Clinical efficacy and pharmacokinetics of colistimethate sodium and colistin in critically ill patients in an Indian hospital with high endemic rates of multidrug-resistant Gram-negative bacterial infections: A prospective observational study

• Main Authors: Merlin Moni, A Sangita Sudhir, T.S. Dipu, Zubair Mohamed, Binny Pushpa Prabhu, Fabia Edathadathil, Sabarish Balachandran, Sanjeev K Singh, Preetha Prasanna, Veena P Menon, Twisha Patel, Payal Patel, Keith S Kaye, Vidya P Menon
• Format: Article
• Language: English
• Published: Elsevier 2020-11-01
• Series: International Journal of Infectious Diseases
• Subjects: Therapeutic drug monitoring; Pharmacokinetics; Colistimethate sodium; Colistin; Multidrug-resistant infections; Clinical efficacy
• Online Access: http://www.sciencedirect.com/science/article/pii/S120197122030638X

Background: Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (PD) data to guide dosing. Aim: To evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function. Materials and Methods: Twenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium – at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later – were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). Results: Among the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 ± 1.1 mg/L (1.75–5.14) and 2.37 ± 1.2 mg/L (1.52–5.54) for ‘cure’ and ‘failure’ groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 ± 1.3 mg/L and 1.78 ± 1.1 mg/L in ‘cure’ and ‘failure’ groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD. Conclusions: Subtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing.