Aminoglycosides: Difference between revisions

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== Dosing ==


=== Initial ===
== Background ==


*Derived from [[Streptomyces species]] (mycins &amp; kacins) or [[Micromonospora species]] (micins)
If actual body weight more than 20% higher than ideal body weight, need to calculate adjusted body weight (ABW)


===Mechanism of Action===
$$ABW = IBW + 0.4 \times (actual BW - IBW)$$


*Requires electron transport chain (ETC) to cross over the membrane
=== Traditional q8h dosing ===
**Anaerobes are therefore inherently resistant
*Reversibly binds 30S ribosomal subunit, which stops proofreading and causes accumulation of bad proteins


===Spectrum of Activity===
* Used for Enterococcus IE, meningitis, septic shock, ascites, AKI/CKD, prefnancy, surgical prophylaxis, burns, osteomyelitis
* 1.7mg/kg (5-7.5mg/kg amikacin)


*Good coverage of Gram-negative aerobes
=== Extended interval dosing ===
**Except Stenotrophomonas and Burkholderia
*Streptomycin also covers mycobacterium
*Some protozoal coverage
*Can cover Gram-positives if cell wall is disrupted (e.g. by beta-lactam)


===Mechanisms of Resistance===
* 7mg/kg (15mg/kg amikacin)
* Use Hartford nomogram with a random level (but remember to halve the amikacin level first)
* CrCl ≥60 q24h
* CrCl 40-59 q36h
* CrCl 20-39 q48h
* CrCl ≤19 don't use


*Altered 50S ribosomal subunit
=== Dialysis ===
*Decreased uptake and accumulation (Pseudomonas)
*Decreased membrane permeability
*Efflux (E. coli)
*Aminoglycoside-modifying enzymes (Enterococcus)


===Pharmacokinetics and Pharmacodynamics===
* Pre-HD levels with post-HD doses, though this may change


*Poor membrane penetration, therefore doesn't cross over into lungs and CSF
=== Synergy ===
*Half-life 2-3 hours (longer in CKD)
*Excreted 99% unchanged in urine
*Displays concentration-depedent killing with a prolonged post-antibiotic effect (2-13 hours)


==Dosing==
* 1mg/kg divided q8-12h, peak target 3-5, trough &lt;2


=== Monitoring ===
===Initial Dose===


If actual body weight more than 20% higher than ideal body weight, need to calculate adjusted body weight (ABW)
=== Peak ===


$$ABW = IBW + 0.4 \times (actual BW - IBW)$$
* 30min after third dose
* Response is based on peak:MIC ratio, target is 8-10 times
* If below target, increase dose


=== Trough ===
===Traditional Dosing===


*Used for Enterococcus IE, meningitis, septic shock, ascites, AKI/CKD, prefnancy, surgical prophylaxis, burns, osteomyelitis
* Prior to 4th dose, or a random level at 24-48h in renal failure
*1.7mg/kg (5-7.5mg/kg amikacin)
* Side effects are predicted by trough levels
* Tobra &lt;0.5 (extended) or &lt;2 (traditional)
* Amikacin &lt;1 (extended) or &lt;?? (traditional)
* If above target, increase interval


=== Hartford Nomogram ===
===Extended Interval Dosing===


*7mg/kg (15mg/kg amikacin)
[[File:Hartford_nomogram.png]]
*Use Hartford nomogram with a random level (but remember to halve the amikacin level first)
*CrCl ≥60 q24h
*CrCl 40-59 q36h
*CrCl 20-39 q48h
*CrCl ≤19 don't use


===Dialysis Dosing===
Double the concentration for [[amikacin]]


*Pre-HD levels with post-HD doses, though this may change
== Origin ==


===Synergy===
* Derived from [[Streptomyces species]] (mycins &amp; kacins) or [[Micromonospora species]] (micins)


*1mg/kg divided q8-12h, peak target 3-5, trough &lt;2
== Mechanism ==


=== Monitoring ===
* Requires electron transport chain (ETC) to cross over the membrane
** Anaerobes are therefore inherently resistant
* Reversibly binds 30S ribosomal subunit, which stops proofreading and causes accumulation of bad proteins


====Peak====
== Spectrum of Activity ==


*30min after third dose
* Good coverage of Gram-negative aerobes
*Response is based on peak:MIC ratio, target is 8-10 times
** Except Stenotrophomonas and Burkholderia
*If below target, increase dose
* Streptomycin also covers mycobacterium
* Some protozoal coverage
* Can cover Gram-positives if cell wall is disrupted (e.g. by beta-lactam)


== Resistance ==
====Trough====


*Prior to 4th dose, or a random level at 24-48h in renal failure
* Altered 50S ribosomal subunit
*Side effects are predicted by trough levels
* Decreased uptake and accumulation (Pseudomonas)
*Tobra &lt;0.5 (extended) or &lt;2 (traditional)
* Decreased membrane permeability
*Amikacin &lt;1 (extended) or &lt;?? (traditional)
* Efflux (E. coli)
*If above target, increase interval
* Aminoglycoside-modifying enzymes (Enterococcus)

====Hartford Nomogram====

[[File:Hartford_nomogram.png]]


