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.

Keywords: colistin; colistin methanesulfonate; combination; polymyxin B; polymyxins.

Figure 1

Representative time-kill curves (left panels) with various clinically achievable concentrations of colistin (Col) and imipenem alone and in combination at an inoculum of ~10⁶ colony-forming units (CFU)/ml against three strains of Pseudomonas aeruginosa: (A) 19,147 n/m (colistin-resistant, imipenem-susceptible, multidrug-resistant (MDR), (B) 20,509 n/m (colistin- and imipenem-susceptible, non-MDR) and (C) 20,891 n/m (colistin-susceptible, imipenem-resistant, MDR). Right panels show the respective population analysis profiles (PAPs) at baseline (0 hour) and after 48 hours of exposure to colistin monotherapy, colistin/imipenem combination therapy, or neither antibiotic (control). The y axis starts from the limit of detection, and the limit of quantification (LOQ) is indicated by the horizontal broken line. (Adapted from reference 20 with permission.)

Figure 2

Representative time-kill curves with colistin and doripenem alone, and in combination, against an extensively drug-resistant (XDR) isolate of Acinetobacter baumannii. (Adapted from reference 23 with permission.)

Figure 3

Left panels: Time-kill curves with various clinically relevant dosage regimens of colistin (Col) and rifampin (Rif) alone and in combination at an inoculum of ~10⁶ colony-forming units CFU/ml (panel A) and ~10⁸ CFU/ml (panel B) against an MDR colistin-susceptible clinical isolate (FADDI-AB030) of Acinetobacter baumannii. Right panels: Population analysis profiles (PAPs) at baseline (0 hr) and after 72 hours of exposure to colistin monotherapy, colistin-rifampin combination therapy, or neither antibiotic (control). (Adapted from reference 34 with permission.)

Figure 4

Population analysis profiles (PAPs) against Pseudomonas aeruginosa ATCC 27853 with colistin monotherapy, colistin plus doripenem combination therapy, or neither antibiotic (control) at 10⁶ colony-forming units CFU/ml inoculum (left panels) and 10⁸ CFU/ml inoculum (right panels), at 24 hours (panels A and B), 72 hours (panels C and D), and 96 hours (panels E and F). Baseline (0-hr) PAPs are shown in all panels. Colonies growing on ≥4 mg/L colistin are considered resistant. The y axis starts from the limit of detection, and the limit of quantification (LOQ) is indicated by the horizontal dashed line. (Adapted from reference 33 with permission.)