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PHRM 865 > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

What kind of cell is this?

A

Gram positive

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2
Q

What kind of cell is this?

A

Gram negative

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3
Q

What color are gram positive bacteria?

A

Purple

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4
Q

What color are gram negative bacteria?

A

pink

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5
Q

Which bacteria has a thicker cell?

A

gram negative

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6
Q

Which bacteria has porins?

A

gram negative

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7
Q

Where are beta lactamases located in gram positive bacteria?

A

External space, thus you need to create larger quantities

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8
Q

where are beta lactamases located in gram negative bacteria?

A

Within in the cell in periplasmic space since it can go through porins

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9
Q

What is the main barrier keeping drugs out of the cell in gram positive bacteria

A

Bacterial membrane

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10
Q

How many membranes does gram positive bacteria have

A

1

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11
Q

How many membranes do gram negative bacteria have

A

two –> inner and outer membranes

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12
Q

What is in gram negative bacteria’s peptidoglycan and how is it cross-linked?

A
  • meso-diaminopimelic acid residue (DAP)
  • peptidoglycan is cross-linked by a bridge between the DAP residue of one strand and the terminal D-Ala of another
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13
Q

What is in gram positive bacteria’s peptidoglycan and how is it cross-linked?

A
  • L-lysine residue
  • Bridge exists between the L-Lys strand and the terminal D-Ala of the second molecule
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14
Q

What is the enzyme that cross-links the peptidoglycan strands?

A

transpeptidases

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15
Q

beta lactam antibiotic mechanism of action

A
  • inhibition of transpeptidases that glue the peptidoglycan strands together by cross-linking
  • beta lactam antibiotics acylate the transpeptidase Ser residue in the enzyme active site to form stable product, which inactivates the enzyme, inhibiting peptiodglycan cross-linking, which results in a defective bacterial cell wall
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16
Q

What is the reactivity of the beta lactam system due to

A
  • highly strained four-membered ring
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17
Q

Bacterial transpeptidases and catalyzation reactions of host cells

A

Bacterial transpeptidases do not catalyze reactions with host cell proteins because the bacterial substrate contains unnatural D-Ala amino acid residues that are not found in the host cell proteins

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18
Q

How can resistance to beta lactam antibiotics occur (4)

A
  • decreased cellular uptake of the drug
  • mutation of the penicillin binding proteins to decrease their affinity for penicillins
  • presence of an efflux pump that pumps the antibiotic out of the cell
  • induction or elaboration of bacterial beta lactamases
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19
Q

Rate of hydrolysis of the actylated beta lactamase

A

Fast, so the enzyme can hydrolyze many drug molecules rapidlyHyd

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20
Q

How much of the US population is allergic to beta lactam antibiotics?

A

6-8%

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21
Q

How does allergenicity of beta lactam antibiotics occur

A

Drugs acts like a hapten and acylates host cell proteins, which then raise antibodies that result in an allergic reaction

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22
Q

Cross reactivity in mild reaction of beta lactams

A

Cephalosporin or carbapenen can be tried since cross-reactivity is 5-15%

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23
Q

Cross reactivity in severe reaction of beta lactams

A

Cephalosporins and carbapenems are avoided, but aztreonam can be used

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24
Q

*Under the acidic conditions, the main degradation of Pen G are:

A
  • Benzylpenicillenic acid
  • Benzylpenillic acid
  • Benzylpenicilloic acid

uses achimeric assistance

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25
Q

*Product of penicillin degradation under basic conditions

A

penicilloic acid

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26
Q

Antibiotic activity of penicillin hydrolysis products

A

no antibiotic activity

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27
Q

Is the hydrolysis of the beta lactam reversible or irreversible

A

Irreversible

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28
Q

Electronegative substituents and nucelophilicity of beta lactams

A
  • Electronegative substituets on the side chain carbonyl reduce the nucleophilicity of the chain amide carbonyl oxygen atom
    • This stabilizes the penicillin against hydrolysis under acidic conditions, since tgeh first step in the hydrolysis reaction is decelerated
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29
Q

Which medication is more stable to hydrolysis in the stomach and why? Penicillin V vs Penicillin G

A

Penicillin V is more stable to hydrolysis in the stomach than Penicillin G because the electronegativity of the ether oxygen dereases the nucleophilicity of the amide carbonyl

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30
Q

What catalyzes penicillin degradation reactions

A

Heavy metal ions- therefore keep away from penicillin solutions

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31
Q

Lipophilic side chains and protein bound relationship

A

penicillins with more lipophilic side chains are more highly protein bound

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32
Q

protein binding and bioavailability relationship

A

protein binding reduces bioavailability by reducing the effective concentration of the free drug

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33
Q

protein binding and degradation relationship

A

protein binding in general protects drug from degradation since they dont react with hydrophilic enzymes

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34
Q

what is rate-limit half life of penicillin

A
  • Renal excretion rate
  • half-lives of penicillins are generally not affected by protein binding, since their dissociation rates from the protein are fast
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35
Q

penicillin excretion routes

A
  • rapidly excreted by the renal or biliaqry routes
    • 10% of renal excretion is by glomerular filtration
  • 90% is by tubular secretion
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36
Q

How does kidney disease or failure effect half-lives of penicillins

A

Half-lives are prolonged

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37
Q

Tubular secretion MOA of pencillins

A

The penicillins are anionic and competition with the anion probenecid for the secretion mechanism causes an increase in half life when probenecid is administered along with the penicillin

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38
Q

Dose range of penicillin

A

3-12 g per day for an average adult

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39
Q

Serum half-lives of penicillin

A

Serum half-lives are generally 0.5 to 2 hours

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40
Q

Penicillin G antimicrobial spectrum

A

Gram + cocci

N. gonorrhoeae and H. influenza

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41
Q

Pencillin beta lactamase sensitivity

A

Yes

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42
Q

Penicillin G administration

A

Orally in large doses, although the most effective route is parenteral

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43
Q

Penicillin G toxicity

A

Acute allergic reactions

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44
Q

Penicillin G precautions

A

Pen G should be used with caution in individuals with histories of signficant allergies and/or asthma

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45
Q

Penicillin Notes

A

Pen G is the drug of choice for treatment of more infections than any other antibiotic

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46
Q

How are synthetic penicillins made by

A

acylation of 6-APA

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47
Q

What structure is this?

A

penam

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48
Q

what structure is this?

A

penem

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49
Q

what structure is this?

A

carbapenem

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50
Q

what structure is this?

A

cephem

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51
Q

what structure is this?

A

monobactam

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52
Q

benylpenicillin benzathine and benzylpenicillin procaine PK

A
  • because of low solubility, the drug is released slowly from the intramuscular injection site
  • duration of action is longer and the blood levels are than with other parenteral penicillins
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53
Q

benylpenicillin benzathine and benzylpenicillin procaine administration

A
  • Should only be administered by deep IM injection
  • Inadvertent IV administration can result in cardiac arrest and death
  • Injection near a nerve can result in permanent neurological damge
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54
Q

benylpenicillin benzathine and benzylpenicillin procaine therapuetic use

A
  • moderately severe to severe infections of the upper-respiratory tract, scarlet fever, and skin and soft tissue infections due to susceptible streptococci
  • Moderately severe pneumonia and otitis media due to susceptible pneumococci
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55
Q

Difference between penicillin V and penicillin G

A
  • Pencillin V is more stable in acid
    • the increase in stability in acid attributed to the electronegative ether oxygen which decreases the nucleophilicity of the side chain amide carbonyl and therefore decreases its participation in the beta lactam hydrolysis reaction
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56
Q

Does methicillin have beta lactamase sensitivity and why

A

No because of steric hindrance of nucleophilic attack by the enzyme on the beta lactan carbonyl

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57
Q

Is methicillin stable to acid

A

No because of electron donation toward the amide carbonyl oxygen by the o-methyoxygroups, making the amide carbonyl oxygen more nucleophilic

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58
Q

How is MRSA resistant to methacillin

A
  • Mutation in a pencilin binding protein (transpeptidase)
    • The gene coding for this protein is called methicillin resistance gene (mecA), and the penicillin binding protein that it codes for is PBP2A
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59
Q

Does nafcilin have beta lactamase sensitivity

A

No

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60
Q

Nafcillin stability in acid

A

Slightly more stable than methicillin in acid, but is clinically identical to methicillin

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61
Q

What drug is this?

A

oxacillin

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62
Q

what drug is this?

A

cloxacillin

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63
Q

what drug is this?

A

dicloxacillin

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64
Q

Does oxacillin, cloxacillin, and dicloxacillin have beta lactamase sensitivity?

A

No

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65
Q

Is oxacillin, cloxacillin, and dicloxacillin preferred treatment for septicemia and why?

A

No because they are highly protein bound

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66
Q

xacillin, cloxacillin, and dicloxacillin cross resistance

A

cross-resistant with methicillin

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67
Q

Ampicillin antimicrobial spectrum and how

A
  • Many gram (-) microorganisms are sensitive, including Salmonella, shegella, proteus mirabilis, e. coli, h. influenza, and n. gonorrhoeae
  • the inner surface of porirns in hydrophilic and porins all transport ionic compounds
    • the charged amino group of ampicillin at physiological pH allows ampicillin to be transported into gram (-) bacteria through the porins
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68
Q

Is ampicillin stable in acid and why

A
  • Yes because the amino group is protonated in the stomach, so the positively charged nitrogen is more electron-attracting
    • This decreases the nucleophilicity of the amide carbonyl oxygen so that it does not participate in ring-opening of the lactam
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69
Q

Does amoxicillin or ampicillin have better absorption and why

A

Amoxicillin because it is an analog of ampicillin in which a phenolic hydroxyl group has been introduced into the aromatic ring

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70
Q

MOA of clavulanic acid and sulbactam

A

acylate the serine hydroxyl group in the active site of the beta lactamase to form a reactive intermediate that then inactivates the ezyme irreversibly

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71
Q

Does azlocillin, mezlocillin, and piperacillin have stronger or weaker potencies and why

A

Enhanced potencies because the added side chain fragments resemble a longer section of the peptidoglycan chain than ampicillin

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72
Q

How to treat piperacillin, resistant bacteria

A

Tazobactam

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73
Q

What is the main starting material for cephalasporins

A

cephalasporin c

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74
Q

what can cephalapsorin C be converted to to make a chemically useful cephalasporn

A

7-aminocephalosporic acid

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75
Q

Cephalosporin MOA

A
  • Reaction with transpeptidases (penicillin-binding proteins) results in inhibition of peptidoglycan cross linking
  • Many cephalosporins contain leaving groups that faciitate beta lactam ring opening
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76
Q

Hydrolysis of cephalosporins

A

Cephalosporins are hydrolyzed by beta lactamases

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77
Q

How does cephalosporin resistance occur

A

Cephalosporins are hydrolyzed by beta lactamases, rendering them inactive

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78
Q

beta-lactamase specificity

A
  • There are over 340 different beta lactamases known
  • They can be specific for certain antibiotics and classes of antibiotics
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79
Q

Allergenicity of cephalosporins

A
  • allergic reactions are less common and less severe than with penicillin
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80
Q

cross allergenicity of cephalosporins

A

since allergenicity is common, cephalosporins should be used with caution, if at all, in patients who are allergc to penicillins

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81
Q

What medications are first generation cephalosporins

A
  • Cefazolin
  • cephanlexin
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82
Q

what are first generation cephalosporins primarily active against

A
  • gram + cocci: staph aeureus and staph pyogenes
  • group b streptococci: s agalactiae and s. pneumoniae
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83
Q

If the cephalosporin substituents at C-3 are chemiccaly reactive, how are they administered?

A

Parenterally

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84
Q

If the cephalosporin substituents at C-3 are not chemiccaly reactive, how are they administered?

A

orally

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85
Q

what medication is this and How is this medication administered?

A

cefazolin; parenteral

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86
Q

what generation is cefazolin

A

first generation

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87
Q

What is this medication how is this medication administered?

A

cephalexin; orally

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88
Q

What generation is cephalexin

A

first generatio

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89
Q

how is cephalexin able to confer oral activity

A
  • Substituent at C-3 is not chemically reactive
  • Contains an ampicillin-type side chain at C-7 that makes it more stable and helps to confer oral activity
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90
Q

what do second generation cephalosporins target

A
  • Retain the anti gram (+) activity of the first generation and h. influenzae as well
  • Some gram (-) activity including some strains of acinetobacter, citrobacter, enterobacter, e. coli, klebsiella, neisseria, proteus, providencia, and serratia
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91
Q

what generation if cefuroxime

A

second

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92
Q

What is special about cefuroxime

A

can be given parenterally and orally

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93
Q

Difference between syn and anti methoximino groups

A
  • *The syn methoximino group is more resistant than the anti isomer
  • the syn isomer can be photochemically isomerized to the anti isomer in solution to for a 1:1 mixture of syn and anti isomers
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94
Q

Third generation cephalosporin activity

A
  • less active against staphlocci than the first generation agents
  • much more active vs gram (-) bacteria than either the first or second agents
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95
Q

what organisms are sensitive against third generation cephalosporins

A
  • morganella
  • bacteroides fragilis
  • pneudomonas aeruginosa
  • some enterobacteria
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96
Q

What is on almost all of the third generation cephalosporin structures

A

an aminothiazole substituent and contain an oxime ether at the 7-position

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97
Q

what drug class does ceftazidine belong to?

A

third generation cephalosporin

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98
Q

What moiety at C-7 conveys enhanced stability vs beta lacatamases

A

large oxime ether moiety

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99
Q

what drug class is cefixime

A

third generation cephalosporin

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100
Q

fourth generation cephalosporin antibacterial spectrum

A

retain the antibacterial spectrum of the third generation cephalosporins and also add pseudomonas aeruginosa and some enterobacteria that are resistant to third generation cephalosporins

more active against gram positive organisms

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101
Q

cefepine drug class

A

fourth gen cephalosporin

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102
Q

route of administration of cefepime

A

parenteral

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103
Q

what drug class is ceftolozane

A

fourth gen cephalosporin

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104
Q

what drug is ceftolozane combined with and what does it treat

A
  • Tazobactam
  • effective against many bacteria that are resistant to other antibiotcs
  • treats both gram positive and gram negative bacteria
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105
Q

what drug class is ceftraoline

A

fifth generation cephalosporin

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106
Q

MOA of ceftraline fosamil

A

ceftraline fosamil is a prodrug that is hydrolyzed metabolically via phosphatase after IV infusion to ceftraroline

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107
Q

Ceftaroline spectrum of activity

A

broad-spectrum, fifth-generation cephalosporin antibiotic that is active vs MRSA and is used vs MRSA and community acquired bacterial pneumonia since it can inhibit the MRSA PBP2a

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108
Q

what drug class is cefiderocol

A

fifth gen cephalosporin

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109
Q

cefiderocol indication

A

complicated UTI

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110
Q

cefideroocol MOA

A

transpeptidase inhibitor

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111
Q

what structual unit does cephamycins have that make them special

A

7-alpha methoxyl group

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112
Q

cefoxitin spectrum activity

A

broad spectrum of gram positive and gram negative bacteria

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113
Q

MOA of cefoxitin

A

beta lacatamase inducer

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114
Q

cefoxitin drug class

A

cephalosporin

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115
Q

cefotetan drug class

A

cephalosporin

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116
Q

Caution point of cefotetan

A

releases N-methylthiotetrazole, which can cause hypothrombinemia, and can also cause a reaction to ethanol that is similar to disulfuram

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117
Q

why can’t thienamycin be used as a drug and how has this been overcame

A
  • thienamycin is too reactive to be used as a drug, since the primary amino group attacks the beta lactam intermolecularly
  • Been overcame by removing n-formiminoyl group to create imipenem
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118
Q

Why are carbapenems more reactive than penicillins

A
  • The sulfur that is present in the thiazolidine ring of the penicillins is replaced by a methylene
    • This increases reactivity because a methylene is smaller than a sulfure, so the ring strain is greater in the carbapenems
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119
Q

MOA of imipenem

A
  • reacts with penicillin binding proteins
  • reacts with and inhibits beta lactamases
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120
Q

what is imipenem hydrolyzed by

A

renal dehydropeptidase-1, but this can be overcome by co-administration of the dehydropeptidase-1 inhibitor cilastatin

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121
Q

what is cilastatin and imipenem spectrum of activity

A

active against both gram + and gram - bacteria: used to treat of the gut, GI tract, bone, skin, and endocardium

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122
Q

meropenem drug class

A

carbapenem

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123
Q

does meropenem have to be administered with cilastatin

A

no because the 1-beta-methyl group confers stability to dehydropeptidase-1

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124
Q

why does ertapenem have an extended half life

A

highly protein bound so that it allows it to be administered iv once every 24 hours

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125
Q

aztreonam drug class

A

monobactams

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126
Q

origin of aztreonam

A
  • aztreonam disodium is totally synthetic but the design was inspired by monocyclic beta lactam natural products called monobactams
    • sulfamic acid group takes place of the c-2 carboxyl group in the penicillins and cephalosporins
      • electronegativity of the sulfamic acid activates the beta lactam ring toward hydrolysis and to reaction with penicillin-binding proteins
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127
Q

aztreonam cross allergenicity

A

cross allergenicity with penicillins and cephalosporins has not been reported except for ceftazidine, which has an indentical oxime ether sidechain

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128
Q

what drug is this?

A

vancomycin

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129
Q

what drug is this?

A

teicoplanin

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130
Q

vancomycin mode of action and what makes it different from penicillins

A
  • vancomycin involves binding to the peptidly side chain d-alanyl-d-alanyl terminus in the peptidoclycan precursor (before cross-linking)
    • transpeptidase reaction that is required for cross-linking is inhibited by the high affinity binding of vancomycin to the the substrates
  • vancomycin also inhibits the transglycosylation step in peptidoglycan synthesis, which penicillins do not do
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131
Q

vancomycin spectrum of activity

A

primarily bactericidal and is active against gram (+) bacteria

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132
Q

why is vancomycin not effective against gram negative bacteria

A

vancomycin is too big to get through the porins

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133
Q

how has vancomycin resistance occurred

A
  • Mechanism of resistance appears to be mutation of the peptidoglycan cell wall precursor from D-Ala-D-Ala to D-Ala-D-lactate
    • vancomycin does not inhibit the transpeptidase when the substrate is d-ala-d-lactate because vanomycin has 1000 times less affinity for the d-ala-d-lactate precursor
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134
Q

vancomycin PK and distribution

A
  • vancomycin does afford appreciable blood levels after oral administration and is usually administered IV
  • vancomycin is highly distributed and 90% eliminated by glomerular filtration with a half life of 4-11 hour
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135
Q

vancomycin therapeutic use

A
  • given orally to treat c. diff
  • strep-induced endocarditis
  • MRSA
  • MRSE
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136
Q

vancomycin toxicity and effects

A
  • hypersensitivity
  • nephrotoxicity
  • ototoxicity
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137
Q

what drug is this?

A

oritavancin

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138
Q

oritavancin drug class

A

semisynthetic lipoglycopeptide antibiotic

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139
Q

oritavancin moa

A

inhibits transpeptidation and transglycosylation, which disrupts the membrane of gram-positive bacteria

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140
Q

oritavancin spectrum of activity

A

gram positive bacteria-MRSA skin infections

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141
Q

telavancin drug class

A

lipoglycopeptide antibiotic

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142
Q

what drug is this

A

telavancin

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143
Q

telavancin MOA

A

like vancomycin, telavancin binds to the D-Ala-D-Ala terminus of the peptidoglycan in the growing cell wall by inhibiting transpeptidation and transglycosylation

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144
Q

telavanvin therapeutic use

A

MRSA and other gram positive infections

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145
Q

what drug is this

A

dalbavancin

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146
Q

dalbavancin drug class

A

second generation lipoglycopeptide antibiotic

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147
Q

dalbavancin mechanisms

A

Identical to vancomycin: binds to the D-Ala-D-Ala residue on growing peptidoglycan chains and prevents transpeptidation and transglycosylation from occurring, thus preventing peptidoglycan elongation and cell membrane formation

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148
Q

what drug is this

A

daptomycin

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149
Q

what drug class is daptomycin

A

lipopeptide antibiotic

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150
Q

daptomycin moa

A

aggregation of daptomycin in the bacterial membrane creates holes that leak ions

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151
Q

daptomycin therpeutic use

A

used parenterally to treat systemic infections caused by gram-positive bacteria, including MRSA

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152
Q

What structure is this

A

penicillin

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153
Q

what structure is this

A

cephalosporin

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154
Q

what structure is this

A

monobactam

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155
Q

what structure is this

A

carbapenem

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156
Q

what are the four classes of beta lactams

A
  1. penicillins
  2. cephalosporins
  3. monobactams
  4. carbapenems
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157
Q

beta lactam MOA

A

inhibit cell wall synthesis

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158
Q

beta lactam mechanisms of resistance

A
  • beta lactamase degradation
  • PBP alteration
  • Decreased penetration
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159
Q

Are beta lactams bacterialstatic or bacterialcidal and in what kind of manner

A

bactericidal in a time dependent manner

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160
Q

average half-life of beta lactams

A

less than 2 hours

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161
Q

how are beta lactams eliminated

A

primarily eliminated unchanged by the kidneys

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162
Q

is cross allergenicity possible in beta lactams

A

yes, except for aztreonam

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163
Q

what do all penicillins share

A

a beta lactam ring attached to a 5-membered thiazolidine ring

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164
Q

penicillin mechanism of action

A

interfere with cell wall synthesis by binding to and inhibiting penicillin-binding proteins PBPs located in bacterial cell walls

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165
Q

what does inhibition of PBPs lead to

A

inhibition of final transpeptidation step of peptidoglycan synthesis

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166
Q

Why are beta lactamases problematic for penicillins

A

The enzyme hydrolyzes the beta lactam ring, which inactivates the antibiotic

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167
Q

what gram positive bacteria produces beta lactamases

A

penicillin resistance staph. aureus

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168
Q

what gram negative bacteia produce beta lactamase enzymes

A
  • h. influenzae
  • moraxella catarhalis
  • n. gonorrhoeae
  • e. coli
  • klebsiella pneumoniae
  • enterobacter spp
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169
Q

what gram negative anaerobes produce beta lactamase

A

bacteroides fragilis

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170
Q

how are PBPs lead to penicillin resistance

A
  • Alteration in structure of PBPs leading to decreased binding affinity
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171
Q

PBP Resistance Examples

A

MRSA and PRSP via that mECA gene

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172
Q

How do porins cause penicillin resistance

A

alteration of outer membrane porin proteins leading to decreased penetration

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173
Q

why were semi-synthetic penicillins developed

A

to provide enhanced antibacterial activity

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174
Q

what are the natural penicillins

A
  1. aqueous penicillin G
  2. benzathine penicillin G
  3. procaine penicllin G
  4. phenoxymethyl penicllin (penicillin VK)
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175
Q

natural penicillins are the drug of choice for what bacteria

A

treponema pallidum

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176
Q

what are penicillinase-resistant penicillins also known as

A

antistaphylococcal penicillins

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177
Q

what are the parenteral penicillinase-resistant penicillins

A

naficillin and methicillin (no longer used)

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178
Q

what is the oral penicillinase-resistant penicillins

A

dicloxacillin

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179
Q

what are penicillinase-resistant penicillins sensitive toward

A

methicillin-susceptible s. aureus (MSSA)

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180
Q

why were aminopenicillins developed

A

in response to the need for agents with some gram-negative activity

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181
Q

parenteral aminopenicllin

A

ampicillin

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182
Q

oral aminopenicillins

A

ampicillin and amoxicillin

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183
Q

what are aminopenicillins

A

semi-synthetic derivative of natural penicillin with the addition of an amino group

