Urogenital Infections and Inflammations

T.E. Bjerklund Johansen, F. M.E. Wagenlehner, Y.-H. Cho, T. Matsumoto, J. N. Krieger, D. Shoskes, K. Naber

Prostate biopsy related infection – Risk factors, prevention strategies and management approaches

Harrison Y. Bennett 1
Patrick N. Harris 1
Michael Holmes 2
Jeremy Grummet 3
 Matthew Roberts 4


1 School of Medicine, The University of Queensland, Brisbane, Australia
2 Urology Department, Waikato Hospital, Hamilton, New Zealand
3 Department of Urology, Alfred Health, Melbourne, Australia
4 Faculty of Medicine, The University of Queensland, Brisbane, Australia

Abstract

Infectious complications following prostate biopsy are reported to be increasing in incidence with associated individual and public health burden. Complication rates parallel a rise in antibiotic resistant colonisation of rectal flora in patients undergoing biopsy. Following systematic review, risk factors for post biopsy infection, preventative strategies, alternative sampling methods, and management of infectious complications are presented. Risk factors for infection should be identified; including urogenital infection or antibiotic use, international travel, hospital exposure, bacteriuria, or previous transrectal biopsy. Patients with risk factors may benefit from an adjusted biopsy protocol-comprising transrectal biopsy under targeted prophylaxis, and/or the use of rectal disinfection techniques as well as a transperineal biopsy approach. Management of post biopsy infection should be based on individual risk, local resistance profiles, and in collaboration with infectious diseases specialty physicians.


Summary of recommendations

Recommendation LoE GoR
1. The proportion of patients undergoing TRUS biopsy harbour antibiotic-resistant bacteria in their gut flora is not insignificant. Routine quinolone-based prophylaxis may no longer be sufficient for all patients. 1B A
2. Risk factors should be identified for all patients scheduled for prostate biopsy to determine if an altered prophylaxis regime is to be considered. These include: 2A B
  Urogenital infection and/or antibiotic use in last 6 months 2A  
International travel in last 6 months 2A  
Hospital admission or exposure (healthcare worker) in last 6 months 2A  
Current bacteriuria/indwelling catheter 2A  
Previous TRUS biopsy 2A  
Planned saturation biopsy 2B  
3. Patients without risk factors may proceed to TRUS biopsy using   quinolone-based prophlyaxis following informed consent of their low risk of sepsis, as well as clear instruction to seek urgent medical attention if they develop symptoms of infection. 1B A
4. Patients with risk factors should prompt the clinician to consider:    
  A transperineal biopsy, requiring only single dose prophylaxis with IV cephazolin, with risk of sepsis less than 1/1,000, OR 2A/3 B
TRUS biopsy following rectal culture and targeted antibiotic prophlyaxis according to culture results, AND/OR 2A B
TRUS biopsy with rectal disinfection using Povidone-iodine 2A B

1 Introduction

Transrectal ultrasound-guided (TRUS) biopsy of the prostate (TRUBP) is the most commonly used modality to diagnose prostate cancer resulting in millions of biopsies performed internationally each year. Widespread use of PSA testing, an ageing population and increasing implementation of active surveillance protocols for low risk disease led to more TRUS biopsies performed over the last two decades. While the U.S. Preventative Services Task Force recommendation in 2012 has resulted in reduced PSA testing and biopsy rates [1], TRUBP are still performed in high numbers worldwide. TRUBP is generally considered a safe procedure performed using local anaesthetic with or without procedural sedation, but infectious complications can occur; including urinary tract infection (UTI), prostatitis, and sepsis [2], [3]. These are due to inoculation of the prostate and surrounding blood vessels with bacterial flora of the rectal mucosa, particularly Gram-negative Enterobacteriaceae such as Escherichia coli. Sepsis occurs in approximately 1% of biopsy procedures and UTI in more than 6%, resulting in substantial health and economic burden [4], [5]. TRUBP is therefore considered a ‘contaminated’ procedure under European Association of Urology (EAU) guidelines, necessitating antibiotic prophylaxis as a standard of care for all cases [6], [7], [8], [9], [10]. Fluoroquinolone-based antimicrobial prophylaxis is recommended by many authorities, including the EAU and the American Urological Association, due to their broad coverage against rectal flora and good penetration into the prostate gland [11]. Duration of prophylaxis is varied between urologists and health services, with no evidence to suggest prolonged duration translates to reduced complications [7], [12], [13].

Despite prophylaxis, observational studies have reported increasing rates of infectious complications over the past two decades and postulate a strong association with changing patterns of antimicrobial resistance [14], [15], [16], [17]. The most clinically significant emerging phenotype is that of fluoroquinolone resistance, which has been reported to affect complication rates for other surgical procedures [4]. Teillant and colleagues have reported that, in the USA, 13,120 post-TRUBP infections per year are attributable to fluoroquinolone resistance, which would increase to 64,000 infections per year in the event of 100% fluoroquinolone resistance [4]. The management of TRUBP complications causes significant financial burden on health systems, reported to cost more than that due to methicillin-resistant Staphylococcus aureus and Clostridium difficile in the UK [18], [19]. The non-financial, unmeasurable burden of disease from TRUBP complications, including psychological burden of significant illness, hospital admission and anxiety regarding future biopsies, must also be considered [20].

In this chapter, we sought to systematically review and critically appraise available published literature on risk factors, prevention and management of TRUBP-associated infectious complications in order to provide recommendations for general use in daily urology practice.

2 Methods

A systematic search of the literature was conducted in January 2016 in accordance with the PRISMA statement and Cochrane Guidelines [21]. The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, and LILACS databases were searched for the following key terms: prostat*, biopsy, infect*, culture*, bacter*, sepsis, fever, UTI. Only peer reviewed manuscripts were considered were inclusion.

A total of 4,494 citations were identified, which after exclusion of duplicates and screening by title and abstract, approximately 600 were considered for full text review. Review of reference lists of included manuscripts for applicable studies was also performed.

Studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using a system used in the EAU guidelines (2015) modified from the Oxford Centre for Evidence-based Medicine [22]. Overall, included studies were contained limited randomised data for most scenarios, and consequently the LoE is mostly 2A/2B and GoR B.

3 Results

3.1 Incidence

Complications following TRUBP are reported with great variability and subject to a lack of complication-specific standardised definitions. Furthermore, the incidence of complications varies according to the geographic region in which studies are conducted. Across published reports, a wide-ranging incidence of emergency department presentations (0–6%), hospitalisation (up to 4%), and severe sepsis of 0–1% is observed [3], [23], [24], [25]. In an attempt to standardise complication estimates across three key measures, hospitalisation, sepsis and acute urinary retention, Bennett and colleagues performed a systematic review and meta-analysis utilising directly standardised prevalence estimates based on cases of new prostate cancer cases according to GLOBOCAN [5]. The reported estimates are presented in table 1.

Table 1: Incidence of TRUBP complications and fluoroquinolone resistance by continent (adapted from Bennett et al. [5] and Zowawi et al. [32])
 

TRUBP Complication

Global estimate
fluoroquinolone
resistance

Continent

Hospitalisation

Sepsis

Acute urinary
retention

Asia

2.2% (0–7.7)

1.0% (0.3–2.0)

1.2% (0.2–6.8)

40% (33–47%)

Europe

0.9% (0.1–4.7)

0.7% (0–2.9)

0.5% (0.4–4.0)

22% (22–25%)

North America

0.8% (0.2–1.7)

0.8% (0.4–5.7)

0.2% (0.1–6.8)

16% (13–18%)

All figures expressed as pooled estimate % (95% confidence interval)

Many recent reports highlight an increasing incidence of TRUBP-related complications with time in parallel with a worldwide trend of increasing antimicrobial resistance and subsequent infection with fluoroquinolone resistant micro-organisms [17], [26], [27], [28], [29]. Despite this trend, 30-day mortality estimates remain between 0.1–1%, lower than the age adjusted population [14], [15], [16], [17], [26], [30], [31]. As fluoroquinolones are the predominant antimicrobial used for TRUBP prophylaxis, estimates of fluoroquinolone resistance have been included in table 1.

Figure 1: Global prevalence of fluoroquinolone resistance in Gram-negative urinary pathogens
Figure 1: Global prevalence of fluoroquinolone resistance in Gram-negative urinary pathogens (adapted from Zowawi et al. [32]) – data from published studies or national surveillance databases 2009–2014.

3.2 Risk factors

An appreciation for risk factors predictive of post-TRUBP infection allows the treating urologist to guide prophylaxis, as well as assist in patient selection for alternative sampling methods [33]. Reported risk factors for post-TRUBP infection are listed in table 2.

