Background:
To verify the appropriate prophylactic agent to prevent ureteroscopic lithotripsy infection, which is safe, effective, convenient, reasonable, and with best pharmacoeconomic benefit ratio, to provide evidence for clinical practice.
Methods:
This study is a multicenter, open-label, randomized, positive drug-controlled trial design. From January 2019 to December 2021, patients with ureteral calculi who were going to undergo retrograde flexible ureteroscopic lithotripsy were selected from urology departments in 5 research centers. The patients enrolled were randomly divided into the experimental group and the control group according to the random number table by blocking randomization. In the experimental group (Group A), 0.5 g levofloxacin was given 2 to 4 hours before surgery. In the control group (Group B), cephalosporin was injected 30 minutes before surgery. The infectious complications, the incidence of adverse drug reactions and the economic benefit ratio were compared between the 2 groups.
Results:
A total of 234 cases were enrolled. There was no statistically significant difference between the 2 groups at baseline. Postoperative infection complications were 1.8% in the experimental group, which was significantly lower than 11.2% in control group. The type of infection complication in both groups was asymptomatic bacteriuria. The cost of drugs in the experimental group was 19.89 ± 13.11 yuan, which was significantly lower than cost of drugs in the control group of 41.75 ± 30.12 yuan. The levofloxacin application had favorable cost-effectiveness ratio. The difference in safety between 2 groups was not significant.
Conclusion:
The application of levofloxacin is safe, effective, and low-cost regimen for postureteroscopic lithotripsy infection prevention.
Keywords: infection, levofloxacin, prevention, ureteroscopic lithotripsy, urinary calculi
1. Introduction
Urinary calculi are high incidence diseases worldwide, with a prevalence of 7% to 13% in North America, 5% in Europe, and 1% to 5% in Asia.[1–3] China is one of the top 3 regions with a high incidence of urinary calculi in the world. In recent years, the incidence of urinary calculi in China has been increasing. With the development of minimally invasive surgery for urinary calculi, such as extracorporeal shock wave lithotripsy, ureterorenoscope lithotripsy, percutaneous nephrolithotripsy, and laparoscopic lithotripsy, the prevention of postoperative infection has received increasing attention from urologists.
Ureteroscopic lithotripsy is a clean-contaminated operation. In the absence of bacteriological results, the choice of prophylactic antimicrobial agents is flexible. First- and second-generation cephalosporins and fluoroquinolones are recommended in China. Worldwide, a wide range of drugs are recommended, including fluoroquinolones, cephalosporins, aminoglycosides plus metronidazole or clindamycin, amoxicillin/clavulanate, ampicillin/sulbactam, etc.[4] Fluoroquinolones and cephalosporins are recommended widely, but there is no evidence-based comparison study between the 2 types of drugs. Based on pharmacokinetics and pharmacodynamics, levofloxacin was selected for a head-to-head comparison with cephalosporin in this study to observe the efficacy, safety, and cost-effectiveness (C/E) of drugs in preventing ureteroscopic lithotripsy infection.
2. Materials and Methods
This study is a multicenter, open-label, randomized, positive drug-controlled trial design. From January 2019 to December 2021, this study was conducted at 5 research centers, including Beijing Tongren Hospital, Capital Medical University; Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University; Beijing Tiantan Hospital, Capital Medical University; Civil Aviation General Hospital; and Liangxiang Hospital of Capital Medical University, Yanjing Medical College. The protocol of this study was approved by the ethics committees of Beijing Tongren Hospital, Capital Medical University [TRECKY2018–046], Informed consent was obtained from all individuals included in this study.
2.1. Sample size and patient selection
Based on previous studies and experience, with a noninferiority test design, a 2-sided alpha level of 0.05, a power of the test (1-beta) of 80%, and a randomization ratio of 1:1, 114 patients were needed in each group. Considering dropping out, 5% was increased, and there were 120 patients in each group for a total of 240 cases.
2.1.1. Inclusion criteria.
Patients with ureteral calculi who were going to undergo retrograde semirigid ureteroscopic lithotripsy; or patients with renal calculi who were going to undergo retrograde flexible ureteroscopic lithotripsy (the maximum diameter of the stone is <2 cm).
Age 18 to 65 years old.
