Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics Flashcards
____________ share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and β-lactamase inhibitors.
Penicillins
All beta-lactam compounds contain a ____________ containing an amide group, which reacts with the active site of enzymes involved in building the bacterial cell wall.
4 membered lactam ring
The basic chemical structure of all penicillins consists of a:
- thiazolidine ring (attached to)
- β-lactam ring
- secondary amino group (6-aminopenicillanic acid)
____________ of the β-lactam ring by bacterial β-lactamases yields ____________, which lacks antibacterial activity
Hydrolysis
yields: penicilloic acid
True or False
The penicillins are susceptible to inactivation by amidases and lactamases
True
T or F
Carbapenems have a the same stereochemical configuration in the lactam ring that imparts resistance to most common β-lactamases.
F
different stereochemical configuration
Substituents of the ________________ determine the essential pharmacologic and antibacterial properties of the resulting molecules.
6-aminopenicillanic acid moiety
What are examples of compounds that are relatively stable to gastric acid and suitable for oral administration
- penicillin V
- amoxicillin
- dicloxacillin
Penicillins can be assigned to one of three groups which are?
- Penicillins (eg. penicillin G)
- Antistaphylococcal penicillins (eg. nafcillin)
- Extended-spectrum penicillins (aminopenicillins and antipseudomonal penicillins)
What group of pencillin is this?
These have the greatest activity against gram-positive organisms, gram-negative cocci, and non-β-lactamase-producing anaerobes.
Penicillins
(eg. penicillin G)
What group of pencillin is this?
These have little activity against gram-negative rods
Penicillins
(eg. penicillin G)
What group of pencillin is this?
These are susceptible to hydrolysis by β-lactamases.
Penicillins
(eg. penicillin G)
What group of pencillin is this?
These penicillins are resistant to staphylococcal β-lactamases.
Antistaphylococcal penicillins
(eg. nafcillin)
What group of pencillin is this?
They are active against staphylococci and streptococci
Antistaphylococcal penicillins
(eg. nafcillin)
What group of pencillin is this?
They are not active against enterococci, anaerobic bacteria, and gram-negative cocci and rods
Antistaphylococcal penicillins
(eg. nafcillin)
What group of pencillin is this?
These drugs retain the antibacterial spectrum of penicillin
Extended-spectrum penicillins
(aminopenicillins and antipseudomonal penicillins)
What group of pencillin is this?
These drugs have improved activity against gram-negative rods
Extended-spectrum penicillins
(aminopenicillins and antipseudomonal penicillins)
Like penicillin, they are relatively susceptible to hydrolysis by β-lactamases
Extended-spectrum penicillins
(aminopenicillins and antipseudomonal penicillins)
T or F
The activity of penicillin G was originally defined in units.
T
The minimum inhibitory concentration (MIC) of any penicillin (or other antimicrobial) is usually given in ____________
mcg/mL
Most penicillins are formulated as the ________ or ____________ of the free acid
sodium or potassium salt
Potassium penicillin G contains about 1.7 mEq of ________ per million units of penicillin (2.8 mEq/g)
K+
Nafcillin contains ________, 2.8 mEq/g.
Na+
What compounds of salt of penicillin G provide repository forms for intramuscular (IM) injection.
- Procaine salts
- Benzathine salts
In ____________ form, penicillin salts are stable for years at 4°C
dry crystalline
Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the ____________ of bacterial cell wall synthesis.
transpeptidation reaction
The cell wall prevents cell ________ from high osmotic pressure
cell lysis
The cell wall is composed of a complex, cross-linked polymer of polysaccharides and peptides known as ____________
peptidoglycan
The polysaccharide of the cell wall contains alternating amino sugars, namely:
- N-acetylglucosamine
- N-acetylmuramic acid
In the polysaccharide of the cell wall that contains an N-acetylmuramic acid sugar, a ____________ is linked to it
5-amino-acid peptide
In the MOA of Penicillin, the peptidoglycan in the cell wall terminates in ___________
D-alanyl-D-alanine
In the MOA of Penicillin, which enzyme is responsible for removing the terminal alanine in the process of forming a cross-link with a nearby peptide
Penicillin-binding protein (PBP)
What gives the cell wall its rigidity?
