Advanced molecular testing for urinary tract infections: Matching the right test with the right patient

Uncomplicated urinary tract infections (UTIs), in the absence of structural abnormalities or comorbid conditions, are routinely diagnosed with standard urine culture (SUC). Most are successfully treated with antibiotics. However, for patients with recurrent or complicated UTIs, traditional diagnostics and empiric treatments frequently fall short, putting people at risk for adverse health outcomes. Indeed, in August 2023, StatPearls reported that approximately 25% of sepsis cases originate from the urogenital tract.

Advanced molecular testing (AMT) often utilizes nucleic-acid amplification to identify pathogens. Additionally, AMT holds promise to overcome some of the limitations of SUC in patients with complex UTI. We asked three physicians to explain how AMT has impacted their management of challenging UTIs: Roger Dmochowski, MD, a urologist at a notable university in Tennessee; Mia Duncan, MD, FPMRS, a urogynecologist in a urology group based in Ohio; and Stephen Zappala, MD, a urologist in the Greater Boston area.

Prevalence and Financial Impact of Urinary Tract Infections

UTIs are quite common in women, with more than half of all women experiencing such infections in their lifetime, according to the American Urological Association (AUA). In addition, the Mayo Clinic reports that 50% of women with UTIs will experience a recurrence within 12 months. Women are also more likely to have UTIs than men due to anatomical differences in the lower urinary tract.

“Urinary tract infection as a diagnosis comprises 1-4% of ambulatory visits and is associated with an estimated cost burden of $1.6 billion annually,” Dmochowski said. Given that “between 20-50% of all women with a UTI will develop a subsequent infection or recurrent urinary tract infection,” it seems evident that the financial stakes are considerable.

Moreover, as the population ages, the prevalence of UTIs is likely to increase. “The post-menopausal population is typically the most affected,” said Duncan. That’s because low estrogen levels can alter vaginal tissue and trigger bacterial changes that increase UTI risk. Duncan noted that preventive care is very important for managing these patients. “Estrogen cream is just not utilized enough,” she said.

As a urologist, Zappala noted that challenging UTI cases represent a larger and increasing proportion of his female patient referrals from primary care providers. “We have to guarantee that we’re not missing something else that could irritate the urinary bladder, such as bladder calculus or a bladder tumor,” he said. “Even still, complicated, recurrent, persistent UTIs are common, and they’re becoming increasingly more prevalent as the population ages.”

Challenges with Standard Urine Culture

SUC, or agar-based clinical culture of urine specimens, has been the standard of care for diagnosing UTIs since the 19th century, with few technical refinements. However, in its latest guidance, the AUA states that “more recent studies demonstrate that a large proportion of urinary bacteria are not cultivatable using the standard conditions.”

For one reason, SUC results are typically dismissed as “contaminated” if more than two microorganisms are detected. Yet a recent study found that up to 72% of recurrent, complicated, or persistent UTIs are indeed polymicrobial. In fact, the Cleveland Clinic urges clinicians to use their discretion in recognizing that “polymicrobial interactions can play a role in urologic infection.”

The timing of standard cultures can pose additional challenges for complex UTI cases. It typically takes 24-72 hours to get SUC results, which may be too long to wait before initiating treatment in certain patients. According to the Mayo Clinic: “It has been shown that inadequate therapy for infections in critically ill, hospitalized patients is associated with poor outcomes, including greater morbidity and mortality as well as increased length of stay.”

For that reason, clinicians will commonly use broad-spectrum antimicrobial agents as initial empiric therapy while awaiting SUC results—a practice that may contribute to antibiotic resistance among patient populations. “More recently, an increase in levofloxacin use as initial therapy for UTI as a result of policy change at a single institution was found to have led to a rapid increase in fluoroquinolone resistance among outpatient urinary E. coli isolates at that institution,” Mayo Clinic stated. The Mayo Clinic went on to recommend that “those involved in antimicrobial stewardship should avoid the excessive prescribing of a single class of antibiotic.”

“Women with complicated UTIs, culture-proven UTI with functional and/or anatomic risk factors, including postmenopausal status, have higher rates of antibiotic resistance to narrow- and broad-spectrum oral antibiotics,” Dmochowski said. He pointed to multiple causative factors, including repeated and prolonged exposure to antibiotics and the presence of polymicrobial UTIs and altered microbiomes.

Where Advanced Molecular Testing Could Be Helpful

A recent study performed in urology and urogynecology settings compared AMT—specifically, a combination of multiplex-PCR and pooled antibiotic susceptibility (P-AST™)—to standard urine culture. PCR/P-AST demonstrated a greater than 50% reduction in the use of empiric treatment and a 37% reduction in negative outcomes, compared to standard urine culture.

This research demonstrates how, in specialized settings, AMT can improve complex UTI management. Getting to the correct antibiotic quickly is important for providers who are often left to rely on empiric therapy when the standard of care is too slow.

