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Infectious Disease > Week 1: Cell wall active antibiotics > Flashcards

Week 1: Cell wall active antibiotics Flashcards

1
Q

Cell-wall active antibiotics class

A

Beta-Lactams

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2
Q

Groups of Beta-lactams

A
  • Penicillins
  • Cephalosporins
  • Beta-lactam/Beta-lactamase inhibitors
  • Carbapenems
  • Monobactams
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3
Q

Penicillins

A
  • Penicillin
  • Nafcillin
  • Ampicllin
  • Amoxicillin
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4
Q

Cephalosporins

8 listed

A
  • Cefazolin
  • Cephalexin
  • Cefoxitin
  • Cefotetan
  • Cefuroxime
  • Cetriaxone
  • Cefepime
  • Ceftaroline
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5
Q

Beta-lactam/Beta-lactamase inhibitors

3 listed pairs

A
  • Ampicillin/sulbactam
  • Amoxicillin/clavulanic acid
  • Piperacillin/tazobactam
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6
Q

Carbapenems

A
  • Ertapenem
  • Imipenem
  • Meropenem
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7
Q

Monobactams

A

Aztreonam

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8
Q

Cell Wall Active Antibiotics

A
  • Vancomycin
  • Daptomycin
  • Colistin
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9
Q

Describe the mechanism of Bacterial cell wall synthesis Staphylococcus aureus

A
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10
Q

Bacterial cell wall synthesis

A
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11
Q

Bacterial cell wall synthesis and transpeptidase

A
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12
Q

Bacterial Cell Wall Synthesis cross linking

A
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13
Q

Describe Transpeptidase inhibitor by penicillin

A
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14
Q

Describe transpeptidase inhibition by penicillin

A
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15
Q

Penicillins MOA

A

Covalently bind PBPs (eg bacterial transpeptidase)

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16
Q

Cephalosporins MOA

A

Covalently bind PBPs (eg bacterial transpeptidase)

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17
Q

What is required for bactericidal effect of penicillins and cephalosporins

A

Bacterial autolysins are required for bactericidal effect

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18
Q

What is required for bactericidal effect of penicillins and cephalosporins?

A
  • Bacterial autolysins are required for a bactericidal effect
  • Time-dependent killing (need to spend 40-70% dosing interval above MIC (Minimum Inhibitory Concentration) in severe infections
  • MOA, resistance by β-lactamase and allergies all relate to the β-lactam ring
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19
Q

Describe time-dependent killing

A
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20
Q

Describe the β-lactam Antibiotics activity

A
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21
Q

Describe the pharmacokinetic properties of β-Lactams

A
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22
Q

Describe the Absorption of β-lactams

A
  • Different formulations for oral vs IV administration
  • Limited oral absorption
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23
Q

Describe the distribution of β-lactams

A
  • Short half-life (t1/2) so frequent dosing or extended infusion used
  • PCN t1/2 ~ 0.5-1 hours
  • Cephalosporins ~0.6-3 hours
  • Distribution can be limited: Pen 50% of TBW
  • Therapeutic concentrations in CNS (penicillins, 3rd and 4th generation cephalosporins, carbapenems) often with increased dosing
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24
Q

Half-life of penicillins

A

t1/2 ~ 0.5-1 hours

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25
Q

Cephalosporins half-life

A

t1/2 ~ 0.6-3 hours

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26
Q

Describe the distribution of Penicillin

A

Pen G 50% of TBW

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27
Q

Describe β-lactam Metabolism/Excretion

A
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28
Q

How/Where are β-lactams metabolized

A
  • Primarily renal but also hepatic, so may require dose adjustment in liver or renal dysfinction
  • Organic acids are eliminated by renal tubular secretion
  • Secondary hepatic lysis of β-lactam ring
  • Pharmacokinetics altered in severe infection/disease
  • Cilastatin, decreases renal metabolism of the carbapenem imipenem, used to treat t1/2 and decreased renal toxicity
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29
Q

Describe the effects of β-lactam toxicities

A
  • Allergic reaction
  • Bone marrow suppression
  • Nephrotoxicity
  • Hepatotoxicity
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30
Q

Describe β-lactam allergic reactions

A
  • Range from mild rash to anaphylaxis
  • Penicillin reaction to β-lactam, cephalosporin reaction to side chains so sometimes can tolerate different side chains
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31
Q

