Antibiotics

• Where do antibiotics come from?

  • natural metabolic products of bacteria or fungi
  • modern antibiotics: fermentation, then modification
• Antimicrobials is an all-encompassing term that covers antibacterials, antifungals, antivirals and antiparasitics.
• For bacteria to grow they need

  • nutrients
  • appropriate physical and chemical environment
• Features of a good antibiotic

  • effective against target bacteria
  • safe (minimal toxicity)
  • slow emergence of resistance
  • long-half life
  • good tissue distribution
  • oral bioavailability
  • cheap
• Narrow spectrum antibiotics are focused specifically which reduces disturbance to natural flora and reduces contribution to antibiotic resistance.
• Broad spectrum antibiotics e.g. penicillin give confidence that you have good coverage or can be used if you are not sure what you are targeting or if there is mixed infection.
• Long half-life reduces number of doses needed and allows us to maintain effective concentration of drug in the system. There is often better compliance with treatment.
• Patients prefer tablets as it is easier and requires less skill than IV injection - therefore antibiotics need to have good bioavailability
• We want antibiotics to be able to be synthesised rapidly and cheaply so they can be mass produced and distributed.
• Selective toxicity

  • ideal antimicrobial agents severely damage microorganisms but have much less effect on human metabolism - reduce side effects
  • magic bullet - target bacterial cells but not human cells. This is possible as they have different structure
• Important bacterial structure:

  • structure related to function
  • flagellum for movement
  • pilli for movement and grip (anchor to tissues)
  • cell wall unique to bacteria - capsule is a defence mechanism
  • 70S ribosomes important in protein synthesis are specific size in bacteria
• Bacteriostatic

  • stops replication but bacteria are not killed
  • halts exponential growth and gives our own immune system time to respond
• Bactericidal

  • interfere with assembly of cell wall or other aspects and cause it to rupture
  • kill bacteria at point of action
• spectrum of bacteria

  • broad or narrow
  • gram staining
  • activity against aerobic and anaerobic bacteria
• gram positive bacteria with thick cell wall

  • staphylococcus
  • clostridium
  • streptococcus
  • listeria
• gram negative bacteria with thin cell wall

  • E. coli
  • pseudomonas
  • klebsiella
  • neisseria
• Bacteria can be classified as anaerobic or aerobic but some can switch if conditions dictate so this is not a foolproof way of targeting them.
• Mechanisms of action

  • simple classification but most useful clinically
  • allows us to identify potential side effects
  • can dictate next steps if one antibiotic fails
• 5 mechanisms of action

  • inhibition of cell wall synthesis
  • metabolic antagonism
  • interference with nucleic acid synthesis
  • inhibition of protein synthesis
  • action on membrane
• Targeting cell wall synthesis

  • peptidoglycan present in bacterial cell walls
  • long polysaccharide chains with short peptide side chains
  • crosslinked amino acids
  • for bacterial growth bonds must be cut
  • if transpeptidation inhibited bacterial cells lyse
  • holes to allow ions etc. to cross
  • water then enters to balance concentrations and the cells explode
• Beta-lactam antibiotics inhibit transpeptidases e.g. penicillins, cephalosporins, carbapanems
• Glycopeptide antibiotics inhibit crosslinking by binding residues on side chains e.g. vancomycin
• Due to the similarity of structure of penicillins, cephalosporins and carbapanems (B-lactam ring is preserved) transferrance of resistance between different drugs occurs.
• Metabolic antagonism

  • interrupt bacterial metabolic pathways that do not happen in humans
  • Folate synthesis - two checkpoints targeted
  • dihydropteroate synthetase conversion of PABA to folate targeted by sulfonamides (e.g. sulfadiazine)
  • dihydrofolate reductase conversion of folate to tetrahydrofolate targeted by trimethoprim (folate antagonist)
  • THF is needed to synthesise thymidylate etc. to form DNA
• Interference with nucleic acid synthesis

