Postoperative Infection Rates in Patients with a Negative Baseline Urine Culture Undergoing Ureteroscopic Stone Removal: A Matched Case–Control Analysis on Antibiotic Prophylaxis from the CROES URS Global Study

Introduction

For urological stones requiring intervention, current management options include ureteroscopy (URS), percutaneous nephrolithotomy (PCNL), and extracorporeal shockwave lithotripsy (SWL); open stone surgery may have a role in selected cases but has become relatively rare (<1% of cases). ^1,2 Technological developments and improved treatment methods have expanded the indications for URS in active stone removal, resulting in the technique increasingly being performed worldwide. The European Association of Urology (EAU) guidelines specify that apart from general problems, for example, with general anesthesia or untreated urinary infections, URS can be performed to remove ureteral stones in all patients without any definite contraindications. ³ Administration of short-term antibiotic prophylaxis before URS is recommended in clinical practice. ^3,4 The rationale for such preemptive use of antibiotic(s) is to minimize the potential infectious complications following the intervention. However, in common with many other urological procedures, there is little evidence for the use of antibiotic prophylaxis with URS, mainly due to the lack of well-designed studies as well as variation in the definition of outcome parameters. ⁵ In the present analysis of the Clinical Research Office of the Endourological Society (CROES) URS Global Study, we examined postoperative infection rates in patients with negative urine cultures undergoing ureteroscopic treatment of urological stones with and without antibiotic prophylaxis.

Patients and Methods

The study was part of a prospective, observational, international multicenter study initiated by the CROES in January 2010. The study collected data on consecutive patients treated with URS for urolithiasis at each participating center over a 1-year period. The prospective global database established by the CROES URS Global Study, which has been described in more detail elsewhere, ⁶ includes data for 11,885 patients who received URS at 114 centers in 32 countries. Patients aged ≥18 years with a negative preoperative urine culture and without a preoperative nephrostomy were selected for the present analysis.

Data were collected electronically through an internet website (www.croesoffice.org) and held in an encrypted form at a central database at the CROES office. Institutional review board approval was obtained at participating centers, as necessary; otherwise, the lead investigator was responsible for ensuring the quality of clinical data collected. Centers were asked to appoint a member of the staff to coordinate the collection and handling and provide regular updates of their center's data to the central database. Data included patient epidemiological characteristics, calculus specification, type of treatment, and postoperative outcomes and complications. Antibiotic prophylaxis was defined as any antibiotics before surgery, including antibiotics at the time of the procedure. A urinary tract infection (UTI) was defined as an infection that affects part of the urinary tract, diagnosed as a positive out come on urine cultured directly (48 hours) postoperation. Centers were asked to treat patients according to the local protocols. The database was censored for inclusion in October 2012.

Nearest neighbor propensity score matching was used to match pairs of patients who underwent URS with or without antibiotic prophylaxis in a ratio of 1:1, to provide an unbiased estimation of the effect of antibiotic prophylaxis on postoperative outcomes. The matching variables included predefined factors that might increase the risk of developing a UTI: gender, a preoperative stent, and American Society of Anesthesiologists (ASA) physical status classification score. Demographic characteristics, operative data, and postoperative outcomes were compared between patients undergoing URS who did or did not receive antibiotic prophylaxis. Differences between groups were evaluated by Pearson's Chi square test or analyses of variance (ANOVA). Risk factors for fever and UTI in the total group were analyzed using a stepwise backward multivariate logistic regression based on the p-value; predefined factors that might increase complication risk were included in the analysis. The level of significance was defined as p<0.05. The data were analyzed using R 3.0.2.

Results

Of 8148 patients with a negative preoperative urine culture, 1404 patients (17.2%) did not receive antibiotic prophylaxis. Of the total group, 7728 had complete data for all parameters used for propensity score matching. A total of 1141 patients with ureteral stones and 184 patients with kidney stones who did not receive antibiotic prophylaxis were matched with an equal number of patients who did receive antibiotic prophylaxis.

