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Ciprofloxacin Decreased Polyoma BK Virus Load in Patients Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation

  1. Anskar Y. H. Leung1,
  2. Maggie T. L. Chan1,
  3. Kwok-Yung Yuen2,
  4. Vincent C. C. Cheng2,
  5. Kwok-Hung Chan2,
  6. Chris L. P. Wong2,
  7. Raymond Liang1,
  8. Albert K. W. Lie1, and
  9. Yok-Lam Kwong1
  1. 1Departments of Medicine and University of Hong Kong, China
  2. 2Departments of Microbiology, University of Hong Kong, China
  1. Reprints or correspondence: Dr. Y. L. Kwong, Dept. of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Rd., Hong Kong, China (ylkwong{at}hkucc.hku.hk).
 
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Abstract

Background. Polyoma BK virus (BKV) is associated with hemorrhagic cystitis during hematopoietic stem cell transplantation (HSCT). The objective of this study was to test whether standard-dose ciprofloxacin might suppress reactivation of BKV infection during HSCT.

Methods. Sixty-eight patients received ciprofloxacin or a cephalosporin as antibiotic prophylaxis after undergoing allogeneic HSCT. Urine samples were collected weekly from day 7 before HSCT to day 50 after HSCT. Laboratory investigations included quantification of BKV load and urinary ciprofloxacin levels and in vitro drug sensitivity of BKV.

Results. Twenty-two patients received ciprofloxacin, 21 received cephalosporins, 12 received concomitant corticosteroids and antibiotics (9 received ciprofloxacin, and 3 received cephalosporins), and 13 received interrupted ciprofloxacin therapy. Ciprofloxacin recipients developed a significantly lower peak BKV load, compared with cephalosporin recipients (median, 3 × 105 copies/mL vs. 2.6 × 109 copies/mL; P = .021), irrespective of concomitant receipt of corticosteroid therapy. Fewer ciprofloxacin recipients than cephalosporin recipients (P = .013) developed BKV viruria with a ⩾3-log increase in BKV load during HSCT, which was associated with significantly more cases of hemorrhagic cystitis (8 of 29 patients with a peak increase of ⩾3 log vs. 0 of 39 patients without a peak increase of this level; P < .001). Ciprofloxacin recipients excreted ciprofloxacin in urine at a mean 24-h rate of 71.7 µg/mL (range, 23.0–152.9 µg/mL), which was comparable with the in vitro inhibitory concentration of 125–250 µg/mL of ciprofloxacin found for 3 of 7 BKV isolates.

Conclusions. Ciprofloxacin decreased urinary BKV reactivation after HSCT.

Polyoma BK virus (BKV) infects >80% of adults [1], remaining latent in the urinary tract. Asymptomatic reactivation of infection with urinary shedding may occur in immunocompetent individuals [2]. During immunosuppression, BKV may be pathogenic [3, 4]. In patients who undergo hematopoietic stem cell transplantation (HSCT), BKV is linked to hemorrhagic cystitis [5, 6]. In patients who undergo renal transplantation, reactivation of BKV infection leads to BKV-associated nephropathy [7, 8].

Hemorrhagic cystitis occurs in 7%–70% of patients after HSCT [9–13]. Severe hemorrhagic cystitis (gross hematuria) occurs in ∼15% of patients [12]. Preengraftment hemorrhagic cystitis is usually mild, but postengraftment cases are more severe [12]. Previously, we established a quantitative relationship between BKV viruria and hemorrhagic cystitis after HSCT [6]. Furthermore, significant BKV viruria invariably occurred in patients with severe hemorrhagic cystitis, suggesting that it was a prerequisite. Moreover, rates of BKV viruria and hemorrhagic cystitis appeared to be decreased among some patients receiving ciprofloxacin (unpublished data). In fact, the quinolone antibiotics have been shown to inhibit BKV replication [14, 15]. These observations led us to test the efficacy of ciprofloxacin, which was among the antibiotics used for routine prophylaxis during HSCT, in reducing the rate of reactivation of BKV infection. The primary objective was suppression of BKV viruria. The secondary objective was a decrease in the rate of severe hemorrhagic cystitis.

