Antibiotics Flashcards
How are antibiotics made?
Natural products of fungi and bacteria - soil dwellers
- They have a natural antagonism and selective advantage towards other organisms
- kill or inhibit the growth of other microorganisms
Most derived from natural products by fermentation,
then modified chemically :-]
- For increased pharmacological properties
- For increased antimicrobial effect
Some are totally synthetic- e.g. sulphonamides
What is meant by the therapeutic margin?
Therapeutic Margin
- The difference between the minimum dose we need for it to be effective and the maximum dose which becomes toxic to the host - active dose (MIC) versus toxic effect - narrow for toxic drugs - e.g. aminoglycosides, vancomycin, ototoxic, nephrotoxic
Why do you have to be careful about microbial antagonism?
The suppression of one line of bacteria can cause overgrowth of usually harmless bacteria to a pathogenic point
This can lead to:
e.g.Antibiotic Associated Colitis :
(clindamycin, broad-spectrum lactams, fluoroquinolones)
- pseudomembranous colitis
Clostridium difficile (part of normal flora of 3% of population)
Ulcerations – inflammation
Severe diarrhoea
Serious hospital cross-infection risks
How do antibiotics treat bacterial infections?
Antibiotic + immunity = bacterial clearance
In people with immunosuppression, treating infections requires different antibiotics or doses in order to achieve bacterial clearance
e.g.:
- cancer chemotherapy, transplantations, myeloma, leukaemias,
- HIV with low CD4
- Neutropenics, asplenics, renal disease,
- diabetes, alcoholics,
Babies, elderly
What is the difference between bactericidal and bacteriostatic antibiotics?
Bactericidal:
- Kill bacteria
- Used when the host defense mechanisms are impaired
- Required in endocarditis, kidney infection
Bacteriostatic:
- Inhibit bacteria
- Used when the host defense mechanisms are intact
- Used in many infectious diseases
Varies for drug and species and concentration
What are the different generations of cephalosporins?
1st gen cephalosporins were effective against streptococci and gram positives but ineffective against gram negatives
2nd gen is evenly distributed
3rd gen is effective against gram negatives and streptococci but not against gram positive
Recall the different types of Penicillins, what they are active and not active against and examples.
Basic penicillins e.g. benzylpenicillin (PenG), penicillin V
- Active against streptococci, pneumococci, meningococci, treopnemes.
- Most strains of Staphylococcus aureus are resistant.
Anti-staphylococcal penicillins e.g. flucloxacillin
- narrow spectrum, some G+ves activtiy, beta-lactamase resistant, less potent that PenG
- Not MRSA
Pen G benzlypenicillin (G= gold standard);
- not acid stable therefore only administered through i.v or i.m
- good for some G-ves as well as G+ves
penV phenoxymethlypenicillin
- oral (more acid stable than penG)
- less active vs G-ves, but same activity vs G+ves as PenG
Broader spectrum penicillins e.g. ampicillin
- Spectrum of activity is similar to basic penicillins but also includes some Gram-negative organisms and also enterococci which are gram+ves
Anti-pseudomonal penicillins e.g. piperacillin
- extended spectrum beta-lactam antibiotic
- also G+ve, G-ve, anaerobes
Beta-lactam+beta-lactamase inhibitor combinations e.g. co-amoxiclav (Augmentin)
- Spectrum like amoxicillin plus activity against some Gram-negatives and Staph aureus
How can we classify antibiotics?
Molecular Structure
- Structural mimics of natural substrates for enzymes e.g. - b-lactams
b-lactam refers to the b-lactam ring that penicillins and cephalosporins possess which is an integral part of the molecule that gives it its activity against bacteria
Bacterial structure
Many targets for selective toxicity including the cell wall
Modes of action
What are the bacterial targets for common antibiotics?
Bacterial targets for common antibiotics, we have:
- Cell wall synthesis inhibitors such as penicillins, cephalosporins and carbapenems
- Protein synthesis which are split into:
· 50S inhibitors such as erythromycin and chloramphenicol
· 30S inhibitors such as tetracycline and streptomycin
- Target DNA replication and RNA processing and examples are quinolones which inhibit DNA gyrase and Rifampin which blocks bacterial RNA polymerase from making mRNA
- Folic acid metabolism enzyme blockers e.g. trimethoprim (targets THFA) and sulfonamides (DHFA)- these antibiotics are often given together
- Target cell membrane which as pretty similar to humans so its pretty toxic e.g. colistin
- Those which generate free radicals inside bacteria e.g. Metronidazole used for treating anaerobic infections
How do antibiotic mechanisms differ for gram+ and gram- bacteria?
The gram+ve bacteria has the outer peptidoglycan structure and the gram-ve bacteria has the peptidoglycan in the periplasmic space and then an outer membrane
In gram+ve bacteria the antibiotics can easily diffuse through the cell wall structure and bind to inhibit the enzymes that make the cell walls causing the bacteria to die
For the gram-ve bacteria, antibiotics have to get through these pores to get to the peptidoglycan which is why some antibiotics that are really effective against gram+ve are not effective against gram-ve
Not to mention that the enzymes that make the peptidoglycan will have different structures
How do beta-lactam antibiotics inhibit bacterial cell wall synthesis on a molecular level?
Monomers with D-alanine-D-alanine terminals get attached to lipid transporter molecules and they get transported across the inner membrane and then they are dimerised and crosslinked
Now they have a pentaglycine chain
These are then polymerised by a chain of enzymes that essentially cleave the D-Ala terminal and cross link it to a pentaglycine chain on another dimer
The enzymes that make this crosslink are called trans-peptidases and carboxy-peptidases AKA penicillin binding proteins
These are the enzymes inhibited by penicillin by b-lactam type antibiotics
Vancomycin binds to the D-ala chain blocking its active site and preventing it from being cleaved
When do we use antibiotics?
Treatment of bacterial infections
Prophylaxis - close contacts of transmissible infections
- Decreased carriage rates (increased ~80% in outbreaks) e.g. meningitis
- prevention of infection e.g. tuberculosis
- peri-operative cover for gut surgery
- people with increased susceptibility to infection
Inappropriate use - viral sore throats - patient pressure
What are the routes of administration of antibiotics?
Community infections often treated orally by GP
Serious infections – hospitalisation - systemic treatment
- e.g. i/v rapid delivery, high [blood]
- often unable to take oral – vomiting, unconscious, poor gut absorption due to trauma
- ?? i/v with perivascular collapse (e.g. septicaemia )
- i/m injection - meningitis case
Topical - conjunctivitis, superficial skin infections, burns, antiseptic creams, heavy metal ointments
What factors determine the dose of antibacterial MIC?
This will depend upon the age, weight, renal and liver function of the patient and the severity of infection
Depend on the susceptibility of the organism
Will also depend upon properties of the antibiotic i.e. enough to give a concentration higher than the MIC (minimum inhibitory concentration)
What is the purpose of antibiotic combinations?
BEFORE an organism identified in life-threatening infections e.g. endocarditis, septicaemia
Polymicrobial infections e.g. abscess, G.I. perforation, anaerobes and aerobes
Less toxic doses of an individual drug possible
Synergy e.g. penicillin and gentamicin
- Co-trimoxazole (sulphonamides + trimethoprim)
Reduces antibiotic resistance e.g. Tuberculosis
