In Tables 1 and 2 we summarize the available publications reporting data regarding the incidence of toxicity, including nephrotoxicity, neurotoxicity, and other adverse effects of polymyxins. Specifically, Tables 1 and 2 refer to old (from 1962 to 1977) and recent (from 1995 to 2005) articles, respectively, reporting adverse effects of polymyxins in patients without cystic fibrosis.
Although most of the studies or case reports published until 1983 did not include the definitions of nephrotoxicity, early reported experience with the use of polymyxins, mainly of colistin, revealed a high incidence of nephrotoxicity. The majority of the studies in the older literature referred to intramuscular administration of colistimethate sodium [4, 19–25]. Notably, the incidence of nephrotoxicity was 36% in a study of patients with pre-existing acute or chronic renal disease and 20.2% in another large study of 288 patients [4, 25]. Additionally, in three studies [26–28], intravenous colistimethate sodium was given for the treatment of patients with Gram-negative bacterial infections, including urinary tract infections, pneumonia, and septicaemia. These studies included 48, 23, and 8 patients, respectively; 10.5% of patients had prolonged increase of blood urea nitrogen levels (average increase of 50 mg/dl) , 26.1% of patients experienced renal impairment during therapy , and 50% had a fall in creatinine clearance (with a range of 16.5 to 38 ml/min) and an increase in serum creatinine levels (with a range of 0.2 to 2 mg/dl) . Another interesting finding was the relatively high number of case reports that were published in the old literature reporting patients who experienced acute renal failure during treatment with colistimethate sodium. A point that deserves to be stressed, however, is that in most of these cases the total daily dose of colistimethate sodium was considerably higher compared to the currently recommended dose [3, 29–34].
During the past seven years, colistimethate sodium has been re-introduced to clinical practice for the treatment of multidrug-resistant bacterial infections, mainly in the intensive care unit setting [9, 10, 12]. Data from recent studies do not corroborate the previously reported high incidence of polymyxin induced nephrotoxicity [11, 35]. Although, the definition of nephrotoxicity was not standardized between the studies, two of them, which were conducted exclusively in intensive care units and used colistimethate sodium, reported that the observed nephrotoxicity was 14%  and 18.6% . Notably, in one study that compared two therapeutic approaches – intravenous colistimethate sodium versus intravenous imipenem/cilastatin for the management of patients with ventilator-associated pneumonia due to Acinetobacter baumannii, nephrotoxicity occurred in 24% and 42% of patients, respectively . Of note, polymyxin B was reported in the old literature to be associated with a relatively increased incidence of toxicity compared to colistimethate sodium. However, these data were not verified in two recent studies that showed that the incidence of nephrotoxicity was 14%  and 10%  among patients receiving polymyxin B therapy. Our experience is similar to that of the investigators of the previous studies [35, 38].
It has been suggested that the toxicity of polymyxins may be partly due to their D-amino acid content and fatty acid component. The proposed mechanism by which polymyxin B induces nephrotoxic events is by increasing membrane permeability, resulting in an increased influx of cations, anions, and water, leading to cell swelling and lysis [39, 40]. An experimental study showed that colistin increased the transepithelial conductance of the urinary bladder epithelium . The magnitude of the conductance's increase was dependent on concentration and length of exposure to polymyxins as well as the divalent cation concentration. The basic molecular mechanisms by which polymyxin B increases the transepithelial conductance in the urinary tract has been proposed to be the same as that of colistin . Renal toxicity associated with the use of polymyxins is considered to be dose-dependent.
Renal insufficiency, manifested by an increase in serum creatinine levels and decrease in creatinine clearance, represents a major adverse effect of the use of polymyxins. Occurrence of haematuria, proteinuria, cylindruria, or oliguria may also be associated with the administration of polymyxins. In addition, acute tubular necrosis can also develop . Histological findings of colistin-induced renal damage usually involve focal irregular dilatation of tubules, epithelial and polymorphonuclear cell cast formation, and degeneration and regeneration of epithelial cells. In addition, separation of tubules by loose collagenous tissue, suggestive of edema, has also been reported. The basement membrane is usually intact, as well as the glomeruli [19, 42].
Nephrotoxicity resulting from the use of colistimethate sodium appears to be less compared with that associated with polymyxin B. It is unclear whether there are independent factors that predispose patients to the development of nephrotoxic events. Children seem to experience less polymyxin-induced toxicity, probably in part because prescription of polymyxins, and generally all medications, is based on individual body weight in this patient population . Concomitant administration of potential nephrotoxic agents, such as diuretics and some antimicrobial agents, increases the likelihood of development of renal adverse effects [4, 43].
