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a path 3 > MICRO: Antimicrobials 1 > Flashcards

MICRO: Antimicrobials 1 Flashcards

1
Q

Give 3 examples of selective targets of antibiotics.

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

Give 2 classes of antibiotics invovled in inhibition of cell wall synthesis.

A
  1. beta lactams
  2. glycopeptides
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3
Q

Give 3 examples of beta-lactam antibiotics.

A
  • penicillins
  • cephalosporins
  • carbapenems
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4
Q

Give 2 examples of glycopeptides.

A
  • vancomycin
  • teicoplanin
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5
Q

Describe the cell walls of gram +ve and gram -ve bacteria.

A
  • Most bacteria have a cell wall - those that do not are atypical organisms such as chlamydia or mycobacteria
  • The cell is made up of peptidoglycan (PTG)
    • thick in Gram positive
    • thinner in Gram negative
  • Between the peptidoglycan precursors, there are glycosidic and peptide bonds which gives the bacterial cell wall its rigidity and protects the bacteria from osmotic pressure, being lysed.
  • Gram -ves have an outer membrane which can stop some antibiotics - this is a reason gram negatives tend to be more antibiotic resistant and are harder to treat
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6
Q

What are transpeptidases also known as? What is their role in the cell wall?

A

penicillin binding proteins - involved in terminal stages of cell wall synthesis (form strong bonds between NAM + NAG peptidoglycan precursors to form a rigid cell wall)

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7
Q

How do beta-lactam antibiotics act?

A

inhibition of transpeptidases –> daughter cell walls are weak and lyse = BACTERICIDAL

beta-lactams are a STRUCTURAL ANALOGUE of the enzyme substrate

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8
Q

Which types of bacteria are beta-lactams most and least effective against (in general)?

A
  • Active against rapidly dividing bacteria- if the bacteria are not dividing, it will not work (i.e. in the stationary phase)
  • Ineffective against bacteria that lack a PTG cell wall
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9
Q

What are the 4 classes of beta-lactam containing antimicrobial structures?

A
  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Monobactam

They all have a beta-lactam ring structure.

Beta lactams can go “BACk to the PEN where the SPORes are ChILLIN”

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10
Q

What chance is there of allergy to cephalosporins in a patient allergic to penicillins?

A

~5%

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11
Q

Give 4 examples of penicillins.

A
  • Amoxicillin
  • Flucloxacillin
  • Piperacillin
  • Clavulanic acid and tazobactam
  • Augmentin/co-amoxiclav
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12
Q

What is tazocin and what is its use?

A

Tazobactam + piperacillin = tazobactam

Tazobactam protects piperacillin from enzymatic breakdown by beta-lactamases

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13
Q

Which combination helps amoxicillin retain coverage against E coli?

A

Augmentin/co-amoxiclav - Clavulanic acid protects amoxicillin from enzymatic breakdown

NB: lots of E coli are now resistant to amox and S. aureus/other gram -ves produce beta-lactamses which also break it down

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14
Q

Compare the actions of penicillin, amoxicillin, flucloxacillin and piperacillin.

A
  • Penicillin
    • Active against Gram +ve organisms (Streptococci, Clostridia)
    • Broken down by beta-lactamase
  • Amoxicillin
    • Broad spectrum penicillin, extends coverage to Enterococci and Gram -ve organisms
    • Now lots of E. coli are resistant
    • Broken down by beta-lactamase
  • Flucloxacillin
    • Similar to penicillin although LESS ACTIVE
    • STABLE to b-lactamase produced by S. aureus
  • Piperacillin
    • Similar to amoxicillin, broad spectrum, extends coverage to Pseudomonas and other non-enteric Gram -ves
    • Broken down by beta-lactamase
    • Used for HAI
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15
Q

What are the advanatages of clavulanic acid and tazobactam?

A

They are beta-lactamase inhibitors

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16
Q

Which beta-lactam is the most active?

A

Penicillin is the MOST ACTIVE b-lactam antibiotic

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17
Q

Give an example of 1st, 2nd and 3rd gen cephalosporins. Compare the groups.

A
  • Increasing activity against gram -ve bacilli
  • 2nd generation- better for +ve organisms, good activity towards E. coli
  • 3rd generation- better towards -ve organisms, weaker towards +ve organisms, used for HAP (especially Pseudomonas)
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18
Q

Which cephalosporin is associated with C diff infection?

A

Ceftraixone (3rd generation)

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19
Q

Which cephalosporin is stable to beta-lactases with similar coverage to co-amoxiclav but less stable against anaerobes?

A

Cefuroxime

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20
Q

Which cephalosporin has good anti-pseudomonas activity?

A

ceftazidime

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21
Q

Which enzyme confers resistance to all cephalosporins?

