Micro 20: Antimicrobial agents 1 Flashcards
What are the 3 main targets for antibiotics?
Peptidoglycan layer of cell wall
Inhibition of bacterial protein synthesis
DNA gyrase and other prokaryote-specific enzymes
Difference in structure of gram +ve v gram -ve bacteria
Gram +ve:
- Thick peptidoglycan cell wall on outside
Gram -ve:
- Thinner peptidoglycan cell wall
- Has an outer membrane which prevents some abx from working on the cell wall
Name two groups of antibiotics that inhibit cell wall synthesis (peptidoglycan layer of cell wall) + group of abx in each / examples
Beta-lactams:
- Penicillins
- Cephalosporins
- Carbapenems
Glycopeptides:
- Vancomycin
- Tiecoplanin
(these are abx not groups like in b-lactams)
MoA of b-lactams?
Beta-lactam is a structural analogue of the enzyme substrate
Inhibits transpeptidases (aka penicillin-binding protein)
Inactivate enzymes that are involved in the terminal stages of cell wall synthesis
This means that there are no peptide crosslinks between peptidoglycan chains so the cell wall is weak
This causes bacteria to burst and die due to osmotic lysis (from osmotic pressure)
Limitations of b-lactams?
They work on the stationary phase of the cell cycle - only effective against rapidly dividing bacteria
They are also ineffective against bacteria w/ no cell wall - intracellular pathogens (eg. Mycoplasma & chlamydia)
4 types of penicilins?
Penicillin
Amoxicillin
Flucloxacillin
Piperacillin
Describe the coverage and mechanism of resistance of penicillin?
Active against Gram-positives (e.g. Streptococci, Clostridia)
Broken down by beta-lactamases (mainly produced by S. aureus)
NOTE: penicillin is the MOST ACTIVE beta-lactam antibiotic
Describe the coverage, mechanism of resistance and limitations of Amoxicillin
Broad-spectrum penicillin
Extends coverage to Enterococci and Gram-negative organisms
Broken down by beta-lactamase produced by S. aureus and many Gram-negatives
Describe the coverage, mechanism of resistance and limitations of Piperacillin
Similar to amoxicillin
Extends coverage to Pseudomonas and other non-enteric Gram-negative organisms
Broken down by beta-lactamase produced by S. aureus and many Gram-negatives
Note: P for Piperacillin, P for Pseudomonas
Describe the coverage and limitations of Flucloxacillin
Similar to penicillin but less active
Does NOT get broken down by beta-lactamase produced by S. aureus
- This is why S. aureus is treated w/ flucloxacillin
Name two beta-lactamase inhibitors.
What is the benefit of giving beta-lactamase inhibitors with beta-lactams?
Clavulanic acid
Tazobactam
Protect penicillins from breakdown by beta-lactamases thereby increasing the coverage to include S. aureus, Gram-negatives and anaerobes
What is co-amoxiclav?
Amoxicillin + Clavulanic Acid
Examples of 1st, 2nd and 3rd gen cephalosporins?
What is the difference between different generations?
1st = Cephalexin
2nd = Cefuroxime
3rd = Cefotaxime, Ceftriaxone, Ceftazidime
NOTE: as you go up the generations you get increasing activity against Gram-negatives and less activity against Gram-positives
Benefit of cephalosporins v penicillins?
Stable to many b-lactams produced by gram -ve bacterias
Coverage of cefuroxime (2nd gen cephalosporin)
Stable to many b-lactamases made by gram -ves
Similar cover to co-amoxiclav
But less active against anaerobes -> combine w/ metronidazole to cover anaerobes
What cephalosporin is the mainstay of bacterial meningitis mx? Why?
What adverse reaction is this associated w/?
Ceftriaxone (3rd gen cephalosporin) - This is excreted less than other b-lactams hence maintains conc in CNS
Associated w/ C.Diff infection
What cephalosporin provides good cover against Pseudomonas?
Ceftazidime (3rd gen cephalosporin)
What are ESBLs?
Type of beta-lactamase that also breaks down cephalosporins as well as penicillins
List three examples of carbapenems
Meropenem (Broadest + anti-pseudomonal activity)
Imipenem (Similar to meropenem, can cause renal failure + seizures - give cilastatin)
Ertapenem (not as broad as others, doesnt cover pseudo or enterococci)
What is the main benefit of carbapenems?
Stable to EBSL enzymes
Outline the key features of beta-lactam antibiotics (5)
Relatively non-toxic
Renally excreted (reduced dose in renal impairment)
Short half-life
Will not cross an intact blood-brain barrier (may cross inflamed meninges in meningitis)
Cross allergenic (penicillins have 5-10% cross-reactivity with cephalosporins and carbapenems)
List examples of bacteria that have shown carbapenem resistance and how?
Acinetobacter and Klebsiella
Presence of carbapenemase enzyme
Examples of glycopeptide ABX?