Table 2: Risk factor summary (adapted from Loeb et al. [2])

Host related

Rectal flora antimicrobial resistance (fluoroquinolone most commonly)

Recent urogenital infection and/or antibiotic use

Hospital admission or exposure (healthcare worker)

Recent international travel

Bacteriuria (pre-biopsy urine culture, indwelling catheter in situ)

Co-morbidities (Diabetes mellitus, cardiac valve replacement, chronic obstructive pulmonary disease, benign prostatic hyperplasia)

Surgeon related

Approach – transrectal, transperineal, MRI-guided

Repeat biopsy

Greater number of biopsy cores

Contaminated ultrasound gel

3.2.1 Host-related

3.2.1.1 Antimicrobial resistance

With fluoroquinolone therapy being most commonly used for TRUBP prophylaxis, the risk factor most predictive of post-TRUBP infection is fluoroquinolone resistance in rectal flora [16], [17], [23], [24], [28], [30], [34], [35]. TRUBP causes translocation of rectal bacteria across the rectal mucosa into the prostate and bloodstream. The mechanism of antimicrobial resistance development in rectal flora is induced by selection pressure following fluoroquinolone use, or acquired by travel to areas of high endemic antimicrobial resistance [3], [28], [36], [37], [38]. Fluoroquinolone resistance in E. coli blood stream isolates has been reported to average 12% in the United States and 20% in Europe, with known fluctuation between 10 and 45% secondary to regional differences [3]. The prevalence of fluoroquinolone resistance has been observed to be higher in Asian countries (26.7–92%) [39], [40].

A recent meta-analysis, reporting on nine studies and 2,541 patients, reported that prevalence of fluoroquinolone resistance in rectal flora may be higher (20.4% vs. 12.8%) after fluoroquinolone therapy prior to TRUBP. There was a higher incidence of TRUBP-associated infections in patients with fluoroquinolone resistant rectal cultures compared with fluoroquinolone sensitive (7.1% vs. 1.1%), which translated to a 7.4% vs. 1.4% risk difference, respectively. Thus, it was estimated that for every 14 men with a fluoroquinolone resistant rectal culture, one additional TRUBP-associated infection was observed compared with men displaying fluoroquinolone-sensitive cultures [35].

These findings were supported by a collaborative analysis of the original source data, with fluoroquinolone resistance associated with an increased overall risk of infection (OR 3.98, 95% CI 2.37–6.71) and hospitalisation (OR 4.77, 95% CI 2.50–9.10), which were highest with fluoroquinolone monotherapy [41]. Further confirmation in independent cohorts further support a causative relationship between TRUBP-associated infections and fluoroquinolone resistance, however are based on non-randomised data [42], [43], [44].

3.2.1.2 Prior urogenital infection and/or antibiotic use

A number of studies in patients undergoing TRUBP have reported antimicrobial use within the past 3–6 months to be significantly associated with fluoroquinolone resistant carriage in the rectal flora [17], [36], [45], [46], [47], [48]. These findings have been corroborated using meta-analysis, with history of genitourinary infection (OR 2.56; 95% CI 1.13–5.79; n=1,218) and prior fluoroquinolone use (OR 4.12; 95% CI 2.30–7.37; n=1,356) reported to be significant risk factors for fluoroquinolone-resistance colonisation. The use of antimicrobials in these scenarios causes selection pressure on the normal rectal flora, resulting in preferential growth of resistant species [49]. Wagenlehner and colleagues demonstrated on rectal swab culture that single dose prophylaxis was sufficient to select for ciprofloxacin resistant organisms, with a four-fold increase in fluoroquinolone resistance after administration [50]. This has also been demonstrated in studies investigating empiric antibiotics for elevated PSA, with extended antibiotic administration leading to significantly higher rates of sepsis and resistance following biopsy [51]. Given the high concordance between fluoroquinolone resistance and extended-spectrum beta-lactamase (ESBL) production, it is unsurprising that the use of fluoroquinolone prophylaxis has also been shown to co-select for ESBL-producing E. coli [52].

3.2.1.3 Hospital admission or exposure (healthcare worker)

Hospitalisation in the year preceding biopsy has also been shown to increase carriage of fluoroquinolone resistant organisms and increase biopsy related infection [11], [17], [46], [53]. Interestingly, this risk has also been observed in physicians [54], as well as relatives of hospital employees [55].

3.2.1.4 Recent international travel

International travel, particularly involving contact with healthcare facilities, also increases carriage of resistant organisms [36], [48]. This was particularly true of exposure to healthcare facilities and water sources in the Indian subcontinent and South-East Asia, where resistance rates are known to be high [5], [38], [56].

3.2.1.5 Bacteriuria (pre-biopsy urine culture, indwelling catheter in situ)

Asymptomatic bacteriuria is an established risk factor and routine testing is recommended in the EAU guidelines, though poor compliance with this recommendation is reported [57], [58]. History of urethral catheterisation or prior urogenital infection (urinary tract infection or prostatitis) is also associated [31], [45], [59].

3.2.1.6 Co-morbidities

The presence of co-morbidities such as diabetes mellitus, cardiac valve replacement, chronic obstructive pulmonary disease, immunosuppression, or benign prostatic hyperplasia have been variably reported to increase the risk of post-TRUBP complications. Higher comorbidity scores have also been associated with a significantly increased risk of hospitalisation post-biopsy in multiple large retrospective cohorts [14], [31], [60]. Diabetes and the metabolic syndrome have been reported to be associated with both increased risk of infectious complications, and carriage of resistant organisms [15], [31], [61], [62], [63]. However, on meta-analysis of available risk factors, diabetes (OR 1.37; 95% CI 0.77–2.46; n=1,140) was not significantly associated with fluoroquinolone-resistant colonisation [35].

3.2.1.7 Compliance

Non-compliance is difficult to reliably assess but may contribute to complication rates in populations with a relatively low baseline prevalence of fluoroquinolone resistance. For instance, Suwantarat and colleagues reported a 43% post-TRUBP infection rate in patients not presenting for rectal swab and thus assigned to empiric prophylaxis, despite an underlying prevalence of fluoroquinolone resistance of 16% [64]. Of greater concern, the compliance of the treating urologist to best practice guidelines can influence sepsis outcomes, with Womble and colleagues reporting that patients on non-compliant regimens were more likely to be hospitalised following TRUBP (3.8 vs. 0.89%) [24]. These findings were supported by a large multicenter study by Bruyere and colleagues reported noncompliance with antibiotic prophylaxis guidelines to be a risk factor for post-TRUBP sepsis (OR 2.3, 95% CI 1.4–3.9) [45].

3.2.2 Surgeon related

3.2.2.1 Mode of biopsy

Transperineal biopsy is an alternative method of sampling providing transcutaneous access to the prostate. Prostate cancer detection rates have been reported to be similar, though some investigators contend that the transperineal approach can better detect anteriorly sited tumours [65], [66]. Transperineal sampling allows thorough skin preparation in line with typical surgical procedures, and prophylactic antibiotics (eg cephazolin) are targeted to skin flora and common urinary pathogens [67], [68]. As transperineal biopsies avoid the rectum, this approach has traditionally been thought to have lower rates of infection than the ‘transfaecal’ route of TRUBP. Transperineal biopsy has been classified as a ‘clean-contaminated’ procedure in the EAU guidelines, however it could even be argued that it is ‘clean’ as there is often no breach of urinary tract mucosa using this approach [10]. This benefit is less clear in practice, and studies with direct comparison of morbidity between transrectal and transperineal biopsy are lacking.

Recent large prospective investigations have sepsis rates approaching zero for transperineal biopsy. In a prospective study of 2,086 patients from Japan no patient required additional therapy for infectious complications; and another prospective report from China, one patient out of 3,007 developed urosepsis post biopsy [69], [70]. No cases of urosepsis were seen in a prospective series of 3,000 patients from Italy [71].

Transperineal biopsy has clear benefits in decreasing infection related morbidity, but is not without drawbacks. It is logistically more involved and time-consuming, requiring admission to hospital, an operating theatre, and usually general anaesthesia. Transperineal biopsy is also associated with higher rates of post-procedure urinary retention [5].

Table 3: Comparing TRUS and transperineal prostate biopsy approach summary (adapted from Bennett et al. [5])
    TRUS biopsy Transperineal biopsy
Complication   Standardised prevalence
(95% CI)
Standardised prevalence
(95% CI)
Acute Urinary Retention Total 0.9% (0–3.6) 4.2% (0.2–12.9)
  Asia 1.2% (0.2–6.8) 1.78% (0–7.5)
  Europe 0.5% (0.4–4.0) 2.6% (0–11.3)
  North America 0.2% (0.1–6.8) 6.2% (0.1–25.6)
Hospitalisation Total 1.1% (0–3.9) 0.9% (0–3.4)
  Asia 2.2% (0–7.7) 0.6% (0.1–1.4)
  Europe 0.9% (0.1–4.7) 1.0% (0.1–5.0)
  North America 0.8% (0.2–1.7) 1.0% (0.2–2.1)
Sepsis Total 0.8% (0–3.0) 0.1% (0–0.2)
  Asia 1.0% (0.3–2.0) 0.0% (0–0.5)
  Europe 0.7% (0–2.9) 0.1% (0.1–0.5)
  North America 0.8% (0.4–5.7) 0.2% (0.1–0.7)
3.2.2.2 Number of cores

The extent of sampling has also been a target for risk reduction. An ‘extended’ biopsy strategy of 12–18 cores is currently recommended to optimise cancer detection, and does not increase complications compared to sextant biopsy [72], [73]. Biopsies of >18 cores do however have a poor side-effect profile and so called ‘saturation’ biopsies (>20 cores including transition zone) are rarely indicated [72], [74]. 18-gauge needles are the most widely used for sampling, and produce similar specimen quality to 16- and 14-gauge needles with low morbidity [75]. Local anaesthetic administration has also not been associated with increased infectious complications [45].

