Reducing Infectious Complications Following Transrectal Ultrasound-guided Prostate Biopsy: A Systematic Review
Systematic Review
SYSTEMATIC REVIEW Reducing Infectious Complications Following Transrectal Ultrasoundguided Prostate Biopsy: A Systematic Review Jordon T. Walker, BS, Nirmish Singla, MD, Claus G. Roehrborn, MD Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX A rise in antimicrobial resistant uropathogens has generated a global increase in infections following transrectal ultrasound-guided prostate biopsy (TRUS-Bx). We performed a systematic search of Ovid MEDLINE® and PubMed to comprehensively review strategies to mitigate infections. Of 1664 articles retrieved, 62 were included. The data suggest that augmented prophylaxis and povidone-iodine bowel preparation warrant consideration in regions with high rates of antimicrobial resistance. Transperineal biopsy may be a safer, equally effective alternative to TRUS-Bx in select cases. Recent international travel appears to increase patients’ risk for experiencing infections. These findings can aid clinicians in minimizing post-TRUS-Bx infectious complications. [Rev Urol. 2016;18(2):73-89 doi: 10.3909/riu0713] ® © 2016 MedReviews , LLC KEY WORDS Transrectal ultrasound • Prostate biopsy • Urinary tract infection • Systematic review T ransrectal ultrasound-guided prostate biopsy (TRUS-Bx) is one of the most common urologic procedures performed worldwide, with over 1 million biopsies annually performed in the United States alone.1 Overall, prostate biopsies are relatively safe and only approximately 5% of men develop infections after TRUS-Bx.2 Fluoroquinolone (FQ) prophylaxis is routinely administered prior to biopsy to minimize infections. Alarmingly, however, there has been a sharp rise in infectious complications following TRUS-Bx in recent years. Nam and colleagues3 reported an increase in 30-day hospital admission rates from 1.0% in 1996 to 4.1% in 2005 in Canada, and similar increases have been Vol. 18 No. 2 • 2016 • Reviews in Urology • 73 4004170006_RIU0713.indd 73 27/07/16 3:13 pm Methodology We conducted a systematic review of the Ovid MEDLINE® and PubMed databases using Boolean search combinations of key terms (prostate biopsy, infection, complication, cost, management, organism, prevalence, resistance, and risk) to identify relevant articles published in English between January 1995 and December 2015. Reference lists of retrieved papers were searched and related articles were manually included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guided the search process, and the results of the systematic review are outlined in Figure 1. Antibiotic Prophylaxis A wide diversity of prophylactic antibiotics have been used (Table 1), and regimens can be divided into three approaches: monotherapy, Records identified through database search (n = 2513) Additional records identified through other sources (n = 8) Eligibility Screening Records after duplicates removed (n = 1664) Included reported in Europe4 and the United States.5 Numerous studies attribute this rise to an increasing prevalence of FQ-resistant organisms6 (specifically Escherichia coli sequence type 131)7,8 and extended spectrum -lactamase (ESBL)producing bacteria.8,9 Current prophylactic recommendations in the American Urological Association Best Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxis heavily rely upon studies conducted before 2005, which predates the rise in antibioticresistant uropathogens.10 Given the proliferation in research on strategies to prevent post-TRUS-Bx infections, existing guidelines lag behind contemporary knowledge. This article systematically reviews optimal techniques to minimize post-TRUS-Bx infections, to aid incorporation of contemporary research findings into clinical practice. Identification Reducing Infectious Complications Following TRUS-Bx continued Records screened by title (n = 1664) Records excluded (n = 1390) Abstracts assessed for eligibility (n = 274) Records excluded (no abstract, commentary only, irrelevant) (n = 172) Full-text articles assessed for eligibility (n = 102) Full-text articles excluded (included in prior metaanalysis, irrelevant) (n = 40) Studies included in qualitative synthesis (n = 62) Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart of the search process. augmented prophylaxis ( 2 antibiotics), or rectal swab–targeted prophylaxis. Monotherapy FQ antibiotics are the mainstay of first-line prophylaxis for and ceftriaxone to be equally effective as FQs in preventing urinary tract infections (UTIs; range P .22-.71) and infectionrelated hospitalizations (range P .47-.96).12,13 Similarly, one study reported no significant dif- FQ antibiotics are the mainstay of first-line prophylaxis for TRUS-Bx. TRUS-Bx.11 However, a rising prevalence of FQ-resistant bacteria prompted multiple authors to investigate alternative monotherapy options. Retrieved studies primarily explored piperacillintazobactam, cephalosporins (eg, ceftriaxone), fosfomycin, and amoxicillin/clavulanic acid as monotherapy substitutes. Two recent meta-analyses reported piperacillin-tazobactam ferences in the rate of afebrile and febrile UTIs in patients receiving either FQs (500 mg ciprofloxacin or 500 mg levofloxacin) or 3 g fosfomycin (P .05).14 Recent data indicate that fosfomycin achieves a mean prostate-to-plasma concentration ratio of 0.67 0.57, which is higher than other more commonly used agents (the prostate-to-plasma ratio of amikacin is 0.49 .21).15,16 Data regarding the 74 • Vol. 18 No. 2 • 2016 • Reviews in Urology 