Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial

Atul Humar, John Gill, Olwyn Johnston, Dean Fergusson, Andrew A House, Louise Lebel, Sandra Cockfield, S Joseph Kim, Jeff Zaltzman, Marcelo Cantarovich, Martin Karpinski, Tim Ramsay, Greg A Knoll, Atul Humar, John Gill, Olwyn Johnston, Dean Fergusson, Andrew A House, Louise Lebel, Sandra Cockfield, S Joseph Kim, Jeff Zaltzman, Marcelo Cantarovich, Martin Karpinski, Tim Ramsay, Greg A Knoll

Abstract

Background: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection.

Methods/design: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol.

Discussion: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition.

Trial registration: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).

References

    1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held P, Port F. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725–1730. doi: 10.1056/NEJM199912023412303.
    1. Russell JD, Beecroft M, Ludwin D, Churchill DN. The quality of life in renal transplantation-a prospective study. Transplantation. 1992;54:656–660. doi: 10.1097/00007890-199210000-00018.
    1. Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996;50:235–242. doi: 10.1038/ki.1996.307.
    1. Healthcare Systems Bureau, Division of Transplantation. 2007 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1997–2006. Rockville, MD: Health Resources and Services Administration; 2008.
    1. BK virus. Am J Transplant. 2004;4(Suppl 10):89–91.
    1. Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol. 2007;2(Suppl 1):36–46.
    1. Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, Mihatsch MJ, Nickeleit V, Ramos E, Randhawa P, Shapiro R, Steiger J, Suthanthiran M, Trofe J. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79:1277–1286. doi: 10.1097/01.TP.0000156165.83160.09.
    1. Schaub S, Hirsch HH, Dickenmann M, Steiger J, Mihatsch MJ, Hopfer H, Mayr M. Reducing immunosuppression preserves allograft function in presumptive and definitive polyomavirus-associated nephropathy. Am J Transplant. 2010;10:2615–2623. doi: 10.1111/j.1600-6143.2010.03310.x.
    1. Cheeseman SH, Black PH, Rubin RH, Cantell K, Hirsch MS. Interferon and BK Papovavirus–clinical and laboratory studies. J Infect Dis. 1980;141:157–161. doi: 10.1093/infdis/141.2.157.
    1. Hariharan S. BK virus nephritis after renal transplantation. Kidney Int. 2006;69:655–662. doi: 10.1038/sj.ki.5000040.
    1. Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant. 2006;6:2000–2005. doi: 10.1111/j.1600-6143.2006.01403.x.
    1. Almeras C, Foulongne V, Garrigue V, Szwarc I, Vetromile F, Segondy M. Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study. Transplantation. 2008;85:1099–1104. doi: 10.1097/TP.0b013e31816a33d4.
    1. De Paolis P, Gervasio E, Tedesco M, Favaro A, Iappelli M, Abbate I, Capobianchi M, Di Giulio S. Impact of preemptive reduction of immunosuppression with serial monitoring for BK virus replication in renal transplant recipients undergoing short-term evaluation. Transplant Proc. 2009;41:1207–1209. doi: 10.1016/j.transproceed.2009.03.091.
    1. Hymes LC, Warshaw BL. Polyomavirus (BK) in pediatric renal transplants: evaluation of viremic patients with and without BK associated nephritis. Pediatr Transplant. 2006;10:920–922. doi: 10.1111/j.1399-3046.2006.00575.x.
    1. Ryan J, Zanabli A, Cosio FG, Stegall MD, Larson TS, Griffin M. Outcomes of immunosuppression reduction in BK viremic kidney transplant recipients screened at 4 months post-transplant. Am J Transplant. 2007;7(Suppl 2):537.
    1. Hardinger K, Koch M, Bohl D, Storch G, Brennan D. BK-Virus and the Impact of Pre-Emptive Immunosuppression Reduction: 5-Year Results. Am J Transplant. 2010;10:407–415. doi: 10.1111/j.1600-6143.2009.02952.x.
    1. Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant. 2005;5:218–227. doi: 10.1111/j.1600-6143.2004.00692.x.
    1. Pneumocystis jiroveci (formerly Pneumocystis carinii) Am J Transplant. 2004;4:135–141. doi: 10.1111/j.1600-6135.2004.00736.x.
    1. Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41(Suppl 2):S144–S157.
    1. Leung AY, Chan MT, Yuen KY, Cheng VC, Chan KH, Wong CL, Liang R, Lie AK, Kwong YL. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40:528–537. doi: 10.1086/427291.
    1. Ali SH, Chandraker A, DeCaprio JA. Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones. Antivir Ther. 2007;12:1–6.
    1. Korzets A, Gafter U, Dicker D, Herman M, Ori Y. Levofloxacin and rhabdomyolysis in a renal transplant patient. Nephrol Dial Transplant. 2006;21:3304–3305. doi: 10.1093/ndt/gfl396.