3.2.2.3 Previous biopsies

Repeat biopsies are indicated in men with persistent suspicion of prostate cancer according to elevated PSA, abnormal DRE or suspicious appearance on imaging [76]. Reports regarding the association between repeat biopsies and an increased risk of infectious complications compared with initial biopsies are mixed [45], [77], [78]. Repeat biopsies are an integral part of active surveillance, a practice commonly used in low grade low volume prostate cancer [76]. Any potential risk is concerning in this context, with a retrospective analysis reported increased odds of an infection (OR 1.33, 95%CI 1.01– 1.74) for every previous biopsy in 591 consecutive men undergoing TRUBP [78].

Repeat biopsy has been reported to be a risk factor for colonisation with resistant E. coli strains [79], with a progressive increase reported for each biopsy undertaken, specifically a 22.8% baseline resistance, not associated with biopsy history, while for men with initially fluoroquinolone sensitive swabs, a progressive increase in prevalence of 10.6% was observed at each of second and third biopsies [42]. Meta-analysis of available data (OR 0.92; 95% CI 0.68–1.25; n=1,615) did not support this association [35].

Table 4 presents a risk assessment questionnaire, based on available data, to aide clinicians in assessing for fluoroquinolone resistance and subsequent risk of post-TRUBP complication.

Table 4: TRUBP risk assessment questionnaire (adapted from Losco et al. [56])

Rectal flora antimicrobial resistance

Recent or recurrent urogenital infection?

Antibiotic use (especially fluoroquinolone)?

Recent hospital admission?

Occupation as healthcare worker?

Recent international travel (especially South-east Asia or South America)?

Bacteriuria

Pre-biopsy urine culture indicated?

Indwelling catheter in situ?

Co-morbidities

Diabetes mellitus?

Cardiac valve disease/replacement?

Chronic obstructive pulmonary disease?

Benign prostatic hyperplasia?

Other immunosuppressive disorder or treatment?

Previous biopsy

Previous biopsy? How many?

3.3 Prevention strategies

3.3.1 Antimicrobial prophylaxis – empiric versus culture-directed (targeted)

An evolving body of evidence supports either an expanded antibiotic protocol or one targeted to rectal cultures. Expanded antibiotic protocols can consist of either a broad spectrum antibiotic or the use of multiple antibiotics. While initial studies cultured isolates on non-selective agar, most studies perform selective culturing on fluoroquinolone-impregnated MacConkey agar plates [80]. The fluoroquinolone concentrations can vary between 1 mg/L and 10 mg/L, often corresponding with pathogen minimum inhibitory concentration (MIC) estimates [35].

Targeted prophylaxis aims to remove antimicrobial resistance as a contributor to post-TRUBP infection. To date, five North American studies have prospectively used this principle of targeted therapy to reduce TRUBP-associated infections [64], [81], [82], [83], [84]. In the absence of high quality randomised data, these matched results were combined using meta-analysis (n=2,302). Patients using empirical prophylaxis demonstrated higher (3.1%, 95% CI 2.1–4.1%) infection rates than those using targeted methods (0.6%, 95% CI 0–1.5%). These updated estimates are similar to those calculated by Roberts and colleagues using unmatched cohorts (n=2,786), which were 3.3% (95% CI 2.6–4.2%) and 0.3% (95% CI 0–0.9%) respectively [35]. When stratified according to fluoroquinolone resistance status (resistant versus sensitive), the greatest risk difference was observed for empiric prophylaxis (7.8%, 95%CI 3.7–12.0%) compared with targeted prophylaxis (1.6%, 95%CI –0.8–4.0%). When applied to patients with fluoroquinolone sensitive rectal cultures, either passively using empiric broad-spectrum prophylaxis or actively using targeted prophylaxis, this equated to a number needed to treat (NNT) of 13 (95%CI 9–28). In contrast, Liss and colleagues analysed a multicenter retrospective database of over 5,000 patients in which 34% received targeted prophylaxis, and observed no difference in complications between targeted and empiric prophylaxis groups [34].

A major criticism of targeted prophylaxis is the unknown cost-benefit estimates, incorporating the extra resources required for this prophylaxis method. Taylor and colleagues estimated that targeted prophylaxis resulted in a cost saving of US$4,499 per TRUBP infectious complication averted [81]. Similarly, Duplessis and colleagues reported the cost of rectal culturing of US$350 per 100 patients (US$2.10 per culture) was less than the ~US$15,000 per 100 patients in the historical control group [82]. Suwantarat reported an estimated overall cost of US$30 per culture.

In addition to potentially reducing complication rates, targeted prophylaxis also serves to facilitate antimicrobial stewardship, as supported by Liss and colleagues [34]. Limiting absolute targeted therapy to narrow spectrum agents is prostatic tissue penetration, which is highest for fluoroquinolones [3], trimethoprim [85] and fosfomycin trometamol [86]. Thus, targeted methods may help to reduce the burden of TRUBP on antimicrobial resistance.

3.3.2 Decontamination

While post-TRUBP complications persist in the face of spreading antimicrobial resistance as well as infection despite adequate antimicrobial prophylaxis, adjunct strategies of ‘decontamination’ prior to biopsy warrant consideration. Strategies including bowel preparation and disinfection of the rectal mucosa are aimed at reducing the bacterial load involved in the inherently ‘dirty-to-clean’ passage of the TRUBP biopsy needle. Decontamination strategies for TRUBP biopsy are inconsistently practiced and reported less compared to antimicrobial-related studies [12], [87].

3.3.2.1 Rectal disinfection

With any transcutaneous intervention, from phlebotomy to major surgery, preparation and disinfection of the skin prior to incision is a worldwide standard of care. The skin preparation agent Povidone-iodine rectal preparation (PIRP) is simple and affordable, not associated with selection of resistant bacteria, and proven safe for colorectal surgery [88]. From seven controlled trials, including 2,049 patients, of rectal disinfection using PIRP prior to TRUBP, significant reductions in fever, bacteriuria and bacteraemia (RR 0.31; 95% CI 0.21–0.45) regardless of prophylaxis used have been reported. PIRP was shown to be superior to antimicrobials in preventing bacteraemia (RR 0.38; 95% CI 0.16–0.90), while a combination of PIRP and antibiotics reduced fever (RR 0.11; 95% CI 0.02–0.85) and bacteraemia (RR 0.25; 95% CI 0.08–0.75) [89]. Outside of this meta-analysis, PIRP has been reported to significantly reduce TRUBP-associated infections (0 vs. 1.8%) and colony counts determined by rectal swab culture (by up to 97%) [90]. However, a randomised controlled trial of prophylactic povidone-iodine use demonstrated insignificantly reduced complication rates (2.6%) compared with control (4.5%), in a study that is likely to have been underpowered [91]. The optimal method of administering PIRP has not been fully eluciadated but the use of a suppository or gauze soaked in povidone-iodine has been reported to be superior to a rectal enema [89], [92]. Chlorhexidine as a rectal preparation agent is currently under investigation [93].

3.3.2.2 Rectal cleansing

Available evidence regarding preparation with a rectal cleansing enema (e.g. Fleet sodium phosphate) is sparse due to implementation by a minority (18–30%) of urologists [13], [94]. Enema use has been demonstrated to reduce rates of bacteraemia following TRUBP, with studies including a small RCT without antibiotic cover and meta-analysis of observational studies where prophylaxis was administered [95], [96] [97]. Other reports have concluded that enema increases patient discomfort without improving clinical outcomes [98]. A retrospective study of 1,438 patients found that Fleet enema administration made no significant difference to the incidence of infection post biopsy [29]. A recent prospective report has suggested rectal enema is equally as effective as full bowel preparation with polyethylene glycol [99]. Of note, limited contemporary data is available in the era of increasing resistant bacteria causing infectious complications.

3.3.2.3 Other approaches

Among novel methods under investigation, needle disinfection prior to each biopsy, using 10% formalin showed similar TRUBP-associated infection rates (0.3%) in 1,642 patients to a historical comparison without formalin disinfection (0.8%). Of further interest, growth of fluoroquinolone resistant E. coli exposed to formalin on MacConkey and blood agars was non-existent, with formalin exposure estimated to be safe [100].

3.3.3 Biopsy method

3.3.3.1 Transperineal biopsy

Recent reports suggest minimal sepsis rates with the transperineal procedure [2], [68], further supported by three large cohort studies totaling 8,093 patients with one case of urosepsis reported and recent meta-analysis estimate of 0.1% [5], [69], [70], [71].

Transperineal sampling has typically been reserved for patients at high risk of sepsis, or for repeat biopsies, especially those with a previous non-diagnostic TRUBP [2]. Nonetheless, preventing the translocation of faecal flora is increasingly important in the era of multi-resistant bacteria. From an antimicrobial stewardship perspective, transperineal biopsy may also avoid selecting for fluoroquinolone- or multi-resistant bacteria, and in particular stem the increasing reliance on an ever expanding range of antibiotics for biopsy prophylaxis.

