Email updates

Keep up to date with the latest news and content from Critical Care and BioMed Central.

Open Access Highly Accessed Research

Toxicity of polymyxins: a systematic review of the evidence from old and recent studies

Matthew E Falagas123* and Sofia K Kasiakou1

Author Affiliations

1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece

2 Department of Medicine, 'Henry Dunant' Hospital, Athens, Greece

3 Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA

For all author emails, please log on.

Critical Care 2006, 10:R27  doi:10.1186/cc3995

The electronic version of this article is the complete one and can be found online at: http://ccforum.com/content/10/1/R27


Received:7 October 2005
Revisions received:13 January 2006
Accepted:18 January 2006
Published:13 February 2006

© 2006 Falagas and Kasiakou; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The increasing problem of multidrug-resistant Gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of Bacillus polymyxa in 1947; only two of them, polymyxin B and E (colistin), have been used in clinical practice. Their effectiveness in the treatment of infections due to susceptible Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been generally questioned. However, their use was abandoned, except in patients with cystic fibrosis, because of concerns related to toxicity.

Methods

We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005).

Results

It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature.

Conclusion

New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature.

Introduction

Polymyxins were discovered in 1947 from different species of Bacillus polymyxa [1,2]. Although the effectiveness of polymyxins against most Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been questioned, early administration of polymyxins was associated with reports of adverse renal and neurological effects in a considerably large number of patients [3,4]. Thus, compounds of this class of antibiotics were gradually withdrawn from clinical practice as newer antibiotics with the same or broader antibacterial spectra and reportedly lower toxicity were introduced, except for patients with cystic fibrosis who suffer from recurrent pulmonary infections due to multidrug-resistant bacteria [5-7]. However, the emergence of Gram-negative bacteria that are resistant to almost all classes of available antibiotics except polymyxins, especially Pseudomonas aeruginosa and Acinetobacter baumannii strains, and the shortage of new antibiotics with activity against them has led to the re-use of polymyxins [8-12]. The objective of this critical review of the old and recent literature is to elucidate the incidence, mechanisms, prevention, and treatment of adverse events of polymyxins, focusing on patients without cystic fibrosis.

This class of antibiotics consists of five chemically different compounds, polymyxin A, B, C, D, and E (colistin). Only polymyxins B and E have been used in clinical practice. Colistin consists of a cyclic heptapeptide and a tripeptide side-chain acylated at the amino terminus by a fatty acid. The amino acid components in the molecule of colistin are D-leucine, L-threonine, and L-α-γ-diaminobutyric acid. Polymyxin B has the same structure as colistin but contains D-phenylalanine instead of D-leucine [13].

Commercially, colistin appears as colistin sulfate, which is used orally for bowel decontamination and topically as a powder for skin infections, and as colistimethate sodium, which is used parenterally and by inhalation. Colistimethate sodium has been found to be less toxic and to have fewer undesirable side effects than colistin, but is also less potent. Polymyxin B is available for clinical use as polymyxin B sulfate and is used parenterally, topically (ophthalmic and otic instillation), intrathecally, by inhalation, and as an irrigation solution [14,15].

Several attempts to generate less toxic derivatives were made [16]. Most of these derivatives lacked the fatty acid and/or the diaminobutyric acid components of their original molecules. Experimental studies demonstrated that these compounds were much less toxic compared to the parent ones, but at the same time they had considerably reduced antibacterial effect [17,18].

Methods

Data for this review were obtained through literature searches of publications included in PubMed from 1950 until May 2005, references cited in relevant articles, and the world-wide web. The main search terms used in searches of literature databases were 'colistin', 'polymyxin E', 'polymyxin B', 'adverse effects', 'nephrotoxicity', 'colomycin', 'colimycin', 'neurotoxicity' and 'toxicity'. Only English language papers were reviewed.

Results and discussion

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.

