Colistin: Difference between revisions
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*Intrinsic resistance in: |
*Intrinsic resistance in: |
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**All [[Gram-positive bacteria]], which lack the lipopolysaccharide target |
**All [[Gram-positive bacteria]], which lack the lipopolysaccharide target |
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− | **[[Enterobacterales]]: [[Morganellaceae]] ([[Proteus |
+ | **[[Enterobacterales]]: [[Morganellaceae]] ([[Proteus]], [[Morganella morganii]], [[Providencia]]), and [[Serratia marcescens]] |
− | **Afermentative Gram-negative bacteria: [[Burkholderia |
+ | **Afermentative Gram-negative bacteria: [[Burkholderia]] |
− | **Other notable bacteria: [[Neisseria |
+ | **Other notable bacteria: [[Neisseria]], [[Moraxella catarrhalis]], [[Helicobacter pylori]], [[Chromobacterium]], [[Brucella]], [[Inquilinus]], [[Pandoraea]] |
===Pharmacokinetics and Pharmacodynamics=== |
===Pharmacokinetics and Pharmacodynamics=== |
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*Concentration-dependent activity |
*Concentration-dependent activity |
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+ | === Clinical Breakpoints === |
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+ | {| class="wikitable" |
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+ | ! rowspan="2" |Species |
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+ | ! rowspan="2" |ECV (μg/mL) |
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+ | ! colspan="4" |Breakpoints (μg/mL) |
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+ | ! colspan="4" |Breakpoints (mm) |
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+ | |- |
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+ | !S |
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+ | !SDD |
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+ | !I |
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+ | !R |
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+ | !S |
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+ | !SDD |
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+ | !I |
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+ | !R |
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+ | |- |
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+ | |[[Acinetobacter baumannii complex]] |
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+ | | |
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+ | |— |
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+ | |— |
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+ | |≤2 |
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+ | |≥4 |
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+ | | |
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+ | |} |
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==Dosing== |
==Dosing== |
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*Dosing is a mess, with a number of different units used by different people, despite having a standardized international unit, usually in millions (MIU) |
*Dosing is a mess, with a number of different units used by different people, despite having a standardized international unit, usually in millions (MIU) |
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− | **1 MIU = 80 mg colistimethate (CMS) in Europe |
+ | **1 MIU = 80 mg colistimethate (CMS) in Europe = 30 mg colistin base activity (CBA) in the US |
− | **1 MIU = 30 mg colistin base activity (CBA) in the US |
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**1 mg of CMS = 0.375 mg of colistin base activity = 12,500 IU |
**1 mg of CMS = 0.375 mg of colistin base activity = 12,500 IU |
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**1 mg of colistin base activity = 2.6 mg of CMS = 32,500 IU |
**1 mg of colistin base activity = 2.6 mg of CMS = 32,500 IU |
Latest revision as of 12:38, 25 January 2022
Background
- A member of the polymyxin class also known as polymyxin E
- Administered intravenously as a prodrug, colistin methanesulphonate (CMS), or orally and topically as colistin sulfate
- Active against most Gram-negative bacteria
- Currently reserved for multidrug-resistant Gram-negative infections, including resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacterales
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
- Intrinsic resistance in:
- All Gram-positive bacteria, which lack the lipopolysaccharide target
- Enterobacterales: Morganellaceae (Proteus, Morganella morganii, Providencia), and Serratia marcescens
- Afermentative Gram-negative bacteria: Burkholderia
- Other notable bacteria: Neisseria, Moraxella catarrhalis, Helicobacter pylori, Chromobacterium, Brucella, Inquilinus, Pandoraea
Pharmacokinetics and Pharmacodynamics
- Distribution:
- CMS is about 50% protein bound
- Distributes well into liver, kidney, heart, and muscle
- Poor distribution into bones, cerebrospinal fluid, lung parenchyma, and pleural cavity
- Metabolism: Can take up to 36 hours to achieve steady state colistin during administration of CMS
- Elimination:
- Two-thirds of CMS is eliminated unchanged by the kidneys
- Colistin is cleared by unknown non-renal and non-biliary routes
- Concentration-dependent activity
Clinical Breakpoints
Species | ECV (μg/mL) | Breakpoints (μg/mL) | Breakpoints (mm) | ||||||
---|---|---|---|---|---|---|---|---|---|
S | SDD | I | R | S | SDD | I | R | ||
Acinetobacter baumannii complex | — | — | ≤2 | ≥4 |
Dosing
Dosing Equivalents
- 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 = 30 mg colistin base activity (CBA) in the US
- 1 mg of CMS = 0.375 mg of colistin base activity = 12,500 IU
- 1 mg of colistin base activity = 2.6 mg of CMS = 32,500 IU
- IU is used in Europe while CBA is used in the US
Intravenous Dosing
- 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
Intrathecal Dosing
- Exists.
Inhalational Dosing
- CMS is dissolved in 4–6 ml of normal saline or sterile water and given by nebulizer
- Results in low systemic levels
- Body weight <40 kg: 0.5 MIU (40 mg) of CMS every 12 h
- Body weight >40 kg: 1.0 MIU (80 mg) of CMS every 12 h
- For recurrent or severe pulmonary infection: 2.0 MIU (160 mg) of CMS every 8 h
Renal Dosing
- Serum creatinine level 115 to 132 μmol/L: 2 MIU (160 mg) of CMS every 8 h
- Serum creatinine level 141 to 221 μmol/L: 2 MIU (160 mg) of CMS every 12 h
- Serum creatinine level ≥230 μmol/L: 2 MIU (160 mg) of CMS every 24 h
- Hemodialysis: 2 MIU (160 mg) of CMS after each hemodialysis
- Peritoneal dialysis: 2 MIU (160 mg) of CMS daily during peritoneal dialysis
- Continuous renal replacement therapy (CRRT): high loading dose followed by a maintenance dose of up to 4.5 MIU every 8 h
- Continuously eliminated, and needs higher dosing
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: 10.1002/phar.2209
- Colistin for lung infection: an update. J Intensive Care. 2015;3(1):3. doi: 10.1186/s40560-015-0072-9