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Exam 1 Therapeutics 2022 > Bacterial Resistance > Flashcards

Bacterial Resistance Flashcards

1
Q

Bacterial DNA

A

a single circular, double-stranded

chromosome that encodes for essential cellular functions (growth, cell division)

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2
Q

plasmids

A
  • Encode for genes whose products are not essential for cell survival
  • self-replicating DNA
  • genes encoding resistance to multiple antibiotics can be located on a single plasmid
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3
Q

Gram positive organisms and peptidoglycan layers (cell wall)

A

thick peptidoglycan layers

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4
Q

Gram-negatives and peptidoglycan layers

cell wall

A

thin peptidoglycan layer, fewer peptide cross-linkages

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5
Q

enzymes vital for cell wall synthesis shape and structural integrity (cell wall)

A

Penicillin binding protein

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6
Q

most vital penicillin binding protein (cell wall)

A

transpeptidase (catalyzes the final cross link between

sugar and peptide in peptidoglycan molecule)

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7
Q

the outer membrane of gram-negative bacteria

A
  • contains (LPS endotoxin)

- contains porins, (which are hydrophilic channels that allow for transport of small molecules

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8
Q

periplasmic space in gram negative organisms

A

located in-between cytoplasmic space (peptidoglycan layers) and the outer membrane (this is where beta lactamases in gram negative organisms are)

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9
Q

Human risk factors for emergence, transmission, of bacterial resistance.

A
  • introduction of broad spectrum antibiotics
  • elderly, immunocompromised
  • homelessness, poor nutrition
  • inadequate medical care
  • reductions in public health care
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10
Q

Microbial risk factors for emergence, persistence, and transmission of bacterial resistance

A
  • propensity to exchange genetic materials
  • intrinsic resistance
  • survival in multiple environments
  • ability to occupy certain ecological niches and interact with other organisms in these niches
  • previous antibiotic exposure
  • selecting for resistant strains
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11
Q

mechanisms of intrinsic resistance

A
  • absence of antibacterial target

- bacterial cell impermeability

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12
Q

acquired resistance

A
  • a change in bacterial DNA acquired through a mutation in hosts DNA, or gaining new DNA
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13
Q

Mutations

A

occur spontaneously in every 10^6 bacterial cells

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14
Q

Conjugation

A

direct contact or mating via sex pili (most common)

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15
Q

Transduction

A

genes transferred between bacteria by bacteriophage (viruses)

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16
Q

Transformation

A

he transfer or uptake of “free floating” DNA from the

environment; then DNA is integrated into the host DNA

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17
Q

Transposons

A
  • Genetic elements flanked by 2 insertion sequence elements that possess the ability to translocate from one location to another
  • capable of moving from a plasmid to a chromosome or vice versa
  • single transposons may encode multiple resistance factors
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18
Q

Phages

A
  • viruses that can transfer DNA from organism to organism
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19
Q

beta-lactamases

A

enzymes that hydrolyze the beta lactic ring by splitting an amide bond and inactivating the drug.

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20
Q

Ambler classification

A

four molecular classes of beta-lactamases based on amino acid sequences

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21
Q

Ambler Classes A (ESBL, CRE), C (AmpC), and D utilize what mechanism of beta lactam inactivation

A

enzymes that hydrolyze the substrate by forming an acyl enzyme through an active serine site

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22
Q

Ambler Class B - utilizes what mechanism of beta lactic inactivation

A

metallo-beta-lactamases that utilize at least 1 active site zinc ion to facilitate hydrolysis

23
Q

Ambler Class C target-

Amp-C

A
  • substrate is cephalosporins (considered cephalosporinases since greater hydrolysis than penicillins)
  • seen in SPICE organisms
24
Q 
SPICE Organisms
(Serratia, Pseudomonas, Indole positive Proteus, Citrobacter, Enterobacter)
A
  • klebsiella aerogenes (enterobacter)

- Indole + proteus (P. vulgaris, Providencia, Morganella)

25
Q

Ambler Class C (Amp-C) and beta-lactamase inhibitors

A
  • previous beta-lactamase inhibitors (clauvanic acid, tazobactam, sulbactam) do not work on Ambler Class C
26
Q

Group 1 Beta Lactamases

AmpC

A
  • inhibited by avibactam
27
Q

Group 1 Beta Lactamases

AmpC

A
  • inhibited by avibactam
  • ## induction of beta-lactamase production (elevation in presence of Beta-Lactam agents)
28
Q

Strong inducers of AmpC Beta Lactamases (weak activity)

A

Penicillin G
Ampicillin
1st generation cephalosporins
Cefoxitin

29
Q

Strong inducers of AmpC (better activity)

A

Imipenem

Meropenem

30
Q

Weak inducer of AmpC( less likely to increase beta-lactamase) less likely to affect antibiotic activity

A

2nd or 3rd generation cephalosporins
ureidopenicillins
monobactams

31
Q

weak inducers of AmpC but better activity

A

carbenicillin

32
Q

Selection of Group 1 (AmpC 1 beta-lactamases)

A

essentially we can select for these pre-existing mutants that are de-repressed and create a population of microbes that are constantly producing beta-lactamase

33
Q

Extended Spectrum Beta-Lactamase-mediated resistance

A
  • plasmid mediated hydrolysis enzyme (TEM & SHV)
  • Seen in Klebsiella and E. coli
  • similar resistance to ceftazidime, cefotaxime, ceftriaxone, and aztreonam; cefepime resistance is variable
  • inhibited by avibactam, may be inhibited by tazobactam
34
Q

risk factors for infection with exile producing pathogens

A
  • exposure to 3rd gen cephalosporins
  • exposure to ciprofloxacin
    exposure to amino glycosides
  • total antibiotic use
  • ventilator days and ARDS
35
Q

Treatment of choice for ESBLs

A
  • carbapenems (choice)
  • ceftazidime-avibactam
  • tigecycline
  • high-dose piperacillin/tazobactam (less effective than carbs unless in urinary tract)
  • fluoroquinolone - high prevalence of cross resistance
  • aminoglycoside (not used as monotherapy)
  • Bactrim
  • Colistin only if multi drug resistant
36
Q

Merino trial

A

determined that pip/tazo was inferior to meropenem in blood stream infections

37
Q

Klebsiella Pneumoniae carbapenemases (Class A)

A
  • plasmid mediated
  • inhibited by bactams (AVycaz), (Vabomere), (Recarbrio)
  • most fruent infection type in the United States
38
Q

New Deli metallo-Beta-lactamase (Class B)

A
  • spreading world-wide
  • easily transmitted among gram negative bacteria
    not inhibited by any current beta-lactamases
  • aztreonam is stable and active
39
Q

Carbapenem resistance

A
  • results in the loss of our safest last line of defense against resistant pathogens
  • requires us to use more toxic agents
40
Q

Carbapenem-resistant-Enterobacteriaceae

A
  • not necessarily possessing carbapenemases as 50% are beta-lactam negative. there are other mechanisms besides bata-lactamases that could make an organisms resistant to carbapenem antibiotics
41
Q

Treating Carbapenemase-producing gram-negative

A
  • serine carbapenemase (Ceftazidime-avibactam, Meropenem-vaborbactam, Imipenem-cilastatin-relebactam, Plazomicin, Cefiderocol, Colistin + meropenem, Colistin + meropenem + tigecycline)
  • metallo-β-lactamase (Aztreonam + ceftazidime-avibactam, Cefiderocol)
42
Q

3 mechanisms of aminoglycoside-modifying enzymes

A
  • acetylation
  • neucleotidylation
  • phosphorylation
43
Q

Penicillin-binding proteins and altered target sites

A
  • altered penicillin binding sites cause decreased binding affinity for target
  • effect on MIC may vary, could be increased MIC or organism could become resistant
  • caused the presence of methicillin resistant S. aureus
  • cause of penicillin and cephalosporin resistance in S. npeumonia
44
Q

Penicillin-binding proteins and altered target sites

A
  • altered penicillin binding sites cause decreased binding affinity for target
  • effect on MIC may vary, could be increased MIC or organism could become resistant
  • caused the presence of methicillin resistant S. aureus (creates a new PBP (new target) by the mecA gene)
  • cause of penicillin and cephalosporin resistance in S. pneumonia
45
Q

altered cell wall precursors in vancomycin resistance in enterococci (altered target sites)

A
  • vanc inhibits cell wall precursors by binding to the end of the D-alanine terminus of pentapeptide (peptidoglycan precursors). loss of the last alanine results in 1000 fold decrease in affinity of vanc
46
Q

Ceftaroline

A
  • only beta-lactam drug that has activity for MRSA. (usually treated with Vanc)
47
Q

vancomycin resistance

A

most concerning is VanA, and VanB. as these are plasmid mediated and their modified target is D-Ala-D-Lac

48
Q

Altered target sites (ribosomes)

A
  • resistance of macrolide and azalide resistance in S. pneumonia is due to the fact that they both target the same ribosomal target.
  • clindamycin also targets this ribosome and if the ribosome is identified with an ermB gene then it is resistant to macrolides, azalides, and clindamycin
49
Q

altered target sites (dna gyrase and topoisomerase IV)

A
  • FLuoroquinolone resistance in gram-negatives and S. pneumoniae. essentially the mutations in dna gyrase and topoisomerase IV cause less affinity to the drug and lead to a mechanism of resistance
50
Q

Antibiotic efflux pumps

A

pump drugs out of the cell through the periplasmic space and into the environment

51
Q

Chromosomal or plasmid mediated efflux pumps

A
  • macrolides, azalides (S. pneumoonia, S. epidermis) from the mefA gene (susceptible to clindamycin)
  • Carbapenems (P. aeruginosa – meropenem > imipenem)
52
Q

mexAB-oprM

A
  • an efflux pump associated with carbapenem resistance in Pseudomonas arginosa
  • resistance is associated more with meropenem than imipenem
  • this is also another place for FQ resistance (floxacin)
53
Q

Porin alterations may manifest by 3 processes

A
  • shift in porin type
  • change in porin expression
  • impairment or loss of porin expression
  • most commonly seen in Enterobacteriacae and P. aeruginosa (imipenem > meropenem, doripenem)
54
Q

Colistin Resistance and Heteroresistance

A
  • MOA is the modification of lipopolysaccharide
  • resistance described in A. baumannii, P. aeruginosa, and K. pneumoniae
  • mcr-1 gene encodes resitance to colistin
  • located on plasmid

Exam 1 Therapeutics 2022 (10 decks)

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