Table 1. Old studies (from 1962 to 1977) reporting data on polymyxin-induced toxicity in patients without cystic fibrosis

Table 2. Recent studies (from 1995 to 2005) reporting data on polymyxin-induced toxicity in patients without cystic fibrosis

Nephrotoxicity

Incidence

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], 26.1% of patients experienced renal impairment during therapy [27], 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) [28]. 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% [11] and 18.6% [12]. 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 [9]. 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% [36] and 10% [37] among patients receiving polymyxin B therapy. Our experience is similar to that of the investigators of the previous studies [35,38].

Mechanisms

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 [41]. 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 [41]. Renal toxicity associated with the use of polymyxins is considered to be dose-dependent.

Clinical manifestations

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 [14]. 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].

Risk factors

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 [4]. Concomitant administration of potential nephrotoxic agents, such as diuretics and some antimicrobial agents, increases the likelihood of development of renal adverse effects [4,43].

Treatment

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 [32]. 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 [45]. 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 [3].

Neurotoxicity

Incidence

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.

Mechanisms

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 [14]. 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.

Clinical manifestations

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 [33]. 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 [4].

Risk factors

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 [4]. Patients with impaired renal function or myasthenia gravis are at higher risk of developing neuromuscular blockade and respiratory paralysis [47].

Treatment

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

Incidence

In studies published in the old literature, the reported incidence of allergic reactions related to colistimethate sodium use was approximately 2% [4]. Mild itching that did not require discontinuation of the drug was reported by approximately 22% of the patients receiving colistimethate sodium intravenously [27]. 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].

Mechanisms

Several milder adverse reactions, including pruritus, dermatitis, and drug fever, probably represent the result of the irritative effects of the active forms of polymyxins [14] and their histamine-releasing action, especially polymyxin B.

Clinical manifestations

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 [24]. 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 [14].

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 [19]. However, no other cases of liver toxicity have been reported in experimental or clinical studies on the use of polymyxins [38,60].

Risk factors

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 [58].

Treatment

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 [61]. Nebulized polymyxins can cause bronchoconstriction even in patients with no history of asthma or atopy, although if these conditions exist the risk is greater [61]. 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 [61].

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 [62]. 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 [63].

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 [64].

Overdoses

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 [29]. 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.

Drug interactions

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 [55]. Co-administration of sodium cephalothin and polymyxins may enhance the development of neurotoxicity, so this combination of antimicrobial medication should also be avoided [4]. 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 [65].

Conclusion

The data from the recent literature suggest that the incidence of toxicity resulting from the use of polymyxins is less frequent and severe compared to what has been previously reported. Possible explanations for the observed discrepancy include the fact that the available formulation of colistimethate sodium for intramuscular administration was used intravenously in the old studies until a new formulation was prepared. In addition, the intramuscular formulation also contained dibucaine hydrochloride, which could potentiate the neurotoxic effect of colistimethate sodium. It should be highlighted that the dosages of polymyxins used in most of the studies published in the old literature were considerably higher compared to the recommended dosages administered nowadays. In fact, several reported cases of polymyxin-induced toxicity were associated with overdose. Thus, this may account for the observed difference in the incidence of polymyxin-induced toxicity noted between the old and recently published studies. A major limitation in the interpretation of polymyxin-induced nephrotoxicity and neurotoxicity in the intensive care unit setting, however, is the frequent existence of multiple organ failure, septic shock, and mechanical ventilation support. These conditions may considerably influence the assessment of polymyxin-induced toxicity. Dosage adjustment of polymyxins in the presence of impaired renal function and prompt discontinuation of polymyxins after development of early signs of their toxicity were not always performed in a timely fashion. Furthermore, the already reported experience regarding the toxicity of polymyxins in the old literature has led to more correct use of these antibiotics by physicians nowadays. In addition, the avoidance of co-administration of potential nephrotoxic and/or neurotoxic agents with polymyxins, as well as the development of critical care supplies, may also explain the observed differences. In the coming years further research is needed to assess the safety profile of polymyxins, clarify several aspects of their toxicity, and investigate the benefits of different dosing regimens, including the administration of these antibiotics in fewer daily doses.

