Urinary Tract Infections (UTIs)

Urinary tract infections (UTIs) are infections that may be located anywhere in the kidneys, ureters, bladder, and/or urethra. The most common uropathogens are Escherichia coli (E. coli), Klebsiella, Staphylococcus saprophyticus (S. saprophyticus), and Proteus mirabilis (P. mirabilis) bacterium. Rarely, UTIs are caused by fungal or viral pathogens. Many of our patients are at risk. Both male and female children are at risk before one year of age, with boys less at risk after this age. Patients with diabetes have UTIs at a greater frequency than non-diabetics. Patients who are recently post-surgery are UTI candidates due to invasive catheterization of the bladder. Universally, women are at the greatest risk for UTI at any age due to normal female anatomy and vaginal sexual intercourse. However, this risk increases after age 40. Men's chances of UTI increase with age as well due to complications connected with the aging prostate. The longer urethra is protective in the younger male, as prostatic involvement is less likely.

Bladder infection or lower UTI is also often referred to as cystitis. Acute pyelonephritis (APN) is the common name for a kidney infection or upper UTI. UTIs can be mild, uncomplicated infections that are easily treated or may be severely complicated and even cause death.

"In the United States, the CDC estimates that UTIs are responsible for nearly 13,000 deaths every year"(Graham et al., 2021, p. 12).

Prevalence worldwide varies; the United States has a lifetime UTI occurrence rate of 12.9%, Europe has a rate of 19.6%, and developing countries have a rate of 24% of the population.

The urinary tract is complex and encompasses the kidneys, ureters, bladder, and urethra. The tract is identical in males and females, except at the urethra, which passes through the prostate in the males and is about 14 centimeters (cm) longer. Recurrent or chronic UTIs are possibly preventable, but scientists do not agree on what prevents them. In 2023, how to treat and prevent recurrent UTIs and even the reasons for recurrent UTIs are still controversial due to different populations, medical coverage, empiric antibiotic dosing, and antibiotic resistance.

Women: Due to the shorter urethra of the woman, she is at greater risk globally for an uncomplicated UTI. If pregnant, she is at risk of a complicated UTI. Women who have had select hysterectomies are at greater risk of UTI due to retained urine because of the new prolapsed shape of the bladder.

Men: Due to the longer urethra and the prostatic involvement of the urethra, when a man gets a UTI, it is automatically called a complicated UTI.

Children: A Polish study by Daniel et al. in 2023 showed that children have UTIs at a rate of 9.5% by age seven and about 11% by age 10. Over three years of study and almost a thousand children, fever was often the only noted symptom of a UTI in non-toilet-trained children, and they are harder to diagnose without lab testing. There are many risk factors for UTIs in children (Renko et al., 2022). Fortunately, many children grow out of these problems. One cause of UTI in children is because as many as 3% of infants are born with incompetent vesicoureteral valves, allowing urine to "back up" into the kidneys, causing hydronephrosis and UTIs in up to 20% of these babies and small children (Mattoo et al., 2021). Normally, the pressure of urine in the bladder against these valves prevents urine reflux. Once children are toilet trained, more classic signs of UTI are noted; see Table 1.

"Virtually all authors, including the American Academy of Pediatrics (AAP) and the UK National Institute for Health and Clinical Excellence (NICE), emphasize the importance of rapid antibiotic treatment (of UTI) in the very young to reduce sequelae" (Coulthard, 2019).

E. coli is still the most common infective agent, and girls are more at risk than boys after the first year (due to the protected anatomy of the male). Children two years and under who are born with a congenital anatomical uropathy are more at risk for acute pyelonephritis. UTIs peak at two to three years old, related to potty training. Lower UTIs (cystitis) with E. Coli are the most common uropathogen, causative in 80% of all UTIs in children. E. coli easily proliferates in female bladders. It creates a biofilm around itself and a polysaccharide outer capsule, making the human immune system's workforce less effective at defeating it. In addition, E. coli's biofilm allows it to embed itself into the interstitial cells of the walls of the bladder; this adherence and embedding cause E. coli to be the most effective uropathic microbe among all uropathogens at any age or gender. "It (UTI) is estimated to be the third most common cause of fever in children after gastrointestinal infections and respiratory diseases" (Obeagu, 2023, p. 44).

