The use of colistin in Cystic Fibrosis
Colistin is an antibacterial cationic cyclic polypeptide belonging to the group of antibiotics called the polymyxins. It is produced as a secondary metabolite from the spore-formingBacillus polymyxa var colistinus. It is structurally identical to polymyxin E and closely related to polymyxin B.
History of colistin
Colistin was first discovered by Koyama et al in 1949, as a fermentation product of the bacteria, Bacillus colistinus (Koyama et al, 1950). In 1959, an intravenous formulation (colistimethate sodium) was released commercially but was then temporarily abandoned in the Seventies and early 1980’s due to reports of a high incidence of nephrotoxicity (Price & Graham, 1970; Koch-Weser et al, 1970) and also the increasing use of gentamicin. However interest in colistin was rekindled following a rise in the prevalence of multiresistant Gram-negative strains and it is now widely used for the treatment and eradication of Pseudomonas infections in people with cystic fibrosis (CF) (Littlewood et al, 2000). Early clinical reports of severe toxicity with the use of colistin are likely to have occurred as a result of inappropriate patient selection, higher than recommended doses and inappropriate monitoring (Li et al, 2005).
Colistin acts as a cationic detergent and interferes with the structure and function of the outer cytoplasmic membrane of bacteria. Colistin also has the ability to bind and neutralise bacterial endotoxins, released during infective exacerbations (Li et al, 2005). Colistin is bactericidal and is active in vitro against a range of Gram negative bacteria and also it is highly active against Pseudomonas aeruginosa with reported resistance being below 5% (Catchpole et al, 1997; Pitt et al, 2003). Colistin also has activity against a number of clinically important organisms such as Acinetobacter species, Citrobacter, Escherichia coli, Enterobacter species, Haemophilus influenzae, Klebsiella species, Salmonella species and Shigella species (Catchpole et al, 1997).
Pharmacokinetics of colistin
Colistin is a multicomponent antibiotic with colistin A (polymixin E1) and colistin B (polymyxin E2) being the two major components (Li et al, 2005). There are two preparations of colistin available for clinical use namely colistimethate and colistin sulphate; both are less toxic than the colistin base. Colistimethate sodium causes less pain upon injection than the base or sulphate and appears to have a superior therapeutic ratio to the sulphate. Colistin sulphate is used orally and topically while sodium colistin methanesulphate is used by injection and inhalation. Sodium colistin methanesulphate is produced by the reaction of colistin with formaldehyde and sodium bisulphite (Li et al, 2005). Following parenteral administration of sodium colistin methanesulphate, the principal route of excretion is via the kidneys (65-75%). Sodium colistin methanesulphate is further hydrolysed to colistin following parenteral administration with a half-life of 82-268 min and 139-385 min respectively (Li et al, 2003). Oral absorption of colistin is very poor.
Prevalence of P. aeruginosa resistance to colistin
A recent survey of reported susceptibility to six commonly prescribed antibiotics of isolates of P. aeruginosa from 417 people with CF from 17 hospitals (Pitt et al, 2003). Almost half were resistant to gentamicin compared to ceftazidime (39%), piperacillin (32%), ciprofloxacin (30%), tobramycin (10%). Only 3% of strains were resistant to colistin, while 40% were resistant to two or more compounds with ceftazidime in combination with gentamicin, piperacillin or ciprofloxacin being the most common cross resistance (Schulin, 2002). Most strains of Burkholderia cepacia complex remain resistant to colistin.
We have recently reported our 10 year prevalence of colistin resistance among isolates of P. aeruginosa in the Leeds Adult CF unit (Clifton et al, 2005). The resistance remained relatively unchanged, despite the frequent use of intravenous and nebulised colistin in the routine management of people with cystic
Long term nebulised colistin for chronic P. aeruginosa infection
The regular twice daily administration of a nebulised antibiotic has been an established treatment for chronic P. aeruginosa chest infection in CF between exacerbations since Hodson et al. published their paper in 1981 comparing nebulised gentamicin and carbenicillin with placebo in a double blind cross-over trial in 20 adult patients (Hodson et al, 1981). Subsequent studies have shown improved lung function, a slower decline in respiratory function, decreased hospital admission rates, better clinical scores, and better weight profile in patients who receive daily nebulised antibiotic treatment. In a meta-analysis of trials using various antibiotics, Mukhopadhyay et al concluded that nebulised antibiotics significantly reduced the density of P. aeruginosa in the sputum and the frequency of respiratory exacerbations (Mukhopadhyay et al, 1996).
