Antibacterial Pharmacology: Beta-Lactams Flashcards
Penicillin discovery
- 1928 Alexander fleming found mould growing on a petri dish of staphyloicoccus bacteria
- mould produced a self-defence chemical that could kill bacteria as no bacteria would grow around it
- Florey and chain developed a method to mass produce it duirng ww2
- it is estimated that penicillin has saved more than 500 million lives
Bacterial cell walls; unique targets for antibiotics
- Peptidoglycan (murein) is essential for bacterial survival, as it is required for the synthesis of the cell wall
- Gram positive and gram negative bacteria differ in their cell wall architexture and permeability
- Murein chains are synthesized then cross-linked by transpeptidases, whose active sites are targets for B-lactam antibiotics
- If bacteria cannot synthesize its cell wall, the bacteria will eventually autolyze and die - because no transpeptidase bc beta-lactam is bound to it
What are the two subclasses of B-lactams that target cell wall synthesis?
- Penicillins
- Cephalosporins
Beta-Lactams Penicillins
- among the most commonly used AMDs
- very safe and effective
- contain the beta-lactam ring (BL)
- B-lactam ring binds to the active site of transpeptidases; confers antibiotic activity - Penicillin resistance: some bacteria secrete enzymes (“penicillinases” or “beta-lactamases”- will destroy any b-lactam) that destroy penicillin upon entry to the cytoplasm
- only effective against bacteria that are synthesizing new cell wall (i.e. growing bacteria) - not bacteriostatic
- all generic names end in “-cillin”
Penicillins work best against what type of bacteria?
- Penicillins tend to work best against gram positive bacteria, which have a thick, unprotected peptidoglycan layer
- more sensitive to bacteria gettibg through to their cytoplasm than gram negative
What are the type of penicillins?
Further divided by spectrum of activity and resistance to penicillinases:
- Narrow spectrum (e.g. Penicillin G)
- Extended spectrum (e.g. Amoxicillin)
- Penicillinase-resistant (e.g. Dicloxacillin)
- all differ slightly in their B-lactam ring structure
Attributes of Penicillin G (benzylpenicillin)
- used for treating pneumonia, strep throat, staph infection, diphtheria, meningitis, gonorrhoea and syphilis
Attributes: - Bactericidal
- narrow spectrum of activity
- excellent against gram positive aerobed (non-resistant) and anaerobes - administered IV (not acid stable); its counterpart, Penicillin V, is acid stable and administered orally to treat/prevent dental infections
- short half life; must be administered frequently
Attributes of Amoxicilli (amino penicillin)
- used for treatment of tonsillitis, bronchitis, sinusitis, pneumonia, ear infections, nose, throat, skin or urinary tract
Attributes: - bactericidal
- excellent against many bacteria
- Gram positive aerobes, anaerobes, plus several medically important gram negative bacteria
- more hydrophilic thus can penetrate gram negative aerobes better than penicillin G - acid stable; oral bioavailability can exceed 90%
- available in combination with penicillinase inhibitors e.g. sulbactam or clavulanic acid → called a “potentiated penicillin”
Attributes of Dicloxicillin (“anti staphylococcal” penicillin)
- used for treating skin and soft tissue (or more serious) staph infections
Attributes: - bactericidal
- structurally resistant to penicillinase produced by staphylococcus, therefore targets Staph species (except MRSA*)
- Relatively hydrophobic; not effective against gram negative aerobes - less effective than penicillin G against other bacteria
- FYI: other types of antistaphylococcal penicillin: Oxacillin, cloxicillin, *methicillin, etc.
distribution and elimination of beta-lactam penicillins
Distribution:
- like most drugs, distributes to most tissues except CNS, prostate (unless inflamed)
Elimination:
- mainly excreted unchanged in urine
- 10% filtration, 90% active tubular secretion → half-life may increase 20-fold in renal failure
- people with renal failure have a harder time excreting the drug so they would need lower doses of the drug
resistance of beta-lactam penicillins
Resistance is fairly common because:
1. poor/no penetration of outer lipid bilayer protecting gram negative cell wall; only hydrophilic drugs can gain access
2. intrinsic production of penicillinases (staph)
3. acquired chromosomal mutations in transpeptidase (MRSA) or plasmid DNA encoding penicillinases → can be transferred from other bacteria
What are the main adverse effects of beta-lactam penicillins?
- hypersensitivity
- mild allergy to (rarely) anaphylactic reaction when administered by any route; not administered topically because the risk of allergic contact dermatitis is high
- all penicillins are cross-sensitizing; can potentiate allergic recation to sephalosporins
- not used topically becuase of risk of allergic contact dermatitis
- 5% of humans report having a penicillin allergy
(note: amoxicillin can cause non-allergic skin rashes and GI effects) - Seizures: B-lactams lower the seizure threshold → avoid high doses in epileptic patients (or in patients with renal disease)
How are beta-lactam cephalosporins similar to and different than penicillin?
Very similar to penicillins:
1. mechanism of action (with a slightly different structure)
2. distribution and elimination
3. main adverse effects
- generic games start with “ceph” or “cef”
What is different?
- not susceptible tp penicicllinases (still somewhat susceptible to b-lactamases)
- most cannot be given orally (not acid stable)
- nomenclature: named 1st-5th generation cephalosporins based on time of discovery; each generation differs slightly based on microbial sensitivity and resistance
- some 3rd generation cephalosporins enter the CNS well (e.g. cefotaxime) → good for brain or spinal cord injuries this can access that
- 3rd gen drugs tend to be effective mainly against gram negative aerobes
- a variety of drug-specific averse effects may be observed with 2nd, 3rd, 4th gen drugs
attributes of 1st generation cephalosporins
- used to treat some UTIs, pneumonia, skin and soft tissue infections, strp throat
Attributes: - bactericidal
- effective against gram _ aerobes and anaerobes as well as some medically important gram negative aerobes (e.coli)
- sensitive to some B-lactamases, but not staph B-lactamase (penicillinase)
- most 1st gen are not acid stable and must be given parenterally (e.g. cefazolin cephapirin)
- oral version: cephalexin
attributes of 3rd generation cephalosporins
- used to treat pneumonia, S. pneumoniae bacterial meningitis, endocarditis, and lyme disease involving the CNS or joints
Attributes: - bactericidal
- less effective against gram positive aerobes and anaerobes, but better against gram negative aerobes
- more stabilityb to B-lactamases than previous generations
- some readily cross the BBB to treat CNS infections (e.g. cefotaxime, ceftriaxone)
- this is the first drug so far that is this good at targeting gram negative bacteria
