Laboratory Diagnosis of Urinary Tract Infections 2C, Cumitech

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2C Laboratory Diagnosis of Urinary Tract Infections YVETTE S. McCARTER, EILEEN M. BURD, GERRI S. HALL, AND MARCUS ZERVOS COORDINATING EDITOR

SUSAN E. SHARP

Cumitech CUMULATIVE TECHNIQUES AND PROCEDURES IN CLINICAL MICROBIOLOGY

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Cumitech 1C Cumitech 2C

Blood Cultures IV (2005)

Cumitech 3B

Quality Systems in the Clinical Microbiology Laboratory (2005)

Cumitech 7B Cumitech 10A

Lower Respiratory Tract Infections (2004)

Cumitech 12A

Laboratory Diagnosis of Bacterial Diarrhea (1992)

Cumitech 13A

Laboratory Diagnosis of Ocular Infections (1994)

Cumitech 16A

Laboratory Diagnosis of the Mycobacterioses (1994)

Cumitech 31

Verification and Validation of Procedures in the Clinical Microbiology Laboratory (1997)

Cumitech 32

Laboratory Diagnosis of Zoonotic Infections: Viral, Rickettsial, and Parasitic Agents Obtained from Food Animals and Wildlife (1999)

Cumitech 33

Laboratory Safety, Management, and Diagnosis of Biological Agents Associated with Bioterrorism (2000)

Cumitech 34

Laboratory Diagnosis of Mycoplasmal Infections (2001)

Cumitech 35

Postmortem Microbiology (2001)

Cumitech 36

Biosafety Considerations for Large-Scale Production of Microorganisms (2002)

Cumitech 37

Laboratory Diagnosis of Bacterial and Fungal Infections Common to Humans, Livestock, and Wildlife (2003)

Cumitech 38

Human Cytomegalovirus (2003)

Cumitech 39

Competency Assessment in the Clinical Microbiology Laboratory (2003)

Cumitech 40

Packing and Shipping of Diagnostic Specimens and Infectious Substances (2004)

Cumitech 41

Detection and Prevention of Clinical Microbiology Laboratory-Associated Errors (2004)

Cumitech 42

Infections in Hemopoietic Stem Cell Transplant Recipients (2005)

Cumitech 43

Cystic Fibrosis Microbiology (2006)

Cumitech 44

Nucleic Acid Amplification Tests for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae (2006)

Laboratory Diagnosis of Urinary Tract Infections (2009)

Laboratory Diagnosis of Upper Respiratory Tract Infections (2006)

Cumitech 18A

Laboratory Diagnosis of Hepatitis Viruses (1998)

Cumitech 21

Laboratory Diagnosis of Viral Respiratory Disease (1986)

Cumitech 23

Infections of the Skin and Subcutaneous Tissues (1988)

Cumitech 24

Rapid Detection of Viruses by Immunofluorescence (1988)

Cumitech 26

Laboratory Diagnosis of Viral Infections Producing Enteritis (1989)

Cumitech 27

Laboratory Diagnosis of Zoonotic Infections: Bacterial Infections Obtained from Companion and Laboratory Animals (1996)

Cumitech 28

Laboratory Diagnosis of Zoonotic Infections: Chlamydial, Fungal, Viral, and Parasitic Infections Obtained from Companion and Laboratory Animals (1996)

Cumitech 29

Laboratory Safety in Clinical Microbiology (1996)

Cumitech 45

Cumitech 30A

Selection and Use of Laboratory Procedures for Diagnosis of Parasitic Infections of the Gastrointestinal Tract (2003)

Infections in Solid-Organ Transplant Recipients (2008)

Cumitech 46

Laboratory Procedures for Diagnosis of Blood-Borne Parasitic Diseases (2008)

Cumitechs should be cited as follows, e.g.: McCarter, Y. S., E. M. Burd, G. S. Hall, and M. Zervos. 2009. Cumitech 2C, Laboratory Diagnosis of Urinary Tract Infections. Coordinating ed., S. E. Sharp. ASM Press, Washington, DC. Editorial Board for ASM Cumitechs: Alice S. Weissfeld, Chair; Maria D. Appleman, Vickie Baselski, Mitchell l. Burken, Roberta Carey, Lynne Garcia, Larry Gray, Amy L. Leber, Andrea J. Linscott, Yvette S. McCarter, Michael Saubolle, Susan E. Sharp, James W. Snyder, Allan L. Truant, Punam Verma. Effective as of January 2000, the purpose of the Cumitech series is to provide consensus recommendations regarding the judicious use of clinical microbiology and immunology laboratories and their role in patient care. Each Cumitech is written by a team of clinicians, laboratorians, and other interested stakeholders to provide a broad overview of various aspects of infectious disease testing. These aspects include a discussion of relevant clinical considerations; collection, transport, processing, and interpretive guidelines; the clinical utility of culture-based and non-culture-based methods and emerging technologies; and issues surrounding coding, medical necessity, frequency limits, and reimbursement. The recommendations in Cumitechs do not represent the official views or policies of any third-party payer. Copyright © 2009 ASM Press American Society for Microbiology 1752 N St. NW Washington, DC 20036-2904, USA ISBN 978-1-55581-517-2 All Rights Reserved 10 9 8 7 6 5 4 3 2 1

Address editorial correspondence to ASM Press, 1752 N St. NW, Washington, DC 20036-2904, USA E-mail: [email protected] Send orders to ASM Press, P.O. Box 605, Herndon, VA 20172, USA Phone: (800) 546-2416 or (703) 661-1593 • Fax: (703) 661-1501 Online: estore.asm.org

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Laboratory Diagnosis of Urinary Tract Infections Yvette S. McCarter Department of Pathology, University of Florida College of Medicine—Jacksonville, 655 W. 8th St., Jacksonville, FL 32209

Eileen M. Burd Department of Pathology and Laboratory Medicine, Emory University Hospital, 1364 Clifton Rd. NE, Atlanta, GA 30322

Gerri S. Hall Section of Clinical Microbiology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195

Marcus Zervos Division of Infectious Diseases, Henry Ford Health System, 2799 West Grand Blvd., CFP3, Detroit, MI 48202

COORDINATING EDITOR: Susan E. Sharp Kaiser Permanente, 13705 N.E. Airport Way, Portland, OR 97230

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Clinical Considerations and Clinical Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 2 Significance of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Clinical Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pathogenesis, Microbial Flora, and Antimicrobial Resistance . . . . . . . . . . . . . . . . . . . . . . . 4 Diagnostic Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Frequency of Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Specimen Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 SPA and Straight (in and out) Catheterization . . . . . . . . Clean-Catch Midstream Specimens . . . . . . . . . . . . . . . Indwelling Catheters . . . . . . . . . . . . . . . . . . . . . . . . . . Bagged and Diaper Specimens from Pediatric Patients Ileal Conduits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Methods of Specimen Collection . . . . . . . . . . . .

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Specimen Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Specimen Handling in the Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Specimen Workup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Communication between the Clinician and the Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . 9 Approach to Laboratory Workup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Guidelines for Specimen Inoculation, Incubation, Workup, and Interpretation of Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Reimbursement and Coding Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Reporting Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Antimicrobial Susceptibility Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Rapid Urine Screens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Microscopic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Enzyme Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Bacteriologic Culture Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Unacceptable Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

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INTRODUCTION

U

rinary tract infection (UTI) is one of the most commonly encountered infectious diseases. Urine cultures account for the majority of the workload in the clinical microbiology laboratory. It is the responsibility of the clinical microbiologist to provide relevant, cost-effective information to health care providers for diagnosis and treatment of this common infection. In contrast to other community and hospital-acquired infections, there have been few new pathogens identified as a cause of UTIs. However, there have been significant changes in antimicrobial resistance patterns and increasing antimicrobial resistance among urinary tract pathogens. This updated Cumitech incorporates expanded clinical information, including additional sections on diagnostic approaches and frequency of testing. For the laboratorians, the guidelines for culture workup and interpretation have been updated and include methods of specimen collection. In addition, new sections on reimbursement, coding issues, and antimicrobial susceptibility testing have been added.

CLINICAL CONSIDERATIONS AND CLINICAL DIAGNOSIS Significance of UTIs UTI is one of the more common infections and results in as many as 8 million office visits per year (109) and about 1 million hospital admissions (73, 121). The exact frequency of UTI is not known; however, according to current evidence from office and hospital surveys, it is estimated that there are approximately 7 million episodes of cystitis (142) and 250,000 episodes of pyelonephritis (159) annually in the United States. One prospective study determined the annual incidence of cystitis to be 0.5 to 0.7% per person-year (68). Although many cases of uncomplicated UTI are transient with mild symptoms, studies suggest that considerable morbidity, mortality, and cost are associated with all forms of UTI. UTI is an illness that can occur from infancy through old age, in otherwise healthy persons, and in those who are compromised or debilitated. The prevalence of UTI varies greatly with age, race, and gender. Between 4.1 and 7.5% of serious bacterial infections in febrile pediatric patients are attributed to UTI, with the highest prevalence (17%) in white females (134, 160). The majority of patients with UTI are female, with a lifetime occurrence rate close to 50% (117, 137). As both sexes age, the incidence of bacteriuria increases from less than 5% in young adult women and less than 0.1% in young adult men to at least 20% of women and 10% of men older than age

CUMITECH 2C

65 (69). UTIs in women vastly outnumber those in men (69). This discrepancy could be related to such factors as the length of the urethra, distance of the urogenital meatus from the anus, and the antibacterial properties of prostatic fluid (89). Younger patients are at low risk for occult genitourinary tract abnormalities and are less likely to have comorbid conditions. Certain patient subgroups, however, have complicating conditions that increase the risk for acquiring invasive or systemic infection that include occurrence in men, children, and pregnant women, but complications are particularly common in the elderly, in immunocompromised patients, and in individuals with neurological disorders, underlying structural abnormalities, and infection due to antimicrobial-resistant organisms. Because UTI is such a common problem and urine specimens are easy to obtain from patients, clinicians submit urine specimens more frequently than almost any other type of specimen. As a result, urine cultures account for a major share of the workload in many clinical microbiology laboratories. Therefore, it is important for microbiology laboratory personnel to have an understanding of the clinical context from which these specimens originate because clinical considerations often profoundly influence the laboratory evaluation of urine specimens (73). Clinical Syndromes UTI encompasses a wide range of clinical syndromes. Each syndrome is characterized by the presence of microorganisms within a normally sterile urinary tract and usually an acute and symptomatic inflammatory response. UTI syndromes differ with respect to the specific site or the extent of infection within the urinary tract, the intensity of the inflammatory response, and the underlying status of the host. The UTI syndromes commonly encountered in clinical practice include asymptomatic bacteriuria, cystitis, pyelonephritis, and complicated and uncomplicated UTI. Asymptomatic Bacteriuria Asymptomatic bacteriuria is defined as the presence of bacteria within the urinary tract in the absence of symptoms (72) and is generally not considered clinically significant except in pregnant women (because of the risk of later development of pyelonephritis), patients who are to undergo an invasive procedure involving the urinary tract, and children with vesicoureteral reflux. Cystitis and Pyelonephritis Cystitis is the term applied to UTI presumed to be confined to the bladder and characterized by symptoms suggesting bladder involvement, such as dysuria or urinary frequency. Pyelonephritis is a clinical

