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Drug Action IV > Beta Lactams (MC) - Block 1 > Flashcards

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

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2
Q

Types of bacteriocides (cell wall synthesis inhibitors)?

A
  1. B-lactam
  2. Glycopeptides
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3
Q

Types of bacteristatics (protein synthesis inhibitors)?

A
  1. Aminoglycosides
  2. Tetracyclines
  3. Macrolides
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4
Q

Types of metabolism inhibiotors?

A

Sulfamethoxazole and Trimethoprim

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5
Q

Types of DNA synthesis inhibitors?

A

Quinolones

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6
Q

Types of RNA synthesis inhibitors?

A

Rifampin

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7
Q

What is the target of b-lactams?

A

Peptidoglycan layers

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8
Q

Describe the the construction of PG layers?

A
  1. Alternating NAG and NAM subunits linked by 1-4 b glycosidic bonds
  2. Linked on NAM is a tetrapeptidee (L-Ala, D-Glu, L-Lys, D-Ala
  3. Monomer is crosslinked by peptaglycyl on Lys, and D-Ala
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9
Q

What is the problem in isolating penicillin?

A
  1. Unstable to base and acid
  2. Unstable in solution at room temp over time
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10
Q

What happens to penicillin in the presence of a weak acid?

A

Inactivates due to the formation of penillic acid

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11
Q

What happens to penicillin in the presence of a weak base?

A

Inactivates do to the diconstruction of b-lactam

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12
Q

Describe the stability of b-lactam ring system?

A

Highly strained -> unstable
*thiazolidine ring increases instability

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13
Q

All penicillin analogues are derived from ____?

A

6-APA scaffold

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14
Q

Describe the SAR of penicillin

A
  1. Sulfer on 5-6 membered ring is typical but not required
  2. COOH is reuired for binding
  3. Beta lactam is required for MOA
  4. R group affects bioavailability, stability, activity of amide and beta-lactam
  5. Amide is required for binding
  6. Cis conformation is required
  7. Ring strain determine reactivity
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15
Q

If the beta-lactam is structurally unstable how does the molecule compensate for the strain?

A

Folded butterfly conformation

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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

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17
Q

What are the types of penicillin classifications?

A
  1. Penicillins (normal)
  2. Antistaphylococcal penicillins (Methicillin - MRSA)
  3. Extended spectrum penicillins (ampicillin, amoxicillin - aminopenicillin)
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18
Q

Characteristics of Normal penicillin?

A

Susceptible to b-lactamase hydrolysis

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19
Q

Characteristics of Antistaphylococcal penicillins?

A

Resistant to staph b-lactamase

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20
Q

Characteristics of extended spec penicillins?

A
  • Susceptible to b-lactamase hydrolysis
  • Improved G- coverage
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21
Q

Describe the MOA of PG crosslinking?

A
  1. PG strand A binds to trans peptidase active site via D-Ala D-Ala bond on NAM
  2. PBP active site serine attacks D-Ala D-Ala bond
  3. Terminal D-Ala unit leaves Strand A
  4. Stand B bind when NH2 of DAP attacks Strand A and PBP bond
  5. Strand A and B crosslink while PBP leaves
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22
Q

Describe the MOA of penicillin?

A
  1. Penicillin mimics D-Ala D-Ala motif and PBP binds to it
  2. Active site serine on PBP (transpeptidase) attacks B-lactam bond
  3. Penicillin is suicide inhibitor (irreversibly binds) -> poping the b-lactam ring open
    * Thiazolidinone ring can’t leave and block nucleophile attacks
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23
Q

What are the PBP categories?

A

High molecular mass (HMM) PBPs
Low molecular mass (LMM) PBPs

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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

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25
Q

What is the function of LMM PBPs?

A

Class C: regulates the degree of PG reticulation and cell separation

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26
Q

What are the PBPs responsible for house keeping?

A

1a, 1c, 3

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27
Q

What is the function of PBP2a? What encodes it?

A

Responsible foe methicillin resistance and encoded by mecA gene

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28
Q

What is the mechanism of methicillin resistance?

A

Altered target PBP to where it doesn’t bind to b-lactams

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29
Q

How do you interpret IC50 score?

A

Increased IC50 -> Requires a higher concentration of drug to eliminate 50% of bugs

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30
Q

What are the factors that contribute to penicillin resistance?

A
  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
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31
Q

What type of bacteria have a natural resistance to penicillin?

A

Gram- bacilli

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32
Q

What are the Amble classes?

A

B - lead to death -> III
AD -> II
C -> I

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33
Q

What is b-lactamase?

A

Most clinically important form of R-factor mediated resistance to b0lactam ABX

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34
Q

What is penicillinase?

A

Produced by s. aureuss, Haemophilus, and E. coli that have narrow substrate speicifity from TEM1, TEM2, SHV1

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35
Q

What are ESBLs?

A

Hydrolyze extended-spectrum cephalosporins with an oxyimino side chain from TEM1, TEM2, SHV1

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36
Q

What drug class in resistant to both b-lactamases and cephalosporinases?

