Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

https://doi.org/10.1016/j.ijantimicag.2016.09.010Get rights and content

Highlights

  • Recent progress in the PK/PD and toxicity of colistin and polymyxin B (PMB)

  • Use of colistin and PMB for treatment of different types of infection

  • Strategies to optimise the clinical utility of colistin and PMB

Abstract

The polymyxin antibiotics [colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available polymyxins have very different pharmacological properties, as colistin (polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the ‘Bad Bugs, No Drugs’ era, polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative ‘superbugs’. Rational approaches to the use of polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.

Introduction

Colistin (polymyxin E) and polymyxin B (PMB) are lipopeptide antibiotics with activity against many Gram-negative bacteria [1], [2]. The polymyxins were approved for clinical use in the late 1950s but fell out of favour during the mid-1970s owing to concerns over their potential to cause nephrotoxicity and neurotoxicity [3]. Over the last two decades, clinical interest in polymyxins has increased due to the emergence of extensively drug-resistant Gram-negative bacteria coupled with the dry antibiotic development pipeline [1]. Colistin and PMB are currently considered a last-line defence against the problematic Gram-negative ‘superbugs’, notably carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, which are classified under ‘Urgent’ or ‘Serious’ threat level by the US Centers for Disease Control and Prevention (CDC) [4]. It is their use against these pathogens that will be the focus of this mini-review.

Colistin and PMB possess very similar chemical structures, differing only by one amino acid at position 6 in the peptide ring, with a d-leucine and d-phenylalanine, respectively [5]. Not surprisingly, they have very similar antimicrobial spectra and resistance mechanisms [6]. A major difference between the polymyxins is the form in which they are administered parenterally. Colistin is administered in the form of an inactive prodrug, colistin methanesulphonate (CMS) (a polyanion at physiological pH), while PMB (a polycation at physiological pH) is administered directly as its active form [1]. The different chemical forms administered have significant impacts on their pharmacokinetics and toxicity [7]. For optimal use of CMS/colistin and PMB, it is important to understand their pharmacological differences. In this mini-review, we will discuss the latest progress in the pharmacokinetics/pharmacodynamics (PK/PD) and toxicity of colistin and PMB as well as the challenges for optimal use of both polymyxins.

Section snippets

Different labelling of polymyxin products

Undoubtedly, a major contributing factor to the confusion surrounding the effective use of CMS is differences in the dosing terminology [2]. In many parts of the world, such as Europe and India, International Units (IU) are used, whereas in North and South America, Southeast Asia and Oceania colistin base activity (CBA) is used [1], [2]. One million IU (MIU) of CMS is equal to ca. 80 mg of CMS or 34 mg of CBA; a more detailed discussion on differences in labelling and dosage recommendations can

Minimum inhibitory concentrations (MICs) and mode of action

As CMS is an inactive prodrug of colistin, colistin sulphate should be used in MIC measurements for colistin [1]. To date, SENTRY Antimicrobial Surveillance Program (2006–2009) is the largest surveillance programme examining the MICs of the polymyxins. The compiled data from this programme showed that PMB and colistin have similar in vitro activities (MIC90, ≤0.5–1 mg/L) against P. aeruginosa, A. baumannii and Klebsiella pneumoniae, with very low resistance rates globally (<0.1–1.5%) [8].

Colistin methanesulphonate/colistin

The positively charged colistin exhibits a markedly different PK profile to that of the sulphomethylated derivative [1]. CMS is eliminated predominantly by the kidneys, whereas colistin is mainly cleared by a route other than renal excretion [2]. Following parenteral administration of CMS, colistin is generally formed slowly, with the plasma concentration increasing slowly. Plachouras et al. [16] showed that it can take >36 h to reach a colistin steady-state plasma concentration of 2 mg/L with

Pharmacodynamics of polymyxins

Most studies examining the pharmacodynamics of the polymyxins have been conducted using colistin [23], [32], [33], [34]. In in vitro studies, colistin shows rapid concentration-dependent killing against A. baumannii, K. pneumoniae and P. aeruginosa, with a minimal post-antibiotic effect at clinically achievable concentrations [32], [33], [34]. However, despite rapid initial killing, re-growth often occurs quickly (as early as within 2 h of the initial exposure). PMB displays very similar

Toxicodynamics of polymyxins

In the early years of their use, polymyxin-associated neurotoxicity occurred in patients with an incidence as high as 27% following parenteral administration [3], [41]. However, recent retrospective clinical studies have not shown neurotoxicity to be a major concern [42], [43]. Nephrotoxicity is by far the most common and dose-limiting side effect associated with parenteral polymyxins, with incidence rates in patients as high as 60% [44], [45]. However, the rate of nephrotoxicity in patients

Conclusions

Significant progress in understanding the pharmacology of polymyxins has been made over the past 15 years, although many gaps still remain. Scientifically-based dosing recommendations have now been developed for i.v. administration of CMS in critically ill patients and more recent studies are generating valuable insights for PMB. It is evident now that only the dose of CMS/colistin, not PMB, should be adjusted according to the patient's renal function. As CRRT can efficiently eliminate both

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