ch20 - antimicrobial medications

review

Discovery of microbial world by van Leeuwenhoek

• Koch – discover that a specific microbe is responsible for a specific disease → Germ Theory of Disease

• Next question: How do we treat these diseases?

History and Development of Antimicrobial Drugs

Search for a “magic bullet” that would kill microbial pathogens without harming human host

Discovery of antimicrobial drugs

• Salvarsan

  • First successful antimicrobial

  • Discovered by Paul Erlich for treatment of syphilis

Discovery of antibiotics

• Alexander Fleming

  • Discovered penicillin accidentally while working with Staphylococcus

  • Produced by Penicillium

  • Fleming unable to purify compound

    • Eventually abandoned his study

• Ernst Chain and Howard Florey successfully purified penicillin

  • 1941 - clinical trials on human subjects with life-threatening S. aureus infection

    • Mass production for treatment of wounded soldiers (WWII)

  • 1960s - drug structure altered to give them new properties

    • Penicillin G altered to create ampicillin

      • Broadened spectrum of drug

derivatives of penicillin

Characteristics of Antimicrobial Medications

Most antibiotics come from soil microbes

• Bacteria: Streptomyces and Bacillus species

• Fungi: Penicillium and Cephalosporium

Antimicrobial action

Bactericidal – kill bacteria

Bacteriostatic – inhibit growth of bacteria

• Rely on host immunity to eliminate pathogen

selective toxicity

Inhibits or kills microbial pathogen but has little or no toxic effect on human host

• Drugs target components that are different from or absent in human cells

spectrum of activity

Range of microbes affected

• Narrow spectrum – affect narrow range of bacteria

  • Requires identification of pathogen, testing for sensitivity

  • Less disruptive to normal microbiota

• Broad spectrum – affect wide range of bacteria

  • Important for treating acute life-threatening diseases

    • Especially when no time to culture for identification

  • Disrupt normal microbiota

Antibiotics must reach area of infection and be excreted

Some antibiotics:

• Are not absorbed from GI tract

• Do not cross blood-brain barrier

• Cannot enter abscesses or phagocytic cells

Time it takes body to eliminate drug

• Dictates frequency of dosage

• Liver or kidney damage tend to excrete drugs more slowly

Mechanisms of Action of Antibacterial Medications

Targets antibacterial medications

• Cell wall synthesis

• Protein synthesis

• Nucleic acid synthesis

• Metabolic pathways

• Cell membranes

antibacterial drugs inhibiting cell wall synthesis

Bacteria cell walls contain peptidoglycan

Does not affect eukaryotic cell

• Lack of cell wall in animals

• Differences in cell wall of plants

• Result: low toxicity, high effectiveness

Antimicrobials include

• β lactam drugs

• Vancomycin

• Bacitracin

β lactam antibacterial drugs

Penicillins and cephalosporins

• Disrupt cell wall synthesis - Inhibits peptide bridge formation between PTG backbone

• Only effective against actively growing cells – kills by osmotic lysis

completely inhibit enzymes that help form cross-links between adjacent glycan chains

vancomycin

• Inhibits formation of glycan polymer and/or peptide chains

  • No effect on Gram (-) organisms - does not cross outer membrane

• Last line of defense against MRSA

• Given intravenously due to poor absorption from GI tract

• bind to the amino acid side chain of NAM molecules, blocking formation of cross-links between adjacent glycan chains

bacitracin

• Interferes with transport of PTG precursors

• High toxicity limits use to topical applications

  • Common ingredient in over-the-counter first-aid ointments

• interferes with the transport of peptidoglycan precursors across the cytoplasmic membrane

inhibition of protein synthesis regarding antibacterial drugs

Target is prokaryotic ribosome

• Selective toxicity = differences in prokaryotic (70S) and eukaryotic (80S) ribosomes

