Beta Lactams (MC) - Block 1 Flashcards
1
Q
What is the difference between bacteriacidal and bacterostatic?
A
Bacteriocidal: death of the bacteria
Bacteriostatic: Inhibits bacterial machinery
2
Q
Types of bacteriocides (cell wall synthesis inhibitors)?
A
- B-lactam
- Glycopeptides
3
Q
Types of bacteristatics (protein synthesis inhibitors)?
A
- Aminoglycosides
- Tetracyclines
- Macrolides
4
Q
Types of metabolism inhibiotors?
A
Sulfamethoxazole and Trimethoprim
5
Q
Types of DNA synthesis inhibitors?
A
Quinolones
6
Q
Types of RNA synthesis inhibitors?
A
Rifampin
7
Q
What is the target of b-lactams?
A
Peptidoglycan layers
8
Q
Describe the the construction of PG layers?
A
- Alternating NAG and NAM subunits linked by 1-4 b glycosidic bonds
- Linked on NAM is a tetrapeptidee (L-Ala, D-Glu, L-Lys, D-Ala
- Monomer is crosslinked by peptaglycyl on Lys, and D-Ala
9
Q
What is the problem in isolating penicillin?
A
- Unstable to base and acid
- Unstable in solution at room temp over time
10
Q
What happens to penicillin in the presence of a weak acid?
A
Inactivates due to the formation of penillic acid
11
Q
What happens to penicillin in the presence of a weak base?
A
Inactivates do to the diconstruction of b-lactam
12
Q
Describe the stability of b-lactam ring system?
A
Highly strained -> unstable
*thiazolidine ring increases instability
13
Q
All penicillin analogues are derived from ____?
A
6-APA scaffold
14
Q
Describe the SAR of penicillin
A
- Sulfer on 5-6 membered ring is typical but not required
- COOH is reuired for binding
- Beta lactam is required for MOA
- R group affects bioavailability, stability, activity of amide and beta-lactam
- Amide is required for binding
- Cis conformation is required
- Ring strain determine reactivity
15
Q
If the beta-lactam is structurally unstable how does the molecule compensate for the strain?
A
Folded butterfly conformation
16
Q
How do we stabilize b-lactam in the presence of acid changes?
A
R groups need to be electron withdrawing to stabilize drug and prevent ring from opeing
17
Q
What are the types of penicillin classifications?
A
- Penicillins (normal)
- Antistaphylococcal penicillins (Methicillin - MRSA)
- Extended spectrum penicillins (ampicillin, amoxicillin - aminopenicillin)
18
Q
Characteristics of Normal penicillin?
A
Susceptible to b-lactamase hydrolysis
19
Q
Characteristics of Antistaphylococcal penicillins?
A
Resistant to staph b-lactamase
20
Q
Characteristics of extended spec penicillins?
A
- Susceptible to b-lactamase hydrolysis
- Improved G- coverage
21
Q
Describe the MOA of PG crosslinking?
A
- PG strand A binds to trans peptidase active site via D-Ala D-Ala bond on NAM
- PBP active site serine attacks D-Ala D-Ala bond
- Terminal D-Ala unit leaves Strand A
- Stand B bind when NH2 of DAP attacks Strand A and PBP bond
- Strand A and B crosslink while PBP leaves
22
Q
Describe the MOA of penicillin?
A
- Penicillin mimics D-Ala D-Ala motif and PBP binds to it
- Active site serine on PBP (transpeptidase) attacks B-lactam bond
- Penicillin is suicide inhibitor (irreversibly binds) -> poping the b-lactam ring open
* Thiazolidinone ring can’t leave and block nucleophile attacks
23
Q
What are the PBP categories?
A
High molecular mass (HMM) PBPs
Low molecular mass (LMM) PBPs
24
Q
What is the HMM PBPs?
A
Broken down in CLass A and B enzymes:
Class A: bifunction - catalyzing the polymerization of NAG-NAM chains and cross links adjacent peptides
Class B: monofunctional - catalyzing the transpeptidase
25
What is the function of LMM PBPs?
