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Micro Exam 1 > Pogue: Antimicrobials IIa > Flashcards

Pogue: Antimicrobials IIa Flashcards

1
Q

AMINOGLYCOSIDES

MOA:
What does it require?
Effective against anaerobes?

Bacteriostatic or Bacteriocidal?

A

MOA: bind 30S subunit of the ribosome to cause a decrease in protein synthesis

Requires active transport into the bacterial cell to exert its action (oxygen dependent)

No activity against anaerobes

Bacteriocidal: except against enterococcus

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2
Q

AMINOGLYCOSIDES

Spectrum of Activity:
G+:
Activity against:
Only used when?

G-:
Active against:
Pseudomonas:

Anaerobes

A

Spectrum of activity
Gram (+)
–Activity against staph, strep
–Only used in this aspect for synergy (1 + 1 = 8) for serious infections

Gram (-)
–Active against many Gram-negative bacilli (including Pseudomonas)
–Pseudomonas: amikacin > tobramycin > gentamicin

Anaerobes
–No activity (remember the mechanism!)

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3
Q

AMINOGLYCOSIDES

Agents:

A

IV: gentamicin, tobramycin, amikacin, streptomycin (all used in hospital)

PO/topical: neomycin (topical creams, ointments etc.)

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4
Q

AMINOGLYCOSIDES

Synergy:

G+
Usually combined with:
What allows more entry into the cell?
Expands spectrum to include:
Use:

G-

A

Synergy

Gram (+)
–Usually combined with ß-lactam for synergistic effect
–Cell wall disruption allows more entry into the cell
–Expands spectrum to include enterococcus
–Only used in serious infections

Gram (-)
–In vitro a similar effect is seen
–This has never translated to improved clinical outcomes

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5
Q

Gentamicin

Most common use:

A

AMINOGLYCOSIDE

Mostly used for synergy for staphylococcal or enterococcal infections

Eye ointments (as well as tobramycin)

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6
Q

Tobramycin/ amikacin

Use:
Amikacin:

A

AMINOGLYCOSIDE

Used for empiric coverage of nosocomial infections (double coverage)
Sometimes continued for definitive therapy

Amikacin has a role in some mycobacterial infections

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7
Q

Neomycin

Oral
Topical

A

AMINOGLYCOSIDE

Orally to decontaminate the GI tract prior to surgery

Often in topical creams (NEOsporin)

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8
Q

Streptomycin

Use (2)

A

AMINOGLYCOSIDE

Enterococcal infection when gentamicin resistance (for synergy)

Mycobacterial infections

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9
Q

Aminoglycoside monotherapy:

A

Should be avoided (for the most part) for definitive monotherapy for Gram (-) infections

Literature does not support outside of urinary tract infections

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10
Q

Aminoglycoside
Pharmacokinetics:

Oral absorption:
Lipophilic?
Affects?

Highly concentrates where?

Therapeutic drug monitoring:

A

Poor oral absorption (PO not used for systemic infections)

Concentration dependent killing
–Optimize PK

Hydrophilic (poor tissue concentration)

Highly concentrated in the urine
–Renal dosing
–Good for UTI

Therapeutic Drug Monitoring
–Cmax/MIC 8-12 mcg/mL
–Cmin< 1 mcg/mL

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11
Q

Aminoglycoside
Mechanisms of Resistance (3):

What does transferase enzyme do?
Mutation in what prevents binding?
What decreases porin production?

A

Enzyme modification
–Transferase enzyme adds an additional side chain to the drugs which prevent appropriate binding

Target-site modification
–Mutation in the 30S subunit, prevents binding

Decreased concentrations in the cell
–Decreased porin production
–Efflux pumps

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12
Q 
Aminoglycoside
Adverse events (3)

Most common?
Strategies to minimize:
What is associated with total drug exposure?

