MISCELLANEOUS The Role of Ciprofloxacin Resistance and Extended-spectrum beta-lactamase (ESBL) Positivity in Infective Complications Following Prostate Biopsy Nesibe Korkmaz1*, Yunus Gürbüz2, Fatih Sandıkçı3, Gülnur Kul4, Emin Ediz Tütüncü2, İrfan Şencan2 Purpose: To evaluate ciprofloxacin resistance (CR) and extended-spectrum beta-lactamase (ESBL) positivity in the rectal flora, antibiotic prophylaxis received, and post-biopsy infectious complications in patients undergoing prostate biopsy. Material & Methods: Rectal swab samples collected from 99 patients suspected of prostate cancer two days be- fore prostate biopsy were tested for microbial susceptibility and ESBL production. All patients were given standard ciprofloxacin and ornidazole prophylaxis. Ten days post-biopsy, the patients were contacted by phone and asked about the presence of fever and/or symptoms of urinary tract infection. Results: Escherichia coli (E.coli) was the most common isolate detected in 82 (75%) of the rectal swab samples. Ciprofloxacin resistance was detected in 33% and ESBL positivity in 22% of the isolated E.coli strains. No mi- croorganisms other than E.coli were detected in blood, urine, and rectal swab cultures of patients who developed post-biopsy complications. CR E.coli strains also showed resistance to other antimicrobial agents. The lowest resistance rates were to amikacin (n = 2, 7.4%) and nitrofurantoin (n = 1, 3.7%). Seven patients (7.6%) developed infectious complications. There was no significant difference in probability of hospitalization between patients with CR strains (14.3%) and those with ciprofloxacin-susceptible strains (14.3% vs. 4.7%; p = 0.194). However, strains that were both CR and ESBL-positive were associated with significantly higher probability of hospitaliza- tion compared to ciprofloxacin-susceptible strains (28.6% vs. 3.8%; p = 0.009). Conclusion: The higher rate of infectious complications with CR and ESBL-positive strains suggests that the agents used for antibiotic prophylaxis should be reevaluated. It is important to consider local resistance data when using extended-spectrum agents to treat patients presenting with post-biopsy infectious complications. Keywords: ciprofloxacin resistance; ESBL; infective complications; prostate biopsy INTRODUCTION Transrectal ultrasound-guided biopsy (TRUS-bx) is the standard diagnostic method for prostate can- cer (PCa).(1) Although TRUS-bx is a safe procedure, the incidence of infective complications has risen in recent years.(2) In multicenter studies, reported rates of infectious complications vary between 0.1% and 7% depending on the antibiotic prophylaxis administered.(2) The pathogenesis of post-biopsy infectious compli- cations is complicated. Risk factors such as diabetes mellitus (DM), prostatitis, immunosuppression, and re- peated prostate biopsies have been identified; however, increasing quinolone resistance (QR) and the presence of extended-spectrum beta-lactamase (ESBL)-produc- ing Enterobacteriaceae have been mostly emphasized. (3,4,5,6) Rising prevalence of fecal carriage of ESBL-positive 1Department of Infectious Diseases and Clinical Microbiology, Kahramankazan State Hospital, Ankara 06080, Turkey. 2Department of Infectious Diseases and Clinical Microbiology, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara 06080, Turkey. 3Department of Urology, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara 06080, Turkey. 4Department of Infectious Diseases and Clinical Microbiology, Kırıkhan State Hospital, Hatay 31440, Turkey. *Correspondence: Department of Infectious Diseases and Clinical Microbiology, Kahramankazan State Hospital, Ankara 06080, Turkey. Tel: 0505 6951975. E-mail: nesibeaydogan@hotmail.com. Received August 2018 & Accepted February 2019 pathogens in healthy populations is accompanied by a rapid increase in the rate of infections caused by ES- BL-producing gram-negative bacteria.(7) ESBL-pos- itive bacterial colonization may also cause urosepsis after TRUS-bx.