**Class C:** regulates the degree of PG reticulation and cell separation
26
What are the PBPs responsible for house keeping?
1a, 1c, 3
27
What is the function of PBP2a? What encodes it?
Responsible foe methicillin resistance and encoded by mecA gene
28
What is the mechanism of methicillin resistance?
Altered target PBP to where it doesn't bind to b-lactams
29
How do you interpret IC50 score?
Increased IC50 -> Requires a higher concentration of drug to eliminate 50% of bugs
30
What are the factors that contribute to penicillin resistance?
1. Changes in the cell wall structure that decreases cellular uptake
2. Emergence of new penicillin binding proteins that are resistant to inactivation (e.g. MRSA)
3. Production of penicillin acylase which hydrolyzes the 6-acyl group (e.g. decreased efficacy of ABX)
4. Production of b-lactamase that hydrolyzes b-lactam ring on certain ABX deeming them inactive
31
What type of bacteria have a natural resistance to penicillin?
Gram- bacilli
32
What are the Amble classes?
B - lead to death -> III
AD -> II
C -> I
33
What is b-lactamase?
Most clinically important form of R-factor mediated resistance to b0lactam ABX
34
What is penicillinase?
Produced by s. aureuss, Haemophilus, and E. coli that have narrow substrate speicifity from TEM1, TEM2, SHV1
35
What are ESBLs?
Hydrolyze extended-spectrum cephalosporins with an oxyimino side chain from TEM1, TEM2, SHV1
36
What drug class in resistant to both b-lactamases and cephalosporinases?
Carbapenems
37
What enzymes hydrolyze carbapenems?
Amp B: metallo-b-lactamases
Amp C: carbapenemases
38
Describe the mechanism of b-lactamases?
39
What is the only b-lactam indicated for MRSA and MSSR?
Cefteraline
40
What contributes to the allergenicity of penicillin
b-lactam carbonyl reacts with nucleophiles in the host's proteins providing a hapten
* Antibodies recognize haptens as foreign protein illiciting an allergic reaction
41
What are the types of natural penicillins?
Penicillin G
Penicillin V
42
What are the types of antistaph penicillins?
1. Semisynthetic: infections caused by b-lactamase producing staph
2. Isoxazolyl (oxacillin, cloxacillin, dicloxacillin): mild to mod localized staph
* Acid stabile
* Food interferes with absorption
43
How do you treat serious systemic staph infections?
Oxacillin or nafcillin
44
Describe the efficacy of extended spectrum penicillins?
Greater G- activity -> more permeability due to the charged amine
* Drug can enter porin channels
Still can be inactivated by b-lactamases
45
What aminopenicillins has the best oral bioavailability?
Amoxicillin
46
What are extended spectrum penicillins used to treat?
UTIs associated with S. pneumoniae, Haemophilus, Moraxella, Staph (non MRSA)
47
What penicillin class are more resident to b-lactamase?
Penicillinase-resistant penicillins:
1. Methicillin
2. Oxacillin
3. Nafcillin
4. Cloxacillin
5. Dicloxacillin
48
Why are penicillins combined with b-lactamase inhibitors?
Amoxicillin, ampicillin, ticarcillin, piperacillin have no resistance to b-lactamase
49
Compare the effectiveness of Penicillin G and V?
G has poor F do to bad EWG, V has better F
50
What contributes to the resistance of methicillin?
Methyl group provides steric hinderance from b-lactamase attack
51
What ABX are slightly better than methicillin?
Oxacillin (X =Y =H)
Cloxacillin (X = H Y = Cl)
Dicloxacillin (X = Y = Cl)
* Better EWG
* Methyl provides steric hinderance
52
What are the types of aminopenicillins?
Ampicillin and Amoxicillin
53
What are classes of penicillins?
1. Natural
2. Penicillinase Resistant penicillins
3. Aminopenicillins
4. Caboxypenicillins
5. Ureidopenicillins
6. Penicillins plus ß-Lactamase Inhibitors
54
Describe the mechanism of aminopenicillins?
NH2 becomes charged in order to facilitate G- entry
* Amoxicillin has a better PK
* Class is formulated with b-lactamase inhibitors due to the lack of b-lactamse resistant and SPACE/ESKAPE coverage
55
What are the types of ureidopenicillins?
1. Azlocillin
2. Mezlocillin
3. Piperacillin
56
Describe the activity of ureidopenicillins?
Active against select G- bacilli (e.g. Klebsiella pneumoniae)
57
What are the carboxypenicillins?
1. Carbenicillin
2. Ticarcillin
58
What are the clincial uses for ureidopenicillins?
Nosocomial pneumonia, empiric coverage in febrile neutropenic host
59
What the clinical use for augmentin?
Upper and lower respiartory infection
60
What are the clincal uses for ticarcillin and clavulanate?
Intra abdominal infections
61
How do cephalosporins differ from penicillins?
1. 6 membered ring provides more stability and less strain on b-lactam compared to penicillins
2. substitution of the 7-acyl side chain
62
What are the precursors of cephalosporins? Which one has better activity?
1. 7-amino cephalosporanic acid (7-ACA): has a easily removable leaving group
2. 7-amino-3-deacetoxycephalosporanic acid (7-ADCA)
63
Describe the stability of cephalosporins
1. The C8-N1 amide bond is sensitive to alkaline and strong acids
2. Solutions cause the C8-N1 bond to deactivate the ABX
64
What are the common usages for cephalosporins?
1. Gram+ (1st gen) and G- (3rd/4th gen)
2. Better at overcoming Ampler AD, not C
65
ADR of cephalosporins?
Allergies, diarrhea
66
Are cephalosporins resistant to b-lactamase?
More resistant, but some lactamases do have selectivity to cephalosporins
67
Describe the metabolism of cephalosporins?
1. 3-acetoxymethyl is cleaved by esterases
2. Hydroxyl metabolite due to the poor leaving group and molecule's transformation by intramolecular cyclization to lactone
68
Describe the activity of 1st ceph?
Predominantly G- aerobes (pneu, strep, staph), limited G- aerobes
69
What is the serious ADR associated Cephs
Toxicity from MTT (Methylthiotetrazole) side chain can increase risk for bleeding (hypothrombinemia) and antabuse rx therefore used for infections above the diaphragm
* Low cross allerginicity with penicillin
* Common SE: rash
70
Types of 1st gen cephs?
1. Cephalothin
2. Cefazolin (Ancef)
3. Cephalexin (Keflex)
4. Cefadroxil
70
Describe the activity of 1st gen ceph?
Primarily active against G+
71
Which 1st gen ceph is subject to esterase hydrolysis?
Cephalothin
72
How does Keflex and Cefadroxil different from one another?
**Keflex:** ceph version of ampicillin
**Cefadroxil:** ceph version of amoxicillin
73
Describe the activity of 2nd gen cephs?
Good activity against G+ and G- bacteria
74
Types of 2nd gen cephs?
1. Cefuroxime IV
2. Cefuroxime Axetil (Ceftin) PO
3. Cefoxitin
4. Cefprozil
5. Cefotetan
75
Describe the structure and indications associated with cefuroxime?
1. Methonine (good leave group and resistant to esterases)
2. Treats CAP from b-lactamase
76
Describe the structure of cefoxitin
Cephamycin (7-OCh3) provides more resistance to b-lactamases
77
Which 2nd gen ceph contains MTT side chain?
Cefotetan
78
What is the common structure associated with 3rd gen ceph? Why are each components improtatme?
ATMO: aminothiazolyl methoxine
**AT:** good G- penetration
**MO:** good resistance to ambler AD b-lactamases
79
What are the types of 3rd gen ceph?
