Exam 1 lecture 4 Flashcards
What are cephamycins? Name a cephamycin drug? spectrum of activity? Why? What does it release? B lactamase susceptibility?
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
What does cefotetan release
It releases N-methylthiotetrazole, which causes hypoprothrombinemia and also causes a rxn to ethanol that is similar to disulfuram.
What type of drug is imipenem? What is it derived from? What is the difference between imipenem and thienamycin?
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
Explain the relationship between carbapenems and penicillin
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
How does imipenem interact with B lactamases
Besides reacting with penicillin binding proteins, imipenem reacts with and inhibits B lactamases
How is imipenem hydrolyzed? How can it be overcome?
by renal dehydropeptidase-, but this can be overcome by co administration of the dehydropeptidase-1 inhibitor cilastatin
What type of spectrum activity does imipenem with cilastin have? What is imipenems B lactamase activity?
broad spectrum. (due to polarity, polar molecules are broad spectrum)
Imipenem is a good B lactamase inducer
How is imipenem-cilastin sodium administered
Parenterally
Name a type of monobactam? Natural or synthetic?
Aztreonam disodium.
It is totally synthetic but was inpired by monobactams
structural difference between monobactams and other penicillins/cephalosporins? What bacteria does it normally treat?
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
Are monobactams B lactamase sensitive or resistant? Is there cross allergenicity? What is the main advantage
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.
What are the two glycopeptide antibiotics that are used?
Vancomycin and teicoplanin
What type of cell wall does vancomycin inhibit
Cell + cell wall biosynthesis
MOA of vancomycin
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
Spectrum of activity of vancomcin? Why?
Gram positive bacteria, no activity against gram negative because it is reeally big to get through porin
Why is vancomycin important
It is the last line of defence in hospital acquired multi drug resistant staphylococcal and streptococcal infections
Why was avoparcin banned
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
What is the mechanism of resistant that causes VRE (Vancomycin resistant enterococcal infection)
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
How is vancomycin administered? How is it eliminated?
Administered IV, (Orally to treat C. diff if is not responsive to metronidazole)
90% eliminated by glomerular filtration.
What is vanc used to treat
Methicillin resistant staphylococcus aureus
Toxicity and side effects of vancomycin
hypersensitivity reaction causing Skin rash and potential anaphylaxis
Nephrotoxicity and ototoxicity
Name a lipoglycopeptide antibiotic? MOA? spectrum of activity?
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)
What are the different half lives of vancomycin, telavancin, dalbavancin and oritavancin
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
What are the two streptogramins? DIfference? WHat is their combination called? WHat is it derived from?
Quinupristin (larger)- derived from pristinamycin I a
Dalfopristin- derived from pristinamycin II a
Synercid is combination of the two
For quinupristin, dalfopristine and synercid, are they bacteriostatic? Bactericidal? How is synercid administered?
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.
Dalfopristin MOA
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
Quinpristin MOA? (Where does it bind the ribosome in comparison to dalfopristine)
Quinpristin binds in the ribosomal tunnel and causes blockage of the tunnel. (quinpristine binds below dalfopristine)
Dalfopristin 2 mechanisms
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
SYnercid indication
1) Vancomycin resistant enterococcus faecium bacteremia (not effective against faecalis)
2) Skin infection caused by MRSA
3) Vancomycin resistant enterococcus faecium urinary tract infection
What is the most common cause of resistance against quinupristin
Adenine 2058 mutation causing methylation, causing steric hinderance of binding of quinipristin
Efflux and enzyme inactivation are also common causes
For the streptogramin treatment of vancomycin resistant E faecium, What is the cure rate? What is the drug reserved for?
70% cure rate.
This drug reserved for serious life threatening infections caused by gram + organisms
What will continue to cause more resistant bacterial strains against streptogramins?
The continued use of streptogramins (virginamycin) in animal feeds
Side effects of syndercid
No known significant toxicities present
several mild side effects like inflammation at site of inj, nausea, diarrhea
Drug interactions of streprogramins
They inhibit cytochrome CYP 3A4
How are streptogramins cleard? avergae t1/2? BBB/Placenta?
clearence is 75% through biliary excretion (fecal matter), remainder through urine.
BBB or placenta not penetrated
avg t1/2 is 1.5 hrs
How do macrophages react to synercid
They concentrate the drug by up to 50X the extraxellular fluid concentration
Explain quinupristin metabolism
Check slide for jan 22 lecture
Occurs in human plasma and forms quinupristine glutathione conjugate and quinupristine cysteine conjugate
Explain dalfopristine metabolism
Occurs in human plasna
Forms pristinamycin IIA and pristinamycin IIA reduction product
Dalfopristin also forms hydrolysis product
Check Jan 22 notes
How do oxazolidinones act
By inhibiting protein synthesis
MOA of oxalidinones
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
Therapeutic use of linezolid? Administration?
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
What is important to not on the use of linezolid
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
How does linezolid resistance occur
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.
side effects of linezolid
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
metabolism of linezolid? Excreted?
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
Describe bioavailability and t1/2 of linezolid
100% bioavailable after oral administration and a t1/2 of 4-6 hrs
What are some drug interactions of linezolid
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.
Who should linezolid be used in caution in? What should patients not consume large quantities of when taking linezolid?
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)
What is a second generation oxazolidinone? Use?Compare potency and MOA against linezolid?
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