3.3.3.2 MRI-Guided biopsy

Multi-parametric magnetic resonance imaging (mp-MRI) has emerged in recent years as a valuable tool in the diagnosis and monitoring of prostate cancer. MRI is used to guide biopsies using ‘cognitive’, ‘in-bore’, or MRI-ultrasound ‘fusion’ biopsy techniques [101]. Tissue diagnosis with MRI-guided biopsies is generally via the transrectal route, and preliminary experience suggests that complication rates are similar to the conventional TRUS approach. Urosepsis rates of 0–2% have been reported with both in-bore and fusion techniques [101]. Improved localisation with mp-MRI can reduce unnecessary biopsies, as well as the need for repeat biopsy in patients on active surveillance [101], [102], [103]. The general availability of MRI remains limited, and approximately 10% of significant lesions are ‘MRI-invisible’, so systematic cores remain necessary [103]. 

3.4 Management of prostate biopsy related infection

When considering the optimal treatment for a patient with an infectious complication following prostate biopsy, several factors need to be taken into account. This includes the severity of the clinical presentation (which may range from relatively mild cystitis or prostatitis to severe sepsis with multi-organ failure), the likelihood of resistance to empirical antibiotics, the co-morbidities of the host and whether anatomical complications co-exist (such as prostate abscesses or urinary tract obstruction). Choosing appropriate initial therapy is critical as these infections can progress quickly and may result in life-threatening complications. Inadequate or delayed empirical therapy has been associated with excess mortality in Gram-negative sepsis, especially in the setting of a high background prevalence of ESBL-producers [104], [105], [106]. Furthermore, inadequate empirical therapy is not uncommon in the setting of post-TRUBP sepsis, occurring in 36% of patients in one study [28]. The use of rectal culturing prior to TRUBP may help better inform initial antimicrobial selection and rationalise treatment options.

3.4.1 Initial assessment and risk of infection with a multi-drug resistant (MDR) organism

Obtaining a detailed history of recent antibiotic use may help assess the risk of resistance and, if fluoroquinolones have been used for prophylaxis, this class of drug should be avoided for empirical therapy. As noted previously, a significant risk factor for the likelihood of infection with a multi-drug resistant pathogen, is recent travel to a country highly endemic for Gram-negative resistance within the preceding 6 months [107]. The prevalence of resistance mechanisms such as ESBLs or carbapenemases in Gram-negative uropathogens varies widely across the world, and the situation is dynamic. In some high-prevalence countries resistance to 3rd generation-cephalosporins (a marker for ESBL production) in Enterobacteriaceae (such as E. coli or K. pneumoniae) can exceed 50% [32]. Resistance to carbapenems is less common but, driven by the recent emergence and spread of carbapenemase genes such as NDM, KPC or OXA-types, trends in some countries are alarming [32]. In Greece, for instance, more than 50% of K. pneumoniae isolates are now resistant to carbapenems [108], and for many parts of the world, reliable surveillance data are lacking [109].

Carbapenemase-producers tend to also possess numerous other resistance determinants, rendering them multi-drug resistant (MDR), extensively-drug resistant (XDR) or even pan-drug resistant (PDR) [110], [111]. Clearly this can dramatically reduce treatment options and makes selecting effective empirical therapy extremely problematic should these strains become predominant. In some patients, who are known to be colonised with MDR pathogens, alternatives to TRUBP or avoidance of any interventional procedure may have to be considered given the risks involved [112].

Risk prediction scores for assessing the likelihood of infections with an ESBL-producing organism in the context of Gram-negative sepsis have been developed for use in high-prevalence settings.  In an Italian cohort, a scoring system based on recent hospitalisation, admission from another healthcare facility, a Charlson co-morbidity score of ≥4, recent beta-lactam or fluoroquinolone therapy, urinary catheterisation or age ≥70 years was predictive high risk for ESBL infection [113]. Such scoring systems have worked well in other settings with minor modifications [114], but require validation in a local context before they can be reliably implemented. 

3.4.2 Early recognition of infectious complications

It is important for patients undergoing TRUBP to be made aware of the signs and symptoms of infection should they occur post procedure. Specifically, they should be advised to urgently seek medical attention if they experience fever, lethargy, difficulty passing urine, perineal pain, testicular swelling or dysuria. 

The early recognition and effective treatment of sepsis is a key factor in improving patient outcomes, and management should broadly follow international guidelines, such as the Surviving Sepsis Campaign [115]. Recently, updated definitions have been developed to aid the early recognition of sepsis [116]. Previous definitions provided limited discrimination between sepsis and other causes of the systemic inflammatory response syndrome (SIRS). The updated 2016 consensus (“Sepsis-3”) definitions place emphasis upon the presence of end-organ dysfunction, using the sequential organ dysfunction assessment (SOFA) score, which can be easily calculated from a variety of clinical and laboratory values, with a score ≥2 associated with a 10% or greater risk of hospital mortality. A simplified bedside assessment tool termed quickSOFA (qSOFA) can be used as a rapid screen for sepsis, where at least 2 of the following criteria are present: respiratory rate ≥22/min, altered mentation, or systolic blood pressure ≤100 mm Hg [116], prompting further assessment and intervention. Within the context of sepsis, patients with septic shock can be identified by the presence of persistent hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mm Hg and serum lactate level >2 mmol/L despite adequate fluid resuscitation. When such parameters are met, in-hospital mortality may exceed 40% [116].

3.4.3 Empirical therapy for infectious complications

Although Gram-positive organisms such enterococci may be implicated in post biopsy complications, Gram-negative bacteria such as E. coli are vastly more common and carry a greater risk of severe life-threatening infection. As such, empirical regimens must have adequate coverage to reflect local patterns of resistance in this species. Knowledge of the local epidemiology and rates of resistance in key uropathogens is essential for developing local guidelines for empirical therapy. Most microbiology laboratories can provide antibiogram data for urinary tract isolates to inform such decisions, or this information may be available from national surveillance data (e.g. [108]). An advantage for the routine use of pre-biopsy rectal screening (close to the date of biopsy) is that positive cultures can guide empirical therapy should infection occur.

Given the difficulty in reliably predicting susceptibility to empirical treatment regimens, it is critical that appropriate microbiological specimens are collected for culture, including a mid-stream urine and blood cultures, if the patient is febrile or shows other signs of sepsis. The results of these tests should also be rapidly available to the treating clinician should they reveal positive cultures. 

In general, given the association with fluoroquinolone prophylaxis and MDR-E. coli infections, patients presenting with urinary sepsis post-TRUBP will require a broader spectrum of antibiotic coverage than patients with community-onset infections without prior healthcare exposure [6]. Therapy with agents such as 3rd generation cephalosporins (e.g. ceftriaxone or ceftazidime), ampicillin, quinolones or gentamicin may have a high likelihood of resistance in this context, especially in areas with an elevated prevalence of ESBL-producing E. coli or in patients exposed to such environments through travel. In the context of relatively low prevalence of resistance, options such as ceftriaxone or ampicillin and gentamicin may be adequate [117]. In other settings, broader-spectrum empirical options need to be considered. This could include, but is not limited to, piperacillin-tazobactam, carbapenems (e.g. ertapenem, imipenem or meropenem) or amikacin (usually in combination with a beta-lactam agent). Although aminoglycosides have several advantages for the treatment of urinary sepsis (rapid bactericidal effect, high concentration in the urine, a post antibiotic effect) toxicity concerns should generally limit their use for no more than 48 hours until a directed agent can be selected according to culture results [118].

3.4.4 Directed therapy for MDR Gram negative pathogens

Treatment guidelines for urinary infections often do not adequately address treatment options for MDR pathogens. Consultation with an infectious disease practitioner or medical microbiologist is recommended for these difficult-to-treat organisms. Reasons for this might include: the need for additional antimicrobial susceptibility testing for less common agents, treatment requiring the use of unfamiliar or potentially toxic agents and, in some circumstances, combination therapy may be warranted. Some agents that may test susceptible against highly resistant strains, may be ineffective in the context of urinary infections. For instance, tigecycline may be one of the agents that remains effective in vitro against XDR isolates, but penetrates poorly into the urinary tract and only achieves limited serum levels, and may be associated with excess mortality in the treatment of sepsis [119]. Hence, treatment of drug-resistant strains can be a challenge. Various therapeutic options are discussed below:

3.4.4.1 Carbapenems

For ESBL-producing Enterobacteriaceae, treatment with ampicillin, aztreonam, cephazolin, or third-generation cephalosporins (such as ceftriaxone or ceftazidime) will generally be ineffective [120]. For several reasons, carbapenems (such as meropenem, imipenem, doripenem or ertapenem) have been regarded as the treatment of choice for ESBL-producers [120], [121]. In vitro, carbapenems are generally stable to the hydrolytic effects of ESBLs [122] and other broad-spectrum beta-lactamases such as AmpC [123]. They are also less prone to inoculum effects and historically most urinary Gram-negative isolates have remained susceptible to this class of drug [120]. However, carbapenem resistance has been increasing in many parts of the world [32].

