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Pharmacology III > Final Exam > Flashcards

Final Exam Flashcards

1
Q

Natural and Producer Immunity

A
  • bacteria making a poison and making sure that poison doesn’t kill the bacteria itself
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2
Q

Acquired resistance

A
  • genetic transfer or point mutation from selective pressure from antibiotics
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3
Q

ESKAPE pathogens (in general)

A
  • six pathogens with growing multi-drug resistance virulence
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4
Q

CRE (carbapenem-resistant enteriobacteriaceae) –> 1 mode of resistance

A
  • have beta-lactamase that can destroy every b-lactam drug

- has NDM1 gene

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5
Q

fitness cost for resistance

A
  • as resistance goes up, fitness goes down

- may need to turn to cocktails to combat resistance

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6
Q

typical gene mutation frequency of bacteria

A
  • 1 in 10^7 bacteria

- resistance inevitable

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7
Q

Gaps in knowledge of antibiotic resistance

A
  • no systematic international surveillance of antibiotic resistance threats
  • have capacity to trace once something is of concern, but aren’t actively surveilling
  • data on antibiotic use in human healthcare and in agriculture are not systematically collected
  • programs to improve antibiotic prescribing are not widely used in the US (too much broad spectrum used)
  • antibiotic stewardship could be the single most important action
  • in clinical environment, these pathogens extremely opportunistic
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8
Q

Three major mechanisms of antibiotic resistance

A
  • Modify the drug (i.e. beta-lactamases)
  • Modify the target (v. specific to antibiotic but sometimes class of drug that acts similarly and modify their target to make the antibiotic inefficient)
  • Pump drug out with efflux pumps (most general, greater likelihood than other mechs for resistance to more than one antibiotic)
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9
Q

Movement of resistance genes (2 broad categories, and subcategories in them)

A
  • Selection for antibiotic resistance
  • nature (protection against endogenous antibiotics etc)
  • medicine (antibiotic consumption, pharma production)
  • agriculture (antibiotic consumption, antibiotics onto fields)
  • Spread of antibiotic resistance genes
  • physical forces (wind, water - runoff and leaching)
  • biological forces (human activities, insects, birds, animals)
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10
Q

Most antibiotics are (synthetics/natural products)

A
  • natural products

- dont’ kill themselves via natural producer immunity

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11
Q

genus streptomyces antibiotics originally purified strains from _____

A
  • soil
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12
Q

one of the major sources of antibiotics is _____

- now also looking in ______

A
  • soil bacteria

- now looking in oceans (sponges)

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13
Q

Natural bacteria have natural resistance mechanisms to keep themselves alive which scientists have known about for a long time. When does this become a problem?

A
  • when these mechs end up in human pathogens

- threat that these will jump to plasmid-mediated rapid transfer in human pathogens

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14
Q

Two super bugs.. how many drugs were they resistant to?

A
  • 15 of 21 drugs
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15
Q

Average amt of drugs the 480 bacteria were resistant to naturally?

A
  • 7 or 8
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16
Q

All 480 strains of soil-derived bacteria had resistance to some of these drugs.. why is this not as much of a problem

A
  • these genes haven’t all jumped to human pathogens yet
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17
Q

May not be new mechanisms to target bacteria to kill… why?

A
  • only a small fraction of genes in bacteria are vital to survival
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18
Q

antibiotic biosynthetic capability and efflux pumps

A
  • like a megaoperon, all genes very close together and usually a self-resistant gene embedded into this, all turned on when there is a threat
  • need a way that the antibiotic made by the bacteria doesn’t kill the producer strain (efflux pump)
  • pump out the antibiotic to kill surrounding bacteria
  • could still make antibiotic if PepT gene was dysfunctional, but build up of antibiotic in the cell would kill the host
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19
Q

Target modification example Streptomyces

A
  • macrolide resistance: streptomyces modified its own 50S ribosome rRNA (ERM gene modification), became resistant to the antibiotic it was producing (erythromycin)
  • this is currently just in non-virulent E. coli strains, would be dangerous in virulent strains
  • erythromycin is selective to prokaryotic ribosomes, if it was for eukaryotic ribosomes as well, would be too toxic to use as a drug
  • methylation had to coevolve with the biosynthesis of erythromycin in evolution, each step needs to be slightly greater fitness
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20
Q

What example does Lantibiotics go with?

A
  • efflux pumps

- found in gram + bacteria

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21
Q

Which enzyme methylates streptomyces making it antibiotic resistant?

A
  • ERM methyltransferase
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22
Q

Drug Target Modification example Vancomycin

A
  • regulation of vanH, vanA, and vanX genes allows cell wall restructuring (from D-ala-D-ala to D-ala-D-lac)
  • vancomycin cannot detect D-ala-D-lac (ester doesn’t have the hydrogen bond and cannot bond as well)
  • whole connection of these 5 genes (VanR and VanS regulate) were transferred to a plasmid and to human pathogenic bacteria
  • vancomycin used to be last line of defense, not anymore
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23
Q

Drug Modification example

A
  • Strategy for self-protection by the oleandomycin producer:
  • glycosylation of oleandomycin by Olel to inactivate the antibiotic
  • export the antibiotic by an efflux pump and reactivate the antibiotic outside the bacteria by its own enzyme OleR
  • used extracellularily as defense mechanism
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24
Q

Natural/Producer immunity… how did resistance mechanisms get there

A
  • resistance mechs co-evolved with ability to produce antibiotics
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25
Q

Acquired resistance.. how did resistance mechanisms get there

A
  • horizontal gene transfer one way
  • mechs did not coevolve with ability to produce antibiotics
  • controlled by mutation and via mobile integrons (gene cassettes)
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26
Q

autonomous parasitic DNA/transposons/jumping genes

A
  • insert themselves into DNA, can mutate and get stuck there to be transcribed, sometimes jump back out
  • for acquired resistance
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27
Q

Examples of Mobile Genetic Elements

A
  • all ways of horizontal gene transfer
  • plasmid (circular or linear)
  • insertion sequence
  • composite transposon
  • complex transposon
  • conjugative transposon
  • transposable bacteriophage
  • other transposable elements
  • integron
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28
Q

Three general ways to get new DNA into a bacteria

A
  • plasmid transfer
  • transfer by viral delivery
  • uptake of free DNA (will do this in times of stress)
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29
Q

Drug destruction or modification examples

A
  • B-lactams –> drug destruction

- aminoglycosides –> drug modification

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30
Q

Efflux pumps examples

A
  • all classes of antibiotics
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31
Q

Target replacement or modification examples

A
  • MRSA- replacement
  • b-lactam resistant S. pneumoniae- replacement and modification
  • macrolides - modification
  • MLSb- modification
  • VRE- replacement
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32
Q

another way of antibiotic resistance not yet discussed

A
  • overexpression of drug target

- mutate promoter upstream of the target gene

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33
Q

Enzymatic destruction or modification of ANTIBIOTICS by resistant bacteria

A
  • hydrolysis results in destruction
  • decoration with different groups results in modification
  • not a major route of resistance for synthetics
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34
Q

Destruction of b-lactam ANTIBIOTICS by b-lactamases (what happens.. what is order of harder to hydrolyze)

A
  • b-lactams work by attacking a serine on the transpeptidase and then inhibiting the linking
  • b-lactamase plus water helps to destroy the b-lactam
  • hydrolyze the keytone to a -COOH
  • penicillins, cephalosporins, carbapenems –> increasingly harder to hydrolyze, aka more power therapeutically
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35
Q

What are chemists current approaches to outwitting the b-lactamases?

A
  • modify the new drugs to make it harder for them to fit inside the b-lactamases
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36
Q

B-lactamases are classified into 4 categories and which categories are what?

A
  • Classes A,C,D –> serine b-lactamase
  • Class B –> metallo b-lactamases
  • evolved from DIFFERENT genes
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37
Q

Serine b-lactamase work by

A
  • nucleophillic attack on the keytone of the b-lactam
  • intermediate forms with enzyme attached
  • addition of water (needs to be a fast step) releases the enzyme
  • antibiotic is inactivated
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38
Q

Classes A,C,D of B-lactamases resemble _____ and relative rate of the two

A
  • transpeptidases
  • relative rate of 10^7 faster action of b-lactamases
  • would need to increase [ ] of b-lactam by 1 mil to overcome b-lactamase
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39
Q

What is special about NDM1s?

