Is There Always a Need to Perform Urine Culture before Bacillus Calmette

Abstract

Objectives:

There are no unanimous recommendations between urology societies regarding the performance of a urine culture before Bacillus Calmette–Guérin (BCG) instillations. The management of a positive urine culture before each instillation depends on the choice of the urologist. The objective of our study was to collect urine cultures performed before instillations and to study their impact on the risk of associated urinary tract infection (UTI) and on the risk of recurrence of bladder tumors.

Patients and Methods:

A retrospective analysis of induction BCG files (six instillations per cycle) associated or not with maintenance BCG (three instillations per cycle) was performed between January 2022 and January 2023. A urine culture was systematically carried out a few days before each instillation. In the event of a positive urine culture, the choice of treatment depended on the referring urologist. Demographic data, tumor characteristics, risk factors for UTI, and bacteriological data (date of urine culture, leukocyturia, hematuria, polymicrobial, sterile, and antibiotic therapy given) were collected.

Results:

Eighty patients were included, all with non-muscle-infiltrating bladder tumors. A total of 812 urine cultures were studied, of which 88 were positive. Among all positive urine cultures, 42 did not receive antibiotics, and yet no febrile UTI was detected. A serious infectious event was reported in two patients including one death, and no risk factor for the occurrence of a positive urine culture could be identified. Bladder tumor recurrence was identified in 17 patients, 3 of whom had positive urine culture treated with antibiotics.

Conclusions:

Performing urine culture before BCG instillation does not seem necessary. Antibiotic therapy for a positive urine culture could expose to a higher risk of recurrence.

Introduction

Bladder cancer is the 10th most commonly diagnosed cancer worldwide.¹

Following a transurethral resection of the bladder, adjuvant intravesical immunotherapy with Bacillus Calmette–Guérin (BCG) is the standard treatment in patients with high-risk, non-muscle-invasive bladder cancer. This treatment reduces the risk of disease recurrence, delays progression, and improves the overall survival.²

BCG is potentially associated with a significant risk of localized or systemic adverse events, such as mycobacterial infections.³ Urinary tract infection (UTI) is considered a risk factor for BCG complications. Hence, symptomatic UTI is an absolute contraindication to this therapy.³ Therefore, many urologists believe that BCG therapy should be performed only in patients with sterile urine.⁴ Some experts believe that bacterial cystitis traumatizes the barrier, allowing BCG to reach the blood stream.⁵

Although urine culture is time-consuming, it is still widely used before any intravesical instillation lacking clinical benefit. Indeed, many urologists administer prophylactic antibiotics before and after BCG treatment based on pyuria in order to prevent acute UTI or urosepsis. In contrast, any antimicrobial treatment could result not only in a delay of the adjuvant oncological treatment but also in an increase in bacterial antibiotic resistance currently seen with the wide use of antibiotics.

Hence, with no actual data available on this subject, it is clear that identifying risk factors of post-BCG UTIs could limit the unnecessary use of antibiotics and could make clear when and why a urine culture is mandatory during BCG treatment.

In the present study, we assess the risk factors of post-BCG UTIs and determine whether a routine urine culture is mandatory before BCG administration.

Patients and Methods

Retrospective review of the medical records of 80 patients treated with instillation of BCG between January 2022 and January 2023 in Tours Regional University Hospital with a high volume of bladder cancer patients. This study was approved by the Institutional Review Board of our institution and was conducted in accordance with the Declaration of Helsinki. Given the retrospective nature of the study, the requirement for informed consent was waived.

Outpatient office records, nursing documentation and remarks, and laboratory records were reviewed to assess for any documented febrile infection but also any local or systematic symptoms associated with intravesical BCG instillation.

In patients who also underwent intravesical BCG treatment, the urine culture was performed weekly during the BCG treatment period. In case of bacteriuria, the patient was treated with antibiotics before starting instillations depending on the referral urologist’s choice.

Furthermore, it has been demonstrated that ofloxacin can reduce severe adverse effects, and many urologists may use this treatment as a routine prevention.⁶

Post-treatment UTI was defined by clinical criteria (fever ± lower urinary tract symptoms) with documented bacteria in the urine ± blood culture in accordance with CDC guidelines.⁷

Multiple patient and procedure-related variables potentially implicated were included: age, gender, ASA score, immunosuppression status, history of endoscopic bladder resection, tumor size, multifocality, stage and grade of the tumor, presence or absence of CIS, leukocyturia, pre-BCG instillation urine culture results, and recurrence after the last bladder resection.

Statistical analysis

The baseline characteristics are presented as frequencies (percentages) for categorical variables and mean (standard deviation) for continuous variables. The baseline patient demographics were analyzed using descriptive statistics. The data were compared using a Mann–Whitney U test and Kruskal–Wallis analysis for the quantitative variables and a chi-square test for the categorical variables. Multivariable logistic regression analyses were performed to assess the respective effects of each variable on the occurrence of UTI after BCG treatment. The value of p < 0.05 was considered significant for all tests. Patients with missing data were excluded from the analysis. Statistical analysis was performed with R studio software® version 2021.09.0.