A

Carbapenems

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37
Q

What enzymes hydrolyze carbapenems?

A

Amp B: metallo-b-lactamases
Amp C: carbapenemases

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38
Q

Describe the mechanism of b-lactamases?

A
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39
Q

What is the only b-lactam indicated for MRSA and MSSR?

A

Cefteraline

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40
Q

What contributes to the allergenicity of penicillin

A

b-lactam carbonyl reacts with nucleophiles in the host’s proteins providing a hapten
* Antibodies recognize haptens as foreign protein illiciting an allergic reaction

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41
Q

What are the types of natural penicillins?

A

Penicillin G
Penicillin V

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42
Q

What are the types of antistaph penicillins?

A
  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
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43
Q

How do you treat serious systemic staph infections?

A

Oxacillin or nafcillin

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44
Q

Describe the efficacy of extended spectrum penicillins?

A

Greater G- activity -> more permeability due to the charged amine
* Drug can enter porin channels

Still can be inactivated by b-lactamases

45
Q

What aminopenicillins has the best oral bioavailability?

A

Amoxicillin

46
Q

What are extended spectrum penicillins used to treat?

A

UTIs associated with S. pneumoniae, Haemophilus, Moraxella, Staph (non MRSA)

47
Q

What penicillin class are more resident to b-lactamase?

A

Penicillinase-resistant penicillins:
1. Methicillin
2. Oxacillin
3. Nafcillin
4. Cloxacillin
5. Dicloxacillin

48
Q

Why are penicillins combined with b-lactamase inhibitors?

A

Amoxicillin, ampicillin, ticarcillin, piperacillin have no resistance to b-lactamase

49
Q

Compare the effectiveness of Penicillin G and V?

A

G has poor F do to bad EWG, V has better F

50
Q

What contributes to the resistance of methicillin?

A

Methyl group provides steric hinderance from b-lactamase attack

51
Q

What ABX are slightly better than methicillin?

A

Oxacillin (X =Y =H)
Cloxacillin (X = H Y = Cl)
Dicloxacillin (X = Y = Cl)

  • Better EWG
  • Methyl provides steric hinderance
52
Q

What are the types of aminopenicillins?

A

Ampicillin and Amoxicillin

53
Q

What are classes of penicillins?

A
  1. Natural
  2. Penicillinase Resistant penicillins
  3. Aminopenicillins
  4. Caboxypenicillins
  5. Ureidopenicillins
  6. Penicillins plus ß-Lactamase Inhibitors
54
Q

Describe the mechanism of aminopenicillins?

A

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
Q

What are the types of ureidopenicillins?

A
  1. Azlocillin
  2. Mezlocillin
  3. Piperacillin
56
Q

Describe the activity of ureidopenicillins?

A

Active against select G- bacilli (e.g. Klebsiella pneumoniae)

57
Q

What are the carboxypenicillins?

A
  1. Carbenicillin
  2. Ticarcillin
58
Q

What are the clincial uses for ureidopenicillins?

A

Nosocomial pneumonia, empiric coverage in febrile neutropenic host

59
Q

What the clinical use for augmentin?

A

Upper and lower respiartory infection

60
Q

What are the clincal uses for ticarcillin and clavulanate?

A

Intra abdominal infections

61
Q

How do cephalosporins differ from penicillins?

A
  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
Q

What are the precursors of cephalosporins? Which one has better activity?

A
  1. 7-amino cephalosporanic acid (7-ACA): has a easily removable leaving group
  2. 7-amino-3-deacetoxycephalosporanic acid (7-ADCA)
63
Q

Describe the stability of cephalosporins

A
  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
Q

What are the common usages for cephalosporins?

A
  1. Gram+ (1st gen) and G- (3rd/4th gen)
  2. Better at overcoming Ampler AD, not C
65
Q

ADR of cephalosporins?

A

Allergies, diarrhea

66
Q

Are cephalosporins resistant to b-lactamase?

A

More resistant, but some lactamases do have selectivity to cephalosporins

67
Q

Describe the metabolism of cephalosporins?

A
  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
Q

Describe the activity of 1st ceph?

A

Predominantly G- aerobes (pneu, strep, staph), limited G- aerobes

69
Q

What is the serious ADR associated Cephs

A

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
Q

Types of 1st gen cephs?

A
  1. Cephalothin
  2. Cefazolin (Ancef)
  3. Cephalexin (Keflex)
  4. Cefadroxil
70
Q

Describe the activity of 1st gen ceph?

A

Primarily active against G+

71
Q

Which 1st gen ceph is subject to esterase hydrolysis?

A

Cephalothin

72
Q

How does Keflex and Cefadroxil different from one another?

A

Keflex: ceph version of ampicillin
Cefadroxil: ceph version of amoxicillin

73
Q

Describe the activity of 2nd gen cephs?

A

Good activity against G+ and G- bacteria

74
Q

Types of 2nd gen cephs?

