Exam 1 lecture 4

Question 1

What are cephamycins? Name a cephamycin drug? spectrum of activity? Why? What does it release? B lactamase susceptibility?

Answer 1

Cephamycin is a 2nd gen cephalosporin that has a 7-a methoxy group.

This 7-a methoxy group increases stability vs B lactamase.

Cefotan is a cephamycin

It is broad spectrum due to carboxylate that will be negatively charged at physiological PH, allowing activity against gram - bacteria

Cefotan is generally stable to B lactamases

Question 2

What does cefotetan release

Answer 2

It releases N-methylthiotetrazole, which causes hypoprothrombinemia and also causes a rxn to ethanol that is similar to disulfuram.

Question 3

What type of drug is imipenem? What is it derived from? What is the difference between imipenem and thienamycin?

Answer 3

Imipenem is a carbapenem

it is an N formiminoyl derivative of thienamycin that occurs naturally.
Thienamycin is too reactive to be used as a drug because the primary amino group attacks B lactam intermolecularly.

The N formiminoyl group prevents this from happening

Question 4

Explain the relationship between carbapenems and penicillin

Answer 4

Carbapenems are carbon analogs of penicillins. The sulfur present in thiazolidine ring in penicillin is replaced by a methylene group. This increases reactivity because methylene is smaller than sulfur, so ring strain increases in carbapenems

Question 5

How does imipenem interact with B lactamases

Answer 5

Besides reacting with penicillin binding proteins, imipenem reacts with and inhibits B lactamases

Question 6

How is imipenem hydrolyzed? How can it be overcome?

Answer 6

by renal dehydropeptidase-, but this can be overcome by co administration of the dehydropeptidase-1 inhibitor cilastatin

Question 7

What type of spectrum activity does imipenem with cilastin have? What is imipenems B lactamase activity?

Answer 7

broad spectrum. (due to polarity, polar molecules are broad spectrum)

Imipenem is a good B lactamase inducer

Question 8

How is imipenem-cilastin sodium administered

Answer 8

Parenterally

Question 9

Name a type of monobactam? Natural or synthetic?

Answer 9

Aztreonam disodium.

It is totally synthetic but was inpired by monobactams

Question 10

structural difference between monobactams and other penicillins/cephalosporins? What bacteria does it normally treat?

Answer 10

Monobactam (aztreonam disodium) has a sulfamic acid group that takes place in the C2 carboxyl group.

Antibiotic spectrum focuses completely on gram - bacteria. Used in severe gram - bacteria

Question 11

Are monobactams B lactamase sensitive or resistant? Is there cross allergenicity? What is the main advantage

Answer 11

B lactamase resistant

Cross allergenicity with penicillins and cephalosporins has not been reported except for ceftazidime.

A main advantage is that it can be used in pts with penicillin allergy.

Question 12

What are the two glycopeptide antibiotics that are used?

Answer 12

Vancomycin and teicoplanin

Question 13

What type of cell wall does vancomycin inhibit

Answer 13

Cell + cell wall biosynthesis

Question 14

MOA of vancomycin

Answer 14

Similar to MOA of B lactams in that it inhibits transpeptidase, but it does it in a completely different way.

It binds to the peptidyl side chain D ala D ala terminus in the peptidoglycan precursor before cross linking. The transpeptidase rxn that is required for cross linking is inhibited. It also inhibits transglycosylation step in peptidoglycan synthesis

Question 15

Spectrum of activity of vancomcin? Why?

Answer 15

Gram positive bacteria, no activity against gram negative because it is reeally big to get through porin

Question 16

Why is vancomycin important

Answer 16

It is the last line of defence in hospital acquired multi drug resistant staphylococcal and streptococcal infections

Question 17

Why was avoparcin banned

Answer 17

Use of avoparcin was connected to vancomycin resistant enterococcal infections (VRE). VRE became less common after its ban. (they have the same structure)

Note: it was never approved in the US on;y europe

Question 18

What is the mechanism of resistant that causes VRE (Vancomycin resistant enterococcal infection)

Answer 18

mutation of the peptidogycan cell wall precursor from D alaD ala to D ala D lactate. Vancomycin has 1000x less affinity for D ala D lactate precursor

Question 19

How is vancomycin administered? How is it eliminated?

Answer 19

Administered IV, (Orally to treat C. diff if is not responsive to metronidazole)

90% eliminated by glomerular filtration.

Question 20

What is vanc used to treat

Answer 20

Methicillin resistant staphylococcus aureus

Question 21

Toxicity and side effects of vancomycin

Answer 21

hypersensitivity reaction causing Skin rash and potential anaphylaxis

Nephrotoxicity and ototoxicity

Question 22

Name a lipoglycopeptide antibiotic? MOA? spectrum of activity?

Answer 22

oritavancin (it is basically vancomycin with lipid chains attached synthetically) and 2nd gen dalbavancin

Inhibits transpeptidation and transglycosylation by binding D ala D ala residue

Active against a broad spectrum of gram positive bacteria, including MRSA (dalbavancin effective againts MRSA and MRSE)

Question 23

What are the different half lives of vancomycin, telavancin, dalbavancin and oritavancin

Answer 23

Vancomycin t1/2- 4-6 h
Telavancin- 7-9 h
Dalbavancin- 204h
Oritavancin- 245 h

The latter two can be used in single dose regimens

Question 24

What are the two streptogramins? DIfference? WHat is their combination called? WHat is it derived from?

