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Fosfomycin for Antibiotic Prophylaxis Prior to Transrectal Ultrasound-Guided Prostate Biopsy
Andrew Colhoun1, Jessica Marinaro2, Jay Sulek1, Zachary McDowell3, Christopher Bednarz1, Tyler Roseman1, Adam Klausner1, Michael Climo4, Leroy Vaughan4 and Baruch Mayer Grob1,5*
1Department of Surgery/Urology, Virginia Commonwealth University School of Medicine, Richmond, USA
2Department of Urology, Georgetown University, Washington, D.C., USA
3Department of Urology, Baylor University School of Medicine, Houston, USA
4Infectious Disease Service, Hunter Holmes McGuire VA Medical Center, Richmond, USA
5Urology Service, Hunter Holmes McGuire VA Medical Center, Richmond, USA

ABSTRACT
Introduction
Infectious complications are known risks of Transrectal Ultrasound (TRUS) prostate biopsy. Increasing fluoroquinolone resistance creates a need for novel prophylactic agents. Fosfomycin is an oral bactericidal agent with high urinary and prostatic tissue concentrations. This study aims to assess the efficacy of fosfomycin in preventing infectious complications after prostate biopsy.
Methods
Under the advice of the infection control service at our hospital, prostate biopsy prophylaxis transitioned from ciprofloxacin to fosfomycin in July 2013. A prospective quality assurance database was maintained. Retrospective review of the periprocedural infectious complications within 30 days of biopsy was performed comparing prophylaxis with ciprofloxacin prior to initiation of fosfomycin prophylaxis and the new fosfomycin regimen. All patients received phosphate enemas prior to biopsy.
Results
Among the 414 patients treated with fosfomycin and 400 patients treated with ciprofloxacin over 26 months, there was no difference in number of biopsy cores obtained or history of prior prostate biopsy. Positive post-biopsy urine cultures occurred in 0.75% and 1.21% of patients in the ciprofloxacin and fosfomycin groups, respectively (p=0.73), and positive post-biopsy blood cultures in 0.75% and 0.72% of patients in the ciprofloxacin and fosfomycin groups, respectively (p=1.0). Bacterial cultures in the ciprofloxacin group demonstrated a significantly higher rate of fluoroquinolone resistance compared to cultures in the fosfomycin group (66% vs. 0%, p=0.015).
Conclusion
Fosfomycin is an effective agent for antimicrobial prophylaxis in patients undergoing TRUS prostate biopsy, comparable to standard therapy. It could be an alternative prophylactic agent particularly in centers with high fluoroquinolone resistance.
Keywords
Antibiotic prophylaxis prostate; Biopsy; Fluoroquinolones; Fosfomycin