So what is the evidence to support the use of nebulised colistin in patients with chronic P. aeruginosa infection?
For over a decade, colistin has been used in the UK as routine therapy for patients chronically infected with P. aeruginosa (Hoiby et al, 2005). Therapy has been found to be safe, and importantly, the emergence of resistant strains does not appear to have become a significant problem.
Two placebo controlled trials looking at the effectiveness of long term nebulised colistin therapy for chronic P. aeruginosa infection have been undertaken to date. The first prospective double-blind placebo-controlled study compared nebulised colistin (1 mega unit b.d.) with normal saline (placebo) in 40 patients (age seven to 35 years) over a three month period. Eighteen patients receiving active treatment and 11 in the placebo group completed the study. Colistin was associated with a significantly better clinical symptom score, slower deterioration of pulmonary function (significant for FVC) and reduced inflammatory parameters (Jensen et al, 1987).
Day et al reported in abstract form, a double blind cross over study comparing colistin (1 mega unit b.d.) with saline in 14 children (age five to 16 years) who were chronically infected with P. aeruginosa (Day et al, 1988). Following six month treatment, they reported no difference in antibiotic usage although lung function was maintained in the colistin group and declined significantly in patients receiving placebo.
While both studies support the use of nebulised colistin in symptomatic patients with chronic P. aeruginosa infection, the study numbers were small. Furthermore, the dose of colistin prescribed could be regarded as suboptimal as most adult CF units in the UK now prescribe 2 mega units b.d. as the standard dose for people over 2 years of age. However, it is unlikely that further studies will be carried out, now that the use of colistin has become part of routine protocol.
Only one study has directly compared tobramycin nebulised solution (TOBI®) and colistin in the clinical setting. Hodson et al investigated the efficacy of colistin and tobramycin nebulised solution in 115 people with CF who were chronically infected with P. aeruginosa (Hodson et al, 2002). Patients were randomised to receive either TOBI (n=53) or colistin (n=62) twice daily for four weeks. Primary end points included the relative change in lung function from baseline. Secondary end points included change in P. aeruginosa density, change in MIC and safety. Treatment with TOBI resulted in a significantly greater improvement in FEV1 (6.7%) when compared to colistin (0.37%), and was associated with a greater improvement in the global rating of change questionnaire with patients showing a relatively greater improvement in their medical condition. Both treatments reduced the bacterial load.
This study had a few weaknesses in its design. Firstly, most patients entered into the study were naïve to TOBI® but many patients had been previously exposed to nebulised colistin prior to the washout period. This exposure was significantly greater than prior exposure to intravenous or nebulised tobramycin in either group. Furthermore the dose of colistin used was only 1 mega unit twice a day which is half the standard dose used by many specialist units in the UK; this may have reduced clinical effectiveness of the drug. Despite the widespread use of colistin over many years, the resistance pattern of P. aeruginosa isolates has remained relatively unchanged and long term microbiological surveillance studies for TOBI will need to be carried out to ensure that significant tobramycin resistance does not ensue. Finally, the long term administration of aminoglycosides may also pose a risk of renal toxicity and close monitoring is needed to ensure that treatment does not result in significant nephrotoxicity.
Eradication of early P. aeruginosa infection with nebulised colistin
The significance of chronic P. aeruginosa infection in CF has lead to developments in strategies to prevent or delay progression from initial acquisition of P. aeruginosa to chronic infection. Chronic infection is associated with the mucoid phenotype of P. aeruginosa. Whilst acquisition of P. aeruginosa may occur quite early in life, the transition from the non-mucoid to the mucoid phenotype may take several years. Evidence from several studies has shown that early administration of antibiotics, soon after colonization with P. aeruginosahas been identified, usually eradicates the organism and significantly reduces the risk of chronic infection (Hoiby et al, 2005).
Nebulised colistin has proved highly effective in the early eradication of P. aeruginosa infection, resulting in reduced prevalence of chronic infection among children with cystic fibrosis (Frederiksen et al, 1997; Lee et al, 2004). Littlewood et al first reported the effect of inhaled colistin (500,000 units b.d.) on early colonization with P. aeruginosa in seven children with CF in 1985. They found that after three to 14 months therapy, there was a significant reduction in the number of positive cultures with three patients having repeatedly negative cultures (Littlewood et al, 1985). This was followed by a study conducted by Valerius et al where 26 patients elected to receive oral ciprofloxacin plus aerosolized colistin twice daily for three weeks or no treatment in response to an initial isolation of P. aeruginosa (Valerius et al, 1991). After 27 months of the trial significantly fewer patients who received treatment were positive for P. aeruginosa (14% versus 58%, p < 0.05). This protocol was further refined by the Copenhagen group to increase the duration of treatment with oral ciprofloxacin and aerosolized colistin to three months. Further follow-up after three-and-a-half years revealed that only 16% of treated patients developed chronic P. aeruginosa infection in comparison to 72% of untreated historical controls (p < 0.005) (Frederiksen et al, 1997).