4004170006_RIU0713.indd 74 27/07/16 3:13 pm Reducing Infectious Complications Following TRUS-Bx -lactamase inhibitor amoxicillin/ clavulanic acid, in contrast, suggest it offers inferior protection compared with FQs.17 Three independent studies in Denmark and the United Kingdom reported large increases in infectious complications following the replacement of ciprofloxacin prophylaxis with amoxicillin/clavulanic acid.11,18,19 These results argue against the use of amoxicillin/clavulanic acid as monotherapy for TRUS-Bx. Although some empiric data support the efficacy of alternative agents for monotherapy, sample sizes are generally quite modest (range 138-620), and further research is required to justify supplanting FQs as first-line prophylaxis. Augmented Prophylaxis Augmented prophylaxis has consistently demonstrated superior protection compared with monotherapy.5,13,20-24 A recent meta-analysis of three randomized controlled trials (RCTs; n 659) documented the protective superiority of augmented prophylaxis in reducing UTIs (relative risk [RR] 4.64, 95% confidence interval [CI], 2.01-10.74; P .0003) and hospitalizations (RR 5.91, 95% CI, 2.2015.87; P .004) following prostate biopsy.13 FQs were most frequently coupled with aminoglycosides, specifically gentamicin and amikacin, in augmented prophylactic protocols.20,21 In a retrospective study, gentamicin (1 mg/kg and 80 mg, respectively) was added to ciprofloxacin prophylaxis in a quality improvement initiative at the Cleveland Clinic (Cleveland, OH; 10% vs 2.5%; P not reported)5 and in a tertiary academic medical center in Texas (3.8% vs 0.6%; P .001).22 Augmented prophylaxis using gentamicin is cost effective (an 80-mg vial costs $0.15),25 and econometric analysis indicates the augmented regimen can produce savings of $15,700 per 100 patients due to avoided hospitalizations.22 Amikacin was the second most frequently used aminoglycoside in augmented protocols. Kehinde and colleagues23 reported a drastic reduction in septic events (1.7% vs 8.0%; P .001) after adding 500 mg intravenous (IV) amikacin before biopsy to standard FQ prophylaxis. Due to its effectiveness against E coli23 and projected cost savings per patient ranging from $9.50 to $69.50 in avoided complication costs, amikacin may be a favorable adjunct to FQ prophylaxis.26 Carbapenems were also frequently used in augmented protocols. In a recent New Zealand study, adding ertapenem to standard prophylaxis (ciprofloxacin and amoxicillin/clavulanic acid) substantially reduced rates of sepsis in a highrisk group (6.7% [95% CI, 2.1-11.3] vs 0%; P .03).24 Likewise, Shakil and associates27 reported zero infectious complications following TRUS-Bx in patients with documented multidrug-resistant E coli FQs were most frequently coupled with aminoglycosides, specifically gentamicin and amikacin, in augmented prophylactic protocols. Lorber and associates21 reported an 83% reduction in urosepsis by augmenting FQ prophylaxis with a single 240-mg dose of intramuscular (IM) gentamicin (3.6% vs 0.6%; P .04).21 Similar results were obtained in two studies when IM given IV ertapenem as prophylaxis. Thus, ertapenem currently appears to be highly effective in preventing microbial infections resistant to other agents. However, carbapenemase-producing bacteria have been reported in diverse regions of the world, including the United States, Israel, Greece, and Colombia.28 Increasing carbapenem resistance may limit the utility of this class of antibiotics for future prophylaxis and justifies restricting carbapenems for treating only severe infections. Given the myriad combinations of augmented prophylaxis, it is reasonable to consider the relative effectiveness of various combinations. One study comparatively evaluated different augmented prophylaxis regimens. In a retrospective study, ciprofloxacin plus an IM aminoglycoside afforded inferior protection to levofloxacin plus an IM aminoglycoside in reducing severe infections (odds ratio [OR] 4.59; 95% CI, 1.12-24.15; P .04).29 Choice of aminoglycoside did not significantly affect infection rates (P .68),29 thereby suggesting equivalent efficacy among different aminoglycosides. Although the literature supporting augmented prophylaxis in TRUS-Bx is robust, a number of shortcomings should be noted. Augmented prophylaxis is only a temporary solution to increased antimicrobial resistance, and widespread use of combinations of antibiotics will further exacerbate selection pressure for resistant microbes. Additionally, there is considerable heterogeneity in local sensitivity patterns of organisms causing post-TRUS-Bx infections. Given such variability, it is important to consider the geographic context of reported literature findings and to evaluate their applicability to local patterns of resistance in urologic practices. Targeted Prophylaxis Targeted prophylaxis based on rectal swab culture has been extensively studied, yet ambiguity remains regarding the utility of routinely performing targeted Vol. 18 No. 2 • 2016 • Reviews in Urology • 75 4004170006_RIU0713.indd 75 27/07/16 3:13 pm 4004170006_RIU0713.indd 76 600 2381 1460 487 235 411 Year 2013 2014 2014 2015 2012 2009 Study Adibi M et al22 Antsupova V et al11 Antsupova V et al11 Dai J et al33 Duplessis CA et al67 Horcajada JP et al17 Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Sample Size Methodology Spain United States United States Denmark Denmark United States Country Selected Studies of Antibiotic Prophylaxis for TRUS-Bx TABLE 1 Oral 500 mg amoxicillin/clavulanic acid 3 times daily for 5d Oral 