People with diabetes mellitus: In a retrospective study performed in Thailand, it was shown that patients with type 2 diabetes with an average glycated hemoglobin (HbA1c) result of 8.6 taking the SGLT2 inhibitors empagliflozin (Jardiance®) and dapagliflozin (Farxiga®) were 3.7% more likely to develop a UTI than diabetic patients who did not use these drugs (Uitrakul et al., 2022). The study shows that when a large amount of glucose is present in the urine, UTIs are more likely to occur; this can be seen in people with diabetes with chronically high HbA1c levels because glucose will "spill" into the urine, feeding the bacteria that may be present around the urethra. Based on 15 studies with a sample size of over 800,000 participants in a meta-analysis, the overall prevalence of UTIs in patients with type 2 diabetes was 11.5% (Salari et al., 2022, p.1). Interestingly, the 2022 study by Salari et al. also reports that due to a host of problems such as neuropathy and increased body mass index (BMI), a diabetic patient is 66% more likely to develop asymptomatic urinary tract infection (AUTI) than someone without diabetes.

Incontinence: Wearing disposable incontinence protection can also be linked to increased UTIs. If not changed at once upon urinating, the fluid makes it easier for bacteria to travel by multiplication from the anus to the area of the urethra.

Men over 40 years old: Prostatic involvement causes men to have greater problems as they age. Nagakura et al. (2022) showed that as men get older, problematic testicular hormonal changes occur. It is well-accepted that benign prostatic hypertrophy (BPH) is the cause of retained urine and urinary infections, mostly in men over forty. Smoking, lack of daily exercise, and even weather (likely because of changes in exercise levels) have been reported as related to developing or increasing BPH (Nakagura et al., 2022).

According to Sabih and Leslie (2023), an uncomplicated UTI can be managed on an outpatient basis with oral antibiotics, achieving a normally excellent patient response. Langner et al. (2021) report that UTIs are traditionally treated with fluoroquinolones, which are no longer recommended as first-line treatment and have black box warnings due to the high side and adverse effect burdens. However, primary care providers still prescribe fluoroquinolones despite the warnings and antibiotic resistance patterns. ESBLs that are considered responsible for UTIs are exhibiting resistance at an increasing rate (Graham et al., 2021). Fluoroquinolones have not been used as much in the last ten years, though it is still predominant in patients older than 40 years old. This is concerning as the FDA released updated black box warnings for fluoroquinolones that say that older people should not be prescribed them unless they have a serious intractable infection for which all other appropriate antibiotics do not work. Since the Infectious Disease Society of America Clinical Guidelines in 2016-2019 recommended nitrofurantoin, trimethoprim-sulfamethoxazole, and fosfomycin as the first-line treatments for UTI, fluoroquinolone prescribing for UTIs has decreased.

Complicated UTIs are those where a patient may incur life-threatening complications such as sepsis, require longer antibiotic courses, and often require additional diagnostic workups. Recurrent UTIs that recur despite adequate antibiotic treatment are considered complicated.

Sabih and Leslie (2023) report that a complex or complicated UTI is labeled as such when the following are factors:

• The patient is male.
• A broad spectrum of pathogens (including atypical) is involved.
• In pregnant females.
• Because of kidney stones.
• With a colovesical fistula.
• In immunocompromised patients.
• In older adult patients.
• In post-surgical patients with catheters (especially urinary tract surgeries).
• In patients with renal transplants.

In Saudi Arabia, Ahmed et al. (2019) report that antibiotic susceptibility and resistance are changing targets and not the same in all the studied countries. For instance, Ahmed et al. (2019) state that Europe's numbers are not the same as Saudi Arabia's or the United States' and, in some cases, are diametric opposites. Physicians and prescribing providers must be alert to which microbes are resistant to which antimicrobials in their distinct regions. They must only prescribe the required amount, and waiting for at least the preliminary cultures before prescribing might be more efficacious.

"…inappropriate and non-judicious usage of antibiotics has resulted in the development of worldwide antibiotic resistance in bacteria, leading to the emergence of multi-resistant strains of bacterial pathogens (Ahmed et al., 2019, p. 65)".

In children where there is an even greater need for speedy microbe identification and efficacy of antimicrobials, Esposito et al. (2022) writes,

"However, to limit the emergence of resistance, every effort to reduce and rationalize antibiotic consumption must be made. An increased use of antibiotic stewardship can be greatly effective in this regard" (p.504).