Introduction
Transrectal Ultrasound-Guided (TRUS) needle biopsy is routinely employed to obtain tissue for prostate cancer diagnosis and is recommended for patients with abnormal digital rectal examination findings or an elevated serum prostate-specific antigen level. TRUS Prostate Biopsy (TRUSPB) provides a definitive, histopathologic diagnosis with sensitivities between 75% and 90% [1]. The majority of TRUSPB are performed on an outpatient basis with minor complications of hematuria and hematospermia; however, major complications including prostatitis, urosepsis or even septic shock can occur [2,3]. In an attempt to mitigate risks of TRUSPB, the American Urological Association recommends routine antibiotic prophylaxis prior to all prostate biopsies with either a fluoroquinolone, cephalosporin or trimethoprim-sulfamethoxazole [4]. Worldwide, ciprofloxacin is the most frequently prescribed drug for TRUSPB antibiotic prophylaxis due to its broad spectrum of activity, enteric administration and high prostatic tissue concentrations [5,6].Despite the use of antibiotic prophylaxis, infectious complications following TRUSPB continue to increase, almost tripling from 1991 to 2007 based on Medicare data and increasing six-fold in Canada from 1996 to 2005 [7-10]. This increase in infectious complications has been found to parallel an increase in Fluoroquinolone-Resistant (FQR) E. coli isolates [9,11]. FQR infections following TRUSPB have risen from 0.6% to 2.6% from 2004 to 2006, an approximate 4-fold increase in 2 years [11]. Specifically, patients colonized with FQR rectal flora demonstrated a seven-fold increase in post-TRUSPB infection rate compared to patients with FQ-sensitive rectal flora [12]. Multiple studies estimate the prevalence of FQR rectal flora among all men to be between 17% and 24% [12-14]. Given these increased rates of colonization and infection with FQR pathogens, there is a pressing need for novel antimicrobial prophylaxis that is easily administered, is well tolerated and is effective against FQR organisms.Fosfomycin is a broad-spectrum, oral bactericidal agent that is approved in the United States for the treatment of uncomplicated acute cystitis caused by E. coli and E. faecalis and is used in Europe for prophylaxis prior to endourologic and transurethral procedures [15,16]. Fosfomycin is administered orally as a water-soluble powder and is distributed in high concentrations to the kidneys, bladder wall, prostate and seminal vesicles within 1-4 hours of consumption [17,18]. The mechanism of action involves inactivation of enolpyruvyl transferase, an enzyme essential for bacterial cell wall synthesis [16,19]. Urinary concentrations remain bactericidal for over 24 hours after administration and the drug is generally well-tolerated, with the most frequent adverse reactions being diarrhea (10.4%), headache (10.3%) and nausea (5.2%) [16]. In an in vitro study comparing fosfomycin to other antibiotics commonly used to treat urinary tract infections, fosfomycin was found to be the most effective drug against E. coli (99% of strains susceptible) with only 88% of E. coli strains showing susceptibility to ciprofloxacin [20]. Fosfomycin has also demonstrated activity against both FQR and extended-spectrum beta-lactamase producing strains of E. coli [19,21]. Additionally, fosfomycin resistance is uncommon with only 1-3% of E. coli strains worldwide demonstrating resistance [19].To our knowledge, no study has compared infectious complications from standard prophylaxis and fosfomycin prophylaxis prior to TRUSPB in a North American population. We aim to determine if fosfomycin is an effective agent for antibiotic prophylaxis prior to TRUSPB.
Materials and Methods
Patients who underwent TRUSPB at the Hunter Holmes McGuire VA Medical Center received a standard prophylactic antibiotic regimen of oral ciprofloxacin 500mg twice daily for 3 days (day before, day of and day after biopsy). In July 2013 hospital epidemiology and the infectious disease service recommended transitioning to a one-time dose of oral fosfomycin 3g approximately 2 to 3 hours prior to TRUSPB instead of the traditional ciprofloxacin regimen due to increasing prevalence of FQR bacterial infections at our institution. Specifically, 3g of Fosfomycin Tromethamine powder mixed with 3-4 oz was administered. A quality assurance database was prospectively maintained to monitor patients for signs and symptoms of infection within 30 days of biopsy after initiation of the new fosfomycin regimen. An infectious complication was defined as any positive blood or urine bacterial culture (irrespective of CFU/mL or presenting symptoms). After Institutional Review Board approval, a retrospective review of the quality assurance database was performed from July 2013 through August 2014 as well as retrospective review of patients undergoing TRUSPB during the 12 months prior to the antibiotic transition who received prophylaxis with ciprofloxacin. All patients received phosphate enemas prior to TRUSPB. Patients were excluded if they received any type of antibiotic prophylaxis other than the two regimens listed or if they took the prescribed antibiotic regimen incorrectly. Demographics and pertinent medical history were obtained including patient age, number of biopsy cores obtained, history of prior TRUSPB and susceptibility to infection (i.e. diabetes mellitus, HIV and immunosuppressive medications). In the event of an infectious complication symptoms and causative organisms were recorded. Statistical analysis was performed using a two-tailed student’s t-test to compare means and Fisher’s exact test to compare event frequency between groups.
Results
A total of 868 consecutive patients were identified over 26 months, 54 were excluded for not meeting criteria. Demographics between the ciprofloxacin group (n=400) and the fosfomycin group (n=414) were similar and are listed in table 1.