A

extended spectrum beta-lactamase producing organisms (ESBLs)

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22
Q

Which beta-lactams are stable to ESBL organisms?

A

Carbapenems

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23
Q

Give an example of carbapenems. Which organisms have shown resistance to carbapenems?

A

Meropenem, Imipenem, Ertapenem

Really broad spectrum, covering almost everything. But some organisms like Acinetobacter and Klebsiella have shown resistance with carbapenemase production.

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24
Q

What is a common use of beta-lactams? What are the cautions for beta-lactam use?

A

Common use - meningitis; will not cross intact BBB but when inflamed can cross. Relatively non toxic

Cautions:

  • Renally excreted
  • Short t1/2 so prescribe multiple times a day
  • Cross-allergenic - 10% cross reactivity of penicillins with cephalosporins/carbapenems
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25
Q

Can glycopeptides be used against gram -ves? Why?

A

No - large molecules so unable to penetrate the outer cell wall.

But active against gram +ve organisms

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26
Q

Which infection are glycopeptides useful for? Why should you monitor drug levels?

A
  1. Serious MRSA infections - treated IV
  2. C. difficile - PO vancomycin can be used

They are nephrotoxic - monitor for accumulation

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27
Q

Are glycopeptides bactericidal?

A

Yes slowly. They are cell wall synthesis inhibitors

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28
Q

What is the mechanims of action of glycopeptides?

A
  • Vancomycin and Teicoplanin bind to the end of this chain (on the right) and stop the transpeptidase from binding and CANNOT form the peptide cross links
  • They also stop the transglycosidase from binding so get no glycosidic bonds too
  • So get a weakened cell wall and similarly, the daughter cells will lyse.
  • = slowly bactericidal
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29
Q

Give 5 examples of inhibitors of protein synthesis.

A
  • Aminoglycosides- e.g. Gentamicin, Amikacin, Tobramycin
  • Tetracyclines- e.g. Doxycycline
  • MLS group - Macrolides- e.g. Erythromycin / Lincosamides- e.g. Clindamycin / Streptogramins- e.g. Synercid (NOT used anymore)
  • Chloramphenicol
    • Used in CAP
    • May use for meningitis and anaphylaxis
  • Oxazolidinones- e.g. Linezolid
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30
Q

What does the clinical effect of aminoglycosides largely depend upon?

A

They have concentration-dependent bactericial activity - so want a high concentration early on for better clinical effect and outcome

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31
Q

What are the cautions with using aminoglycosides?

A
  • Nephrotoxicity
  • Ototoxicity

monitor levels

  • Most will have 1 dosing a day- enough to trough and not reach toxicity but monitor accumulation
  • High trough levels over 24-48 hours are associated with toxicity
  • Okay to give 1 big dose first (as this is where the physical effect comes from) but then follow policies for monitoring toxicity
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32
Q

Are aminoglycosides useful for abscesses? Why?

A

Aminoglycosides are inhibited by low pH and so are not very effective in abscesses

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33
Q

Give 2 examples of aminoglycosides and their activity.

A
  • Gentamicin and tobramycin particularly active against Pseudomonas aeruginosa
  • They also have a SYNERGISTIC combination with b-lactams
  • NO activity against anaerobes
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34
Q

What is the MOA of aminoglycosides?

A
  • Prevent elongation of the polypeptide chain
    • Bind to the 30S subunit of the ribosome and prevent elongation
  • Cause misreading of the codons along the mRNA
35
Q

What types of organisms are tetracyclines especially effective against?

A

Broad-spectrum agents with activity against IC pathogens (CRaMe.g. chlamydiae, rickettsiae and mycoplasma) as well as most conventional bacteria

*these have a cell wall so penicillins are ineffective

36
Q

What is the MOA of tetracyclines? How do they kill bacteria?

A
  • Reversibly binds to the ribosomal 30S subunit
  • Prevents binding of aminoacyl-tRNA (transfer RNA) to the ribosomal acceptor site, so inhibiting protein synthesis
  • They are not bactericidal but BACTERIOSTATIC -
37
Q

Which new tetracycline is not affected by most resistance mechanims that usually affect tetracyclines?

A

Tigecycline - so active against most MDR

38
Q

When should tetracyclines not be given?

A
  1. Children
  2. Pregnant women

= they can be deposited in growing bone and discolour growing teeth

= can also cause a light sensitive rash so avoid sun

39
Q

What is the MOA of macrolides?

