Antibiotics - drug classes and mechanisms

Question 1

prokaryotic cells

Answer 1

Bacteria

Question 2

eukaryotic cells

Answer 2

fungi (yeasts/ mounds)
parasites (protozoa)

Question 3

acellular

Answer 3

viruses
prions

Question 4

Difference with human cells compared to prokaryotic

Answer 4

Without a nucleus (different DNA arrangements)
* Without membrane-bound organelles
* Simple organisation and smaller
* Different components (cell walls, glycocalyx, sex pili,
fimbriae, flagella)
* Different compositions of ribosomes (70s vs 80s)

Question 5

Antimicrobial chemotherapy

Answer 5

Drugs to treat infectious diseases, having selective
toxicity against the pathogens involved, while damaging the host as little as possible

Question 6

antibiotics to treat

Answer 6

bacterial infections

Question 7

Selective toxicity

Answer 7

Ability of drug to kill or inhibit pathogen while damaging host as little as possible
* Degree of selective toxicity is expressed by the therapeutic index

Question 8

Therapeutic index

Answer 8

Ratio of toxic dose to therapeutic dose
The larger the index, the safer/better the agent

Question 9

Therapeutic dose

Answer 9

▪ drug level to treat/resolve an infection

Question 10

Toxic dose

Answer 10

drug level that is toxic for the host

Question 11

Spectrum of activity

2 types

Answer 11

narrow spectrum drugs

broad spectrum drugs

Question 12

Narrow-spectrum drugs

Answer 12

effective only against a limited
variety of bacteria
✓When the microorganism is identified
✓Minimise the disruption of normal
flora

Question 13

Broad-spectrum drugs

Answer 13

Target and inhibit many kinds of
bacteria (e.g. Gram+ and Gram-)
✓Serious bacterial infections by an
unidentified organism
✓Infection with multiple bacteria

Question 14

Bacteriostatic

Answer 14

Prevent bacterial
growth (no killing)
* Reversible effect
* Bacterial clearance
depends on the
immune system

Question 15

Bactericidal

Answer 15

Kill the target
bacteria
* Irreversible effect
* Appropriate in poor
immunity

Question 16

How to measure effectivness of antimicrobial drugs?

Answer 16

• Minimal inhibitory concentration (MIC)
• Minimum bactericidal concentration (MBC)

Question 17

MIC

Answer 17

lowest concentration of drug that
prevents the visible growth of the pathogen
* It varies against different bacterial species (spectrum of activity)
* Indicator for assessing bacterial drug resistance

Question 18

MBC

Answer 18

lowest concentration of drug
that kills the pathogen

Question 19

Calculation for effectiveness of antimicrobial drugs?

Answer 19

MBC / MIC

Question 20

Ratios that determines if drug is bactericidal or bacteriostatic

Answer 20

Bactericidal = MBC/MIC ratio <4

Bateriostatic = MBC/MIC ratio <10

Question 21

Antimicrobial Activity Can Be Measured by Specific Tests

Answer 21

✓Dilution Susceptibility Tests
✓Disk Diffusion Tests (Kirby-Bauer Method)
✓The Etest

Question 22

1) Dilution Susceptibility Tests
STEP by STEP

Answer 22

Used to determine MIC and MBC values.
* Inoculating media with different concentrations
of a drug and fixed number of bacteria.
* Broth or agar with lowest concentration
showing no growth is MIC.
* MBC is ascertained when tubes that show no
growth are then cultured into fresh medium
lacking antibiotic.
* The lowest antibiotic concentration that fails to
support the microbe’s growth is the MBC.

Question 23

2) Disk Diffusion Tests
➢Disk Diffusion Tests (Kirby-Bauer test)

Answer 23

Disks impregnated with different antibiotics
are placed on agar plates inoculated with a
microbe.
* Antibiotic diffuses from disk into agar,
establishing concentration gradient.
▪ Higher concentrations near the disk

Question 24

What does Measurement of the clear zones diameter
(no growth) around disks compared to a
standardized chart show?

