Toxicity of polymyxins: a systematic review of the evidence from old and recent studies

BACKGROUND: The increasing problem of multidrug-resistant Gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of Bacillus polymyxa in 1947; only two of them, polymyxin B and E (colistin), have been used in clinical practice. Their effectiveness in the treatment of infections due to susceptible Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been generally questioned. However, their use was abandoned, except in patients with cystic fibrosis, because of concerns related to toxicity. METHODS: We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005). RESULTS: It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature. CONCLUSION: New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature

Toxicity after prolonged (more than four weeks) administration of intravenous colistin

BACKGROUND: The intravenous use of polymyxins has been considered to be associated with considerable nephrotoxicity and neurotoxicity. For this reason, the systemic administration of polymyxins had been abandoned for about 20 years in most areas of the world. However, the problem of infections due to multidrug-resistant (MDR) Gram-negative bacteria such us Pseudomonas aeruginosa and Acinetobacter baumanniii has led to the re-use of polymyxins. Our objective was to study the toxicity of prolonged intravenous administration of colistin (polymyxin E). METHODS: An observational study of a retrospective cohort at "Henry Dunant" Hospital, a 450-bed tertiary care center in Athens, Greece, was undertaken. Patients who received intravenous colistin for more than 4 weeks for the treatment of multidrug resistant Gram-negative infections were included in the study. Serum creatinine, blood urea, liver function tests, symptoms and signs of neurotoxicity were the main outcomes studied. RESULTS: We analyzed data for 19 courses of prolonged intravenous colistin [mean duration of administration (± SD) 43.4 (± 14.6) days, mean daily dosage (± SD) 4.4 (± 2.1) million IU, mean cumulative dosage (± SD) 190.4 (± 91.0) million IU] in 17 patients. The median creatinine value increased by 0.25 mg/dl during the treatment compared to the baseline (p < 0.001) but returned close to the baseline at the end of treatment (higher by 0.1 mg/dl, p = 0.67). No apnea or other evidence of neuromuscular blockade was noted in any of these patients who received prolonged treatment with colistin. CONCLUSIONS: No serious toxicity was observed in this group of patients who received prolonged intravenous colistin. Colistin should be considered as a therapeutic option in patients with infections due to multidrug resistant Gram-negative bacteria

Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis

INTRODUCTION: The clinical and economic consequences of the emergence of multidrug-resistant Gram-negative bacteria in the intensive care unit (ICU) setting, combined with the high mortality rate among patients with nosocomial pneumonia, have stimulated a search for alternative therapeutic options to treat such infections. The use of adjunctive therapy with aerosolized colistin represents one of these. There is extensive experience with use of aerosolized colistin by patients with cystic fibrosis, but there is a lack of data regarding the use of aerosolized colistin in patients without cystic fibrosis. METHODS: We conducted the present study to assess the safety and effectiveness of aerosolized colistin as an adjunct to intravenous antimicrobial therapy for treatment of Gram-negative nosocomial pneumonia. We retrospectively reviewed the medical records of patients hospitalized in a 450-bed tertiary care hospital during the period from October 2000 to January 2004, and who received aerosolized colistin as adjunctive therapy for multidrug-resistant pneumonia. RESULTS: Eight patients received aerosolized colistin. All patients had been admitted to the ICU, with mean Acute Physiological and Chronic Health Evaluation II scores on the day of ICU admission and on day 1 of aerosolized colistin administration of 14.6 and 17.1, respectively. Six of the eight patients had ventilator-associated pneumonia. The responsible pathogens were Acinetobacter baumannii (in seven out of eight cases) and Pseudomonas aeruginosa (in one out of eight cases) strains. Half of the isolated pathogens were sensitive only to colistin. The daily dose of aerosolized colistin ranged from 1.5 to 6 million IU (divided into three or four doses), and the mean duration of administration was 10.5 days. Seven out of eight patients received concomitant intravenous treatment with colistin or other antimicrobial agents. The pneumonia was observed to respond to treatment in seven out of eight patients (four were cured and three improved [they were transferred to another facility]). One patient deteriorated and died from septic shock and multiple organ failure. Aerosolized colistin was well tolerated by all patients; no bronchoconstriction or chest tightness was reported. CONCLUSION: Aerosolized colistin may be a beneficial adjunctive treatment in the management of nosocomial pneumonia (ventilator associated or not) due to multidrug-resistant Gram-negative bacteria

Secular trends of antimicrobial resistance of blood isolates in a newly founded Greek hospital

BACKGROUND: Antimicrobial resistance is one of the most challenging issues in modern medicine. METHODS: We evaluated the secular trends of the relative frequency of blood isolates and of the pattern of their in vitro antimicrobial susceptibility in our hospital during the last four and a half years. RESULTS: Overall, the data regarding the relative frequency of blood isolates in our newly founded hospital do not differ significantly from those of hospitals that are functioning for a much longer period of time. A noteworthy emerging problem is the increasing antimicrobial resistance of Gram-negative bacteria, mainly Acinetobacter baumannii and Klebsiella pneumoniae to various classes of antibiotics. Acinetobacter baumannii isolates showed an increase of resistance to amikacin (p = 0.019), ciprofloxacin (p = 0.001), imipenem (p < 0.001), and piperacillin/tazobactam (p = 0.01) between the first and second period of the study. CONCLUSION: An alarming increase of the antimicrobial resistance of Acinetobacter baumannii isolates has been noted during our study