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Phar 747 Infectious Disease > Unit 2 > Flashcards

Unit 2 Flashcards

1
Q

Streptomycin spectrum:

A

aerobic Gram- bacteria

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2
Q

Streptomycin toxicity:

A

ototoxic and nephrotoxic

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3
Q

Aminoglycoside central structure:

A

2-Deoxystreptoamine

Streptidine for Streptomycin

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4
Q

Aminoglycoside mechanism of action:

A

Transport:
- Alter outer membrane to pass through.
- Actively transported by 02-dependent transport.
Cellular target:
- Bind 16S rRNSA of 30S irreversibly.
- Misreads the mRNA: improper folding.
- Inhibit initiation of protein synthesis.
- Polysomes dissociate into non-functional monosomes.

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5
Q

Gentamycin Family includes (SIGN):

A

G - Gentamicin (mixture of 3 compounds)
S - Sisomicin
N - Netilmicin
I - Isepamicin

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6
Q

Kanamycin Family includes:

A

Kanamycin (mixture of 3 compounds)
Amikacin
Tobramycin

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7
Q

Neomycin Family includes:

A

Neomycin (neomycin B and C, and neamine)

Paromomycin

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8
Q

Aminoglycoside Class includes what families?

A

Streptomycin
Gentamycin
Kanamycin
Neomycin

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9
Q

Aminoglycoside Resistance (4-types):

A

Three forms:
Decrease in drug uptake, or Accumulation.
- Altered porin channels
- Active efflux
- Altered ability to cross cytoplasmic membrane
Alter Ribosomal Structure.
- Altered protein or rRNA decreases acces/binding affinity.
Aminoglycoside Modifying Enzymes (AMEs)
- Group transerases that modify OH or NH2 groups:

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10
Q

Types of AMEs:

A 
Aminoglycoside O-Phosphotransferases (APH)
- adds Pi
Aminoglycoside O-Nucleotidyltransferases (ANT)
- adds nucleotide
Aminoglycoside N-Acetyltranserases (AAC)
- adds acetyl group
Bifunctional AMEs - most important:
- AAC(6')-APH(2'')
    - adds acetyl and Pi groups.
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11
Q

Tetracyclines spectrum:

A

Both gram+ and gram- bacteria

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12
Q

Tetracycline absorption depends on:

A

di- and trivalent metal ions
usually Mg2+
Caution with dairy and calcium supps.

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13
Q

Tetracyclines movement with Mg2+

A

Tc-M enter porin.
Tc and M dissociate in periplasmic space.
Tc passes the cytoplasmic membrane alone.
Tc joins M in cytosol.
TC-M attack ribosome.

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14
Q

Tetracycline mechanism of action:

A

Bind 16S rRNA of 30S.
Block binding of aminoacyl-tRNA reversibly.
Prevents elongation of peptide chain.
May be bad to use with penicillins - wall can’t be destroyed if it isn’t being built.

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15
Q

Types of Tetracyclines:

A 
Chlortetracycline.
Tetracycline.
Doxycycline.
Minocycline.
Tigecycline.
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16
Q

Tetracycline Resistance (4-types):

A 
Enzymatic inactivation.
Target modification.
Energy-dependent efflux mechanism.
Ribosomal protection proteins
- Tet(O) and Tet(M)
- act like EF-Tu and EF-G elongation factors.
- GTPases needed for protein synthesis
- mech: dissociate tetracyclines from ribosome
- revive the ribosomes function.
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17
Q

Macrolides spectrum of activity:

A

Similar to penicillins; gram+

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18
Q

Macrolide mechanism of action:

A

Bind 50S subunit reversibly.
Inhibit protein synthesis.
Usually bacteriostatic.
*Same for Lincosamides.

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19
Q

Macrolides include:

A 
Erythromycin A and salts/ester-prodrugs:
- Erythromycin Stearate
- Erythromycin Ethyl Succinate
- Erythromycin Estolate
Second Generation Macrolides:
- Azithromycin: "azalide"
- Clarithromycin
- Telithromycin: "Ketolide"
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20
Q

Macrolide Resistance:

A

Intrinsic: Gram- impermeability of outer membrane to hydrophobic macrolides.
Acquired Resistance, 3:
1 - Target modification; methylation of 23S rRNA
-MLS
-*M=Marolides, L=Lincosamides, S=StreptograminB
2 - Drug Inactivation
- Erythromycin Esterases I and II: open to linear chain.
-Macrolide 2’-Phosphotransferase
3 - Active efflux

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21
Q

Lincosamides include:

A

Clindamycin

Lincomycin

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22
Q

Lincosamides spectrum:

A

Gram+ and some anaerobes.

