Antibiotics
Learning Outcomes
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Understand the causes of infections
Know about the Classification of Antibacterial agents
Understand what Factors guide Antibiotic Choice
Know and understand key concepts about the following
antibiotics:
Penicillins
Cephalosporins
Macrolides
Tetracyclines
Aminoglycosides
Quinolones
Metronidazole
Definitions
• Antibiotic, antibacterial, antimicrobial, antiinfectives, anti-fungals, anti-virals
• BNF classification
• Natural, semi synthetic and synthetic
Importance
• Host immune system
• Resistance
Causes of infections
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3 types of micro-organisms:
Bacteria
Fungi
Viruses
Give an example of a disease caused by
each of the above
Identification of Bacterial
Organisms
• Gram staining is a basic microbiologic procedure for
detecting and identification of bacteria.
• The main structural component of cell wall is
peptidoglycan.
• Peptidoglycan and cell wall structural differences form
the basis of the different staining properties.
• With Gram staining:
– Gram +ve stain purple
– Gram –ve stain pink
• Why is Gram staining important?
• Cell shapes(cocci/rods)
• Aerobic/anaerobic
Gram Positive and Negative
organisms
• What is a Gram stain?
• Gram positive organisms:
– Staphylococcus aureus (cocci)
– Streptococcus pneumoniae (diplcocci)
– Coagulase negative staphylococcus (cocci)
• Gram negative organisms:
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Escherichia coli (rods)
Klebsiella pneumoniae
Pseudomonas aerguinosa
Salmonella typi (rods)
Neisseria meningitidis (diplococci)
Factors guiding Antibiotic
Choice
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The presumed site of infection
Positive microbiological culture results
Suspected or known organisms
Resistance patterns of the common microbial flora.
Properties of the antibiotic: e.g. route of
administration, pharmacokinetic aspects
– Patient’s health status:
e.g. immune status (especially neutropenia and
immunosuppressive drugs), allergies, renal
dysfunction, and hepatic dysfunction
Choosing An Antibiotic
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Cost
Local resistance
Environment
Patient factors
Site
Choosing An Antibiotic
• BACTERIAL FACTORS
- Use only for bacterial infections
- Identify bacteria involved, or best guess
HOST FACTORS
- site, route, allergies, renal function, hepatic
function, pregnancy
DRUG FACTORS
- activity, site,bactericidal/bacteriostatic route, cost
Classification of Antibacterial
agents
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main ways:
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Whether they are bacteriostatic or bactericidal
By target site
By chemical structure
Bacterial spectrum
targets for antibacterials:
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Cell wall synthesis
Protein synthesis
DNA synthesis
Metabolic pathways
Selective Toxicity
• Kill/harm micro-organism without harming
host organism
• Antibiotics-> high therapeutic index
• TI = toxic dose/therapeutic dose
Aspects of antibiotics
• Method of action –
bactericidal/bacteriostatic
• Spectrum of activity
- Broad
- Narrow
Penicillins
• Bactericidal agents
• Contain a β-lactam ring in structure.
• They inhibit synthesis of the bacterium cell wall by
affecting synthesis of peptidoglycan.
• Peptidoglycan cell wall surrounds certain bacteria and is
essential for their survival.
• This results in dividing cells not being able to maintain
the osmotic gradient.
• Net effect is cell swelling, rupture and death of the
bacterium.
Penicillins
• Spectrum:
– Aerobic Gram +ve
– Gram –ve cocci
– Many anaerobic micro-organisms
– Not all penicillins are considered broad
spectrum antibiotics
Benzylpenicillin or Penicillin G
• Very poor oral absorption
• Given IV or IM (single doses > 1.2g IV
route only)
• High Na+ content 1.68mmol/600mg vial,
3.36mmol/3.2g vials.
• Slow IV injection or infusion over 30-60
minutes.
Benzylpenicillin
• Unwanted effects:
– Allergic reaction in up to 10% of exposed individuals
– Anaphylaxis less common in 0.05%
– Immediate anaphylaxis, urticaria, rash after penicillin
administration should not receive penicillin.
