Antimicrobial Agents 1 Flashcards
What are the inhibitors of cell wall synthesis?
Beta-lactam antibiotics - Penicillins, cephalosporins and carbapenems
Glycopeptides - Vancomycin and Teicoplanin
What is the difference between Gram positive and Gram negative bacteria?
Gram positive - peptidoglycan cell wall, cytoplasmic membrane
Gram negative - outer membrane, peptidoglycan cell wall, cytoplasmic membrane
What are the features of beta-lactam antibiotics?
Inactivate the enzymes that are involved in the terminal stages of cell wall synthesis (transpeptidases also known as penicillin binding proteins) – β-lactam is a structural analogue of the enzyme substrate
Bactericidal
Active against rapidly-dividing bacteria
Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)
What are the common penicillins?
Penicillin - Gram positive organisms, Streptococci, Clostridia
Broken down by an enzyme (β-lactamase) produced by S. aureus
Amoxicillin – Broad spectrum penicillin, extends coverage to Enterococci and Gram negative organisms
Broken down by β-lactamase produced by S. aureus and many Gram negative organisms
Flucloxacillin- Similar to penicillin although less active.
Stable to β-lactamase produced by S. aureus.
Piperacillin – similar to amoxicillin, extends coverage to Pseudomonas and other non-enteric Gram negatives
Broken down by β-lactamase produced by S. aureus and many Gram negative organisms.
What are some adjuncts for penicillins?
Clavulanic acid and tazobactam
β-lactamase inhibitors.
Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes.
What are some examples of cephalosporins?
First generation: Cephalexin
Second generation: Cefuroxime
Stable to many β-lactamases produced by Gram negatives. Similar cover to co-amoxiclav but less active against anaerobes.
Third generation: Cefotaxime, Ceftriaxone (associated with C.diff), Ceftazidime (anti-Pseudomonas)
These increase in activity against Gram negative bacteria as you progress through the generations.
What is resistant to cephalosporins regardless of in vitro results?
Extended Spectrum β-lactamase (ESBL) producing organisms
What are the carbapenems?
Stable to Extended Spectrum β-lactamase (ESBL) enzymes
Meropenem, Imipenem, Ertapenem
Carbapenemase enzymes becoming more widespread. Multi drug resistant Acinetobacter and Klebsiella species.
What are the pharmacodynamics and pharmacokinetics of beta-lactams?
Relatively non-toxic
Renally excreted (so ↓dose if renal impairment)
Short half life
Will not cross intact blood-brain barrier
Cross-allergenic (penicillins approx 10% cross-reactivity with cephalosporins or carbapenems)
What are the pharmacodynamics and pharmacokinetics of glycopeptides?
Large molecules, unable to penetrate Gram –ve outer cell wall; active against Gram +ve organisms
Inhibit cell wall synthesis
Important for treating serious MRSA infections (iv only)
Oral vancomycin can be used to treat serious C. difficile infection
Vancomycin and Teicoplanin are examples of glycopeptides
Slowly bactericidal
Nephrotoxic – hence important to monitor drug levels to prevent accumulation
What are inhibitors of protein synthesis?
Aminoglycosides (e.g. gentamicin, amikacin,tobramycin)
Tetracyclines
Macrolides (e.g. erythromycin) / Lincosamides (clindamycin) / Streptogramins (Synercid) – The MSL group
Chloramphenicol
Oxazolidinones (e.g. Linezolid)
What are the features of aminoglycosides?
Bind to amino-acyl site of the 30S ribosomal subunit
Rapid, concentration-dependent bactericidal action
Require specific transport mechanisms to enter cells (accounts for some intrinsic R)
Ototoxic & nephrotoxic, therefore must monitor levels
Gentamicin & tobramycin particularly active vs. Ps. aeruginosa
Synergistic combination with beta-lactams
No activity vs. anaerobes
In summary, how do aminoglycosides work?
Prevent elongation of the polypeptide chain
Cause misreading of the codons along the mRNA
What are tetracyclines and when are they used?
Broad-spectrum agents with activity against intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas) as well as most conventional bacteria
Bacteriostatic
Widespread resistance limits usefulness to certain defined situations
Do not give to children or pregnant women
Light-sensitive rash
How do tetracyclines work?
Reversibly bind to the ribosomal 30S subunit
Prevent binding of aminoacyl-tRNA to the ribosomal acceptor site, so inhibiting protein synthesis.
What are macrolides and how do they work?
Bacteriostatic
Minimal activity against Gram –ve bacteria
Useful agent for treating mild Staphylococcal or Streptococcal infections in penicillin-allergic patients
Also active against Campylobacter sp and Legionella. Pneumophila
Newer agents include clarithromycin & azithromycin with improved pharmacological properties
How do macrolides work?
Bind to the 50s subunit of the ribosome, interfering with translocation, thus stimulating dissociation of peptidyl-tRNA
What are the features of chloramphenicols?
