Antibiotics Flashcards
What are antibiotics?
natural products produced by fungi and bacteria in the soil, give the microbes a selective advantage by killing/inhibiting the
growth of other microorganisms
most derived from natural products by fermentation, then modified chemically to give them:
- pharmacological properties (eg. not secreted with toxic metabolites, doesn’t bind proteins in the blood)
- an antimicrobial effect
but, some antibiotics can be totally synthetic, e.g. sulphonamides
Alexander Fleming’s original culture of Staphylococcus aureus
contaminated with Penicillium notatum
Agar plate with colonies of staph aureus left at the window sill
Mould grew on the agar, and the colonies around the mould had lysed - penicillin had diffused out of the mould and lysed the colonies
main principle of antibiotics?
the idea of selective toxicity
select a target that is only in the microbe and not the host, so you don’t harm the host - based on the differences in structure and metabolic pathways between host and pathogen
difficult targeting viruses because they are intracellular, fungi and parasites
variation between microbes
-even within the same species of bacteria, strains can have variation in susceptibility to antibiotics
Therapeutic Margin - what is this?
active dose (MIC) versus toxic effect
MIC = minimum inhibitory concentration – the concentration at which you have to give a drug in order for it to a microbiological effect. Need to achieve this MIC without inducing too much toxicity.
Balancing whether an antibiotic has good therapeutic activity vs how toxic it can be (host damage)
If the dose between which the effect switches from effective to toxic is narrow, the drug is said to have a narrow therapeutic margin/index (eg. aminoglycosides, vancomycin)
If a drug is very safe and there is little toxicity, it has a wide therapeutic margin/index.
explain the importance of microbial antagonism
one organism can produce something that inhibits another
eg. in the gut, organisms coexisting together, secreting antimicrobial peptides/compounds
Limits growth of competitors and PATHOGENS
all coexist together which MAINTAINS FLORA - loss of means BACTERIAL/PATHOGEN OVERGROWTH
give an example of loss of flora and the consequence?
Antibiotic Associated Colitis :
- pseudomembranous colitis
Clostridium difficile - taking broad spectrum antibiotics (broad-spectrum lactams, fluoroquinolones, etc.) messes up balance and allows overgrowth of pathogens including clostridium difficile.
- Serious hospital cross-infection risks
- easy to pick up/breathe in the spores
- if they enter your gut you can then get an infection. - Ulcerations causing inflammation
- Severe acute watery diarrhoea
- Inflamed colon, lots of mucus being produced
- loss of colon function (water reabsorption) because c diff produces toxins that affect the colonocytes
- lack of water absorption from food
- acute watery diarrhoea - can be life threatening.
do antibiotics work alone?
don’t work alone, and its difficult to treat immunosuppressed patients (cancer, babies, elderly, alcoholics, HIV with low CD4) with antibiotics – much more difficult to clear an infection, you need a combination of antibiotics or more toxic antibiotics etc.
Antibiotics in a normal immunocompetent person relies partly on the immune system to help clear the infection.
how can antibiotics be classified?
Classified by:-
Type of activity
Structure
Target site for activity
Bactericidal v. Bacteriostatic
Type of activity
Bactericidal:
Kill bacteria
Used when the host defense mechanisms are impaired
Required in endocarditis, kidney infection
Bacteriostatic:
Inhibit bacterial growth so immune system can clear it, eg. tetracycline
Used when the host defense mechanisms are intact
Used in many infectious diseases
Spectrum of Activity
Type of activity
Broad Spectrum Antibiotics:
Effective against many types
Example: Cefotaxime
Narrow Spectrum Antibiotics:
Effective against very few types
Example: Penicillin G
Some antibiotics only work against gram negative not gram positive
Molecular Structure
beta lactams
- beta lactam ring is a chemical structure in some antibiotics
- pencilllins and cephalosporins contain beta-lactam structure
Beta lactams act as natural competitor substrates for enzymes that are involved in making the bacterial cell wall
Target site for activity
Bacteria are complex multimeric structures, and have molecules that don’t exist anywhere else - good targets for selective toxicity, eg. pili, capsule, flagellum
- cell wall synthesis - penicillin
- folic acid metabolism - sulfonamides
- DNA and RNA processing - quinolones target DNA gyrase,
- Protein synthesis - 30S and 50S inhibitors
- Free radicals such as metronidazole, damage lipids, enzymes
- bacterial membrane - toxic because affects eukaryotic membranes too, eg. colistin
explain how cell wall inhibitors work
GRAM POSITIVE
Big area of cross linking peptidoglycan. Antibiotics that inhibit cell wall synthesis target the enzymes that make peptidoglycan, and the enzymes have to be on the outer side of the inner layer. This is a porous structure, antibiotics can easily penetrate this porous structure to get to and target and enzymes making the peptidoglycan structure. Things like beta lactams are very effective here.
