20 Antimicrobial Medications

magic bullet

The search of a “[__]” → drug that would kill microbial pathogens without harming human host, led to discovery of antimicrobials drugs

» Salvarsan: first successful antimicrobial drug, discovered by Paul Erlich for treatment of syphilis

» Penicillin: antibiotic. accidentally discovered by Alexander Fleming in Penicillium mushroom; refined and isolated by Emst Chain and Howard Florey

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

→ mass produced for soldiers in WWII

→ 1960s drug structure was altered (natural Penicillin isolated from fungi, Penicillin G, originally only affected gram-positive cocci)

created ampicillin: affects other gram-positive and gram-negative bacteria

Penicillin

There are many variations of [__]; all have a beta-lactam ring and differ with their side chains

original: [__] G → given via IV fluids; another natural one is [__] V

• methicillin → resistant to penicillinase enzyme

• ampicillin → increased spectrum to affect Gram-negative bacteria as well; acid resistant » can be taken orally

• amoxicillin → more active form of ampicillin; don’t need as much doses

penicillinase

Bacteria with this enzyme is resistant to penicillin as it breaks down the beta-lactam ring of the compound

soil

Most antibiotics come from [__] microbes

• Bacteria: Streptomyces and Bacillus species

• Fungi: Penicillium and Cephalosporium

Produces antibiotics (chemical produced by one organism to kill another organism) to rid of competition that is prevalent in the soil

antimicrobial medication

The characteristics of [__] are:

1. Antimicrobial action

• bactericidal → kills bacteria

• bacteriostatic → inhibits growth of bacteria

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2. Selective toxicity » inhibits or kills microbial pathogen but has little or no toxic effect on human host

→ drugs target components that are different or absent in human cells (eg. peptidoglycan)

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3. 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 → affects wide range of bacteria

» important for treating acute life-threatening diseases, especially when no time to culture for identification

» disrupts normal microbiota

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4. antibiotics must reach area of infection and be excreted

some antibiotics can’t:

be taken orally (Gi tract doesn’t absorb) → IV » vancomycin

cross blood-brain barrier (important for treating meningitis and encephalitis)

enter abscesses or phagocytic cells » important for TB and treating the Mycobacterium tuberculosis that inhabit macrophages in this disease

also varies in time taken by body to eliminate drug

» dictates the frequency of dosage → must maintain conc. of antibiotic

» liver or kidney damage are exceptions as they excrete drugs more slowly

inhibition of cell wall synthesis

Mechanism of action for antibacterial drugs such as:

• Beta lactam drugs → inhibits formation of peptide chain between peptidoglycan (PTG) backbone. only effective against actively growing cells

  • includes Penicillins and cephalosporins

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• Vancomycin → prevent formation of peptide chain AND break down the PTG backbone

  • ineffective against Gram-negative bacteria due to its outer membrane

  • developed as last line of defense against MRSA

  • given intravenously due to poor absorption from GI tract

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• Bacitracin → interferes with transport of PTG precursors

  • PTG made inside cell and then transported out

  • quite toxic to even humans as it also affects our own transport proteins → limited to topical applications

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

» does not affect eukaryotic cell as [__] only affects bacteria that has peptidoglycan

Result: low toxicity, high effectiveness

inhibition of protein synthesis

Mechanism of action for antibacterial drugs such as:

• Chloramphenicol → targets 50S subunit (rRNA) and prevents formation of peptide bond between proteins

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• Macrolides → prevent the continuation of protein synthesis by binding to the 50S subunit

  • includes Erythromycin and azithromycin

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• Aminoglycosides → binds to 30S (part of ribosome that touches mRNA) and prevents translation

  • big. causes mRNA to go out and lead to mis-readings

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• Tetracycline → blocks tRNA from attaching to ribosome

  • small. can get into phagocytes and tissues

» selective toxicity in its targeting of prokaryotic ribosomes that are 70S; no effect on eukaryotic ribosomes (80S)

» however, our mitochondria is 70S as well → muscle fatigue and tiredness

inhibition of nucleic acid synthesis

Mechanism of action for antibacterial drugs such as:

• Fluoroquinolones → inhibits action of DNA gyrase

  • DNA gyrase relieves supercoiling of DNA as it is replicated

  • eg. Ciprofloxacin and ofloxacin

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• Rifamycins → blocks prokaryotic RNA polymerase and initiation of transcription

  • eg. Rifampin → used to treat TB and Hansen’s disease

  • also prevents meningitis after exposure to N. meningitidis

» [__] targets DNA or RNA synthesis

inhibition of metabolic pathways

Mechanism of action for antibacterial drugs such as:

• Sulfanamide → inhibits 1st enzyme in pathway

• Trimethoprim → inhibits 3rd enzyme in pathway

(both are also known as Sulfur drugs)

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» inhibits enzymes by competitively binding with products (metabolites or growth factors) in a folic acid pathway

» selective toxicity as humans lack folic acid pathway

Polymixin B

Drug that damages cell membrane by altering membrane permeability of Gram-negative cells → leakage and cell death

Common in first-aid skin ointments

» not many drugs like [__], as inhibition of cell membrane offers no selective toxicity → applied topically only.

Mycobacterium

Drugs against [__] species have limited range/effect on them due to:

• chronic nature of disease and slow growth of bacteria → grows so slowly antibiotics targeting cell growth has no impact

• waxy lipids in cell wall → mycolic acid is impervious to many drugs

First-line drugs

Effective drugs used against Mycobacterium. Low toxicity, used in combination with each other to treat TB

• Rifampin → inhibits mRNA synthesis

• Streptomycin → inhibits protein synthesis

• Isoniazid* → inhibits synthesis of mycolic acid

• Ethambutol* → inhibit enzyme putting together precursors (like mycolic acid) for cell wall synthesis

• Pyrazinamide → interferes with protein synthesis

(*): exclusive to Mycobacterium

Second-line drugs

Drugs treating TB that are less effective and have more toxicity risks. Used for more resistant Mycobacterium strains as second to last resort.

treatment

For [__] we can:

• try different drugs until getting favorable response

• identify pathogen > determine susceptibility > prescribe drug that acts against target organism only

  • better approach, but more time-consuming

susceptibility: the inability of a microorganism to grow in the presence of an antimicrobial drug

MIC

[__]: Minimum inhibitory concentration

Found through a quantitative test that determines the lowest conc. of an antimicrobial drug needed to prevent growth of a specific organism

Disk diffusion method

Susceptibility testing, also known as Kirby-Baur disk diffusion

Method: spread bacteria onto plate and plate antibiotic impregnated disks on plate and incubate it

» determines susceptibility of bacterial strain to different antibiotics

» the greater the susceptibility, the greater the zone of inhibition

» zone of inhibition: area of no growth around disc

E test

Modification of disk diffusion test that uses filter paper strips with a concentration gradient of the antibiotic

» zone of inhibition is tear-drop shaped (red in image); will line up with the strip at the conc. bacteria no longer grows

» where it ends = MIC

broth dilution method

Susceptibility test where you do a serial dilution of antibiotic and add bacteria

» measures growth (brown in image) by turbidity

» MIC = lowest conc. that prevents growth (yellow tube closest to the brown tube/tube with growth)

90

Increasing use or misuse of antibiotics selects for resistant microorganisms

» tons to hundreds of used yearly

» originally only 3% of S. aureus resistant to penicillin G

» now >[__]% are resistant

» how will we treat disease when all microbes left are resistant?

combination therapy

Bacteria may have acquired resistance due to:

1. spontaneous mutations → changes 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

» achieved by transfer of R plasmid (resistance plasmid) or transposons that contain resistant genes

[__]: combinations of antibiotics done to prevent resistance

» tries to mitigate possibility of bacteria being resistant to one antibiotic, so has multiple

responsibilities

What can be done to slow emergence and spread of resistance?

1. [__] of Physicians and Healthcare Workers

• prescribe antibiotics for specific organisms

• educate patients on proper use of antibiotics

2. [__] of patients

• follow instructions carefully to get rid of the microbe entirely; else it’ll grow resistant

3. Educate public

• concerning appropriateness and limitations of antibiotics

• antibiotics have no effect on viral infections

• misuse selects antibiotic resistance in normal floar

4. Be wary of global impacts

• overuse of antibiotics lead to increased selection of resistant bacteria

» antimicrobials are readily available without prescription

» antibiotics present in animal feed as well → selects for antimicrobial resistant organisms (resistant Salmonella strains)

• transport of resistant strains globally

Superinfection

Overgrowth of normal microbiota that is resistant to antibiotics

eg. S. aureus to penicillin G