Vancomycin
Teicoplanin
MoA of Glycopeptides?
Glycopeptides bind to amino acid chains at the end of peptidoglycan precursors
This prevents glycosidic bonds being formed (via transglycosidase) and prevents peptide crosslinks being formed (via transpeptidase)
NOTE: they are similar to beta-lactams but instead of binding to the enzymes, they bind to substrates (cell wall component precursors)
What are glycopeptides often used to treat?
Serious MRSA infections
C. difficile infections (oral vancomycin)
Which type of bacteria are glycopeptides effective against and why?
Gram-positives
They are large molecules so they cannot cross the outer membrane of Gram-negative cell walls
Major side effect of glycopeptides? prevention?
Nephrotoxic - monitor blood levels to prevent accumulation
How are Bacterial ribosome different to human ribosomes?
Both have 2 subunits but bacterial is smaller:
- Human = 60S + 40S
- Bacterial = 50S + 30S
What are some antibiotics that work by inhibiting protein synthesis?
ATMCO
Aminoglycosides - 30S subunit Tetracyclines - 30S subunit MLS Group (Macrolides, Lincosamides, Streptogramins) - 50S subunit Chloamphenicol - 50S subunit Oxazolidinones - 23S subunit of 50S
MoA of aminoglycosides?
Which class of antibiotics can be used in combination to produce a synergistic effect?
Binds to amino-acyl site of the 30S ribosomal subunit and prevents elongation of the polypeptide chain
B-lactams (eg. in endocarditis)
Major side effect of aminoglycosides? prevetion?
Ototoxic and nephrotoxic - monitor levels
Limitations of aminoglycosides?
No activity against anaerobes
Inhibited by low pH - won’t work in abscesses
Examples of Aminoglycosides?
Gentamicin
Amikacin
Tobramycin
What are tetracyclines? activity against what?
Examples of tetracyclines?
Broad-spectrum agents with activity against intracellular pathogens - no cell wall (e.g. Chlamydiae, Rickettsiae and Mycoplasmas) as well as most conventional bacteria
Doxycycline
Lymecycline
MoA of tetracyclines?
Binds to the ribosomal 30S subunit and prevents the binding of aminoacyl-tRNA to the ribosomal acceptor site, thereby inhibiting protein synthesis
Major issue w/ tetracycline use in terms of effectiveness?
How has this been overcome?
Most gram -ves show widespread resistance
Tigacycline - broadened spectrum of tetracyclines
Characteristic side effect of tetracyclines?
Who should not recieve tetracycline treatment and why?
Light sensitive rash
Children and pregnant women - Because it can deposit in bone and cause discoloration of growing teeth
Examples of macrolides?
Erythromycin
Clarithromycin
Azithromycin
MoA of macrolides?
Limitation
Binds to the 50S ribosomal subunit and interferes with translation
Also stimulates the dissociation of peptidyl-tRNA
Limited activity against gram -ves due to outer membrane (generally gram -ve are macrolide resistant)
What does the MLS group of abx consist of + examples of each?
Macrolides - Azithromycin
Lincosamides - Clindamycin
Streptogramins - Synercid
MoA of Oxazolidinones + example?
Binds to the 23S components of the 50S subunit to prevent the formation of a functional 70S initiation complex (needed for translation)
Linezolid
What are Oxazolidinones active against?
Drawbacks of their use?
Highly active against gram-positives (including MRSA and VRE)
Not active against Gram-negatives
Expensive + may cause optic neuritis, thrombocytopaenia and anaemia
What types of abx inhibit DNA synthesis + examples of each?
Quinolones:
Ciprofloxacin
Moxifloxacin
Levofloxacin
Nitroimidazoles:
Metronidazole
Tinidazole
MoA of Quinolones?
Acts on the alpha-subunit of DNA gyrase predominantly with other actions
What are quinolones active against?
Broad antibacterial activity, especially against Gram-negatives, including Pseudomonas aeruginosa
NOTE: newer agents (levofloxacin, moxifloxacin) increased activity against Gram-negatives and intracellular organisms (eg chlamydia)
Uses of quinolones? - think conditions (not organisms)
Limitations? (reasons why use has decreased)
UTI
Pneumonia
Atypical pneumonia
Bacterial gastroenteritis
Use has decreased due to resistance against E.Coli and side effects (tinnitus)
Note - well absorbed after oral administration
MoA of nitroimidazoles? Coverage?
Under anaerobic conditions, an active intermediate is formed, which causes DNA strand breakage
Only active against anaerobic bacteria and protozoa (e.g. Giardia)
- low resistance against anaerobes
What is a related compound to nitroimidazoles + what are their advantages?
R
Nitrofurans (eg. Nitrofurantoin)
Benefits:
- Concentrates in bladder - hence doesnt cause C. Diff
- Active against lots of EBSL organisms - not inhibited by mechanisms of resistance
What drugs are inhibitors of bacterial RNA synthesis?
Examples?
Rifamycins such as:
Rifampicin
Rifabutin
Main activity of rifampicin? MoA?
Mainly Mycobacteria and Chlamydiae
Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation
Side effects of Rifampicin?
Inducer of CYP450 - important to monitor interactions (OCP, warfarin) + LFTs
May turn urine + contact lenses orange
Can rifampicin be used as single agent? Why?
No, rifampicin should never be used alone
Resistance develops rapidly due to chromosomal mutation (single amino acid change in beta-subunit of RNA polymerase)
Name two cell membrane toxins
Daptomycin
Colistin
Describe the activity of:
Daptomycin
Colistin
+specific organisms?
Daptomycin
- Gram-positives
- Likely to be used in treating MRSA and VRE
NOTE: it is a cyclic lipopeptide
Colistin
- Active against Gram-negatives including Pseudomonas aeruginosa, Acinetobacter baumanii and Klebsiella pneumoniae
NOTE: it is a polymyxin
Name two families of antibiotics that work by inhibiting folate metabolism + examples?
MoA?
Sulphonamides - sulphamethoxazole
Diaminopyrimidines - trimethoprim
Act indirectly on DNA through interference with folic acid metabolism
NOTE: they act on sequential stages in same pathway so have synergistic action
What is co-trimoxazole? why is this used and when?
Sulphamethoxazole + trimethoprim
Sulphonamide RESISTANCE is common - hence extends coverage
Useful for PCP (immunocompromised), HAP (less likely to cause C. Diff)
What is used to treat community-accquried UTIs?
Trimethoprim
List some mechanisms of antibiotic resistance.
INACTIVATION - Chemical modification or inactivation of the drug
ALTERED TARGET - Modification or replacement of the target
REDUCED ACCUMULATION - Reduced antibiotic accumulation (impaired uptake or enhanced efflux)
BYPASS - Bypass antibiotic-sensitive step in cell division
Which bacteria produce beta-lactamases?
S. aureus and Gram-negative bacilli (coliforms)
NOTE: this is not the mechanism of resistance in pneumococcus and MRSA
In which groups of bacteria is penicillin resistance not reported in?
Group A, B, C and G beta-haemolytic streptococci
Describe how MRSA uses ‘altered targets’ as a mechanism of resistance.
MRSA has a mecA gene which encodes novel PBP2a (peptidoglycan transpeptidase)
This has a low affinity for binding beta-lactams therefore is not inactivated by beta-lactams
Describe the mechanism of resistance in Streptococcus pyogenes.
Results from acquisition of a series of stepwise mutations in PBP genes
Lower level resistance can be overcome by increasing the dose
What are extended spectrum beta-lactamases?
Where is this more common? Advice?
Able to breakdown cephalosporins as well as penicillins
Becoming more common in E. coli and Klebsiella
NOTE: if there is > 10% resistance then empirical therapy is not advised
What are AmpC beta-lactamases?
Breakdown penicillins and cephalosporins but are not inhibited by clavulanic acid
MoA of resistance to Macrolides?
Adenine-N6 methyltransferase modifies the 23S RNA
This reduces the binding of macrolides thereby resulting in resistance
Encoded by erm (erythromycin ribosome methylation) genes
NOTE: caution when using clindamycin in Staphylococcus and Streptococcus which is resistant to macrolides because lincosamides can induce this mechanism of resistance
Which abx have resistance due to chemical modification or inactivation of the drug ? - INACTIVATION
B-Lactams
Aminoglycosides
Chlroamphenical
Which abx have resistance due to modification or replacement of the target ? ALTERED TARGET
B-Lactams Glycopeptides Macrolides Chloramphenicol Linezolid Quinolones Rifampicin
Which abx have resistance due to reduced antibiotic accumulation (impaired uptake or enhanced efflux) ?- REDUCED ACCUMULATION
B-lactams Aminoglycosides Tetracyclines Chloramphenicol Quinolones
Which abx have resistance due to bypass antibiotic-sensitive step in cell division
?
Trimethoprim
Sulphonamides
What does bactericidal and bacterostatic mean?
Bactericidal - Kills bacteria
Bacteriostatic - Stops bacterial growth
Which classes of Abx are bactericidal and bacteriostatic?
Bactericidal:
- Anything that doesn’t work via inhibition of protein synthesis
- Protein synthesis abx = Aminoglycosides + Oxazolidinones (against strep)
Bacteriostatic:
- Only protein synthesis abx
- Except aminoglycosides + oxazolidinones (work for staph + enterococci)
What abx work against Gram +ve?
What work against gram -ve?
Gram +ve:
- B-lactams (penicillins, cephalosporins, carbapenems)
- Glycopeptides
- Macrolides - useful in penicillin allergy
- Oxazolidinones
Gram -ves:
- Aminoglycosides
- Fluroquinolones
MoA of Chloramphenicol?
- Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit
- And inhibits the formation of peptide bonds during translation
