Microbio - Antimicrobials 1 Flashcards
What are the three broad targets for antibiotics
Peptidoglycan layer of the cell wall
Inhibition of bacterial protein synthesis
DNA gyrase and other prokaryote-specific enzymes
Which antibiotic classes are inhibitors of cell wall synthesis
Beta-lactam antibiotics e.g. penicillins, cephalosporins, carbapenems
Glycopeptides e.g. vancomycin and teicoplanin
What is the difference between gram positive and gram negative bacteria
Gram positive - thick peptidoglycan wall, stains purple
Gram negative - thin peptidoglycan wall and an extra outer membrane, stains pink
What is the MOA for beta-lactams
Structural analogue that inactivates transpeptidase enzymes (involved in forming crosslinks between peptidoglycans in the cell wall) → weakened cell wall → osmotic lysis during division
In what situation are beta-lactams ineffective
They are only bactericidal against rapidly-dividing bacteria, so are not effective when they are not dividing
e.g. Biofilms, abscesses
Ineffective against bacteria lacking a peptidoglycan cell wall e.g. mycoplasma, chlamydia
What are the following features of beta lactams (toxicity, safety in pregnancy, excretion, half life, ability to cross the BBB, cross-reactivity)
Relatively non-toxic, safe in pregnancy
Renally excreted, so may need to reduce the dose if there is renal impairment
Short half life
Will not cross an intact blood-brain barrier, but will cross the meninges and therefore can be used in meningitis
Cross-allergenic (Penicillin approx. 10 % cross reactivity with cephalosporins or carbapenems)
What is the coverage for penicillin and what is the mechanism of resistance against it
Gram positive organisms, Streptococci, Clostridia
Broken down by an enzyme (β-lactamase)
produced by S. aureus (although most S. aureus is resistant to penicillin)
What is the coverage for amoxicillin and what is the mechanism of resistance against it
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
What is the coverage for flucloxacillin
Similar to penicillin although less active.
Stable to β-lactamase produced by S. aureus. Mainstay treatment for S. aureus
What is the coverage for piperacillin and what is the mechanism of resistance against it
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 clavulanic acid and tazobactam and what do they cover
β-lactamase inhibitors. Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes
What do cephalosporins cover (separated by generation)
First
Cephalexin: E. Coli
Second
Cefuroxime: Klebsiella, GI infections
Third
Cefotaxime: sepsis in neonates
Ceftriaxone: Haemophilus and meningococcus meningitis
Ceftazidime: Pseudomonas
Which cephalosporin is associated with C. difficile
Ceftriaxone
What do carbapenems cover
Stable to ESBL (but becoming widespread → multi drug resistance)
Meropenem: broad-spectrum, S. Aureus, streptococcus, pseudomonas, ESBLs
Ertapenem: broad spectrum, ESBLs
How do the properties of antibiotic change with each generation of cephalosporin
Activity against gram negative bacilli increases with each generation
Activity against E. Coli decreases with each
What are the mechanisms of resistance against beta-lactam antibiotics
Beta lactamases
Extended spectrum beta-lactamases (ESBL)
Altered target
Describe the beta lactamase mechanism of resistance
Beta lactamases are enzymes produced by bacteria such as S.aureus and gram -ve bacilli (Coliforms)
Separated in to 4 groups: broad-spectrum, extended-spectrum, AmpC, carbapenemase (not inhibited by beta-lactamase inhibitors)
It is NOT the mechanism of resistance in penicillin resistance pneumococci and MRSA
Describe the altered target mechanism of resistance to beta-lactams
MRSA: mecA gene which encodes a novel transpeptidase (PBP) (2a), which has a low affinity for binding beta lactams
Streptococcus pneumoniae: acquisition of a series of stepwise mutations in PBP genes.
What are ESBLs and what do they confer resistance to + what organisms are they seen in
Extended spectrum beta-lactamases
Resistance to cephalosporins
More common in E. coli and klebsiella
Describe glycopeptides and what they can be used for
Active against Gram +ve organisms (NOT gram -ve - unable to penetrate outer wall)
Inhibit cell wall synthesis by binding to the peptide cross link that comes out of the peptide precursors → blocks transpeptidase from forming the links
Important for treating serious MRSA infections (IV only)
Vancomycin - C. difficile
Give examples of antibiotics classes that inhibit protein synthesis
Aminoglycosides e.g. gentamicin, amikacin, tobramycin
Tetracyclines
Macrolides e.g. erythromycin/lincosamides (clindamycin)
Chloramphenicol
Oxazolidinones e.g. Linezolid
What is the MOA for aminoglycosides and what side effect do clinicians worry about
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 - must monitor levels
No activity against anaerobes
What is the MOA for Tetracyclines, what do they cover, and what is a common side effect
Bacteriostatic - Binds to the ribosome and prevents binding of tRNA
Broad-spectrum agents with activity against intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas) as well as most conventional bacteria
Useful for MRSA
SE: light-sensitive rash, teratogenicity (do not give to children or pregnant women)
What is the MOA for Macrolides, what do they cover
Bacteriostatic
Binds to the 50S subunit of the ribosome
Pencillin allergic0: Useful for staphylococcal or streptococcal infection
Campylobacter and legionella
What is the mechanism of resistance against macrolides
Altered targets encoded by erythromycin ribosome methylation (erm) gene
Modification of the 23s rRNA that reduces binding of antibiotics → resistance
Same resistance fo clindamycin - be cautious using where there is known macrolide resistance
What is the MOA for chloramphenicol, what do they cover, and what is a common side effect
Bacteriostatic
Binds to 50S ribosome and inhibits peptide bond formation
very broad activity, though rarely used
Used in eye preparations
SE: aplastic anaemia, grey baby syndrome
What is the MOA for Oxazolidinone (linezolid), what do they cover, and what is a common side effect
Binds to the 23S component of the 50S subunit, prevents formation of a functional 70S initiation complex
Highly active against Gram +ve organisms, including MRSA and VRE
SE: thrombocytopenia
Which antibiotic classes are inhibitors of DNA synthesis
Quinolones e.g. ciprofloxacin, levofloxacin
Nitroimidazoles e.g. metronidazole, tinidazole
What is the MOA for Fluoroquinolones, what do they cover
Act on 𝛼-subunit of DNA gyrase predominantly
Bactericidal
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
Use for UTIs, pneumonia, atypical pneumonia & bacterial gastroenteritis
What is the MOA for Nitroimidazoles, what do they cover
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
Which antibiotics are inhibitors of RNA synthesis
Rifamycins e.g. rifampicin, rifabutin
Sulfonamides - used for UTIs
What is the MOA for Rifampicin, what do they cover, and what is a common side effect
Binds to DNA-dependent RNA polymerase thereby inhibiting initiation
Bactericidal
Active against Mycobacteria, chlamydia
SE: hepatotoxicity (monitor LFTs), turns urine and contact lenses orange, high risk of resistance in monotherapy (always use in combination)
What is the most common mechanism of resistance against rifampicin
Chromosomal mutation - a single amino acid change in the beta-unit of RNA polymerase, which fails to bind rifampicin.
What is daptomycin and what does it cover
Cell membrane toxin, a cyclic lipopeptide
MRSA, VRE, gram +
What is colistin and what does it cover
Polymyxin cell membrane toxin
Gram negative, pseudomonas, acinetobacter, klebsiella
How to inhibitors of Folate metabolism work and give examples
Acts directly on DNA through interference with folic acid metabolism
Sulphonamide, trimethoprim (UTI)
When are sulphonamides used
As a combination - Co-trimoxazole
Used for PCP
What are the four main mechanisms of resistance and give examples of 2 ABx that they work against
Chemical modification or inactivation of the antibiotic - beta-lactams, aminoglycosides
Modification or replacement of target - beta lactams, macrolides
Reduced antibiotic accumulation - tetracyclines, aminoglycosides
- Impaired uptake
- Enhanced efflux
Bypass antibiotic sensitive step - trimethoprim, sulphonamides