500 mg ciprofloxacin twice daily for 3 d Oral 500 mg ciprofloxacin (3 doses perioperatively) Oral 500 mg ciprofloxacin twice daily for 1 d Oral 500 mg ciprofloxacin twice daily for 1 d Oral 500 mg ciprofloxacin twice daily for 3 d Standard Prophylaxis 2 g cefoxitin 1 h before biopsy and oral 750 mg ciprofloxacin twice daily for 5 d Rectal swab-targeted prophylaxis Rectal swab-targeted prophylaxis 400 mg pivmecillinam plus 500/125 mg amoxicillin/clavulanic acid daily for 2 d before biopsy 400 mg pivmecillinam plus 500/125 mg amoxicillin/clavulanic acid daily for 2 d before biopsy and three times daily for 2 d after biopsy Standard 80 mg IM gentamicin Alternative Prophylaxis Bacteremia, sepsis Infectious complications (bacteremia, fever, prostatitis, pyelonephritis, UTI, sepsis) Infectious complications (cystitis, bacteriuria, pyelonephritis, bacteremia, sepsis) Bacteremia Bacteremia Hospitalization Outcome Variables Reducing Infectious Complications Following TRUS-Bx continued 76 • Vol. 18 No. 2 • 2016 • Reviews in Urology 27/07/16 3:13 pm 4004170006_RIU0713.indd 77 5355 4655 170 2015 2013 2014 Liss MA et al31 Lorber G et al21 Losco G et al24 4134 1197 2013 Kehinde EO et al23 2015 263 2015 Hsieh T-Y et al25 Luong B et al54 229 2010 Hori S et al18 Retrospective Prospective Retrospective Retrospective Prospective Retrospective Prospective United States New Zealand Israel United States Kuwait Taiwan United Kingdom Oral 500 mg ciprofloxacin twice daily for 4 d Oral 500 mg ciprofloxacin and oral 625 mg amoxicillin/clavulanic acid 1 h before biopsy and twice daily for 3 d after biopsy Oral ciprofloxacin or ciprofloxacin twice daily for 3 d Oral 500 mg ciprofloxacin twice daily 4 doses of oral 500 mg ciprofloxacin twice daily for 3 d Oral 500 mg levofloxacin once daily for 5 d Oral 500 mg ciprofloxacin 1 h before biopsy and twice daily for 3 d Sepsis Sepsis Sepsis Sepsis Infectious complications (chills, fever, macroscopic hematuria with blood clots, and severe LUTS) (Continued) Oral 500 mg ciprofloxacin Infectious complications plus 1 g IM ceftriaxone (hospitalization, sepsis) Standard 1 g IM ertapenem Standard 240 mg IM gentamicin Rectal swab-targeted prophylaxis Standard 500 mg IV amikacin Standard 80 mg IM gentamicin Oral 625 mg pamoxicillin/ Sepsis clavulanic acid 1 h before biopsy and three times daily for 3 d Reducing Infectious Complications Following TRUS-Bx Vol. 18 No. 2 • 2016 • Reviews in Urology • 77 27/07/16 3:13 pm 255 620 2676 9 2926 1189 9115 Year 2011 2012 2014 2014 2015 2015 2015 Study Madden T et al19 4004170006_RIU0713.indd 78 Ongün S et al14 Roberts MJ et al30 Shakil J et al27 Summers SJ et al32 Unnikrishnan R et al29 Womble PR et al20 Prospective Retrospective Retrospective Prospective Meta-analysis Retrospective Retrospective Sample Size Methodology United States United States United States United States Multinational Turkey United Kingdom Country Selected Studies of Antibiotic Prophylaxis for TRUS-Bx (Continued) Oral 500 mg ciprofloxacin twice daily for 1 d Oral 500 mg ciprofloxacin plus 80-120 mg IM aminoglycoside Oral 500 mg ciprofloxacin 1 h before biopsy and twice daily for 3 d after biopsy No comparator Empiric fluoroquinolone prophylaxis Oral 500 mg ciprofloxacin or 500 mg levofloxacin before biopsy and twice daily for 5 d after biopsy Oral 500 mg ciprofloxacin before biopsy and twice daily for 3-5 d after biopsy Standard Prophylaxis Standard 120 mg IM gentamicin 750 mg levofloxacin 80-120 mg IM aminoglycoside Rectal swab-targeted prophylaxis 1 g ertapenem IV for 2-3 d Rectal swab-targeted prophylaxis Oral 3 g fosfomycin Oral 375-625 mg amoxicillin/clavulanic acid three times daily for 3 d after biopsy 120 mg gentamicin IV 10 min before biopsy Alternative Prophylaxis Hospitalization Mild infections (infections treated as outpatient), severe infections (infections requiring emergency room evaluation, hospital admission, or overnight stay within observation unit) Infectious complications (cystitis, bacteremia, pyelonephritis, sepsis) Infectious complications (not defined) Infectious complications (not defined) Afebrile UTI, febrile UTI Infectious complications (epididymo-orchitis, fever, prostatitis, sepsis, UTI) Outcome Variables Reducing Infectious Complications Following TRUS-Bx continued 78 • Vol. 18 No. 2 • 2016 • Reviews in Urology 27/07/16 3:13 pm 4004170006_RIU0713.indd 79 Meta-analysis Meta-analysis Meta-analysis Meta-analysis Meta-analysis Meta-analysis Meta-analysis Prospective Multinational Multinational Multinational Multinational Multinational Multinational Multinational United States IM, intramuscular; IV, intravenous; LUTS, lower urinary tract symptoms; UTI, urinary tract infection. 138 138 2011 Zani EL et al12 2011 269 2011 Zani EL et al12 Zani EL et al12 522 2015 Yang L et al13 269 659 2015 Yang L et al13 2011 502 2015 Yang L et al13 Zani EL et al12 9115 2015 Womble PR et al20 Fluoroquinolone (ciprofloxacin or levofloxacin) Fluoroquinolone (ciprofloxacin or levofloxacin) Fluoroquinolone (ciprofloxacin or levofloxacin) Fluoroquinolone (ciprofloxacin or levofloxacin) Fluoroquinolone (ciprofloxacin or levofloxacin) Monotherapy Monotherapy Oral 500 mg ciprofloxacin twice daily for 1 d Piperacillin-tazobactam Ceftriaxone Piperacillin-tazobactam Ceftriaxone Ceftriaxone, chloramphenicol, or piperacillin-tazobactam Augmented prophylaxis Augmented prophylaxis Rectal swab-targeted prophylaxis UTI UTI Hospitalization Hospitalization Fever, hospitalization, UTI Hospitalization, UTI Antimicrobial resistant bacteria on blood or urine culture, bacteremia, bacteriuria