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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

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
Q

BL/BLI active against KPC

A

Ceftazidime-avibactam
Meropenem-vaborbactam
Imipenem-relebactam

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26
Q

Mechanism of resistance in staph/strep (its Gram +)

A

Change in binding protein target site

penicillin binding proteins

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27
Q

resistance to Fluoroquinolone is due to….

A

Altered DNA gyros and/or topoisomerase IV

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28
Q

Ribosomal alterations responsible for resistance to….

A 
Macrolides
Azalides
Aminoglycosides
Tetracyclines
Clindamycin
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29
Q

Reduced outer membrane permeability most common in….

A

Enterobacteriaceae and P. aeruginosa (gram -)

30
Q

Antibiotic efflux pumps common in…

A

Huge problem among Pseudomonas aeruginosa

RND family of transporters responsible for this
Majority of RND efflux systems chromosomal encoded

31
Q

Aminoglycosides include

A

Gentamicin
Tobramycin
Amikacin
Plazomicin

32
Q

Aminoglycosides MOA

A

Inhibit protein synthesis

Bactericidal

33
Q

Target for Aminoglycosides

A

A-site of 16S, part of 30S ribosomal subunit

34
Q

Gentamicin Gram + Activity

A

** only one we use for Gram + synergy **

Must be used in combo with anti-staph penicillin or vancomycin as “synergy”

Never used alone

35
Q

Gentamicin Gram - Activity

A

Good against susceptible Enterobacteriaceae

Good against Pseudomonas aeruginosa, used combo with beta-lactam often

common pathogens that cause UTI

36
Q

Gentamicin Anaerobe + Atypical activity

A

Doesn’t really have any

37
Q

Tobramycin, Amikacin, Plazomicin don’t have activity in…

A

Gram +
Anaerobic
Atypical

38
Q

Tobramycin, Amikacin, Plazomicin Gram - activity

A 
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
Q

Aminoglycoside Synergy

A

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
Q

High Dose Aminoglycosides

A

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
Q

Aminoglycoside excretion & Metabolism

A

Most Renal excretion, no hepatic so have to adjust w/ poor renal function

42
Q

Aminoglycoside Adverse effects

A

** 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
Q

Risk factors for Nephrotoxicity of Aminoglycosides

A

Older & preexisting renal disease
Hypotension, volume depletion
Hepatic dysfunction

44
Q

Dose related risk factors for Nephrotoxicity of Aminoglycosides

A 
Recent aminoglycoside therapy
Larger doses
treatment > 3 days
Frequent dosing interval 
Gent>ami+tobra>strepto
45
Q

Concomitant drugs associated with Nephrotoxicity risk

A 
Vanco
Amphotericin B
Furosemide
Clindamycin
Piperacillin
46
Q

Cochlear toxicity (Aminoglycosides)

A

anyone getting > 2 wks therapy should have baseline + followup audiology exams

3-14% incidence

47
Q

Vestibular Toxicity (Aminoglycosides)

A

functional recovery in 53% of pts at 10 days - 9 months after stoping drug exposure

48
Q

Polymyxins

A

Colistin (CMS,given as prodrug)

Polymyxin B

49
Q

Polymyxins MOA

A

Permeabilize outer membrane via direct interaction with the lipid A component of the lipopolysaccharide

Bactericidal

50
Q

Where do Polymyxins not have activity?

A

Gram +
Anaerobic
Atypical

51
Q

Polymyxins Gram - activity

A

V.good against Enterobacteriaceae (ESBL + carbapenem-resistant organisms)

Good against nn-fermenters, even MDR strains

52
Q

Polymyxin Antimicrobial Activity

A

Conc dependent killing
Post-antibiotic effect - for P.aeruginusa
Rapid in vitro resistance** always use in combo

53
Q

Polymyxin Adverse effects

A

Nephrotoxicity ~ 30-60% occurrence, dose related, reversible

Neurotoxicity, rare, dose related, reversible

54
Q

Nitrofurantoin MOA

A

Inhibit ribosomal translation
Bacterial DNA damage
Interference w/ kern cycle

Metabolized by bacterial nitroreductases turning it into reactive intermediate

55
Q

Nitrofurantoin Gram + activity

A

none against Strep or Staph

Good against Enterococcus including VRE

56
Q

Nitrofurantoin Gram - activity

A

E.coli

none against non fermentors

57
Q

Nitrofurantoin doesn’t have activity in…

A

Atypical and Anaerobes

58
Q

Nitrofurantoin Metabolism & Excretion

A

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
Q

When is Nitrofurantoin not used

A

Upper tract disease
pyelonephritis
perinephric abscesses

60
Q

Nitrofurantoin Adverse effects

A

Generally well tolerated

Some GI = most common

Some when used chronically ie Hepatic, hematologic, Peripheral neuropathy**

61
Q

When is Nitrofurantoin not recommened

A

CrCl < 60 = package insert
> 65 or CrCl < 30 Beers Criteria

due to peripheral neuropathy

62
Q

Fosfomycin MOA

A

Blocks cell wall synthesis by inactivating the enzyme perusal transferase

Req transport into cell

63
Q

Fosfomycin Gram + activity

A

Good against staph, both MRSA/MSSA

none for Strep

Good against Enterococcus, including VRE

64
Q

Fosfomycin Gram - activity

A

E.coli, including ESBL
Some K.pneumoniae

Not used against Pseudomonas

65
Q

Fosfomycin dont have activity in…

A

Atypical

Anaerobic

66
Q

Fosfomycin Metabolism & Excretion

A

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
Q

Fosfomycin common side effects

A

Diarrhea
Nausea
Headache

overall well tolerated

68
Q

Methenamine MOA

A

Hydrolyzed to formaldehyde and ammonia in acidic urine

** useful in suppressive therapy after infection is cleared **

69
Q

Methenamine uses

A

suppressive therapy

70
Q

Methenamine Adverse effects

A

Nausea
Vomiting
Rash
overall well tolerated

Anti-Infectives Exam 2 (8 decks)

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