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POM Block > Micro POM > Flashcards

Micro POM Flashcards

1
Q

Major targets for antibacterials

A
  • Cell wall synthesis
  • Membrane structure
  • Folate synthesis
  • DNA synthesis
  • Protein synthesis
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2
Q

Targets that are unique to microbes (humans don’t have)

A
  • Cell envelope
  • Prokaryotic ribosome
  • Prokaryotic nucleic acid metabolism
  • Essential nutrient synthesis
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3
Q

Minimum Inhibitory Concentration:

A

The smallest amount of drug needed to INHIBIT the growth of a particular bacterial species (smaller value than MBC)

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4
Q

Minimum Bactericidal Concentration:

A

The smallest amount of drug needed to KILL a particular bacterial species (larger value than MIC)

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5
Q

Bacteriostatic:

A

Bacteria are stopped from growing but aren’t killed.

e.g. tetracycline

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6
Q

Bacteriocidal:

A

Bacteria are killed.

e.g. penicillin

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7
Q

Methods to determine microbial susceptibility/resistance:

A
  • Culture-based (E-test and Disk diffusion e.g. A disk)

- Molecular detection of resistance mutations (PCR, sequencing, etc.)

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8
Q

Hospital antibiograms:

A
  • Periodic summaries of antibiotic susceptibilities of local isolates sent to clinical micro lab (results are % of strains tested that are susceptible)
  • Aid in selecting empiric therapy
  • Track resistance trends
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9
Q

The efficacy of antimicrobial drugs is limited by:

A
  • Mechanism of action
  • Susceptibility of the target organism
  • Side effects on the host
  • Pharmacodynamics
  • Cost
  • Patient compliance
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10
Q

Cmax

A

The max concentration that can be achieved from a given dose of a drug
-always the peak of the curve

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11
Q

Area Under Curve (AUC)

A

Area under the curve tells the total amount of drug that has accumulated in the patient. Want to maximize the amount of time that this is above the MIC level.

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12
Q

Time-dependent killing (TDK)

A

GOAL: Maximize time above MIC
Drug > MIC for at least 50% of dosing interval
e.g. penicillins and cephalosporins

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13
Q

Concentration-dependent killing (CDK)

A

GOAL: Maximize Cmax and therefore AUC
AUC/MIC > 30 for G+
AUC/MIC > 130 for G-

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14
Q

Post-antibiotic effect (PAE):

A

The time it takes bacteria to return to log-phase growth following removal of antibiotic
(usually minimal for TDK because already tried to extend the time the drug is above the MIC; CDK usually has a longer PAE)

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15
Q

______ PAEs reduce required frequency of dosing, and reduce toxicities and costs

A

LONGER PAEs reduce required frequency of dosing, and reduce toxicities and costs

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16
Q

Classes of agents that interfere with the bacterial cell envelope:

A
  1. B-lactams
  2. Glycopeptides
  3. Isoniazid
  4. Ethambutol
  5. Bacitracin
  6. Phospho(no)mycin
  7. Cycloserine
  8. Lipopeptides
  9. Polymyxins
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17
Q

Structures unique to gram negative cells:

A

Outer membrane beyond the peptidoglycan, composed of LPS (lipopolysaccharide) and Lipid A (the toxic molecule of LPS)

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18
Q

Structures unique to gram positive cells:

A

Lipoteichoic acid (LTA) within peptidoglycan

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19
Q

General structure of peptidoglycan:

A

Alternating NAM and NAG sugars make the basic backbone chain of peptidoglycan (connected via transglycosylation)
On the NAM molecules, we see an extension of 4 amino acids that can be used to create the cross-linking and provide rigidity. (connected via transpeptidation)

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20
Q

What are the last two amino acids in the peptide chains of peptidoglycan?

A

D-Ala-D-Ala

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21
Q

Penicillin Binding Proteins (PBP)

A

PBPs have transpeptidase activity (some also have transglycosylase activity)

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22
Q

Where do penicillins and cephalosporins target?

