2: Antimicrobials 1 Flashcards
3 targets of antimicrobials
Peptigolycan layer of cell wall
Inhibition of bacterial protein synthesis
DNA gyros and other prokaryote specific enzymes
what are the 2 types of inhibitors of cell wall synthesis and examples of them, differences
B-lactam abx = penicillins, cephalosporins, carbapenems
- Broad spectrum
Glycopeptides = vancomycine, teicoplanin
- Gram +ve
Gram +ve vs Gram -ve
Gram-positive cell wall – thick peptidoglycan cell wall (made of NAG and NAM components)
Gram-negative cell wall – thinner peptidoglycan cell wall, outer membrane conferring resistance to some antibiotics
- Can be more resistant and harder to treat due to outer membrane
How do B-lactams work?
Inactivate enzymes involved in terminal stages of cell wall synthesis = transpeptidases / penicillin binding proteins
- Beta lactam is a structural analogue of the enzyme substrate
Bactericidal (active against rapidly dividing bacteria) – if cell wall has already been formed, they haveno effect**
- Ineffective against bacteria lacking peptidoglycan cell walls (mycoplasma, chlamydia)
- Cause cell lysis
Give examples of penicillins (5)
Penicillin
Amoxicillin
Flucloxacillin
Piperacillin
Clavulanic acid + amoxicillin (co-amoxiclav) and tazobactam (tazocin/piptazobactam)
Penicillin
gram +ve, streptococci, clostridia
- Broken down by beta lactamase (produced by SA and many other gram -ve organisms)
- Allergy – need to get a clear history
Amoxicillin
broad-spectrum (enterococci to gram -ve)
- Broken down by beta lactamase (produced by SA and many other gram -ve organisms)
Flucloxacillin
SA
- Not broken down by beta-lactamase produced by SA
- Similar to penicillin, less reactive
Piperacillin
broad-spectrum (pseudomonas, non-enteric gram -ve)
- Broken down by beta lactamase (produced by SA and many other gram -ve organisms)
- Similar to amoxicillin
Co-amoxiclav and tazobactam
- Clavulanic acid = beta lactamase inhibitors → protect penicillin from enzymatic breakdown
- Increase coverage to include SA, gram -ve (i.e. E. coli), anaerobes
What bacteria (G+ve) produced b-lactamase?
Staph aureus
Give examples of cephalosporins (4)
Cefuroxime
Ceftriaxone
Ceftazidime
Cefotaxime
Cefuroxime
- Stable to many beta lactamases made by gram -ve
- Similar cover to co-amox (less active against anaerobes)
Ceftriaxone
- Associated with C. difficile
- Treat meningitis (IM ceftriaxone)
- NO COVER against Pseudomonas
Ceftazidime
- Activity against pseudomonas (HAIs often)
Cefotaxime
The paediatric ceftriaxone
Give examples of Carbapenems
Meorpenem, imipenem, ertapenem (STABLE TO ESBL enzymes)
Give an example of monobactams
carumonam
Key features of beta lactase
- Relatively non-toxic
- Renally excreted so decrease dose if renal impairment
- Short T1/2 (many are type 2 drugs so aim to maximise the time > MIC)
- Will not cross BBB
- Cross allergenic – penicillin has 10% cross reactivity with cephalosporins and carbapenems
Glycopeptides
Active against gram +ve (inhibit cell wall synthesis)
- Large molecules so unable to penetrate gram -ve
Important uses:
- MRSA infections (IV)
- C. difficile infection (oral – Vancomycin, teicoplanin)
Slowly bactericidal
Nephrotoxic – must monitor for accumulation
Gove 5 examples of inhibitors of protein synthesis
Aminoglycosides
Tetracyclines
Macrolides
Chloramphenicol
Oxazolidinones
Give 3 examples of aminoglycosides
Gnetamicin, amikacin, tobramycin
G-ve action
Aminoglycoside MoA
- Bind to amino-acyl site of 30s ribosome subunit
- Rapid, concentration-dependent bactericidal
- Require specific transport mechanisms to enter
- Accounts for some intrinsic resistance
- Ototoxic and nephrotoxic – monitor levels
- Gentamicin and tobramycin are particularly active against pseudomonas aeruginosa
-
Synergistic combination with beta lactams
- Endocarditis treatment, pneumonia
- No activity against anaerobes
tetracylines MoA
Broad spectrum, activity against intracellular pathogens – chlamydia, rickettsia, mycoplasma
Bacteriostatic (stops bacteria from reproducing)
Widespread resistance now
Deposited in growing bone
- Don’t give to children, pregnant women
- SE: photosensitivity rash (summer effect)
TETRACYLINE, DOXYCYCLINE
Give examples of Macrolides and their MoA
Erythromycin**, **lincosamides** – **clindamycin**, **streptogramins** – **synercid** – **MLS group
- Bacteriostatic
- Useful agent for treating mild staphylococcal or streptococcal infections in pen-allergic patients
- Active against campylobacter species, legionella, pneumophilia
- Newer agents include clarithromycin and azithromycin due to a better half-life
- Little activity against gram -ve bacteria (membrane)
Useful to inhibit toxins produced by bacteria
Chloramphenicol use and MoA
(if pen-allergic, used for meningitis)
- Bacteriostatic
- Broad antibacterial activity
-
Rarely used apart from eye preparations
- Risk of aplastic anaemia
- Risk of grey-baby syndrome in neonates because of inability to metabolise the drug
Oxazolidinones (Linezolid) use and MoA
- Highly active against gram +ve (MRSA & VRE)
- Not active against most gram -ve
- Expensive, may cause thrombocytopenia & optic neuritis; should only be used with micro/ID approval
- Binds to 23S component of 50s subunit → prevents formation of a functional 70s initiation complex
Give 2 examples of inhibitors of DNA synthesis
Quinolones/Fluoroquinolones
Nitroimidazoles
Quinolones/fluoroquinolones
Ciprofloxacin, levofloxacin, moxifloxacin
- Act on alpha unit of DNA gyrase, bactericidal
- Broad antibacterial activity versus gram -ve (pseudomonas aeruginosa)
- Newer agents (levofloxacin, moxifloxin) better against gram +ve and intracellular bacteria (Chlamydia spp.)