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Patients and Methods

Patients and HSCT protocols. Consecutive patients who had undergone myeloablative allogeneic HSCT at Queen Mary Hospital, Hong Kong, were studied. HSCT protocols have been described elsewhere [6, 12, 16, 17]. Hemorrhagic cystitis was defined as painful hematuria not due to infection or bleeding diathesis. Severe hemorrhagic cystitis was treated with hydration, bladder irrigation, cystoscopy, and alum or formalin instillation.

Antibiotics regimen. From the conditioning period to day 50 after HSCT, patients received either continuous oral (500 mg b.i.d.) or intravenous (200 mg b.i.d.) ciprofloxacin or oral ceftibuten (400 mg q.d.) (or intravenous cephalosporin or imipenem). The protocol was approved by the institutional review board at Queen Mary Hospital.

Urinary sample collection. Twenty-four—hour urine specimens were collected before conditioning, on the day of marrow infusion (day 0), and weekly thereafter until day 50. A 50-mL sample was aliquoted and centrifuged at 2000 g for 10 min. DNA was extracted from 200 µL of free urine by the QIAamp Blood Minikit (Qiagen) and eluted with 200 µL of buffer [6].

Quantification of urinary ciprofloxacin level by high-performance liquid chromatography (HPLC). Two hundred microliters of urine was mixed with 20 µL of internal standard (pipemidic acid at 100 µg/mL; Sigma). The samples were vortex-mixed with acetonitrile (BDH) and centrifuged. Twenty microliters of the supernatant was injected into the Agilent 1100 HPLC system (Agilent Technologies). Urine standards containing ciprofloxacin, 0.5–100 µg/mL, were prepared by spiking standard ciprofloxacin solutions to aliquots of drug-free urine.

Real-time quantitative PCR for BKV. Real-time quantitative PCR (Q-PCR) was performed with the ABI Prism 7700 Sequence Detector (PE Biosystems). Sequences of the Q-PCR primers and TaqMan probe (targeting the BKV VP1 gene), amplification protocols, and quality assurance were reported elsewhere [6].

Inhibition of BKV replication in vitro. Thirty-one urine samples obtained at the time of maximum BKV load from 20 patients who had undergone HSCT were used in the study. Two hundred microliters of urine was inoculated into a human embryonic lung fibroblast line HEL and incubated until cytopathic effects occurred or for 30 days. In the latter case, the cells were further passaged so that cytopathic effects of slow-growing BKV could be observed. Results for successful isolates were confirmed by PCR [18]. The anti-BKV activity of ciprofloxacin was tested at concentrations of 500, 250, and 125 µg/mL. The anti-BKV activities of foscarnet (at concentrations of 500, 1000, and 2000 µg/mL), cidofovir (at 31.25, 62.5, and 125 µg/mL), levofloxacin (at 125, 250, and 500 µg/mL), and novobiocin (at 50, 100, and 200 µg/mL) were also tested. The inhibition test was performed in a 96-well microtiter plate containing 0.1 mL of HEL cells. A mixture of 0.1 mL containing 10 or 100 TCID50 (1 TCID50 is equivalent to the highest viral dilution that led to cytopathic effects in 50% of cells [19]) of BKV and different concentrations of drugs was prepared and inoculated into duplicate wells. The plate was incubated for 28–35 days. The virus-drug mixtures were then removed and replaced by 0.2 mL of culture medium after 7 days. One-half of the medium in each well was changed weekly. Concentrations that inhibited BKV at dilutions of 10 or 100 TCID50 were defined as the concentrations that prevented cytopathic effects in HEL cells at the viral dosage tested. For quality assurance, dilutions of 10 and 100 TCID50 were back-titrated to 1 TCID50 to demonstrate cytopathic effects in 50% of cells [19].

Statistical analysis. Results were expressed as median values, unless otherwise indicated. Comparison of categorical data was performed with the Pearson χ2 test and of numerical data with the Mann-Whitney U test and Student's t test (SPSS software, version 11.5; SPSS). P values of <.05 were considered to be statistically significant.