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diagnosis of infection that involves the kidney and renal pelvis and is often associated with signs of systemic infection, such as fever and rigors. Other findings include back pain or tenderness and nausea. Clinical criteria are notoriously inaccurate in localizing the site of UTI. The differential diagnosis of UTI also includes vaginitis and urethritis that can produce symptoms similar to UTI. UTIs in the Elderly The majority of patients with UTI present with unambiguous symptoms and signs suggestive of this disease process; therefore, these patients present few diagnostic challenges for the clinician. However, a minority of infections, especially those encountered in the elderly or immunocompromised individual, can be more clinically challenging. For example, most clinicians have little difficulty making the diagnosis of UTI in a young woman presenting with 1 day of dysuria and frequency, whereas diagnostic challenges are likely to surface when UTI causes obtundation in an elderly male. There are many diagnostic methods available for diagnostic evaluation, so the practitioner must determine which laboratory tests and/or imaging methods are appropriate and cost-effective in individuals presenting with symptoms suggestive of UTI. The elderly are especially susceptible to acquiring UTI. In fact, UTIs are the most common group of acute infections observed in nursing home residents and are the most frequent cause of bacteremia in both institutionalized and community-dwelling elders. The case fatality rate associated with bacteremic UTI is approximately 10 to 30% in this population (114). UTIs in the elderly frequently present in an atypical manner. For example, the classic lower tract symptoms of frequency, urgency, and dysuria, accompanied by upper tract findings of chills, flank pain, and tenderness, may be altered or absent in the elderly patient or in those with indwelling catheters. Geriatric patients can be afebrile and, in some cases, can even be hypothermic (16). Although acute pyelonephritis in the elderly typically exhibits a septic syndrome with such manifestations as fever, tachycardia, and altered mental status, UTI in the elderly can present with a wide range of chief complaints, which can include mental status deterioration, nausea, vomiting, abdominal pain, or respiratory distress (1, 113, 127). In the elderly patient residing in a long-term care (LTC) or hospitalized setting, bacteremic UTI can present as confusion, cough, and dyspnea. In one study, new urinary symptoms were the chief complaints in only 20% of cases (15). In another study, only one-half of older bacteremic UTI patients were febrile. However, older patients were no more likely to be afebrile than were younger bacteremic patients

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(40% of whom had normal temperatures) (128). Because of the wide range of presenting symptoms, the misdiagnosis of UTI in the geriatric patient ranges from approximately 20 to 40% (113, 128). Complicated versus Uncomplicated UTI Experts have found it problematic to agree on a precise definition of complicated UTI (cUTI). However, in the medical literature, the term cUTI has typically been used to describe an infection that occurs in a patient with a structural or functional abnormality impeding urine flow or in a host with altered defenses that predispose the patient to a higher risk of treatment failure and/or complications. From a practical, clinical perspective, the distinction between cUTI and uncomplicated UTI is important because, when complicating factors are present, antimicrobial resistance is more common, the diagnosis can be more difficult, and the response to therapy is often disappointing, even with the use of agents active against the causative microbial pathogen. Severe complications in patients with cUTI are common and can include urosepsis, renal scarring, or end-stage disease. Some patients with cUTI are not likely to respond satisfactorily to short-term antibiotic treatment (98, 147). UTIs occurring in the presence of catheterization or functional or anatomical abnormalities of the urinary tract are also considered cUTIs (131, 133). The term cUTI is also used to categorize infections occurring in a host with compromised immune function, altered mechanical barriers, and other comorbid conditions. The natural history of UTI in patients with abnormal urinary tracts and/or altered host defenses has not been accurately defined. There are various morphological and functional changes in the urinary tract that do not influence the natural history of UTI. On the other hand, there are numerous other factors beside morphological and functional abnormalities that might result in failure of short-term antimicrobial therapy. Despite problems in developing a precise definition of cUTI with predictable prognostic value, the distinction between complicated and uncomplicated infections remains important. The spectrum of uropathogens encountered in uncomplicated UTI and cUTI is different, with Pseudomonas, Enterococcus, Proteus, and antimicrobial-resistant Escherichia coli more likely to be implicated as pathogens in cUTI. Although UTI is common and its prevalence increases with age (reaching about 7% in women 50 years old or older and 3.6% in men 70 years old or older) (148), renal scarring leading to end-stage disease is rare. It seems probable that the presence of complicating factors is necessary to exacerbate the natural history of the disease. cUTIs, as defined above, occur in less than 5% of patients with UTI,

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most of whom also have recurrent infections. If one defines cUTI according to guidelines of the Infectious Diseases Society of America (133), which include azotemia due to renal disease as a criterion for cUTI, this proportion can become somewhat higher. Special note should be taken of factors that increase the risk of acquiring bacteriuria (such as the presence of an indwelling catheter), promote an infection, and/or contribute to the persistence of an infection that may lead to more serious consequences, including the development of renal insufficiency (112). Infections that involve the prostate and urinary tract in ambulatory or nonambulatory elderly patients are often considered complicated. Whereas most UTIs in younger women are uncomplicated, those in older women are often complicated. Although uncomplicated cystitis does occur in men, it is uncommon. Therefore, UTIs in men are generally considered complicated (133). Bacterial factors, such as resistant pathogens of nosocomial origin or infection following recent antimicrobial therapy, also have been proposed as possible indicators of cUTI. These criteria, however, should not be used as singular factors determining cUTI but rather as an indication for a thorough search for other complicating factors interfering with the normal function of the urinary tract. Obstruction to urine flow, one of the most consistent elements associated with a cUTI, encompasses intrinsic and extrinsic disorders of the kidney and renal pelvis (e.g., congenital abnormalities, calculi, neoplasms, aberrant vessels, strictures, inflammatory bowel disease, retroperitoneal hematoma, and fibrosis); intrinsic or extrinsic abnormalities of the urethra (e.g., calculi, tumors, vesicoureteral reflux, radiation inflammatory sequelae, and retroperitoneal fibrosis); pathology of the bladder and/or bladder neck (e.g., benign prostatic hyperplasia, prostate or bladder cancer, bladder neck contraction, and vesical calculi); neurogenic bladder dysfunction; and disease of the urethra (e.g., polyps, structure, and valves). cUTIs also encompass those UTIs experienced by hosts with altered defenses, namely, diabetics, renal transplant recipients, persistently granulocytopenic patients, and patients who receive immunosuppressive therapy, particularly prednisone (131, 133). Pathogenesis, Microbial Flora, and Antimicrobial Resistance UTI is most commonly caused by bacteria from the patient’s own intestinal flora that enter the urinary tract by the ascending route via the urethra (16, 55, 72, 73). In children and adults, the fact that E. coli is by far the most common etiological agent of UTI reflects not only the predominance of E. coli in stool but also specific virulence factors, such as its ability

CUMITECH 2C

to adhere to uroepithelial cells. Occasionally, UTI develops from the bacteremic route from a distant site of infection, such as with Staphylococcus aureus. Staphylococcus saprophyticus accounts for a minority of UTIs in women and presumably arises from an ascending route. The reservoir of this organism, however, has not been determined. For many years, pathogens associated with uncomplicated UTI remained constant, with E. coli identified as the etiologic agent in 75 to 90% of infections (69). Five to fifteen percent of uncomplicated UTIs are caused by S. saprophyticus (55), with Klebsiella, Proteus, Enterococcus, and Pseudomonas species seen in much smaller percentages (57, 75, 173). Whereas in uncomplicated UTI, E. coli is by far the predominant causative pathogen, in hospitalacquired and cUTI, gram-negative, aerobic bacilli other than E. coli (e.g., Enterobacter spp., Klebsiella spp., Serratia spp., Citrobacter spp., Providencia spp., Acinetobacter spp., and Pseudomonas spp.) as well as gram-positive cocci (e.g., enterococci and staphylococci) also are implicated frequently (104, 141). In elderly men, E. coli continues to be an important organism, but Proteus, Klebsiella, Serratia, and Pseudomonas species, and enterococci have become increasingly important (104). Enterococci are far more frequent in cUTIs than in uncomplicated UTIs (104, 130, 163). Group B streptococcus (GBS) infection is observed in neonates secondary to inoculation from a colonized mother during delivery through the vaginal canal. Anaerobic bacteria rarely cause UTI despite their prevalence in fecal flora. Lactobacillus species, coagulase-negative staphylococci, and Corynebacterium species are not considered clinically significant isolates in the urine of healthy children between the ages of 2 months and 2 years (88, 145). Corynebacterium, Lactobacillus, and Streptococcus species are identified only rarely; when present, they nearly always represent contamination of the specimen. Candida species are being increasingly recognized as causes of UTI, especially in catheterized patients and in patients who received previous treatment for enterococcal UTI (63). Antimicrobial resistance in urinary tract pathogens is an ever-increasing problem, particularly in hospitals and extended care facility settings. Emerging resistance of E. coli species to trimethoprimsulfamethoxazole (TMP-SMX) is about 22% nationally, and resistance to ciprofloxacin is up to 20% nationally. In the inpatient setting, however, a recent evaluation of antimicrobial susceptibility data from 1999 to 2002 reveals increasing resistance to both ciprofloxacin and levofloxacin among E. coli isolates derived from the in-hospital environment and LTC setting (66, 176). European studies have shown E. coli

