Micro: Antimicrobials Flashcards
3 main selective targets for antibiotics
- Inhibition of cell wall synthesis (peptidoglycan layer of cell wall)
- Inhibition of bacterial protein synthesis
- Inhibition of DNA gyrase and other prokaryote specific enzymes
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 is the broad mechanism of action of beta lactams?
Inhibition of cell wall synthesis
What 3 groups of antibiotics are classified as beta lactams?
Penicillins
Cephalosporins
Carbapenems
(used in sequence depending on resistance)
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. (Bacterialcidal)
They are effective against rapidly dividing bacteria, which are constantly using transpeptidase to form their cell wall - NOT useful in bacteria that is not dividing as the cell wall has already been formed
Which bacteria are beta-lactams ineffective against
Ineffective against bacteria that lack a peptidoglycan cell wall (hence not gram pos or gram negative as both have a peptidoglycan cell wall).
Examples of such bacteria are: Chlamydia and Mycoplasma
Common examples of penicillins
Penicillin
Amoxicillin
Flucloxacillin
Piperacillin
What bacteria is penicillin mainly active against?
Gram +ve (specifically Strep and Clostridia - behind gastroenteritis )
Not effective against organisms with no peptidoglycan cell wall e.g. mycoplasma and chlamydia
What bacteria is amoxicillin active against?
Broad spectrum: gram +ve and many gram -ve
What is the main indication for Flucloxacillin
Skin infections (Staph A)
Main indication for Piperacillin
Commonly used in Hospital neutropaenic sepsis as covers pseudomonas (used as Tazocin)
Mechanism of resistance bacteria gain aganist penicillin
Beta lactamase (drug inactivation)
Examples of cephalosporins (3)
Cefuroxime (2nd generation)
Ceftriaxone (3rd generation)
Ceftazidime (3rd generation)
As cephalosporins progressed from 1st to 3rd generation, they became more effective against gram negative and less effective against gram positive - newer generation does not act against Staph A.
Important features of Cefuroxime
- Stable to many beta lactamases by gram +ve
- less active against anaerobes - hence used in combination with metronidazole in GI cases
Important features of Ceftriaxone
- Broad spectrum
- good cover against community acquired meningitis as has good penetration of CNS
- associated with C. Diff
- increasingly decreased utility due to ESBL
Important features of Ceftazidime
- Activity against pseudomonas (useful for HAP)
- Note it is less active against Staph A compared to other 1st and 2nd gen cephalosporins
Mechanism of resistance bacteria gain aganist cephalosporins
Extended Spectrum Beta Lactamase (ESBL) - these bacteria are resistant to both penicillins and cephalosporins
drug inactivation
Which beta lactam antibiotics are stable to ESBL organisms?
Carbapenems
Examples of Carbapenems (beta lactam)
Meropenem
Ertapenem
Main indication of Carbapenem
Used for ESBL producing bacteria
Mechanism of resistance bacteria gain aganist carbapenems- list specific bacteria this has been seen on
Carbapenamase (especially in Acinetobacter and Klebsiella) - drug inactivation
this has lead to an returned use of Monobactam antibiotics to treat carbapenamase bacteria
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)
Note that clavulanic acid and Tazobactam are only effective at inhibiting group A beta lactamase
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 (becoming less common)
What is the mechanism of action of glycopeptide antibiotics?
Inhibition of cell wall synthesis by preventing 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
Name 2 glycopeptide antibiotics
Vancomycin
Teicoplanin
What type of bacteria are glycopeptides effective against?
Gram pos only - they are large molecules so can’t penetrate gram -ve cell wall
Good for MRSA (IV) and C.Diff (Oral)
What are glycopeptides particularly useful for?
MRSA infection (especially in bacteriaemia and endocarditis). This is because MRSA is resistant to all beta lactam antibiotics
Vancomycin specififcally useful for C-Diff
What is a caution of glycopeptide antibiotics?
They are nephrotoxic
Hence important to monitor drug level (mainly the trough level - lowest level maintained after initial peak of intake lowers).
List antibiotic classes which inhibit protein synthesis
(TAMCO)
Tetracyclines
Aminoglycosides
Macrolides
Chloramphenicol
Oxazolidinones
Recall the broad mechanism of action of aminoglycosides
Bind to 30s ribosomal subunit, preventing elongation of polypeptide chain and cause misreading of codons along mRNA
However this does not fully explain their antimicrobial effect
Recall 2 examples of aminoglycoside antibiotics
Gentamicin
Amikacin
Tobramycin
What type of bacteria are aminoglycoside antibiotics effective against?
Gram -ve
- sepsis
- good cover for pseudomonas
Aerobes
- no activity against anaerobes as oxygen is required for the uptake of the antibiotic into the bacteria
Have synergetic effect with beta lactams and used to treat G+ve endocarditis
What pharmokinetic pattern of activity do aminoglycosides
Rapid concentration dependent effect - meaning the high initial peak dose is crucial for its antimicrobial action, and following it they have a post-antibiotic effect where the antimicrobial action is maintained.
This is why many aminoglycosides are given as a one-off high dose.
Recall 2 toxicities of aminoglycosides
Ototoxicity
Nephrotoxicity
Mechanism of actions of Macrolides
Act on 50s ribosome
Inhibit translocation
Bacteriostatic action (doesn’t kill bacteria it prevents it from dividing)
Examples of 2 macrolide antibiotics
Azithromycin
Clarithromycin
What type of bacteria are macrolides effective against?
Gram +ve
cannot cross polar gram -ve outer membrane
Recall 2 specific gram -ve bacteria that macrolides are effective against
Campylobacter sp
Legionella pneumophila
(macrolides = erythromycin/ azithromycin/ clarithromycin)
What are macrolides particularly useful for?
Used if patients have penicillin allergy - especially for mild staph or strep infections
Recall the broad mechanism of action of tetracyclines
Bind to 30s subunit of ribosomes
Bacteriostatic - not useful for sepsis but still useful in certain situations, especially with MRSA
Example of a Tetracycline
Doxycyline
What type of bacteria are tetracylines effective against?
Broad spectrum (good cover for MRSA) + some intracellular bacteria (e.g. Chlamydia)
Used for lyme disease
Who is contra-indicated to recieve tetracycline
Children under 12 or pregnant women
Recall one side effect of tetracycline antibiotics
Light-sensitive rash
Mechanism of action of Chloramphenicol
Acts on 50s ribosome inhibiting formation of peptide bonds in translocation
Bacteriostatic
What type of bacteria is chloramphenicol effective against?
Broad spectrum HOWEVER is only used if beta lactams cannot be utilised (e.g. meningitis in pts with severe allergy to beta lactams
Why is chloramphenicol rarely used?
Due to severe side effects:
- Aplastic anaemia
- Grey baby syndrome in neonates due to inability to metabolise drug
What is the sole indication to use chloramphenicol
Bacterial conjunctivitis
Recall the broad mechanism of action of oxazolidinones
Binds to the 23s portion of the 50s ribosome subunit to prevent 70s subunit formation
Recall an example of oxazolidinones
Linezolid
Recall two types of bacteria that oxazolidinones are particularly active against
Highly active against gram positive organisms - especially MRSA and VRE
Recall one potential side effect of oxazolidinones
Bone marrow suppression (commonyl resulting in thrombocytopaenia)
Irreversible optic neuritis if used longer than 4 weeks
Antibiotic class that inhibits DNA synthesis
Fluoroquinolones
Nitroimidazole
Recall the broad mechanism of action of fluoroquinolones
Act on alpha subunit of DNA gyrase
Bacterialcidal
Recall 2 examples of fluoroquinolone antibiotics
Ciprofolaxin
Levofloxacin
Recall 4 uses of fluoroquinolones
Broad antibacterial activity especially against gram negatives
- UTI
- Atypical pneumonia (particularly pseudomonas)
- Bacterial gastroenteritis
Side effects of Fluoroquinolones
- Lower seizure threshold (not to be used in epileptic patients)
- Tendinitis
How do nitroimidazoles work?
Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage
Bacterialcidal
Give examples of nitromidazole antibiotics
Metronidazole
Tinidazole
Nitrofurantoin is a related component of nitromidazole antibiotics
Recall types of organisms that metronidazole is effective against
Anaerobes
Protozoa (giardia, amoeba)
Commonly in which cases do we use Nitroimidazole (specifically Metronidazole)
Commmonly used in combination with Cephalosporin for GI tract cases to allow cover for anaerobic bacteria (which is not achieved with cephalosporin alone)
Indication for nitrofurantoin and when should it be taken?
Simple UTIs
Right after visiting the toilet as it sits in bladder
Recall the broad mechanism of action of Rifamycin (rifampicin)
Binds to DNA-dependent RNA polymerase to inhibit RNA synthesis
Recall the main use of rifampicin
TB treatment - always used in combination as resistance develops quickly as it requires solely one amino acid change
Recall one side effect of rifampicin
Turns secretions orange (red urine)
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)
Colistin is very toxic. Why is it coming back into use?
It is active against certain multi-drug resistant bacteria
What is daptomycin (type of colistin) 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
Sulfamethoxazole
*Sulfonamides aren’t used on their own due to common resistance - should be in combination with trimethoprim (co-trimoxazole)
What is the main use of trimethoprim
Uncomplicated UTI
Common indication of Sulphamethoxazole
pneumocystis jirovecii (PCP)
As co-trimoxazole
What are the 4 main mechanisms of resistance
- Inactivation of the antibiotic (eg beta lactamases)
- Modification of drug’s target target - so antibiotic no longer binds (e.g. MRSA, Strep pneumoniae)
- Reduced accumulation of drug by either impaired uptake or enhanced efflux (e.g. common in gram -ves)
- Bypass antibiotic-sensitive step in pathway
Note that often resistance occurs from more than 1 mechanism happening
How is MRSA resistant to all beta lactams?
It is resistant by modifying the drug’s target in the microbe.
MRSA has mecA gene which encodes novel penicillin binding protein (2A) / novel PBP 2a. This has 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
As it is a stepwise acquisiton resistance, depending on level of mutations, resistance can range from lower level to high level. In the UK lower level resistance is commonest. This can be overcome by increasing dose of penicillin used - hence why for CAP abx regimes we begin with a high dose of amoxicillin. This is not the case in meningitis - because of the already existing difficulty in abx to cross the BBB, the concentration of abx is never enough to overcome lower level resistance. In cases of strep. p. meningitis you’d add vancomycin if any concern about resistance - note that here co-amoxiclav would not help as there beta lactamase is NOT the source of resistance
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
Define the MIC
The minimum amount of abx required to inhibit bacterial growth (calculated in lab). It shows how susceptible an organism is to an antibiotic.
Can compare to the breakpoint to see if clinically indicated. if breakpoint is lower than MIC then yes, if not then minimum concentration is too high and should not be given.
Outline the different pattern of activity antibiotics may exhibit
Type 1 = Concentration-dependent killing and prolonged persistent effects
- You are trying to maximise the peak concentration of antibiotic above the MIC value. - Goal of therapy = maximising initial concentration of abx given
- In these antibiotics they are often given as one-off high doses
- Examples = Aminoglycosides, Fluoroquinolones, Daptomycin
Type 2 = Time-Dependent killing and minimal persistent effects
- You are trying to maximise the amount of time in which abx concentration is above the MIC
- Goal of therapy = maximise duration of exposure to concentration > MIC
- These antibiotics are often given as infusions or dose regimens require being taken more than once a day
- Examples = Beta lactams, Erythromycin
Type 3 = Time-dependent killing and moderate/prolonged persistent effects
- You are trying to maximise the concentration of the drug, and also keep it as long as possible in maximised concentration above the MIC
- A junction per say of the two above
- Examples = Azithromycin, Tetracycline, Oxalidinones
Specific antibiotic recommendation for:
N. Meningitidis
Acute Osteomyelitis (adults)
Bacterial endocarditis
Group A Strep
Simple Cystitis
N. Meningitidis –> 7 days
Acute Osteomyelitis (adults) –> 6 weeks
Bacterial endocarditis –> 4-6 weeks
Group A Strep –> 10 days (7d in new NICE guide)
Simple Cystitis –> 3 days (if pregnant, men, catheter = 7 days)
Common antibiotic regiment used for CAP
Beta Lactam + Macrolide
(beta lactam covers against the common pathogens while macrolides covers against the atypicals which lack a cell wall and therefore bypass beta lactam action)
1st line abx for pseudomonas
aminoglycosides (gentamicin)
Outline the resistance mechanism seen in each circumstance below:
1. ESBL E. coli resistance to ceftriaxone
1. Resistance to macrolides
1. Resistance to trimethoprim and sulphonamides
1. MRSA resistance to flucloxacillin
1. Resistance to Rifampicin
- ESBL E. coli resistance to ceftriaxone - Enzymatic inactivation of the antibiotic
- Resistance to macrolides - Alteration of the target
- Resistance to trimethoprim and sulphonamides - Bypass of antibiotic-sensitive step
- MRSA resistance to flucloxacillin - Alteration of the target
- Resistance to Rifampicin - Alteration of the target
