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The Unintended Deleterious Consequences of the ‘Routine’ Urinalysis
EDITORIAL
The Unintended Deleterious Consequences of the ‘Routine’ Urinalysis Modern day medicine’s liberal access to a multitude of medications, medical devices, and surgical and nonsurgical invasive procedures has tangibly transformed the practice of medicine from what was essentially once a diagnostic profession to one now focused on treatment. Historically, medical diagnosis and prognosis evolved from the early era of bedside medicine and hospital medicine to the birth of the modern day clinical laboratory, which now provided physicians with a resource and opportunity to account for that which previously was only an observation in their patients. Routine testing of urine, referred to as the “urinalysis,” by test strip, dipstick, or microscopic examination, is among today’s most frequently performed clinical laboratory tests. However, reliance on the visual examination of a patient’s urine as a means of diagnosing disease dates back thousands of years to the ancient Greeks, who ascribed all human maladies to disorders of bodily fluids called “humors.” In the Aphorisms,1 Hippocrates described foaming or bubbles on the surface of urine, presumably as a consequence of high protein concentration, to be indicative of kidney disease and hematuria as the failure of the kidneys to properly filter the blood. Throughout the Middle Ages, uroscopy, or urinalysis by the senses designated “water casting,” was heavily relied on as the major diagnostic tool of medieval medicine. In fact, the urine flask, or matula, served as that era’s symbol of medical practice. Nevertheless, what now is considered to be the first laboratory test fell prey to those who would use it fraudulently, often making rogue diagnostic and prognostic claims that came under criticism by Thomas Brian in his 1637 publication entitled The PisseProphet, or Certaine Pisse Pot Lectures2 as uroscopic quackery. The incorporation of chemical reagents into a test strip of paper allowed for the development of the convenient modern day screening urine “dipstick.” Originally introduced into clinical practice in the 1950s, the initial strips were Funding: None. Conflict of Interest: None. Authorship: Both authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Larry M. Bush, MD, Comprehensive Infectious Diseases, 10115 Forest Hill Blvd, Suite 102, Wellington, FL 33414. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.08.014
capable only of glucose measurement. Tests for protein, ketones, pH, blood, bilirubin, and urobilinogen were added in subsequent years. The current day nitrite test used to indicate the presence of bacteria and leukocyte esterase analysis, intended to estimate white blood cells and degree of pyuria, did not become components of the dipstick until 1972 and 1984, respectively. Arguably, the routine urinalysis performed by dipstick or microscopic examination is most times ordered for purposes of diagnosing a urinary tract infection. Unfortunately, however, the urinalysis has become part of routine medical practice and is often obtained for no clear clinical indication or part of the initial “workup” in patients presenting with a variety of signs and symptoms, which on initial evaluation would appear to have no relationship to the urinary system. The detection of clinically irrelevant findings in the urinalysis serves to potentially delay making the patient’s correct diagnosis and frequently leads to the prescribing of antimicrobial agents for the treatment of asymptomatic bacteriuria, further fueling bacterial antimicrobial resistance and potentially serious Clostridium difficile-related diarrheal infections. Asymptomatic bacteriuria has been defined as the presence of at least 105 cfu/mL of a uropathogen from 2 consecutive voided urine specimens in women or 1 specimen in men, or >102 cfu/mL of 1 bacterial species from a catheterized urine specimen in women or men, in all cases with absence of local or systemic signs or symptoms of an active infection. Depending on variables such as age, sex, and genitourinary abnormalities, the prevalence of asymptomatic bacteriuria has been found to be as low as 1% to 5% in healthy premenopausal women (w2%-10% in pregnant women) to 100% in patients with long-term indwelling urinary catheters. However, the populations accounting for the majority of cases of asymptomatic bacteriuria are elderly women and men with a respective prevalence of 11% to 16% and 4% to 19% in the community, increasing to 25% to 50% and 15% to 40% in long-term care facilities.3 Escherichia coli remains the most common bacterial isolate, although other species of Enterobacteriaceae and gram-positive cocci are not infrequent pathogens. Except in few specific groups of patients, well-designed studies have proven that, although persons with bacteriuria are at an increased risk of symptomatic urinary tract infections, the