– Minor rash >72 hrs after exposure is probably not a true allergy
– Those allergic to one penicillin are allergic to all
• Elimination:
– Renal excretion
– Rapid, short half life
– Dose reduced in severe renal impairment
Amoxicillin/Ampicillin
• Broad spectrum
• Use e.g. community acquired respiratory tract
infections- H Influenza and S. Pneumoniae
• Renal excretion
• Amoxicillin preferred oral route
Co-amoxiclav
• Consists of amoxicillin combined with a betalactamase inhibitor clavulanic acid
• Spectrum:
– Active against Gram-ve rods resistant to amoxicillin
due to beta-lactamases
– E.g. resistant strains of E.coli, S. aureus and H.
influenzae.
– Clavulanic acid has no antibacterial activity
Flucloxacillin
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Bactericidal antibiotic
A beta-lactamase-resistant penicillin
Used for penicillin-resistant staphylococci.
Can be less effective against bacterium that
does not produce beta-lactamase
• It is less active against Streptococcus
pneumoniae and Str. pyogenes than penicillin.
Flucloxacillin
• IV dose: 0.25-2g every 6 hours
• Elimination:
– Mainly renally excreted as unchanged drug
– Small extent of metabolism
• Unwanted effects:
– Hypersensitivity as in penicillin
– Hepatitis & cholestatic jaundice were reported several weeks
after treatment was stopped.
– Risk factor are increasing age and > 2weeks treatment.
Cephalosporins
• Bactericidal agents
• Semi-synthetic antibiotics, related to penicillins
and contain β-lactam ring.
• Some are susceptible to β-lactamase activity, so
less activity against staphylococcal infections.
• β-lactamase are enzymes that catalyse the
hydrolysis of beta-lactam, resulting in loss of
antibacterial activity.
Cephalosporins
• 1st, 2nd 3rd generation
• Mostly given IV, IM, except cefalexin(1st gen.) and
cefuroxime(2nd gen.)
• They distribute into many tissues.
• Spectrum:
– Second line in many infections
– Broad spectrum antibiotics
– Generally 3rd generations have higher activity against Gram –ve
bacterium, but less activity against Gram +ve ones.
Cephalosporins
• Unwanted effects:
– Hypersensitivity reactions.
– 10% of penicillin-sensitive patients are also allergic to
cephalosporins
– 2nd & 3rd generation higher risk of infection with
Clostridium difficile
• Elimination:
– Mainly renal via tubular secretion
– Some like 40% ceftriaxone in bile
Macrolides
• E.g. erythromycin, clarithromycin.
• Similar antibacterial spectrum to penicillins
• Mechanism: inhibit bacterial protein synthesis by
binding to bacterial ribosome.
• Bacteriostatic
• Can be effective against unusual organisms
Macrolides
• Generally safe drugs
• Erythromycin can cause gastrointestinal
problems which are less common with other
agents.
• Azithromycin has a long half life
• Macrolides can inhibit cytochrome P450 leading
to accumulation of drugs.
Tetracyclines
• E.g. tetracycline, doxcycline
• Mechanism inhibit protein synthesis
• Absorption of tetracyclines is affected by calcium and
magnesium ions, food and iron preparations.
• Broad spectrum antibiotics
• Bacteriostatic
• Should be avoided in pregnancy, breast feeding and
children under 12 years as they bind to calcium in
growing bones and teeth causing discoloration.
Aminoglycosides
• These include: gentamicin, streptomyocin,
, neomycin.
• They resemble each other in:
– Antibacterial activity
– Pharmacokinetic properties
– toxicity
Aminoglycosides
• Mechanism:
– Bactericidal activity
– Inhibit bacterial protein synthesis
– They do this by binding to the 30S ribosomal
subunit.
– They stop the translation of mRNA into the
proteins.
Aminoglycosides
• Spectrum:
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Many Gram-ve (Including Pseudomonas)
Some Gram+ve
Inactive against anaerobes
Used in serious Gram –ve infections in combination
with agents that disrupt cell wall synthesis (e.g.
penicillin)
– Synergistic effect with penicillin
– Not absorbed orally so only given IM or IV.