At the Leeds CF centre we use three months of nebulised colistin in combination with oral ciprofloxacin on first isolation of P. aeruginosa. If first line treatment fails we prescribe a further three months of nebulised colistin and two weeks of intravenous (IV) anti-Pseudomonal antibiotics. Alternative nebulised antibiotics such as TOBI are used as part of third line eradication therapy or if colistin is not tolerated. A Leeds audit (unpublished) found no significant difference between the various eradication regimens although there was a trend towards a higher success rate in those individuals who received two weeks IV antibiotics in combination with three months of nebulised colistin.
Intravenous colistin therapy for exacerbations of chest infection
Colistin has proved to be a valuable parenteral antibiotic for the treatment of pulmonary exacerbations in CF. While resistance of P. aeruginosa to colistin was unusual; there was an anxiety among health professionals concerning reports of nephrotoxicity and neurotoxicity (Gold and Richardson, 1965; Price & Graham, 1970; Koch-Weser et al, 1970; Bosso et al, 1991). Reported experience of adverse reactions did not include patients with CF and appears to be both reversible and dose dependent. Conway et al carried out a randomised study comparing the use of colistin (2 Mega units t.d.s.) versus colistin in combination with a second anti-Pseudomonal antibiotic (Conway et al, 1997). A total of 53 patients were entered into the study, 18 of whom were enrolled twice. All patients showed clinical improvement and resolution of their acute exacerbation with no significant difference between the two antibiotic regimens in terms of change in FEV1, FVC, overnight oxygen saturations and clinical scores after 12 days of therapy. The only difference in clinical response was that more patients who received dual therapy had a normal C-reactive protein at the end of treatment. Antibiotic therapy was associated with a statistically significant rise in blood urea and not creatinine at day 12 in both groups. While a significant number of adverse neurological events (dizziness, numbness, tingling, incoordination, unsteadiness, muscle weakness) were reported after direct questioning, only one patient described the symptoms of dizziness and muscle weakness as severe and withdrew from the study. All mild and moderate symptoms were well tolerated and resolved shortly after treatment.
A more recent study by Ledson et al reported their four year experience of intravenous colistin in an adult CF unit (Ledson et al, 1998). Over the study period, 135 courses (2,414 patient days) of IV colistin (2 Mega units t.d.s.) with an additional anti-Pseudomonal antibiotic were administered to 52 adults with cystic fibrosis. The colistin was safe and effective with treatment being associated with significant improvement in spirometry. There were no adverse effect on renal function and no neurotoxicity. One patient developed a skin rash and another myositis. The addition of colistin to other anti-Pseudomonal drugs also appears to produce greater killing of P. aeruginosa than monotherapy (Rynn et al, 1999).
It is our opinion that colistin as a bolus should not be given to patients without central venous access as in some it may induce significant phlebitis. Colistin can be administered as an intravenous bolus in patients with totally indwelling venous access systems. A small safety study found no serious adverse events (Conway et al, 2000); we regularly administer bolus colistin to patients with Port-A-Caths or PAS ports. However patients with peripheral lines experienced mild to moderate injection pain.
Colistin (Colomycin) comes as a sterile powder for solution. It has a shelf life of three years and once in solutions it remains stable for 28 days at 4 0C. Following reconstitution with sterile water, the solution should be used within seven days (Li et al, 2001). Colistin ampoules should be protected from light.
Dose of intravenous colistin
Children – (Up to 60 kg) 50,000 to 75,000 units/kg bodyweight per day in three divided doses. (Maximum 75,000 units/kg, in 24 hours)
Adults -75,000 units/kg/day. Standard dose in adults > 60 kg is 2 MU 3 times daily. (Maximum 6 MU per 24 hrs).
The colistin should be diluted with 50 ml 0.9% saline and infused over 30 minutes. If mild neurological side-effects occur, a lower dose of 75,000 units/kg/day in three divided doses should be considered instead of 2 Mega units three times a day.