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resistance rates to multiple antibiotics, specifically TMP-SMX, in as many as one-third of patient isolates (167). In a cross-sectional survey of urine cultures obtained in the emergency departments of urban tertiary care centers in the United States, microbial resistance was as high as 48% to ampicillin, 25% to tetracycline, 14 to 28% to TMP-SMX, and 13% to nitrofurantoin (56). Similar susceptibility trends have been identified in gram-negative isolates from LTC facilities, which are known to be a source of outbreaks for resistant bacterial infections and colonization. Although there have been numerous reports about the resistance patterns of such bacteria as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in LTC facilities, there are few comprehensive resistance surveillance studies in this setting. One study evaluating resistance trends in nursing homes has shown that 36.5% of E. coli showed complete resistance to ciprofloxacin, whereas 2% were resistant to ceftriaxone and 0.8% were resistant to cefepime and piperacillin-tazobactam (136). Diagnostic Approach Clinical experience suggests that many uncomplicated lower UTIs encountered in the outpatient setting can be diagnosed clinically and without the use of urine cultures. Patients who present with symptoms consistent with cystitis or urethritis should undergo a history, physical exam, and urinalysis. The use of dipstick urinalysis and/or microscopic urinalysis provides a diagnostic yield that is sufficiently specific and sensitive to establish the diagnosis of uncomplicated UTI. However, urine culture continues to be important in patients with recurrent UTI or treatment failure (171). In view of increasing antimicrobial resistance in urinary pathogens, culture is necessary for performing antimicrobial susceptibility testing. Urinalysis Urinalysis continues to be the “workhorse” laboratory evaluation for establishing the diagnosis of UTI in a broad range of patients. The primary utility of a urinalysis is to examine for and document the presence of pyuria, hematuria, nitrates, leukocyte esterase, and bacteria. Semiquantitative dipstick and microscopic urinalysis are widely used (14, 71, 78, 81, 103, 161). The presence of red or white cells in the urine can help differentiate the location of the infection. Pyuria is present in almost all patients with urethritis, cystitis, and pyelonephritis. The laboratory or clinical definition of pyuria (number of white blood cells [WBC] per high-power field [HPF]) will affect its sensitivity and specificity for establishing the diagnosis

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of UTI. One group found that the presence of more than 5 WBC/HPF was 85% sensitive for UTI (157), whereas other authors have reported that more than 10 WBC/HPF was a more reliable breakpoint for making the diagnosis (14). The presence or absence of pyuria should be interpreted within the context of other findings in the urinalysis. Hematuria can be present with cystitis and pyelonephritis but is rarely seen in urethritis. Hematuria can be diagnosed semiquantitatively with a urine dipstick or quantitatively on a microscopic urinalysis. Studies looking at dipstick hematuria have found a sensitivity of 44% and a specificity of 88% (108). Microscopic analysis of the urine also can demonstrate red cell casts that are indicative of upper tract disease. Several unique esterases produced by neutrophils in the urine form the basis of one of the screening tests for UTI. Leukocyte esterase can be rapidly detected by using a urine dipstick and appears to provide a reliable method for detecting pyuria with a sensitivity of 74 to 96% and a specificity of 94 to 98% (49, 78, 80), although it may not distinguish the presence of pyuria with this degree of accuracy in the hands of nonlaboratorians (21, 172). The nitrite test on a urinalysis dipstick is a rapid screening test for bacteriuria and has been found to be 39% sensitive and 93% specific for bacteria in the urine in both prospective and retrospective studies (14, 20, 161). One investigation combined nitrate results with the presence of microscopic bacteriuria and/or pyuria (
10 WBC/HPF) and found a sensitivity and specificity of 71 to 95% and 54 to 86%, respectively (14). Other studies have found that the accuracy of this test can be affected by a low level of infection (e.g., organisms producing a small amount of nitrite) or the type of infecting microorganism (e.g., organisms that do not reduce nitrate to nitrite) (65). Urine Culture Bacteriuria is considered by most clinicians to be the definitive marker of UTI. Studies conducted in the 1950s found that 105 CFU per ml of urine were indicative of a UTI (65, 76). However, more recent studies suggest that this level of bacteriuria can miss a large group of patients with UTI and support the concept that lower levels (102 to 104 CFU/ml) should be considered positive (48, 79, 171). In one provocative study, patients provided urine samples when a diagnosis of UTI was suspected, but they were not treated for 2 days after the onset of symptoms. A repeat urine culture was obtained 2 days later, at which time empiric treatment was started. Interestingly, urine cultures cleared spontaneously in only 5% of the patients who had a low colony count initially, while 48% now had a colony count of 105 CFU/ml or more (11).

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Lower levels of bacteriuria have been shown to predict UTI in a variety of settings. Levels greater than 102 CFU/ml have shown a sensitivity of 95% and a specificity of 85% for the diagnosis of cystitis in women (158). Male patients with urine samples growing greater than 103 CFU/ml are considered positive for UTI (91). All patients with pyelonephritis have a higher level of bacteriuria, with cultures almost uniformly growing at levels greater than 104 CFU/ml. In summary, studies suggest that antibiotic therapy should be considered for any patient with symptoms of a UTI and a culture positive for a urinary tract pathogen at 103 CFU/ml or greater. For S. saprophyticus, lower colony counts, even as low as 103 CFU/ml, may be considered significant. Frequency of Testing More than one urine culture may be necessary to establish a diagnosis of UTI because factors such as timing of specimen collection, excessive fluid intake, and contaminated voided midstream urine can affect culture results. After initiation of treatment with an antimicrobial agent to which the organism is susceptible, bacteria are eliminated from urine within 48 h in nearly all patients with uncomplicated UTI (37, 118, 155, 166). Therefore, reculturing for proof of bacteriologic cure is not recommended (37, 118, 155, 166). If symptoms do not resolve or if symptoms recur, a urine culture should be obtained (155). Fever beyond 48 h is common in children hospitalized with UTI in spite of negative follow-up urine cultures (37). Follow-up cultures are recommended at 1 to 2 weeks after completion of therapy to detect relapses in pregnant women and patients at high risk for renal damage, even if they are asymptomatic (155).

SPECIMEN COLLECTION Appropriate collection of microbiology urine specimens has an important influence on the usefulness of culture results. Even the most carefully collected specimens can easily become contaminated with perineal, vaginal, and periurethral flora. Proper urine collection techniques are critical, since an unreliable collection often results in the production of inaccurate data. SPA and Straight (in and out) Catheterization Suprapubic aspiration (SPA) is considered the gold standard for obtaining bladder urine because the specimen is the least likely to be contaminated. SPA is relatively easy and safe, and it remains the method of choice for the diagnosis of UTIs in infants, especially those who appear septic and require immediate therapy (19, 53, 86, 146). SPA is not routinely per-

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formed on older children and adults. SPA is performed primarily in the inpatient setting. To perform the procedure appropriately, the bladder must be full. Skin overlying the bladder is disinfected and the bladder is punctured above the symphysis pubis by using a needle and syringe. In older children and adults, a more commonly used method for the collection of an uncontaminated specimen is straight catheterization, also referred to as “in and out” catheterization. Straight catheterization is performed when patients are unable to produce a reliable self-collected specimen, e.g., patients with altered mental status or an inability to void due to neurologic or urologic complications. It is also used when results from clean-catch midstream specimens are equivocal and a diagnosis is essential. To avoid potential contamination, meticulous attention must be paid to proper skin preparation and catheterization technique. Following insertion of the catheter into the bladder, the first few milliliters of urine are discarded and the remaining urine is collected into a sterile container. The first few milliliters of urine are discarded to eliminate the risk of false-positive cultures caused by urethral flora that could have collected on the catheter during insertion (86). Although a properly performed straight catheterization can yield a specimen free of urethral contaminants, catheterization does carry a risk of introducing bacteria into the bladder and inducing infection in up to 5% of patients (61). For this reason, it should not be used to obtain urine specimens from pregnant patients (10). Clean-Catch Midstream Specimens Collection of a clean-catch midstream specimen, often referred to as a clean-catch specimen, is the most frequently used and preferred method of urine collection because it is noninvasive and avoids the risks inherent to catheterization (88, 120). The clean-catch method is often recommended despite the fact that there is little rigorous scientific research that supports a clean-catch urine sample as the standard for urine collection. Despite the effort that goes into instruction for a clean-catch urine sample, these samples are among the most prone to contamination with perineal, vaginal, and urethral flora. Patient instruction in appropriate collection has been shown to be important in reducing potential contamination (24). In women, the appropriate collection of a cleancatch sample requires the cleansing of the periurethral area and perineum with two or three cleansing pads (usually soap and water) and a front-to-back wiping motion, followed by rinsing with water-soaked pads or gauze. While the patient holds the labial folds apart, the patient should void the first few milliliters

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of urine to flush bacteria from the urethra. Without stopping the stream, the patient should use a widemouthed sterile container to collect the midstream portion of the urine. The container should have a tight-fitting lid to prevent leakage, and the lid must be screwed on tightly to prevent leakage of urine. In men, it is usually sufficient to clean the urethral meatus with water just before collection, but cleansing pads may also be used. Care must be taken to retract the foreskin in uncircumcised males to minimize contamination. Urine is then collected in the same manner as for women. It is important to keep in mind that the optimum specimen for nucleic acid amplification assays for Chlamydia trachomatis and Neisseria gonorrhoeae is a first-void specimen that has been collected without cleansing. Thus, if clean-catch midstream specimens are required for culture, multiple specimens may need to be collected. The necessity of performing the clean-catch midstream technique has been called into question because the collection of a clean-catch midstream urine specimen is often difficult to obtain in a standardized fashion. In women, is it the cleansing, the midstream collection, or the parting of the labial folds that contributes to minimizing contamination? Numerous studies have compared the contamination rates of clean-catch specimens with midstream specimens (samples collected midstream without cleansing) and found that there was not a significant difference in the two collection methods (13, 19, 64, 85, 125). These studies concluded that there is minimal to no benefit to cleansing the perineum in women prior to collection of a midstream specimen. Some studies have indicated that the procedure that plays the most important role in decreasing contamination in women is holding the labia apart during sample collection (12, 13). In addition, studies have shown that the collection of a clean-catch midstream specimen does not minimize contamination compared to a first-void specimen in either men or women (21, 70, 88, 90, 91). These studies were performed primarily on young to middle-aged men and women in the ambulatory setting. The collection of clean-catch midstream urine samples in elderly patients is often problematic because of issues with coordination, incontinence, and poor hygiene. Catheterization is often required to obtain an adequate sample in this population (113). Some studies have suggested that reliable samples can be collected by cleaning the vulval region with water or an iodine solution prior to collection and collecting samples in a clean container placed inside the toilet or bedpan (100, 119). In elderly men, a clean “condom” catheter can be as useful as bladder catheterization (115).

