EXAM 3- AUSTIN

What is the essential pharmacophore of beta-lactam antibiotics? Describe each component.

• LACTAM group with BETA cyclization

  • lactam group= cyclic amide functional group

  • beta position is 2nd carbon= refers to position of cyclization

Which image picture is the pharmacophore of beta-lactams?

How does the reactivity of amides in vivo compare to b-lactams?

• amides—> pretty stable

• b-lactams—> aka non-cyclic amides—> more reactive

  • bc of angle/torsional strain

What are the 4 important derivatives of b-lactams?

• penicillin

• cephalosporin

• carbapenem

• monobactam

Which of the following describes b-lactams?

a. time-dependent

b. conc-dependent

c. AUC:MIC

a

Which of the following describes b-lactams?

a. bacteriostatic

b. bactericidal

b

What is the overall MOA of b-lactams?

• how do they bind? (hydrogen bonds, intermolecular, covalent?)

• reversible? irreversible?

• why is the target of b-lactams ideal?

• MOA: bind COVALENTLY to penicillin binding proteins (PBPs) also called transpeptidases (TPs)

  • IRREVERSIBLE inhibition

• why are transpeptidases ideal? UNIQUE to bacteria, accessible, and essential for bacteria

What process of cell wall synthesis do b-lactams target?

a. NAG-NAM monomer synthesis

b. polymerization

c. cross-linking

c

Describe in detail, the mechanism of how beta-lactams inhibit the cell walls of bacteria. (idk how important, sorry lot of words)

1. SIMILARITY—>Beta-lactam abx have a shape that closely resembles a part of the bacterial cell wall (specifically, the D−ala−D−ala) during the process of building the cell wall.

2. “ENZYME MISTAKE”- the enzyme responsible for building the cell wall (TPs/PBPs) mistakes the B-lactam for the D-ala-D-ala part and so the TPs/PBPs bind to the b-lactam at its active site instead

3. “ENZYME ATTACK”- The enzyme's (TPs/PBPS) active site has a serine group that attacks and opens the beta-lactam ring, forming a strong covalent bond between the enzyme and the antibiotic.

4. “ENZYME INACTIVATION”- This bond creates a STERIC barrier that prevents the enzyme (TPs/PBPS) from functioning properly. result: the bacteria can't build a strong cell wall—> cell wall defects—> bacterial death

For the mechanism of beta-lactams, what acts as the electrophile and nucleophile?

electrophile- DRUG

nucleophile- enzyme (PBPs/TPs)

Which beta-lactam abx are active again all Gram + and - bacteria?

NONE

It’s easier for beta-lactams to target G+ bacteria… why?

in G- the abx has to get through porins

What enzyme breaks down b-lactams?

b-lactamase

There is 1 exception, but IN GENERAL… what bacteria are b-lactams inactive against?

• MRSA/VRSA

• atypicals

What are the most common ADRs of penicillins?

(NOTE: OVERALL considered generally safe class)

• GI (n/v/d)

  • POTENTIALLY—> pseudomembranous colitis

  • bc incomplete oral absorption disrupts normal GI bacteria (broader spectrum= more GI)

• hypersensitivity

  • hydrolysis by nucleophilic proteins

• neurotoxicity (confusion, dizzy, seizures)

  • typically at high doses of lipophilic ones

• renal

  • interstitial nephritis

  • electrolyte disturbances

What makes the β-lactam ring in penicillins highly reactive? Why is high reactivity a problem?

• Angle and torsional strain

  • results in decreased resonance

• HIGH REACTIVITY= DECREASES stability

  • easily cleaved/inactivated by nucleophiles like water

What is the pharmacophore of PENICILLINS?

THINK: PENICILLIN= PENT = 5 RING

How can the challenges of penicillins be addressed? What are the 4 ways?

MODIFY THE R GROUPPPPPPP!!!!!

• add an electroneg to R group

• add an amine to R group

• add a large, bulky R group

• add a hydrophilic/ionizable R group

What’s the result of adding an electronegative atom to the R group of a penicillin?

e- withdrawing effect by induction = increases acid stability= able to give oral

What’s the result of adding an amine to the R group of penicillins? Example?

• ENHANCES SPECTRUM= BROAD SPECTRUM (G-)

  • how? ENHANCES PORIN PENETRATION!!!

• ex: AMINOPENICILLINS

Addition of an amine to the R group of penicillins also fixes what other challenge/problem with penicillins?

acid stability/oral admin—> bc amine group is also electroneg

IN GENERAL: How do lipophilic and hydrophilic groups affect penicillin activity?

• lipophilic- shift towards G+ activity

• hydrophilic- shift towards G- activity

What’s the result of adding a large, bulky R group to penicillins? Why must we be careful with the type of group we add?