When primary signs of renal dysfunction are present, early discontinuation of polymyxins is necessary. Quick diuresis by intravenously administered mannitol has also been proposed to enhance renal clearance of the drug and thus to reduce serum drug levels . Meticulous supportive care, including close monitoring of fluid intake and output, frequent determinations of electrolytes, and appropriate management to maintain balance of fluids and electrolytes, is required when renal adverse effects of polymyxin use are detected. The influence of hemodialysis and peritoneal dialysis in decreasing serum levels of polymyxins has not been clarified. Old reports suggested that the amount of drug that is removed from blood by these two methods is relatively small [44, 45]. Patients that underwent peritoneal dialysis lost approximately 1 mg of colistimethate sodium per hour . Thus, in cases of polymyxin-induced renal failure, both therapeutic approaches have been used, not to decrease serum drug levels but in order to manage renal complications. Exchange transfusions have been proposed as an effective method for the removal of polymyxins .
The incidence of neurotoxicity related to the use of polymyxins reported in the old literature was considerably less compared to nephrotoxicity. Specifically, the most frequently experienced neurological adverse effects were paresthesias that occurred in approximately 27% and 7.3% of patients receiving intravenous and intramuscular colistimethate sodium, respectively [4, 26]. Furthermore, at least eight cases were published between 1964 and 1973 correlating the intramuscular administration of polymyxins with the development of episodes of respiratory apnea [22, 33, 46–51]. However, recently performed studies in patients without cystic fibrosis are not in accordance with the previously reported data regarding the incidence of polymyxin-induced neurotoxicity [11, 12, 38]. No episodes of neuromuscular blockade or apnea induced by polymyxins have been reported in the literature over the past 15 years or more.
The interaction of polymyxins with neurons, which have a high lipid content, has been associated with the occurrence of several neurotoxic events. In addition, the probability of development of neurotoxicity has been directly associated with the concentration of the active form of polymyxins in the blood . Neuromuscular blockade induced by polymyxins has been attributed to a presenaptic action of polymyxins that interferes with the receptor site and blocks the release of acetylcholine to the synaptic gap [33, 52]. Other investigators have suggested a biphasic mechanism to explain this neurotoxic event; a short phase of competitive blockade between acetylcholine and polymyxins is followed by a prolonged phase of depolarization associated with calcium depletion [51, 53, 54]. Neurotoxicity resulting from the use of polymyxins is also considered to be dose-dependent.
The reported neurological toxicity is associated with dizziness, generalized or not muscle weakness, 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 respiratory failure or apnea due to respiratory muscle paralysis . Paresthesias appear to be usually benign, and their mechanism seems to be unrelated to the interference with nerve transmission. An old study that assessed the safety of intramuscularly administered colistimethate sodium during 317 courses revealed that neurological adverse effects were manifested during the first four days of therapy in 83% of the patients who experienced neurotoxic events .
Risk factors that may potentially trigger the development of neurotoxicity include hypoxia and the co-administration of polymyxins with muscle-relaxants, narcotics, sedatives, anesthetic drugs, or corticosteroids [22, 55]. A patient's gender may influence the likelihood of development of adverse effects. Specifically, neurotoxicity seems to be more common in women, although nephrotoxicity seems to be gender-independent . Patients with impaired renal function or myasthenia gravis are at higher risk of developing neuromuscular blockade and respiratory paralysis .
Mild neurological manifestations of polymyxins usually subside after prompt cessation of the drugs. In the presence of neuromuscular blockade, immediate discontinuation of polymyxins and other neurotoxic agents is also the first-line approach. Further management consists of mechanical respiratory support if apnea has been developed. The intravenous administration of calcium and cholinesterase inhibitors, such as neostigmine and edrophonium, has led to conflicting results [33, 48]. Hemodialysis is indicated only in patients with co-existing acute renal failure.
Other adverse events
In studies published in the old literature, the reported incidence of allergic reactions related to colistimethate sodium use was approximately 2% . Mild itching that did not require discontinuation of the drug was reported by approximately 22% of the patients receiving colistimethate sodium intravenously . In addition, a few patients with episodes of rash were also reported [20, 56]. In the recent literature, a few patients with episodes of contact dermatitis (eczema and erythematous eruption) have been reported in connection with topical use of colistin sulfate and ophthalmic administration of colistimethate sodium [57, 58].
Several milder adverse reactions, including pruritus, dermatitis, and drug fever, probably represent the result of the irritative effects of the active forms of polymyxins  and their histamine-releasing action, especially polymyxin B.
Pruritus, contact dermatitis, macular rash or urticaria, ototoxicity, drug fever, and gastrointestinal disturbances may develop, although rarely, during treatment with polymyxins [26, 57, 59]. After intramuscular administration, pain may occur at the injection site . Moreover, the development of pseudomembranous colitis represents a rare side effect of polymyxins. Intraventricular or intrathecal administration of polymyxins, especially in high doses, may lead to convulsions and signs of meningismus. During repeated ophthalmic application of polymyxin, low-grade conjunctivitis may develop .