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184
Q

what is ampicillin the drug of choice for

A

enterococcus spp

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185
Q

what gram positive bacteria does aminopenicillin enhance activity against

A

listeria monocytogenes

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186
Q

what gram negative bacterias does aminopenicillin enhance activity against

A
  • SHEP
    • salmonella/shigella
    • h. influenzae BL
    • e. coli (some)
    • proteus mirabilis
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187
Q

why were carboxypenicllins developed

A

in response to the need for agents with enhanced activity against gram negative bacteria

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188
Q

carboxypenicllin structure

A

semi-synthetic derivatives of natural penicillin with the addition of a carboxyl group

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189
Q

parental carboxypenicllin

A

ticarcillin

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190
Q

do carboxypenicllins have increased activity against gram positive aerobes

A

marginal

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191
Q

what gram negative aerobes do carboxypenicllins cover

A
  • SHEPMEPP
    • salmonella/shigella
    • h. influenza BL+
    • e. coli (some)
    • proteus mirabilis
    • morganella
    • enterobacter
    • pseudomonas aeruginosa
    • proteus mirabilis
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192
Q

what penicllin do you use to treat MSSA

A

naficillin

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193
Q

what medication do we use to treat syphillis

A

IM benzathin penicllin

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194
Q

why were ureidopenicillins developed

A

in response to the need for agents with even more enhanced activity against gram-negative bacteria

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195
Q

ureidopenicillin structure

A

semi-synthetic derivatives of the amino-penicllins with acyl side chain adaptations

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196
Q

ureidopenicllin parenteral agent

A

piperacillin

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197
Q

what additionnal gram negative aerobes do ureidopenicillins cover

A
  1. serratia marcescens
  2. some klebsiella spp
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198
Q

MOA of beta lactamase inhibitors

A

irreversibly bind to catalytic site of beta lactamase enzyme

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199
Q

Parental beta lactamase inhibitor combinations

A

Unasyn and Zosyn

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200
Q

Unasyn component

A

ampicillin-sulbactam

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201
Q

Zosyn

A

Piperacillin-tazobactam

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202
Q

oral beta lactamase inhibitor

A

augmentin

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203
Q

augmentin components

A

amoxicillin-clavulanate

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204
Q

target organism of beta lactamase inhibitor combos

A

bacteroides spp

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205
Q

What bacterial killing depenedent on in penicllins

A

time

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206
Q

what correlated with efficacy of penicllins

A

time above MIC

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207
Q

Goal of penicllin dosing

A

Administer agents to maintain serum concentrations > MIC of infection bacteria for 50% of dosing interval

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208
Q

Many penicllins are degraded by what

A

gastric acid

Lower concentrations achieve with PO versus IV so that oral penicllins should only be used for mild to moderate infections

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209
Q

Two best orally available penicillins

A

PEN VK and Amoxicillin

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210
Q

Do penicillins have csf permeabilit

A

Adequate CSF concetrations of penicillins (but NOT beta lactamase inhibitors) are achieved ONLY in the presence of inflamed meninges with high-dose parenteral administration

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211
Q

Penicllin primary elimination

A

most are eliminated unchanged by the kidney so that dosage adjustment is required in the presence of renal insufficiency; probenacid blocks tubular secretion

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212
Q

penicllin elimination exceptions

A

nafcillin and oxacillin are eliminated primarily by the liver- do not require adjustment in renal insufficiency

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213
Q

Why is sodium load in penicllin cause issues?

A

High contents of sodium must be used in caution in patients with CHF or renal insufficiency because of electrolyte abnormalities and fluid retention

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214
Q

Penicllins with sodium content (5)

A
  • Sodium Penicllin G
  • Nafcillin
  • Carbenicillin
  • Ticarcillin
  • Piperacillin
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215
Q

Sodium Penicllin G sodium content

A

2.0 mEq per 1 million units

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216
Q

Nafcillin sodium content

A

2.9 mEq/gram

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217
Q

Carbenicllin sodium content

A

4.7 mEq/g

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218
Q

ticarcillin sodium content

A

5.2, which is the highest

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219
Q

piperacillin sodium load

A

1.85 mEq/gram

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220
Q

Which penicllin has the highest sodium load

A

ticarcillin

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221
Q

Natural penicillin clinical use

A

potential drug of drug for syphillis

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222
Q

penicillinase-resistant penicillins clinical uses

A

MSSA

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223
Q

augmentin clinical uses

A

sinusitis and otitis media, bite wounds

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224
Q

Unasyn, Zosyn, Timentin clinical uses

A

polymicrobial infections

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225
Q

Zosyn clinical use

A

empiric therapy for febrile neutropenia or hospital acquired infections

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226
Q

cross reactivity of penicillins

A

cross reactivity exists among all penicllins and even some other beta lactams

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227
Q

two main adverse effects of penicllins

A

neurologic and hematologic

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228
Q

how does penicllins cause neurologic adverse effects

A

direct toxic effect, especially in patients receiving high IV doses in the presence of renal insufficiency

seizures are common

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229
Q

hematolic penicllin adverse effects

A

netropenia and thrombocytopeni occur usually during prolonged therapy greater than 2 weeks but reversible upon discontinuation

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230
Q

GI adverse effects of penicllins

A

increased lfts, nausea, vomiting, diarrhea, C. diff

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231
Q

what is interstitial nephritis

A

immune mediated damage to renal tubules characterized by an abrupt increase in serum creatinine, eosinophilia, and eosinophiluria

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232
Q

what agents cause interstitial nephritis

A

methicillin or nafcillin

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233
Q

what classes fall under beta lactams

A
  • penicillins
  • cephalosporins
  • monobactams
  • carbapenems
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234
Q

what do cephalosporins contain

A
  • contain a beta lactam ring attached to a 6-membered dihydrothiazine ring, which confers greater stability against some beta lactamase enzymes
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235
Q

how are cephalosporins active against anaerobes

A

cephamycins have methoxy group at C-7 and are active against anaerobes

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236
Q

cephalosporin mechanism of action

A

interfere with cell wall synthesis by binding to penicillin-binding proteins located in bacterial cell walls

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237
Q

how does cefiderocol enter the bacterial membrane

A

Acts as a siderophere by binding to free ferin that enters the bacterial cell well

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238
Q

What does inhibition of PBPs lead to

A

inhibition of the final transpeptidation step of peptidoglycan synthesis, which exposes a less osmotically stable cell wall that leads to decreased bacterial growth, lysis, and death

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239
Q

T/F: cephalosporins are bactericidal

A

true

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240
Q

cephalosporin mechanism of resistance

A

production of beta lactamase enzymes: most important and most common where enzyme hydrolyzes beta lactam ring causing inactivation

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241
Q

what is the one cephalosporin that is active against MRSA

A

cefteroline

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242
Q

which cephalosporin generation are the most active verses gram positive aereobes

A

first generation

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243
Q

how do you lose gram positive activity and increase in gram negativity within cephalosporin generations

A

Lose gram-positive activity with an increase in gram negative activity as you go from 1st -> 2nd -> 3rd to 4th

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244
Q

how does beta lactamase activity change with cephalosporin generations

A

greater beta lactamase stability as you go from 1st -> 2nd -> 3rd -> 4th

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245
Q

what are the two main first generation cephalosporins

A

cefazolin and cephalexin

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246
Q

what gram positives are first gen cephalosporins active against

A
  • pen-susc S. pneumoniae
  • meth-susc S. aureus
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247
Q

what gram negatives are first generation cephalosporins are active against

A

p. mirabilis
e. coli
k. pneumoniae

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248
Q

what additional activity do several second generation cephalosporins have

A

several second generation agents have activity against anaerobes (the cephamycins)

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249
Q

are first or second generation cephalosporins better for treating meth-susc S. aueres

A

first generations

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250
Q

what gram negatives do second generation cephalosporins cover

A
  • p. mirabilis
  • e. coli
  • k. pneumoniae
  • h. influenzae
  • enterbacter spp
  • neisseria spp
  • m. catarrhalis
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251
Q

what anaerobes are second geneneration cephalosporins active against

A

bacteroides fragilis

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252
Q

what are the three common second generation cephalosporins

A
  1. cefuroxime
  2. cefprozil
  3. cefoxitin
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253
Q

what are the three most common third generation cephalosporins

A
  1. ceftriaxone
  2. ceftazidime
  3. cefpodoxime
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254
Q

third generation cephalosporins are active against what gram negative aerobes

A
  • p. mirabilis
  • e. coli
  • k. pneumoniae
  • h. influenzae
  • m. catarrhalis
  • n. gonorrhoeae
  • n. meningitidis
  • citrobacter
  • enterbacter
  • acinetobacter
  • morganella
  • serratia
  • providencia
  • salmonella
  • shigella
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255
Q

what third generation cephalosporins are active against pseudomonas aeruginosa

A

ceftazidime and cefoperazone

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256
Q

does ceftriaxone have activity against pseudomonas aeruginosa

A

NO

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257
Q

What are the three third generation cephalosporins

A
  • ceftriaxone
  • ceftazidime
  • cefpodoxime
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258
Q

what is the only fourth generation cephalosporin available

A

cefpime

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259
Q

what are fouth generation cephalosporins poor inducers of

A

poor inducer of inducible AmpC beta lactamse enzymes

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260
Q

what is the anti-MRSA cephalosporin

A

ceftaroline

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261
Q

ceftaroline does or does not cover pseudomonas aeruginosa

A

does not

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262
Q

cefiderocol spectrum of activity

A

many ESBLs, AmpCs, CREs

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263
Q

what is ceftolozane and tazobactam sensitive to

A

pseudomonas aeruginosa

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264
Q

Overall, cephalosporins are NOT active against (6)

A
  1. MRSA (except ceftaroline)
  2. Enterococcus spp
  3. listeria monocytogenes
  4. stenotrophomonas maltophilia
  5. clostridium difficile
  6. atypical bacteria, including legionella
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265
Q

which cephalosporin is considered a potential drug of choice for infections due to MSSA

A

cefazolin

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266
Q

which cephalosporin does NOT have activity against pseudomonas aeruginosa

A

ceftriaxone

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267
Q

what is cephalosporins bactericidal activity dependent on

A

Time –> Time > MIC is PD parameter that correlates with efficacy

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268
Q

cephalosporins absorption

A

oral cephalosporins are well absorbed, but achieve lower serum concentrations than parenteral products; food decreases the absorption of cefaclor and loracarbef

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269
Q

cephalosporins distribution

A
  • Widely distributed into tissues and fluids
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270
Q

cephalosporins CSF distribution

A

CSF concentrations achieved ONLY with PARENTERAL cefuroxime, 3rd and 4th generation agents

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271
Q

cephalosporin primary elimination

A

most are primarily eliminated unchanged by the kidney via glomerular filtration and tubular secretion; dosage adjustment of these agents is required in the presence of renal insuffiency

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272
Q

what cephalosporins are not eliminated by the kidney

A
  • ceftriaxone (biliary)
  • cefoperazone (liver)
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273
Q

what is the half life of most cephalosporins

A

< 2 hours

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274
Q

what is the notable half life of cephalosporin

A

most cephalosporins have short elimination half-lives (<2 hours)- on noteable exception is ceftriaxone whose half-life is 8 hours

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275
Q

ceftaroline clinical use

A

skin and soft tissue infections including those caused by MRSA

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276
Q

can you use caftaroline to treat pseudomonas aeruginosa

A

NOOOOOOO

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277
Q

cefiderocol clinical uses

A

use limited to infections caused by resistant Gram-negative bacteria (ESBL, AmpC, or carbapenemases), but current place in therapy is still being determined

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278
Q

cephalosporin hypersensitivity

A

5 to 15% cross-reactivity with penicillins (esp 1st generation)

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279
Q

Can you try cephalosporin with a rash/itching to penicllin

A

PK to try

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280
Q

which cephalosporins have MTT side chain and why is it a problem

A
  • cefamandole, cefotetan, cefmetazole, cefoperazone, moxalactam
    • hypoprothrombinemia- due to reduction in vitamin K-producing bacteria in GI tract
    • Ethanol intolerance
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281
Q

cephalosporins other adverse effects

A
  • IV calcium and ceftriaxone precipitate, nonconvulsive statis epilepticus
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282
Q

true/false: a patient who developed anaphylaxis to penicllin can safely receive any cephalosporin

A

FALSE: a patient who developed anaphylaxis to penicllin may develop anaphylaxis to a cephalosporin (esp 1st gen) due to common nucleus/side chains. Therefore, skin testing and/or desensitization may be necessary before using a cephalosporin in this patient

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283
Q

what are the four commericial carbapenems

A

imipenem, meropenem, ertapenem, doripenem

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284
Q

carbapenem basic structure and what does it result in

A
  • beta lactam ring attached to a 5-membered ring like the penicillins
    • structural changes result in extended spectrum of activity and greater beta lactamase stability
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285
Q

carbapenem mechanism of action

A

inhibitors of cell wall synthesis by binding to and inhibting PBPs; primary target is PBP-2

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286
Q

are carbenems bactericidal? If so, in what manner?

