儿童重症肺炎病原学调查及病原菌耐药性分析

目的 分析厦门市儿童医院住院患儿重症肺炎病原学特点,并指导抗生素的合理运用。方法 选取2016 年1 月～2018 年12 月住院的重症肺炎患儿367 例作为研究对象。对患儿鼻咽部的分泌物做病原学检测及细菌药敏分析。结果 367 例患儿中,病原检测阳性288 例（78.47%）。288 例病原检出阳性的患儿中共检出病原株395 株,包括细菌222 株,占总病原的56.20%,革兰阴性菌、革兰阳性菌分别为142 株、80 株,以流感嗜血杆菌（51 例）,肺炎链球菌（41 例）为主;检出病毒93 株,以呼吸道合胞病毒（45 例）及腺病毒（35 例）为主,真菌感染9 例,以白色假丝酵母菌为主。肺炎支原体71 例。药敏试验结果显示,革兰阴性菌对氨苄西林、复方新诺明、庆大霉素及头孢噻肟耐药;革兰阳性菌对红霉素、四环素、青霉素及苯唑西林耐药。结论 细菌是厦门市儿童医院重症肺炎患儿鼻咽部分泌物的主要病原体,且革兰阴性菌占优势,早期进行病原菌的检测及细菌药敏实验分析对临床治疗及预后有重要作用。     

Antibiotic discovery: history,methods and perspectives

Antimicrobial resistance is considered a major public-health issue. Policies recommended by the World Health Organization (WHO) include research on new antibiotics. No new class has been discovered since daptomycin and linezolid in the 1980s, and only optimisation or combination of already known compounds has been recently commercialised. Antibiotics are natural products of soil-living organisms. Actinobacteria and fungi are the source of approximately two-thirds of the antimicrobial agents currently used in human medicine; they were mainly discovered during the golden age of antibiotic discovery. This era declined after the 1970s owing to the difficulty of cultivating fastidious bacterial species under laboratory conditions. Various strategies, such as rational drug design, to date have not led to the discovery of new antimicrobial agents. However, new promising approaches, e.g. genome mining or CRISPR-Cas9, are now being developed. The recent rebirth of culture methods from complex samples has, as a matter of fact, permitted the discovery of teixobactin from a new species isolated from soil. Recently, many biosynthetic gene clusters were identified from human-associated microbiota, especially from the gut and oral cavity. For example, the antimicrobial lugdunin was recently discovered in the oral cavity. The repertoire of human gut microbiota has recently substantially increased, with the discovery of hundreds of new species. Exploration of the repertoire of prokaryotes associated with humans using genome mining or newer culture approaches could be promising strategies for discovering new classes of antibiotics.     

Groups of coevolving positions provide drug resistance to Mycobacterium tuberculosis: A study using targets of first-line antituberculosis drugs

Drug resistance has been associated with point mutations in coding regions leading to an altered protein sequence and structure. Such changes have been seen as isolated events occurring at various positions in a sequence. However, we hypothesise that it is not a single mutation at a specific position but a group of positions that coevolve in a correlated fashion to increase the fitness of a target protein against a drug. To prove the hypothesis, selected protein sequences of Mycobacterium tuberculosis drug resistance genes were successfully screened using a bioinformatics approach to detect groups of coevolving amino acids at important structural and functional positions in the targets of first-line antituberculosis drugs (isoniazid, rifampicin, ethambutol and pyrazinamide). The algorithmically characterised genetic mutations and the lineage-specific single nucleotide polymorphisms (SNPs) detected previously in drug resistance genes of M. tuberculosis complex genomes were also found in the identified coevolving groups. Mapping of coevolving positions to the secondary structure of proteins clearly indicates the preference of amino acid residues in the helix to coevolve. Moreover, active-site residues of some candidate proteins were also found in coevolving groups. The coevolving groups detected in this study will be useful to gain new insights into the molecular and evolutionary basis of drug resistance. This work provides an important first step towards finding solutions to the multidrug resistance problem through coevolution analysis of proteins, in turn helping to develop new drug regimens against pathogens, including M. tuberculosis.     

药品管理法律责任的制度创新

目的：评析2019年版《药品管理法》中的法律责任制度的创新,明确药品市场主体的主体责任和药品监管者的监管责任,以期减少药品违法事件的发生,保证公众用药安全。方法：对比2001年版《药品管理法》,结合行政法原理,加之比较法的视角,对2019年版《药品管理法》进行解析。结果与结论：2019年版《药品管理法》强化了法律责任的重要性,设定了更为严格的法律责任,通过体系化的制度设计和完善的法律责任机制,提高了违法者的违法成本,有助于遏制和惩戒违法行为。