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Microbiology + Immnuology > Antibiotics > Flashcards

Antibiotics Flashcards

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1
Q

What are antibiotics?

A

natural products of fungi and bacteria which live in the soil that kill or inhibit the growth of other microorganisms through natural antagonism and selective advantage

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2
Q

How have humans developed antibiotics from natural products of fungi/bacteria?

A

Natural products undergo fermentation, then modified chemically to have:

  • better pharmacological properties/activity
  • better antimicrobial effect/activity

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

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3
Q

Considerations when using antibiotics as therapeutic agents

A

Selective Toxicity

Therapeutic Margin

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4
Q

What is selective toxicity?

A

ability of drug to kill or inhibit pathogen while damaging host as little as possible:

  • target in microbe, not host
  • difficult for viruses (intracellular), fungi and parasites
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5
Q

How good is selective toxicity of antibiotics?

A

There are many unique targets in bacteria not present in humans which can be inhibited by antibiotics. We have a range of different antibiotics which have low toxicity because we have very good selective toxicity.

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6
Q

What is the therapeutic margin?

A

margin between the therapeutic (beneficial) dose and the toxic dose of a given substance :
-active dose (MIC) vs toxic effect

*you want to ensure the therapeutic dose is enough dose to kill of the infection (MIC), without inducing too much toxicity

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7
Q

What does it mean if the dose between active dose and toxic dose is narrow?

A

Therapeutic margin is narrow and drug is toxic

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8
Q

What does it mean if the dose between active dose and toxic dose is wide?

A

Therapeutic margin is wide and drug is safe to use (not very toxic)

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9
Q

Therapeutic margin of aminoglycosides & vancomycin

A

Narrow therapeutic margin, meaning they are toxic drugs

  • ototoxic
  • nephrotoxic
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10
Q

How do we monitor a patient on toxic drugs aminoglycosides & vancomycin?

A

Take blood samples to ensure MIC is being achieved, but drug levels haven’t reached toxic levels (ototoxic and nephrotoxic)

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11
Q

What is the minimum inhibitory concentration (MIC)?

A

the concentration at which you have to give an active dose in order for it to be effective microbiologically

-need to achieve this MIC without inducing too much toxicity

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12
Q

What is microbial antagonism?

A

competition between microbes

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13
Q

How do we maintain our normal flora?

A

Via microbial antagonism, as flora limit the growth of competitors and pathogens

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14
Q

Negative effect of antibiotics on flora

A

Some antibiotics can disrupt the homeostatic balance of our natural commensal flora (e.g. gut, skin), causing loss of normal flora and bacterial/pathogen overgrowth, leading to disease

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15
Q

Which disease arises from antibiotics disrupting commensal balance?

A

Antibiotic Associated Colitis (Pseudomembranous Colitis)

  • clindamycin
  • broad-spectrum lactams
  • fluoroquinolones
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16
Q

What causes pseudomembranous colitis?

A

Overgrowth of Clostridium difficile.

This is a spore-forming organism which causes:

  • ulcerations →inflammation
  • severe watery diarrhoea
  • hospital cross-infection risks (spreads easily)
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17
Q

Why is it difficult to treat infections with antibiotics in immunocompromised patients?

A

Because antibiotics rely partly on the immune system to help clear the infection (do not work alone)

Therefore, antibiotics aren’t very effective during immunosuppression:

  • Cancer chemotherapy, transplantations, myeloma, leukaemias
  • HIV with low CD4
  • Neutropenics, asplenics, renal disease, diabetes, alcoholics
  • Babies, elderly etc.
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18
Q

How are antibiotics classified?

A

Type of Activity

Structure

Target Site for Activity

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19
Q

How are antibiotics classified by “Type of Activity”?

A

Bactericidal
Bacteriostatic

Broad-Spectrum
Narrow Spectrum

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20
Q

Bactericidal antibiotics

A

Antibiotics which KILL bacteria

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21
Q

When are bactericidal antibiotics used?

A

Used when the host defence mechanisms are impaired

-required in endocarditis, kidney infection (life-threatening infections)

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22
Q

Bacteriostatic antibiotics

A

Antibiotics that do not actually kill bacteria but rather inhibit their growth

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23
Q

When are bacteriostatic antibiotics used?

A

Used in many infectious diseases when the host defence mechanisms are intact which clears the infection

24
Q

What are broad spectrum antibiotics?

A

Antibiotics effective against many types of bacteria

-e.g. Cefotaxime

25
Q

What are narrow spectrum antibiotics?

A

Antibiotics effective against very few types of bacteria

-e.g. Penicillin G

26
Q

How can we develop antibiotics with different spectrums of activity?

A

Via pharmaceutical modification

E.g.:

  • 1st gen cephalosporins good at killing gram-positives but not gram-negatives
  • 2nd gen better at killing gram-negatives, but as a result not as good at killing gram-positives
  • 3rd gen good at killing gram-negatives, but not gram-positives
27
Q

How are antibiotics classified by “Molecular Structure”?

A

Families of antibiotics are used to differentiate them from one another

-e.g. β-lactam antibiotics

28
Q

What is β-lactam?

A

β-lactam is the active chemical structure of a chemical compound seen in penicillin and cephalosporin antibiotics.

29
Q

Action of β-lactam antibiotics

A

Competitive Inhibitors

They are structural mimics of natural substrates for bacterial enzymes involved in making the bacterial cell wall/peptidoglycan
-cell wall synthesis inhibitors

30
Q

How do some organisms develop resistance to β-lactam antibiotics?

A

They acquire enzymes called β-lactamases which degrade the β-lactam ring

Once this ring is destroyed, β-lactam antibiotics (e.g. penicillin and cephalosporin) no longer have any antimicrobial properties

31
Q

How are antibiotics classified by “Target Site for Activity”?

A

Antibiotics can be identified depending on what bacterial processes they will inhibit:

  • cell wall synthesis inhibitors
  • protein synthesis inhibitors
  • DNA&RNA processing inhibitors
  • folic acid metabolism inhibitors
  • cell membrane inhibitors
  • free radical generators
32
Q

Cell wall synthesis inhibitors

A

Target the enzymes which make peptidoglycan

β-lactam antibiotics & Vancomycin
-inhibit bacterial cell wall synthesis → bacteria die

*different in gram-ve and gram+ve bacteria

33
Q

Selective toxicity of cell wall synthesis inhibitors

A

Good selective toxicity because human eukaryote cells don’t have a cell wall

34
Q

Protein synthesis inhibitors

A

Erythromycin & Chloramphenicol
-inhibit 50S ribosomal subunit

Tetracycline & Aminoglycosides (Streptomycin)
-inhibit 30S ribosomal subunit

35
Q

Selective toxicity of protein synthesis inhibitors

A

Good selective toxicity because ribosome in bacterial prokaryote different to ribosome in human eukaryote

36
Q

DNA & RNA processing inhibitors

A

Antibiotics which inhibit bacterial enzymes involved in DNA replication or mRNA formation

Quinolones
-inhibit DNA gyrase, a topoisomerase involved in coiling and uncoiling of genome during replication

Rifampicin
-inhibits DNA-directed RNA polymerase → no mRNA, no bacterial proteins→ death

37
Q

Selective toxicity of DNA & RNA processing inhibitors

A

Good selective toxicity because bacterial enzymes involved in DNA replication and mRNA formation different to enzymes in eukaryotes

38
Q

Folic acid metabolism inhibitors

A

Folic acid (vitamin) is an important co-factor for many enzymes, so if bacteria can’t make folic acid, many enzymes can’t carry out reactions and bacteria dies

Sulfonamides
-blocks dihydropteroate synthetase by competing against natural substrate PABA, inhibiting DHFA production

Trimethoprim
-blocks dihydrofolate reductase, inhibiting THFA production

39
Q

Selective toxicity of folic acid metabolism inhibitors

A

Good selective toxicity because humans don’t have the enzymes that make folic acid in bacteria

40
Q

Cell membrane inhibitors

A

Antibiotics which damage bacterial membrane

  • Colistin
  • Daptomycin
41
Q

Selective toxicity of cell membrane inhibitors

A

Poor selective toxicity because bacterial cell membrane is similar to eukaryotic cell membrane

42
Q

Free radical generators

A

Antibiotics which generate free radicals that mainly damage bacterial DNA

Metronidazole
-used to treat anaerobic bacteria

Nitrofurantoin
-used to treat UTIs

43
Q

What has to be taken into consideration when prescribing a cell wall synthesis inhibitor?

A

Whether the bacteria is a gram+ve or a gram-ve organism

44
Q

Where are the enzymes which make peptidoglycan located?

A

Enzymes which make the peptidoglycan layer are on the outer side of the inner bacterial cell plasma membrane.

45
Q

Gram+ve bacterial cell wall

A

Large peptidoglycan layer which contains components of the bacterial cell wall including teichoic and lipoteichoic acid

46
Q

Action of cell wall synthesis inhibitors against gram+ve bacteria

A

Plasma membrane is a porous structure, and antibiotics penetrate this porous structure to target enzymes which make the peptidoglycan and inhibit them

47
Q

Gram-ve bacterial cell wall

A

Small peptidoglycan layer which sits within the periplasmic space and has an impermeable outer membrane, with lipopolysaccharides on the outside.

48
Q

Action of cell wall synthesis inhibitors against gram-ve bacteria

A

Outer membrane is an impermeability barrier, and the only way anything can get across it is through porins. Antibiotics are transported through porins into the outer side of the inner plasma membrane to target enzymes that make peptidoglycan

Many antibiotics you can’t use on gram-negative organisms because they can’t get through this impermeable outer membrane barrier.

49
Q

Peptidoglycan synthesis

A

1) Disaccharide precursor monomers containing 5 peptides, with last two peptides being terminal alanine isomers (terminal D-ala D-ala) are synthesised in the cytoplasm.
2) Precursors will be transported across cytoplasmic membrane by phospholipid carried molecule and into the cell wall
3) Trans carboxypeptidases/PBPs then cleave D-ala and cross-link the peptide chains to the growing peptidoglycan structure (polymerisation)

50
Q

MOA of cell wall synthesis inhibitors (preventing peptidoglycan synthesis)

A

Cycloserine
-inhibits incorporation of terminal D-ala D-ala into cell wall precursor

Bacitracin
-inhibits dephosphorylation of phospholipid carrier, preventing regeneration of carrier necessary for the synthesis to continue

Vancomycin
-binds to terminal D-ala D-ala residues and prevent incorporation of the peptides into the growing peptidoglycan

β-lactam antibiotics
-bind to and inhibit trans carboxypeptidase enzymes/PBPs which catalyse the cross-linking

51
Q

What are penicillin binding proteins?

A

Cross-linking enzymes (trans carboxypeptidases) which synthesise the peptidoglycan and also competitively bind penicillin and cephalosporin (β-lactam antibiotics)

52
Q

Action of β-lactam antibiotics on PBPs in Gram-ve bacteria

A

If you come in with a β-lactam antibiotic like a penicillin or cephalosporin, the antibiotic has to be able to get through the outer membrane porin and bind to and inhibit the penicillin binding protein (PBP). This prevents the bacteria from cross-linking, and as a result most bacteria have an autolytic response to not being able to produce its peptidoglycan, lysing itself → death.

53
Q

Bacteria that don’t have peptidoglycan layer

A

Mycoplasma
Chlamydia

*can’t be treated with β-lactam antibiotics

54
Q

Use of antibiotics

A

· Treatment of bacterial infections

· Prophylaxis

  • given if in close contacts of transmissible infections to reduce carriage rates
  • prevention of infection (e.g. meningitis, tuberculosis)
  • peri-operative cover for gut surgery
  • people with increased susceptibility to infection
55
Q

Route of antibiotic administration

A

Oral
-community infections

I/V
-serious infections requiring hospitalisation

Topical (antiseptic creams, heavy metal ointments)

  • conjunctivitis
  • superficial skin infections
56
Q

What does the MIC dose depend?

A

· Depend on age, weight, renal & liver function of patient and the severity of infection
· Depend on the susceptibility of the organism
· Will also depend upon properties of the antibiotic e.g. enough to give a concentration high than the MIC at the site of infection

57
Q

When do we give antibiotic combinations?

A

Before an organism identified in life-threatening infections
-E.g. endocarditis, septicaemia

Polymicrobial infections
-E.g. abscess, GI perforation anaerobes and aerobes

To reduce antibiotic resistance (e.g. tuberculosis)

Microbiology + Immnuology (26 decks)

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