Schedule H

Intravenous, Inhalational (nebulised), Intrathecal (specialist use only)

Formulation Salt Form Strength Equivalence

Injection (vial) Colistimethate sodium (CMS) 1 million IU per vial ≈80 mg CMS ≈ 34 mg colistin base activity

Injection (vial) Colistimethate sodium (CMS) 2 million IU per vial ≈160 mg CMS ≈ 68 mg colistin base activity

Critical Note: All dosing in India follows international convention using million IU (International Units). Always specify units clearly when prescribing — confusion between IU and mg can cause fatal dosing errors.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Multidrug-Resistant Gram-Negative Infections (IV)

For infections caused by extensively drug-resistant (XDR) or pan-drug-resistant (PDR) organisms including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenem-resistant Klebsiella pneumoniae.

Parameter Recommendation

Starting dose (Loading) 9 million IU IV stat (may use up to 12 million IU in severe sepsis/septic shock with normal renal function)

Titration Adjust based on renal function (CrCl) and clinical response

Usual maintenance dose 4.5 million IU IV every 12 hours (total 9 million IU/day)

Maximum dose 12 million IU/day in 2–3 divided doses

Clinical Notes:

• Loading dose should be administered regardless of renal function to achieve rapid therapeutic concentrations

• Infuse each dose over 30–60 minutes to reduce nephrotoxicity risk

• Reserve for documented or strongly suspected XDR/PDR organisms with confirmed or anticipated susceptibility

• Avoid monotherapy in bloodstream infections — combination with carbapenem, aminoglycoside, or tigecycline preferred

• Susceptibility testing mandatory before or immediately after initiation

1. Ventilator-Associated Pneumonia (VAP) / Hospital-Acquired Pneumonia (HAP) due to MDR Gram-Negative Organisms

Intravenous Component:

Parameter Recommendation

Starting dose (Loading) 9 million IU IV stat

Titration Based on renal function and clinical response

Usual maintenance dose 4.5 million IU IV every 12 hours

Maximum dose 12 million IU/day

Adjunctive Nebulised Colistin (Standard ICU Practice):

Parameter Recommendation

Starting dose 1–2 million IU nebulised every 8–12 hours

Titration Not applicable

Usual maintenance dose 2 million IU nebulised every 8 hours

Maximum dose 6 million IU/day via nebulisation

Clinical Notes for Nebulisation:

• Use jet nebuliser or vibrating mesh nebuliser — avoid ultrasonic nebulisers (drug degradation)

• Reconstitute IV vial with sterile water or normal saline immediately before use

• Pre-treat with short-acting bronchodilator (salbutamol) in patients with reactive airways

• Administer via ventilator circuit in intubated patients or via face mask in non-intubated

• Duration: Continue until clinical resolution or culture clearance (typically 7–14 days)

Secondary Indications – Adults (Off-label)

Indication Dose Duration Notes

MDR Gram-negative meningitis/ventriculitis (Intrathecal/Intraventricular) 125,000–250,000 IU once daily via lumbar puncture or ventricular drain 10–21 days or until CSF sterility OFF-LABEL; Specialist only (neurosurgery/ID); Indicated for post-neurosurgical or shunt-related MDR infections; Evidence: Indian ICU case series, international cohort studies

MDR Gram-negative peritonitis (CAPD-related) 300,000 IU intraperitoneally per exchange 14–21 days OFF-LABEL; Nephrology/ID specialist; Evidence: ISPD guidelines adapted for Indian practice

PAEDIATRIC DOSING (Specialist Only)

⚠️ Use only under paediatric infectious diseases or paediatric intensive care supervision.

⚠️ Extreme caution in neonates and infants <2 years — higher nephrotoxicity and neurotoxicity risk.

Primary Indications (Approved/Standard Use in India)

MDR Gram-Negative Infections (IV Colistimethate Sodium)

Weight/Age Category Loading Dose Maintenance Dose Maximum

Neonates (<1 month) 75,000 IU/kg IV stat 75,000 IU/kg/day divided every 12 hours 150,000 IU/kg/day

Infants 1–12 months 75,000–100,000 IU/kg IV stat 75,000–100,000 IU/kg/day divided every 12 hours 150,000 IU/kg/day

Children 1–12 years 100,000–150,000 IU/kg IV stat 75,000–100,000 IU/kg/day divided every 8–12 hours 150,000 IU/kg/day or 9 million IU/day (whichever lower)

Adolescents ≥12 years (≥40 kg) Adult loading dose (9 million IU) Adult maintenance dosing 12 million IU/day

Nebulised Colistin in Paediatrics (VAP/HAP):

Age Dose Frequency

All ages (weight-based) 50,000–75,000 IU/kg/day Divided every 8–12 hours

Maximum per dose 2 million IU Every 8 hours

Clinical Notes:

