提示: 手机请竖屏浏览!

plazomicin每日1次用药治疗复杂性尿路感染
Once-Daily Plazomicin for Complicated Urinary Tract Infections


Florian M.E. Wagenlehner ... 其他 • 2019.02.21

摘要


背景

革兰阴性尿路病原体多药耐药的情况不断增加,因此严重感染需要新的疗法。plazomicin是一种氨基糖苷类药物,对耐多药(包括对碳青霉烯类耐药)肠杆菌具有杀菌活性。

 

方法

我们以1∶1的比例将609例复杂性尿路感染(UTI;包括急性肾盂肾炎)患者随机分组,分别接受plazomicin(每日1次,每次15 mg/kg体重)或美罗培南(每8小时1 g)静脉治疗,并且在至少4日的静脉治疗后可以选择采用降级口服治疗(oral step-down therapy),总共治疗7~10日。主要目的是证明在复杂性UTI(包括急性肾盂肾炎)的治疗中,plazomicin不劣于美罗培南,非劣效性界值为15个百分点。主要终点是在微生物学改良意向治疗人群中,第5日和治愈验证(test-of-cure)访视(治疗开始后15~19日)时的复合治愈(临床治愈并且微生物学根除)。

 

结果

对于主要疗效终点,plazomicin不劣于美罗培南。第5日时,在plazomicin组88.0%的患者(191例患者中的168例)和美罗培南组91.4%的患者(197例患者中的180例)中观察到复合治愈(差异,-3.4个百分点;95%置信区间[CI],-10.0~3.1)。治愈验证访视时,分别在81.7%(191例患者中的156例)和70.1%(197例患者中的138例)的患者中观察到复合治愈(差异,11.6个百分点;95% CI,2.7~20.3)。治愈验证访视时,plazomicin组微生物学根除的患者百分比高于美罗培南组,包括对氨基糖苷类药物不敏感的肠杆菌(78.8% vs. 68.6%)和产超广谱β-内酰胺酶的肠杆菌(82.4% vs. 75.0%)的根除。后期随访时(治疗开始后24~32日),与美罗培南组相比,plazomicin组微生物学复发(3.7% vs. 8.1%)或临床复发(1.6% vs. 7.1%)的患者较少。plazomicin组7.0%患者和美罗培南组4.0%患者的血清肌酐水平升高至比基线水平高≥0.5 mg/dL(≥40 μmol/L)。

 

结论

对于肠杆菌(包括耐多药菌株)引起的复杂性UTI和急性肾盂肾炎的治疗,plazomicin每日1次用药不劣于美罗培南(由Achaogen和美国生物医学高级研究与发展管理局[Biomedical Advanced Research and Development Authority]资助;EPIC在ClinicalTrials.gov注册号为NCT02486627)。





作者信息

Florian M.E. Wagenlehner, M.D., Daniel J. Cloutier, Pharm.D., Allison S. Komirenko, Pharm.D., Deborah S. Cebrik, M.S., M.P.H., Kevin M. Krause, M.B.A., Tiffany R. Keepers, Ph.D., Lynn E. Connolly, M.D., Ph.D., Loren G. Miller, M.D., M.P.H., Ian Friedland, M.D., and Jamie P. Dwyer, M.D. for the EPIC Study Group*
From the Justus Liebig University, Giessen, Germany (F.M.E.W.); Achaogen, South San Francisco (D.J.C., A.S.K., D.S.C., K.M.K., T.R.K., L.E.C., I.F.), the David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles (L.G.M.), and Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance (L.G.M.) — all in California; and Vanderbilt University Medical Center, Nashville (J.P.D.). Address reprint requests to Dr. Wagenlehner at the Clinic for Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Rudolf-Buchheim Str. 7, 35392 Giessen, Germany, or at florian.wagenlehner@chiru.med.uni-giessen.de. *A complete list of the principal investigators in the EPIC Study is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014;28:1-13.

2. Johnson JR, Russo TA. Acute pyelonephritis in adults. N Engl J Med 2018;378:48-59.

3. Bonkat G, Pickard R, Bartoletti R, et al. EAU guidelines on urological infections. Arnhem, the Netherlands: European Association of Urology (https://uroweb.org/guideline/urological-infections/#1).

4. Guidance for industry — complicated urinary tract infections: developing drugs for treatment. Silver Spring, MD: Food and Drug Administration, February 2015.