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Results

Patients and antibiotic therapy. Sixty-eight patients who had undergone HSCT were recruited (33 were recruited prospectively, and 35 were recruited retrospectively [6]) (tables 1–3). Twenty-two patients received ciprofloxacin. Fourteen patients received ceftibuten. Seven patients received ciprofloxacin initially, but their regimens were later changed to a cephalosporin and/or imipenem. These 21 patients constituted the nonciprofloxacin group. Twelve patients (9 ciprofloxacin recipients and 3 ceftibuten recipients) were given corticosteroids (for graft-versus-host disease [GVHD; 10 patients], as a conditioning regimen [1 patient], or for treatment of rashes [1 patient]). Ciprofloxacin therapy was interrupted for 13 patients, and data for these patients were excluded from analysis of the effect of ciprofloxacin on BKV viruria. There was no difference in demographic or clinical characteristics between the patient groups (P > .05, by χ2 test) (table 1).

Quantification of BKV load. Sixty-five (95.6%) of 68 patients had quantifiable BKV viruria, with 605 samples assayed in triplicate. The peak BKV load ranged from 1.3 × 103 genome copies/mL to 3.2 × 1014 genome copies/mL. Two patterns of BKV viruria were observed. The first pattern occurred in 29 patients and involved increases in the BKV load and a significant peak (defined as an increase of ⩾3 log), occurring at a median of 21 days after HSCT (range, 7–35 days after HSCT) (table 2 and figure 1A). The second pattern occurred in 32 patients, who had quantifiable but fluctuating BKV loads not associated with significant peaking (table 3 and figure 1B); a subgroup of 5 patients in this category had a decrease in the BKV load (figure 1B). The peak BKV load differed (patients with a ⩾3-log increase, 4.0 × 109 copies/mL; patients with a <3-log increase, 7.9 × 104 copies/mL; P < .001). Furthermore, mean BKV loads also differed significantly between the second and the seventh week after HSCT (figure 2). Seven patients had indefinable patterns of viruria (no quantifiable viruria, 3 patients; progressive low-level increases in virus load, 2 patients; incomplete urine samples collected, 2 patients). These 3 groups did not differ with regard to any clinicopathological parameters (P > .05, by χ2 test) (table 4).

Figure 1
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Figure 1

Recurrent patterns of BK virus (BKV) viruria in patients after hematopoietic stem cell transplantation (HSCT). A, Profile of significant peaking in the BKV load (⩾3-log increase) for a typical patient with this pattern. Such peaking occurred in 29 patients. B, Profile of fluctuations of BKV level in a typical patient without significant peaking (i.e., a <3-log increase). Such fluctuations occurred in 32 patients. Inset, Profile of 1 of 5 patients with this pattern of peaking who had the highest BKV load at admission, with a progressive decrease in the BKV load during HSCT. All 5 of these patients received ciprofloxacin.

Figure 2
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Figure 2

Mean BK virus (BKV) load during hematopoietic stem cell transplantation (HSCT) for patients with (diamond) and without (square) significant increases in BKV load. Each time point represents the mean BKV load for the whole cohort (the error bar denotes 1 SEM). In some patients, collection of urine samples was extended up to day 63 after HSCT. There was no significant difference (P = not significant [NS]) before conditioning and at days 56 and 63 after HSCT. However, a significant difference in the BKV load occurred from the second to the seventh week. *P < .05; **P < .01; ***P < .001.

BKV viruria and the risk of severe hemorrhagic cystitis. Eight patients developed severe hemorrhagic cystitis, all of whom had an increase in the BKV load of ⩾3 log, compared with none of the patients without significant increases in BKV load (8 of 29 vs. 0 of 32; P < .001, by χ2 test) (table 4). With use of ⩾3-log increases in BKV load, the sensitivity and specificity for severe hemorrhagic cystitis were determined to be 100% and 65%, respectively, whereas the positive and negative predictive values were 28% and 100%, respectively. In all 8 patients with severe hemorrhagic cystitis, the peak BKV load preceded the onset of hemorrhagic cystitis (median time to onset of hemorrhagic cystitis, 29 days; range, 2–118 days).