• Calculate dose based on actual body weight

• Adjust for renal impairment using paediatric CrCl calculations

• Use appropriate paediatric nebuliser devices

• Pre-treat with bronchodilator in children with bronchospasm history

Safety Monitoring in Paediatrics:

• Daily serum creatinine and electrolytes

• Twice-weekly neurological assessment

• Urine output monitoring

• Weight-based dose recalculation if significant fluid shifts

Secondary Indications – Paediatrics (Off-label)

Indication Dose Duration Notes

MDR Gram-negative meningitis/ventriculitis (Intrathecal) 40,000–125,000 IU once daily (age-dependent) 10–21 days OFF-LABEL; Specialist only (paediatric neurosurgery/ID); Post-shunt or post-surgical MDR infections; Evidence: Case series from Indian tertiary PICUs

Age Restrictions:

• Neonates: Use only when no alternative exists; mandatory neonatology/ID consultation

• Children <2 years: Extreme caution; increased toxicity risk; specialist supervision mandatory

IV Colistimethate Sodium — Maintenance Dose Adjustment

Creatinine Clearance (mL/min) Maintenance Dose Dosing Interval

80 4.5 million IU Every 12 hours (9 million IU/day)

50–79 3–4.5 million IU Every 12 hours (6–9 million IU/day)

30–49 2.25–3 million IU Every 12 hours (4.5–6 million IU/day)

10–29 1.5 million IU Every 12–24 hours (1.5–3 million IU/day)

<10 (non-dialysis) 1 million IU Every 24–48 hours

Dialysis Considerations

Modality Recommendation

Intermittent haemodialysis Supplemental dose of 1–2 million IU after each dialysis session

CRRT (CVVH/CVVHDF) 4.5–6 million IU/day divided every 12 hours; adjust based on effluent rate

Peritoneal dialysis 1–2 million IU every 24 hours

• Known hypersensitivity to colistin, colistimethate sodium, or polymyxin B

• Myasthenia gravis (risk of severe neuromuscular blockade and respiratory failure)

• Pre-existing renal impairment — dose adjustment mandatory; enhanced monitoring required

• Concurrent use of other nephrotoxic agents (aminoglycosides, vancomycin, amphotericin B, NSAIDs)

• Concurrent use of neuromuscular blocking agents — enhanced paralysis risk

• Pre-existing neurological disorders — increased neurotoxicity susceptibility

• Prolonged therapy (>14 days) — cumulative nephrotoxicity and neurotoxicity risk increases

• Critically ill patients with unstable renal function — frequent dose reassessment needed

• Hypoalbuminaemia — may alter drug distribution

• Cystic fibrosis patients — altered pharmacokinetics; specialist dosing required

• Obesity — use adjusted body weight for dosing calculations

Parameter Recommendation

Risk Category Category C equivalent (limited human data; animal studies show risk)

Overall Recommendation Use only if potential benefit justifies potential risk to fetus and no safer alternative exists

Preferred Alternatives Carbapenems, piperacillin-tazobactam, or cefoperazone-sulbactam where organism susceptibility permits

When it may be used Life-threatening MDR infections where colistin is the only active agent; ID/obstetric specialist decision

Monitoring Maternal renal function, amniotic fluid volume, fetal growth parameters

Parameter Recommendation

Compatibility Likely compatible; limited data but poor oral bioavailability in infant suggests low risk

Drug Levels in Milk Expected to be low due to large molecular size and poor membrane permeability

Preferred Alternatives Consider alternatives for mild-moderate infections; continue colistin if life-threatening MDR infection

Infant Monitoring Gastrointestinal disturbances (diarrhoea, feeding difficulties), weight gain; rare systemic effects unlikely

Parameter Recommendation

Starting Dose Loading dose as per adults (9 million IU); maintenance at lower end of range

Titration Slower titration; reassess renal function before each dose escalation

Special Risks Age-related decline in renal reserve (even with normal serum creatinine); higher nephrotoxicity and neurotoxicity susceptibility; dehydration risk

Monitoring Daily renal function; cognitive and neurological assessment; hydration status; avoid concurrent nephrotoxic agents

Interacting Drug Mechanism/Effect Management

Aminoglycosides (gentamicin, amikacin) Additive nephrotoxicity and neurotoxicity Avoid combination if possible; if essential, monitor renal function daily and consider reduced aminoglycoside dosing

Neuromuscular blocking agents (vecuronium, atracurium, rocuronium) Enhanced and prolonged neuromuscular blockade → respiratory failure Use with extreme caution; extended post-operative ventilation may be needed; monitor neuromuscular function

Vancomycin Additive nephrotoxicity Close renal monitoring; consider vancomycin TDM if available; avoid if alternative anti-Gram-positive available

Amphotericin B Synergistic nephrotoxicity Avoid concurrent use; if essential, aggressive hydration and daily renal monitoring

Interacting Drug Effect Management

NSAIDs Reduced renal perfusion → increased colistin nephrotoxicity Avoid prolonged NSAID use; prefer paracetamol for analgesia

