A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure.
A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure.
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DOI：
10.7554/elife.14003
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发表时间：
2016-03-11
期刊：
影响因子：
7.7
通讯作者：
Baker S
中科院分区：
文献类型：
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作者：
Pham Thanh D;Karkey A;Dongol S;Ho Thi N;Thompson CN;Rabaa MA;Arjyal A;Holt KE;Wong V;Tran Vu Thieu N;Voong Vinh P;Ha Thanh T;Pradhan A;Shrestha SK;Gajurel D;Pickard D;Parry CM;Dougan G;Wolbers M;Dolecek C;Thwaites GE;Basnyat B;Baker S
细菌抗菌药物敏感性、细菌遗传学和患者结局之间的相互作用知之甚少。在尼泊尔的伤寒临床治疗试验中，我们观察到几次治疗失败，并分离出高度耐氟喹诺酮的伤寒沙门氏菌（S。伤寒）。78 S伤寒分离株进行基因组测序，临床观察，治疗失败和发热清除时间（FCT）分层的谱系。大多数氟喹诺酮耐药的S.伤寒属于一个特定的H58亚型。治疗失败的S。头孢曲松组（3/31; 9.7%）的伤寒-H58发生率显著低于加替沙星组（15/34; 44.1%）（风险比0.19，p=0.002）。此外，对于加替沙星治疗的患者，感染氟喹诺酮类耐药微生物的患者的中位FCT（8.2天）显著高于感染敏感微生物（2.96天）或中度耐药微生物（4.01天）的患者（p<0.001）。H58为优势菌株。伤寒分支在国际上存在，但没有有关该生物体疾病结局的数据。本文报道了一个新的S.与氟喹诺酮类药物治疗失败相关的伤寒-H58。临床试验注册：ISRCTN 63006567。http://dx.doi.org/10.7554/eLife.14003.001摄入一种叫做伤寒沙门氏菌的细菌的人会出现伤寒的症状。这种疾病在亚洲和非洲的低收入环境中很常见，并且在未使用抗菌药物治疗的人群中导致高死亡率。在尼泊尔的一项研究中，Thanh等人试图评估两种抗菌剂中哪一种更适合治疗伤寒。其中一种叫做加替沙星的药物对一些患者不起作用。为了理解这种治疗失败的原因，Thanh等人解码了研究期间分离的所有伤寒沙门氏菌的整个DNA序列。将这些基因数据与患者的临床数据进行比较，发现了一种新的伤寒沙门氏菌变体。这些细菌具有特定的基因突变组合，使它们对加替沙星所属的氟喹诺酮类药物具有耐药性。感染变异细菌并接受加替沙星治疗的患者极有可能完全失败，并有更长时间的发热。在进一步的调查中，Thanh等人发现这些生物可能是最近从印度引入尼泊尔的。氟喹诺酮类药物是用于治疗伤寒和其他细菌感染的最有效和最常见的抗菌药物之一。然而，在南亚存在对这些化合物具有耐药性的细菌意味着它们不应该再成为该地区治疗伤寒的首选药物。DOI：http://dx.doi.org/10.7554/eLife.14003.002网站
The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(p<0.001). H58 is the dominant S. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure. Clinical trial registration: ISRCTN63006567. DOI: http://dx.doi.org/10.7554/eLife.14003.001 People who ingest a type of bacteria called Salmonella Typhi can develop the symptoms of typhoid fever. This disease is common in low-income settings in Asia and Africa, and causes a high rate of death in people who are not treated with antimicrobial drugs. During a study in Nepal, Thanh et al. tried to evaluate which of two antimicrobials was better for treating typhoid fever. One of the drugs – called gatifloxacin – did not work in some of the patients. To understand why this treatment failed, Thanh et al. decoded the entire DNA sequences of all the Salmonella Typhi bacteria isolated during the study. Comparing this genetic data to the clinical data of the patients identified a new variant of Salmonella Typhi. These bacteria have a specific combination of genetic mutations that render them resistant to the family of drugs that gatifloxacin belongs to – the fluoroquinolones. Patients infected with the variant bacteria and treated with gatifloxacin were highly likely to completely fail treatment and have longer-lasting fevers. On further investigation Thanh et al. found these organisms were likely recently introduced into Nepal from India. Fluoroquinolones are amongst the most effective and common antimicrobials used to treat typhoid fever and other bacterial infections. However, the presence of bacteria that are resistant to these compounds in South Asia means that they should no longer be the first choice of drug to treat typhoid fever in this location. DOI: http://dx.doi.org/10.7554/eLife.14003.002