Answer 24

susceptibility or resistence

Question 25

the diameter in disks diffusion tests correlates with

Answer 25

MIC

Question 26

Wider clear zone indicates that a microbe is more ______ to that antibiotic

Answer 26

susceptible

Question 27

Narrower clear zone indicates drug _______

Answer 27

resistance

Question 28

3) The Etest

Answer 28

Bacterial is inoculated on agar, then Etest® strips are placed on the surface. * Etest® strips contain a gradient of an antibiotic. * Intersection of elliptical zone of inhibition with strip indicates MIC 17 * Sirirat/Shutterstock

Question 29

Gram-Positive Cell Walls

Answer 29

Thick peptidoglycan (including teichoic acids)

Question 30

Gram-Negative Cell Walls

Answer 30

Thin peptidoglycan * Outer membrane (LPS, porins)

Question 31

Peptidoglycan formation:

Answer 31

Bacterial transpeptidase (or penicillin-binding proteins) form peptide cross-link bridges between tetrapeptide of NAMs of peptidoglycan strands

Question 32

MoA of B-Lactam

Answer 32

β-Lactams bind to and block transpeptidases (PBP), mimicking the substrate * β-Lactams block the transpeptidation of peptidoglycan strands * Prevent the synthesis of complete cell walls, leading to lysis of bacteria ▪ Only effective against bacteria reproducing * Activates enzymes to break down peptidoglycan

Question 33

B-Lactam role

Answer 33

* block NEW cell wall formation * bacterial lysis

Question 34

1) Inhibitors of Cell Wall Synthesis: β-Lactam antibiotics

Answer 34

ontaining a β-lactam ring — core structure ▪ Essential for bioactivity β-lactam ring * Same mechanism of action: ▪ Blocking the formation of peptide bridges between peptidoglycan chains ▪ Bactericidal effect and high therapeutic index ▪ Some resistant bacteria produce β -lactamase (penicillinase, more common in Gram-negative bacteria) which hydrolyses and inactivate the ring.

Question 35

1) β-Lactam antibiotics subclasses

Answer 35

Penicillins Cephalosporins Carbapenems Monobactams

Question 36

Natural Penicillins – the first antibiotics

Answer 36

Penicillin G Penicillin V

Question 37

Penicillin G (Benzylpenicillin)

Answer 37

- Narrow (most Gram +ve - Parenteral (degraded by stomach acid pH) - Very low (easily inactivated by bacterial beta-lactamases

Question 38

Penicillin V (Phenoxymethylpenicillin)

Answer 38

- Narrow (most Gram +ve) - Oral (Resistant to acid pH - Very low (similarly)

Question 39

Bacterial β-lactamases cut the β-lactam ring to _______ antibiotics of this class

Answer 39

inactivate

Question 40

Semisynthetic Penicillins

Answer 40

1. Antistaphylococcal penicillins 2. Aminopenicillins (Broad-spectrum penicillins) 3. Antipseudomonal penicillins (Extended broad-spectrum)

Question 41

Antistaphylococcal penicillins - Penicillinase-resistant penicillins EXAMPLE

Answer 41

Flucloxacillin – acid-stable (oral and iv) ▪ Bulkier side chains – Resistant to β-lactamase of Staphylococci ▪ Retain a narrow-spectrum activity (not active against Gram-)

Question 42

Aminopenicillins/Broad-spectrum penicillinsAminopenicillins/Broad-spectrum penicillins

Answer 42

Ampicillin (oral) ➢ Amoxicillin (oral) ❖ the most prescribed antibiotic in the UK Brand name (Generic) Antibiotic (generic) Β-lactamase inhibitor Augmentin (Co-amoxiclav) Amoxicillin clavulanic acid ▪ Amoxicillin is also combined with Flucloxacillin in co-fluampicil (Magnapen) ▪ Active against Gram-negative (e.g. E. coli, Salmonella spp) o Hydrophilicity allows passage through porins of outer membrane in Gram-negative only) ▪ combined with beta-lactamase/penicillinase inhibitor o inactivating bacteria producing β-lactamases o beta-lactamase inhibitors do not have anti-bacterial activity

Question 43

Antipseudomonal penicillins – extended broad-spectrum ➢ Piperacillin, Ticarcillin * Only available in combination with the beta-lactamase inhibitors

Answer 43

Piperacillin, Ticarcillin * Only available in combination with the beta-lactamase inhibitors

Question 44

Penicillins: Adverse effects

Answer 44

- hypersensitivity - check for any allergies before (mild/ mod/ severe rash) - GI distress, diarrhoea + nausea

Question 45

Contraindications: of penicillin

Answer 45

hypersensitivity and history of hepatic impairment Penicillin resistance ➢Mainly due to the production of β-lactamases to cleave the β-lactam ring ➢Mutations changing the transpeptidase conformational structure