Aminoglycosides

Question 1

Are Aminoglycosides hydrophilic or lipophilic?

Answer 1

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

Question 2

What are Aminoglycosides sensitive to due to their Vd?

Answer 2

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???

Question 3

How are Aminoglycosides eliminated?

Answer 3

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

Question 4

Toxicities of Aminoglycosides!

Answer 4

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

Question 5

Which Aminoglycosides are used for Pseudomonas?

Answer 5

better Pseudomonal activity:
Tobramycin
Amikamicin

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

Question 6

Which Aminoglycosides are interchangeable?

Answer 6

Gentamicin and Tobramycin

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

Question 7

Spectrum of Activity for Aminoglycosides

Answer 7

-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:

Question 8

MOA of Aminoglycosides

Answer 8

-Passive diffusion via porin channels across the outer membrane

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

Question 9

Conditions where Aminoglycoside activity is weakened

Answer 9

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

Question 10

What causes an acidic environment in the body?

Answer 10

Infections
Q: what are anaerobic environments in the body?

Question 11

What increases the activity of Aminoglycosides?

Answer 11

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

Question 12

Which disease state requires Synergystical therapy?

Answer 12

Endocarditis

Question 13

Pharmacodynamic properties of Aminoglycosides

Answer 13

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

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

Question 14

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

Answer 14

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

Question 15

Example of time-dependent killing drug

Answer 15

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

Question 16

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

Answer 16

-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

Question 17

Postantibiotic effect of Gentamicin

Answer 17

-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?

Question 18

Which drug is not effective against Enterococcus?

Answer 18

Cephalosporins

Question 19

Risk factors for Nephrotoxicity

Answer 19

-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

Question 20

Drugs causing Nephrotoxicity

Answer 20

-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

Question 21

How to monitor renal function

Answer 21

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

Question 22

Target Concentration of Gentamicin and Tobramycin

Answer 22

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

Question 23

Target Concentration of Amikamicin

Answer 23

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

Question 24

Why is the target concentration lower for UTIs?

Answer 24

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

exception: Urosepsis -> higher dose

Question 25

Extended Interval Dosing

Answer 25

-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)

Question 26

What are the benefits of Extended Interval Dosing?

Answer 26

-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

Question 27

Which dose is used in the Hartford Nomogram?

Answer 27

7 mg/kg of Gentamicin or Tobramycin

Question 28

Which dose is used in the Urban & Craig Nomogram?

Answer 28

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

Question 29

The approach in Extended Interval Dosing

Answer 29

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

Question 30

Concentration plotted to the Nomogram

Answer 30

-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

Question 31

When should the Urban & Craig dosing be used?

Answer 31

-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

Question 32

When should the Hartfor dosing be used?

Answer 32

-7 mg/kg -Nosocomial (hospital-acquired) infections -Pathogen MIC: >2mcg/ml -Pneumonia -osteomyelitis (swelling of bone tissue from an infection) -Meningitis

Question 33

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

Answer 33

-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

Question 34

What patient population is excluded from Extended Interval dosing?

Answer 34

-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

Question 35

Dosing for Synergy treatment

Answer 35

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

Question 36

Which patient population is not appropriate for Synergy dosing?

Answer 36

-Renal insuffient patients -elderly

Question 37

Which Aminoglycoside is used for Synergy?

Answer 37

Gentamicin -has supportive data