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MedEd + PathSoc + Laz's Qs + Romesh Path > Micro 20: Antimicrobial agents 1 > Flashcards

Micro 20: Antimicrobial agents 1 Flashcards

1
Q

What are the 3 main targets for antibiotics?

A

Peptidoglycan layer of cell wall

Inhibition of bacterial protein synthesis

DNA gyrase and other prokaryote-specific enzymes

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2
Q

Difference in structure of gram +ve v gram -ve bacteria

A

Gram +ve:
- Thick peptidoglycan cell wall on outside

Gram -ve:

  • Thinner peptidoglycan cell wall
  • Has an outer membrane which prevents some abx from working on the cell wall
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3
Q

Name two groups of antibiotics that inhibit cell wall synthesis (peptidoglycan layer of cell wall) + group of abx in each / examples

A

Beta-lactams:

  • Penicillins
  • Cephalosporins
  • Carbapenems

Glycopeptides:
- Vancomycin
- Tiecoplanin
(these are abx not groups like in b-lactams)

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4
Q

MoA of b-lactams?

A

Beta-lactam is a structural analogue of the enzyme substrate

Inhibits transpeptidases (aka penicillin-binding protein)

Inactivate enzymes that are involved in the terminal stages of cell wall synthesis

This means that there are no peptide crosslinks between peptidoglycan chains so the cell wall is weak

This causes bacteria to burst and die due to osmotic lysis (from osmotic pressure)

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5
Q

Limitations of b-lactams?

A

They work on the stationary phase of the cell cycle - only effective against rapidly dividing bacteria

They are also ineffective against bacteria w/ no cell wall - intracellular pathogens (eg. Mycoplasma & chlamydia)

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6
Q

4 types of penicilins?

A

Penicillin
Amoxicillin
Flucloxacillin
Piperacillin

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7
Q

Describe the coverage and mechanism of resistance of penicillin?

A

Active against Gram-positives (e.g. Streptococci, Clostridia)

Broken down by beta-lactamases (mainly produced by S. aureus)

NOTE: penicillin is the MOST ACTIVE beta-lactam antibiotic

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8
Q

Describe the coverage, mechanism of resistance and limitations of Amoxicillin

A

Broad-spectrum penicillin

Extends coverage to Enterococci and Gram-negative organisms

Broken down by beta-lactamase produced by S. aureus and many Gram-negatives

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9
Q

Describe the coverage, mechanism of resistance and limitations of Piperacillin

A

Similar to amoxicillin

Extends coverage to Pseudomonas and other non-enteric Gram-negative organisms

Broken down by beta-lactamase produced by S. aureus and many Gram-negatives

Note: P for Piperacillin, P for Pseudomonas

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10
Q

Describe the coverage and limitations of Flucloxacillin

A

Similar to penicillin but less active

Does NOT get broken down by beta-lactamase produced by S. aureus

  • This is why S. aureus is treated w/ flucloxacillin
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11
Q

Name two beta-lactamase inhibitors.

What is the benefit of giving beta-lactamase inhibitors with beta-lactams?

A

Clavulanic acid
Tazobactam

Protect penicillins from breakdown by beta-lactamases thereby increasing the coverage to include S. aureus, Gram-negatives and anaerobes

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12
Q

What is co-amoxiclav?

A

Amoxicillin + Clavulanic Acid

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13
Q

Examples of 1st, 2nd and 3rd gen cephalosporins?

What is the difference between different generations?

A

1st = Cephalexin

2nd = Cefuroxime

3rd = Cefotaxime, Ceftriaxone, Ceftazidime

NOTE: as you go up the generations you get increasing activity against Gram-negatives and less activity against Gram-positives

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14
Q

Benefit of cephalosporins v penicillins?

A

Stable to many b-lactams produced by gram -ve bacterias

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15
Q

Coverage of cefuroxime (2nd gen cephalosporin)

A

Stable to many b-lactamases made by gram -ves

Similar cover to co-amoxiclav

But less active against anaerobes -> combine w/ metronidazole to cover anaerobes

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16
Q

What cephalosporin is the mainstay of bacterial meningitis mx? Why?

What adverse reaction is this associated w/?

A

Ceftriaxone (3rd gen cephalosporin) - This is excreted less than other b-lactams hence maintains conc in CNS

Associated w/ C.Diff infection

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17
Q

What cephalosporin provides good cover against Pseudomonas?

A

Ceftazidime (3rd gen cephalosporin)

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18
Q

What are ESBLs?

A

Type of beta-lactamase that also breaks down cephalosporins as well as penicillins

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19
Q

List three examples of carbapenems

A

Meropenem (Broadest + anti-pseudomonal activity)

Imipenem (Similar to meropenem, can cause renal failure + seizures - give cilastatin)

Ertapenem (not as broad as others, doesnt cover pseudo or enterococci)

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20
Q

What is the main benefit of carbapenems?

A

Stable to EBSL enzymes

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21
Q

Outline the key features of beta-lactam antibiotics (5)

A

Relatively non-toxic

Renally excreted (reduced dose in renal impairment)

Short half-life

Will not cross an intact blood-brain barrier (may cross inflamed meninges in meningitis)

Cross allergenic (penicillins have 5-10% cross-reactivity with cephalosporins and carbapenems)

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22
Q

List examples of bacteria that have shown carbapenem resistance and how?

A

Acinetobacter and Klebsiella

Presence of carbapenemase enzyme

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23
Q

Examples of glycopeptide ABX?

A

Vancomycin

Teicoplanin

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24
Q

MoA of Glycopeptides?

A

Glycopeptides bind to amino acid chains at the end of peptidoglycan precursors

This prevents glycosidic bonds being formed (via transglycosidase) and prevents peptide crosslinks being formed (via transpeptidase)

NOTE: they are similar to beta-lactams but instead of binding to the enzymes, they bind to substrates (cell wall component precursors)

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25
Q

What are glycopeptides often used to treat?

A

Serious MRSA infections

C. difficile infections (oral vancomycin)

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26
Q

Which type of bacteria are glycopeptides effective against and why?

A

Gram-positives

They are large molecules so they cannot cross the outer membrane of Gram-negative cell walls

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27
Q

Major side effect of glycopeptides? prevention?

A

Nephrotoxic - monitor blood levels to prevent accumulation

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28
Q

How are Bacterial ribosome different to human ribosomes?

A

Both have 2 subunits but bacterial is smaller:

  • Human = 60S + 40S
  • Bacterial = 50S + 30S
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29
Q

What are some antibiotics that work by inhibiting protein synthesis?

A

ATMCO

Aminoglycosides - 30S subunit
Tetracyclines - 30S subunit
MLS Group (Macrolides, Lincosamides, Streptogramins) - 50S subunit
Chloamphenicol - 50S subunit
Oxazolidinones - 23S subunit of 50S
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30
Q

MoA of aminoglycosides?

Which class of antibiotics can be used in combination to produce a synergistic effect?

A

Binds to amino-acyl site of the 30S ribosomal subunit and prevents elongation of the polypeptide chain

B-lactams (eg. in endocarditis)

31
Q

Major side effect of aminoglycosides? prevetion?

A

Ototoxic and nephrotoxic - monitor levels

32
Q

Limitations of aminoglycosides?

A

No activity against anaerobes

Inhibited by low pH - won’t work in abscesses

33
Q

Examples of Aminoglycosides?

A

Gentamicin

Amikacin

Tobramycin

34
Q

What are tetracyclines? activity against what?

Examples of tetracyclines?

A

Broad-spectrum agents with activity against intracellular pathogens - no cell wall (e.g. Chlamydiae, Rickettsiae and Mycoplasmas) as well as most conventional bacteria

Doxycycline
Lymecycline

35
Q

MoA of tetracyclines?

A

Binds to the ribosomal 30S subunit and prevents the binding of aminoacyl-tRNA to the ribosomal acceptor site, thereby inhibiting protein synthesis

36
Q

Major issue w/ tetracycline use in terms of effectiveness?

How has this been overcome?

A

Most gram -ves show widespread resistance

Tigacycline - broadened spectrum of tetracyclines

37
Q

Characteristic side effect of tetracyclines?

Who should not recieve tetracycline treatment and why?

A

Light sensitive rash

Children and pregnant women - Because it can deposit in bone and cause discoloration of growing teeth

38
Q

Examples of macrolides?

A

Erythromycin

Clarithromycin

Azithromycin

39
Q

MoA of macrolides?

Limitation

A

Binds to the 50S ribosomal subunit and interferes with translation
Also stimulates the dissociation of peptidyl-tRNA

Limited activity against gram -ves due to outer membrane (generally gram -ve are macrolide resistant)

40
Q

What does the MLS group of abx consist of + examples of each?

A

Macrolides - Azithromycin

Lincosamides - Clindamycin

Streptogramins - Synercid

41
Q

MoA of Oxazolidinones + example?

A

Binds to the 23S components of the 50S subunit to prevent the formation of a functional 70S initiation complex (needed for translation)

Linezolid

42
Q

What are Oxazolidinones active against?

Drawbacks of their use?

A

Highly active against gram-positives (including MRSA and VRE)
Not active against Gram-negatives

Expensive + may cause optic neuritis, thrombocytopaenia and anaemia

43
Q

What types of abx inhibit DNA synthesis + examples of each?

A

Quinolones:
Ciprofloxacin
Moxifloxacin
Levofloxacin

Nitroimidazoles:
Metronidazole
Tinidazole

44
Q

MoA of Quinolones?

A

Acts on the alpha-subunit of DNA gyrase predominantly with other actions

45
Q

What are quinolones active against?

A

Broad antibacterial activity, especially against Gram-negatives, including Pseudomonas aeruginosa

NOTE: newer agents (levofloxacin, moxifloxacin) increased activity against Gram-negatives and intracellular organisms (eg chlamydia)

46
Q

Uses of quinolones? - think conditions (not organisms)

Limitations? (reasons why use has decreased)

A

UTI
Pneumonia
Atypical pneumonia
Bacterial gastroenteritis

Use has decreased due to resistance against E.Coli and side effects (tinnitus)

Note - well absorbed after oral administration

47
Q

MoA of nitroimidazoles? Coverage?

A

Under anaerobic conditions, an active intermediate is formed, which causes DNA strand breakage

Only active against anaerobic bacteria and protozoa (e.g. Giardia)
- low resistance against anaerobes

48
Q

What is a related compound to nitroimidazoles + what are their advantages?

R

A

Nitrofurans (eg. Nitrofurantoin)

Benefits:

  • Concentrates in bladder - hence doesnt cause C. Diff
  • Active against lots of EBSL organisms - not inhibited by mechanisms of resistance
49
Q

What drugs are inhibitors of bacterial RNA synthesis?

Examples?

A

Rifamycins such as:
Rifampicin
Rifabutin

50
Q

Main activity of rifampicin? MoA?

A

Mainly Mycobacteria and Chlamydiae

Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation

51
Q

Side effects of Rifampicin?

A

Inducer of CYP450 - important to monitor interactions (OCP, warfarin) + LFTs

May turn urine + contact lenses orange

52
Q

Can rifampicin be used as single agent? Why?

A

No, rifampicin should never be used alone

Resistance develops rapidly due to chromosomal mutation (single amino acid change in beta-subunit of RNA polymerase)

53
Q

Name two cell membrane toxins

A

Daptomycin

Colistin

54
Q

Describe the activity of:
Daptomycin
Colistin

+specific organisms?

A

Daptomycin

  • Gram-positives
  • Likely to be used in treating MRSA and VRE

NOTE: it is a cyclic lipopeptide

Colistin
- Active against Gram-negatives including Pseudomonas aeruginosa, Acinetobacter baumanii and Klebsiella pneumoniae

NOTE: it is a polymyxin

55
Q

Name two families of antibiotics that work by inhibiting folate metabolism + examples?

MoA?

A

Sulphonamides - sulphamethoxazole
Diaminopyrimidines - trimethoprim

Act indirectly on DNA through interference with folic acid metabolism

NOTE: they act on sequential stages in same pathway so have synergistic action

56
Q

What is co-trimoxazole? why is this used and when?

A

Sulphamethoxazole + trimethoprim

Sulphonamide RESISTANCE is common - hence extends coverage

Useful for PCP (immunocompromised), HAP (less likely to cause C. Diff)

57
Q

What is used to treat community-accquried UTIs?

A

Trimethoprim

58
Q

List some mechanisms of antibiotic resistance.

A

INACTIVATION - Chemical modification or inactivation of the drug

ALTERED TARGET - Modification or replacement of the target

REDUCED ACCUMULATION - Reduced antibiotic accumulation (impaired uptake or enhanced efflux)

BYPASS - Bypass antibiotic-sensitive step in cell division

59
Q

Which bacteria produce beta-lactamases?

A

S. aureus and Gram-negative bacilli (coliforms)

NOTE: this is not the mechanism of resistance in pneumococcus and MRSA

60
Q

In which groups of bacteria is penicillin resistance not reported in?

A

Group A, B, C and G beta-haemolytic streptococci

61
Q

Describe how MRSA uses ‘altered targets’ as a mechanism of resistance.

A

MRSA has a mecA gene which encodes novel PBP2a (peptidoglycan transpeptidase)
This has a low affinity for binding beta-lactams therefore is not inactivated by beta-lactams

62
Q

Describe the mechanism of resistance in Streptococcus pyogenes.

A

Results from acquisition of a series of stepwise mutations in PBP genes

Lower level resistance can be overcome by increasing the dose

63
Q

What are extended spectrum beta-lactamases?

Where is this more common? Advice?

A

Able to breakdown cephalosporins as well as penicillins

Becoming more common in E. coli and Klebsiella

NOTE: if there is > 10% resistance then empirical therapy is not advised

64
Q

What are AmpC beta-lactamases?

A

Breakdown penicillins and cephalosporins but are not inhibited by clavulanic acid

65
Q

MoA of resistance to Macrolides?

A

Adenine-N6 methyltransferase modifies the 23S RNA

This reduces the binding of macrolides thereby resulting in resistance

Encoded by erm (erythromycin ribosome methylation) genes

NOTE: caution when using clindamycin in Staphylococcus and Streptococcus which is resistant to macrolides because lincosamides can induce this mechanism of resistance

66
Q

Which abx have resistance due to chemical modification or inactivation of the drug ? - INACTIVATION

A

B-Lactams

Aminoglycosides

Chlroamphenical

67
Q

Which abx have resistance due to modification or replacement of the target ? ALTERED TARGET

A 
B-Lactams
Glycopeptides
Macrolides
Chloramphenicol
Linezolid
Quinolones
Rifampicin
68
Q

Which abx have resistance due to reduced antibiotic accumulation (impaired uptake or enhanced efflux) ?- REDUCED ACCUMULATION

A 
B-lactams
Aminoglycosides
Tetracyclines
Chloramphenicol
Quinolones
69
Q

Which abx have resistance due to bypass antibiotic-sensitive step in cell division
?

A

Trimethoprim

Sulphonamides

70
Q

What does bactericidal and bacterostatic mean?

A

Bactericidal - Kills bacteria

Bacteriostatic - Stops bacterial growth

71
Q

Which classes of Abx are bactericidal and bacteriostatic?

A

Bactericidal:

  • Anything that doesn’t work via inhibition of protein synthesis
  • Protein synthesis abx = Aminoglycosides + Oxazolidinones (against strep)

Bacteriostatic:

  • Only protein synthesis abx
  • Except aminoglycosides + oxazolidinones (work for staph + enterococci)
72
Q

What abx work against Gram +ve?

What work against gram -ve?

A

Gram +ve:

  • B-lactams (penicillins, cephalosporins, carbapenems)
  • Glycopeptides
  • Macrolides - useful in penicillin allergy
  • Oxazolidinones

Gram -ves:

  • Aminoglycosides
  • Fluroquinolones
73
Q

MoA of Chloramphenicol?

A
  • Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit
  • And inhibits the formation of peptide bonds during translation

MedEd + PathSoc + Laz's Qs + Romesh Path (99 decks)

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