The Effect of Local Antibiogram–based Augmented Antibiotic Prophylaxis on Infection-related Complications Following Prostate Biopsy

Original Research

Original Research The Effect of Local Antibiogram–based Augmented Antibiotic Prophylaxis on Infection-related Complications Following Prostate Biopsy Raoul S. Concepcion, MD, FACS,1,2 Edward M. Schaeffer, MD, PhD,3 Neal D. Shore, MD, FACS,4 Deepak A. Kapoor, MD, FACPE,5,6 Jeffrey A. Scott, MD,1 Gary M. Kirsh, MD7 1Integra Connect, West Palm Beach, FL; 2Vanderbilt University School of Medicine, Nashville, TN; 3Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL; 4Atlantic Urology Clinics, Myrtle Beach, SC; 5Integrated Medical Professionals, New York, NY; 6Urology Department, Icahn School of Medicine at Mount Sinai, New York, NY; 7The Urology Group, Cincinnati, OH Given the number of prostate biopsies performed annually in the United States and associated infectious events as a result, we sought to determine if implementation of a standardized biopsy protocol utilizing antibiotic prophylaxis based on locally derived antibiograms would result in a decrease, relative to a contemporary control population, in the incidence of infection-related complications among community-based practices. A total of nine member groups of LUGPA participated in both a retrospective review and a prospective study of infection-related complications following prostate biopsy. Historic infectious complications, defined as chills/rigor, temperature higher than 101 °F, or documented positive blood or urine cultures, were self-reported by a retrospective review of patients undergoing prostate biopsy under the practice’s current protocol in the year prior to the study. The prospective phase of the study required each group to develop a locally derived augmented prophylaxis regimen (.2 antibiotics) based on local antibiograms. After implementation, the practices enrolled patients undergoing prostate biopsy over an 8-week period. Monitoring for infection-related complication took place over the ensuing 3 weeks post-biopsy. Seven hundred fifty-nine patients over nine practices were enrolled into the study utilizing the augmented locally determined prophylaxis protocol. There was a 53% reduction in the incidence of infection-related complication, relative to the historical rate. By developing a standardized biopsy protocol with specific emphasis on incorporating an augmented antibiotic prophylactic regimen based upon local antibiograms, we were able to demonstrate in a prospective trial Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 93 Antibiotic Use and Infections Following Prostate Biopsy continued across nine geographically distinct community practices a significant reduction in the incidence of infection-related complications. [Rev Urol. 2019;21(2/3):93–101] KEY WORDS Biopsy • Antibiogram • Prophylaxis, antibiotic • Prostate • Drug-resistant bacteria T he simultaneous, and fortuitous, introduction and approval of widespread prostate-specific antigen (PSA) testing and transrectal ultrasonography in the late 1980s resulted in the development of new biopsy techniques with a marked increase in the number of prostate biopsies performed yearly by urologists. With this came a stage migration and increase in the number of lower grade/organ-confined prostate cancer cases in those newly diagnosed. As evidence continues to mount regarding the role of active surveillance in management of low-risk prostate cancer, a challenge for many urologists is to determine which patients will in fact benefit from prostate biopsy in order to define potentially lethal disease. Recent data suggests that the number of biopsies performed by a urologist in the United States was a median of 29 cases per year.1 However, with the 2012 United States Preventive Services Task Force (USPSTF) D recommendation on PSA testing, there has been a reported 28.7% decrease in the number of biopsies performed annually after this controversial governmental decision, resulting in a drop to 21 biopsies annually per urologist.1,2 Nonetheless, more than 1 million biopsies are performed annually.3 Complications arising from traditional sextant transrectal ultrasound-guided prostate biopsy (TRUSBx) are uncommon but can be broadly categorized as infectious, bleeding, urinary obstruction/ retention, and erectile dysfunction.4 It has been well documented that the number of infection-related complications (IRC), which can range in severity from a urinary tract infection to full-blown sepsis necessitating in-patient hospitalization, as a direct result of prostate biopsy has been increasing.5 The transrectal approach with direct introduction of fecal flora from the GI tract, thus seeding the prostate tissue, has been presumed to be the major source of these pathogens.6 There are conflicting data on whether the number of cores taken result in a higher 94 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology incidence of infection.7,8 Obtaining a detailed patient medical history is critical (Table 1) as a number of these associated factors appear to render the patient at higher risk for infectious events.4 In 2012, the American Urological Association (AUA) published a white paper/best practice policy guideline for the prevention and treatment of IRC related to prostate needle biopsy; this guideline was updated in 2016.4 Oral fluoroquinolones (FQ) were the recommended antibiotic. It has been shown, however, that there is an emergence of fluoroquinolone resistance (FQR) worldwide, which may explain the increasing incidence of post-biopsy infection in certain patients treated with FQ antibiotics.9 Specifically, FQR Escherichia coli prevalence has been estimated at 23.5% in North America.10 There are a number of mechanisms that appear to be contributing, including target-site mutation, transmissible plasma–mediated FQR genes, changes in membrane permeability, and the presence of chromosomal multidrug efflux pumps.11 Table 2 lists associated risk factors that appear to increase the susceptibility for development of a clinical infection with a FQR pathogen.12 Because of these FQR patterns, multiple strategies have been adopted to address this burgeoning problem. These would include routine use of targeted prophylaxis with rectal swab cultures prior to prostate biopsy, augmented prophylaxis (defined as .2 antibiotics with extended E coli coverage based on local antibiograms), and a movement back towards a transperineal approach for prostate biopsy.13 In 2016, LUGPA (https://lugpa.org), partnering with Integra Connect (https://www.integraconnect. com) and the Department of Urology at the Feinberg School of Medicine, Northwestern University, conducted a prospective, multi-center trial utilizing nine LUGPA member practices to determine if the development of a standardized prostate biopsy protocol that included tissue handling and the use of Antibiotic Use and Infections Following Prostate Biopsy an augmented prophylaxis antibiotic regimen would result in a decrease number of IRC compared with the practice’s historical data. Additionally, with the transition from volume- to value-based care, we recognize that in order to succeed, practices will be increasingly called upon to adopt and adhere to clinical protocols. Therefore, we wanted to determine if urology groups would be able to broadly operationalize standardized antibiotic prophylactic regimens, and if such regimens, once adopted, lead to a decreased incidence of IRC and/or healthcare savings. TABLE 1 Co-morbidities Associated With Higher Risk of Infectious Complications in Patients Undergoing Prostate Biopsy Diabetes Immunosuppression History of prior biopsy History of prostatitis Prior fluoroquinolone exposure within 6 months International travel Healthcare provider Current use of corticosteroids Current use of tumor necrosis factor inhibitors Data from American Urological Association.4 Materials and Methods TABLE 2 Risk Factors for Potential Fluoroquinolone Resistance Poor health Urinary catheterization Recent hospitalization Previous urinary tract infection with prior antibiotic exposure Data from Van der Starre WE et al.12 TABLE 3 List of Practices Included in the Study Albuquerque Urology Associates, New Mexico Chesapeake Urology, Maryland Comprehensive Urologic Care, Illinois Florida Urology Partners, Florida Foothills Urology, Colorado Golden Gate Urology, Northern California Regional Urology,* Louisiana Tower Urology, Southern California Urology of Central PA, Pennsylvania Urology Associates,* Tennessee Urology Centers of Alabama, Alabama *Original participants not included in final study either because they did not participate in both the historical and prospective components or already had a local antibiogram-based approach to infection-related complication prophylaxis. A total of nine geographically distinct integrated LUGPA member practices with aggregate number of 220 urologists participated in this prospective study providers (Table 3). A lead-in, historical prospective phase (based on 819 patients who received a prostate biopsy between January 1, 2016 and July 31, 2016, self-reported by the groups) was used to determine the current antibiotic protocol for prostate biopsy at each practice. Utilizing an internally developed case report form, the existing infectious complication and subsequent hospitalization rate was determined for each practice as part of this data collection. The second phase involved the development of locally derived augmented prophylaxis regimens (.2 antibiotics) based on local antibiograms and consistent with AUA best practice guidelines regarding antibiotic duration. These regimens were reviewed by the physicians on the project leadership team (ES, GK, RC). In general terms, regimens were selected with a goal of .90% E coli sensitivity for each of two antibiotics, based upon the local antibiogram. Secondary regimens, with Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 95 Antibiotic Use and Infections Following Prostate Biopsy continued similar sensitivity targets, were also formulated for reported penicillin allergy. Once developed and implemented, the practices were to enroll all patients undergoing prostate needle biopsy continuously over an 8-week period. Monitoring with clinical follow up for 2 to 3 weeks post-biopsy was used to determine if an IRC had occurred. Tables 4 and 5 detail the complete protocol and augmented prophylaxis regimens for each practice. Results Phase 1 (Historical Review) Nine LUGPA member practices were chosen to participate in this project. In total, 819 patients (91 per practice site) who had undergone prostate biopsy, regardless of indication, were retrospectively reviewed to determine the historic IRC rate from January through July 2016. An IRC was defined as one or more of the following: chills/rigor, T .101°F, or documented positive blood or urine cultures. Using these criteria, a 3.1% overall incidence of IRC was noted across the reporting groups. This historical review was also used to determine the individual current antibiotic protocol in place at the time of the biopsies: 3 of 9 (33%) had practice-wide prophylaxis not based on antibiograms and 6 of 9 (67%) had no protocols in place (Table 5). Figure 1 shows the IRC rate based on the historical protocol in place. TABLE 4 LUGPA Prostate Biopsy Protocol Patient History Survey (Prior to Biopsy) Prior usage of antibiotics for any conditions within the preceding 6 months (Y/N) Diabetic (any type) (Y/N) Healthcare worker, including animal care (Y/N) Prior history of prostate infection (Y/N) Prior infection from prostate biopsy (Y/N) Current use of TNF inhibitorsa (Y/N) Day of Prostate Biopsy Post-biopsy Follow-up Have office staff call patients 2-3 weeks after biopsy to determine if Verify patients were administered prophy- patient had ANY healthcare encounter lactic antibiotics as per protocol (below) Obtain healthcare encounter record Determine whether patients were at high to verify if patients indicate they had a post-biopsy healthcare encounter. risk for infections based on the survey Urologist to review record to determine if related to prostate biopsy Rinsing/wiping the biopsy needle with infection-related complication. formalin during procedure Fleet enema All patients receive augmented prophylactic antibiotics. This is defined as 2 different antibiotics, ideally each with $ 90% sensitivity to E coli, based on an annually updated local antibiogram. Antibiotics may be oral or parenteral. Current use of corticosteroidsb (Y/N) Recent urine culture (Y/N) If Yes, list sensitivities Prior history of organ transplantation (Y/N) aTumor necrosis factor (TNF) inhibitors include adalimumab, etanercept, infliximab, infliximab, golimumab, and certolizumab. include, but are not limited to, prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, dexamethasone, betamethasone, and budesonide. bCorticosteroids 96 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology Antibiotic Use and Infections Following Prostate Biopsy TABLE 5 Augmented Antibiotic Regimen by Individual Practicea Augmented Antibiotics (Day of Biopsy) Drug Sensitivity to E coli Dosage Formulation Sig 1g 500 mg 2g 500 mg IM PO IM PO At time of biopsy bid 1 h before biopsy bid Practice 