The use of antibiotic prophylaxis differed widely across the participating countries ranging from 13% to 100% (Fig. 1). The most infrequent use of antibiotics was in Iran, Tunisia, and Germany. Table 1 provides an overview of the antibiotic prophylaxis that was provided. A variety of antibiotics were prescribed for a variable interval, as the protocol on antibiotic prophylaxis was to the discretion of the investigators. Among patients with ureteral stones, those given antibiotic prophylaxis were significantly more likely to have diabetes mellitus, to be receiving anticoagulation medication, had lower rates of prior URS but higher rates of prior ureterolithotomy, were more likely to have kidney stones, and to have a lower stone burden than patients not given antibiotic prophylaxis (Table 2). Among patients with kidney stones, the frequency of prior ureterolithotomy and stone burden was higher among those given antibiotic prophylaxis rates compared with patients without antibiotic prophylaxis (Table 2). Other baseline characteristics, such as mean age, mean BMI, being on prednisone medication, and having Crohn's disease or a cardiovascular disease, were similar for these two subgroup-paired comparisons.

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FIG. 1.

Percentage of patients who did or did not receive antibiotic prophylaxis in participating countries.

In patients with ureteral stones who received antibiotic prophylaxis, the procedure duration was shorter, use of a semirigid ureteroscope was less frequent, stones were more often located in the proximal or mid-ureter, and uneventful procedures were less common, with more bleeding, perforation, and other complications compared with patients who received no antibiotic prophylaxis (Table 3). In the patients with kidney stones, operative characteristics, stone location, and complications were similar with or without antibiotic prophylaxis (Table 3).

The prevalence of fever or UTI was low overall (≤2.2%) and similar irrespective of antibiotic prophylaxis in patients undergoing ureteral or kidney stone removal (Table 4), also when corrected for stone burden (fever: odds ratio [OR] 1.84, 95% confidence interval [CI] [0.69, 4.94]; UTI: OR 1.27, 95% CI [0.40, 4.00]). Because patients in Iran represent more than half of the patients who did not receive antibiotic prophylaxis, further analyses were conducted to test for this potential bias. Both a random-effects model that assumes a random effect for country and a penalized logistic regression model with country as the penalized covariate showed no effect of antibiotic prophylaxis on postoperative UTI or fever. A lack of effect was also found when the Iran cohort was excluded from the analysis. The results shown therefore include all participating countries analyzed according to the study plan.

Patients with ureteral stones who received antibiotic prophylaxis had a significantly lower stone-free rate and less frequent need for postoperative stent placement, but a higher risk of stone impaction, postoperative complications, and to be readmitted within 3 months than those without antibiotic prophylaxis (p≤0.001; Table 4). Patients with kidney stones who received antibiotic prophylaxis had a significantly lower stone-free rate, and the postoperative complications were generally less severe as defined by the Clavien classification (p<0.05).

To investigate possible risk factors for postoperative infection, we analyzed the characteristics of 7728 patients with complete records, showing the full model with all the predefined factors that might increase complication risk and the final best-fit model (Table 5). Of this group, 58 (0.8%) patients were diagnosed with a UTI and 94 (1.2%) patients developed fever after ureteral or kidney stone removal by URS. Multivariate logistic regression analysis showed that females, patients with Crohn's or cardiovascular disease, and patients with an ASA score of III or IV were significantly more likely to develop a postoperative UTI. Females were also more likely to develop fever as a postoperative complication of ureteroscopic stone treatment, as were patients with an ASA score of II, III, or IV and patients on anticoagulation therapy and with a higher stone burden.

Discussion

This analysis from the CROES URS Global Study has revealed some important findings. First, the use of antibiotic prophylaxis in URS for uncomplicated urological stone removal varies widely around the world; administration of antibiotic prophylaxis differed from 13% to 100%. Second, females and patients with a high ASA score were more likely to develop fever or UTI as a postoperative complication of ureteroscopic stone treatment. Third, the prevalence of postoperative fever or UTI in patients with a baseline negative urine culture undergoing ureteral or kidney stone removal was low and unaffected by antibiotic prophylaxis.

