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W3 - Antimicrobial agents 1 Flashcards

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1
Q

What are 3 general sites on the bacteria for abx to target?

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

Which abx classes (2) are inhibitors of cell wall synthesis?

A

(a) B-lactam antibiotics (penicillins, cephalosporins and carbapenems)
(b) Glycopeptides (Vancomycin and Teicoplanin)

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3
Q

Briefly describe Gram staining of G+ and G- bacteria

A

G+ = stain is trapped = stains purple

G- = peptidoglycan is thinner, and they have an outer membrane also = don’t retain the colour = stain pink

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4
Q

What are the subunits of a typical peptidoglycan wall?

A 
NAG = N-acetylglucosamine 
NAM= N-acetylmuramic acid

and interdispersed peptide bonds

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5
Q

Describe MOA of B-lactams?
Which group of bacteria are they most efficient against?

A

MOA:
Inactivate the enzymes that are involved in the terminal stages of cell wall synthesis called transpeptidases (also known as penicillin binding proteins)

β-lactam is a structural analogue of the enzyme substrate = results in no peptide cross-links = cell walls not formed properly = bacteriolysis

  • Active against rapidly-dividing bacteria
  • Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)
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6
Q

Are B-lactams bactericidal or bacteriostatic?

A

Bactericidal

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7
Q

Name the 4 main groups of B-lactam abx

A
  1. Penicillin (i.e. ampicillin)
  2. Cephalosporin (i.e. cefotaxime)
  3. Carbapenems (i.e. imipenem)
  4. Monobactam (i.e. carumonam)
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8
Q

Describe antibacterial spectrum of penicillin

A

Gram positive organisms; Streptococci, Clostridia; broken down by an enzyme (β-lactamase) produced by S. aureus

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9
Q

Describe antibacterial spectrum of amoxicillin

A

Broad spectrum penicillin; extends coverage to Enterococci and Gram negative organisms; broken down by β-lactamase produced by S. aureus and many Gram negative organisms

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10
Q

Describe antibacterial spectrum of flucloxacillin

A

Similar to penicillin although less active. Stable to β-lactamase produced by S. aureus.

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11
Q

Describe antibacterial spectrum of piperacillin

A

similar to amoxicillin, extends coverage to Pseudomonas and other non-enteric Gram negatives; broken down by β-lactamase produced by S. aureus and many Gram negative organisms

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12
Q

What are clavulanic acid and tazobactam? MOA?

A

β-lactamase inhibitors.

Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes

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13
Q

What is the difference between first, second, and third generation cephalosporins?

A

Increasing activity against G- bacilli with newer generations

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14
Q

Give drug names of cephalosporins belonging to 1st, 2nd, and 3rd generations

A

First generation = cephalexin

Second generation = cefuroxime

Third generation = cefotaxime, ceftriaxone, ceftazidime

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15
Q

Difference when prescribing co-amoxiclav and cefuroxime

A

Similar cover to co-amoxiclav but less active against anaerobes. Cefuroxime must be given with metronidazole to cover G-

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16
Q

Describe antibacterial spectrum of ceftriaxone

A

G+ and G-, but is associated with C diff - avoid usage in elderly patients if possible

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17
Q

Describe the antibacterial spectrum of ceftazidime

A

G+ and G-, anti-psuedomonas

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18
Q

What is the current issue with cephalosporins?

A

The rise in ESBL - extended spectrum beta-lactamase producing organisms which are resistant to ALL cephalosporins

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19
Q

Give drug names of carbapenems

A

Meropenem, Imipenem, Ertapenem

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20
Q

Describe antibacterial spectrum of carbapenems

A

G+ and G-, stable to ESBL enzymes

carbapenemase enzymes becoming widespread - multi-drug resistant Actinobacter and Klebsiella

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21
Q

Describe toxicity, excretion, half life, BBB coverage, and allergic profile of b-lactams

A
  • Relatively non-toxic
  • Renally excreted (so ↓dose if renal impairment)
  • Short half life
  • Will not cross intact BBB
  • Cross-allergenic (penicillins approx 10% cross-reactivity with cephalosporins or carbapenems)
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22
Q

Describe antibacterial spectrum of glycopeptides

A

Large molecules = unable to penetrate G- outer cell wall
ONLY active against G+ organisms

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23
Q

Give 2 uses of glycopeptides

A

MRSA (esp UTI)
serious C difficile

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24
Q

Are glycopeptides bactericidal or bacteriostatic?

