Antimicrobials 1 Flashcards
What are some selective targets of antibiotics?
Peptidoglycan layer of cell wall
Inhibition of bacterial protein synthesis
DNA gyrase and other prokaryote specific enzymes
What are inhibitors of cell wall synthesis?
(a) beta-lactam antibiotics (penicillins, cephalosporins and carbapenems, monobactams)
(b) Glycopeptides (Vancomycin and Teicoplanin)
What is the difference between gram positive and gram negative cell walls?
Gram negative have an LPS outer membrane
What do beta lactams do?
Inactivate the transpeptidases (PBP) that are involved in the terminal stages of cell wall synthesis
β-lactam is a structural analogue of the enzyme substrate
Osmotic Lysis occurs
When are beta lactams used?
Bactericidal
Active against rapidly-dividing bacteria
Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)
What can penicillin work on?
penicillin - Gram positive organisms, Streptococci, Clostridia; broken down by an enzyme (β-lactamase) produced by S. aureus
Describe pipericillin
piperacillin – similar to amoxicillin, extends coverage to Pseudomonas and other non-enteric Gram negatives; broken down by β-lactamase produced
What are some examples of cephalosporins?
1st gen: cephalexin
2nd gen: cefuroxime
3rd gen: cefotaxime, ceftriaxone, ceftazidime
What are cefuroxime, ceftriaxone and ceftazidime use for?
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
What are 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 key features of beta lactams?
Relatively non-toxic
Short half life (require frequent dosing)
Will not cross intact blood-brain barrier (good for meningitis)
Renally excreted (so ↓dose if renal impairment)
Cross-allergenic (penicillins approx 10% cross-reactivity with cephalosporins or carbapenems)
What are glycopeptides?
Large molecules, unable to penetrate Gram –ve outer cell wall so G+ve only
Important for treating serious MRSA infections (iv only)
Oral vancomycin can be used to treat serious C. difficile infection
Slowly bactericidal
Give examples of glycopeptides
Vancomycin and Teicoplanin
Can Glycopeptides be toxic?
Nephrotoxic - must monitor to prevent accumulation
What are the 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 aminoglycosides?
Amino-acyl site of 30S ribosome subunit
Fast, conc-dependent bactericidal action
Require specific transport mechanisms to enter cells (accounts for some intrinsic R)
Gentamicin & tobramycin active vs. Ps. aeruginosa
Synergistic w/ beta-lactams
What is the MOA of aminoglycosides?
Binds to 30s sub unit
Prevents elongation of polypeptide chain
Causes misreading of codons in mRNA
No activity vs. anaerobes
Summarise tetracyclines
Broad-spectrum agents with activity against most conventional bacteria and intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas)
Bacteriostatic
Widespread resistance
Do not give to children or pregnant women
Light-sensitive rash (esp. doxacycline)
What is the MOA of tetracyclines?
Reversibly bind to the ribosomal 30S subunit
Prevent binding of aminoacyl-tRNA to the ribosomal acceptor site, so inhibiting protein synthesis.
Give examples of macrolide antibiotics and two key features of the class
Erythromycin
Newer agents include clarithromycin & azithromycin with improved pharmacological properties
Bacteriostatic
Check with pharmacy for pregnancy warning
What is the MOA of macrolides?
Binds with 50s subunit of ribosome
Interferes with translocation
Stimulate dissocication of peptidyl-tRNA
What is chloramphenicol?
Bacteriostatic
Very broad antibacterial activity
Meningococcal and pneumococcal meningitis for penicillin anaphylactic patients
What is the MOA of chloramphenicol?
Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation
Describe Oxazolidinones (linezolid)
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).
Mostly G+ve including MRSA and VRE
expensive, thrombocytopoenia and should be used only with consultant Micro/ID approval (2-4 weeks but need review)
What are the inhibitors of DNA synthesis?
Quinolones (ciprofloxacin etc.)
Nitroimidazoles (metronidazole)
What is the MOA of fluoroquinolones?
Act on alpha-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
What are nitroimidazoles?
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 the inhibitors of RNA synthesis?
Rifamycins (rifampicin)
What does rifampicin do/ need?
Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation
Bactericidal
Active against certain bacteria, including Mycobacteria & Chlamydiae
How does resistance occur in rifampicin?
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?
a cyclic lipopeptide with activity limited to G+ve pathogens.
Active against MRSA and VRE
Recently Licensed alternative to linezolid and synercid
What is colistin?
Polymyxin antibiotic
Active against Gram negative organisms, including Ps aeruginosa, Acinetobacter baumannii and K. pneumoniae
NO PO PRESCRIPTION: It is not absorbed by mouth
It is nephrotoxic and should be reserved for use against multi-resistant organisms
What are inhibitors of folate metabolism?
sulfonamides
diaminopyrimidines (trimethoprim)
How do sulfonamides 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
How does resistance work for Abx?