An old case report suggested that the administration of colistimethate sodium intramuscularly in a patient with Gram-negative rod bacteremia was possibly associated with hepatotoxicity because an observed rise in serum glutamic oxaloacetic transaminase levels returned to normal after the drug was discontinued; in addition, post-mortem histological examination of the liver revealed non-specific changes (focal vacuolization of hepatic cells in the centrilobular fields with areas of focal necrosis), which were interpreted as drug-induced toxicity . However, no other cases of liver toxicity have been reported in experimental or clinical studies on the use of polymyxins [38, 60].
Patients with known allergy to bacitracin are also at higher risk of developing hypersensitivity reactions with the use of polymyxins, as cross-reaction between bacitracin and polymyxins exists .
In most instances, withdrawal of polymyxins in combination with appropriate supportive treatment is adequate for the treatment of such adverse effects.
Adverse events related to aerosolised colistin
Treatment with aerosolized colistin may be complicated by sore throat, cough, bronchoconstriction, and chest tightness. The nature of bronchoconstriction that develops during nebulization of polymyxins has been proposed to be associated with several mechanisms. Among them are direct chemical stimulation, the liberation of histamine, allergy in the airway, irritation from chemicals or from the foam that is produced during nebulization, and hyperosmolarity in the airway . Nebulized polymyxins can cause bronchoconstriction even in patients with no history of asthma or atopy, although if these conditions exist the risk is greater . Bronchoconstriction usually requires discontinuation of the medication, the administration of bronchodilators and supplemental oxygen.
Prevention of adverse events
Early and correct adjustment of the dose of polymyxins in the presence of impaired renal function, frequent urinalyses and serum urea or creatinine measurements, close daily monitoring of urinary output and of neurological status, and the avoidance of concurrent administration of other agents with known nephrotoxicity or neurotoxicity may help prevent the development of adverse effects. Bronchoconstriction usually responds to treatment with bronchodilators; thus, pre-treatment of patients receiving inhaled colistimethate sodium with these medications could prevent the occurrence of this adverse event .
Recommendations regarding the dosage of polymyxins differ between various manufacturers. Colistin manufactured in the United States contains colistimethate sodium equivalent to 150 mg colistin base activity in each vial. The recommended dosage is 2.5 to 5 mg/kg per day, divided into 2 to 4 equal doses in adult patients with normal kidney function . Manufacturers in the United Kingdom recommend a dosage of 4 to 6 mg/kg (50,000 to 75,000 IU/kg) intravenous colistimethate sodium per day, in 3 divided doses for adults and children with body-weight ≤ 60 kg, and 80 to 160 mg (1 to 2 million IU) every 8 hours for body-weight >60 kg .
The recommended dosage for intravenous polymyxin B sulphate is 1.5 mg to 2.5 mg/kg/day (15,000 IU to 25,000 IU/kg/day), divided into 2 equal doses for adults and children older than 2 years with normal renal function; 1 mg of polymyxin B is equal to 10,000 IU. Infants with normal renal function may receive up to 4 mg/kg/day (40,000 IU/kg/day) in cases of life-threatening infections .
Overdoses with polymyxins, mainly with colistimethate sodium, have been reported several times in the old literature. Although, one case of a three year old child who received intramuscularly 450 mg (approximately 5.5 million IU) of colistimethate sodium reported no adverse effects, the majority of cases with polymyxin overdose resulted in acute renal failure and various manifestations of neurotoxicity, including neuromuscular blockade and apnea [3, 31, 33, 34]. It should be emphasized that cases of polymyxin overdose with fatal consequences are scarce . There is no antidote for polymyxin overdose. Management requires early cessation of the medication and appropriate supportive treatment. In the presence of established acute renal failure, haemodialysis and peritoneal dialysis can only manage renal complications, since they have little influence on the elimination of polymyxins, as discussed above. If apnea occurs, mechanical ventilation support is needed.
The concurrent use of polymyxins with curariform muscle relaxants and other neurotoxic drugs such as ether, tubocurarine, succinylcholine, gallamine, decamethonium, and sodium citrate must be avoided, since these agents may trigger the development of neuromuscular blockade . Co-administration of sodium cephalothin and polymyxins may enhance the development of neurotoxicity, so this combination of antimicrobial medication should also be avoided . In addition, antimicrobial agents with known neurotoxic effect, such as aminoglycosides, should generally be avoided or given with great caution in patients who receive polymyxins. In such instances, close monitoring of the patients receiving these antibiotics is mandatory. Experimental studies showed that application of polymyxins in combination with glutamic acid to a peripheral nerve could cause transgaglionic degenerative atrophy .