Hospitalization Reducing Infectious Complications Following TRUS-Bx Vol. 18 No. 2 • 2016 • Reviews in Urology • 79 27/07/16 3:13 pm Reducing Infectious Complications Following TRUS-Bx continued prophylaxis in patients undergoing TRUS-Bx. A meta-analysis of eight studies (n 2767) published between 2010 and 2013 strongly supports the efficacy of targeted prophylaxis over empirical FQ monotherapy for reducing infectious complications following TRUS-Bx (0.3% [95% CI, 0%-0.9%] vs 3.3% [95% CI, 2.6%-4.2%]; P .0003).30 However, more recent studies failed to find a reduction in severe infectious complications with targeted prophylaxis. Liss and colleagues31 found no difference in sepsis rates between patients receiving targeted prophylaxis versus empiric prophylaxis in a large study (n 5355) of 13 Kaiser Permanente Centers throughout the United States (0.44% vs 0.56%; P .568). Moreover, a recent statewide prospective study in Michigan (n 4087) reported similar hospitalization rates between patients receiving rectal culture-directed antibiotics and augmented prophylaxis (0.47% vs 0.58%; P not reported).20 Similarly, two smaller studies conducted at a Veterans Affairs Hospital32 and a US academic medical center33 did not detect a significant difference in infectious complications between patients receiving targeted prophylaxis and those receiving empiric prophylaxis (P .13 and P .58, respectively). The failure of targeted prophylaxis to reduce severe infectious complications in large-scale studies calls Quality Improvement Summit, including costs of additional labor, multiple clinic visits by patients, lack of adoption by microbiology laboratories, and requirements for special culture media.5,23 Overall, the utility of targeted prophylaxis appears to be limited. Reports suggest only 6% to 9% of patients with FQ-resistant bacteria detected in their rectal flora develop infections Prebiopsy Bowel Preparation Evidence supporting the protective effect of prebiopsy bowel preparation varies based upon the agent used for rectal cleansing. The majority of studies investigating enemas (using sodium phosphate or saline) … studies specifically evaluating povidone-iodine rectal cleansing, strongly support the use of a prebiopsy bowel preparation (topical, enema, or suppository) to reduce post-TRUS-Bx infections. following TRUS-Bx.34,35 Hwang and coworkers36 did not find an association between FQ-resistant bacteria or ESBL-producing bacteria on rectal culture and subsequent infectious complications (P .512 and P .363, respectively). Due to the considerable additional labor associated with targeted prophylaxis, the cost-to-benefit profile is unlikely to be favorable in the majority of patients. Nevertheless, as targeted prophylaxis mitigates concerns regarding accelerating antibiotic resistance, there may be a role for targeted prophylaxis in specific subgroups of patients most at risk for post-TRUS-Bx infection. Biopsy Procedure The rising incidence of antimicrobial resistance has generated greater interest in using procedural The failure of targeted prophylaxis to reduce severe infectious complications in large-scale studies calls into question whether it is appropriate for routine clinical practice. into question whether it is appropriate for routine clinical practice. Additionally, there are numerous economic and logistic challenges to implementing targeted prophylaxis. Many of these challenges were highlighted at the 2014 AUA approach to prostate biopsy has also generated interest in reducing infectious complications. techniques to minimize infections. The majority of published literature focuses on three aspects of TRUS-Bx: prebiopsy bowel preparation, number of sampled cores, and biopsy needle disinfection techniques (Table 2). The transperineal found no protective effect against post-TRUS-Bx infections.12,37-41 In contrast, studies specifically evaluating povidone-iodine rectal cleansing36,42 strongly support the use of a prebiopsy bowel preparation (topical, enema, or suppository) to reduce post-TRUS-Bx infections. In a meta-analysis of seven RCTs (n 2049), povidoneiodine disinfection plus antibiotics significantly reduced the rate of overall infectious complications compared with antibiotics alone (RR 0.23; 95% CI, 0.10-0.54; P .0006), with significant reductions in both bacteremia (P .01) and fever (P .03).42 Additionally, Hwang and colleagues36 reported povidone-iodine enemas significantly reduced the incidence of bacteremia and sepsis (P .001) in a retrospective analysis at a Korean hospital.36 Povidone-iodine offers a number of advantages in reducing post-TRUS-Bx infections by decreasing rectal microbial counts prior to procedures in vitro, rapidly exerting its effects, and discouraging antimicrobial resistance.43 These results can be used to guide the agent used for prebiopsy bowel preparation, as prebiopsy enemas are commonly performed by approximately 81% of US urologists,44 but are not recommend in European guidelines.45 80 • Vol. 18 No. 2 • 2016 • Reviews in Urology 4004170006_RIU0713.indd 80 27/07/16 3:13 pm 4004170006_RIU0713.indd 81 Sample Size 162,577 5957 2718 448 5798 245 6609 263 814 Year 2016 2004 2015 2001 2012 2014 2014 2015 2015 Study Bennet HY et al51 Berger AP et al55 Bruyere F et al38 Carey and Korman41 Carignan A et al65 Grummet JP et al47 Grummet JP et al47 Hsieh T-Y et al25 Hwang EC et al36 Retrospective Retrospective Systematic review Prospective Retrospective Retrospective Prospective Retrospective Meta-analysis Methodology Korea Taiwan Australia Australia Canada