A

Bactericidal in time-dependent manner

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287
Q

carbapenems mechanisms of resistance

A
  • beta lactamase production
  • decreased permeability
  • alteration in PBPs
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288
Q

carbapenems spectrum of activity

A

have activity against gram-positive and gram-negative aerobes AND anaerobes

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289
Q

what specific gram positive aerobe does carbapenems have activity against

A

enterococcus faecalis

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290
Q

do carbapenems have activity against pseudomonas aeruginosa?

A

Yes, all of them except ertapenem

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291
Q

are carbapenems active against c. difficile

A

no

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292
Q

what gram negative anaerobe is carbapenem active against

A

bacteroides spp

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293
Q

are carbapenems active against MRSA

A

nope

294
Q

are carbapenems active against VRE?

A

no

295
Q

True/False: Carbapenems are highly stable against many beta lactamase enzymes and are considered the drugs of choice for serious infections due to ESBL- and AmpC-producing bacteria

A

True

296
Q

True/False: Meropenem-vaborbactam and imipenem-relebactam were developed to provide activity against KPC-producing Enterobacteriaceae

A
297
Q

how do carbapenems display dependent bactericidal activity

A

Time-dependent –> time >MIC is PD parameter that correlates with efficacy

298
Q

what are carbapenems bacteriostatic versus

A

enterococcus

299
Q

carbapenem distribution

A

widely distributed into body tissues and fluids

300
Q

do carbapenems penetrate CSF

A

Yes –> meropenem is the best

301
Q

how are carbapenems eliminated

A

all are primarily eliminated by the kidney; need dosage adjustment with renal dysfunction

302
Q

carbapenems half lives

A

short: except ertapenem half-life= 4 hours

303
Q

which carbapenem is co-formulated with cilastatin to prevent DHP degradation in the renal brush border and subsequent nephrotoxicity

A

imipenem

304
Q

carbapenem clinical uses (4)

A
  • empiric therapy for hospita acquired infections
  • polymicrobial infections
  • infections due to beta lactamase producing organisms
  • complicated uti due to KPC-producing enterobacteriaceae
305
Q

which carbapenem do you not use to treat ertapenem

A
306
Q

do carbapenems have cross reactivity with penicllins

A

yes 5-15%

307
Q

carbapenem central nervous system adverse effects

A

risk factors for seizures include pre-existing CNS disorder, high doses, and renal insufficiency

308
Q

what is the only monobactam available

A

aztreonam

309
Q

monobactam MOA

A

inhibits cell wall synthesis like other beta lactams by binding to PBPs (primarily PBP-3 of gram-negative aerobes)

310
Q

are monobactams bactericidal or bacteristatic and in what manner

A

bactericidal in a time dependent manner

311
Q

how does monobactam resistance occurs

A

through hydrolysis by beta lactamases or decreased permeability

312
Q

what does monobactams have little to no activity against

A

little to no activity against gram-positive aerobes or anaerobes

313
Q

what is monobactams target organism

A

pseudomonas aeruginosa

314
Q

monobactams distribution

A

widely distributed into body tissues and fluids; penetrates the CSF in the presence of inflamed meninges

315
Q

monobactams elimination

A

excreted in the urine as unchanged drug

316
Q

when do monobactams need dose adjustment

A

doses need adjustment with renal dysfunction; is removed by hemodialysis

317
Q

aztreonam clinical uses

A

susceptible gram negative aerobes and used in patients with significant penicillin allergies

318
Q

which of the following antibiotics can be used in a patient who developed angioedema and hives after an IM injection of penicllin?

A

Aztreonam

319
Q

what is the common streptogramin antibiotic

A

synercid

320
Q

what is synercid made up of

A

quinupristin and dalfopristin

321
Q

what is this structure

A

quinupristin

322
Q

what structure is this?

A

dalfopristin

323
Q

synercid mixture weight ratio

A

30% quinupristin and 70% dalfopristin

324
Q

is quinupristin bacteriostatic or bactericidal

A

bacteriostatic

325
Q

is dalfopristin bacteriostatic or bactericidal

A

bacteriostatic

326
Q

what is synercid bacteriostatic against

A

enterococcus faecium

327
Q

what is synercid bactericidal against

A

strains of mssa and mrsa

328
Q

how is synercid administered

A

parenterally

329
Q

dalfopristin MOA

A
  • Dalfopristin directly interferes with the peptidyl transferase-catalyzed step in the 50S subunit
    • During peptide synthesis, when the second tRNA base pairs with the appropriate codon in the mRNA, peptidyl transferase catalyzes the formation of a peptide bond between the two amino acids present
330
Q

quinupristin MOA

A

binds in the ribosomal tunnel and causes blockage of the tunnel in the 50S subunit

331
Q

pristinamycins parent nautral product mixture solubility

A

lacks suitable solubility for reliable dosages

332
Q

quinupristin and dalfopristin solubility

A

they both have amino side chains that allow salt formation and enhance the water solubility needed to make a useful formulation

333
Q

synercid therapuetic use (3)

A
  1. vancomycin resistant e. faecium bacterim
  2. skin infections caused by MRSA
  3. vancomycin resistant by enteroccus faecium UTI
334
Q

quinupristin resistance

A

adenine methylation of A2058 in the 23S rRNA as in the case of erythromycin and clindamycin. Susceptibility of the organism to dalfopristin is not affected by this rRNA modifaction, but renders synercid a bacteriostatic agent at the normal dose. Extension of the dosing to 3X a day is well tolerated and allows for more sustained tissue drug levels

335
Q

synercid side effects

A
  • No significant toxicity presented
    • Several mild side effects have been reported and include inflammation and pain at the site of injection, nausea, diarrhea, muscle weakness and rash
336
Q

synercid pharmacokinetics

A

complicated because of the different elimination rates for each component and their metabolites

337
Q

Does synercid penetrate BBB

A

No

338
Q

synercid clearance

A

clearance is 75% through biliary excretion (fecal matter) and the remainder appears in the urine

339
Q

synercid drug interactions

A

synercid inhibits cytochrome 3a4, which metabolizes a long list of commonly used drugs

340
Q

quinupristin metabolism

A
341
Q

dalfopristin metabolism

A
342
Q

what drug is an oxazolidinones

A

linezolid

343
Q

oxazolidinones MOA

A
  • linezolid acts early by potent interaction with 50S ribosomal subunit
    • In the intiation step of bacterial translation, the 50S subunit associates with fMet-tRNA and a complex composed of the 30S ribosomal subunit and mRNA to form the functional 70S initiation complex
      • Linezolid ineracts with the 50S subunit with micromolar affinity (and it has no affinity to the 30S subunit)
        • This interaction prevents the formation of the 70S initiation complex
344
Q

what does linezolid directly interact with

A

23S rRNA

345
Q

linezolid therapeutic use

A
  1. vancomycin resistant e. faecium
  2. nosocomial pneumonia caused by methacillin resistant strains of staph aureus
  3. skin infection caused by methicillin resistant strains of staph aureus
346
Q

does linezolid have good oral bioavailability

A

yes- it is excellent

347
Q

how to reduce development of drug-resistant bacteria and maintain the effectiveness of linezolid

A

should be used only to treat or to prevent infections that are proven or strongly suspected to be caused by multiply drug resistan gram (+) bacteria

348
Q

how has linezolid resistance occur

A

target site modification

349
Q

linezolid side effects

A

nausea, vomiting, diarrhea

350
Q

linezolid metabolism

A

metabolism via morpholine ring oxidation

351
Q

linezolid half life

A

4-6 hours

352
Q

linezolid drug interactions

A

since linezolid is a moderately potent, reversible, nonselective inhibitor of monoamine oxidase. Therefore it has the potential for interaction with adrenergic and serotonergic agents

353
Q

what drug is a second generation oxazolidinone

A

tedlizolid

354
Q

is tedizolid and linezolid more potenent vs MRSA

A

tedizolid

355
Q

vancomycin MOA

A

inhibits bacterial cell wall synthesis at a site diffeernt than beta lactams during the second stage of cell wall synthesis by binding firmly to D-alanyl-D-alanine portion of cell wall precursors to prevent cross-linking and further elongation of peptidoglycan –> weakens cell wall

356
Q

is vancomycin cidal or static and in what manner

A

time dependent bactericidal activity; slowly kills bacteria (static against enterococcus)

357
Q

vancomycin mechanism of resistance

A
  • Resistance in VRE and VRSA is due to modificatio of D-alanyl-D-alanine binding site of peptidoglycan
  • VISA causes a thickened cell wall, leading to increased dose of vancomycin required
358
Q

What does modification of D-alanyl-D-alanine cause

A
  • terminal D-alanine replaced by D-lactate
  • Loss of critical hydrogen bond
  • Loss of antibacterial activity
359
Q

Vancomycin spectrum of activity

A

Gram positive bacteria: MSSA, MRSA, C. diff

360
Q

Vancomycin synergy

A

displays synergy with aminoglycosides

361
Q

vancomycin absorption

A

absorption from GI tract is neglible after oral administration, except in patients with intense colitis

362
Q

vancomycin distribution

A

widely distributed into body tissues and fluids, includising adipose tissue- use TBW for VD calculation

363
Q

vancomycin CSF penetation

A

variable penetration into CSF, even in th epresence of inflames meninges

364
Q

vancomycin elimination

A

primary eliminated unchanged by the kidney via glomerular filtration

365
Q

what is vancomycin elimination half-life dependent on

A
  • renal function
    • 6-8 hrs with noram renal function
    • 7-14 days with ESRD
366
Q

vancomycin serum concentration monitoring

A
  • AUC-based guided dosing and monitoring is recommended using peak and trough
367
Q

when to pull vanco peak and target level

A

draw peak 60 minutes after end of infusion: target 30-40 mcg/mL

368
Q

vanco target trough level

A

10-15 mcg/mL

369
Q

vanco target AUC/MIC

A

400-600

370
Q

vancomycin and hemodialysis

A

vanco is removed by hemodialysis (30-40% removed per 3-4 hour HD session with new membranes)

371
Q

normal renal function vanco dosing

A

15-20 mg/kg/dose every 12 hours (typically 1 to 1.5g)

372
Q

when do you use oral vanco

A

c. diff colitis

373
Q

vancomycin clinical uses

A
  • MRSA infections
  • Endocariditis
  • serious gram-positive infections in beta lactam allergic patients
  • PRSP
374
Q

vancomycin adverse effects

A
  1. red-man syndrome
  2. nephrotoxicity
  3. ototoxicity
  4. thrombophlebitis
  5. interstitial nephritis
375
Q

what causes red-man syndrome and treatment for it

A
  • flushing and prutitis on upper torso related to rate of IV infusion
    • No faster than 15mg per min
  • resolves spontaneously after d/c
376
Q

what drug is a streptogramin and why was it developed

A

synercid was developed in response to the need for antibiotics with activity against resistant gram positive bacteria, namely VRE

377
Q

what is synercid a combo of

A

two semi-synthetic pristinamycin derivatives in a 30:70 w/w ratio: quinupristin and dalfopristin

378
Q

synercid MOA

A

each agents acts individually on 50S (reversibly) ribosomal subunit to inhibit early and late stages of protein synthesis near the site where the macrolides and clindamycin bind

379
Q

is synercid primarily static or cidal and in what manner

A

bacteriostatic in a time dependent manner

380
Q

synercid MOR

A
  • Alterations in ribosomal binding sites by erm gene
  • enzymatic inactivation
381
Q

synercid spectrum of activity

A
  • s. pneumonia (PRSP)
  • e. faecium ONLY (VRE)
  • MSSA
  • MRSA
  • coag-negative staph
382
Q

synercid absorption

A

only available parenterally

383
Q

synercid distribution

A

penetrates into extravascular tissue, lung, skin/soft tissue

384
Q

synercid CSF penetration

A

minimal CSF penetration

385
Q

synercid elimination

A

both agents are metabolized: t 1/2 is 0.6-1 hour for quinu and 0.3 hours for dalfo

386
Q

synercid drug interactions

A
  • cytochrome p450 3A4 inhibitor
    • HMG-COA reductase inhibitors
    • Cyclosporin, tacrolimus
    • carbamazepine
387
Q

synercid adverse effects

A
  1. venous irritation- esp when administered through a peripheral vein
  2. severe myalgias, arthralgias
388
Q

linezolid drug class

A

oxazolidinones

389
Q

tedizolid drug class

A

oxazolidinones

390
Q

why were oxazolidinones developed

A

in response to need for antibiotics with activity against resistant gram-positives (VRE, MRSA, VISA)

391
Q

oxazolidinones MOA

A

binds to the 50S ribosomal subunit near the surface interface of 30S subinut (unique binding site) –> causes inhibition of 70S initiation complex, which inhibits protein synthesis

392
Q

are oxazolidinones primarily static or cidal

A

primarily bacteriostatic

393
Q

oxazolidinones MOR

A
  1. alterations in ribosomal binding sites- rare
  2. cross-resistance with other protein synthesis inhibitors is unlikely
394
Q

oxazolidinones spectrum of activity

A
  1. PRSP strep pneumoniae
  2. e. faecium
  3. e. faecalis (VRE)
  4. MRSA
  5. MSSA
  6. VRSA
395
Q

linezolid absorption

A

100% bioavailable

396
Q

tedizolid absorption

A

91% bioavailable

397
Q

oxazolidinones distribution

A

readily distributes into well-perfused tissued

398
Q

oxazolidinones CSF penetration

A

linezolid CSF penetration is 30%

399
Q

oxazolidinones elimination

A
  • both renally and nonrenally
400
Q

oxazolidinones half-lives

A
  • 4 to 5 hours for linezolid
  • 12 hours for tedizolid
401
Q

is dose adjustments needed for RI in oxazolidinones

A

NO

402
Q

are oxazolidinones removed by HD

A

yes

403
Q

oxazolidinones reserved use

A
  • serious/complicated infections caused by resistant Gram-positive bacteria
404
Q

linezolid and tedizolid drug interactions

A

serotonin syndrome with SSRIs

405
Q

Linezolid AE

A
  1. optic and peripheral neuropathy
  2. thrombocytopenia or anemia
406
Q

what drug class is daptomycin

A

lipopeptides

407
Q

why was daptomycin developed

A

in response to the need for antibiotics with activity against Gram-positives (VRE, MRSA, VISA0

408
Q
A
409
Q

daptomycin MOA

A

binds to bacterial membranes and inserts lipophilic tail into cell wall to form trans-membrane channel –> leakage of cellular contents and rapid depolarization of the membrane potential, which causes inhibition of protein, DNA, and RNA synthesis

410
Q

is daptomycin static or cidal ande in what manner

A

concentration dependent bactericidal activity

411
Q

daptomycin MOR

A

rarely reported in VRE and MRSA due to altered cell membrane binding

412
Q

daptomycin spectrum of activity

A
  1. s. pneumoniae (PRSP)
  2. e. facecium and faecalis (VRE)
  3. MSSA
  4. MRSA
  5. VRSA
  6. coagulase-negative staphylococci
413
Q

daptomycin distribution

A

readily distributes into well-perfused tissue: protein binding 90%

414
Q

daptomycin CSF penetration

A

poor penetration

415
Q

daptomycin elimination

A

excreted primarily by the kidneys

416
Q

daptomycin half life

A
  • 7.7 to 8.3 hours in normal renal function
417
Q

daptomycin RI anda HD

A
  • dosage adjustments are required in the presence of RI
  • NOT removed by HD
418
Q

daptomycin pneumonia treatment

A

daptomycin should not be used in the treatment of pneumonia

419
Q

daptomycin adverse effects

A
  1. myopathy and CPK elevation
  2. acute eosinophilic pneumonia
420
Q

daptomycin drug interactions

A

HMG CoA-reductase inibitors- may lead to increased incidence of myopathy

421
Q

what drugs are lipoglycopeptides

A
  1. telavancin
  2. dalvance
  3. orbactiv
422
Q

why were lipoglycopeptides developed

A

to address the need for antibiotics with activity against resistant gram-positive (VRE, MRSA, VISA)

423
Q

lipoglycopeptides MOA

A

all 3 interfere with polymerization and cross-linking of peptidoglycan by binding to D-Ala-D-Ala terminal

424
Q

is lipoglycopeptides is static or cidal

A

concentration-dependent bactericidal acitivity

425
Q

lipoglycopeptides MOR

A
  • alteration in peptidoglycan terminus
426
Q

lipoglycopeptides spectrum of activity

A
  1. e. faecium and faecalis
  2. MSSA
  3. MRSA
  4. Vanco-intermediate staph aureus
427
Q

is lipoglycopeptides static or cidal and in what manner

A

concentration dependent bactericidal activity

428
Q

lipoglycopeptide distribution

A

distributes fairly well into tissue

429
Q

lipoglycopeptides CSF distribution

A

poor CSF penetration

430
Q

lipoglycopeptides protein binding

A

90%

431
Q

telavancin elimination

A

excreted primarily by the kidneys –> dosage adjustments needed in the presence of RI

432
Q

dalbavancin elimination

A

33% unchanged in urine –> dose adjustment needed in RI

433
Q

oritavancin elimination

A

Unknown –> no adjustment needed in RI

434
Q

are lipoglycopeptides removed by HD

A

no

435
Q

lipoglycopeptide lab interactions

A
  • telavancin and oritavancin interfere with coagulation tests (PT, INR, aPTT) by binding to artificial phospholipid surfaces
436
Q

telavancin adverse effects

A
  • nephrotoxicity
  • QTc prolongation
  • taste disturbances
437
Q

lipoglycopeptides adverse effects

A

infusion related reactions –> red man syndrome, N/V/D

438
Q

lipoglycopeptide pregnancy category

A
  • pregnancy category C
    • telavancin with black box warning on use during pregnancy
      • perform pregnancy test in women before use
439
Q

T/F: vancomycin is the drug of choice for infections due to MRSA

A

True

440
Q

aminoglycoside core structure

A

1,3-diaminocyclitol: aka streptidine and 2-deoxystreptamine

441
Q

what structure is this

A

streptidine

442
Q

what structure is this

A

2-deoxystreptamine

443
Q

what drug is this

A

tobramycin

444
Q

what drug is this

A

plazomicin

445
Q

what drug is this

A

amikacin A

446
Q

what drug is this

A

gentamicin C2

447
Q

what drug neomycin B

A

neomycin b

448
Q

what drug is this

A

streptomycin

449
Q

aminoglycoside MOA

A

inibit protein synthesis by binding to the 30S ribosomal subunit

450
Q

how do aminoglycosides result in cell death

A
  • the binding to the 16S rRNA that forms the A site interferes with formation of the initiation complex, blocks further translation, and elicits premature termination
    • It also causes impairment of the proofreading function of the ribosome and formation of nonsense proteins resulting form selectrion of the wrong aminco acids during translation
451
Q

why are nonsense proteins problematic for bacteria

A
  • Nonsense proteins impair bacterial cell wall function
    • Damanged membranes have altered permeability characteristics and actually allow transport of larger amount aminoglycoside, and protein synthesis ceases altogether
      • ultimately, the aminoglycosidees lead to leakage of ions and disruption of the cytoplasmic membrane, resulting in cell death
452
Q

how does bacterial aminoglycoside uptake occur

A
  • the intial entry of the positively charged aminoglycosides through the outer membrane involves the displacement of Mg and Ca ions that form salt bridges with phosphates of the phospholipids in the membrane
    • This makes the membrane more permeable to the aminoglycosides
      • Passage through the cytoplasmic membrane is an active transport process
453
Q

how can metabolism cause aminoglycoside resistance

A
  • bacteria inactivate aminoglycosides by acetylation, adenylation, and phosphorylation
    • The genes responsible for metabolism can be transferred to other bacteria
454
Q

how can altered ribosomes cause aminoglycoside resistance

A

The 16S rRNA binding site can be altered through point mutations

455
Q

how can altered aminoglycoside cause aminoglycoside resistance

A
  • the rate of emergence is far less than resistance due to metabolism, and the phenotype reverts after the drug is removed
456
Q

aminoglycoside toxicities

A
  • ototoxic (irreversible) –> esp when taking loop diuretics/vanco
  • nephrotoxic (reversible)
457
Q

aminoglycoside drug interations

A
  • concurrent use with loop diuretics (furosmide or ethacrynic acid) or other nephrotoxic antimicrobial drugs (vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided
458
Q

aminoglycoside ototoxicity symptoms

A
  1. tinnitus/high frequency hearing loss
  2. vestibular damage resulting in vertigo, loss of balance, and ataxia
459
Q

respiratory issues with aminoglycosides and how to treat it

A
  • calcium increases the degree of depolarization at the NMJ caused by ACh, causing respiratory paralysis
    • can usually be reversed by neostigmine or calcium gluconate, but mechanical respiratory assistance may be necessary
460
Q

aminoglycoside toxicity risk relationship

A

likelihood of aminoglycoside toxicity increases with the treatment period, and is more likely to occur is treatment is extended more than 5 days

461
Q

therapeutic use of aminoglycosides

A

although they have broad spectrum activity against both gram + and gram - bacteria, in practice their use is almost always reserved for treatment of gram - bacteria

462
Q

what happens when you give aminoglycosides and penicillins together

A

chemical reaction render both drugs inactivated; therefore should be administered in different compartments

463
Q

how is bacterial endocarditis treated

A

penicillin/aminoglycoside

464
Q

what does streptomycin treat

A

TB

465
Q

amikacin clinical use

A
  • used competitively with gentamicin for treatment of mycobacterium tb, francisella tularnesis, and severe pseudomonas aeruginosa
  • aminoglycoside resistant nosocomial infections in hospitals
466
Q

tobramycin clinical use

A

widely used parenterally to treat gentamicin-resistnat p. aeruginosa infections, as well as other difficult infections

467
Q

bacterial metabolism of tobramycin

A
  • tobramycin is produced by fermentation of streptomyces tenebrarius
    • lacks a 3’-hydroxyl group and cannot be phosphorylated at that position
    • adenylated at c-2’
    • acetylated at c-3
468
Q

amikacin potency vs kanamycin potency

A
  • the presence of the l-hydoxyaminobuteryl amide moiety inhibits bacterial metabolism by r-factors, so amikacin is more potent than kanamycin
469
Q

gentamicin clinical use

A
  • uti
  • joint and bone infections
  • skin infections/burns
  • eye infections
470
Q

why is gentamicin the most important aminoglycoside

A

low cost and reliable activity against all but the most resistant gram negative aerobes

471
Q

what are the orally used aminoglycosides

A
  • neomycin B
  • paromomycin
472
Q

why are macrolides polyketides

A

they are produced by sequential addition of propionate groups to a growing chain. This results in methyl groups on alternate carbon atoms in the macrolide ring

473
Q

how is erythromycin more soluble

A
  • the pKa of the amine in erythromycin is 8.8
    • the amine can form salts that are more soluble
474
Q

macrolide MOA

A
  • macrolides inhibit bacterial protein synthesis by bind reversibly to the P site of the bacteria ribosome, thereby inhibiting translocation of peptidyl-tRNA from the A site to the P site
475
Q

where does macrolide binding occur

A

bacterial 23S RNA

476
Q

are macrolides mainly static or cidal

A

bacteriostatic

477
Q

where do macrolides tend to accumulate

A

within leukocytes, and are therefore actually transported into the site of infection