A
  • can hydrolyze pretty much any b-lactam

- broader specificity of the b-lactamase, the more drugs it can be resistant to

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40
Q

strategies to neutralize b-lactamases (2)

A
  • slow substrates

- suicide substrates

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41
Q

strategies to neutralize b-lactamases: Slow Substrates method of action

A
  • these slow the attack of water and keep the b-lactamase stuck in the intermediate
  • modification is in the acyl side chain of the b-lactam (ANTIBIOTIC)
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42
Q

strategies to neutralize b-lactamase: Suicide substrates

A
  • use a beta-lactamase inhibitor in combination with the normal transpeptidase inhibitor
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43
Q

Names of the 4 suicide substrate b-lactamase pairs

A
  • augmentin
  • timentin
  • unasyn
  • zocin
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44
Q

Augmentin (what it is and names of the two drugs that make it)

A
  • b-lactamase suicide substrate + transpeptidase inhibitor

- clavulanate/amoxacillin

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45
Q

Timentin (what it is and names of the two drugs that make it)

A
  • b-lactamase suicide substrate + transpeptidase inhibitor

- clavulanate/ticarcillin

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46
Q

Unasyn (what it is and names of the two drugs that make it)

A
  • b-lactamase suicide substrate + transpeptidase inhibitor

- Sulbactam/ampicillin

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47
Q

Zocin (what it is and names of the two drugs that make it)

A
  • b-lactamase suicide substrate + transpeptidase inhibitor

- tazobactam/piperacillin

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48
Q

why can’t beta-lactamase suicide inhibitors be used alone to kill bacteria?

A
  • not strong enough.. need the transpeptidase inhibitor b-lactam also
  • BLI inhibit the b-lactamase while the transpeptidase inhibits the crosslinking.
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49
Q

Metallo-B-lactamases (MBLs)

A
  • contain divalent ions in the active site
  • MBLs contain 1 or 2 zinc ions in the active site (or Mg)
  • 1 metal activates the water, one activates the carbonyl
  • more resistant to inhibitors –> adds H2O w/o any intermediate
  • importance: can hydrolyze carbapenem (hardest b-lactam class to hydrolyze)
  • resistance to inhibitors (no inhibitors currently)
  • at least 9 types of acquired metallo-b-lactamases
  • acquired through horizontal gene transfer- mobile DNA elements from other bacteria - 70% are gene encoded so can spread very fast
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50
Q

Worldwide dist of metallo-b-lactamases

A
  • only 2 or 3 types in US

- many different types in Europe

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51
Q

extended spectrum b-lactamases

A
  • substrate binding site is larger, can hydrolyze larger variety of drugs –> this is selected for by the bacteria
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52
Q

Resistance by DRUG MODIFICATION (by the bacteria): amino-glycoside-modifying enzymes

A
  • ex with gentamicin, streptomycin
  • 3 enzymatic routes to aminoglycoside deactivation
  • there are patterns of regioselective enzymatic modifications and deactivation of aminoglycoside antibiotics
  • bacteria want to inhibit binding of streptomycin with the 16S rRNA of the 30S subunit so they make the antibiotic less polar and increase steric hinderance so there is a decreased affinity for the 16S rRNA
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53
Q

3 enzymatic routes to aminoglycoside deactivation

A
  • categorized under resistance by drug modification: amino-glycoside modifying enzymes
  • acetylation by Acetyl CoA
  • phosphorylation by ATP
  • adenylation by ATP
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54
Q

3 classes of enzymes that modify aminoglycosides

A
  • Aminoglycoside acetyltransferase (AAC)
  • Aminoglycoside phosphotransferase (APH)
  • Aminoglycoside nucleotydyltransferase (ANT)
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55
Q

Antibiotic Resistance by efflux pumps

A
  • active efflux mediated by transmembrane proteins, both in cytoplasmic membranes and in outer membranes of gram (-)s
  • these export the antibiotics
  • active efflux has been observed for both natural and synthetic antibiotics
  • it is to the bacteria’s advantage to have broad specificity in efflux, can pump more types of antibiotics out of the cytoplasm
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56
Q

five (4) families of membrane efflux pumps

A
  • ATP-binding cassette (ABC) superfamily
  • Major Facilitator Superfamily (MFS)
  • Multidrug and toxic compound extrusion (MATE) family
  • Small Multidrug Resistance (SMR) family (subgroup of MATE)
  • Resistance-Nodulation-Division (RND) superfamily
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57
Q

How are families of membrane efflux pumps classified?

A
  • based on number of components, trans-membrane spanning regions, and energy that drives the pump
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58
Q

Which families of membrane efflux pumps are in gram (+)?

which one is the major family

A
  • ABC superfamily
  • MFS (major facilitator superfamily)
  • MATE family
  • SMR family
  • -> MFS is the major family in Gram (+)
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59
Q

Which families of membrane efflux pumps are in gram (-)?

which one is the major family

A
  • RND family
  • ABC superfamily
  • MFS
  • RND is major family in Gram (-)
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60
Q

Which efflux pumps are the most well characterized and their structure?

A
  • RND
  • Resistance-Nodulation-Division Superfamily
  • structure is a tunnel through both membranes with a piece in the middle for stability
  • major family in gram (-)
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61
Q

Which type of pumps predominate in bacteria? in eukaryotes?

A
  • H+ pumps

- ATP-pumps predominate in eukaryotes

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62
Q

Which pump is an ATP pump?

A
  • ABC (ATP-binding cassette superfamily)
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63
Q

When looking at data for resistance associated with efflux, how do you know a bacteria has resistance to a certain antibiotic?

A
  • knock out genes for the efflux pump in the bacteria and see if the MIC changes greatly
  • if the MIC lowers greatly when the pump gene is knocked out, then shows the gene and pump is involved in lowering the effectiveness of the drug
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64
Q

RND Family of efflux pumps: lots of substrates or no

A
  • yes diversity of substrates
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65
Q

MAKE CHART FOR 12/18 page 6!!

A
  • DO IT
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66
Q

How is replacement or modification of the antibiotic target done?

A
  • mutation at one or more sites in the target gene or importation of a gene that specifies a new replacement enzyme that has markedly decreased sensitivity to the drug
  • usually a fitness cost but still survive
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67
Q

Methicillin resistance in MRSA: explain resistance

A
  • wasn’t elaborating an improved version of B-lactamase, it acquired a new PBP (PBP2A) which was the main target for methicilin
  • this PBP2A is a bifunctional transglycosylase/ transpeptidase with low affinity to b-lactams
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68
Q

Development of B-lactams against MRSA

A
  • large hydrophobic substituents
  • antigenic and can cause hypersensitivity (in 5-10% of patients, but can be life threatening)
  • can have non-specific acylation which can become antigenic
  • get more immune response with larger drugs
  • reduce immunogenicity by excluding the antigenic sidechain
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69
Q

how do you reduce immunogenicity of antibiotics?

A
  • exclude the antigenic sidechain (regarding development of B-lactams against MRSA)
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70
Q

Carbapenems with activity against MRSA?

A
  • molecules with aryl side chains substituents

- release the immunogenic side chain of the carbapenem on attack of the B-lactam by the active site Ser of PBP2A

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71
Q

How many binding sites for ceftaroline? and what does it treat?

A
  • 2 binding sites, binds the active site and allosteric domain 60A away
  • works on MRSA
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72
Q

5th generation cephalosporins (2)

A
  • ceftaroline (prodrug) US
  • phosphate of ceftaroline makes it more soluble in water
    (hydrolyzed when absorbed to release the free amine which is the active drug that inhibits PBP2A)
  • Ceftobiprole (canada and europe)
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73
Q

B-lactam resistance in S. pneumoniae

A
  • does not use b-lactamase as major route to penicillin resistance
  • five PBPs contribute to killing of S. pneumoniae by b-lactams (PBP1A, 1B, 2A, 2B, 2X)
  • in clinical isolates with high b-lactam resistance, mutations can be found in all 5 PBPs
  • reflects rapid genetic plasticity of bacteria when facing extinction by an antibiotic
  • prime example of target modification
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74
Q

Major route of resistance to macrolides and examples of macrolides

A
  • modification of the 23S rRNA in the 50S ribosome subunit
  • efflux can also be significant
  • ex. macrolides (erythromycin, oleandomycin, tylosin)
  • raises Kd and MIC
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75
Q

Resistance to macrolides by 23S rRNA methylation what enzyme and 30S or 50S subunit?

A
  • ERM methyltransferase methylates the 50S ribosome
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76
Q

how many ERM genes/enzymes have been discovered?

A
  • more than 2 dozen in resistant bacteria
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77
Q

MLSb phenotype of resistance

A
  • because there is overlap in the binding sites for macrolides, lincosamides, and streptogramin B you get cross-resistance when the rRNA is methylated in macrolide resistance (target modification)
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78
Q

What drug is not affected by the methylated ribosome at 50S for normal drug resistance?