A
  • Bind to the 50S subunit of the ribosome
  • Interfere with translation
  • Stimulate dissociation with peptidyl-tRNA
  • Inhibit protein synthesis
40
Q

Which antibiotics can be given against:

  • atypical pneumonia e.g. mycoplasma?
  • penicillin allergic patients with staph infection ?
A

Both MACROLIDES

They have minimal activity against gram -ve organisms due to their outer membrane but useful for:

  • Staphylococcus + Streptotoccus in penicillin allergic patients
  • Campylobacter/legionella pneuumophilia/mycoplasma
41
Q

What are the advatages of newer macrolides?

A

Clarithromycin/azithromycin have improved pharamacological properties:

  • longer t1/2 so less frequent dosing
  • azithromycin has some gram -ve activity and can be used for Salmonella typhi or bronchiectasis in CF patients
42
Q

Why are macrolides often combined with beta lactams e.g clindamycin and flucloxacillin?

A

To inhibit protein synthesis when bacteria make toxins in the stationary phase of growth (when beta-lactams are not effective) E.g. in Group A Streptococcus and necrotising fasciitis

43
Q

What is the MOA of chloramphenicol?

A
  • Binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation
  • BACTERIOSTATIC
44
Q

Why is chloramphenicol rarely used/what are its risks?

A
  • Rarely used (apart from the eye preparations and special indications) because of risk of:
    • Aplastic anaemia
    • Grey baby syndrome in neonates due to inability to metabolise drug
45
Q

Which clinical situation is chloramphenicol often used for?

A

Penicillin allergic patients with meningitis (because they have activity against pneumococcus and meningococcus)

Sometimes for CAP as the side-effects are less problematic than beta-lactams

46
Q

What is the MOA of Oxazolidinones (Linezolid)?

A
  • Binds to the 23S component of the 50S subunit to prevent formation of a functional 70S initiation complex (required for the translation process to occur)
    • Novel MoA and NOT derived from a natural source
47
Q

Which organisms are oxazolidinones effective against?

A

Gram +ve including MRSA and VRE

NOT effective against most gram -ves

48
Q

What are the side-effects of oxazolidinones?

A

Thrombocytopeanie with prolonged use (2-4 weeks)

Optic neuritis (>4 weeks)

Resistance is rare

49
Q

What class are ciprofloxacin, levofloxacin and moxifloxacin? Compare their actions.

A

Fluoroquinolones

  • Ciprofloxacin- good for Gram -ves including P. aeruginosa
  • Levofloxacin- in the middle
  • Moxifloxacin- good for Gram +ves (inc. pneumococcus) but worse for Gram-ves
50
Q

Name 2 classes of inhibitors of DNA synthesis. What is their general action?

A

Bind to topoisomerase and DNA gyrase

  1. Quinolones e.g. ciprofloxacin
  2. Nitromidazoles e.g. metromidazole
51
Q

What is the MOA of fluoroquinolones?

A

Act on the a-subunit of DNA gyrase predominantly, but together with other antibacterial actions, are essentially bactericidal.

52
Q

What organisms are fluoroquinolones effective against?

A

Broad antibacterial activity especially gram -ve e.g. pseudomonas aeruginosa

Newer agents (levo/moxi) have increased gram +ve activity and IC e.g. against chlamydia and legionella, pneumococcus and haemophilus

53
Q

What are the side effects of fluoroquinolones/quinolones?

A
  • Tendonitis
  • C. diff outbreaks

Other:

  • Resistance - 25% of E coli
  • Caution in hypotensive/tachycardic patients
54
Q

What route of administration is good for quinolones?

A

PO - well absorbed and good bioavailability

55
Q

What is the MOA of nitromidazole?

A

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

Rapidly bactericidal + resistance is rare

56
Q

What are… useful for treating clinically?

  1. Quinolones
  2. Nitromidazoles
A
  1. UTI, pneumonia, atypical pneumonia, bacterial gastroenteritis
  2. UTI - nitrofurans are related compounds (e.g. nitrofurantoin); not absorbed systemically
57
Q

What organisms are nitromidazoles effective against?

A

Active against anaerobic bacteria and protozoa (e.g. Giardia)

58
Q

Name a class of inhibtors of RNA synthesis and give 2 examples.

A

Rifamycins e.g. rifampicin, rifabutin

59
Q

What is the MOA of rifamycins? What organisms are they useful against?

A

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

Bactericidal

Active against certain bacteria, including Mycobacteria and Chlamydiae

60
Q

What is the only way that rifampicin should be used and why?

A

IN COMBINATION with another antibiotic as resistance develops rapidly

except for short-term prophylaxis e.g. against meningococcal infection otherwise never use alone

61
Q

What is the MOA of resistance against rifampicin?

A
  • ALTERED TARGET
  • Resistance due to chromosomal mutation
  • This causes a single AA change in the b-subunit of RNA polymerase which then fails to bind to Rifampicin
62
Q

Which infections is rifampicin useful for clinically?