478
Q

hydrolase mechanism resistance in macrolides

A

lactone ester hydrolase induced to degrade the macrolides by hydrolysis of the macroycle

479
Q

RNA methylase resistance in macrolides

A
  • drug-induced production of RNA methylase
    • a specific adenine base A2058 on the 23S RNA molecule of the 50S ribosomal subunit is methylated
      • this inhibits the bidning of macrolides to the 50S subunit
480
Q

Mutation resistance of macrolides

A

mutation of adenine to guanine at A2058 results in a 10,000 fold reduction in binding of erythromycin and clarthromycin to the 23S ribosomal RNA

481
Q

efflux resistance of macrolides

A

an efflux pump ejects drugs from the cell by an active transport process

482
Q

intrinsinc resistance of macrolides

A
  • pseudomonas spp and enterobacteer spp. exhibit intrinsic resistance by not allowing entry of these drugs
    • there are specific genes associated with these organisms that confer this intrinsic resistance
483
Q

what route should erythromycin not be adminsitered and why

A
  • should not be administered orally because the parent molecuple can be inactivated under acidic conditions by a process involving the 6-OH and the 12-OH groups
    • the reaction is an intramolecular acid-catalyzed ketal formation that is inactive
484
Q

how to achieve acid stabilitty in macrolides

A
  • Using a 6-OCH derivative, which blocks ketal formation at low pH
485
Q

what macrolide is formed when replacing 6-OH with OCH3

A

Clarithromycin

486
Q

what macrolide is formed when replacing the C-9 ketone for an N-methylated methyleneamino moiety

A

azithromycin

487
Q

main route of erythromycin metabolism

A

demethylation in the liver

488
Q

erythromycin half life

A

1.5 hours

489
Q

will enteric coated erythromycin be absorbed orally

A

yes

490
Q

erythromycin and clarithromycin drug interactions

A
  • bind and inhibit CYP3A and related P450 isoztmes
    • carbamaepine, cyclosporin, quinidine
491
Q

clinical use of erythromycins

A

primarily used for infections of skin and soft tissues primarily caused by gram (+) bacteria

492
Q

erythromycin is drug of choice for what organisms (6)

A
  1. mycoplasmA
  2. Group A
  3. Legionella
  4. Bordetella
  5. campylobacter
  6. corynebacterium
493
Q

what are macrolides used prophylactically for (3)

A
  1. endocarditis
  2. large bowel surgery
  3. oral surgery
494
Q

what do macrolides treat (5)

A
  1. bronchitis
  2. otitis media
  3. acne
  4. sinusitis
  5. PID
495
Q

macrolide GI side effects

A

the 14-membered macrolides strongly stimulate gastrointestinal motor activity and can cause vomiting, gastric cramps, and abdominal pain

496
Q

macrolide biliary adverse events

A
  • long term use (10-20 days) can induce a reversible cholestatic hepatitis which will manifest as a jaundice with cramping and fever
    • relieved upon termination of the drug therapy
497
Q

phagocytes use for macrolides

A
  • erythromycin is very rapidly absorbed and diffuses into most tissues and phagocytes
    • due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where during active phagocytosis, large concentrations of erythromycin are released
498
Q

why are aminoglycosides a special group of antibiotics

A
  • dosed individually for each patient and require serum concentration monitoring due to:
    • interpatient variability in Vd and Cl
    • narrow therapeutic window/index
499
Q

aminoglycoside derivatives

A

all derived from an actinomycete or are semisynthetic derivatives

500
Q

aminoglycoside chemistry

A
  • consist of 2 or more amino sugars linked to an aminocyclitol ring by glycosidic bonds
  • are very polar compounds that are polycationic (PK), water soluble, and incapable of crossing lipid-containing cell membranes
501
Q

aminoglycosides MOA

A
  • irreversibly bind to 30S ribosomes
    • disrupts the initiation of protein synthesis, decrease overall protein synthesis, and causes misreading of mRNA
      • Must bind to and diffuse through outer membrane (passive) and cytoplasmic membrane (energy-dependent) to reach the ribosome
502
Q

are aminoglycosides cidal or static and in what manner

A

bactericidal in a concentration-dependent manner

503
Q

aminoglycoside MOR

A
  1. alteration in aminoglycoside uptake
  2. synthesis of aminoglycoside-modifying enzymes
  3. alteration in ribosomal binding sites
504
Q

Aminoglycoside spectrum of activity GPA (3)

A
  1. enterococcus spp
  2. s. aureus (most(
  3. Coag negative staph
505
Q

aminoglycoside spectrum of activity GNA (8)

A
  1. e. coli
  2. k. pneumonia
  3. pseudomonas aeruginosa
  4. providencia
  5. serratia
  6. salomonella
  7. shigella
  8. morganella
506
Q

are aminoglycosides active against anaerobes

A

no

507
Q

PAE of aminoglycosides

A
  • suppression of bacterial growth after serum concentrations have fallen below MIC
    • finite duration= 2 to 4 hours from gram-negatives
508
Q

aminoglycoside synergy

A

observed with AGs and cell wall active agents against enterococcus, staph, viridans, gram negatives

509
Q

True/False: aminoglycosides can be used as monotherapy for the treatment of infections due to gram positive aerobes

A

false

510
Q

aminglycoside pharmacology

A

poorly absorbed from GI tract, must use parenteral administration for systemic infections

511
Q

preferred aminoglycoside administration

A

intermittent IV infusion preferred- doses should be infused over 30 to 60 minutes

512
Q

aminoglycoside distribution

A

primarily distribute into extracellular fluid volume –> body fluids, urinary tract, bloodstream

513
Q

poor distrubition sites for aminoglycosides

A
  1. CSF
  2. lungs
  3. adipose tissue
514
Q

IBW or TBW for dosing aminoglycosides

A

IBW

515
Q

volume status for aminoglycosides

A

volume status must be taken into account to calculate appropriate dose- concentration dependent killers

516
Q

aminoglycoside elimination

A

85-95% is eliminated unchanged by the kidney via glomerular filtration –> high urinary concentrations

517
Q

t 1/2 of aminoglycosides

A
  • dependent on renal function
    • normal is 2.5-4 hours
518
Q

aminoglycosides and dialysis

A
  • 30-50% removed by hemodialysis
  • 25% removed by peritoneal dialysis
519
Q

when to draw peak aminoglycoside level

A

30-60 minutes after end of infusion

520
Q

when to draw trough aminoglycoside level

A

prior to next dose

521
Q

gram positive synergy dosing aminoglycoside

A

1 mg/kg gent

522
Q

gent/tobra dosing (LD+MD)

A
  • LD= 2-2.5 mg/kg
  • MD= 1.5-2 mg/kg/dose
523
Q

amikacin dosing

A

7.5-10 mg/kg/dose

524
Q

mod infection gent/tobra peak/trough

A
  • Peak: 4-6
  • Trough: 0.5-1.5
525
Q

mod infection amikacin peak/trough

A
  • PEAK: 20-25
  • TROUGH: <8
526
Q

mod-severe infection gent/tobra peak/trough

A
  • peak: 6-8
  • trough: 1-1.5
527
Q

mod-severe infection amikacin peak/trough

A
  • 25-30
  • <8
528
Q

severe infection gent/tobra peak/trough

A
  • peak: 8-10
  • trough: <2
529
Q

severe infection amikacin peak/trough

A
  • peak: 25-30
  • torugh: <8
530
Q

gent/tobra extended dosing

A

5-7 mg/kg q 24H

531
Q

amikacin extended interval dosing

A

15 to 25 mg/kg q 24 h

532
Q

gent/tobra peak/trough qd dosing

A
  • peak: 13-20
  • trough: <0.5
533
Q

amikacin peak/trough qd dosing

A
  • peakL 40-50
  • trough: <8
534
Q

True/False: all patients can receive the same aminoglycoside dose since there is little interpatient variability in Vd and Cl

A

False

535
Q

plazomicin dosing

A

15mg/kg IV

536
Q

amikasin, gentamicin, tobramycin clinical uses

A

infections to due gram negative aerobes (usually with beta lactams)

537
Q

gentamicin, streptomycin clinical uses

A
  • for syndergy with cell active antibiotics for serious infections due to gram positive aerobes
538
Q

streptomycin clinical uses

A

tuberculosis

539
Q

amingolycoside nephrotoxicity causes

A

nonliguric azotemia due to proximal tubular damange; increase in BUN and serum Cr

540
Q

is aminoglycoside nephrotoxicity reversible or irreverible

A

reversible

541
Q

amingolycoside nephrotoxicity risk factors (6)

A
  1. prolonged high troughs
  2. long duration of therapy
  3. underlyding renal dysfunction
  4. elderly
  5. hypovolelmia
  6. use of concomitant nephrotoxins
542
Q

ototoxicity causes in aminoglycosides

A

8th cranial nerve damage- vestibular and/or auditory toxicity; irreversible

543
Q

FQ MOA

A
  • inhibit DNA synthesis by inhibiting bacterial topoisomerases necessary for DNA synthesis
544
Q

How do FQs affect DNA gyrase and its target

A
  • removes excess positive supercoiling helix
    • forms stable complex with DNA and DNA gyrase, which blocks DNA replication
  • primary target in gram negative bacteria
545
Q

How do FQs affect topoisomerase IV and its target

A
  • essential for separation of interlinked daughter DNA molecules, but interfere with separation of daughter cells
  • primary target for many gram + bacteria
546
Q

Are FQs static or cidal and in what manner

A

rapid, concentration-dependent bactericidal activity

547
Q

4 MOR of FQ

A
  1. altered binding sites
  2. expression of active efflux
  3. altered cell wall permeability –> decreased porin expression
  4. cross-resistance occurs between FQs
548
Q

older FQs and route of admin

A

cipro: PO/IV

549
Q

newer FQs and routes of administation

A
  1. levofloxacin: PO/IV
  2. moxifloxacin: PO/IV
  3. Delafloxacin: PO/IV
550
Q

FQs GPA

A
  • group and viridans strep
  • strep pneumoniae: PRSP
  • enterococcus
  • MSSA
551
Q

what FQ is active against MRSA

A

delafloxacin

552
Q

FQs Spectrum of Activity GNA

A
  • h. influenzae, m. catarrhalis, neisseria
  • enterobacteriaceae
  • pneudomonas aeruginosa
553
Q

what FQ is not active aginst p. aeruginosa

A

moxifloxacin

554
Q

what atypical bacteria are FQs active against (4)

A
  1. legionella
  2. chalmydia
  3. mycoplasma
  4. ureaplasma
555
Q

what other bacteria are FQs active against (2)

A
  1. mycobatcerium tuberculosis
  2. bacillus anthracis
556
Q

delafloxacin oral bioavailability

A

59%- so higher dose has to be used

557
Q
A
558
Q

cipro oral bioavailability

A

70-75%

559
Q

levo/moxifloxacin oral bioavailability

A

>90%

560
Q

FQs distribution

A

lung; skin/soft tissue and bone, urinary tract and prostate

561
Q

FQs CSF penetration

A

minimal

562
Q

FQs elimination

A
  • most are renally eliminated thus dosage adjustment required in the renal insufficiency, but still would use to treat UTIs
563
Q

which FQ is not renally eliminated

A
  • moxifloxacin: hepatically eliminated
564
Q

which FQ is removed during HD

A

NONE

565
Q

which FQs treat community acquired pneumonia (2)

A
  1. levo
  2. moxi
566
Q

which FQs treat nosocomial pneumonia

A
  1. cipro
  2. levo
567
Q

FQ neurologic AE

A

peripheral neuropathy (new black box warning)

568
Q

FQ cardiac AE

A

prolongation of QTC interval- case reports with current FQs- use with caution in pts with hypokalemia, pre-existing QT prolongation, concomitant antiarrhythmics (amiodarone/sotalol)

569
Q

FQ and pregnancy relationship

A

contraindicated in pediatric patients and pregnant/breastfeeding women because of articular cartilage damage

