Reducing Infectious Complications Following Transrectal Ultrasound-guided Prostate Biopsy: A Systematic Review

Abstract

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.

Transrectal 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 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 β-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.

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.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart of the search process.

Antibiotic Prophylaxis

A wide diversity of prophylactic antibiotics have been used (table 1), and regimens can be divided into three approaches: monotherapy, augmented prophylaxis (> 2 antibiotics), or rectal swab–targeted prophylaxis.

Table 1.

Selected Studies of Antibiotic Prophylaxis for TRUS-Bx

Study	Year	Sample Size	Methodology	Country	Standard Prophylaxis	Alternative Prophylaxis	Outcome Variables
Adibi M et al22	2013	600	Retrospective	United States	Oral 500 mg ciprofloxacin twice daily for 3 d	Standard + 80 mg IM gentamicin	Hospitalization
Antsupova V et al11	2014	2381	Retrospective	Denmark	Oral 500 mg ciprofloxacin twice daily for 1 d	400 mg pivmecilli-nam plus 500/125 mg amoxicillin/davulanic acid daily for 2 d before biopsy and three times daily for 2 d after biopsy	Bacteremia
Antsupova V et al11	2014	1460	Retrospective	Denmark	Oral 500 mg ciprofloxacin twice daily for 1 d	400 mg pivmecilli-nam plus 500/125 mg amoxicillin/davulanic acid daily for 2 d before biopsy	Bacteremia
Dai J et al33	2015	487	Retrospective	United States	Oral 500 mg ciprofloxacin (3 doses perioperatively)	Rectal swab-targeted prophylaxis	Infectious complications (cystitis, bacteriuria, pyelonephritis, bacteremia, sepsis)
Duplessis CA et al67	2012	235	Retrospective	United States	Oral 500 mg ciprofloxacin twice daily for 3 d	Rectal swab-targeted prophylaxis	Infectious complications (bacteremia, fever, prostatitis, pyelonephritis, UTI, sepsis)
Horcajada JP et al17	2009	411	Prospective	Spain	Oral 500 mg amoxicillin/davulanic acid 3 times daily for 5 d	2 g cefoxitin 1 h before biopsy and oral 750 mg ciprofloxacin twice daily for 5 d	Bacteremia, sepsis
Hori S et al18	2010	229	Prospective	United Kingdom	Oral 500 mg ciprofloxacin 1 h before biopsy and twice daily for 3 d	Oral 625 mg pamoxicillin/davulanic acid 1 h before biopsy and three times daily for 3 d	Sepsis
Hsieh T-Y et al25	2015	263	Retrospective	Taiwan	Oral 500 mg levofloxa-cin once daily for 5 d	Standard + 80 mg IM gentamicin	Infectious complications (chills, fever, macroscopic hematuria with blood clots, and severe LUTS)
Kehinde EO et al23	2013	1197	Prospective	Kuwait	4 doses of oral 500 mg ciprofloxacin twice daily for 3 d	Standard + 500 mg IV amikacin	Sepsis
Liss MA et al31	2015	5355	Retrospective	United States	Oral 500 mg ciprofloxacin twice daily	Rectal swab-targeted prophylaxis	Sepsis
Lorber G et al21	2013	4655	Retrospective	Israel	Oral ciprofloxacin or ciprofloxacin twice daily for 3 d	Standard + 240 mg IM gentamicin	Sepsis