Informed consent was obtained in written forms with signatures.
2.2.1. Exclusion criteria.
Patients with positive urine bacteria culture before surgery (colony count ≥ 104 CFU/mL).
Patients with preoperative indwelling Double J Ureteral Catheter for ≥ 2 weeks.
Patients with preoperative fever (body temperature ≥ 38°C).
Patients receive nephrostomy before surgery.
Patients with moderate to severe hydronephrosis.
Patients with a history of diabetes.
Patients with immunocompromised diseases or using immunosuppressive agents.
Patients with abnormal liver function.
Patients with abnormal renal function.
Patients who are allergic or have contraindications to the research drugs.
Patients who have received antimicrobial treatment within 72 hours before enrollment.
Patients with neuropathy or mental disorders.
Pregnant or breastfeeding women.
The investigator considered that patients are not suitable to participate in this study.
2.2. Randomization and intervention
The enrolled patients were randomly divided into the experimental group and the control group according to the random number table. In the experimental group (group A), 120 patients used 0.5 g levofloxacin 2 to 4 hours before surgery. In the control group (group B), 120 patients were injected with cephalosporin 30 minutes before surgery. Surgery was performed on the day of randomization, and the operation time was recorded. Within 3 days after the operation, the urinary catheter was removed. Within 1 to 4 weeks after surgery, body temperature, routine urine tests, urine bacterial cultures, and liver and kidney function were recorded, and residual stones were diagnosed. If the body temperature was higher than 38°C, routine blood tests and bacterial cultures were also performed. The Double J Ureteral catheter was removed as ordered, and adverse drug events were recorded.
2.3. Efficacy and safety assessment
The primary efficacy outcome: incidence of postoperative infectious complications, including asymptomatic bacteriuria, symptomatic urinary tract infection, fever, urinary sepsis, and genital infection. Asymptomatic bacteriuria refers to patients with positive postoperative urine bacterial culture; symptomatic urinary tract infection refers to a positive urine bacterial culture with clinical symptoms such as frequent urination, urgency, and painful urination; fever refers to a body temperature higher than 38°C (blood culture was performed when the body temperature of the patient was higher than 38°C) and excludes other infectious diseases; urosepsis refers to urinary tract infection with clinical symptoms and accompanied by systemic inflammatory response syndrome; reproductive system infections, such as epididymitis.
The secondary efficacy outcome: C/E of research antimicrobial drugs. The safety outcome: incidence of drug-related adverse events (excluding postoperative infectious complications).
2.4. Statistical analysis
A full analysis set (FAS), per-protocol set (PPS), and safety analysis set (SS) were used in the analyses. FAS (the main analysis set): A collection of cases that participated in randomization, used research drugs, and had at least 1 outcome evaluation result. When the primary efficacy outcome was missing, the last observation was carried forward to the intention to treat analysis set. PPS: A collection of cases that met the inclusion and exclusion criteria, completed the treatment protocol, and completed the case report form as needed. SS: a collection of cases that have received at least 1 treatment and have safety outcome record. Missing values were discarded. Cases that did not meet the inclusion exclusion criteria were included, but cases in which safety could not be judged due to the use of prohibited drugs were excluded. The incidence of adverse reactions was determined using the number of cases in the SS as the denominator. FAS was used for baseline comparison and comparisons of all efficacy outcomes. PPS was used for the analysis of the primary efficacy outcome and supported the FAS analysis. SS was used for safety analysis.
For descriptive statistics, the mean, standard deviation, and median (minimum and maximum) were calculated for continuous variables according to distribution, and the case number and percentage were computed for categorical values. The incidence outcomes of infective complications and adverse events were tested by chi-square (x2). The t test or Wilcoxon tests were used to compare the cost of antimicrobial drugs. All analyses were performed using SAS 9.4 statistical software (SAS Institute, Cary, NC). All statistical tests were performed using a 2-sided test, and a P value <.05 was considered statistically significant.
