Colistin (Colistimethate Sodium)
Colistimethate sodium (CMS) must always be prescribed in terms of colistin base activity (CBA) to avoid dosing errors. The conversion is: ~33 mg CBA ≈ ~80 mg CMS ≈ 1 million IU. The FDA PI and international consensus guidelines use CBA. Each Coly-Mycin M vial contains 150 mg CBA. Confusing CBA with CMS has caused fatal overdose errors.
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute or chronic infections due to sensitive gram-negative bacilli (Enterobacter aerogenes, E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) | Adults & paediatrics (incl. neonates) | Monotherapy or combination | FDA Approved |
Colistin (polymyxin E) is a cationic polypeptide antibiotic that disrupts the gram-negative outer membrane via electrostatic interaction with lipopolysaccharide (LPS). It is administered as colistimethate sodium (CMS), an inactive prodrug that undergoes in vivo hydrolysis to release active colistin. Colistin’s clinical role has been revived as a last-resort agent for infections caused by multi-drug resistant (MDR) and extensively drug resistant (XDR) gram-negative organisms, including carbapenem-resistant Enterobacterales (CRE), MDR Acinetobacter baumannii, and MDR Pseudomonas aeruginosa. The 2019 International Consensus Guidelines recommend polymyxin B as the preferred polymyxin for most systemic infections due to its more predictable PK, but endorse colistin (CMS) as preferred for urinary tract infections because CMS is renally excreted and converts to active colistin within the urinary tract. Colistin is not active against Proteus, Providencia, Morganella, Serratia, Burkholderia cepacia, and Neisseria species.
MDR/XDR gram-negative infections (CRE, MDR Acinetobacter, MDR Pseudomonas) — IV salvage therapy: Most common contemporary use; typically in combination with a carbapenem or another active agent. Endorsed by international consensus guidelines (Tsuji 2019). Evidence quality: Moderate.
Inhaled colistin for MDR gram-negative pneumonia (VAP/HAP): Nebulised CMS used as adjunctive therapy; not FDA-approved for inhalation. Evidence quality: Moderate.
Intrathecal/intraventricular colistin for MDR gram-negative meningitis/ventriculitis: Used when systemic therapy alone is insufficient due to poor CNS penetration. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario (All doses in CBA unless stated)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Serious gram-negative infection — FDA-approved dosing | 2.5–5 mg/kg/day CBA | Divided into 2–4 equal doses | 5 mg/kg/day CBA | FDA PI (Coly-Mycin M); direct intermittent: slowly inject one-half total daily dose over 3–5 min; continuous infusion: first half over 3–5 min, remaining half added to compatible IV fluid Note: FDA-approved dosing is widely considered suboptimal by current pharmacokinetic data; see consensus dosing below |
| MDR gram-negative infection — International Consensus loading dose | 300 mg CBA IV loading dose | Maintenance by CrCl (see below) | 360 mg CBA/day | Tsuji 2019 / Nation 2017 consensus dosing; loading dose given regardless of renal function to achieve therapeutic levels rapidly Target Css,avg of colistin: 2 mg/L. Start maintenance 12–24 h after loading dose (24 h delay if CrCl ≤40 mL/min) |
| MDR gram-negative infection — consensus maintenance dosing | Total daily CBA dose calculated by CrCl using Garonzik/Nation algorithms (typically 130–360 mg CBA/day), divided q12h | 360 mg CBA/day | Higher CrCl requires higher doses; patients with CrCl ≥80 mL/min may not achieve target Css,avg ≥2 mg/L even at maximum dose — consider combination therapy Use IBW for dosing in obese patients | |
| Lower urinary tract infection (preferred polymyxin per consensus) | 2.5–5 mg/kg/day CBA | Divided q8–12h | 5 mg/kg/day CBA | CMS is renally excreted; converts to active colistin in urine. Colistin preferred over polymyxin B for UTI (Tsuji 2019) Higher urinary concentrations achieved than with polymyxin B |
| Renal impairment — maintenance adjustment | Loading dose 300 mg CBA (unchanged) | Reduce maintenance per CrCl per consensus algorithms | Per algorithm | CMS is renally cleared; active colistin levels rise as renal function declines (less CMS excreted, more converted to colistin) Delay maintenance by 24 h if CrCl ≤40 mL/min. Unknown if removed by HD/PD (FDA PI); supplement per consensus guidelines for patients on RRT |
Paediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Neonates, infants, children — serious infection | 2.5–5 mg/kg/day CBA | Divided into 2–4 doses | 5 mg/kg/day CBA | FDA PI applies to all paediatric ages including neonates. CMS half-life is 2–3 h in paediatrics including premature infants (FDA PI) Close clinical monitoring recommended; subjective symptoms may not be reported by young patients |
CMS is a prodrug that requires in vivo hydrolysis to release active colistin. Without a loading dose, it takes approximately 2–3 days for colistin to reach steady-state therapeutic concentrations. The 2019 International Consensus Guidelines recommend a 300 mg CBA loading dose for all patients (regardless of renal function) to achieve target colistin Css,avg of 2 mg/L more rapidly. The loading dose has not been associated with increased nephrotoxicity in available data. Note that the therapeutic window is extremely narrow: the target Css,avg of 2 mg/L overlaps with the nephrotoxic threshold (Css,avg ≥4 mg/L may substantially increase AKI risk), and patients with CrCl ≥80 mL/min may be unable to achieve therapeutic levels even at maximum doses, necessitating combination therapy.