* Double the concentration for [[amikacin]]
== PK/PD ==


== Safety ==
* Poor membrane penetration, therefore doesn't cross over into lungs and CSF
* Half-life 2-3 hours (longer in CKD)
* Excreted 99% unchanged in urine
* Displays concentration-depedent killing with a prolonged post-antibiotic effect (2-13 hours)


===Adverse Drug Reactions===
== Side Effects ==


* Nephrotoxicity (0-50%), usually non-oliguric AKI with decreased Ca/Mg resorption, often reversible
*Nephrotoxicity (0-50%), usually non-oliguric AKI with decreased Ca/Mg resorption, often reversible
** Decreased protein synthesis
**Decreased protein synthesis
** Decreased cellular respiration
**Decreased cellular respiration
** Increased apoptosis
**Increased apoptosis
** Necrosis in proximal tubules
**Necrosis in proximal tubules
* Ototoxicity (0-60%), irreversible
*Ototoxicity (0-60%), irreversible
** Cumulative effect
**Cumulative effect
** Distribute into the perilymph of the ear, and cause free radical formation causing apoptosis of hair cells
**Distribute into the perilymph of the ear, and cause free radical formation causing apoptosis of hair cells
** Needs hearing tests, because it can be subclinical
**Needs hearing tests, because it can be subclinical
*** Monitor audiometry weekly
***Monitor audiometry weekly
* Vestibulotoxicity (0-20%), irreversible
*Vestibulotoxicity (0-20%), irreversible
* Rarely, neuromuscular blockade
*Rarely, neuromuscular blockade


== Monitoring ==
===Monitoring===


* Trough levels
*Trough levels
* Creatinine
*Creatinine
* Weekly audiometry
*Weekly audiometry


[[Category:Antibiotics]]
[[Category:Antibiotics]]

Revision as of 22:51, 29 August 2020


Background

Mechanism of Action

  • Requires electron transport chain (ETC) to cross over the membrane
    • Anaerobes are therefore inherently resistant
  • Reversibly binds 30S ribosomal subunit, which stops proofreading and causes accumulation of bad proteins

Spectrum of Activity

  • Good coverage of Gram-negative aerobes
    • Except Stenotrophomonas and Burkholderia
  • Streptomycin also covers mycobacterium
  • Some protozoal coverage
  • Can cover Gram-positives if cell wall is disrupted (e.g. by beta-lactam)

Mechanisms of Resistance

  • Altered 50S ribosomal subunit
  • Decreased uptake and accumulation (Pseudomonas)
  • Decreased membrane permeability
  • Efflux (E. coli)
  • Aminoglycoside-modifying enzymes (Enterococcus)

Pharmacokinetics and Pharmacodynamics

  • Poor membrane penetration, therefore doesn't cross over into lungs and CSF
  • Half-life 2-3 hours (longer in CKD)
  • Excreted 99% unchanged in urine
  • Displays concentration-depedent killing with a prolonged post-antibiotic effect (2-13 hours)

Dosing

Initial Dose

If actual body weight more than 20% higher than ideal body weight, need to calculate adjusted body weight (ABW)

$$ABW = IBW + 0.4 \times (actual BW - IBW)$$

Traditional Dosing

  • Used for Enterococcus IE, meningitis, septic shock, ascites, AKI/CKD, prefnancy, surgical prophylaxis, burns, osteomyelitis
  • 1.7mg/kg (5-7.5mg/kg amikacin)

Extended Interval Dosing

  • 7mg/kg (15mg/kg amikacin)
  • Use Hartford nomogram with a random level (but remember to halve the amikacin level first)
  • CrCl ≥60 q24h
  • CrCl 40-59 q36h
  • CrCl 20-39 q48h
  • CrCl ≤19 don't use

Dialysis Dosing

  • Pre-HD levels with post-HD doses, though this may change

Synergy

  • 1mg/kg divided q8-12h, peak target 3-5, trough <2

Monitoring

Peak

  • 30min after third dose
  • Response is based on peak:MIC ratio, target is 8-10 times
  • If below target, increase dose

Trough

  • Prior to 4th dose, or a random level at 24-48h in renal failure
  • Side effects are predicted by trough levels
  • Tobra <0.5 (extended) or <2 (traditional)
  • Amikacin <1 (extended) or <?? (traditional)
  • If above target, increase interval

Hartford Nomogram

Hartford nomogram.png

Safety

Adverse Drug Reactions

  • Nephrotoxicity (0-50%), usually non-oliguric AKI with decreased Ca/Mg resorption, often reversible
    • Decreased protein synthesis
    • Decreased cellular respiration
    • Increased apoptosis
    • Necrosis in proximal tubules
  • Ototoxicity (0-60%), irreversible
    • Cumulative effect
    • Distribute into the perilymph of the ear, and cause free radical formation causing apoptosis of hair cells
    • Needs hearing tests, because it can be subclinical
      • Monitor audiometry weekly
  • Vestibulotoxicity (0-20%), irreversible
  • Rarely, neuromuscular blockade

Monitoring

  • Trough levels
  • Creatinine
  • Weekly audiometry
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