Colistin and polymyxin B: peas in a pod, or chalk and cheese?

Abstract

Colistin and polymyxin B have indistinguishable microbiological activity in vitro, but they differ in the form administered parenterally to patients. Polymyxin B is administered directly as the active antibiotic, whereas colistin is administered as the inactive prodrug, colistin methanesulfonate (CMS). CMS must be converted to colistin in vivo, but this occurs slowly and incompletely. Here we summarize the key differences between parenteral CMS/colistin and polymyxin B, and highlight the clinical implications. We put forth the view that overall polymyxin B has superior clinical pharmacological properties compared with CMS/colistin. We propose that in countries such as the United States where parenteral products of both colistin and polymyxin B are available, prospective studies should be conducted to formally examine their relative efficacy and safety in various types of infections and patients. In the meantime, where clinicians have access to both polymyxins, they should carefully consider the relative merits of each in a given circumstance.

Keywords: colistin; differing clinical pharmacological behaviors; polymyxin B; therapeutic implications.

Figure 1.

Structures of colistin A and B and polymyxin B1 and B2 (upper panel). In polymyxin B, D-Phe (phenylalanine) replaces the D-Leu (leucine, *). Structures of colistin methanesulfonate A and B are shown (lower panel). Abbreviations: fatty acid: 6-methyloctanoic acid for colistin A and polymyxin B1, and 6-methylheptanoic acid for colistin B and polymyxin B2; Thr, threonine; Dab, α,γ-diaminobutyric acid. α and γ indicate the respective -NH₂ involved in the peptide linkage.

Figure 2.

Overview of the pharmacokinetic pathways for colistin methanesulfonate (CMS, also known as colistimethate) and colistin (left panel) and polymyxin B (right panel). The thickness of the arrows indicates the relative magnitude of the respective clearance pathways when kidney function is normal. CMS includes fully and all partially methanesulfonated derivatives of colistin. After administration of CMS, extensive renal excretion of the prodrug occurs with some of the excreted CMS converting to colistin within the urinary tract.

Figure 3.

Observed plasma concentrations of formed colistin in 10 individual critically ill patients after administration of the first dose of colistin methanesulfonate in a regimen. Reproduced with permission from the American Society for Microbiology (Mohamed et al [28]).

Figure 4.

Relationship of physician-selected daily dose of colistin base activity (CBA) (A) and the resultant steady-state plasma concentration of formed colistin (B) with creatinine clearance in 105 critically ill patients. A daily dose of 300 mg CBA is the currently approved upper limit dose. Reproduced with permission from the American Society for Microbiology (Garonzik et al [22]).

Figure 5.

Polymyxin B clearance vs calculated creatinine clearance in individual critically ill patients. Open circles represent patients not receiving any form of renal replacement therapy. The filled symbols are for 2 patients receiving continuous venovenous hemodialysis. From Sandri et al [27].