• helps protect from b-lactamase enzyme degradation

• balance—> too large of a group and the drug loses ability to bind to PBPs

  • we also might lose acid stability and might not be able to give oral

What is considered a “large” R group on a penicillin?

• PAY ATTENTION

≥ 1 ortho-poly-substituted aromatic ring (either ≥2 substituents or attached to a second ring)

• basically that means the R group has the 2 groups in the ortho position (like the pic shown)

  • or would have 2 rings

What’s the result of adding hydrophilic/ionizable R groups to penicillins?

• EXTENDS THE SPECTRUM!!!!!

  • NOW WE COVER PSEUDOMONAS

  • hydrophilic groups, with peptide like characteristics facilitate PORIN penetration and decrease efflux pump affinity

  • kind of like adding an amine, but even more porin penetration= extended spectrum

A problem to consider with adding a hydrophilic/ionizable R group to penicillins is what?

not resistant to b-lactamases (remember bulky R groups that are lipophilic vs. hydrophilic)

What are 2 examples of hydrophilic/ionizable R groups added to penecillins?

• urea derivatives—> “ureidopenicillins”

• carboxylate derivatives—> “carboxypenicillins”

What penicillins are “natural penicillins”?

(austin said to know the bolded ones)

• penicillin G

• penicillin V

What penicillins are “amino-penicillins”?

(austin said to know the bolded ones)

• ampicillin

• amoxicillin

What penicillins are “anti-staphylococcal”?

(austin said to know the bolded ones)

• methicillin

• oxacillin

• nafcillin

• dicloxacillin

What penicillins are “anti-pseudomonal”?

(austin said to know the bolded ones)

• carbenicillin

• piperacillin

• ticarcillin

What penicillins have a narrow, broad, and extended spectrum?

narrow- natural and anti-staph penicillins

broad- aminopenicillins

extended- anti-pseudomonal pencillins

Why are B-lactamase inhibitors highly effective?

Is the binding reversible/irreversible?

What are some examples?

Why do we co-administer these with some penicillins?

• effective bc LOW K_off values (aka means that these inhibitors bind to b-lactamase and don’t let go)

• IRREVERSIBLE binding—> suicide inhibitors

• examples: clavulanate, sulbactam, tazobactam

• co-administer with some penicillins that are susceptible to b-lactamase

  • DO NOT GIVE ALONE!!

What are 3 resistance mechanisms for penicillins?

• G- bacteria in general

  • have porins and pumps/enzymes

  • few penicillins are effective towards these bacteria despite modifications

• modified PBPs

  • bacteria modify the PBP so penicillins can’t bind

• penicillinases/b-lactamases

  • these enzymes cleave/break the lactam ring of penicillins= loss of activity

    • DOES THIS BY HYDROLYSIS

Why with MRSA does a penicillin + b-lactamase combination still not work?

bc the issue with MRSA is binding to the active site (modified PBP), not b-lactamase breaking the abx down…

• why would we add a b-lactamase inhibitor when that’s not our issue here

What are some examples of penicillin + b-lactamase inhibitor combinations? (I don’t think that important)

• aminopenicillins + b-lactamase inhibitor

  • amoxicillin + clavulanate (Augmentin)

  • ampicillin + sulbactam (Unasyn)

• extended spectrum + b-lactamase inhibitor

  • piperacillin + tazobactam (Zosyn)

  • ticarcillin + clavulanate (Timentin)

What are the general pharmacokinetic properties of all penicillins?

• short t ½

• mostly renal elimination

• hydrophobic penicillin are highly protein bound

Anti-staph penicillins are inducers of ______________.

CYP3A4

It varies by disease state, but in general natural penicillins have what PK considerations?

• incomplete absorption—> best on empty stomach

• variable BBB penetration

What drug combo can be employed to clinically increase b-lactam levels? How does this work?

• PROBENACID + b-lactams

• probenacid works by inhibiting OAT transporters and b-lactams use this transporter to get out the body

What happens when warfarin is combined with antibiotics? Why is this so?

• INCREASED BLEEDING RISK!!!!!!!!

• why?

  • warfarin antagonizes the action of vit K

  • antibiotics destroy normal gut flora that produce vitamin K

  • together= both decrease vit K = increase bleeding risk

What is the only antibiotic proven to decrease oral contraceptive efficacy?

rifampin (use backup method)

What is the interaction between antibiotics and oral contraceptives? results?

• OC is metabolized by CYP3A4 and conjugation

• abx induce 3A4

• results: decrease concentrations of estrogens

PRACTICE:

True or false: no penicillins are active against MRSA.

