Lecture 6: Cephalosporins, Carbapenems, Monobactams, Vancomycin, Lipoglycopeptides

Question 1

What are the two clinically useful starting materials for the synthesis of Cephalosporins?

Answer 1

• 7-aminocephalosporanic acid [from Cephalosporin C hydrolysis]
• 7-amino-3-deacetoxycaphalosporanic acid [from phenoxymethylpenicillin]

Question 2

What is the main mechanism of action for the Cephalosporins?

Answer 2

• React with transpeptidase to inhibit Peptidoglycan cross-linking
• Many Cephalosporins having leaving groups, “-X”, that breaks the ring

Question 3

How are Cephalosporins acted on my B-lactamase?

Answer 3

• Hydrolyzed by B-lactamase [Some are called Cephalosporinases]
• Breaks open the four membered ring

Question 4

What is the way that Cephalosporins are similar to Penicillins in terms of Allergenicity?

Answer 4

• Cross-reactivity is common; caution if penicillin allergiy
• Fever or Rash

Question 5

What is the main classification scheme that is assoicated with Cephalosporins?

Answer 5

• 1st to 4th Gen = Decrease in Gram (+) activity and Increase in Gram (-) activity

Question 6

What are the main cephalosporins [1st to 4th gen] and the main structural differences between them?

Answer 6

• 1st gen: Cephalexin [Methyl group]
• 3rd gen: Aminothiozole

Question 7

What is the main difference between orally or parenterally active cephalosporins?

Answer 7

• Good Leaving Group = NOT orally active [Parenteral]
• Bad Leaving Group = Orally active

Question 8

What are the chemical structures, found at C-3, help confer to acid stability?

Answer 8

• Those that are not chemically active = increase oral activity
• i.e. Methyl, Carbamates, Vinyl [very stable]

Question 9

What is the difference between Syn & Anti Oxime Ether on C-7 and how does it affect B-lactamase?

Answer 9

• Syn = Resistance
• Anti = Susceptible
• So, in SYN formation it make it block the b-lactam carbonyl - stopping hydroylsis

Question 10

What is the way that carbamate side chains at C-3 are effected my enzymatic hydrolysis?

Answer 10

• Less reactive b/c of electron-donating
• Neutralizes partial positves = less susceptible to nucleophilic attack

Question 11

What is the way that Cefturoxime differs in terms of Distrubtions compared to the other Cephalosproins?

Answer 11

• Able to enter the CSF

Question 12

What is the relationship of cefuroxine and cefuroxine axetil and compare there bioavailability and route?

Answer 12

• Axetil is a prodrug for Cefuroxime
• More lipophilic & absorbed in GI tract [increased bioavailabilty]
• Hydroluzed to cefuroxime

Question 13

What is the Biologically active metabolite of Cefuroxime axetil?

Answer 13

• 1(acetyloxy)ethyl ester ??

Question 14

What is the effect that the large oxime ether on C-7 has on Ceftazidime against stability?

Answer 14

• Will ENHANCE stability vs b-lactamase at C-7

Question 15

What does the Charged Pyridinium Ring do for Ceftzaidime toward b-lactamase reactivity and solubility?

Answer 15

• Charged Pyridium Ring: Good Leaving Group & activates the lactam ring
• Solubility: Enchanced making it more Parenterally Active

Question 16

What is the effect of the N-methylpyrrolidine moiety have on Cefepime toward B-lactam reactivity?

Answer 16

• GOOD leaving; increases reactivity of b-lactam = Parenterally active

Question 17

What is the effect of Syn Methoximinno on the C-7 side chain of Cefepime to stability vs B-lactamase?

Answer 17

• Increases the resistance toward B-lactamase

Question 18

What is an important structural feature about Cephamycins?

Answer 18

• 7a-methoxyl Group = increased stablility to B-lactamase

Question 19

What is the reasoning behind Theinamycin not being used as a drug and how was this overcome?

Answer 19

• TOO reactive; primary amino group attacks the b-lactam intermolecularly
• On Imipenem, N-foriniminoyl stops this from happening

Question 20

What happens when the sulfur atoms of the penicillin is replaced with a methylene group in the carbapenem?

Answer 20

• Increased reactivity b/c methylene is smaller than sulfur = greater strain

Question 21

What effect does Dehydropeptidase-1 have on Imipenem and what is the way that it was overcome?

Answer 21

• Hydrolyzed by it
• Overcome by giving Cilastatin

Question 22

How does the stability to Dehydropeptidase-1 differ in Meropenem compared to Imipenem?

Answer 22

• Meropenem has a 1-b-methyl group that CONFERS stability to it
• NO CILASTATIN

Question 23

With the Monobactams not having a Carboxylic Acid Group, how are they biologically active?

Answer 23

• Sulfamic acid group on C-2; activates the b-lactam ring to hydrolysis = reactions

Question 24

What part of the antibactierial spectrum does the Monobactams cover?

Answer 24

• Almost completely Gram (-); especially hospital aquired ones

Question 25

What is the Cross-allergenicity of the Monobactams?

Answer 25

• NO cross-reactivity with Penicillins and Cephalosporins

Question 26

What are these structures?

Answer 26

• Left: Vancomycin
• Right: Teicoplanin

Question 27

Compare and contrast the MOA of Vancomycin and Penicillins?

Answer 27

• Inhibits cell wall synthesis [Vanc does Gram (+) tho]
• Binds to the Peptidyl side chain D-Ala-D-Ala BEFORE crosslinking & inhibits tranglycosylation

Question 28

What is the Antibiotic Spectrum of activity for Vancomycin?

Answer 28

• Gram (+); the molecule is too big to fill through the porins of Gram (-)

Question 29

What is the mechanism of Resistance in Vancomycin?

Answer 29

• Mutation of cell wall precusor D-Ala-D-Ala to D-Ala-D-Lac; Vanc is 1000x less effective toward D-lac

Question 30

What is the route of administration for Vancomycin?

Answer 30

• NO appreciable blood levels orally so usually given IV

Question 31

What are the main theraputics uses for Vancomycin?

Answer 31

• Orally for C. Diff [when Metro dont work]
• Endocarditis
• MRSA
• Surgical Prophylaxis when hospitals have high MRSE counts
• When serious allergies to B-lactams

Question 32

What are the toxic effects of Vancomycin/

Answer 32

• Hypersensitivity [Rash, Anaphyaxis]
• Nephrotoxicity and Ototoxicity