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Antibiotics
- chemo-therapeutic agents that interfere with bacterial cell growth without
affecting the host organism.
- exploit differences between the bacteria and the host cells to interfere
specifically with bacterial growth
- falling loosely into the category of antibiotics are
- antifungal
- antihelminth
- antiviral agents.
Definition
- A substance that inhibits the growth of micro-organisms
4 groups according to their target
- Cell membrane
- Cell wall
- Protein synthesis
- Nucleic acid synthesis
Bacteriostatic/Bactericidal
- bacteriostatic antibiotics prevent cell growth, but do not cause lysis
- interfere with processes within the cell that do not affect the
production of the cell wall
- bactericidal agents cause lysis
- interfere with the cell wall
- choice of whether to use a bactericidal antibiotic or a bacteriostatic
antibiotic depends on whether or not the bacteria produce secreted toxins
- if they do, it is necessary to kill the cells using a bacteriocidal
agent.
- Otherwise it is preferable to use a bacteriostatic agent as the
bacterial lipopolysaccharides released on lysis may themselves act as
toxins
Cell Membrane
- Prokaryotic cell membranes do not contain sterols
- some antibiotics having different penetrations in prokaryotic and
eukaryotic cells
- antibiotics affecting the cell membrane are of limited use as they may
also be effective against mammalian cell membranes
- cyclic peptides e.g. polymixins
- bacterial-specific cationic detergents
- work by interacting with membrane phospholipids
- lead to disruption of membrane structure
- ionophore antibiotics e.g. valinomycin, monensin and nigercin
- these antibiotics interfere with membrane permeability
- forming helical intramembrane channels
- allow potassium ions (and other cations) to leak out of the cell
- All these agents are bactericidal in action as they leave the cell wall
intact.
- Fungal cell membranes contain ergosterol instead of cholesterol
- polyene antibiotics such as Amphotericin B and Nystatin
- preferentially bind to ergosterol
- more specific to fungi
- low therapeutic index as they can still bind to eukaryotic cell
membranes
- azole family of drugs
- interfere with the synthesis of ergosterol
- block last enzyme in the ergosterol synthetic pathway
- affects the functioning of a number of membrane-associated
proteins leading to cell death
Cell Wall
- unique to prokaryotes and is therefore an excellent target for drug action
- disruption at
- Intracellular events in synthesis e.g.
- cycloserine (disrupts a racemase) and
- fosfomycin (disrupts the addition of phosphoenolpyruvate)
- steps occurring at the cell membrane
- bacitracin prevents the recycling of the lipid carrier necessary
to bring the cell wall precursors synthesised in the cytoplasm to
the cell wall.
- last step in cell wall synthesis (see beta-lactams)
- The most important group of these are the beta-lactam
antibiotics e.g.
- penicillins,
- cephalosporins,
- monobactams,
- carbapenems
- target of beta-lactams is the transpeptidation reaction that is
required to link the precursors to the cell wall structures already
present
- beta-lactam acts as a structural analogue of D-alanine
- irreversibly inactivates the transpeptidase enzyme
- other penicillin binding proteins (PBPs) present in the cytoplasmic
membrane which are involved in other processes such as
transglycosylation and cell elongation
- in gram negative bacteria, the activity of the b-lactams
induces activation of autolysins leading to lysis.
