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MICRO - Abbie > 1. Antimicrobial agents I > Flashcards

1. Antimicrobial agents I Flashcards

1
Q

What are examples of selective targets in antimicrobial agents?

A
  1. Peptidoglycan layer of cell wall. 2. Inhibition of bacterial protein synthesis. 3. DNA gyrase and other prokaryote-specific enzymes
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2
Q

Difference between gram positive cell wall and gram negative cell wall, in terms of the layers?

A

Gram positive cell wall has a cytoplasmic membrane and a THICK peptidoglycan layer. Gram negative cell wall has a cytoplasmic membrane, peptidoglycan layer and outer membrane (which is part of the reason why some antibiotics don’t work on gram-negatives).

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3
Q

What are examples of beta-lactam antibiotics?

A

Penicillins, cephalosporins and carbapenams (and monobactams)

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4
Q

What do glycopeptides act against and what are some examples?

A

Glycopeptides only act against Gram-positives. Examples are vancomycin and tiecoplanin

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5
Q

How do beta-lactams work?

A
  1. Beta-lactams inactivate the enzymes that are involved in the terminal stages of cell wall synthesis (transpeptidases AKA penicillin binding proteins)
  2. This means cells will have no peptide crosslinks and hence have a weak cell wall
  3. This is bactericidal.
  4. Activate against rapidly-dividing bacteria, so have no effect on bacteria in stationary phase of cell cycle.
  5. Ineffective against bacteria that do NOT have a peptidoglycan cell wall e.g. Mycoplasma and Chlamydia
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6
Q

If you are allergic to penicillin, what is the chance that you will also be allergic to other classes?

A

5%

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7
Q

What is penicillin active against, and give some examples:

A

Active against gram-positives and examples include Streptococci and Clostridia.

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8
Q

What is penicillin broken down by?

A

Broken down by beta-lactamase which is produced by S aureus.

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9
Q

What is the most active beta-lactam antibiotic?

A

Penicillin

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10
Q

What is amoxicillin and what does it extend its coverage to?

A

Broad-spectrum penicillin. Extends coverage to: Enterococci and gram-negative organisms

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11
Q

What is amoxicillin broken down by?

A

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

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12
Q

What is flucloxacillin similar to? How is it different?

A

Similar to penicillin but less active. Does NOT get broken down by beta-lactamase produced by S aureus

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13
Q

What is piperacillin similar to?

A

Similar to amoxicillin. Extends coverage to Pseudomonas and other non-enteric Gram-negative organisms. It is broken down by beta-lactamase produced by S. aureus and many Gram-negative organisms

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14
Q

What do clavulanic acid and tazobactam do?

A

These are both beta-lactamase inhibitors. Protect penicillin from breakdown by beta-lactamase. This increases the coverage of antibiotics to include S aureus, gram-negatives and anaerobes.

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15
Q

What issues are there with combining drugs such as clavulanic acid and tazobactam?

A

There are pharmacological issues with combining these drugs with the antibiotics because it means that the pharmacokinetics of two drugs must be considered

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16
Q

What happens to the activity of cephalosporins against Gram-negatives and Gram-positives as you go up generations?

A

o As you go up the generations, you get increasing activity against Gram-negatives and decreasing activity against Gram-positives

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17
Q

Example(s) of first generation cephalosporins?

A

Cephalexin

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18
Q

Example(s) of second generation cephalosporins

A

Cefuroxime

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19
Q

Example(s) of third generation cephalosporins

A

Cefotaxime, ceftriaxone, ceftazidime

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20
Q

What is cefuroxime stable to and what does it cover?

A

Stable to many beta-lactamases produced by Gram negatives. Similar cover to co-amoxiclav but less active against anaerobes.

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21
Q

What generation is ceftriaxone? What is the mainstay of treatment and what infection is it associated with?

A

3rd generation cephalosporin, mainstay of treatment for bacterial meningitis, associated with (/causes) C. difficile infection

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22
Q

What does ceftazidime cover?

A

Good anti-Pseudomonas cover

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23
Q

What does extended spectrum beta-lactamase (ESBL) break down and why is it a big problem?

A

These are a type of beta-lactamase that also breakdown cephalosporins as penicillins. This was a big problem because cephalosporins were the mainstay of treatment for a lot of severe infections.