Pharmacology
Mechanism of Action
Colistin is a cationic polypeptide that exerts bactericidal activity by binding to lipopolysaccharide (LPS) in the outer membrane of gram-negative bacteria. This electrostatic interaction displaces divalent cations (Ca2+, Mg2+) that stabilise LPS, disrupting outer membrane integrity and increasing permeability. The resulting osmotic imbalance leads to rapid cell lysis and death. Colistin exhibits rapid concentration-dependent killing, and the pharmacokinetic/pharmacodynamic index best associated with efficacy is the free-drug AUC:MIC ratio (fAUC/MIC). Unlike aminoglycosides, colistin has a limited post-antibiotic effect. A significant clinical limitation is that therapeutic plasma concentrations for antibacterial efficacy (Css,avg ~2 mg/L) closely approach the nephrotoxic threshold (~4 mg/L), creating an extremely narrow therapeutic window.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Not orally absorbed; administered IV or IM as CMS prodrug. After a 150 mg CBA dose, peak serum levels occur at ~10 min (IV) or 1–2 h (IM) | Parenteral administration mandatory for systemic infections; CMS must undergo in vivo conversion to active colistin |
| Distribution | CMS Vd: ~0.09–0.34 L/kg (small, hydrophilic). Poor CNS penetration. Crosses placenta. Colistin: higher Vd than CMS, distributes to tissues | Poor CNS penetration may necessitate intrathecal dosing for meningitis; tissue distribution increases with duration of therapy |
| Metabolism | CMS is an inactive prodrug hydrolysed in vivo to active colistin (conversion is non-enzymatic). Neither CMS nor colistin undergoes hepatic metabolism | CMS conversion rate is patient-variable; slow conversion delays therapeutic levels without a loading dose; no hepatic dose adjustment needed |
| Elimination | CMS: t½ 2–3 h; primarily renally excreted (unchanged CMS + converted colistin). Colistin: t½ longer and variable; eliminated by non-renal mechanisms. Unknown if removed by HD/PD (FDA PI) | CMS clearance is CrCl-dependent — in renal impairment, less CMS is excreted renally, and more converts to colistin (paradoxically increasing active drug levels). This is why maintenance dose decreases but colistin levels may actually increase in renal failure |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nephrotoxicity (AKI, rising BUN/SCr, oliguria, tubular necrosis) | 20–50% | Dose-dependent; reported at 20–50% in international consensus guidelines, 36% in RCT meta-analysis (Eljaaly 2021), up to 52% in some observational cohorts. Usually reversible on discontinuation. Risk factors: advanced age, concurrent nephrotoxins, dehydration, high colistin trough levels (≥4 mg/L), and ICU admission |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Neurotoxicity — paraesthesias (circumoral, extremity numbness/tingling) | ~7% (historical); 0–7% in contemporary studies | Most common neurological symptom; dose-dependent and usually reversible with dose reduction (FDA PI). Koch-Weser 1970 reported neurotoxicity in 7.3% of utilizations. Patients should be warned about driving and operating machinery |
| Dizziness / vertigo | Reported (FDA PI) | Part of the neurotoxicity spectrum; may not be apparent in sedated ICU patients |
| Slurred speech | Reported (FDA PI) | Transient; dose reduction usually alleviates symptoms |
| Generalised pruritus / urticaria / rash | Reported (FDA PI) | Dermatological reactions; discontinue if severe |
| GI disturbance (nausea, diarrhoea) | Reported (FDA PI) | Monitor for C. difficile if persistent diarrhoea |
| Pseudo-Bartter syndrome (hypokalaemia, metabolic alkalosis, hypocalcaemia, hypomagnesaemia) | Post-marketing reports | Renal tubulopathy; monitor electrolytes during treatment; may require drug discontinuation for normalisation |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Acute kidney injury / renal failure | 20–50% | Median ~10 days into therapy | Monitor SCr daily; consider stopping if AKI develops and alternative agents available; usually reversible on discontinuation (FDA PI) |
| Neuromuscular blockade / respiratory arrest | Rare but potentially fatal | During or shortly after IM injection; increased risk with renal impairment | Respiratory arrest reported following IM administration (FDA PI). Impaired renal function increases risk. Monitor respiratory function; have ventilatory support available |
| Seizures / encephalopathy | Rare | Variable | Discontinue colistin; supportive care; may be dose-related |
| Clostridioides difficile-associated diarrhoea | Reported (FDA PI) | During or up to 2 months post-therapy | Test for C. difficile toxin; discontinue colistin if confirmed; initiate appropriate therapy |
Colistin-associated nephrotoxicity occurs in 20–50% of patients and is the major dose-limiting toxicity. It manifests primarily as acute tubular injury and is usually reversible on discontinuation. Risk factors include advanced age, pre-existing renal impairment, concurrent nephrotoxic agents (vancomycin, aminoglycosides, amphotericin B, NSAIDs), dehydration, ICU admission, and colistin Css,avg ≥4 mg/L. Maintain adequate hydration, monitor serum creatinine daily, and monitor electrolytes (K, Mg, Ca) for Pseudo-Bartter syndrome. If AKI develops, consider stopping colistin if the infection diagnosis is uncertain or an alternative less nephrotoxic agent is available. Therapeutic drug monitoring of colistin levels (where available) can guide dose optimisation within the narrow therapeutic window.
Drug Interactions
Colistin/CMS is not metabolised via CYP450 and has no significant protein displacement interactions. Clinically important interactions are pharmacodynamic (additive nephrotoxicity and neuromuscular blockade).
Monitoring
- Renal Function (SCr, BUN, CrCl, urine output)Baseline, then daily
RoutineNephrotoxicity occurs in 20–50% of patients. Monitor SCr daily and CrCl frequently, as CMS dosing must be adjusted with changing renal function. Rising SCr warrants dose reduction or discontinuation. AKI usually reversible (FDA PI). - Electrolytes (K, Mg, Ca, bicarbonate)Baseline, then at least twice weekly
RoutinePost-marketing cases of Pseudo-Bartter syndrome (renal tubulopathy) with hypokalaemia, metabolic alkalosis, hypocalcaemia, and hypomagnesaemia reported. Electrolyte normalisation may require drug discontinuation. - Neurological StatusThroughout therapy
RoutineMonitor for paraesthesias, dizziness, slurred speech, muscle weakness, visual disturbances, confusion, and seizures. Symptoms may not be apparent in sedated ICU patients. Dose reduction may alleviate symptoms (FDA PI). - Respiratory FunctionDuring and after administration
Trigger-basedRespiratory arrest reported following IM administration. Impaired renal function increases apnoea and NMB risk. Have ventilatory support available (FDA PI). - Colistin TDM (where available)Steady-state (typically after 2–3 days of maintenance dosing)
Trigger-basedTarget Css,avg ~2 mg/L for efficacy; Css,avg ≥4 mg/L associated with increased nephrotoxicity. The therapeutic window is very narrow and overlaps with the toxic range. TDM is recommended where assays are available (Tsuji 2019).
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to colistimethate sodium, colistin, or polymyxin B (FDA PI).
Relative Contraindications (Specialist Input Recommended)
- Pre-existing significant renal impairment — substantially increased nephrotoxicity risk; loading dose still recommended but maintenance dose must be reduced per CrCl.
- Myasthenia gravis or other neuromuscular disorders — colistin may precipitate or worsen neuromuscular blockade and respiratory failure.
- Pregnancy — CMS crosses the placenta; talipes varus reported in animal studies. Use only if benefit clearly outweighs risk (FDA PI).
Use with Caution
- Elderly patients — higher AKI risk; start at low end of dosing range per FDA PI.
- Concurrent nephrotoxic agents — avoid when possible; if essential, monitor renal function daily.
- Patients with CrCl ≥80 mL/min — may not achieve therapeutic colistin levels even at maximum dose; consider combination therapy or alternative agent.
- Obesity — use ideal body weight for dosing; CMS distributes in ECF.
- Inhaled use — not FDA-approved for inhalation; one CF patient death reported with pre-mixed nebulised CMS. Always prepare freshly before inhalation.
Colistimethate sodium is potentially nephrotoxic, neurotoxic, and can cause neuromuscular blockade. Maximum daily dose should not exceed 5 mg/kg/day CBA with normal renal function (FDA PI). Nephrotoxicity is dose-dependent and usually reversible. Respiratory arrest has been reported following IM administration. Impaired renal function increases the risk of apnoea and neuromuscular blockade. Transient neurological disturbances including circumoral paraesthesias, extremity numbness, dizziness, vertigo, and slurred speech may occur. Patients should be warned not to drive or operate machinery during therapy.
Patient Counselling
Purpose of Therapy
Colistin is a last-resort antibiotic used to treat serious bacterial infections caused by organisms resistant to other antibiotics. It is given through a vein or as an injection in a hospital setting. It requires close monitoring of kidney function and neurological symptoms throughout treatment.
How to Take
Colistin is administered by healthcare professionals. Treatment duration depends on the type and severity of infection. Regular blood tests are essential to monitor kidney function and drug levels.
Sources
- Coly-Mycin M Parenteral (Colistimethate for Injection, USP) — Full Prescribing Information. FDA Label (NDA 050108)Primary FDA label source for all dosing, indications, adverse reactions, and PK data. Vial contains 150 mg colistin base activity.
- Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus guidelines for the optimal use of the polymyxins. Pharmacotherapy. 2019;39(1):10–39. doi:10.1002/phar.2209Landmark consensus guideline (endorsed by ACCP, ESCMID, IDSA, ISAP, SCCM, SIDP) providing loading dose strategy, CrCl-based maintenance dosing, and recommendation for polymyxin B over colistin for most systemic infections.
- Nation RL, Garonzik SM, Thamlikitkul V, et al. Dosing guidance for intravenous colistin in critically ill patients. Clin Infect Dis. 2017;64(5):565–571. doi:10.1093/cid/ciw839Population PK study in 214 critically ill patients developing the CrCl-based dosing algorithms and confirming the 300 mg CBA loading dose; target Css,avg of 2 mg/L.
- Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients. Antimicrob Agents Chemother. 2011;55(7):3284–3294. doi:10.1128/AAC.01733-10Original population PK model for CMS/colistin in critically ill patients that formed the basis for the loading dose and CrCl-adjusted dosing recommendations.
- Eljaaly K, Bidell MR, Gandhi RG, et al. Colistin nephrotoxicity: meta-analysis of randomized controlled trials. Open Forum Infect Dis. 2021;8(2):ofab026. doi:10.1093/ofid/ofab026Meta-analysis of RCTs finding colistin nephrotoxicity incidence of 36.2% with 2.4-fold increased risk vs beta-lactam comparators.
- Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant gram-negative bacterial infections. Lancet Infect Dis. 2006;6(9):589–601. doi:10.1016/S1473-3099(06)70580-1Comprehensive review of colistin’s mechanism of action, PK/PD, clinical uses, and toxicity profile during its clinical resurgence.
- Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005;40(9):1333–1341. doi:10.1086/429323Early review of colistin’s re-emergence covering efficacy, safety, and the rationale for its use as salvage therapy in MDR infections.
- Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009;53(8):3430–3436. doi:10.1128/AAC.01361-08Population PK analysis demonstrating the delayed conversion of CMS to colistin and the rationale for loading dose strategies.
- Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis. 2009;48(12):1724–1728. doi:10.1086/599225Early clinical study documenting colistin-associated nephrotoxicity incidence and risk factors in a contemporary cohort.
- Lim LM, Ly N, Anderson D, et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010;30(12):1279–1291. doi:10.1592/phco.30.12.1279Review of colistin PK/PD, resistance mechanisms, dosing strategies, and toxicity management.
- Mohamed AF, Karaiskos I, Plachouras D, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012;56(8):4241–4249. doi:10.1128/AAC.06426-11PK study supporting the use of a 9 MIU (~300 mg CBA) loading dose for rapid attainment of therapeutic colistin concentrations.