Polymyxins

General adverse effects and adverse reactions

Even in patients with normal renal function, adverse reactions have occurred in up to 25%, contributing to death in 5% [ ]. At therapeutically equivalent doses, suggestions of differences in nephrotoxicity or neurotoxicity between polymyxin B and colistin are not convincing. In view of their potential for adverse effects, the polymyxins have now been largely replaced by other antibacterial drugs.

Observational studies

In a randomized study of the effects of a triple antibiotic ointment (polymyxin B + bacitracin + neomycin) and simple gauze-type dressings on scarring of dermabrasion wounds, the ointment was superior to the simple dressing in minimizing scarring; the beneficial effect on pigmentary changes was especially pronounced [ ].

Cardiovascular

Transient hypotension occurred in a 62-year-old man after simultaneous administration of intravenous colistin 2 million IU and aerosolized colistin 2 million IU for the management of multidrug-resistant Pseudomonas aeruginosa [ ]. Two possible explanations were considered. First, colistin is a relatively potent stimulator of degranulation of rat mast cells, and histamine released from mast cells reduces blood pressure. Secondly, colistin stimulates the activity of pseudomonal elastase, which might play a role in causing hypotension.

Respiratory

The polymyxins are bronchial irritants, probably by histamine release [ ]. Treatment with aerosolized colistin can be complicated by bronchoconstriction and chest tightness [ ]. This reaction can be very rapid, but treatment with aerosolized beta ₂ -adrenoceptor agonists before starting treatment with aerosolized colistin can prevent it [ ].

In 58 children with bronchoconstriction in response to nebulized colistin, FEV ₁ was significantly reduced for 15 minutes [ ]. In 20 children the reduction was greater than 10% from baseline FEV ₁ and was still at that level in five children after 30 minutes. Subjective assessment, baseline FEV ₁ , and serum IgE did not distinguish susceptible children.

In 62 children with cystic fibrosis there was increased dyspnea in seven and pharyngitis in three in response to nebulized colistimethate (80 mg dissolved in 3 ml of preservative-free isotonic saline, by inhalation twice daily for 4 weeks) [ ].

Nine patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa participated in a double-blind, randomized, crossover comparison of nebulized colistin sulfate or colistin sulfomethate [ ]. Nebulized colistin sulfate caused a significantly larger mean reduction in lung function than nebulized colistin sulfomethate. In three patients, there was a reduction in FEV ₁ of 10% or more. Seven patients were not able to complete the course of nebulized colistin sulfate because of throat irritation and severe cough.

Colistin caused bronchospasm in 20 patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa in a placebo-controlled clinical trial with a crossover design testing colistin 75 mg in 4 ml of saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration [ ]. However, treatment with inhaled beta ₂ -adrenoceptor agonists before the start of treatment can prevent bronchoconstriction [ ].

Nervous system

During treatment with any of the polymyxins, neurotoxicity can occur in up to 7% of patients with normal renal function. Circumoral paresthesia, vasomotor instability, ataxia, dizziness, convulsions of varying severity, and apnea have been reported. Of 31 patients with cystic fibrosis 21 had one or more adverse effects attributed to colistin [ ]. The most common reactions involved reversible neurological effects, including oral and perioral paresthesia (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these effects, although bothersome, were benign and reversible. There was no relation between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetics.

Paresthesia occurs in about 27% and 7.3% of patients receiving intravenous and intramuscular colistimethate sodium respectively. This is associated with dizziness, muscle weakness, which can be generalized, facial and peripheral paresthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and neuromuscular blockade. The last of these usually produces a myasthenia-like clinical syndrome, as well as apnea due to respiratory muscle paralysis [ ].

Meningeal irritation rarely occurs in daily doses of 50 000 units (5 mg) given intrathecally, but higher doses can cause a stiff neck with CSF pleocytosis [ ] and sometimes convulsions [ ].

Neuromuscular function

In animals the polymyxins can cause neuromuscular blockade similar to that observed with the aminoglycosides, aggravated by curare, ether, and suxamethonium, and antagonized by calcium. Neuromuscular blockade induced by polymyxins has been attributed to a presynaptic action, through blockade of the release of acetylcholine into the synaptic gap [ ]. This can be noted first as fatiguability 1–26 hours after dosing, and can progress to severe muscular weakness, including respiratory paralysis [ ]. This complication has been reported both in neurologically normal subjects exposed to high plasma concentrations of the polymyxins, and also in some individuals with concentrations that were considered to be in the target range. Particularly at risk are patients with myasthenia gravis, who may require increased doses of neostigmine.

In patients with chronic pulmonary disease, polymyxin-induced neuromuscular block can result in fatal apnea. Finally, after anesthesia involving muscle relaxants the polymyxins can cause relapse of muscle weakness and inadequate ventilation [ ].

Effective treatment of polymyxin-induced neuromuscular blockade requires awareness of the complication, with appropriate supervision and immediate ventilatory support, if required. Calcium gluconate and neostigmine are not of proven efficacy and should not be relied on [ ].