2 treatment of asymptomatic bacteriuria does not decrease the frequency of symptomatic infections or improve other outcomes, and in fact is associated with a higher prevalence of potentially dangerous antibiotic-resistant strains in women who do go on to have an active urinary tract infection. Opposite the recommendation against asymptomatic bacteriuria screening put forth by the Infectious Diseases Society of America, and stressed in the American Board of Internal Medicine’s “Choosing Wisely” campaign, such practice still pervades as unwarranted urinalysis tests continue to be ordered in various patient care settings on a daily basis. Of note, contrary to the knowledge that the presence of pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment, leukocytes detected in the urine seem to provide practitioners with a misinformed rationale to prescribe unnecessary antibiotics. Moreover, some hospital clinical laboratories have been instructed to perform reflex cultures on any urine sample that has been found to have >10 white blood cells/high power field and/or >1þ bacteria and <5 squamous epithelial cells/high power field, independently of the clinical reason for the ordering of the urinalysis. One of the authors (MTV-P) found that of the 18,484 urinalysis specimens performed in a local hospital last year, 4062 (22%) underwent reflex cultures based on the listed criteria, which led to the inappropriate administration of antibiotics to a significant number of patients whose urinalysis demonstrated bacterial growth. Special consideration has been given to the handling of asymptomatic bacteriuria in pregnant women, those undergoing invasive urologic procedures or elective orthopedic surgery, recipients of renal transplants, and patients with diabetes and profound neutropenia. Routine screening and treatment of bacteriuria beginning in early pregnancy and periodically after therapy are based on the known increased prevalence of asymptomatic bacteriuria in this group of women, which has been demonstrated to lead to a 20- to 30fold increased risk of pyelonephritis and preterm delivery, low-birth-weight infants, and poor fetal outcomes. However, more recently, a large randomized prospective cohort trial of 4283 pregnant women conducted in The Netherlands looked at the maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria where the proportion of preterm births did not differ between women with or without asymptomatic bacteriuria, including those who received treatment or placebo. However, the investigators did find that there was a significant association with pyelonephritis and untreated asymptomatic bacteriuria, although the absolute risk was low, thus leading to their questioning of the routine screen-treat-policy currently standard of care.4 The use of prophylactic antibiotics before minor urologic events such as cystoscopy and urodynamic studies does not provide any benefit and is recommended against,3 but it still remains prudent to screen for and treat asymptomatic bacteriuria before any invasive urologic procedures that may lead to mucosal bleeding, because these have been proven to be associated with a heightened risk of bacteremia and
The American Journal of Medicine, Vol -, No -,
-
2016
severe systemic infection. However, after the procedure, antibiotic therapy is only recommended when an indwelling catheter is to be left in place. Furthermore, the routine use of a fluoroquinolone antibiotic for this purpose has come into question in light of the significant increase in E. coli isolates now having resistance to these agents. On the other hand, the contentious practice of screening for and treating asymptomatic bacteriuria in patients about to undergo orthopedic surgery including total joint arthroplasties is without proven merit. In a recent prospective randomized trial, rates of surgical wound or site infection were statistically similar in both treated and untreated bacteriuric patients. Moreover, in those diagnosed with postoperative infections, the bacterial pathogens cultured from the infected site were distinct from those isolated from the urine preoperatively.5 Last, at this point in time, data remain insufficient to recommend the routine treatment of asymptomatic bacteriuria in diabetic patients, renal transplant recipients, and neutropenic patients. Pending new asymptomatic bacteriuria guidelines and recommendations, the question remains, ”What are you treating?”6 Perhaps the time has come in the practice of medicine to return full circle, back to a time when those physicians who came before us focused their efforts on making an accurate diagnosis before offering the appropriate treatments of their time, all the while keeping in mind the adage that often times, “less is more.” Larry M. Bush, MDa,b Maria T. Vazquez-Pertejo, MDc a
Charles E. Schmidt College of Medicine Florida Atlantic University Boca Raton b University of Miami-Miller School of Medicine Palm Beach County Fla c Department of Pathology and Laboratory Medicine Wellington Regional Medical Center BlueHealth, LLC Palm Beach County Fla
References 1. Berger D. A brief history of medical diagnosis and the birth of the clinical laboratory. Part 1-Ancient times through the 19th century. MLO Med Labs Obs. 1999;7:28-40. 2. White WL. A new look at the role of urinalysis in the history of diagnostic medicine. Clin Chem. 1991;37:119-125. 3. Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40:643-654. 4. Kazemier BM, Koningstein FN, Schneeberger C, et al. Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomized controlled trial. Lancet Infect Dis. 2015;15:1324-1333. 5. Cordero-Ampuero J, Gonzalez-Fernandez E, Martinez-Velez D, et al. Are antibiotics necessary in hip arthroplasty with asymptomatic bacteriuria? Seeding risk with/without treatment. Clin Orthop Relat Res. 2013;417:3822-3829. 6. Weiskopf J, Scott S. Asymptomatic bacteriuria, what are you treating? JAMA Intern Med. 2015;175:344-345.
