Polymyxin Combinations: Pharmacokinetics and Pharmacodynamics for Rationale Use

Abstract

Since their reintroduction into the clinic in the 1980s, the polymyxin antibiotics colistin—administered intravenously as an inactive prodrug, colistin methanesulfonate (CMS)—and polymyxin B have assumed an important role as salvage therapy for otherwise untreatable gram-negative infections. However, the emerging pharmacodynamic and pharmacokinetic data on CMS/colistin and polymyxin B indicate that polymyxin monotherapy is unlikely to generate plasma concentrations that are reliably efficacious. Additionally, regrowth and the emergence of resistance with monotherapy are commonly reported even when concentrations exceed those achieved clinically. Given this situation, polymyxin combination therapy, which is increasingly being used clinically, has been suggested as a possible means of increasing antimicrobial activity and reducing the development of resistance. Although considerable in vitro data support this view, investigations of polymyxin combination therapy in patients have only recently commenced. The currently available clinical data for polymyxin combinations are generally limited to retrospective analyses and small, low-powered, prospective studies using traditional dosage regimens that achieve low plasma concentrations. Considering the potential for rapid development of resistance to polymyxins, well-designed clinical trials that include higher-dose polymyxin regimens are urgently required to provide a more definitive answer regarding the role of polymyxin combination therapy compared with monotherapy. In this article, we provide an overview of key in vitro and clinical investigations examining CMS/colistin and polymyxin B combination therapy.

Colistin in Pig Production: Chemistry, Mechanism of Antibacterial Action, Microbial Resistance Emergence, and One Health Perspectives

“…In vitro and clinical investigations examining synergism of colistin combined with other antimicrobials in human medicine has been investigated recently and reviewed (Bergen et al, 2015a,b). The ultimate objective of this combination is to overcome the suboptimal exposure and the resistance emergence associated with the use of colistin in monotherapy.…”

Polymyxin B in Combination with Antimicrobials Lacking In Vitro Activity versus Polymyxin B in Monotherapy in Critically Ill Patients with Acinetobacter baumannii or Pseudomonas aeruginosa Infections

“…The first reason for this is that in clinical practice, susceptibility of GNB (particularly A. baumannii and P. aeruginosa) only to polymyxins is a quite common, if not the most common, phenotype of these XDR organisms (1). The second reason is that it suggests that a synergic action might have occurred in vivo, possibly resulting in a more potent microbiological action (16), since with the high-level resistance to carbapenems (most MICs were Ͼ32 mg/liter) presented by the isolates, the pharmacokinetic/pharmacodynamic target was unlikely to be attained even with high-dose extended infusion schemes (17). One strength of this study is that we aimed to control for the potential for indication bias, either by evaluating variables potentially associated with combination therapy use one by one in the multivariate model or by including a propensity score in the model, created with these same variables.…”

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…It is implied that patients in both groups received i.v. colistin alone with or without inhaled colistin, which can no longer be recommended given the difficulty in achieving adequate PK/PD indices and the documented regrowth and emergence of resistance with monotherapy (298). Emergence of colistin-resistant Gram-negative isolates was not explicitly reported in this study.…”