Exam 2 Flashcards by Jon Beckloff

Strategies to overcome B-lactamase hydrolysis

Preparation of B-lactamase ta

Preparation of B-lactamase stable penicillins, cephalosporins, carbapenems,
Combination therapy with B-lactamase inhibitor

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Amox vs Amp

Available form?

Gi absorb?

Dosing frequency?

Effect of food?

Activity against Pen resistant staph?

Salmonella activity?

Activity against shigella?

SEs?

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Advantages of B-lactams?

4 things

Concerns of B lactams?

Clinical applications

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MDM test

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First gen oral

Cephalexin or Cefadroxil

Amoxicillin like side chain ____

Non-activating C-3 subsituent making it less potent but is more metabolically stable ____

Very popular drug ___

Rapidly and completely absorbed in the GI tract ____

Long T1/2 prolonged duration of action, related to slow urinary excretion qDay dosing ___

Useful against gram (-) UTI, Gram (+) infections of soft tissue, pharyngitis, minor wounds ___

Antibacterial actiivty similar to cephalexin ___

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Enzymatic Hydrolytic products of Penicillins

What are the two products and what enzymes are involved in them?

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Ampicillin and Amox structures

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Metabolic Deactivations Via? At what carbon position and what enzymes? What is formed once deactivated?

Double bond isomerization leads to? These have similar conformations but?

Which carbon ester tends to form double isomers?

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Avibactam

Novel

Inhibitor of serine B-lactamase in what way?

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Cross allergies to penicillins?

Which meds are the most likely to have cross allergy?

Which ones are least?

Ocassionally with?

Usually with other penicillins
Ocassionally with cephs (5-8%)
Imipenem (most) likely
Aztrenam least likely

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Second gen oral

Ampicillin-like side C-7 side chain. Additionally, a chlorine (Cl) substituent at C-3 position. Increased acid stability. 95% of oral dose absorbed. Stable to metabolism ______

Prodrug of Cefuroxime. A more lipophilic drug. The prodrug moiety is cleaved metabolically and the free drug is absorbed in the blood stream._____

Particularly often used against acute otitis media, also upper and lower respiratory tract, Skin, UTI ____

Enhanced activity against H. Influenza (however, not active against ampicillin resistant H. influenza) _____

Enhanced absorption of this oral drug, when adminis- tered with food ! The tablets can be dispersed in apple juice without loss of activity. ____

Well tolerated drug. Few side effects: GI (2.6%), rashes (1.5%), but serum-sickness-like illness in children frequent (Symptoms: rashes, arthritis, fever) ____

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Natural Penicillins

Oral one that is considered more stable?

What Spectrum does this have?

Resistance?

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Ceftolozane/ Tazobactam

Only available in what combination?

Broad spectrum against? Highly potent activity against?

Lacks activity against?

Highly stable against? Including?

What forms?

Indicated for tx of patients of what age what is this due to?

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Allergic Rxns in decreasing frequency

9) Anaphylaxis - Hitamine release from mast cells
10) Angioedema

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Amox + Clav

Clav is known as?

What does the spectrum now include?

SHEN HPK

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3rd gen oral

Syn-oxime ether at C-7 replaced with a cis-ethylidene carboxylic acid; No side-chain at C-3 ____

Prodrug, cleaved enzymatically to release cefpodoxim (active drug), acetaldehyde, CO2, and isopropanol. An ether side-chain at C-3 ____

Oral bioavailability 75 - 90%, but decreased by food ___

Oral bioavailability of active drug ~ 50%. Absorption enhanced by food, but reduced by antacids ____

Activity similar to cefixime. Resistant to β-Lactamases ___

Better activity against S. aureus than cefixime ___

Acute otitis media; Pharyngitis; Acute bacterial exacerbations of chronic bronchitis _____

UTI; Pharyngitis; Upper and lower respiratory tract infections; Otitis media; Skin and soft tissue infections; Gonorrhea ___

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Carbapenems

Thienamycin

Structural feature:

The sulfur atom in the ring is replaced by?

Double bond where?

___ containing sidechain at?

trans carbons?

C-6 different than?

Spectrum of Thienamycin?

Resistanct to? Also an inhibitor of?

Why cant this be used?

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Carbenicillin Indanyl Sodium

Prodrug of?

Stable in?

Oral absorption

What happens with high doses?

Cant treat?

What reduces the risk of Electrolyte abnormalities?

Useful for?

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B-lactamase resistant penicillins?

2 of them

What are the 4 points about Isoxazolyls? What type of compound? No activity against?

These are the drug of choice for?

Indication is only for?

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Mechanisms for cell wall cross linking and termination of cross-linking by PBPs

Path A

Path B

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Penicillin G

Stability in acid?

Hydrolyzed by?

Spectrum?

Oral vs. IV dose?

Elimination where?