1. Cefotaxime (Calforan)
2. Cefetamet
3. Cefixime (Suprax)
4. Cefdinir (Omnicef)
5. Ceftazidime
6. Ceftibuten
7. Ceftriaxone
80
Why is Omnicef used so often in a clinical setting?
Good coverage for:
1. S. pneumoniae
2. M. catarrhalis
3. H. influenzae
* Effective for CAP, sinusitis, otitis caused by the 3 bacterias
81
How does Ceftazidine differ from other 3rd gens?
Excellent G- activity against P. aeruginosa
* Weaker G+ activity
* Dimethyl carboxylate and permanent + charge enhances PA activity
82
3rd gen ceph that is used for bacterial meningitis?
Ceftriaxone due to CNS penetration
83
What stucture on a drug is more selective towards Pseudomonas?
dimethyl carboxylate
84
Describe the activity of 4th gen cephs?
extremely good activity against gram-(-) and gram-(+) bacteria
85
What gives 4th and 5th gens better activity?
Quaternary nitrogen -> zwitterion -> bactericidal activity by penetration through the porin channels in the outer G- membrane
86
What are the types of 4th gens?
1. Cefepime
2. Cefoselis
3. Ceftolazone
87
Which 4th gen ceph is good against Pseudomonas? Why?
Ceftolozane has a dimethl carboxylate
88
5th gen cephs?
1. Ceftaroline (no coverage against pseudomonas or VRE)
2. Ceftobiprole
89
Describe the activity of 5th gen cephs?
Broad coverage that includes both gram + and – organisms
90
What are the types of carbapenems? Activity?
1. Thienamycin
2. Imipenem
3. Meropenem
4. Ertapenem
* Not effective against E. faecium, C. diff, MRSA
91
Desribe the formulation of imipenem?
Substrate for renal dehydropeptidase (gets inactivated in the kidneys -> low urinary content) and must be combined with cilastatin (inhibitor of dihydropeptidase)
92
Why are carbapenems good for UTIs?
All get renally cleared
93
Describe the bacteriocidal activity of carbapenems?
Time dependant killing
94
Activity of carbapenems?
Severe Gram +ve and Gram –ve infections (good distribution and CSF)
95
How does meropenem and ertaoenem differ from other carbapenems?
2-methyl on the core prevents metabolism by renal dehydropeptidase -> doesn't require cilastatin
96
What is the difference between meropenem and ertapenem?
**Meropenem:** gorilla-cillin due to Acinetobacter, Pseudomonas, Enterococcus activity
**Ertapenem:** monkey-cillin, not as good
97
What drug is known as the trojan horse?
Cefiderocol (Fetroja)
98
What are the types of monobactams? Activity?
Aztreonam (Azactam)
* G- infections
* No G+ or anaerobic activity
* PA activity due to dimethyl carboxylase
* Retains acidic functional group
99
What beta-lactamase inhibitors are effective against Class A?
Tazobactam, clavulanate, sulbactam
100
What beta-lactamase inhibitors are good against Class A, C, D?
Avibactam, vaborbactam, relebactam
101
Why are there no b-lactamase inhibitors against Class B?
1. Class B beta-lactamases cleave beta-lactams by a mechanism similar to that of metalloprotease
2. No covalent intermediate is formed, the mechanism of action of marketed beta-lactamase inhibitors does not work
102
Most active against Ambler class A β-lactamases?
Clavulanic acid: plasmid encoded transposable element b-lactamases
103
What bacteria are not affected by clavulanic?
**SPACE:** Serratia, Pseudomonas or Proteus, Acinetobacter, Citrobacter, and Enterobacter
* Because they are chromosomally encoded and inducible
104
Describe the irreversible nature of b-lactamase inhibitors?
105
ABX in combo with clavulanate?
Amoxicillin and ticarcillin
106
ABX in combo with Sulbatam?
Ampicillin
107
ABX in combo with tazobactam?
Piperacillin, Ceftolozane
108
What b-lactamase inhibitors are used for complicated UTIs?
1. Avibactam
2. Relebactam
3. Vaborbactam