Observational studies have supported the use of carbapenems for infections caused by ESBL-producers. Poor outcomes have been demonstrated in bacteraemic patients treated with non-carbapenems drugs (especially cephalosporins or quinolones) [124], [125], [126], [127]. In a meta-analysis of studies comparing carbapenems with cephalosporins, quinolones or other alternatives (except beta-lactam/beta-lactamase inhibitor drugs such as piperacillin-tazobactam), the pooled RR for mortality when carbapenems were used for definitive therapy was 0.65 (95% CI: 0.47–0.91) and 0.50 for empirical therapy (95% CI: 0.33–0.77) [127].

Given the rise in carbapenem resistance around the world, it has been increasingly necessary to consider alternatives to carbapenems, as excess carbapenem use is likely to be a key driver for resistance. This has given rise to some reconsideration of drugs that were previously considered less effective, including drugs such as cefepime, beta-lactam/beta-lactamase inhibitor (BLBLI) drugs like piperacillin-tazobactam and amoxicillin-clavulanate, or older agents such as fosfomycin, pivmecillinam or temocillin.

3.4.4.2 Cefepime

ESBL-producers may often test resistant to cefepime, but not invariably; for ‘susceptible’ isolates there is some uncertainty as to whether cefepime remains an effective option. It is not stable to the hydrolytic activity of ESBLs and is subject to inoculum effects in vitro [128] – whereby the MIC significantly increases in the presence of a heavy bacterial load. A retrospective study found the use of cefepime compared to carbapenems to treat bacteraemia caused by ESBL-producers was independently associated with increased 30-day mortality on multivariate analysis (OR 9.9; 95% CI 2.8–31.9) [129]. However, some authors have suggested that if the organism MIC is low (e.g. ≤1 mg/L by European Committee on Antimicrobial Susceptibility Testing standards cefepime may remain effective, but higher or more frequent dosing may be necessary if the MIC falls in a higher range but below the breakpoint for resistance (e.g. MIC range 2–4 mg/L) [130]. In general, cefepime should probably be reserved as a treatment option against ESBL-producers only in specific circumstances, under specialist advice and when other options are unavailable. In contrast, cefepime remains stable to other broad-spectrum beta-lactamases such as AmpC – a chromosomally encoded and inducible enzyme found in some species such as Enterobacter cloacae or Citrobacter freundii [123]. Some observational studies suggest that cefepime remains an effective treatment for AmpC-producers [131], [132]. In a meta-analysis of 8 observational studies comparing mortality following the use of cefepime or carbapenems for the treatment of bloodstream infection caused by AmpC-producers such as Enterobacter spp., there was no significant difference in outcome (OR 0.61; 95% CI 0.27–1.38), even after adjustment for potential confounders (adjusted OR 0.59; 95% CI 0.14–2.52) [133]. Patients with bloodstream infections caused by Enterobacter spp. with MICs in the range of 4–8 mg/L (the new ‘susceptible dose dependent’ [SDD] category defined by the Clinical and Laboratory Standards Institute), experienced worse outcome in one study [134]. Some concerns over the efficacy of cefepime for the treatment of sepsis arose following meta-analyses that suggested cefepime may be associated with a small but significantly increased risk of death (RR 1.26; 95% CI 1.08–1.49) [135], although a larger analysis by the FDA, including patient-level data, found no statistically significant increased risk of mortality [136]. These findings are complicated by the fact that the original dosing regimens for cefepime may have been set too low or infrequently (e.g. 1 g 12-hourly), whereas higher dosing (e.g. 2 g 8-hourly) may be necessary to achieve adequate pharmacokinetic-pharmacodynamic targets, especially in severe infections with organisms showing elevated MICs [137].

3.4.4.3 Beta-lactam/beta-lactamase inhibitors (BLBLIs)

By definition, ESBL enzymes are inhibited in vitro by beta-lactamase inhibitors such as clavulanate or tazobactam.  Although susceptibility to BLBLIs may vary considerably across the world and by species (ESBL-E. coli are generally more likely to be susceptible to piperacillin-tazobactam than ESBL-K. pneumoniae), a significant proportion of ESBL-producers remain susceptible to piperacillin-tazobactam, or even amoxicillin-clavulanate [138]. However, until recent years, there were limited clinical data to support their use as therapy against ESBL-producers.

Concerns over inoculum effects in infections with a high bacterial burden [139], the presence of multiple beta-lactamases that may not be well inhibited by the inhibitor component [140] and some animal model data suggesting worse outcomes when compared with carbapenems, especially with ‘high inoculum’ infections [141] limited enthusiasm for their clinical use.  In recent years this concept has been questioned in light of some observational studies that suggest that BLBLIs may be non-inferior to carbapenems for treating ESBL-producers, and may reduce the risk of subsequent colonisation or infection with other MDR pathogens [138], [142], [143], [144]. A meta-analysis of 21 observational studies reporting mortality outcome for patients with bacteraemia caused by ESBL-producers demonstrated that non-inferior outcomes were seen with patients treated with BLBLIs compared with carbapenems either for empirical (RR 0.91; 95% CI 0.66–1.25) or definitive (RR 0.52; 95% CI 0.23–1.13) therapy [127]. This meta-analysis used crude mortality, unadjusted for co-morbidity, which will tend to bias against carbapenems – which may be given in ‘sicker’ patients. A recent well-designed observational study, which adjusted for the propensity to prescribe carbapenems, suggested that empirical piperacillin-tazobactam may be associated with increased mortality when used for treating bacteraemia caused by ESBL-producers [145]. However, in the largest international observational cohort of patients with bacteraemia caused by ESBL-producers, BLBLIs demonstrated equivalent efficacy to carbapenems when used either for empirical or directed therapy [146]. These discrepant findings reflect the difficulties in drawing conclusions from observational studies. It is worth noting that no randomised controlled trials have yet been reported that directly compare carbapenems with alternatives for ESBL-infections, although such studies are being undertaken [147], [148]. In the meantime, piperacillin-tazobactam is likely to be a reasonable carbapenem-sparing option for treating ESBL-producers that test susceptible in vitro, especially from a urinary tract source in a patient without features of septic shock or multi-organ dysfunction.

3.4.4.4 Fosfomycin

Fosfomycin has been used for many years as an effective single dose therapy for uncomplicated UTI, and is now part of international guidelines for this indication [149]. In recent years, it has been re-evaluated as a useful therapy for infections caused by ESBL or AmpC-producing Enterobacteriaceae. Probably because it has not been widely used, resistance rates tend to be low, even amongst MDR strains [150], [151]. It has shown broadly similar efficacy in comparison to carbapenems for patients with lower tract infections caused by ESBL-producers, including for patients with complicating factors such as catheterisation or recent prostate surgery [152]. Although published experience with using fosfomycin for treating infections post TRUBP are sparse, it is notable that fosfomycin appears to achieve adequate prostate tissue levels and may be an option for prophylaxis in patients known to be colonised with MDR Gram-negative pathogens [86], [153]. However, as uncertainty exists over the ability of the drug to adequately penetrate renal tissue, guidelines have suggested alternatives to oral fosfomycin for the treatment of pyelonephritis [154]. While fosfomycin is usually available orally, but intravenous formulations do exist which may be difficult to access in some countries. When treating serious MDR infections with few other treatment options, intravenous fosfomycin may be an effective option. It has been reported to have successfully treated a complex MDR-E. coli infection post TRUBP with prostatic and metastatic multifocal abscesses [20]. There are also case reports of successful therapy for prostatitis [155].

3.4.4.5 (Piv)mecillinam

Mecillinam is an aminidopenicillin with a broad range of activity against Gram-negative pathogens.  However, given its poor oral bioavailability, the pro-drug pivmecillinam is used. It is now recommended in the IDSA guidelines for the treatment of uncomplicated UTI in women [149], although there are some concerns for its efficacy in more complex urinary infections.

It has the advantage of stability to ESBL and AmpC enzymes and retains good activity against most ESBL-producing E. coli [156]. It is another ‘rediscovered’ antibiotic that has been available for use in Europe for many years, but is not widely employed or licensed elsewhere. In vitro, at least, it appeared effective against ESBL-producing E. coli, especially when combined with the beta-lactamase inhibitor clavulanate [157]. There are no published data with respect to pivmecillinam treatment for men with infections post-TRUBP. As such, more established options should be considered first. However, it does appear to penetrate well into prostate tissue [158], and may have equivalent efficacy to co-trimoxazole for prophylaxis in prostate surgery [158]. A combination of pivmecillinam with amoxicillin/clavulanate was as effective as ciprofloxacin for prophylaxis prior to TURP, and was associated with a reduction in the prevalence of ESBL-producing Enterobacteriaceae [159].