A

These target the transpeptidation reactions that are essential for bacterial synthesis

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23
Q

Antibiotic resistance mechanisms:

A
  • Enzymatically inactivate drug (B-lactamases) - often on mobile genetic elements and can be transferred between bacteria
  • Alter drug target (mutation, can occur via horizontal exchange)
  • Alter drug exposure (decreased uptake in G-, increase efflux)
24
Q

B-lactamases:

A

Break a bond in the B-lactam ring of penicillin to disable the molecule. Bacteria with this enzyme can resist the effects of penicillin and other B-lactam antibiotics.

25
Q

2 Important B-lactamases:

A
  • ESBL (extended spectrum B-lactamases): mostly derived from active site mutations in TEM/SHV; results in activity against extended-spectrum cephalosporins
  • Metal-Dependent (New Delhi Metallo B-lactamase): NDM-1
26
Q

Clavulanic Acid:

A

Category of drugs that were developed as B-lactamase inhibitors. Deactivate the microbial enzyme B-lactamase.

27
Q

Alternative Penicillin-Resistant PBPs:

A
  • Some PBPs have low affinities from B-lactams but still retain transpeptidase activity
  • Can arise through mutation (e.g. gonorrhea)
  • Can be acquired horizontally (e.g. mecA gene in MRSA)
28
Q

Antibiotic resistance often exacts a ______ cost.

A

Antibiotic resistance often exacts a FITNESS cost (The resistant bacteria don’t grow as well because their PBOs aren’t as good at making peptidoglycan as the original susceptible version of the enzyme).

29
Q

Gram negative cell bacterial resistance:

A
  • Outer membrane helps keep things out. Also have porin proteins in membrane that can both prevent entry.
  • B-lactamases located between the inner and outer membranes
  • Can acquire an efflux pump that allows them to quickly push out antibiotics
30
Q

Glycopeptide drug class:

A

VANCOMYCIN

Inhibit the transglycosylation of peptidoglycan.

31
Q

Vancomycin

A

Binds to the D-Ala-D-Ala residues, which normally function to direct transglycosylation sugar linkages. By binding, vancomycin prevents this by directly covering the actual peptide residues.

32
Q

Vancomycin resistance mechanisms:

A
  • The D-Ala-D-Ala target of glycopeptides is not encoded by a gene (so spontaneous mutation can’t confer resistance)
  • No known enzymes capable of inactivating glycopeptide antibiotics
  • Vancomycin is primarily used to treat Gram positive infections
  • Target is extracellular precluding altered drug uptake as a resistance mechanism
33
Q

D-ala-D-lac

A

Resistance mechanism developed by some bacteria that mutates a D-Ala residue, thus preventing Vancomycin from binding and blocking transglycosylation. BUT this peptidoglycan isn’t as strong, and makes the bacteria more susceptible to a lot of other things.

34
Q

Bacitracin:

A
  • Cell-wall active agent

- Inhibits regeneration of peptidoglycan lipid carrier

35
Q

Phosphomycin:

A
  • Cell wall active agent

- Prevents attachment of NAG to NAM + peptide

36
Q

Cycloserine:

A
  • Cell wall active agent

- Prevents attachment of peptide to NAM

37
Q

Mycobacterium species:

A

M. tuberculosis and M. leprae

  • Mycolic acid: waxy long-chain branched hydrocarbons
  • Arabinogalactan (sugar-like molecule that adds to the structural integrity)
  • Acid-fast stain, not gram stain
38
Q

Agents that act on Mycobacterial cell walls:

A
  • Isoniazid

- Ethambutol

39
Q

Isoniazid:

A

Inhibits mycolic acid synthesis

40
Q

Ethambutol:

A

Thought to inhibit arabinotransferases

41
Q

Lipopeptides:

A

Disrupt the cell membrane of G+ bacteria.