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Indwelling Catheters Specimens from patients with indwelling (Foley) catheters should be collected by using sterile techniques and by collecting urine from the collection port. The collection port, usually a soft rubber diaphragm, should be disinfected prior to specimen collection with a needle and syringe. The catheter and collection tubing should not be disconnected (i.e., a closed system must be maintained) to minimize the risk of infection (36). Urine samples should never be collected from the collection bag because bag urine is usually contaminated. Instead, the collection tubing can be clamped for a brief period of time to allow urine to collect for sampling. Although relied on for diagnosis, urine obtained through an indwelling catheter might not be representative of urine in the urinary system, especially in patients with long-term indwelling catheters (168). Organisms colonizing the catheter usually are associated with a biofilm and do not always colonize the bladder. Thus, it is more useful to collect samples following the placement of a new catheter rather than from an old one (52). Bagged and Diaper Specimens from Pediatric Patients Midstream urine samples from toilet-trained children and older adolescents are often as reliable as specimens collected from adults. As with adults, there remains a question as to whether cleansing prior to collection is necessary (42, 146). However, in infants, collection of midstream specimens, while technically possible, is rarely performed. Adhesive (“tinkle”) bags are frequently used for specimen collection in infants, especially in the outpatient primary care setting, because these bags are noninvasive. Obtaining interpretable results from bag urine is frequently difficult. Bagged urine specimens often yield unacceptably high false-positive results and poor specificity (8, 144, 152). Contamination is most frequent in females and uncircumcised males (143). One study showed the use of bagged specimens for culture can result in more adverse clinical outcomes, delays in diagnosis and treatment, unnecessary treatment, and hospitalization and concluded that the risks of culturing bagged specimens outweighed the benefits (5). Most studies agree that negative cultures obtained from bagged urine effectively rule out a UTI but that positive cultures, even those containing a single pathogen, should be confirmed by collection of urine by straight catheterization or SPA (8, 42, 53, 146). Several studies have also advocated the use of urine from diapers or urine collection pads for culture and found a good correlation with samples

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collected by catheterization or SPA (35, 149). However, most studies have determined that urine collection pads, while comfortable and easy to use, produce specimens with unacceptably high contamination rates similar to those of bagged specimens (3, 87, 96, 126). Despite the frequent contamination of bagged and diaper specimens, their use is likely to continue because collection is noninvasive and requires limited time and expertise. Contamination can be minimized with bag specimens by properly cleansing and rinsing the perineum prior to applying the bag and removing the bag promptly following collection (8). Ileal Conduits Ileal conduits are created when urine flow from the kidneys is diverted through a segment of small bowel (ileum) to an opening or stoma in the abdominal wall. Urine is captured in an external appliance, usually a collection bag. Collection of urine from ileal conduits is performed by trained health care professionals. The external bag is removed, and the urine is discarded. The stoma is appropriately disinfected, and urine is obtained following insertion of a doublelumen catheter through the stoma into the conduit. Culture of urine from the collection bag should not be performed because the urine is usually contaminated. Although the ileum is not heavily colonized with bacteria, issues with colonization of the conduit and the stoma make the results of urine cultures collected from this site difficult to interpret. Other Methods of Specimen Collection Urine specimens occasionally need to be collected from specific areas of the urinary tract by invasive methods. Samples collected via percutaneous nephrostomy, a thin catheter which passes through the skin of the back into the kidney parenchyma and renal collecting system, represent urine from high in the urinary tract (e.g., kidney). Specimens collected during cystoscopy following passage of a fiberoptic cystoscope through the urethra into the bladder are representative of urine in the lower urinary system (urethra, bladder, and occasionally, the ureter). These procedures are performed by surgeons, interventional radiologists, or urologists. Cultures of these samples can be used to determine the site of infection in the urinary tract (50). Multiple samples can be submitted in an effort to localize the site of infection. This is particularly true in the diagnosis of prostatitis. The gold standard segmented culture technique, which requires the collection of multiple urine specimens and prostatic secretions, is rarely used today because it is labor-intensive and costly. A more commonly used technique involves the collection of urine directly before and after pro-

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static massage (40). Multiple specimens can also be collected to distinguish between upper and lower tract infections when using Fairley’s bladder washout technique in which a urine sample is collected following insertion of an indwelling catheter. Subsequently, sterile saline and antibiotic are instilled into the bladder. After the bladder is emptied and washed, urine is collected at 10-min timed intervals. Although this technique is reliable, it is cumbersome, expensive, and invasive.

SPECIMEN TRANSPORT Urine specimens should be collected appropriately as outlined above, and the correct label indicating the usual patient information should be affixed to the container. The label should include the method for collection of the urine, i.e., whether the urine is a clean-catch, catheter-collected, SPA, or other specimen. Because laboratories can have guidelines for processing urine specimens differently when the specimens come from various types of patients, patient locations, or clinical services, such critical information should be included on the container label. The exact time of collection, prior or current antibiotic treatment, and excess fluids that the patient is receiving are also important pieces of information for the laboratory to obtain for each patient sample. Urine should be processed as near to the time of collection as possible to minimize chances for increase in the actual colony count of any pathogens and contaminants present. If the urine will not be processed at the point of collection, transport should be immediate. If it is not possible to transport the urine to the lab within 2 h, the urine should be refrigerated or preserved during transport; if delays exceed 24 h, a transport device with preservative (usually boric acid) should be used (44, 51). Preservative vials or tubes have been demonstrated to preserve the colony count in urine for 24 to 48 h. The volume of urine placed into the preservative tube or container should be
3 ml to ensure growth of most pathogens. Use of lesser amounts of urine can result in organism inhibition by the boric acid and reduce the optimal growth of some bacteria, in particular Enterococcus spp. (111). There are also several culture media onto which a urine sample can be immediately cultured at the point of collection to reduce issues with transport delays.

SPECIMEN HANDLING IN THE LABORATORY After the urine specimens are received in the laboratory, they should be processed immediately or refrigerated. Since the colony count of the urine in culture

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is a significant part of the interpretation of whether a pathogen is truly present, efforts should be made to preserve the urine as close as possible to what it was like when it was collected. If specimens arrive and there is no information included as to the time of collection, the ordering site should be contacted to determine the appropriateness of further processing. If inappropriately collected or transported urine arrives in the laboratory, it should never be discarded before the physician is contacted and a determination of whether another sample can be collected and submitted is made.

SPECIMEN WORKUP Communication between the Clinician and the Laboratory Continual communication between the clinical microbiology laboratory and health care providers has been and will continue to be the primary means for ensuring that specimens are appropriately collected. Because voided urine specimens are easily contaminated with periurethral and perineal flora, it is the responsibility of the microbiologist to educate health care providers on methods of proper specimen collection, preservation, labeling, and transport. Such education ensures that resulting cultures will yield the most meaningful and clinically relevant results. Health care providers should particularly be made aware that the method of collection plays a significant role in selection of media and quantitative inoculum as well as the workup and reporting of results. Health care providers should inform the laboratory with requests to culture for unusual pathogens or organisms that can require longer incubation times. Microbiologists should also be available for consultations from health care providers regarding the interpretation of culture and antimicrobial susceptibility results. Approach to Laboratory Workup Although UTIs are caused by many species of microorganisms, the majority of infections are caused by relatively few species. Many of these organisms can be found as part of the commensal urethral and fecal flora. Factors such as host age, underlying conditions (e.g., diabetes and structural abnormalities), and instrumentation have an impact on the etiology of UTIs. The amount of polymicrobial bacteriuria is not well established. One older study has shown that if the urine is collected appropriately, less than 5% of urine samples should contain mixed organism types (18). Another study examined the incidence and significance of mixed cultures and concluded that, in most cases, the mixed finding was significant and not

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necessarily due to improper collection or inappropriate processing (150). The number of mixed-culture urine specimens that will occur in a laboratory depends on several factors, the most important of which are how appropriately the specimen was collected, the type of specimen, the time from collection to processing, and the means of transport during that time. If the specimen is collected from an indwelling catheter or from a patient with conditions that might increase the chance for contamination, mixed cultures can be expected to be as high as 30 to 80% of all urine cultures (67, 170). Common Urinary Pathogens Gram-negative bacilli account for the majority of UTIs, specifically E. coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Among the gram-positive cocci, Enterococcus spp., S. saprophyticus, and GBS are the major etiologic agents. Although the etiologies of community and hospitalacquired UTI are different, E. coli remains the single most common etiologic agent of UTI regardless of age. E. coli is responsible for up to 90% of cases of uncomplicated UTI in college-aged women (58), 70% of community-onset cases of uncomplicated UTI, and as much as 66% of cases of cUTI or acute pyelonephritis (83, 122). K. pneumoniae is often second in incidence to E. coli in community-onset cases and has been reported to have increased clinical importance in the renal transplant population, in which isolates are often multidrug resistant (4). P. mirabilis and Morganella spp. are often associated with older patients and patients with renal calculi or stones. P. aeruginosa is more commonly found in nosocomial UTI than in community-onset cases. S. saprophyticus is the most common species of coagulase-negative staphylococci to cause UTI. S. saprophyticus causes UTI in adolescents and young adult women who experience their first UTI and has been found in up to 11% of UTIs in college-aged women (82). However, it is a rare cause of UTI in elderly females (129). Enterococcus spp. have been reported in as many as 10% of all UTI (46) and up to 16% in the subset of nosocomial UTI (140). Enterococci can be more often associated with patients with underlying structural abnormalities or in patients who had prior urologic manipulations (102). S. aureus is much rarer as a causative agent of UTI and often represents infection in association with S. aureus bacteremia or in catheterized patients (106). Isolation of GBS from urine can be used to determine vaginal carriage in the pregnant female instead of isolation of GBS from vaginal-rectal swab specimens. In such cases, the laboratory must be informed by the health care provider that the patient is pregnant. GBS can cause UTI in pregnant females and in the nonpregnant population,