- in gram positive bacteria, where the cell wall is much thinner, b-lactams
cause lysis purely through disruption of the cell wall
- in the presence of bacteriostatic agents, b-lactams
do not cause lysis as they only cause lysis in proliferating cells
Protein Synthesis
At each stage of protein synthesis, antibiotics can disrupt the process
- Mupirocin competitively inhibits isoleucyl-tRNA-synthetase, thereby
preventing the formation of isoleucine-tRNA
- Tetracyclines are broad spectrum antibiotics that are actively transported
into bacterial cells where they bind to the 30S ribosome subunit in such a
way as to prevent the binding of aminoacyl-tRNA leading to the prevention of
chain elongation
- aminoglycosides also bind to the 30S subunit, but they inhibit initiation
of protein synthesis or translocation of the growing polypeptide. This leads
to the formation of abnormal proteins which cause cell lysis
- These antibiotics are concentrated in the renal tubules and are therefore
nephrotoxic
- Chloramphenicol binds to the 50S ribosomal subunit and acts on the
peptidyl transferase enzyme that links amino acids to the growing poly
peptide leading to a halt in chain elongation
- Fusidic acid also blocks chain elongation but by binding to an elongation
factor and reversibly inactivating it. Fusidic acid does not penetrate gram
negative bacteria very well
- Macrolide antibiotics also bind to the 50S ribosomal subunit and they
interrupt the completion of the peptide chain, although the mechanism of
action of these drugs is not clear. An example of these drugs is
erythromycin
- Puromycin is structurally similar to the aminoacyl end of tRNA and causes
premature chain termination. These agents tend to be bacteriostatic,
although streptomycin and other aminoglycosides can cause lysis
Nucleic Acid Synthesis
- Nucleic acid synthesis requires folate
- synthetic pathway for folate is found in prokaryotes but not in eukaryotes
- Sulphonamides competitively inhibit an enzyme in the synthetic pathway
- utilisation of folate (as THFA) can also be interfered with by agents such
as methotrexate
- assembly of nucleic acids into DNA and RNA is another target
- Chloroquine intercalates within the DNA, thereby altering the base-pairing
properties of it, and cause a frame shift mutation
- Bacterial RNA polymerase is the target of rifampicin (used in TB therapy)
- the final enzyme that is targeted by drugs in the nucleic acid synthesis
pathway is DNA gyrase, which is necessary for replication
- Ciprofloxacin inhibits this enzyme
- All these agents are bacteriostatic, and not bactericidal as they do not
cause bursting of the cell wall of the bacteria
Some antibiotics used in clinical practice
Cardiovascular System
- Endocarditis caused by streptococci
- Benzylpenicillin + low-dose gentamicin
- Endocarditis caused by staphylococci
- Flucloxacillin + gentamicin
- Endocarditis caused by entercocci
- amoxycillin + low-dose gentamicin
- vancomycin (penicillin-allergic patients)
- methicillin-resistent staphylococci
Respiratory System
- Haemophilus influenzae epiglottitis
- Exacerbations of chronic bronchitis
- Pneumonia
- Uncomplicated community-acquired
- Severe community-acquired
- Erythromycin + Cefotaxime
- Hospital-acquired
- (Suspected) atypical
- (In community-acquired pneumonia add flucloxacillin if staphylococcus
suspected)
Gastro-intestinal System
- Campylobacter enteritis, invasive salmonellosis, shigellosis and typhoid
fever
- Antibiotic-associated colitis
- Oral metronidazole or oral vancomycin
-
Biliary-tract infection
- A cephalosporin
- gentamicin
- Peritonitis
- A cephalosporin + metronidazole
- Peritoneal dialysis-associated peritonitis
- Vancomycin + gentamicin added to dialysis fluid
Urinary Tract
- Acute pyelonephritis, prostatitis & lower urinary-tract infection
Genital system
- Syphilis
- Gonorrhoea
- Amoxycillin with probenecid
- Pelvic inflammatory disease
Metronidazole+ doxycycline
- Uncomplicated genital clamydial infection, non-gonococcal urethritis and
non-specific genital infection
Central Nervous System
- Meningitis caused by
- meningococci
- pneumococci
- Haemophilus influenza
- Listeria
- GPs are advised to give a single dose of benzylpenicillin before
urgent transportation to hospital ( Initial blind therapy)
Blood
Skin
- Impetigo
- Topical fusidic acid
- oral flucloxacilin if widespread
- Erysipelas
- Animal bites, Cellulitis
ENT
- Dental infections
- Throat infections
- Sinusitis
- Otitis externa
- Otitis media
Eye
- Purulent Conjuctivis
- Chloramphenicol
- gentamicin eye-drops
Musculoskeletal system
- Osteomyelitis, septic arthritis
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