Infection/Inflammation The Impact of Repeat Biopsies on Infectious Complications in Men with Prostate Cancer on Active Surveillance Behfar Ehdaie,* Emily Vertosick,* Massimiliano Spaliviero,* Anna Giallo-Uvino,* Ying Taur,* Maryellen O Sullivan,* Jennifer Livingston,* Pramod Sogani,* James Eastham,* Peter Scardino and Karim Touijer*, From the Urology Service, Sidney Kimmel Center for Prostate and Urologic Cancers (BE, MS, AG-U, MO, JL, PS, JE, PS, KT), Department of Epidemiology and Biostatistics (BE, EV), and Department of Medicine, Infectious Diseases Service (YT), Memorial Sloan-Kettering Cancer Center, and Department of Urology, Weill Medical College of Cornell University (PS, JE, PS, KT), New York, New York Abbreviations and Acronyms AS ¼ active surveillance ESBL ¼ extended spectrum beta-lactamase FQ ¼ fluoroquinolone PSA ¼ prostate specific antigen TRUS ¼ transrectal ultrasound UTI ¼ urinary tract infection Accepted for publication August 30, 2013. Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers. The data used in this study were reviewed by the institutional review board, which determined use of the data to be exempt from the human subject research consent requirement and granted a waiver of authorization. * Nothing to disclose. Financial interest and/or other relationship with Steba Biotechnology, National Cancer Institute, National Institutes of Health and Prostate Cancer Foundation. Correspondence: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, New York 10065 (e-mail: touijera@mskcc.org). Editor s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 878 and 879. Purpose: Prostate biopsy related infectious complications are associated with significant morbidity. The risk of infectious complications in patients with prostate cancer on active surveillance remains under studied. Materials and Methods: A total of 591 consecutive men who underwent prostate biopsy were prospectively enrolled in a study evaluating prostate biopsy related complications between January 2011 and January 2012. Of these men 403 were previously diagnosed with prostate cancer and were included in this study. They underwent a 14-core transrectal ultrasound guided prostate biopsy as part of an active surveillance regimen. A nurse contacted all men within 14 days of biopsy, and information was collected on potential complications, antibiotics received and bacterial culture results. Results: Fourteen patients (3.5%) had infectious complications including 13 requiring hospitalization. Five patients had positive urine cultures, and fluoroquinolone resistant isolates were identified in 4 patients, including 2 with extended spectrum beta-lactamase producing isolates. We evaluated the impact of risk factors including diabetes, benign prostatic hyperplasia and antibiotic regimen. However, only the number of previous prostate biopsies was significantly associated with an increased risk of infectious complications (p ¼ 0.041). For every previous biopsy the odds of an infection increased 1.3 times (OR 1.33, 95% CI 1.01e1.74). Conclusions: In men with prostate cancer on active surveillance the number of previous prostate biopsies is associated with a significant risk of infectious complications and every previous biopsy increases the risk of infectious complication. Fluoroquinolone resistant and extended spectrum beta-lactamase producing isolates represent the most commonly identified organisms. Men with prostate cancer on active surveillance should be informed of the risks associated with serial repeat prostate biopsies. Key Words: prostatic neoplasms, biopsy, infection, sepsis, treatment outcome IN 2012 an estimated 241,740 men were diagnosed with prostate cancer. 1 Prostate needle biopsy with TRUS guidance is the standard technique to obtain a histological diagnosis of prostate cancer and some men endure multiple negative prostate needle biopsy results before diagnosis. 2 660 j www.jurology.com 0022-5347/14/1913-0660/0 THE JOURNAL OF UROLOGY 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. http://dx.doi.org/10.1016/j.juro.2013.08.088 Vol. 191, 660-664, March 2014 Printed in U.S.A.
