Mechanism and Action of Antibiotics

Question 1

What are the main principles of antibiotic use?

Answer 1

• they target processes that humans do not possess (eg. bacterial cell wall)
• target processes that humans possess but bacterial versions are sufficiently different
• selective toxicity: antibiotics have greater toxicity to bacteria than human

Question 2

What are the antibiotics that are active against the cell membrane?

Answer 2

• beta-lactam and cephalosporin
• glycopeptide
• cyclic peptide
• phosphonic acids
• lipopeptides

Question 3

What are the targets, mechanisms and examples of beta-lactam and cephalosporin?

Answer 3

• target: penicillin binding proteins
• mechanism: prevent peptidoglycan cross-linking

Examples:

• penicillin G
• flucloxacillin
• tazobactam

Question 4

What are the targets, mechanisms and examples of glycopeptides?

Answer 4

• target: C-terminal D-Ala-D-Ala
• mechanism: prevents transglycolation and transpeptidation (blocks addition of new peptidoglycan building blocks)

Examples:

• vancomycin
• teicoplanin

Question 5

What are the targets, mechanisms and examples of cyclic peptides?

Answer 5

• target: C 55-isopropyl pyrophosphate
• mechanism: prevents carriage of building-blocks of peptidoglycan bacterial cell wall outside of the inner membrane

Examples:

• bacitracin
• polymyxin

Question 6

What are the targets, mechanisms and examples of phosphonic acids?

Answer 6

• target: murA protein
• mechanism: inhibits first stage of peptidoglycan synthesis
• example: fosphomycin

Question 7

What are the targets, mechanisms and examples of lipopeptides?

Answer 7

• target: cell wall stress stimulon
• mechanism: calcium dependent membrane depolarisation
• example: daptomycin

Question 8

What are the 3 main classes of bacterial cell wall inhibitors?

Answer 8

• beta-lactams (penicillins and cephalosporins)
• vancomycin
• bacitracin

Question 9

What effect does inhibiting cell wall synthesis have?

Answer 9

• normally leads to death of bacteria

- imbalance in cell wall architecture triggers bacterial autolysins that kill cell

Question 10

What are the 3 types of bacteria that penicillins G and V attack (with examples)?

Answer 10

• gram positive and gram negative cocci:
• staphylococcus (infections of wounds)
• streptococcus - haemolytic (septic infections)
• enterococcus (endocarditis)
• pneumococcus
• neisseria gonorrhoeae
• neisseria menigitidis
• gram positive rods:
• clostridium (tetanus, gangrene)
• spirochaetes:
• treponema (syphilis)
• actinomyces (abcesses)

Question 11

What are examples of B-lactamase-resistant penicillans and the spectrum of bacteria is covers?

Answer 11

• methicillin
• oxacillin
• naficillin
• covers same spectrum as penicillins G and V

Question 12

What are examples of broad-spectrum penicillins and the spectrum of bacteria it covers?

Answer 12

• ampicillin
• amoxicillin
• covers same spectrum as penicillins G and V
• covers B-lactamase-free strains of:
• H. influenzae
• N. Gonorrhoeae
• E. Coli
• salmonella
• morasella catarrhalis (sinusitis)

Question 13

What are examples of extended-spectrum penicillins and the spectrum of bacteria it covers?

Answer 13

• carbenicillin
• ticaracillin
• azlocillin
• piperacillin
• covers same as broad-spectrum
• plus pseudomonas aeruginosa

Question 14

What are carbapenems and their features?

Answer 14

• broader anti-bacterial spectrum than B-lactase
• generally resistant to typical beta-lactamases
• bind PBPs permanently acylating them (penicillin binding proteins)
• poorly active against MRSA
• not active against bacteria with no cell wall

Question 15

What is the role of PBPs?

Answer 15

involved in final synthesis of bacterial cell wall

Question 16

What are the 3 mechanisms of bacterial resistance to B-lactam antibiotics with examples?