Key messages

• Polymyxins are valuable antibiotics for use in patients in the intensive care setting.

• Polymyxins have been recently re-introduced in clinical practice for the treatment of patients with multidrug-resistant Gram-negative bacterial infections.

• Nephrotoxicity and neurotoxicity represent the major adverse effects of polymyxins.

• Data from the recent literature suggest that the use of polymyxins is associated with lower and less severe toxicity compared to that reported in the old literature.

• Caution is needed when polymyxins are administered, particularly in patients with renal dysfunction.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MEF conceived the study idea. Both authors contributed to the reviewing of the articles and writing of the manuscript. Both authors approved the final manuscript. MEF had full access to all the data in the study and takes responsibility for the integrity of the review of the data.

References

  1. Storm DR, Rosenthal KS, Swanson PE: Polymyxin and related peptide antibiotics.

    Annu Rev Biochem 1977, 46:723-763. PubMed Abstract | Publisher Full Text OpenURL

  2. Koyama Y, Kurosasa A, Tsuchiya A, Takakuta K: A new antibiotic "colistin" produced by spore-forming soil bacteria.

    J Antibiot (Tokyo) 1950, 3:457-458. OpenURL

  3. Brown JM, Dorman DC, Roy LP: Acute renal failure due to overdosage of colistin.

    Med J Aust 1970, 2:923-924. PubMed Abstract OpenURL

  4. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE: Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy.

    Ann Intern Med 1970, 72:857-868. PubMed Abstract OpenURL

  5. Jensen T, Pedersen SS, Garne S, Heilmann C, Hoiby N, Koch C: Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection.

    J Antimicrob Chemother 1987, 19:831-838. PubMed Abstract OpenURL

  6. Conway SP, Pond MN, Watson A, Etherington C, Robey HL, Goldman MH: Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis.

    Thorax 1997, 52:987-993. PubMed Abstract OpenURL

  7. Frederiksen B, Koch C, Hoiby N: Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis.

    Pediatr Pulmonol 1997, 23:330-335. PubMed Abstract | Publisher Full Text OpenURL

  8. Levin AS, Barone AA, Penco J, Santos MV, Marinho IS, Arruda EA, Manrique EI, Costa SF: Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii.

    Clin Infect Dis 1999, 28:1008-1011. PubMed Abstract OpenURL

  9. Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, Barrero-Almodovar AE, Garcia-Garmendia JL, Bernabeu-WittelI M, Gallego-Lara SL, Madrazo-Osuna J: Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP.

    Clin Infect Dis 2003, 36:1111-1118. PubMed Abstract | Publisher Full Text OpenURL

  10. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D: Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa.

    Clin Infect Dis 2003, 37:E154-E160. PubMed Abstract | Publisher Full Text OpenURL

  11. Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, Gregorakos L: Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients.

    Crit Care 2003, 7:R78-R83. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  12. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME: Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic.

    Clin Microbiol Infect 2005, 11:115-121. PubMed Abstract | Publisher Full Text OpenURL

  13. Falagas ME, Kasiakou SK: Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.

    Clin Infect Dis 2005, 40:1333-1341. PubMed Abstract | Publisher Full Text OpenURL

  14. Hoeprich PD: The polymyxins.

    Med Clin North Am 1970, 54:1257-1265. PubMed Abstract OpenURL

  15. Reed MD, Stern RC, O'Riordan MA, Blumer JL: The pharmacokinetics of colistin in patients with cystic fibrosis.

    J Clin Pharmacol 2001, 41:645-654. PubMed Abstract | Publisher Full Text OpenURL

  16. Barnett M, Bushby SR, Wilkinson S: Sodium sulphomethyl derivatives of polymyxins.

    Br J Pharmacol Chemother 1964, 23:552-574. PubMed Abstract OpenURL

  17. Kurihara T, Takeda H, Ito H, Sato H, Shimizu M: Studies on the compounds related to colistin. IX. On the chemical deacylation of colistin and colistin derivatives.