(8) E.coli and K.pneumonia are the two most prevalent bacteria that synthesize ESBL and cause morbidity. Gram-negative bacteria that produce one of the ESBL enzymes are generally resistant to all extend- ed-spectrum cephalosporins and aztreonam.(9) The frequency of QR together with ESBL positivity in E.coli ranges from 50% to 100%.(10) Co-resistance to extended-spectrum beta-lactams and quinolone may be attributed to the wide use of quinolones like beta-lactam agents, as well as to multi-resistant gene transfer be- tween patients via plasmids carrying ESBL-encoding genes.(11) It is believed that there is a strong correlation between ESBL-positive and ciprofloxacin-resistant bacteria and infectious complications after prostate bi- Urology Journal/Vol 17 No. 2/ March-April 2020/ pp. 192-197. [DOI: 10.22037/uj.v0i0.4755] Vol 17 No 02 March-April 2020 193 opsy.(12) Due to increasing rates of complications after prostate biopsy in our hospital, we conducted this study to deter- mine antibiotic resistance profiles of the rectal flora and the frequency of ESBL production among patients un- dergoing prostate biopsy, and evaluate the relationship between post-biopsy infectious complications and flo- ral resistance profiles, comorbidities, and other factors. MATERIALS AND METHODS Study population This prospective study was conducted at Ankara Dışkapı Training and Research Hospital, which has a patient ca- pacity of 850. Ninety-nine patients were scheduled for TRUS-bx between October 2015 and October 2016 for suspected prostate cancer (suspicious digital rectal ex- amination and/or prostate specific antigen [PSA] over 2.5 ng/mL). Patients and their relatives were questioned about antibiotic use on the day the rectal swab culture was taken. Patients taking antibiotics were not included in the study. Presence / absence of post-biopsy infective complications were the main analyzed outcome (prima- ry outcome) of this study. Study design Ethics committee approval was obtained from Anka- ra Dışkapı Training and Research Hospital (decision number 36/10) and informed consent was obtained from all patients included in the study. Rectal swab samples were obtained two days before prostate biop- sy. The patients were questioned regarding risk factors, including age, smoking, use of ciprofloxacin in the last six months, catheterization history, urogenital infection, previous biopsy history, and comorbidities such as DM, chronic obstructive pulmonary disease (COPD), cancer, hypertension (HT), hemorrhoids, immunosuppression, history of heart valve replacement, benign prostatic hy- perplasia (BPH). After culture incubation, isolates found to be gram-neg- ative and oxidase negative were identified using citrate agar, Triple Sugar Iron (TSI) agar, and Motility-In- dole-Lysine(MIL) agar broths. API 20E kit was used for bacteria that could not be identified by those meth- ods. Antibiotic susceptibility tests were done using Kir- by-Bauer disc diffusion method as per the recommen- dations of the European Committee on Antimicrobial Susceptibility Testing. ESBL production was detect- ed using modified disc (combined disc) diffusion test (EUCAST V. 6.0, 2018). Antibiotic susceptibility was determined using ciprofloxacin (CIP, 5µg), levofloxa- cin (LEV, 5µg), ampicillin (AMP, 10µg), amoxicillin/ clavulanic acid (AMC, 20/10µg), cefepime (FEP, 30µg), cefuroxime (CXM, 30µg), gentamicin (GM, 10µg), amikacin (AK, 30µg), TMP-SXT (1.25/23.75µg), ce- foxitin (FOX, 30µg), cefotaxime (CTX, 5µg), ceftriax- one (CRO, 30µg), and ceftazidime (CAZ, 10µg) discs. Biopsy technique and patient follow-up Patients were prescribed 500 mg ciprofloxacin and 500 mg ornidazole every 12 hours for 5 days (taken the day before the procedure, in the morning of the procedure, and for 3 days post-biopsy)(1,13,14). All patients under- went bowel cleansing about 2-4 hours prior to biop- sy. Transrectal ultrasound-guided 12-core systematic biopsy using an 18-gauge biopsy needle was done as an outpatient procedure in an examination room in the urology ward. The patients were contacted by phone 10 days after biopsy and questioned about symptoms of fever, urinary incontinence, rectal blinding, bloody voiding, frequent urination, and