Describe β-lactam Bone marrow suppression

A
  • Neutropenia > thrombocytopenia
  • anemia
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32
Q

Describe β-lactam nephrotoxicity

A
  • interstitial nephritis > Acute tubular necrosis
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33
Q

Describe β-lactam hepatotoxicity

A

Cholestatic jaundice > hepatitis

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34
Q

1st generation cephalosporins

A
  • Cefazolin (IV)
  • Cephalexin (po)
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35
Q

2nd generation cephalosporins

A
  • Cefoxitin (IV)
  • Cefotetan (IV)
  • Cefuroxime (po)
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36
Q

3rd generation cephalosporins

A

Ceftriaxone (IV, IM)

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37
Q

4th generation cephalosporins

A

Cefepime

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38
Q

Advanced generation cephalosporins

A

Ceftaroline

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39
Q

Other cell wall active antibiotics other than β-lactams

A
  • Vancomycin
  • Daptomycin
  • Colistin
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40
Q

β-lactam Cross Reactivity

A
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41
Q

Penicillin is cross-reactive with

A

Cefoxitin

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42
Q

Amoxicillin is cross-reactive with?

A
  • Ampicillin
  • Cephalexin
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43
Q

Ampicillin is cross-reactive with?

A
  • Amoxicillin
  • Cephalexin
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44
Q

Cephalexin is cross-reactive with?

A
  • Amoxicillin
  • Ampicillin
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45
Q

Cefuroxime is cross-reactive with?

A
  • cefoxitin
  • Ceftriaxone
  • cefotaxime
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46
Q

Cefoxitin is cross-reactive with?

A
  • Penicillin
  • Cefuroxime
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47
Q

Ceftriaxone is cross-reactive with?

A
  • Cefuroxime
  • Cefotaxime
  • cefepime
  • ceftazidime
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48
Q

Cefotaxime is cross-reactive with?

A
  • Cefuroxime
  • Ceftriaxone
  • Ceftazidime
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49
Q

Cefepime is cross-reactive with?

A
  • Ceftriaxone
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50
Q

Ceftazidime is cross-reactive with?

A
  • Ceftriaxone
  • Cefotaxime
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51
Q

What are β-lactamases

A

enzymes produced by bacteria that degrade β-lactam antibiotics as a mechanism of bacterial resistance

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52
Q

β-lactamases against penicillin

A

Penicillinase by S. aureus: breaks down penicillin

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53
Q

β-lactamases against carbapenems

A

Carbapenamase by Klebsiella pneumoniae (AKA KPC)

Klebsiella pneumoniae Carbapenamase

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54
Q

What is NMD-1

A

Metallo-β-lactamases, eg (New Delhi-1 (NMD-1))

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55
Q

What are some Bacterial Resistance Mechanisms

A
  • β-lactamases
  • Reduced entry
  • Increased efflux
  • Altered penicillin binding protein (Transpeptidase; PBP)
  • Acquisition of novel PBPs via plasmid
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56
Q

Describe Gram positive bacterial cell wall structures

A
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57
Q

Describe gram-negative bacterial cell wall structures

A
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58
Q

Describe structural variation in Penicillin molecules

A
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59
Q

“Natural” Penicillins

A
  • Penicillin G
  • Penicillin V
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60
Q

Describe the spectrum of Penicillin

A

Active against many GPC, less GNR, oral anerobes that do not make Penicillinase

Examples:

  • Strep pyogenes
  • Strep agalactiae
  • Strep viridans
  • Clostridium perfringens
  • Listeria monocytogenes
  • Treponema pallidum
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61
Q

What is the depot preparation of penicillin?

A

Bicillin

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62
Q

What is Bicillin?

A

Depot preparation for single IM injection for long-term therapy with penicillin

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63
Q

Describe the Absorption of Bicillin

A

Low-solubility results in prolonged low but therapeutic levels of PCN for susceptible infections (eg syphilis)

  • Procaine penicillin G is detectable in blood 24 hours
  • Benzathine penicillin G at low levels for 2-3 weeks
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64
Q

Bicillin C-R

A

Contains equal amounts of benzathine and procaine salts of PCN for deep IM injection

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65
Q

Antistaphylococcal penicillins

A

Naficilin

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66
Q

Naficilin spectrum

A
  • Narrow-spectrum, penicillinase-resistant
  • MSSA (Methicillin-sensitive Staph aureus)
  • also covers what penicillin covers
    • S. aureus is tested for oxacillin susceptibility, call it methicillin-sensitive, treat with naficillin
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67
Q

Naficilin resistance

A

S. aureus that carries mecA gene which encodes a resistant PBP

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68
Q

What portion of S. aureus are resistant to methicillin?

