A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis

Lynn E Connolly, Valerie Riddle, Deborah Cebrik, Eliana S Armstrong, Loren G Miller, Lynn E Connolly, Valerie Riddle, Deborah Cebrik, Eliana S Armstrong, Loren G Miller

Abstract

Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.).

Keywords: aminoglycosides; antibacterial therapy; clinical trials; complicated urinary tract infection; plazomicin; pyelonephritis.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1
FIG 1
Patient disposition and analysis populations. a, patients could have more than one reason for exclusion.

References

    1. Zimlichman E, Henderson D, Tamir O, Franz C, Song P, Yamin CK, Keohane C, Denham CR, Bates DW. 2013. Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 173:2039–2046. doi:10.1001/jamainternmed.2013.9763.
    1. Foxman B. 2014. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 28:1–13. doi:10.1016/j.idc.2013.09.003.
    1. Nicolle LE. 2005. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol 16:349–360.
    1. Cek M, Tandogdu Z, Wagenlehner F, Tenke P, Naber K, Bjerklund-Johansen TE. 2014. Healthcare-associated urinary tract infections in hospitalized urological patients—a global perspective: results from the GPIU studies 2003-2010. World J Urol 32:1587–1594. doi:10.1007/s00345-013-1218-9.
    1. Zowawi HM, Harris PN, Roberts MJ, Tambyah PA, Schembri MA, Pezzani MD, Williamson DA, Paterson DL. 2015. The emerging threat of multidrug-resistant Gram-negative bacteria in urology. Nat Rev Urol 12:570–584. doi:10.1038/nrurol.2015.199.
    1. Bouchillon S, Hoban DJ, Badal R, Hawser S. 2012. Fluoroquinolone resistance among Gram-negative urinary tract pathogens: global SMART program results, 2009-2010. Open Microbiol J 6:74–78. doi:10.2174/1874285801206010074.
    1. Hoban DJ, Lascols C, Nicolle LE, Badal R, Bouchillon S, Hackel M, Hawser S. 2012. Antimicrobial susceptibility of Enterobacteriaceae, including molecular characterization of extended-spectrum beta-lactamase-producing species, in urinary tract isolates from hospitalized patients in North America and Europe: results from the SMART study 2009-2010. Diagn Microbiol Infect Dis 74:62–67. doi:10.1016/j.diagmicrobio.2012.05.024.
    1. Lob SH, Nicolle LE, Hoban DJ, Kazmierczak KM, Badal RE, Sahm DF. 2016. Susceptibility patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and the United States, SMART 2010–2014. Diagn Microbiol Infect Dis 85:459–465. doi:10.1016/j.diagmicrobio.2016.04.022.
    1. Tandogdu Z, Cek M, Wagenlehner F, Naber K, Tenke P, van Ostrum E, Johansen TB. 2014. Resistance patterns of nosocomial urinary tract infections in urology departments: 8-year results of the global prevalence of infections in urology study. World J Urol 32:791–801. doi:10.1007/s00345-013-1154-8.
    1. Doi Y, Park YS, Rivera JI, Adams-Haduch JM, Hingwe A, Sordillo EM, Lewis JS, Howard WJ, Johnson LE, Polsky B, Jorgensen JH, Richter SS, Shutt KA, Paterson DL. 2013. Community-associated extended-spectrum beta-lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis 56:641–648. doi:10.1093/cid/cis942.
    1. Guh AY, Bulens SN, Mu Y, Jacob JT, Reno J, Scott J, Wilson LE, Vaeth E, Lynfield R, Shaw KM, Vagnone PM, Bamberg WM, Janelle SJ, Dumyati G, Concannon C, Beldavs Z, Cunningham M, Cassidy PM, Phipps EC, Kenslow N, Travis T, Lonsway D, Rasheed JK, Limbago BM, Kallen AJ. 2015. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012-2013. JAMA 314:1479–1487. doi:10.1001/jama.2015.12480.
    1. Talan DA, Takhar SS, Krishnadasan A, Abrahamian FM, Mower WR, Moran GJ. 2016. Fluoroquinolone-resistant and extended-spectrum β-lactamase-producing Escherichia coli infections in patients with pyelonephritis, United States. Emerg Infect Dis 22:160148. doi:10.3201/eid2209.160148.
    1. Weiner LM, Fridkin SK, Aponte-Torres Z, Avery L, Coffin N, Dudeck MA, Edwards JR, Jernigan JA, Konnor R, Soe MM, Peterson K, Clifford McDonald L. 2016. Vital signs: preventing antibiotic-resistant infections in hospitals—United States, 2014. Am J Transplant 16:2224–2230. doi:10.1111/ajt.13893.
    1. Bartsch SM, McKinnell JA, Mueller LE, Miller LG, Gohil SK, Huang SS, Lee BY. 2017. Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect 23:48.e49–48.e16. doi:10.1016/j.cmi.2016.09.003.
    1. MacVane SH, Tuttle LO, Nicolau DP. 2014. Impact of extended-spectrum beta-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med 9:232–238. doi:10.1002/jhm.2157.
