Antimicrobial agents Flashcards
Which drugs target bacterial cell wall synthesis?
- Beta-lactams (Penicillins, Cephalosporins, Carbapenems)
- Glycopeptides (Vancomycin)
How do Beta-lactams work?
By binding to penicillin-binding proteins (PBPs), e.g. transpeptidase, prevent the formation of peptide cross-links in daughter cell walls
The daughter cells are therefore weak and prone to osmotic lysis.
They are effective against rapidly dividing bacteria.
They are not effective against bacteria which lack a cell wall e.g. Mycoplasma.
Penicillin
Penicillin is the most active Beta-lactam. It covers Gram +ve organisms including - Staph - Strep - Clostridium
It is broken down by B-lactamases from
- S. aureus
Pharmacokinetics
- TIME-DEPENDENT killing
- Give 3-4 doses per day
Flucloxacillin coverage
Flucloxacillin is a narrow-spectrum antibiotic. It covers - Staph - Strep - Clostridia
It is STABLE to Beta-lactamases from S. aureus and is therefore the mainstay of S. aureus infection.
It is less active than penicillin
Amoxicillin
Amoxicillin is a broad-spectrum antibiotic. It covers - Staph - Strep - Enterococi - Some G-ve organisms
It is broken down by beta-lactamases from
- S. aureus
- E. coli
it can be made stable to beta-lactamased by addignf clavulanic acid (This is Co-amoxiclav, aka Augmentin)
Piperacillin
Piperacillin is a broad-spectrum antibiotic it covers: - Staph - Strep - Some Gram -ves, including Pseudomonas
It is broken down by beta-lactams from:
- S. aureus
- E. coli
It can be combined with tazobactam to form tazocin, therefore stable to Beta-lactams.
Overview of cephalosporins
Cephalosporins are generally stable to beta-lactamases.
1st gen: Cefalexin
2nd gen: Cefuroxime
3rd gen: Ceftazidime, Ceftriazone and Cefataxime
As you go up the generations there is more G-ve coverage and less G+ve coverage
Cefuroxime has no G+ve coverage except for E. coli, whereas Ceftazidime has only G-ve coverage.
Cefuroxime
2nd gen,
Cefuroxime covers the same as co-amoxiclav
It is stable to many B-lactamases produced by G-ves
It is combined with metronidazole to treat anaerobic infections.
Ceftriaxone
3rd gen
- Ceftriaxone covers G+ve and G-ve organisms including NHS organisms (N. meningitidis, Haemophilus and S. pneumoniae)
- It is the mainstay of treatment for meningitis
- IM ceftriaxone is given for gonorrhea
Caution:
- It can cause C. difficile infection, so reserve for serious infection and avoid in the elderly
- Do not use in neonates, as it can displace bilirubin form albumin and cause biliary sludging
Beta-lactams - metabolism
Metabolised in kidneys
Can be nephrotoxic (renal tubular acidosis)
Carbapenems
Stable to ESBLs
e.g. Meropenem
Can be used for MRSA
Ceftazidime
Covers G-ve only including Pseudomonas
Glycopeptides
MOA - bind to amino-acid chain on peptidoglycan precursor, this blocks formation of glycosidic bonds.
Cover G+ve only (because they cannot penetrate G-ve)
Vancomycin can be used for:
- MRSA (IV)
- C. difficile (PO)
Pharmacokinetics
- Both time-dependent and concentration-dependent killing, so do infusion
- NEED TO MONITOR LEVELS, as it is nephrotoxic.
Aminoglycosides
Inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit.
Covers gram negatives and all ESBLs.
Uses:
- Gram negative sepsis
Caution:
- Need to monitor levels due to ototoxicity and nephrotoxicity
- Inhibited by low pH (e.g. in abscesses)
Pharmacokinetics
- They have CONCENTRATION-DEPENDENT killing effects, so give ONE BIG DOSE per day.
- Monitor the TROUGH level after 24h to see if toxic levels have accumulated.
- If so, adjust frequency
Tetracycline
Inhibits bacterial protein synthesis by blocking the binding of aminoacyl-tRNA to the 30S ribosomal subunit.
Coverage: G+ve (most G-ve bugs are resistant to tetracycline)
Uses:
- Oral treatment for MRSA
- Intracellular pathogens e.g Chlamydia
- Staph and Strep
Caution:
- Deposited in growing bone
- Discolouration of teeth
- Light sensitive rash
- Contra-indicated in pregnancy and in children
Macrolides
- Bind to the 50S subunit of the bacterial ribosome
- Erythromycin is given 4x daily; clarithromycin and azithromycin are given less often
Coverage
- Mainly G+ve
- Azithromycin has some G-ve coverage
Uses
- Staph and Strep infections in penicillin-allergic
- Also useful in Campylobacter (although this is usually self-resolving), Legionella and Helicobacter infections
Caution
- Limited use in sepsis as they are bacteriostatic
- Macrolide resistance can confer clindamycin resistance
Chloramphenicol
- Broad spectrum
- Binds to peptidyl transferase of the 50S subunit
Coverage:
- Good coverage against Pneumococcus
Uses
- Eyedrops for bacterial conjunctivitis
- Meningitis treatment in penicillin-anaphylactic
Side-effects
- Aplastic anaemia
- Grey baby syndrome
Linezolid
- Broad-spectrum
- Binds to 23S subunit of the 50S ribosomal subunit, which blocks to formation of 70S, therefore blocking translation
Uses
- Gram +ve, including MRSA and VRE
Caution
- Can cause thrombocytopenia
- Optic neuritis
- Expensive, so use only with microbiology approval
Fluoroquinolones
MOA - block alpha subunit of DNA gyrase
Coverage
- Ciprofloxacin covers Pseudomonas and other G-ve organisms
- Levofloxacin and Moxifloxacin cover G+ve coverage, they do not cover Pseudomonas
Uses
- Bacterial UTI
- Bacterial gastroenteritis
- Atypical pneumonia
NB these are well absorbed after oral administration.
Nitromidazoles
- Produce an active intermediate which causes DNA breakage
Metronidazole
- Covers anaerobes and protozoa (e.g. Giardia)
- However infections are never purely anaerobic, so combine with another antibiotic e.g. cefuroxime
Nitrofurans
- Related to nitromidazoles
- Covers E. coli, used in lower UTI
- Concentrates in bladder
- Needs contact time with bladder, so take after voiding
- Not suitable for catheter-associated UTI
Rifampicin
- Belongs to rifamycin class
- Inhibitor of DNA-dependent RNA polymerase
Uses
- Mycoplasma (TB)
- Chlamydia
- Legionella
- Staph and Strep
Caution
- Metabolised in liver, so monitor LFTs
- Can interact with other liver-metabolised drugs
- Orange urine, faeces and contact lenses
Resistance
- Resistance develops quickly (from a single amino acid change) so do not use as a single agent
- The exception is prophylaxis for close contacts in meningitis infection
Inhibitors of folate metabolism
Sulfomethoxazole + Trimethoprim (co-trimoxazole, e.g. Septrin)
- Used in PCP, toxoplasmosis and G-ve organisms
Trimethoprim
- Can be used for lower UTI, but 40% E.coli is resistant
- Cannot be used in the first trimester of pregnancy
Daptomycin
- Cell membrane toxin
- Cyclic lipopeptide
- Gram positive coverage only
- MRSA and VRE
- Specific conditions only, so seek microbiology advice