Effective for staph in bones and joints (my knee this summer!)

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23
Q

Lincosamide mechanism of action:

A

Bind 50S subunit reversibly.
Inhibit protein synthesis.
Usually bacteriostatic.
*Same for Macrolides.

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24
Q

Oxazolidinones include:

A

Linezolid

Tedizolid (newer)

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25
Q

Oxazolidinone Mechanism of Action:

A

Overall: Disrupt protein biosynthesis - bacteriostatic.
Specifically: Bind 23S rRNA of 50S subunit - at site near 30S subunit; blocks the formation of 70S.

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26
Q

Oxazolidinone SAR:

A

3’-fluorine: activity

Oxazolidinone ring: intact

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27
Q

Chloramphenicol

A 
New class of antibiotic
Broad Spectrum
Inhibit 50S - peptide formation
- near macrolide/clindamycin site: not in conjunction.
Good CNS access - meningitis
Grey Baby Syndrome - Pancytopenia
- low blood cells
Resistance: Chloramphenicol Acetyltransferase (CAT)
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28
Q

Retapamulin used for:

A

Topical treatment of Impetigo.

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29
Q

Retapamulin MOA:

A

Acts on 50S subunit:
Unique binding involving L3 of P-site.
Inhibits peptidyl transer, blocking P-site interactions, and therefore preventing formation of active 50S.

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30
Q

Retapamulin Resistance:

A

Mutation in L3 protein.

Efflux.

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31
Q

Fidaxomicin used for:

A

Clostridium difficile.
*Little to no effect on normal fecal flora.
Fewer CDI recurrences.
Not absorbed.

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32
Q

Fidaxomicin MOA

A

Inhibits “sigma-dependent” transcription of bacterial RNA polymerase.
Bactericidal.

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33
Q

Fluoroquinolones inhibit:

A

Nucleic acid metabolism and function.

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34
Q

DNA Gyrase

A

Relaxes supercoiled DNA.

  • relieves torsional strain during replication.
  • the only enzyme that can also supercoil DNA.
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35
Q

DNA Topoisomerase IV

A

A decatenating enzyme:

- resolves interlinking daughter chromosomes following DNA replication.

36
Q

Fluoroquinolone/Quinolone MOA:

A

Bind Gyrase-DNA complex

37
Q

Nalidixic Acid

A

First Generation Fluoroquinolone.
Rirst Quinolone - prototype of the rest.
Strong acid - pKa of 1.
Extensively metabolized to 7-OH-Methyl-nalidixate
Nonfluorinated and resistance to it is wide spread, so today it is limited to uncomplicated UTI’s
- usually due to Gram- bacteria.

38
Q

Norfloxacin

A

Second Generation Fluoroquinolone.
C-6 F-group.
100x more potent than nalidixic acid.
Broader Gram- and some Gram+

39
Q

Ciprofloxacin

A

Second Generation Fluoroquinolone.
Top 200
More potent than Norfloxacin
Better absorption - distribute to bone/soft tissues.
Safe, but: Q/T prolongation, photosensitivity.
With penicillin for Anthrax.

40
Q

Ofloxacin and Levofloxacin

A 
Second Generation Fluoroquinolones.
Top 200
S+R = Oflaxacin, S only = Levofloxacin
High CSF - Meningitis.
Q/T prolongation.
Active against MDR-TB - second line treatment.
41
Q

Sparfloxacin

A

Third Generation Fluoroquinolone.
Two F-groups.
Q/T prolongation and photosensitivity.

42
Q

Gatifloxacin

A

Third Generation Fluoroquinolone.
Topical eye drop.
Sever blood glucose fluctuations - insulin secretion.

43
Q

Moxifloxacin

A

Fourth Generation Fluoroquinolone.
Top 200.
“Respiratory quinolone” - pneumonia and TB.
long t1/2.

44
Q

Gemifloxacin

A

Fourth Generation Fluoroquinolone.
Pneumonia or bronchitis
Recently, skin infections
- something about women under 40, and skin rashes, and hormone therapy.

