Antimicrobial Agents Flashcards
Inhibitors of cell wall synthesis (2)
Beta-lactam antibiotics (penicillins, cephalosporins and carbapenems)
Glycopeptides (vancomycin and teicoplanin)
Difference between gram +ve and gram -ve cell wall
Gram +ve = single thick layer of peptidoglycan
Gram -ve = peptidoglycan between an inner and outer membrane
Features of bata-lactams
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)
Beta lactam target
Transpeptidases (PBPs)
How do beta lactams cause cell death
Weakened cell wall results in osmotic lysis of the bacterial cell
Beta-lactam antibiotics
Penicillin
Amoxicillin
Flucloxacillin
Piperacillin
Indications for penicillin
Gram positive organisms, Streptococci, Clostridia; broken down by an enzyme (β-lactamase) produced by S. aureus
Indications for 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
Indications for flucloxacillin
Similar to penicillin although less active. Stable to β-lactamase produced by S. aureus.
Indications for 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 beta-lactamase inhibitors
Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes
Clauvanic acid and tazobactam
First generation cephalosporin
Cephaliexin
Second generation cephalosporin
Cefuroxime
Third generation cephalosporins
Cefotaxime
Ceftriaxone
Ceftazidime
What changes over the generations of cephalosporins
Increasing activity against gram negative bacilli
cefuroxime
Stable to many β-lactamases produced by Gram negatives. Similar cover to co-amoxiclav but less active against anaerobes
Ceftriaxone
3rd generation cephalosporin
Associated with C.difficile
Ceftazidime
Anti-pseudomonas
Extended spectrum beta-lactamase (ESBL)
Organisms producing these are resistant to all cephalosporins
Indications for carbapenems
Stable to ESBL enzymes
Examples of carbapenems
Meropenem
Imipenem
Ertapenem
Difficulties with carbapenems
Carbapenemase enzymes becoming more widespread. Multi drug resistant Acinetobacter and Klebsiella species.
Key features of beta-lactams
Relatively non-toxic
Renally excreted (so low 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)
MOA glycopeptides
Inhibit cell wall synthesis
Bactericidal
Indications for glycopeptides
IV treatment of serious MRSA
Oral vancomycin for c.difficile
Why must you be cautious with glycopeptides
Nephrotoxic - important to monitor drug levels to prevent accumulation
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)
Aminoglcoside MOA
Bind to amino-acyl site of the 30S ribosomal subunit
Rapid, concentration-dependent bactericidal action
Require specific transport mechanisms to enter cells
Prevent elongation of the polypeptide chain
Cause misreading of the codons along the mRNA
Toxicity of glycopeptides
Nephrotoxic
Toxicity of aminoglocosides
Ototoxic and nephrotoxic
Aminoglycosides and beta-lactams
Synergistic effect
Aminoglocosides have no activity against
Anaerobes
Treatment of ps.aeruginosa
Gentamicin and tobramycin
Tetracyclines active against
Intracellular pathogens (chlamydiae, rickettsiae, mycoplasmas)
Tetracycline toxicity
Do not give to children or pregnant women
Light sensitive rash
Tetracycline MOA
Reversibly bind to the ribosomal 30S subunit
Prevent binding of aminoacyl-tRNA to the ribosomal acceptor site, so inhibiting protein synthesis.
Bacteriostatic
Macrolides
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
Macrolide examples
Erythromycin
Clarithromycin
Azithromycin
Macrolides MOA
Bind to 50S subunit of the ribosome
Interfere with translocation
Stimulate dissociation of peptidyl-tRNA
Chloramphenicol indication s
Rarely used, apart from eye preparations and special indications
Chloramphenicol toxicity
Aplastic anaemia
Grey baby syndrome in neonates because of an inability to metabolise the drug
Chloramphenicol MOA
Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation
Oxazolinones (linezolid) MOA
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).
Oxazolidinones indications
Highly active against Gram positive organisms, including MRSA and VRE.
Not active against most Gram negatives.
Oxazolidinones toxicity
Thrombocytopoenia
Inhibitors of DNA synthesis
Quinolines (ciprofloxacin, levofloxacin, mocifloxacin)
Nitromidazoles (metronidazole and tinidazole)
MOA floroquinolones
Act on -subunit of DNA gyrase predominantly, but, together with other antibacterial actions, are essentially bactericidal
Indications for fluoroquinolones
Broad antibacterial activity, especially vs Gram –ve organisms, including Pseudomonas aeruginosa
Newer agents (e.g. levofloxacin, moxifloxacin) increased activity vs G +ves and intracellular bacteria, e.g. Chlamydia spp
Well absorbed following oral administration
Use for UTIs, pneumonia, atypical pneumonia & bacterial gastroenteritis
Name a nitroimidazole
Metronidazole
MOA nitromidazoles
Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage
Rapidly bactericidal
Indications for nitromidazoles
Anaerobic bacteria and protozoa (e.g. giardia)
What are nitrofurans
Related to nitoimidazoles.
Nitrofurantoin is useful for treating simple UTIs
Rifamycins
Inhibitor of RNA synthasis
Example of rifamycin
Rifampicin
MOA rifampicin
Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation
Bactericidal
Indications for rifampicin
Mycobacteria
Chlamydiae
What must be monitored with rifampicin
LFTs
Beware of interactions with other drugs that are metabolised in the liver (e.g oral contraceptives)
What effect does rifampicin have on urine
May turn urine and contact lenses orange
Why can you not use rifampicin 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.
Cell membrane toxins
Cyclic lipopeptides
Polymyxin
Daptomycin
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
Colistin
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
Folate metabolism inhibitors
Sulfanamides
Diaminopyrimidines
Example of a diaminopyrimidine
Trimethoprim
MOA folate metabolism inhibitors
Includes sulfanamides and diaminopyrimidines
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
Community acquired UTIs
Mechanisms of resistance
Chemical modifications or inactivation of the antibiotic
Modification or replacement of target
Reduced antibiotic accumulation (impaired uptake, enhanced efflux)
Bypass antibiotic sensitive step
Beta lactamases
Beta Lactamases are a major mechanism of resistance to ß Lactam antibiotics in Staphylococcus aureus and Gram Negative Bacilli (Coliforms).
NOT the mechanism of resistance in penicillin resistant Pneumococci and MRSA.
Penicillin resistance not reported in Group A (S. pyogenes), B, C, or G ß haemolytic Streptococci.
MRSA beta-lactam resistance
ecA gene encodes a novel PBP (2a).
Low affinity for binding beta Lactams.
Substitutes for the essential functions of high affinity PBPs at otherwise lethal concentrations of antibiotic.
Streptococcus pneumoniae beta lactam resistane
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
What are extended spectrum beta lactamases
Able to break down cephalosporins (cefotaxime, ceftazidime, cefuroxime)
Becoming more common in E. coli and Klebsiella species.
Treatment failures reported with ß Lactam/ ß Lactamase inhibitor combinations (eg. Augmentin/Tazocin).
Macroline altered target resistance mechanism
Adenine-N6 methyltransferase modifies 23S rRNA
Modification reduces the binding of MLS antibiotics and results in resistance
Encoded by erm (erythromycin ribosome methylation) genes.