• Mitochondria also have 70S ribosomes

  • May account for some toxicity of these antibiotics

inhibition of nucleic acid synthesis

1. Fluoroquinolones

• Inhibit action of DNA gyrase

  • Supercoiling of DNA occurs

• Examples: Ciprofloxacin and ofloxacin

2. Rifamycins

• Block prokaryotic RNA polymerase

  • Block initiation of transcription

• Example: Rifampin

  • used to treat tuberculosis and Hansen’s disease

  • preventing meningitis after exposure to N. meningitidis

Inhibition of metabolic pathways

• Competitive inhibitors of essential metabolites or growth factors (vitamins)

• Examples: Sulfonamides and trimethoprim

  • Inhibit folic acid production

  • Basis for selective toxicity: Human lack folic acid pathway (enzymes)

damage cell membrane

Few drugs

• Example = Polymixin B

  • Common ingredient in first-aid skin ointments

  • Alters permeability of membranes of Gram (-) cells

    • Leads to leakage and cell death

• Limits use to topical application

Drugs against Mycobacterium species

Limited range of antimicrobial treatment due to

• Chronic nature of disease

• Slow growth

• Waxy lipid in cell wall

  • Mycolic acid is impervious to many drugs

First-line drugs – effective, low toxicity; use in combination

• Rifampin – inhibits mRNA synthesis

• Streptomycin → inhibits protein synthesis

• Isoniazid → inhibits synthesis of mycolic acid

• Ethambutol → inhibits enzymes for cell wall synthesis

• Pyrazinamide → interferes with protein synthesis

Second-line drugs

• Used for resistant strains

• Less effective, have greater toxicity risk

Antimicrobial Susceptibility Testing

Susceptibility of organism to specific antimicrobials is unpredictable

For treatment

• Try different drugs until get favorable response

  • For serious infection, use several drugs at one time with hope that one is effective

• Better approach

  • Identify pathogen

  • Determine susceptibility

  • Prescribe drug that acts against target organism only

To determine MIC

• MIC = Minimum Inhibitory Concentration

  • Quantitative test

    • determine lowest concentration of antimicrobial drug needed to prevent growth of specific organism

Disk diffusion method (Kirby-Bauer disk diffusion)

Determine susceptibility of bacterial strain to different antibiotics

Method:

• Spread bacteria onto plate

• Place antibiotic impregnated disks on plate and incubated

• Measure clear zone around disk

  • Zone of inhibition reflects susceptibility

epsilometer (E) test

Modification of disk diffusion test

Uses strips impregnated with gradient concentrations of antibiotic

Zone of inhibition

• Is tear-drop shaped

• Zone will intersect strip at MIC

Broth dilution method

1. Growth determined by turbidity

2. MIC = Lowest concentration that prevents growth

Resistance to Antimicrobial Medications

increasing use/misuse selects for resistant microorganisms

• Hundreds of tons used each year

• Antimicrobial resistance is alarming

  • Impact on cost, complications, and outcomes of treatment

Bacteria may develop acquired resistance due to

1. Spontaneous mutations

• Changes in existing genes during replication and passed to next generation = vertical transfer

2. Horizontal gene transfer between organisms

• Resistance genes spread to different strains, species, even genera

• Achieve via transfer of plasmid (R plasmids) or transposons

Combination therapy of multiple antibiotics

• Often used to prevent resistance

What can we do to slow emergence and spread of resistance?

1. Responsibilities of Physicians and Healthcare Workers

• To prescribe antibiotics for specific organisms

• Educate patients on proper use of antibiotics

2. Responsibilities of Patients

• Follow instructions carefully

• Not skipping doses and complete prescribed treatment

3. Educate public

• Concerning appropriateness and limitations of antibiotics

  • Antibiotics have no effect on viral infections

  • Misuse selects antibiotic resistance in normal flora

4. Resistance to Antimicrobial Medications

• Overuse is a worldwide concern

• Transport of resistant organisms globally

• Antimicrobials available without prescription

• Use of antibiotics in animal feed

  • Enhances growth of animals

  • Selects for antimicrobial resistant organisms

    • Resistant Salmonella strains linked to animals

Why should we be concerned about antibiotic resistance?

• Antibiotic resistant bacteria are harder to kill therefore, harder to treat disease

• Superinfection: overgrowth of normal microbiota that is resistant to antibiotics

  • Originally only 3% of S. aureus resistant to penicillin G; now >90% are resistant