A
  1. TB
  2. complex prosthetic joint infections + endocarditis (has biofilm disrupting activity)
63
Q

Name two drugs which are membrane toxins.

A

daptomycin

colistin

64
Q

What are ths uses of daptomycin? What is its MOA? What can be used as an alternative for?

A
  • Cyclic lipopeptide
  • Gram +ve ONLY [utility against enterococci is limited and resistance can develop. Good activity mainly against S. aureus]
  • MRSA and VRE as an alternative to linezolid and Synercid
65
Q

What are the uses of colistin? What is its MOA?

A
  • A polymyxin antibiotic that destroys the outer cell membrane of Gram -ve organisms including;
    • P. aeruginosa,
    • Acinetobacter baumannii
    • Klebsiella pneumoniae.
  • Particularly useful for MDR carbapenemase producing organisms

Cons:

  • It is not absorbed by mouth
  • Nephrotoxic
  • Should be reserved for use against multi-resistant organisms
66
Q

Give 2 examples of inhibitors of folate metabolism.

A

Sulfonamides and Diaminopyrimidines (e.g. trimethoprim)

67
Q

What is the MOA of sulfonamides/diaminopyrimidines?

A

Act directly on DNA through interference with folic acid metabolism

Act sinergistically - they act on sequential parts of the same pathway

68
Q

What are the cilnical uses of diaminopyrimidines? What is a disadvantage?

A

trimethoprim - community acquired UTI but up to 40% of E coli is resistant

69
Q

How can resistance to sulfonamides be overcome?

A

Sulphonamide resistance is common

Combination of sulphamethoxazole + trimethroprim (Co-trimoxazole) is useful in certain situations e.g. treating Pneumocystis jiroveci pneumonia)

Broad spectrum- covers lots of coliforms

70
Q

What is co-trimoxazole? What is it useful for?

A

Sulphamethoxazole and trimethoprim - pneumocystis jiroveci pneumonia

71
Q

Name 4 ways in which bacteria can become resistant to an antibiotic.

A

Can be affected by multiple mechanisms

  1. Chemical modification or inactivation of the antibiotic E.g. b-lactamase enzyme production
  2. Modification or replacement of target in the microbe
  3. Reduced antibiotic accumulation - Impaired uptake/ enhanced efflux
  4. Bypass antibiotic sensitive step
72
Q

How do coliforms and S aureus become resistant to beta-lactams?

A

Beta-lactamase production

73
Q

What type of resistance does MRSA display? Describe it.

A

Altered target - mecA gene encodes a new PBP (2a) –> low affinity for all beta-lactam antibiotics.

74
Q

What is the type of resistance of S. pyogenes to penicillin? Can it be overcome?

A

Altered target - stepwise mutations in PBP genes

Sometimes can be overcome with:

  • increasing dose but not in meningitis (as not all crosses the BBB anyway)
  • adding vancomycin in pneumococcus infection
75
Q

What antibiotic class do ESBLs confer resistance against? What organisms most commonly produce this?

A

Break down cephalosporins - especially produced by E. coli and Klebsiella

76
Q

In which infections is beta-lactamase production not the mechanim or resistance against penicillin?

A

pneumococci and MRSA

77
Q

Why is tonsillitis treated with penicillins (hint: resistance)?

A

Penicillin resistance not reported in Group A (S. pyogenes), B, C, or G ß haemolytic Streptococci.

78
Q

Which beta-lactam/beta-lacatamase inhibitor combination can sometimes be used for ESBLs?

A

Augmentin/Tazocin - but treatment failures have been reported

79
Q

What is the danger with ESBLs?

A

They spread quickly - via plasmids or transposons

80
Q

What is the % resistance indicating you can no longer use an antibiotic for empiric treatement?

A

10%

e.g. ESBLs in E coli

81
Q

What is the mechanim of resistance against macrolides? Describe it.

A

Altered targets

  • Adenine-N6 methyltransferase modifies 23S RNA –> reduces the binding of macrolides –> resistance
  • Encoded by erm (erythromycin ribosome methylation) genes
  • It is an inducible mechanism
    • IV- clindamycin does NOT induce this mechanism so it can look sensitive but eventually it will select out resistant organisms –> treatment failure
82
Q

What 2 ways can be used to reduce the spread of antibiotic resistance?

A
  1. Control antibiotic usage and encourage good prescribing habits
  2. Improve standards of hospital hygiene and encourage handwashing to reduce dissemination of resistant organisms
83
Q

Which mechanism mediates Flucloxacillin resistance in S. aureus?

A

Alteration of the target

84
Q

By which mechanism is ESBL E. coli resistant to Ceftriaxone?

A

Enzymatic inactivation of the antibiotic (as it is extended spectrum b-lactamase)

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