What are the guidelines for administering colistin (polymyxin E) to a patient with a urinary tract infection (UTI) caused by a multidrug-resistant Gram-negative organism, particularly with regards to dosage, duration, and monitoring for potential nephrotoxicity and neurotoxicity?

Colistin Administration in Urinary Tract Infections

For UTIs caused by multidrug-resistant Gram-negative organisms, colistin should be reserved as a last-resort option when newer agents (ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, or plazomicin) are unavailable or the organism is resistant to these alternatives, and you must accept a 29-44% risk of nephrotoxicity while using specific dosing protocols. 1

When to Consider Colistin for UTI

Colistin is NOT a preferred agent for UTI. The 2022 guidelines explicitly recommend newer beta-lactam/beta-lactamase inhibitors and other alternatives before colistin for carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA). 1

Preferred Alternatives (Use These First):

• Ceftazidime-avibactam 2.5 g IV q8h for complicated UTI due to CRE 1
• Meropenem-vaborbactam 4 g IV q8h for complicated UTI due to CRE 1
• Imipenem-cilastatin-relebactam 1.25 g IV q6h for complicated UTI due to CRE 1
• Plazomicin 15 mg/kg IV q12h for complicated UTI due to CRE (with lower nephrotoxicity than colistin: 16.7% vs 50%) 1

Reserve Colistin When:

• All newer agents are unavailable or organism is resistant 1
• Organism is susceptible only to polymyxins 1
• Patient has DTR-PA or carbapenem-resistant Pseudomonas aeruginosa (CRPA) with no other options 1

Dosing Protocol for UTI

Loading Dose (Critical - Never Skip):

Administer 9 million IU (300 mg colistin base activity) as a loading dose regardless of renal function. 1, 2, 3

• This loading dose is mandatory to rapidly achieve therapeutic levels 2
• Never reduce the loading dose even in renal impairment - this is a common pitfall that leads to treatment failure 2, 4

Maintenance Dosing (Adjust for Renal Function):

For normal renal function (CrCl ≥80 mL/min):

• 4.5 million IU (150 mg CBA) IV every 12 hours 1, 3

For renal impairment, adjust maintenance dose only:

• CrCl 50-79 mL/min: 2.5-3.8 mg/kg divided into 2 doses per day 3
• CrCl 30-49 mL/min: 2.5 mg/kg once daily or divided into 2 doses 3
• CrCl 10-29 mL/min: 1.5 mg/kg every 36 hours 3

Administration Method:

• Slow IV injection over 3-5 minutes for half the daily dose, then continuous infusion for the remaining dose over 22-23 hours 3
• Alternatively, intermittent dosing every 12 hours 3

Special Considerations for UTI

Lower UTI may require lower doses than systemic infections. A 2019 study demonstrated that for lower complicated UTI caused by XDR Pseudomonas aeruginosa with low MIC values (≤0.5 mg/L), clinical cure was achieved in 89.5% of cases even when plasma concentrations were suboptimal, suggesting that urinary concentrations (which are 25-100 fold higher than plasma) may be sufficient. 5

Critical insight: Colistimethate sodium (the prodrug) is excreted in urine and converts to active colistin after glomerular filtration, resulting in very high urinary concentrations. 5

Combination Therapy

Use combination therapy whenever possible. 1

• Combine colistin with one or more agents to which the pathogen shows in vitro susceptibility 1
• If no susceptible agent exists, combine with a carbapenem or other agent with the lowest MIC, even if technically "resistant" 1
• For CRPA infections, combination with carbapenem showed superior outcomes (SUCRA 83.6) compared to colistin monotherapy (SUCRA 18.8) 1

Exception for lower UTI: Monotherapy may be acceptable for uncomplicated lower UTI when the organism has low MIC (≤0.5 mg/L) and the patient is not critically ill. 5

Duration of Therapy

Duration depends on infection severity:

• Simple cystitis: 7-10 days (consider shorter courses with low MIC organisms) 5
• Complicated UTI/pyelonephritis: 10-14 days 1
• Mean duration in clinical studies: 9.1 ± 4.8 days 6

Shorten duration when possible - total cumulative dose is directly associated with nephrotoxicity risk. 7

Mandatory Monitoring for Nephrotoxicity

Nephrotoxicity is the primary concern with colistin, occurring in 29-44% of patients. 1, 2, 7, 5

Monitoring Protocol:

• Measure serum creatinine 2-3 times per week during therapy 1, 2
• Monitor blood urea nitrogen 8
• Check electrolytes, particularly magnesium (hypomagnesemia is common) 4
• Baseline renal function before starting therapy 1

Risk Factors That Increase Nephrotoxicity:

• Shock states 7
• Hypoalbuminemia 7
• Concomitant nephrotoxic drugs (especially aminoglycosides - avoid combination unless absolutely necessary) 4, 7
• Chronic kidney disease 1
• Elderly patients 6
• Higher cumulative doses 7

Expected Nephrotoxicity Pattern:

• Median creatinine increase of 0.25 mg/dL during treatment 8
• Usually reversible - creatinine returns near baseline after stopping therapy 8
• Acute kidney injury during treatment predicts clinical failure and increased mortality 1, 2

Neurotoxicity Monitoring

Neurotoxicity is less common than nephrotoxicity but must be monitored. 7

• Watch for apnea or neuromuscular blockade (rare with modern dosing) 4, 8
• No apnea was observed in patients receiving prolonged treatment (>4 weeks) in recent studies 8
• Neurotoxicity does not appear to be a major issue with current dosing regimens 7

Critical Pitfalls to Avoid

1. Do not skip the loading dose - this is the most common error leading to treatment failure 2, 4
2. Do not reduce the loading dose for renal impairment - only adjust maintenance doses 2, 4, 3
3. Do not use colistin as first-line when alternatives exist - newer agents have superior efficacy and safety 1
4. Do not underdose to avoid nephrotoxicity - subtherapeutic levels cause treatment failure while still carrying nephrotoxic risk 2
5. Do not combine with aminoglycosides unless absolutely necessary - dramatically increases nephrotoxicity 4
6. Do not use monotherapy for severe/complicated UTI - combination therapy improves outcomes 1

Quality of Life and Mortality Considerations

Acute kidney injury during colistin treatment is a major predictor of clinical failure and mortality. 1, 2 The 2.4-fold increased nephrotoxicity risk compared to beta-lactams must be weighed against the mortality risk of untreated multidrug-resistant infections. 2

When treating elderly patients or those with chronic kidney disease, the risk-benefit calculation shifts further toward using newer alternatives (ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam) that have dramatically lower nephrotoxicity rates. 1