A

Nephrotoxicity
–Most common, and most serious adverse event
–Strategies to minimize
•Shorter durations
•Minimize trough levels (level at the end of the dosing interval)

Vestibular/ototoxicity
–Associated with total drug exposure (optimize PK)

Neuromuscular blockade
–Additive with other drugs; disease states (myasthenia)

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13
Q

Fluoroquinolones

MOA:

A

MOA: inhibit bacterial DNA replication (unique)

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14
Q

Fluoroquinolones

Agents of clinical relevance (5):

A 
–Moxifloxacin
–Gemifloxacin (not available)
–Ciprofloxacin
–Levofloxacin
–Norfloxacin (different)
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15
Q

Fluoroquinolones

Bacteriostatic or Bactericidal

Bioavailability:
exception

A

Bactericidal, concentration-dependent killing

Excellent bioavailability
–80% ciprofloxacin; ~100% levofloxacin, moxifloxacin
–NOT norfloxacin (as we will see)

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16
Q

Fluoroquinolones
Spectrum of activity

G+:
Comparison of 3
Why shouldn’t levofloxacin be relied on to treat staph and enterococcus?
What has excellent strep coverage?

A

Gram (+)
–Levofloxacin > moxifloxacin > ciprofloxacin
–Levofloxacin has some activity against staph and enterococcus, but should NOT be relied on to treat clinically (simple one step mutation for resistance)
–Levofloxacin and moxifloxacin have excellent streptococcus coverage (including s.pneumoniae)

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17
Q

The “respiratory fluoroquinolones”:

Excellent activity against:

Why isn’t cipro a respiratory FQ?

A

–Levofloxacin and moxifloxacin (and gemifloxacin)

–Excellent activity against all CAP organisms (S.pneumo, H.influenzae, M.cat, atypicals)

Not effective against most common pathogens

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18
Q 
The Gram (-) fluoroquinolones:
Coverage against:

Anaerobic FQ:

A

Ciprofloxacin and levofloxacin

Coverage against enteric Gram (-) as well as pseudomonas

Anaerobic FQ
–Moxifloxacin

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19
Q

FQ PK

Bioavailability?
What is notable about norfloxacin?

Hydrophilic or lipophilic?

A

Excellent bioavailability

–NOT norfloxacin –> clinically used for Selective Gut Decontamination (SGD), UTI

Highly lipophilic, allows to be used for infections in many body sites
-CSF, lungs, skin, tissue, bone, joint, blood

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20
Q

FQ

G-:
Comparison of 3
What has anti-pseudomonal activity?

A

Gram (-)
–Ciprofloxacin > Levofloxacin > Moxifloxacin
–Ciprofloxacin and levofloxacin have anti-pseudomonal activity (C > L)
–Resistance increasing in Gram (-) organisms likely secondary to overuse

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21
Q

FQ
Anaerobic:
What has activity?
Reliable against B. fragilis?

A

Only moxifloxacin has activity (not reliable against b. Fragilis)

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22
Q

Fluoroquinolones
Elimination:
Exceptions:

A 
Renally eliminated (dose adjustment needed)
–Exception is moxifloxacin
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23
Q 
Fluoroquinolones
Side Effects (5):
A

Central nervous system toxicity

Damage to growing cartilage

Tendon rupture

Dysglycemia

Cardiac arrhythmias and possible torsades

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24
Q

Fluoroquinolones
Side Effects

CNS:
Cartilage:
Tendon Rupture:

A

Central nervous system toxicity
–Headaches, dizziness, insomnia, seizures
–More common in elderly, h/oseizures, etc.

Damage to growing cartilage
–Only seen in animals so far
–Reason for soft contraindication in pediatrics

Tendon rupture (rare)

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25
Q

Fluoroquinolones
Side Effects

Dysglycemia:
Cardiac arrhythmias:

A

Dysglycemia
–Remember the story of gatifloxacin!