TRUE

In general, as you increase cephalosporin generation you increase what?

G- activity

Be able to identify the pharmacophore of cephalosporins. What is the name of the 6 membered ring in its pharmacophore?

dihydrothiazine

How does the chemistry of cephalosporins compared to penicillins?

• cephalosporins—> less angle/torsional strain and an ADDITIONAL reaction (has 2 R groups we can modify)

What’s the result of adding an electronegative atom to the R2 group of cephalosporins?

• similar to penicillins

• e- withdrawing effect by induction = increases acid stability= able to give oral

What’s the result of have a more reactive group at the R1 of cephalosporins?

decreases stability—> parenteral admin only

What’s the result of adding an oxime to the R2 group of cephalosporins?

• enhances stability to b-lactamase

RECOGNIZE AN OXIME

Even with an oxime to enhance stability to b-lactamases, cephalosporins are still all inactivated by…

ESBL (extended-spectrum B-lactamase)

What’s the result of adding a methoxy group on position Z/carbon of the pharmacophore of cephalosporins? What are these drugs referred to as?

• enhances spectrum—> includes ANAEROBES

• also increase b-lactamase stability

• CALLED CEPHAMYCINS

RECOGNIZE A METHOXY GROUP ON A CEPHALOSPORIN

What’s the result of adding a large, aminothiazole to the R2 group of cephalosporins?

• enhances G- activity

What are the ONLY 2 cephalosporins with pseudomonas activity?

• SAID TEST QUESTION!!!!!

• ceftazidime

• cefepime

List the names of the cephalosporins in each class:

• 1st gen

• 2nd gen

• 3rd gen

• 4th gen

• 5th gen/ newer abx

(these are the ones austin wants us to know)

• 1st gen- cefazolin, cephalexin

• 2nd gen- cefuroxime, cefotetan

• 3rd gen- ceftriaxone, cefdinir, ceftaxidime

• 4th gen- cefepime

• 5th gen/ newer abx- ceftaroline, caftolozane

What is the coverage of each of the following cephalosporins:

• 1st gen

• 2nd gen

• 3rd gen

  • which agent has anti-pseudomonal coverage?

(remember the generalization as you increase gens)

• 1st gen- aerobic G+, few G-

  • MSSA, streptococci, limited Enterobacteriaceae

• 2nd gen- less G+ than 1st gen, more G-

  • true cephalosporins

    • G- like Haemophilus, Neisseria, limited Enterobacteriaceae

  • cephamycins

    • ANAEROBES!!!!!!!!!!!!!!

• 3rd gen- low G+, BROAD G- coverage

  • ceftazidime—> ONLY 3rd GEN ANTI-PSEUDOMONAL

What is the coverage of each of the following cephalosporins:

• 4th gen

• 5th gen/ newer cephalosporins

• 4th gen—> broadest spectrum of G+ and G-

  • MSSA, strep, enteric G-, P. aeruginosa

• 5th gen

  • Ceftaroline—> ACTIVATE AGAINST MRSA/VRSA

  • Ceftolozane—> ACTIVE AGAINST PSEUDOMONAS

Avycaz is a combination of what 2 antibiotics? What does this combination protect against that is unique?

• Avycaz= ceftazidime + Avibactam

  • AVIBACTAM IS A NON B-LACTAM CONTAINING B-LACTAMASE INHIBITOR

• protects ceftazidime against ESBL’s, KPCs, and AmpC

Which cephalosporin is one of the few beta-lactams with no renal adjustments?

Ceftriaxone (3rd gen)

Why does Cefotetan react with alcohol?

• Cefotetan has an MTT side chain

• when co-administered with alcohol this can form a dimer that inhibits the enzyme aldehyde dehydrogenase.

  • This enzyme is responsible for breaking down acetaldehyde (a metabolite of alcohol)

• if we can’t break down the acetaldehyde—> it builds up and causes disulfiram like reaction!!!

Cefepime (a 4th gen ceph) is a combo of what two cephalosporins?

cefazolin + ceftazidime

Common ADRs of cephalosporins?

• like penicillins

• GI

• hypersensitivity

• renal

Resistance mechanisms of cephalosporins?

• like pencillins

• G- porins/efflux pumps

• modified PBPs

• b-lactamases

What is the name of the 1 abx in the monobactam class?

Aztreonam

How does the pharmacophore of monobactams/aztreonam compare to other beta-lactams? What unique groups does it have?

(be able to recognize the pharmacophore)

• MONOBACTAM= mono= 1 ring

• has a SULFAMIC ACID GROUP—> strong electron-withdrawing

What’s the coverage of monobactams/Aztreonam?

