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Anti-Infectives Exam 2 > Lecture 7 - Resistance Mechanisms & Aminoglycosides, Polymyxins, Fosfomycin, Nitrofurantoin, & Methenamine > Flashcards

Lecture 7 - Resistance Mechanisms & Aminoglycosides, Polymyxins, Fosfomycin, Nitrofurantoin, & Methenamine Flashcards

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1
Q

Bacterial Resistance Risk factors

A
  1. Overuse of antibiotics
  2. Introduction & use of broad-spectrum antimicrobials
  3. Animal Antibiotic consumption
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2
Q

Intrinsic Resistance

A

some organisms are notorious for intrinsic ability to express multiple types of resistance

examples:
Vancomycin too large for Gram - porin channels
Beta Lactams need cell wall, mycoplasma dont have

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3
Q

Acquired Resistance

A

some organisms acquire genes, which enable a mechanism of resistance, from another species of bacteria that already had it through transfer of Millie genetic elements

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4
Q

Examples of Mechanisms of Resistance

A

Efflux
Immunity & Bypass
Target Modification
Inactivating enzymes

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5
Q

Mechanisms of intrinsic resistance

A

Absence of antibacterial target

Bacterial cell impermeability

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6
Q

Acquired Resistance can occur through…

A

Mutations

Genetic Exchange - Plasmids most common**

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7
Q

What are Plasmids

A
  1. Self replicating extrachromosomal DNA
  2. Genes encoding for resistance to many antibiotics can exist on 1
  3. Conjugative plasmids contain additional genes that can initiate transfer from one bacterium to another
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8
Q

Common Mechanisms of Resistance for Gram +

A

Modify target sites

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9
Q

Common Mechanisms of Resistance for Gram -

A

Some changes at target sites

More common to change Efflux pumps/ Porin channel / enzymes

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10
Q

3 Types of Beta-lactamases

A

ESBLs ( Extended-spectrum beta-lactamases)
AmpC beta-lactamases
Carbapenemases (KPC)

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11
Q

How do Beta-lactamase inhibitors work?

A

When combined to beta-lactams, bind to beta-lactamases and protect active antibiotic from inactivation

Activity is specific to certain Beta-lactamases depending on drug

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12
Q

Which antibiotics are ESBL able to hydrolyze?

A

Penicillins and cephalosporins up through 3rd gen

Carbapenemases work against these**

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13
Q

Hint that its an ESBL

A 
Susceptible to....
Amox/Clav
Ampicillin/Sulbactam
Piperacillin/Tazobactam
Carbapenems

Resistant to...
Ampicillin
Aztreonam
Cefazolin
Ceftriaxone
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14
Q

Treatment of ESBLs

A

Carbapenems are drugs of choice

Newer inhibitor combos work, but reserved for carbapenems resistant organisms

Pip/taz = not used due to worse outcomes

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15
Q

AmpC cause resistant in…

A

SPICE or SPACE

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16
Q

Space & Spice

A 
Serratia
Pseudomonas aeruginosa
Proteus vulgaris, Providencia spp.
Citrobacter freundii
Enterobacter cloacae, Klebsiella aerogenes

A = Acinetobacter spp.

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17
Q

Difference between AmpC and ESBL

A

Susceptible to….
Ceftriaxone - dont use tho
Aztreonam

Resistant to…
Amox/Clav

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18
Q

Why worry about AmpC

A

Exposure to antibiotics causes a developed resistance during therapy

in up to ~40% of cases

3rd gen cephalosporins not recommended

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19
Q

AmpC treatment options

A 
Carbapenems
Fluoroquinolones
TMP/SMX
Cefepime
Aminoglycosides
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20
Q

Avoid what drugs for AmpC

A

Ceftriaxone
Piperacillin-tazobactam

cause induction of resistance

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21
Q

Carbapenemases

A

Target carbapenems, most broad spectrum Beta-lactamases

become resistant to most other treatment options when becoming resistant

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22
Q

Carbapenemases found in many Gram -

A

Metallo-beta lactamases

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23
Q

Serine carbapenemases (KPC)

A

transmitted ia plasmid

found worldwide in many Gram -

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24
Q

Options for Carbapenemases

A 
Tigecycline
BL/BLI activate against KPC
\+/- aminoglycosides
Polymixins (colistin/ polymyxin B)
data for double carbapenem therapy
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25
BL/BLI active against KPC
Ceftazidime-avibactam Meropenem-vaborbactam Imipenem-relebactam
26
Mechanism of resistance in staph/strep (its Gram +)
Change in binding protein target site penicillin binding proteins
27
resistance to Fluoroquinolone is due to....
Altered DNA gyros and/or topoisomerase IV
28
Ribosomal alterations responsible for resistance to....
``` Macrolides Azalides Aminoglycosides Tetracyclines Clindamycin ```
29
Reduced outer membrane permeability most common in....
Enterobacteriaceae and P. aeruginosa (gram -)
30
Antibiotic efflux pumps common in...
Huge problem among Pseudomonas aeruginosa RND family of transporters responsible for this Majority of RND efflux systems chromosomal encoded
31
Aminoglycosides include
Gentamicin Tobramycin Amikacin Plazomicin
32
Aminoglycosides MOA
Inhibit protein synthesis | Bactericidal
33
Target for Aminoglycosides
A-site of 16S, part of 30S ribosomal subunit
34
Gentamicin Gram + Activity
** only one we use for Gram + synergy ** Must be used in combo with anti-staph penicillin or vancomycin as "synergy" Never used alone
35
Gentamicin Gram - Activity
Good against susceptible Enterobacteriaceae Good against Pseudomonas aeruginosa, used combo with beta-lactam often common pathogens that cause UTI
36
Gentamicin Anaerobe + Atypical activity
Doesn't really have any
37
Tobramycin, Amikacin, Plazomicin don't have activity in...
Gram + Anaerobic Atypical
38
Tobramycin, Amikacin, Plazomicin Gram - activity
``` Tobra = 2nd gen Amik = 3rd gen Plazo = 4th gen ``` Broadens as gen increase Good against ESBL & Carbapenem-resistant Limited against non-fermentors, best against Pseudomonas.
39
Aminoglycoside Synergy
more than additive effect true when add gentamicin w/ drugs active against cell wall ie. give w/ penicillin for penicillin resistant strain and it will work against it
40
High Dose Aminoglycosides
Once-daily dosing, as efficacious as traditional multi-dose method but lowers risk of side effects simpler, more cost effective, less time consuming usually when using for gram - therapy
41
Aminoglycoside excretion & Metabolism
Most Renal excretion, no hepatic so have to adjust w/ poor renal function
42
Aminoglycoside Adverse effects
** nephrotoxicity ** accumulate in kidney can develop dialysis dependent renal failure need several days/doses for this to occur ** Ototoxicity ** Plazomicin appears to have less ototoxicity ** Neuromuscular blockade = rare**
43
Risk factors for Nephrotoxicity of Aminoglycosides
Older & preexisting renal disease Hypotension, volume depletion Hepatic dysfunction
44
Dose related risk factors for Nephrotoxicity of Aminoglycosides
``` Recent aminoglycoside therapy Larger doses treatment > 3 days Frequent dosing interval Gent>ami+tobra>strepto ```
45
Concomitant drugs associated with Nephrotoxicity risk
``` Vanco Amphotericin B Furosemide Clindamycin Piperacillin ```
46
Cochlear toxicity (Aminoglycosides)
anyone getting > 2 wks therapy should have baseline + followup audiology exams 3-14% incidence
47
Vestibular Toxicity (Aminoglycosides)
functional recovery in 53% of pts at 10 days - 9 months after stoping drug exposure
48
Polymyxins
Colistin (CMS,given as prodrug) | Polymyxin B
49
Polymyxins MOA
Permeabilize outer membrane via direct interaction with the lipid A component of the lipopolysaccharide Bactericidal
50
Where do Polymyxins not have activity?
Gram + Anaerobic Atypical
51
Polymyxins Gram - activity
V.good against Enterobacteriaceae (ESBL + carbapenem-resistant organisms) Good against nn-fermenters, even MDR strains
52
Polymyxin Antimicrobial Activity
Conc dependent killing Post-antibiotic effect - for P.aeruginusa Rapid in vitro resistance** always use in combo
53
Polymyxin Adverse effects
Nephrotoxicity ~ 30-60% occurrence, dose related, reversible Neurotoxicity, rare, dose related, reversible
54
Nitrofurantoin MOA
Inhibit ribosomal translation Bacterial DNA damage Interference w/ kern cycle Metabolized by bacterial nitroreductases turning it into reactive intermediate
55
Nitrofurantoin Gram + activity
none against Strep or Staph Good against Enterococcus including VRE
56
Nitrofurantoin Gram - activity
E.coli none against non fermentors
57
Nitrofurantoin doesn't have activity in...
Atypical and Anaerobes
58
Nitrofurantoin Metabolism & Excretion
Metabolized to active metabolite and excreted into urine BUT doesn't have high conc in kidney ** not used in upper tract disease, pyelonephritis, perinephric abscesses **
59
When is Nitrofurantoin not used
Upper tract disease pyelonephritis perinephric abscesses
60
Nitrofurantoin Adverse effects
Generally well tolerated Some GI = most common Some when used chronically ie Hepatic, hematologic, Peripheral neuropathy**
61
When is Nitrofurantoin not recommened
CrCl < 60 = package insert > 65 or CrCl < 30 Beers Criteria due to peripheral neuropathy
62
Fosfomycin MOA
Blocks cell wall synthesis by inactivating the enzyme perusal transferase Req transport into cell
63
Fosfomycin Gram + activity
Good against staph, both MRSA/MSSA none for Strep Good against Enterococcus, including VRE
64
Fosfomycin Gram - activity
E.coli, including ESBL Some K.pneumoniae Not used against Pseudomonas
65
Fosfomycin dont have activity in...
Atypical | Anaerobic
66
Fosfomycin Metabolism & Excretion
Doesn't have hepatic metabolism Excreted in Urine but doesn't achieve high conc in kidney...only urine Not used in pyelonephritis but used in cystitus
67
Fosfomycin common side effects
Diarrhea Nausea Headache overall well tolerated
68
Methenamine MOA
Hydrolyzed to formaldehyde and ammonia in acidic urine ** useful in suppressive therapy after infection is cleared **
69
Methenamine uses
suppressive therapy
70
Methenamine Adverse effects
Nausea Vomiting Rash overall well tolerated

Anti-Infectives Exam 2 (8 decks)

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