European Urology

1. Introduction

Intravesical Mycobacterium bovis bacille Calmette-Guérin (BCG) is standard therapy for high-grade noninvasive bladder cancer. BCG induces a robust immune response in the bladder, characterized by cytokine production, inflammation, and recruitment of immune cells [1]. Neoplastic cells slough in the urine when destroyed, leaving denuded mucosa in responding patients. BCG may persist in the bladder wall for up to 2 yr and may induce continued destruction of urothelial cancer cells [2]. Invading uropathogens trigger similar cellular responses that cause rapid shedding of infected bladder epithelial cells in the urine, known as exfoliation[3]. Bacteria can evade exfoliation by invading deeper epithelial cells [4]. Established uropathogens cause acute cystitis or serve as a reservoir for recurrent urinary tract infections (UTIs). They may also lead to chronic asymptomatic bacteriuria, which is defined as large numbers of bacteria in the urine without associated dysuria or fever. Methods to enhance epithelial exfoliation may help eradicate bacterial infection [5].

This study involves bladder cancer patients who have asymptomatic bacteriuria. Intravesical BCG therapy is contraindicated in acute cystitis [6]. We showed, however, that BCG is safe and effective in antibiotic-naïve patients who have asymptomatic bacteriuria [7]. We hypothesize that the enhanced immune response generated by BCG against tumor cells augments innate immune defenses to eradicate infected bladder epithelial cells. Net beneficial effect may be to clear the urine of chronic bacteriuria without the use of antibiotics.

2. Materials and methods

Consecutive bladder tumor patients agreed to participate in an ongoing prospective pattern-of-care study approved by the institutional review board, and they gave informed consent. Evaluable patients were accrued from May 1, 2010, to May 31, 2011, allowing 1-yr follow-up to fulfill the required end points.

No patient was febrile or had symptoms of a UTI, and none was taking antibiotics. Patients with high-grade tumors started weekly induction BCG therapy. Another cohort with low-grade tumors who had not received BCG therapy underwent surveillance cystoscopy. Before the start of either procedure, patients submitted clean-catch voided urine samples collected in sterile containers and delivered immediately to the laboratory for bacteriologic study. Significant bacteriuria was defined as >10⁴ or >10⁵ colony-forming units per milliliter (CFU/ml) with a single isolated organism. BCG was instilled through a urethral catheter weekly for 6 wk. Flexible outpatient cystoscopy was performed sterilely. Procedures averaged 5–10 min. No patient was given routine antibiotics. Patients received a fact card instructing them to call if they had fever >101 °F or received antibiotics from a physician for any reason. BCG patients underwent transurethral biopsy at 3 mo to determine response. At that evaluation, they received a single dose of broad-spectrum antibiotic after a urine culture had been submitted. Both groups of patients underwent cystoscopy every 3 mo for a minimum of 1 yr. Patients were not given antibiotics before or after these procedures. At each follow-up examination, patients were assessed for signs or symptoms of UTI. Follow-up urine cultures were obtained at 3, 6 and 12 mo. A nurse phoned patients at least once between examinations to inquire whether they had taken antibiotics for any reason. In addition, we relied on patients to report whether they received antibiotics. If they had tumor at 6 mo, patients were eligible to receive another BCG induction course.

Infected patients with asymptomatic bacteriuria were the focus of this report. Infected cystoscopy patients were selected as controls because the procedure does not induce a vigorous immune response.

The end point of the study was the number of patients who had negative urine cultures maintained for 1 yr. A positive follow-up culture indicated evidence of persistent infection, and only patients who had three consecutive urine cultures showing no growth were considered to be continuously free of bacteriuria. This included the urine culture obtained at 3 mo before patients received single-dose antibiotic during transurethral resection to evaluate response to BCG therapy. Patients who developed breakthrough febrile UTI after BCG or cystoscopy that required antibiotics were recorded. Differences in rates of persistent bacteriuria were compared in BCG and cystoscopy patients with the χ² test. In BCG-infected patients, freedom from bacteriuria was correlated with response. The χ² test was also used to test relation of the procedure with onset of febrile UTI. A two-sided significance level of 0.05 was deemed significant.

3. Results

Ninety infected patients completed induction BCG therapy. None received antibacterials before or during weekly instillations. Ninety-five infected patients who had not had BCG in the past underwent outpatient flexible surveillance cystoscopy for recurrent low-grade papillary tumors. They received no antibiotics before, during, or after the procedure, even if small tumors were fulgurated.

Febrile UTI occurred in two patients after completing BCG therapy (2.2%) and in six patients (6%) after initial cystoscopy (p = 0.21; odds ratio [OR]: 0.36 [95% confidence interval [CI], 0.08–1.7]). UTIs resolved in each case with oral antibiotics, and no patient was admitted for bacterial or BCG sepsis.

Table 1 shows the characteristics and results for both cohorts of patients who were followed for a minimum of 1 yr and did not receive antibiotics for UTI. However, one BCG-treated patient and four cystoscopy patients received antibacterial therapy before percutaneous cardiology procedures (three patients), joint replacement surgery (one patient), and for sinus infection (one patient) and are included in the analysis. Nine patients required a second 6-wk induction course of BCG; however, they did not receive antibiotics. The groups were similar in age, sex, bacterial burden, and known risk factors for UTI [8].

Of 88 bacteriuric BCG-treated patients receiving no antibiotic during any follow-up, 58 (66%) became continuously infection free compared with 16 of 89 cystoscopy patients (18%) (p = 0.001; OR: 3.6 [95% CI, 2.1–6.4]). Significant bacteriuria persisted in 34% of BCG patients and 82% of cystoscopy patients. The majority of patients were infected with uropathogens Escherichia coli (47%) or Enterococcus (40%). Other patients had Staphylococcus or Klebsiella (13%). There was no difference in distribution of organisms between BCG-treated or cystoscopy patients (p = 0.29). Persistent bacteriuria in subsequent cultures involved the same organism. Eighty percent of patients responded completely to BCG, and 79% of the 72 complete responders were infection free compared with 23% of the 18 nonresponders (p = 0.03). Infection-free rates were also similar in both groups of patients, whether they had >10⁴ or >10⁵ CFU/ml initially, suggesting an effect of BCG rather than transient bacteriuria (p = 0.41; OR: 1.2 [95% CI, 0.82–1.6]).

4. Discussion

The original finding of this study is that the majority of infected bladder tumor patients were rendered free of bacteriuria after intravesical BCG therapy for up to 1 yr, without receiving antibiotics. Patients undergoing surveillance cystoscopy, for the most part, remained infected. Fewer patients had breakthrough febrile UTIs after BCG than cystoscopy; however, owing to the small number of events, this finding was not significant.

Intravesical BCG induces an intense local immune response in the bladder wall, marked by antigen recognition, recruitment of immune cells, and release of cytokines, including interferons, interleukins, and tumor necrosis factor. Many of these cytokines are involved in the initiation and maintenance of inflammation, resulting in shedding of neoplastic as well as presumably infected epithelial cells in the urine. Recently, it has been shown that BCG and inflammation recruit neutrophils to the bladder, and this is related directly to the degree of epithelial exfoliation [9]. Adaptive immune response to BCG coupled with augmented innate immunity to presence of bacteriuria might explain why infection is preferentially cleared in BCG-treated patients over cystoscopy patients [10].

A weakness of the study is that it represents a single-surgeon, single-center experience and relied on patient self-reporting, which may have underestimated antibiotic usage. Only a few patients took antibiotics for medical reasons during the follow-up period, and most of these were cystoscopy patients unlikely to influence overall differences between the two groups. Could a single dose of antibiotic in the BCG-treated patients at 3 mo have resulted in subsequent negative cultures? This is considered unlikely because antibiotics do not prevent further episodes of asymptomatic bacteriuria [11].

Although this is a prospective cohort study, selection bias within groups cannot be excluded. Causal effect of BCG on prevalence of bacteriuria cannot be inferred from a nonrandomized observational study. A strength, however, is that the study describes a prospective comparison of similar cohorts of antibiotic-naïve bacteriuric patients undergoing treatment, evaluation, and follow-up in a standardized fashion. Bacteriuria >10⁴ CFU/ml with any organism was also considered significant because that would likely persuade most urologists to use antibiotics before BCG therapy or cystoscopy.

There are three reasons to avoid routine antibiotics before intravesical BCG therapy. First, screening urinalysis and cultures are unable to predict which patients will develop symptomatic UTIs [12]. Second, intravesical BCG has been shown to be safe and effective in antibiotic-naïve asymptomatic infected patients [7]. Clinically significant UTIs are rare and resolve with oral antibiotics. Third, this study shows that BCG may confer added benefit by clearing the urine of chronic bacteriuria, perhaps making future invasive urologic procedures safer. Avoiding injudicious use of routine antibiotics facilitates timely administration of intravesical BCG therapy and reduces the emerging frequency of multidrug bacterial resistance.

5. Conclusions

Intravesical BCG therapy appears to eradicate urinary tract uropathogens and malignant cells in antibiotic-naïve bladder cancer patients, possibly due to active and augmented innate host immunity. The study design, however, does not allow inference of a causal effect of BCG on bacteriuria.

Author contributions: Harry W. Herr had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Herr.

Acquisition of data: Herr.

Analysis and interpretation of data: Herr.

Drafting of the manuscript: Herr.

Critical revision of the manuscript for important intellectual content: Herr.

Statistical analysis: Herr.

Obtaining funding: None.

Administrative, technical, or material support: Herr.

Supervision: Herr.

Other (specify): None.

Financial disclosures: Harry W. Herr certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Acknowledgment statement: The author acknowledges Sue Robles, RN, and Anne Kelly, RN, who conducted follow-up phone calls with patients between cystoscopies to determine health status, outside physician visits, and antibiotics prescribed for any reason.