查看更多>>摘要：Colistin, also referred to as polymyxin E, is an effective antibiotic against most multidrug-resistant Gram-negative bacteria and is currently used as a last-line drug for treating severe bacterial infections. Colistin resistance has increased gradually for the last few years, and knowledge of its multifaceted mechanisms is expanding. This includes the newly discovered plasmid-mediated colistin resistance gene mcr-1, which has been detected in over 20 countries within 3 months of its first report. We previously reported all of the known mechanisms of polymyxin resistance in our first review in 2014, but an update seems necessary in 2016, considering the significant recent discoveries that have been made in this domain. This review provides an update about what is already known, what is new, and some unresolved questions with respect to colistin resistance. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
Velkov, TonyNation, Roger L.Forrest, AlanTran, Thien B....
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查看更多>>摘要：The polymyxin antibiotics [ colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available polymyxins have very different pharmacological properties, as colistin (polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the 'Bad Bugs, No Drugs' era, polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative 'superbugs'. Rational approaches to the use of polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
查看更多>>摘要：Colistin has been used in veterinary medicine for decades, mainly for the prevention and treatment of Enterobacteriaceae infections. However, data regarding colistin resistance in bacteria from animals and food of animal origin are relatively scarce, partly because there are methodological difficulties hampering the analysis of susceptibility to colistin. Most data regarding clinical isolates are related to enteropathogenic Escherichia coli and Salmonella. The resistance percentages are sometimes high for pathogenic strains, and the mcr-1 gene has been detected in pathogenic E. coli isolates from pigs, cattle and poultry in different countries. The prevalence of colistin resistance in Salmonella from healthy animals is usually low but depends on the proportion of intrinsically colistin-resistant serotypes. For indicator E. coli, the resistance levels are often very low, although higher levels have been observed in Asia. The mcr-1 gene has been detected in indicator E. coli from pigs, cattle, poultry and their products. Thus, there is an urgent need to re-assess the use of colistin in livestock throughout the world to ensure a global strategy for preserving this last-resort antimicrobial. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
查看更多>>摘要：The proliferation of extensively drug-resistant Gram-negative pathogens has necessitated the therapeutic use of colistin and polymyxin B. However, treatment failures with polymyxin monotherapies and the emergence of polymyxin resistance have catalysed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and-resistant organisms. This mini-review examines recent (20112016) in vitro and in vivo studies that have attempted to identify synergistic polymyxin combinations against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Clinical evidence for the use of combination regimens is also discussed. (C) 2016 Published by Elsevier B.V.
查看更多>>摘要：Confronting the storm of carbapenemase-producing Gram-negative pathogens and thus facing the threat of untreatable infections, the medical community revived colistin. Not long since its re-introduction and despite the fact that resistance to colistin at least in Escherichia coli is rare, chromosomally-mediated colistin resistance in metallo-beta-lactamase-producing Klebsiella pneumoniae strains was reported in 2004 from Greece. Subsequent studies revealed the highest predominance in Italy (38%) and Greece (26%), with colistin-resistant (Col-R) strains frequently carrying a carbapenemase. On the other hand, the international prevalence of Col-R Acinetobacter baumannii varied, predominantly in Southern Europe and Southeast Asia, with rates exceeding 80% in Italy and Greece. Risk factors have mainly incriminated the selective pressure of excess consumption of colistin both in animals and humans. In November 2015, emergence of plasmid-mediated colistin resistance due to the mcr-1 gene was reported from China, mostly in community-derived E. coli strains. As of 1 September 2016, the mcr-1 gene was detected in 35 countries worldwide in livestock/retail meat and in human sources from 29 and 22 countries, respectively. Heavy usage of polymyxins in animals has been incriminated as the reservoir of the mcr-1 gene. Therefore, it is imperative that: (i) polymyxins are banned as growth promoters and for prophylaxis in animals; (ii) targeted surveillance plus molecular epidemiology is performed in hospitals; (iii) carriers or patients infected with isolates harbouring both mcr-1 and carbapenemase genes are strictly isolated; (iv) susceptibilities are based on exact colistin minimum inhibitory concentration (MIC) determination; and (v) rational use of colistin is audited in hospitals. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
