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‘Urinary Tract Infection’ and the Microbiome

  • Thomas E. Finucane
    Correspondence
    Requests for reprints should be addressed to Thomas E. Finucane, MD, School of Medicine, Division of Geriatric Medicine and Gerontology, Johns Hopkins Bayview Medical Center, 5200 Eastern Avenue, MFL-C, Suite 2200, Baltimore, MD 21224.
    Affiliations
    Johns Hopkins Bayview Medical Center, Baltimore, Md
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Published:September 01, 2016DOI:https://doi.org/10.1016/j.amjmed.2016.08.018
      The current paradigm for managing uncomplicated “urinary tract infection” (“UTI”) is deeply flawed. “UTI” is ambiguously defined, and coupled with a belief that “bacteria are not normal inhabitants of the urinary tract,”
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • Colgan R.
      • Geerlings S.E.
      • Rice J.C.
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.
      the diagnosis often leads to unnecessary, harmful antibiotic treatment. Although bacteriuria identified by standard clinical cultures (which we will call standard bacteriuria) is central to most definitions, more sensitive diagnostic tests now demonstrate that “urine is not sterile”
      • Hilt E.E.
      • McKinley K.
      • Pearce M.M.
      • et al.
      Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.
      and that standard bacteriuria represents a fraction of the diverse microbiota hosted by the urinary tract. Knowledge of this complex, generally beneficial microbiome deeply undermines the current paradigm, which relies on the findings of standard culture. By acknowledging this microbiome, a successor paradigm will generate new questions about relationships among host, microbiome, and antibiotic use, and will almost surely show additional serious harms from antibiotic overtreatment.
      Shifting the paradigm for managing the urinary microbiome will be slow and difficult. Emphasizing the current paradigm's shortcomings may reduce antibiotic overuse in the short run, and in the long run help in development of a successor.
      This discussion concerns medically stable, nonpregnant adults with normal urinary tract structure and function. The role of antibiotics in patients with abnormalities of anatomy or physiology, such as spinal cord injury, urinary obstruction, or catheters, will require careful investigation. New insight into pyelonephritis and bacteremic bacteriuria is likely to develop.

      Diagnosis and Management of “UTI”

      The ambiguous definition of “UTI” seems to promote antibiotic overuse. In one common usage, “urinary tract infection is defined as microbial infiltration of the normally sterile urinary tract.”
      • Barber A.E.
      • Norton J.P.
      • Spivak A.M.
      • et al.
      Urinary tract infections: current and emerging management strategies.
      With this definition, asymptomatic bacteriuria is a “UTI” and is often treated, even in patient groups where strong evidence shows lack of benefit.
      • Nicolle L.E.
      • Bradley S.
      • Colgan R.
      • et al.
      Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.
      A second common definition, “significant bacteriuria in a patient with symptoms or signs attributable to the urinary tract and no alternate source”
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • Colgan R.
      • Geerlings S.E.
      • Rice J.C.
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.
      seems more restrictive but does not define what symptoms or signs may be attributed to the urinary tract. This ambiguity creates opportunities for overtreatment. “UTI” may be suspected in patients without urinary tract symptoms who develop any of a wide variety of nonspecific findings, such as change in cognitive or physical function, or change in the appearance or odor of urine. The diagnosis is confirmed (using the first definition) if bacteriuria is present. To satisfy the second definition a clinician need only attribute the nonspecific findings to the urinary tract. Antibiotic treatment of “UTI” often follows, even though no data have shown that these changes respond to treatment.
      Canonically, “all symptomatic UTI should be treated,”
      • Sobel J.D.
      Urinary tract infections.
      but actual benefit is limited. Hooton
      • Hooton T.M.
      Uncomplicated urinary tract infection.
      emphasizes that in acute uncomplicated cystitis, “the primary goal of treatment is to ameliorate symptoms.” Foxman
      • Foxman B.
      The epidemiology of urinary tract infection.
      summarizes that symptoms are usually self-limited, of brief duration, and only slightly shortened by antibiotic treatment; that cystitis rarely progresses to pyelonephritis; and that randomized trials show no reduction in the risk of progression to pyelonephritis with antibiotic treatment. The generally benign (other than symptoms) nature of “symptomatic UTI” is suggested by the billions of persons around the world and over the eons who have suffered “UTI” without access to antibiotics and have recovered fully.

      Paradigm Shift?