An extensive study by Autore et al. (2023) noted that continuous antibiotic prophylaxis was instituted in the past to prevent recurrent UTIs in children. However, it is now only recommended for a short term until significant urinary blockage can be corrected by surgery. These conclusions are supportive of antibiotic stewardship. Empiric prescribing of antibiotics is a large part of the multidrug resistance found in uropathogens (Goodman et al.,2023). Originally, this method was an attempt to prevent renal scarring and other long-term effects from recurrent UTIs in children, which can be serious. Providers must ask themselves, "Do the benefits of empirical prescribing for UTIs outweigh the risks"?

Isolating the bacteria and culturing them to find the sensitivity has not changed substantially since Fleming discovered penicillin in 1928 (Lajiness & Lajiness, 2019). Following urinalysis, C&S is commonly used to test the microbes cultured in agar dishes (or other growth media) with small discs of antibiotics added. Each disc is part of the set of antibiotics currently used in a particular region at each laboratory.

It is not easy to get a good urine sample from children for urinalysis, specifically for C&S. For infants up to potty-trained age, the method to obtain a "clean" sample is to perform suprapubic aspiration (Diviney & Jaswon, 2021; Kaufman et al., 2019). Squeezing a diaper pad or holding a "cleaned" baby over an open cup until it urinates are ineffective ways to get a clean, uncontaminated sample. After potty training, a midstream "clean catch" urine sample is possible.

Pregnant women are at an increased risk of UTIs due to normal hormonal increases that occur during pregnancy. Progesterone dilates the uterus, and the progression of the pregnancy causes compression of the ureters by the then heavier uterus. Further, this ureteral compression leads to retained (static) urine, which is then vesicoureteral reflux with ascending bacterial growth. The cascade of expected changes leads to UTIs in roughly 8% of all pregnancies in the United States (Committee on Clinical Consensus—Obstetrics, 2023). As in most other populations, E. coli represents about 85% of all UTI infections; this increased risk is serious enough that there are published guidelines for screening, treating, and re-treating, whether prophylactically or not. The possible serious complications to mother and baby of an untreated or incorrectly treated UTI, upper or lower, are too great to ignore.

While many countries or regions choose different first-line antibiotic therapies, most published guidelines direct five to seven days of treatment for ASB and cystitis. If the infection is pyelonephritis, targeted treatment is to be increased to 14 days; post-treatment screening and prophylaxis are still decided case by case as there is no unequivocal evidence to make guidelines for this currently. In general, antibiotic choices in the United States for cystitis or ASB are nitrofurantoin and fosfomycin, as resistance to amoxicillin is high here. In Australia, sulfamethoxazole and trimethoprim oral are the first-line treatment for cystitis, and ASB for pyelonephritis or upper UTI treatment is intravenous (IV) gentamicin or gentamicin plus ampicillin. In China and the United Kingdom oral amoxicillin combined with clavulanate or cephalexin are used first line. In the United States, fosfomycin is not used for upper UTIs because of the difficulty that medication has reaching the deeper cells of the kidneys.

Pediatric patients' treatment for mild and uncomplicated cystitis is amoxicillin combined with clavulanate or two to three doses of one of several antibiotics from the second generation of cephalosporins. In targeted cultures, only ciprofloxacin or trimethoprim-sulfamethoxazole may be used. With serious, complicated, febrile UTIs, inpatient IV treatment with the same medications plus added choices of amikacin, gentamicin, and ampicillin combined with ceftazidime for three to four doses are needed. Infants up to three months of age can be empirically treated with three to four doses of IV ampicillin combined with sulbactam and gentamicin. Vancomycin combined with gentamicin can be used for hospital-acquired UTIs in newborns. If there is a further neurologic complication, cefotaxime may be added in three doses (Ramsay et al., 2022).

Patient and Provider

It's Friday morning, and you're seeing Sharon Jones. She's a 31-year-old nurse who's been pregnant twice and has two living children. She's had no abortions, no stillbirths, and her last menstrual period was two weeks ago. Today, she is complaining about a three-day bout of frequent burning during urination and strong-smelling urine. She is afebrile, and her heart rate, respiratory rate, and blood pressure are all within normal limits. On examination, she does have tenderness over her lower abdomen centrally. Her abdomen is non-distended, and her bladder is not distended but tender on palpation. She has no costovertebral tenderness to palpation.