Bacteriostatic
Very broad antibacterial activity
Rarely used (apart from eye preparations and special indications) because risk of aplastic anaemia (1/25,000 – 1/45,000 patients) and grey baby syndrome in neonates because of an inability to metabolise the drug
How do chloramphenicols work?
Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation
How do oxazolidinones (Linezolid) work?
Binds to the 23S component of the 50S subunit to prevent the formation of a functional 70S initiation complex (required for the translation process to occur).
When is linezolid used?
Highly active against Gram positive organisms, including MRSA and VRE. Not active against most Gram negatives.
Is expensive, may cause thrombocytopoenia and should be used only with consultant Micro/ID approval
What are some examples of DNA synthesis?
Quinolones e.g. Ciprofloxacin, Levofloxacin, Moxifloxacin
Nitroimidazoles e.g. Metronidazole & Tinidazole
How do Fluoroquinolones work?
Act on beta-subunit of DNA gyrase predominantly, but, together with other antibacterial actions, are essentially bactericidal
Broad antibacterial activity, especially vs Gram –ve organisms, including Pseudomonas aeruginosa
Newer agents (e.g. levofloxacin, moxifloxacin) have increased activity vs G +ves and intracellular bacteria, e.g. Chlamydia spp
When are fluoroquinolones used?
UTIs
Pneumonia
Atypical pneumonia
Bacterial gastroenteritis
How do Nitroimidazoles work?
Include the antimicrobial agents metronidazole & tinidazole
Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage
Rapidly bactericidal
Active against anaerobic bacteria and protozoa (e.g. Giardia)
Nitrofurans are related compounds: nitrofurantoin is useful for treating simple UTIs
What are inhibitors of RNA synthesis?
Rifamycins, e.g. rifampicin & rifabutin
How do rifampicins work?
Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation
Bactericidal
Active against certain bacteria, including Mycobacteria & Chlamydiae
Monitor LFTs
Beware of interactions with other drugs that are metabolised in the liver (e.g oral contraceptives)
May turn urine (& contact lenses) orange
Why should you never use rifampicins as a single agent?
Except for short-term prophylaxis (vs. meningococcol infection) you should NEVER use as single agent because resistance develops rapidly
Resistance is due to chromosomal mutation.
This causes a single amino acid change in the ß subunit of RNA polymerase which then fails to bind Rifampicin.
What is daptomycin and when is it used?
A cyclic lipopeptide with activity limited to G+ve pathogens. It is a recently-licenced antibiotic likely to be used for treating MRSA and VRE infections as an alternative to linezolid and Synercid
What is colistin and when is it used?
A polymyxin antibiotic that is active against Gram negative organisms, including Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella. pneumoniae.
It is not absorbed by mouth. It is nephrotoxic and should be reserved for use against multi-resistant organisms
What are inhibitors of folate metabolites?
Sulfonamides
Diaminopyrimidines (e.g. trimethoprim)
How do sulphonamides and diaminopyrimidines work?
Act indirectly on DNA through interference with folic acid metabolism
Synergistic action between the two drug classes because they act on sequential stages in the same pathway
Sulphonamide resistance is common, but the combination of sulphamethoxazole+trimethoprim (Co-trimoxazole) is a valuable antimicrobial in certain situations (e.g. Treating Pneumocystis. jiroveci pneumonia)
Trimethoprim is used for Rx community-acquired UTIs
What are the common mechanisms of resistance?
Chemical modification or inactivation of the antibiotic
Modification or replacement of target
Reduced antibiotic accumulation (impaired uptake or enhanced efflux)
Bypass antibiotic sensitive step
Which antibiotics are resisted through inactivation?
Penicillins
Aminoglycosides
Chloramphenicols
Which antibiotics are resisted through altered target sites?
Beta lactams
Macrolides
Quinolones
Rifampicin
Chloramphenicol
Linezolid
Glycopeptides
Which antibiotics are resisted through reduced accumulation?
Tetracylcines
Beta lactams
Aminoglycosides
Quinolones
Chloramphenicols
Which antibiotics are resisted through bypass?
Trimethoprim
Sulphonamides
Which pathogens inactive beta lactams?
ß Lactamases are a major mechanism of resistance to ß Lactam antibiotics in Staphylococcus aureus and Gram Negative Bacilli (Coliforms).
Which pathogens alter target site for beta lactams?
Methicillin Resistant Staphylococcus aureus (MRSA)
mecA gene encodes a novel PBP (2a).
Low affinity for binding ß Lactams.
Substitutes for the essential functions of high affinity PBPs at otherwise lethal concentrations of antibiotic.
Streptococcus pneumoniae
Penicillin resistance is the result of the acquisition of a series of stepwise mutations in PBP genes. Lower level resistance can be overcome by increasing the dose of penicillin used.