The Unintended Deleterious Consequences of the ‘Routine’ Urinalysis Modern day medicine’s liberal access to a multitude of medications, medical devices, and surgical and nonsurgical invasive procedures has tangibly transformed the practice of medicine from what was essentially once a diagnostic profession to one now focused on treatment. Historically, medical diagnosis and prognosis evolved from the early era of bedside medicine and hospital medicine to the birth of the modern day clinical laboratory, which now provided physicians with a resource and opportunity to account for that which previously was only an observation in their patients. Routine testing of urine, referred to as the “urinalysis,” by test strip, dipstick, or microscopic examination, is among today’s most frequently performed clinical laboratory tests. However, reliance on the visual examination of a patient’s urine as a means of diagnosing disease dates back thousands of years to the ancient Greeks, who ascribed all human maladies to disorders of bodily fluids called “humors.” In the Aphorisms,1 Hippocrates described foaming or bubbles on the surface of urine, presumably as a consequence of high protein concentration, to be indicative of kidney disease and hematuria as the failure of the kidneys to properly filter the blood. Throughout the Middle Ages, uroscopy, or urinalysis by the senses designated “water casting,” was heavily relied on as the major diagnostic tool of medieval medicine. In fact, the urine flask, or matula, served as that era’s symbol of medical practice. Nevertheless, what now is considered to be the first laboratory test fell prey to those who would use it fraudulently, often making rogue diagnostic and prognostic claims that came under criticism by Thomas Brian in his 1637 publication entitled The PisseProphet, or Certaine Pisse Pot Lectures2 as uroscopic quackery. The incorporation of chemical reagents into a test strip of paper allowed for the development of the convenient modern day screening urine “dipstick.” Originally introduced into clinical practice in the 1950s, the initial strips were Funding: None. Conflict of Interest: None. Authorship: Both authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Larry M. Bush, MD, Comprehensive Infectious Diseases, 10115 Forest Hill Blvd, Suite 102, Wellington, FL 33414. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.08.014
capable only of glucose measurement. Tests for protein, ketones, pH, blood, bilirubin, and urobilinogen were added in subsequent years. The current day nitrite test used to indicate the presence of bacteria and leukocyte esterase analysis, intended to estimate white blood cells and degree of pyuria, did not become components of the dipstick until 1972 and 1984, respectively. Arguably, the routine urinalysis performed by dipstick or microscopic examination is most times ordered for purposes of diagnosing a urinary tract infection. Unfortunately, however, the urinalysis has become part of routine medical practice and is often obtained for no clear clinical indication or part of the initial “workup” in patients presenting with a variety of signs and symptoms, which on initial evaluation would appear to have no relationship to the urinary system. The detection of clinically irrelevant findings in the urinalysis serves to potentially delay making the patient’s correct diagnosis and frequently leads to the prescribing of antimicrobial agents for the treatment of asymptomatic bacteriuria, further fueling bacterial antimicrobial resistance and potentially serious Clostridium difficile-related diarrheal infections. Asymptomatic bacteriuria has been defined as the presence of at least 105 cfu/mL of a uropathogen from 2 consecutive voided urine specimens in women or 1 specimen in men, or >102 cfu/mL of 1 bacterial species from a catheterized urine specimen in women or men, in all cases with absence of local or systemic signs or symptoms of an active infection. Depending on variables such as age, sex, and genitourinary abnormalities, the prevalence of asymptomatic bacteriuria has been found to be as low as 1% to 5% in healthy premenopausal women (w2%-10% in pregnant women) to 100% in patients with long-term indwelling urinary catheters. However, the populations accounting for the majority of cases of asymptomatic bacteriuria are elderly women and men with a respective prevalence of 11% to 16% and 4% to 19% in the community, increasing to 25% to 50% and 15% to 40% in long-term care facilities.3 Escherichia coli remains the most common bacterial isolate, although other species of Enterobacteriaceae and gram-positive cocci are not infrequent pathogens. Except in few specific groups of patients, well-designed studies have proven that, although persons with bacteriuria are at an increased risk of symptomatic urinary tract infections, the
