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Colistin: Re-emergence of the 'forgotten' antimicrobial agent AK Dhariwal, MS TulluDepartment of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.118040
The treatment of the emerging multidrug resistant (MDR) gram-negative organisms is a challenge. The development of newer antibiotics has recently slowed down. This has led to the re-emergence of the 'old forgotten' antibiotic "Colistin", whose use had almost stopped (after 1970's) due to the high incidence of nephrotoxicity and neurotoxicity. Colistin (polymyxin E) is a polypeptide antibiotic belonging to polymyxin group of antibiotics with activity mainly against the gram-negative organisms. Use of colistin has been increasing in the recent past and newer studies have shown lesser toxicity and good efficacy. Colistin acts on the bacterial cell membrane resulting in increased cell permeability and cell lysis. Colistin can be administered orally, topically, by inhalational route, intramuscularly, intrathecally, and also intravenously. Parenteral Colistin (in the form of colistimethate sodium) has been used to treat ventilator-associated pneumonia (VAP) and bacteremia caused by MDR bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Inhaled Colistin is used for treating pneumonia/VAP due to MDR gram-negative organisms and also used prophylactically in patients with cystic fibrosis. This manuscript is a brief review of Colistin and its clinical applications in the pediatric population. Keywords: Antibiotic, antibacterial, bacteremia, bacteria, colistin, drug-resistant, infections, nosocomial, sepsis
The rapid spread of multidrug-resistant (MDR) Gram-negative bacteria (GNB), such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Stenotrophomonas maltophilia, and Enterobacter (especially in intensive care units (ICUs), burn units, and immunocompromised patients) has been of concern. [1] Gram-negative Enterobacteriaceae with resistance to carbapenems (conferred by New Delhi metallo-β-lactamase 1 (NDM-1)) are an emerging problem. Kumarasamy et al., (2009), while studying the prevalence of multidrug resistant (MDR) Enterobacteriaceae found that, 75 Escherichia More Details coli, 60 Klebsiella spp, and six other Enterobacteriaceae resistant to carbapenems were isolated from 3,521 Enterobacteriaceae isolates (Chennai). [2] Of 141 carbapenem resistant organisms, 44 were NDM-1 positive. [2] During same period, 47 from 198 isolates (24%) were identified as carbapenem-resistant from Haryana. [2] Of these, 26 (13%) were K. pneumoniae positive for NDM-1. [2] These Indian isolates were primarily from community acquired urinary tract infections, pneumonia, and blood-stream infections and most isolates were susceptible to Colistin and Tigecycline. [2] The slow rate of development of newer antimicrobials has led to the re-discovery of the 'old' and 'forgotten' antibiotic-"Colistin", and it is increasingly being used as salvage therapy in patients with MDR GNB infections. [3] Colistin was initially discovered in Japan in 1949 and was more frequently used during the 1960s and early 1970s. [1] The use of Colistin was restricted later because of concerns regarding its neurotoxicity and nephrotoxicity; however in recent studies, Colistin has been found to be efficacious with lower toxicity. [1] The aim of this review is to discuss about the pharmacology and uses of Colistin for treatment of MDR GNB infections.
Colistin belongs to polymyxin group of antibiotics, of which two (polymyxin B and E) have been used. [1] The difference between polymyxin B and Colistin lies in the amino-acid components. [1],[4] Colistin is the more commonly used because of lesser toxicity. [1] Though Colistin has been available for use in GNB infections since 1959, its use got limited when the potentially safer/less-toxic aminoglycosides and anti-pseudomonal agents became available and thus, the use of Colistin declined from 1970s to the early 2000s. [5]
Colistin is a multi-component polypeptide antibiotic composed of Colistin A and Colistin B. [3],[4],[5] Colistin sulfate and Colistimethate sodium (CMS) are the forms of Colistin. Although CMS is the form administered parenterally, it undergoes conversion (in vivo) to form Colistin (which has antibacterial activity). [3],[4],[5],[6]
The antibacterial activity of Colistin is concentration-dependent (bacteriostatic in low concentrations and bactericidal in higher concentrations). [1],[4] CMS is characterized by a moderate and prolonged post-antibiotic effect (at higher concentrations) against MDR A. baumannii and P. aeruginosa strains. [1],[4] Colistin acts on the bacterial cell membrane. The cationic polypeptide (Colistin) interacts with the anionic lipopolysaccharide (LPS) molecules in the outer membrane of GNB (gram-negative bacilli) and displaces magnesium and calcium, which are the stabilizers of the LPS molecules of the outer membrane of the GNB. [1],[4] This process results in increased cell permeability, leakage of cell-contents, lysis of cell, and finally, bacterial cell death. [1],[4] Colistin also has a potent action against endotoxin-it inhibits the elaboration of cytokines and neutralizes the endotoxin. [1],[4] Hydrophilic antibiotics (rifampicin, carbapenems, glycopeptides, and tetracyclines) can work synergistically owing to the disruption of membrane integrity by Colistin. [5]
Colistin can be administered orally, topically (as otic solution and skin powder as Colistin sulfate), intramuscularly, via inhalation, intrathecally, and intravenously as CMS. [4] Colistin is mostly active against Gram-negative clinical isolates including Enterobacteriaceae. [5] The non-fermentative GNB-P. aeruginosa and Acinetobacter species are naturally susceptible to Colistin. [5] Colistin is also effective against-Haemophilus influenzae, E. coli, Salmonella More Details spp., Shigella spp., Klebsiella spp., Legionella pneumophila, Aeromonas spp., Citrobacter spp., Bordetella pertussis., and Campylobacter species (variable susceptibility). [4],[5],[7]
The pharmacokinetics (PK) of Colistin appear to be complex. [4] Most formulations contain CMS, which is hydrolyzed to various partial derivatives and Colistin in vivo. [4] Various pharmaceutical formulations often describe their contents differently, and thus, uniform and rational dosing of Colistin is challenging. [4] Both forms (Colistin sulfate and CMS) are not absorbed by the gastrointestinal (GI) tract. [1] After administration of CMS, Colistin appears rapidly in the plasma. [6] The serum half-life of this medication is 4.5-6 hours. [1] CMS is predominantly cleared by the renal route, and a fraction of the dose is converted in vivo to Colistin. [3] The Colistin formed is mainly cleared by non-renal mechanisms. In renal impairment, elimination of colistimethate (by the kidney) would be decreased and a greater fraction of colistimethate would be converted to Colistin; thus the need to decrease the dose of colistimethate in renal-impaired patients. [3] Following parenteral administration of CMS, the overall disposition of formed Colistin is rate limited by its elimination (rather than formation) as indicated by the substantially longer terminal half-life of formed Colistin (compared with that of the administered CMS). [8] The general minimum inhibitory concentration (MIC) breakpoint to identify bacteria susceptible to CMS is up to 4 mg/l based on the British Society for Antimicrobial Chemotherapy Guidelines (if MIC ≥ 8mg/l, the GNB are resistant). [1] Many authorities consider susceptibility to Colistin if the respective MIC 90 of Colistin is a maximum of 2 microg/ml (against a variety of GNB including E. coli, Klebsiella spp., Enterobacter spp., A. baumannii, and P. aeruginosa). [1] Colistin concentrations in the vicinity of MICs or above result in extremely rapid initial killing, with large decreases in colony forming units per mL (cfu/mL) occurring as early as 5 minutes following exposure. [8]
There are two forms of Colistin available commercially: Colistin sulfate (tablets or syrup for oral use and powder for topical use), which is also available as an aqueous suspension solution for topical use in eyes and ears and CMS for parenteral use. [4],[7] Both these forms can be delivered by inhalation route. Colistimethate sodium is administered parenterally (less toxic than Colistin sulfate). [9] The doses of Colistin through the various routes of administration are given in [Table 1]. [4],[5],[10],[11],[12] The dosage of intravenous CMS (as recommended by the manufacturers in the USA) is 2.5-5 mg/kg (31,250-62,500 IU/kg) per day, divided into two to four equal doses. [5],[13] Dosage adjustments are recommended for patients with mild-to-moderate renal dysfunction as shown in [Table 2]. [5],[14] For patients with renal failure, the recommended intravenous dosages of CMS are 2-3 mg/kg after each hemodialysis treatment and 2 mg/kg daily during peritoneal dialysis. [5],[15],[16]
In India, parenteral colistin is available in two brands: Xylistin TM by Cipla pharmaceuticals [available as 1 million IU (International Units) and 2 million IU vials)] and Colinem TM by Macleods pharmaceuticals (available as 1 million IU per vial); the dosage being similar to that being used in United Kingdom. [17],[18] There is a substantial difference in the recommended doses of the European and US products. However, according to recent clinical experience, higher daily doses of intravenous Colistin, up-to 720 mg (9 million IU) per day, administered in large series of patients did not exhibit higher toxicity. [1],[19],[20],[21] Colistin base has been assigned a potency of 30,000 IU/mg and CMS has a potency of 12,500 IU/mg. Hence, the recommendations regarding dosing should clearly refer to Colistin base and CMS to avoid possible confusion. [5],[22] The recommended dose of Colistin when given by inhalation is given in [Table 1]. For recurrent or severe pulmonary infections, the dose can be doubled to 160 mg (2,000,000 