Losco G et al24	2014	170	Prospective	New Zealand	Oral 500 mg ciprofloxacin and oral 625 mg amoxicillin/davulanic acid 1 h before biopsy and twice daily for 3 d after biopsy	Standard + 1 g IM ertapenem	Sepsis
Luong B et al54	2015	4134	Retrospective	United States	Oral 500 mg ciprofloxacin twice daily for 4 d	Oral 500 mg ciprofloxacin plus 1 g IM ceftriaxone	Infectious complications (hospitalization, sepsis)
Madden T et al19	2011	255	Retrospective	United Kingdom	Oral 500 mg ciprofloxacin before biopsy and twice daily for 3–5 d after biopsy	Oral 375–625 mg amoxicillin/davulanic acid three times daily for 3 d after biopsy + 120 mg gentamicin IV10 min before biopsy	Infectious complications (epididymo-orchitis, fever, prostatitis, sepsis, UTI)
Ongiin S et al14	2012	620	Retrospective	Turkey	Oral 500 mg ciprofloxacin or 500 mg levoflox-acin before biopsy and twice daily for 5 d after biopsy	Oral 3 g fosfomycin	Afebrile UTI, febrile UTI
Roberts MJ et al30	2014	2676	Meta-analysis	Multinational	Empiric fluoroquinolone prophylaxis	Rectal swab-targeted prophylaxis	Infectious complications (not defined)
Shakil J et al27	2014	9	Prospective	United States	No comparator	1 g ertapenem IV for 2–3 d	Infectious complications (not defined)
Summers SJ et al32	2015	2926	Retrospective	United States	Oral 500 mg ciprofloxacin 1 h before biopsy and twice daily for 3 d after biopsy	Rectal swab-targeted prophylaxis	Infectious complications (cystitis, bacteremia, pyelonephritis, sepsis)
Unnikrishnan R et al29	2015	1189	Retrospective	United States	Oral 500 mg ciprofloxacin plus 80–120 mg IM aminoglycoside	750 mg levofloxa-cin + 80–120 mg IM aminoglycoside	Mild infections (infections treated as outpatient), severe infections (infections requiring emergency room evaluation, hospital admission, or overnight stay within observation unit)
Womble PR et al20	2015	9115	Prospective	United States	Oral 500 mg ciprofloxacin twice daily for 1 d	Standard + 120 mg IM gentamicin	Hospitalization
Womble PR et al20	2015	9115	Prospective	United States	Oral 500 mg ciprofloxacin twice daily for 1 d	Rectal swab-targeted prophylaxis	Hospitalization
Yang L et al13	2015	502	Meta-analysis	Multinational	Monotherapy	Augmented prophylaxis	Antimicrobial resistant bacteria on blood or urine culture, bacteremia, bacteriuria
Yang L et al13	2015	659	Meta-analysis	Multinational	Monotherapy	Augmented prophylaxis	Hospitalization, UTI
Yang L et al13	2015	522	Meta-analysis	Multinational	Fluoroquinolone (ciprofloxacin or levofloxacin)	Ceftriaxone, chloramphenicol, or piperacillin-tazobactam	Fever, hospitalization, UTI
Zani EL et al12	2011	269	Meta-analysis	Multinational	Fluoroquinolone (ciprofloxacin or levofloxacin)	Ceftriaxone	Hospitalization
Zani EL et al12	2011	138	Meta-analysis	Multinational	Fluoroquinolone (ciprofloxacin or levofloxacin)	Piperacillin-tazobactam	Hospitalization
Zani EL et al12	2011	269	Meta-analysis	Multinational	Fluoroquinolone (ciprofloxacin or levofloxacin)	Ceftriaxone	UTI
Zani EL et al12	2011	138	Meta-analysis	Multinational	Fluoroquinolone (ciprofloxacin or levofloxacin)	Piperacillin-tazobactam	UTI