flank pain. Sympto- Prostate biopsy infection complications and antibiotic resistance- Korkmaz et al. Table 1. Patients characteristics. Number of patients 92 Age, year; mean ± SD 63.6 ± 7.2 Variables n (%) Smoking Status 22 (23.9) Antibiotic use in the last 6 months 59 (64.8) Ciprofloxacin use in the 6 months 43 (46.7) Clinical History Urogenital infection 9 (9.8) Catheterization history 8 (8.7) Previous biopsy history 32 (34.8) Number of prior biopsies 1 26 (81.3) 2 5 (15.6) 3 1 (3.1) Comorbidities COPD 7 (7.6) DM 20(21.7) HT 32 (34.8) Hemorrhoids 13 (14.1) BPH 41 (44.6) Biopsy Results a (n=86) BPH 4 (4.7) Adenocarcinoma 19 (22.1) Benign prostate tissue 39 (45.3) Chronic active inflammation 26 (28.3) Stool Culture Pathogen b(n=102) E. coli 76 (74.5) Klebsiella 10 (9.8) Enterobacter 6 (5.9) Proteus 4 (3.9) Pantoea 3 (2.9) Citrobacter 2 (2.0) Hafnia 1 (1.0) Post-biopsy Complications Hospital admission 7 (7.6) Abbreviations: COPD, Chronic Obstructive Pulmonary Disease; DM, Diabetes Mellitus; HT, Hypertension; BPH, Benign Prostatic Hyperplasia; a Biopsy results were available for 86 patients. b Numbers and percentages are based on total agents isolated. Figure 1. Ciprofloxacin resistance and ESBL positivity detected in 99 patients. matic patients were advised to seek medical attention immediately. Patients who presented to the emergency department with fever ≥38°C and/or urinary symptoms, and met the systematic inflammatory response syndrome (SIRS) criteria for sepsis were admitted. Hospitalized patients had blood and urine cultures and were evaluated for infection-related complications based on three criteria: symptomatic urinary system infection, acute prostatitis, and sepsis. Statistical Analysis Descriptive and advanced analyses were performed us- ing SPSS, Open Epi, and Excel programs. Potential risk factors were evaluated using estimated odds ratio (OR), 95% confidence interval (CI), and 5% margin of error. P value < 0.05 was considered statistically significant. Chi square test and Fischer’s exact test swere used to test relationships between categorical variables. Resist- ance levels to other antibiotics tested in the study were evaluated in ciprofloxacin-resistant isolates. A logistic regression model was used to predict the risk factors for ciprofloxacin resistance. The model included the following variables: history of catheter use, history of repeat biopsy, history of urogenital infections, and cip- rofloxacin use in the last 6 months. The Wald test (enter method) was used in the model. RESULTS The rectal swab samples of 99 patients were analyzed for ESBL positivity, ciprofloxacin resistance, and relat- ed risk factors. On the day of biopsy, seven patients ob- jected to the procedure for various reasons. Therefore, post-biopsy complications were assessed in 92 patients. Evaluation of the study group is presented in Table 1. E.coli was the predominant agent isolated from rectal swab samples. E.coli was also the only agent isolated in blood and urine cultures and rectal swab samples of patients who had complications; no other microorgan- isms were detected. The prevalence of ciprofloxacin resistance was 27.5% and rate of ESBL positivity was 19.3% in the fecal flora of the 109 agents isolated from 99 patients (Figure 1). Most of the ciprofloxacin-resistant E.coli strains also exhibited resistance to other antimicrobial agents. Re- sistance was lowest to amikacin (n = 2, 7.4%) and nitro- furantoin (n = 1, 3.7%). Ciprofloxacin-resistant E.coli strains were significantly resistant to all antibiotics test- ed (Table 2). Ciprofloxacin use in the previous six months was identified as a significant risk factor for ciprofloxacin resistance (p = .008). CR was not associated with the presence of DM, HT, BPH, history of repeated biopsies, or the use of antibiotics other than quinolone. After con- trolling for other factors, the logistic regression model indicated that catheter use increased the risk of devel- oping ciprofloxacin resistance by 7.4 fold, urogenital infection history by 5.4 fold, and ciprofloxacin use in the last 6 months by 2.9 fold (Table 