Cardiac arrhythmias and possible torsades
–Moxifloxacin is considered higher risk
–Minimal risk unless prone to arrhythmias or on other QT prolonging drugs

26
Q

Fluoroquinolones

Drug Interactions:

A

Reduced oral absorption when taken with divalent cations
–Ca, Mg, Fe
–Due to chelation

27
Q

Fluoroquinolones

Mech of resistance:
How does this affect unrelated antibiotics?

A

Efflux pumps
–Known inducers of efflux pumps which are able to carry many structurally unrelated antibiotics out of the cell as well (e.g. b-lactams, carbapenems, tetracyclines)

Target site modification
–Decrease binding at the site of action

28
Q

Vancomycin

Class:
Overseas equivalent:
G+/-?
Aerobic vs anaerobic

A 
Until recently, only commercially available antibiotic from the glycopeptide class in the USA
–Overseas: Teicoplanin

Gram (+) organisms only

Aerobic coverage > anaerobic coverage

29
Q

Vancomycin

Mechanism of Action

A

Binds to D-ala D-ala terminal portion of peptidoglycan precursors and prevents further cross-linking (slowly cidal)

30
Q

Vancomycin

IV vs. PO

A

IV and PO formulations available
–IV for systemic infections
–PO formulation not absorbed; only used clinically to treat c. difficile colitis

31
Q

Vancomycin

Type of elimination:

Trough levels:

A

Renally eliminated
–Dose adjustments needed in renal insufficiency

Trough levels monitored for efficacy
–15-20 mcg/mL goal for more serious infections

32
Q

Vancomycin

Used empirically to cover:

Inferior to β-lactams for:

Use in pts with allergy to:

A

Used empirically to cover for MRSA
–Inferior to β-lactams for MSSA

Patients with β-lactam allergy

33
Q

Vancomycin

Activity against streptococcus and enterococcus:
Compare to β-lactam:

A

Vancomycin has activity against streptococcus and enterococcus as well but inferior to β-lactam based therapy

Broader-spectrum, but weaker killing

34
Q

What is MRSA?

Effect of β-lactams:

A

Penicillin-blinding protein alteration (addition of PBP2A)

β-lactams will not bind to PBP2A, thus β-lactams have no activity against MRSA

Continual problem in hospitals

~70% of staph in DMC is MRSA
Growing problem in community as well

35
Q

Vancomycin and MRSA

A

Empiric regimens for hospital-acquired infections almost always include vancomycin to cover for MRSA

Vancomycin has been the standard of care for MRSA for many years

Elevation in vancomycin MIC’s have recently occurred in MRSA
–Much debate about the current optimal therapy

36
Q 
Vancomycin 
Side Effects (4):
A

Nephrotoxicity
–Historical incidence is smaller than most people believe
•Usually in combinations with other nephrotoxic agents
–Controversial newer data showing an increased incidence with higher doses

Ototoxicity
–Extremely rare. Associated with very high peaks

Rash
“Red-Man’s Syndrome”

37
Q

“Red-Man’s Syndrome”

Definition
How do you overcome it?

A

Not a true allergy

Histamine response related to rapid infusion

Can overcome by slowing down infusion (no greater rate than 1g over 1 hr) and premedication with diphenhydramine

38
Q

What does MSSA have that makes it resistant to penicillin?

What does MRSA have that makes it resistant to Nafcillin?

A

Penicillinase

PBP alteration

39
Q

Telavancin

MOA

A

Second generation glycopeptide (came to market 2010)

MOA: same as vancomycin, plus direct binding to the bacterial membrane disrupting barrier function

40
Q

Telavancin
Comparative effect against G+:
Activity against MRSA:

A

Increased bactericidal activity against Gram positives

–Some activity against MRSA with elevated vancomycin MIC’s

41
Q

Telavancin

Pharmacological issues (3)

A

–Nephrotoxicity (higher than vancomycin)
–Interference with coagulation tests (significant!)
–Teratogenicity in animal studies

42
Q

DAPTOMYCIN

MOA:
Bactericidal?
Spectrum of action:

A

IV only

MOA: embeds in membrane and creates a K+ efflux channel, leading to depolarization of the membrane and cell death

Bactericidal: HIGHLY

Spectrum of Action: GRAM (+) ONLY; staphylococcus, streptococcus and enterococcus

43
Q

DAPTOMYCIN

Clinical applications:

A

Major uses: MRSA and VRE bloodstream infections, endocarditis, and soft tissue infections

44
Q

Daptomycin

Issues:
Cross resistance:

A

Some cross-resistance seen with strains of MRSA that have elevated vancomycin MICs
–Cell wall thickening (VISA)

Overall, still one of the safest drugs

45
Q

What is the only available oxazolidinone?

A

Linezolid

46
Q

Linezolid

MOA

A

Inhibits protein synthesis by binding to the 50S ribosomal subunit

47
Q

Linezolid

Spectrum of activity

A

Gram (+) only (staph and enterococcus)

48
Q

Linezolid
Pharmacokinetics
Elimination

A 
Great absorption (~100%)
IV and PO dose the same
Not renally eliminated (no dosage adjustment)
49
Q

Linezolid

Clinical application

A

Drug of choice for VRE infections

Some use for MRSA (particularly pneumonia +/- elevated vancomycin MIC)

50
Q

DOC for VRE Infections

A

Linezolid

51
Q

Linezolid

Side effects of concern (WILL BE ASKED!)

A

Thrombocytopenia –> Usually seen with long courses (~day 14 of therapy)

Rare peripheral/optic neuropathy

52
Q

Linezolid
DDIs

Serotonin syndrome

A

Linezolid is a weak MAOI

Concern for serotonin syndrome with drugs which work on serotonergic receptors (e.g. SSRIs)

Serotonin syndrome: fever, agitation, mental status changes, etc.

Can also occur if tyramine is given (good pharmacologic jeopardy question!)

53
Q

Daptomycin
Adverse event of concern:

Effect in lungs:
Avoid:

A

Adverse event of concern
–CPK elevations and rhabdomyolysis
–Infrequent; caution with statins

Irreversible binding to pulmonary surfactant
– Surfactant is like a G+ membrane

– Avoid in pneumonia

54
Q

Vancomycin-resistant enterococcus

Common in what?

A

Common in e.faecium; occasionally occur in e.faecalis
–Detroit is oddly enough the capital of the vancomycin resistant e.faecalis

In e.faecium, ampicillin resistance also common

55
Q

Treatment choices for VRE (4)

A

–Linezolid
–Daptomycin
–Quinupristin/dalfopristin (e.faecium only)
–Tigecycline (maybe other tetracyclines)

56
Q

Vancomycin mechanism of action

A

Binds to D-ala D-ala terminal portion of peptidoglycan precursors and prevents further cross-linking (slowly cidal)

57
Q

What happens to D-ala D-ala in VRE? How does this affect vancomycin?

A

In VRE: D-ala D-ala becomes D-ala D-lac (or d-ser) in which vancomycin cannot bind

–Same mechanism in VRSA, although rarely seen
•(again Detroit is the place to go for this bug as well!)

58
Q

What was the first drug for treatment of VRE?

A

quinupristin/dalfopristin

59
Q

Why has quinupristin/dalfopristin fallen out of favor?

A

High rates of infusion reactions, arthralgias, and myalgias, hepatotoxicity

Availability of other agents

No activity versus e.faecalis

60
Q

Quinupristin/dalfopristin

Class:
MOA:
Brand name:

A

Streptogramin
Ribosomal as well (50S)
Brand name: Synercid

61
Q

One more look at S. aureus

A 
VISA-Cell wall thickening
(vanco MIC 4-16 mcg/mL)
↑
MRSA
↓
VRSA-Transfer of VRE resistance gene
(vanco MIC > 32 mcg/mL)

Micro Exam 1 (18 decks)

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