570
Q

other FQ AE

A

tendonitis and tendon rupture: >60 years old, on corticosteroids, transplant

571
Q

FQ Drug Interactions

A
  • Divalent and trivalent cations
    • Impairs absorption of orally-administered FQs –> may lead to clinical failure
  • Warfarin –> Increases PT/INR
572
Q

what are the three main macrolides

A
  1. erythromycin
  2. azithromycin
  3. clarithromycin
573
Q

Macrolide MOA

A
  • inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit
    • induces dissociation of peptidyl transfer RNA from the ribosome during the elongation phases
574
Q

macrolides are static or cidal and in what manner

A
  • typically bacteriostatic
  • time dependent for erythro and clarithro
  • concentration dependent for azithro
575
Q

Macrolides MOR

A
  • active reflux
  • altered binding sites
  • cross-resistance occurs between all macrolides
576
Q

macrolide spectrum of activity

A
  1. group and viridans strep
  2. PSSP
  3. MSSA
  4. bacillus, corynebacterium
577
Q

what macrolide is best for gram positive aerobes

A

clarithro

578
Q

what macrolide is best for gram negative aerobes

A

azithro

579
Q

do macrolides have activity against enterobacteriaceae

A
580
Q

what atypical bacteria do macrolides have activity against

A
  1. legionella
  2. chlamydia
  3. mycoplasma
  4. ureaplasma
581
Q

macrolides are active against what other bacteria

A

mycobacterium avium complex

582
Q

erythromycin absorption

A
  • variable absorption (15-45%)- food may decrease absorption
    • bases are destroyed by gastric acid
583
Q

clarithromycin absorption

A

acid stable and well absorbed (52-55%) regardless of presence of food

584
Q

azithromycin absorption

A

acid stable at 37% regardless of presence of food

585
Q

macrolides distribution

A

extensive tissue and cellular distribution- clarithromycin and azithromycin with very large Vds

586
Q

macrolides CSF penetration

A

minimal csf penetration

587
Q

erythromycin elimination

A

exreted in bile and metabolized (cyp 450)

588
Q

clarithromycin elimination

A

metabolized and also partially eliminated by the kidney; requies dose adjustment when CrCl <30 mL/min

589
Q

azithromycin elimination

A

biliary excretion

590
Q

what macrolides are removed by HD

A

none

591
Q

azithromycin half life

A

68 hours

592
Q

macrolides clinical uses

A
  1. commonity-acquired pneumonua
  2. stds
  3. MAC
  4. alternative for penicillin-allergic patients
593
Q

Macrolides AE

A
  1. GI - take with food if possible
  2. thrombophlebitis- dilute dose, slow admin, large vein
  3. QTc prolongation
594
Q

macrolides drug interactions

A
  • erythromycin and clarithromycin are inhibitors of cytochrome P450 system in the liver and may increase concentrations of:
    • theophylline
    • cabamazepine
    • cyclosporine
    • phenytoin
    • warfarin
    • digoxin
    • valproic acid
595
Q

clindamycin synthesis

A

synthesized from the naturally occurring antibiotic lincomycin by treatment with chlorine and triphenylphosphine in acetonitrile

596
Q

Clindamycin MOA

A

Inhibits protein synthesis by binding to the bacterial 50S ribosomes

597
Q

can antagonism and cross-resistance between clinda and erythro occur and why

A

yes because clindamycin and erythromycin bind to the same site of the 50S ribosome

598
Q

Clindamycin clinical use

A
  • aerobic gram + cocci: Staph and streph
  • anaerobic gram - bacilli: bacteroides and fusobacterium: MRSA
599
Q

clindamycin metabolism

A

clindamycin is extensive metabolized by cytochrome P450 enzymes in the liver to the sulfoxide and N-demethylated derivative

600
Q

what drug is this

A

clindamycin

601
Q

clindamycin PK

A

90% of the administered dose is absorbed from the GI tract. It is widely distributed and penetrates the CNS in high enough concentrations

602
Q

clindamycin elimination

A

clindamycin and its metabolites are mainly excreted in the urine and bile

603
Q

clindamycin dose adjustment

A

accumulation of clindamycin can occur in patients with hepatic failure, and adjustment of the dosage may be required

604
Q

clindamycin adverse effects

A

GI

605
Q

What lethal condition can clindamycin cause

A

Pseudomembranous colitis is potentially lethat due to overgrowth of clostridium difficile, which results in the production of a toxin

606
Q

what drug is this

A

tetracycline

607
Q

tetracycline chemical properties

A

chelation: tetracyclines form stable chelates with polyvalent metal ions such as Ca, Al, Cu, Mg

608
Q

tetracycline food cautions

A

should no tbe administerd with foods that are rich in calcium, should be administered 1 hour before or 2 hours after the tetracycline

609
Q

should children be given tetracyclines

A

No, tetracyclines chelate calcium during formation of teethm resulting in permanently brown or gray teeth

610
Q

why are tetracyclines injected with EDTA

A

to chelate the insoluble calcium, and they are buffered to acidic pH where chelation is suppressed to decrease pain

611
Q

preferred route of tetracycline

A

oral

612
Q

how do tetracyclines bind to heavy metals

A

through chelation

613
Q

describe tetracycline epimerization, and the effect that this has on biological activity

A
  • hydrogen on the amine-bearing carbon atom is acidic, resultin gin enolization and epimerization, which is inactive and loses half of their potencies
614
Q

state the pH at which tetracycline epimerization is most rapid, and the relative
rate of epimerization in the solid state vs. in solution

A
  • pH 4
  • epimerization is slow in the solid state
615
Q

describe tetracycline dehydration

A

the tertiary, benzylic hydroxyl group at c-6 has an antiperiplanar relationship with the proton at c-5a, so it is set up for elimination, leading to an inactive product of 4-epianhydrotetracycline, which is toxic to the kidneys

616
Q

explain why minocycline and doxycycline lack the renal toxicity of tetracyclines

A

both lack a c-6 hydroxyl group annd are therefore completely free of this potential for toxicity

617
Q

describe how tetracyclines cleave in under basic conditions

A

cleavage occurs at pH 8.5 or above, the lactone product is inactive

618
Q

describe the mechanism of action of the tetracyclines

A
  • bind to the 30S ribosomal subunit and inhibit bacterial protein sythnesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome, resulting in termination of peptide chain growth
619
Q

describe the basis for selective toxicity of tetracyclines to bacteria, but not hosts

A

eukaryotic cells do not have a tetracyline uptake mechanism

620
Q

do tetracyclines bind to the same spot as erythromycin

A

no

621
Q

list the main therapeutic uses of the tetracyclines.

A
  • acne
  • chlamydia
  • rickettsia
  • spirochetal
  • anthrax
  • plague
  • legionnaires
622
Q

Be able to describe the main advantages of using tetracycline itself rather than one of the other antibiotics in the tetracycline class

A

generic and relatively inexpensive

623
Q

is demeclocycline is more or less stable to dehydration than tetracycline

A

more

624
Q

explain why demeclocycline is more stable to dehydration than tetracycline

A

it has a secondary hydroxyl group at c-6 instead of the tertiary hydroxyl group: secondary cation intermediate formed from demeclocycline in the dehydration reaction is less stable

625
Q

do minocycline and doxycyline undergo dehydration

A

No

626
Q

explain why minocycline and doxycycline do not undergo dehydration

A

they both lack a c-6 hydroxyl group and therefore do not undergo acid-catalyzed dehydration

627
Q

describe the unique toxicities of minocycline in comparison with the other tetracyclines

A

vestibular toxicites

628
Q

explain why doxycycline is widely considered to be the tetracycline of choice

A

fewer side effects and has 90-100% oral bioavailability, which permits once a day dosing

629
Q

does why tigecycline have the potential for 4-epianhydrotetracycline-mediated toxicity and why

A

No because it lacks a c-6 hydroxyl group and therefore does not undergo acid-catalyzed dehydration. it therefore has no potential for 4-epianhydrotetracycline-mediated toxicity

630
Q

tigecycline AE

A
  1. hepatoxicity
  2. pancreattis
  3. anaphlactoid reaction
631
Q

sarecycline main therapuetic use

A

moderate to severe acne

632
Q

omadacycline clinical use

A

skin infections and community acquired bacterial pneumonia

633
Q

can sarecycline and omadacycline be given while pregnant

A

no

634
Q

chloramphenicol MOA

A

binds reversible to the 50S ribosomal subunit at a site that is near the site for erythromycin and clindamycin to block peptide bond formation between the P site and the A site

635
Q

chloramphenicol and peptidyl transferase activity

A

chlorampenicol inhibits the peptidyl transferase activity of the ribosome and thus blocks peptide bond formation between the P site and the A site

636
Q

chlorampenicol therapuetic use

A
  1. bacterial meningitis
  2. typhoid fever
  3. ricketts
  4. intraocular infections
637
Q

metabolism of chloramphenicol sodium succinate

A

chloramphenicol sodium succinate is a prodrug for IV and IM administration that is hydrolyzed to chloramphenicol in the liver

638
Q

solubility characteristics and distribution of chloramphenical

A
  • lipid soluble, and it remains relatively unbound to plasma proteins
  • penetrates effectively into all tissues of the body, including the brain
639
Q

describe the main bacterial resistance mechanisms to chloramphen

A
  1. reduced membrane permeability
  2. mutation of the 50S ribosomal subunit
  3. Elaboration of chloramphenicol acetyltransferase
640
Q

describe how resistant bacteria metabolize chloramphenicol, and what effect this
has on biological activity

A

elaboration of chloramphenicol acetyltransferase, which acetylates one or both of the hydroxy groups to form metabolites that do not bind to the 50S ribosomal subunit

641
Q

show how chloramphenicol is metabolized in humans

A
  • metabolized to its glucoronide in the liver
    • inactive and excreted by the kidneys
  • reactions involves nucleophilic attack of the less hindered primary alcohol on UDPGA, catalyzed by glucuronyl transferase
642
Q

describe the most serious potential toxicity of chloramphenicol, and how it limits
the use of chloramphenicol.

A
  • aplastic anemia
    • effect usually becomes apparent weeks or months after chloramphenicol treatment has been stopped
  • bone marrow suppression due to impairment of mitochondrial function resulting from inhibition of protein synthesis
643
Q

when should the dose of chloramphenicol be reduced

A

if hepatic function is impaired

644
Q

Should neonates receive chloramphenicol

A

NO! they cannot metabolize chloramphenicol

645
Q

compare the risk of serious toxicity of chloramphenicol eye drops vs. oral
chloramphenicol

A
  • lowest risk occurs with eye drops
  • highest risk is with oral chloramphenicol
646
Q

describe how chloramphenicol toxicity can be minimize

A

Keep concentrations less than 25 ug/mL and give less than 20g

647
Q

is chloramphenicol bone marrow suppression is a predictor of
aplastic anemia?

A

NO!

648
Q

describe the relationship between chloramphenicol bone marrow suppression
and cumulative dose

A

the effect occurs quite predictably once a cumulative dose of 20 g has been given

649
Q

describe the relationship between chloramphenicol-induced childhood leukemia
and length of treatment with chloramphenicol

A

there is an increased risk of childhood leukemia and the risk increases with length of treatment

650
Q

specify the risk of drug interactions with chloramphenicol and the mechanism involved

A

chloramphenicol inhibits cytochrome p450 so drug interactions can be expected with drugs that are metabolized by cytochrome p450

651
Q

describe the effect that inflammation of the meninges has on brain
concentrations of chloramphenic

A
  • concentration achieved in brain and CSF is about 30 to 50% that of the plasma when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed
652
Q

recognize the core structures of the quinolone antibiotic

A

two rings with CO2H at C3 potition and o double bond at c4

653
Q

state the characteristics of first, second, and third generation quinolones

A
  • first generation
    • d/c but gram (-)
  • second generation
    • fluorine substituent at c-6 and a heterolytic ring (usually piperazine) at c-7
    • more potent for gram (-) but have extended activity again
  • third generation/fourth generation
    • gram +
    • not as potent as gram - from cipro
654
Q

specify the function of topoisomerases and gyrase

A

cleave DNA by carrying out a nucleophilic attack on a phosphodiester linkage, so one part of the strand becomes “free” and the other one becomes enzyme-linked

655
Q

describe the difference between topoisomerase I and topoisomerase II enzymes

A
  • topoisomerase 1 cuts one strand of the DNA helix
  • topoisomerase 2 cuts both strands of the DNA helix
656
Q

describe the common mechanistic features of bacterial gyrase, bacterial DNA
topoisomerase IV, and mammalian topoisomerase II.

