Exam 2 Flashcards
Strategies to overcome B-lactamase hydrolysis
Preparation of B-lactamase ta
2
- Preparation of B-lactamase stable penicillins, cephalosporins, carbapenems,
- Combination therapy with B-lactamase inhibitor
Amox vs Amp
Available form?
Gi absorb?
Dosing frequency?
Effect of food?
Activity against Pen resistant staph?
Salmonella activity?
Activity against shigella?
SEs?
Advantages of B-lactams?
4 things
Concerns of B lactams?
Clinical applications
MDM test
First gen oral
2
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 ___
Enzymatic Hydrolytic products of Penicillins
What are the two products and what enzymes are involved in them?
Ampicillin and Amox structures
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?
Avibactam
Novel
Inhibitor of serine B-lactamase in what way?
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
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) ____
Natural Penicillins
Oral one that is considered more stable?
What Spectrum does this have?
Resistance?
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?
Allergic Rxns in decreasing frequency
10
9) Anaphylaxis - Hitamine release from mast cells
10) Angioedema
Amox + Clav
Clav is known as?
What does the spectrum now include?
7
SHEN HPK
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 ___
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?
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?
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?
Mechanisms for cell wall cross linking and termination of cross-linking by PBPs
Path A
Path B
Penicillin G
Stability in acid?
Hydrolyzed by?
Spectrum?
Oral vs. IV dose?
Elimination where?
Coadmin with what does what?
Amp and Sul
What type of inhibitor?
What enhances reactivity?
only use for what form
PPL test
Info
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
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
- Cefotaxime
- Ceftazidime
- Ceftriaxone
- Cefixime
- Cefdinir
- Cefpodoxime proxetil
- Ceftibuten
- 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
- Carbenicillin indanyl
- Piperacillin
- Ticarcillin
- Pip + Tazobactam
- 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?