    1. Wagenlehner FM, Kinzig-Schippers M, Sorgel F, Weidner W, Naber KG. Concentrations in plasma, urinary excretion and bactericidal activity of levofloxacin (500 mg) versus ciprofloxacin (500 mg) in healthy volunteers receiving a single oral dose. Int J Antimicrob Agents. 2006;28:551–559. doi: 10.1016/j.ijantimicag.2006.07.026.
    1. Brennan DC, Agha I, Bohl DL, Schnitzler MA, Hardinger KL, Lockwood M, Torrence S, Schuessler R, Roby T, Gaudreault-Keener M, Storch GA. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant. 2005;5:582–594. doi: 10.1111/j.1600-6143.2005.00742.x.
    1. Bressollette-Bodin C, Coste-Burel M, Hourmant M, Sebille V, Andre-Garnier E, Imbert-Marcille BM. A prospective longitudinal study of BK virus infection in 104 renal transplant recipients. Am J Transplant. 2005;5:1926–1933. doi: 10.1111/j.1600-6143.2005.00934.x.
    1. Gault MH, Longerich LL, Harnett JD, Wesolowski C. Predicting glomerular function from adjusted serum creatinine. Nephron. 1992;62:249–256. doi: 10.1159/000187054.
    1. Repchinsky C. Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2007.
    1. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004;4:611–620. doi: 10.1111/j.1600-6143.2004.00382.x.
    1. Humar A, Snydman D. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S78–S86.
    1. Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S227–S233.
    1. Hirsch HH, Drachenberg CB, Steiger J, Ramos E. Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management. Adv Exp Med Biol. 2006;577:160–173. doi: 10.1007/0-387-32957-9_11.
    1. Josephson MA, Gillen D, Javaid B, Kadambi P, Meehan S, Foster P, Harland R, Thistlethwaite RJ, Garfinkel M, Atwood W, Jordan J, Sadhu M, Millis MJ, Williams J. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006;81:704–710. doi: 10.1097/01.tp.0000181149.76113.50.
    1. Kuypers DRJ, Vandooren AK, Lerut E, Evenepoel P, Claes K, Snoeck R, Naesens L, Vanrenterghem Y. Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients. Am J Transplant. 2005;5:1997–2004. doi: 10.1111/j.1600-6143.2005.00980.x.
    1. Sener A, House AA, Jevnikar AM, Boudville N, McAlister VC, Muirhead N. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81:117–120. doi: 10.1097/01.tp.0000181096.14257.c2.
    1. Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med. 2002;347:488–496. doi: 10.1056/NEJMoa020439.
    1. Humar A, Michaels M. American society of transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006;6:262–274. doi: 10.1111/j.1600-6143.2005.01207.x.
    1. Pang XL, Doucette K, LeBlanc B, Cockfield SM, Preiksaitis JK. Monitoring of polyomavirus BK virus viruria and viremia in renal allograft recipients by use of a quantitative real-time PCR assay: one-year prospective study. J Clin Microbiol. 2007;45:3568–3573. doi: 10.1128/JCM.00655-07.
    1. Federico S, Carrano R, Capone D, Gentile A, Palmiero G, Basile V. Pharmacokinetic interaction between levofloxacin and ciclosporin or tacrolimus in kidney transplant recipients: ciclosporin, tacrolimus and levofloxacin in renal transplantation. Clin Pharmacokinet. 2006;45:169–175. doi: 10.2165/00003088-200645020-00003.
    1. Wrishko RE, Levine M, Primmett DR, Kim S, Partovi N, Lewis S. Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients. Transplantation. 1997;64:996–999. doi: 10.1097/00007890-199710150-00011.
    1. Borrows R, Chusney G, Loucaidou M, James A, Van Tromp J, Cairns T. The magnitude and time course of changes in mycophenolic acid 12-hour predose levels during antibiotic therapy in mycophenolatemofetil-based renal transplantation. Ther Drug Monit. 2007;29:122–126. doi: 10.1097/FTD.0b013e31803111d5.
    1. Moyses NM, Costa RS, Reis MA, Ferraz AS, Saber LT, Batista ME. Use of ciprofloxacin as a prophylactic agent in urinary tract infections in renal transplant recipients. Clin Transplant. 1997;11:446–452.
    1. Hibberd PL, Tolkoff-Rubin NE, Doran M, Delvecchio A, Cosimi AB, Delmonico FL, Auchincloss H, Jr, Rubin RH. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial. Online J Curr Clin Trials. 1992. Doc No 15.
    1. Nickel JC, Downey J, Clark J, Casey RW, Pommerville PJ, Barkin J. Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial. Urology. 2003;62:614–617. doi: 10.1016/S0090-4295(03)00583-1.
    1. Bundrick W, Heron SP, Ray P, Schiff WM, Tennenberg AM, Wiesinger BA. Levofloxacin versus ciprofloxacin in the treatment of chronic bacterial prostatitis: a randomized double-blind multicenter study. Urology. 2003;62:537–541. doi: 10.1016/S0090-4295(03)00565-X.

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