There was not a significant difference in the number of post-TRUSPB infections between the two groups (Table 2). A total of 8 (1.93%) infectious complications were identified in the fosfomycin group and 6 (1.50%) infectious complications were identified in the ciprofloxacin group which was not significantly different (p=0.47). Three patients in both the fosfomycin arm (0.72%) and ciprofloxacin arm (0.75%) developed bacteremia (p=1.0), all six of these patients were hospitalized. No infectious complications were observed in patients with suspected or confirmed immune compromised status. There were no deaths from infection within 30 days of the biopsies.

The majority of patients with infectious complications in the fosfomycin group (5/8) demonstrated only bacteriuria and 2 of these 5 patients had chronic kidney disease stage III or greater. The majority of infectious complications in the ciprofloxacin group (66%) were secondary to FQR E. coli isolates. All 8 infectious complications in the fosfomycin group were secondary to Gram negative rods (Enterobacter sp., E. coli and K. pneumoniae) with 50% demonstrating only ampicillin resistance and the remainder demonstrating pan-sensitivity on susceptibility testing. The ciprofloxacin group demonstrated a significantly higher rate of FQR complications when compared to the fosfomycin group (66% vs. 0%, p=0.02). Of note, 2 of the 3 patients developing bacteremia in the ciprofloxacin group had a prior TRUSPB and blood cultures at time of presentation demonstrated FQR E. coli.

Patients with history of prior TRUS prostate biopsy demonstrated a relative risk of 2.03 (95% CI [0.42-9.92], p=0.38) for the ciprofloxacin group and 2.51 (95% CI [0.64-9.87], p=0.19) for the fosfomycin group for developing post-biopsy infectious complications when compared to biopsy-naïve patients in their respective cohorts.
Discussion
Infectious complications are serious sequelae of TRUSPB and increased efforts are needed to mitigate the risks of infection. Patients hospitalized for post-TRUSPB infectious complications have a significantly greater 30 day mortality risk when compared to patients hospitalized for noninfectious complications [7]. An increase in FQR infections after TRUSPB indicates that novel prophylactic agents or approaches are necessary [11]. Some groups have demonstrated improved rates of infection with the addition of intravenous or intramuscular antibiotics to augment standard prophylaxis and provide targeted therapy directed at FQR bacteria discovered on pre-TRUSPB rectal cultures [22-24]. Other studies have demonstrated efficacy of rectal povidone-iodine preparation prior to TRUSPB, although this method does not provide any prophylactic benefit to the prostate tissue itself since the antiseptic agent is contained in the rectal vault [25].

Fosfomycin tromethamine is a bactericidal agent that is particularly effective against E. coli, E faecalis, Citrobacter, Proteus, Enterobacter, Klebsiella, Serratia and Enterococcus species. In the oral form, it has a bioavailability of 34-41% [26]. Once absorbed Fosfomycin has no metabolic transformation and is primarily excreted in the urine. Doses used in this study were sufficient enough to have bactericidal effects [26]. ].

Preliminary studies have already investigated the efficacy of fosfomycin as a prophylactic antibiotic prior to TRUSPB in Europe. Ongun et al., performed a retrospective analysis comparing the rates of infectious complications among patients who received either one 3g dose of oral fosfomycin, one 500mg dose of oral levofloxacin or 5 days of 500mg oral ciprofloxacin BID prior to TRUSPB. The rate of febrile Urinary Tract Infection (UTI) following fluoroquinolone prophylaxis was 3.4%; in contrast, the rate of febrile UTI following fosfomycin prophylaxis was only 0.9%, although this was not statistically significant [26]. Another study by Lista et al., randomized patients to receive either two 3g doses of fosfomycin or ten 500mg doses of ciprofloxacin as antibiotic prophylaxis prior to TRUSPB with no significant difference in the rates of post-TRUSPB febrile episodes [27].

Recent research has also shown favorable evidence for the use of fosfomycin prophylaxis prior to TRUSPB in Mediterranean populations. Roberts et al., investigated efficacy through a meta-analysis that was comprised of three prospective randomized trials and two retrospective cohorts. Results from the meta-analysis demonstrated a decreased relative odds of infection in patients treated with fosfomycin trometamol compared to fluoroquinolone prophylaxis for TRUSPB (OR 0.22, 95% CI [0.09-0.54]) [28].].

In the present study, we incurred similar rates of infectious complications between patients treated with ciprofloxacin prophylaxis and those treated with fosfomycin prophylaxis for TRUSPB. Our overall prevalence of post-TRUSPB infectious complications requiring hospitalization was similar to larger series [29]. Although there was not a significant difference in infectious complication rates between the two groups, a significantly higher number of patients in the ciprofloxacin group developed FQR infections. Our findings of an increased risk of infectious complications among patients with a history of prior TRUSPB and that 66% of patients who developed bacteremia in the ciprofloxacin group grew FQR E. coli suggests these patients may harbor FQR organisms in their rectal vault as sequelae of prior biopsy. Therefore, fosfomycin may be considered a reasonable alternative for antibiotic prophylaxis prior to TRUSPB, especially in areas with high FQR or in patients with history of prior TRUSPB. ].

Fosfomycin was well-tolerated and no adverse events were reported after patient self-administration. The ease of administration 2-3 hours prior to TRUSPB is similar to a one-time oral quinolone. However, when compared to ciprofloxacin (approximately $5 for one 500mg tablet), fosfomycin has significantly higher monetary costs (approximately $72 for a one-time 3g dose) [30-32]. In centers with high percentages of FQR organisms, the cost of administration of intravenous antimicrobials including advanced generation cephalosporins prior to TRUSPB and the expense and morbidity of a hospital stay may balance the cost of the drug.].

Limitations of this study include the nonrandomized nature and retrospective review of patient data. Although we demonstrated no significant difference between fosfomycin and quinolone prophylaxis, this study was underpowered to detect such a significant difference. However fosfomycin does appear to have similar efficacy and more rigorous study in a larger randomized trial appears warranted. Another limitation was the reliability of patient-reported compliance and time of fosfomycin administration. Although patients were educated on the proper administration of fosfomycin at their pre-biopsy appointment, actual administration times or noncompliance may have influenced drug bioavailability at time of biopsy and led to potentially avoidable infectious complications. Given the significant difference in the cost of fosfomycin compared to ciprofloxacin, there may be a cost barrier to widespread usage. Finally, the administration of fosfomycin to patients with renal insufficiency may not have allowed for adequate urinary concentrations at time of TRUSPB and predisposed these patients to infectious risks.
Conclusion
This is the first study in North America demonstrating that fosfomycin may be an effective agent for antimicrobial prophylaxis prior to TRUSPB when compared to standard prophylaxis. With a broad spectrum of activity against FQR organisms, fosfomycin could be considered as an alternative to standard prophylaxis in areas with high FQR.

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Tables

 

Fosfomycin

Ciprofloxacin

p

n

414

400

 

Average age (years)

64

64

0.28

Diabetes mellitus (%)

128 (31)

108 (27)

0.25

Immunocompromised (%)

7 (2)

4 (1)

0.55

Average number of biopsy cores (range)

11 (10-20)

11 (10-20)

0.71

History of prior prostate biopsy (%)

118 (29)

132 (33)

0.17

Table 1: Patient demographics.

 

Fosfomycin

Ciprofloxacin

p

Patients (%)

8 (1.93)

6 (1.50)

0.47

Positive urine culture (%)

6 (1.45)
2 Enterobacter
3 K. pneumoniae
1 FQS E.coli

4 (1.00)
3 FQR E.coli
1 Group B Strep

0.75

Positive blood culture (%)

3 (0.72)
1 FQS E.coli
2 K. pneumoniae

3 (0.75)
1 FQS E.coli
2 FQR E.coli

1.0

Patients with FQR isolates (%)

0 (0)

4 (66)

0.02

Relative risk of post-biopsy infection in patients with history of prior biopsy [95% CI]

2.51 [0.64-9.87]

2.03 [0.42-9.92]

NS

Table 2: Infectious complications.
Note: FQS: Fluoroquinolone-Sensitive; FQR: Fluoroquinolone-Resistant.

Citation: Colhoun A, Marinaro A, Sulek J, McDowell Z, Bednarz C, et al. (2018) Fosfomycin for Antibiotic Prophylaxis Prior to Transrectal Ultrasound-Guided Prostate Biopsy. Arch Urol 1: 004.
Copy Right: © 2018 Colhoun A, et al., This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits un­restricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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