Colistin: Difference between revisions

Revision as of 09:48, 26 August 2020

Background

A member of the polymyxin class also known as polymyxin E
Active against most gram-negatives except for Proteus species and several others (see Resistance, below)
Currently reserved for resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae

Mechanism of Action

Given as a prodrug, which is converted in vivo into the active drug (compared to polymixin B, which is given in its active form)
Disrupt membranes by interacting with membrane phospholipids to displace divalent cations
Also bind lipid A in the cell wall lipopolysaccharide

Mechanisms of Resistance

Conferred by alterations in lipid A, either reducing its charge or eliminating it altogether
May be chromosomal (e.g. pmrC, pmrF, pmrAB, lpxA, lpxC, lpxD, OprH) or plasmid-mediated (e.g. mcr-1 gene)

Spectrum of Activity

Broadly active against Gram-negative bacteria, including Enterobacterales and afermentative Gram-negative bacilli
Not active against Gram-positive bacteria, given that they don't have lipopolysaccharide
Resistance often seen in:
- Brucella
- Burkholderia
- Inquilinus limosus
- Morganellaceae (Proteus, Providencia, Morganella)
- Neisseria
- Pandoraea
- Serratia

PK/PD

Concentration-dependent activity
Poor distribution into pleural fluid, joints, and CSF

Dosing

Dosing is a mess, with a number of different units used by different people, despite having a standardized international unit, usually in millions (MIU)
- 1 MIU = 80 mg colistimethate (CMS) in Europe
- 1 MIU = 30 mg colistin base activity (CBA) in the US
For European dosing, using IU of CMS:
- Weight ≤60 kg: 50-75 kIU/kg/day divided q8h
- Weight >60 kg: 1-2 MIU q8h, dose-adjusted to q12-18h for CrCl 10-20 and q18-24h for CrCl <10
For US dosing, using mg of CBA:
- 2.5-5 mg/kg ideal body weight daily divided q12h to q6h
- E.g. 300 mg CBA (10 IU) daily for a 60 kg patient, compared to 3 to 4.5 MIU daily in Europe
Critically ill patients may benefit from a loading dose of 300 mg CBA followed by regular maintanance dosing in 12 to 24 hours
Per Mandell:
- 5 mg CBA/kg IBW as loading dose (max 300 mg) followed by 5 mg CBA/kg IBW daily divided q8h
- Maintenance is renally adjusted to 3.5 mg/kg/day divided q12h for CrCl 30-49, 2.5 mg/kg/day divided q12h for CrCl 10-29, and 1.5 mg/kg q24h for CrCl <10 or hemodialysis

Safety

Adverse Effects

Prominent and common nephrotoxicity, which is dose-related and usually reversible
Rarely, neuromuscular blockage, which can cause weakness and apnea
Other neurological effects include peripheral paresthesia, tingling of tongue, dizziness, vertigo, blurred vision, slurred speech, ataxia

@@ Line 1: / Line 1: @@
+==Background==
 *A member of the polymyxin class also known as polymyxin E
 *Active against most gram-negatives except for [[Proteus species]] and several others (see ''Resistance'', below)
 *Currently reserved for resistant [[Pseudomonas aeruginosa]], [[Acinetobacter baumannii]], and carbapenem-resistant Enterobacteriaceae
-==Background==
 ===Mechanism of Action===
+*Given as a prodrug, which is converted in vivo into the active drug (compared to [[polymixin B]], which is given in its active form)
 *Disrupt membranes by interacting with membrane phospholipids to displace divalent cations
 *Also bind lipid A in the cell wall lipopolysaccharide
@@ Line 14: / Line 16: @@
 *May be chromosomal (e.g. pmrC, pmrF, pmrAB, lpxA, lpxC, lpxD, OprH) or plasmid-mediated (e.g. mcr-1 gene)
-=== Spectrum of Activity ===
+===Spectrum of Activity===
-* Broadly active against Gram-negatives
+*Broadly active against [[Gram-negative bacteria]], including [[Enterobacterales]] and [[afermentative Gram-negative bacilli]]
-* Not active against Gram-positives
+*Not active against [[Gram-positive bacteria]], given that they don't have lipopolysaccharide
-* Resistance often seen in:
+*Resistance often seen in:
-** ''[[Brucella species|Brucella]]''
+**''[[Brucella species|Brucella]]''
-** ''[[Burkholderia species|Burkholderia]]''
+**''[[Burkholderia species|Burkholderia]]''
-** [[Inquilinus limosus]]
+**[[Inquilinus limosus]]
-** [[Morganellaceae]] (''[[Proteus species|Proteus]]'', ''[[Providencia species|Providencia]]'', ''[[Morganella species|Morganella]]'')
+**[[Morganellaceae]] (''[[Proteus species|Proteus]]'', ''[[Providencia species|Providencia]]'', ''[[Morganella species|Morganella]]'')
-** ''[[Neisseria species|Neisseria]]''
+**''[[Neisseria species|Neisseria]]''
-** [[Pandoraea]]
+**[[Pandoraea]]
-** ''[[Serratia species|Serratia]]''
+**''[[Serratia species|Serratia]]''
+=== PK/PD ===
+* Concentration-dependent activity
+* Poor distribution into pleural fluid, joints, and CSF
 ==Dosing==
@@ Line 38: / Line 45: @@
 **2.5-5 mg/kg ideal body weight daily divided q12h to q6h
 **E.g. 300 mg CBA (10 IU) daily for a 60 kg patient, compared to 3 to 4.5 MIU daily in Europe
+*Critically ill patients may benefit from a loading dose of 300 mg CBA followed by regular maintanance dosing in 12 to 24 hours
 *Per Mandell:
 **5 mg CBA/kg IBW as loading dose (max 300 mg) followed by 5 mg CBA/kg IBW daily divided q8h
 **Maintenance is renally adjusted to 3.5 mg/kg/day divided q12h for CrCl 30-49, 2.5 mg/kg/day divided q12h for CrCl 10-29, and 1.5 mg/kg q24h for CrCl <10 or hemodialysis
-==Adverse Effects==
+== Safety ==
+===Adverse Effects===
 *Prominent and common '''nephrotoxicity''', which is dose-related and usually reversible
 *Rarely, '''neuromuscular blockage''', which can cause weakness and apnea
+*Other neurological effects include peripheral paresthesia, tingling of tongue, dizziness, vertigo, blurred vision, slurred speech, ataxia
+== Further Reading ==
+* International Consensus Guidelines for the Optimal Use of the Polymyxins. ''Pharmacotherapy''. 2019;39(1):10-39. doi: [https://doi.org/10.1002/phar.2209 10.1002/phar.2209]
 [[Category:Polymyxins]]