INFECTION AND PROSTATE BIOPSY 661 Similarly, many men diagnosed with low risk prostate cancer managed with AS will endure several years of serial TRUS biopsies. AS has emerged as the preferred management strategy for men with low risk prostate cancer and the National Comprehensive Cancer Network guidelines recommend annual prostate biopsy. 3,4 Approximately 1 million prostate needle biopsies are performed annually in the United States and the numbers will increase as more men are enrolled in AS. 5 The impact of increasing the frequency of prostate needle biopsies on the risk of infection related complications in patients on AS is under studied. Several observational studies have reported that significant morbidity is associated with initial prostate needle biopsy. In a study using administrative data of elderly men enrolled in Medicare, the rates of 30-day hospitalization after initial prostate biopsy were 2.65-fold higher than among randomly selected control subjects. 5 In that same study the authors demonstrated that the risk for 30-day hospitalization after initial prostate needle biopsy because of infection had increased between 1991 and 2007. An analysis of patients enrolled in the European Organization for Research and Treatment of Cancer prostate cancer screening clinical trial revealed a high proportion of urine cultures with trimethoprim sulfa resistant isolates after prostate needle biopsy. 6 These observations suggest an increasing incidence of antimicrobial resistance contributing to infectious complications after prostate needle biopsy. Despite accumulating evidence demonstrating an increase in infectious complications after prostate needle biopsy, the impact of repeat prostate needle biopsies in a population of men undergoing AS for low risk prostate cancer is unknown. We conducted a prospective observational study during 1 year at a single institution to determine the incidence and characteristics of infectious complications after prostate needle biopsy in men diagnosed with prostate cancer on AS. MATERIALS AND METHODS Patient Cohort Men who underwent at least 1 prostate biopsy at Memorial Sloan-Kettering Cancer Center between January 2011 and January 2012 and were diagnosed with prostate cancer on biopsy were eligible for inclusion in this study (403). Each man underwent only 1 biopsy during this period, and data were collected prospectively from the most recent biopsy and used for analysis. Prostate Biopsy Technique and Prophylactic Antibiotic Use The standard technique for prostate needle biopsy at our institution involved TRUS guidance using an 18 gauge needle, and obtaining 14 cores from the apical, mid and base regions as well as the transitional zone of the prostate. Individual physicians determined the antibiotics used for prophylaxis before prostate needle biopsy. Most physicians at our institution prescribed an oral FQ antibiotic beginning the evening before the biopsy and continued for 24 hours after the procedure. Assessment of End Point Our primary outcome of interest was infection within 14 days after biopsy, which we defined as hospitalization for infection, positive blood or urine culture, or fever greater than 100.3F. This was assessed by telephone call by our nursing staff to the patient within 14 days. In addition, nursing staff contacted doctors or outside hospitals to collect information on antibiotic use, urine and blood culture results as well as symptoms of infection at presentation, and recorded these data in a prospective database. Followup Schedule For patients enrolled on AS the standard followup regimen includes routine serum PSA measurement and digital rectal examination every 6 months, and repeat TRUS guided prostate needle biopsy as often as annually or once every 3 years based on disease characteristics. Statistical Methods We evaluated the impact of the number of prior biopsies on the risk of post-biopsy infectious complications. The null hypothesis tested was that the number of prior biopsies is not associated with an increased risk of infectious complications. In addition, we sought to identify if the previous class of prophylactic antibiotics, diagnosis of diabetes and increasing age are associated with the risk of infectious complications after prostate biopsy. We used univariate logistic regression to test for these associations. Due to a limited number of events, we were unable to use multivariate models in this analysis. All analyses were conducted using StataÒ 12.0. RESULTS Of the 403 men in this study more than half (55%) had undergone only 1 previous prostate biopsy. Only 40 (10%) of 403 patients had undergone 4 or more previous biopsies (table 1). FQ antibiotics were given to 92% of patients before undergoing the on-study biopsy. Intramuscular gentamicin was administered to 114 (28%) patients. There were 14 patients (3.4%, 95% CI 1.7e5.3) who had an infection after prostate biopsy, of whom 5 had positive urinary cultures and 9 had negative urinary cultures. Among the patients with growth on urine culture 4 were found to have ciprofloxacin resistant Escherichia coli including 2 with an ESBL producing isolate. One patient had aminoglycoside resistant Enterococcus. The number of previous biopsies was significantly associated with an increased risk of post-biopsy infection. On average, the odds of infection increased
