MI: Antimicrobials 1 Flashcards
Examples of selective targets for antibiotics
Peptidoglycan layer of cell wall
Inhibition of bacterial protein synthesis
Inhibition of DNA gyrase and other prokaryote specific enzymes
What is the broad mechanism of action of beta lactams?
Inhibition of cell wall synthesis
What is the broad mechanism of action of glycopeptide antibiotics?
Inhibition of cell wall synthesis
What 3 groups of antibiotics are classified as beta lactams?
Penicillins
Cephalosporins
Carbapenems
Name 2 glycopeptide antibiotics
Vancomycin
Teicoplanin
Describe the mechanism of action of beta lactams
Inhibits transpeptidase, which is an enzyme that forms cross links during the formation of the cell wall.
The resulting cell wall is therefore weak, and so the bacteria lyse because of osmotic pressure.
*They are effective against rapidly dividing bacteria - not useful if the cell wall has already been formed*
How does the cell wall of gram pos and gram neg bacteria differ?
Gram pos: thick peptidoglycan layer, no outer membrane
Gram neg: thin peptidoglycan layer, has an outer membrane (some antibiotics can’t get through this)
*Gram pos stain purple, gram neg stain pink*
What bacteria is penicillin active against?
Gram pos
Not effective against organisms with no peptidoglycan cell wall e.g. mycoplasma and chlamydia
What bacteria is amoxicillin active against?
Broad spectrum: gram pos and many gram neg
*Broken down by beta lactamase produced by S. aureus and other microorganisms*
Which beta lactam antibiotic is effective against pseudomonas?
Piperacillin
*Broken down by beta lactamase*
That’s why it’s used as tazocin
How can beta lactam resistance be overcome?
Include a beta lactamase inhibitor
Eg. Clavulanic acid + amoxicllin (in co-amoxiclav aka augmentin)
Eg. Tazobactam + piperacillin (in tazocin)
Alternatively, create antibiotics that are stable to beta lactamase eg. flucloxacillin
Recall an antibiotic that is associated with C. difficile
Ceftriaxone (cephalosporin)
Examples of cephalosporins
Cefalexin (1st generation)
Cefuroxime (2nd generation)
Ceftriaxone (3rd generation)
Ceftazidime (3rd generation)
Cefotaxime (3rd generation, paediatric cefotriaxone)
*As cephalosporins progressed from 1st to 3rd generation, they became more effective against gram negative and less effective against gram positive*
What limits the use of cephalosporins?
Extended spectrum beta lactamase (ESBL) producing organisms are resistant to cephalosporins
Which beta lactam antibiotics are stable to ESBL organisms?
Carbapenems
*However, carbapenemase enzyme producing organisms (acinetobacter and klebsiella) are becoming more prevalent*
Recall the key features of beta lactams
Relatively non-toxic
Renally excreted so decrease dose if renal impairment
Short T1/2 (many are type 2/time-dependent drugs so aim to maximise the time where concentration > MIC)
Will not cross intact BBB (but can cross in meningitis)
Cross allergenic – penicillin has 10% cross reactivity with cephalosporins and carbapenems
What type of bacteria are glycopeptides effective against?
Gram pos only - they are large molecules so can’t penetrate gram neg cell wall
What are glycopeptides particularly useful for?
MRSA infection
What is a caution of glycopeptide antibiotics?
They are nephrotoxic
Recall the broad mechanism of action of glycopeptide antibiotics
Prevent peptide cross links in cell wall
They bind to the amino acid chains at the end of peptidoglycan precursors, to prevent glycosidic bond formation. They prevent transpeptidase activity without directly binding to the enzyme.
Recall the broad mechanism of action of aminoglycosides
Bind to 30s ribosomal subunit, preventing elongation of polypeptide chain
*This doesn’t explain their rapid bactericidal activity - full mechanism is unknown*
Recall 2 examples of aminoglycoside antibiotics
gentamicin
amikacin
What type of bacteria are aminoglycoside antibiotics effective against?
Gram neg
Aerobes (no activity against anaerobes)
Recall 2 toxicities of aminoglycosides
Ototoxicity
Nephrotoxicity
What type of bacteria are macrolides effective against?
Gram pos
What are macrolides particularly useful for?
Mild staph or strep infections in patients who are allergic to penicillin
Recall 2 macrolide antibiotics
Azithromycin
Clarithromycin
What type of bacteria are tetracylines effective against?
They are broad spectrum
Recall a class of antibiotic you should never give to children or pregnant women
Tetracyclines
Recall one side effect of tetracycline antibiotics
Photosensitivity –> Light-sensitive rash (believed to be because tetracycline can absorb UV light and release that energy to skin cells in form of reactive oxygen species)
Recall the broad mechanism of action of macrolides
Bind to the 50s subunit of ribosomes
Recall the broad mechanism of action of tetracyclines
Bind to 30s subunit of ribosomes
*Bacteriostatic - still useful in certain situations, especially with MRSA*
What type of bacteria is chloramphenicol effective against?
Many - it is v broad spectrum
Why is chloramphenicol rarely used?
