There are increasing concerns related to the treatment of multi-resistant bacteria especially gram-negative pathogens due to significantly increased risk of mortality, morbidity and economic burden on patients. [1] The growing problem of infections caused by multidrug-resistant gram-negative bacteria resulting in severe infections and limited options for treatment of such patients [2] has led to the re-emergence of interest in polymyxins. [3] In this article, Dr. Anant Patil reviews this group of medications and details on the available evidence regarding their use in serious infections caused by gram-negative bacteria.

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Polymyxins are antibiotics derived from different species of Bacillus polymyxa. [2] Polymyxins, bactericidal antimicrobial agents are valuable options for the treatment of serious infections caused by multidrug-resistant microorganisms such as Enterobacteriaceae (including carbapenem-resistant), Pseudomonas aeruginosa and Acinetobacter baumannii. They are useful in the treatment of infections in the urinary tract, meninges or bloodstream infections caused by these microorganisms. [4]

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Types of polymyxins

1. There are different examples of polymyxins (A to E) based on their chemical structure. [1] Aerosporin and polymyxin were the former names of polymyxin A and D, respectively. Chemically, all polymyxins belong to the category of cationic decapeptides. [5]
2. The examples of polymyxin used in clinical practice include Polymyxin B and Polymyxin E. Polymyxin E is also known as colistin. [4] Polymyxin B is a combination of four components of polymyxin i.e. PB1 to PB4. PB1 is the major component of polymyxin B. [6]
3. Although the chemical structure of colistin and polymyxin B is similar, there are differences in their pharmacokinetic properties. [3]
4. Polymyxin B can be used by intravenous, intrathecal, aerosol/inhalation or topical route. [6] For intravenous use, polymyxin B is given as an active compound, polymyxin B sulphate. [5]
5. Colistin is available as colistin sulphate for topical and oral use. [1] Colistin is given as a prodrug named colistin methanesulfonate/colistimethate sodium (CMS) for parenteral use. CMS is considered to have fewer adverse events as compared to colistin sulphate. CMS does not have intrinsic antibacterial action on its own unless it is converted into colistin in the body after its administration. [5] Polymyxin B differs from colistin in amino acid composition. These agents are not absorbed from the gastrointestinal tract after oral use. [1]

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Mechanism of action of polymyxins

Polymyxin B and colistin show their antibacterial action mainly by action on the cell membrane of the bacteria. They cause dysfunction/disruption of the outer bacterial membrane of gram-negative bacteria. It results in increased permeability, leaking of the contents in the cell leading to bacterial cell death. [1, 4] Polymyxins also have anti-endotoxin effects. [1, 4] Polymyxin B shows rapid in vitro bactericidal activity against important multi-drug resistant Gram-negative bacteria. [7]

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Dose for intravenous use

Intravenous polymyxin B is generally used in the dose of 1.5 to 2.5 mg/kg/day (~ 2 mg/kg/day) given in two equally divided doses in patients with normal renal functions. [1, 8] As colistin is available in different formulations, the dose is based on the recommendation by the manufacturer. Modification of dosage is required in patients with renal impairment. [1]

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Evidence and uses of polymyxin in serious infections caused by gram-negative bacteria

Investigators from Brazil evaluated the efficacy and safety of intravenous polymyxin B in patients with multidrug-resistant bacteria in a prospective study. In this study, patients received polymyxin B for 72 hours or more. Treatment success was seen in 25.1% of patients whereas nephrotoxicity was observed in 40.5% of patients. Mortality in the study was 32.8%. [9]

A phase II clinical study from Thailand evaluated the efficacy and safety of polymyxin B in the treatment of extensively drug-resistant gram-negative bacterial infections in 73 adults, hospitalised patients (54.8% males). A total of 94.5% of patients had underlying comorbidities and 95.9% of patients had received some antimicrobial agents in the previous two weeks. Carbapenems were received by 40.2% of patients. In these patients, intravenous polymyxin B was given in the dose of 100 mg per day every 12 hours for one to two weeks. Pneumonia was present in 60.3% of cases. Two important causative organisms in study participants included Acinetobacter baumannii (51.5%) and Pseudomonas aeruginosa (24.6%).

Good clinical responses were observed in 78.1% of patients with an overall 28-day mortality rate from all causes of 28.7%. Nephrotoxicity was observed in 24.7% of patients. Neurotoxicity (reversible numbness) was seen in two patients. [10] Colistin can be a good option for urinary tract infections, as it achieves higher levels than polymyxin B. [4] The reported nephrotoxicity rate with colistimethate sodium is 40%. [10]

Ramasubban S and colleagues [11] conducted a retrospective study to evaluate the response of polymyxin B in multidrug-resistant gram-negative severe sepsis and septic shock among 45 patients admitted in intensive care units despite carbapenem use. In this study, overall mortality was 52%. Clearance of the target organism was observed in 88% of patients.

Inhalational colistin or polymyxin B can be useful adjunctive in multi-drug resistant gram-negative pneumonia. [1]

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Safety profile

The usefulness of polymyxin in the treatment of infections caused by susceptible gram-negative bacteria (e.g. Pseudomonas aeruginosa and Acinetobacter baumannii) was not a problem, but their usage was significantly decreased due to their toxicity profile. [2]

An important adverse effect associated with intravenous administration of polymyxins is nephrotoxicity. Renal function needs close monitoring during the administration of polymyxin. Physicians should possibly avoid the concomitant use of other medicines associated with the potential to cause nephrotoxicity. [4] In patients showing signs of renal impairment as indicated by reduced urine output, and increased blood urea nitrogen and creatinine, systemic treatment with polymyxins need to be discontinued. [4]

Polymyxin B offers advantages of faster achievement of adequate levels than colistin and is associated with a lesser incidence of nephrotoxicity. [4] A prospective study by Aggarwal and Dewan among adult patients admitted in intensive care unit receiving more than 48 hours of colistin (n=61; median dose 233.3 mg/day; median duration 7 days) or polymyxin B (n=51; median dose 200 mg/day; median duration 7 days) reported nephrotoxicity in 39.3% versus 11.8% patients respectively. [12]

Neurotoxicity is another reported adverse event with intravenous use of polymyxins. The symptoms suggesting neurotoxicity include dizziness, tingling, paresthesia, numbness, vertigo etc. Sometimes, respiratory failure may be a complication of neuromuscular blockade caused by polymyxin. [4]

A systematic review published in 2006 comparing toxicities with polymyxin reported in older versus newer studies showed lesser rates and severity of nephrotoxicity in later studies compared to older ones. Similarly, it reported differences in the neurotoxic adverse effects with the polymyxins. The authors contributed these differences to a better understanding of the drug usage in terms of dosing, concurrent use of other nephrotoxic or neurotoxic agents with polymyxins, proper management of fluid and electrolyte imbalance. The utilisation of critical care services may also contribute to these differences. [2]

Other uncommon adverse events associated with the use of polymyxins include hypersensitivity reactions. Therefore, polymyxins should be avoided in patients with prior history of hypersensitivity to polymyxins or any component in the formulation. [4]

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Disclaimer: This is for education purpose only. Clinicians are requested to refer to the updated prescribing information of polymyxin B and colistin before their use.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author is a Professor of Pharmacology from Mumbai.