Answer 16

• bacteria produces B-lactamase which destructs antibiotic (eg. S. aureus)
• failure to reach target enzyme, gram negative organism changes outer membrane porins and polysaccharide components (eg. pseudomonas)
• failure to bind to the transpeptidase (eg. S.pneumoniae)

Question 17

What are the 4 classes of B-lactamases and their mechanisms of action?

Answer 17

• A, B, C and D
• ACD uses serine to hydrolyse
• B uses zinc ions to hydrolyse

Question 18

What is the use of B-lactamase inhibtors?

Answer 18

can be used with B-lactam antibiotic as an alternaltive to B-lactamase-resistant antibiotcs

Question 19

What are cephalosporins with examples, the infections they treat and the possible complication

Answer 19

• alternative to penicillins
• classified by generations (1st, 2nd, 3rd)

treats:

• septicaemia
• pneumonia
• meningitis
• biliary tract infections
• UTIs
• sinusitis

Examples:

• cefalexin
• cefuroxime
• cefotaxime
• cefadroxil
• complication: overuse facilitates emergence of C. difficile

Question 20

Describe how vancomycin works and the problem with resistance

Answer 20

• binds to peptide chain of peptidoglycan
• interferes with elongation of peptidoglycan backbone
• very specific interaction with D-Ala-D-Ala (so minimal resistance)
• resistance in MRSA and some strep/entero-cocci

Question 21

Describe how bacitracin works and what it can be used for

Answer 21

• bactericidal
• interferes with dephosphorylation of lipid carrier which moves early cell wall components through membrane
• can be used in ointment to treat skin and eye infections by streptococci/staphylococci

Question 22

What antibiotics are folate antagonists?

Answer 22

• sulphonamides

- trimethoprim

Question 23

Describe how sulphonamides and trimethoprims work

Answer 23

• act through inhibition of folate pathway in bacteria (important in cell metabolism)
• bacteria must make own supply of folate (but we do not)
• makes bacteria susceptible to drugs which interfere with folate metabolism (selective toxicity target)

Question 24

What are the clinical uses of sulphonamides and trimethoprim?

Answer 24

• trimethoprim: community UTIs
• sulphamethoxazole used with pyrimethamine for drug-resistant malaria and toxoplasmosis
• can both be used in combination as Co-trimoxazole for
• toxoplasmosis
• with other drugs for opportunistic infections in AIDS (eg. pneumocystis jiroveci)

Question 25

Describe how chloramphenicol, streptomycin, erythromycin and tetracycline interfere with the bacterial ribosome

Answer 25

- chloramphenicol: binds to 50S r-RNA and inhibits formation of peptide bond - streptomycin: changes shape of 30S r-RNA and causes m-RNA to be read incorrectly - erythromycin: binds to 50S r-RNA and prevents movement along m-RNA - tetracycline: interferes with t-RNA anticodon reading of m-RNA codon

Question 26

What are examples of macrolides and what are they used for?

Answer 26

- erythromycin - clarithromycin - used as alternative to penicillins in patients who are penicillin sensitive used for: - mycoplasma chlamydia - management of LRTI - leigonella can be used for: - corynebacterium (diptheria) - camphylobacter (diarrhoea) - chlamydia trachomatis - toxoplasma gondii

Question 27

What are the side effects of erythromycin and clarithromycin?

Answer 27

- erythromycin: * mild gut disturbances * hypersensitivity reactions * transient hearing disturbances * rare - cholestatic jaundice - clarithromycin: same but with QT prolongation

Question 28

What are the side effects of clindamycin?

Answer 28

- mainly GI disturbances (but potentially fatal) - pseudomembraneous colitis (acute inflammation of colon due to necrotising toxin produced by clindamycin-resistant C. diff)

Question 29

What class is clindamycin in and what is it used for?

Answer 29

- lincosamide class - active against gram-positive cocci - active against aerobic species - combination use against anaerobic sepsis and necrotising faciitis, for staph infections of joints and bones - used in eye drops for staph conjuntivitis

Question 30

What are aminoglycosides used to treat and why are they only for serious infections?

Answer 30

- enterobacteriaceae and pseudomonas that give rise to septicaemia and serious UTIs - hospital acquired pneumonia, respiratory and intra-abdominal infection due to pseudomonas - rare problematic infections such as brucellosis - only used in serious infections due to relative toxicity and parenteral administration

Question 31

What are the side effects of aminoglycosides?

Answer 31

- renal toxicity - ototoxicity with progressive damage to and destruction of sensory cells in cochlea and vestibular organ of the ear * results in vertigo, ataxia, loss of balance and auditory disturbances (can cause deafness) - neuromuscular block (if given with neuromuscular blocker)

Question 32

What are the cautions for aminoglycosides?

Answer 32

- caution for elderly - caution with renal failure - interaction with other renal toxic drugs - caution in severe sepsis that is causing acute renal failure

Question 33

What are tetracyclines used to toreat?

Answer 33

- rickettsia - mycoplasma - chlamidya - brucellosis - cholera - plague - lyme disease - tigecycline used in management of resistant gram negative infection - COPD - chronic acne

Question 34

What are the side effects of tetra cyclines?

Answer 34

- gut upset - hepatic and renal dysfunction - photosensitivity - binding to bone and teeth causing staining, dental hypoplasia and bone deformities - vestibular toxicity (dizziness/nausea)

Question 35

What is chloramphenicol used for and why can it only be used as a last resort?

Answer 35

- broad spectrum - meningitis - brain abscess - only used as last resort due to low risk of aplastic anaemia

Question 36

Describe the action of topoisomerase IV

Answer 36

- tetrameric enzyme of 2 ParC and 2 ParE sub-units - involved in chromosomal partitioning - catalyses ATP dependent relaxation of negatively and positively supercoiled DNA and unknotting of un-nicked duplex DNA - no action against super-coiling

Question 37

Describe the action of DNA gyrase

Answer 37

- tetrameric enzyme of 2 GyrA and 2 GyrB - forms transient covalent bond with DNA - breaks DNA - passes DNA through break - repairs break

Question 38

What are fluroquinolones used for?

Answer 38

- against enterobacteriaceae - H. influenzae - B-lactamase-producing N. gonorrhea - camphylobacter (diarrhoea) - pseudomonas aeruginosa - salmonella

Question 39

What are the quinolone antibiotics?

Answer 39

- naladixic acid - norfloxacin - ciprofloxacin - moxifloxacin - gatifloxacin - gemifloxacin

Question 40

What is the spectrum and use of naladixic acid?

Answer 40

- spectrum: gram negative bacilli | - use: UTI

Question 41

What is the spectrum and use of nor/ciprofloxacin

Answer 41

- spectrum: gram negative bacilli, mycobacteria, chlamydia | - use: systemic infection

Question 42

What is the spectrum and use of moxi/gati/gemifloxacin?

Answer 42

- gram positive bacteria - gram negative bacilli - mycobacteria - chlamydia use: UTI, systemic infection and LRTIs

Question 43

What is metronidazole and how does it work?

Answer 43

- antiprotozoal agent | - under anaerobic conditions it generates toxic radicals that damage bacterial DNA

Question 44

What is metronidazole used for?

Answer 44

- anaerobic bacteria like bacteriodes, clostridia, streptococci - anaerobic infections such as sepsis secondary to bowel disease - pseudomembranous colitis - used with other drugs for helicobacter pylori infections that give rise to peptic ulceration

Question 45

What are the inhibitors of bacterial ribosomal actions?

Answer 45

- macrolides eg. erythromycin and clarithromycin - clindamycin - aminoglycosides - tetracyclines - chloramphenicol

Question 46

What are the antibiotics which affect topoisomerase II?

Answer 46

- fluoroquinolones - quinolone (naladixic acid/norfloxacin/ciprofloxacin) - metronidazole