3. Results
A total of 234 patients were included in this study, and 2 were discontinued due to personal reasons. In FAS, 232 cases were enrolled, including 117 cases in the experimental group and 115 cases in the control group. In PPS, 220 cases were enrolled, including 113 cases in the experimental group and 107 cases in the control group. Twelve patients deviated from the protocol, including overage (n = 6), diabetes (n = 4), positive urine bacterial culture (n = 1), and voluntary withdrawal (n = 1) (Fig. 1). In SS, there were 232 cases. The comparisons of the 2 groups at baseline are shown in Table 1. There were no statistically significant differences in sex, age, body mass index, stone location, stone size, preoperative temperature, operative time, or duration of catheterization between the groups. The cephalosporins in the control group included cefazolin, cefuroxime, cefoxitin, cefotiam, cefonicid, and cefoperazone (Table 2).
Figure 1.
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Table 1.
Demographic data and baseline analysis based on FAS.
| Index | Experimental group# | Control group# | Statistics | P value |
|---|---|---|---|---|
| Number | 117 | 115 | - | - |
| Male | 87 (74.4) | 85 (73.9) | 0.006 | .938 |
| Age | 43.03 ± 12.18 | 45.32 ± 12.70 | 1.399 | .162 |
| BMI | 24.83 ± 3.10 | 25.41 ± 3.16 | −1.085 | .28 |
| Stone location | ||||
| Kidney | 10 | 14 | 2.333 | .426 |
| Proximal ureter | 57 | 49 | ||
| Middle ureter | 19 | 28 | ||
| Distal ureter | 31 | 24 | ||
| Stone size (in diameter) | ||||
| <0.6 cm | 56 | 67 | 1.059 | .991 |
| 0.6–1.0 cm | 38 | 31 | ||
| >1.0 cm | 23 | 17 | ||
| Preoperative temperature (°C) | 36.42 ± 0.30 | 36.40 ± 0.26 | −0.428 | .669 |
| Operative time (min) | 27.85 ± 15.71 | 28.91 ± 14.10 | −0.456 | .649 |
| Duration of catheterization (d) | 13.84 ± 2.99 | 13.67 ± 3.23 | 3.306 | .508 |
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# = data are presented as the mean ± standard deviation, and a t test was used for comparison.
BMI = body mass index, FAS = full analysis set.
Table 2.
The cephalosporins used in the control group.
| Type of cephalosporin | Number of patients |
|---|---|
| Cefazolin 1 g | 11 |
| Cefuroxime 1.5 g | 34 |
| Cefoxitin 1 g | 23 |
| Cefotiam 1 g | 8 |
| Cefonicid 1 g | 13 |
| Cefoperazone 1.5 g | 26 |
| Total | 115 |
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For the primary efficacy outcome, the overall incidence of postoperative infection complications was 6.4% (14/220). The incidence in the experimental group (1.8%, 2/113) was significantly lower than that in the control group (11.2%, 12/107) (P = .0041) (Table 3). Only asymptomatic bacteriuria was observed in both groups, and its incidence is shown in Table 4. On the 1st to 3rd day after the operation, the incidence of asymptomatic bacteriuria was 1.8% (2/113) in the experimental group and 8.4% (9/107) in the control group. On the 7th to 28th day after the operation, the incidence in the test group was 0.0% (0/113) and that in the control group was 5.6% (6/107). There were no subjects with body temperatures higher than 38°C at postoperative visits. Therefore, blood test was not performed in this work.
Table 3.
The incidence of postoperative infection complications based on PPS.
| Postoperative infection complications# | Experimental group (n = 113) | Control group (n = 107) | Statistics | P value |
|---|---|---|---|---|
| Yes (%) | 2 (1.8) | 12 (11.2) | ||
| No (%) | 110 (97.3) | 94 (87.9) | ||
| Miss (N) | 1 | 1 | 8.239 | 0.0041 |
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# = Number of patients meeting at least one of the infectious complications.
PPS = per-protocol set.
Table 4.
The incidence of asymptomatic bacteriuria during the follow up period based on PPS.
| Follow up | Experimental group (n = 113) | Control group (n = 107) | Statistics | P value |
|---|---|---|---|---|
| Phase 1 (1st to 3rd d after operation) | ||||
| Negative (%) | 88 (77.9) | 89 (83.2) | 4.127 | .042 |
| Positive (%) | 2 (1.8) | 9 (8.4) | ||
| Total (miss) | 90 (23) | 98 (9) | ||
| Phase 1 (7th to 28th d after operation) | ||||
| Negative (%) | 68 (60.2) | 72 (67.3) | 3.678 | .055 |
| Positive (%) | 0 (0.0) | 6 (5.6) | ||
| Total (miss) | 68 (45) | 78 (29) |
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PPS = per-protocol set.
