Bacterial Interference in the Urinary Tract

Device-related bacterial colonization of the urinary tract and, occasionally, invasive infection are among the most common management problems encountered by infectious diseases consultants. Our usual response is to urge limits on catheter use, avoid treating asymptomatic infection, and anticipate occasional, sometimes life-threatening invasive infections. This advice is generally viewed as being not very helpful. During the 1960s, progress was made with the introduction of closed urinary drainage systems for patients requiring short-term catheterization and intermittent catheter use for patients with neurologically impaired bladders. Otherwise, little has changed in the past quarter-century. We have learned that pyuria accompanying bacteriuria has no particular significance, that even though we may only identify 1 pathogen in a urine culture, multiple organisms are frequently resident in the urinary tract—which is overgrown by the most rapidly grown organism—and that impregnation of catheters with antimicrobial substances has limited (if any) value in the prevention of bacteriuria. None of this substantially helps the patient who requires long-term urinary catheter drainage. In Houston in 1999, Hull et al. [1] and Trautner et al. [2] identified an Escherichia coli isolate in a culture of urine obtained from an asymptomatic patient; the isolate reproduced readily in urine, and subsequent studies have shown that its presence prevents other urinary pathogens from adhering to a foreign body. It has limited identified expressed `invasive capacity,' although many virulence genes are present [1]. Could such a strain establish itself in the urine and prevent other pathogenic organisms from establishing residence and causing illness? Indeed, pilot studies have suggested that it might be feasible and safe to introduce this strain into the bladder of catheterized patients, with the idea that excluding more-virulent pathogens would result in fewer complications [3, 4]. The article by Darouiche et al. [5] provides further evidence that this “safe” strain of E. coli (strain 83972) lives up to this reputation. After an effort was made to rid the urinary tract of existing bacteria with systemic antimicrobial agents, the bladders of 21 catheterized male patients with spinal cord injury were inoculated 6 times over 3 days via the catheter. In 4 patients, the bladder was successfully colonized for a full year, whereas the bladders of 9 patients were colonized temporarily (mean duration, 3.5 months). With successful colonization, no symptoms were attributed to the presence of this strain during a total of 5.6 years of catheterization. These 13 successfully colonized patients had significantly fewer symptomatic infections (which were presumably due to other infecting pathogens) than did a combined group of 14 patients that included 6 controls who were inoculated with saline and 8 patients whose bladders did not achieve colonization, despite undergoing bladder inoculation. In earlier studies from these same investigators, data demonstrated that colonization of patients with this E. coli strain resulted in a substantially reduced number of infections and no symptomatic infections during 18.4 years of successful colonization in one study [3] and resulted in 2 infections during 34 patient-years in another study [4]. In no instance did the introduced E. coli cause symptomatic episodes. From my perspective, as we await the next chapter of this important but slow-moving story, we have more questions than answers. First, these investigators need to solicit multiple groups to contribute to the further development of this strategy, possibly partnering with a commercial interest to speed up the process. We have no shortage of chronically catheterized patients with catheters in our institutions, and if this strain of E. coli or another bioengineered variant could markedly reduce complications of catheterization, patients and their caregivers would be most grateful. Studies must be designed well and carefully blinded, because interpreting symptoms in the neurogenic urinary tract is fraught with difficulties. Fever, increased generalized spasticity, and bladder spasms may be caused by multiple etiologies in this patient population. Second, is this strain, indeed, impotent with respect to invasion of the host or causing an inflammatory host response? Does it stay in the bladder, or does it also migrate into the upper tracts? Do any renal changes result from chronic infection of the renal pelvis or other structures? Can the strain be virulent in the obstructed urinary tract or the immunocompromised host? Can it cause infections at any site other than the urinary tract? Will bacteremia or serious infection ever result in any situation and cause medical legal issues? Some of us recall the Staphylococcus aureus 502a strain used as a nasal replacement strategy in the 1970s that failed, because the inoculated strain also caused disease [6]. Currently, the medical use of live organisms to exclude other pathogenic microbes has not made much headway, despite its potential. What kind of evidence will regulatory agencies require to permit packaging and distribution of this strain for use as a prescribed regimen for instillation into urinary tracts? What additional studies are required to ascertain its safety? Should the US Food and Drug Administration and other regulatory agencies be involved with study design and analysis? Third, what routines for inoculation into the bladder will ensure the more or less permanent establishment of E. coli 83972 with the least effort and cost? Will repeated doses be required to maintain colonization? Can the strain prevent other strains from invading if they cohabit the urinary system, or does it need to crowd out all others to be effective? How will success of colonization be monitored? Can we prevent antimicrobial use for purposes other than eradicating designer E. coli? If we make the strain more resistant to antimicrobials with genetic manipulation, is there risk that it will transmit these genes to other pathogens? Are other patients at any risk for cross-infections? Fourth, what (if any) undesirable effects will E. coli 83972 produce in infected urine? Will there be any new unpleasant odors emanating from E. coli–infected urine that is stored in containers or that has been splashed on surfaces? Can E. coli 83972 be given a gene that might reduce undesirable urinary odors? This innovative concept may be a significant breakthrough in the management of the chronically catheterized patient with a catheter. The multiple pilot studies reported to date are intriguing, but the findings are not absolutely convincing [3–5]. Presumably, this treatment could be administered in all situations that require months or years of urinary drainage, regardless of the etiology of the bladder malfunction, and, thus, it could be offered to millions of patients, perhaps resulting in substantially reduced morbidity and increased financial savings. But we require a research strategy to be planned and implemented that includes several investigator groups, regulatory agencies, and perhaps potential consumers that addresses all of these questions and others within a reasonable time frame. Financial support. Pfizer has funded the Academic Alliance Foundation, which currently pays part of A.R.R.'s stipend. Potential conflicts of interest. A.R.R.: no conflicts.

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