The “Simple” Urinary Tract Infection?
A few controversies - do we treat the asymptomatic bacteriuria, can we rely on urine dipsticks, which colony count on a culture plate actually signifies an infection, how long do we treat, and which antibiotic?
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by Stuart M Caplen, MD and Arno Housman, MD
Diagnosing and treating the “simple” uncomplicated urinary tract infection (UTI), also called simple cystitis, has become a complex issue. Controversies include whether to treat asymptomatic bacteriuria, the sensitivity of urine dipsticks, which colony count on a culture plate actually signifies an infection, the length of antibiotic therapy, and the choice of antibiotic given the emergence of resistant strains of bacteria. This article will look at those issues and report on the latest science on adult UTIs. Pyelonephritis, infections in children and complicated infections will not be discussed.
Incidence
UTIs are common with an estimated 40% of women reporting having had one episode in the past. It is the most common source of gram-negative bacteremia.[1]
Symptoms
Typically, a patient with a non-complicated UTI, will not have any evidence of fever, back pain or other systemic involvement. Symptoms of a UTI may include urinary frequency, dysuria, gross or microscopic hematuria, suprapubic pain, urinary urgency and urge incontinence (which may be denied by patients but is manifested by the need to wear absorbent pads.*)
Other Infections That May Mimic UTI Symptoms
Urethritis, vulvovaginitis. prostatitis, and Candida balanitis can all cause dysuria which may be misdiagnosed as a UTI. Dysuria or urinary frequency symptoms which are not improving despite therapy should be a clue for the clinician to look for an alternate etiology. History, physical exam and specific testing for other causes such as Chlamydia, gonorrhea, and occult Trichomonas in men may be needed to make the correct diagnosis.[2]
What Defines a Urinary Tract Infection?
In the past, 100,000 colony-forming units per milliliter (CFU per ml) in a urine culture was considered the gold standard for diagnosing a UTI. However, some research has suggested that lower levels of CFU per ml in certain situations actually also indicate an infection. In a young woman with symptoms of cystitis, a bacterial count of more than 100 CFU per mL may be sufficient for diagnosis.[1,3,4] In young men, a urine culture with a bacterial count of over 1,000 CFU per mL of urine may be considered positive. Some laboratories do not report counts of less than 10,000 CFU per mL of urine and as a result, low-coliform-count infections may not be diagnosed.[1]
Thus, what has been considered a negative test for UTI based on 100,000 CFU per mL, may still indicate an infection depending on the clinical setting and method used to collect the urine sample.
There is some evidence that for young non-pregnant women with a UTI, a urine culture may not need to be sent initially. The European Association of Urology guideline for uncomplicated infections in non-pregnant women is that a urine culture is recommended in patients with atypical symptoms, as well as those who fail to respond to appropriate antimicrobial therapy.[5] Patients with risk factors or symptoms of complicated UTIs, pregnant women, women with UTI symptoms and a vaginal discharge, and male patients with symptoms should all have cultures sent.[6]
Clean Catch Urine Specimens
The use of the clean-catch midstream technique to collect urine samples is considered the standard to try to prevent contamination of the sample from skin and urogenital organisms. Although intuitively it seems that the clean-catch midstream technique with cleaning of the urogenital region should be a better technique, a number of studies have found that there was no significant difference in the rate of contamination in women using a clean-catch midstream technique versus just voiding into a collection cup.[7,8,9] A systematic review found that no specific collection technique affected diagnostic accuracy in non-pregnant women, but did note the evidence was limited.[10] (It is also possible that some female patients, even with careful instruction, may not provide a true clean catch urine specimen. For this reason, when obtaining a truly non-contaminated specimen is required, a straight catheterized specimen might be considered.*)
However, there are studies that demonstrated that midstream urine collection in men is more accurate than first void urine and recommended that technique when collecting urine samples.[11,12]
Asymptomatic Bacteriuria
Asymptomatic bacteriuria (ASB) is defined as the presence of one or more species of bacteria in a urine culture at a CFU growth level considered to be an infection with the patient having no signs or symptoms of a UTI. Subtle signs of a UTI without dysuria such as urinary urgency, incontinence or urinary frequency (defined as voiding more than 5X/day) should be ruled out before diagnosing ASB.*
The presence or absence of pyuria, or white blood cells in the urine is not used in defining ASB. In women with no symptoms who have ASB, it is recommended that two specimens be obtained within two weeks, as 10% to 60% of women may not have persistent bacteriuria found on a repeat specimen. For men, a single positive urine specimen is considered adequate for ASB diagnosis.