The reasons for the wide variation in administration of antibiotic prophylaxis in clinical practice are unclear, multifold, and merit further investigation, but are beyond the scope of the present study. Such variation, which has been noted more widely in urology practice, ⁷ is likely to reflect the national, regional, and local practice, but it may also, in part, reflect differences in clinical management guidelines. The American Urological Association (AUA), for example, recommends antibiotic prophylaxis for all patients undergoing URS, ⁴ whereas the EAU recommends antibiotic prophylaxis only for those patients treated by URS for proximal or impacted stone and percutaneous stone extraction, but not for URS of uncomplicated distal stones. ⁸ The EAU guidelines note that, however, for URS in stone treatment, there have been few studies that have defined the risk of infection following URS and percutaneous stone removal, and no clear-cut evidence exists. Distinguishing between low- and high-risk procedures is reasonable, but many factors in addition to stone location need to be considered before assessing a particular URS procedure as uncomplicated. ^8,9 The EAU guidelines identify general and specific risk factors for infectious complications that are important in preoperative assessment of the patient (Table 6), of which an indwelling catheter, previous urogenital infection, and a long preoperative hospital stay are the most important. ⁸ The findings of this study confirm the female gender as a specific risk factor for infectious complications post-URS treatment for urological stone. The finding of a higher ASA score and the impaired immunity of Crohn's disease as risk factors for postoperative UTI or fever is also consistent with current understanding. ⁸

The EAU and AUA guidelines acknowledge that their recommendations for antibiotic prophylaxis are based on limited evidence regarding the choice of antimicrobial agents, dose, timing, and duration of procedure. Few randomized clinical trials of antibiotic prophylaxis in ureteroscopic stone removal have been reported. A prospective, randomized double-blind study in 120 patients undergoing endoscopic stone extraction (both PCNL and URS) found bacteriuria 3 days after URS in 3.5% of patients who received antibiotic prophylaxis compared with 13% of patients given placebo. The lack of statistical significance for the treatment comparison reflects the small size of the study. ¹⁰ However, a more recent randomized study involving 113 patients undergoing URS for stone removal also found a lower incidence of postoperative bacteriuria after a single oral dose of levofloxacin given 60 minutes before URS compared with no antimicrobial treatment (12.5% vs. 1.8%, p=0.026). ¹¹

We acknowledge that as a matched case–control study, this analysis does not provide the same level of evidence as a randomized controlled trial. The use of propensity score to match two patient groups with similar characteristics on three significant predisposing factors associated with UTI strengthens the analysis. We believe that this approach will have substantially reduced the effect of potential confounders.

In undertaking this study, we anticipated that withholding preoperative antibiotic treatment would result in a higher complication rate, but the results demonstrated otherwise. In a separate global investigation, the CROES PCNL Global Study found a significant reduction in postoperative fever in patients undergoing PCNL who received antibiotic prophylaxis compared with those who did not. ¹² In PCNL, the invasive puncture and dilation of the renal parenchyma and trauma to vasculature may create access for opportunistic microbial pathogens in stones or urine, which is increased further by stone disintegration or by the pressure generated by the technique. The greater microbial challenge would then emphasize the protective effect of prior antibiotic administration. Similarly, a higher risk for fever and UTI might be expected in patients treated for kidney stones compared with ureteral stones, given the higher pressure and reflux generated by URS in the renal pelvis compared with ureteral URS, but that was not found in this study. In addition, the finding of more ureteroscopic complications in patients receiving antibiotic prophylaxis compared with those not receiving antibiotics was unexpected, but could suggest that such prophylaxis was more often administered to patients considered more likely to have complications, that is, higher risk patients.

The observation of no apparent beneficial effect of antibiotic prophylaxis in this clinical setting is important. All clinicians, including urologists, are responsible for combating the development and spread of antibiotic-resistant bacterial pathogens. A fundamental aspect of antibiotic stewardship is avoiding the indiscriminate use of antibiotics and ensuring the appropriate evidence-based use of these agents for prophylaxis and treatment. ¹³ This study supports the suggestion that low-risk cases, such as URS for urological stone removal in patients with manageable risk factors, could be treated without antibiotic prophylaxis. ¹⁴ The results of this study need to be confirmed in a randomized controlled trial to balance possible unknown allocation bias that was not accounted for in the matched case–control analysis in a population at low risk for postoperative complications, that is, males with low ASA scores. Another limitation is that we did not capture in the database, a possible course of antibiotics resulting in a negative urine culture just before surgery. This may incidentally have happened in both arms and the opinion of the investigators has not jeopardized the present work.

The benefits of implementing this approach across the urological community are likely to include reduced healthcare costs, fewer treatment-related adverse effects, and decreased selective pressure for resistant organisms.

Conclusions

In patients with a negative baseline urine culture undergoing URS for ureteral or renal stones, rates of postoperative UTI and fever were not reduced by preoperative antibiotic prophylaxis. Female gender and a high ASA score were specific risk factors for postoperative infection in this patient group.