How to manage colistin (polymyxin E) resistance due to high activity of efflux pumps in a patient with impaired renal function and potential for nephrotoxicity and neurotoxicity?

From the Guidelines

To manage colistin resistance due to high activity of efflux pumps in a patient with impaired renal function, it is crucial to adjust colistin dosing based on creatinine clearance and consider therapeutic drug monitoring to minimize toxicity while maintaining efficacy. When dealing with impaired renal function, the dose of colistin should be carefully adjusted to avoid nephrotoxicity and neurotoxicity, as these are significant concerns with colistin use, especially in patients with compromised renal function 1.

Key Considerations

• Monitoring renal function is essential during polymyxin treatment, and therapeutic drug monitoring (TDM) should be performed where possible to ensure that plasma concentrations are within a safe and effective range 1.
• The use of ototoxic and nephrotoxic drugs, including other antimicrobial agents, should be avoided in combination with polymyxin to minimize the risk of adverse effects 1.
• Combination therapy with other antibiotics, such as carbapenems, may be considered to allow for lower doses of colistin while maintaining efficacy against infections caused by carbapenem-resistant gram-negative bacilli (CRGNB) 1.

Dosing Considerations

• The dose unit of polymyxin is expressed in different ways, requiring careful attention to the correct conversion of dosage to avoid errors 1.
• For patients with impaired renal function, the dosing of colistin should be adjusted based on creatinine clearance, and alternative administration routes such as nebulized colistin may be considered for respiratory infections to minimize systemic exposure.

Management Approach

• Using reduced doses of colistin in combination with efflux pump inhibitors (EPIs) and closely monitoring renal function and signs of neurotoxicity is a balanced approach to managing colistin resistance due to efflux pump overactivity in patients with impaired renal function. This approach aims to minimize toxicity while maintaining the efficacy of colistin against resistant gram-negative infections 1.

Additional Recommendations

• Ensure adequate hydration and avoid concurrent nephrotoxic agents when possible to further reduce the risk of nephrotoxicity.
• Consider the use of polymyxin B as an alternative to colistin, as it may be associated with fewer side effects, especially in patients undergoing continuous renal replacement therapy 1.

From the FDA Drug Label

The daily dose and frequency should be reduced for the patients with renal impairment Suggested modifications of dosage schedule for patients with renal impairment are presented in Table 1. Note: The suggested total daily dose is calculated from colistin base activity. In the presence of impaired renal function, reduce the infusion rate depending on the degree of renal impairment.

The management of colistin resistance due to high activity of efflux pumps in a patient with impaired renal function requires caution and dose adjustment.

• The patient's renal function should be closely monitored, and the dose of colistin should be reduced according to the suggested modifications in Table 1 2.
• The infusion rate should also be reduced depending on the degree of renal impairment.
• It is essential to balance the need to manage the infection with the potential risks of nephrotoxicity and neurotoxicity associated with colistin use.
• However, the provided drug label does not directly address the management of colistin resistance due to high activity of efflux pumps.

From the Research

Managing Colistin Resistance due to High Activity of Efflux Pumps

• Colistin resistance is a significant concern in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae (CRE) 3.
• Efflux pumps play a crucial role in colistin resistance, and the use of efflux pump inhibitors (EPIs) can help restore colistin sensitivity 4, 5.
• Studies have shown that EPIs such as CCCP, NMP, and PAβN can reverse colistin resistance in various bacterial strains, including those with mcr-1 plasmid-mediated colistin resistance 4, 5.
• The combination of colistin with EPIs such as BC1 and salicylate has been shown to be effective in restoring colistin sensitivity in colistin-resistant E. coli strains 3.

Considerations for Patients with Impaired Renal Function

• Colistin can be nephrotoxic, and patients with impaired renal function require careful monitoring and dose adjustment to minimize the risk of nephrotoxicity 6.
• The use of EPIs in combination with colistin may help reduce the required dose of colistin, potentially minimizing the risk of nephrotoxicity 4, 5.
• Alternative treatment options, such as the combination of aztreonam, ceftazidime/avibactam, and colistin, may be considered for patients with carbapenemase-producing Klebsiella pneumoniae infections 6.

Potential for Neurotoxicity

• Colistin can also be neurotoxic, and patients require careful monitoring for signs of neurotoxicity, such as neuropathy or seizures 6.
• The use of EPIs in combination with colistin may help reduce the required dose of colistin, potentially minimizing the risk of neurotoxicity 4, 5.
• Further studies are needed to fully understand the potential benefits and risks of using EPIs in combination with colistin to manage colistin-resistant infections 5, 7.