Loop diuretics (furosemide) Volume depletion enhances nephrotoxicity; potential ototoxicity Maintain euvolaemia; monitor electrolytes and renal function

Carbapenems (meropenem, imipenem) No pharmacokinetic interaction; commonly co-administered for synergy Monitor for carbapenem-associated seizures; no dose adjustment needed

Cyclosporine/Tacrolimus Additive nephrotoxicity Frequent calcineurin inhibitor level monitoring; consider dose reduction of immunosuppressant

• Nephrotoxicity (elevated serum creatinine, decreased urine output) — dose-dependent, occurs in 30–60% of patients

• Neurotoxicity: paraesthesias (perioral and peripheral numbness/tingling), dizziness, vertigo

• Headache

• Bronchospasm and cough (with nebulised administration)

• Throat irritation (nebulised form)

• Injection site reactions

Adverse Effect Clinical Significance

Acute kidney injury / Acute tubular necrosis Dose-dependent; usually reversible upon discontinuation; may require temporary dialysis support

Neuromuscular blockade Can cause respiratory failure, particularly with concurrent muscle relaxants or in myasthenia gravis; requires immediate ventilatory support

Seizures Rare; associated with high doses or drug accumulation in renal impairment; discontinue therapy

Anaphylaxis Rare; immediate discontinuation and standard anaphylaxis management

Severe bronchospasm With nebulised form; discontinue nebulisation; bronchodilator rescue

Action: Discontinue colistin immediately for severe nephrotoxicity (AKI requiring dialysis), neuromuscular blockade with respiratory compromise, or anaphylaxis.

During therapy (daily in ICU) Serum creatinine, urea, electrolytes, urine output, neurological symptoms (paraesthesias, weakness, confusion)

Every 48–72 hours Reassess CrCl and adjust maintenance dose accordingly

Weekly (if therapy >7 days) Complete renal panel, neurological assessment, repeat cultures to assess microbiological response

For nebulised therapy Respiratory function, bronchospasm symptoms, sputum cultures

Single-agent formulations:

• XYLISTIN® (Cipla) — 1 million IU, 2 million IU vials

• COLISTOP® (Zydus) — 1 million IU vial

• COLMYCIN® (Samarth Pharma) — 1 million IU vial

• COLSTIN® (Biocon) — 1 million IU vial

• POLYMYXIN-E® (Glenmark) — 1 million IU vial

• CMX® (Neon Labs) — 1 million IU vial

Note: No fixed-dose combinations available; all formulations contain colistimethate sodium (CMS). IV vials may be reconstituted for nebulisation (off-label but standard practice).

Regulatory Notes:

• Not included in NLEM

• Not under NPPA price control

• Available through government hospital supply (ICU/infectious diseases departments) at subsidised rates

• High cumulative cost for full treatment course (₹5,000–₹15,000+ per day depending on dose)

1. Unit clarity is critical: Always prescribe in "million IU" — never in mg. Confusion between colistin base activity (CBA), colistimethate sodium (CMS), and IU leads to fatal overdosing or subtherapeutic dosing.

1. Loading dose is mandatory: Even in renal impairment, administer full loading dose (9 million IU) to achieve therapeutic concentrations rapidly. Only maintenance doses require renal adjustment.

1. Never monotherapy for bacteraemia: Colistin resistance develops rapidly with monotherapy. Combine with carbapenems, aminoglycosides, tigecycline, or fosfomycin based on susceptibility.

1. Nephrotoxicity is usually reversible: Early detection and temporary drug withholding often allow recovery. Monitor creatinine trends rather than absolute values; rising trend warrants dose reduction or temporary hold.

1. Nebulisation technique matters: Use jet or vibrating mesh nebulisers only — ultrasonic nebulisers inactivate colistin. Reconstitute immediately before use; do not store reconstituted solution.

1. Not for empiric therapy: Reserve strictly for documented or strongly suspected XDR/PDR Gram-negative infections. Obtain cultures before starting whenever possible.

colistin; polymyxin E; MDR gram-negative; XDR Acinetobacter; carbapenem-resistant; nephrotoxic; neurotoxic; ICU antibiotic; nebulised colistin; ventilator-associated pneumonia; specialist use; renal adjustment critical

RxIndia v1.0 — 05 Jan 2025

• CDSCO Approved Product Information (Drugs@India database)

• Indian Pharmacopoeia 2018

• ICMR: Antimicrobial Resistance Surveillance and Research Network Guidelines

• National Treatment Guidelines for Antimicrobial Use in Infectious Diseases (MoHFW, 2016)

• AIIMS Antimicrobial Stewardship Guidelines (2023)

• API Textbook of Medicine (Antimicrobial Therapy Chapter)

• Indian Society of Critical Care Medicine — ICU Antimicrobial Protocols

• International consensus guidelines and RCTs — referenced for off-label indications (intrathecal use) only