      With its various meanings, convenient diagnosis, long tradition, suggestive link to treatment, and uncritical acceptance by clinicians, patients, families, and insurers, “UTI” remains heavily embedded in practice; “one of the most common bacterial infections worldwide.”
      • Barber A.E.
      • Norton J.P.
      • Spivak A.M.
      • et al.
      Urinary tract infections: current and emerging management strategies.
      The paradigm provides tidy management for a patient with “UTI” who expects antibiotics. Further, the current paradigm does account for several findings. Standard bacteriuria is associated with pyuria, fever, and dysuria, for example; and these often improve with treatment, as do a wide variety of findings seemingly unconnected with the urinary tract. Antibiotic treatment improves outcomes for asymptomatic pregnant women who have standard bacteriuria. Pyelonephritis and bacteremic bacteriuria probably arise in the urinary tract and do require antibiotic treatment.
      To diagnose “UTI” and determine antibiotic sensitivity based on results of standard cultures, however, is to rely on familiar, accessible data and to ignore the dozens of bacterial species,
      • Hilt E.E.
      • McKinley K.
      • Pearce M.M.
      • et al.
      Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.
      as well as intracellular bacterial colonies and urinary virome
      • Sobel J.D.
      Urinary tract infections.
      known to reside in the urinary tract. Current discussions of symptomatic or asymptomatic bacteriuria or sterile urine are similarly problematic. To attribute delirium to standard bacteriuria seems unjustifiable, knowing that most or all people with or without delirium have bacteriuria. The current paradigm is defensible only if all pathogenic organisms are identified with standard cultures and all organisms more difficult to identify can be safely ignored.
      We propose instead that urinary symptoms, bacteremia, pyelonephritis, and other recognizable disturbances of the urinary tract are the dysbiotic tip of a much larger iceberg of complex host–microbe interactions that are occurring out of sight of standard cultures. As expected in the era of the microbiome, stable bacterial communities are generally beneficial. For example, compared with the instillation of sterile saline, “bladder colonization with (the nonpathogenic) E. coli HU2117 safely reduces the risk of symptomatic urinary tract infection in patients with spinal cord injury.”
      • Darouiche O.
      • Green B.G.
      • Donovan W.H.
      • et al.
      Multicenter randomized controlled trial of bacterial interference for prevention of urinary tract infection in patients with neurogenic bladder.
      Of 699 young women with asymptomatic bacteriuria, half of whom were randomized to receive no antibiotic treatment, “treatment was associated with a higher rate of symptomatic UTI … (thus) asymptomatic bacteriuria … may play a protective role in preventing symptomatic recurrence” during 12-month follow-up.
      • Cai T.
      • Mazzoli S.
      • Mondaini N.
      • et al.
      The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat?.
      The normal urinary tract is an open system bearing urine from renal tubules to urethra without discrete anatomic interruption. Sensitive diagnostic techniques, for example, gene-sequencing and expanded quantitative urine cultures, confirm that the tract hosts diverse bacterial communities.
      • Hilt E.E.
      • McKinley K.
      • Pearce M.M.
      • et al.
      Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.
      The respiratory tract–open from alveolus to mouth, traditionally considered sterile, now known to host complex microbial communities–may provide useful analogies for investigation. Could viruses, common respiratory pathogens, be pathogenic in the urinary tract? Might cystitis be analogous to pharyngitis? Might uropathogenic E. coli be analogous to pneumococcus, prevalent and sporadically pathogenic? Do fever, pyuria, duration of symptoms or other clinical features help distinguish between patients who would do well with urinary tract analgesia and those who would be safer with antibiotic treatment?

      Body-as-Battleground vs Human-as-Habitat

      Costello et al
      • Costello E.K.
      • Stagaman K.
      • Dethlefsen L.
      • Bohannan B.J.
      • Relman D.A.
      The application of ecological theory toward an understanding of the human microbiome.
      outline a broader paradigm shift in the general approach to infection; “transitioning clinical practice from the Body-as-Battleground to the Human-as-Habitat perspective will require rethinking how one manages the human body.” To help in this transition, mindful language will be important. We suggest that authors use “UTI” only within quotation marks and that clinicians use the bimanual “air quotes” gesture in discussions. This small, repetitive annotation is intended to disrupt the term's complacent usage and encourage rethinking of how one manages bacteriuria. The term “urinary tract dysbiosis” may be useful for otherwise well patients with urinary tract symptoms. When improved technology provides laboratory results that display the full array of microbes resident in a patient's urinary tract, antibiotic overuse may be reduced. Current within-paradigm efforts aiming to reduce overuse should continue, and more are needed.
      “UTI” is an ill-defined, glibly over-diagnosed and over-treated “infection.” Current management ignores modern science. The associated antibiotic overuse causes serious harm to patient safety and to public health. Instead of the current-paradigm question, “Does this patient have a UTI?,” the successor-paradigm question will be, “Does evidence show that antibiotic treatment is likely to benefit this patient?” Shifting the paradigm is an urgent matter.

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