The Remergence of Colistin and Polymyxin B

Disease and Therapy , Knowledge Base / October 4, 2016

The development of antibiotics against life-threatening infections has always been seen as the most important achievement of modern medicine. The emergence, however, of multi-drug resistant (MDR) gram negative bacteria has drastically narrowed down the therapeutic options against them; a limitation which recently has led clinicians to reevaluate the clinical application of polymyxins, an old class of antibiotics. Polymyxins are active against selected gram-negative bacteria, including the Acinetobacter species, Pseduomonas aeruginosa, Klebsiella species, and Enterobacter species.

Polymyxins are a group of cationic polypeptide antibiotics consisting of 5 chemically different compounds (polymyxins A-E), discovered in 1947. Only polymyxins B and E (colistin), produced from Bacillus spp., have shown use in clinical practice. Soon after their introduction into clinical use in 1949, concerns arose about adverse effects, such as nephrotoxicity, ototoxicity, and neuromuscular blockade associated with their use; however, the recent antibiotic therapeutic void against gram-negative organisms has resulted in a steep rise in their use in clinical practice since the late 1990s.

Colistin and polymyxin B have their antimicrobial activity directed mainly against the bacterial cell membrane, where the cationic polypeptides of colistin and polymyxin B interact with anionic lipopolysaccharide (LPS) molecules in the outer membrane of gram-negative bacteria, leading to displacement of calcium and magnesium ions, which stabilize the LPS membrane, thus causing derangement of the cell membrane. This results in an increase in the permeability of the cell membrane, leakage of cell contents, and ultimately cell death. Colistin also has potent anti-endotoxin activity.  The endotoxin of gram-negative organisms is the lipid A portion of LPS molecule and colistin binds and neutralizes this LPS molecule.

Colistin is available commercially in two forms: colistin sulfate, which is used topically and orally and CMS (colistemethate sodium, colistin methanesulfate, pentasodium colistimethanesulfate, and colistin sulfonly methane) used for parenteral and inhalational use. CMS is an inactive prodrug of colistin and is less potent and less toxic than colistin sulphate. Polymyxin B and colistin differ only in their amino acid components. These antimicrobials are not absorbed by the gastrointestinal tract with oral administration. Colistimethate is not stable in vitro and in vivo and is hydrolyzed into a complex mixture of partially sulfomethylated derivatives and colistin.

CMS and colistin differ in their pharmacokinetics. CMS is excreted primarily by the kidneys and involves renal tubular secretion. On the other hand, colistin is mainly excreted by non-renal mechanisms that are as yet not fully understood. In renal impairment, excretion of colistimethate by the kidney is decreased and a greater fraction of CMS is converted to colistin, which explains the rationale behind decreasing the dose of CMS in patients with renal impairment who are not receiving renal replacement therapy. Polymyins concentrate in the liver, kidney, heart, muscle, and lungs but do not cross the blood-brain barrier in non-inflamed meninges.

Colistin has excellent bactericidal activity against most gram-negative aerobic bacilli, including Acinetobacter species, P. aeruoginosa, K. pneumonia, E. coli, Enterobacter spp. It also may be active against Salmonella spp., Shigella spp, Citrobacter spp., Yersinia pseduotuberculosis, Haemophilus influenza, and several mycobacterial species. Providentia spp, Serratia spp, Brucella spp are all resistant to colistin.

Colistin is available comercially in two different formulations. Colomycin has half million, 1 million or 2 million IU per vial. Colomycin manufacturers recommend 50,000 to 75,000 IU/kg/day in three divided doses. Various studies support an acceptable safe dose of 6-9 mg/kg/day of Colomycin. So there is a possibility of under-dosing with Colomyin if it is administered at the recommended doses stated by the manufacturers. The recommended doses of intravenous polymxin B is 1.5-2.5 mg/kg/day divided in two equal doses.