Results

Baseline patient characteristics are described in Table 1.

Table 1.

Baseline Characteristics of Patients Who Underwent BCG Treatment

Variable	Total (n = 80)	Mean or %
Age (mean, SD)	70, 2	10, 16
ASA score (n, %)
1	95	11, 70%
2	448	55, 17%
3	257	31, 65%
4	12	1, 48%
Gender (male n, %)	709	87, 32%
Grade (high) n (%)	805	99, 14%
Stage T1, n (%)	780	96, 06%
CIS, n (%)	19	2, 34%
Leukocyturia /mm³ \|(>10), n (%)	596	73, 40%
History of TURBT, n (%)	79	9, 73%
Multifocality, n (%)	50	6, 16%
Tumor >3 cm, n (%)	28	3, 45%
Immunosuppression, n (%)	25	3, 08%
History of UTI, n (%)	23	2, 83%
Urine culture
Negative	591	73, 20%
Positive	88	10, 80%
Polymicrobial	130	16, 00%

BCG = Bacillus Calmette–Guérin; SD = standard deviation; UTI = urinary tract infection.

Eighty patients underwent a six-weekly induction BCG course, followed or not by maintenance courses with a total of 812 BCG instillations.

All patients had a urine culture before BCG treatment.

Eighty-eight of 812 urine cultures were positive, whereas 143 had a polymicrobial culture.

Of the 88 instillations with bacteriuria, 46 patients were treated with antibiotics for a period ranging from 3 to 5 days with only 1 subsequent post-treatment UTI, whereas the other 42 patients did not receive any treatment, and yet no single patient experienced a febrile UTI.

Post-BCG UTI was documented in only 8 patients (8 UCs out of 812 BCG instillations).

The eight UTI cases had the following pre-BCG UCs: one polymicrobial UC, one positive UC with Escherichia coli treated with sulfamethoxazole, and six sterile UCs.

Two patients had to be admitted and treated in the hospital basis fashion. One patient had a severe septic shock and had to be admitted to the intensive care unit; he died a few days later.

A uni-variable analysis (Table 2) showed that none of the variables were associated with UTI after the BCG treatment, with a highlight on pre-treatment urine culture which had a p value of 0.887 that is not deemed significant.

Table 2.

Uni-variable Analysis Predicting UTI after BCG Treatment

Variable	Odds ratio	95% confidence interval	p value
Age	1.03	0.96–1.1	0.409
Gender	1.98	0.13–19.2	0.998
ASA score
1 (reference)
2	2..39	0.43–13.23	0.319
3	2.74	0.38–19.75	0.317
4	2.4	0.12–18.7	0.82
History of UTI	1.5	0–2.8	0.68
Immunosuppression	1.38	0–2.9	0.78
History of TURBT	1.21	0.18–3.25	0.79
Tumor size >3 cm	1.38	0.22–3.7	0.81
Multilocality	1.6	0.82–6.5	0.88
Stage
pTa (reference)
T1	1.3	0.21–7.8	0.89
CIS	2.2	0.58–6.5	0.91
High grade	0.98	0.21–3.8	0.812
Urine culture
Negative (reference)
Positive	1.12	0.22–5.61	0.887
Polymicrobial	1.5	0.18–12.3	0.705
Leukocyturia > 10/mm³	0.39	0.05–3.2	0.382
Induction/maintenance	0.93	0.22–3.92	0.923

BCG = Bacillus Calmette–Guérin; UTI = urinary tract infection.

Enterococcus faecalis was the most common uropathogen documented in urine culture, followed by E. coli, then other species as shown in Table 3. 17 patients had tumor recurrence during follow-up period. Three of these patients had a positive urine cultures and were treated with antibiotics highlighting the possible negative effect of antibiotics on BCG efficacy and therefore bladder tumor recurrence (Fig. 1).

FIG. 1.

Correlation between treatment of bacteriuria and post-BCG UTI and rates of tumor recurrence. BCG = Bacillus Calmette–Guérin; UTI = urinary tract infection.

Table 3.

Types of Encountered Bacteria in the Urine Culture Samples Done Before Every BCG Instillation

Bacteria	N
Enterococcus faecalis	39
Escherichia coli	26
Klebsiella oxytoca	7
Proteus Mirabilis	4
Klebsiella pneumoniae	2
Morganella morganii	2
Citrobacter koseri	1

BCG = Bacillus Calmette–Guérin.

Discussion

BCG is a potent intravesical biological agent that decreases the recurrence and progression rates of high-grade urothelial carcinoma. Many patients receiving BCG treatment have lower urinary tract symptoms, such as dysuria, frequency, urgency, and hematuria, which cannot be differentiated from UTI symptoms.⁸

There is insufficient evidence on whether irritative bladder symptoms are sufficient to decide on whether to pursue antibiotic therapy and postpone or continue BCG treatment. These symptoms might not be because of UTI because mild to moderate irritative urinary symptoms are common in cases of a recent transurethral resection and in situ carcinoma. Irritative symptoms, such as frequency and urgency, are commonly seen in patients recently treated with a TURBT.

