| Polymyxins, a group of polypeptide antibiotics, which consist of 5 chemically different compounds (polymyxin A-E), were discovered in 1940s. Only polymyxin B and polymyxin E (colistin) have ever been used as ’salvage’ therapy for infections However, the intravenous formulations of colistin and polymyxin B were gradually abandoned because of the reported high incidence of nephrotoxicity. So how to reduce the polymyxin-induced nephrotoxicity and clarify its safety, efficacy and dosing design is important.Section 1. The efficacy and safety of colistin combined with other antibiotics: A M eta-analysisObjective:To evaluate the efficacy and safety of colistin in combination with other antibacterials(combination therapy) and its monotherapy(monotherapy).Methods:We searched clinical trials on comparing combination therapy with monotherapy from the Cochrane Library, Pubmed and Embase up to May 2013. System analysis was conducted by RevMan 5.0 software.Results:14 controlled studies meeting the inclusion criteria were included, of which 5 studies were included in mortality rate outcomes,11 studies in clinical response outcomes,4 studys in microbiological outcome and 4 studies in nephrotoxic outcomes. Monotherapy had a higher mortality rate than combination therapy(OR=2.30,95%CI [1.28,4.13], P=0.005). The overall clinical response of monotherapy was superior to combination therapy(OR=1.59,95%CI [1.03,2.45],P=0.04),but subgroup analysis about prospective study design showed that clinical response did not differ significantly between monotherapy and combination therapy (OR=1.02,95%CI [0.53,1.94], P=0.96). Microbiological eradication had not difference significantly between monotherapy and combination therapy (OR=1.25,95%CI [0.66,2.36], P=0.50) and nephrotoxicity had also not difference(OR=0.90,95%CI [0.31,2.61,P=0.85).Conclusion:Combination therapy in the clinical response and microbiological eradication is similar to monotherapy, but in survival rates better than monotherapy. Combination therapy does not increase the nephrotoxicity of polymyxin E. Monotherapy had a higher mortality rate than combination therapy(OR=2.30,95%CI [1.28,4.13], P=0.005). The overall clinical response of monotherapy was superior to combination therapy(OR=1.59,95%CI [1.03,2.45],P=0.04),but subgroup analysis about prospective study design showed that clinical response did not differ significantly between monotherapy and combination therapy (OR=1.02,95%CI [0.53,1.94], P=0.96). Microbiological eradication had not difference significantly between monotherapy and combination therapy (OR=1.25,95%CI [0.66,2.36], P=0.50) and nephrotoxicity had also not difference(OR=0.90,95%CI [0.31,2.61,P=0.85).Conclusion:Combination therapy in the clinical response and microbiological eradication is similar to monotherapy, but in survival rates better than monotherapy. Combination therapy does not increase the nephrotoxicity of polymyxin E.Section 2. The effect of cytochrome c on the accumulation and tubular toxicity of polymyxin B in kidneyObjective This study aimed to examine the nephroprotective effect of cytochrome c against nephrotoxicity induced by polymyxin B (PMB).Methods We established an HPLC and LC-MS/MS method for rapid determination of PMB concentration in the kidney of SD rats. The homogenate of kidneys was deproteinized with sulfosalicylic acid. The separation was performed on ①a Platisil ODS C18 column, the mobile phase comprises acetonitril-sodium sulphate (0.7%, w/v)-phosphoric acid (6.8%, v/v)-water(22.25:50:5:22.75) at a flow rate of 1.0 ml/min. Detection was by UV at 205 nm(HPLC). ②MSLAB-C18(50 mm×4.6 mm,5μm) with methanol containing 0.1% formic acid-acetonitrile containing 0.1% formic acid (95:5, 0～0.5 min; 75:25,1 min; 5:95,4.1-7 min; 95:5,7.1min stop), column temperature at 50℃(LC-MS/MS).Adult Sprague-Dawley rats were treated intraperitoneally once a day for 5 days with physiological saline, PMB (4 mg·kg-1) and PMB plus cytochrome C (50,100 and 200 mg·kg-1).Drug concentration in kidney tissue,24-h NAG excretion in the urine, blood biochemical indicators and renal tissue pathology were analyzed.Results:The linear range of HPLC and LC-MS/MS was 2-20 μmL-1 (R2=0.9978) and 100～10000 ng·mL-1(R2=0.9996), respectively. The average absolute recovery was 97%～102% for the high, middle and low concentrations. The relative standard deviation obtained for inter-and intra-day assay were both less than 5%.Significantly higher drug concentrations in kidney tissue were observed in the PMB group (36.38±3.81μg·g-1) than PMB+cytochrome c (100 or 200 mg·kg-1) group (22.10±2.24,22.94±3.48 μg·g-1, respectively). The 24-h urinary NAG excretion of PMB group (1784.48 ± 270.64 mU·d-1) was significantly higher than control rats (873.85 ± 237.72 mU·d4) and PMB±cytochrome c (50,100 and 200 mg·kg-1) groups (1384.23± 221.27,1063.55±125.84 and1060.47±72.43 mU·d-1, respectively). There was almost no significant difference in SCr, BUN and β2-GM amount among all groups. Semiquantitative analysis displayed that scores of renal tissue insult in PMB group, PMB+cytochrome c 50 mg·kg-1 group, PMB+cytochrome c 100 mg·kg-1 group, PMB +cytochrome c 200 mg·kg-’group and physiological saline control group was 1.2±0.2, 0.8±0.2,0.4±0.1,0.4±0.1 and 0, respectively.Conclusion The combined treatment of polymyxin B plus 100 mg·kg-1 cytochrome c may have a beneficial role in reducing polymyxin B-Induced nephrotoxicity in rats.Review:The research status of polymyxins’Old’ colistin and polymyxin B are increasingly used as last-line therapy against multidrug-resistant gram-negative bacteria Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Over the last decade, significant progress has been made in understanding their chemistry, pharmacokinetics(PK), pharmacodynamics (PD), toxicity and so on. Those characteristics are summarized by searching the latest literatures in this review in order to provide the references for establishing rational schemes and improving clinical efficacy and safety of drug use. |
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