesis Mechanism of Resistance Mutation of binding molecules Inactivation

Tetracyclines
Macrolides (erythromycin) Quinolones (ciprofloxacin) Rifamycins (rifampin) Antimetabolites (Trimethoprimsulfonamide)

Block protein synthesis

Block protein synthesis Inhibit DNA replication Inhibits bacterial RNA polymerase Block formation of nucleic acids

Inactivation
Ribosome protection Mutation in binding molecules Mutation in binding molecules Mutation in binding molecules

Alteration of Drug Target Site

Vancomycin

Antibiotic Efflux Pumps

Acquisition of Foreign DNA

Plasmid Carry Drug-Resistant Genes

International Spread of Resistant Clones of Pneumococcus