The incidence of ASB varies with the population studied. In premenopausal women the incidence is 1%-5%, post-menopausal women 2.8%–8.6%, and women over 70 years of age 10.8%–16%. In men over 70 years of age, the incidence is 3.6%–19%. In elderly residents living in a long-term care facility the incidence is 15%-50%. Patients with a long-term indwelling bladder catheter have an ASB incidence of close to 100%.[13] Elderly female patients in long term care facilities may develop urinary incontinence which should be addressed to try to reduce ASB and UTI incidence in that population.*
A number of studies have not found any benefit of antimicrobial therapy in ASB, with the exception of pregnant women and for endoscopic urologic procedures. In pregnancy, treatment of ASB has been found to reduce the incidence of pyelonephritis, premature labor, and low birth weight. For endoscopic urologic procedures, a short course of one to two doses of antibiotics starting 30 to 60 minutes before the procedure is recommended to reduce the incidence of post-operative sepsis. In urologic surgery where the mucosal barrier will be broken, standard practice is to administer prophylactic antibiotics regardless of whether there is ASB or not.[14] The Infectious Diseases Society of America guidelines recommend against routine screening for ASB in almost all circumstances except pregnancy and pre-operatively. For all other groups, ASB has not been linked to an increase in the incidence of renal failure or pyelonephritis. Treating ASB increases the risks of adverse side effects from the use of antibiotics as well as possibly increasing antibiotic resistance. Trying to maintain a sterile, bacteria free urine for extended periods of time in patients with ASB may not prove possible in some patients.[13]
Patients with indwelling bladder catheters frequently have multiple organisms in their urine, some of which are present at lower CFU counts. Organisms present in lower CFU counts may represent contamination of the urine specimen from biofilm organisms along the device rather than true bacteriuria and for those patients 100,000 CFU/mL appears to be an appropriate level to define bacteriuria in an asymptomatic patient with an indwelling catheter.[13] Long-term indwelling urinary catheters should be avoided whenever possible by use of clean intermittent urinary catheterization to try to reduce the incidence of UTIs.*
Lower CFU counts from urine specimens collected by a one-time in and out catheterization or following insertion of a new indwelling catheter suggests bacteriuria, but the clinical significance of lower quantitative counts in asymptomatic patients without UTI symptoms is not clear.[13]
There are no specific recommendations by the Infectious Diseases Society of America to screen for ASB prior to removal of bladder catheter in an asymptomatic patient as a way of possibly reducing post-catheter removal infections.[13]
Urine Dipsticks
As urine cultures can take two days or more to produce results, urine dipsticks that can test for blood, leukocyte esterase (LE) and nitrites as signs of a UTI are used to assist in more rapid diagnosis. How accurate are they?
Neutrophils produce leukocyte esterase proteins. Nitrites are an indirect measure of nitrate-reducing bacteria, but to have good sensitivity, the urine must contain sufficient dietary nitrates which have been retained in the bladder for more than 4 hours. Nitrate-reducing bacteria include Enterobacteriaceae. However, Candida, Streptococci, and Enterococci do not reduce nitrates and will not test positive on a urine dipstick.[15]
In one study, the sensitivity** for UTI for a positive nitrite test compared to urine culture was 23.3%. LE had a UTI sensitivity of 48.5% and finding blood in the urine had a UTI sensitivity of 63.9%. When all three were combined; if nitrite and/or LE and/or blood was positive, the UTI sensitivity was 74%. False positive LE results may be seen in conditions when the urine is not a clean catch specimen and contaminated with bacteria or Trichomonas. A false negative LE test may be due to proteinuria, vitamin C in the urine, or technical error.[15]
A meta-analysis of urine dipstick trials found that testing positive for one or both nitrites and LE had a sensitivity of 68 to 88% for UTI, compared to urine culture. The specificity*** was 70% to 87%. Requiring both nitrite and LE to be positive to diagnose a UTI had a sensitivity of 17% to 72% with a specificity of 77% to 100%. The authors concluded that both tests being negative may be useful in ruling out a UTI, although it is not 100% accurate. A positive result may need to be confirmed by culture.[16]
Interestingly, one meta-analysis found that clinical examination by itself did not aid in the diagnosis of uncomplicated UTI in women, but did find the urine dipstick helpful.[17]