662 INFECTION AND PROSTATE BIOPSY Table 1. Patient characteristics Mean pt age at biopsy (range) 64 (60, 69) Mean ng/ml PSA at biopsy (range)* 4.5 (3.1, 6.4) No. No. previous biopsies (%): 1 221 (55) 2 98 (24) 3 44 (11) 4 23 (5.7) 5 10 (2.5) 6 3 (0.7) 7 3 (0.7) 12 1 (0.2) No. current biopsy FQ prophylaxis (%) 371 (92) No. prior biopsy FQ prophylaxis (%) 263 (65) No. current biopsy gentamicin (%) 114 (28) No. prior biopsy gentamicin (%) 12 (3) No. diabetes (%) 36 (9) No. benign prostatic hyperplasia (%) 50 (12) No. coronary artery disease (%) 25 (6) No. chronic obstructive pulmonary disease (%) 25 (6) * In 402 men. by 1.33 for each additional previous biopsy (95% CI 1.01e1.74, p ¼ 0.041). To further explore the relationship between number of prior biopsies and the risk of infection we used locally weighted scatterplot smoothing (lowess). The results are shown in figure 1. The risk of post-biopsy infection for a man who has undergone 1 or 2 previous biopsies is about 2%. Risk then starts to increase until it reaches 15% for patients who have undergone 5 or more biopsies. We found that a history of gentamicin use for a prior biopsy significantly increased the risk of infection after the current biopsy (OR 6.32, 95% CI 1.25e32.0, p ¼ 0.026). The extremely wide confidence intervals are due to only 12 of 403 (3%) patients receiving gentamicin before prior biopsy. In addition, using FQ for the current biopsy resulted in a significantly decreased risk of contracting an infection (OR 0.19, 95% CI 0.06e0.66, p ¼ 0.008). Finally, patients with a diagnosis of diabetes were Probability of Infection after Biopsy (%) 0% 2.5% 5% 7.5% 10% 12.5% 15% 17.5% 1 2 3 4 5 6 7 Number of Previous Biopsies Figure 1. Risk of post-biopsy infection by number of previous biopsies. not found to have an increased risk of infectious complications after prostate needle biopsy (OR 1.74, 95% CI 0.37e8.10, p ¼ 0.5). Increased patient age was also not associated with infectious complications (OR 0.92, 95% CI 0.66e1.29, p ¼ 0.6, table 2). We observed significant variability among antibiotic regimens used by urologists at our institution (fig. 2). Overall 10 unique regimens were administered using 7 different classes of antibiotics. The incidence of infectious complications was distributed across most of the urologists (fig. 3). DISCUSSION Active surveillance has emerged as the standard management strategy for men with low risk prostate cancer. All of these men will be exposed to a series of routine prostate needle biopsies as part of the accepted surveillance pathway. Although infrequent, infectious complications after prostate needle biopsy cause significant morbidity, and the growing number of biopsies performed annually will substantially increase the public health burden associated with sepsis. Despite the increased attention to complications associated with incident prostate needle biopsy, the prevalence is underestimated by studies assessing only hospitalized patients, and few have detailed the impact of previous biopsies on the risk of infectious complications in men previously diagnosed with prostate cancer. In this study we found the number of previous prostate needle biopsies was associated with an increased risk of infectious complications on subsequent biopsy among men with a previous diagnosis of prostate cancer. We also report that the annual incidence rate of infectious complications after prostate needle biopsy was 3.5% in this population. Fever developed in all of the patients with an infectious complication. These patients presented to an emergency department within 14 days after prostate needle biopsy and were treated with intravenous antibiotics. Finally, our study confirmed previous reports of incidental prostate needle biopsies, and identified FQ resistant and ESBL producing isolates in the urine cultures of the majority of men with infectious complications. Table 2. Risk factors for infectious complications OR 95% CI p Value No. previous biopsies 1.33 1.01, 1.74 0.041 Age at biopsy (per 5 yrs) 0.92 0.66, 1.29 0.6 Diabetes 1.74 0.37, 8.1 0.5 Benign prostatic hyperplasia 1.98 0.53, 7.37 0.3 FQ prophylaxis (current biopsy) 0.19 0.06, 0.66 0.008 FQ prophylaxis (prior biopsy) 0.52 0.18, 1.51 0.2 Gentamicin prophylaxis (current biopsy) 1.95 0.66, 5.75 0.2 Gentamicin prophylaxis (prior biopsy) 6.32 1.25, 32.0 0.026
INFECTION AND PROSTATE BIOPSY 663 Total Antibiotic Use, by Antibiotic Class 0% 20% 40% 60% 80% 100% Numerous studies have reported prostate needle biopsy complications using administrative data linked to population based registries. Recently Loeb et al reported that the repeat biopsy session was not associated with an increased hospitalization rate for infectious complications compared to the initial biopsy using the SEER (Surveillance, Epidemiology and End Results)-Medicare database in all men who underwent a prostate needle biopsy. 7 It is difficult to compare the findings of this study with our study because of the significant differences in patient populations. Loeb et al did not characterize men who may have undergone biopsy before age 65 years Percentage of Infections in All Biopsies, By Surgeon 0% 2.5% 5% 7.5% 10% A B C D E F G H I J Figure 2. Antibiotic use by surgeon. Blue indicates fluoroquinolone, red indicates fluoroquinolone plus aminoglycoside, green indicates penicillin plus aminoglycoside, and orange indicates all other antibiotic combinations. C D E I J Figure 3. Proportion of cases resulting in infectious complications by surgeon. (Five surgeons were excluded from study for having no patients with infectious complications during this time frame.) and enrollment into Medicare. Perhaps cases characterized as initial biopsies may have undergone biopsy before age 65 years and before enrolling in Medicare. Excluding men with a prior diagnosis of prostate cancer does not diminish this misclassification, and instead may increase the proportion of initial biopsy cases with misclassified men who have had a persistently increased PSA and prior negative biopsies. We believe this population may represent a group at higher risk for post-biopsy infectious complications and may bias the results toward the null hypothesis. We restricted our cohort to men on AS who underwent routine scheduled repeat biopsy, thereby mitigating the impact of confounding due to the risk of infectious complications associated with biopsies performed for increased PSA due to prostatitis. Moreover, in the study by Loeb et al the hospital admissions for infectious complications were not validated with chart review or patient communication, and were instead based on hospital discharge diagnoses. Therefore, after an initial biopsy men may have a lower threshold to visit an emergency room and may have been admitted with mild symptoms of inflammation compared to those who have previously undergone biopsy. We prospectively identified infectious complications after prostate needle biopsy through personal communication with patients and restricted our cohort to men on AS, thereby mitigating misclassification and ascertainment biases. A range of infectious complications may occur after prostate needle biopsy, including asymptomatic bacteriuria, UTI and bacteremia accompanied by sepsis. Observational studies report that approximately 25% of patients hospitalized with bacteremia after prostate needle biopsy require admission to an intensive care unit. 8,9 Conversely, less severe infectious complications are managed in the community. 6 Therefore, studies that report hospitalization associated complication rates may underestimate the incidence of infectious complications. The mechanism of prostate needle biopsy infection has not been delineated. However, it is presumed that the principal pathway stems from direct inoculation of bacteria from the rectal mucosa by the biopsy needle into prostatic vasculature or the urinary tract. Preexisting infection or inflammation may also contribute to infectious complications. Lindstedt et al reported a febrile UTI rate of 27% among patients with asymptomatic UTI before prostate needle biopsy compared to 0.9% among men with negative pre-biopsy urine culture. 10 Perhaps the men in our study who had undergone biopsy and had exposure to antibiotics from a prior biopsy had altered bowel flora and harbored resistant organisms.
664 INFECTION AND PROSTATE BIOPSY The antibiotic resistance patterns of isolates in urine cultures observed in our study support recent evidence that approximately 62% of bloodstream infections were FQ resistant E. coli. 9 In addition, recent studies have reported that 11% to 22% of men undergoing prostate needle biopsy harbor FQ resistant organisms within the rectum. 11 In our study all of the E. coli isolated after prostate needle biopsies among men with infectious complications were FQ resistant and/or produced an ESBL. The rate of co-resistance to FQ among ESBL producing E. coli ranges from 50% to 100%. 12 In addition, contemporary studies have reported an increase in aminoglycoside resistant isolates, which represents another important resistant phenotype commonly encountered alongside FQ resistance and ESBL production. 13 Sepsis developed in 2 of our patients with aminoglycoside resistant E. coli, which highlights the importance of routine antibiotic use before biopsy. Our study is not without limitations. We did not obtain routine urine and blood cultures before biopsy. Therefore, we cannot exclude the possibility that some men harbored asymptomatic infections. Furthermore, we did not collect urine and blood cultures on every patient after biopsy. However, we identified every patient with a clinically relevant infectious complication by establishing personal communication with every patient within 14 days after biopsy, which is a strength of our study. The findings of this study have led to quality improvement measures for reducing infectious complications after prostate needle biopsy and preventing the increasing prevalence of infectious complications associated with repeat biopsy in men with prostate cancer on AS. We observed significant variability in antibiotic prophylaxis regimens among urologists in our department. Therefore, we initiated a task force with infectious disease specialists to develop an antibiotic prophylaxis protocol before prostate needle biopsy. We also identified FQ resistant and ESBL producing E. coli as the primary isolate in the urine of patients with infections. In view of an increasing prevalence of FQ resistance in E. coli across many studies, recent data suggest that a tailored approach to prophylaxis may be clinically beneficial and cost-effective. In particular, it is suggested that screening for FQ resistant pathogens before biopsy using rectal swab culture can direct antibiotic prophylaxis and significantly reduce infectious complications. 14 Therefore, we have adopted a targeted approach to antibiotic prophylaxis using rectal swab cultures before all prostate needle biopsies and are prepared to participate in a pivotal multiinstitutional study to evaluate the efficacy of this standard regimen to prevent infectious complications. CONCLUSIONS The management of men with low risk prostate cancer on AS requires serial repeat biopsies, which exposes these men to infectious complications with each biopsy. This study informs patients and physicians about the risks associated with repeat serial biopsies and raises concerns about the increasing incidence of infections caused by resistant organisms. Future studies should include evaluation of strategies to reduce prostate needle biopsies in AS regimens. REFERENCES 1. Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10. 2. Hodge KK, McNeal JE, Terris MK et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142: 71. 3. Silberstein JL, Vickers AJ, Power NE et al: Reverse stage shift at a tertiary care center: escalating risk in men undergoing radical prostatectomy. Cancer 2011; 117: 4855. 4. National Comprehensive Cancer Network Guidelines: Prostate Cancer 2013. 5. 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