United States France Austria Multinational Country Antibiotics alone 12-16 biopsy cores No comparator No comparator Antibiotics alone Antibiotics alone Antibiotics alone 6 or 10 biopsy cores TRUS-Bx Standard Technique Antibiotics plus povidoneiodine disinfection 10 biopsy cores Transperineal prostate biopsy Transperineal prostate biopsy Antibiotics plus enema Antibiotics plus enema Antibiotics plus enema 15 biopsy cores Transperineal prostate biopsy Alternative Technique Selected Studies on Procedural Techniques Impacting Infectious Complications Following TRUS-Bx TABLE 2 (Continued) FQ-resistant rectal culture, Infectious complications (fever, bacteremia, prostatitis, UTI, sepsis) Infectious complications (chills, fever, macroscopic hematuria with blood clots, severe LUTS) Sepsis Sepsis Infectious complications (not defined) Infectious complications (epididymitis, hospitalization, prostatitis, UTI) Infectious complications (fever with positive urine culture, LUTS) Infectious complications (epididymitis, fever, hospitalization, mortality, prostatitis) Hospitalization, sepsis Outcome Variables Reducing Infectious Complications Following TRUS-Bx Vol. 18 No. 2 • 2016 • Reviews in Urology • 81 27/07/16 3:13 pm 4004170006_RIU0713.indd 82 Sample Size 2632 1083 1083 4134 1684 3000 1901 140 Year 2013 2014 2014 2015 2014 2013 2014 2014 Study Issa MM et al52 Kam SC et al56 Kam SC et al56 Luong B et al54 Park DS et al43 Pepe P et al50 Pu C et al42 Pu C et al42 Meta-analysis Meta-analysis Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Methodology Multinational Multinational Italy Korea United States Korea Korea United States Country Antibiotics alone Placebo 12 biopsy cores Antibiotics alone 14 biopsy cores 6 biopsy cores Antibiotics alone Antibiotics alone Standard Technique Antibiotics plus povidoneiodine disinfection Povidone-iodine disinfection 18-24 biopsy cores Antibiotics plus povidoneiodine disinfection 18-24 biopsy cores 12 biopsy cores Antibiotics plus enema Antibiotics plus formalin (10%) disinfection of biopsy needle Alternative Technique Selected Studies on Procedural Techniques Impacting Infectious Complications Following TRUS-Bx (continued) Infectious complications (bacteremia, bacteriuria, and fever) Infectious complications (bacteremia, bacteriuria, and fever) Infectious complications (emergency department visit, epididymo-orchitis, fever, hospitalizations, prostatitis, UTI, sepsis) Rectal bacterial count Infectious complications (hospitalization, sepsis) Infectious complication (prostatitis) Infectious complication (prostatitis) Sepsis, UTI Outcome Variables Reducing Infectious Complications Following TRUS-Bx continued 82 • Vol. 18 No. 2 • 2016 • Reviews in Urology 27/07/16 3:13 pm 4004170006_RIU0713.indd 83 Retrospective Meta-analysis Meta-analysis Meta-analysis Prospective Retrospective Retrospective Retrospective Retrospective Meta-analysis United States Multinational Multinational Multinational Multinational United Kingdom United States Turkey Canada Multinational Oral 500 mg ciprofloxacin 1 h before biopsy Antibiotics alone (varied regimen) Antibiotics alone (varied regimen) Antibiotics alone (varied regimen) Varied number of biopsy cores (range1-40) No comparator Antibiotics alone Varied number of biopsy cores Antibiotics alone Antibiotics alone Oral 500 mg ciprofloxacin for 3 d enema Antibiotics enema Antibiotics enema Antibiotics enema N/A Transperineal prostate biopsy Antibiotics formalin (10%) disinfection of biopsy needle N/A Antibiotics enemas Antibiotics plus povidoneiodine disinfection FQ, fluoroquinolone; LUTS, lower urinary tract symptoms; TRUS-Bx, transrectal ultrasound-guided prostate biopsy; UTI, urinary tract infection. 1438 2011 Zaytoun OM et al37 147 2011 Zani EL et al12 209 521 2013 Wagenlehner FM et al2 2011 634 2014 Vyas L et al49 Zani EL et al12 917 2015 Singla N et al (unpublished data) 68 2023 2010 Simsir A et al53 2011 407 2011 Ruddick F et al40 Zani EL et al12 68 2014 Pu C et al42 Infectious complications (positive urine culture), sepsis Fever Bacteremia Bacteriuria UTI Epididymo-orchitis, hospitalization, sepsis UTI Sepsis Sepsis Infectious complications (bacteremia, bacteriuria, and fever) Reducing Infectious Complications Following TRUS-Bx Vol. 18 No. 2 • 2016 • Reviews in Urology • 83 27/07/16 3:13 pm Reducing Infectious Complications Following TRUS-Bx continued Transrectal Versus Transperineal Biopsy Initial research indicates transperineal prostate biopsy may be equally effective as TRUS-Bx for detecting prostate cancer with a lower incidence of severe infections.46-48 Transperineal biopsy Formalin Disinfection Formalin disinfection has been proposed as a cost-neutral means to reduce infectious complications. A recent report by Issa and colleagues52 suggests that using formalin (10%) wash to disinfect the needle tip after each biopsy Transperineal biopsy poses a lower risk for infection because the method avoids seeding of the prostate gland with rectal flora. poses a lower risk for infection because the method avoids seeding of the prostate gland with rectal flora.46,47,49,50 A study on transperineal biopsies performed in Melbourne, Australia, found a 0% rate of sepsis among 245 patients.47 The authors also conducted an analysis of the literature published from 2003 to 2013 and found only a 0.076% sepsis rate among 6609 patients undergoing transperineal biopsy.47 A more recent meta-analysis of 165 studies (n 162,577) directly compared rates of hospitalization and sepsis following TRUS-Bx versus transperineal biopsy and found fewer