In patients with renal impairment, the dosage of colistin and polymyxin B needs modification. For a serum creatinine level of 1.3-1.5 mg/dl, 1.6-2.5 mg /dl, or above 2.6 mg/dl, the recommended dosage of IV colistin is 160 mg (2 million IU) every 12 hours, 24 hours, or 36 hours, respectively. For patients undergoing hemodialysis, the dosage of colistin is 80 mg (1 million IU) after each hemodialysis treatment. A dose adjustment of polymycin B in renal failure has not been well established but one such dose adjustment is based of polymyxin B in renal failure has not been well established but one such dose adjustment is based on creatinine clearance (CrCl). If CrCl is 20-50 mL/minute, administer 75% to 100% of the normal daily dose in divided doses every 12 hours. If CrCl is <5 mL/min, administer 15% of the normal daily dose in divided doses every 12 hours.

Aerosolised colistin in a dosage of 80 mg/day (1 million IU) for patients ≤ 40 kg and 160 mg/day (2 million IU) for patients > 40 kg are being used as an adjunctive intervention in treatment for MDR pneumonia. Bronchoconstriction, cough, and chest tightness have been reported during colistin nebulisation.

Intraventricular or intrathecal administration of colistin may prove to be life-saving intervention for patients with meningitis caused by MDR gram-negative organisms not responding to intravenous colistin. Various case reports suppor this route of administration and according to these studies, the recommend dose is 3.75-10 mg colistin per day.

For intravenous administration, 2 million units are to be dissolved in 300-500 ml of 5% dextrose for a continuous intravenous drip. In patients with renal failure not on any renal replacement therapy, dissolve the 24-hour dose in 50 ml of normal saline and administer it as a 24-hour infusion via an infusion pump. The antibiotic can also be given at regular intervals by dividing the daily dosage into 3-4 equal doses and dissolving it in 100 ml 5% dextrose.

Intramuscular administration is not recommended as it is very painful at the injection site.

For intrathecal administration, half a million units should be dissolved in 10 ml of sterile physiologic saline for a concentration of 50,000 units per ml.

For patients breathing spontaneously, 80 mg (1 million IU) of colistin is added to 4 ml of normal saline and nebulized with 8 litres/min oxygen flow via a face mask. For patients on mechanical ventilation, aerosolized colistin can be delivered just like any other nebulization.

The most common potential toxicities with intravenous administration of polymyxins are nephrotoxicity and neurotoxicity. Both of these toxicities are dose-dependent. Renal toxicity mainly includes acute tubular necrosis leading to an increase in serum urea and creatinine levels. Polymyxins can also lead to hematuria, proteinuria, and cylindruria. However, the high incidence of nephrotoxicity in earlier studies was due to a lack of understanding of pharmacokinetics, pharmacodynamics, and inappropriate dosage schedules of polymxins; recent investigations have revealed CMS to be less nephrotoxic than amikacin or tobramycin. Neurotoxic effects include oral and perioral paraesthesia, headache, ataxia, vertigo, visual disturbances, confusion, vasomotor instability, and reversible neuromuscular blockade. In the last decade, no case reports have reported the neurological side effects of these antimicrobials.

Other miscellaneous side effects are hypersensitivity reactions, fever, ototoxicity, and mild gastrointestinal disorders. Side effects due to aerosolized administration of polymyxins are cough, bronchoconstriction, and chest tightness. A high-dose administration of intrathecal colistin may cause convulsions.

The mechanism of resistance to the polymyxins remains poorly understood. Various studies have suggested the alterations of the outer membrane of the bacterial cell membrane, like loss of LPS, reduction of specific outer membrane proteins, reduction in cell envelope Mg2+ and Ca2+ contents, and lipid alterations are related to the development of resistance.

Very few studies were carried out that report the efficacy of combination therapy of colistin with other antimicrobials. A few studies have shown the synergistic activity of colistin with other antipseudomonal antibiotics like carbapenems, piperacillin/tazobactam, ceftazidime, or ciprofloxacin. Colistin and rifampicin have shown some synergistic activity against MDR strains of A. baumanii.

Since there is little information on the pharmacokinetic and pharmacodynamic propertie of colistin and polymyxin B, its appropriate use has been hampered. These agents have been recently used for MDR gram-negative organisms mostly P. Aeruginosa and A. baumnnii responsible for pneumonia, bacteremia, and urinary tract infections. The dosage used should be 160-240 mg (2-3 million IU) per day for life-threatening infections and these doses should be adjusted according to the renal functions. Inhalational therapy with colistin or polymyxin B acts as adjunctive therapy in MDR gram-negative pneumonia.

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