  • Form pores in cytoplasmic membrane
  • Too big to get through porins in Gram- outer membrane
  • Bind to phosphatidylglycerol, which is an abundant component of bacterial cell membranes but rare in eukaryotic cells
42
Q

Lipopeptide example:

A

Daptomycin

43
Q

________ can NOT be used to treat pneumonia.

A

LIPOPEPTIDES can NOT be used to treat pneumonia, because the surfactant found in human lungs is rich in phosphatidylglycerol

44
Q

Bacterial folate synthesis inhibitors:

A
  • Sulfonamides

- Trimethoprim

45
Q

Sulfonamides:

A

-Bacteriostatic on their own, active against G+ and G-
-Many bacteria synthesize their own folate (humans don’t - thus, selectivity)
E.g. SULFAMETHOXAZOLE

46
Q

Resistance to sulfonamides:

A
  • Altered drug target (spontaneous mutation in dhps gene), horizontal acquisition of alternate DHPS encoded on mobile genetic elemenet
  • Swamp the system (increased production of folate precursor PABA)
  • Altered drug exposure (decreased uptake)
47
Q

Trimethoprim inhibits DHFR

A
  • bactericidal, used in combo with sulfamethoxazole
  • Bacterial DHFR is much more sensitive to drug than human enzyme
  • tmp/smx combo is synergistic - smx becomes bactericidal using lower doses of both drugs
  • targeting 2 separate steps in the same pathway reduces likelihood of resistance
48
Q

Quinolones/Fluoroquinolones inhibit prokaryotic _____ synthesis

A

Quinolones/Fluoroquinolones inhibit prokaryotic DNA synthesis.

  • Bactericidal (G- better than G+)
  • Inhibit DNA gyrase (aka topoisomerase II) and topoisomerase IV
    e. g. ciprofloxacin
49
Q

What class of antibiotics is ciprofloxacin in?

A

Quinolones/Fluoroquinolones

50
Q

Fluoroquinolones inhibit _______ and _______

A

Fluoroquinolones inhibit Gyrase (topoisomerase II), inducing damage during DNA replication, and Topoisomerase IV, preventing newly-replicated chromosomes from separating into daughter cells.

51
Q

_________ should be reserved for patients who have no other treatment options due to its black box warning related to tendon rupture.

A

FLUOROQUINOLONES should be reserved for patients who have no other treatment options due to its black box warning related to tendon rupture.

52
Q

Resistance to quinolones:

A
  • Altered Drug Target (chromosomal mutations in gyrase and topoisomerase genes)
  • Altered Drug Exposure (decreased uptake via mutations in gram negative porin proteins, increased efflux due to mutations that increase efflux pump activity, cross-resistance between quinolones and other antibiotics and host-derived antimicrobial factors = multi drug resistance)
53
Q

Rifamycins inhibit _____ synthesis:

A

Rifamycins inhibit mRNA synthesis:
-Can be bactericidal or bacteriostatic depending on concentration
-primarily used for tuberculosis or meningococcal prophylaxis
-Bind to bacterial DNA-dependent RNA polymerase with higher affinity than to human enzyme
E.g. rifampin

54
Q

Resistance to rifamycins:

A
  • Rarely used as monotherapy because of high rate of resistance
  • Resistance can occur with spontaneous mutations in RNA polymerase gene (this mutation has a very low fitness cost so it happens fast)
55
Q

Nitroimidazoles damage _______.

A

Nitroimidazoles damage DNA (by oxidative mechanisms)

  • Are taken in inactive form and must be converted by microbial enzyme ferredoxin to active form (ferredoxin removes nitro group).
  • Activated drug forms free radicals that damage DNA
    e. g. metronidazole
56
Q

Resistance to nitroimidazoles:

A

Failure to enzymatically activate drug (mutations in microbial enzymes that convert the prodrug to the active compound)

57
Q

Name the subclasses of B-lactam antibiotics (4):

A

Penicillins, cephalospirins, carbapanems, and monobactams

POM Block (9 decks)

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