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Name 5 beta lactam compounds
- penicillins
- cephalosporins
- monobactams
- carbapenems
- b-lactamase inhibitors
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What is a lactam?
a cyclic amide
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what is a b-lactam ring?
- lactam with a heteroatomic ring structure
- consists of 3 carbon atoms and one nitrogen atom
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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
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Hydrolysis of b-lactam ring by ________ yields __________ which lacks ________________.
- b-lactamases
- penicilloic acid
- antibacterial acivity
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Substituents of 6-aminopenicillanic acid determine what?
pharmacologic and antibacterial properties of each molecule
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What are the 3 groups of penicllins?
- 1. penicillins (penicillin g)
- 2. Antistaphylococcal penicillins ( Nafcillin)
- 3. extended-spectrum penicillins (ampicillin and antipseudomonal penicillins)
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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
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Antistaphylococcal Penicillins (Nafcillin) are resistant to _______________ and active against ___________________ and little activity against _______________.
Staphylococcal B-lactamases
staphylococci, streptococci
enterococci, anaerobic bacteria, and gram-neg cocci and rods
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Extended spectrum penicillins (ampicillin, and antipseudomonal penicillins (amoxicillin)) retain ______________ and have improved activity against _____________ but relatively susceptible to ______________.
retain antibacterial spectrum of penicillin
gram-neg organisms
hydrolysis by B-lactamases
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MIC of any penicillin given in ?
mcg/ml
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Most penicillins are dispensed as what?
sodium or potassium salt of the free acid
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Dry crystalline form of penicillin are stable for?
years at 4 degrees celcius
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Penicillin Solutions _________________ and must be _______________.
loose their activity rapidly (24 hr at 20 degree celcius)
prepared fresh for administration.
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Penicillins mechanisms of action?
inhibit bacterial growth by interfering with transpeptidation reaction of bacterial cell wall synthesis
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Bacterial cell wall is composed of what 3 cross linked polymers
- polysaccharides
- polypeptides
- peptidoglycans
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Bacterial cell wall polysaccharide chain contains alternating amino sugars __________, and ___________.
- N-acetyglucosamine (G)
- N-acetymuramic acid (M)
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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
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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
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B-lactam antibiotics are structural analogs of ____________________ and can bind to _______________.
- natural D-Ala-D-Ala substrate
- covalently bind to active site of PBP
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The binding of b-lactam antibiotics to PBP does what?
- inhibits transpeptidation reaction
- halts peptidoglycan synthesis
- cell dies
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B-Lactam antibiotics only kill bacterial cells when.....
- they are actively growing and
- synthesizing cell wall
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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
- Efflux
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What is the most common mechanism of resistance?
- B-lactamase production
- (many hundreds of B- lactamases have been identified)
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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.
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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
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penicillin oral absorption depends greatly on ?
- acid stability
- protein binding
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What 3 penicillins are acid stable and relatively well absorbed?
- dicloxacillin
- ampicillin
- amoxicillin
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How should penicillins be taken orally and why? (except for amoxicillin)
- impaired by food
- take 1-2 hours before or after a meal
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Absorption of parenteral administration is ?
complete and rapid
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Intravenous administration is preferred to intramuscular route because....
irritation and local pain from intramuscular injection of large doses
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Penicillins are widely distributed to
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Penicillins are ________ molecules, so _________ conc are well below those found in ________ fluids
- polar
- intracellular
- extracellular
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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
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Penicillin concentration in most ________ are equal to those in ___________.
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Penicillins are excreted by ________ and also into ____________.
- kidneys (rapidly)
- sputum and milk
- 10% by glomerular filtration
- 90% by tubular secretion
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Penicillin penetration is poor into where?
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Half life of penicillin G
- 30 minutes
- renal failure can be as long as 10 hours
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Half live of ampicillin and extended-spectrum penicillins
- 1 hour
- secreted more slowly than penicillin G
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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.
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What penicillin is excreted primarily by biliary excretion?
Nafcillin
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What penicillins are excreted by kidney and biliary excretion?
- oxacillin
- dicloxacillin
- cloxacillin
- (no adjustments needed in renal failure)
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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
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Penicillins shouldn't be given with food to minimize what?
- binding to food proteins
- acid inactivation
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Blood levels of penicillins can be raised by administration of __________ which impairs what?
- Probenecid
- renal tubular secretion of weak acids such as B-lactam compounds
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Penicillin G is drug of choice for what?
- streptococci
- meningococci
- enterococci
- penicillin-susceptible pneumococci
- non-b-lactamase producing staphlococci
- treponema pallidum and other spirochetes
- clostridium
- actinocyces
- gram+ rods
- non-B-lactamase broducing gram - anaerobic organisms
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What penicillins are given IM and yield low but prolonged drug levels?
- benzathine penicillin
- procaine penicillin G
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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
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What is an effective treatment in syphilis?
- Benzathine penicillin G
- 2.4 million units IM once a week for 1-3 weeks
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What penicillins are resistant to staphylococcal beta lactamase? what infections are they used for?
- Methicillin
- Nafcillin
- Isoxazolyl penicillins
(used for infection of b-lactamase-producting staphylococci)
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What infections are resistant to methicillin, nafcillin, and isoxazolyl?
- listeria
- enterococci
- methicillin-resistant strains
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What are the extended-spectrum penicillins?
- aminopenicillin
- carboxypenicillins
- ureidopenicillins
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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
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What do aminopenicillins, ampicillin, and amoxicillin treat?
- UTI
- sinusitis
- otitis
- lower respiratory tract infections
- (amoxicillin is best orally absorbed)
- (all have identical spectrum and activity)
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Ampicillin and amoxicillin are most active agains what?
- penicillin-resistant pneumococci
- preferred antibiotics for treating infections suspected to be caused by these resistant strains
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Penicillin Advers reactions
- remarkably nontoxic
- hypersensitivity
- anaphylactic shock (rare 0.05%)
- skin rashes
- oral lesions
- fever
- interstitial nephritis (autoimmune rxn to penicillin-protein complex)
- eosinophilia
- hemolytic anemia
- vasculitis
- seizures (high doses in renal failure)
- GI upset, NV, diarrhea
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Nafcillin associated with what adverse rxn?
neutropenia
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Oxacilllin can cause what adverse rxn?
hepatitis
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Ampicillin and amoxicillin can cause what?
- skin rashes not allergic in nature
- happen when aminopenicillins are inappropriately prescribed for viral illness
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What are the antigenic determinants of penicillins?
- degradation products
- penicilloic acid
- products of alkaline hydrolysis bound to host protein
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