IU) administered every 8 hours. [10] The recommended dose for spontaneously breathing patients is 80 mg (1,000,000 IU). [10] Colistin is added to 4 ml of normal saline or sterile water and the solution is nebulized with 8 L/min oxygen flow and inhaled via a face mask. [10],[13] The optimal nebulized dosing remains unclear. Colistin is not approved by the Food and Drug Administration (FDA) to be inhaled via a nebulizer. [10] CMS is mostly administered for 10-14 days. [5] Dose regimens vary considerably and should be adjusted for renal function depending on serum creatinine levels or creatinine clearance. [5] Colistin pharmacokinetics are different in critically ill patients as they have frequent fluctuations in renal clearance. Many authors reported the administration of CMS at a dose of 3 MIU every 8 hours, especially in critically ill patients with normal renal function. [16],[23],[24] There is inadequate data available on the safety of Colistin during pregnancy and in patients with liver function impairment. [17],[18]
The adverse effects of Colistin are-nephrotoxicity (acute tubular necrosis in up to 20% of patients), neurotoxicity (0-7% of patients), dizziness, weakness, facial and peripheral paresthesia, vertigo, confusion, ataxia, and neuromuscular blockade (can lead to respiratory failure or apnea). [1],[5] Recent studies have reported significantly lower nephrotoxicity rates associated with Colistin administration (especially CMS). [19] The toxicity is dose-dependent and reversible on discontinuation of the treatment. [1],[5] Concomitant administration of other potential nephrotoxic agents (such as diuretics, aminoglycosides or vancomycin) increases the likelihood of nephrotoxicity. [1] Other adverse reactions include-hypersensitivity reactions, rash, urticaria, generalized itching, fever, gastro-intestinal disorders, and pseudomembranous colitis. [17],[18] The incidence of allergic reactions due to Colistin use has been reported to be about 2%. [1],[25] Bronchoconstriction and chest tightness are reported as rare complications when Colistin is used by inhalation route. [1]
Concomitant use of Colistin with other drugs of neurotoxic and/or nephrotoxic potential (diuretics, aminoglycosides or vancomycin) should be avoided. [1] Neuromuscular blocking drugs and ether should be used with extreme caution in patients receiving CMS. [17],[18]
It is contraindicated in patients with known hypersensitivity to Colistin or polymyxin B and in patients with myasthenia gravis. [17],[18] Colistin should be used with extreme caution in patients with porphyria.
Colistin has been shown to be active (even) in the presence of extended spectrum β-lactamases and metallo-β-lactamases. [1] Still, relatively high Colistin resistance rates in GNB (such as Acinetobacter spp., P. aeruginosa strains, and Enterobacteriaceae produced carbapenemases) have been recently reported worldwide. [1] Although the mechanisms of Colistin resistance have not been completely understood, alteration of the outer membrane of the (bacterial) cell, the reduction in cell envelope Mg 2+ and Ca 2+ contents and efflux pumps or production of enzyme(s) could be possible mechanisms. [1],[4],[26] The emergence of MDR or pandrug-resistant Gram-negative isolates, and especially, the emergence of Colistin resistance, are of concern. [1],[27] Colistin-resistant K. pneumoniae, A. baumannii, and P. aeruginosa pathogens may be encountered in clinical practice. [1] Hence, Colistin should be used judiciously (as treatment options for Colistin-resistant GNB are very limited). [1],[28] In a recent study on the emergence of MDR A. baumanii in patients with complicated urinary tract infections (North India); out of the total 224 isolates studied, 3.5% of total and 16% of the carbapenem-resistant MDR strains were found to be resistant to both Colistin and Tigecycline. [29] The pathogenic Neisseria More Details spp., M. catarrhalis, H. pylori, P. mirabilis, S. marcescens, Morganella morganii, Chromobacterium, and Brucella More Details species are naturally resistant to Colistin. [5],[30],[31],[32],[33],[34] Also, isolates of Inquilinus, Pandoraea, and Burkholderia associated with cystic fibrosis are intrinsically resistant to Colistin. [5],[35],[36],[37],[38] In P. mirabilis, Burkholderia cepacia, and Chromobacterium violaceum, polymyxin resistance has been associated with the changes in the lipid A. [5],[34],[39]