45
Q

Fluoroquinolone Resistance:

A

Mutate Gyrase and topo IV genes.
- gyrA gene for Gyrase: chromosomal.
Decrease intracellular accumulation of drug.
recG gene - repair fluoroquinolone damage.
Plasmid resistances
- Qnr proteins interfere with binding.
- Fluoroquinolone Modifying Enzymes; mutated AAC
- Efflux pumps

46
Q

Fluoroquinolone Toxicity/Side Effects:

A 
*Tendon Rupture
Q/T prolongation
Photoxicity
Peripheral neuropathy
Skin lesions, blisters, second degree burns, vasodisturbances.
47
Q

Sulfonamides in general:

A

Antifolates

48
Q

Sulfonamide MOA:

A

Inhibit folic acid biosynthesis needed for:

  • synthesis of thymidine and purines.
  • synthesis of several amino acids.

Specifically: inhibit DHPS -or- serve as DHPS substrate.

  • mimic PABA
  • ends pathway.

Selective toxicity: mammals do not synthesize folate; target-DHPS is not present.
Also, bacteria cannot take in our folate to make up for it.

49
Q

Protonsil

A

Prototype Sulfonamide antibiotic
In cells - converted to Sulfanilamide.
pKa = 10; crystallizes in kidney
Hypoglycemic inducing property lead to development of sulfonylurea diabetic drugs.

50
Q

Trisulfa Pyrimidine

A

Sulfadiazine, Sulfamerazine, and Sulfamethazine.
Equal parts to total 500mg dose.
Reduced crystallization problem.

51
Q

Sulfisoxazole

A

Sulfonamide Antibiotic.
pKa = 5
Bitter taste.

52
Q

Sulfamethoxazole

A

Sulfonamide Antibiotic.
Used with Trimethoprim
- achieve 20:1 ratio with 20:4 dose
- Trimethoprim inhibits DHFR; way more so for bacterial DHFR than mammalian.

53
Q

Sulfacetamide

A

Sulfonamide Antibiotic.
Topical use only
acne and eye infection

54
Q

Mupirocin

A

Miscellaneous
Top 200.
External use - Impetigo.
Blocks synthesis of isoleucyl-tRNA.

55
Q

Metronidazole

A

Miscellaneous
Top 200.
For C. diff
NO2 moiety forms radical (like Nitrofurantoin)
Discolors urine reddish-brown
With alcohol - Disulfiram-like effects; very sick.
MOA: 1-electron transfer to form radical using ferredoxin.

56
Q

Nitrofurantoin

A 
Miscellaneous
Top 200
Broad spectrum, not ps.
For UTIs
NO2 moiety forms radical (like Metronidazole)
Discolors urine yellow-brown.
57
Q

Mycobacterium TB

A 
Why difficult?
- complex outer wall; mycolic acid.
- divide very slowly.
- mostly dormant.
Treatment times:
- typically 6 months
- MDR for 2 years
- Extensive Drug Resistant for 2 years in hospital.
Patients with HIV: 1/3 will die.
58
Q

Isoniazid (INH)

A

Anti-TB antibiotic.
Perfect: selective, cheap, oral, low toxicity.

MOA: inhibit mycolic acid biosynthesis.

Specifically: Targets inhA (Enoyl-Acyl Carrier Protein Reductase) involved in mycolic acid synthesis.

INH oxidized by KatG; releases active metabolite.

Metabolite reacts with NADH-cofactor of inhA

Resistance: mutation of inhA.

59
Q

Rifampin

A

Anti-TB antibiotic.
First-Line treatment

MIC = 5ng/mL, but is selective under 5ug/mL - it’s very safe.

MOA: Inhibits DNA-dependent-RNA-Polymerase - binds to it’s P-site.

Works better in conjunction with cell wall inhibitors - Ethambutol.

  • Strong CYP-inducer:
  • bad for HIV patients on CYP sensitive drugs.

Can cause harmless discoloration of body fluids.

60
Q

Rifabutin

A

Anti-TB antibiotic.
Less CYP inducing than Rifampin - different side chain
Better for HIV patients on CYP sensitive drugs.

61
Q

Rifapentine

A

Anti-TB antibiotic.

Long t1/2.

62
Q

Rifaximin

A

Not for TB

Less than 1% absorbed; used for GI infections.

63
Q

Ethambutol (EMB)

A

Anti-TB antibiotic

Synergistic with Rifampin.

MOA: EMB inhibits the cell wall biosynthesis of actively dividing cells by inhibiting Arabinosyltransferase.

Also, EMB may interfere with the transfer of arabinose to the cell wall acceptor.
- This causes an accumulation of the lipid carrier called decaprenyl phosphoarabinose.

May cause a decreases in visual acuity.

64
Q

Pyrazinamide (PZA)

A

Anti-TB antibiotic

PZA is able to target dormant/semidormant bacteria within the macrophages they reside.
- Key component needed to shorten therapy to 6 months.