A
  • Telithromycin because it has a lipophilic side chain which allows it to bind better
  • is considered a ketolid (3rd gen erthyromycin) which have sufficient affinity for methylated ribosome 50S subunits
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79
Q

VRE reprogramming the peptidoglycan termini: what stimulated this?

A
  • Vancomycin-resistant enterococcus
  • used vancomycin to treat MRSA in late 1980s and 90s which selected for drug-resistant enterococci
  • needs to be given by IV
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80
Q

Van RS two component regulatory system in VRE reprogramming

A
  • VanS (sensor kinase) senses change in peptidoglycan (i.e. vancomycin binding) and makes a single polypeptide change (ala to lac)
  • Van R (response regulator) is also phosphorylated and then becomes activated –> stimulates transcription of genes downstream (Van H, A, X)
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81
Q

3 Major Clinical phenotypes of VRE

A
  • VanA
  • VanB
  • VanC
  • more but not clinically relevant
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82
Q

VanA (transferable resistance y/n, induction y/n, does teicoplanin work?)

A
  • Transferrable resistance Yes
  • Induction Yes
  • Teicoplanin –> higher level resistance
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83
Q

VanB (transferable resistance y/n, induction y/n, does teicoplanin work?)

A
  • Transferrable resistance Yes
  • Induction Yes
  • Sensitive to teicoplanin
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84
Q

VanC (transferable resistance y/n, induction y/n, does teicoplanin work?)

A
  • Transferrable resistance No
  • Induction No
  • sensitive to teicoplanin
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85
Q

Which Van phenos are plasmid borne?

A
  • VanA and VanB
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86
Q

VanC… is it high or low level resistance to vancomycin

A
  • low level resistance
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87
Q

VanC phenotype uses what instead of D-Lac?

A
  • D-Ser
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88
Q

What causes the loss in affinity of vancomycin to VRE?

A
  • loss of middle H-bond, also ground state repulsions between the two oxygens
  • loss of one H-bond = 1000x weaker
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89
Q

Were VanR,S,H,A,X found on a plasmid?

A
  • yes
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90
Q

Strategies to overcome VanB resistance

A
  • tested different analogs of teicoplanin and vancomycin to see what triggered the sensor kinase
  • then used this as info on how to modify antibiotics so it can bind to the new target, and/or not induce resistance gene turn-on
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91
Q

Dalbavancin (what it do)

A
  • used in VRE
  • similar to teicoplanin but only induces VanA (not VanB)
  • VanA types still resistant ^
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92
Q

Telavancin (what it do)

A
  • used in VRE
  • similar to teicoplanin, but only induces VanA (not VanB)
  • VanA types still resistant ^
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93
Q

Ortivancin (what it do)

A
  • Used in VRE

- Active against VanA, VanB, and VanC

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94
Q

Virulence Factors (what they are, what it allows them to do, how they are encoded)

A
  • features or molecules expressed or produced (and excreted) by pathogens that allow them to:
  • colonize the host
  • evade the immune system
  • suppress the immune system
  • allow entry or exit out of cells
  • obtain nutrition from the host (e.g. iron acquisition via production of siderophores)
  • can be chromosomal or plasmid encoded (many are plasmid encoded)
  • these factors help the bacteria to overcome our natural defense systems
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95
Q

limiting factor of many bacteria is what?

A
  • iron intake

- bacteria need iron

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96
Q

Types of virulence factors (4)

A
  • Adhesins
  • Capsules
  • Invasion enzymes
  • Toxins (3 main types)
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97
Q

Capsules as type of virulence factor

A
  • help evade innate immune system by blocking attack by phagocytic cells
  • like camouflage for bacteria
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98
Q

Invasion Enzymes as type of virulence factor

A
  • assist with entry into host and colonization
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99
Q

Toxins as types of virulence factors (name the three types)

A
  • Type I: superantigens
  • Type 2: Cytolytic exotoxins (enzymes)
  • Type 3: A-B toxins
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100
Q

Virulence Factors- Adhesins – what they are and what they do

A
  • polymeric structures that extend out form bacterial cell surface (Pili)
  • assist with colonization or adhesion to cells
  • also have receptor interactions (pro- or anti- inflammatory)
  • inflammatory response mediated through innate immune system
  • allow bacteria to “stick” somewhere, variety depending on the bacterium
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101
Q

5 broad categories of adhesions (don’t need to know each separately.. but how are they different in general?)

A
  • chaperone-usher pili
  • type IV pili
  • Curli
  • trimeric autotransporter adhesins
  • sortase assembled pilli
  • differences lie in how they’re made and how they’re transported
  • can bind to both cells and prosthetics/catheters
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102
Q

how are adhesins synthesized and released from bacteria? What step would be a useful target for drug therapy?

A
  • monomers synthesize in the nucleus, transport system is there to get to other side of membrane
  • target transport of adhesins to outside of membrane –> potential useful drug therapy
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103
Q

“lifecycle” of adhesins

A
  • bind to cell
  • invasion and replication
  • biofilm formation
  • cell rupture: biomass dispersion and cell exit
  • spread to new cells
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104
Q

adhesins as drug targets

A
  • target conserved areas on chaperones
  • block ability of E. coli to make pili
  • if cannot adhere to cell, body can clear easier
  • also thought to be less likely to develop resistance
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105
Q

Virulence factors: exotoxins (names of types and which is best chance to target for antibiotic therapy?)

A
  • Type 1: superantigens
  • Type 2: cytolytic exotoxins (enzymes) (best type to target for antibiotic therapy)
  • Type 3: A-B
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106
Q

Type 1 exotoxin virulence factor

A
  • superantigens
  • stimulate host cells and lead to extensive imflammatory rxns
  • ex. Toxic shock syndrome (staph aureus)
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107
Q

Type 2 exotoxin virulence factor

A
  • cytolytic exotoxins (enzymes)
  • toxins that disrupt integrity of cells and tissues
  • ex. kappa toxin breaks down connective tissues
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108
Q

Type 3 exotoxin virulence factor

A
  • Type A-B
  • A component inactivates host cell target or signalling pathway
  • B component binds to receptor on host cell (cell type determining)
  • ex. botox and c. diff
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109
Q

Why are bacterial biofilms inherently resistant to antibiotic therapy? (3)

A
  • diffusion limitations due to extracellular matrix
  • antibiotic inactivation by metal concentration and low pH
  • presence of metabolically inactive persister cells
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110
Q

biofilm bacteria up to ______x more resistant to antibiotics thatn planktonic cells

A
  • 1000x
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111
Q

cellular reprogramming of biofilms alter:

A
  • expression of surface molecules
  • nutrient utilization
  • virulence factors
  • biofilms allow survival under unfavorable conditions
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112
Q

what are biofilms surrounded by? and facts about it

A
  • extracellular polymeric substance (EPS)
  • accounts for 90% of biomass (makes it very hard for antibiotics to get through)
  • creates stable structure
  • cells are less active in biofilms so not as susceptible to antibiotic therapy
  • things like carb-binding proteins, pili, flagella, adhesive fibers, and extracellular DNA (eDNA) stabilize the structure
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113
Q

Quorum Sensing: what is it and what does it control?

A
  • bacterial cell to cell communication that controls:
  • bioluminescence
  • sporulation
  • antibiotic production
  • biofilm formation
  • virulence factor secretion
  • helps bacteria sense population densities
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114
Q

Quorum sensing: 4 steps

A
  1. production of signaling molecules (autoinducer)
  2. release of signaling molecules
  3. recognition of signaling molecules
  4. changes in gene expression
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115
Q

Where did the concept of quorum sensing originate?