complications with the transperineal approach (1.1% vs 0.9% and 0.8% vs 0.1%, respectively), although the differences were not statistically significant.51 Considering transperineal biopsy is equivalent to TRUS-Bx in the diagnosis of prostate cancer,48 transperineal biopsy may represent a highly effective alternative to TRUS-Bx for reducing severe infectious complications. Despite the suggested greater safety profile, there are a number of disadvantages associated with transperineal biopsy, such as the requirement for general anesthesia, higher costs, greater labor time, and the necessity for specialized equipment.47 Nonetheless, the lower rate of severe complications makes transperineal biopsy a promising alternative to TRUS-Bx. core sampling may minimize postTRUS-Bx infections (0.30% vs 0.80%; P .13). Although the use of formalin failed to reach statistical significance in the clinical sample, the authors performed ex vivo experiments that offer strong empiric support for the ability of formalin to completely inhibit the growth of FQ-resistant bacteria. Indeed, in a recent retrospective study formalin (10%) wash demonstrated a protective effect in reducing postbiopsy infections (OR 0.37; 95% CI, 0.17-0.81; P .013) (N. Singla, unpublished data, 2015). Formalin disinfection of the biopsy needle directly lowers the inoculum of bacteria present on the biopsy needle and is effective against both FQ-sensitive and FQ-resistant bacteria (N. Singla, unpublished data, 2015).52 Moreover, formalin disinfection is cost neutral and requires minimal additional labor on the part of the clinician. However, no prospective studies or RCTs have explored the efficacy of formalin disinfection of the biopsy needle. Well-powered RCTs are warranted before formalin disinfection can be recommended for widespread clinical implementation. Number of Sampled Cores Although one retrospective study reported an increased risk of infection with a greater number of sampled biopsy cores,53 most studies found no significant relationship between the number of cores sampled during TRUS-Bx and postbiopsy infection rates or complications.25,37,54-56 Risk Factors A number of reports recommended limiting the use of more intensive and costly preventive measures to patients at high risk for infection.20,26,57,58 To do so, there is a clear need to accurately identify high-risk patients. Although the literature is replete with putative risk factors for post-TRUS-Bx infection, few offer definitive prognostic value. Below we present a qualitative synthesis of the risk factors for post-TRUS-Bx infection most extensively studied in the literature (see Table 3 for all risk factors studied). Prior Antibiotic Exposure Among the variables found to be associated with post-TRUS-Bx infection, prior antibiotic exposure is the most extensively studied.6,30,36,38,39,59 Multiple studies document a strong association between prior antibiotic exposure and risk of harboring FQ-resistant organisms. Pooled analysis of nine studies (n 2541) in a recent metaanalysis identified prior FQ use (OR 4.2; 95% CI, 2.30-7.37; P .02) as a significant risk factor for the presence of FQ-resistant bacteria in the rectal flora.30 Similarly, Tsu and associates60 recently reported that patients with antimicrobial exposure in the past 5 years were more likely to harbor antimicrobialresistant organisms in their rectums (OR 1.550; P .04). Contrary to the expected results based on these studies, prior antibiotic exposure has not been consistently linked to greater rates of severe infectious complications. Multivariate analysis of patient records at a Korean hospital indicated FQ exposure was 84 • Vol. 18 No. 2 • 2016 • Reviews in Urology 4004170006_RIU0713.indd 84 27/07/16 3:13 pm 4004170006_RIU0713.indd 85 2718 5798 814 487 235 591 263 814 1083 2011 2015 2012 2015 2015 2012 2014 2015 2015 2014 2008 Akduman B et al59 Bruyere F et al38 Carignan A et al65 Cohen JE et al63 Dai J et al33 Duplessis CA et al67 Ehdaie B et al61 Hsieh T-Y et al25 Hwang EC et al36 Kam SC et al56 Kamdar C et al68 378 558 Year Study Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Prospective Retrospective Prospective Retrospective Sample Size Methodology Risk Factors Age, chronic renal failure, COPD, diabetes, metastatic neoplasm, prior hospitalization within 1 mo, PSA, urinary catheter, and urologic pathology Age, antibiotic exposure, history of prostatitis, PSA, type and duration of antibiotics FQ-resistant rectal flora Infectious complications (not defined) Infectious complications (fever with positive urine culture, LUTS) Sepsis Outcome Variables Age, prostate volume, and PSA Antibiotic exposure, diabetes, povidoneiodine enema, prostate volume, and PSA Age, antibiotic prophylaxis, diabetes, hypertension, and prostate cancer United States Hospital employee and relative of hospital employee Korea Korea Taiwan United States Age, antibiotic exposure, benign prostatic hypertrophy, diabetes, and prior biopsies United States Age, antibiotic exposure, prior biopsies, prophylaxis (ciprofloxacin), and race/ethnicity Bacteremia (Continued) Infectious complication (prostatitis) FQ-resistant rectal culture, Infectious complications (fever, bacteremia, prostatitis, UTI, sepsis) Infectious complications (chills, fever, macroscopic hematuria with blood clots, severe LUTS) Infectious complications (fever, hospitalization for infection, positive blood or urine culture) Infectious complications (bacteremia, fever, prostatitis, pyelonephritis, UTI, sepsis) United States Age, prior biopsy, prior hospitalization, PSA, FQ-resistant