A

1/3 of S. aureus isolates at UNMH are resistant to methicillin

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69
Q

Aminopenicillins

A
  • Ampicillin (IV)
  • Amoxicillin (po)
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70
Q

Aminopenicillins spectrum

A

broad-spectrum, penicillinase-resistant

  • GPC, aerobic GNR, some anaerobes
  • Strep pyogenes
  • Strep viridans
  • Enterococcus
  • E. coli
  • H. influenza
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71
Q

Compounds which augment penicillins

A

β-lactamase inhibitors

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72
Q

What are β-lactamase inhibitors

A

Covalent-inhibitors of penicillinase with no Penicillin activity

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73
Q

What are some β-lactamase inhibitors

A
  • Clavulanate
  • Sulbactam
  • tazobactam
  • avibactam
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74
Q

Describe the distribution of β-lactamase inhibitors

A

Large molecules that do not cross the blood-brain barrier

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75
Q

Examples of Penicillins combined with β-lactamase inhibitors with broad specturm of activity

A
  • Amoxicillin/Clavulanate (Augmentin) po
  • Ampicillin/Sulbactam (Unasyn) IV
  • Piperacillin/Tazoactam (Zosyn) IV
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76
Q

(AMpicillin) β-lactam/β-lactamase inhibitor (Sulbactam)

A

β-lactamase inhibitors broadens the spectrum of ampicillin (ie Staph aureus, β-lactamase producing H. influenzae)

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77
Q

Extended-spectrum Anti-Pseudomonal Carboxypenicillins

A

Piperacillin/Tazobactam

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78
Q

Piperacillin/Tazobactam spectrum

A
  • Ampicillin + additional GNR (Pseudomonas) and Anaerobes (Baceroides fragilis)
  • addition of β-lactamase inhibitor adds: Staphylococcus, GNRs with β-lactamase production and Anaerobes
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79
Q

Piperacillin/Tazobactam what does Tazobactam add to the spectrum

A

addition of β-lactamase inhibitor adds: Staphylococcus, GNRs with β-lactamase production and Anaerobes

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80
Q

Why are cephalosporins classified in generations

A

Cephalosporins are classified in generations based on sequence of development and specturm of activity

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81
Q

Cephalosporins spectrum

A
  • Start with excellent GPC coverage, with the exception of Enterococci (intrinsically resistant to cephalosporins)
  • With subsequent generations there is increasing effectiveness against GNRs
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82
Q

Cephalosporins cross-reactivity and toxicity

A

Some cross-reactivity with PCNs so can be allergic to both

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83
Q

1st generations Cephalosporins

A

Cefazolin (IV)

Cephalexin (po)

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84
Q

1st generation cephalosporins spectrum

A
  • GPC
  • Some aerobic GNR
  • Examples: Group A Strep, Group B Strep, Methicillin-sensitive Staph aureus, E. coli, K. pneumonia
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85
Q

1st generation cephalosporins NOT active against

A
  • Enterococci
  • Listeria
  • Anaerobes
86
Q

1st generation cephalosporins distribution limitations

A

Does not cross BBB

87
Q

2nd generation cephalosporins

A
  • Cefotetan (IV)
  • Cefoxitin (IV)
  • Cefuroxime (po)
88
Q

2nd generation cephalosporins spectrum

A
  • Covers more GNR and some aerobes
  • Not as active as 1st gen cephalosporins against GPCs
  • More penicillinase resistant
  • examples
    • E. coli
    • K. pneu
    • Proteus
    • Haemophilis influenza
    • Moraxella catarrhalis
    • B. frag (cefoxitin)
89
Q

3rd generation cephalosporins

A
  • Ceftriaxone (IV)
90
Q

3rd generation cephalosporins spectrum

A
  • GPCs
  • Enterobacteriacea
  • Neisseria
91
Q

3rd generation cephalosporins distribution

A

Good CNS penetration (requires more frequent dosing; q12 hours)