** (Sensitivity-The percentage of people who have a UTI and test positive.)
*** (Specificity -The percentage of people who do not have a UTI and test negative.)
Antibiotic Resistance
A 2019 Saudi Arabian study found that more than 92 percent of bacteria that cause UTIs are resistant to at least one common antibiotic, and almost 80 percent are resistant to at least two.[18]
In a U.S. study of ambulatory patients with positive urine cultures there was a 55.8% resistance to beta-lactams, 22.4% resistance to trimethoprim/sulfamethoxazole, 21.6% resistant to nitrofurantoin, and 21.6% resistance to fluoroquinolones. In addition, 8.6% of the positive cultures were extended-spectrum beta-lactamase–producing. Multidrug resistance for two or more antibiotics was 17.7% and 6.4% for three or more antibiotics.[19]
The rise of extended spectrum beta-lactamase organism UTIs, the most common being Escherichia coli and Klebsiella pneumoniae, may complicate what appears to be a simple UTI due to the multiple drug resistances of those organisms.
Antibiotic Recommendations
The 2010 Practice guidelines for the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases are being updated and have not yet been released. The European Association of Urology guidelines are from 2023. The recommendations for treating uncomplicated UTIs are similar in the two guidelines.[5,20]
In women, antibiotics recommended as first line treatment include nitrofurantoin 100 mg twice a day for 5 days, fosfomycin 3 grams once, pivmecillinam 400 mg three times a day for 3–5 days (not currently approved for use in the U.S.). Cephalosporins such as cefadroxil, 500 mg twice a day for 3 days are an alternative choice. If local resistance is less than 20%, Trimethoprim-Sulfamethoxazole, 160/800 mg twice a day for 3 days can be considered, except during the first trimester of pregnancy.
In the European Association of Urology guidelines, Trimethoprim-Sulfamethoxazole 160/800 mg twice a day for 7 days depending on local sensitivities can be a first line choice for men, with fluoroquinolones as a second choice. Cystitis in men may also involve the prostate gland which may require more prolonged treatment, and by definition is considered a complicated infection which may require urologic evaluation. [5,20]
Extended spectrum beta-lactamase organism urinary infections may require intravenous antibiotics, but depending on sensitivities, oral fosfomycin, nitrofurantoin, trimethoprim-sulfamethoxazole and fluroquinolones may be effective.[21]
The fluoroquinolones can be effective for treating UTIs, but due to adverse side effects such as tendinopathy and tendon rupture, peripheral neuropathy and aortic aneurysm,[22] should not be used routinely for uncomplicated UTIs. Fosfomycin is only one dose but may not be as effective as other short course regimens. Beta lactams such as amoxicillin-clavulanate, cefdinir, cefaclor, and cefpodoxime-proxetil can be used but may not be as effective as other first line drugs. Amoxicillin or ampicillin should not be used for UTI treatment as world-wide bacterial resistance is high.[5,20]
Conclusion
Treating the “simple” uncomplicated UTI is actually a complex issue. A clinician needs to take into account varying definitions of what a positive urine culture is depending upon the clinical scenario, decide if a patient has asymptomatic bacteriuria that does not require treatment, understand the advantages and limitations of a urine dipstick, know the antibiotic sensitivities in one’s community to try to prescribe the best antibiotic in an era of increasing bacterial resistance, and be on the lookout for UTI mimics such as vaginitis, or contaminated urine samples.
While clean-catch midstream urine sample collection is still used as the standard, in a number of studies it has not been found to be superior at reducing specimen contamination in women more than a simple voided specimen. There is evidence that a midstream urine in men is better at reducing contamination than a first void specimen.
* Clinical observation/suggestion by Dr. Housman
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