    Yakugaku Zasshi 1974, 94:1491-1494. PubMed Abstract OpenURL

  18. Danner RL, Joiner KA, Rubin M, Patterson WH, Johnson N, Ayers KM, Parrillo JE: Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide.

    Antimicrob Agents Chemother 1989, 33:1428-1434. PubMed Abstract | PubMed Central Full Text OpenURL

  19. Katz R: Renal and possibly hepatic toxicity from coly-mycin. Report of a case.

    Med Ann Dist Columbia 1963, 32:408-413. PubMed Abstract OpenURL

  20. Pines A, Lydon TI, Plucinski K, Barkley H: Colimycin in chronic purulent respiratory disorders.

    Practitioner 1963, 190:502-504. PubMed Abstract OpenURL

  21. Lawson JS, Hewstone AS: Toxic effects on colistin methane sulphonate in the new-born.

    Med J Aust 1964, 14:917-919. PubMed Abstract OpenURL

  22. Perkins RL: Apnea with intramuscular colistin therapy.

    JAMA 1964, 190:421-424. PubMed Abstract OpenURL

  23. Gold GN, Richardson AP: Myasthenic reaction to colistimethate.

    JAMA 1965, 194:1151-1152. PubMed Abstract | Publisher Full Text OpenURL

  24. Rodger KC, Nixon M, Tonning HO: Treatment of infections with colistimethate sodium (coly-mycin).

    Can Med Assoc J 1965, 93:143-146. PubMed Abstract OpenURL

  25. Tallgren LG, Liewendahl K, Kuhlbaeck B: The therapeutic success and nephrotoxicity of colistin in acute and chronic nephropathies with impaired renal function.

    Acta Med Scand 1965, 177:717-728. PubMed Abstract OpenURL

  26. Fekety FR Jr, Norman PS, Cluff LE: The treatment of gram-negative bacillary infections with colistin. The toxicity and efficacy of large doses in forty-eight patients.

    Ann Intern Med 1962, 57:214-229. PubMed Abstract OpenURL

  27. Olesen S, Madsen PO: Intravenous administration of sodium colistimethate in urinary tract infections.

    Curr Ther Res Clin Exp 1967, 9:283-287. PubMed Abstract OpenURL

  28. Baines RD Jr, Rifkind D: Intravenous administration of sodium colistimethate.

    JAMA 1964, 190:278-281. PubMed Abstract OpenURL

  29. Ryan KJ, Schainuck LI, Hickman RO, Striker GE: Colistimethate toxicity. Report of a fatal case in a previously healthy child.

    JAMA 1969, 207:2099-2101. PubMed Abstract | Publisher Full Text OpenURL

  30. Price DJ, Graham DI: Effects of large doses of colistin sulphomethate sodium on renal function.

    Br Med J 1970, 4:525-527. PubMed Abstract OpenURL

  31. Rothner AD, Parker JJ: Overdosage of colistin.

    J Pediatr 1970, 77:515-516. PubMed Abstract OpenURL

  32. Tripathi VN, Stulberger EA, Takacs FJ: Colistimethate overdosage.

    J Urol 1970, 104:176-178. PubMed Abstract OpenURL

  33. Duncan DA: Colistin toxicity. Neuromuscular and renal manifestations. Two cases treated by hemodialysis.

    Minn Med 1973, 56:31-35. PubMed Abstract OpenURL

  34. Devlieger H, Casteels-Van Daele M, ki MB, Proesmans W: Acute renal failure due to colistin intoxication.

    Acta Paediatr Belg 1977, 30:179-181. PubMed Abstract OpenURL

  35. Kasiakou SK, Michalopoulos A, Soteriades ES, Samonis G, Sermaides GJ, Falagas ME: Combination therapy with intravenous colistin for the management of infections due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis.