3.4.4.6 Nitroxiline

Nitroxiline is a 5-nitro-8-hydroxyquinoline drug that has been available for many years, but is not widely used outside some countries in Europe. Perhaps as a result, there is limited or no resistance to this drug in organisms like E. coli, although it has no significant activity against Pseudomonas spp. It has been effectively in the treatment of uncomplicated UTI since the 1960s and a meta-analysis of published studies including more than 10,000 patients concluded that it was non-inferior to norfloxacin or co-trimoxazole for eradication of bacteriuria and was well tolerated [160]. Whether it has a role in the treatment of MDR-infections related to TRUBP is not known, but such agents may deserve re-evaluation in this context.

3.4.4.7 Temocillin

Temocillin, a derivative of ticarcillin, has received renewed interest in recent years. It has been approved for the treatment of urinary infections in the UK and Belgium for some time, but is not widely used elsewhere. It shows stability to a range of ESBL and AmpC beta-lactamases, and even retains some activity against carbapenem-resistant KPC-producers [161], although it is inactive against Pseudomonas spp. In a study of 92 adults with mainly urinary or bloodstream infections caused by ESBL or AmpC-producers treated with temocillin, good clinical cure rates were observed [162]. It has even been used in addition to ciprofloxacin for routine prophylaxis prior to TRUBP in patients at high risk of colonisation with resistant E. coli strains [163].

3.4.5 New BLBLI drugs for MDR pathogens

In recent years there has been a renewed interest in developing novel beta-lactam/beta-lactamase inhibitor combinations [164]. Although several such compounds are in development, two new agents have recently become available for clinical use with activity against resistant Gram-negative uropathogens.

3.4.5.1 Ceftazidime/avibactam

Avibactam is a novel beta-lactamase inhibitor that has activity against ESBLs, AmpC enzymes, KPC and some OXA-type carbapenemases, although is not effective against metallo-beta-lactamases such as NDM, VIM or IMP [165]. Avibactam tends to restore the restore the activity of ceftazidime, reducing the MIC by 128-fold, usually to below clinical breakpoint against KPC [166], ESBL-producing Enterobacteriaceae [167] and AmpC-hyperproducing P. aeruginosa [168].

Several microbiological surveys have demonstrated good in vitro activity against collections of Gram negative organisms from the US, including MDR strains [169], [170], although it has limited activity against MDR Acinetobacter baumanii [168], [169]. It has recently been granted accelerated FDA approval in combination ceftazidime for the treatment of complicated UTI and abdominal infections, on the basis of Phase II trials, interim results from phase III trials and long-term safety data from ceftazidime [171]. It is interesting to note that a subset of patients with moderate baseline renal impairment experienced lower clinical cure rates, which may reflect under-dosing in patients whose renal function improved without a concomitant adjustment in the dose of ceftazidime/avibactam [171]. Although ceftazidime-avibactam is a promising agent, given the relatively limited clinical data available, it should be reserved for circumstances were no alternative effective options are available.

3.4.5.2 Ceftolozane/tazobactam

Ceftolozane is a novel cephalosporin with excellent activity against P. aeruginosa [172]. It can be inactivated by ESBLs, so is formulated with the inhibitor tazobactam. Ceftolozane/tazobactam shows good in vitro activity against a range of Gram-negative organisms, including MDR strains such as ESBL-producing Enterobacteriaceae and carbapenem-resistant P. aeruginosa [169], [173], [174]. It was granted FDA approval for the treatment of complicated UTI and intra-abdominal infections in December 2014. In a phase III randomised double-blind trial comparing ceftolozane/tazobactam with levofloxacin for the treatment of complicated UTI (the ASPECT-cUTI study), ceftolozane-tazobactam was non-inferior to levofloxacin for an endpoint of clinical cure (76.9% vs. 68.4%, 95% CI 2.3–14.6); indeed, the outcome data suggested superiority over levofloxacin, probably reflecting high rates of resistance to levofloxacin at baseline [175].

4 Management summary

Table 5: Options for definitive therapy (i.e. once susceptibility results are known)
Indication IV therapy options for sepsis/
bacteraemia if susceptible in vitro
Oral therapy options1 if susceptible in vitro Remarks
Enterobacteriaceae – non-MDR strains
  • Ampicillin2
  • Gentamicin
  • Cephazolin
  • Ceftriaxone
  • Amoxicillin +/ clavulanate
  • Cephalexin
  • Co-trimoxazole or trimethoprim
  • Fluoroquinolone
Use narrowest spectrum according to susceptibility results. Generally gentamicin should only be given for <48 h
ESBL-producing Enterobacteriaceae
  • Carbapenems
  • Piperacillin-tazobactam3
  • Aminoglycoside (may be susceptible to amikacin, but usually gentamicin resistant)
  • Fosfomycin
  • Temocillin
  • Pivmecillinam
  • Amoxicillin-clavulanate3
  • Nitroxiline (Co-trimoxazole or Fluoroquinolone but often resistant)

If piperacillin-tazobactam is used should be dosed maximally
(e.g. 4.5 g 6-hourly).

Generally aminoglycosides should only be given for <48 h and not used as monotherapy.

Cefepime should be dosed at
2 g Q8 h if normal renal function
AmpC-producing Enterobacteriaceae
(e.g. Enterobacter cloacae/aerogenes, Citrobacter freundii, Serratia marcescens, Morganella morganii)
  • Carbapenems
  • Cefepime
  • Piperacillin-tazobactam
    (if susceptible, but resistance can develop in complex infections)
  • Aminoglycosides
  • Co-trimoxazole or trimethoprim
  • Fluoroquinolone
  • Fosfomycin
  • Temocillin
Pseudomonas aeruginosa
  • Piperacillin-tazobactam
  • Ceftazidime
  • Cefepime

       (All +/– aminoglycoside)

  • Fluoroquinolone (only oral agent active against Pseudomonas spp.)
Carbapenem-resistant/
XDR organisms
  • Ceftazidime/avibactam:
    (for KPC, some OXA-type carbapenemase; not NDM or IMP types)
  • Ceftolozane/tazobactam: often effective for MDR-Pseudomonas spp.
  • Combination therapy: e.g. carbapenem + polymixin
    (or aminoglycoside, e.g. amikacin); dual carbapenems
  • Usually very few oral options available
  • Fosfomycin may be effective
Seek specialist advice; carbapenems may still be used if dosed to maximise exposure (e.g. extended infusions) with reference to the MIC, or used in combination

1 Consider IV to oral switch once patient is afebrile, with resolved clinical signs of sepsis, tolerating oral intake, gastrointestinal absorption is not compromised and source control has been achieved; longer IV duration may be required if positive blood cultures or other complications (e.g. undrained abscess). Total duration is typically 7–14 days.
2 Note >50% of E. coli and all K. pneumoniae are resistant to ampicillin.
3 If susceptible in vitro: use against ESBL-producers is controversial, specialist advice is recommended.

5 Further research

With decreasing effectiveness of antibiotic prophylaxis and increasing requirement for broad spectrum agents, further research is required into adjunct methods to prevent TRUBP-related complications. Currently, one randomised trial assessing targeted versus empiric antimicrobial prophylaxis is underway (ClinicalTrials.gov identifier NCT01659866), while the efficacy of PIRP is also being assessed in a randomised setting (NCT02245334; WHO ICTRP CTRI/2016/04/006843). Registered trials to assess the prevalence of fluoroquinolone resistance (NCT02140502, NCT00915213) as well as complications reported from comparisons between MRI-guided biopsy versus TRUS/transperineal biopsy, will be valuable additions to this literature.

While randomised comparisons between complications observed from TRUS and transperineal biopsy approaches are sparsely published yet desirable, it is likely that a large study population derived from multiple centres would be required to obtain statistical power. Underlying this may be attitudes and concerns from clinicians regarding randomisation, in that some who are advocates for either approach would be personally and ethically opposed to an inferior modality for their patients.

Prevention and reduction of TRUBP-related infections requires collaboration between colleagues in the fields of urology, infectious diseases and microbiology to determine the optimal prophylactic regimen, taking into account local resistance patterns and patient demographics. Future research areas in identifying the optimal solution relate to the role of targeted prophylaxis using selective rectal cultures and/or analysis of patient risk factors.

6 Conclusions

Despite heterogeneous reporting, infectious complications following prostate biopsy appear to be increasing due to fluoroquinolone resistance. Preventing TRUBP-related infections therefore requires collaboration between colleagues in the fields of urology and infectious diseases to determine the optimal prophylactic regimen, taking into account local resistance patterns and patient demographics. Nonetheless, it is clear with the decreasing effectiveness of prophylaxis and increasing use of broad spectrum agents that we require a new approach to minimising the harm of post biopsy complications. Effective preventative strategies are available, including targeted prophylaxis, extended antibiotic regimes, and alternative sampling methods, though the cost effectiveness of these strategies is yet to be elucidated. Randomised evidence is desired to establish these adjunctive tools to improve patient outcomes. In the meantime, our review supports the specific screening for risk factors predictive of post biopsy infection, to aid in the selection of patients for these preventative strategies.

7 Acknowledgement

Mathew J. Roberts is supported by a Doctor in Training Research Scholarship from Avant Mutual Group Ltd., a Cancer Council Queensland PhD Scholarship and Professor William Burnett Research Fellowship from the Discipline of Surgery, School of Medicine, The University of Queensland, Australia.

