Treatment of BK viremia after renal transplantation: are fluoroquinolones a false dawn?

Fluoroquinolones, DNA gyrase inhibitors, display anti-BK properties through inhibition of DNA topoisomerase and polyomavirus-associated large T-antigen helicase (1,2). An in vitro analysis using older fluoroquinolone compounds, nalidixic acid and oxolinic acid, demonstrated that these agents are capable of inhibiting replication of BK virus (BKV) DNA. Another analysis using contemporary fluoroquinolones (i.e., levofloxacin, trovafloxacin, ciprofloxacin, and ofloxacin) showed that these antibiotics, in vitro, have the ability to inhibit viral DNA replication and T-antigen helicase activity of simian virus 40; this monkey polyomavirus has been associated with FSGS and other human diseases, including polyoma virus–associated nephropathy (3). Several previous studies have investigated the use of fluoroquinolones in immunosuppressed patients. In a clinical analysis of renal transplant recipients, 2months after a 10-day course of gatifloxacin, 7 of 10 recipients with urine decoy cells had reduction in viremia or disappearance of urinary decoy cells without any reduction in immunosuppression. In another retrospective analysis, 1-month treatment with ciprofloxacin, 250mg twicedaily, or levofloxacin, 250mgdaily, as part of an antipneumocystis prophylaxis strategy after renal transplantation, was associated with significantly lower rates of BK viremia at 1 year compared with patients without fluoroquinolone exposure (4). A third relevant study retrospectively compared the effect of no BKV prophylaxis in 106 patients with that of BKV prophylaxis with ciprofloxacin, 250 mg twice daily, for 30 days on the rate of BKV infection during the first 12 months after kidney transplantation. Ciprofloxacin prophylaxis was associated with less BK viremia at 3 months but not at 1 year (5). All three studies have significant limitations. Nevertheless, the findings were provocative and suggest that fluoroquinolones may prevent BK reactivation in kidney transplantation. In a related study of allogeneic hematopoietic stem cell transplant (HSCT) recipients, 90 days of prophylaxis with ciprofloxacin, 500 mg twice daily, was associated with a reduction in the incidence of BKassociated hemorrhagic cystitis, from20.9% to 2.6% (6). However, in a different study in HSCT recipients (7), ciprofloxacin reduced the reactivation of BK viruria but did not decrease the incidence of hemorrhagic cystitis. The authors surmised that ciprofloxacin resistance might have been a contributing factor because four of the seven BKV isolates were ciprofloxacin resistant in vitro. Inadequate dosing may have contributed to poor efficacy because the antibiotic dosing was not consistent in this partly retrospective study. Patients in this study received continuous oral (500 mg twice daily) or intravenous (200 mg twice daily) ciprofloxacin, but of 51 patients who initially received ciprofloxacin, 13 had their therapy interrupted and data from these patients were excluded from analysis. In addition, 7 patients were switched to ceftibuten after 1 week of therapy. Urinary ciprofloxacin levels were measured in 20 ciprofloxacin recipients, and 1 ciprofloxacin recipient was excluded from analysis because of an indefinable BKV viruria pattern. Themean urinary concentration of ciprofloxacin was 23–152.9 mg/ml compared with a level of 350 mg/ml, which would be expected after a single oral dose of 500 mg (8). In this issue of the CJASN, Lee et al. report on a prospective, multicenter, double-blinded, placebocontrolled trial performed to determine whether fluoroquinolones can effectively treat BK viremia (9). Initially, 46 patients were enrolled after diagnosis of BK viremia, but only 39 patients were randomly assigned: 20 to receive levofloxacin and 19 to receive placebo. Study patients received levofloxacin, 500 mg daily, for 30 days after detection of BK viremia, with the dose adjusted for GFR. Levofloxacin levels were notmeasured, and the duration of therapywas chosen on the basis of the earlier work by the authors (4). The two groups were fairly well matched except that more patients in the placebo group (n56) had received previous transplants compared with the levofloxacin group (n51). Despite a variety of nonstandardized secondary interventions, the percentage reduction in BK viral load at 1, 2, 3, or 6 months did not differ between groups. There was also no difference in the number of patients who achieved at least a 50% reduction in BK viral load at 3 and 6 months. The authors should be commended on several aspects of their study. First, by conducting a prospective, multicenter, double-blinded, placebo-controlled trial, they minimized the confounding associated with observational studies. Second, they used BK viremia, rather than BK viruria, to initiate treatment because BK Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri