Studies offer hope for rapid diagnosis of common pathogens

August 15, 2008

Studies in urinary tract infections provided the foundation for rapid diagnosis of common urinary tract infection pathogens and opened windows into the mechanisms underlying chronic prostatitis and interstitial cystitis, two diseases characterized by their resistance to treatment.

Key Points

Two new techniques for identifying bacteria without culture hold promise. One uses nuclear magnetic resonance spectroscopy, and the other targets the 16S rRNA of the most common uropathogens, which are immobilized on an electrochemical biosensor array.

With bacterial resistance to antibiotics increasing, the race is on to develop more sophisticated means for identifying and measuring pathogens.

"The quicker you make an accurate diagnosis, the sooner you can initiate reliable treatment," he said. "Right now, we treat empirically, which is not the best idea because bacterial resistance is increasing."

Researchers at the Centre of Biomedical Magnetic Resonance, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, had earlier reported using nuclear magnetic resonance (NMR) technology to identify and quantify E. coli, K. pneumoniae, and P. aeruginosa, the most common urinary pathogens. This year, they reported using NMR to identify P. mirabilis, which causes <3% of UTIs. The technology detects not the pathogens, but metabolites produced by the pathogens.

In addition, a team at Stanford University School of Medicine, Stanford, CA, used an electrochemical bioarray to identify E. coli and P. aeruginosa in urine specimens within 40 minutes. The researchers reported that the technology they were developing would be particularly suited for patients with recurrent, complicated polymicrobial infections.

The modulation of the immune response between bacteria and the surface of the urothelial cells resulted in the stimulation of a cytokine release.

Dr. Schaeffer and colleagues at Northwestern showed that there is an exchange of information (crosstalk) between the host's immune response and pathogen-initiated cell death. The response is moderated to the benefit of the pathogen.

"This offers a potential new therapeutic paradigm. When you know the mechanism, you can thwart that with novel therapies. These would be directed at early intervention, most likely for those with recurrent infection and those at risk for infection, such as those with catheters and spinal cord injuries," Dr. Schaeffer explained.

A mouse model bridged the gap between the expression of cytokines and the evidence of leukocytes in prostatic secretions and the evidence of leukocytes in the prostatic lobes.

A Chicago team has created a mouse model that characterizes the pelvic pain seen in chronic prostatitis and chronic pelvic pain syndrome, offering the opportunity to identify the regulating mechanisms and evaluate new analgesic therapies.

"We now have a model that replicates the human scenario of pain and we also know that the prostate is perturbed," Dr. Schaeffer noted. "This is exciting.

"Up until now, people have wondered whether there was a linkage between prostate disease and symptoms. This provides evidence of a direct linkage between the prostate disease and pain.

"Researchers also showed that the pain was alleviated by lidocaine. It may be that in at least some men with chronic pelvic pain, the pain may have its origins in the prostate, and that they may respond to topical or systemic therapy directed at the prostate," said Dr. Schaeffer.

Mast cells cause cystitis pain and bladder inflammation through the separable actions of histamine and tumor-necrosis factor, respectively, and identify histamine receptors as therapeutic targets for pelvic pain.

Interstitial cystitis pain can be induced in mice by introducing pseudorabies virus into the tail vein, leading to a neurogenic cystitis. Northwestern researchers found the procedure did not work in mice that were deficient in histamine-producing mast cells.

They also found that pain was attenuated in mice lacking histamine receptors and in mice given agents that antagonize those receptors.

Earlier studies showed that tumor necrosis factor (TNF) was necessary for neurogenic cystitis pathophysiology, but not for pain. Researchers concluded that cystitis pain and bladder inflammation evolved from separate actions of TNF and histamine.

"Once again, this is a good model," Dr. Schaeffer said. "It offers insights into what may be going on in humans. The mice were treated with antihistamines for specific histamine receptors and the pain was diminished. It has yet to be shown that antihistamines work in humans, although there is anecdotal evidence that they sometimes help.

"Both of these papers illustrate that if you can phenotype the mouse or human and determine pathophysiology in detail, then you can apply directed therapies that are likely to be more effective than generic therapies."