  • bacterial DNA stored supercoiled
  • uncoiled for replication (DNA polymerase) and transcription to mRNA (RNA polymerase)
  • DNA gyrase assists with unwinding of DNA (negative twists put in to release tension of unwinding DNA)
• Quinolones e.g. ciprofloxacin inhibit DNA gyrase - causes DNA fault and cells viability fails
• Rifamycins e.g. rifampicin inhibits DNA polymerase - no transcription
• Metronidazole (prodrug - needs to be converted)

  • very specific to certain types of infection
  • converted to toxic metabolite (only in anaerobic conditions)
  • Inhibits DNA synthesis and breaks down existing DNA
  • Careful of contraindications e.g. warfarin as it breaks down DNA needed for metabolism of these drugs
• inhibition of protein synthesis

  • bacterial ribosomes differ from human ones
  • Bacterial are 70S and humans are 80S
  • both have light subunit and heavy subunit (come in pairs)
  • bacterial subunits are 50S and 30S
  • drugs bind the ribosomes
  • macrolides e.g. clarithromycin bind 50S
  • aminoglycosides e.g. gentamicin bind 30S
  • tetracyclines e.g. doxycycline bind 30S
• Aminoglycosides bind primarily to 30S bacterial ribosomes, however also bind less preferentially to 50S. They also cause membrane destabilisation via unclear mechanisms and are considered more bactericidal.
• Targeting cell membrane

  • less commonly used
  • colistimethate sodium
  • reserved for Gram-negative infections resistant to other antibacterials
  • polymyxin B
  • neurotoxicity and nephrotoxicity
  • unlike most other drugs it is used topically
  • but very important target in antifungal drugs e.g. amphotericin B
• Bactericidal antibiotics (BANG Q RIP)

  • Beta-lactams
  • Aminoglycosides
  • Nitroimidazoles
  • Glycopeptides
  • Quinolones
  • Rifampicin
  • Polymyxins
• Bacteriostatic antibiotics (MS COLT)

  • macrolides
  • sulfonamides
  • chloramphenicol
  • oxazolidinones
  • lincosamides
  • tetracyclines
• effective use of antibiotics

  • knowledge of likely infecting organism
  • based on symptoms
  • likely bacterial susceptibility
  • resistance pattern
  • organism structure
  • site of infection
  • spectrum of action needed
  • absorption and distribution of antibiotics
• Pharmacological considerations in effective use

  • target site of infection by:
  • route of administration
  • knowledge of route of excretion
  • gentamicin not absorbed in GI tract - needs administration parenterally
  • meningitis treatments need to cross the blood brain barrier
  • urinary tract infections - systemic drugs have to be renally cleared to get the drug to the site of action
  • modify dose according to patient - liver or renal disease affects excretion of drug leading to accumulation or toxicity
• Antibiotic resistance

  • some microorganisms are naturally resistant against some antibiotics whilst others acquire resistance, especially when under selective pressure
  • natural - penicillin cannot penetrate cell wall of gram-negative bacteria
  • acquired - bacteria produce beta-lactamase and inactivate penicillin
• Four mechanisms of acquired resistance

  • spontaneous mutation
  • changes susceptibility of bacteria to drug
  • horizontal transformations (from one bacteria to another)
  • conjugation
  • transduction
  • transformation
  • all genes responsible for resistance cluster - resistance is conserved in genetic material of bacteria
• • conjugation - bacterial sex using plasmid or transposons carrying DNA from one bacteria to another
  • transduction - phage-mediated - virus infects bacteria and carries DNA when it infects new host bacteria/replicates
  • transformation - bacteria incorporates naked DNA from environment around it into its genome to confer resistance - unusual
• mechanisms of resistance

  • altered uptake
  • reduce entry to bacteria by removing transporters
  • active exit - removal of drugs from cell
  • drug inactivation
  • altered target site
  • altered metabolic pathways
  • modifications to enzymes