Antibiotics Flashcards

1
Q

How widespread is the use of antibiotics?

A

They are the most widely used and most misused drugs (20-50% questionable use).

In hospitals - 30% of drug budget goes to antibiotics.
~25% of patients have received antibiotics within the previous 24h.
In ITU, 50% of patients are on antibiotics.

50 million prescriptions for antibiotics are written per year.

80% of human use is in the community, rather than the hospital:

  • 50% - respiratory infections
  • 15% - urinary tract infections
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2
Q

Describe antibiotics.

A

They are the natural products of fungi and bacteria (soil dwellers).
There is natural antagonism and selective advantages between microorganisms, as they competitively produce substances that kill or inhibit the growth of other microorganisms for survival.

Most antibiotics are derived from natural products by fermentation, then modified chemically. This is done to increase their pharmacological properties and antimicrobial effect.

Some antibiotics, however, are totally synthetic (e.g. sulphonamides)

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3
Q

List some principles of selective toxicity of antibiotics as therapeutic agents.

A

It is based on the differences in structure and metabolic pathways between host and pathogen.

It harms the microorganisms, not the host.

We want the target to be in the microbe, not the host (if possible).

Selective toxicity is difficult for viruses (intracellular), fungi and parasites because they’re intracellular organisms.

We need to understand that there is variation between microbes, strains within the same species.

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4
Q

Describe the therapeutic margin.

A

We need to make sure that the dose is high enough to kill off the infection you’re trying to treat without producing too much toxicity.

The dose between the therapeutic/active dose and the toxic dose is called the therapeutic margin.

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5
Q

What is the MIC?

A

The MIC (minimum inhibitory concentration) is the concentration at which you have to give a drug in order or it to be effective microbiologically.

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6
Q

What is microbial antagonism?

A

Microbial antagonism is the concept of one microorganism producing a substance that inhibits the growth of another.

This maintains flora, as they have complex interactions between themselves that maintain them at a certain level.
They limit the growth of competitors and flora.

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7
Q

Describe what can happen due to loss of flora as a result of antibiotic use.

A

Sometimes, antibiotics can come about and mess up the balance of bacteria in your gut. They can also affect your skin flora, and flora in other parts of your body.

Sometimes, it can lead to disease.
If you take too much clindamycin, broad-spectrum lactams or fluoroquinolones for example, you can cause a condition called Pseudomembranous Colitis. It is caused by the overgrowth of a bacteria called Clostridium difficile (which is normally 3% of the normal flora).

It is very easily transmittable, as it creates spores that live everywhere (e.g. diarrhoea), and can spread through aerosolization.

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8
Q

Explain how antibiotics interact with the immune system.

A

Antibiotics don’t work alone.

The antibiotics in an immune competent patient rely partly on the immune system to clear the infection.

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9
Q

What are the three classifications of antibiotics?

A

They are classified by:

  • type of activity
  • structure
  • target site for activity
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10
Q

Compare bactericidal antibiotics vs. bacteriostatic.

A

BACTERICIDAL:

  • kill bacteria
  • used when the host defense mechanisms are impaired
  • required in endocarditis, kidney infection

BACTERIOSTATIC:

  • inhibit bacteria
  • used when the host defense mechanisms are intact
  • used in many infectious diseases
  • example: tetracyclin
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11
Q

How can antibiotics be categorised according to spectrum of activity?

A

Broad Spectrum Antibiotics:

  • effective against many types
  • example: Cefotaxime

Narrow Spectrum Antibiotics:

  • effective against very few types
  • example: Penicillin G
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12
Q

Describe cephalosporins.

A

Cephalosporins are essentially ‘modified penicillin’.

This illustrates the idea that, as we modify the antibiotics, they change up their efficacy against different microorganisms. It is a balance.
We now use different generation cephalosporins to treat different microorganisms, based on their efficacy.

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13
Q

Describe the implications of the β-lactam ring.

A

Both penicillins and cephalosporins have retained this β-lactam ring in their molecular structure.

It is the active component of the chemical compound.

This is important when talking about resistance because some organisms have acquired enzymes called β-lactamases that degrade that β-lactam structure.

Once it has been destroyed, the antibiotics have no antimicrobial properties whatsoever.

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14
Q

There are many bacterial targets for selective toxicity.

List some of them.

A
  • infolding of the plasma membrane
  • capsule
  • cell wall
  • DNA coiled into nucleoid
  • basal body
  • ribosomes
  • cytoplasm
  • plasma membrane
  • pili
  • cytoplasmic inclusion
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15
Q

Describe the different kinds of antibiotics based on their cellular targets.

A

CELL WALL SYNTHESIS: These bacteria inhibit bacterial cell wall synthesis. If it cant make it’s cell wall, it will die and be cleared.

PROTEIN SYNTHESIS INHIBITORS: The drugs bind to the ribosome in different places, and are thus categorised differently. Both eukaryotes and prokaryotes have ribosome, but they are different in structure. This means that antibiotics can inhibit bacterial ribosomes within necessarily inhibiting eukaryotic ribosomes, so the drugs are essentially quite safe.

DNA AND RNA PROCESSING: These are key antibiotics that inhibit either the way that the bacteria replicates its DNA, or makes its mRNA.
DNA Gyrase is a type of isomerase; they are the coiling and uncoiling enzymes when the genome is trying to replicate itself. DNA Gyrase is unique to bacteria.

Rifampin is the key drug in treating TB. Rifampin targets the enzyme that makes mRNA (DNA-dependant RNA Polymerase).

FOLIC ACID METABOLISM: These inhibit folic acid metabolism.
Humans cannot synthesise folic acid; we can only get it form our diet.
Using both of the drugs gives us a synergetic, broad range, which is bactericidal.