    Antimicrob Agents Chemother 2005, 49:3136-46. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  36. Ouderkirk JP, Nord JA, Turett GS, Kislak JW: Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria.

    Antimicrob Agents Chemother 2003, 47:2659-2662. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  37. Sobieszczyk ME, Furuya EY, Hay CM, Pancholi P, Della-Latta P, Hammer SM, Kubin CJ: Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections.

    J Antimicrob Chemother 2004, 54:566-569. PubMed Abstract | Publisher Full Text OpenURL

  38. Falagas ME, Rizos M, Bliziotis IA, Rellos K, Kasiakou SK, Michalopoulos A: Toxicity after prolonged (more than four weeks) administration of intravenous colistin.

    BMC Infect Dis 2005, 5:1. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  39. Berg JR, Spilker CM, Lewis SA: Modulation of polymyxin B effects on mammalian urinary bladder.

    Am J Physiol 1998, 275:F204-F215. PubMed Abstract | Publisher Full Text OpenURL

  40. Berg JR, Spilker CM, Lewis SA: Effects of polymyxin B on mammalian urinary bladder.

    J Membr Biol 1996, 154:119-130. PubMed Abstract | Publisher Full Text OpenURL

  41. Lewis JR, Lewis SA: Colistin interactions with the mammalian urothelium.

    Am J Physiol Cell Physiol 2004, 286:C913-C922. PubMed Abstract | Publisher Full Text OpenURL

  42. Ito J, Johnson WW, Roy S III: Colistin nephrotoxicity: report of a case with light and electron microscopic studies.

    Acta Pathol Jpn 1969, 19:55-67. PubMed Abstract OpenURL

  43. Elwood CM, Lucas GD, Muehrcke RC: Acute renal failure associated with sodium colistimethate treatment.

    Arch Intern Med 1966, 118:326-334. PubMed Abstract | Publisher Full Text OpenURL

  44. Curtis JR, Eastwood JB: Colistin sulphomethate sodium administration in the presence of severe renal failure and during haemodialysis and peritoneal dialysis.

    Br Med J 1968, 1:484-485. PubMed Abstract OpenURL

  45. Goodwin NJ, Friedman EA: The effects of renal impairment, peritoneal dialysis, and hemodialysis on serum sodium colistimethate levels.

    Ann Intern Med 1968, 68:984-994. PubMed Abstract OpenURL

  46. Anthony MA, Louis DL: Apnea due to intramuscular colistin therapy. Report of a case.

    Ohio State Med J 1966, 62:336-338. PubMed Abstract OpenURL

  47. Decker DA, Fincham RW: Respiratory arrest in myasthenia gravis with colistimethate therapy.

    Arch Neurol 1971, 25:141-144. PubMed Abstract OpenURL

  48. Gold GN, Richardson AP Jr: An unusual case of neuromuscular blockade seen with therapeutic blood levels of colistin methanesulfonate (Coly-Mycin).

    Am J Med 1966, 41:316-321. PubMed Abstract | Publisher Full Text OpenURL

  49. Lindesmith LA, Baines RD Jr, Bigelow DB, Petty TL: Reversible respiratory paralysis associated with polymyxin therapy.