A
  1. Cefuroxime IV
  2. Cefuroxime Axetil (Ceftin) PO
  3. Cefoxitin
  4. Cefprozil
  5. Cefotetan
75
Q

Describe the structure and indications associated with cefuroxime?

A
  1. Methonine (good leave group and resistant to esterases)
  2. Treats CAP from b-lactamase
76
Q

Describe the structure of cefoxitin

A

Cephamycin (7-OCh3) provides more resistance to b-lactamases

77
Q

Which 2nd gen ceph contains MTT side chain?

A

Cefotetan

78
Q

What is the common structure associated with 3rd gen ceph? Why are each components improtatme?

A

ATMO: aminothiazolyl methoxine
AT: good G- penetration
MO: good resistance to ambler AD b-lactamases

79
Q

What are the types of 3rd gen ceph?

A
  1. Cefotaxime (Calforan)
  2. Cefetamet
  3. Cefixime (Suprax)
  4. Cefdinir (Omnicef)
  5. Ceftazidime
  6. Ceftibuten
  7. Ceftriaxone
80
Q

Why is Omnicef used so often in a clinical setting?

A

Good coverage for:
1. S. pneumoniae
2. M. catarrhalis
3. H. influenzae

  • Effective for CAP, sinusitis, otitis caused by the 3 bacterias
81
Q

How does Ceftazidine differ from other 3rd gens?

A

Excellent G- activity against P. aeruginosa
* Weaker G+ activity
* Dimethyl carboxylate and permanent + charge enhances PA activity

82
Q

3rd gen ceph that is used for bacterial meningitis?

A

Ceftriaxone due to CNS penetration

83
Q

What stucture on a drug is more selective towards Pseudomonas?

A

dimethyl carboxylate

84
Q

Describe the activity of 4th gen cephs?

A

extremely good activity against gram-(-) and gram-(+) bacteria

85
Q

What gives 4th and 5th gens better activity?

A

Quaternary nitrogen -> zwitterion -> bactericidal activity by penetration through the porin channels in the outer G- membrane

86
Q

What are the types of 4th gens?

A
  1. Cefepime
  2. Cefoselis
  3. Ceftolazone
87
Q

Which 4th gen ceph is good against Pseudomonas? Why?

A

Ceftolozane has a dimethl carboxylate

88
Q

5th gen cephs?

A
  1. Ceftaroline (no coverage against pseudomonas or VRE)
  2. Ceftobiprole
89
Q

Describe the activity of 5th gen cephs?

A

Broad coverage that includes both gram + and – organisms

90
Q

What are the types of carbapenems? Activity?

A
  1. Thienamycin
  2. Imipenem
  3. Meropenem
  4. Ertapenem
  • Not effective against E. faecium, C. diff, MRSA
91
Q

Desribe the formulation of imipenem?

A

Substrate for renal dehydropeptidase (gets inactivated in the kidneys -> low urinary content) and must be combined with cilastatin (inhibitor of dihydropeptidase)

92
Q

Why are carbapenems good for UTIs?

A

All get renally cleared

93
Q

Describe the bacteriocidal activity of carbapenems?

A

Time dependant killing

94
Q

Activity of carbapenems?

A

Severe Gram +ve and Gram –ve infections (good distribution and CSF)

95
Q

How does meropenem and ertaoenem differ from other carbapenems?

A

2-methyl on the core prevents metabolism by renal dehydropeptidase -> doesn’t require cilastatin

96
Q

What is the difference between meropenem and ertapenem?

A

Meropenem: gorilla-cillin due to Acinetobacter, Pseudomonas, Enterococcus activity
Ertapenem: monkey-cillin, not as good

97
Q

What drug is known as the trojan horse?

A

Cefiderocol (Fetroja)

98
Q

What are the types of monobactams? Activity?

A

Aztreonam (Azactam)
* G- infections
* No G+ or anaerobic activity
* PA activity due to dimethyl carboxylase
* Retains acidic functional group

99
Q

What beta-lactamase inhibitors are effective against Class A?

A

Tazobactam, clavulanate, sulbactam

100
Q

What beta-lactamase inhibitors are good against Class A, C, D?

A

Avibactam, vaborbactam, relebactam

101
Q

Why are there no b-lactamase inhibitors against Class B?

A
  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
Q

Most active against Ambler class A β-lactamases?

A

Clavulanic acid: plasmid encoded transposable element b-lactamases

103
Q

What bacteria are not affected by clavulanic?

A

SPACE: Serratia, Pseudomonas or Proteus, Acinetobacter, Citrobacter, and Enterobacter
* Because they are chromosomally encoded and inducible

104
Q

Describe the irreversible nature of b-lactamase inhibitors?

A
105
Q

ABX in combo with clavulanate?

A

Amoxicillin and ticarcillin

106
Q

ABX in combo with Sulbatam?

A

Ampicillin

107
Q

ABX in combo with tazobactam?

A

Piperacillin, Ceftolozane

108
Q

What b-lactamase inhibitors are used for complicated UTIs?

A
  1. Avibactam
  2. Relebactam
  3. Vaborbactam

Drug Action IV (28 decks)

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