Lecture 6: Cephalosporins, Carbapenems, Monobactams, Vancomycin, Lipoglycopeptides Flashcards
Cushman's Section
What are the two clinically useful starting materials for the synthesis of Cephalosporins?
- 7-aminocephalosporanic acid [from Cephalosporin C hydrolysis]
- 7-amino-3-deacetoxycaphalosporanic acid [from phenoxymethylpenicillin]
What is the main mechanism of action for the Cephalosporins?
- React with transpeptidase to inhibit Peptidoglycan cross-linking
- Many Cephalosporins having leaving groups, “-X”, that breaks the ring
How are Cephalosporins acted on my B-lactamase?
- Hydrolyzed by B-lactamase [Some are called Cephalosporinases]
- Breaks open the four membered ring
What is the way that Cephalosporins are similar to Penicillins in terms of Allergenicity?
- Cross-reactivity is common; caution if penicillin allergiy
- Fever or Rash
What is the main classification scheme that is assoicated with Cephalosporins?
- 1st to 4th Gen = Decrease in Gram (+) activity and Increase in Gram (-) activity
What are the main cephalosporins [1st to 4th gen] and the main structural differences between them?
- 1st gen: Cephalexin [Methyl group]
- 3rd gen: Aminothiozole
What is the main difference between orally or parenterally active cephalosporins?
- Good Leaving Group = NOT orally active [Parenteral]
- Bad Leaving Group = Orally active
What are the chemical structures, found at C-3, help confer to acid stability?
- Those that are not chemically active = increase oral activity
- i.e. Methyl, Carbamates, Vinyl [very stable]
What is the difference between Syn & Anti Oxime Ether on C-7 and how does it affect B-lactamase?
- Syn = Resistance
- Anti = Susceptible
- So, in SYN formation it make it block the b-lactam carbonyl - stopping hydroylsis
What is the way that carbamate side chains at C-3 are effected my enzymatic hydrolysis?
- Less reactive b/c of electron-donating
- Neutralizes partial positves = less susceptible to nucleophilic attack
What is the way that Cefturoxime differs in terms of Distrubtions compared to the other Cephalosproins?
- Able to enter the CSF
What is the relationship of cefuroxine and cefuroxine axetil and compare there bioavailability and route?
- Axetil is a prodrug for Cefuroxime
- More lipophilic & absorbed in GI tract [increased bioavailabilty]
- Hydroluzed to cefuroxime
What is the Biologically active metabolite of Cefuroxime axetil?
- 1(acetyloxy)ethyl ester ??
What is the effect that the large oxime ether on C-7 has on Ceftazidime against stability?
- Will ENHANCE stability vs b-lactamase at C-7
What does the Charged Pyridinium Ring do for Ceftzaidime toward b-lactamase reactivity and solubility?
- Charged Pyridium Ring: Good Leaving Group & activates the lactam ring
- Solubility: Enchanced making it more Parenterally Active
What is the effect of the N-methylpyrrolidine moiety have on Cefepime toward B-lactam reactivity?
- GOOD leaving; increases reactivity of b-lactam = Parenterally active
What is the effect of Syn Methoximinno on the C-7 side chain of Cefepime to stability vs B-lactamase?
- Increases the resistance toward B-lactamase
What is an important structural feature about Cephamycins?
- 7a-methoxyl Group = increased stablility to B-lactamase
What is the reasoning behind Theinamycin not being used as a drug and how was this overcome?
- TOO reactive; primary amino group attacks the b-lactam intermolecularly
- On Imipenem, N-foriniminoyl stops this from happening
What happens when the sulfur atoms of the penicillin is replaced with a methylene group in the carbapenem?
- Increased reactivity b/c methylene is smaller than sulfur = greater strain
What effect does Dehydropeptidase-1 have on Imipenem and what is the way that it was overcome?
- Hydrolyzed by it
- Overcome by giving Cilastatin
How does the stability to Dehydropeptidase-1 differ in Meropenem compared to Imipenem?
- Meropenem has a 1-b-methyl group that CONFERS stability to it
- NO CILASTATIN
With the Monobactams not having a Carboxylic Acid Group, how are they biologically active?
- Sulfamic acid group on C-2; activates the b-lactam ring to hydrolysis = reactions
What part of the antibactierial spectrum does the Monobactams cover?
- Almost completely Gram (-); especially hospital aquired ones
What is the Cross-allergenicity of the Monobactams?
- NO cross-reactivity with Penicillins and Cephalosporins
What are these structures?
- Left: Vancomycin
- Right: Teicoplanin
Compare and contrast the MOA of Vancomycin and Penicillins?
- Inhibits cell wall synthesis [Vanc does Gram (+) tho]
- Binds to the Peptidyl side chain D-Ala-D-Ala BEFORE crosslinking & inhibits tranglycosylation
What is the Antibiotic Spectrum of activity for Vancomycin?
- Gram (+); the molecule is too big to fill through the porins of Gram (-)
What is the mechanism of Resistance in Vancomycin?
- Mutation of cell wall precusor D-Ala-D-Ala to D-Ala-D-Lac; Vanc is 1000x less effective toward D-lac
What is the route of administration for Vancomycin?
- NO appreciable blood levels orally so usually given IV
What are the main theraputics uses for Vancomycin?
- Orally for C. Diff [when Metro dont work]
- Endocarditis
- MRSA
- Surgical Prophylaxis when hospitals have high MRSE counts
- When serious allergies to B-lactams
What are the toxic effects of Vancomycin/
- Hypersensitivity [Rash, Anaphyaxis]
- Nephrotoxicity and Ototoxicity