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especially diabetics, where GBS infection is two to three times more common than in nondiabetic patients (45, 129). Rare or Unusual Urinary Tract Pathogens Special culture conditions are sometimes indicated for patients with specific diagnoses, suspected fastidious organisms, or particular patient groups. Corynebacterium urealyticum

Corynebacterium urealyticum (at one time referred to as Corynebacterium D-2) is an uncommon cause of UTIs. The organism can be a catalyst for struvite stone formation because of its strong urease activity and has been found associated with alkalineencrusted cystitis and pyelitis in children and adults with urinary tract symptoms and the formation of calculi (99). In one study, the main risk factors for these conditions were underlying urinary tract disease, antibiotic treatment, prolonged hospitalization, and urological manipulation (110). Renal transplant patients seem to be at particular risk for severe disease with C. urealyticum (2). In these patients, it is highly related to obstructive uropathy (94). C. urealyticum should be looked for either when specifically requested by the ordering physician or in specific high-risk populations, such as the renal transplant patient in which routine cultures are negative or in which the presence of kidney stones is listed on the requesting order. C. urealyticum will grow on blood agar plates (BAP) but not MacConkey agar (MAC). There is a selective medium that contains heart infusion, cysteine, urea, Tween 80, glucose, polymyxin, aztreonam, fosfomycin, amphotericin B, and a phenol red indicator that can be used for isolation of C. urealyticum (94). When this medium was used in a study of 163 renal transplant patients, urine from 16 patients yielded C. urealyticum. Twenty-two patients (13.5%) were found to have skin colonization with the organism (94). A prevalence study in 1994 suggested that because the organism is such an unusual cause of UTI, routine cultures are unnecessary; the organism should be sought only if the following are noted: crystals, alkaline urine, and red blood cells and/or leukocytes in the urine (110). Linezolid and quinupristin-dalfopristin have been found to be universally effective in treating UTI caused by C. urealyticum (138). Aerococcus spp.

Members of the Aerococcus genus have emerged as potentially significant pathogens in UTIs. The colonies can bear a very close resemblance to Enterococcus spp. and are not easily recognized when isolated from urine cultures. Aerococcus spp. are catalase-negative, gram-positive cocci in tetrads and clusters, rather than the usual pairs and chains of Enterococcus spp.

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Aerococcus urinae is alpha-hemolytic, pyrrolidonyl aminopeptidase (PYR) negative, and leucine aminopeptidase (LAP) positive. Aerococcus viridans, much less commonly associated with UTIs, is PYR positive and LAP negative. A rarely isolated species, Aerococcus sanguinicola, has been associated with UTIs. It is usually PYR positive and LAP positive, although there may be some cross-reaction with other species of Aerococcus. Gram staining of alpha-hemolytic, catalase-negative cocci should be performed, and if the smear resembles staphylococci instead of streptococci or enterococci, identification as Aerococcus spp. should be considered. Colonies that are alphahemolytic, catalase negative, PYR negative, and LAP positive can be presumptively identified as A. urinae. In one study, most patients found to be infected with A. urinae were elderly males with predisposing conditions and who presented with UTI (178). In another study of 54 patients in which A. urinae was isolated in urine cultures, only 31% of patients with UTI and 45% of colonized patients had A. urinae isolated in pure cultures. Both groups had significant but similar underlying medical conditions, with urologic conditions being predominant. In this study, more patients were elderly females and significantly more patients in the UTI group had urinary catheters (151). Lack of standardized methods and interpretive criteria for this group of organisms makes it difficult to assess susceptibility patterns. Aerococcus spp. are generally susceptible to penicillin, but resistance to sulfonamides is common in A. urinae. Gardnerella vaginalis

There are few published reports describing UTIs with Gardnerella vaginalis. Two reports written more than 14 years ago describe the finding of this organism in urine cultures from men. In one study, G. vaginalis was isolated from 0.1% of male urine samples, and 10 of 15 (67%) patients were symptomatic or were also found to have significant neutrophils in the urine (153). In a study from Spain in 1994, G. vaginalis was isolated in pure or mixed culture from 76 specimens of 1,365 (5.6%) urine specimens examined (9). In 12 of these 76 urine specimens, G. vaginalis was isolated in pure culture, 8 in females and 4 in males. Six patients had symptoms of a UTI; two patients were pregnant. Pyuria was only detected in 2 of 12 patients. The authors concluded that isolation of G. vaginalis from urine does not always imply a UTI. Certainly in the female patient, where G. vaginalis is part of the normal vaginal flora, its isolation from urine could suggest contamination with vaginal flora. If a laboratory isolates G. vaginalis from a urine culture without the presence of symptoms and/or the presence of pyuria or in mixed cultures, care should be taken before reporting this as a probable patho-

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gen. If isolated in pure culture, consultation with the clinician is suggested before reporting it as a potential cause of the UTI. Routinely extending culture incubation time specifically to recover G. vaginalis is discouraged.

ile pyuria. Sterile pyuria is also frequent in catheterized patients. Sterile pyuria can also be associated with systemic or localized diseases and can be a result of a variety of infectious and noninfectious causes (39). In cases of sterile pyuria, Gram staining is important. If organisms are seen on Gram stain but not recovered in culture and if clinical symptoms persist, it is appropriate to culture for anaerobes and more slowly growing organisms, particularly if the patient has a chronic UTI or anatomic abnormality. The incidence of anaerobic UTI without the presence of these specific risk factors is very low. UTIs caused by anaerobes have also been reported in children (22). Anaerobes have been involved in cases of periurethral cellulitis or abscess, acute and chronic prostatitis, prostatic or scrotal abscesses, and retroperitoneal or perinephric abscesses. The organisms most commonly seen in anaerobic UTIs are similar to those colonizing the distal urethra. Bacteroides and Fusobacterium spp. are encountered more frequently. Other potential anaerobic pathogens include Peptostreptococcus, Clostridium, Eubacterium, and Lactobacillus. If anaerobic infection is suspected, a suprapubic bladder aspirate should be submitted rather than clean-catch or catheterized urine. Culturing of specimens obtained by other collection methods should only be performed after consultation with the ordering physician or when bacteria suggestive of anaerobes are seen in direct Gram stain but fail to grow in aerobic culture (23). Sterile pyuria can also be associated with Chlamydia trachomatis, Ureaplasma urealyticum, Mycobacterium tuberculosis, systemic fungal infections, or Leptospira. The genitourinary tract is the most common site of extrapulmonary M. tuberculosis. Concomitant pulmonary findings are present in only about 66% of newly diagnosed cases of genitourinary tuberculosis (6). In genitourinary tuberculosis, urine mycobacteriology cultures grow M. tuberculosis in about 90% of cases. Early diagnosis and treatment are sometimes difficult because these infections are often clinically silent; however, early diagnosis is very important to prevent irreversible renal destruction (6). PCR that detects insertion sequence IS6110 has been shown to provide rapid detection of M. tuberculosis in urine (105). Because routine urine cultures will be negative for M. tuberculosis, the laboratory must rely on the health care provider to request mycobacterial culture. In cases of suspected renal tuberculosis, three consecutive first-morning urine samples should be submitted for mycobacterial culture (101). UTIs caused by atypical mycobacteria are rare. Mycobacterium kansasii has been recovered in urine from patients with prostatic, epididymal, and disseminated infection (62, 92).

Haemophilus influenzae

Rarely is Haemophilus influenzae isolated from a urine culture, and its true incidence is unknown because urine specimens are not routinely cultured on chocolate agar or other media that would support its growth. However, if it is isolated, perhaps in conjunction with an organism like staphylococcus that supplies the NAD it needs for growth on blood agar, the significance of the isolation could be discussed with the ordering physician. A recent article looked at UTI caused by H. influenzae and Haemophilus parainfluenzae in children (60). Over 24 years, 36 cases of Haemophilus spp. bacteriuria were found in
5,000 episodes of UTI in pediatric patients. All but one child had a prior urinary tract abnormality, including malformation, gross reflux, or bladder dysfunction. H. influenzae was isolated more often from girls and H. parainfluenzae from boys. With recent overall decreasing incidence of systemic Haemophilus influenzae infections, one would expect that the incidence is very rare. It is recommended that, with the exception of specific requests for Haemophilus isolation from urine, chocolate agar should not be added to routine urine cultures. GBS

Laboratories which serve hospitals or physicians’ offices that include obstetrical practices should provide cultures of vaginal-rectal specimens to detect the presence of GBS during the third trimester of all pregnant females. In addition, urine can be used for recovery of GBS in the pregnant female. The CDC currently recommends reporting the presence of any amount of GBS in the urine of pregnant females (29). This recommendation is based on studies that used standard laboratory criteria to define bacteriuria rather than the presence of any amount of GBS in urine. Previous studies have shown increased risk only in those women having symptomatic UTIs (17). The laboratory should work closely with pediatrics and obstetrics to determine the best process for implementing urine culture reporting. It is imperative that urine specimens from pregnant females be labeled as being from a pregnant patient to facilitate laboratory reporting of GBS in these women. Sterile Pyuria

The finding of WBC (5 to 8 WBC per HPF) in a urinalysis in the absence of bacteria in concurrent routine urine culture is referred to as “sterile pyuria.” Almost any injury to the urinary tract can cause ster-

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C. trachomatis urethritis should be considered if the patient is sexually active with multiple partners. Ureaplasma urealyticum and Mycoplasma hominis have been implicated as causes of chronic pyelonephritis, although this association remains controversial and culture for these organisms is not generally justified. Urethritis due to Mycoplasma genitalium or Mycoplasma fermentans has been described in HIVinfected individuals (38). Leptospirosis has a broad spectrum of clinical manifestations and should be considered in patients with possible occupational or recreational exposure or after flooding (175). Leptospira appears in urine after the first week of illness. Prompt recognition and appropriate antibiotic treatment can dramatically reduce patient morbidity and mortality even with severe multiple-organ damage. Culture for leptospires is performed in reference laboratories and requires neutralizing the pH of urine to ensure survival of leptospires during transport of the specimen. Culture is done on Fletcher’s, Stuart’s, or EllinghausenMcCullough-Johnson-Harris semisolid media for up to 13 weeks of incubation. Molecular methods and serologic tests are preferred for diagnosis and offer more rapid diagnosis. These tests are performed by a few reference laboratories. Noninfectious conditions of the urogenital tract that can produce sterile pyuria include vesicoureteral reflux, interstitial cystitis, polycystic kidney disease, staghorn calculi and stones of smaller size, anatomic abnormalities, or contiguous infection or tumor resting on the ureter or bladder. In addition, the finding of pyuria does not necessarily indicate infection and does not add significantly to the diagnostic evaluation in patients with indwelling urinary catheters (162). Yeast