查看更多>>摘要：The polymyxins (colistin and polymyxin B) have emerged over the past 20 years as essential antibacterial agents that often are the only remaining active class against troublesome multidrug-resistant Gram-negative bacilli such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. The utility of this class is limited by its dose-dependent nephrotoxicity, which can occur in more than one-half of patients receiving therapy with either agent. Strategies are urgently needed to optimise the use of this class of agents to ensure optimal activity while minimising the treatment-limiting nephrotoxicity. This review will focus on risk factors for polymyxin-associated nephrotoxicity, potential strategies for limiting this exposure-dependent toxicity and, finally, unknowns and future research directions pertinent to this topic. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
查看更多>>摘要：Reports of treatment failure and the emergence of resistance to topical head lice treatments have become increasingly common, driving the need for continued development of new therapeutic options for pediculosis. Ivermectin has been proposed as a potential alternative for the treatment of pediculosis but has not been sufficiently evaluated. In this study, the effectiveness of oral ivermectin versus shampoo in the treatment of pediculosis in Senegal was compared. The study was conducted in two neighbouring villages of Sine-Saloum, Senegal: Dielmo (ivermectin trial group; 201 female participants) and Ndiop (shampoo trial group; 239 female participants). In the ivermectin group, patients received two doses of oral ivermectin (400 mu g/kg body weight; Mectizan (R)) 7 days apart. In contrast, the shampoo group received a shampoo treatment based on D-phenothrin (0.23%; Hegor (R)). At the beginning of the study, 70 (34.8%) of 201 participants in the ivermectin group were infested by head lice versus 145 (60.7%) of 239 participants in the shampoo group. At Day 15 post-treatment, the efficacy of the treatment against head lice reached 41/53 (77.4%) in the ivermectin group (53 patients were tested in this group) versus 42/130 (32.3%) in the shampoo group (130 patients were tested in this group) (P < 10(-7)). However, 4 (7.5%) of the 53 females in the ivermectin group exhibited probable ivermectin treatment failure, suggesting the emergence of ivermectin-resistant lice. This study demonstrates that oral ivermectin is highly effective for the treatment of pediculosis compared with shampoo, but also suggests that ivermectin resistance may emerge during treatment. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
查看更多>>摘要：French and American guidelines recommend increased dosage regimens of cefazolin (CFZ) for surgical prophylaxis in patients with a body mass index (BMI) >= 35 kg/m(2) or with a total bodyweight (TBW) >= 120 kg. The objective of this study was to evaluate the accuracy of these cut-offs in identifying patients who require CFZ dose adjustment. A pharmacokinetic study was conducted in patients of varying TBW and BMI who received 2 g of CFZ intravenously for prophylaxis prior to digestive surgery. Adequacy of therapy, defined as a serum concentration of unbound CFZ (fCFZ) >= 4 mg/L, was evaluated 180 min (T-180) and 240 min (T-240) after the start of CFZ infusion. Possible factors associated with insufficient fCFZ levels were also assessed. A P-value of < 0.05 was considered statistically significant. A total of 63 patients were included in the study, categorised according to BMI (< 35 kg/m(2), 20 patients; and >= 35 kg/m(2), 43 patients) and TBW (< 120 kg, 41 patients; and >= 120 kg, 22 patients). All patients had adequate drug levels at T-180 but only 40/63 patients (63%) had adequate levels at T-240. At T-240, therapy was adequate in 15/20 patients (75%) and 25/43 patients (58%) with BMI < 35 kg/m(2) and >= 35 kg/m(2), respectively (P = 0.20), and in 28/41 patients (68%) and 12/22 patients (55%) with TBW < 120 kg and = 120 kg, respectively (P = 0.28). No factor associated with insufficient fCFZ was identified. In conclusion, current BMI and TBW cut-offs are poor indicators of which patients could benefit from increased CFZ dosage regimens. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.
查看更多>>摘要：Malaria, an infectious disease that kills more than 438,000 people per year worldwide, is a major public health problem. The emergence of strains resistant to conventional therapeutic agents necessitates the discovery of new drugs. We previously demonstrated that various substances, including terpenes, have antimalarial activity in vitro and in vivo. Nerolidol is a sesquiterpene present as an essential oil in several plants that is used in scented products and has been approved by the US Food and Drug Administration as a food-flavouring agent. In this study, the antimalarial activity of nerolidol was investigated in a mouse model of malaria. Mice were infected with Plasmodium berghei ANKA and were treated with 1000 mg/kg/dose nerolidol in two doses delivered by the oral or inhalation route. In mice treated with nerolidol, parasitaemia was inhibited by >99% (oral) and >80% (inhalation) until 14 days after infection (P < 0.0001). On Day 30 post-infection, the survival rate of orally treated mice was 90% compared with 16% in controls (P < 0.0001). In contrast, inhalation-treated mice showed a survival rate of 50% vs. 42% in controls (P > 0.05). The toxicity of nerolidol administered by either route was not significant, whilst genotoxicity was observed only at the highest dose tested. These results indicate that combined use of nerolidol and other drugs targeting different points of the same isoprenoid pathway may be an effective treatment for malaria. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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