Answer 24

Quinupristin (larger)- derived from pristinamycin I a
Dalfopristin- derived from pristinamycin II a

Synercid is combination of the two

Question 25

For quinupristin, dalfopristine and synercid, are they bacteriostatic? Bactericidal? How is synercid administered?

Answer 25

Quinupristine and dalfopristine are bacteriostatic alone, but synercid is bacteriostatic against enterococcus faecium and bactericidal against strains of methicillin susceptible and methicilllin resistant staphylococci, administered parenterally.

Question 26

Dalfopristin MOA

Answer 26

Dalfopristin directly interferes with the peptidyl transferase catalyzed step. This step includes the fusion of the P site tRNA and A site t RNA so that proteins in ribosome are made

Question 27

Quinpristin MOA? (Where does it bind the ribosome in comparison to dalfopristine)

Answer 27

Quinpristin binds in the ribosomal tunnel and causes blockage of the tunnel. (quinpristine binds below dalfopristine)

Question 28

Dalfopristin 2 mechanisms

Answer 28

Inhibits peptidyl transferase catalyzed rxn and also changes confirmation of ribosome and facilitatets strong binding of quinipristine, so we get a stable ternary structure of ribosome, dalfopristin , quinipristine structure

Question 29

SYnercid indication

Answer 29

1) Vancomycin resistant enterococcus faecium bacteremia (not effective against faecalis) 2) Skin infection caused by MRSA 3) Vancomycin resistant enterococcus faecium urinary tract infection

Question 30

What is the most common cause of resistance against quinupristin

Answer 30

Adenine 2058 mutation causing methylation, causing steric hinderance of binding of quinipristin Efflux and enzyme inactivation are also common causes

Question 31

For the streptogramin treatment of vancomycin resistant E faecium, What is the cure rate? What is the drug reserved for?

Answer 31

70% cure rate. This drug reserved for serious life threatening infections caused by gram + organisms

Question 32

What will continue to cause more resistant bacterial strains against streptogramins?

Answer 32

The continued use of streptogramins (virginamycin) in animal feeds

Question 33

Side effects of syndercid

Answer 33

No known significant toxicities present several mild side effects like inflammation at site of inj, nausea, diarrhea

Question 34

Drug interactions of streprogramins

Answer 34

They inhibit cytochrome CYP 3A4

Question 35

How are streptogramins cleard? avergae t1/2? BBB/Placenta?

Answer 35

clearence is 75% through biliary excretion (fecal matter), remainder through urine. BBB or placenta not penetrated avg t1/2 is 1.5 hrs

Question 36

How do macrophages react to synercid

Answer 36

They concentrate the drug by up to 50X the extraxellular fluid concentration

Question 37

Explain quinupristin metabolism

Answer 37

Check slide for jan 22 lecture Occurs in human plasma and forms quinupristine glutathione conjugate and quinupristine cysteine conjugate

Question 38

Explain dalfopristine metabolism

Answer 38

Occurs in human plasna Forms pristinamycin IIA and pristinamycin IIA reduction product Dalfopristin also forms hydrolysis product Check Jan 22 notes

Question 39

How do oxazolidinones act

Answer 39

By inhibiting protein synthesis

Question 40

MOA of oxalidinones

Answer 40

Heavy ribosomal subunit (50s) and 30 S chain come to gether and form 70S initiation complex. Linezolid stops this from happening by binding between A site and P site and stopping them from binding, inhibiting formation of initiation complex

Question 41

Therapeutic use of linezolid? Administration?

Answer 41

1) Vancomycin resistant enterococcus faecium 2) Nosocomial pneumonia caused by methacillin resistant strains of staphylococcus aureus 3) Skin infection caused by methicillin resistant strains of staph aureus Linezolid has excellent oral bioavailability and is also available vi IV

Question 42

What is important to not on the use of linezolid

Answer 42

To reduce the development of drug resistant bacteria and maintain the effectiveness of linezolid, it should be used to treat or prevent infections that are proven or strongly suspected to be caused by multiple drug resistant gram + bacteria or when patients are allergic to otherwise effective alternatives

Question 43

How does linezolid resistance occur

Answer 43

When there is a change from G to U substitution in the peptidyl transferase center of 23S rRNA at position 2576, reducing affinity for linezolid.

Question 44

side effects of linezolid

Answer 44

Oral candidiasis Tongue discoloration GI nausea, vomiting, diarrhea More serious- thrombocytopenia, GI bleeding and anemia reversible myelosuppression seen neuropathy if used for more than 6 months

Question 45

metabolism of linezolid? Excreted?

Answer 45

metabolized via morpholine ring oxidation. 30% of linezolid is excreted in urine as parent drug. The two major metabolites do not appear to have significant toxicity or antimicrobial activity

Question 46

Describe bioavailability and t1/2 of linezolid

Answer 46

100% bioavailable after oral administration and a t1/2 of 4-6 hrs

Question 47

What are some drug interactions of linezolid

Answer 47

Does not interact with CYP450 It is a potent reversible non selective inhibitor of monoamine oxidase. SO it may interact with adrenergic and serotonergic agents.

Question 48

Who should linezolid be used in caution in? What should patients not consume large quantities of when taking linezolid?

Answer 48

On pateints who are sensitive to increases in BP due to preexisting conditions. Patients taking linezolid should not consume large quantities of foods, beverages containing tyramine (cheese and wine)

Question 49

What is a second generation oxazolidinone? Use?Compare potency and MOA against linezolid?

Answer 49

Tedizolid phosphate (it is a prodrug that is activated by plasma phosphatases) Used for treatment of acute bacterial skin and skin structure infections It is more potent than linezolid vs MRSA Same MOA as linezolid