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Effectiveness and Tolerability of A Polymyxin B Dosing Protocol

TO THE EDITOR: Optimal dosing of polymyxin B is not well defined. Limited in vitro pharmacodynamic data suggest that polymyxin B killing correlates most closely with an area under the curve/minimum inhibitory concentration (AUC/MIC) ratio.1 At our institution, historical conventional dosing of polymyxin B was based on 15,000-25,000 units/kg/day in 2 divided doses, with adjustment for renal function based on the physician’s discretion. We implemented a new polymyxin B dosing protocol to address observed clinical failures. All patients were given a loading dose of polymyxin B 25,000 units/kg on day 1. Subsequent doses and dosing interval were adjusted as follows: creatinine clearance (CrCl) >80 mL/min: 25,000 units/kg administered once every 24 hours; CrCl 30-80 mL/min: 15,000 units/kg once every 24 hours; CrCl <30 mL/min or continuous renal replacement therapy: 15,000 units/kg once every 48 hours; and CrCl <10 mL/min or hemodialysis: 10,000 units/kg once every 72 hours. Polymyxin B doses were calculated using ideal body weight.2 The objective of this study was to evaluate the effectiveness and tolerability of the new protocol as compared to conventional dosing. Methods. A retrospective chart review of sequential patients who received polymyxin B before and after protocol implementation was conducted. Patients 18 years of age or older with infections caused by multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter baumannii who were treated with polymyxin B for 72 hours or longer were included. An isolate was considered to be multidrug-resistant if it was nonsusceptible to 3 or more antimicrobial classes.3 Only the first treatment course of polymyxin B was included. Microbiologic clearance, clinical response at the end of therapy that was based on the physician’s assessment as stable/improved or deteriorating, mortality at end of therapy and at the end of hospitalization, and nephrotoxicity assessed by risk, injury, failure, loss, and end-stage kidney disease (RIFLE) criteria were evaluated.4 Results. Forty patients in each group were compared (Table 1). The mean single dose of polymyxin B was significantly higher in the protocol group compared to the conventional group, with no significant difference between groups for the mean daily dose. Microbiologic eradication was 73.3% versus 54.5% (p = 0.06) in the protocol group and conventional group, respectively, and 73.3% versus 44.4% (p = 0.01) after exclusion of catheter-related bloodstream infections (CRBSIs), since all patients with CRBSIs in the conventional group had their catheters removed with subsequent negative cultures. Microbiologic eradication was 66.7% versus 25% (p = 0.05) for respiratory infections in the protocol and conventional groups, respectively.5 Clinical response was 65% and 58% (p = 0.49) in the protocol and conventional groups, respectively. Mortality at end of therapy was 15% in the protocol group and 20% in the conventional dosing group (p = 0.56). Mortality at end of hospitalization was 30% and 38% (p = 0.48) in the protocol and conventional groups, respectively. In the protocol group, 58% of the patients met RIFLE criteria for nephrotoxicity at the time of peak serum creatinine (SCr) level compared to 20% in the conventional dosing group (p = 0.002). One week after the last polymyxin B dose, nephrotoxicity was 26.3% in the protocol group and 15.4% in the conventional group (p = 0.67). Among patients 70 years of age and older, the nephrotoxicity rate at peak SCr was 59% in the protocol group and 14% in the conventional dosing group (p = 0.008); 1 week after the last polymyxin B dose, nephrotoxicity was 30.8% in the protocol group and 0% in the conventional group (p = 0.13). In patients who developed nephrotoxicity, the mean time to peak SCr was 9 days in both groups. In this single-center retrospective evaluation, we observed a trend toward better microbiologic eradication in the protocol group, with no significant difference in clinical response and mortality. Using polymyxin B once daily for a prolonged duration may put patients at increased risk of nephrotoxicity, particularly the elderly. We also conclude that a loading dose did not correlate with nephrotoxicity, given that the time to peak SCr was identical in both groups, and might provide some benefits.