92
Q

4th generation cephalosporins

A
  • Cefepime (IV)
93
Q

4th generation cephalosporins spectrum

A
  • Adds coverage against Pseudomonas
94
Q

Advanced generation cephalosporins

A

Ceftaroline (IV)

95
Q

Advanced generation cephalosporins spectrum

A

Adds coverage against MRSA

(Is the ONLY β-Lactam with activity against MRSA)

96
Q

Which β-lactams have activity against MRSA

A

Ceftaroline is the ONLY β-Lactam with activity against MRSA

97
Q

New cephalosporin combininations

A
98
Q

Spectrum of Carbapenems?

A
  • Broad spectrum against GPCs, GNRs (including Pseudomonas), anaerobes
  • Typically reserved for resistant infections
  • Is penicillinase resistant however, their is emergence of Carbapenem Resistent Enterobacteriaceae
99
Q

Carbapenems

A
100
Q

How to prevent renal toxic metabolites from Carbapenems

A

Imipenem is combined with cilstatin to prevent rapid renal degradation to renal toxic metabolites

101
Q

Ertapenem spectrum

A

no coverage against Enterococcus or Pseudomonas

102
Q

Summary of Penicillins and Cephalosporins

A
103
Q

Monobactams

A

Aztreonam

104
Q

Aztreonam cross-reactivity

A

Not cross-reactive with β-lactams so useful when allergic to PCN if Gram-negative infection

105
Q

Aztreonam spectrum

A
  • Actvity against aerobic GNR ONLY
  • Enterobacteriacea (eg E. coli) and Pseudomonas
  • Penicillinase resistent
  • Activity against NMD1
  • Not cross-reactive with β-lactams so useful when allergic to PCN if Gram-negative infection
106
Q

What is Vancomycin?

A

Glycopeptide

107
Q

What is Vancomycin’s Site of Action

A
108
Q

Vancomycin MOA

A

Glycopeptide binding to D-ala end of the GP cell-wall building block, preventing cross-linking by transglycolases

Unable to penetrate GNs

109
Q

Mechanism of Vancomycin Resistance

A
  • Associated with substituition of another amino acid (D-lactate or D-serine) for the Vancomycin binding site (Terminal D-ala)
  • Increase in cell wall thickness of Staph aureus will increase MIC of Vancomycin without conferring true resistance
110
Q

Vancomycin Pharmacokinetics

A
  • IV
  • Oral not absorbed so only used for treating GI lumen infection with C. diff
  • t1/2 ~ 6 hours
  • eliminated by glomerular filtration
111
Q

Daptomycin half-life

A

t1/2 ~ 8-9 hours

112
Q

Vancomycin metoblism and excretion

A

Vancomycin is eliminated by glomerular filtration

113
Q

Vancomycin Route of administration

A

IV because oral is not absorbed so it is only useful for treating GI lumen infections with C. diff by oral route

114
Q

Vancomycin t1/2

A

t1/2 ~ 6 hours

115
Q

Dosing considerations of Vancomycin

A
  • Requires loading dose to reach steady state fast
  • Therapeutic monitoring of (Steady-state) serum trough concentration after the 3rd or 4th dose
116
Q

What is the AUC:MIC ratio?

A

Area under curve:Minimum inhibitory concentration

117
Q

AUC:MIC ratio of Vancomycin

A

AUC24:MIC >400 correlates with treatment success in Staph aureus

118
Q

Vancomycin Spectrum of Activity

A
  • S. aureus (including MRSA)
  • S. epidermidis
  • Streptococcus spp.
  • Enterococci spp.
  • Corynebacterium
  • Clostridium
119
Q

Vancomycin Toxicities

A
  • Nephrotoxicity
  • Concern about nephrotoxic effect of combiniation Pip/Tazo and vancomycin
  • Histamine release (flushing or Red Man Syndrome) *NOT a true allergy* *this is historically related with fast infusions
120
Q

Red Man Syndrome

A

Is historically related with fast infusions of Vancomycin

121
Q

Daptomycin type of molecule

A

Lipopeptide

122
Q

Daptomycin MOA

A

Binds to bacterial cell-membrane causing depolarization and loss of membrane potential; bactericidal