Detection of yeast, virtually always Candida spp., in urine is uncommon in healthy individuals but is an increasingly important problem in hospitalized patients, particularly in intensive care units and LTC institutions (7, 26, 77). Candida albicans is the yeast most frequently isolated from urine (77). The primary risk factors for candiduria include diabetes mellitus, neoplasms, urinary catheterization, periodic use of broad-spectrum antibiotics or steroids, surgical procedures within the preceding month, female sex, increased age, and hospitalization longer than 7 days (7, 26, 77). Diabetes and previous treatment with antifungals are independent risk factors for isolation of Candida species other than C. albicans (7, 77). Most patients with candiduria are asymptomatic, and candiduria most likely indicates only colonization of the urinary bladder, perineum, or indwelling urinary catheter by endogenous Candida species inhabiting the genital and perineal areas (77). Pyelonephritis or

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nephritis caused by Candida spp. is thought to be a result of retrograde migration of endogenous organisms (26, 43). Hematogenous seeding of the kidney cortex can also occur in the course of disseminated candidiasis (77). The main difficulty in interpreting the significance of Candida in the urine is the inability to distinguish infection from colonization (77). Studies have not been able to establish clear quantitative criteria for urine cultures in UTI due to Candida. The detection of concurrent pyuria can be helpful but only for patients without long-term indwelling urinary catheters. For patients with indwelling urinary catheters, renal infection has been documented with as few as 104 CFU/ml, and colonization has been associated with 104 to 105 or more CFU/ml (77). Therefore, any concentration of Candida in the urine could indicate renal involvement. The presence of candiduria as an isolated observation probably does not have much clinical significance and generally does not indicate risk of subsequent invasive disease. Candiduria may be more significant in diabetics and patients with obstruction, since unusual complications occur more often in these patients. In neonates, candiduria is significant and usually indicates hematogenous spread to the kidneys. It is not necessary to inoculate fungal culture media when yeast cultures are requested. However, to recover yeast, it is important to inoculate at least 0.01 ml of urine per plate and hold the cultures for 48 to 72 h to detect yeast that grows more slowly or is present in low numbers. Since clinical significance is not associated with quantity, clear guidelines for workup of yeast in urine cultures are not established. Antifungal treatment is recommended for infants with very low birth weight, patients undergoing invasive genitourinary procedures, neutropenic patients, renal transplant recipients, and symptomatic patients, and workup may be warranted in these instances (95). Because clinical information is not routinely available to the laboratory, identification of C. albicans and Candida glabrata is recommended when present in quantities considered significant for bacteria, with others identified on request (124). Guidelines for Specimen Inoculation, Incubation, Workup, and Interpretation of Results A uniform or standard method of urine processing for all laboratories does not exist. The amount of urine cultured, the type of media utilized, and the length of incubation will vary with the type of laboratory and the patient population the laboratory services (outpatients versus inpatients, nursing home patients, or the mix of patients that has special needs [e.g., infants, transplant patients, patients with spinal

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cord injuries, etc.]). In many situations, there will be a need for guidelines that specifically address the variety of patient types. Every laboratory should develop its own guidelines for the processing of urine samples for culture. Table 1 shows a simple, useful, and adaptable urine processing and culture interpretation scheme based on method of collection. Specimens that are easiest to collect, such as clean-catch, indwelling catheter, and pediatric bag samples, are more likely to contain colonizing organisms. More invasively collected specimens, such as straight catheter, SPA, cystoscopy, and nephrostomy samples, are less likely to contain contaminating organisms.

Selection of Media It is generally accepted that urine cultures should be processed on blood agar and a gram-negative selective medium (MAC or eosin-methylene blue [EMB] agar). Some laboratories also choose to add colistinnalidixic acid agar (CNA) or phenylethyl alcohol agar to facilitate detection of gram-positive organisms when overgrowth of gram-negative organisms is anticipated. A variety of chromogenic media are available for the identification and differentiation of urine pathogens. These chromogenic media can be used for all urine specimens or those that might be considered to be at a higher risk for contamination. There are three chromogenic media: BBL CHROMagar Orientation

Table 1. Scheme for processing and workup of urine cultures based on method of collection Type of collection

Noninvasive: cleancatch voided, indwelling (Foley) catheter, pediatric bag

Processing inoculum and plating media

Minimum length of incubation (h)

0.001 ml onto BAP and MAC (or other suitable gram-negative selective medium); CNA or phenylethyl alcohol agar optional

16

No. of isolates 1

2

10,000
10,000 Both 10,000 Both
10,000 1 isolate 10,000 1 isolate
10,000


3

1 isolate ≥100,000

2 isolates 10,000 Any other amt

Invasiveb: straight catheter, SPA, cystoscopy, nephrostomy

0.01 ml onto BAP and MAC (or other suitable gram-negative selective medium)

48

MMIa ID and AST (if appropriate) MMI (both isolates) ID and AST (if appropriate) (both isolates) MMI (10,000 CFU/ml) ID and AST (if appropriate) (≥10,000 CFU/ml) ID and AST (if appropriate) (
100,000 CFU/ml) MMI (10,000 CFU/ml) MMI (all isolates): report with message indicating presence of multiple bacterial morphotypes and suggestion for re-collection

1

1,000
1,000

MMI ID and AST (if appropriate)

2

Both isolates 1,000 Both isolates
1,000

MMI (both isolates) ID and AST (if appropriate) (both isolates) MMI (1,000 CFU/ml) ID and AST (if appropriate) (
1,000 CFU/ml)

1 isolate 1,000 1 isolate
1,000


3

1 isolate
10,000 2 isolates 1,000 Any other amt

a

Extent of workupa

Colony count (CFU/ml)

ID and AST (if appropriate) (
10,000 CFU/ml) MMI (1,000 CFU/ml) MMI

Minimal morphologic identification (MMI) indicates morphologic identification of organisms based on colony/Gram stain morphology, hemolysis, and rapid same-day biochemical or serological tests. ID, definitive identification; AST, antimicrobial susceptibility testing. b This includes urine specifically cultured for yeast or organisms such as Corynebacterium urealyticum that may require extended incubation.

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(BD Diagnostics), CPS ID 3 (bioMérieux), and Spectra UTI chromogenic medium (Remel). Specific organisms will produce colored colonies depending upon the enzymes they produce and substrates incorporated into the medium. The major advantage of these media is the ability to quickly detect mixed cultures and to reduce the number of identifications that need to be performed. Several studies have reported favorable results with use of chromogenic media as a complement to the other urine culture media (30, 31, 41, 139). Specimen Inoculation and Incubation As indicated in Table 1, culture of noninvasive specimens should include quantitative cultures of the urine that would allow the detection of 104 to 105 CFU/ml. This detection is usually accomplished by inoculation of 0.001 ml of the urine onto appropriate media. The urine should be spread across the solid media using a back and forth streaking method. For more invasively collected specimens or when detection of a low colony count is requested, 0.01 ml of the urine along with the routine 0.001 ml sample should be cultured onto appropriate media. Requests for detection of low colony counts can be ordered specifically or can be automatically performed on certain urine types in which
102 CFU/ml is considered significant for certain pathogens (e.g., urine specimens collected from transplant patients, urology patients, or women in their reproductive years). Plates should be incubated at 35 to 37°C overnight (minimum of 16 h) before being examined (27, 74, 171). Examination of plates that have been incubated for less than 16 h is not recommended; colonies are often very small and it is difficult to differentiate organisms in mixed cultures (27). There is literature to support the practice of some laboratories that incubate plates for 1 day (24 h) before discarding them as negative (74, 107). There are some laboratories that routinely hold urine specimens for up to 48 h, in particular, cultures from invasively collected specimens and if asked to isolate pathogens such as C. urealyticum, Haemophilus spp., or other more fastidious bacteria or yeasts (84, 135). All culture methods should routinely be able to detect the common urinary pathogens, such as the Enterobacteriaceae, staphylococci, streptococci, Enterococcus spp., and GBS. Reimbursement and Coding Issues The CPT codes used for billing standard bacterial urine cultures include the following: 87086: Culture, bacterial; quantitative colony count, urine 87088: Culture, bacterial; with isolation and presumptive identification of isolates, urine

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87077: Aerobic isolate, additional methods required for definitive identification, each isolate 87184: Susceptibility studies, antimicrobial agent; disk method, per plate (12 or fewer agents) 87186: Susceptibility studies, antimicrobial agent; microdilution or agar dilution (minimum inhibitory concentration or breakpoint), each multiantimicrobial, per plate The Center for Medicare and Medicaid Services (CMS) has developed National Coverage Determinations (NCD) for some common laboratory tests, including urine cultures. The NCD for urine cultures became effective on 25 November 2002 and lists the indications and limitations of coverage (28). The following guidelines may be used for billing for bacterial urine cultures: • Use CPT 87086 for a quantitative urine culture. This code may be used only one time per encounter. If a culture shows no growth, this is the only code billed. • For each distinct isolate that is presumptively identified, add CPT 87088. CPT 87088 was revised in 2007 to permit its use multiple times, since UTIs may be polymicrobial. There are no colony count restrictions associated with the use of CPT 87088, since significant counts may vary depending upon the syndrome or clinical circumstance. This code is most frequently used when multiple organism morphotypes are isolated and definitive identification is not performed. • For each distinct aerobic isolate that is definitively identified, add CPT 87077. This code may be used multiple times, since UTIs may be polymicrobial. Note that only the most definitive procedure used should be coded and billed. Therefore, if a presumptive identification is reported for a potential pathogen but it is followed up by definitive identification, only the definitive method should be coded and billed. • If identification requires immunologic agglutination (for Streptococcus, Staphylococcus aureus etc.), CPT 87147 (immunologic method, other than immunofluorescence [e.g., agglutination grouping], per antiserum) may be used in place of CPT 87077. If other methods are used, the corresponding codes should be reported. • For anaerobic cultures of suprapubic urine, use CPT 87075 (any source, except blood, anaerobic with isolation and presumptive identification of isolates) or CPT 87076 (anaerobic isolate, additional methods required for definitive isolation, each isolate). • Use CPT 87184 and/or CPT 87186, as appropriate, for susceptibility testing of each isolate.