Aside from irritative symptoms, intravesical BCG instillation can cause influenza-like symptoms, fever, and rarely, BCG sepsis. Active UTI can promote intravasation, leading to infectious complications. Abnormal urinalysis or UTI is considered a contraindication to intravesical BCG.⁸

Larsen et al. have shown in their registry-based cohort analysis that the incidence of BCG infections after BCG instillations was 1%.⁹

Serious side effects are encountered in <5% of patients and can be treated effectively.

Side effects requiring treatment cessation were seen more often in the first year of therapy.

BCG instillations should also be used with caution in immunocompromised patients.¹⁰

It has also been shown that the maintenance course is not associated with an increase in the risk of side effects when compared with the induction course.¹¹

In addition, the presence of leukocyturia, non-visible hematuria, or asymptomatic bacteriuria is not a contraindication to BCG application, and antibiotic prophylaxis is not necessary in these cases.¹²

UTIs are considered a risk factor for BCG complications, and symptomatic UTIs are an absolute contraindication to the therapy.²

The association between UTI and the safety of BCG therapy was poorly studied, and the evidence in this field is limited. Many urologists consider sterile urine to be a necessary condition for intravesical BCG instillation. Moreover, they believe that bacterial cystitis traumatizes the barrier for the BCG to reach the blood stream.⁵

The antimicrobial treatment during BCG treatment delays adjuvant oncological treatment and potentially contributes to the increase in bacterial resistance to antibiotics, but the clinical benefit is unclear.⁴

Herr et al.¹² reported that the instillation of BCG for bladder cancer patients with asymptomatic bacteriuria did not result in sepsis or a reduced response.

To date, there are no clear consensus guidelines that address the prevention of infection-related complications arising from intravesical chemotherapy or intravesical biological therapy.

Multi-variable analysis in our study showed that bacteriuria was not associated with UTI after the BCG treatment (p = 0.887). If the findings are replicated, a urine culture to detect bacteriuria and prophylactic antibiotics may be unnecessary in asymptomatic patients with bladder cancer.

Asymptomatic patients can be excluded safely from antibiotic therapy during BCG instillation,² and routine urine analysis can be omitted safely before BCG instillation.¹³

Rapid UTI diagnosis using Sysmex UF-1000i can be used to determine whether to treat an infection and to avoid unnecessary BCG discontinuation and urine culture tests.¹⁴

Eun et al. evaluated prospectively approximately 25% of the patients who suffered from bacteriuria during intravesical BCG treatment. Old age, female gender, diabetes mellitus, and postoperative bacteriuria were found to be the risk factors of bacteriuria during BCG treatment. Predictive factors could aid in clinical decisions during BCG treatments as well as decisions on BCG discontinuation.³

In our study, the overall incidence of culture-documented UTI after BCG treatment was 0.98%. No single variable was found to be an independent risk factor for UTI occurrence during the BCG treatment.

On the basis of the study findings, positive urine culture is not a risk factor for developing post-BCG installation, and therefore, it could be omitted from daily practice in order to prevent bacteria resistance to antibiotics.

Our study has several limitations, including the limited number of patients, the single institution, and the retrospective aspect of the study. Indeed, there were insufficient guidelines about bacteriuria treatment in asymptomatic patients. Therefore, there is no consensus till now on the optimal management of symptoms related to therapy and the use of antibiotics in patients who have a positive urine culture.

Conclusion

Additional prospective multicentric studies are necessary to evaluate the management of urine culture prescription before BCG therapy, leading the weight to new guidelines and limiting the use of this analysis to symptomatic patients with fever.

Footnotes

Acknowledgments

The authors specially thank Camille Brocail for the help in data collection.

Authorship Confirmation

All authors have read and approved the final version of the article and agree with the order of presentation of the authors.

Authors’ Contributions

A.B.: Conceptualization, methodology, formal analysis, investigation, data curation, writing—original draft, and writing—review and editing. O.G.: Methodology, formal analysis, investigation, writing—review and editing, and visualization. C.B.: Methodology, data collection, and investigation. F.B.: Writing—review and editing and supervision.

Author Disclosure Statement

No conflict of interests.

Funding Information

No sources of funding for our research.

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Is There Always a Need to Perform Urine Culture before Bacillus Calmette–Guérin Instillation for Bladder Cancer?

Abstract

Objectives:

Patients and Methods:

Results:

Conclusions:

Introduction

Patients and Methods

Statistical analysis

Results

Discussion

Conclusion

Footnotes

Acknowledgments

Authorship Confirmation

Authors’ Contributions

Author Disclosure Statement

Funding Information

References