123
Q

Daptomycin spectrum of activity

A

GPC only

includes

MRSA (Methicillin-resistent Staph aureus)

VRE (Vancomycin-Resistent Enterococci)

124
Q

Daptomycin dosing considerations

A
  • Dosed IV q24 hours
125
Q

Daptomycin metabolism and elimination

A

Renal elimination

126
Q

Daptomycin distribution

A

Does not get into CNS

127
Q

Daptomycin caveat inactivation

A

Surfactant in lungs inactivates drug

128
Q

Daptomycin PAE

A

Concentration dependent killing with Post-antibiotic effect

129
Q

Daptomycin toxicities

A
  • Rhabdomyolysis (monitor CPK level weekly)
  • eosinophilic pnemonia
130
Q

Colistin type of antibiotic

A

Polymyxin antibiotic

131
Q

Colistin MOA

A

Acts as a detergent to rapidly solubilize membranes in GN bacteria *Concentration depedent*

132
Q

Colistin Spectrum of Activity

A
  • GN only
  • Used in salvage therapy for milti-drug resistent Pseudomonas, Acinetobacter (monotherapy avoided)
133
Q

Colistin toxicity

A
  • Cationic drug with nephrotoxicity and neurotoxicity (cf aminoglycosides, cis-platinol)
  • Nephrotoxic, vertigo, slurred speech
  • Interferes with neuromuscular junction: Muscle weakness, apnea, paresthesias
134
Q

The miracle of antibiotics

A
135
Q

Antibiotic resistance

A
136
Q

Question

A
137
Q

Question

A
138
Q

Question

A
139
Q

Question

A
140
Q

How to achieve high levels of natural penicillins

A

Probenecid (gout drug, also inhibits renal secretion of penicillins) thus allowing for greater concentrations in the body

141
Q

What are the natural penicillins?

2 listed

A

get their name because they are similar to the penicillins found in nature

  • Penicillin G (IM and/or IV)
  • Penecillin VK (oral)
    • Probenecid (gout drug but also inhibits renal secretion of PCNs)
142
Q

Mechanisms of resistance to natural penicllins and example organisms

A
  • modified Penicillin binding proteins (mutations) S. pneumonia
  • Reduced bacterial cell penetration (gram neg, also bacteria with porins which can be downregulated)
  • Beta-lactamase enzymes
143
Q

Bacteria that produce beta-lactamase

8 listed

A
  • Staphylococcus aureus
  • Haemophilus influenzae
  • Gram-negative rods
  • Moraxella catarrhalis
  • Neisseria gonorrhoeae
  • Legionella pneumophila
  • Anaerobic Gram-negative bacilli (Bacteroides, Prevotella, and Porphyromonas spp.)
  • Fusobacterium spp.
144
Q

Beta-lactamase AKA

A

Penicillinase

145
Q

list of Beta-lactamase inhibitors

3 listed

A
  • Clavulanic acid
  • Sulbactam
  • Tazobactam
146
Q

Clinical uses of natural penicillins

A
  • strep pyogenes (strep throat)
  • Actinomyces (gram positive anaerobe in mouth
  • treatment of choice for Treponema pallidum (syphilis)
  • Rarely (only in susceptible isolates) - Neisseria meningitides, Strep pneumonia
147
Q

Adverse reactions to penicillin

A
  • C. diff infection (diarrhea) -> pseudomembraneous colitis
  • Jarisch-Herxheimer reaction
  • Type I IgE hypersensitivityanaphylaxis
  • Type II hemolytic anemia from IgG antibodies bind to PCN which are bound to RBCs (hapten) (Coombs test: positive)
  • Type III immune complex serum sickness IgG fever urticaria arthritis
  • Type IV T-cell-mediated delayed maculopapular rash (more common with people that have a viral infection) (EBV pharyngitis)
  • Steven-Johnson syndrome
  • Type IV T-cell-mediated - Interstitial nephritis (PCN acts as hapten causing immune response in kidneys)
148
Q

Antibiotics associated with Stevens Johnson syndrome

A
  • Sulfonamides
  • Aminopenicillins
  • Cephalosporins
149
Q

Signs and symptoms of interstitial nephritis

A
  • fever
  • oliguria
  • increased BUN/Cr
  • Eosinophils in urine
  • white cells and WBC casts (sterile pyuria)
150
Q

What is the Coombs Test?