rectal flora and race/ethnicity United States Age, diabetes, dyslipidemia, heart disease, hypertension, prostate volume, and PSA Canada France United States Prolonged FQ antibiotic exposure Country Selected Studies Investigating Risk Factors for Antimicrobial Resistance or Infectious Complications Following TRUS-Bx TABLE 3 Reducing Infectious Complications Following TRUS-Bx Vol. 18 No. 2 • 2016 • Reviews in Urology • 85 27/07/16 3:13 pm 4004170006_RIU0713.indd 86 2673 17523 4134 107 316 2023 2926 371 521 47 2013 2014 2011 2015 2011 2012 2010 2015 2015 2013 2012 Kehinde EO et al23 Liss MA et al31 Loeb S et al1 Luong B et al54 Mosharafa AA et al39 Patel U et al57 Simsir A et al53 Summers SJ et al32 Tsu JH et al60 Wagenlehner FM et al2 Williamson DA et al7 Retrospective Prospective Prospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Prospective Chronic renal failure, diabetes, prostatitis, steroid therapy, and UTI Risk Factors Age, diabetes, prior biopsies, prostate volume, prostatitis at biopsy, PSA, and urethral catheter Antibiotic exposure and international travel Age, chronic constipation/diverticular disease, diabetes, enema use, FQ exposure, hypertension, and prostatitis at biopsy New Zealand Multinational China International travel Age, antibiotic exposure, prebiopsy bacteriuria, preoperative bowel preparation, presence of inflammation in biopsy samples, prior biopsies, prostate volume, PSA, use of anesthesia at biopsy, and UTI history Antibiotic exposure and diabetes United States Antibiotic exposure, diabetes, immunosuppression, prior biopsies Turkey United Kingdom Egypt United States Age, antibiotic exposure, PSA, and race/ethnicity United States Prior biopsy United States Augmented prophylaxis, diabetes, FQ-resistant bacteria on rectal culture Kuwait Country ESBL-producing bacteria in rectal flora UTI ESBL-producing bacteria and FQ-resistant bacteria in rectal flora Infectious complications (bacteremia, cystitis, pyelonephritis, sepsis) Sepsis Sepsis Prostatitis Infectious complications (hospitalization, sepsis) Hospitalization, infectious complications (bacteremia, cystitis, endocarditis, hypotension, postoperative infection, prostatitis, pyelonephritis, sepsis, UTI) Hospitalization, infectious complication (not defined) Sepsis Outcome Variables COPD, chronic obstructive pulmonary disease; ESBL, extended-spectrum -lactamase; FQ, fluoroquinolone; LUTS, lower urinary tract symptoms; PSA, prostate-specific antigen; UTI, urinary tract infection; TRUS-Bx, transrectal ultrasound-guided prostate biopsy. 1197 Year Study Sample Size Methodology Selected Studies Investigating Risk Factors for Antimicrobial Resistance or Infectious Complications Following TRUS-Bx (continued) Reducing Infectious Complications Following TRUS-Bx continued 86 • Vol. 18 No. 2 • 2016 • Reviews in Urology 27/07/16 3:13 pm Reducing Infectious Complications Following TRUS-Bx independently associated with infectious complications following prostate biopsy (OR 6.10; 95% CI, 1.6-23.0; P .008).36 However, an international prospective study failed to find an association between prior antibiotic exposure and increased risk for infectious complications (P .05).2 Prior antibiotic use was also not a significant predictor of post-TRUS-Bx hospitalization in a recent study (P .61).54 Other reports have documented a disconnect between rates of FQ-resistant bacteria in the rectal flora and subsequent symptomatic infections. In a study by Liss and coworkers,34 only approximately 3% of patients with rectal swab culture results positive for FQ-resistant organisms developed an infection due to FQ-resistant bacteria. However, a subsequent study by the same group found that rectal colonization with FQ-resistant bacteria significantly predicted both infections and hospitalizations following TRUS-Bx.35 More data are needed to establish a definitive relationship. Perhaps antibiotic exposure increases the quantity of FQ-resistant microbes in the rectal flora, but this increase may not suggest a greater number of prior biopsies increases patients’ risk of harboring FQ-resistant organisms,53,61 a meta-analysis of nine studies indicates that previous biopsies are not a statistically significant risk factor for harboring FQ-resistant rectal bacteria (OR 0.92; 95% CI, 0.68-1.25; P .29).30 Furthermore, in a recent, large analysis of Surveillance, Epidemiology and End Results (SEER)-Medicare data (n 17,523), repeat biopsy was not associated with a greater risk of infectious complications compared with initial biopsy (OR 0.81; 95% CI, 0.49-1.32; P .39).62 The risk of hospitalization was significantly lower for repeat biopsies than initial biopsies (OR 0.63; 95% CI, 0.54-0.73; P not reported) and the duration between biopsies did not predict hospitalization.62 Numerous other studies also failed to find a significant association between the number of prior biopsies and post-TRUS-Bx infection.2,21,33,37,63 Presence of FQ-resistant Bacteria in the Rectal Flora Limited data exist supporting the association between harboring FQ-resistant organisms in the … the prognostic significance of prior antibiotic exposure may be limited in predicting patients most likely to experience post-TRUS-Bx infections. directly translate into an increase in clinically significant infections. Thus, the prognostic significance of prior antibiotic exposure may be limited in predicting patients most likely to experience post-TRUS-Bx infections. Number of Prior Biopsies A history of prior biopsies has not been definitively shown to increase patients’ risk