Effectiveness of fosfomycin-based antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: A Korean multicenter study

With the increasing incidence of prostate cancer, transrectal ultrasound-guided prostate biopsy (TRUSPB) is being more commonly used as a diagnostic procedure. In general, TRUSPB is considered as a safe procedure with minor complications such as pain, hematuria, and rectal bleeding [1, 2, 3]. Despite the rare incidence of infectious complications after TRUSPB, when complications occur, they can be life-threatening. According to a review article, the post-biopsy infection rate after TRUSPB is 5%–7%, and the rate of more severe infections requiring treatment on hospital admission is 1%–3% of prostate biopsies [4].

With increasing antibiotic-resistant bacterial infections, particularly high fluoroquinolone (FQ) resistance in the Republic of Korea [5, 6], alternative antimicrobial prophylaxis is required to prevent post-TRUSPB-related infections. Owing to its good permeability into prostate tissue and lower resistance rate [7], FM trometamol has emerged as an alternative to FQ for the prophylaxis of post-biopsy infectious complications. Although the efficacy of FM compared with FQ has been demonstrated [8], a combination of FM and FQ remains to be investigated.

A previous study examined the efficacy of a combined regimen of FM and FQ as prophylactic antibiotics compared with FQ alone for TRUSPB at a single center in the Republic of Korea [9]. This retrospective study was conducted with patients from seven different institutions located in the Republic of Korea. The purpose of this study was to determine the efficacy of FM-based prophylaxis compared with FQ alone for TRUSPB and to identify risk factors for infectious complications after TRUSPB.

A total of 2,595 patients undergoing TRUSPB at seven different institutions were retrospectively evaluated. According to the antibiotics used, the patients were assigned to three groups: FQ (group 1, n=417), FM (group 2, n=795), and FM and FQ (group 3, n=1,383). The antibiotics were administered for 1 or 2 days, including the day of the biopsy.

As shown in Table 1, the overall post-prostate biopsy infectious complication rate was 1.27%. The infectious complication rates were 2.4%, 1.9%, and 0.5% in groups 1, 2, and 3, respectively. The incidence of diabetes mellitus was higher in group 3 than in groups 1 and 2 (22.5% [n=311] vs. 15.3% [n=64] and 16.7% [n=133], respectively; p<0.001). Previous antibiotic exposure within 6 months was also more common in groups 2 and 3 than in group 1 (p<0.001).

Table 1
General characteristics of patients

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As shown in Table 2, multivariable analysis identified health care utilization (adjusted odds ratio [aOR], 4.66; 95% confidence interval [CI], 1.74–12.4; p=0.002) and combination antibiotic prophylaxis (FQ and FM; aOR, 0.26; 95% CI, 0.09–0.69; p=0.007) as predictors of post-biopsy infectious complications.

Table 2
Univariable and multivariable analysis of clinical parameters affecting infectious complications after prostate biopsy

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Table 3 shows detailed information for patients with infectious complications. This information included the patient group; type of infectious complications, such as acute prostatitis, bacteremia, SIRS, and sepsis; results of urine and blood culture; FQ resistance; and extended-spectrum beta-lactamase (ESBL) positivity.

Table 3
Culture results of patients with infectious complications

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A retrospective multicenter study in the Republic of Korea showed that infectious complications were reduced with a combined regimen of FM and FQ compared with FQ alone after TRUSPB. This study was extended from a single retrospective study conducted in the same country to investigate the efficacy of a combination of FM and FQ for antibiotic prophylaxis before TRUSPB [9]. Our results showed that health care utilization and a combination of FM and FQ were predictors of post-biopsy infectious complications.

As shown in Table 1, the incidence of diabetes mellitus was higher in group 3 (FQ and FM) than in group 1 (FQ alone) and group 2 (FM alone) (22.5% [n=311] vs. 15.3% [n=64] and 16.7% [n=133], respectively; p<0.001). In addition, previous antibiotic exposure within 6 months was also more common in groups 2 and 3 than in group 1 (p<0.001). Taken together, the results suggest that patients with a high risk of infection due to diabetes mellitus and previous exposure to antibiotics within 6 months may consider FM-based antibiotic prophylaxis instead of FQ alone to reduce possible infectious complications after TRUSPB.