Prodrug - needs to be hydrolyzed by Pyranizamidase.

MOA: PZA Inhibits trans-translation (the destruction of improperly folded proteins).
- Binds to RpsA: ribosomal protein S1.

PZA-resistant strains have mutated Pyranizamidase
- pnCA gene.

May cause some mild hyperuricemia.

65
Q

Second Line Treatment for TB

A 
Aninoglycosides
Ethionamine
Cycloserine
Aminosalicylin
Capreomycin
Fluoroquinolones
66
Q

Streptomycin

A

Sort of Aminoglycoside.
Streptidine ring.
Gram- aerobes and TB.
Ototoxic and Nephrotoxic.

67
Q

Gentamicin

A 
AG antibiotic - Gentamicin Family.
Three compound mixture.
Parenteral for serious gram-
Topical for ps.
Physically incompatible with B-lactams.
68
Q

Kanamycin

A

AG antibiotic - Kanamycin Family
Three compound mixture; mostly A.
Ototoxic
Used for MDR-TB.

69
Q

Amikacin

A 
AG antibiotic - Kanamycin Family
Derivative of Kanamycin
Added AHBA group.
Half as potent
Much less prone to AG modifying enzymes.
70
Q

Tobramycin

A

AG antibiotic - Kanamycin Family
Derivative of Kanamycin
3’-DeoxykanamycinB
For Ps., not TB
Often used with B-lactams (not physically)
Active towards Gentamicin resistant strains.

71
Q

Neomycin

A

AG antibiotic - Neomycin Family.

Topically only b/c of Nephrotoxicity severity.

72
Q

Paromomycin

A

AG antibiotic - Neomycin Family.

Used for Dysentery.

73
Q

Tetracycline

A

Tetracycline Antibiotic

No chlorine - better oral bioavailability and duration than Chlortetracycline.

74
Q

Doxycycline

A 
Tetracycline Antibiotic
Top 200
No Chlorine
C-6 hydroxyl group - improved activity.
STIs - gonorrhea and syphillis
Lime disease, malarial prevention.
Not with dairy or Calcium supps - reduce absorption; superinfections.
75
Q

Minocycline

A 
Tetracycline Antibiotic
Top 200
Additional di-methy-amine group
No C-6 hydroxy
Better absorption, longer t1/2
76
Q

Tigecycline

A 
Tetracycline Antibiotic
Most recent.
Only injectable.
"protected glycine side chain"
- 9-tert-butyl-glycylamido group.
Less convenient but active against tetracycline resistant strains.
77
Q

A2058 Ribosomal Residue

A

Bacteria - A: can be methylated as a form of resistance.

Mammals - G: extra methyl group provides steric protection from Macrolide antibiotics.

78
Q

Erythromycin A

A

First Generation Macrolide
Prototype.
Acid sensitive, bitter taste.

79
Q

Erythromycin Ethyl Succinate

A

First Generation Macrolide
Better absorption
Most common oral form of Erythromycin.
Will be hydrolyzed by our esterases.

80
Q

Erythromycin Estolate

A

First Generation Macrolide
Propionate ester form as an acid salt with laurel sulfate.
Increased absorption and decreased bitter taste.

81
Q

Clarithromycin

A 
Second Generation Macrolide
Top 200
C-6 hydroxymethyl group - protects from acid.
Better absorption than first gen.
Better activity for Gram- and Gram+
*Used for MAC
*Q/T prolongation
*Hepatotoxic
82
Q

Azithromycin

A

Second Generation Macrolide
Top 200
Oxime intermediate leads to addition of Hydroxylamine and then rearrangement reaction; N pulled down into skeleton; 15 membered ring.
“Azalide” - Acid stable, Better activity, long t1/2
Gonorrhea

83
Q

Lincomycin

A

Lincosamide Antibiotic
Very active against Gram+ and some anaerobes
Staph in bones and joints.

84
Q

Clindamycin

A 
Lincosamide Antibiotic
Chlorinated version
Usually IV, but also oral for C. diff
- superinfection possible
- use with vancomycin, metronidazole, or fidaxomicin
85
Q

Linezolid

A 
Oxazolidinone Antibiotic
First of class
Good for Gram+, MRSA, and VRE strains.
Side Effects bad:
- Myelosuppression
- Acts as MOAI reversibly; depression
86
Q

Tedizolid

A

Oxazolidinone Antibiotic
Newer
Longer t1/2 - reduced dose

Phar 747 Infectious Disease (2 decks)

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