A

The Coombs’ test is used to detect antibodies that act against the surface of your red blood cells. The presence of these antibodies indicates a condition known as hemolytic anemia, in which your blood does not contain enough red blood cells because they are destroyed prematurely.

151
Q

Serum sickness signs and symptoms

A
  • urticaria
  • fever
  • arthritis
  • lymphadenopathy
152
Q

What is the Jarisch-Herxheimer reaction?

A

occurs usually 2 hours after PCN therapy for spirochete infections (classically in syphilis)

  • fever
  • chills
  • flushing
  • hyperventilation

Mimics hypersensitivity reaction but is the result of bacteria dying off and causing an acute immune response

153
Q

What are the Antistaphylococcal Penicillins?

4 listed

A
  • Prototype was Methicillin (no longer used because high incidence of adverse effects particularly interstitial nephritis)
  • Oxacillin
  • Nafcillin
  • Dicloxacillin
154
Q

What is different about the Antistaphylococcal Penicillins?

A

The side-chain protects the beta-lactam ring from staph penicillinase

155
Q

Antistaphylococcal Penicillins coverage

A

Covers basic PCNs and also non-MRSA S. aureus and most Strep

156
Q

What are the aminopenicillins?

2 listed

A
  • Amoxicillin (oral)
  • Ampicillin (IV)
157
Q

What is different about the aminopenicillins?

A

they have an amino group attached

allows them to penetrate porin-channel of GNeg bacteria

They are however, still sensitive to beta-lactamases

158
Q

Aminopenicillins coverage

A

penicillin bacteria and some gram negatives

159
Q

Common uses for Antistaphylococcal Penicillins

A
  • community acquired cellulitis
  • Impetigo
  • Staph endocarditis based on culture data
160
Q

Antistaphylococcal Penicillins adverse effects

A

same as PCNs

161
Q

Aminopenicillins coverage

A
  • H. influenza
  • E. coli
  • Proteus
  • Salmonella
  • Shigella
  • Listeria (gram +)
    *
162
Q

Aminopenicillins common uses

A
  • Otitis media
  • Bacterial sinusitis
  • Meningitis
    • newborns and elderly
    • Listeria coverage
163
Q

Aminopenicillins adverse effects

A

Same as PCNs

  • Type IV delayed maculopapular rash is most likely with Aminopenicillins
  • Steven-Johnson syndrome also
164
Q

What are the Beta-lactamase inhibitors and Aminopenicillins

A
  • amoxicillin/Clavulonic Acid (augmentin)
  • Ampcillin/Sulbactam (Unasyn)
165
Q

Beta-lactamase inhibitors and Aminopenicillins coverage

A

increases activity against S. aureus and H. flu and also against anaerobes (B. fragilis)

166
Q

Common uses of Beta-lactamase inhibitors and Aminopenicillins

A
  • Otitis media/sinusitis (Broad-spectrum)
  • Bite wounds (polymicrobial with anaerobes
167
Q

What are the Antipseudomonal Penicillins?

A
  • Ticarcillin
  • Piperacillin
168
Q

Whats different about the Antipseudomonal Penicillins

A

they have greater porin channel penetration

169
Q

Antipseudomonal Penicillins coverage

A

Same as PCN but effective against more Gneg than aminopenicllins and also effective against Pseudomonas aeruginosa

170
Q

Carboxypenicillins

A

Ticarcillin

171
Q

Beta-lactamase inhibitors and Antipseudomonal Penicillins

A
  • Ticarcillin/Clavulanate (Timentin)
  • Piperacillin/tazobactam (Zosyn)
172
Q

Beta-lactamase inhibitors and Antipseudomonal Penicillins coverage

A
  • Most Gpos (NOT MRSA!)
  • More Gneg (including Pseudomonas)
  • Most anaerobic bacteria
173
Q

Clinical uses of Beta-lactamase inhibitors and Antipseudomonal Penicillins

A

Usually reserved for very sick patients such as

  • Sepsis
  • Pneumonia
174
Q

Groups of Beta-lactam antibiotics

A
  • Penicillins
  • Carbapenems
  • Aztreonam
  • Cephalosporins
175
Q

What are the Carbapenems?