Oral and topical route Colistin sulfate is used orally for bowel decontamination and topically (as a powder) for the treatment of skin infections. [1] Intravenous or intramuscular route CMS has been used to treat ventilator-associated pneumonia (VAP) and bacteremia caused by MDR bacteria, such as P. aeruginosa, K. pneumoniae and A. baumannii. [30],[40] Intramuscular route is avoided as it is very painful and local irritation at the site of injection may occur. [17],[18] Inhalational route Prophylactic use Colistin has been administered for the eradication of pathogens from the respiratory tract in cystic fibrosis (CF) patients in combination with ciprofloxacin administered orally for at least 3 weeks (or, even better, for 3 months) or by means of inhaled tobramycin as monotherapy for 4 weeks or longer. The therapeutic results of this preventive strategy have been successful. [10],[41] Therapeutic use Recent data in (critically ill) patients receiving Colistin by nebulization for management of pneumonia/VAP due to MDR GNB show favorable results. [10] High drug concentrations are usually achieved in sputum and bronchial secretions, maintained for 8-12 hours in the majority of patients. [16] However, further controlled trials are required in this regards. [1] Intraventricular or intrathecal route Colistin is usually administered intravenously, although adequate concentrations may not be achieved in the cerebrospinal fluid due to poor penetration of Colistin across the blood-brain barrier. [1],[3] Hence, Colistin can also be administered by the intraventricular or intrathecal route (considered if the ventriculitis is refractory to systemic antimicrobial therapy). [1],[3] Direct instillation of Colistin into the central nervous system (CNS) may cause chemical meningitis or ventriculitis. [1] Toxicity (probably or possibly) related to the topical administration of Colistin is seen in about 15% of patients. [1],[42] Administration of Colistin directly into the CNS appears to be successful and well tolerated. [1] Intra-ventricular and intrathecal administration of Colistin is an effective (and safe) option for treatment of post-neurosurgical meningitis (or ventriculitis) due to MDR GNB (especially when the intravenous route is not feasible/available). [1] Combination therapy Colistin can be used as combination therapy to improve its antibacterial activity. [5] A synergistic effect has been reported in different studies as regards the combination of Colistin with other antibiotics. [5],[40],[43],[44] Combination therapy with rifampicin and polymixin is one of the alternatives for treatment of MDR-GNB infections. [5],[45],[46],[47],[48],[49] Synergistic effect was detected in most of the studies that examined the combination of Colistin and rifampicin, whereas carbapenems exhibited a synergistic effect in a few studies. [5],[43] Sulbactam may be considered an option in association with Colistin, in the treatment of MDR A. baumannii infections. [5],[50],[51] Combinations of Colistin/Meropenem, Colistin/Rifampicin, and Colistin/Minocycline are synergistic in vitro against extensive drug-resistant A. baumannii. [5],[52] Wareham et al., have documented a synergistic effect of Colistin in combination with teicoplanin against MDR A. baumannii strains. [53] Glycopeptides have also shown synergy with polymyxin. [5],[44],[54]
Colistin is permitted for use in all children including infants. [55] Few efficacy data from controlled trials of its systemic use in infants and children are available because of the relative non-use of Colistin during the past 30 years. [55] Data on pharmacokinetic properties, drug behavior and dosing in children are also inadequate. [55] Published reports on the use of Colistin in children describe its use in case-series/case reports. Most published clinical data in children describes Colistin use in patients with cystic fibrosis. [55] Falagas et al., (2009) reviewed the literature on the systemic use of Colistin in children without cystic fibrosis. [56] Included in this review were 326 children from 10 case series and 15 case reports, of which only 17 children were evaluated in reports published after 1977. [56] Of these children, 271 were evaluable for clinical outcome-more than 90% were cured of infection or improved. [56] Nephrotoxicity occurred in 2.8% and no neurotoxicity was reported. Indications for use of colistin included sepsis, meningitis, pneumonia, and pyelonephritis. [56] [Table 3] [57],[58],[59],[60],[61],[62],[63] gives a summary of the recent case series and studies on systemic (intravenous) use of Colistin in pediatric population in the last 3 years (2009-2012) and includes only one Indian study (hence more data is required on the efficacy and safety of Colistin in Indian children). [59] Recent case series on the use of inhaled Colistin for the treatment of VAP and tracheobronchitis due to MDR A. baumanii and P. aeruginosa in critically-ill pediatric patients and neonates, have found Colistin treatment to be effective, safe, and tolerable without any adverse effects. [64],[65],[66]
In conclusion, recent studies and case reports have found Colistin to be safe and effective in the treatment of critically ill children with MDR GNB infections (more studies are required for confirming these findings). [57],[58],[59],[60],[61],[62],[63],[64],[65],[66]
The authors thank Dr. Sandhya Kamath, Dean of Seth G. S. Medical College and K. E. M. Hospital for granting permission to publish this manuscript.
[Table 1], [Table 2], [Table 3]
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