- Well absorbed after PO administration (good bioavailability)
- Use for UTI*, *pneumonia*, *atypical pneumonia*, *bacterial gastroenteritis
Nitroimidazoles
Metronidazole, tinidazole
- Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage
- Rapidly bactericidal
- Active against anaerobic bacteria and protozoa (Giardia)
- Nitrofurans are related compounds (nitrofurantoin is good for cystitis and lower UTIs)
What is an inhibitor of RNA synthesis?
Rifamycins – rifampicin and rifabutin
How do Rifamycins work?
- Inhibits protein synthesis by binding to DNA-dependent RNA polymerase, inhibiting initiation
- Bactericidal
- Active against mycobacteria and chlamydia
- Interactions with other drugs metabolised in the liver (OCP) and so need to monitor LFTs
- Turns secretions orange (urine and contacts) – can check compliance
Rifampicin resistance (never used as a single):
- Resistance due to chromosomal mutation
- Causes single amino acid change in beta subunit of RNA polymerase which fails to bind rifampicin
Give 2 examples of cell membrane toxins
Daptomycin and colistin
Daptomycin
- Cyclic lipopeptide with activity limited to gram +ve
- MRSA and VRE infections as an alternative to linezolid and synercid
Colistin
- Polymyxin antibiotic; not absorbed PO though
- Active against gram -ve including pseudomonas aeruginosa, Acinetobacter baumannii, klebsiella pneumoniae
- Nephrotoxic and reserved for use against multi-resistant organisms
Give 2 examples of inhibitors of folate metabolism
Solphonamdes and diaminopyrimidines
4 mechanisms of abx resistance
- Bypass antibiotic-sensitive step
- Enzyme chemical modification/inactivation of abx
- Accumulation reduced of abx (impaired uptake, enhanced efflux)
- Target modification or replacement
what are the three ways beta lactams are inactivated?
- Beta-lactamases (SA and gram-ve bacteria aka coliforms)
- MRSA resistance (altered target)
- mecA gene encodes novel PBP2A
- low affinity for binding beta lactase
- substitutes for essential functions of high affinity PBPs at otherwise lethal concentrations of antibiotics
3. Streptococcus pneumonia
- penicillin resistance is the result of stepwise mutations in PBP genes
- lower level resistance can be overcome by increasing dose of penicillin used
What is the mechanism of macrolide resistance?
- Adenine-N6 methyltransferase modifies 23S rRNA → reduces binding of MLS antibiotics and results in resistance
- Encoded by erm (erythromycin ribosome methylation) genes.
ESBL-based resistance (extended spectrum beta lactamases)
- ESBLs can enzymatically break down cephalosporins (cefotaxime, ceftazidime, cefuroxime) as well as penicillins
- But, not carbapenems
- More common in E. coli and Klebsiella
- Treatment failures reported with beta lactam and beta lactamase inhibitor combinations – augmentin/tazocin
- Aminoglycoside used in combinations
- New beta-lactamases are spreading MDR instead of just the ESBL-component of resistance (big problem)
- If something is erythromycin-resistant, be careful about giving clindamycin (may make the bacteria MDR)
- HPA guidance:
By which mechanism is an ESBL E. coli resistance to ceftriaxone?
Enzymatic inactivation of the antibiotics
Which mechanism mediates flucloxacillin resistance in S. aureus?
alteration of the target (flucloxacillin is stable to b-lactamases and its PBP2A alteration of target instead)
Oxazolidinones (Linezolid) use and MoA
- Highly active against gram +ve (MRSA & VRE)
- Not active against most gram -ve
- Expensive, may cause thrombocytopenia & optic neuritis; should only be used with micro/ID approval
- Binds to 23S component of 50s subunit → prevents formation of a functional 70s initiation complex
