Antibiotics - drug classes and mechanisms Flashcards
prokaryotic cells
Bacteria
eukaryotic cells
fungi (yeasts/ mounds)
parasites (protozoa)
acellular
viruses
prions
Difference with human cells compared to prokaryotic
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)
Antimicrobial chemotherapy
Drugs to treat infectious diseases, having selective
toxicity against the pathogens involved, while damaging the host as little as possible
antibiotics to treat
bacterial infections
Selective toxicity
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
Therapeutic index
Ratio of toxic dose to therapeutic dose
The larger the index, the safer/better the agent
Therapeutic dose
▪ drug level to treat/resolve an infection
Toxic dose
drug level that is toxic for the host
Spectrum of activity
2 types
narrow spectrum drugs
broad spectrum drugs
Narrow-spectrum drugs
effective only against a limited
variety of bacteria
✓When the microorganism is identified
✓Minimise the disruption of normal
flora
Broad-spectrum drugs
Target and inhibit many kinds of
bacteria (e.g. Gram+ and Gram-)
✓Serious bacterial infections by an
unidentified organism
✓Infection with multiple bacteria
Bacteriostatic
Prevent bacterial
growth (no killing)
* Reversible effect
* Bacterial clearance
depends on the
immune system
Bactericidal
Kill the target
bacteria
* Irreversible effect
* Appropriate in poor
immunity
How to measure effectivness of antimicrobial drugs?
- Minimal inhibitory concentration (MIC)
- Minimum bactericidal concentration (MBC)
MIC
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
MBC
lowest concentration of drug
that kills the pathogen
Calculation for effectiveness of antimicrobial drugs?
MBC / MIC
Ratios that determines if drug is bactericidal or bacteriostatic
Bactericidal = MBC/MIC ratio <4
Bateriostatic = MBC/MIC ratio <10
Antimicrobial Activity Can Be Measured by Specific Tests
✓Dilution Susceptibility Tests
✓Disk Diffusion Tests (Kirby-Bauer Method)
✓The Etest
1) Dilution Susceptibility Tests
STEP by STEP
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.
2) Disk Diffusion Tests
➢Disk Diffusion Tests (Kirby-Bauer test)
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
What does Measurement of the clear zones diameter
(no growth) around disks compared to a
standardized chart show?
susceptibility or resistence
the diameter in disks diffusion tests correlates with
MIC
Wider clear zone indicates that a microbe
is more ______ to that antibiotic
susceptible
Narrower clear zone indicates drug
_______
resistance
3) The Etest
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
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* Sirirat/Shutterstock
Gram-Positive Cell Walls
Thick peptidoglycan
(including teichoic acids)
Gram-Negative Cell Walls
Thin peptidoglycan
* Outer membrane (LPS, porins)
Peptidoglycan formation:
Bacterial transpeptidase (or penicillin-binding
proteins) form peptide cross-link bridges between
tetrapeptide of NAMs of peptidoglycan strands
MoA of B-Lactam
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
B-Lactam role
- block NEW cell wall formation
- bacterial lysis
1) Inhibitors of Cell Wall Synthesis: β-Lactam antibiotics
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.
1) β-Lactam antibiotics subclasses
Penicillins
Cephalosporins
Carbapenems
Monobactams
Natural Penicillins – the first antibiotics
Penicillin G
Penicillin V
Penicillin G
(Benzylpenicillin)
- Narrow (most Gram +ve
- Parenteral
(degraded by stomach acid pH) - Very low (easily inactivated by
bacterial beta-lactamases
Penicillin V
(Phenoxymethylpenicillin)
- Narrow (most Gram +ve)
- Oral
(Resistant to acid pH - Very low (similarly)
Bacterial β-lactamases cut the β-lactam ring
to _______ antibiotics of this class
inactivate
Semisynthetic Penicillins
- Antistaphylococcal penicillins
- Aminopenicillins (Broad-spectrum penicillins)
- Antipseudomonal penicillins (Extended broad-spectrum)
Antistaphylococcal penicillins - Penicillinase-resistant penicillins
EXAMPLE
Flucloxacillin – acid-stable (oral and iv)
▪ Bulkier side chains – Resistant to β-lactamase of Staphylococci
▪ Retain a narrow-spectrum activity (not active against Gram-)
Aminopenicillins/Broad-spectrum penicillinsAminopenicillins/Broad-spectrum penicillins
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
Antipseudomonal penicillins – extended broad-spectrum
➢ Piperacillin, Ticarcillin
* Only available in combination with the beta-lactamase inhibitors
Piperacillin, Ticarcillin
* Only available in combination with the beta-lactamase inhibitors
Penicillins: Adverse effects
- hypersensitivity
- check for any allergies before (mild/ mod/ severe rash)
- GI distress, diarrhoea + nausea
Contraindications: of penicillin
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