In her urogynecology practice, Duncan uses AMT in combination with SUC. “I’m a big believer that, for the kind of recurrent UTIs being seen by a specialist like me, urology or urogynecology, [clinicians should] use all of the testing modalities,” she said.

She highlighted two scenarios where AMT comes into play in her practice. The first is with her recurrent UTI population. “If I do a cystoscopy and I see that their bladder appears inflamed, I take the catheterized samples obtained on that day, and I send them for a standard urine culture,” she noted. Then, she asks patients to return so she can look into their bladder and assess for resolution. “If they come back and they have persistent bladder inflammation, I do make sure to include AMT on my repeat panel of sampling,” she added.

The second scenario is with patients with bladder, urethral, or urination pain despite testing negative on standard cultures, who may remain concerned they have a UTI. In those cases, “I use the AMT to rule in or, probably more so, rule out if they do have an infectious etiology,” Duncan said. “I think the AMT negative result is a great tool and helps [my patients] buy into their other care plans,” she added.

Advanced UTI testing has numerous roles in the university setting where Dmochowski practices. “Algorithms controlling treatment are important in the unique circumstances of either urinary tract recurrence or in those circumstances where complicating factors are present,” he noted. “It is fairly evident, however, that these testing modalities should not be used in uncomplicated and isolated infection diagnoses, where standard cultures are still the baseline for therapy,” he added.

AMT can be a helpful tool for urologists as well, according to Zappala. “I believe after the first time you fail, you go to specialized testing,” he said. “I think it’s incumbent upon the urologist to use advanced methods of diagnostics.”

“Advanced testing has provided the potential for much more focused urinary assessment in the circumstances of either recurrent UTI infection or complicated presentations,” said Dmochowski. “Additionally, advanced testing has a role to play in the assessment of individuals with chronic urinary syndromes that may be either exacerbated or complicated by bacterial infection. In fact, it is very common to have patients who have been previously diagnosed with a chronic urinary syndrome, such as interstitial cystitis/painful bladder syndrome, or urgency and frequency syndrome, who report symptomatic variability, which can be influenced by the presence of pathogenic bacteria.”

He highlighted that, “the ability to render effective and targeted therapy based upon advanced testing benefits these scenarios, which are quite common in focused and general urologic practice.”

Zappala added, “I believe in pinpoint accuracy with both diagnostics and intervention. That’s why I'm requesting conventional cultures, but I'm also sending one [for advanced diagnostic testing].”

Selecting The Right Test for UTI

Once providers have determined the right clinical scenario for using AMT, how do they go about choosing the right test? There are multiple options.

PCR testing alone is quite common and can detect pathogens as well as antibiotic resistance genes with high levels of accuracy. However, this method only detects DNA. It cannot determine which genes are being expressed. In fact, by using PCR-resistance gene data alone, providers are significantly limiting their treatment options.

A recent study showed a 40% discordance between resistance gene detection and phenotypic resistance. That is one of Dmochowski’s main concerns when choosing a test. “In considering the use of advanced UTI testing, the real ability to identify specific genotypes and phenotypes of pathogenic organisms will reduce and improve antibiotic selection criteria and also potential antibiotic therapy duration,” he said. For practitioners, “even more important is the ability to phenotype certain organisms and match that to the patient’s presentation.”

Dmochowski believes implementing appropriate AMT algorithms will not only improve patient outcomes and decrease healthcare costs, but also assist in expediting research. “Focused use of advanced testing, as guided by diagnostic testing algorithms, will almost certainly improve patient outcomes and have a durable effect on reduction of healthcare spending related to incomplete or poorly focused management of unique symptom presentations,” he stated.

“Furthermore, the use of algorithmic-based reflex ordering will increase the appropriateness of care and provide evidence for payment coverage for these unique testing modalities by various third-party entities, including CMS,” Dmochowski said. In addition, “it would be expected that guideline-based management of an infection will adopt appropriate use of advanced testing where supported by evidence and improved outcomes.”

Zappala would like to see more data to guide decision-making when choosing among AMT options. “I think you need long-term clinical studies that show, has there really been a change?” he said. “Was there a cost savings? Have we changed clinical decision-making because of this?”

Conclusion

Recent studies have begun to demonstrate changes in clinical decision-making as well as improved outcomes and cost savings when AMT is used for complicated, persistent, or recurrent UTI management, and the body of evidence is growing.

Still, Duncan agrees with Zappala that more research is needed. “My patients address the limitations of our test (standard urine culture) on online forums, and they know there are other tests out there,” she said. “That's why [AMT] companies are at national meetings talking about it. Everyone is aware that cultures are limited. We're also aware that PCR testing alone may be a little bit too sensitive,” she said. “We’re still learning.”