2 treatment of asymptomatic bacteriuria does not decrease the frequency of symptomatic infections or improve other outcomes, and in fact is associated with a higher prevalence of potentially dangerous antibiotic-resistant strains in women who do go on to have an active urinary tract infection. Opposite the recommendation against asymptomatic bacteriuria screening put forth by the Infectious Diseases Society of America, and stressed in the American Board of Internal Medicine’s “Choosing Wisely” campaign, such practice still pervades as unwarranted urinalysis tests continue to be ordered in various patient care settings on a daily basis. Of note, contrary to the knowledge that the presence of pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment, leukocytes detected in the urine seem to provide practitioners with a misinformed rationale to prescribe unnecessary antibiotics. Moreover, some hospital clinical laboratories have been instructed to perform reflex cultures on any urine sample that has been found to have >10 white blood cells/high power field and/or >1þ bacteria and <5 squamous epithelial cells/high power field, independently of the clinical reason for the ordering of the urinalysis. One of the authors (MTV-P) found that of the 18,484 urinalysis specimens performed in a local hospital last year, 4062 (22%) underwent reflex cultures based on the listed criteria, which led to the inappropriate administration of antibiotics to a significant number of patients whose urinalysis demonstrated bacterial growth. Special consideration has been given to the handling of asymptomatic bacteriuria in pregnant women, those undergoing invasive urologic procedures or elective orthopedic surgery, recipients of renal transplants, and patients with diabetes and profound neutropenia. Routine screening and treatment of bacteriuria beginning in early pregnancy and periodically after therapy are based on the known increased prevalence of asymptomatic bacteriuria in this group of women, which has been demonstrated to lead to a 20- to 30fold increased risk of pyelonephritis and preterm delivery, low-birth-weight infants, and poor fetal outcomes. However, more recently, a large randomized prospective cohort trial of 4283 pregnant women conducted in The Netherlands looked at the maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria where the proportion of preterm births did not differ between women with or without asymptomatic bacteriuria, including those who received treatment or placebo. However, the investigators did find that there was a significant association with pyelonephritis and untreated asymptomatic bacteriuria, although the absolute risk was low, thus leading to their questioning of the routine screen-treat-policy currently standard of care.4 The use of prophylactic antibiotics before minor urologic events such as cystoscopy and urodynamic studies does not provide any benefit and is recommended against,3 but it still remains prudent to screen for and treat asymptomatic bacteriuria before any invasive urologic procedures that may lead to mucosal bleeding, because these have been proven to be associated with a heightened risk of bacteremia and
The American Journal of Medicine, Vol -, No -,
-
2016
severe systemic infection. However, after the procedure, antibiotic therapy is only recommended when an indwelling catheter is to be left in place. Furthermore, the routine use of a fluoroquinolone antibiotic for this purpose has come into question in light of the significant increase in E. coli isolates now having resistance to these agents. On the other hand, the contentious practice of screening for and treating asymptomatic bacteriuria in patients about to undergo orthopedic surgery including total joint arthroplasties is without proven merit. In a recent prospective randomized trial, rates of surgical wound or site infection were statistically similar in both treated and untreated bacteriuric patients. Moreover, in those diagnosed with postoperative infections, the bacterial pathogens cultured from the infected site were distinct from those isolated from the urine preoperatively.5 Last, at this point in time, data remain insufficient to recommend the routine treatment of asymptomatic bacteriuria in diabetic patients, renal transplant recipients, and neutropenic patients. Pending new asymptomatic bacteriuria guidelines and recommendations, the question remains, ”What are you treating?”6 Perhaps the time has come in the practice of medicine to return full circle, back to a time when those physicians who came before us focused their efforts on making an accurate diagnosis before offering the appropriate treatments of their time, all the while keeping in mind the adage that often times, “less is more.” Larry M. Bush, MDa,b Maria T. Vazquez-Pertejo, MDc a
Charles E. Schmidt College of Medicine Florida Atlantic University Boca Raton b University of Miami-Miller School of Medicine Palm Beach County Fla c Department of Pathology and Laboratory Medicine Wellington Regional Medical Center BlueHealth, LLC Palm Beach County Fla
References 1. Berger D. A brief history of medical diagnosis and the birth of the clinical laboratory. Part 1-Ancient times through the 19th century. MLO Med Labs Obs. 1999;7:28-40. 2. White WL. A new look at the role of urinalysis in the history of diagnostic medicine. Clin Chem. 1991;37:119-125. 3. Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40:643-654. 4. Kazemier BM, Koningstein FN, Schneeberger C, et al. Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomized controlled trial. Lancet Infect Dis. 2015;15:1324-1333. 5. Cordero-Ampuero J, Gonzalez-Fernandez E, Martinez-Velez D, et al. Are antibiotics necessary in hip arthroplasty with asymptomatic bacteriuria? Seeding risk with/without treatment. Clin Orthop Relat Res. 2013;417:3822-3829. 6. Weiskopf J, Scott S. Asymptomatic bacteriuria, what are you treating? JAMA Intern Med. 2015;175:344-345.