IM, intramuscular; IV, intravenous; LUTS, lower urinary tract symptoms; UTI, urinary tract infection.

Monotherapy

FQ antibiotics are the mainstay of first-line prophylaxis for 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.

FQ antibiotics are the mainstay of first-line prophylaxis for TRUS-Bx.

Two recent meta-analyses reported piperacillin-tazobactam 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 differences in the rate of afebrile and febrile UTIs in patients receiving either FQs (500 mg ciprofloxacin or 500mg 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 β-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, 2.20–15.87; 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, 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 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

FQs were most frequently coupled with aminoglycosides, specifically gentamicin and amikacin, in augmented prophylactic protocols.

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 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 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 into question whether it is appropriate for routine clinical practice.

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.

Additionally, there are numerous economic and logistic challenges to implementing targeted prophylaxis. Many of these challenges were highlighted at the 2014 AUA 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 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.

… 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.

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 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 approach to prostate biopsy has also generated interest in reducing infectious complications.

Table 2.

Selected Studies on Procedural Techniques Impacting Infectious Complications Following TRUS-Bx

Study	Year	Sample Size	Methodology	Country	Standard Prophylaxis	Alternative Prophylaxis	Outcome Variables
Study	Year	Size	Methodology	Country	Standard Technique	Alternative Technique	Outcome Variables
Bennet HY et al51	2016	162,577	Meta-analysis	Multinational	TRUS-Bx	Transperineal prostate biopsy	Hospitalization, sepsis
Berger AP et al55	2004	5957	Retrospective	Austria	6 or 10 biopsy cores	15 biopsy cores	Infectious complications (epididymitis, fever, hospitalization, mortality, prostatitis)
Bruyere F et al38	2015	2718	Prospective	France	Antibiotics alone	Antibiotics plus enema	Infectious complications (fever with positive urine culture, LUTS)
Carey and Korman41	2001	448	Retrospective	United States	Antibiotics alone	Antibiotics plus enema	Infectious complications (epididymitis, hospitalization, prostatitis, UTI)
Carignan A et al65	2012	5798	Retrospective	Canada	Antibiotics alone	Antibiotics plus enema	Infectious complications (not defined)
Grummet JP et al47	2014	245	Prospective	Australia	No comparator	Transperineal prostate biopsy	Sepsis
Grummet JP et al47	2014	6609	Systematic	review	Australia	No comparator	Transperineal prostate biopsy	Sepsis
Hsieh T-Y et al25	2015	263	Retrospective	Taiwan	12–16 biopsy cores	10 biopsy cores	Infectious complications (chills, fever, macroscopic hematuria with blood clots, severe LUTS)
Hwang EC et al36	2015	814	Retrospective	Korea	Antibiotics alone	Antibiotics plus povidone-iodine disinfection	FQ-resistant rectal culture. Infectious complications (fever, bacteremia, prostatitis, UTI, sepsis)

FQ, fluoroquinolone; LUTS, lower urinary tract symptoms; TRUS-Bx, transrectal ultrasound-guided prostate biopsy; UTI, urinary tract infection.

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) found no protective effect against post-TRUS-Bx infections.^12,37-41

In contrast, studies specifically evaluating povidone-iodine rectal cleansing^36,42 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

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 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.

Transperineal biopsy poses a lower risk for infection because the method avoids seeding of the prostate gland with rectal flora.

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.

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 core sampling may minimize post-TRUS-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).

Table 3.

Selected Studies Investigating Risk Factors for Antimicrobial Resistance or Infectious Complications Following TRUS-Bx

Study	Year	Sample Size	Methodology	Country	Risk Factors	Outcome Variables
Study	Year	Size	Methodology	Country	Risk Factors	Outcome Variables
Akduman B et al59	2011	558	Retrospective	United States	Prolonged FQ antibiotic exposure	Sepsis
Bruyere F et al38	2015	2718	Prospective	France	Age, antibiotic exposure, history of prostatitis, PSA, type and duration of antibiotics	Infectious complications (fever with positive urine culture, LUTS)
Carignan A et al65	2012	5798	Retrospective	Canada	Age, chronic renal failure, COPD, diabetes, metastatic neoplasm, prior hospitalization within 1 mo, PSA, urinary catheter, and urologic pathology	Infectious complications (not defined)
Cohen JE et al63	2015	814	Prospective	United States	Age, diabetes, dyslipidemia, heart disease, hypertension, prostate volume, and PSA	FQ-resistant rectal flora
Dai J et al33	2015	487	Retrospective	United States	Age, prior biopsy, prior hospitalization, PSA, and race/ethnicity	FQ-resistant rectal flora
Duplessis CA et al67	2012	235	Retrospective	United States	Age, antibiotic exposure, prior biopsies, prophylaxis (ciprofloxacin), and race/ethnicity	Infectious complications (bacteremia, fever, prostatitis, pyelonephritis, UTI, sepsis)
Ehdaie B et al61	2014	591	Prospective	United States	Age, antibiotic exposure, benign prostatic hypertrophy, diabetes, and prior biopsies	Infectious complications (fever, hospitalization for infection, positive blood or urine culture)
HsiehT-Y et al25	2015	263	Retrospective	Taiwan	Age, antibiotic prophylaxis, diabetes, hypertension, and prostate cancer	Infectious complications (chills, fever, macroscopic hematuria with blood clots, severe LUTS)
Hwang EC et al36	2015	814	Retrospective	Korea	Antibiotic exposure, diabetes, povidone-iodine enema, prostate volume, and PSA	FQ-resistant rectal culture. Infectious complications (fever, bacteremia, prostatitis, UTI, sepsis)
Kam SC et al56	2014	1083	Retrospective	Korea	Age, prostate volume, and PSA	Infectious complication (prostatitis)
Kamdar C et al68	2008	378	Retrospective	United States	Hospital employee and relative of hospital employee	Bacteremia

COPD, chronic obstructive pulmonary disease; ESBL, extended-spectrum β-lactamase; FQ, fluoroquinolone; LUTS, lower urinary tract symptoms; PSA, prostate-specific antigen; UTI, urinary tract infection; TRUS-Bx, transrectal ultrasound-guided prostate biopsy.

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 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 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.

… 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 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 rectal flora and likelihood of post-TRUS-Bx infection. FQ-resistant rectal cultures were recently demonstrated to significantly increase patients’ risk of developing an infection (OR 3.98; 95% CI, 2.37–6.71; 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 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, 0.83–0.98; 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.

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 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.

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.