Urinary ciprofloxacin levels. Urinary ciprofloxacin levels were measured in 20 of 21 ciprofloxacin recipients (7 patients with a ⩾3-log increase in the BKV load and 14 with a <3-log increase). All samples had measurable ciprofloxacin levels (median, 71.7 µg/mL; range, 23.0–152.9 µg/mL) (tables 2 and 3). One ciprofloxacin recipient was excluded because of an indefinable BKV viruria pattern (table 4). Of 21 cephalosporin recipients (15 with a ⩾3-log increase in the BKV load and 6 with a <3-log increase), 18 had negligible ciprofloxacin levels (median, 0 µg/mL; range, 0–1.3 µg/mL). Three patients who received agents other than ciprofloxacin were not tested.

Figure 3
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Figure 3

BK virus (BKV) loads in patients receiving different antibiotics. Each point represented the highest BKV load in an individual patient during hematopoietic stem cell transplantation HSCT. Patients receiving ciprofloxacin (Cip) had a significantly lower median BKV load (bar) than did those who received antibiotics other than ciprofloxacin (Non-Cip). This pattern was apparently unaffected by corticosteroid treatment (steroid+).

Table 1
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Table 1

Demographic and clinical characteristics of patients who underwent hematopoietic stem cell transplantation (HSCT), by treatment regimen.

Table 2
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Table 2

Clinical and virological characteristics of 29 patients who had significant peak BK virus (BKV) loads after hematopoietic stem cell transplantation (HSCT).

Table 3
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Table 3

Clinical and virological characteristics of 32 patients without a significant peak BK virus (BKV) load during the course of hematopoietic stem cell transplantation (HSCT).

Table 4
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Table 4

Demographic and clinical characteristics of and development of severe hemorrhagic cystitis in patients who underwent hematopoietic stem cell transplantation (HSCT) and manifested different patterns of polyoma BK virus (BKV) viruria.

Antibiotic regimens and BKV viruria. Ciprofloxacin recipients developed lower median peak BKV loads than did recipients of agents other than ciprofloxacin (2.8 × 105 copies/mL vs. 2.4 × 109 copies/mL; P = .044) (figure 3). When these patients were analyzed together with those who were receiving concomitant corticosteroid therapy, the median peak BKV load was still lower in the ciprofloxacin group than in the nonciprofloxacin group (3 × 105 copies/mL vs. 2.6 × 109 copies/mL; P = .021). Furthermore, significantly fewer ciprofloxacin recipients developed a ⩾3-log increase in the BKV load than did recipients of agents other than ciprofloxacin (P = .013) (table 5). Finally, all 5 patients with a steady decrease in the BKV load (figure 1B) received ciprofloxacin. However, the rates of occurrence of severe hemorrhagic cystitis did not differ between the ciprofloxacin and nonciprofloxacin groups.

Table 5
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Table 5

Relationship between antibiotic regimens received, level of polyoma BK virus (BKV) viruria, and occurrence of severe hemorrhagic cystitis (HC).

Inhibition of BKV replication in vitro. BKV was cultured in HEL cells from 7 of 31 urine samples (table 6). For 100 TCID50 of BKV, cidofovir (at concentrations of <31.25–125 µg/mL) consistently inhibited all clinical isolates and the standard BKV strain VR-837. Foscarnet was ineffective against 100 TCID50 of BKV, but at a concentration of 2000 µg/mL, it inhibited 10 TCID50 of BKV in 1 clinical isolate and the VR-837 strain. Levofloxacin at a concentration of 250 µg/mL inhibited 10 TCID50 of BKV in 3 of 7 clinical isolates, but at 500 µg/mL, it inhibited 10 TCID50 of BKV in all 7 clinical isolates and the VR-837 strain. On the other hand, novobiocin at a concentration of 200 µg/mL inhibited 10 TCID50 of BKV in only 1 of 7 clinical isolates. For 10 TCID50 of BKV, ciprofloxacin inhibited 3 of 7 clinical isolates (at concentrations of 125 µg/mL for 2 isolates and 250 µg/mL for 1 isolate). Four BKV isolates were ciprofloxacin resistant, of which 2 (isolates 1 and 7 in table 6) were from ciprofloxacin recipients with a ⩾3-log increase in the BKV load (patients 24 and 5, respectively, in table 2). All 4 patients with BKV isolates that were ciprofloxacin resistant had significant increases in the BKV load. Only 1 patient developed hemorrhagic cystitis, but this patient was receiving ceftibuten. For the other 3 patients without hemorrhagic cystitis, the treatment was ciprofloxacin, ceftibuten, and a corticosteroid or ciprofloxacin. For 100 TCID50 of BKV, ciprofloxacin showed no inhibitory effects.