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24
Q

What are carbapenems stable to?

A

ESBL enzymes

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25
Q

What are examples of carbapenems?

A

Meropenem, imipenem, ertapenem

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26
Q

What is the last line of beta-lactams?

A

Carbapenems

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27
Q

Carbapenemase enzymes are becoming more widespread. What are the multi-drug resistant species?

A

Acinetobacter and Klebsiella species

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28
Q

What are key features of beta-lactams?

A

Relatively non-toxic; renally excreted (so reduced dose needed in renal impairment); short half-life; will not cross an intact blood-brain barrier; but they do cross inflamed meninges (e.g. meningitis); cross allergenic (penicillins approximately 5-10% cross-reactivity with cephalosporins and carbapenems)

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29
Q

What are glycopeptides active against and why?

A

Large molecules which are unable to pass the Gram-negative outer membrane because of their size. So they are active against Gram-positive. They work by inhibiting cell wall synthesis.

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30
Q

Why are glycopeptides important?

A

Important for treating serious MRSA infections (IV). (It is slowly bactericidal)

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31
Q

What is glycopeptide oral vancomycin used for?

A

Oral vancomycin can be used to treat serious C. difficile infection

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32
Q

What are examples of glycopeptides?

A

Vancomycin and teicoplanin

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33
Q

Why is it important to monitor drug levels when glycopeptides are administered?

A

It is important to monitor drug levels to prevent accumulation as glycopeptides are nephrotoxic

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34
Q

What is the mechanism of glycopeptides?

A
  1. At the end of peptidoglycan precursors there is an amino acid chain
  2. The glycopeptide will bind to this amino acid chain and it prevents glycosidic bonds and peptide crosslinks.
  3. They are similar to beta-lactams, however, instead of binding to the enzymes themselves, they bind to the binding sites of the enzymes on the cell wall component precursors.
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35
Q

What are inhibitors of protein synthesis?

A

Aminoglycosides (e.g. gentamicin, amikacin, tobramycin), tetracyclines, the MSL group (macrolides (e.g. erythromycin), lincosamides (e.g. clindamycin), streptogramins (e.g. Synercid)), chloramphenicol, oxazolidinones (e.g. Linezolid)

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36
Q

What are examples of aminoglycosides?

A

Gentamicin, amikacin, tobramycin

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37
Q

What is the MSL group

A

Macrolides, lincosamides, streptogramins

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38
Q

What is an example of a macrolide?

A

Erythromycin

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39
Q

What is an example of a lincosamide?

A

Clindamycin

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40
Q

What is an example of a streptogramin?

A

Synercid

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41
Q

What is an example of an oxazolidinones?

A

Linezolid

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42
Q

How do aminoglycosides work?

A
  • They bind to amino-acyl sites of the 30S ribosomal subunit.
  • It has a rapid, concentration-dependent bactericidal action.
  • Require specific transport mechanisms to enter the cells (this feature is responsible for some of the mechanisms of intrinsic resistance)
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43
Q

Why must you monitor the levels of aminoglycosides?

A

Ototoxic and nephrotoxic

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44
Q

Which aminoglycosides are particularly active against Pseudomanas aeruginosa?

A

Gentamicin and tobramycin

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45
Q

What can aminoglycosides be used in synergistic combinations with?

A

Beta-lactams (e.g. in endocarditis)

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46
Q

What are aminoglycosides not effective against?

A

NO activity against anaerobes. They are also inhibited by low pH so they will not be effective in abscesses.

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47
Q

What is the mechanism of action of aminoglycosides?

A

The full MOA is not fully understood. They prevent elongation of the polypeptide chain. They cause misreading of codons along the mRNA.

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48
Q

What type of agents are tetracyclines and what are they active against?

A

Broad-spectrum agents with activity against intracellular pathogens (E.g. Chlamydiae, Rickettsiae and Mycoplasmas) as well as most conventional bacteria.

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49
Q

Tetracyclines are bacteriostatic (NOT bactericidal). What does this mean?

A

“bacteriostatic” means that the agent prevents the growth of bacteria (i.e., it keeps them in the stationary phase of growth), and “bactericidal” means that it kills bacteria.

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50
Q

How is the usefulness of tetracyclines limited?

A

WIDESPREAD resistance limits their usefulness. Most Gram-negatives are resistant to tetracyclines. This has been overcome to some extent with the advent of tigacycline (which has broadened the spectrum of tetracyclines).

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51
Q

Who should not be given tetracycline and why?

A

Do NOT give to CHILDREN or PREGNANT WOMEN. They deposit in bone and can cause discoloration of growing teeth.

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52
Q

Which antibiotic is associated with a light-sensitive rash?

A

Tetracyclines

53
Q

What is the mechanism of action of tetracyclines?

A

They bind to the ribosomal 30S subunit. Prevent binding of aminoacyl-tRNA to the ribosomal acceptor site, thereby inhibiting protein synthesis.

54
Q

Are macrolides bacteriocidal or bacteriostatic?

A

Bacteriostatic

55
Q

What do macrolides have minimal activity against?

A

Gram-negatives (because of the outer membrane)

56
Q

What are macrolides useful for?

A

Useful for mild Staphylococcal or Streptococcal infections in penicillin-allergic patients. Also active against: Campylobacter spp., Legionella, Pneumophila.

57
Q

What new agents have better pharmacological properties than macrolides?

A

clarithromycin and erythromycin

58
Q

What is the mechanism of action of macrolides?

A

Bind to the 50S subunit of the ribosome, and: interfere with translocation and stimulate dissociation of peptidyl-tRNA

59
Q

Is chloramphenicol bacteriocidal or bacteriostatic?

A

Bacteriostatic

60
Q

What type of activity does chloramphenicol have?

A

BROAD antibacterial activity

61
Q

When is chloramphenicol used and why is it RARELY used?

A

Rarely used apart from eye preparations and special considerations. Risk of aplastic anaemia and caution must be taken in neonates because they have a reduced ability to metabolise the drug and they can get Grey Baby Syndrome.

62
Q

What is the mechanism of action of chloramphenicol?

A

Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation.

63
Q

How do oxalidinones work?

A

Mechanism: Binds to the 23S component of the 50S subunit to prevent the formation of a functional 70S initiation complex (which is required for translation)

64
Q

What are oxalidinones highly active against?

A

Gram-positive organisms (including MRSA and VRE)

65
Q

What are oxalidinones not active against?

A

NOT ACTIVE against most Gram-negatives

66
Q

What are the disadvantages of oxalidinones?

A

Expensive, may cause thrombocytopenia and optic neuritis.

67
Q

What are inhibitors of DNA synthesis?

A

Quinolones e.g. ciprofloxacin, levofloxacin, moxifloxacin. Nitroimidazoles e.g. metronidazole, tinidazole.

68
Q

What is the mechanism of action of fluoroquinolones?

A

Act on the alpha-subunit of DNA gyrase predominantly, with other antibacterial actions. It is bactericidal.

69
Q

Are fluoroquinolones bactericidal or bacteriostatic?

A

bactericidal

70
Q

What are fluoroquinolones active against?

A

BROAD antibacterial activity, especially against Gram-negative organisms, including Pseudomonas aeruginosa

71
Q

Newer fluoroquinolone agents (e.g. levofloxacin, moxifloxacin) have increased activity against …

A

Gram-negatives and intracellular bacteria e.g. Chlamydia.

72
Q

How are fluoroquinolones administered?

A

Well absorbed following oral administration

73
Q

What are the uses of fluoroquinolones?

A

UTIs, pneumonia, atypical pneumonia and bacterial gastroenteritis

74
Q

What are examples of nitroimidazoles?

A

Metronidazole, tinidazole

75
Q

How do nitroimidazoles work?

A

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

76
Q

Are nitroimidazoles bactericidal or bacteriostatic?

A

Rapidly bactericidal

77
Q

What are nitroimidazoles active against?

A

Anaerobic bacteria and protozoa (e.g. Giardia)

78
Q

What are related compounds to nitroimidazoles and why are they useful?

A

Nitrofurans (e.g. nitrofurantoin) are related compounds. Nitrofurantoin is particularly useful because it concentrates in the bladder.

79
Q

What is the mechanism of action of rifampicin?

A

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

80
Q

Is rifampicin bactericidal or bacteriostatic?

A

Bactericidal

81
Q

What is rifampicin active against?

A

Active against certain bacteria, including Mycobacteria and Chlamydiae

82
Q

What is important to be aware of with rifampicin? What are its side effects?