4 listed

A

Beta-lactam antibiotics

Older carbapenems

  • Imipenem and Meropenem

Newer carbapenems

  • Ertapenem
  • Doripenem
176
Q

MOA of beta lactam antibiotics

A

same as for penicillin

they bind the Pencillin binding protein or peptiidoglycan transpeptidase and prevent it from cross-linking the peptidoglycan cell wall resulting in bacterial autolysis

Thus all beta lactams are bactericidal

They are all POTENTIALLY susceptible to beta-lactamases

177
Q
A
178
Q

What is different about Carbapenems?

A

they are not penicillins but are beta-lactams and they are resistant to cleavage from most beta-lactamases

179
Q

What is ESBL?

A

Extended spectrum beta-lactamase

plasmid-mediated bacterial enzymes that confer resistance to most beta-lactam antibiotics (penicillins, cephalosporins and aztreonam)

180
Q

Where is ESBL found?

A

Found only in some Gneg bacteria such as

  • E. coli
  • Klebsiella
  • Pseudomonas
  • Enterobacter
  • Salmonella
  • Serratia
  • Shigella
181
Q

Carbapenems coverage

A

The drug of choice for ESBL bacteria!

  • Gram (+)
  • Gram (-) including pseudomonas, enterobacter
  • anaerobes including B. fragilis
182
Q

Carbapenems prototype

A

imipenem

unique problem in that it was metabolized in the kidneys by dehydropeptidase 1 and therefore lost antibacterial effect as well as gave off nephrotoxic metabolites

So imipenem was given with Cilastatin (dehydropeptidase 1 inhibitor) to prevent this

183
Q

What is different about ertapenem?

A

once daily dosing but it has some resistance in ESBL bacteria and also weak activity against pseudomonas

184
Q

Carbapenems adverse effects

A
  • Common side effects
    • NVD
    • Skin rash
  • Neurotoxicity
    • Seizures
    • inhibition of GABA receptors
    • especially at high doses or with renal failure
    • reduced risk with Meropenem
185
Q

What are the monobactams?

A

Aztreonam

(the Beta-lactam ring is not fused to another ring)

186
Q

Aztreonam MOA

A

binds to pencillin binding protein 3 (PBP-3) which is found in Gneg bacteria and prevents cross-linking of peptidoglycan and thus is bactericidal

Has limited susceptibility to Beta-lactamase (has some resistance in ESBL bacteria)

187
Q

Aztreonam coverage

A
  • only active against Gneg bacteria
    • Doesn’t bind PBP of Gpos bacteria thus has no activity against Gpos or anaerobes
  • Is active against Pseudomonas
188
Q

Aztreonam route of administration

A

IV

189
Q

Aztreonam clinical uses

A

usually reserved for hospitalized patients

synergystic with aminoglycosides

Does NOT have cross-reactivity for patients allergic to penicillins

*****Key niche: PCN allergy****

190
Q

What are the cephalosporins?

A

beta-lactam antibiotics that are divided into 4 generations

starting out covering Gpos but with each generation progressively covering more Gneg

191
Q

1st generation Cephalosporins

A
  • Cefazolin
  • Cephalexin
192
Q

2nd generation Cephalosporins

A
  • Cefuroxime
  • Cefoxitin
  • Cefotetan
193
Q

3rd generation Cephalosporins

A
  • Ceftriaxone
  • Cefotaxime
  • Ceftazidime
194
Q

Coverage of 1st generation Cephalosporins?

A
  • They were developed to treat S. aureus resistant to penicillin
  • covers many Gpos bacteria including S. aureus (NOT MRSA)
    • stable against S. aureus’ beta-lactamases
  • Does NOT cover Enterococcus or Listeria
  • Remains susceptible to Gneg beta-lactamases
195
Q

Clinical uses of 1st generation Cephalosporins

A
  • Surgical wound (skin) infections
  • Cefazolin is given pre-op for prevention
196
Q

2nd generation Cephalosporins were designed for?

