Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

Abstract

The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high-and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7-and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P ‫؍‬ 0.013) in bivariate and multivariate analyses (odds ratio [OR] ‫؍‬ 3.40; 95% confidence interval [CI], 1.37 to 8.45; P ‫؍‬ 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

“…Whether use of a loading dose and higher daily doses is associated with improved efficacy is again controversial. No comparative randomized trials have been found, although several observational or quasi-experimental studies with discrepant results have been published (269)(270)(271)(272)(273)(274)(275)(276). In most studies, renal toxicity was more frequent with higher doses.…”

Clinical and Microbiological Outcomes in Obese Patients Receiving Colistin for Carbapenem-Resistant Gram-Negative Bloodstream Infection

“…In a retrospective, single-center cohort study by Falagas and colleagues, it was concluded that mortality among patients who received an average daily colistin dose of 100 mg CBA (38.6%) was higher than the mortality among patients who received 200 mg CBA (27.8%) and 300 mg CBA (21.7%) (15). Furthermore, Gibson and colleagues, using a classification and regression tree analysis-derived cutoff, determined that patients who received Ͼ4.4 mg CBA/kg/day based on IBW were more likely to achieve global cure, microbiological clearance, and day 7 survival (16). As such, the findings of the present study appear to be contrary to those of previous studies, since obese patients were being dosed more aggressively but had similar or worse outcomes.…”

“…Assuming a global cure rate of 50% in the nonobese group (16,28), 166 patients would be needed to achieve an 80% power with an alpha of 0.05 in a one-tail test to detect a 20% absolute difference between groups. Categorical data were analyzed using either the 2 test or Fisher's exact test, as appropriate.…”

Actualización acerca de colistina (polimixina E): aspectos clínicos, PK/PD y equivalencias

“…y Acinetobacter baumannii complex y como resistente con una CIM > 2 mg/l (17,18) . Es importante destacar que el uso de colistina debería reservarse para el tratamiento específico de infecciones producidas por microorganismos resistentes a los betalactámicos, en particular los carbapenemes, o como parte del tratamiento empírico de pacientes con infecciones graves (siempre asociada a otros antimicrobianos) si se sospecha la participación de un microorganismo con ese perfil de resistencia (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) .…”

“…La resistencia a colistina se explica por mutaciones en los genes que conducen a modificaciones en la capa de LPS, sitio de acción de esta molécula (13,20) . Adicionalmente a esta modalidad, en noviembre de 2015 se informó sobre la aparición de un nuevo mecanismo de resistencia a colistina a través de plásmidos, relacionado al gen mcr-1 (Mobile Colistin Resistance), productor de una enzima responsable de la resistencia, por lo que se puede diseminar fácilmente la misma a otras bacterias (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) . Desde abril de 2016 en nuestro continente se ha identificado este mecanismo de resistencia en E. coli y otras enterobacterias, aisladas a partir de muestras de alimentos y animales, pero también de muestras clínicas de pacientes.…”