Patrick Harris is supported by an Australian Postgraduate Award from the University of Queensland.


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[112] Williamson DA, Freeman JT, Roberts SA, Heffernan H, Dyet K, Paterson DL, Rogers BA, Sidjabat HE, Masters J. Rectal colonization with New Delhi metallo-β-lactamase-1-producing Escherichia coli prior to transrectal ultrasound (TRUS)-guided prostate biopsy. J Antimicrob Chemother. 2013 Dec;68(12):2957-9. DOI: 10.1093/jac/dkt266
[113] Tumbarello M, Trecarichi EM, Bassetti M, De Rosa FG, Spanu T, Di Meco E, Losito AR, Parisini A, Pagani N, Cauda R. Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission: derivation and validation of a scoring system. Antimicrob Agents Chemother. 2011 Jul;55(7):3485-90. DOI: 10.1128/AAC.00009-11
[114] Johnson SW, Anderson DJ, May DB, Drew RH. Utility of a clinical risk factor scoring model in predicting infection with extended-spectrum β-lactamase-producing enterobacteriaceae on hospital admission. Infect Control Hosp Epidemiol. 2013 Apr;34(4):385-92. DOI: 10.1086/669858
[115] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. DOI: 10.1097/CCM.0b013e31827e83af
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[145] Tamma PD, Han JH, Rock C, Harris AD, Lautenbach E, Hsu AJ, Avdic E, Cosgrove SE; Antibacterial Resistance Leadership Group. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis. 2015 May 1;60(9):1319-25. DOI: 10.1093/cid/civ003
[146] Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, de Cueto M, Calbo E, Almirante B, Viale P, Oliver A, Pintado V, Gasch O, Martínez-Martínez L, Pitout J, Akova M, Peña C, Molina J, Hernández A, Venditti M, Prim N, Origüen J, Bou G, Tacconelli E, Tumbarello M, Hamprecht A, Giamarellou H, Almela M, Pérez F, Schwaber MJ, Bermejo J, Lowman W, Hsueh PR, Mora-Rillo M, Natera C, Souli M, Bonomo RA, Carmeli Y, Paterson DL, Pascual A, Rodríguez-Baño J. A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016 Jul;60(7):4159-69. DOI: 10.1128/AAC.00365-16
[147] Harris PN, Peleg AY, Iredell J, Ingram PR, Miyakis S, Stewardson AJ, Rogers BA, McBryde ES, Roberts JA, Lipman J, Athan E, Paul SK, Baker P, Harris-Brown T, Paterson DL. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial. Trials. 2015 Jan;16:24. DOI: 10.1186/s13063-014-0541-9
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[149] Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar 1;52(5):e103-20. DOI: 10.1093/cid/ciq257
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[151] Nakamura T, Komatsu M, Yamasaki K, Fukuda S, Higuchi T, Ono T, Nishio H, Sueyoshi N, Kida K, Satoh K, Toda H, Toyokawa M, Nishi I, Sakamoto M, Akagi M, Mizutani T, Nakai I, Kofuku T, Orita T, Zikimoto T, Natsume S, Wada Y. Susceptibility of various oral antibacterial agents against extended spectrum β-lactamase producing Escherichia coli and Klebsiella pneumoniae. J Infect Chemother. 2014 Jan;20(1):48-51. DOI: 10.1016/j.jiac.2013.08.004
[152] Senol S, Tasbakan M, Pullukcu H, Sipahi OR, Sipahi H, Yamazhan T, Arda B, Ulusoy S. Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection. J Chemother. 2010 Oct;22(5):355-7. DOI: 10.1179/joc.2010.22.5.355
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[154] Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar;52(5):e103-20. DOI: 10.1093/cid/ciq257
[155] Grayson ML, Macesic N, Trevillyan J, Ellis AG, Zeglinski PT, Hewitt NH, Gardiner BJ, Frauman AG. Fosfomycin for Treatment of Prostatitis: New Tricks for Old Dogs. Clin Infect Dis. 2015 Oct;61(7):1141-3. DOI: 10.1093/cid/civ436
[156] Wootton M, Walsh TR, Macfarlane L, Howe RA. Activity of mecillinam against Escherichia coli resistant to third-generation cephalosporins. J Antimicrob Chemother. 2010 Jan;65(1):79-81. DOI: 10.1093/jac/dkp404
[157] Lampri N, Galani I, Poulakou G, Katsarolis I, Petrikkos G, Giamarellou H, Souli M. Mecillinam/clavulanate combination: a possible option for the treatment of community-acquired uncomplicated urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli. J Antimicrob Chemother. 2012 Oct;67(10):2424-8. DOI: 10.1093/jac/dks215
[158] Jeppesen N, Frimodt-Møller C. Serum concentrations and penetration into prostate of mecillinam and ampicillin. Curr Med Res Opin. 1984;9(3):213-8. DOI: 10.1185/03007998409109582
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The ZB MED – Information Center for Life Sciences, Germany, together with the European Association of Urology (EAU) provided the opportunity to publish a “Living Textbook” on “Urogenital Infections and Inflammations” in an open access form. This “Living Textbook” represents also an update of the Textbook on Urogenital Infections published 2010 by the International Consultation on Urological Infections and the EAU: http://www.icud.info/urogenitalinfections.html.

The “Living Textbook” will cover infections and inflammations of the kidney, the urinary tract, as well as the male and female genital tract considering pathogenesis, diagnostics, treatment, prophylaxis and future aspects. The “Living Textbook” will be structured into about 26 Sections each with two section co-chairs responsible for peer review of the chapters of each section. Each chapter should reflect the background to the topic and highlight all of the critical evidence relating to the subject. The intention is to provide an up to date, concise synthesis of the literature on that topic, and for clinical topics also recommendations based on levels of evidence for contemporary clinical practice, as well as suggested research recommendations.

The editors hope that this “Living Textbook” may become a useful instrument for physicians of different specialties taking care about patients suffering from these diseases.

Truls E. Bjerklund Johansen (Norway),

Florian ME Wagenlehner (Germany),

Yong-Hyun Cho (South Korea),

Tetsuro Matsumoto (Japan),

John N Krieger (USA),

Daniel Shoskes (USA),

Kurt G. Naber (Germany).

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The textbook will be structured in sections with two co-chairs each. Each section will start with an introductory chapter written by the two respective co-chairs presented like an editorial commentary in regard to the following chapters (see proposed contents of the book). The two co-chairs of each section will also peer review all chapters in their section and stimulate a consensus discussion within their section together with the authors and the main editors if needed.

Chapters

Each chapter should reflect the background to the topic and highlight all of the critical evidence relating to the subject. The intention is to provide an up to date, concise synthesis of the literature on that topic, and for clinical topics also recommendations based on levels of evidence for contemporary clinical practice, as well as suggested research recommendations.

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Each manuscript should have up to approximately 3,000 words (excluding abstract, tables/figures and references). The abstract should count about 300 words.

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The outline of each chapter should be structured as follows (similar as in the edition 2010, which can be downloaded for free: http://www.icud.info/urogenitalinfections.html):

  1. Abstract
  2. Summary of recommendations*/key notes*
    (*which ever term is more appropriate)
  3. Introduction
  4. Methods
  5. Results
  6. Further research
  7. Conclusions
  8. Acknowledgement
  9. Conflict of interest of each author
  10. References

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Please mark your references in the text with square brackets ([1], [2], ...).

Summary of recommendations

We would like to have the Summary of recommendations at the beginning after the abstract (as in the edition 2010). However, we do not expect as in the edition 2010, that each recommendation is also specified according to Level of Evidence and Grade of Recommendation, because such a claim would not only need a systematic literature search (see below), but also a structured discussion in a defined group of experts.

Systematic literature search

A systematic literature search should be performed, at least of PUBMED/MEDLINE but ideally of several relevant databases in addition (like Cochrane CENTRAL) to find recent, high quality systematic reviews and/or primary research studies. It is not expected to perform for all chapters a de novo systematic review, if such reviews are already published recently, but it still may be indicated for some items. For questions relating therapy, it should be focused on evidence from (systematic reviews of) randomized controlled trials if available.

The method of the systematic literature search needs to be fully described in the section “Methods”, e.g.:

“A systematic literature search was performed for the last ... (usually 10) years in MEDLINE, Cochrane etc. with the following key words ... and the following limitations: e.g. UTI, age (adult?), ... clinical studies ... English ... abstract available ... only peer reviewed ...

A total of ... publications were identified, which were screened by title and abstract ... After exclusion of duplicates ... a total of ... were included into the review (analysis), supplemented by citations or known to the authors ... ”.

Clinical topics

Clinical topics should be focused on the importance to clinical practice according to the up to date scientific knowledge as presented in the literature. It should relate to questions/complaints/symptoms of patient/population concerning definition, diagnosis, therapy/prevention, intervention, and outcome in comparison, if different approaches are feasible. Please choose patient-important outcomes and focus on those, which you deem critical for decision-making.