1 Standard If penicillin allergy Standard If penicillin allergy High-risk patients Ceftriaxone Ciprofloxacin Aztreonam Ciprofloxacin 95% 83% 96% 83% Practice 2 Ceftriaxone 92% 1g IM At time of biopsy Levofloxacinb 68% 750 mg PO Single dose 2 h prior to biopsy Gentamicin 86% 3 mg/kg IV At time of biopsy Levofloxacinb 68% 750 mg PO Single dose 2 h prior to biopsy A rectal swab may be performed roughly 3 weeks prior to procedure (by referring urologist) to guide choice of prophylactic antibiotics. Practice 3 Standard If penicillin allergy Standard If penicillin allergy Ceftriaxone Ciprofloxacin Aztreonamc Ciprofloxacin 99% 82% 99% 82% Practice 4 1g 500 mg 2g 500 mg IM PO IV PO At time of biopsy bid 1 h prior to biopsy bid Amikacin Ceftriaxone or cefepime Amikacin 100% 77% 500 mg 1g IV IM 30 min before biopsy At time of biopsy 100% 2g 500 mg IV IV 30 min before biopsy Aztreonam 77% 2g IV 1 h before biopsy Practice 5 Standard Ceftriaxone 95% 1g IM At time of biopsy Ciprofloxacin or levofloxacin 89% 500 mg or 750 mg PO bid or qd (Continued) Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 97 Antibiotic Use and Infections Following Prostate Biopsy continued Augmented Antibiotics (Day of Biopsy) Sensitivity to E coli Drug Dosage Formulation Sig 2g 500 mg or 750 mg IV PO 1 h before biopsy bid or qd 1 gram 500 mg 2g 500 mg IM oral IV PO At time of biopsy BID 1 h before biopsy bid 3-5 mg/kg 500 mg 3-5 mg/kg 750 mg IV bolus PO IV bolus PO At time of biopsy bid At time of biopsy Single dose 78% 875 mg PO Single dose 86% 86% 86% 1g 1g 5 mg/kg IM IM IM At time of biopsy At time of biopsy 30 min prior to biopsy 1g 500 mg 3-5 mg/kg 500 mg IM PO IV bolus PO At time of biopsy bid At time of biopsy bid Practice 5 (cont’d) If penicillin allergy Aztreonam Ciprofloxacin or levofloxacin 95% 89% Practice 6 Standard If penicillin allergy Ceftriaxone Ciprofloxacin Aztreonam Ciprofloxacin 91% 81% Not reported 81% Practice 7 Standard If penicillin allergy Gentamicin Cefuroxime Gentamicin Levofloxacin 90% Not reported 90% 73% Practice 8 Standard If penicillin allergy Amoxicillin/ clavulanic acid Ceftriaxone Ceftriaxone Gentamicin Practice 9 Standard If penicillin allergy Ceftriaxone Ciprofloxacin Gentamicin Ciprofloxacin 94% 88% 91% 88% aImportant to note that the order of practices listed does not correspond to the order of practices in Figure 2 to maintain blinding. quinolone allergy, sulfamethoxazole and trimethoprim can be used as an alternative for levofloxaxin. cIf stable source of supply for aztreonam not available, an alternative is gentamicin 3-5 mg/kg IV. bIf Phase 2 (Prospective Capture) After submission of the local antibiogram, we noted geographic differences in FQR (Table 6). Siteby-site accommodations were made considering prohibitive drug costs to the practice and patient, when applicable in some markets, and the ability to administer IV antibiotics within a practice at the site of service for prostate biopsies. A total of 759 patients were accrued for evaluation by the nine practices over a consecutive 8-week period. Eight of 98 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology the nine practices accrued patients from July 31, 2017 to September 22, 2017, with one practice accruing patients August 28, 2017 to October 20, 2017. An IRC was determined by a urologist review at each site. After implementation Antibiotic Use and Infections Following Prostate Biopsy Practice did not have standard antibiotic protocol in place; did not consider local antibiograms (n=6) Practice had standard antibiotic protocol in place; did not consider local antibiograms (n=3) 6.6% 5.5% 4.4% 4.4% 3.3% 2.2% 1.1% A B C D E F 0.0% 0.0% I J G Figure 1. Infectious-related complications based on historic protocol by practice. TABLE 6 Quinolone Resistance to E coli by State/Region Based on Local Antibiograms Provided State/Region Florida Alabama Louisiana Tennessee Maryland Southern California Northern California Illinois New Mexico Pennsylvania Colorado of the protocol, the infection rate dropped from 3.1% in phase 1 to 1.4% in phase 2 or a statistically significant 53% reduction in IRC (P = 0.031; Figure 2). This statistical analysis was performed using the IBM SPSS Statistics package. All comparisons were two-tailed and a P , 0.05 was considered statistically significant. Equal variances were not assumed. Quinolone Resistance to E coli 56% 47% 39% 38% 32% 27% 19% 18% 17% 12% 11% Discussion Since the 1980s, one of the most common procedures performed by the practicing urologist has been transrectal ultrasound–guided biopsy of the prostate (TRUSBx).3 The genesis stems from the concomitant development and introduction of PSA testing and affordable transrectal ultrasonography, thus allowing the urologic provider to offer prostate biopsy in the office or outpatient setting. The result was a dramatic increase in the number of biopsies performed annually in the United States, with a significant percentage of those newly diagnosed patients having low-risk disease.14 We now possess a better understanding of the natural history of low-grade prostate cancer and that certain lowrisk patients may be safely followed with active surveillance.15 Coupled with a notable risk of complications arising from TRUSBx, it becomes prudent for the urologist to be more judicious as to which patient needs to undergo prostate biopsy to identify the presence of significant prostate cancer, as well as limiting the possible complications and reducing the cost of care to manage these unplanned events. The incidence of post-biopsy IRC has risen over the past decade, with some recent estimates at approximately 2.15/100 biopsies, up from 0.7/100 biopsies performed a decade earlier. It is also of note that there has been a rise in FQR E coli strains during this same time period.3 A number of studies have documented, in both the United States and abroad, that the hospitalization rate as a result of IRC may be as high as 4%.16 Given the number of biopsies performed annually, IRC and their subsequent management represent a significant cost. A recently published large retrospective study of over 5000 patients over a 1-year period from a large metropolitan community-based practice documented a 1.1% IRC after adopting a targeted prophylaxis antibiotic protocol.17 In the era of value-based medicine and pathway adherence, it was the goal of this study, in a prospective fashion, to standardize the biopsy protocol, including identification of risk factors, handling of tissue at the time of biopsy, and incorporation of an Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 99 Antibiotic Use and Infections Following Prostate Biopsy continued Infection Rate for Practices Who DID NOT Incorporate Local Antibiogram Reviews in Antibiotic Selection in Phase I Prospective Phase I 6 6. 1/2 % 5% 5. 4% .4% 4 4% 4. 4. 3% 3. 8% 8% 1. 1. 0% 0% *Limited prospective phase to 9 physicians and MRI/US % fusion .6 –2 biopsies only 1% .1% 2 0. % .5 –1 – 2 2. 6% % 0% 0. Infectionrelated complications went from 0 patients in phase 1 to 1 patient during the prospective phase 3. 2. 2. 0% 0. 0. 1% 9% 2% 2. % 4% 0. % .1 –5 1 1. 8% 1. 4% 1. 0% .0% .0% 0 0 0. Infectionrelated complications went from 1 patient in phase 1 to 2 patients during the prospective phase % .6 –1 53% Reduction in infection-related complication rate . –6 Practice 1 Practice 2 Practice 3* Practice 4 Practice 5 Practice 6 Practice 7 Practice 8 Practice 9 Total Figure 2. Infection-related complications rates by individual practice. The incorporation of local antibiogram reviews in antibiotic selection is associated with meaningful infection rate reductions. augmented antibiotic protocol that was based on local antibiograms. We observed a statistically significant 53% aggregate decrease (3.1% → 1.4%) in IRC across the nine groups that participated in the trial via implantation of the standardized, local antibiogram–based augmented prophylactic regimen. Limitations of this study included the retrospective nature of determining the historic complication rate(s) of the individual practices based on a finite number of patients (819), as well as the limited number of patients (759) enrolled during the prospective phase. It is likely under-reporting of postbiopsy IRC was greater in the retrospective cohort, which would only strengthen our conclusions. Additionally, notwithstanding the geographic diversity of the participating groups, the total number of groups participating was less than 10. Conclusions By developing a standardized biopsy protocol with specific emphasis on incorporating an augmented antibiotic prophylactic regimen based upon local antibiograms, we were able to demonstrate in a prospective trial across nine geographically distinct community practices a significant reduction in the incidence of IRC. 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