Flashcards in topic 9 Deck (30):
What are the categories of penicillin?
•Penicillin G, Penicillin V
•Anti-staphylococcus, aka Beta-lactamase resistant
•Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin
•Aminopenicillins (2nd generation)
•Antipseudomonal (3 rd and 4 th generation)
What are the important parts of the structure of penicillins?
There is a beta lactam ring. The different penicillins are made by adding different groups to the central structure. Destroying the b-lactam ring will make any b-lactam ineffective.
What should be considered when thinking of the administration and absorption of penicillin?
Most penicillins are available in oral and IV forms, choice depends severity of infection (IV for more severe), convenience (oral is usually more convenient), bioavailability e.g. stability to gastric acid. IM for longer lasting depot (e.g. Procaine Pen G)
Pen G, Pen K, and the beta-lactamase resistant penicillins are less stable in an acid environment. Food increases gastric acid secretion, and these penicillins should be taken away from meals.
How are penicillins eliminated?
•The beta-lactamase resistant penicillins are excreted through a hepatic route.
•The rest of penicillins are excreted by the kidneys by filtration and tubular secretion in an unchanged form. Need to adjust dose in renal failure
In general, penicillins have relatively short half-life and are given at short dosing intervals
How are penicillins distributed?
Generally well distributed throughout body
Poor penetration across meninges into CSF, but
increased permeability when meninges inflamed
Crosses placenta, class B pregnancy risk
What is the general mechanism of action of penicillins?
•Penicillins bind to and inhibit Penicillin Binding Proteins (PBPs)
•PBPs are needed for cell wall (peptidoglycan) synthesis in bacteria
•Cell wall becomes less stable
•Bacteria die from lysis from fragile cell wall (osmotic stress)
•Penicillins work only on organisms with a cell wall
•Penicillins work only when the organisms are
modifying or synthesizing new cell walls, which
occurs during growth
How do penicillins react with gram + and gram- strains? Are they bactericidal or bacteristatic?
Penicillins are bactericidal.
since both gram + and gram - strains have a peptidoglycan layer (even though gram - strains have an outer membrane around it), penicillins work on both.
What is the molecular mechanism of penicillin on peptidoglycans? What is the peptidoglycan monomer made up of? What does PBP do?
The peptidoglycan monomer consists of two monosaccharides (NAM/NAG) that are bound to each other. NAM is also bound to a tetra peptide made of specific amino acids.
PBP functions to cross link the different monomers.
Penicillin resembles the tetrapeptide chain and thus covalently binds to PBP making it ineffective.
What are beta lactamases? How do they work?
Beta lactamases are enzymes that cleave the beta lactam ring. By doing so, they convert penicillin to penicilloic acid which lacks antibacterial properties.
They are widespread.
How do beta lactamases work in both gram + and gram - bacteria?
In gram + bacteria, beta-lactases are secreted extracellularly and are produce in large quantities. They work mainly against penicillins. Staphylococcus is the main strain that develops beta-lactamase and it usually does so quickly.
In gram - bacteria, they secrete beta-lactamase in periplasmic space in lower quantities. They work against both penicillins and cephalosporins.
What are 3 other ways in which bacteria can gain resistance to penicillins and how do they work?
Mutations in the PBP-make it so it doesn't bind penicillin as well.
Efflux pumps-gram- strains have pumps that transport penicillin from periplasm across outer membrane.
Mutated porins-Gram negative bacteria have porins in their outer membrane that allow things to enter periplasm. Mutations in them can make it so penicillin can't enter.
What is the most common untoward effect of penicillin?
Hypersensitivity reactions are the most common adverse effect
• About 5% of patients will have an adverse reaction
• Symptoms range from a maculopapular rash
(most common with ampicillin), fever, to severe
including serum sickness, angioedema and
• Rash is seen in nearly 100% of patients with
mononucleosis treated with ampicillin
• Penicillins are generally cross-sensitizing and
• Adverse effects can occur without prior known
• Previous hypersensitivity is generally a contraindication for use.
What are major/minor antigenic determinants?
They are the macromolecule that causes the allergic reaction.
Major/minor refers to the frequency with which they cause Ab production, not the severity of the reaction.
The major determinant is penicilloic acid, but only when it is bound to other proteins which makes it a hapten.
The minor determinant is intant penicillin and penicillanic acid derivatives.
What are two other untoward effects of penicillin?
•Nausea, abdominal discomfort, diarrhea as is
common with all antibiotics, in part due to disruption of normal gut flora
•C. Difficile colitis , which may occur with any
antibiotic (when normal gut flora die, it takes advantage and grows).
• All penicillins have been associated with interstitial nephritis, but methicillin historically had a much higher rate and is not available clinically any more (allergic RXN in kidneys).
What are the two penicillins in the category "the penicillins"? What is their spectrum? What is the difference between the two?
Penicillin G and V.
•gram positives, anaerobes, gram neg. cocci, spirochetes, but Not effective against gram-negative bacilli
Resistance has now developed in many organisms.
They are adminstered differently. Penicillin V is more stable in an acidic environment and thus can be given orally. Penicillin G is usually given IM/IV
What are the anti-staph or beta-lactamase resistant penicillins? What are their general characteristics?
Methacillin, cloxacillin, oxacillin, dicloxacillin, flucoxacillin.
They are used to treat staphylococcal infections that are resistant to pen G and really nothing more.
In 1961, a methacillin resistant staphylococcus aureus (MRSA) was found. Vancomyscin was used to treat it. In 1996, a VRSA was found.
Oral preparations should be given on an empty stomach.
What are the aminopenicillins and what are their general characteristics?
Ampicillin-Used for acute bacterial meningitis due to Listeria. Also available as a combination drug with Sulbactam (beta lactamase inhibitor)
Amoxicillin-Also available as a combination drug with Clavulanic acid (beta lactamase inhibitor)
•Aminopenicillins have similar spectrum to penicillin G plus gram-negative bacilli coverage. They are useful for H. influenzae, used for ear infections and respiratory infections in children. They have better coverage of proteus mirabilis, E. Coli, and shigella/salmonella.
What are the antipseudomonal penicillins and what are their characteristics?
Carbenicillin, Ticarcillin, Piperacillin
•Pseudomonas aeruginosa and complicated G(-) respiratory tract infections
•Other penicillins are better for typical G(+) organisms (only used when others won't work).
•Usually only one is available at a given hospital as standard therapy
What gives antipseudomonal and aminopenicillins better gram - coverage?
They are better able to penetrate the porins.
What are beta-lactamase inhibitors? What are 3 examples
• Beta-lactamase inhibitors contain the lactam ring, but are not antimicrobial by themselves.
• They inhibit beta-lactamases (basically distract them from killing penicillins), and are often used in conjunction with penicillins.
Clavulanic acid, sulbactam, tazobactam
What are the important parts of the structure of cephalosporins?
Beta-lactam ring (active part)
The R groups are connected to the main structure.
What are some general properties of cephalosporins including administration, elimination, distrubution, and bactericidal properties?
Administration : PO/IV forms. Absorbed from the small intestine
Elimination : mostly unchanged in urine by renal
filtration and secretion. Most require dose adjustment in renal failure. An exception is Ceftriaxone, mainly excreted in the bile.
Distribution : throughout all tissues. Generally poor CNS penetration even with inflamed meninges. Some 3 rd -generation and cefepime (4 th generation) have adequate penetration into the CSF and are used for meningitis (Ceftriaxone, cefotaxime, cefepime)
bactericidal: Basically the same mechanism as penicillin but they are more resistant to beta lactamases.
What are some untoward effects of cephalosporins?
Cephalosporins are capable of producing all the
untoward effects that are seen with penicillins,
including interstitial nephritis, rash, anaphylaxis,
diarrhea, C. diff colitis.
Which drugs are included in the first generation of cephalosporins? How are they administered? What do they cover? Distribution?
Cephalexin , given orally; Cephazolin , given IV
Good activity against gram (+) cocci & E. coli
Cannot reach high concentrations in CSF
Can be thought of as a Pen G + antistaph penicillin substitute
Effective against methicillin sensitive Staph Aureus
Effective against Proteus mirabilis, E. coli, Klebsiella pneumonia (PEcK organisms)
Which are included in the 2nd generation? What do they cover?
• Cefaclor, Cefuroxime, Cefoxitin, Cefotetan
• Less active against Gram positive, but broader gram negative coverage compared to 1st generation
• Adds the following gram negative coverage: H. influenza, Enterobacter aerogenes, and some Neisseria (HENPEcK organisms)
• Used for the treatment of pneumonia and throat
Cefoxitin and cefotetan have additional anaerobic coverage, mainly B. Fragilis (involved in 90% of peritoneal anaerobic infections)
Which are included in the 3rd generation? What do they cover?
In general, they are more effective against gram negatives and are able to enter the CSF.
Cefotaxime and Ceftriaxone-Not effective against pseudomonas, but are more effective against meningitis b/c they are more effective against gram positives.
Ceftazadime-effective against pseudomonas aeruginosa, but not effective against meningitis b/c they aren't as effective against gram +.
Which drug is in the 4th generation? What does it cover?
Cefepime-Very broad spectrum, good activity against gram (+) cocci, P. aeruginosa , and many Enterobacteriae. Useful in treating P. aeruginosa. Used in treatment of meningitis
What are the 2 5th generation drugs? What do they cover?
Ceftaroline and Ceftobiprole.
coverage is similar to ceftriaxone but with better gram + coverage. Bind PBP2 more tightly and are effective against MRSA, vancomycin intermediate staph aureus (VISA) and hetero-VISA. Also against strep pneumonia which is resistant to penicillin and ceftriaxone.
Not effective against pseudomonas.
What are carbapenas?
Drug name ends in -penem: Imipenem, Meropenem
Beta lactam ring attached to another ring.
Highly resistant to beta-lactamases, Broad spectrum, Usually restricted in use for treatment of bacteria resistant to other antibiotics, or broad empiric coverage in certain situations (neutropenic
fever). Most are effective against pseudomonas aeruginosa.
Only given orally.