Aminoglycosides
• Elimination:
– Renally by glomerular filtration
– In renal impairment accumulation occurs
rapidly
– Result is an increase in toxicity (ototoxicity
and nephrotoxicity)
– Dose adjustment is essential in renal
impairment
Aminoglycosides
• Unwanted effects:
– Serious effects that are dose related.
• Ototoxicity:
– Progressive damage to sensory cells
– Result can be irreversible: vertigo, loss of balance,
auditory disturbances, deafness.
– Effect is increased by ototoxic drugs e.g. loop
diuretics.
Aminogylcosides
• Nephrotoxicity:
– Due to damage to kidney tubules which can be
reversed by stopping the drug
– Risk factors:
• Pre-existing renal damage
• Reduced urine output
• Concomitant use of nephrotoxic drugs (administer far apart if
possible)
• elderly
• Monitoring of plasma levels is necessary
Quinolones
• These include ciprofloxacin, levofloxacin.
• Spectrum of activity may differ between agents.
• Active against aerobic G – but not active against
anaerobes
• Use: prostate, UTI, respiratory
• Mechanism:
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Bactericidal
Inhibition of replication of bacterial DNA
They block the action of the enzyme DNA gyrase.
DNA gyrase is responsible for forming DNA supercoils for
replication and repair.
Quinolones
• Elimination
– Hepatic metabolism
– Renal excretion
• Unwanted effects
– CNS effects: dizziness, headache, tremor,
convulsions.
– Tendon pain and inflammation, damage and rupture,
especially in elderly and concomitant use of
corticosteroids.
– Drug interactions with many agents
Metronidazole
• Spectrum
– Bactericidal activity
– Active against anaerobic bacteria & protozoa
– Inhibit DNA synthesis and breaks down
existing DNA
Metronidazole
• Used IV, oral and rectal.
• Elimination:
– Metabolised by the liver
• Unwanted effects;
– Nausea and vomiting
– Metallic taste
– Disulfiram-like reaction when taken with alcohol
Trimethoprim
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Mechanism
Inhibits enzyme – DHFR
DHFR = dihydrofolate reductase
Folate-> dihydrofolate->tetrahydrofolate->
DHFR-> DNA synthesis
Bacteriostatic
Spectrum: E Coli+ most urinary pathogens
Narrow spectrum (inactive against anaerobes)
1st line UTI
oral
Antibiotic Resistance
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Innate Acquired
3 main biochemical mechanisms of
acquired resistance
a)  bacterial permeability to an antibiotic
b) Bacterial enzymes
c) Altered target site for antibiotic
Revision Mechanisms
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Inhibition of cell wall synthesis
Inhibition of bacterial protein synthesis
Inhibition of bacterial DNA synthesis
Inhibition of metabolic pathway (e.g.folate)
synthesis
1) Inhibition of cell wall synthesis
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Beta Lactams – 3 major classes
Penicillins
Cephalosporins
Carbapenems
1) Inhibition of cell wall synthesis
• No cell wall in mammals/present in
bacteria
• Peptidoglycan
• Beta lactam ring
• Bactericidal
• High therapeutic index
• Mainly excreted in kidney
• Safe in pregnancy
2) Inhibition of bacterial protein
synthesis
• Inhibition of ribosomal protein synthesis
• Formation of amino acids:
• Gene transcription-> messengerRNA->
ribosomes-> translation-> amino acids->proteins
• Antibiotics bind to bacterial ribosome
• Selective toxicity
• Ususally bacteriostatic but aminoglycosidescidal
• Macrolides, aminoglycosides, tetracyclines,
3) Inhibition of bacterial DNA synthesis
• Bactricidal
• Selective toxicity – mammals do not
contain DNA gyrase
• Quinolones, metronidazole,
• Quinolones: Inhibit DNA gyrase, DNA
gyrase is responsible for forming DNA
supercoils for replication and repair.
4) Inhibition of folate synthesis
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DNA requires folate
Folate-> tetrahydrofolate-> DNA
Inibition of enzyme DHFR(DHF->THF_
E.g. trimethoprim
DHFR= dihydrofolate reductase
DHF = dihydrofolate
THF = tetrahydro folate
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