Coadmin with what does what?

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Amp and Sul

What type of inhibitor?

What enhances reactivity?

only use for what form

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PPL test

Info

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Penicillin Binding Proteins

Usually?

S. Aureus has how many? E coli.?

The PBPs vary in?

Lethal effect of antibacterial is due to?

Several PBPs, S. Aureus- 4, E. Coli-5
PBPs vary in their affinity for different B-lactam antibiotics
Lethal due to binding

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MOA of Penicillins

* Irreversibly inhibits PBP enzymes responsible for processing the development of peptidoglycan layer of bacterial cell wall

Bacterial resistanct to B-lactam How common is it? What are the four basic mechanisms for development of resistance? What is the major cause for resistance though? What do the enzymes do? What are the 2 types of B-lactamases? What contains?

Contains Zinc

Degradation Rxns of Cephs

First Generation Cephs Spectrum wise are similar to? But they are more stable to? Good activity against? Modest activity against? Good Alternative to ____ pens? But they arent good for what type of infection? Most commonly used drug for surgerical? Spectrum of activity? 7 things to know, what is it not active against? First gen ceph examples Parenteral agents 2 Oral agents? 2

Cephalosporin SAR? What is essential? C-4 ___ required for? Modifications at ___ and ___ cause changes in what things?

Penicillin Allergy Slide

Pen G repository forms two kinds What route only? What are the uses for each?

P. Aeruginosa? Increasingly? Why? Diminished? Loss or Modified?

* Increased resistance to B-lactams * Permeability of the Outer membrane bu B-lactams is abou t100-500 fold less than for E. Coli * Diminished Penetration through hydrophilic porins * Porins

Cefoxitin Na Belons to what sub class? Characterized by what substituent at the C-7? Increased ____ increased stability against? What group increases metabolic stability? Increased actiivty to many ___ in the GI tract Uses?

Clinically significant Cephs 4th and MRSA Cephs

* Cefepime * Ceftaroline, Ceftalozone (Combo with Tazo)

Cefuroxime Contains a ____ ether in what carbon position? This increases the stability towards? What is the reason for this? What type of ether is not effective? What type of group at C-3 causes? Antibacterial activitu similar to? With additional acitivty to ampicillin resistant? Penetrates the? This makes it effective for the treatment of? But it isnt the?

Comparison of Pens 16 Acid stability Stable to B lactamase Spectrum With food? Special Toxicities?

Instability of B-lactams to nucleophiles What is formed?

Clinically significant Cephs 3rd 8

1. Cefotaxime 2. Ceftazidime 3. Ceftriaxone 4. Cefixime 5. Cefdinir 6. Cefpodoxime proxetil 7. Ceftibuten 8. Cefditoren pivoxil

Meropenem C-4 sub? What does this prevent? No need for co admin of? C3 side chain? Improved acitivty against? Spectrum? Uses? SEs?

Aztreonam Disodium Synewrgistic with? uses? affinity for\> Only active against?

Bactericidal Action of B-lactams The overall pathway

The newest member of the 3rd oral generation In vivo enzymatic hydrolysis releases the active drug meaning this is? A novel substituent at C-3 Activity is comparable to what 2 other drugs? Indicated for? Not indicated for children under? Special toxicities? What pts cant take this?

PBPs of E. Coli anf their functions PBP1a/1b PBP-2 PBP-3 PBP4,5,6

Second Gen oral Contains an amoxicillin like side-chain at C-7, while at C-3 there is now a 1-propenyl group conjugated with the double bond inside the six-membered ring. Both cis- and trans- forms of this side-chain are active. \_\_\_\_ Uses : Otitis media; Bronchitis; Pharyngitis; Skin and skin-structure infections etc. \_\_\_\_\_ Not active against MRSA, Enterobacter, Serratia, Proteus, Pseudomonas, B. fragilis \_\_\_\_ About 90% bioavailable following oral administration\_\_\_

Ceftriaxone disodium Activity similar to? Longest ___ among the cephalosporins due to? A ____ dose is effective in the tx of? Other uses? SEs?

Other B-lactam anti twp classes of compounds

Carbapenems and Monobactams

Aminopenicillins What isomer is more active? What type of compounds? better action against? Why is this? What provides acid stability? Not stable to? To the window

SAR of Pens 3 points

Extended Spectrum Pens First pen with activity against? What makes the compound hydrophillic? Oral availability? Decarb in?

Aminopenicillins 2 of them Spectrum? Stable in? What forms? Not stable to?

Ertrapenem Form? Longest ___ among the carbapenems Spectrum similar to meropenem but doesnt cover? Stable to?

Gene Locations for B-lactamases The information for the production of B-lactamases is encoded in Chromosomes or Plasmids Chromosomes? Plasmids? Transduction? Conjugation? transposition? Transformation?