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Laboratory Diagnosis of Urinary Tract Infections

For bacteriologic culture systems, use the following CPT codes:

several factors, including the previous experience of the practitioner and the patient, practice guidelines, drug marketing, and data on antibiotic susceptibility patterns of uropathogens in the geographic area. The data on cumulative antibiotic susceptibility patterns are generally reported by organism and not by specimen type; therefore, the data can be biased and incorrectly estimate the rates of resistance for uropathogens in the community (93). Even if data are stratified by specimen type, bias may exist relating to referral patterns (e.g., culture of treatment failures only) and clinical condition (e.g., complicated versus uncomplicated UTI). Optimal empiric therapy should be based on data that distinguish complicated from uncomplicated UTI and resistance percentages of unselected uropathogens (116). Antibiotic susceptibility testing should be performed on isolates from symptomatic patients with bacteriuria and colony counts that are clinically significant for a particular condition (11, 79, 158). The laboratory should be willing to accommodate special requests such as workup of low-count bacteriuria in patients who may have urethral syndrome, etc. Each laboratory should decide which antibiotics to test and report after consultation with the infectious disease practitioners and pharmacy staff. Routine susceptibility testing for most antibiotics is standardized, and interpretation of results is based on anticipated responses to bloodstream infections. However, there is poor correlation between the disappearance of bacteria in the urine and levels of antibiotics in blood (156). However, there is good correlation between the disappearance of bacteria from the urine and the level of antibiotic achieved in the urine (156). Many antibiotics are concentrated in the renal tubules and achieve high urine levels that are inhibitory for susceptible microorganisms. The clinical significance of resistance is not completely known because susceptibility testing does not usually reflect urinary concentrations of antibiotic. In one recent outcomes study, clinical results correlated with organism susceptibility in that patients with UTI due to a susceptible organism had a better clinical outcome than those with a resistant organism (97). In another study, symptoms resolved without further treatment in 11 of 18 patients with resistant organisms (54). The practice of performing direct antimicrobial susceptibility testing of urine specimens has the advantage of next-day reporting of antimicrobial susceptibilities and has been evaluated over many years. However, the performance of direct susceptibility testing from urine specimens is not recommended because it is not as accurate compared to standard methods (124, 154). By special request, direct susceptibility testing can be performed if the direct Gram stain suggests that the infection is monomicrobial. If

87081: Culture, presumptive, pathogenic organisms, screening only 87084: with colony estimation from density chart NCD does not specify limitations on frequency of testing for urine cultures. Modifier -59 or -91 should be used to indicate multiple urine cultures for the same beneficiary on the same date of service if they are obtained by a different procedure. Testing for asymptomatic bacteriuria is generally not indicated and is considered screening in the absence of clinical or laboratory evidence of infection (165). Although it is medically appropriate to screen pregnant women for asymptomatic bacteriuria using urine culture at 12 to 16 weeks of gestation, it is also considered screening and, therefore, not covered by CMS.

REPORTING RESULTS Regardless of the algorithm used to guide interpretation, laboratories should report cultures with interpretations and clinical comments to help the provider assess the clinical relevance of results. Negative culture results should not be reported merely as “negative” or “no growth.” Instead, they should be reported as “sterile or 100 CFU/ml” or “no growth of 100 CFU/ml” if 0.01 ml was cultured or “sterile or 1,000 CFU/ml” or “no growth of 1,000 CFU/ml” if 0.001 ml was cultured. Positive cultures should be reported with the colony count and either minimal morphologic or definitive identification of each potential pathogen isolated. Guidelines for rapid identification of many common urinary tract pathogens are available to facilitate rapid reporting (34, 124). Cultures that yield mixed species of organisms in varying quantities should indicate the presence of mixed flora, the quantity found, and a message suggesting re-collection (124). Unusual positive cultures should be brought to the attention of the health care provider.

ANTIMICROBIAL SUSCEPTIBILITY TESTING Treatment of uncomplicated UTI is usually empiric (54, 97, 169). Although management of UTI has become more complicated because of increasing resistance to commonly used antibiotics, in general, clinicians reserve urine culture and susceptibility testing for complicated cases, treatment failures, and those patients with risk factors for resistant isolates (e.g., repeated infections, recent hospitalization, or recent antibiotics) (59, 97, 177). The choice of antibiotic to be used for empiric treatment can be influenced by

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performed, results must be interpreted by experienced microbiologists and should be reported with a disclaimer. Direct susceptibility testing must be followed by standard susceptibility testing (32, 33, 124).

RAPID URINE SCREENS Rapid urine screens are nonautomated procedures used to detect bacteria and/or leukocytes directly in urine specimens, and they include microscopic and nonmicroscopic methods (Table 2). The purpose of rapid urine screens is to provide evidence of UTI before culture results are available. Rapid testing can be used to screen urine specimens prior to culture, to provide a more rapid turnaround time for reporting negative urine specimens, and to potentially reduce the number of cultures that have to be performed. If screening tests are positive, the urine culture is performed. If negative, the urine culture is usually not performed, but the urine can be saved for a defined period of time in case the physician requests culture. In general, these rapid tests are less sensitive than culture, and the nonmicroscopic methods are best used in clinics or physicians’ offices, where there is better control over how and when samples are collected. Because of their simplicity, the nonmicroscopic tests are granted waived status under the Clinical Laboratory Improvement Amendments (www.cms.hhs.gov/ CLIA/downloads/waivetbl.pdf). Microscopic Methods Microscopy of urine from symptomatic patients can be helpful in rapidly determining the type and count of bacteria in urine and should be performed upon request. Microscopic bacteriuria is found in over Table 2.

90% of specimens from patients whose infections are associated with colony counts of at least 105 CFU/ml and is best assessed with a Gram stain of uncentrifuged urine (164). Bacteria cannot usually be detected microscopically in infections which yield lower colony counts (104 CFU/ml). The detection of bacteria by urinary microscopy is thus very specific for infection but not sensitive (the absence of microscopically detectable bacteria does not exclude the diagnosis). The urine for the Gram stain is prepared by placing 0.01 ml of well-mixed, uncentrifuged urine on a clean glass slide and allowing the specimen to air dry. Following staining, bacteria are enumerated per oil immersion field with each bacterium corresponding to a count of 105CFU/ml of urine. Although the Gram stain is not a primary stain to show cellular morphology, the presence and relative quantity of cells should also be reported. The presence of WBC indicates pyuria. The presence of many squamous epithelial cells and multiple bacterial morphotypes suggests contamination. Enzyme Methods Dipstick Urinalysis The nitrate reduction test is based on the reduction of nitrate in the urine (from diet) to nitrite by the action of gram-negative bacteria in the urine. The test is most accurate on a first-morning urine specimen or on a sample that has been collected 4 h or more after the last voiding to allow organisms in the bladder time to metabolize the nitrate. The test is reasonably effective in identifying infection due to members of the family Enterobacteriaceae but fails to identify infection due to gram-positive organisms, Pseudomonas spp., or yeast (171).

Microscopic and nonmicroscopic rapid urine screens

Screening system (manufacturer)

Configuration

Comment(s)

Gram stain

Microscopic method based on staining reaction of microorganisms; cells are also observed

Each bacterium seen corresponds to a count of 105 CFU/ml; the presence of many squamous epithelial cells and multiple bacterial morphotypes suggests contamination

Chemstrip urine test strips (Roche Diagnostics Corp., Indianapolis, IN) Multistix (Siemens Medical Solutions Diagnostics, Tarrytown, NY)

Enzyme dipstick for detection of bacteria and WBC

Measures nitrate reductase (gram-negative bacteria) and leukocyte esterase; most useful in screening symptomatic patients

Uriscreen (Savyon Diagnostics, Ashdod, Israel, distributed by J&S Medical Associates, Framingham, MA) AccuTest (Jant Pharmacal Corp., Encino, CA)

Enzyme tube test with dehydrated reagent

Measures release of catalase from bacteria, leukocytes, and erythrocytes by the addition of hydrogen peroxide to urine; primarily intended for screening asymptomatic patients

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Laboratory Diagnosis of Urinary Tract Infections

Pyuria is demonstrated in almost all acute bacterial UTI, and its absence should call the diagnosis into question. The leukocyte esterase test for pyuria will detect both lysed and intact leukocytes and is based on the presence of intracellular esterases that catalyze the hydrolysis of esters, releasing components that yield a purple color. The leukocyte esterase test is less sensitive than microscopy in identifying pyuria but is a useful alternative when microscopy is not feasible (69). In commercially available systems such as Chemstrip urine test strips (Roche Diagnostics Corp., Indianapolis, IN) and Multistix (Siemens Medical Solutions Diagnostics, Tarrytown, NY), the nitrate test and a test for leukocyte esterase (along with other chemical parameters) are present on a single reagent strip that can be read in less than 2 min. The reagent strip is dipped into the urine and read by comparing the reactions to a color chart or in an automated reagent strip reader. Dipstick tests are most useful in screening symptomatic patients. Dipstick methods are very simple to perform and an inexpensive method of screening. However, in patients who urinate frequently, dilution of the two enzymes may result in reduced detection. Ascorbic acid concentrations of 25 mg/dl or greater may cause false-negative results in specimens containing only small amounts of nitrite. Other interfering substances include elevated glucose concentrations, high specific gravity, the presence of cephalexin or cephalothin, and high concentrations of oxalic acid or tetracycline.

affect urine culture results. The use of these systems permits the direct inoculation of urine onto growth media, minimizing false-positive cultures. The advantages of these systems include ease of inoculation by unskilled personnel and minimal requirements for incubator space. The use of chromogenic agar in these systems (CPS ID 3 and DipStreak) also offers the added advantage of accurate presumptive identification of common urinary tract pathogens and differentiation of mixed cultures (139). Although most systems claim a detection limit of 103 CFU/ml, the sensitivities of these systems are highest when only one pathogen is likely and at concentrations of 105 CFU/ml (25, 124, 174). Other disadvantages include the use of broad interpretive standards by some systems rather than exact colony counts and the inability of some systems to detect potential pathogens such as group A streptococcus (47). The disadvantages of the conventional dipslides (e.g., Dip N Count, Uri-Check, and Uricult) include confluent growth at high organism concentrations, difficulty in sampling low volumes of urine, and the possibility of antimicrobial carryover resulting in false-negative results (132). The addition of a specimen sampling apparatus in some systems (onSite urine culture device and DipStreak) has alleviated some of these problems. Overall, these self-contained culture systems are simple to use and incorporate many advantages of conventional culture.