For the secondary efficacy outcome, the cost of drugs in the experimental group (19.89 ± 13.11 yuan) was significantly lower than that in the control group (41.75 ± 30.12 yuan) (P < .001) (Table 5). The cost of levofloxacin was 2236.61 yuan, the ratio of no postoperative infection complications was 97.3, and the ratio C/E was 23.0; the cost of cephalosporins was 4379.14 yuan, the ratio of no postoperative infection complications (E) was 87.9, and the ratio C/E was 49.8. The experimental group had a favorable C/E ratio (Table 6).
Table 5.
Analysis of drug cost based on PPS.
| Cost (yuan) | Experimental group (n = 113) | Control group (n = 107) | Statistics | P value |
|---|---|---|---|---|
| Mean ± SD | 19.89 ± 13.11 | 41.75 ± 30.12 | 6.828 | <.001 |
| 95% CI | 17.45–22.34 | 35.98–47.53 | ||
| Median | 11.43 | 24.12 | ||
| Q1–Q3 | 11.43–18.28 | 18.68–67.11 | ||
| Min–Max | 7.03–45.72 | 8.85–88.60 |
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CI = confidence interval, PPS = per-protocol set, Q1 = first quartile, Q3 = third quartile, SD = standard deviation.
Table 6.
Analysis of the cost-effectiveness ratio based on PPS.
| Index | Experimental group | Control group |
|---|---|---|
| Number of patients (miss) | 106 (1) | 112 (1) |
| Total cost (yuan) | 4379.14 | 2236.61 |
| Incidence of no postoperative infection complications (%) | 87.9 | 97.3 |
| Cost-effectiveness ratio | 49.8 | 23 |
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PPS = per-protocol set.
For safety assessment, 1 mild liver function abnormality occurred in the experimental group (1/117, 0.9%), which was “possibly related” to the study drug. No adverse events occurred in the control group.
4. Discussion
Many studies have demonstrated that perioperative prophylactic application of antimicrobials during ureteroscopic lithotripsy reduces the incidence of postoperative fever and urinary tract infections.[5–7] Knopf et al[8] showed that oral administration of a single dose of 250 mg levofloxacin before ureteroscopic lithotripsy significantly reduced the incidence of postoperative bacteriuria compared with the control, which was 1.8% in the levofloxacin group and 12.5% in the control group. In our study, the main postoperative infectious complication was asymptomatic bacteriuria, which was 1.8% in the levofloxacin group and 11.2% in the cephalosporin group, which is similar to previous reports.[9] The incidence of asymptomatic bacteriuria in the levofloxacin group was significantly lower than that in the cephalosporin group, probably because in the cephalosporin group, second-generation cephalosporins were mainly applied, which are pharmacokinetically time-dependent drugs, while levofloxacin is a concentration-dependent drug.
On the other hand, Chinese drug resistance data[10] showed that the proportion of extended-spectrum β-lactamases producing Escherichia coli and Enterococcus spp. among common pathogens of urinary tract infections is gradually increasing, and the resistance rate to quinolones is also rising, leading many urologists to have less confidence in quinolones and to prefer cephalosporins in clinical practice.[11] The results of this study confirmed that oral single-dose levofloxacin was superior to cephalosporins for perioperative infection prevention during ureteroscopic lithotripsy. It is worth noting that most of the Chinese drug resistance data on quinolone come from urinary tract infection strains obtained in hospitals, while prophylactic drugs are more targeted at community-acquired strains that are different from therapeutic drugs. Therefore, there is inevitably a deviation in using the drug resistance data of therapeutic drugs to guide the use of prophylactic drugs. In pharmacokinetics, levofloxacin is different from cephalosporin in that the concentration of levofloxacin in urine is much higher than that in blood, making it more suitable for urinary tract infection prevention. However, due to the high drug resistance rate of quinolones in the treatment, the use of quinolones in the treatment of infectious complications after ureteroscopic lithotripsy should be avoided.
