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Clinical Pharmacokinetics > Aminoglycosides > Flashcards

Aminoglycosides Flashcards

Dr. Lugo EXAM I

1
Q

Are Aminoglycosides hydrophilic or lipophilic?

A

Hydrophilic
-drugs with a Vd below 0. 7 L/kg will be distributed into water in the body

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2
Q

What are Aminoglycosides sensitive to due to their Vd?

A

Fluid shifts and fluid status
-Volume overload - (more often, patients with CHF or renal insufficiency develop fluid overload, or patients with low BP receive fluids)
-Dehydration

Q: How does that affect drug dosing???

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3
Q

How are Aminoglycosides eliminated?

A

-kidney
-100% filtered by the glomerulus
-excreted unchanged in the urine (no metabolites)

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4
Q

Toxicities of Aminoglycosides!

A

-Nephrotoxicity (renal impairment)
-Ototoxicity (inner ear (cochlea) damage, hearing loss, balance problems)
-Neuromuscular blockade: muscle weakness (myasthenia gravis), paralysis

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5
Q

Which Aminoglycosides are used for Pseudomonas?

A

better Pseudomonal activity:
Tobramycin
Amikamicin

(Gentamicin: most common used Aminoglycoside, first-line)

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6
Q

Which Aminoglycosides are interchangeable?

A

Gentamicin and Tobramycin

-in terms of physicochemical properties and pharmacodynamic activity
-some difference in the activity against Pseudomonas (Tobramycin with more activity)

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7
Q

Spectrum of Activity for Aminoglycosides

A

-against gram negatives (exception gram-positive: some activity against Staph aureus, Enterococcus - but not used for S. aureus as monotherapy but in combination with ß-lactams or other cell-wall active agents)

Cell wall active agents:

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8
Q

MOA of Aminoglycosides

A

-Passive diffusion via porin channels across the outer membrane

-Irreversible inhibition of protein synthesisby binding to the 30S unit

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9
Q

Conditions where Aminoglycoside activity is weakened

A

-Anaerobic conditions and low pH (acid) -> Transport is decreased

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10
Q

What causes an acidic environment in the body?

A

Infections
Q: what are anaerobic environments in the body?

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11
Q

What increases the activity of Aminoglycosides?

A

Combination therapy with cell wall active drugs such as penicillins (like ampicillin) and vancomycin -> Transport is increased
-> Synergy

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12
Q

Which disease state requires Synergystical therapy?

A

Endocarditis

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13
Q

Pharmacodynamic properties of Aminoglycosides

A

-Concentration-dependent killing (others are time-dependent or AUC-dependent kill)

-Postantibiotic effect (PAE) -> increased in a high Peak:MIC

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14
Q

Which relation (ratio) is important for the efficacy of Aminoglycosides?

A

Peak Cmax to MIC
-10:1 -> the Cmax is 10x higher than the MIC

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15
Q

Example of time-dependent killing drug

A

Penicillin
-killing depends on how much time is spent above the MIC

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16
Q

Why might the AG drug concentration in a healthy and septic patient differ when given the same dose?

A

-the septic patient has a low BP due to the infection
-> may be treated with fluids that increase the Vd and decrease the drug concentration

17
Q

Postantibiotic effect of Gentamicin

A

-the drug is still inhibiting growth after it was removed from the environment

-delay of regrowth of the bacteria after the antibiotic has been eliminated

-allowing a less frequent dosing, while maintaining its efficacy

Q: Does it mean that it still suppresses inhibition after dropping below the MIC or after the drug has been completely eliminated?

18
Q

Which drug is not effective against Enterococcus?

A

Cephalosporins

19
Q

Risk factors for Nephrotoxicity

A

-high dose and long duration
Q: is there a maximum time a patient should be on aminoglycosides?
-patient characteristics: elderly, dehydrated, pre-existing kidney disease or impaired renal function

20
Q

Drugs causing Nephrotoxicity

A

-Amphotericin,
-Vancomycin
-Cyclosporine
-Cisplatin
-high dose of furosemide
-High-dose NSAIDs
-troughs above 2 mg/L

-be aware when using these drugs at the same time

21
Q

How to monitor renal function

A

-SCr
-urine output
-especially required in patients who are treated with aminoglycosides for a longer period of time

22
Q

Target Concentration of Gentamicin and Tobramycin

A

Life-threatening and Pneumonia:
peak: 8-10 mcg/mL
trough: 1-2 mcg/mL

Serious infection:
Peak: 6-8 mcg/mL
trough: 1-2 mcg/mL

UTI:
Peak: 4-6 mcg/mL
trough: 1-2 mcg/mL

23
Q

Target Concentration of Amikamicin

A

Life-threatening and Pneumonia:
peak: 25-30 mcg/mL
trough: 4-8 mcg/mL

Serious infection:
Peak: 20-25 mcg/mL
trough: 4-8 mcg/mL

UTI:
Peak: 15-20 mcg/mL
trough: 4-8 mcg/mL

24
Q

Why is the target concentration lower for UTIs?

A

Because aminoglycosides are eliminated by the kidneys -> higher concentration in the urine

exception: Urosepsis -> higher dose

25
Q

Extended Interval Dosing

A

-a long period dose (q8 or q12) given in one dose
-consolidated dosing

-give a large dose once a day to maximize the Peal:MIC ratio -> increase kill and postantibiotic effect (PAE)

26
Q

What are the benefits of Extended Interval Dosing?

A

-the renal cortex absorbing gentamicin over time is a saturable process

-reduce toxicity bc the the transport and the accumulation in the renal cortex is saturated

-higher peaks do not necessarily increase the risk of toxicity, but giving the drug more frequently results in a greater AUC -> more toxicity

27
Q

Which dose is used in the Hartford Nomogram?

A

7 mg/kg of Gentamicin or Tobramycin

28
Q

Which dose is used in the Urban & Craig Nomogram?

A

5 mg/kg of Gentamicin or Tobramycin in patients without renal dysfunction

29
Q

The approach in Extended Interval Dosing

A
  1. give the high dose
  2. measure the concentration within 6-14h (usually after 10h)
    -> This concentration is not a peak, and it is NOT at ss
  3. Plot the measured concentration on the Nomogram
  4. Repeat conformation (measurement) at appropriate interval
30
Q

Concentration plotted to the Nomogram

A

-measure the concentration within 6-14h (usually 10h)

-If below the line: the patient is clearing the drug appropriately fast to keep the q24 regimen

-if above the line: change regimen to q48h or change to traditional dosing

31
Q

When should the Urban & Craig dosing be used?

A

-5mg/kg
-Pathogen MIC: <1 mcg/ml or infection is due to a removed source (line infection (catheter)

-UTI source (pyelonephritis, urosepsis, complicated UTI)

-less dosing is needed bc the concentration of aminoglycosides is higher (100x) in the urine

32
Q

When should the Hartfor dosing be used?

A

-7 mg/kg

-Nosocomial (hospital-acquired) infections
-Pathogen MIC: >2mcg/ml
-Pneumonia
-osteomyelitis (swelling of bone tissue from an infection)
-Meningitis

33
Q

Which type of weight is used to determine the dose in External interval dosing?

A

-if the patient’s BW is below IBW: TBW (patient’s BW)
-if the patient’s BW is within IBW range (100-120% of IBW): use TBW (patient’s BW)
-if the patient’s BW is above IBW: use adjusted BW

34
Q

What patient population is excluded from Extended Interval dosing?

A

-Renal insufficiency (<30 ml/min) - since we are giving a high dose of aminoglycoside which needs to be cleared

-Pregnancy
-Synergy for gram-positive (different dosing used in synergy)
-Ascites - fluid in the stomach, greater Vd
-Burns (>20%): burned patients exuding drugs through their skin

35
Q

Dosing for Synergy treatment

A

-1 mg/kg every 8 hours
-3 mg/kg every 24 hours for alpha-hemolytic strep

36
Q

Which patient population is not appropriate for Synergy dosing?

A

-Renal insuffient patients
-elderly

37
Q

Which Aminoglycoside is used for Synergy?

A

Gentamicin
-has supportive data

Clinical Pharmacokinetics (5 decks)

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