A Technical Read: Improved UTI Diagnostics: AST without Identification – Ready for “Primetime”?

By Pete Dailey, Senior Technical Officer, FIND-The Global Alliance for Diagnostics and CARB-X support team

There is great interest by funders and developers in improved diagnostic assays for both uncomplicated and complicated Urinary Tract Infections (uUTI, cUTI) to better direct treatment of patients, prevent progression to urosepsis and pyelonephritis, and prevent over (or under) prescribing of antibiotics. Although some rapid tests (e.g., gram stains, dipsticks) have existed for decades, development of accurate, sensitive and specific tests to identify the presence of urinary pathogens and/or to provide rapid information to guide antimicrobial therapy, has lagged in comparison with the advances made with testing in other syndromes.

Some researchers and developers have proposed assays that report Antimicrobial Susceptibility Testing (AST) without Identification (ID) of the microorganism. They argue that the correct selection of antibiotics and patient treatment is what is important, not the identification of the organism. This is true. However, there are several significant problems with this approach that must be recognized and addressed by developers.

First, identification of a pathogen at a level above specific CFU/mL thresholds (e.g., >10,000) is an important part of accurately diagnosing a patient with a UTI. Gram stains and dipsticks have poor positive and negative predictive values and treating only based on symptoms can lead to 50% inappropriate treatment (1).

Second, the Minimum Inhibitory Concentration (MIC) breakpoints that underlie AST testing are different depending on the identity of the organism. The breakpoints for enterococci are different from Pseudomonas aeruginosa, and different from the Enterobacterales. There are many examples where the same MIC value can be interpreted as Susceptible to Intermediate to Resistant depending on the organism being tested. As Belkum et al. wrote, “It should be noted that most clinical microbiologists are not yet ready to accept the implementation of AST only systems, given the importance of establishing the identity of microbial species in the context of clinical decision making. According to EUCAST and CLSI guidelines, identification of pathogens at the species level is currently an essential element in interpreting minimum inhibitory concentrations (MICs) of antibiotics for particular pathogens. A paradigm shift will first be needed if physicians are to base their clinical decision making on AST-only platforms.” (2).

Third, some organisms are intrinsically resistant to certain antibiotics and identification of these organisms is essential so that an AST is not reported to the clinician for specific antibiotic-organism pairs. In some cases, the organism may appear susceptible by AST even though it is intrinsically resistant. An example from UTIs is nitrofurantoin. This is an appropriate choice for susceptible Escherichia coli, but both Proteus mirabilis and Pseudomonas aeruginosa are intrinsically resistant and this drug and any AST result should not be reported. “…objective knowledge of the causative pathogen is necessary to provide timely, effective treatment for the large number of patients with nitrofurantoin-resistant pathogens” (3).

Lastly, urine specimens from patients with UTIs are not pure cultures. Even specimens that are properly collected can often contain contaminating organisms at low levels and they may contain multiple pathogens. Polymicrobial infections (multiple recognized uropathogens in midstream urine at levels >100,000 CFU/ml) are more common in cUTIs and can be as high as 39% of specimens (4). Addressing contaminated specimens (growth of more than 2 isolates at >10,000 CFU/ml) is also a major challenge for developers. Even in the outpatient setting, the frequency of contaminated specimens has been reported to be high in a recent review (5). Overall, 15.0% of cultures were contaminated with the median contamination rates being 17.3% for females and 7.4% for males. It is important that new UTI diagnostics be designed so that they accurately identify polymicrobial infections and do not trigger prescription for unnecessary antibiotics by failing to recognize contaminated urine specimens. The AST result needs to be connected with the correct organism ID.

So, are UTI diagnostics that report AST without determining ID ready for “primetime”? Not yet. Major challenges must be resolved to provide clinically relevant therapeutic guidance for UTI from an AST only diagnostic.