Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study

Monica Rocco 0 Luca Montini Elisa Alessandri 0 Mario Venditti Amalia Laderchi 0 Gennaro De Pascale Giammarco Raponi Michela Vitale 0 Paolo Pietropaoli 0 Massimo Antonelli 0 Anesthesiology and Intensive Care, Sapienza University of Rome , Viale del Policlinico 155, 00161 Rome , Italy Introduction: Use of colistin methanesulfonate (CMS) was abandoned in the 1970s because of excessive nephrotoxicity, but it has been reintroduced as a last-resort treatment for extensively drug-resistant infections caused by gram-negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia). We conducted a retrospective cohort study to evaluate risk factors for new-onset acute kidney injury (AKI) in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics. Methods: The cohort consisted of 279 adults admitted to two general ICUs in teaching hospitals between 1 April 2009 and 30 June 2011 with 1) no evidence on admission of acute or chronic kidney disease; and 2) treatment for more than seven days with CMS and/or other nephrotoxic antimicrobials (NAs, that is, aminoglycosides, glycopeptides). Logistic regression analysis was used to identify risk factors associated with this outcome. Results: The 279 cases that met the inclusion criteria included 147 patients treated with CMS, alone (n = 90) or with NAs (n = 57), and 132 treated with NAs alone. The 111 (40%) who developed AKI were significantly older and had significantly higher Simplified Acute Physiology Score II (SAPS II) scores than those who did not develop AKI, but rates of hypertension, diabetes mellitus and congestive heart failure were similar in the two groups. The final logistic regression model showed that in the 147 patients who received CMS alone or with NAs, onset of AKI during the ICU stay was associated with septic shock and with SAPS II scores 43. Similar results were obtained in the 222 patients treated with CMS alone or NAs alone. Conclusions: In severely ill ICU patients without pre-existing renal disease who receive CMS high-dose for more than seven days, CMS therapy does not appear to be a risk factor for this outcome. Instead, the development of AKI was strongly correlated with the presence of septic shock and with the severity of the patients as reflected by the SAPS II score. - Introduction Throughout the world, Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumonia have emerged as major causes of nosocomial infections [1], particularly in patients who are critically ill and/or immunocompromised. Concern has been raised by reports of a stepwise trend towards extensive drug-resistance in these organisms [1]. Infections caused by extensively drug-resistant (XDR) bacterial strains are associated with high mortality rates, especially in intensive care units (ICUs), where outbreaks are extremely difficult to control. The limited therapeutic options in these cases often lead clinicians to resort to salvage therapy with colistin methanesulfonate (CMS). This older polymyxin antibiotic, which is converted in vivo to colistin [2], was widely abandoned in the 1970s because of its unfavorable pharmacokinetic properties and frequent adverse effects, particularly nephrotoxicity. The modern polymyxin era [3], which began in the late 1990s, is characterized by a variety of dosing schedules, but to date there is still a dearth of information on the clinical pharmacokinetics of CMS and colistin in critically ill patients [4]. Higher doses appear to be beneficial in these cases [5], but it is unclear whether the improved efficacy comes at a cost of increased toxicity. The aim of this retrospective cohort study was to evaluate the potential risk factors for acute kidney injury (AKI), as defined by the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, End-stage kidney disease) classification system [6], in severely ill ICU patients without pre-existing renal disease who received high-dose intravenous CMS therapy for more than seven days. Materials and methods This study was conducted in two large tertiary-care teaching hospitals in Rome, Italy (Policlinico Umberto I and the Policlinico Gemelli), and it involved retrospective analysis of prospectively collected data. Cases were identified through searches of the ICU patient databases, and data were collected from the patients electronic medical records. The study cohort consisted of adults (18 years) consecutively admitted to the general ICUs of the participating facilities between April 2009 and June 2011 (Figure 1). Inclusion criteria were: 1) no evidence on ICU admission - as well as at protocol admission - of chronic renal failure and normal estimated glomerular Adult patients admitted to general ICUs of two university-teaching hospitals of Rome (Policlinico Umberto I and Policlinico Gemelli) between April 2009 and June 2011 Pts without AKI considered eligible for the study. CMS n=90 CMS/NAs n=57 Figure 1 Study design. AKI, acute kidney injury (defined according to RIFLE criteria); CMS, colistin methanesulfonate sodium; NAs, nephrotoxic antibiotics (aminoglycosides, glycopeptides); Pts, patients. filtration rate (GFR) relative to serum creatinine (SCr) based on age, race and sex formula assuming a glomerular filtration rate of 75 mL/min/1.73 m2, as recommended by the Acute Dialysis Quality Initiative (ADQI) Working Group [6]. Most ICU patients, in fact, have not a prior measure of renal function and a simplified modification of diet in renal disease (MDRD) formula provides a simple and precise estimation of baseline GFR and SCr 2) onset >48 h after ICU admission of an XDR bacterial infection treated for seven or more days with intravenous (iv) CMS and/or other nephrotoxic antimicrobial agents (NAs, that is, aminoglycosides and glycopeptides). Extensively drug-resistant (XDR) was defined as nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories (that is, bacterial isolates remain susceptible to only one or two categories) [7]. Patients were excluded if the antibiotic therapy described above had been started prior to ICU admission. The primary end point of the study was to evaluate the potential risk factors for acute kidney injury (AKI) in severely ill ICU patients without pre-existing renal disease who received high-dose intravenous CMS therapy with or without other nephrotoxic antimicrobials. For this purpose, patients were classified daily using the RIFLE criteria and AKI was defined using the serum creatinine compared to the baseline value of the SCr previously obtained from the MDRD equation. A patient was considered to have AKI when he had an increase in SCr of at least 50% from baseline (defined as Risk) or if he doubled the SCr level from the baseline (defined as Injury) or had a three times increase in SCr (defined as Failure) [6,8] (Figure 2). For each pati (...truncated)