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Name 5 beta lactam compounds
- b-lactamase inhibitors
What is a lactam?
a cyclic amide
what is a b-lactam ring?
- lactam with a heteroatomic ring structure
- consists of 3 carbon atoms and one nitrogen atom
What are the basic structural components of penicillins?
- thiazolidine ring(A)
- b-lactam ring (B) that carries a secondary amino group with r group
- 6-aminopenicillanic acid nucleus (rings A and B) key for activity
- r group determines different penicillins
Hydrolysis of b-lactam ring by ________ yields __________ which lacks ________________.
- penicilloic acid
- antibacterial acivity
Substituents of 6-aminopenicillanic acid determine what?
pharmacologic and antibacterial properties of each molecule
What are the 3 groups of penicllins?
- 1. penicillins (penicillin g)
- 2. Antistaphylococcal penicillins ( Nafcillin)
- 3. extended-spectrum penicillins (ampicillin and antipseudomonal penicillins)
Penicillins (ex. Penicillin G) greatest activity against ______________ and little activity against _____________.
gram-positive, gram-neg cocci, non-B-lactamase producing anaerobes
gram-negative rods which are susceptible to hydrolysis by B-lactamases
Antistaphylococcal Penicillins (Nafcillin) are resistant to _______________ and active against ___________________ and little activity against _______________.
enterococci, anaerobic bacteria, and gram-neg cocci and rods
Extended spectrum penicillins (ampicillin, and antipseudomonal penicillins (amoxicillin)) retain ______________ and have improved activity against _____________ but relatively susceptible to ______________.
retain antibacterial spectrum of penicillin
hydrolysis by B-lactamases
MIC of any penicillin given in ?
Most penicillins are dispensed as what?
sodium or potassium salt of the free acid
Dry crystalline form of penicillin are stable for?
years at 4 degrees celcius
Penicillin Solutions _________________ and must be _______________.
loose their activity rapidly (24 hr at 20 degree celcius)
prepared fresh for administration.
Penicillins mechanisms of action?
inhibit bacterial growth by interfering with transpeptidation reaction of bacterial cell wall synthesis
Bacterial cell wall is composed of what 3 cross linked polymers
Bacterial cell wall polysaccharide chain contains alternating amino sugars __________, and ___________.
- N-acetyglucosamine (G)
- N-acetymuramic acid (M)
A 5 amino acid peptide of bacterial cell wall is linked to _____________ and this peptide terminates in what?
- N-acetylmuramic acid sugar
- terminates in D-alanyl-D-alanine
What does Penicillin-binding protein (PBP) in bacterial cell wall do?
- removes the terminal alanine
- allows for cross link with nearby peptide
- gives cell wall its rigidity
B-lactam antibiotics are structural analogs of ____________________ and can bind to _______________.
- natural D-Ala-D-Ala substrate
- covalently bind to active site of PBP
The binding of b-lactam antibiotics to PBP does what?
- inhibits transpeptidation reaction
- halts peptidoglycan synthesis
- cell dies
B-Lactam antibiotics only kill bacterial cells when.....
- they are actively growing and
- synthesizing cell wall
What are the 4 general mechanisms of penicillin resistance
- Inactivation of antibiotic by B-lactamase
- modification of target PBPs
- impaired penetration of drug to targe PBPs
What is the most common mechanism of resistance?
- B-lactamase production
- (many hundreds of B- lactamases have been identified)
What is the basis of resistance in pneumococci and enterococci?
- altered target of PBPs
- these PBP have low affinity for binding antibiotics
- consequently they aren't inhibited except in relatively high, unachievalbe drug conc.
What mechanisms of resistance happens in gram-negative species and why?
- impaired penetration of antibiotic to target PBP
- due to impermeable outer cell wall membrane (absent in gram-positive)
- absence of proper channel (porins) or down regulation of its production impair drug entry into the cell.
Efflux pump in gram-negative can transport some B-lactam antibiotics from periplasm back across the outer membrane
penicillin oral absorption depends greatly on ?
- acid stability
- protein binding
What 3 penicillins are acid stable and relatively well absorbed?
How should penicillins be taken orally and why? (except for amoxicillin)
- impaired by food
- take 1-2 hours before or after a meal
Absorption of parenteral administration is ?
complete and rapid
Intravenous administration is preferred to intramuscular route because....
irritation and local pain from intramuscular injection of large doses
Penicillins are widely distributed to
Penicillins are ________ molecules, so _________ conc are well below those found in ________ fluids
What 2 penicillins are formulated to delay absorption? what does this result in? and what does it treat?
- Benzathine and procaine
- result in prolonged blood and tissue conc
- treat B-hemolytic streptococcal infection
Penicillin concentration in most ________ are equal to those in ___________.
Penicillins are excreted by ________ and also into ____________.
- kidneys (rapidly)
- sputum and milk
- 10% by glomerular filtration
- 90% by tubular secretion
Penicillin penetration is poor into where?
Half life of penicillin G
- 30 minutes
- renal failure can be as long as 10 hours
Half live of ampicillin and extended-spectrum penicillins
- 1 hour
- secreted more slowly than penicillin G
How do you adjust the dose of penicillins that are excreted by the kidney?
- adjust according to renal function
- 1/4 to 1/3 normal dose if CC is 10 ml/min or less.
What penicillin is excreted primarily by biliary excretion?
What penicillins are excreted by kidney and biliary excretion?
- (no adjustments needed in renal failure)
Doses adjusted on weight alone for newborns results in what? and why?
- Higher systemic conc for longer periods of time than in adults
- clearence is less efficient in newborns
Penicillins shouldn't be given with food to minimize what?
- binding to food proteins
- acid inactivation
Blood levels of penicillins can be raised by administration of __________ which impairs what?
- renal tubular secretion of weak acids such as B-lactam compounds
Penicillin G is drug of choice for what?
- penicillin-susceptible pneumococci
- non-b-lactamase producing staphlococci
- treponema pallidum and other spirochetes
- gram+ rods
- non-B-lactamase broducing gram - anaerobic organisms
What penicillins are given IM and yield low but prolonged drug levels?
- benzathine penicillin
- procaine penicillin G
What is an effective treatment for B-hemolytic streptococcal pharyngitis?
- Single IM injection of benzathine penicillin
- 1.2 million units
- once q 3-4 weeks prevents reinfection
What is an effective treatment in syphilis?
- Benzathine penicillin G
- 2.4 million units IM once a week for 1-3 weeks
What penicillins are resistant to staphylococcal beta lactamase? what infections are they used for?
- Isoxazolyl penicillins
(used for infection of b-lactamase-producting staphylococci)
What infections are resistant to methicillin, nafcillin, and isoxazolyl?
- methicillin-resistant strains
What are the extended-spectrum penicillins?
How does the activity of extended-spectrum penicillins differ from penicillin G?
They have greater activity against gram neg bacteria because of enhanced ability to penetrate gram neg outer membrane
Like penG they are inactivated by B-lactamases
What do aminopenicillins, ampicillin, and amoxicillin treat?
- lower respiratory tract infections
- (amoxicillin is best orally absorbed)
- (all have identical spectrum and activity)
Ampicillin and amoxicillin are most active agains what?
- penicillin-resistant pneumococci
- preferred antibiotics for treating infections suspected to be caused by these resistant strains
Penicillin Advers reactions
- remarkably nontoxic
- anaphylactic shock (rare 0.05%)
- skin rashes
- oral lesions
- interstitial nephritis (autoimmune rxn to penicillin-protein complex)
- hemolytic anemia
- seizures (high doses in renal failure)
- GI upset, NV, diarrhea
Nafcillin associated with what adverse rxn?
Oxacilllin can cause what adverse rxn?
Ampicillin and amoxicillin can cause what?
- skin rashes not allergic in nature
- happen when aminopenicillins are inappropriately prescribed for viral illness
What are the antigenic determinants of penicillins?
- degradation products
- penicilloic acid
- products of alkaline hydrolysis bound to host protein