Extended spectrum Pens 5 including combinations

1. Carbenicillin indanyl 2. Piperacillin 3. Ticarcillin 4. Pip + Tazobactam 5. Ticarcillin + Clavulanate

First gen parenteral Cephs The first ceph drug? Spectrum is similar to? Stable to? And is a substitute for methicillin and dicloxacillin Metabolic Hydrolysis at what carbon? May enhance ____ toxicity of AGs What type of injection is painful? Which one is preferred?

What are the 4 major structural subclasses of B-lactams? What is their common MOA? Potent and Rapid? However development of what is a major concern?

Metallo lactamase is special because of? What are the 2 roles of this during hydrolysis?

Carb Disodium Spectrum? Uses? Combo? Not to be given with? SEs?

Cannot be coadministered with AGs must wait

Mechanism of B-lactamase inhibition

Reason for NMTT Mediated SEs?

3rd gen parenterals Metabolically vulnerable acetoxy group at C-3 \_\_\_ A charged pyridinium group at C-3 increases activity of the β-lactam carbonyl.\_\_\_\_\_ Highly water-soluble (zwitter ionic)\_\_\_\_\_\_ polar aminothiazole ring increases Gram - activity\_\_\_\_ syn-Oxime ether moiety conveys β-lactamase resistance \_\_\_ Meningitis; Many serious infections (including nosocomial) , _____ + ampicillin is a combination of choice for the empiric therapy of neonatal and infant meningitis \_\_\_\_\_ Most active cephalosporin against P. aeruginosa (also better than antipseudomonal penicillins). Used in combination with an aminoglycoside in penicillin allergic patients \_\_\_\_ Pseudomonas UTI; Nosocomial pneumonia; Cystic fibrosis pulmonary infections; Meningitis\_\_\_\_\_

4th generation ceph Characterized by enhanced activity to? Broader fram (\_) activity\> Increased stability against what type of mediated B-lactamases? Primarily used for the empiric treatments of? What type of agent is it? Broad spectrum against? Including? Due to ___ it has good cell wall penetration \_\_\_ stable low affinity for? Not active against? Uses?

Monobactam

Amox uses? What combo has been approved for H. Pylori? Ampicillin?

Cephalosporins What family of antibiotic? All of the drugs in this class are of what origin? Exhibited resistance to? But are what compared to Pen-G? Modifications at what position leads to more active compounds? MOA similar to? Rarelt drug of? Broader or comparable intrinsic activity to? Often ____ than the comparing penicillins? More resistant to? How does resistance go from generations? Cidal or Static for what types of bacteria? SEs and Allergies compared to pens. Shouldnt be used with what patients?

Gram Positive vs. Gram Negative What is generally present in gram negatives that make it difficult for drugs to get in?

Porins

Extended Spectrum Pens Antipseudomonal Acidic Pens 3 Contain? Spectrum? Susceptible to?

3rd generation Frame shift towards anti gram (\_) away from? Less active against? But are much more active against gram (\_) than either 1/2 gen Spectrum now includes? Enhanced ____ stability? Longer \_\_\_. Good what penetrations? Drug of Choice for? Disadvantages? Parenteral 3 Oral? 5

Clinically significant Cephs 1st gen 3

Cefazolin, Cephalexin, Cefadroxil

Where do penicillins cause cell wall destruction? What indirect effect do they have? What are the portions of the cell wall? What cross linkes them together? PBP binds to?

D-ala-Dala

Combo Pen and B-lactamase inhibitors? B-Lactam inhibitors block the breakdown of aminopenicillins by? B-lact inhibitors are only? What are the 3 in clinical use?

Ceftotetan Disodium Belongs to what subclass? Contains what group at the C-3 This drug has special affinity to? These things make it stable to many? and it is also a? More effective than cefazolin against? Surgical? Chemically incompatable with what 3 drugs? what forms with one of them? Special SEs?

Fifth gen ceph What gives these activity with MRSA? Broad spectrum activity against including? Not active against? In vivo hydrolysis generates? Approved for the treatment of? Most common adverse Rxns? What is another 5th gen?

Classifications of B-lactamases? Ambler classifications A-D based on?

Forms of Pen G What is the preferred formulation? What form is a repository? What form is inactivated?

Ambler classifications Substrate Affinity and Selected Examples

Infection overview

Allergy testing Skin tests Useful only for? What needs to be present? What are the 2 tests?

Pip + Tazo Spectrum? Uses?

Bacterial resistance Current Problem Areas? What gram (-) organisms are still a problem?

First generation Parenteral cephs Cefazolin Acetyl side chain at C-3 replaced by? What is the importance of this change? Drug of Choice for? 3 Broader gram (\_) activity than? Higher ___ and longer \_\_\_\_ Good penetration where? what forms? Not stable to? Least stable of the?