GRAM NEGATIVE
Peptidoglycan sits in the periplasmic space. Outer membrane is an impermeability barrier, the only way things can get across is by porins. If the membrane doesn’t have a transport mechanisms to transport an antibiotic, the antibiotic won’t get through.
How does a bacteria make peptidoglycan structures?
FIRST PRECURSOR MOLECULE = terminal (last 2 peptides) on the monomer are isomers for alanine, labelled d-ala, d-ala - specific and needed for peptidoglycan synthesis
then it travels across the cytoplasm by linking to a lipid transport molecule – this transport can be inhibited
cross linking of 5 amino acids, then polymerisation in the cell wall via transcarboxypeptidases - these enzymes recognise the D-ala D-ala, cleaves off the last D-ala and links the other D-ala to another pentapeptide
-these enzymes are in bacterial cell walls and inhibited by beta lactams
vancomycin binds to D-ala D-ala, and the enzymes then can’t get to the structure as the big vancomycin structure blocks them from having their effect.
give an example of an antibiotic acting as a structural mimic for bacterial enzymes?
beta lactams
act as substrate mimicks and competitive inhibitors for the cross linking enzymes
but, some bacteria have enzymes have destroy the beta lactam ring, breaking up the 3D structure - means it no longer acts as a competitive inhibitor for the enzyme
PBP, penicillin binding proteins, synthesise the peptidoglycan and beta-lactams bind here. This means bacteria cannot make peptidglycan, so it lyses itself and dies – this is why most beta lactans are bactericidal
also sulphonamides are structural mimics for p-benzoic acid
Folic Acid Synthesis Inhibitors
structure of sulfonamide is almost identical to structure of p–aminobenzoic acid – competes against it and therefore blocks it from binding
Protein synthesis inhibitors
erythromycin blocks translocation of peptidyl t-RNA
eryhtromycin is an example of a macrolide, used to treat Gram-positive infections esp. in those allergic to beta-lactams
When do we use antibiotics ?
treat bacterial infections
use them propholactically to prevent someone from getting an infection
use them peri-operatively before an operation, particularly gut operation where there are lots of bacteria
people with increased subceptiblity to infection, eg. COPD patient, people with sickle cell disease or patients that lack a spleen
Inappropriate use - viral sore throats - patient pressure
Route of Administration
often orally by GP
systemic infections resulting in hospitalisation often mean rapid delivery of antibiotics via an i/v - often unable to take oral due to vomiting, unconscious, poor gut absorption due to trauma
Topical - conjunctivitis, superficial skin infections, burns, antiseptic creams, heavy metal ointments
what is MIC and what factors affect MIC dose?
minimum inhibitory concentration
-the concentration at which the antibiotic will kill off or inhibit the growth of the organism
depends on:
- age, weight, renal and liver function of the patient
- severity of infection
- the susceptibility of the organism
- depend upon properties of the antibiotic i.e. enough to give a concentration higher than the MIC (minimum inhibitory concentration)
why might antibiotic combinations be favourable?
- with polymicrobial infections
- to achieve less toxic doses of individual drugs
- reduce antibiotic resistance
penicillins
Basic eg. penicillin V
- Active against streptococci, pneumococci, meningococci, treopnemes.
- Most strains of Staphylococcus aureus are resistant
Anti-staphylococcal penicillins e.g. flucloxacillin
- narrow spectrum, G+ves, beta-lactamase resistant, less potent that PenG
- Not MRSA
Beta-lactams: Cephalosporins
cefalexin - oral agent primarily used to treat UTIs
- bactericidal activity
- binds to and inactivates PBP’s located on the inner membrane of the bacterial cell wall
Aminoglycosides
This group includes gentamicin and streptomycin
- cannot be absorbed from the gut and must be given parenterally
- active predominantly against Gram-ve bacteria including Pseudomonas aeruginosa
- nephrotoxic (kidney) and ototoxic (ear), so serum levels must be monitored
Glycopeptides
vancomycin
Active only against Gram-positive organisms
Parenteral only (administered or occurring elsewhere in the body than the mouth and alimentary canal)
Usually reserved for situation when other agents cannot be used e.g. against MRSA
Tetracyclines
Includes oxytetracycline, doxycycline
Broad spectrum Used mainly for treating: Chlamydia Mycoplasma pneumoniae Acne
Quinolones
Includes ciprofloxaxin, moxifloxacin
Older drugs such as ciprofloxacin active mostly against Gram-negatives
-useful for complicated UTIs and gastrointestinal infections
Newer agents have better anti-Gram-positive activity
-useful for some respiratory tract infections
Fusidic acid
narrow spectrum, used in combination to treat Staphylococcal infections only.
