indication

For the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli, particularly Pseudomonas aeruginosa.

pharmacology

Colistimethate is a polymyxin antibiotic agent. Originally, colistimethate sodium was thought to be less toxic than polymyxin B; however, if the drugs are administered at comparable doses, their toxicities may be similar. Polymyxins are cationic polypeptides that disrupt the bacterial cell membrane through a detergentlike mechanism. With the development of less toxic agents, such as extended-spectrum penicillins and cephalosporins, parenteral polymyxin use was largely abandoned, except for the treatment of multidrug-resistant pulmonary infections in patients with cystic fibrosis. More recently, however, the emergence of multidrug-resistant gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, and the lack of new antimicrobial agents have led to the revived use of the polymyxins.

mechanism of action

Colistimethate is a surface active agent which penetrates into and disrupts the bacterial cell membrane. Colistimethate is polycationic and has both hydrophobic and lipophilic moieties. It interacts with the bacterial cytoplasmic membrane, changing its permeability. This effect is bactericidal. There is also evidence that polymyxins enter the cell and precipitate cytoplasmic components, primarily ribosomes.

toxicity

Oral LD₅₀ in rats is 5450 mg/kg. Overdosage with colistimethate can cause neuromuscular blockade characterized by paresthesia, lethargy, confusion, dizziness, ataxia, nystagmus, disorders of speech and apnea. Respiratory muscle paralysis may lead to apnea, respiratory arrest and death.

biotransformation

As 80% of the dose can be recovered unchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug is inactivated in the tissues, however the mechanism is unknown.

absorption

Very poor absorption from gastrointestinal tract.

half life

2-3 hours following either intravenous or intramuscular administration in adults and in the pediatric population, including premature infants.

drug interactions

Amikacin: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Due to the potential for additive or synergistic toxicities (including both nephrotoxicity and neuromuscular blockade) between colistimethate and the aminoglycoside antibiotics, this combination should be avoided whenever possible. If these agents must be used together, patients' renal and neuromuscular function should be monitored closely.

Amphotericin B: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Due to the potential for additive or synergistic nephrotoxicity between colistimethate and other nephrotoxic drugs, such as amphotericin B, this combination should be avoided whenever possible. If these agents must be used together, patients' renal function should be monitored closely.

Atracurium: Colistimethate may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. If possible, avoid concomitant use of these products. Monitor for deeper, prolonged neuromuscular-blocking effects (respiratory paralysis) in patients receiving concomitant neuromuscular-blocking agents and polymyxin antibiotics (e.g., colistimethate, polymyxin B).

Cisatracurium Besylate: Colistimethate may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. If possible, avoid concomitant use of these products. Monitor for deeper, prolonged neuromuscular-blocking effects (respiratory paralysis) in patients receiving concomitant neuromuscular-blocking agents and polymyxin antibiotics (e.g., colistimethate, polymyxin B).

Gentamicin: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Due to the potential for additive or synergistic toxicities (including both nephrotoxicity and neuromuscular blockade) between colistimethate and the aminoglycoside antibiotics, this combination should be avoided whenever possible. If these agents must be used together, patients' renal and neuromuscular function should be monitored closely.

Kanamycin: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Due to the potential for additive or synergistic toxicities (including both nephrotoxicity and neuromuscular blockade) between colistimethate and the aminoglycoside antibiotics, this combination should be avoided whenever possible. If these agents must be used together, patients' renal and neuromuscular function should be monitored closely.

Neomycin: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Due to the potential for additive or synergistic toxicities (including both nephrotoxicity and neuromuscular blockade) between colistimethate and the aminoglycoside antibiotics, this combination should be avoided whenever possible. If these agents must be used together, patients' renal and neuromuscular function should be monitored closely.

Pancuronium: Colistimethate may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. If possible, avoid concomitant use of these products. Monitor for deeper, prolonged neuromuscular-blocking effects (respiratory paralysis) in patients receiving concomitant neuromuscular-blocking agents and polymyxin antibiotics (e.g., colistimethate, polymyxin B).

Rocuronium: Colistimethate may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. If possible, avoid concomitant use of these products. Monitor for deeper, prolonged neuromuscular-blocking effects (respiratory paralysis) in patients receiving concomitant neuromuscular-blocking agents and polymyxin antibiotics (e.g., colistimethate, polymyxin B).

Streptomycin: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Due to the potential for additive or synergistic toxicities (including both nephrotoxicity and neuromuscular blockade) between colistimethate and the aminoglycoside antibiotics, this combination should be avoided whenever possible. If these agents must be used together, patients' renal and neuromuscular function should be monitored closely.

Tobramycin: Increased risk of nephrotoxicity

Vancomycin: Additive nephrotoxic effects may occur. Consider alternate therapy or monitor for renal function during concomitant therapy.

Vecuronium: Colistimethate may increase the neuromuscular blocking action of Vecuronium. Risk of respiratory depression and apnea. Consider alternate therapy or monitor for prolonged neuromuscular blocking effects, such as respiratory paralysis.