Infectious complications are one of the most common and serious complications of ureteroscopic lithotripsy, especially for retrograde intrarenal surgery (RIRS). The incidence of febrile urinary tract infection after ureteroscopic lithotripsy is approximately 14.1%, and a long operation time is an independent risk factor.[12] The incidence of infectious complications after RIRS was 7.1% (2.8%–7.5%). Independent risk factors included long operation time, recent history of positive urine bacteria culture or urinary tract infection or antibiotic use, pyuria/nitrites positive, small caliber of ureteral access sheath, struvite stone, high irrigation rate, and comorbidities.[13] Both ureteroscopic lithotripsy and RIRS were included in our study, with an overall postoperative infectious complication incidence of 6.4% and no febrile urinary tract infections. This is probably because we excluded patients with positive urine bacterial cultures, urinary tract infections, and those who had used antimicrobial drugs from this study. Then, the included patients were relatively young with fewer comorbidities. Stone size was also the main factor affecting the operative time. This study included patients with ureteral stones or renal stones <2 cm, so the mean operative time was <30 minutes, compared with 61 to 82 minutes in previous studies.[14,15]
Our study also found that the use of oral single-dose levofloxacin was less costly. In terms of the C/E ratio, even excluding infusion devices and related labor costs, oral levofloxacin still has a better ratio than intravenous cephalosporin.
The limitation of this study is that there was no uniform cephalosporin in the control group, which is related to our original intention of trial design. We wanted to accurately reflect the current status of perioperative antimicrobial application for ureteroscopic lithotripsy by urologists in China through a control group and through the results of this study to put an end to the current chaotic antimicrobial application. Therefore, there was no head-to-head comparison of levofloxacin and a single cephalosporin. The analysis of stone composition was omitted in the study design. Therefore, this study was unable to compare whether there was a difference in the stone composition between the 2 groups.
5. Conclusion
In conclusion, the incidence of postoperative infection complications of levofloxacin in ureteroscopic lithotripsy was lower than that of intravenous cephalosporin. Levofloxacin application also had a favorable C/E ratio. There was no significant difference in adverse events. Therefore, the application of levofloxacin is a safe, effective, and low-cost regimen for postureteroscopic lithotripsy infection prevention.
Author contributions
Conceptualization: Zhen Du, Hui Sun, Yong Zhang, Liang Cui, Jianping Hou, Jun Chen, Shan Chen, Ludong Qiao.
Data curation: Zhen Du, Hui Sun, Yong Zhang, Liang Cui, Jianping Hou, Jun Chen, Shan Chen, Ludong Qiao.
Formal analysis: Zhen Du, Hui Sun, Ludong Qiao.
Investigation: Zhen Du, Hui Sun.
Methodology: Hui Sun.
Resources: Zhen Du, Hui Sun, Yong Zhang, Liang Cui, Jianping Hou, Jun Chen, Shan Chen.
Writing – original draft: Zhen Du, Hui Sun, Ludong Qiao.
Writing – review & editing: Zhen Du, Hui Sun, Shan Chen, Ludong Qiao.
Abbreviations:
- C/E
cost-effectiveness
- FAS
full analysis set
- PPS
per-protocol set
- RIRS
retrograde intrarenal surgery
- SS
safety analysis set
The protocol of this study was approved by the ethics committees of Beijing Tongren Hospital, Capital Medical University [TRECKY2018–046], Informed consent was obtained from all individuals included in this study.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
The authors have no conflicts of interest to disclose.
How to cite this article: Du Z, Sun H, Zhang Y, Cui L, Hou J, Chen J, Chen S, Qiao L. Effectiveness of prophylactic antimicrobial levofloxacin against postureteroscopic lithotripsy infection: A multicenter prospective open-label randomized controlled trial. Medicine 2023;102:14(e33364).
Contributor Information
Zhen Du, Email: qucor@126.com.
Hui Sun, Email: sunhuimichael@126.com.
Yong Zhang, Email: doctorzhy@126.com.
Liang Cui, Email: yb_caac@163.com.
Jianping Hou, Email: houjinping701@sina.com.
Jun Chen, Email: shanchentr001@163.com.
Shan Chen, Email: shanchentr001@163.com.
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