Chemical modification or inactivation of the antibiotic
Modification or replacement of target
Reduced antibiotic accumulation
1) Impaired uptake 2) Enhanced efflux
Bypass antibiotic sensitive step
Which types of antibiotics have inactivation as their resistance pathway?
Beta lactams
Aminoglycosides
Chloramphenicol
Which types of antibiotics have altered targets as their resistance pathway?
Beta lactams
Glycopeptides
macrolides
chloramphenicol
linezolid (Oxazolidinones)
(fluoro) quinolone
rifampicin
Which types of antibiotics have reduced accumulation as their resistance pathway?
beta lactams
aminoglycosides
tetracyclines
chloramphenicol
quinolones
Which types of antibiotics have bypass as their resistance pathway?
trimethoprim (diaminopyramidine)
sulphonamides
How does inactivation work in beta lactams?
ß 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.
How does altered targets work in beta lactams in MRSA?
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.
How does altered targets work in beta lactams in S. 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.
How do ESBL work?
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).
How do altered targets work in macrolides?
Encoded by erm (erythromycin ribosome methylation) genes and results in reduced binding of antibiotics.
Adenine-N6 methyltransferase modifies 23S rRNA.
How does the BSAC guidance guide us on use of macrolides?
Isolate has MLSb and clindamycin (looks sensitive in vitro but isn’t in vivo) should be used with caution if sensitive
How do you reduce AR spread in hospital?
Control antibiotic usage and encourage good prescribing habits
Improve standards of hospital hygiene – and ENCOURAGE HANDWASHING-to reduce dissemination of resistant organisms
What can amoxicillin work on?
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 can flucloxacillin work on?
Similar to penicillin although less active. Stable to β-lactamase produced by S. aureus.
How do Clavulinic acid and tazobactam help protect against beta lactamase activity?
clavulanic acid and tazobactam –
β-lactamase inhibitors. Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes
Why do we use metronidazole with cephalosporins?
Cephalosporins do not have adequate anaerobe cover (but co amoxiclav does)
What are ESBL organisms resistant too?
Beta lactamases: Penicillin
Extended Spectrum β-lactamase (ESBL): also cephalosporins regardless of in vitro results
What is the MOA of vancomycin?
Vancomycin binds to D-Ala- D-Ala at the end of one side of the peptidoglycan chain and stops peptide bonds
Do you need to monitor aminoglycosides?
Yes
Ototoxic & nephrotoxic, therefore must monitor levels
Why is chloramphenicol barely used?
Rarely used (apart from eye preparations and special indications) because risk of
aplastic anaemia (1/25,000 – 1/45,000 patients) grey baby syndrome
(in neonates because of an inability to metabolise the drug)
When are fluoroquinolones used?
vs G +ves and intracellular bacteria, e.g. Chlamydia spp (Newer agents (e.g. levofloxacin, moxifloxacin) increases activity)
Well absorbed following oral administration
Use for UTIs, pneumonia, atypical pneumonia & bacterial gastroenteritis
What are the risks of fluoroquinolones?
Lowers seizure threshold
Cause tendonitis- careful in older pts or those on steroids
How do you use nitrofurantoin?
Needs to be taken after urination to maintain good dose for max time
What are the risks of rifampicin?
Monitor LFTs/ INR due to enzyme inducer activity
Beware of interactions with other drugs that are metabolised in the liver (e.g oral contraceptives)
May turn urine (& contact lenses) orange
What are the cell membrane toxin (metabolic inactive bacteria) antibiotics?
Daptomycin
Colistin
Why did cephalosporins stop being used routinely?
In vitro sensitivity did not correlate with treatment in vivo due to the presence of ESBL organisms.
There are multiple types of beta lactamase
There are multiple types of beta lactamase
What is the problem with new beta lactamase resistance?
These organisms tend to be Multi drug resistant
What are the 5 big classes of carbapenemases?
NDM VIM IMP KPC (Generally most common) OXA-48 (most common in NW London)
What do macrolides work against?
G+ve (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
Which antibiotics are narrow spectrum?
Penicillin Macrolides Clindamycin (MSL) Metronidazole (Nitroimadazole) Colistin(polymixin) Vancomycin
What are extended spectrum antibiotics?
Aminoglycosides Carbapenems Ceohalosporins Extended spectrum penicillins Fluoroquinolones
What are broad spectrum antibiotics?
Tetracycline
Chloramphenicol
Sulfonamides
Trimethoprim (folate synthesis inhibitor)