A

designed to treat amoxicillin resistent-infections

197
Q

Coverage of 2nd generation Cephalosporins

A
  • increased affinity for Gneg PBPs
    • H. influenzae, Enterobacter, Proteus
    • E. coli, Klebsiella, Serratia, N. gonorrhea
  • More resistant to beta-lactamase
  • Increased anaerobic coverage
    • B. fragilis
198
Q

2nd generation Cephalosporins clinical uses

A
  • Cefuroxime (oral)
    • Otitis media (S. penumonia, H. flu)
    • UTI in children (E. coli, no fluoroquinolones)
  • Cefoxitin/Cefotetan (IV)
    • PID (covers Neisseria, also give doxycycline for Chlamydia)
    • Pre-op in children with appendicitis
      • E. coli
      • covers Gnegs and some anaerobes
      • usually given with metronidazole
199
Q

3rd generation Cephalosporins coverage

A
  • broad Gneg coverage
    • more Gneg PBP affinity
  • even greater resistance to beta-lactamases
  • Ceftriaxone, Cefotaxime: poor coverage of pseudomonas
  • Ceftazidime: covers Pseudomonas
  • Most achieve good CSF penetration (meningitis)
200
Q

Pseudomonas and 3rd generation Cephalosporins

A
  • Ceftriaxone, Cefotaxime: poor coverage of pseudomonas
  • ***Ceftazidime: covers Pseudomonas****
201
Q

3rd generation Cephalosporins clinical uses

A

Ceftazidime:

  • covers pseudomonas
  • typically reserved for hospitalized patients with Gneg infections
  • Sepsis/Pneumonia

Ceftriaxone

  • good CSF penetration so used often for meningitis
    • active against S. pneumoniae, N. meningitidis
  • Commonly used for N. gonorrhea
202
Q

Ceftriaxone clinical uses

A
  • good CSF penetration so used often for meningitis
    • active against S. pneumoniae, N. meningitidis
  • Commonly used for N. gonorrhea
203
Q

What are 4th generation Cephalosporins?

A

Cefepime: Broad spectrum

204
Q

4th generation Cephalosporins Coverage

A

Broad spectrum

  • MSSA
  • Many Gpos
  • Many Gneg (including Pseudomonas)
  • Resistent to some ESBL
205
Q

4th generation Cephalosporins clinical uses

A

Hospitalized patients with Gneg infections

206
Q

Beta-lactam antibiotics susceptibility to beta-lactamases frow most to least susceptible

A

Most

Penicillins (NOT antistaph PCNs)

1st gen cephalosporins

2nd gen cephalosporins

3rd gen cephalosporins

4th gen cephalosporins

Aztreonam

Carbapenems (ESBL drug of choice)

Least

207
Q

What are the 5th generation Cephalosporins?

A

Ceftaroline

208
Q

5th generation cephalosporins coverage

A
  • ***Active against MRSA***
    • Binds PBP2a (MRSA specific PBP)
  • Covers MRSA and VRSA
  • Some Gnegs (NOT Pseudomonas)
  • Studied in skin infections and pneumonia
209
Q

Resistance mechanisms to cephalosporins

A
  • modify PBPs
  • Altered cell permeability
  • beta-lactamase
210
Q

Cephalosporins adverse effects

A

Hypoprothrombinemia - associated with N-methylthiotetrazole (NMTT) side chains (Cefotetan, Cefozolin) which inhibits epoxide reductase (similarly to warfarin) decreasing hepatic synthesis of clotting factors, prolong the PT/INR (reversible with Vitamin K (common in malnourished pts)

  • Vitamin K deficiency (increased INR and potential bleeding from the killing of bacteria which generate Vitamin K2 in the gut) *problem for patients on warfarin (can be caused by any antibiotic)
  • increased risk of Nephrotoxicity w/ aminoglycosides
  • Disulfiram reaction

Basically same as penicillins

  • Type I anaphylaxis
  • Type II hemolytic anemia
  • Type III serum sickness
  • Type IV interstitial nephritis
  • Type IV Steven Johnson syndrome/TEN
  • Also shares some cross-reactivity with penicillins traditionally cited as 10% but may be lower
211
Q

What is the Disulfiram reaction?

A
  • alcohol consumption with cephalosporins or disulfiram
  • warmth, flushing, sweating
  • from inhibition of acetaldehyde dehydrogenase leading to accumulation of acetaldehyde
  • occurs with some certain side chains such as (Cefoperazone, Cefamandole, Cefotetan)

Infectious Disease (82 decks)

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