    1. Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. 2017. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis 17:279. doi:10.1186/s12879-017-2383-z.
    1. Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. 2010. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant Gram-negative bacteria. Antimicrob Agents Chemother 54:109–115. doi:10.1128/AAC.01041-09.
    1. Schwaber MJ, Carmeli Y. 2007. Mortality and delay in effective therapy associated with extended-spectrum beta-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis. J Antimicrob Chemother 60:913–920. doi:10.1093/jac/dkm318.
    1. Vardakas KZ, Rafailidis PI, Konstantelias AA, Falagas ME. 2013. Predictors of mortality in patients with infections due to multi-drug resistant Gram negative bacteria: the study, the patient, the bug or the drug? J Infect 66:401–414. doi:10.1016/j.jinf.2012.10.028.
    1. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States, 2013. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA.
    1. World Health Organization. 2014. Antimicrobial resistance: global report on surveillance. World Health Organization, Geneva, Switzerland.
    1. Leibovici L, Vidal L, Paul M. 2009. Aminoglycoside drugs in clinical practice: an evidence-based approach. J Antimicrob Chemother 63:246–251. doi:10.1093/jac/dkn469.
    1. Avent ML, Rogers BA, Cheng AC, Paterson DL. 2011. Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. Intern Med J 41:441–449. doi:10.1111/j.1445-5994.2011.02452.x.
    1. Grabe M, Bartoletti R, Bjerklund-Johansen TE, Cai T, Cek M, Koves B, Naber K, Pickard RS, Tenke P, Wagenlehner C, Wullt B. Guidelines on urological infections. European Association of Urology, Arnhem, The Netherlands: Accessed 29 September 2016.
    1. Pallett A, Hand K. 2010. Complicated urinary tract infections: practical solutions for the treatment of multiresistant Gram-negative bacteria. J Antimicrob Chemother 65(Suppl 3):iii25–iii33. doi:10.1093/jac/dkq298.
    1. Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Louie A. 2007. Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis 45:753–760. doi:10.1086/520991.
    1. ter Braak EW, de Vries PJ, Bouter KP, van der Vegt SG, Dorrestein GC, Nortier JW, van Dijk A, Verkooyen RP, Verbrugh HA. 1990. Once-daily dosing regimen for aminoglycoside plus beta-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone. Am J Med 89:58–66. doi:10.1016/0002-9343(90)90099-Y.
    1. Barza M, Ioannidis JP, Cappelleri JC, Lau J. 1996. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 312:338–345. doi:10.1136/bmj.312.7027.338.
    1. Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. 1999. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 43:1549–1555.
    1. Vidal L, Gafter-Gvili A, Borok S, Fraser A, Leibovici L, Paul M. 2007. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 60:247–257. doi:10.1093/jac/dkm193.
    1. Aggen JB, Armstrong ES, Goldblum AA, Dozzo P, Linsell MS, Gliedt MJ, Hildebrandt DJ, Feeney LA, Kubo A, Matias RD, Lopez S, Gomez M, Wlasichuk KB, Diokno R, Miller GH, Moser HE. 2010. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 54:4636–4642. doi:10.1128/AAC.00572-10.
    1. Zhanel GG, Lawson CD, Zelenitsky S, Findlay B, Schweizer F, Adam H, Walkty A, Rubinstein E, Gin AS, Hoban DJ, Lynch JP, Karlowsky JA. 2012. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther 10:459–473. doi:10.1586/eri.12.25.
    1. Landman D, Babu E, Shah N, Kelly P, Backer M, Bratu S, Quale J. 2010. Activity of a novel aminoglycoside, ACHN-490, against clinical isolates of Escherichia coli and Klebsiella pneumoniae from New York City. J Antimicrob Chemother 65:2123–2127. doi:10.1093/jac/dkq278.
    1. Haidar G, Alkroud A, Cheng S, Churilla TM, Churilla BM, Shields RK, Doi Y, Clancy CJ, Nguyen MH. 2016. Association between presence of aminoglycoside modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin and plazomicin against KPC and ESBL-producing Enterobacter spp. Antimicrob Agents Chemother 60:5208–5214. doi:10.1128/AAC.00869-16.
    1. Lopez-Diaz MD, Culebras E, Rodriguez-Avial I, Rios E, Vinuela-Prieto JM, Picazo JJ, Rodriguez-Avial C. 2017. Plazomicin activity against 346 extended-spectrum-beta-lactamase/AmpC-producing Escherichia coli urinary isolates, related to aminoglycoside-modifying enzymes characterized. Antimicrob Agents Chemother 61:e02454-16. doi:10.1128/AAC.02454-16.
    1. Walkty A, Adam H, Baxter M, Denisuik A, Lagace-Wiens P, Karlowsky JA, Hoban DJ, Zhanel GG. 2014. In vitro activity of plazomicin against 5,015 Gram-negative and Gram-positive clinical isolates obtained from patients in Canadian hospitals as part of the CANWARD study, 2011-2012. Antimicrob Agents Chemother 58:2554–2563. doi:10.1128/AAC.02744-13.
    1. Galani I, Souli M, Daikos GL, Chrysouli Z, Poulakou G, Psichogiou M, Panagea T, Argyropoulou A, Stefanou I, Plakias G, Giamarellou H, Petrikkos G. 2012. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J Chemother 24:191–194. doi:10.1179/1973947812Y.0000000015.
    1. Almaghrabi R, Clancy CJ, Doi Y, Hao B, Chen L, Shields RK, Press EG, Iovine NM, Townsend BM, Wagener MM, Kreiswirth B, Nguyen MH. 2014. Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents. Antimicrob Agents Chemother 58:4443–4451. doi:10.1128/AAC.00099-14.
    1. Endimiani A, Hujer KM, Hujer AM, Armstrong ES, Choudhary Y, Aggen JB, Bonomo RA. 2009. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob Agents Chemother 53:4504–4507. doi:10.1128/AAC.00641-09.
    1. Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, Woodford N. 2011. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 66:48–53. doi:10.1093/jac/dkq408.
    1. Riddle VD, Cebrik DS, Armstrong ES, Cass RT, Clobes TC, Hillan KJ. 2012. Plazomicin safety and efficacy in patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP). Abstr 52nd Intersci Conf Antimicrob Agents Chemother, San Francisco, CA, abstr L2-2118a.
    1. Clinical and Laboratory Standards Institute. 2012. Performance standards for antimicrobial susceptibility testing; 22nd informational supplement. Document M100-S22. Clinical and Laboratory Standards Institute, Wayne, PA.
    1. European Committee on Antimicrobial Susceptibility Testing. 2012. Breakpoint tables for interpretation of MICs and zone diameter, version 2.0. Accessed 25 October 2017.
    1. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. 2012. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268–281. doi:10.1111/j.1469-0691.2011.03570.x.
    1. Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Caliz I, Gonzalez-Jimenez A, Ulzurrun E, Gonzalez AF, Fernandez MC, Romero-Gomez M, Jimenez-Perez M, Bruguera M, Prieto M, Bessone F, Hernandez N, Arrese M, Andrade RJ. 2014. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology 147:109–118. doi:10.1053/j.gastro.2014.03.050.
    1. Sturm W. 1995. Isepamicin versus amikacin in the treatment of urinary tract infection. J Chemother 7(Suppl 2):S149–S154.
    1. Ipekci T, Seyman D, Berk H, Celik O. 2014. Clinical and bacteriological efficacy of amikacin in the treatment of lower urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae. J Infect Chemother 20:762–767. doi:10.1016/j.jiac.2014.08.007.
    1. Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, Yates K, Gasink LB. 2016. 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 63:754–762. doi:10.1093/cid/ciw378.
    1. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. 2015. 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 385:1949–1956. doi:10.1016/S0140-6736(14)62220-0.
    1. Fasugba O, Gardner A, Mitchell BG, Mnatzaganian G. 2015. Ciprofloxacin resistance in community- and hospital-acquired Escherichia coli urinary tract infections: a systematic review and meta-analysis of observational studies. BMC Infect Dis 15:545. doi:10.1186/s12879-015-1282-4.
    1. Bader MS, Loeb M, Brooks AA. 2017. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgrad Med 129:242–258. doi:10.1080/00325481.2017.1246055.
    1. French MA, Cerra FB, Plaut ME, Schentag JJ. 1981. Amikacin and gentamicin accumulation pharmacokinetics and nephrotoxicity in critically ill patients. Antimicrob Agents Chemother 19:147–152. doi:10.1128/AAC.19.1.147.
    1. Cass RT, Brooks CD, Havrilla NA, Tack KJ, Borin MT, Young D, Bruss JB. 2011. Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects. Antimicrob Agents Chemother 55:5874–5880. doi:10.1128/AAC.00624-11.
    1. Cockcroft DW, Gault MH. 1976. Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41. doi:10.1159/000180580.
    1. Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S, Schaeffer AJ, Tambayh PA, Tenke P, Nicolle LE. 2010. 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 50:625–663. doi:10.1086/650482.
    1. Notermans NC, van Dijk GW, van der Graaf Y, van Gijn J, Wokke JH. 1994. Measuring ataxia: quantification based on the standard neurological examination. J Neurol Neurosurg Psychiatry 57:22–26. doi:10.1136/jnnp.57.1.22.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться