Antibiotics - Mechanism and Spectrum Flashcards

1
Q

What is the central principle of antibiotic use ?

A

• Anti-bacterials target processes that humans to not possess (e.g., bacterial cell wall) OR processes that humans possess but the bacterial versions are sufficiently different (in that case, the toxicity of anti-bacterials is greater to bacteria than it is to human, i.e. selective toxicity)

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2
Q

What processes/structures in bacteria do the main antibiotics target ?

A
  • Bacterial Cell Wall Inhibitors
  • Bacterial Folate Antagonists
  • Inhibitors of Bacterial Ribosomal Action
  • Topoisomerase II Inhibitors
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3
Q

Explain the general mechanism used by bacterial cell wall inhibitors.

A

Inhibit cell wall synthesis which creates an inbalance in the cell wall architecture which triggers bacterial autolysis that kill the cell.

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4
Q

Identify the main classes of bacterial cell wall inhibitors, giving examples for each class and identify the main target of each.

A

1) b-Lactams (penicillins, cephalosporins, carbapenems)- peptidoglycan cross-linking (by targeting penicillin binding protein)
2) Glycopeptides (Vancomycin)- synthesis of peptidoglycan (especially transglycolation and transpeptidation)
3) Cyclic peptides: Bacitracin- prevents carriage of building-blocks of peptidoglycan bacterial cell wall outside of the inner membrane

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5
Q

Identify the main kinds of penicillin. State whether each of these is narrow or broad spectrum.

A
  • Penicillins G and V (natural penicillins)- Narrow
  • B-Lactamase-resistant Penicillins (synthetic)- Narrow
  • Broad-spectrum penicillins- Broad
  • Extended-spectrum penicillins- Extended
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6
Q

What classes of pathogens does penicillin G and V target ? Name specific pathogens in these classes and the illnesses they might cause.

A

(a) Gram positive and gram negative Cocci.
– Staphyloccus (infections of wounds, boils)
– Streptococcus haemolytic types (septic infections)
– Enterococcus (endocarditis)
– Pneumococcus (pneumonia)

(b) Gram positive rods. Clostridium (tetanus, gangrene)

(c) Spirochaetes
Treponema (syphillis)
Actinomyces (abscesses)

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7
Q

Identify examples of beta-lactamase resistant penicillins.

A

Methicillin, Oxacillin, Nafcillin

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8
Q

Identify examples of broad-spectrum antibiotics. Name specific pathogens they target and the illnesses they might cause.

A

Ampicillin and Amoxicillin

B-lactamase-free strains of H. Influenzae, N. Gonorrhoeae, E. Coli, Salmonella, Morasella catarrhalis (sinusitis)

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9
Q

Identify examples of extended-spectrum antibiotics. What classes of pathogens do extended spectrum antibiotics target ? Name specific pathogens in these classes.

A

Carbenicillin, Ticaracillin, Azlocillin

Broad-spectrum bacteria plus Pseudomonas Aeruginosa.

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10
Q

Describe the following features of carbapenems:

  • Spectrum:
  • Mechanism of action:
  • Target pathogens:
  • Other special features:
A

CARBAPENEMS
-Spectrum: Broad antibacterial spectrum, much broader than other penicillins and cephalosporins
-Mechanism of action: Bind β-lactamase and acylating the enzyme, rendering it inactive (therefore prevent peptidoglycan cross-linking)
-Target pathogens: Active against both Gram positive and Gram negative bacteria
and anaerobes, poorly active against MRSA, not active against bacteria lacking a cell wall
-Other special features: Generally resistant to the typical beta-lactamases

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11
Q

Explain the possible mechanisms of bacterial resistance to beta-lactam antibiotics.

A
  • Destruction by b-lactamase e.g., S. aureus
  • Failure to reach target enzyme- changes to outer membrane porins and polysaccharide components of gram-negative organisms Pseudomonas spp.,
  • Failure to bind to the transpeptidase S. pneumoniae
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12
Q

What antibiotics can we use in case of bacterial resistance to beta-lactam antibiotics ?

A

• Co-administration of b-lactamase inhibitors with a b-lactam antibiotic OR use of b-lactamase-resistant antibiotics.

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13
Q

Identify specific beta-lactamase inhibitors and which beta lactamase each inhibitor targets.

A

B-lactam compounds CLAVULANIC ACID and SALBACTAM act as strong inhibitors of class A but not B or C or D beta-lactamases.

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14
Q

What are the indications for cephalosporins ?

A
  • Similar indications as penicillins and are often alternatives to penicillins (same group, beta lactams)
  • Specifically, septicaemia, pneumonia, meningitis, biliary tract infections, urinary tract infections, sinusitis..
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15
Q

Identify examples of cephalosporins.

A

Cefalexin, cefuroxime, cefotaxime, cefadroxil.

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16
Q

What is a possible issue arising as a result of cephalosporin overuse ?

A

Overuse of cephalosporins may facilitate emergence of C. difficile.

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17
Q

What group of antibiotics does vancomycin belong to ? What is the specific mechanism of this group of antibiotics ?

A

Glycopeptides
Glycopeptides prevent synthesis of peptidoglycan, especially by binding to the peptide chain of the peptidoglycan and interfering with the elongation of the peptidoglycan backbone. They specifically target C-terminal D-Ala-D-Ala.

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18
Q

What explains the minimal development of antibiotic resistance in glycopeptides ?

A

Very specific interaction with C-terminal D-Ala-D-Ala explains the minimal development of resistance to this antibiotic.

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19
Q

What are the indications for vancomycin ?

A

MRSA and resistant streptococci and enterococci

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20
Q

What group of antibiotics does bacitracin belong to ? What is the specific mechanism of this group of antibiotics ?

A

Cyclic peptides
Prevent carriage of building-blocks of peptidoglycan bacterial cell wall outside of the inner membrane by interfering with the dephosphorylation of the lipid carrier which moves the early cell wall components through the membrane.

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21
Q

What is the indication for bacitracin ?

A

Can be used in an ointment to treat infections of the skin and eye by streptococci and staphylococci.

22
Q

True or false: bacitracin is bactericidal.

A

True, bacitracin is bactericidal.

23
Q

What are the main groups of bacterial folate antagonists ? What is the mechanism of bacterial folate antagonists ? What is the specific target of each of the main groups of bacterial folate antagonists ?

A

♦ Sulphonamides and Trimethoprim

♦ Inhibit folate pathway in bacteria. Folate system important in cell metabolism; bacteria must make their own supply but we don’t as we get it in diet, so selective toxicity.

♦ Sulphonamides targets dihydropteroate synthase enzyme.
Trimethoprim targets dihydrofolate reductase enzyme.

24
Q

List the main indications/spectrum of bacterial folate antagonists (sulphonamides and trimethoprim).

A
  • Trimethoprim commonly used in the treatment of community UTI
  • Sulphamethoxazole combined with pyrimethamine used for drug-resistant malaria and toxoplasmosis.
  • Co-trimoxazole, combination treatment of Sulphamethoxazole + trimethoprim used in toxoplasmosis, and in combination with other drugs for the for opportunistic infections in AIDS patients such as Pneumocystis jiroveci (pneumonia). Also rarely used in Salmonellosis and Typhoid due to resistance.
25
Q

Identify the main classes of inhibitors of bacterial ribosomal action, giving examples of antibiotics within each class. Identify the mechanism of each class.

A

♠ Macrolides (e.g. Erythromycin and clarithromycin): binds to 50s r-RNA and prevents movement along mRNA.
♠ Lincosamide (e.g. Clindamycin): same mechanism as macrolides.
♠ Aminoglycosides (e.g. Streptomycin): changes shape of 30s tRNA and causes misreading of of mRNA.
♠ Tetracyclines: interferes with t-RNA anticodon reading of mRNA codon.
♠ Chloramphenicol: binds to 50S r-RNA and inhibits formation of peptide bond.

26
Q

What are the main macrolide drugs ?

A

Erythromycin and clarithromycin

27
Q

What are the main indications/spectrum for macrolides ?

A

○ Primarily as an alternative to penicillins in patients who are penicillin- sensitive (i.e. broad spectrum)
○ Active against mycoplasma Chlamydia, Legionella and used in management of community acquired lower respiratory tract infection
○ Limited gram-negative spectrum but active against H. Influenzae (but dosing is an issue)
○ May be used:
-Corynebacterium (diphtheria)
-Camphylobacter (diarrhoea)
-Chlamydia trachomatis
-Toxoplasma gondii in the context of pregancy
○ Can also be used against Helicobacter pylorii in combination with other agents

28
Q

What are the main side effects of erythryomycin and clarithromycin ?

A

ERYTHROMYCIN.

  • Mild gut disturbances
  • Hypersensitivity reactions
  • Transient hearing disturbances
  • (rarely) Cholestatic jaundice.

CLARITHROMYCIN
-As above but also QT prolongation (more prominent problem)

29
Q

What are the main indications/spectrum of Clindamycin ?

A
  • Active against gram-positive Cocci including staphylococci
  • Active against wide range of anaerobic species including Bacteroides species,
  • Used in combination against anaerobic sepsis and necrotising fasciitis, for staphylococcal infections of joints and bones.
  • Used in eye drop to treat staphylococcal conjunctivitis.
30
Q

What are the main sides effects of clindamycin ?

A
  • GI disturbances
  • Pseudomembraneous colitis (acute inflammation of the colon due to necrotising toxin produced by clindamycin-resistant C. difficile which may be part of the normal gut flora.
31
Q

What are the indications/spectrum of amino-glycosides ?

A

The relative toxicity and parenteral administration means that these agents should be reserved for the treatment of serious infections

  • Enterobacteriaceae and Pseudomonas which give rise to septicaemia and serious UTIs
  • Hospital acquired pneumonia, respiratory and intra- abdominal infections due to Pseudomonas
  • Rare problematic infections such as complicated Brucellosis, Yersinia pestis (the plague)
32
Q

What are the side effects of amino-glycosides ?

A
  • Renal toxicity due to damage of the kidney tubules.
  • Ototoxicity with a progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ of the ear. This can result in vertigo, ataxia and loss of balance as well as auditory disturbances including deafness.
  • Neuromuscular block which is usually only seen when the drug is given concomitantly with a neuromuscular blocker and is due to the block of calcium entry into nerves which is necessary for transmitter release.
33
Q

What are the main cautions in the use of amino-glycosides ?

A
  • Caution in elderly
  • Caution with renal failure
  • Caution in severe sepsis that is causing acute renal failure
  • Interaction with other renal toxic drugs
  • Consider the pharmacokinetics carefully
34
Q

What are the basics of the pharmacokinetics of amino-glycosides ?

A
  • Polar agent confined to extracellular fluid
  • Does not cross the BBB
  • Excreted by the kidney
  • Have to be administered intravenously
35
Q

What are the main indications for the use of tetracyclines ?

A
  • Drugs of first choice for rickettsial, mycoplasma and chlamydial infections, brucellosis, cholera, plague and Lyme disease
  • Used in management of resistant Gram negative infection
  • Can be used in COPD
  • Role in treating chronic acne
36
Q

What are the side effects of tetracyclines ?

A
  • Gut upsets (due to changing gut flora populations)
  • Hepatic and renal dysfunction
  • Photosensitivity
  • Binding to bone and teeth causing staining; dental hypoplasia and bone deformities
  • Vestibular toxicity (dizziness and nausea)
37
Q

What are the main indications/spectrum for the use of chloramphenicol ?

A
  • Broad Spectrum
  • Low risk of aplastic anaemia means that its use is limited to serious infections when no other drug is suitable, which includes meningitis and brain abscess when other agents cannot be used
38
Q

Describe the structure and function of topoisomerase IV.

A

-Tetrameric enzyme consisting of two ParC and two ParE sub-units.
-Involved in chromosomal partitioning, catalyses ATP dependent relaxation of
negatively and positively supercoiled DNA and unknotting of un-nicked duplex DNA.

39
Q

Does topoisomerase IV have any action against supercoiling ?

A

No, topoisomerase II does not have any action against supercoiling.

40
Q

Describe the structure and function of DNA gyrase.

A

-Tetrameric enzyme (type of topoisomerase II enzyme) consisting of two GyrA and two GyrB sub-units.
-Can introduce supercoils as well as remove them. To wind or unwind DNA it must form transient covalent bond with DNA, break both strands of DNA, capture another segment of the same DNA molecule and pass this through the double strand
break before resealing.

41
Q

Explain the role of quinolone in the function of DNA gyrase.

A

Quinolones act by binding to complexes that form between DNA and gyrase. Shortly after binding, the quinolones induce a conformational change in gyrase. The enzyme breaks the DNA and the quinolone prevents re-ligation of the broken DNA strands. The enzyme is trapped on the DNA resulting in the formation of a quinolone–
enzyme–DNA complex.
This leaves double stranded DNA breaks which is lethal to the cell.

42
Q

What are the main reasons to modify an antibiotic drug ?

A

♣ Change its pharmacokinetics (i.e. make it better absorbed and thus spreads to body well)
♣ Changes its spectrum of activity (i.e. range of targets against which a drug is biologically active)

43
Q

State an example of fluoroquinolone.

A

Ciprofloxacin

44
Q

What are the main indications/spectrum of Ciprofloxacin ?

A

♪ Enterobacteriaceae (gram-negative enteric bacteria)
♪ Good against H. influenzae.
♪ b-lactamase-producing N. gonorrhoea (A single dose can cure gonorrhoea!)
♪ Camphylobacter (diarrhoea)
♪ Pseudomonas aeruginosa
♪ Salmonella (including typhoid but resistance is emerging)

45
Q

Identify an example of antiprotozoal which also works as an antibiotic. How is it also an antibiotic ?

A
  • Metronidazole
  • Originally an antiprotozoal agent, but under anaerobic conditions it generates toxic radicals that damage bacterial DNA
46
Q

What are the main indications/spectrum of Metronidazole ?

A

♥ Active against anaerobic bacteria such as bacteroides, clostridia, and some streptococci
♥ Important in the treatment of anaerobic infections such as sepsis secondary to bowel disease
♥ Effective in therapy of pseudomembraneous colitis
♥ Used with other drugs (omeprazole, amoxicillin) to treat Helicobacter Pylori infections which give rise to peptic ulceration.

47
Q

Identify any “miscellaneous” antibacterial agents.

A

Nitrofurans, Polymixins

48
Q

Describe the spectrum and indications for nitrofurans use.

A

→ Broad spectrum of activity against bacteria and development of resistance to it is rare.
→ Used to treat UTIs due to
Enterobacteriaceae.

49
Q

Describe the mechanism of action of Polymixins.

A

Interaction with phospholipids in the cell membrane and disruption of its structure, resulting in breach of cell membrane, and loss of intracellular contents.

50
Q

What is the structure of polymixins ?

A

Branched chain decapeptides with cationic detergent properties

51
Q

Describe the indications for polimixins use.

A

Topical use for cutaneous Pseudomonas infections.

52
Q

Describe the processes involved in choosing the correct antimicrobial.

A
  1. What are bacterial causes (microbiology) ?
  2. What is the pharmacokinetics of the disease ?
  3. What is the resistance status of the bacteria ?