Colistin may be given as a bolus through a central venous access device with two Mega units being diluted in 10 ml NaCl 0.9% and given over three to five minutes (Conway et al, 2000). Bolus colistin should not be given through peripheral lines.
Children less than two years – one Mega unit colistin twice daily.
Children over two years of age and standard adult dose – two Mega unit colistin twice daily.
The Ventstream and Pari LC Plus, which are used for antibiotics, direct the patient’s inspiratory flow through the nebuliser chamber, thereby increasing the effective inhaled nebuliser output. For this to occur the patient’s respiratory flow must exceed the compressor flow rate through the nebuliser for a significant proportion of the inspiratory period. This does not always occur in very young children and patients with poor lung function. A mouthpiece rather than a facemask should be used to maximise pulmonary deposition. Relaxed tidal volume breathing through the mouth and not the nose is recommended.
Other devices are available which have perforated oscillating membranes that create the mist for inhalation. This technology creates a more uniform particle size within the respirable therapeutic range. There are currently two devices available – a continuous delivery device called E-flo rapid® (Pari Medical Ltd) and the I-neb® (Respironics / Philips). The I-neb® is an Adaptive Aerosol Device (AAD) which continuously monitors the user’s breathing pattern, and only delivers the drug during the first part of inspiration – that being the only part of the inhaled medication which is retained within the lung with continuous delivery devices. This has the added benefit of further reducing treatment time, and does not require venting or filtering of exhaust gases. At present, the I-neb® is only available to those patients on Promixin® (colistimethate sodium) powder for nebulisation (Profile Pharma) which remains more expensive than colomycin.
Assessment of nebulised antibiotics
A formal challenge with pre and post inhalation lung function should be undertaken before instituting therapy.
All patients should be assessed for compliance with therapy and reviewed on a regular basis. It is recommended that patients use nebulised antibiotics after physiotherapy and bronchodilators to ensure maximum deposition and protection from bronchoconstriction.
Adverse effects and contraindications
Colistin and renal disease
Dosage must be decreased in patients with renal dysfunction. Avoid using with aminoglycosides and other nephrotoxic drugs such as non-steroidal anti-inflammatory drugs.
Colistin and liver disease
Although hepatic disease is unlikely to alter the elimination of colistin, no information is available.
5% of serum level ends up in breast milk. Colistin crosses the placental barrier.
Airway reactivity occurs following the administration of all nebulised antibiotics and in some patients this may lead to the discontinuation of therapy. Bronchoconstriction with a transient fall of FEV1 after nebulisation has been reported to occur in up to 17.7% of patients (Dodd et al, 1997; Cunningham et al 2001; Hodson et al, 2002; Alothman et al, 2005). It is therefore vital that a formal challenge with pre and post inhalation lung function should be undertaken before instituting therapy. Bronchoconstriction can be prevented or lessened by the addition of a beta-2 agonist either before or during nebulisation. A degree of drug tolerance appears to develop over time.
Tonicity of colistin solution
Dodd et al conducted a study examining the relationship of chest tightness and change in lung function in response to the inhalation of a range of tonicities of nebulised colistin and their influence on patients’ preference (Dodd et al, 1997). Twenty seven adult patients with cystic fibrosis inhaled a hypertonic, isotonic, and hypotonic nebulised solution over three consecutive days in random order in a double blind fashion. Measurements of chest tightness, using a visual analogue scale (VAS), and FEV1 were recorded before and 0, 15, 30, 60, and 90 minutes following inhalation. They found no differences between hypertonic, isotonic, and hypotonic solutions in terms of fall in FEV1 % predicted and increase in chest tightness. However, the mean time to the maximum fall in FEV1 % predicted was significantly different between the solutions (hypertonic 7.8 (2.1) min, isotonic 19.2 (5.5) min, and hypotonic 34.2 (5.9) min). There was no correlation between the objective and subjective measurements for any solution.
Other adverse reactions to colistin – general
– Visual disturbance
– Numbness, facial paraesthesia
– Vasomotor instability
– Slurred speech
– Local irritation
– ApnoeaSome important contraindications
– Myasthenia gravis (Gold & Richardson, 1965)
Important drug interactions
– Alendronate, etidronate- increased risk of hypocalcaemia
– Aminoglycosides – increases risk of nephrotoxicity, reduce doses if concurrent use essential
– Amphotericin -increased risk of nephrotoxicity
– Loop diuretics – increased risk of ototoxicity
– Muscle relaxants – enhance muscle relaxant effect
Dry powder colistin
Studies on a new dry powder formulation of colistin are in progress and the provisional results are encouraging (Le Brun et al, 2002; de Boer et al, 2002; Westerman et al, 2005). Such therapy appears suitable and highly efficient alternative to nebulisation of antibiotic drugs in CF (de Boer et al, 2002). If proven effective, their introduction will result in improvement in patient’s compliance and quality of life.
