The Pharmacokinetics of Colistin in Patients with Cystic Fibrosis

Abstract

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Polymyxins Revisited

“…There are no clinical data regarding outcomes of patients treated with polymyxins for infections due to organisms with an MIC of 4 g/ml. Studies suggested that peak serum concentrations of colistin can reach 10 to 30 g/ml (144). Similarly, peak polymyxin B concentrations can reach 15 g/ml after repeated dosing (89).…”

“…More prolonged administration of Coly-Mycin at 5 to 7 mg/kg/day of colistin base (equivalent to 12 to 16.8 mg/kg/day of colistimethate) produced higher serum levels (13 to 32 g/ml) (144). The serum half-life has been estimated to be ϳ3 to 4.5 h with normal renal function and increases with declining renal function (64,112,144). The data regarding Colomycin are similar: single doses of 2 to 4 mg/kg of colistimethate produced serum levels of 11 to 25 g/ml and urinary concentrations of 200 g/ml of bioactive colistin (119).…”

“…Urinary concentrations typically achieved levels of 250 to 500 g/ml (Coly-Mycin M Parenteral package insert; Monarch Pharmaceuticals, Inc., Bristol, TN) (52). More prolonged administration of Coly-Mycin at 5 to 7 mg/kg/day of colistin base (equivalent to 12 to 16.8 mg/kg/day of colistimethate) produced higher serum levels (13 to 32 g/ml) (144). The serum half-life has been estimated to be ϳ3 to 4.5 h with normal renal function and increases with declining renal function (64,112,144).…”

Efficacy and Safety Profile Comparison of Colistin and Tigecycline on the Extensively Drug Resistant <i>Acinetobacter baumannii</i>

“…In a study done in 31 cystic fibrosis patients, 21 patients (68%) were reported neurologic adverse events, like paresthesia or ataxia. 27) There are several limitations in this study. This is retrospective study based on the medical record.…”

The Re-Discovering of Old Molecules to face the Antibiotic Crisis

“…The revival of colistin, a polimixin produced by Paenibacillus polymyxa subspecies colistinus, is a significative example of the reintroduction in the treatment of infectious diseases of an old antibiotic [5]. Briefly, colistin was discovered in 1949, it was introduced in Japan and in Europe during the 1950s and used in the United States in the form of colistimethate sodium in 1959 [6]. Unluckily, the use of colistin in intravenous formulations was abandoned in the early 1980s due to significant adverse effects as nephrotoxicity [7].…”