• significant G-

  • INCLUDING PSEUDOMONAS

  • no anaerobes

  • no G+

What groups on Aztreonam protect from b-lactamases and help with porin penetration?

• methyl group= helps protect from b-lactamase

• ring= porin penetration

Aztreonam is safe to use in what kind of allergy? What is the exception?

• IMPORTANT

• safe to use in penicillin/cephalosporin allergy

  • no cross reactivity

• 1 EXCEPTION—> CEFTAZIDIME

Why can’t Ceftazidime and Aztreonam be given together if a patient has a penicillin/cephalosporin allergy?

• both SHARE a side chain

List some examples of Carbapenems:

• Doripenem

• Ertapenem

• Imipenem

What’s the coverage/spectrum of Carbapenems?

• “ULTRA BROAD SPECTRUM”

  • G+ and -

  • anaerobes

  • pseudomonas

    • except ertapenem

Because of it’s ultra broad spectrum, carbapenems have an increased risk of…

C. diff/ CDI

ADRs of carbapenems?

• like other b-lactams

• GI

• hypersensitivity

• neurotoxic—> highest seizure rates

MOAs of resistance to carbapenems?

• like other b-lactams but less

• modified PBPs (like PBP2a, PBP5)

• G- and porins (like OprD)

• MDR—> efflux pumps

Are any carbapenems active against MRSA?

no

recognize the pharmacophore of carbapenems.

What’s unique compared to other b-lactams?

• unique

  • TRANS stereochemistry

  • severe angle/torsional strain

  • most reactive lactam

What might carbapenems be co-administered with do reduce hydrolysis?

cilastatin

What R1 group can be added to carbapenems to reduce hydrolysis?

methyl group on C4

For carbapenems with anti-pseudomonal activity what is the most potent group that can be placed on the structure?

sulfamide

What drug interaction exists with carbapenems?

What does that do to the seizure threshold?

• carbapenems + valproic acid

  • AVOID COMBO

• lowers seizure threshold

Answer the following about Vancomycin:

• MOA

• oral route is only for what?

• what happens in renal impairment?

• _________ dependent

• bactericidal/static?

• ADRs

• doesn’t cover what kind of bacteria?

• MOA—> cell wall inhibitor (binds to D-ala-D-ala) blocks elongation and cross linking

• oral route only for C.diff

• half-life is prolonged in renal impairment

• AUC:MIC dependent

• bacteriacidal

• ADRs- nephrotoxicity, ototoxicity, red man syndrome

• no G- coverage

Answer the following about Telavancin:

• what type of peptide?

• bactericidal/static?

• _________ dependent

• MOA?

• ADRs

• BBW

• glycopeptide

• bactericidal

• concentration dependent

• MOA like vanco—> cell wall inhibitor (binds to D-ala-D-ala) blocks elongation and cross linking

• ADRs: nephrotoxicity, QT prolongation

• BBW—> MODERATE to severe renal impairment

Answer the following about Dalbavancin:

• what type of peptide?

• MOA

• half-life

• lipoglycopeptide

• MOA like vanco—> cell wall inhibitor (binds to D-ala-D-ala) blocks elongation and cross linking

• LONG HALF LIFE

Answer the following about Oritavancin:

• what kind of peptide?

• MOA

• lipoglycopeptide

• MOA like vanco cell wall inhibitor (binds to D-ala-D-ala) blocks elongation and cross linking

  • PLUS RNA SYNTHESIS INHIBITION

Answer the following about Bacitracin:

• what kind of peptide?

• MOA

• bactericidal/static?

• route of admin

• cyclic peptide mixture

• cell wall inhibitor

• bactericidal

• TOPICAL ONLY

Answer the following about Fosfomycin:

• MOA

• bactericidal/static?

• coverage?

• MOA

  • Inhibits enzyme UDP-N-acetylglucosamine-3-enolpyruvytransferase (MurA)

  • Binds to cysteine residue of active site and blocks addition of phosphoenolpyruvate to UDP-N-acetylglucosamine

  • BASICALLY BLOCKS NAG/NAM MONOMER SYNTHESIS!!!!

• bactericidal

• mostly G-

Answer the following about Daptomycin:

• what kind of peptide?

• bactericidal/static?

• MOA

  • depends on what?

• ___________ dependent

• administration

• cyclic lipopeptide

• bactericidal

• MOA

  • binds to inner membrane of bacteria, cause depolarization, membrane potential is lost= cell death

  • CALCIUM DEPENDENT

• concentration dependent

• ONLY IV

Answer the following about Polymyxin:

• what kind of peptide?

• bactericidal/static?

• ADRS

• cyclic polypeptide

• bactericidal

• ADRs—> nephrotoxicity, neurotoxicity