A

slowly bactericidal

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25
Caution with using glycopeptides?
Nephrotoxic – hence important to monitor drug levels to prevent accumulation
26
MOA of glycopeptides
the peptide at the end of peptidoglycan precursors is formed of aa subunits. . Glycopeptide binds to the D-ala D-ala at the end --\> stops formation of peptide bonds --\> creates weak peptidoglycan walls --\> daughter cells lyse
27
Which abx classes (5) are inhibitors of protein synthesis?
1. Aminoglycosides (e.g. gentamicin, amikacin, tobramycin) 2. Tetracyclines 3. Macrolides (e.g. erythromycin) / Lincosamides (clindamycin) / Streptogramins (Synercid) – The MSL group 4. Chloramphenicol 5. Oxazolidinones (e.g. Linezolid)
28
MOA of aminoglycosides
Require specific transport mechanisms to enter cells --\> bind to amino-acyl site of the 30S ribosomal subunit = Prevent elongation of the polypeptide chain & causes MISREADINGS of the codons along the mRNA
29
Are aminoglycosides bactericidal or bacteriostatic?
Rapid, concentration-dependent bactericidal action
30
Caution with using aminoglycosides?
Ototoxic & nephrotoxic, therefore must monitor levels \* hence usually only SHORT doses are used
31
Describe antibacterial spectrum of aminoglycosides
broad-spectrum abx - Gentamicin & tobramycin particularly active vs. Ps. aeruginosa - Synergistic combination with B-lactams - No activity vs. anaerobes
32
Describe antibacterial spectrum of tetracyclines
Broad-spectrum agents with activity against intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas, Legionella pneumophila) as well as most conventional bacteria
33
Are tetracyclines bactericidal or bacteriostatic?
Bacteriostatic
34
Caution with using tetracyclines?
Do not give to children under 12, pregnant and breastfeeding women Light-sensitive rash G- are becoming resistant
35
MOA of tetracyclines
Reversibly bind to the ribosomal 30S subunit = prevent binding of aminoacyl-tRNA to the ribosomal acceptor site = inhibiting protein synthesis.
36
Are macrolides bactericidal or bacteriostatic?
Bacteriostatic
37
Describe antibacterial spectrum of macrolides
G+ coverage, minimal activity against Gram –ve bacteria
38
Give 2 example of usage for macrolides
1. Useful agent for treating mild Staphylococcal or Streptococcal infections in penicillin-allergic patients 2. Also active against Campylobacter sp and Legionella Pneumophila
39
MOA of macrolides
Bind to the 50s subunit of the ribosome --\> interfere with translocation = stimulate dissociation of peptidyl-tRNA
40
Are chloramphenicols bactericidal or bacteriostatic?
bacteriostatic
41
Describe antibacterial spectrum of chloramphenicol
Very broad antibacterial coverage
42
Usage of chloramphenicol and why?
Rarely used (apart from eye preparations and special indications) because risk of aplastic anaemia (1/25,000 – 1/45,000 patients) AND grey baby syndrome in neonates because of an inability to metabolise the drug
43
MOA of chloramphenicol
Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit = inhibits formation of peptide bonds during translation
44
What is the main oxazolidinone currently in use?
Linezolid
45
MOA of oxazolidinones
Binds to 23S component of the 50S subunit = prevents formation of a functional 70S initiation complex\* \*required for the translation process to occur
46
Describe antibacterial spectrum of oxazolidinones
Highly active against Gram + organisms, including MRSA and VRE Not active against most Gram - .
47
Give 2 S/Es of oxazolidinones and 2 issues with its prescription
S/Es: 1. thrombocytopaenia 2. neuritis (usually after 4 weeks of use) Issues with prescription: 1. expensive 2. only used with consultant ID approval
48
Which abx classes (2) are inhibitors of DNA synthesis?
1. Quinolones e.g. Ciprofloxacin, Levofloxacin, Moxifloxacin 2. Nitroimidazoles e.g. Metronidazole & Tinidazole
49
MOA of fluoroquinolones
act on a-subunit of bacterial DNA gyrase - block DNA synthesis
50
Describe antibacterial spectrum of fluoroquinolones
Broad antibacterial activity, especially vs Gram –ve organisms, including Pseudomonas aeruginosa Newer agents (e.g. levofloxacin, moxifloxacin)  activity vs G +ves and intracellular bacteria, e.g. Chlamydia spp
51
Name 4 general uses for fluoroquinolones
1. UTIs 2. Pneumonia 3. Atypical pneumonia 4. Bacterial gastroenteritis
52
Name 2 S/Es of fluoroquinolones
1. Lower seizure threshold 2. Achilles tendonitis so should be used with caution in elderly patients and those on steroids
53
Describe antibacterial spectrum of nitroimidazoles
Anaerobic bacteria and protozoa (i.e. Giardia)
54
Name drugs of fluoroquinolone class
Ciprofloxacin, Levofloxacin, Moxifloxacin
55
Name drugs of nitroimidazole class
metronidazole & tinidazole
56
MOA of nitroimidazole
Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage
57
What are nitrofurans? usage?
Related compounds to nitroimidazole; used for treating simple UTI
58
What abx class (1) are inhibitors of RNA synthesis?
1. Rifamycins, e.g. rifampicin & rifabutin
59
MOA of rifampicin
binds to DNA-dependent RNA polymerase = inhibits initiation of RNA = inhibits protein synthesis
60
Are nitroimidazoles bactericidal or bacteriostatic?
Rapidly bactericidal
61
Are fluoroquinolones bactericidal or bacteriostatic?
Bactericidal
62
Are rifampicin bactericidal or bacteriostatic?
Bactericidal
63
Describe antibacterial spectrum of rifampicin
Active against certain bacteria, including Mycobacteria & Chlamydia reduced use with other bacteria as it is used to treat TB
64
Caution with using rifampicin?
1. enzyme inducer = monitor LFTs 2. interacts with other drugs metabolised by liver, i.e. oral contraceptives and warfarin 3. Urine, tear, and sputum may turn orange 4. Except for short-term prophylaxis (i.e. meningococcal infection), should NEVER be used as single agent because resistance develops rapidly
65
Name 2 classes of cell membrane toxins abx
1. Daptomycin - cyclic lipopeptide 2. Colistin - polymyxin abx
66
Describe antibacterial spectrum of daptomycin
G+ pathogens - recently licenced for treating MRSA and VRE as an alternative to linezolid
67
Describe antibacterial spectrum of colistine, cautions, use, & ROA
G- organisms, including Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella. pneumoniae. - not orally absorbed - nephrotoxic - reserved for use against multi-resistant organisms
68
What abx classes (2) are inhibitors of folate metabolism?
1. Sulfonamides 2. Diaminopyrimidines (i.e. trimethoprim)
69
Describe MOA of Sulphonamides & diaminopyrimidines
Act indirectly on DNA through interference with folic acid metabolism Synergistic action between the two drug classes because they act on sequential stages in the same pathway
70
What is co-trimoxazole? use?
combination drug of Sulphamethoxazole (sulphonamide) and trimethoprim (diaminopyrimidine) - use: treatment of Pneumocystis. jiroveci pneumonia
71
Common use of trimethoprim
Community-acquired UTIs
72
Name 4 general mechanisms of bacterial drug resistance?
1. Modification/inactivation of the abx 2. Modification or replacement of target 3. Reduced antibiotic accumulation A) Impaired uptake B) Enhanced efflux 4. Bypass antibiotic sensitive step
73
Describe mechanism of resistance to B lactams by staphylococcus aureus and G - bacilli (coliforms)
B lactamases
74
Describe mechanism of resistance in penicillin resistant Pneumococci and MRSA
altered targets MRSA - mecA gene encodes novel PBP(2a) = low affinity for binding B lactam = high level resistance Penicillin-resistant pneumococci (streptococcus pneumoniae) = acquisition of a series of stepwise mutations in PBP genes = low level resistance = CAN be overcome by increasing [penicillin]
75
Are ESBLs inhibited by co-amixoclav?
No - Treatment failures reported with ß Lactam/ ß Lactamase inhibitor combinations (eg. Augmentin/Tazocin)
76
Bacterial groups known to produce ESBLs include... (3)
- Escherichia coli (E. coli) - Klebsiella pneumoniae - Pseudomonas aeruginosa
77
How many classes of beta-lactamases?
5
78
How many main carbapenemases? Name them. which is most common in the UK
5 - NDM, VIM, IMP, KPC, OXA-48 OXA-48 followed by NDM in NW London
79
Describe mechanism of resistance to Macrolides
Adenine-N6 methyltransferase modifies 23S rRNA = modification reduces the binding of MLS abx (Macrolide, lincosamide and streptogramin) Encoded by erm (erythromycin ribosome methylation) genes.
80
MLS resistance - interpretation of susceptibility testing 1. Erythromycin S/Clindamycin S 2. Erythromycin R/Clindamycin R 3. Erythromycin R/Clindamycin S
1. susceptible to both 2. Resistant to both (constitutive MLS-b) 3. may have inducible resistance (inducible MLS-b)
81
A pt has grown a fully susceptible E coli in their urine. Which of the following is the narrowest spectrum agent you should de-escalate to? 1. Amoxicillin 2. Ceftriaxone 3. Co-amoxiclav 4. Meropenem 5. Piperacillin/tazobactam
amoxicillin

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