3). Post-biopsy infectious complications were evaluated in 92 patients. The infectious complications and features of the bacteria isolated in 7 (7.6%) patients who were hospitalized are summarized in Figure 2. Two of the 7 patients were treated in the intensive care unit. There were no mortalities. In terms of comorbidities, when compared as inpatients and outpatients, the estimated relative risk of DM was 1.5 times higher among inpatients than outpatients, but the difference was not statistically significant (95% CI: 0.3-8.3) (p = .643). There was no significant difference in probability of hospitalization between patients with ciprofloxacin-re- sistant strains and those with ciprofloxacin-susceptible strains (p = .194). However, the probability of hospi- talization was significantly greater in patients showing rectal flora colonization with ciprofloxacin-resistant Table 2. Resistance Rates to Other Antimicrobial Agents in Ciprofloxacin-susceptible and resistant E. coli Isolates Antibiotic resistance Ciprofloxacin-resistant Ciprofloxacin-sensitive P OR (95% CI) levels and ESBL positivity E. coli n=27 E. coli n=55 n % n % Ampicillin 21 77.8 23 41.8 .002 4.8 (1.7-14.8) AMC 18 66.7 15 27.3 .001 5.2 (1.9-14.7) Cefuroxime 11 40.7 6 10.9 .002 5.5 (1.7-18.4) Cefoxitin 8 29.6 2 3.6 .001 10.8 (2.3-80.0) Ceftriaxone 10 37.0 6 10.9 .005 4.7 (1.5-15.9) Cefotaxime 12 44.4 6 10.9 .001 6.4 (2.1-21.3) Ceftazidime 11 40.7 6 10.9 .002 5.5 (1.8-18.4) Cefepime 9 33.3 4 7.3 .002 6.2 (1.7-25.8) Amikacin 2 7.4 - - .187 6.8 (0.4-261.0) Gentamicin 8 29.6 1 1.8 < .001 21.8 (3.2-516.5) Nitrofurantoin 1 3.7 - - .220 4.1 (0.3-124.3) SXT 17 63.0 14 25.5 .001 4.9 (1.8-13.6) ESBL 12 44.4 6 10.9 .001 6.4 (2.1-21.3) Abbreviations: AMC, Amoxicillin-clavulanate; SXT, Trimethoprim-sulfamethoxazole; ESBL, Extended-spectrum beta-lactamases Risk factors p OR adj 95% CI Catheter history (Yes/No) 0.030 7.4 1.2-45.6 Repeated biopsy (Yes/No) 0.249 1.9 0.6-5.5 Urogenital infection history (Yes/No) 0.057 5.4 1.0-30.9 Ciprofloxacin use in the last 6 months (Yes/No) 0.037 2.9 1.1-8.2 Constant 0.244 - - Table 3. Logistic Regression Analysis of Ciprofloxacin Resistance and Related Risk Factors. Prostate biopsy infection complications and antibiotic resistance- Korkmaz et al. Miscellaneous 194 Vol 17 No 02 March-April 2020 195 and ESBL-positive strains compared to those with sus- ceptible strains (p = .009). DISCUSSION Increasing rates of quinolone resistance and ESBL-pro- ducing bacteria pose the greatest concern regarding post-biopsy infectious complications.(4,6) The preva- lence of fluoroquinolone resistance in rectal flora was reported as 10.6% by Batura et al. in 2010, compared to 25% in a study by Liss et al. in 2015.(15,16) In our study, quinolone resistance was calculated as 27% overall and 33% in the predominant agent, E. coli. In another study conducted in our region in 2014, fluoroquinolone resist- ance was reported at a similar rate (32.7%).(17) Tigen et al., who also analyzed patient data in our region, report- ed the prevalence of ESBL in rectal samples as 18%.(18) In our study, the prevalence of ESBL positivity in the rectal swab samples of 99 patients was 19.3% for all agents and 22% for E. coli. Although it is known that the use of quinolone antibiot- ics increases the prevalence of resistant bacteria in fecal flora, Yağcı et al. pointed out that there is a paucity of data regarding how long the flora maintains such resistance after antibiotics are discontinued.(19) In line with previous studies, our analysis of CR and related risk factors showed that the use of ciprofloxacin in the previous six months was a statistically significant risk factor. E.coli may also develop resistance to other antibiotics by means of efflux pumps, enzymatic target modifica- tion and reduced membrane permeability.(20) Minami- da et al. compared quinolone-resistant and susceptible E.coli isolates with regard to their resistance to other antimicrobials and reported that resistant strains de- veloped stronger resistance to other antibiotics com- pared to the quinolone-susceptible strains.(21) In this study, amikacin and phosphomycin resistance were not detected in quinolone-resistant isolates. Similarly, Hasanzadeh et al. showed that antibiotics with the least resistance in quinolone-resistant strains were amikacin (10.6%), phosphomycin (5.3%), and nitrofurantoin. When we performed a similar comparison between the two groups in our study, we observed higher resistance to antibiotics other than amikacin and nitrofurantoin.(22) Although resistance to nitrofurantoin was low, this an- tibiotic does not have good tissue penetration and hence is not suitable for the treatment of infectious compli- cations of the kidney parenchyma or prostate tissue.(23) Phosphomycin resistance was not detected. The find- ings suggest that multidrug-resistant bacteria are be- coming a major concern and are restricting the already limited treatment options. In multicenter studies, rates of post-biopsy infectious complications vary between 0.1% and 7% and sepsis rates between 0% and 3.6% depending on the antibiotic prophylaxis used.(2) In our study, 7 of the 92 patients (7.6%) were hospitalized and urosepsis was diagnosed in 5 patients (5.4%). Our high rate of infectious compli- cations may be related to the higher resistance rates. In hospitalized patients, the predicted relative risk of cip- rofloxacin resistance and ESBL positivity in the case of rectal swabs is 10.0 fold (95% CI: 2.0-51.3). Among the 5 patients diagnosed with urosepsis, 4 had strains that were both ESBL-positive and ciprofloxacin-resistant. Previous studies have demonstrated that agents with both ESBL positivity and ciprofloxacin resistance are strongly associated with post-biopsy infections.(12) Of the 7 patients who were hospitalized in this study, 2 patients who had negative rectal swabs for ciproflox- acin-resistant, ESBL-positive bacteria had a history of uncontrolled DM. DM has been shown to be an impor- tant risk factor for the development of infectious com- plications.(24,25) Post-biopsy infectious complications developed in 10% of our diabetic patients. Diabetes was also associated with a 1.5-fold higher risk of hos- pitalization, but this relationship was not statistically significant. Due to increasing rates of ESBL and quinolone resist- ance, a combination of quinolones with aminoglyco- sides is suggested in studies.(26,27) Lorber et al. reported Figure 2. Outcome of the patients hospitalized post-biopsy due to infectious complications. Prostate biopsy infection complications and antibiotic resistance- Korkmaz et al. an 83% reduction in urosepsis cases with the adminis- tration of intramuscular gentamicin and ciprofloxacin prophylaxis.(27) On the other hand, Miyazaki et al. com- pared patients given only levofloxacin prophylaxis and patients given combined amikacin and levofloxacin, and found no significant difference between the groups in terms of post-biopsy pyretic urinary tract infection. The authors attributed this to the effectiveness of the route of administration on the prostatic tissue and un- derlined the need for further investigation.(28) The present study has some limitations. Although infor- mation regarding antibiotic use was obtained verbally from patients and confirmed using the hospital records system, there remains the possibility that some drugs were taken without a prescription or the patient did not recall taking them. Resistance rates can also vary depending on the culture methods. Moreover, if ES- BL-producing strains carry an additional enzyme not in- hibiting byclavulanic acid (e.g. metallo-beta-lactamase or AmpC enzyme), the sensitivity of the test decreases significantly. This can be avoided by using chromoge- nic agar, using agar containing cloxacillin, supplement- ing with EDTA to inactivate metallo-beta-lactamases, and using cefepime, which is a weak substrate for most AmpC enzymes. Despite the fact that most automated systems have these capabilities, the diagnostic sensi- tivity of these methods is lower than that of classical methods.(29) CONCLUSIONS Quinolone-resistant strains can develop co-resistance to multiple agents. 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