A
  • with vibrio fischeri in squid

- uses quorum sensing to generate light molecules that assist the squid in luminescing and avoiding predation

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116
Q

Canonical G (-) quorum sensing in vibrio fischeri (generally what goes on)

A
  • LuxI synthesizes AIs (autoinducers)
  • AIs reach a critical threshold
  • AIs bind to LuxR to drive transcription of target genes
  • LuxR is the response regulator (transcription factor), very similar to aspects of VanA pheno
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117
Q

Autoinducers (AIs)

A
  • biosynthesized from serine
  • gram (+) tend to be peptides (auto-inducing peptides [AIPs])
  • gram (-) tend to be lactones (acyl homoserine lactone [AHL])
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118
Q

Bacterial two component signaling system (TCS)

A
  • extracellular signals are transduced into bacterial cells through TCS
  • composed of a sensor kinase and a response regulator
  • VRE reprogramming of peptidoglycan happens via a TCS
  • usually a phosphotransfer from the sensor kinase to the response regulator
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119
Q

Canonical G (+) quorum sensing staph aureus (generally what goes on)

A
  • cyclized AIPs
  • signal then induces the histidine on the sensor kinase to be phosphorylated, and after activating the histidine kinase, cascade to phosphorylate an aspartic acid on a response regulator
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120
Q

Canonical G (-) quorum sensing vibrio cholerae

A
  • two component system
  • unique b/c more of a gram (+) system
  • has a histidine kinase and uses AIs
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121
Q

Gram positive.. two canonical quorum sensing methods

A
  • either histidine kinase on the cell membrane that the AIP can directly act on after being transported (and processed [sometimes by the transporter]) out of the cell OR the receptor is inside the cell and the AIP needs to be transported back in to stimulate the receptor
  • in the second version, the AIP is not processed from a Pro-AIP to an AIP until it’s been secreted out of the cell
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122
Q

AHLs

A
  • highly lipophilic, can cross cell membranes
  • no transport system needed
  • used in gram (-) b/c need to get through both membranes easily
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123
Q

Two systems of gram (-) canonical quorum sensing

A
  • either AHL diffuses out of cell, and then back into cell to bind to the receptor OR like vibrio cholerae where it is like gram (+) with histadine kinase on the inner membrane that can activate the response regulator
124
Q

Targeting Quorum sensing: Staph Aureus

A
  • AgrD: gene that encodes pro-peptide
  • goes through transport and processing in ArgB (transporter)
  • AIP then is outside the cell and finds receptor AgrC which phosphorylates AgrA to induce RNAIII transcription and transcription of all the Agr genes
  • escalates very quickly
125
Q

RNA III

A
  • RNA pol that increases transcription of virulence factors, toxin also encoded.
  • encodes delta-hemolysin (lyses RBCs)
  • increases production of A-B toxin, enterotoxins, toxic shock syndrome toxin, hemolysins alpha, beta, gamma
126
Q

Staph aureus mutants: 2 facts

A
  • defective in virulence

- higher propensity to form biofilms

127
Q

Quorum sensing P. aeruginosa

A
  • 3 systems as of 2012
  • LasR system appears to be master control
  • LasI in cytoplasm makes the AHL, it diffuses out of cell, then diffuses into target cell or back into self, binds the LasR which induces many genes
  • lots of feedback of these systems
  • inhibition of this system is new drug target
128
Q

What happens when LasR is inhibited?

A
  • weak and poor formations of biofilms that are more sensitive to antibiotics
  • virulence production also decreased
  • GOOD POTENTIAL TARGET
129
Q

Targeting Quorum Sensing in Staph Aureus and Vibrio Cholerae

A
  • staph aureus, decrease in virulence factors, but INCREASE in inclination to form biofilms
  • vibrio cholerae, decrease in virulence factors but STIMULATES biofilm formation
130
Q

Staph Aureus and drug targeting quorum sensing

A
  • decrease in virulence factors, but increase in inclination to form biofilms
  • questionable target b/c most of the time don’t see patient in early stages of this, problem is in later stage treatment can induce biofilms
131
Q

Vibrio Cholerae and drug targeting quorum sensing

A
  • decrease in virulence factors, but stimulates biofilm formation
  • would depend on timing, stage of disease
132
Q

Human microbiome project general information

A
  • est. 2008
  • analysis of its role in human health and disease
  • establish “core” microbiome at each body site
  • generate resources for comprehensive characterization of the human microbiome
133
Q

It is thought that bacterial cells in the gut do what that influences the rest of the body?

A
  • produce small molecules that regulate environment of the gut
  • they can also enter systemic circulation
  • new evidence that microbiome is connected to autoimmune diseases
134
Q

what shapes the gut microbial community?

A
  • one’s diet
135
Q

C. diff –> threat level, excess medical costs, infections per year, deaths

A
  • threat level urgent
  • 1 billion excess costs/ year
  • 250,000 infections / year
  • 29,000 deaths / year in US as of 2016
136
Q

C. diff infection (CDI) general info

A
  • anaerobic, toxin-producing, spore-forming bacteria
  • gram positive
  • hypervirulent strain is the problem
  • mild disease –> absence of colitis (not the big problem)
137
Q

Hypervirulent strain of C. diff and what it does

A
  • NAP1/B1/ribotype 027
  • more resistant to antibiotics
  • produces more toxins that lead to ulcerative colitis
  • induce apoptosis of the gut lining
138
Q

Highest risk in terms of antibiotic induced CDI (3)

A
  • Clindamycin, cephalosporins, flouoroquinolones
139
Q

CDI therapy

A
  • Metronidazole, Vancomycin, Fidaxomicin (expensive)
  • Fecal microbiotic transplantation (FMT)
  • Cadazolid in clinical trials
  • LFF571 also in clinical trials, close to approval
140
Q

Fecal Microbiota Transfer (FMT)

A
  • suspension from a healthy donor
  • CDI leads to a decrease in microbial diversity in the gut
  • FDA has approved FMT as an investigational new drug for use in refractory and recurrent disease
  • high success rate but new treatment, do not know adverse or long term effects yet
141
Q

Recurrence with CDI

A
  • 10-20% of CDI recur

- after recurrence, rates for further recurrence jump to 40-60%

142
Q

LFF571

A
  • in late stage clinical trials for CDI therapy
  • close to approval
  • structure is closely related to one produced in the microbiome
  • has been modified from the endogenous RiPP structure to improve water solubility
143
Q

Timeline of a C. diff infection

A
  • Ingest/exposure to C. diff spores (very stable, can stick around a long time) –> colonize lower GI –> antibiotic treatment for something different knocks down microbiome –> C. diffs starts to spread and release its toxins –> need to undergo more antibiotic therapy to attack the C. diff
144
Q

Antibiotic Origins

A
  • vast majority of antibiotic phamacophores are from natural products (i.e. genetically encoded small molecules from bacteria)
  • knowledge of the genetics underlying biosynthesis (how antibiotics are made by bacteria) allows one to evaluate other bacteria for production
  • combined with advances in DNA sequencing, scientists can begin probing the microbiota for antibiotics
145
Q

Two major groups of endogenous antibiotics

A
  • Polyketides (derived from acetate, made from a keto group)
  • Peptides
  • Non-ribosomal peptide synthesis (NRPS)
  • Ribosomally synthesized and post-translationally modified peptides (RiPPs)
146
Q

Relationships among RiPPs

A
  • thiazoles (S, N rings) synthesized from cysteine cycling

- LFF571 has additional group added to improve water solubility in fighting C. diff

147
Q

Polyketide biosynthesis: general info

A
  • many modules who’s genes are encoded by DEBS (1,2,3) that stim condensation rxns to grow the gain, then chain is cyclized and released from the enzyme to get the product
148
Q

NRPS biosynthesis: very general info

A
  • biosynthesis by giant complex protein machinery
  • modules as well like polyketide
  • genetically encoded by biosynthetic gene clusters
149
Q

There is evidence that ______ can modulate the immune system

A
  • small molecules from microbiota
150
Q

Analysis of biosynthetic gene clusters (BCGs) in microbiome

A
  • found lots of potential for small molecule production and lots of diversity
  • these can alter our immune systems
  • still do not understand the function of many of the molecules
151
Q

Lactocillin

A
  • new antibiotic from the microbiome
  • many similarities in structure to LFF571
  • smae MOAs –> inhibit protein synth
152
Q

Microbiota supplement therapies for C. diff

A

Focus on getting right microbiota into the gut to use its innate antibiotic activity against C. diff

  • FMT (fecal matter transplant)
  • SER109 (bacterial spore preparation)
  • VP20621 (spore prep of nontoxigenic C. diff)
  • idea this would compete with the toxic C. diff and take over instead
  • clinical trials ongoing for SER109 and VP20621
  • long-term effects still unknown
153
Q

Microbiome-based therapeutics: SER 109

A
  • example of an ecobiotic drug -> spore prep/probiotic
  • derived from “healthy” human donor
  • SER109 is an oral single-dose capsule aimed at restoring a healthy microbiome
154
Q

What is the overall idea behind treating Dysbiosis?

also success rate with FMT

A
  • if disease was CAUSED by antibiotics, don’t treat with more antibiotics
  • 95% success rate with FMT
155
Q

Empiric Combination therapy

A
  • don’t know the specific bacteria
  • seriously ill patient
  • high resistance rates to what has been tried so far
  • use a broad spectrum for this combination therapy
  • usually this is used in a complex patient, but occasionally use in simple as well
156
Q

Directed Combination therapy

A
  • directed at specific bacteria.. know the pathogen
  • usually at MDR pathogens like pseudomonas, baumanii, TB, or ones with carbapenemases (E. coli, klebsiella)
  • know a particular combo will work based on the profile of the bacteria
  • not a lot of other options at this point b/c these MDRs knocked out the first line agents
157
Q