for post-TRUS-Bx infection. Although some data rectal flora and likelihood of postTRUS-Bx infection. FQ-resistant rectal cultures were recently demonstrated to significantly increase patients’ risk of developing an infection (OR 3.98; 95% CI, 2.376.71; P .001) and hospitalization (OR 4.77; 95% CI, 2.50-9.10; P .001) following TRUS-Bx in a large (n 2673) multi-institutional study.35 However, only 6.6% of men with positive rectal culture results actually developed infections.35 Therefore, positive rectal culture results appear to increase a patient’s risk for post-TRUS-Bx infections, but such infections are still relatively uncommon in this higherrisk group. International Travel Recent international travel has consistently been linked to increased risk of infection in published reports. In a prospective study of all men undergoing TRUS-Bx in a United Kingdom hospital, patients with recent international travel (RR 2.7; 95% CI, 1.0-7.1; P .04) and patients with antibiotic use within 4 weeks of the biopsy (RR 4.0; 95% CI, 1.4-11.0; P .025) had a greater risk of infectious complications requiring hospitalization.57 Risk of infection was not associated with travel to a specific country (P .05).57 The finding that international travel increases the risk of infection after TRUS-Bx corresponds with a report noting an increase in the percentage of patients with antimicrobial resistant E coli in their rectal flora after traveling abroad, from 7.8% (95% CI, 3.8-14.9) before travel to 49% (95% CI, 39.5-58.6) after travel.64 Diabetes Data regarding the relationship between diabetes and enhanced risk for infection are equivocal. In a number of series, diabetics were at significantly greater risk for developing infectious complications.23,54,60,63,65,66 However, multiple studies failed to replicate this association.25,29,35,39,61 Race Asian and nonwhite race emerged as a risk factor for post-TRUS-Bx infections in a number of series,1,34,67 but not others.63 The correlation between Asian race and increased risk of harboring FQ-resistant pathogens may be Vol. 18 No. 2 • 2016 • Reviews in Urology • 87 4004170006_RIU0713.indd 87 27/07/16 3:13 pm Reducing Infectious Complications Following TRUS-Bx continued linked to the higher prevalence of FQ-resistant and ESBL-producing uropathogens in Asian countries.60 Prostate Volume and Prostate-specific Antigen Two studies reported prostate volume or enlargement (benign prostatic hypertrophy) as a risk factor for infection,53,66 but multiple other studies did not support this association.2,38,56,61,63 No study reported prostate-specific antigen as a significant predictor of infectious risk.2,21,38,54,60,61 Age One study found age to be a significant predictor of infectious risk. In this report, age was significantly associated with reduced risk of infection (OR 0.91; 95% CI, 0.830.98; P .02).29 In the majority of studies, however, age did not predict risk of infection.2,21,25,53,54,60,61,63 Other Factors Multiple other risk factors for infectious complications have been cited in the literature, including chronic obstructive pulmonary disease,36,65 heart disease,63 medical occupation,68 and presence of an indwelling catheter,53,65 but insufficient data exist to make definitive statements regarding their relevance to predisposing patients for infectious complications. as the most appropriate adjunct to FQ prophylaxis. The ultimate choice for prophylaxis should be tailored to regional susceptibility patterns and local antibiograms, however. Povidone-iodine bowel preparation and transperineal biopsy are two procedural techniques that effectively lower infection rates. Among risk factors, only history of recent international travel is consistently associated with greater risk for infectious complications, and heightened vigilance may be warranted in these patients. Given recent concerns regarding over-diagnosis of prostate cancer,69 it is critical that the urology community continues to minimize risks and costs in performing TRUS-Bx. 12. 13. 14. 15. 16. 17. 18. 19. References 1. 2. 3. 4. 5. 6. Conclusions Rising infection rates following TRUS-Bx are an urgent concern given the increased associated cost and morbidity. Herein, we have systematically reviewed contemporary methods to reduce infections following TRUS-Bx and identified a number of actionable strategies. Data suggest that augmented prophylaxis is warranted in regions with high rates of antimicrobial resistance, with aminoglycosides 11. 7. 8. 9. 10. Loeb S, Carter HB, Berndt SI, et al. Complications after prostate biopsy: data from SEER-Medicare. J Urol. 2011;186:1830-1834. 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MAIN POINTS • Augmented prophylaxis consisting of standard fluoroquinolones and aminoglycosides is warranted in areas burdened by high rates of antimicrobial resistance. • Povidone-iodine bowel preparation, prior to transrectal ultrasound-guided prostate biopsy (TRUS-Bx), effectively lowers the rate of post–TRUS-Bx infections. • The transperineal biopsy approach is associated with fewer severe complications and should be considered as an alternative to TRUS-Bx in select cases. • Recent international travel is the only risk factor consistently associated with greater risk for experiencing infectious complications following TRUS-Bx. • The increasing prevalence of antimicrobial-resistant uropathogens justifies the timely implementation of effective methods to reduce the rate of infections after TRUS-Bx. Vol. 18 No. 2 • 2016 • Reviews in Urology • 89 4004170006_RIU0713.indd 89 27/07/16 3:13 pm