5. Sammon JD, Sharma P, Rahbar H, et al. Predictors of admission in patients presenting to the emergency department with urinary tract infection. World J Urol 2014;32:813-819.

6. Bader MS, Loeb M, Brooks AA. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgrad Med 2017;129:242-258.

7. Lee YC, Hsiao CY, Hung MC, et al. Bacteremic urinary tract infection caused by multidrug-resistant Enterobacteriaceae are associated with severe sepsis at admission: implication for empirical therapy. Medicine (Baltimore) 2016;95(20):e3694-e3694.

8. Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis 2017;17:279-279.

9. Golan Y. Empiric therapy for hospital-acquired, Gram-negative complicated intra-abdominal infection and complicated urinary tract infections: a systematic literature review of current and emerging treatment options. BMC Infect Dis 2015;15:313-313.

10. Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st century — a clinical super-challenge. N Engl J Med 2009;360:439-443.

11. Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis 2016;3:15-21.

12. Castanheira M, Woosley LN, Doyle TB, et al. Aminoglycoside-resistance genes among 2014-2015 US carbapenem-resistant Enterobacteriaceae isolates and activity of plazomicin against characterized isolates. Presented at the American Society of Microbiology (ASM) Microbe 2017, New Orleans, June 1–5, 2017 (poster).

13. Castanheira M, Doyle T, Woosley LN, et al. Plazomicin activity against European Enterobacteriaceae isolates carrying aminoglycoside-modifying enzymes and 16S rRNA methylases. Presented at the Annual European Congress of Clinical Microbiology and Infectious Diseases, Vienna, April 22–25, 2017 (poster).

14. Aggen JB, Armstrong ES, Goldblum AA, et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 2010;54:4636-4642.

15. Castanheira M, Davis AP, Mendes RE, Serio AW, Krause KM, Flamm RK. In vitro activity of plazomicin against gram-negative and gram-positive isolates collected from U.S. hospitals and comparative activities of aminoglycosides against carbapenem-resistant Enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob Agents Chemother 2018;62(8):e00313-18.

16. Castanheira M, Doyle TB, Serio AW, et al. In vitro activity of plazomicin and comparator agents against urinary tract infection isolates from the United States and Europe. Presented at the American Society of Microbiology (ASM) Microbe 2017, New Orleans, June 1–5, 2017 (poster).

17. Thwaites M, Hall D, Shinabarger D, et al. Evaluation of the bactericidal activity of plazomicin and comparators against multidrug-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2018;62(8):e00236-18-e00236-18.

18. McKinnell JA, Dwyer JP, Talbot GH, et al. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med 2019;380:791-793.

19. Guidance for industry: antibacterial therapies for patients with an unmet medical need for the treatment of serious bacterial diseases. Silver Spring, MD: Food and Drug Administration, August 2017 (https://www.fda.gov/downloads/Drugs/Guidances/UCM359184.pdf).

20. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

21. Performance standards for antimicrobial susceptibility testing: 25th informational supplement. Wayne, PA: Clinical and Laboratory Standards Institute, 2015.

22. Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol 2009;20:672-679.

23. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-3370.

24. Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm 1974;8:5-5.

25. Bone RC. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 1992;268:3452-3455.

26. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268-281.

27. Spivak ES, Burk M, Zhang R, et al. Management of bacteriuria in Veterans Affairs hospitals. Clin Infect Dis 2017;65:910-917.

28. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010;50:625-663.

29. Köves B, Cai T, Veeratterapillay R, et al. Benefits and harms of treatment of asymptomatic bacteriuria: a systematic review and meta-analysis by the European Association of Urology Urological Infection Guidelines Panel. Eur Urol 2017;72:865-868.

30. Ellis-Grosse E, Eckburg P, Skarinsky D, et al. Phenotypic antibiotic resistance in ZEUS: a multi-center, randomized, double-blind phase 2/3 study of ZTI-01 versus piperacillin-tazobactam (P-T) in the treatment of patients with complicated urinary tract infections (cUTI) including acute pyelonephritis (AP). Presented at: IDWeek, San Diego, CA, October 4–8, 2017 (poster).

31. Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial. JAMA 2018;319:788-799.

32. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015;385:1949-1956.

33. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999;43:1003-1012.

34. Hsu CY, Ordoñez JD, Chertow GM, Fan D, McCulloch CE, Go AS. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int 2008;74:101-107.

35. Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis 2016;63:754-762.

服务条款 | 隐私政策 | 联系我们