Table 6
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Table 6

The inhibitory effects of novobiocin, levofloxacin, ciprofloxacin, foscarnet, and cidofovir on BK virus (BKV) replication in HEL cells.

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Discussion

We showed that the occurrence of severe hemorrhagic cystitis was confined to patients with a ⩾3-log peak in BKV load. Furthermore, peak BKV load invariably preceded the onset of hemorrhagic cystitis. These imply that BKV inhibition might prevent hemorrhagic cystitis after HSCT.

We further showed that ciprofloxacin at concentrations of 125–500 µg/mL inhibited some BKV isolates. Patients taking ciprofloxacin had mean urinary concentrations of 23–152.9 µg/mL, which was close to the level of 350 µg/mL reported after receipt of an oral dose of 500 mg [20]. The ciprofloxacin level in the urinary epithelium may be even higher [21]. Thus, standard-dose ciprofloxacin therapy achieved adequate urinary levels for inhibition of BKV replication.

These observations were confirmed clinically. Ciprofloxacin decreased the rate of reactivation of BKV infection after HSCT, as shown by the decreased number of peaks (⩾3 log) in the BKV load and lower median peak levels of BKV. Furthermore, a pattern of steady decreases in the BKV load was only observed in ciprofloxacin recipients. However, ciprofloxacin did not prevent reactivation of BKV infection in all patients. One contributing factor might be ciprofloxacin-resistant BKV. At least 1 ciprofloxacin recipient was infected with a ciprofloxacin-resistant BKV strain, with a corresponding significant increase in the BKV load. Of the other 3 patients who were infected with ciprofloxacin-resistant BKV, 2 were receiving ceftibuten (1 developed severe hemorrhagic cystitis), and 1 was receiving a corticosteroid or ciprofloxacin.

The etiology of hemorrhagic cystitis is multifactorial [22]. Acute GVHD is an important risk factor [15, 23, 24]. Adenovirus has also been implicated [25], although there were no quantitative relationships between hemorrhagic cystitis and adenovirus viruria [6]. Importantly, none of the 32 patients without significant peaking of the BKV load in this study developed severe hemorrhagic cystitis. These results suggest strongly that reactivation of BKV infection, among other possible causes, is an important prerequisite for hemorrhagic cystitis. On the basis of these results, we propose a tentative pathogenesis of post-HSCT severe hemorrhagic cystitis. During conditioning, intensive chemoirradiation damages the urinary epithelium, leading to cellular regeneration. This provides a permissive microenvironment, because host cell proliferation is required for BKV replication [26]. Furthermore, the use of immunosuppressive therapy reduces the level of immunosurveillance for BKV, allowing cytopathic replication to occur inside the urinary epithelium. After hematopoietic engraftment, the donor lymphocytes mount an immunologic reaction against viral antigens expressed on the urinary epithelium, thus causing extensive mucosal hemorrhages characteristic of severe hemorrhagic cystitis. Additional studies will be needed to validate this hypothesis.

Finally, we demonstrated that standard-dose ciprofloxacin therapy led to inhibition of urinary BKV replication. However, compared with cidofovir, ciprofloxacin is relatively weak in inhibiting BKV. Therefore, ciprofloxacin might be most efficacious if used as prophylaxis after HSCT, when the BKV load is low, possibly before the conditioning regimen for HSCT. Although none of the patients who took ciprofloxacin and who had low levels of BKV developed hemorrhagic cystitis, a direct beneficial effect of ciprofloxacin use on hemorrhagic cystitis could not be demonstrated, because of the relatively small number of patients who actually developed severe hemorrhagic cystitis (1 patient in the ciprofloxacin group and 3 patients in the ceftibuten group). Finally, our in vitro results suggest that levofloxacin may be more effective than ciprofloxacin, and clinical studies of its use are warranted.

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Acknowledgments

Potential conflicts of interest. All authors: no conflicts.

  • Received August 2, 2004.
  • Accepted September 22, 2004.
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  1. Clin Infect Dis. (2005) 40 (4): 528-537. doi: 10.1086/427291
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