A

Important to monitor LFTs (metabolised by the liver). Beware of INTERACTIONS with other drugs metabolised by the liver e.g. warfarin, oral contraceptive. Its side effects are that it may turn urine and contact lenses orange.

83
Q

Why should rifampicin never be used as a single agent?

A

(Altered targets). Except for short-term prophylaxis (e.g. meningococcal infection) rifampicin should NEVER be used as a single agent. This is because resistance develops rapidly. Resistance is due to chromosomal mutation. A single amino acid change in the beta-subunit of RNA polymerase can confer resistance.

84
Q

What are some cell membrane toxins?

A

Daptomycin and colistin

85
Q

What is daptomycin?

A

Cyclic lipopeptide

86
Q

What is daptomycin active against? What is daptomycin used for?

A

Activity limited to Gram-positive organisms. Likely to be used in treating MRSA and VRE infections as an alternative to linezolid and Synercid.

87
Q

What is colistin? Is it absorbed orally?

A

Polymyxin antibiotic. Not absorbed orally.

88
Q

What is colistin active against?

A

Active against Gram-negative organisms, including: Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumoniae.

89
Q

What must you be aware of with colistin?

A

Nephrotoxic - should be reserved for use against multi-resistant organisms

90
Q

What are some inhibitors of folate metabolism?

A

Sulphonamides and diaminopyrimidines

91
Q

How do sulphonamides and diaminopyrimidines work?

A

They are inhibitors of folate metabolism. They act directly on DNA through interference with folic acid metabolism.

92
Q

Why do sulphonamides and diaminopyrimidines have synergistic action?

A

These two drug classes have synergistic action because they act on sequential stages in the same pathway (inhibiting folic acid metabolism).

93
Q

Is resistance common in inhibitors of folate metabolism?

A

Sulphonamide RESISTANCE is common. Combination of sulphamethoxazole + trimethoprim (co-trimoxazole) is very useful in certain situations (e.g. Pneumocystis pneumonia)

94
Q

Trimethoprim is used for …

A

Treatment of community-acquired UTI

95
Q

What are the different mechanisms of resistance?

A
  1. Inactivation, 2. Altered target, 3. Reduced accumulation, 4. Bypass
96
Q

What are examples of drugs that develop resistance via inactivation?

A

beta-Lactams, aminoglycosides, chloramphenicol

97
Q

What are examples of drugs that develop resistance via altered target?

A

beta-Lactams, macrolides, quinolones, rifampicin, chloramphenicol, linezolid, glycopeptides

98
Q

What are examples of drugs that develop resistance via reduced accumulation?

A

Tetracyclines, beta-Lactams, aminoglycosides, quinolones, chloramphenicol

99
Q

What are examples of drugs that develop resistance via bypass?

A

Trimethoprim (diaminopyrimidine), sulphonamides

100
Q

How does reduced antibiotic accumulation occur as a mechanism of resistance?

A

Impaired uptake, enhanced efflux

101
Q

How does bypass occur as a mechanism of resistance?

A

Bypass antibiotic-sensitive step in cell division

102
Q

How is inactivation a mechanism of resistance of beta-Lactams?

A

Beta-lactamases are a major mechanism of resistance to beta-lactams in S. aureus and Gram-negative bacilli (coliforms).

103
Q

In what infections is inactivation of beta-lactams NOT a mechanism of action?**

A

NOT the mechanism of resistance in penicillin-resistant Pneumococcus and MRSA. So, in patients with pneumoccocal infection that is unresponsive to amoxicillin, changing it to co-amoxiclav wont make any difference because the mechanism of resistance is not through beta-lactamases.

104
Q

What is penicillin resistance NOT reported in?

A

Group A (S. pyogenes), B, C, or G beta-haemolytic streptococci

105
Q

How is altered targets a mechanism of resistance against beta-lactams in MRSA?

A

MRSA has a mecA gene which encodes novel PBP2a. This has a low affinity for binding beta-lactams. This can take over the function of normal PBP which would be inactivated at high concentrations of ABx.

106
Q

How is altered targets a mechanism of resistance against beta-lactams in streptococcus pneumoniae?

A

Penicillin resistance results from acquisition of a series of stepwise mutations in PBP genes. The mutation isn’t as clear as with MRSA. Lower level resistance can be overcome by increasing the dose of penicillin.

107
Q

Lower level resistance to penicillin by altered targets can be overcome by increasing the dose of penicillin. Why can this be difficult in meningitis?

A

This can be difficult in meningitis because it is difficult to achieve high CSF drug concentrations. Vancomycin may be used in these situations.

108
Q

What are extended-spectrum beta-lactamases (ESBLs) able to break down?

A

Able to break down cephalosporins as well as penicillins.

109
Q

What bacterial infections are ESBLs becoming more common in?

A

E. coli and Klebsiella sp.

110
Q

Give examples where there have been treatment failures reported with beta-lactam/beta-lactamase inhibitor concentrations

A

Augmentin, tazocin

111
Q

At what level of resistance is antibiotic for empirical therapy not advised?

A

if there is > 10% resistance, then using that antibiotic for empirical therapy is not advised

112
Q

What started being used as beta-lactam resistance became increasingly common?

A

Carbapenems

113
Q

What started being used as carbapenem-resistance became more common?

A

Aminoglycosides

114
Q

What doe AmpC beta-lactamases breakdown but are NOT inhibit by?**

A

AmpC beta-lactamases breakdown penicillins and cephalosporins but they are NOT inhibited by clavulanic acid

115
Q

What are the types of carbapenemase?

A

NDM, VIM, IMP, KPC, OXA-48

116
Q

Describe the geographic distribution of NDM (carbapenemase)

A

Widespread in Enterobacteriaceae (esp. K. pneumonoae and E. coli in India and Pakistan). Imported to UK via patients with travel/ hospitalisation/ dialysis in India/ Pakistan.

117
Q

Describe the molecular epidemiology of NDM (carbapenemase)

A

Diverse strain types in UK. Plasmid spread among strains and species is more important than clonal spread among patients. Nevertheless there have been a few cases of cross-infection in the UK.

118
Q

Describe the geographic distribution of VIM (carbapenemase)

A

Scattered globally, endemic in Greece, mostly K. pneumoniae. Sometimes imported to UK via patients previously hospitalised in Greece.

119
Q

Describe the molecular epidemiology of VIM (carbapenemase)

A

Plasmid spread among strains is more important than clonal spread of producer strains.

120
Q

Describe the geographic distribution of IMP (carbapenemase)

A

Scattered worldwide; no clear associations

121
Q

Describe the molecular epidemiology of IMP (carbapenemase)

A

Mostly plasmid spread

122
Q

Describe the geographic distribution of KPC (carbapenemase)

A

USA since 1999. Prevalent also Israel, and Greece; outbreaks elsewhere in Europe. Some UK cases imported via patient transfers, but local spread in NW England.

123
Q

Describe the molecular epidemiology of KPC (carbapenemase)

A

Some plasmid spread; mostly among K. pneumoniae, occasionally to other Entero-bacteriaceae. Also clonal spread, including global K. pneumoniae ST258 lineage.

124
Q

Describe the geographic distribution of OXA-48 (carbapenemase)

A

Widespread K. pneumoniae in Turkey, Mid-East and N Africa. Some import to UK and an outbreak in one London renal unit 2008-9

125
Q

Describe the molecular epidemiology of OXA-48

A

Mixture of plasmid and clone spread

126
Q

How can resistance to macrolides occur through altered targets?

A
  • Adenine-N6 methyltransferase modifies the 23S RNA. - This reduces the binding of macrolides, resulting in resistance.
  • Encoded by erm (erythromycin ribosome methylation) genes.
  • It is easy to express this resistance in the laboratory.
127
Q

What are measures to reduce the spread of ABx resistance in hospital?

A

Control antibiotic usage and encourage good prescribing habits. Improve standards of hospital hygiene - encourage handwashing.

128
Q

If you have Staphylococcus or Streptococcus that is resistant to macrolides, what do you give?

A
  • You use clindamycin with CAUTION
  • With lincosamides, this mechanism of resistance is inducible so it is often unclear whether clindamycin does or doesn’t naturally have this mechanism of resistance.
  • This is because clindamycin resistance isn’t always easy to elicit from the laboratory.
  • Macrolide resistance may also make the organism clindamycin resistant.

MICRO - Abbie (19 decks)

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