A
  • Bacterial Gyrase
    • that catalyzes the ATP-dependent negative super-coiling of double-stranded closed-circular DNA
  • Bacterial Toposiomerase IV
    • Inhibition prevents separation of the daughter strands
    • usually targets gram + bacteria
  • Toposiomerase II
    • prevent relaxation of supercoiled DNA
    • ususally targeted by gram - bacteria
657
Q

describe DNA unwinding by the strand passage mechanism catalyzed by gyrase,
bacterial DNA topoisomerase IV, and mammalian topoisomerase II

A
  1. Cleavage of PD bond of each strand of DNA
  2. dsDNA induce a conformation change
  3. PD backbone is rejoined by nucelophilic displacement of the protein tyrosine residue by the 3’-OH of the cleaved strand
  4. To repeat the cycle, the ATP has to be hydrolyzed
658
Q

describe the mechanism of action of the quinolone

A
  • inhibition of DNA replication
  • Quinolones bind to the topoisomerase IV/DNA gyrase–DNA complexes and this results in the inhibition of DNA replication.
659
Q

describe the therapeutic uses of the quinolones

A
  1. UTI
  2. prostatitis
  3. STI
  4. GI
  5. RTI
  6. Bone, joint, and soft tissue infections
660
Q

describe the main bacterial resistance mechanisms to the quinolones

A
  1. decreased cellular permeability
  2. efflux pumos
  3. mutation of the taregt enzymes
661
Q

describe the main features of quinolone absorption, distribution, and elimination.

A
  1. absorbed orally amd jabe a high degree of bioavailability
  2. all are widely distributed –> will reach brain more when meninges are inflamed
  3. renal and hepatic clearance is important
662
Q

describe how ciprofloxacin is metabolized

A

UDPGA attacks OH group of Cipro and uses UGT to make a major inactive metabolite (glucornide)

663
Q

what are the main adverse effects of the quinolone antibioe main adverse effects of the quinolone antibiotics

A

nausea, vomiting, diarrhea

664
Q

describe how the inactive prontosil can be converted to an active antibiotic after oral admiistration

A

actively directed fractionation causes to prontosil prodrug to be isolated to the active metabolite of p-aminobenzenesulfonamide

665
Q

specify the therapeutic use of sulfanilamide

A

vaginal candida albicans

666
Q

how is tetrahydrofolic acid formed, and why is it an important metabolite

A
  • from dihyhydrofolate acid, you use DHFR to reduce dihydrofolic acid to tetrahydrofolic acid to use PABA
  • incorporation of PABA into the folic acid nucleus in inhibited competitively by the sulfonamides, which are bioisoteres
667
Q

explain why the sulfonamides are toxic to pathogenic bacteria but not humans

A

since mammalian cells utilize preformed folates in the diet and some bacterial cells are required to make their own folic acid, the sulfonamides have selective toxicity for bacterial cells as opposed to mammalian cells

668
Q

sulfonamides MOA

A

sulfonamides inhibits PABA, which prevents the formation of thymine, which is necessary for the bacteria to make DNA

669
Q

can sulfonamide activity be reversed

A

yes

670
Q

describe how the antibiotic activities of the sulfonamides can be reversed

A

by adding large quantities of PABA to the diet

671
Q

how does the acidity and pKa of p-aminobenzoic acid compares with that of sulfanulamide

A
  • PABA has a pKa of 4.9 and is mainly anionic at physiological pH
  • sulfanilamide has a pKa of 10.4 and is a week acid at physiological pH with anion:acid ration 1:1000
672
Q

explain how aromatic substituents on the sulfonamide nitrogen can increase acidity and what does that increasing acidity cause

A
  • the increase in acidity is due to the electronegativity of the aromatic substituent as well as resonance stabilization of the anion
  • increased acidity means increased potency
673
Q

how does the increase in the acidities of the sulfonamides can lead to a decrease in the incidence of crystalluria.

A

The increased acidity also greatly improves the water solubility of sulfonamide antimicrobials, which is important since the undissociated forms of these molecules and their acetate metabolites tend to have low solubility, which can be responsible for crystalluria.

674
Q

what drug is this

A

sulfacetamide

675
Q

what drug is this

A

sulfadiazine

676
Q

what drug is this

A

sulfamethoxazole

677
Q

what drug is this

A

sulfasalazine

678
Q

characterize the antibiotic spectrum of the sulfonamides

A

inhibit both gram + and gram - bacteria

679
Q

are sulfonamides used in combination? If so, why?

A

yes because the resistance factors are too widespread for these drugs to be used in a single drug therapy

680
Q
  1. AIDs infections (pneumocystis jiroveci)
  2. Crohns/Colitis
  3. acute tocoplasmosis
A
681
Q

describe how sulfasalizine is metabolized by intestinal bacteria, and characterize the biological activities of the metabolites

A
  • bacteria in the GI tract metabolize it to sulfapyridine and 5-aminosalicylic acid, which has antiinflammatory activity
682
Q

describe the mechanism of action of pyrimethamine, and its therapeutic uses when combined with certain sulfonamides

A
  • Pyrimethamine is an DHFR inhibitor
  • saulfadiazine in combination with pyrimethamine to treat acute toxoplasmosis
683
Q

describe the main bacterial resistance mechanisms to sulfonamid

A
  1. mutations that cause overproductions of PABA
  2. mutations in the taregt enzyme (dihydropteroate synthase) that decreases its affinity for the sulfonamides
  3. muations that result in a decrease in cell permeability to the sulfonamides
684
Q

characterize the pharmacokinetics of the main sulfonamides

A
  • SMX is widely distributed in the body including the CSF and is also rapidly elimination
685
Q

specify how the sulfonamides are metabolized in humans

A
  • sulfonamides are generally metabolized by N-4 N-acetylation and in some cases N-1 glucuronidation
  • Metabolites have no antibiotics activity
  • hydroxylamine and nitroso metabolits are toxic
686
Q

what drug is this

A

collstin

687
Q

colistin MOA

A
  • its ammonium cations are able to displace cations in the bacterial cell membrane (Mg and Ca) and facilitate binding of the antibiotic to anionic lipopolysaccharides in the cell membrane
688
Q

what drug is this

A

metronidazole

689
Q

metronidazole use

A

treatment of anerobic bacteria and protozoa: C. diff

690
Q

metronidazole MOA

A

partial reduction of the nitro group in anaerobic bacteria leads to a radical anion that degrades bacterial DNA

691
Q

what drug is this, its MOA, and therapeutic use

A
  1. lefamulin acetate
  2. selective binding to the peptidyl transferase center of the 50S ribosomal subunit to prevent bacterial protein synthesis
  3. community acquired bacterial pneumonia
692
Q

what drug is this, its MOA, and therapeutic use

A
  1. pretomanid
  2. inhibits mycolic acid biosynthesis through an unknown mechanism, and poisons respiration (mitochondria) through generation of nitric oxide
  3. treatment resistant TB
693
Q

what is a disinfectant

A

a compound that kills the vegetative form of microorganisms, but not spores, inanimate surfaces

694
Q

what is a sterilant

A

compound that kills or removes all types of living microorganisms, including spores and viruses

695
Q

what is an antispetic

A

compound that is applied to living tissue for the purpose of preventing infection

696
Q

disinfectant examples

A
  • alcohols
  • phenols
  • heavy metals
697
Q

antiseptics examples

A
  1. alcohols
  2. chlorhexidine
  3. oxychlorosene
698
Q

Alcohol MOA

A

denature protein

699
Q

chlorhexidine MOA

A

strongly adsorbs to bacterial membranes, causing leakage of small molecules, and it also causes precipitation of cytoplasmic proteins

700
Q

iodine MOA

A

iodinates phenylalanyl and tyrosyl groups in proteins and oxidizes sulfhydryl groups in proteins

701
Q

povidone-iodine MOA

A

free iodine that is liberated from the complex, causion ionation of phylalanyl and tyrosyl groups in proteins and oxidizes sulfhydryl groups in proteins

702
Q

sodium hypochlorite MOA

A

variety of functional groups present in proteins and nucleic acids are oxidized by hypochlorous acid

703
Q

halazone MOA

A

slowly liberates hyochlorous acid in water

704
Q

chloroazodin MOA

A

diluted to liberate hypochlorous acid in water

705
Q

oxychlorosene MOA

A

liberates HOCl in solution

706
Q

phenol MOA

A

disrupt the cell wall and membranes, precipitate proteins, and inactivate enzymes

707
Q

quaternary ammonium compounds MOA

A

inactivation of energy-producing enzymes, denaturation of proteins, and disruption of cell membranes

708
Q

aldehydes MOA

A

react with amino groups in proteins and nucleic acids

709
Q

hydrogen peroxide and peracetic acid MOA

A

powerful oxidizers

710
Q

ethylene oxide MOA

A

reacts covalently with a variety of nucleophulic groups present in biological systems

711
Q

alcohols use

A

antiseptic and disinfectant

712
Q

chlorhexidine use

A

topical antiseptic against vegetative bacteria and has moderate activity vs fungi and virus, inhibits germination of spores

713
Q

iodine use

A
  • most active antisepctic for intact skin
  • is bactericidal and kills spores, but can cause skin irritation
714
Q

povidone-iodine use

A
  • antiseptic that is available in aerosols, ointments, surgical scrubs, antiseptic gauze pads, sponges, and mouth washed
  • kills bacteria, fungi, and lipid containing viruses
  • prolonged exposure can kill spores
715
Q

specify the chemical species that are present when sodium hypochlorite is
dissolved in water, and also when chlorine is dissolved in water

A
  • hypochlorous acid is the active germicidal species that forms when chlorine is dissolved in water
  • ammonia in urine can react with bleack to form chloramine, which is toxic
716
Q

sodium hypochlorite use

A
  • chlorine and its derivatives disinfect water
  • disinfection of blood spils
  • kill mircoorganisms at different concentrations
717
Q

halazone and sodium dichloroisocyanurate uses

A

disinfect small quantities of water

718
Q

chloroazodin use

A

dressing wounds, lavage, and irrigation

719
Q

oxychlorosene use

A

used as an antiseptic to treat local infections, to remove necrotic tissue in massive infections, and to treat wounds

720
Q

phenols use

A

disinfect hard surfaces

721
Q

quaternary ammonium compounds use

A

Use as sanitizers

722
Q

should quaternary ammonium compounds be used as antiseptics? Why or why not

A

no because they may contain infectious gram negative bacteria (pseudomonas)

723
Q

aldehyde us

A

sterilize instruments such as fiberoptic endoscopes that cannot be sterilized by steam in an autoclave

724
Q

which aldehyde is a carcinogen

A

formaldehyde

725
Q

hydrogen peroxide use

A

sterilize respirators, acrylic resin implants, milk and juice cartons, plastic eating utensils, and contact lenses

726
Q

ethlene oxide use

A

sterilize equipment that cannot be sterilized by heat in an autoclave (instruments with lenses, plastic, or rubber)

727
Q

what are the tetracycline analogs

A
  1. tigecycline
  2. omadacycline
  3. eravacycline
728
Q

tetracycline and analogs MOA

A

inhibit bacterial protein synthesis by reversibly binding to the 30S ribosomal subunits by blocking the A site

729
Q

tetracyclines and analogs display what type of activity

A

typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms

730
Q

tetracyclines and analogs mechanisms of resistance

A
  1. decreased accumulation of tetracycline within bacteria due to decreased permeability or the presence of efflux
  2. decreased access of tetracycline to the ribosome due to the presence of ribosomal protection proteins
  3. enzymatic inactivation

PHRM 865 (59 decks)

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