    Ann Intern Med 1968, 68:318-327. PubMed Abstract OpenURL

  50. Parisi AF, Kaplan MH: Apnea during treatment with sodium colistimethate.

    JAMA 1965, 194:298-299. PubMed Abstract | Publisher Full Text OpenURL

  51. Zauder HL, Barton N, Bennett EJ, Lore J: Colistimethate as a cause of postoperative apnoea.

    Can Anaesth Soc J 1966, 13:607-610. PubMed Abstract OpenURL

  52. McQuillen MP, Cantor HA, O'Rourke JR: Myasthenic syndrome associated with antibiotics.

    Trans Am Neurol Assoc 1967, 92:163-167. PubMed Abstract OpenURL

  53. Kubikowski P, Szreniawski Z: The mechanism of the neuromuscular blockade by antibiotics.

    Arch Int Pharmacodyn Ther 1963, 146:549-560. PubMed Abstract OpenURL

  54. Sabawala PB, Dillon JB: The action of some antibiotics on the human intercostal nerve-muscle complex.

    Anesthesiology 1959, 20:659-668. PubMed Abstract OpenURL

  55. de Gouw NE, Crul JF, Vandermeersch E, Mulier JP, van Egmond J, Van Aken H: Interaction of antibiotics on pipecuronium-induced neuromuscular blockade.

    J Clin Anesth 1993, 5:212-215. PubMed Abstract | Publisher Full Text OpenURL

  56. Lamb R: Colistin sulphate in the treatment of specific bacterial intestinal infections.

    Scott Med J 1968, 13:9-12. PubMed Abstract OpenURL

  57. Inoue A, Shoji A: Allergic contact dermatitis from colistin.

    Contact Dermatitis 1995, 33:200. PubMed Abstract OpenURL

  58. Sasaki S, Mitsuhashi Y, Kondo S: Contact dermatitis due to sodium colistimethate.

    J Dermatol 1998, 25:415-417. PubMed Abstract OpenURL

  59. Morizono T: Toxicity of ototopical drugs: animal modeling.

    Ann Otol Rhinol Laryngol Suppl 1990, 148:42-45. PubMed Abstract OpenURL

  60. Meleney Fl, Prout GR Jr: Some laboratory and clinical observations on coly-mycin (colistin) with particular reference to Pseudomonas infections.

    Surg Gynecol Obstet 1961, 112:211-217. PubMed Abstract OpenURL

  61. Alothman GA, Ho B, Alsaadi MM, Ho SL, O'Drowsky L, Louca E, Coates AL: Bronchial constriction and inhaled colistin in cystic fibrosis.

    Chest 2005, 127:522-529. PubMed Abstract | Publisher Full Text OpenURL

  62. Monarch Pharmaceuticals Inc: Coly-mycin M Parenteral (package insert). Bristol (TN): Monarch Pharmaceuticals, Inc; 2002.

  63. Forest Laboratories: Colomycin (package insert). Bexley, Kent (DA): Forest Laboratories, UK Limited; 2002.

  64. Bedford Laboratories: Polymyxin B for injection (package insert). Bedford, OH 44146: Bedford Laboratories; 1999.

  65. Tajti J, Penke B, Kovacs K, Csillik B: Competitive mechanisms of basic peptides inducing transganglionic degenerative atrophy.

    Acta Morphol Hung 1988, 36:7-14. PubMed Abstract OpenURL

  66. Mann PH: A report on the use of colistimethate sodium in a general hospital.

    Curr Ther Res Clin Exp 1963, 23:491-499. PubMed Abstract OpenURL

  67. Brumfitt W, Black M, Williams JD: Colistin in Pseudomonas pyocycanea infections and its effect on renal function.

    Br J Urol 1966, 38:495-500. PubMed Abstract OpenURL

  68. Rose HD, Pendharker MB, Snider GL, Kory RC: Evaluation of sodium colistimethate aerosol in gram-negative infections of the respiratory tract.

    J Clin Pharmacol J New Drugs 1970, 10:274-281. PubMed Abstract | Publisher Full Text OpenURL

  69. Randall RE, Bridi GS, Setter JG, Brackett NC: Recovery from colistimethate nephrotoxicity.

    Ann Intern Med 1970, 73:491-492. PubMed Abstract OpenURL

  70. Marschke G, Sarauw A: Polymyxin inhalation therapeutic hazard.

    Ann Intern Med 1971, 74:144-145. PubMed Abstract OpenURL

  71. Vanhaeverbeek M, Ectors M, Vanhaelst L, Franken L: Myopathy caused by polymyxin E: functional disorder of the cell membrane.