Cross-links
In the MOA of Penicillin, what binding inhibits the transpeptidation reaction and halts peptidoglycan synthesis, and the cell dies
Covalently binding of D-Ala-D-Ala substrate to the active site of PBPs
T or F
Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall
T
The cell envelope of a gram-negative bacterium has an outer membrane that is ___________
lipid bilayer
T or F
The lipid bilayer in a cell envelope of a bacterium is only present in a gram-negative and not in gram-positive organisms
T
The lipid bilayer of a cell envelope of a gram-negative bacterium is penetrated by ________, which are proteins that form channels providing hydrophilic access to the cytoplasmic membrane
porins
The cell envelope of a bacteria also has a ________ layer that is unique to bacteria and is much thicker in gram-positive organisms than in gram-negative ones.
peptidoglycan layer
What are the layers that constitutes the cell wall of a bacteria?
- outer membrane (lipid bilayer in gram-negative)
- peptidoglycan
What enzymes/membrane proteins are responsible for cross-linking peptidoglycan
Penicillin-binding proteins (PBPs)
If Beta-lactamases are present where do they reside in the cell wall, where they may destroy β-lactam antibiotics that penetrate the outer membrane
periplasmic space or outer surface of cytoplasmic membrane
T or F
In order to halt the peptidoglycan synthesis, the Beta-lactam works by binding the transpeptidase at the penicillin-binding protein site, resulting in inhibition of transpeptidation
T
Resistance to penicillins and other β-lactams is due to one of four general mechanisms namely:
- inactivation of antibiotic by β-lactamase
- modification of target PBPs
- impaired penetration of drug to target PBPs
- antibiotic efflux
What is the most common mechanism of penicillin resistance?
production of beta-lactamase
Other β-lactamases, like AmpC β lactamase produced by Pseudomonas aeruginosa and Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in Enterobacteriaceae,** hydrolyze both** ____________ and ___________
cephalosporins and penicillins
________________ are highly resistant to hydrolysis by penicillinases and cephalosporinases
Carbapenems
____________ are hydrolyzed by metallo-β-lactamases and carbapenemases, instead of hydrolysis of penicillinases and cephalosporinases
Carbapenems
What are the basis of methicillin resistance in staphylococci and of penicillin resistance in pneumococci and most resistant enterococci.
Altered target PBPs
(These resistant organisms produce PBPs that have low affinity for binding β-lactam antibiotics)
Resistance due to impaired penetration of antibiotic occurs only in ____________ because of the impermeable outer membrane (lipid bilayer) of their cell wall, which is absent in gram-positive bacteria.
gram-negative species
Beta-lactam antibiotics cross the outer membrane and enter gram-negative organisms via outer membrane protein channels called ____________
porins
Gram-negative organisms also may produce an ____________, which consists of cytoplasmic and periplasmic protein components that efficiently transport some β-lactam antibiotics
efflux pump
Gastrointestinal absorption of ____________ is erratic, so it is not suitable for oral administration
nafcillin
What penicillin drugs are acid-stable and relatively well absorbed, producing serum concentrations in the range of 4–8 mcg/mL after a 500-mg oral dose
- Dicloxacillin
- Ampicillin
- Amoxicillin
Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the drugs should be administered at least ____________ before or after a meal
1–2 hours
________________ of penicillin G is preferred to the intramuscular route because of irritation and local pain from intramuscular (IM) injection of large doses.
Intravenous administration (IV)
Highly protein-bound penicillins like ____________ generally achieve lower free-drug concentrations in serum than less protein-bound penicillins
nafcillin
Penicillins are ________, thus it works well in intracellular concentrations than those found in extracellular fluids.
polar
____________ and ____________ penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentrations
Benzathine and procaine
T or F
Penicillin is also excreted into sputum and breast milk to levels 3–15% of those in the serum
T
Penicillin is rapidly excreted by the _______
kidneys (majority)
The normal half-life of penicillin G is approximately ____________ but, in renal failure, may be as long as 10 hours
30 minutes
T or F
Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour
T
Give the ROA
Penicillins: Penicillin G
Intravenous (IV)
Give the ROA
Penicillins: Penicillin V
Oral Administration (PO)
Give the ROA
Antistaphylococcal penicillins: Cloxacillin, dicloxacillin
Oral Administration (PO)
Give the ROA
Antistaphylococcal penicillins:
Nafcillin
Intravenous (IV)
Give the ROA
Antistaphylococcal penicillins:
Oxacillin
Intravenous (IV)
Give the ROA
Extended-spectrum penicillins:
Amoxicillin
Oral Administration (PO)
Give the ROA
Extended-spectrum penicillins:
Amoxicillin/potassium
clavulanate
Oral Administration (PO)
Give the ROA
Extended-spectrum penicillins:
Piperacillin/tazobactam
Intravenous (IV)
Nafcillin is primarily cleared by ____________ excretion
biliary excretion
