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The polymyxins: Renewed interest in old antibiotics
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Multidrug-resistant organisms, especially gram-negative bacteria, are an increasing health care problem in the United States and worldwide. The CDC estimates that each year in the US, there are approximately 2 million people infected with a bacteria that is resistant to at least one antibiotic.
Even more concerning is the increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant (MDR) Acinetobacter spp., and MDR Pseudomonas spp. The increasing prevalence of these organisms and the dramatic decrease in the number of antibiotics in the pipeline has led to the increased use of antibiotic combinations, including an increased reliance on older antibiotics. Recently, there has been a resurgence in the use of polymyxins (colistin, also known as polymyxin E, and polymyxin B) for the treatment of MDR infections, and their increased use has shed new light on the most effective dosing strategies for polymyxin antibiotics.
Brent Bastian
The polymyxin antibiotics were first used clinically in the 1950s, but due to high rates of toxicities (nephrotoxicity up to 50% and neurotoxicity up to 7% in early reports), they were put aside in favor of the seemingly safer aminoglycoside antibiotics in the 1970s. Colistin and polymyxin B are polypeptides with a fatty acid chain that interacts with the lipopolysaccharide (LPS) of gram-negative bacteria to exert its antibacterial effect. However, their exact mechanism of action remains unclear. They display concentration-dependent bactericidal activity against gram-negative bacteria, with the unbound area under the curve (fAUC) to minimum inhibitory concentration (MIC) being the best predictor of efficacy. They have a narrow therapeutic index, with nephrotoxicity representing the dose-limiting toxicity.
As a result of the era in which the polymyxins were developed, the dosing recommendations for colistin present in the package insert are based on limited pharmacokinetic and pharmacodynamic data and may no longer represent the most optimal dosing strategy. The package insert of colistin — formulated as colistimethate sodium (CMS) — recommends dosages of 2.5 mg/kg/day to 5 mg/kg/day of colistin base activity (1 million international units [MU] CMS=80 mg CMS=30 mg colistin base activity [CBA]) based on ideal bodyweight (IBW). This variety of formulations adds to the confusion and difficulty in dosing colistin.
There are many pharmacokinetic challenges associated with using colistin. These particularly stem from the formulation of colistin as the prodrug — colistimethate sodium. CMS was developed to lessen the pain associated with intramuscular administration; however, it has no antibacterial activity. It must first undergo hydrolysis to active colistin, which can take upwards of several hours and subsequently, therapeutic drug concentrations also may not be achieved during this time frame. The use of CMS further complicates colistin use, as CMS is predominantly renally eliminated, while the active drug, colistin, is predominantly eliminated by nonrenal pathways. This leads to difficulties in achieving therapeutic colistin concentrations in patients with normal renal function, as CMS can be renally eliminated before conversion to colistin. It has been estimated that in patients with unimpaired renal function, only 20% to 25% of CMS is converted to colistin. While it may be tempting to increase the dose of colistin in these patients, higher doses (>5 mg/kg/day CBA based on IBW) have been associated with increased nephrotoxicity. Conversely, in patients with renal impairment, the decreased elimination of CMS can lead to prolonged exposure to colistin through continued CMS hydrolysis. While colistin is not substantially renally eliminated, the dosage must be adjusted for renal insufficiency.
Kimberly D. Boeser
Recent studies have provided much-needed insight into colistin pharmacokinetics, demonstrating a prolonged half-life, and subsequently, an extended time to achieve steady-state concentrations based on traditional dosing recommendations. These studies suggest alternative dosing strategies, focusing on using high-dose extended interval dosing to overcome the pharmacokinetic limitations of colistin. The dosing strategy suggested is to administer a loading dose of 9 MU CMS to 12 MU CMS followed by 4.5 MU CMS every 12 hours. This dosing strategy was examined by Dalfino and colleagues, who found a high rate of clinical cure (82%) and decreased nephrotoxicity (17.8%) in treating MDR ventilator-associated pneumonias and bloodstream infections, albeit in a limited number of patients (n=28). Garonzik and colleagues proposed an alternative strategy by administering loading and maintenance doses based on a dosing equation utilizing body weight, renal function and the desired steady-state concentration. Additionally, recommendations were provided for how to dose in intermittent hemodialysis and in those patients receiving continuous renal replacement therapy. The clinical efficacy of this dose strategy has yet to be reported.
Historically, of the polymyxins, colistin has seen greater use due to early reports of higher rates of nephrotoxicity with polymyxin B. An ongoing debate continues in the clinical setting as to whether or not polymyxin B should replace colistin as the preferred polymyxin antibiotic. Recent studies indicate similar ranges of nephrotoxicity rates for colistin and polymyxin B, if not decreased nephrotoxicity with polymyxin B. Importantly, in contrast to colistin, polymyxin B is available in the active drug form. This eliminates the lag time associated with CMS conversion to colistin and allows for polymyxin B loading doses to rapidly achieve therapeutic concentrations. Another important advantage of polymyxin B is it is unnecessary to dose adjust in renal impairment, as polymyxin B is primarily eliminated by nonrenal pathways. This allows for more consistent plasma active drug concentrations than those achieved with CMS. While polymyxin B may offer significant advantages over colistin in terms of its pharmacokinetic profile, its historically limited use has resulted in sparse clinical efficacy literature compared with colistin.
Given the aforementioned challenges in dosing polymyxin antibiotics and their narrow therapeutic index, they are prime candidates for therapeutic drug monitoring (TDM). TDM would be particularly useful for colistin, with its wide variability in plasma drug concentrations. However, obtaining accurate levels is a challenge of its own, due to continued hydrolysis of CMS to colistin. This challenge would not apply to TDM for polymyxin B. Unfortunately, TDM for the polymyxins has not been widely implemented.
The renewed need to use the polymyxin antibiotics has resulted in an increased understanding of their pharmacokinetic and pharmacodynamic profiles. It appears from several studies that the proposed higher dosing results in improved clinical outcomes. However, significant challenges remain in attaining timely therapeutic colistin concentrations, particularly in patients with normal renal function. The superior pharmacokinetic profile of polymyxin B, while potentially advantageous, has yet to be extensively examined in clinical practice. Additional long-term studies are needed to evaluate the clinical effectiveness of these essential antibiotics. Ultimately, with the increasing prevalence of MDR gram-negative bacteria, it is imperative that the polymyxins are used appropriately in order to retain their ability to treat infections resistant to nearly all other antibiotics.
References:
Dalfino L. Clin Infect Dis. 2012;54:1720-1726.
Garonzik SM. Antimicrob Agents Chemother. 2011;55:3284-3294.
Nation RL. Clin Infect Dis. 2014;59:88-94.
Ortwine JK. Pharmacotherapy. 2014;doi:10.1002/phar.1484.
Roberts JA. Clin Infect Dis. 2014;54:1727-1729.
For more information:
Brent Bastian, PharmD, MS, is a PGY2 infectious diseases pharmacy resident at the University of Minnesota Medical Center.
Kimberly D. Boeser, PharmD, BCPS AQ-ID, is an infectious diseases clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center-Fairview and the University of Minnesota Amplatz Children’s Hospital.
Disclosure: Bastian and Boeser report no relevant financial disclosures.