An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen.
An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen.
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DOI：
10.7554/elife.58147
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发表时间：
2020-12-01
期刊：
影响因子：
7.7
通讯作者：
Read AF
中科院分区：
文献类型：
--
作者：
Morley VJ;Kinnear CL;Sim DG;Olson SN;Jackson LM;Hansen E;Usher GA;Showalter SA;Pai MP;Woods RJ;Read AF
抗生素管理的一个关键挑战是弄清楚如何在治疗上使用抗生素而不促进抗生素耐药性的演变。在这里，我们展示了一种辅助疗法的概念证明，该疗法允许静脉注射抗生素治疗，而不会推动耐药性的进化和继续传播。我们重新利用 FDA 批准的胆汁酸螯合剂考来烯胺（我们证明它与抗生素达托霉素结合）作为“抗抗生素”，以阻止全身给药的达托霉素到达肠道。我们假设辅助考来烯胺可以在血液中实现达托霉素治疗，同时防止在胃肠道定植的机会性病原体出现传播性耐药性。我们在屎肠球菌胃肠道定植的小鼠模型中测试了这个想法。在用达托霉素治疗的小鼠中，辅助考来烯胺治疗使耐达托霉素屎肠球菌的粪便排出量减少了 80 倍。这些结果为减少重要医院病原体抗生素耐药性传播的方法提供了概念证明。抗生素对于治疗感染至关重要。但它们的使用可能会无意中导致对抗生素药物没有反应的耐抗生素细菌的出现，从而使这些细菌的感染难以或不可能治疗。寻找防止抗生素耐药性的方法对于保持抗生素的有效性至关重要。许多引起医院感染的细菌生活在肠道中，在那里它们是无害的。但这些细菌进入血液后可能会导致危及生命的感染。当血液感染患者接受抗生素治疗时，肠道中的细菌也会接触到药物。这可以杀死所有对抗生素敏感的细菌，只留下那些具有突变的细菌，这些突变使它们能够在药物中生存。这些耐药细菌随后会传播给其他患者，导致难以治疗的感染。为了阻止抗生素治疗和抗生素耐药性的循环，莫利等人。测试了一种名为考来烯胺的药物与静脉注射抗生素是否可以保护肠道细菌。在实验中，小鼠接受了一种名为达托霉素的抗生素的全身治疗，这种抗生素导致小鼠肠道中耐达托霉素菌株的生长。在实验室中，莫利等人。发现考来烯胺可以灭活达托霉素。同时给小鼠服用考来烯胺和达托霉素可以防止小鼠肠道内抗生素耐药细菌的生长。此外，考来烯胺是口服的，不会被吸收到血液中。因此，它只会使肠道中的抗生素失活，但不会使血液中的抗生素失活。这些实验提供了初步证据，表明考来烯胺与抗生素一起服用可能有助于防止耐药性的传播。考来烯胺已被用于降低人类胆固醇水平。需要更多的研究来确定考来烯胺是否可以保护肠道细菌并防止人们对抗生素产生耐药性。
A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens. Antibiotics are essential for treating infections. But their use can inadvertently lead to the emergence of antibiotic-resistant bacteria that do not respond to antibiotic drugs, making infections with these bacteria difficult or impossible to treat. Finding ways to prevent antibiotic resistance is critical to preserving the effectiveness of antibiotics. Many bacteria that cause infections in hospitals live in the intestines, where they are harmless. But these bacteria can cause life-threatening infections when they get into the bloodstream. When patients with bloodstream infections receive antibiotics, the bacteria in their intestines are also exposed to the drugs. This can kill off all antibiotic-susceptible bacteria, leaving behind only bacteria that have mutations that allow them to survive the drugs. These drug-resistant bacteria can then spread to other patients causing hard-to-treat infections. To stop this cycle of antibiotic treatment and antibiotic resistance, Morley et al. tested whether giving a drug called cholestyramine with intravenous antibiotics could protect the gut bacteria. In the experiments, mice were treated systemically with an antibiotic called daptomycin, which caused the growth of daptomycin-resistant strains of bacteria in the mice’s intestines. In the laboratory, Morley et al. discovered that cholestyramine can inactivate daptomycin. Giving the mice cholestyramine and daptomycin together prevented the growth of antibiotic-resistant bacteria in the mice's intestines. Moreover, cholestyramine is taken orally and is not absorbed into the blood. It therefore only inactivates the antibiotic in the gut, but not in the blood. The experiments provide preliminary evidence that giving cholestyramine with antibiotics might help prevent the spread of drug resistance. Cholestyramine is already used to lower cholesterol levels in people. More studies are needed to determine if cholestyramine can protect gut bacteria and prevent antibiotic resistance in people.
影响因子：
6.7
作者：
Pollitt LC;Reece SE;Mideo N;Nussey DH;Colegrave N
通讯作者：
Colegrave N