Preliminary Method for Direct Quantification of Colistin Methanesulfonate by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy

Abstract

bColistin use has increased in response to the advent of infections caused by multidrug-resistant organisms. It is administered parenterally as an inactive prodrug, colistin methanesulfonate (CMS). Various formulations of CMS and labeling conventions can lead to confusion about colistin dosing, and questions remain about the pharmacokinetics of CMS. Since CMS does not have strong UV absorbance, current methods employ a laborious process of chemical conversion to colistin followed by precolumn derivatization to detect formed colistin by high-performance liquid chromatography. Here, we report a method for direct quantification of colistin methanesulfonate by attenuated total reflectance Fourier transform infrared spectroscopy (ATR FTIR). Colistin is an antibiotic of the polymyxin family. First available in the 1950s (1), its use diminished by the 1970s due to toxicity concerns and the advent of better-tolerated antibiotics. With the emergence of multidrug-resistant Gram-negative organisms, however, colistin has reappeared in clinical use (1, 2). Colistin is produced naturally by Paenibacillus polymyxa subsp. colistinus and consists of at least 30 separate components. For parenteral administration, it is converted chemically to a sulfonated prodrug, colistin methanesulfonate (CMS) (3). CMS is cleared renally, with a small fraction converted back to the active antibiotic in vivo in humans with healthy kidney function (4). CMS also converts readily to colistin in plasma ex vivo or in acidic aqueous solution (5, 6). Direct measurement of the prodrug in pharmaceutical formulations would reduce existing confusion in dosing regimens, (7,8) and the ability to directly measure the prodrug and the active drug in plasma and tissues is important for better understanding of the metabolic characteristics of colistin. Like colistin, however, CMS is a heterogeneous mixture of molecules due to differing degrees of sulfomethylation, and this heterogeneity combined with weak UV absorbance has hindered the direct measurement of this increasingly used, last-resort antibiotic prodrug.High-performance liquid chromatography (HPLC) with UV detection can be used to detect CMS but only at concentrations (0.5 to 5 mg/ml) above those expected in plasma after administration according to current dosing recommendations (9, 10). Recently, Nation and colleagues (5, 11-13) developed an HPLCfluorescence method that enables detection at the physiologically relevant level (0.5 to 30 g/ml) (4, 14, 15). In this process, CMS is converted to colistin, subsequently derivatized with fluorescent 9-fluorenylmethoxy carbonyl chloride (FMOC-Cl), and then quantified by HPLC with fluorescence detection. If the CMS is already partially converted to colistin, as in a degraded pharmaceutical preparation or a partially metabolized sample, the amount of colistin measured in the fully converted CMS is compared against the amount in the original CMS sample, which must also be derivatized using the same process (12). This method has become widely used and has enabled a n...

Targeted Delivery of Antibiotic Therapy to Inhibit Pseudomonas aeruginosa Using Lipid-Coated Mesoporous Silica Core–Shell Nanoassembly

“…The peak at 1099 cm −1 confirmed the presence of sulfate counter ion found in commercial colistin. 50 The successful liposome coating was also confirmed by the FT-IR functional groups (Figure 1e).…”

An Approach to Measuring Colistin Plasma Levels Regarding the Treatment of Multidrug-Resistant Bacterial Infection

“…Various environmental factors such as oxidative stress, high temperature or salicylate affect porin expression through micF regulation [30,31]. Mutations in outer membrane porins (OmpU, OmpA and PorB) are associated with resistance to polymyxin B ([32]. Several types of multidrug efflux pumps (MtrC–MtrD–MtrE, RosAB, AcrAB–TolC ( Escherichia coli ), NorM, KpnEF and VexAB) play an important role in tolerance toward polymyxin B (Neisseria gonorrhoeae) .…”

Estimation of the Difference in Colistin Plasma Levels in Critically Ill Patients with Favorable or Unfavorable Clinical Outcomes

“…However, recent developments in TDM for other antibiotics, such as Beta-lactams, quinolones, linezolid, or daptomycin, with their broader therapeutic indices, suggest a valid use for TDM in outcomes related to efficacy [26]. Regarding colistin, TDM includes microbiological bioassays [27,28], Fourier-transform infrared spectroscopy (FTIR) [29,30], high-resolution liquid chromatography (HPLC) [31,32], liquid chromatography-mass spectrometry (LC-MS) [33][34][35], and ultra-performance liquid chromatography-electrospray tandem mass spectrometry with electrospray ionization (UPLC-ESI-MS/MS) [36]. The HPLC technique has been widely used due to its robustness, sensitivity, and accuracy compared to other techniques, such as bioassays.…”