As she is being examined, you check her current social history for evidence of multiple sexual partners or even recent sexual activity. She denies these. You can rule out a sexually transmitted infection or irritated urethra from sexual activity. You know that sometimes if a woman forgets to empty her bladder after vaginal sexual intercourse, uropathic bacteria that has been forced into the end of the urethra will not be flushed out. However, that's not applicable here. You also know that it has been proven that female nurses have higher rates of UTIs compared to other professions (Nerbass et al., 2021); this is due to extended periods of "holding in" their urine and insufficient water during long shifts.

Her clean catch urine sample looks tawny and cloudy. The automatic dipstick urinalysis shows positive results for nitrites and leukoesterase. Because leukoesterase is an enzyme present in WBCs, you know there's an infection under attack in Sharon's body. Plus, nitrates are normal in urine. However, if it's positive for nitrites, gram-negative uropathogens have broken the nitrates down into nitrites. The positive protein of acidic pH and increased urine specific gravity with the physical symptoms show that Sharon has a UTI, probably uncomplicated. You note that Sharon has no drug allergies, and she's not pregnant or breastfeeding. The only medications Sharon takes are lisinopril and a multivitamin daily. The first line of treatment is nitrofurantoin extended release of 100 milligrams orally every 12 hours for five days. You recommend that she take it with food. You also advised her to take her two 15-minute breaks and half-hour lunch breaks to drink water to keep hydrated and take bathroom breaks, flushing out her urinary system.

Although she's a nurse, you still want to perform complete education for prevention and antimicrobial stewardship. You remind her to take all her medicine so she doesn't grow antimicrobial-resistant uropathogens. Recurrent UTIs can be damaging to the kidneys in all populations. You tell Sharon to come back if her symptoms persist and if any new symptoms, such as fever or flank pain, develop. If her uncomplicated UTI becomes a complicated one or continues to persist or recur, a C&S test will be ordered on a new urine sample after the antibiotic is completed. A C&S test will help to target her more resistant uropathogens. You know that antimicrobial resistance has been increasing, and depending on the resistance profile in your area, you might order a C&S anyway.

Sharon reports she will make a more determined effort to drink water at work and to use her break time for herself. Instead of soldiering against all the warnings she knows and has taught others, she will consider her own needs. You electronically send the script for her nitrofurantoin to her pharmacy. You chart the automated urinalysis values, signs and symptoms she is experiencing, vital signs, education performed, and prescriptions. In your note, you added your specific instructions to Sharon to take this medicine with food and to return to the office in the future if needed. You scanned through her problem list and diagnosis codes to see how many urinary infections Sharon has had in the last couple of years, noting that it's been over a year since the last one; you chart this as well. Sharon's uncomplicated lower UTI responds to treatment, and further investigation with diagnostic lab tests is unnecessary.

Preventative antibiotics are not the best plan. Prophylaxis is not used except in select cases, such as patients with long-term indwelling catheters, certain physical manifestations caused by spinal or neurological injuries or illnesses, select pregnant ladies, and some children.

Speed is the thing. The old methods are cheap but much too slow to prevent blind, empiric prescribing. Interestingly, in 2022, Webber et al. showed that the antibiotic discs could be put onto the Petri dishes at the start of the culture process. It costs no more and provides accurate susceptibility results 18 hours sooner than waiting until after the culture has matured. The results can be quantified as early as six hours after the antibiotic discs are applied. This method can also be read by automation; this would lead to specific antibiotic prescriptions within six hours. The plan supports antibiotic stewardship and the patient's need for the right antibiotics. However, many levels of acceptance and change are required for the world to switch to a new "old" method after more than 50 years. Modern alternatives to C&S are on the way. Polymerase chain reactions can now evaluate which specific microbes are in the urine much faster than culture on agar-coated Petri dishes. However, they still cannot determine if the uropathogens are sensitive or antibiotic-resistant. Fortunately, fast, automated microfluid testing combined with special optical and biomarker science is available and is in further development (Salam et al., 2023). Eventually, scientists can quickly check a specific microbe's DNA for surface antigens and peculiarities that infer resistance to antimicrobials. Between cost, speed, size, regulatory hurdles, and habits, global acceptance and use of faster methods is the dream—a medical diagnostic kumbaya, so to speak.

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Resources for the health care provider:

• E. coli fact sheet
• Fluoroquinolones Boxed Warning
• American College of Obstetricians and Gynecologists position paper on UTI and Pregnancy
• Medical Dictionary Online