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Clifton I, Peckham D, Conway SP.10 years of use of colistin in a regional cystic fibrosis centre. J Cystic Fibrosis Med 2005 202:S54
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Cunningham S, Prasad A, Collyer L, et al. Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child 2001; 84:432-433. [PubMed]
Day AJ, Williams J, Mckeown C, et al. Evaluation of inhaled colomycin in children with cystic fibrosis. 10th International Cystic Fibrosis Congress, Sydney, Australia. Excerpta Medica Asia Pacific Congress Series1988; 74; 206 (Poster R9c03).
De Boer AH, Le Brun PP, van der Woude HG, et al. Dry powder inhalation of antibiotics in cystic fibrosis therapy, Part 1: development of a powder formulation with colistin sulfate for a special test inhaler with an air classifier as de-agglomeration principle. Eur J Pharm Biopharm 2002; 54:17-24. [PubMed]
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Lee TWR, Brownlee KG, Denton M, et al. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a Regional Pediatric Cystic Fibrosis Center. Pediatr Pulmonol 2004; 37:104-110. [PubMed]
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Also note recent relevant communications:-
Bugge B, Rosenvinge A, Pressler T, et al. High dose intravenous colistin once a day is a safe and effective treatment of multi-resistant Pseudomonas aeruginosa in adults with cystic fibrosis. Pediatr Pulmonol 2005: Suppl 28: 267 (poster 224).
Brannon MK, Pier M, Stevens L, et al. Colistin treated cystic fibrosis patients harbor polymyxin-resistant strains of Pseudomonas aeruginosa some with mutation of PMRAB, a two-component regulator of lipid structure. Pediatr Pulmonol 2005; Suppl 28:289 (Poster 288)
Westerman EM, de Boer EH, Le Brun PPH, et al. Colistin dry powder inhalation in cystic fibrosis: novel Twincer inhaler compared to nebulisation: a pilot study. J Cyst Fibros 2005: 4(Suppl 1):S64 (Poster 244). [Said to be more efficient with no bronchocontriction]
Goldman MH. “MU (160mg) Colistimethate twice daily is a safe nebulized dose for adults and children with cystic fibrosis. Goldman MH, Stramik SJ, Girdwood K. J Cyst Fibros 2005; 4 (Suppl 1): S53 (poster 200). [nothing new in this one]
Perpati G, Pouliou E, Stefanatou E, et al. Long-term effect of inhaled colomycin on exercise capacity in adult patients with cystic fibrosis. J Cyst Fibros 2005; 4 (Suppl 1):S54 (Poster 201). [Improves clinical status and exercise capacity when added to conventional therapy]
Clifton I, Denton M, Etherington C, et al. 10 years of colistin use in a Regional Cystic Fibrosis Centre. J Cyst Fibros 2005; 4 (Suppl 1):S54 (Poster 202). [Little change in the prevalence of colistin resistance among isolates of Pseudomonas aeruginosa over 10 years despite extensive use (0.38% pa to 2000 and then 0.18% pa to 2004]
Hansen CR, Pressler T, Hoiby N. Experiences from 15 years use of colistin in treatment of P.aeruginosa in a CF-clinic. J Cyst Fibros 2005; 4 (Suppl 1):S54 (Poster 203). [0.4% of chronically infected patients had colistin resistant strains at some time. No intermittently colonised patients had colistin resistant strains.39 (26.7%) of 146 intermittently infected became chronically infected]
Mullinger B, Brand P, Pechtold O, et al. In vitro based comparison of deposition efficiency of two inhalations systems for inhalation of colistin. J Cyst Fibros 2005; 4 (Suppl 1): S54 (Poster 204). [Pari LC Plus with Pari Turbo Boy compressor Vs. Pari LC Star with “intelligent compressor Akita. – the latter more efficient drug delivery]
Potter R, Hatley RHM. Precise dose delivery of colistimethate sodium using prototype I-neb AAD system. J Cyst Fibros 2005; 4 (Suppl 1): S30 (poster 109). [The I-neb able to deliver precise doses of suitable particle size for delivery into the lung]