Semisynthesis of Cephs What was improved?

2nd Gen cephs Spectrum of activity Retained activity of ___ gen cephs with increased activity against? H. \_\_\_\_\_\_, N. \_\_\_\_\_ \_\_\_\_- positive proteus like? Stool bacteria? Low? Some strains of? Increased ____ stability in comparison to ____ gen? Not useful in what type of infections? Parenteral 4 Oral 3

Comparison of Potency between Pen and cephs

Classification, Resistance, Mechanism and Other general features of cephs How many generations? These are based on? Similar to Penicillins, resistance to cephs is usually due to what of 3 things? Cephalosporins are secreted primarily through the? Dose adjustments should be made in what pts?

Structural features and Nomenclature of Cephs What is the difference between the rings of pens vs. cephs

Degradation of penicillin in acid involves what carbon and what side chain?

Aminopencillins Spectrum? Gram (+) - Gram (-) What are they not affective against?

WHO drug resistance

What can be used in combination with Imipenem to make it safer? What effecr? What are its uses? SEs?

Doripenem form? Stable to? Increased stability against? among the penems most potent against? Faropenem- Indevelopment good against anaerobes

B-lactam Clincally useful spectra

Ticarcillin Bioisostere of? Not stable in? usually what form? half life? Ticar + Clav? uses?

Untoward Rxns to Penicillins In general direct toxicity of Penicillins is? Most common SE? Caused by? Spontaneous? AS a general rule children are more or less likely ro have an allergic rxn? IV or Oral less likely?

Structural Featurs of Penicillins 4 points

Nafcillin Resitant to? Spectrum? Can be taken in what form? What is recommended Special toxicities? 4 Not be used in?

Clinically significant Cephs 2nd gen 4 2nd gen cephamycins 2

Cefuroxime, Cefuroxime axetil, Cefaclor, Cefprozil Cefoxitin, Cefotetan

Imipene Analog of? What increase chemical stability? What was fixed compared to thienamycin? Spectrum: Important! High degree of stability against? Inhibitor of? Not active in what form? What enzyme causes hydrolysis when used in UTIs?

Activity of B-lactams is Dependent on?

* Ability to penetrate wall * Ability to bind to PBP * Sensitivity to beta-lactamases/amidase * Concentration of antibiotic * Presence of aoutlysin-inhibitor complex * Presence of Efflux systems, and other factors

B-lactamase Resistant Pens What prevents attack of penicillinase? Methicillin What are less tolerant to seric hinderance then PBPs? Oral Stability? Resistance? And why? SEs?

Piperacillin Derivative of? What makes it hydrophillic? Longer c6? Not active against? Important for serious Gram (\_) infections Uses? oral? Stability?

Isoxazolyl Penicillins Oral agents 4 Replacement of Phenyl with? Stable to? Primarily used against ____ producing what? Stability in? Adequate? Also available in? Inferior? Most active one? Which one can act as a B-lactamase inhibitor? Not active against? Special toxicities with the drugs?

3rd gen oral Modified syn-oxime ether at C-7; Vinyl group at C-3. Oral bioavailability 40 - 50% \_\_\_\_ Complexes with iron. Food rich in iron / iron supplements reduces absorption (reddish stools possible!) \_\_\_\_\_ Resistant to many β-lactamases of Gram- bacteria (better than second generation drugs) \_\_\_ Fatty foods and antacids diminishes blood level. \_\_\_\_ Poor activity against Staph. aureus \_\_\_ • Acute exacerbation of chronic bronchitis • Sinusitis, pharyngitis, tonsillitis, otitis media • Uncomplicated skin and skin structure infections \_\_\_ Otitis media; Pharyngitis or Tnsillitis; Bronchitis Uncomplicated UTI; Uncomplicated gonorrhea \_\_\_\_ 20 - 25% Absorbed on oral administration. \_\_\_\_ An unsubstituted syn-oxime at C-7 side chain; Vinyl group at C-3 \_\_\_\_

PPSA drugs 3

* Nafcillin * Oxacillin * Dicloxacillin

Which B-lactam is the most potent? Why is this the case? What does that mean for the safety of the drug? In general what type of antibiotics are less potent than the traditional 4-5 rings Which B-lactam is the least potent? What does that mean with safety?

* Carbapenems most potent, most side effects most strained * Cephs are in general less potent than B-lactams * Monobactam is the least potent, it is the safest, least strained and least SEs

Mechanism of transpeptidase Cross-linking and Inhibition by the Pens? What portion of the transpeptidase binds to Pen initially? Attraction via what other portion? Cool feature? There is an ester link why isnt it degraded quickly?

Ester linkage is so much stronger due to steric hinderance block water from entering the active site DOPE!!

Drug interaction between B-lactam antibiotics and? What does this lead to?

New generation of B-lactamase inhibitors 2 Spectrum?