Antimicrobial Agents & Microbial Resistance Flashcards

1
Q

What are antimicrobial agents?

A

Have activity against microbes; antibacterials, antibiotics (produced by a microbe)

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2
Q

Antibacterial mechanisms of action

A
  1. cell wall synthesis
  2. membrane structure
  3. DNA synthesis
    • Folate synthesis
    • DNA replication
  4. Protein synthesis
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3
Q

Minimum Inhibitory Concentration (MIC) vs Minimum Bactericidal Concentration (MBC)

A

MIC: minimum to inhibit growth

MBC: minimum to kill bug

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4
Q

Bacteriostatic vs. Bactericidal

A

Bacteriostatic, MBC ≫ MIC

Bactericidal, MBC ≊ MIC

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5
Q

Methods to determine microbial susceptibility/resistance

A

Culture-based

  1. Disk diffusion
  2. E-test

Molecular detection of resistance mutations

  1. PCR/sequencing
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6
Q

Efficacy of antimicrobial drugs is limited by:

A
  1. Mechanism of action
  2. Susceptibility of the target organism
  3. Side effects on the host
  4. Pharmacodynamics
  5. Cost
  6. Patient compliance
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7
Q

Time-dependent killing (TDK)

A

Goal is to maximize time above MIC; Serum [drug] > MIC for at least 50% of dosing interval

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8
Q

Time-dependent killing (TDK) Examples

A

Wall inhibitors: Penicillins, Cephalosporins

Protein inhibitors: Macrolides, Clindamycin

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9
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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10
Q

Concentration-dependent killing (CDK) Examples

A

DNA inhibitor: Fluoroquinolones

Protein inhibitor: Aminoglycosides

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11
Q

Post-antibiotic effect (PAE)

A

The time it takes bacteria to return to log-phase growth following removal of antibiotic

TDK: minimal PAE

CDK: prolonged PAE - reduced frequency of dosing/toxicity/cost

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12
Q

Bacterial cell envelope

A
  1. Cell membrane (a.k.a. inner or plasma membrane)
  2. Peptidoglycan layer
  3. Outer membrane (for Gram-negatives)
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13
Q

Gram -/+ cell envelope

A

Gram (-): lipopolysaccharide + lipid A + small peptidoglycan

Gram (+): larger peptidoglycan + lipoteichoic acid

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14
Q

Peptidoglycan

A

N-acetylmuramic acid (NAM) + N-acetylglucosamine (NAG) with cross-linked peptides

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15
Q

β-lactams

A

bind Penicillin Binding Proteins (PBPs) and prevent transpeptidation; structurally similar to D-Ala-D-Ala

Examples: penicillins and cephalosporins

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16
Q

Antibiotic Resistance Mechanisms

A
  1. Enzymatically Inactivate Drug (β-lactamases)
  2. Alter Drug Target
  3. Alter Drug Exposure
17
Q

β-lactamases

A

Breaks bond in β-lactam ring of penicillin to disable molecule; penicillin resistance

18
Q

β-lactamase classifications (2)

A
  1. ESBL (extended spectrum β-lactamases)
    • Mostly derived from active site mutations in TEM/SHV, activity against extended-spectrum cephalosporins
  2. Metal-dependent/New Delhi Metallo-β-lactamase
    • NDM-1
19
Q

Clavulanic Acid

A

Inhibits β-lactamases

20
Q

Alternative Penicillin-Resistant PBPs

A

Some have low affinities for β-lactams but retain transpeptidase activity; can be aquired through mutation or horizontally (MRSA)

21
Q

Selective pressure and reversibility of resistance

A

Antibiotic resistance often exacts a fitness cost; additional mutations can compensate for fitness cost; low fitness cost = less reversible

Choose antibiotics with higher fitness cost for resistance

22
Q

Altered Penicillin Transport

A
  1. Decreased membrane permeability (gram -); spontaneous mutations in porin genes
  2. Incrased efflux; horiztontal aquisition of new pump/mutation that alters specificity or expression
23
Q

Glycopeptides

A

Inhibit transglycosylation of peptidoglycan (Ex. Vancomycin)

24
Q

Glycopeptide resistance

A

Synthesizes D-Ala-D-Lac, which vancomycin cannot bind and therefore cannot prevent from incorporation into peptidoglycan chain

25
Q

What characterizes mycobacterium?

A

Mycolic acid: waxy long-chain branched hydrocarbons; requires acid-fast stain instead of gram stain

26
Q

Drugs that act on mycobacterial cell walls

A
  1. Isoniazid (inhibits mycolic acid synthesis)
  2. Ethambutol (inhibits arabinotransferases)
27
Q

Lipopeptides

A

Disrupt cell membrane of gram + bacteria

Form pores in cytoplasmic membrane; bind to phosphatidyl-glycerol (lots in bacterial, rare in eukarotic, cell membranes)

28
Q

What are lipopeptides not used to treat?

A

Pneumonia; lung surfactant is rich in phospatidyl-glycerol

29
Q

Bacterial folate synthesis inhibitors

A
  1. Sulfonamides
  2. Trimethoprim
30
Q

Sulfonamides + example

A

Inhibit folate precursor synthesis; bacteriostatic; actie against G+/-, some protozoa; selective – humans don’t synthesize own folate

Example: sulfamethoxazole (smx)

31
Q

Resistance to sulfonamides

A
  1. Altered drug target (spontaneous mutations in dhps gene or horizontal acquisition of alternate dhps
  2. Swamp system with folate precursor PABA
  3. Altered drug exposure (decrease uptake)
32
Q

Combination Therapy

A
  1. Prevent the emergence of resistance
  2. Treatment of emergency cases when etiology is still unknown
  3. Take advantage of combinatorial synergy
33
Q

Trimethoprim

A

Inhibits DHFR

Bactericidal, used in combo with smx – synergistic

34
Q

Quinolones/Fluoroquinolones + Example

A

inhibit prokaryotic DNA synthesis - inhibit DNA gyrase, inducing DNA damage

Bactericidal (G- > G+)

2nd gen fluoroquinolone: ciprofloxacin

35
Q

Quinolone resistance

A
  1. Altered drug target (gyrase mutations)
  2. Altered drug exposure (decrease uptake, increase efflux, cross resistance –> multidrug resistance MDR
36
Q

Rifamycins + Example

A

Inhibit mRNA synthesis

bactericidal or bacteriostatic depending on concentration, primarily used for Mycobacterium tuberculosis or for meningococcal prophylaxis

Bind to bacterial DNA-dependent RNA polymerase w/ higher affinity than to human enzyme

example: rifampin

37
Q

Resistance to rifamycins

A

COMMON/QUICK

  1. Altered drug target – spontaneous mutation in RNA polymerase gene
38
Q

Nitroimidazoles + Example

A

Damage DNA; Pro-drugs; Activated drugs form free radicals

Bactericidal vs. anaerobic microbes including bacteria and some protozoa

Example: Metronidazole

39
Q

Resistance to nitroimidazoles

A
  1. Failure to enzymatically activate drug