Level of evidence and grade of recommendations

Any recommendation should be based on the level of evidence and the grade of recommendation. For this purpose the following system, modified from the Oxford Centre for Evidence-based Medicine should be used (EAU guidelines 2015):

Level of evidence (LE)

Level Type of evidence
1a Evidence obtained from meta-analysis of randomised trials
1b Evidence obtained from at least one randomised trial
2a Evidence obtained from one well-designed controlled study without randomization
2b Evidence obtained from at least one other type of well-designed quasi-experimental study
3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports.
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities.

Grade of Recommendations (GoR)

Grade Nature of recommendations
A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial
B Based on well-conducted clinical studies, but without randomised clinical trials
C Made despite the absence of directly applicable clinical studies of good quality

Comments (EAU guidelines 2015)

The aim of assigning a LE and grading recommendations is to provide transparency between the underlying evidence and the recommendation given.

It should be noted that when recommendations are graded, the link between the level of evidence and grade of recommendation is not directly linear. Availability of randomized controlled trials may not necessarily translate into a grade “A” recommendation where there are methodological limitations or disparity in published results.

Alternatively, absence of high level evidence does not necessarily preclude a grade A recommendation, if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where corroborating studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal recommendations are considered helpful for the reader. The quality of the underlying scientific evidence - although a very important factor – has to be balanced against benefits and burdens, values and preferences and costs when a grade is assigned.

Since the same rating system should be used in all chapters, for the sake of brevity the same sentence could be used in “Methods” for all manuscripts, because the rating system will be described in details in the Preface of the book:

“The studies were rated according to the level of evidence and the strength of recommendations graded according to a system used in the EAU guidelines modified from the Oxford Centre for Evidence-based Medicine [1].”

References

[1] European Association of Urology. Guidelines. Methodology section. 2015 ed. Arnhem: European Association of Urology; 2015. p. 3. ISBN/EAN: 978-90-79754-80-9. Available from: http://uroweb.org/wp-content/uploads/EAU-Extended-Guidelines-2015-Edn..pdf

The Living Handbook of Urogenital Infections and Inflammations is issued by:

European Association of Urology
att. Maurice Schlief, EAU executive manager business affairs

P.O.Box 30016
NL-6803 AA Arnhem, The Netherlands

Phone: 0031-26-38.90.680
E-mail: m.schlief@uroweb.org

Editor in Chief

responsible for the contents according to § 5 TMG and § 55 Abs. 2 RStV (Germany):

Kurt G. Naber, MD, PhD
Assoc. Professor of Urology

Technical University of Munich
Karl-Bickleder-Str. 44c
94315 Straubing, Germany

E-mail: kurt.naber@nabers.de

John N. Krieger MD, PhD

University of Washington Section of Urology

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Daniel Shoskes MD, PhD

Cleveland Clinic Glickman Urological and Kidney Institute

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Yong-Hyun Cho MD, PhD

St. Mary's Hospital, The Catholic University of Korea Department of Urology

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Tetsuro Matsumoto MD, PhD

University of Occupational and Environmental Health Department of Urology

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Florian M. E. Wagenlehner MD, PhD

Justus-Liebig University of Giessen Clinic of Urology and Andrology

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Truls Erik Bjerklund Johansen MD, PhD

Oslo University Hospital Urology Department

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Kurt G. Naber MD, PhD

Technical University of Munich

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Riccardo Bartoletti

University of Pisa
Department of Translational Research and New Technologies

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Truls Erik Bjerklund Johansen MD, PhD

Oslo University Hospital
Urology Department

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PD Dr. med. Gernot Bonkat

University Basel
alta uro AG, Merian Iselin Klinik, Center of Biomechanics & Calorimetry (COB)

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Prof. Tommaso Cai MD

Santa Chiara Regional Hospital
Dept. of Urology

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Dr Leyland Chuang

Ng Teng Fong Hospital, National University Health System
Department of Medicine

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Prof. Milan Cizman

University Medical Centre
Department of Infectious Diseases

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Alison Crawford MSc

Queen's University
Department of Psychology

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Pfofessor Svetlana Dubrovina MD, PhD

Rostov Medical State University
Obstetrics and Gynaecology

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Dr Valerie Huei Li Gan MBBS (S'pore), MRCS (Edin), MMed (Surg), FAMS (Urology)

Singapore General Hospital
Department of Urology

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Philip Hanno

University of Pennsylvania

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Ass prof MD Gundela Holmdahl

Queen Silvia Childrens Hospital, Sahlgrens Academy
Pediatric surgery and urology

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Udo B. Hoyme

HELIOS Hospital Erfurt Ltd.
Department of Gynecology and Obstetrics

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David Hunstad

Washington University School of Medicine
Pediatrics / Molecular Microbiology

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Gitte M. Hvistendahl

Aarhus University Hospital

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Prof. Michael KOGAN M.D., PhD

Rostov State Medical University
Department of Urology

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Dr Akihiro Kanematsu

Hyogo College of Medicine
Department of Urology

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Frieder Keller

University Hospital Ulm
Department Internal Medicine 1, Nephrology

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Professor Katarzyna Kilis-Pstrusinska PhD, MD

Wroclaw Medical University
Department of Pediatric Nephrology

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MD, PhD Tae-Hyoung Kim

Chung-Ang University
Urology

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John N. Krieger MD, PhD

University of Washington
Section of Urology

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Prof Ekaterina Kulchavenya

Novosibirsk Research TB Institute, Novosibirsk State Medical University

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Dr Christina Kåbjörn Gustafsson

Ryhov Hospital Jönköping
Pathology

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Dr. Bela Köves

South Pest Teaching Hospital
Department of Urology

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Dr. med. Giuseppe Magistro

Ludwig-Maximilians-University of Munich
Department of Urology

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Vittorio Magri

ASST-North
Urologic Clinic

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András Magyar

South-Pest Hospital
Department of Urology

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Professor Emeritus Brian Morris

University of Sydney
School of Medical Sciences

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Baerbel Muendner-Hensen

ICA-Deutschland e.V.

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Stephen F. Murphy

Feinberg School of Medicine, Northwestern University
Department of Urology

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Kurt G. Naber MD, PhD

Technical University of Munich

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Prof. Yulia Naboka

Rostov State Medical University
Department of Microbiology

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Dr. J. Curtis Nickel MD

Queen's University
Department of Urology

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Professor Ralph Peeker MD PhD

University of Gothenburg
Department of Urology

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Tamara Perepanova

N.A. Lopatkin Research Institute of Urology and Interventional Radiology

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Prof. Gianpaolo Perletti M. Clin. Pharmacol.

University of Insubria
Department of Biotechnology and Life Sciences

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Felice Petraglia

Department of Biomedical, Experimental and Clinical Sciences, University of Florence
Obstetrics and Gynecology

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Dr. Jörgen Quaghebeur PhD. Med. Sci.

University Hospital Antwerp and University Antwerp
Department of Urology

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Yazan F. Rawashdeh

Aarhus University Hospital
Paediatric Urology Section, Department of Urology

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Professor Claus Riedl MD

-
Urology

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Matthew Roberts

The University of Queensland
Faculty of Medicine

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PD Dr. med Guido Schmiemann MPH

Institut für Public Health und Pflegeforschung, Universität Bremen
Abteilung Versorgungsforschung

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Caroline Schneeberger MD PhD

Academic Medical Center (AMC)

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Prof. Dr. med. Peter Schneede

Klinikum Memmingen
Department of Urology

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Aaron C. Shoskes

Des Moines University Medical College of Ostheopathic Medicine

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Daniel Shoskes MD, PhD

Cleveland Clinic
Glickman Urological and Kidney Institute

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Prof. Dr. Roswitha Siener

University of Bonn
University Stone Centre, Department of Urology

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Sofia Sjöström

Queen Silvia Childrens Hospital, Sahlgrens Academy
Pediatric surgery and urology

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Mathew Sorensen

University of Washington School of Medicine
Department of Urology

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Prof. Dr. Dr. Walter Ludwig Strohmaier FEBU

Regiomed-Klinikum Coburg. Medical School Regiomed
Urology and Paediatric Urology

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Satoshi Takahashi

Sapporo Medical University School of Medicine
Department of Infection Control and Laboratory Medicine

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Professor Paul Anantharajah Tambyah

Yong Loo Lin School of Medicine, National University Hospital
Department of Medicine

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Peter Tenke

South-Pest Hospital
Department of Urology

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Praveen Thumbikat


Department of Urology

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Dr. Jose Tiran Saucedo

IMIGO / Universidad de Monterrey
Obstetrics and Gynaecology

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Dominic Tran-Nguyen

Des Moines University

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Dean Tripp

Queen's University
Psychology, Anesthesia & Urology

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Prof. SEONGHEON WIE

The Catholic University of Korea, St. Vincent's Hospital
Division of Infectious Diseases, Department of Internal Medicine

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Florian M. E. Wagenlehner MD, PhD

Justus-Liebig University of Giessen
Clinic of Urology and Andrology

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Assoc. Prof. Christian Wejse

Aarhus University, Aarhus University Hospital
Department of Infectious Diseases/Center for Global Health, Dept of Public Health

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Prof. Dr. Mete Çek

Trakya University, School of Medicine
Urology

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