Catalase Commercially available tests such as Uriscreen (Savyon Diagnostics, Ashdod, Israel, distributed by J&S Medical Associates, Framingham, MA) and AccuTest (Jant Pharmacal Corp., Encino, CA) measure the release of catalase from bacteria, leukocytes, and erythrocytes in urine (123). Urine is added to a test tube containing reagent powder. Hydrogen peroxide is added, and the contents of the tube are mixed. The formation of foam on the surface of the liquid within 1 to 2 min indicates a positive reaction. This test is primarily intended for the screening of symptomatic patients.

Several procedures sometimes used for the diagnosis of UTIs are considered unacceptable. These include the following:

BACTERIOLOGIC CULTURE SYSTEMS

• Request a repeat specimen or obtain the information when the collection time and method of collection have not been provided.

Self-contained culture systems have been developed to aid physicians’ offices and alternate laboratory sites in the diagnosis of UTI at the point of care. These systems allow for semiquantitation, isolation, and presumptive identification of common bacterial urinary tract pathogens. The currently available systems are listed in Table 3. Delays in transport and improper storage of specimens are known to adversely

17

UNACCEPTABLE PROCEDURES

Cultures • Do not culture urine specimens delayed longer than 2 h without refrigeration or preservative. • Do not culture 24-h urine collections. • Do not culture Foley catheter tips. • Do not culture urine from the bag of a catheterized patient. • Do not culture urine from a container that has leaked.

• Consider specimens obtained with the same collection method within 24 h to be duplicate specimens. Reculturing for proof of bacteriologic cure is not recommended. If symptoms do not respond by 48 h, or if symptoms recur, new urine for culture should be obtained.

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Summary of bacteriologic culture systems for common urinary tract pathogens

Culture system (manufacturer)

Configurationa

Inoculation and incubation

Comment(s)

Bullseye urine plate (HealthLink Diagnostics, Jacksonville, FL)

Five-chambered plate containing TSA with 5% sheep blood, EMB, XLD, and citrate urinary agar surrounding a central chamber with MuellerHinton agar (for susceptibility testing)

Inoculation: disposable calibrated inoculating loops (provided) Incubation: plate, 18–24 h at 33–37°C; susceptibility testing, 16–18 h at 33–37°C

Actual colony count or estimated colony count Presumptive identification by comparing growth reactions to reference texts or identification chart provided Susceptibility testing can be performed

CPS ID 3 (bioMérieux Vitek Inc., Durham, NC)

Chromogenic culture media containing substrates for
-D-glucosidase and
-D-glucuronidase

Inoculation: 10-l loop Incubation: 18–24 h at 37°C

Estimated colony count Identifies E. coli, Proteeae, Enterococcus, and KESC group; identification of other organisms requires additional biochemical tests Presumptive identification of GBS

onSite urine culture device (Trek Diagnostic Systems, Cleveland, OH)

Transparent hinged plastic case containing CLED and MAC

Inoculation: attached plastic sampler containing 2 bent tips; the sampler is dipped into the urine specimen to take up a standard volume of urine and is then pulled out through the case, simultaneously inoculating the surfaces of the media with a streaking dilution. Incubation: 18–24 h at 37°C

Estimated colony count Presumptive identification of E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, Proteus vulgaris, S. aureus, Staphylococcus epidermidis, Enterococcus faecalis

Dip N Count (Starplex Scientific, Etobicoke, Ontario, Canada)

Dip paddle with MAC-CLED or EMB-CLED attached to a screw cap and suspended in a clear plastic vial

Inoculation: paddle is immersed in the urine specimen and returned to the plastic vial Incubation: 18–24 h at 35°C

Estimated colony count Presumptive identification of E. coli, Proteus spp., K. pneumoniae, Enterobacter spp., P. aeruginosa, E. faecalis, S. aureus

Uri-Check, Uri-Check Plus (Troy Biologicals, Troy, MI)

Dip paddle in various combinations: CLED-EMB CLED-polymyxin-EMB CLED-polymyxin-MAC Paddle is attached to a screw cap and suspended in a clear plastic vial (“Plus” versions have larger surface areas)

Inoculation: paddle is immersed in the urine specimen and returned to the plastic vial Incubation: 18–24 h at 35–37°C

Estimated colony count Presumptive identification of E. coli, Proteus spp., K. pneumoniae, Enterobacter spp., P. aeruginosa, E. faecalis, S. aureus

Uricult (Orion Diagnostica, Espoo, Finland, distributed by LifeSign LLC, Somerset, NJ)

Dip paddle in various combinations: CLED-MAC CLED-polymyxin-MAC CLED-EMB CLED-polymyxin-EMB Paddle is attached to a screw cap and suspended in a clear plastic vial

Inoculation: paddle is immersed in the urine specimen and returned to the plastic vial Incubation: 18–24 h at 35–37°C

Estimated colony count

DipStreak (NovaMed, Jerusalem, Israel)

Plastic paddle with various media attached back-toback: CLED-MAC TSA-blood-MAC Columbia CNA-MAC CLED-UriSelectb TSA-blood/UriSelectb MacConkey/UriSelectb

Inoculation: a ring with elongated prongs is attached to the end of the paddle; the ends of the prongs are dipped into the urine sample; upon reinsertion into the plastic tube, the prongs inoculate the agar surfaces Incubation: 18–24 h at 35–37°C

Estimated colony count Presumptive identification of E. coli, Proteus spp., KESC group, E. faecalis, S. aureus

a

CLED, cystine lactose electrolyte-deficient agar; TSA, tryptic soy agar; XLD, xylose lysine deoxycholate agar; KESC, Klebsiella/Enterobacter/Serratia/ Citrobacter. UriSelect is a nonselective agar with chromogenic substrates for
-glucosidase and
-glucuronidase and tryptophan for detection of tryptophanase and tryptophan deaminase activity.

b

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• Discourage submission of voided or bagged specimens from infants. A catheterized specimen should be collected. • Except for suprapubic bladder aspirates, do not culture specimens for anaerobic culture except by special request or when bacteria suggestive of anaerobes are seen in direct smear but fail to grow on culture. • It is not necessary to inoculate fungal culture media when yeast cultures are requested. However, to recover yeast, it is important to inoculate at least 0.01 ml per plate and hold the cultures for 48 to 72 h to detect yeast in low numbers or that grow more slowly. • Do not perform a urine screen without also culturing screen-positive specimens, except in acute cystitis in females. Identification Always identify organisms to the species level if they are oxidase positive and indole positive because gram-negative bacilli such as Vibrio spp. and Aeromonas spp. are considered pathogens regardless of count. Susceptibility Testing Avoid doing susceptibility testing directly from urine specimens. By special request, direct susceptibility testing can be performed if the direct Gram stain suggests that the infection is monomicrobial. Results must be interpreted by experienced microbiologists and should be reported with a disclaimer. Direct susceptibility testing must be followed by standard susceptibility testing. Reporting Results • Low-count bacteriuria with members of the family Enterobacteriaceae, even in midstream urine samples, can indicate the early phase of infection in symptomatic patients. Avoid reporting results as “mixed flora.” • Although a count of fewer than 102 CFU/ml is evidence against UTI, avoid reporting “no growth” if organisms are present. Instead, use 100 CFU/ml. REFERENCES

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Bunn. 2005. Comparison of urine contamination rates using three different methods of collection: clean catch, cotton wool pad and urine bag. Ann. Trop. Paediatr. 25:29–34. 4. Alangaden, G. 2007. Urinary tract infections in renal transplant recipients. Curr. Infect. Dis. Rep. 9:475–479. 5. Al-Orifi, F., D. McGillivray, S. Tange, and M. S. Kramer. 2000. Urine culture from bag specimens in young children: are the risks too high? J. Pediatr. 137: 221–226. 6. Altintepe, L., H. Z. Tonbul, I. Ozbey, I. Guney, A. R. Odabas, R. Cetinkaya, M. M. Piskin, and Y. Selcuk. 2005. Urinary tuberculosis: ten year’s experience. Ren. Fail. 27:657–661. 7. Alvarez-Lerma, F., J. Nolla-Salas, C. Leon, M. Palomar, R. Jorda, N. Carrasco, and F. Bobillo. 2003. Candiduria in critically ill patients admitted to intensive care medical units. Intensive Care Med. 29:1069– 1076. 8. American Academy of Pediatrics Committee on Quality Improvement Subcommittee on Urinary Tract Infection. 1999. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 103:843–852. 9. Andreu, A., M. Navarro, and F. Fernandez. 1994. Gardnerella vaginalis as urinary pathogen. Enferm. Infecc. Microbiol. Clin. 12:346–349. 10. Andriole, V. T., and T. F. Patterson. 1991. Epidemiology, natural history, and management of urinary tract infections in pregnancy. Med. Clin. N. Am. 75:359–373. 11. Arav-Boger, R., L. Leibovici, and Y. L. Danon. 1994. Urinary tract infections with low and high colony counts in young women. Spontaneous remission and single-dose vs. multiple-day treatment. Arch. Intern. Med. 154:300–304. 12. Baerheim, A., A. Digranes, and S. Hunskaar. 1992. Evaluation of urine sampling technique: bacterial contamination of samples from women students. Br. J. Gen. Pract. 42:241–243. 13. Baerheim, A., A. Digranes, S. Hunskaar, and E. Laerum. 1991. Bacteriological findings in urine specimens from women. Association with urinary tract symptoms and sampling methods. Scand. J. Urol. Nephrol. 25:125–127. 14. Bailey, B. L., Jr. 1995. Urinalysis predictive of urine culture results. J. Fam. Pract. 40:45–50.

1. Ackermann, R. J., and P. W. Monroe. 1996. Bacteremic urinary tract infection in older people. J. Am. Geriatr. Soc. 44:927–933.

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16. Barnett, B. J., and D. S. Stephens. 1997. Urinary tract infection: an overview. Am. J. Med. Sci. 314:245–249.

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