Polymyxins are valuable antimicrobials for the management of multidrug-resistant Gram-negative bacteria; however, nephrotoxicity associated with these drugs is a very common side effect that occurs during treatment. This article briefly reviews nephrotoxic mechanisms and risk factors for polymyxin-associated acute kidney injury (AKI) and discusses dosing strategies that may mitigate kidney damage without compromising antimicrobial activity. Polymyxins have a very narrow therapeutic window and patients requiring treatment with these drugs are frequently severely ill and have multiple comorbidities, which increases the risk of AKI. Notably, there is a significant overlap between therapeutic and toxic plasma polymyxin concentrations that substantially complicates dose selection. Recent dosing protocols for both colistin and polymyxin B have been developed and may help fine tune dose adjustment of these antibiotics. Minimizing exposure to modifiable risk factors, such as other nephrotoxic agents, is strongly recommended. The dose should be carefully selected, particularly in high-risk patients. The administration of oxidative stress-reducing drugs is a promising strategy to ameliorate polymyxin-associated AKI, but still requires support from clinical studies.

Nephrotoxicity is the main adverse effect of colistin and polymyxin B (PMB). It is not clear whether these two antibiotics are associated with different nephrotoxicity rates. We compared the incidences of renal failure (RF) in patients treated with colistimethate sodium (CMS) or PMB for ≥48 h. A multicenter prospective cohort study was performed that included patients aged ≥18 years. The primary outcome was renal failure (RF) according to Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE) criteria. Multivariate analysis with a Cox regression model was performed. A total of 491 patients were included: 81 in the CMS group and 410 in the PMB group. The mean daily doses in milligrams per kilogram of body weight were 4.2 ± 1.3 and 2.4 ± 0.73 of colistin base activity and PMB, respectively. The overall incidence of RF was 16.9% (83 patients): 38.3% and 12.7% in the CMS and PMB groups, respectively ( P < 0.001). In multivariate analysis, CMS therapy was an independent risk factor for RF (hazard ratio, 3.35; 95% confidence interval, 2.05 to 5.48; P < 0.001) along with intensive care unit admission, higher weight, older age, and bloodstream and intraabdominal infections. CMS was also independently associated with a higher risk of RF in various subgroup analyses. The incidence of RF was higher in the CMS group regardless of the patient baseline creatinine clearance. The development of RF during therapy was not associated with 30-day mortality in multivariate analysis. CMS was associated with significantly higher rates of RF than those of PMB. Further studies are required to confirm our findings in other patient populations.

The objectives of this study were to assess risk factors for acute kidney injury (AKI) in patients treated with polymyxin B, a last resort antibiotic against Gram-negative bacteria, with a focus on dose, and to determine the impact of AKI on mortality of these patients. A multicentre prospective cohort study was performed including patients ≥18 years treated with intravenous polymyxin B for ≥48 h. The primary outcome was AKI defined by RIFLE criteria. Secondary outcomes were 30 day mortality and failure stage of AKI. Multivariate analysis with a Cox regression model was performed. The probability of developing AKI was determined in a logistic regression model. Four-hundred-and-ten patients were included. AKI occurred in 189 (46.1%) patients. Polymyxin B dose ≥150 mg/day was a risk factor for AKI: adjusted HR = 1.95, 95% CI = 1.31–2.89, P = 0.01. Higher weight and age were also independently associated with AKI. The probability of developing AKI significantly increased with doses between 150 and 199 mg/day, regardless of patient weight, with no significant increase with higher doses. Higher weight also increased the risk in patients receiving the same daily doses. AKI was barely associated with increased risk for 30 day mortality (adjusted HR = 1.35, 95% CI = 0.99–1.85, P = 0.06), while ≥150 mg/day did not increase this risk despite its association with AKI. Polymyxin B total dose is highly related to the risk of AKI, regardless of patient weight. Thirty-day mortality tended to be higher in patients who developed AKI. The relationship between dose, AKI and mortality must be further investigated in studies specifically designed to evaluate this latter outcome.

There is no clinical evidence supporting the use of polymyxin B in combination with another antimicrobial for infections caused by extensively drug-resistant Acinetobacter baumannii or Pseudomonas aeruginosa isolates. We developed a cohort study of patients in two intensive care units from teaching hospitals to evaluate treatment with intravenous polymyxin B for ≥48 h for severe A. baumannii or P. aeruginosa infections. Covariates potentially associated with 30-day mortality were evaluated in a Cox proportional hazards model. A total of 101 patients were included; 33 (32.7%) were treated with polymyxin B in combination with an antimicrobial lacking in vitro activity and 68 (67.3%) with polymyxin B in monotherapy. The overall 30-day mortality was 59.4% (60 patients), comprising 42.4% (14 of 33) and 67.6% (46 of 68) in combination and monotherapy groups, respectively ( P = 0.03). The mortality rates were 18.5/1,000 patient days and 36.4/1,000 patient days in the combination and monotherapy groups, respectively ( P = 0.02). Combination therapy was independently associated with lower 30-day mortality (hazard ratio, 0.33; 95% confidence interval, 0.17 to 0.64; P = 0.001). Creatinine clearance of ≥60 ml/min was also a protective factor, while a higher acute physiology and chronic health evaluation (APACHE II) score and polymicrobial infection were associated with increased mortality. The results did not change after adding a propensity score for prescribing combination therapy into the model. The protective effect remained when only combination with β-lactam or carbapenem was considered and in both subgroups of patients: those with A. baumannii infection and those with lower respiratory tract infections. To our knowledge, this is the first clinical study to show a benefit of combination over monotherapy with polymyxin B for severe extensively drug-resistant A. baumannii or P. aeruginosa infections.

To compare the efficacy of intravenous polymyxin B with other antimicrobials in the treatment of nosocomial Pseudomonas aeruginosa bacteraemia, assessing many potential confounding factors, including optimal dosage regimens of drugs. A retrospective cohort study was performed. Patients ≥18 years of age and who received appropriate therapy for ≥48 h for P. aeruginosa bacteraemia were analysed. Clinical covariates were assessed and compared between patients treated with polymyxin B and other drugs (comparators). Data were retrieved from medical records. Renal toxicity was also assessed. A Cox regression model was performed including variables with a P ≤ 0.20 in the comparison between both groups. A total of 133 patients were included: 45 (33.8%) treated with polymyxin B and 88 (66.2%) with comparators. Most comparators (83.0%) were β-lactams. The overall in-hospital mortality was 41.4% (55/133): 66.7% (30/45) and 28.4% (25/88) in polymyxin B and comparator groups, respectively (P ≤ 0.001). The final multivariate model showed that treatment with polymyxin B was independently associated with in-hospital mortality (adjusted hazard ratio 1.91, 95% confidence interval 1.05–3.45), after adjustment for Pitt bacteraemia score, and the presence of mechanical ventilation and primary bloodstream infection. Patients treated with polymyxin B presented a higher rate of ≥100% increase in creatinine level from baseline than comparators [11/45 (24.4%) versus 4/88 (4.5%); P = 0.002], although this was not subjected to multivariate analysis. Intravenous polymyxin B therapy was inferior to other drugs in the treatment of P. aeruginosa bacteraemia, as indicated by the higher rate of in-hospital mortality.