Aminoglycosides: Difference between revisions

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== Dosing ==
==Background==


*Derived from [[Streptomyces]] (mycins & kacins) or [[Micromonospora]] (micins)
=== Initial ===


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


*Requires electron transport chain (ETC) to cross over the membrane
$$ABW = IBW + 0.4 \times (actual BW - IBW)$$
**Anaerobes are therefore inherently resistant
*Reversibly binds 30S ribosomal subunit, which stops proofreading and causes accumulation of bad proteins


===Spectrum of Activity===
=== Traditional q8h dosing ===


*Good coverage of Gram-negative aerobes
* Used for Enterococcus IE, meningitis, septic shock, ascites, AKI/CKD, prefnancy, surgical prophylaxis, burns, osteomyelitis
**Except [[Stenotrophomonas]] and [[Burkholderia]]
* 1.7mg/kg (5-7.5mg/kg amikacin)
*[[Streptomycin]] also covers mycobacterium
*Some protozoal coverage
*Can cover Gram-positives if cell wall is disrupted (e.g. by beta-lactam)


===Mechanisms of Resistance===
=== Extended interval dosing ===


*Altered 50S ribosomal subunit
* 7mg/kg (15mg/kg amikacin)
*Decreased uptake and accumulation ([[Pseudomonas]])
* Use Hartford nomogram with a random level (but remember to halve the amikacin level first)
*Decreased membrane permeability
* CrCl ≥60 q24h
*Efflux pump ([[Escherichia coli]])
* CrCl 40-59 q36h
*Aminoglycoside-modifying enzymes ([[Enterococcus]])
* CrCl 20-39 q48h
* CrCl ≤19 don't use


===Pharmacokinetics and Pharmacodynamics===
=== Dialysis ===


*Poor membrane penetration, therefore doesn't cross over into lungs and CSF
* Pre-HD levels with post-HD doses, though this may change
*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)


=== Synergy ===
==Dosing==


===Initial Dose===
* 1mg/kg divided q8-12h, peak target 3-5, trough <2


*If actual body weight more than 20% higher than [https://www.mdcalc.com/ideal-body-weight-adjusted-body-weight ideal body weight], need to calculate [https://www.mdcalc.com/ideal-body-weight-adjusted-body-weight adjusted body weight] (ABW)
=== Monitoring ===


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


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


*Q8H dosing
=== Trough ===
*Used for [[Enterococcus]] IE, [[meningitis]], [[septic shock]], [[ascites]], [[AKI]]/[[CKD]], [[pregnancy]], surgical prophylaxis, [[Burn infection|burns]], [[osteomyelitis]]
*1.7 mg/kg (5-7.5 mg/kg [[amikacin]]) IV q8h


===Extended Interval Dosing===
* 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


*Q24H dosing, which is safer but less well-studied
=== Hartford Nomogram ===
*7 mg/kg (15 mg/kg [[amikacin]]) IV, frequency depends on [[CrCl]]
**[[CrCl]] ≥60 q24h
**[https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation CrCl] 40-59 q36h
**[https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation CrCl] 20-39 q48h
**[https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation CrCl] ≤19 don't use
*Use [[Hartford nomogram]] with a random level (but remember to halve the [[amikacin]] level first)


===Dialysis Dosing===
[[File:Hartford_nomogram.png]]


*Pre-HD levels with post-HD doses, though this may change
Double the concentration for [[amikacin]]


== Origin ==
===Synergy===


*1 mg/kg divided q8-12h, peak target 3-5, trough <2
* Derived from [[Streptomyces species]] (mycins & kacins) or [[Micromonospora species]] (micins)


== Mechanism ==
===Monitoring===


====Peak====
* 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


*30 minutes after third dose
== Spectrum of Activity ==
*Response is based on peak:MIC ratio, target is 8-10 times
*If below target, increase dose


====Trough====
* 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)


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


====Hartford Nomogram====
* Altered 50S ribosomal subunit

* Decreased uptake and accumulation (Pseudomonas)
[[File:Hartford_nomogram.png]]
* Decreased membrane permeability
* Efflux (E. coli)
* Aminoglycoside-modifying enzymes (Enterococcus)


*Dosing interval is whichever is the line just above the random level
== PK/PD ==
*Double the concentration for [[amikacin]]


==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]]

Latest revision as of 18:46, 11 January 2024

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
  • Streptomycin also covers mycobacterium
  • Some protozoal coverage
  • Can cover Gram-positives if cell wall is disrupted (e.g. by beta-lactam)

Mechanisms of Resistance

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

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

Traditional Dosing

Extended Interval Dosing

  • Q24H dosing, which is safer but less well-studied
  • 7 mg/kg (15 mg/kg amikacin) IV, frequency depends on CrCl
  • Use Hartford nomogram with a random level (but remember to halve the amikacin level first)

Dialysis Dosing

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

Synergy

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

Monitoring

Peak

  • 30 minutes 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 to 48h in renal failure
  • Side effects are predicted by trough levels
  • Tobramycin <0.5 (extended) or <2 (traditional)
  • Amikacin <1 (extended) or <?? (traditional)
  • If above target, increase interval

Hartford Nomogram

Hartford nomogram.png

  • Dosing interval is whichever is the line just above the random level
  • Double the concentration for amikacin

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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