Abstract
延长使用梅洛宁/阿莫西林 - 束缚治疗XDR-TB可能与肾脏FANCONI综合征有关http://ow.ly/dFSD30gCKti
到编辑:
W.e read with interest the papers by T伊贝利et al.[1那2[描述了梅洛宁/克拉维酸盐在治疗多药(MDR)和广泛的耐药性(XDR)结核(TB)患者中的有效性。在这些分析中,96名患者用705例(综合体范围(IQR)49-156)天中位的梅洛涅姆/克拉维酸盐治疗,六个不良事件,84名患者用ImipeNem / Clavulanate治疗187名中位数(IQR)治疗(60-428)天和三个不良事件,无肾脏相关。我们报告了XDR-TB的患者,XDR-TB患者显然是由于梅洛涅姆/阿莫西林 - 克拉维酸盐显然。
A 25-year-old South Asian female with intermittently treated pulmonary XDR-TB since 2006, presented to the National Institutes of Health (NIH) in 2015 for treatment under an institutional review board-approved clinical protocol. She was started on daily linezolid, bedaquiline, clofazimine and meropenem 1.5 gI.v.with amoxicillin-clavulanate 500/125 mg orally, both every 8 h. Within 1 month, she developed mild hypophosphataemia (1.8–2.0 mg·dL-1)。Her renal function and urinalysis remained normal at 3 months. Her sputum cultures converted to negative after 98 days of treatment. At 4 months, she developed a mild normal anion gap metabolic acidosis (bicarbonate 18–19 mmol·L-1)。6 - 7个月后,她于疲劳,moderate proteinuria (600 mg/24 h), aminoaciduria, glycosuria (2–3+ with normal serum glucose), worsening hypophosphataemia with a high urine fractional excretion of phosphorus (24%) consistent with inappropriate urinary phosphate wasting, and hypouricaemia (uric acid 0.9 mg·dL-1), in addition to the normal anion gap metabolic acidosis, all consistent with generalised proximal tubular dysfunction and renal Fanconi syndrome. The aetiology was presumed secondary to medications as the patient did not have other diseases associated with acquired renal Fanconi syndrome. Renal Fanconi syndrome had not been reported with any of her active drugs so, initially, all medications were continued. Renal function remained stable but proteinuria gradually increased to 1200 mg/24 h. Urine electrophoresis was consistent with tubular protein losses. Beta-2-microglobulin levels were also elevated, consistent with proximal tubular dysfunction.
Although bedaquiline was considered the most likely culprit due to its limited long-term clinical experience, its 5.5 month half-life made evaluating the effect of stopping this drug challenging. As proteinuria continued to worsen (figure 1)患者发育间歇性感觉,LINEZOLID首先停止。在没有改善的情况下几天后,重新启动LINEZOLID并停止BEDAQUILIN。1个月后,所有TB药物都是由于疲劳恶化和尿蛋白排泄增加(2000mg / 24h; EGFR>每分钟每分钟100毫升)2)。Over the next week, the patient's fatigue, metabolic acidosis, and hypophosphataemia improved and proteinuria declined to 575 mg/24 h, despite measurable serum bedaquiline and clofazimine levels. Linezolid was restarted; proteinuria continued to decline and serum phosphorous and bicarbonate returned to baseline. Meropenem/amoxicillin-clavulanate were added next. Within 48 h, proteinuria and hepatic transaminases increased (figure 1)。Meropenem/amoxicillin-clavulanate were again discontinued with improvement in proteinuria and liver function within 3 days.
L.inezolid was subsequently discontinued after 1 year of therapy due to lower extremity neuropathy and weakness; she was maintained on bedaquiline and clofazimine alone. Follow-up urinalysis 3 months after meropenem/amoxicillin-clavulanate were discontinued showed resolution of proteinuria, glycosuria, hypouricemia, hypophosphataemia, and metabolic acidosis. She completed 11 months of meropenem/amoxicillin-clavulanate, 12 months of linezolid, and 27 months of bedaquiline and clofazimine, amounting to 2 years of treatment after sputum culture conversion. Mean QTc interval on treatment was 421.7 ms (397 ms on admission). There was no evidence of renal/urinary abnormalities at treatment completion.
虽然在常规细菌感染中有广泛的短期安全数据,但存在很少的长期数据。最近对MDR / XDR-TB的Clavulanate进行克拉巴蛋白的综述发现了良好的疗效和耐受性,没有蛋白尿或肾不良事件的报告[3.]。由于肾上腺近侧小管的功能障碍,肾小管综合征的特征在于葡萄糖,碳酸氢盐,磷酸盐,尿酸,钾和氨基酸不足,导致尿液排泄增强。FANCONI综合征可以是由于遗传突变或从接触毒素中获得的突变,这些突变损伤了近端小管的毒素(e.g.重金属,药物如氨基糖苷,替诺福韦,顺铂)或影响近端小管的疾病(e.g.multiple myeloma, amyloidosis, Sjogren syndrome). When caused by a drug, stopping the offending drug usually resolves the disease. Renal Fanconi syndrome has only been attributed to anti-tuberculous treatment twice, both times with rifampin [4.那5.]。药物诱导的肾小序综合征在我们的患者中,基于低血清碳酸氢盐,具有正常阴离子间隙酸中毒(没有其他可识别的原因如腹泻),Normoglycay糖尿病,低血清尿酸和磷浓度,具有磷酸脲,氨基遗传症和管状蛋白尿。它在时间上与Meropenem / Amoxicillin-Clavulanate相关。目前没有其他报道的Carbapems,Amoxicillin或克拉维酸盐含有肾脏综合征。Meropenem或Amoxicillin-clavulanate可能导致肾小油蛋白综合征的机制尚不清楚,但我们认为由于伴随阿莫西林 - 克拉维酸盐酸治疗药物的长期使用碳青霉蛋白来提高对这种潜在不良反应的认识是重要的抗性TB。
Disclosures
S.upplementary Material
K.N. OlivierERJ-02023-2017_Olivier
Footnotes
S.upport statement: This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases, all at the National Institutes of Health. Funding information for this article has been deposited with theCrossref Funder Registry。
利益冲突:可以在本文中找到披露www.qdcxjkg.com
- R.eceivedS.eptember 29, 2017.
- 公认October 12, 2017.
- The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2017.