With the increasing prevalence of FQ-resistant Escherichia coli, there is an increased need for an alternative prophylaxis to FQ before TRUSPB [7], which is stated in the 2017 American Urological Association guidelines. FM trometamol has emerged as an alternative prophylactic antibiotic to FQ for TRUSPB owing to its effective penetration into prostatic tissue, less E. coli resistance, and ease of oral use with fewer adverse effects [11, 12, 13, 14].

Although several studies examining the effectiveness of FM compared with FQ showed that the use of FM alone would be an attractive alternative to FQ as prophylaxis for TRUSPB [11, 12, 13, 14], this was not the case in the Republic of Korea. However, a combination of FM and FQ was observed to be effective in reducing post-biopsy infections [9], which may be attributed to regional differences in the antibiotic resistance pattern [6].

According to a study that examined the drug susceptibility profiles of ESBL-producing bacteria in a single center in the Republic of Korea, E. coli was more susceptible than Klebsiella to FM [10]. In addition, ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole, and ampicillin-clavulanate appeared to be the least active against pathogens [10].

As shown in Table 3, patients in group 2 who received FM alone showed susceptibility to Klebsiella spp. Although FM has a very low minimum inhibitory concentration (MIC ≤ 4 µg/mL) against uropathogens, some antibiotic-resistant strains might exist [15]. This may explain the greater effectiveness of a combination of FM and FQ compared with FM alone or FQ alone in reducing post-biopsy infections.

To the best of our knowledge, thus far, two studies have compared FQ monotherapy with a combination of FM and FQ. One of them was carried out in the Republic of Korea, which revealed the clinical efficacy of a combined regimen of FM and FQ in reducing overall infectious complications [9]. The other study focused on the incidence of sepsis within 1 month after TRUSPB in Canada, which also showed that the use of FM and FQ together was more effective than FQ alone in decreasing sepsis [16].

Following a study that evaluated the efficacy of a combined regimen of FM and FQ as prophylaxis for TRUSPB in a single center in the Republic of Korea, this multicenter study was designed to investigate the effectiveness of FM-based antimicrobial prophylaxis for TRUSPB [9]. A total of 2,595 patients from seven tertiary hospitals located in the Republic of Korea were enrolled, and the data were retrospectively analyzed. One-way ANOVA and chi-square tests revealed that the use of FM and FQ together rather than FM alone was more effective in reducing the infectious complication rate.

Because of its retrospective design, this study had several limitations. First, there was an imbalance in patient characteristics. In particular, the rate of well-known reported risk factors such as health care utilization and diabetes mellitus could not be controlled. Because FM-based antibiotic prophylaxis was used for the patients with high rates of diabetes mellitus in group 3, diabetes mellitus may have been excluded from the risk factors.

Second, there was inconsistency in several factors such as who performed the biopsy and whether pre-biopsy rectal cleansing was done. In general, those who performed biopsies were either urologists or radiologists; thus, biopsy skill may have been uneven among the seven different institutions. In the case of rectal cleansing using povidone-iodine, most of the providers who performed the biopsy did rectal cleansing just before the biopsy (group 1, 100%; group 2, 87%; group 3, 100%).

Regarding the use of antibiotics, there were inconsistencies in the time of use, the number of doses, the route of administration, and the kind of antibiotics used by hospitals, which may have affected the study results. Depending on the institutions, patients received antibiotics for only 1 day (the day before biopsy or the day of biopsy) or for 2 days (the day of biopsy and the day before or after). The route of administration of FQ could be either oral or intravenous because of equivalent serum drug concentrations of oral and intravenous FQ. The kind of FQ used in the study differed by hospital. Because the use of levofloxacin is restricted in the Republic of Korea, only one institution used levofloxacin and the other six institutions used ciprofloxacin. To reduce the bias related to antibiotics use, a prospective randomized trial that controls the use of antibiotics such as the timing of antibiotic administration (e.g., the night before biopsy or the morning of the procedure), the number of doses (1 or 2 doses of antibiotics), the route of administration (oral or intravenous), and the kind of antibiotics (ciprofloxacin or levofloxacin) should be carried out.

The results of this multicenter retrospective study of the efficacy of prophylactic antibiotics showed that coadministration of FM and FQ was associated with reduced post-biopsy infectious complications. Although post-biopsy infections are rare, the use of appropriate antibiotics according to the regional antibiotic resistance pattern is crucial if antibiotic prophylaxis is to reduce the incidence of infectious complications, especially life-threatening urosepsis. To confirm the clinical efficacy of FM-based antibiotics, further research is needed.