Colistin: Uses, Administration, Toxicity, Mechanism of Action, Adverse Effects and Interactions

It is a polymyxin antibiotic produced by certain strains of the Paenibacillus polymyxa var colistinus bacteria.

Colistin (also known as polymyxin E) has been marketed as its inactive prodrug colistin methanesulfonate (CMS) for fifty years.

Uses of colistin

Colistin is an effective polypeptide against gram-negative organisms.

Management

It is sometimes used orally for intestinal decontamination , by inhalation through a saline nebulizer in cystic fibrosis patients who are infected with Pseudomonas aeruginosa, and applied to the skin, including external ear infections.

Colistin was one of the first antibiotics with significant activity against gram-negative bacteria, especially Pseudomonas aeruginosa.

It has a rapid, concentration-dependent bactericidal activity.

CMS was largely replaced by aminoglycosides in the 1970s due to concerns about nephrotoxicity and neurotoxicity.

However, in the last 10 to 15 years, CMS / colistin has been a limited option and has been used as a ‘rescue’ therapy for infections caused by multiresistant Gram-negative bacteria (MDR), in particular:

  • P. aeruginosa.
  • Acinetobacter baumannii.
  • Klebsiella pneumoniae.

The lack of alternative antibiotics has been compounded by the development of dry antimicrobial drugs.

Having entered clinical use in 1959, CMS / colistin was never subjected to drug development procedures that are now mandated by international drug regulatory agencies, such as the Food and Drug Administration.

As a result, there is a paucity of pharmacological information reporting rational use, which aims to maximize antibacterial activity while minimizing toxicity and development of resistance.

There are no scientifically based dosing regimens for various categories of patients, particularly people with cystic fibrosis (CF) and subsets of critically ill patients (eg, with different levels of kidney function, including those on therapy renal replacement).

Although rates of resistance to colistin have been relatively low, probably due to its infrequent use, there have recently been several outbreaks of infections caused by colistin-resistant bacteria.

Toxicity

Colistin has significant toxicity, mainly renal and neurological.

Renal side effects include decreased urine output with increased blood urea nitrogen and serum creatinine, proteinuria, hematuria, and acute tubular necrosis.

Because colistin is eliminated by renal excretion, it is imperative to closely monitor renal function during therapy, decreasing the dose if any degree of renal failure is observed.

Drug accumulation and additional kidney toxicity occur if the dose is not altered when kidney failure first occurs.

Kidney toxicity is generally reversible if caught early. Neuromuscular side effects have been observed in adults and children treated with colistin.

Mechanism of action of colistin

Colsitin alters the phospholipids in the membrane of bacterial cells.

Pharmacodynamics

Peak: MIC and AUC: MIC ration correlates better with efficacy.

Pharmacokinetics

Dosis de 150 mg

Cmax: 18mg //L; Tmax: 2 hours; Average life: 2-3 hours

Adverse effects of colistin

  • Kidneys: nephrotoxicity.
  • Skin : pruritis, dermatosis.
  • GI : gastrointestinal disorder.
  • Hematologic : leukopenia, granulocytopenia.
  • Others: neurotoxicity.

Dosage

  • Dosage in adults: 2.5-5mg / kg / day divided q6-12h.
  • Dosage in pediatrics: 2.5-5mg / kg / day divided q6-12h.

Dosage based on disease status:

  • Renal failure: CrCl> 50 ml / min: standard dosage
  • CrCl 10-50 ml / min: 50% of the normal dose.
  • CrCl <10 ml / min: 25% de la dosis normal.
  • Hepatic failure : dose changes are not recommended at this time.

Dosage during continuous renal replacement therapy:

  • CVVH (continuous venous hemofiltration): 2.5 mg / kg IV q48h.
  • CVVHD (continuous venovenous hemodialysis): 2.5 mg / kg IV q48h.
  • CVVHDF (hemodiafiltración venovenosa continua): 2,5 mg / kg IV q48h.

A recent pharmacokinetic study suggests that conventional dosing recommendations in CVVHD and CVVHDF are not appropriate for critically ill patients and doses higher than 2-3 mg / kg IV q12h may be more appropriate. (Li J, et al. Antimicrob Agents Chemother 2005; 49: 4814-4815).

Note: CVVH is primarily for fluid removal. Many institutions will employ more CVVHD or CVVHDF that combine dialysis with fluid removal.

Contraindications / Warnings / Precautions

Precautions : kidney failure.

Drug interactions

Non-depolarizing neuromuscular blockers: can lead to additive neuromuscular blockade.

The pregnancy

This drug is in category C: Unknown risk. Inadequate human studies.

Monitoring requirements

Therapeutic : culture and sensitivities, serum levels, signs and symptoms of infection, white blood cell count.