    J Neurol Neurosurg Psychiatry 1974, 37:1343-1345. PubMed Abstract OpenURL

  72. Fernandez-Viladrich P, Corbella X, Corral L, Tubau F, Mateu A: Successful treatment of ventriculitis due to carbapenem-resistant Acinetobacter baumannii with intraventricular colistin sulfomethate sodium.

    Clin Infect Dis 1999, 28:916-917. PubMed Abstract OpenURL

  73. Hamer DH: Treatment of nosocomial pneumonia and tracheobronchitis caused by multidrug-resistant Pseudomonas aeruginosa with aerosolized colistin.

    Am J Respir Crit Care Med 2000, 162:328-330. PubMed Abstract | Publisher Full Text OpenURL

  74. Jimenez-Mejias ME, Pichardo-Guerrero C, Marquez-Rivas FJ, Martin-Lozano D, Prados T, Pachon J: Cerebrospinal fluid penetration and pharmacokinetic/pharmacodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter baumannii meningitis.

    Eur J Clin Microbiol Infect Dis 2002, 21:212-214. PubMed Abstract | Publisher Full Text OpenURL

  75. Michalopoulos A, Kasiakou S, Rosmarakis E, Falagas M: Cure of multidrug-resistant Acinetobacter baumannii bacteraemia with continuous intravenous infusion of colistin.

    Scand J Infect Dis 2005, 37:142-145. PubMed Abstract | Publisher Full Text OpenURL

  76. Karabinis A, Paramythiotou E, Mylona-Petropoulou D, Kalogeromitros A, Katsarelis N, Kontopidou F, Poularas I, Malamou-Lada H: Colistin for Klebsiella pneumoniae-associated sepsis.

    Clin Infect Dis 2004, 38:E7-E9. PubMed Abstract | Publisher Full Text OpenURL

  77. Berlana D, Llop JM, Fort E, Badia MB, Jodar R: Use of colistin in the treatment of multiple-drug-resistant gram-negative infections.

    Am J Health Syst Pharm 2005, 62:39-47. PubMed Abstract | Publisher Full Text OpenURL

  78. Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME: Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis.

    Crit Care 2005, 9:R53-R59. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  79. Daram SR, Gogia S, Bastani B: Colistin-associated acute renal failure: revisited.

    South Med J 2005, 98:257-258. PubMed Abstract | Publisher Full Text OpenURL

  80. Bukhary Z, Mahmood W, Al Khani A, Al Abdely HM: Treatment of nosocomial meningitis due to a multidrug resistant Acinetobacter baumannii with intraventricular colistin.

    Saudi Med J 2005, 26:656-658. PubMed Abstract OpenURL

  81. Reina R, Estenssoro E, Saenz G, Canales HS, Gonzalvo R, Vidal G, Martins G, Das Neves A, Santander O, Ramos C: Safety and efficacy of colistin in Acinetobacter and Pseudomonas infections: a prospective cohort study.

    Intensive Care Med 2005, 31:1058-65. PubMed Abstract | Publisher Full Text OpenURL

  82. Kallel H, Hamida CB, Ksibi H, Bahloul M, Hergafi L, Chaari A, Chelly H, Bouaziz M: Suspected acute interstitial nephritis induced by colistin.

    J Nephrol 2005, 18:323-326. PubMed Abstract | Publisher Full Text OpenURL

  83. Petrosillo N, Chinello P, Proietti MF, Cecchini L, Masala M, Franchi C, Venditti M, Esposito S, Nicastri E: Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events.

    Clin Microbiol Infect 2005, 11:682-683. PubMed Abstract | Publisher Full Text OpenURL

  84. Kwa AL, Loh C, Low JG, Kurup A, Tam VH: Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

    Clin Infect Dis 2005, 41:754-757. PubMed Abstract | Publisher Full Text OpenURL