Risk of aplastic anaemia and grey baby syndrome in neonates due to inability to metabolise drug
*Still useful for meningitis when patients have penicillin anaphylaxis*
Recall 2 specific bacteria that macrolides are effective against
Campylobacter sp
Legionella pneumophila
(macrolides = erythromycin/ azithromycin/ clarithromycin)
Recall the broad mechanism of action of chloramphenicol
Binds to 50s subunit of ribosomes - inhibits formation of peptide bonds during translation
Recall the broad mechanism of action of oxazolidinones
Binds to the 23s portion of the 50s ribosome subunit to prevent 70s subunit formation
Recall two types of bacteria that oxazolidinones are particularly active against
Highly active against gram positive organisms - especially MRSA and VRE
Recall an example of oxazolidinones
Linezolid
Recall one potential side effect of oxazolidinones
Thrombocytopaenia and neurological side effects if used longer than 4 weeks
Which antibiotics inhibit protein synthesis by binding to the:
30s subunit
50s subunit
30s = aminoglycosides, tetracyclines
50s = macrolides, chloramphenicol, oxazolidinones (binds to the 23s portion)
Recall the broad mechanism of action of fluoroquinolones
Act on alpha subunit of DNA gyrase
Recall the uses of fluoroquinolones
Which bacteria types are susceptible
Complicated UTI
Meningococcal chemoprophylaxis
Pneumonia
Atypical pneumonia
Bacterial gastroenteritis
*BROAD SPECTRUM antibacterial activity against gram negatives*
Recall examples of fluoroquinolone antibiotics
Levofloxacin
Moxifloxacin
Ciprofloxacin
How do nitroimidazoles work?
Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage
Give examples of nitromidazole antibiotics
Metronidazole
Tinidazole
Recall types of organisms that metronidazole is effective against
Anaerobes
Protozoa
When should metronidazole be taken?
Right after visiting the toilet as it sits in bladder
Recall the broad mechanism of action of rifampicin
Binds to DNA-dependent RNA polymerase to inhibit RNA synthesis
Recall the main use of rifampicin
TB treatment
Recall one side effect of rifampicin
Turns secretions orange
Recall one condition of rifampicin prescription
Should never be prescribed alone as resistance develops very quickly
*Resistance is caused by a single amino acid change*
Colistin is very toxic. Why is it coming back into use?
It is active against certain multi-drug resistant bacteria
What is daptomycin licensed for the treatment of?
MRSA
VRE
Recall the 2 classes of antibiotic that inhibit folate synthesis
Sulphonamides
Diaminopyrimidines (e.g. trimethoprim)
Give an example of a sulphonamide
Sulfamethazole
*Sulfonamides aren’t used on their own - should be in combination with trimethoprim (co-trimoxazole)
What is the main use of trimethoprim
Uncomplicated UTI
Which antibiotic is best for treating pneumocystis jirovecii?
Co-trimoxazole
Give 2 examples of cell membrane toxins
Daptomycin (lipopeptide with limited activity to gram positives - potential alternative to linezolid and synercid for MRSA and VRE infections)
Colistin (old antibiotic which is very nephrotoxic but it is active against gram negative organisms like pseudomonas)
What are the 4 main mechanisms of resistance
- Inactivation of the antibiotic (eg beta lactamases)
- Altered target - so antibiotic no longer binds
- E.g. penicillin resistant pneumococci or MRSA where bacteria change the penicillin-binding protein
- E.g. protein-synthesis inhibitors where the binding of the ribosome subunit is prevented
- Reduced accumulation (most important in gram negs - either due to enhanced efflux or to reduced uptake)
- Bacteria bypasses antibiotic sensitive step (particularly important for folate inhibitors - bacteria can change the enzyme they use)
How is MRSA resistant to all beta lactams?
mecA gene encodes novel penicillin binding protein (2A) / novel PBP 2a
Low affinity for binding beta lactams
Substitutes for essential functions of high affinity PBPs at otherwise lethal concentrations of antibiotics
How does Strep pneumoniae develop beta lactam resistance?
Penicillin resistance is the result of acquisition of stepwise mutations in PBP genes
*Lower level resistance can be overcome by increasing dose of penicillin used*
How do bacteria become resistant to macrolides?
Adenine-N6 methyltransferase modifies 23S rRNA -> reduces binding of MLS antibiotics and results in resistance
Encoded by erm gene (erythromycin ribosome methylation)
*If bacteria is resistant to erythromycin in this manner but still sensitive to clindamycin, only use clindamycin with caution - sometimes the in-vitro tests aren’t reliable*
Which bacteria typically forms “gram pos cocci in clusters”?
Staphylococcus
Which bacteria typically forms “gram pos cocci in chains”?
Streptococcus
Strep sounds like ‘stripe’ = chain
What gram stain status are enterococci?
Positive
(“Enter-o-coccus” = like letting someone in, positive thing to do)
Is streptococci gram pos or neg?
Gram pos
Is pseudomonas gram pos or gram neg?
Gram neg
(Pseudo”moan”as - ‘moan’ = negative)
Is neisseria meningitis gram pos or gram neg?
Gram neg
(Neisseria starts with N = negative)
Is haemophilus gram pos or neg?
Gram neg
Ha”emo”philus - emo = negative
Is listeria gram pos or neg?
Positive
Lister = good man = positive