Case of Endocarditis at UWHC

A
  • had a staph aureus bloodstream infection
  • endocarditis was due to daptomycin resistance
  • daptomycin usually inserts lipophilic tail into membrane and depolarizes (potent mechanism)
  • second agents were added after failure with primary therapy
  • increasingly difficult to achieve microbiologic eradication
  • combination therapy as empiric treatment more likely lead to successful cure
    • they added a b-lactam (5th gen cephalosporin with action against MRSA) to the daptomycin treatment and patient was cleared of infection
158
Q

Non-antibiotics in combo with antibiotics: inhibition of B-lactam elimination

A
  • usually B-lactams are renally secreted
  • Add Probenecid to therapy which competes for excretion with B-lactams
  • this leaves more B-lactam to be reabsorbed
  • positive effects:
  • better B-lactam pharmacodynamics –> keep drug around longer, the longer its around, the more effective it is
  • and can lower dose needed
  • negative effects:
  • greater potential for B-lactam toxicity –> bone marrow, nephrotoxicity, and change in platelets
  • OVERALL BENEFITS OUTWEIGH RISK
159
Q

Non-antibiotics in combination: Imipenem-cilastin (and probenecid)

A
  • Imipenem: carbapenem b-lactam
  • cilastin: blocks DHP (enzyme in kidney that degrades cilastin
  • probenecid: blocks active transport pump for imipenem
  • active combo produced by pharmaceutical companies, formulated this way
160
Q

Non-antibiotics in combination: Statins

A
  • statins may show mortality benefits in S. aureus infections
  • they inhibit pigments of bacteria from being produced, limits virulence of bacteria
  • also have immunomodulatory effects on host
  • potential mechanism of statins: inhibition of staphyloxanthin in cell membrane
161
Q

Rational for use of antimicrobial combinations (5)

A
  • decreased emergence of resistance
  • decrease dose-related toxicity
  • polymicrobial infections
  • virulence suppression
  • synergy
162
Q

Rational for use of antimicrobial combinations: Decreased emergence of resistance

A
  • covering broadly to hopefully cover organism and prevent resistance to a primary agent
163
Q

Decrease emergence of resistance: examples and facts

A
  • ex. TB –> 4 drug regimen
  • each drug unique target, makes it difficult for bacteria to produce resistance to any of the agents
  • ex. Pseudomonas –> Vancomycin/Daptomycin plus rifampin
  • dual target cell wall/membrane plus RNA pol inhib (efficacy against inactive bacteria)
  • useful for deep foci of infection (i.e. biofilm) where large antibiotics have decreased penetration
  • increases chances of positive coverage of a pathogen
164
Q

Antibiogram

A
  • specific to an institution
  • predicts two best antibiotics to cover a pathogen
  • by using two, covering more strains that may be resistant to one of the antibiotics
  • hopefully prevent further resistance
  • useful in predicting whether a patient has something before culture is ready based on susceptibility/resistance to antibiotics already tried
165
Q

Decrease dose related toxicity: examples

A
  • sulfonamide combos historically used to decrease crystaluria
  • one high dose sulfonamide by itself likely to cause nephrotoxicity and crystaluria
  • 3 low dose solfonamides are still effective and also do not cause toxicity
  • new example: b-lactams can be used in combo with vancomycin or daptomycin to lower their doses and reduce their toxicities
  • also penicillins preferred over aminoglycosides b/c safer
166
Q

Polymicrobial infections: example

A
  • target each of several major pathogens for antimicrobila therapy (cover as much as you can)
  • most common for enterobacteriaceae and anaerobe mixed infection (ex. diabetic wound or pressure ulcer)
  • cephalosporins or aminoglycosides protect against early morbidity/mortality from enterobacteriaceae
  • clindamycin is active against anaerobes and prevent late abscess formation
  • metronidazole: activity against gram (-) in gut
  • broad spec carbapenems and b-lactams/b-lactamase inhibitors have reduced use of this combination
  • b/c these have polymicrobial profile, don’t need two different agents as often
167
Q

Virulence Suppression: example

A
  • protein synthesis inhibitors combined with b-lactams or vancomycin for virulent staph and strep (necrotizing disease)
  • typically use a protein synthesis inhibitor to prevent toxins and then use a more rapidly active antibiotic to kill bacteria
  • protein synthesis inhibitors are typically not very potent and usually do not kill so not used as monotherapy
168
Q

Synergy and antagonism: qualitative methods for determining synergistic combinations (3)

A
  • checkerboard testing
  • agar dilution
  • dynamic kill curve
169
Q

Checkerboard testing

A
  • tests for synergy or antagonism in combo therapy
  • most frequently used to assess combination in vitro
  • 2+ antibiotics tested in combo in concentrations equal to, above, and below their MIC
  • look at fractional inhibitory concentrations (FIC) to determine synergy, additivity, or antagonism
170
Q

How do you calculate an FIC?

A
  • sum of lowest value of inhibition of each combo divided by MIC of drug alone
  • <0.5 = synergy
  • <1 additivity
  • > 2 antagonism
171
Q

Agar dilution synergy

A
  • can use disk diffusion or Etest diffusion
  • can get additive (indifferent), synergistic, antagonistics
  • synergistic could be working better together than alone, and not working alone at all but working together
172
Q

Kill curve for synergy and antagonism

A
  • put drug A and B in separate test tubes and then together

- look at how fast the drug killed the organism

173
Q

Mechanisms of synergy (4)

A
  • serial inhibition of pathway
  • inhibition of protective enzymes
  • combination targets of cell wall or cell membrane antibiotics
  • use of cell wall agents to enhance uptake of a secondary antibiotic
174
Q

Mechs of synergy: Serial inhibition of pathway example

A
  • serial inhibition of folate synthesis
  • both TMP and SMX are bacteriostatic as single agents but bactericidal when used in combination
  • commercially available
175
Q

Mechs of synergy: inhibition of protective enzymes example and 4 criterial that must be present for effect

A
  • most well developed for a clinical product
  • ex. beta-lactams/beta-lactamase inhibitors
  • 4 criteria that must be met for an effect
  • b-lactamase production by bacteria
  • BLI must be resistant to the b-lactamase (sacrifice so b-lactam can work)
  • BLI has greater affinity than BL to enzyme (don’t want B-lactamase targeting the B-lactam)
  • BLI has relatively weak antibiotic activity (cause otherwise would just use the BLI alone)
176
Q

combination targets of cell wall or cell membrane antibiotics (rationale and what is a common antibiotic used)

A
  • rationale: dual targets within cell walls or membrane function to synergize antibiotic effect
  • beta-lactams are common target for cell wall/membrane combos due to action at cross-linking step
  • b-lactams foundation of the combo plus something else
  • still need two distinct targets within the cell wall/membrane
177
Q

Vancomycin and B-lactams combo therapy

A
  • this is gaining popularity
  • thought that the b-lactams increase activity of vancomycin and cause it to be more potent
  • best documented with PCN and cephalosporins
178
Q

Combo of vancomycin and b-lactam therapy for MRSA bacteremia

A
  • lowered duration of bacteremia by 1 day
  • no significant differences in mortality
  • in general, MRSA is resistant to B-lactams but when combined with vancomycin it increases vanco’s potency significantly
  • clears infection quicker
179
Q

Daptomycin and b-lactams in combination therapy

A
  • used clinically to clear refractory S. aureus and enterococcal infections
  • potential mechs: dual target DAP (membrane) with BL (cell wall)
  • dapto: binds to gram (+) membranes
  • B-lactams: prevent flipping of the membrane so dapto can bind (don’t work alone)
  • bacteria normally resist dapto by flipping their membrane over to repel the cationic dapto
180
Q

B-lactam antibiotics targeting PBP1 selectively enhance dapto activity –> general info

A
  • 2 mech approach
  • Cefoxitin (a cephalosporin b-lactam): specific to one PBP but high doses bind more initially and then falls off, back to just one
  • when bacteria exposed to dapto, cause overproduction of PBP1… can then target PBP1 with B-lactams
181
Q

Use of cell wall agents to enhance uptake of antibiotics example

A
  • Aminoglycosides plus b-lactams
  • Aminoglycosides plus vancomycin
  • in a resistant/borderline resistant bacteria, the aminoglycoside cannot get through the cell wall
  • use a b-lactam/vancomycin to degrade the cell wall so that the aminoglycoside can get through to inhibit protein synthesis
  • also applies to daptomycin plus b-lactams allowing increased binding of b-lactams
182
Q

Two examples of non-synergistic combinations of aminoglycosides plus _____

A
  • Aminoglycoside plus Nafcillin (also nephrotoxicity)
  • Aminoglycoside plus Vancomycin (also renal and ototoxicity)
  • not enough improvement to rationalize the toxicities that may occur
183
Q

Antagonism in combination

A
  • more commonly seen in laboratory setting
  • lack of reporting in clinical setting
  • under-recognized
  • clinically under-reported
  • host factors may play a role in lack of clinically significance demonstrated
184
Q

Antagonism: Bacteriostatic agents plus bacteriocidal agents

A
  • primarily occurs with b-lactams, vancomycin, daptomycin
  • potential antagonists: tetracyclines, MLS antibiotics, linezolid
  • historical clinical example: bacterial meningitis
  • PCN alone: 21% mortality
  • PCN plus chlortetracycline: 79% mortality
  • likely that bacteria must be actively growing for max effect
  • static antibiotics would decrease targets for cidal antibiotics
185
Q

Antagonism: aminoglycosides with bacteriostatic antibiotics

A
  • bactericidal activity of aminoglycosides is compromised by combination with static agents
  • tetracyclines, chlorampenicol, MLS, linezolid
  • mech: inhibit active transport mechs necessary for energy-dependent uptake of aminoglycosides into bacterial cells… also prevent movement from ribosome along mRNA preventing formation of the initiation complex
  • most antagonism reports with these combinations have come from in vitro and animal models
186
Q

Combinations of two B-lactams

A
  • usually avoided b/c potential antagonism
  • may induce production of b-lactamases
  • cephalosporins can induce production of chromosomally-mediated b-lactamases
  • more relevant antagonism with gram (-)s
    • results in competition for PBPs and bumping each other off**
  • less effective binding and activity
  • if both very specific, then it could work
187
Q

Example of when combo of two b-lactams would work

A
  • enterococcus spp. have 5 PBPs (not a particular resistance mech, all have this)
  • use 3rd gen cephalosporins to bind PBP2 and PBP3
  • use ampicillin or amoxicillin to bind PBP4 and PBP5
  • at high doses ampicillin or amoxicillin will bind PBP1 as well
  • by binding up all the PBPs, better outcome than one of these agents alone
188
Q

Ampicillin plus cefriaxone is as effective as ampicillin plus gentamicin for treating enterococcus faecalis infective endocarditis: why is this good?

A
  • avoids toxicities you get with gentamicin
189
Q

What is the most likely approach for combination therapy going forward?

A
  • synergy
190
Q

Significance of combination therapy in clinic

A
  • very few clinical scenarios to unequivocally demonstrate the benefit of combination therapy
  • decisions often made on risk to benefit ratio
191
Q

Dynamic Models; antibiotic development and resistance

A
  • because drug discovery is limited, trying to figure out new ways to overcome resistance and prevent resistance in the future
  • good place to look is pharmacodynamics
192
Q

Pharmacokinetics vs Pharmacodynamics

A
  • Pharmacokinetics: concentrations vs time in different areas of body, dosage
  • Pharmacodynamics: how those concentrations have an effect vs time, what their pharmacological or toxicological effect is
193
Q

Antimicrobial pharmacokinetics

A
  • Absorption –> IV administration rapid and complete
  • Distribution –> dependent on class
  • Metabolism –> many hepatic metabolism
  • Elimination –> most are renally eliminated and therefore require dosage adjustment in renal dysfunction
  • ADME principles*
194
Q

Factors that influence antimicrobial PK/PD (4)

A
  • ability to penetrate to infection site
  • size, charge, hydrophobic properties
  • impact of inoculum size (more bacteria, harder to treat)
  • influence on the MIC ( drugs like b-lactams and glycopeptides need active bacteria in order to work.. biofilms and large inoculum less active)
  • environmental factors
  • pH etc.
  • protein binding
  • only free drug is biologically active
  • high protein drugs have increased MIC in presence of protein
195
Q

Cp max

A
  • peak
196
Q

Cp min

A
  • trough
197
Q

Concentration vs time profile on repeated dosing

A
  • get to steady state after a few half lives (?)
  • relatively predictable Cmin and Cmax
  • graph looks like mountain peaks
198
Q

Pharmacodynamic properties: Concentration-dependent killing

A
  • a positive and direct relationship between antibiotic concentration and bactericidal effect
  • ex. aminoglycosides
199
Q

Pharmacodynamic properties: Concentration-independent killing

A
  • no direct relationship between antibiotic concentration and bactericidal effect (i.e. time dependent)
  • ex. b-lactams
200
Q

Pharmacodynamic properties: Post-antibiotic effect (PAE)

A
  • describes persistent suppression of bacterial growth after antimicrobial exposure
  • does the drug have activity on the organism after it has been removed?
  • if yes, may not have to give the antibiotic as frequently even though it may be below the MIC of the organism
201
Q

Dose vs Interval Antibiotic effect

A
  • Higher dose = higher peak/MIC
  • shorter interval = higher T>MIC
  • same amt of drug but split up, lower Cmax but higher concentration over time
202
Q

Two true time-dependent killing classes of drugs

A
  • B-lactams (classic example)

- Oxazolidinones (Linezolid, Tedizolid)

203
Q

True concentration-dependent killing class of drugs

A
  • Aminoglycosides (gentamicin, streptomycin)
204
Q

Which Gram (+/-) has a greater number of drug classes that demonstrate a PAE

A
  • Gram (+) many more, Gram (-) only 4 classes
205
Q

Dose response curves show what in terms of pharmacodynamic testing?

A
  • how a drug responds to dosages below and above its MIC
  • there is a point of limitation, at some concentration of the MIC it won’t do much extra than the one before it
  • ex. pseudomonas–> 64MIC not much difference than 16MIC
  • also not necessarily clinically obtainable dosages
206
Q

Post-antibiotic effect testing

A
  • expose the antibiotic to the culture, remove it, then see how long it takes to grow back
  • High PAE: long time for bacteria to bounce back –> good
207
Q

Determining the optimal PD parameter

A
  • dose animals and figure out which one best response

- which line is most linear when comparing (AUC/MIC) (Peak/MIC) (Time above MIC)

208
Q

AUC/MIC optimization (for S. pneumo)

A
  • general info:
  • minimum efficacy and minimum resistance prevention might be different values for AUC/MIC
  • test standard doses of drugs
  • S. pneumo
  • takes more antibiotic to prevent resistance than it does to treat
  • testing fluorquinolones… Cipro under the minimum efficacy line, Levofloxacin straddling both lines, Gemi and Moxi above the minimum resistance prevention
209
Q

AUC = ?

A
  • dose/clearance

- ex.) if you have an MIC of 4, would need an AUC of 500 to get to the optimal outcome of >125

210
Q

Levofloxacin Pharmacodynamics and high dose resistance prevention

A
  • lower doses are primed to have resistance, but at some point a high dose becomes toxic
  • higher doses: AUC increases and can prevent resistance in the long run
211
Q

Beta-Lactams and pharmacodynamics

A
  • problem is they have short half-lives
  • AUC/MIC and Time above MIC appear to correlate with bacterial eradication and outcome
  • intermittent dosage regimens usually achieve serum concentrations well above typical MICs for most organisms during dosing interval
  • high therapeutic index
  • since they do not possess a PAE against gram (-) organisms (except carbapenems), intermittent dosing against pathogens with MICs close to breakpoint may result in sub-therapeutic concentrations
  • can’t really extend the dose intervals
212
Q

Selective doses for B-lactams

A
  • intermittent dosing better than one bolus.. time above MIC greater and don’t reach far below MIC
  • best option would be continuous infusion, never falls below the MIC.. not realistic for outpatient
  • overall want to maximize attainment of antibiotic
213
Q

Differences among b-lactams for target attainment times (carbapenems, monobactams, penicillins, cephalosporins)

A
  • each class needs to be above the MIC for ____% of the time of the dosing interval
  • carbapenems 30-40%
  • monobactams 40-50%
  • Penicillins 50-60%
  • Cephalosporins >60%
  • ex. dose every 10 hours, carbapenems need to be 3-4 hrs of that time above MIC to work
214
Q

Prolonged infusion with B-lactams

A
  • longer than usual infusions but not continuous
  • ex. drawing out a 30 min infusion over 3 hours as long as it stays above the MIC
  • prolongs the effect b/c drug is continued to be administered while its being metabolized
215
Q

Aminoglycosides and pharmacodynamics: rationale for single dose aminoglycoside

A
  • higher peak concentrations should increase efficacy
  • significant PAE allows for longer dosing intervals
  • lower trough concentrations should improve safety
  • longer dosing intervals may decrease resistance
  • originally given every 8-12 hours
216
Q

Aminoglycosides are driven by what?

A
  • peak to mic ratio
217
Q

Aminoglycosides and pharmacodynamics: probability of toxicity by cumulative AUC

A
  • cumulative AUC accumulates the same with 1x daily dosing BUT serum creatinine (toxic effects) accumulates much slower
218
Q

Vancomycin and pharmacodynamics

A
  • AUC-driven
  • activity is slowly cidal compared to other agents
  • bacterial density or inoculum can affect activity
  • penetration into some body sites is limited b/c large drug
  • there is limited data to support that specific concentrations are related to outcomes
  • concentrations <10 mg/L may increase resistance
  • Most PK/PD studies support AUC/MIC not T>MIC
  • alternative agents should be considered in patients not responding to vancomycin therapy
219
Q

Comparison of Vancomycin days to eradication for MRSA infections –> general things important

A
  • AUC/MIC >400 has much faster time to eradication than <400

- many hospitals set a target efficacy –> “need to achieve an AUC/MIC of 400” often changes based on new info

220
Q

When looking at AUC what are you actually looking at?

A
  • AUC in serum not AUC at site of infection
  • most infections not happening in serum, so actual AUC is lower
  • ex. 4 fold decrease from serum to lungs where site of infection is.. sometimes hard to extrapolate data
221
Q

HCV facts

A
  • single plus-stranded RNA virus
  • genome encodes poly protein precursor of 3,000 AA
  • four structural proteins that form viral particle, encapsulate the RNA
  • 10 non-structural proteins (NS) –> involved in replication cycle
222
Q

HCV distribution and how that affects drug therapy

A
  • genetic variation in HCV and in human host
  • HCV is an RNA virus w/ error prone RNA pol
  • six to seven major genotypes that differ by 30-50%.. group by geographical region
  • subgenotypes differ by 20-25%
223
Q

core of the HCV is a _____

A
  • capsid.. encases the genome
224
Q

genome of HCV is translated as ____ and then what happens/

A
  • translated as one major poly protein

- protease come and cleave

225
Q

NS2 function HCV

A
  • protease assembly
226
Q

NS3 function HCV

A
  • protease helicase
227
Q

NS4A function HCV

A
  • cofactor in protease helicase?
228
Q

NS4B function HCV

A
  • membrane reorganization
229
Q

NS5A function HCV

A
  • unknown function in replication..
230
Q

NS5B

A
  • RNA-dep-RNA-pol
231
Q

Hep C viral entry into cell

A
  • binds to receptor and is endocytosed into cell

- then uncoats and releases its RNA genome

232
Q

Hep C viral replication and maturation

A
  • hijacks part of ER lumen and creates membranous webs where replication takes place
  • form complex and encorporates lipids
  • makes a lipo-viral particle –> camouflages itself from innate immune system
  • high density HCV particle to low density MATURE HCV particle
233
Q

5 main targets of therapy for HCV

A
  • the viral particle (neutralizing antibodies, virocidal peptides)
  • target entry into cell
  • target translation and processing
  • target RNA replication
  • target assembly and maturation
234
Q

Potential targets for HCV: targeting entry.. what happens in entry and where can be targeted

A
  • LVP binds to receptor, gets endocytosed, nucleocapsid undergoes uncoating process to release RNA
  • can target any of these aspects
235
Q

Potential targets for HCV: targeting translation and processing

A
  • can inhibit the protease.. block formation of the individual proteins (can’t cut the poly protein)
  • NS3-NS4A protease inhibitors were the first direct acting antiviral approved.. now pulled from the market
236
Q

Potential targets for HCV: Targeting HCV RNA replication

A
  • NS5A inhibitors approved by the FDA
  • not clear how drugs inhibit this protein and also not clear what NS5A’s role is
  • NS5B polymerase inhibitors also approved by the FDA
  • don’t get formation of mature viral particle so also kind of targeting assembly and maturation
237
Q

Potential targets for HCV: targeting assembly and maturation

A
  • has not been targeted yet in HCV but has been in other viruses
238
Q

HCV: IFN

A
  • IFN involved in innate immune response to infection
239
Q

HCV: IFN alpha general overview

A
  • HCV needs to evade hosts defenses to replicate and spread to other cells in the liver
  • upon viral infection, host response leads to interferon alpha/beta production
  • HCV has elaborate mechanisms to block host response including activation of IFN and signaling in response to IFN
  • IFN much more effective in combination
240
Q

IFNalpha vs pegylated interferon (PEG-IFN)

A
  • IFNalpha: short half-life

- Pegylated IFN: increased half-life

241
Q

IFNalpha “normal” response to HCV

A
  • RNA of HCV can bind TLRs (is the PAMP) on a cell and can detect it
  • induces signalling cascade
  • genes targeted are IFNalpha and IFNbeta
  • these go through a cascade using the jak-STAT pathway that drives the IFN-stimulated genes
242
Q

how HCV NS3/4A inhibit signaling of IFNalpha

A
  • NS3/4A block signaling of RIG-1 and TLR pathway
  • RIG-1: intracellular innate receptor that can recognize RNA (double-stranded).. and when activated, drives transcription of IFN-stimulated genes
  • doesn’t matter that it’s double stranded recognizable.. b/c it’s blocked anyways
243
Q

how HCV NS5A and other proteins inhibit response to IFN

A
  • core protein can block stat pathway and other functions

- NS5A blocks IL-8

244
Q

Ribavirin: what it’s used in, how it works

A
  • broad-spec antiviral used in HCV therapy
  • modulates balance of helper-T 1 and 2 –> unclear MOA
  • enters cell, is phosphorylated to look like a nucleotide (called RTP then) and can get incorporated into the RNA via a replication cycle
  • also inhibit RNA-dep-RNA-pol (NS5B)
  • incorporation tends to be a consistent theme for RNA viruses
245
Q

Direct acting antivirals for HCV: NS3-NS4A target and 2 drugs

A
  • main therapy currently
  • inhibit some aspect of life-cycle
  • highly specific targeted drugs
  • NS3-NS4A target
  • heterodimer
  • NS3: N-terminal serine protease domain
  • NS4A: helicase domain and acts as a cofactor for protease activity
  • Grazoprevir, Paritaprevir
246
Q

First approved direct acting antivirals (DAAs) for HCV

A
  • both removed from the market before 5 yrs b/c of unpredictable response
247
Q

Direct acting antivirals for HCV: NS5B target and 2 drugs

A
  • RNA-dep-RNA-pol
  • role is to replicate viral RNA
  • sofosbuvir and dasabuvir
248
Q

direct acting antivirals for HCV: NS5A target and 5 drugs

A
  • multiple roles in replication, not sure exactly what they are but know it’s required
  • ledipasvir, ombitasvir, elbasvir, velpatasvir, ombitasvir
249
Q

SVR

A
  • sustained viral response

- at a certain time point, percent of patients that have no HCV left

250
Q

IFN/RBV combo

A

more effective for HCV than IFN only therapy

251
Q

First generation NS3/NS4A DAAs improved ___ but for which genotype only?

A
  • improved SVR

- only for genotype 1

252
Q

Retroviruses (2)

A
  • HIV

- HTLV-1 (T-cell leukemias)

253
Q

Lifecycle of a retrovirus

A
  • bind to chemokine and CD4 receptors on a CD4+ T-cell
  • fusion into cell (nucleocapsid)
  • penetration and uncoating
  • reverse transcriptase to make cDNA
  • RNase to remove RNA
  • make double stranded DNA
  • integration into host chromosome
  • then vRNA assembled, budding, and release
  • maturation after release
  • or vDNA is transcribed into viral mRNA and translated into regulatory and structural proteins
254
Q

GAG

A
  • incorporated into particle when budding and encodes all of the proteins necessary for maturation of the HIV extracellular virion
255
Q

Overview of HIV therapy (in general)

A
  • typically 3 drugs (may have different mechanisms)
  • patient compliance is critical as only one missed dose may cause resistance
  • methods to simplify pill burden has been a major goal
256
Q

Classes of antiviral drugs for HIV infections (6)

A
  • nucleoside reverse transcriptase inhibitors (NRTIs)
  • nucleotide reverse transcriptase inhibitors (NtRTIs)
  • Non-nucleoside reverse transcriptase inhibitors (NNRITIs) (bind to different site)
  • Protease Inhibitors (PIs)
  • Fusion inhibitors (FIs)
  • Integrase Inhibitors (IIs)
257
Q

difference between nucleoside and nucleotide

A
  • nucleoside –> no phosphate group
258
Q

first approved drug to treat HIV

A

AZT

259
Q

Multiclass products for HIV

A
  • usually 2 or 3 drugs in one
  • 1x daily pills
  • can combine an inhibitor of a cyp that metabolizes a drug in the combination to make it last longer
260
Q

Ritonavir.. what is it used for

A
  • often used to boost therapeutic levels of protease inhibitors (inhibits CYP3A4)
  • Used in HIV and HCV
261
Q

Tell me about Tenofovir

A
  • two variations
  • Tenofovir disoproxil fumarate and Tenofovir alafenamide fumarate
  • TAF has better penetration into lymphoid tissue, 5-15x higher than TDF
  • also has [ ] in peripheral blood mononuclear cells 150x greater than in plasma
  • overall message: can use much lower doses of TAF for same thing
  • both prodrugs and both same active molecule
262
Q

Reverse Transcriptase Inhibitors

A
  • AZT original one
  • look like a nucleotide/nucleoside so can be incorporated into the DNA and stop transcription
  • need to be phosphorylated to work
263
Q

Acyclic nucleoside phosphonates

A
  • key class of antiviral agents
  • Acyclovir and Adefovir belong to this
  • rate limiting step of these reverse transcriptase inhibitors is that they need phosphates put on.. first phosphate is rate limiting
264
Q

What does adding a carbon -P bond do for reverse transcriptase inhibitors?