These 4 are the key modes of action.
Others include:

CELL MEMBRANE: Bacterial membrane is very similar to eukaryotic membranes so the drugs targeting the cell wall are very toxic.

GENERATE FREE RADICALS: Free radicals will damage many components of the cell, mainly DNA, but they can also damage membranes, lipids, enzymes involved in metabolism, etc.

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16
Q

Give examples of each of the different types of antibiotics based on their cellular targets.

A

CELL WALL SYNTHESIS:

  • Vancomycin
  • Penicillins
  • Cephalosporins

PROTEIN SYNTHESIS INHIBITORS:
50S:
- Clindamycin
- Erythromycin

30S:

  • Streptomycin
  • Tetracycline
  • Gentamicin

DNA AND RNA PROCESSING:
DNA Gyrase:
- Quinolones

DNA-dependant RNA Polymerase:

  • Fidaxomicin
  • Rifampin

FOLIC ACID METABOLISM:

  • Trimethoprim
  • Sulfonamides

CELL MEMBRANE:

  • Colostin
  • Daptomycin

GENERATE FREE RADICALS:

  • Metronidazole
  • Nitrofurantoin
17
Q

How do cell wall inhibitors work?

A

In gram-positive bacteria, the cell wall is a massive structure of peptidoglycan. This is the structure of cross-linked peptides and polysaccharides.

The antibiotics that inhibit cell wall synthesis target the enzymes that make peptidoglycan. Those enzymes are on the outer side of the membrane.

The antibiotics can easily penetrate the porous plasma membrane of gram-positive bacteria to get to the peptidoglycan layer. In gram-negative bacteria, the peptidoglycan is in the periplasmic space. It is covered by the outer membrane, which is essentially a permeability barrier. Substances can only pass through via porins.

That’s why there are some antibiotics that don’t work against gram-negative bacteria; they cannot get through the outer membrane, either because they are too big or the wrong charge, etc.

18
Q

Briefly, recap the structure of peptidoglycan.

A

The peptidoglycan structure is made up of pentapeptides that are cross-linked together that hold the matrix together.
The long polysaccharide chains are held together by the cross-linking peptide chains.

The peptidoglycan layer is different for each bacteria. That means the enzymes that synthesise them are going to have slightly different specificity for being inhibited by the β-lactam antibodies. Thus, not all β-lactam antibodies will work for all bacteria.

19
Q

Describe, in detail, the site of action of inhibitors of bacterial cell wall synthesis.

A

We start off with a precursor monomer of a di-polysaccharide with five peptides. The last two peptides in the monomer are alanines which are very specific to bacteria.
Some antibiotics inhibit the production of these two peptides. If they don’t have them, they can’t go on to make peptidoglycan.

Once it’s made, it goes across the cytoplasm by linking to a transport molecule (which can also be inhibited by certain antibiotics). Enzymes on the cell wall recognize the D-ala D-ala (D-alanine) and cleave the terminal one off, binding the remainder of the chain to the long chain of peptidoglycan.

The chains are linked by enzymes called trans-carboxypeptidases; they’re only found in bacterial cell walls. The antibiotics thus work by inhibiting these specific enzymes that create the peptidoglycan layer.

Vancomycin, despite not being a β-lactam antibiotic can also act on the D-ala D-ala. It binds to them, stopping them from being recognised by the enzymes, halting the extension of the cell wall.

20
Q

Use the inhibitors of bacterial cell wall synthesis to explain how antibiotics are able to carry out their effect.

A

Antibiotics are often structural mimics of natural substrates for bacterial enzymes.

For example, the β-lactam backbone is nearly identical to the D-ala D-ala structure.

21
Q

Describe the mechanism of action of folic acid synthesis inhibitors.

A

There are multiple enzymes that lead to the production of tetrahydrofolic acid.

Sulfonamides inhibit dihydropteroate synthetase, which is unique to bacteria.
Dihydropteroate synthetase converts dihydropteroate diphasphate (cmbined with p-aminobenzoic acid, or PABA) to dihydropteroic acid.
The structure of sulphonamides is nearly identical to the precursor PABA that is required to make the dihydropteroic acid.

There is another enzyme that is unique to the bacteria, dihydrofolate reductase, which is targeted by trimethoprim. Thus, it has selective toxicity.

22
Q

When do we use antibiotics?

A

1) TREATMENT OF BACTERIAL INFECTIONS
2) PROPHYLAXIS - against close contacts of transmissible infections.

  • decreases carriage rates (more than ~80% in outbreaks) [e.g. meningitis]
  • prevention of infection [e.g. tuberculosis]
  • peri-operative cover for gut surgery
  • people with increased susceptibility to infection

3) INAPPROPRIATE USE: for viral sort throats, etc.; normally occurs as a result of patient pressure

23
Q

What does the dose of antibacterial MIC depend on?

A
  • the age, weight, renal and liver function of the patient and the severity of infection
  • the susceptibility of the organism
  • properties of the antibiotic i.e. enough to give a concentration higher than the MIC (minimum inhibitory concentration) at the site of infection
24
Q

When and why do we combine antibiotics?

A

WHEN:

  • BEFORE an organism identified in life-threatening infections
    e. g. endocarditis, septicaemia
  • Polymicrobial infections e.g. abscess, G.I. perforation anaerobes and aerobes

WHY:
- less toxic doses of an individual drug possible

  • synergy e.g. penicillin and gentamicin, co-trimoxazole (sulphonamides + trimethoprim)
  • reduce antibiotic resistance e.g. tuberculosis