A
  • eliminates rate limiting step
  • makes them resistant to esterases
  • can lower dose
265
Q

Cidofovir and Adefovir

A
  • acts as chain terminator of DNA synthesis by the viral DNA-dep-DNA pol
  • poor substrate for viral DNA pol and terminates DNA elongation
266
Q

Reverse transcriptase inhibitors: where do they act?

A
  • act in the active site and get incorporated into chain and terminate
267
Q

Nonnucleoside RT inhibitors example, facts, where they act

A
  • bind to allosteric site 15A away
  • these are specific to HIV cannot use in other viruses
  • don’t look similar to each other b/c not a pseudosubstrate
268
Q

Protease inhibitors: what do they mimic, MOA, one example

A
  • all mimic the transition state of the protease (phenylalanine and -OH)
  • all have a C-C-OH bond in them (hydroxyethylene core)
  • Protease has high affinity for the transition state
  • protease cleaves Gag and Gag-pol precursor proteins to structural and functional proteins
  • can have many mutations
  • Ritonavir
269
Q

Entry inhibitor name and MOA

A
  • Maraviroc

- binds to CCR5 (chemokine receptor), preventing GP120 binding, and then fusion and entry

270
Q

HIV integrase inhibitor name and MOA

A
  • Raltegravir
  • thought of as a potential area of target for cure
  • binds both ends of proviral DNA and prevents its integration into the host genome
271
Q

lifecycle of a DNA virus

A
  • not incorporated into host genome
  • attachment
  • uncoating and transfer of viral DNA to host nucleus
  • transcription into viral mRNA and synthesis of viral DNA
  • protein synthesis by host cell ribosome into regulatory proteins, viral enzymes, and structural proteins
  • assembly of virion
  • budding and release
272
Q

Enfuviritide

A
  • peptide that binds HIV pg41 and disrupts interaction with cell receptors
  • substrate mimic
  • need very high dose to be effective– ridiculously large af
  • does proved alternative target
273
Q

HSV undergoes ____ within host

A
  • circulization
274
Q

what do regulatory proteins in HSV do?

A
  • help control viral enzyme synth
275
Q

what do structural proteins do in HSV?

A
  • involved in assembly of mature virion particle
276
Q

Inhibitors of HSV DNA replication (4 general categories) what do most drugs inhibit?

A
  • nucleoside analog target viral DNA pol
  • non-nucleoside drugs that target viral DNA pol (allosteric site)
  • Helicase-primase inhibitors
  • inhibitors that block protein-protein interactions (ex. ribonucleotide reductase)
  • *most drugs inhibit DNA replication**
277
Q

Ribonucleotide reductase

A
  • converts sugars and nucleotides to de-oxy version incorporated into DNA
  • if this is shut down, stop production of precursors for DNA synth
278
Q

Nucleoside analogs that target viral DNA for HSV (2) and MOA

A
  • Acyclovir (also used in HIV)
  • Valacyclovir (has valine)
  • both same active molecule for both
  • valacyclovir is a substrate for intestinal peptide transporters (prodrug), acyclovir is not
  • both have base like guanine (look like a nucleoside)
  • MOA: incorporated into growing chain and stop replication
  • first step of both is to phosphorylate (rate limiting)
279
Q

Inhibitors that block protein-protein interactions for HSV

A
  • BILD1263
  • can inhibit ribonucleotide reductase b/c blocks inbetween small and large subunit
  • these give alternative therapeutic target
280
Q

Inhibitors of HSV assembly, encapsidation, and nuclear egress (4 categories)

A
  • acridones
  • thioureas
  • phenylenediamine-sulfonamides
  • ribosylbenzimidazoles
281
Q

Non-retroviral RNA Virus example

A

influenza

282
Q

What flu virus subtype means

A
  • H: hemaglutinin: responsible for recognition of specific sugar on outside of human cell
  • N: neuroaminidase: enzyme function that releases particle from a cell to go on and infect other cells
283
Q

which part of flu name determines whether it can be zoonotic?

A
  • Hemaglutinin

- H part

284
Q

Lifecycle of a RNA virus (nonretroviral)

A
  • cell binding to hemoglutinin
  • endocytosis
  • fusion and uncoating
  • RNA into nucleus where it can be replicated to cRNA and then to vRNA by RNApol OR replicated by RNApol to mRNA
  • vRNA to budding and release
  • mRNA to protein synthesis
285
Q

M2 protein

A
  • in RNA virus (nonretroviral) ex. flu
  • pulls protons from endosome into interior of virus
  • induces confirmational change in structural proteins that leads to fusion and uncoating
286
Q

Inhibitors of influenza virus uncoating

A
  • amantadine and rimantadine

- both act on M2 by blocking the channel

287
Q

Inhibitors of neuroaminidase

A
  • for flu
  • neuroaminidase is the enzyme function that releases the newly budded viral particle from the hemaglutinin that it’s stuck to
  • specifically cleaves off sialic acid
  • Rabivab, Tamiflu
  • mimics transition state
  • drastically reduces symptoms and time to recovery
288
Q

Sialic Acid

A
  • on cell receptor for influenza virus that makes the hemaglutinin stick to the cell
  • neuramidases can cleave whatever position the galactose is in (usually 3 or 6 depending on location of cell)
289
Q

Comparison of fungi and bacteria

A

Bacteria:

  • cell wall = peptidoglycan
  • prokaryotic
  • no sterols in membrane

Fungi:

  • cell wall= glucan, mannan, chitin
  • cell membrane = ergosterol (humans cholesterol)
  • Eukaryotic
290
Q

Morphological classification of fungi

A
  • Filamentous (molds)
  • Yeast
  • Dimorphic Fungi: two forms of growth
  • filamentous form(at room temp) and yeast form (at body temp)
291
Q

Filamentous fungi growth and repro

A
  • grow as hyphae and reproduce asexual spores
292
Q

Yeast growth and repro

A
  • grow as single cells and repro by budding

- may form chains for elongated cells (pseudohyphae)

293
Q

Why fewer drug targets in fungi than bacteria?

A
  • closer related to humans
294
Q

Systemic fungal infections- pathogenic fungi

A
  • uncommon
  • natural immunity is high
  • physiological barriers
  • skin and mucous membranes, fungi grow better below 37C, redox potential in-vivo conditions are too reducing for most fungi
295
Q

Systemic fungal infections opportunistic fungi

A
  • cause disease in immunocompromised

- weakened immune function from variety of things

296
Q

Most common opportunistic fungi infections

A
  • candidiasis
  • aspergillosis
  • crytococcus
  • zygomycosis/mucormycosis
  • pneumocystis carinii (jiroveci)
297
Q

What is the #1 cause of mortality in cancer and transplant patients?

A
  • drug-resistant fungi
  • only 3 effective drug classes
  • emerging resistance to last line of defense
298
Q

5 major classes of antifungals

A
  • azoles
  • polyenes
  • allyamines
  • pyrimidines
  • echinocandins
299
Q

three major mechs of resistance in fungus

A
  • target modification
  • efflux pumps
  • other-biofilms
300
Q

Mode of action of azoles (fungi)

A
  • inhibit ergosterol
301
Q

mode of action of polyenes

A
  • form pores/channels
302
Q

mode of action of allylamines

A
  • inhibit lanosterol biosynth
303
Q

mode of action of pyrimidines

A
  • inhibit DNA/RNA synth
304
Q

mode of action of echinocandins

A
  • inhibit glucan biosynth
305
Q

b-glucan is synoynmous to what in bacteria?

A
  • peptidoglycan

- adds stability to membrane

306
Q

which antifungal is the newest? oldest?

A
  • newest is candins

- oldest is pyrimidines

307
Q

both azoles and allylamines act on the ____

A
  • cell membrane

Pharmacology III (18 decks)

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