Urinary tract infections, or UTIs, are a serious health problem affecting millions of people each year. They result in more than 8 million office visits* and over a million hospitalizations each year. The total cost for treatment reaches into the billions of dollars. A large share of that expense comes from waiting 48 hours for a urine sample to be cultured in the lab. That's why a new electrochemical sensor that detects and identifies bacterial DNA in 45 minutes is such welcome news.
"Present practice, which involves culturing urine for 48 hours, is so slow that doctors frequently over-prescribe broad-spectrum antibiotics to begin treatment promptly. This has led to unnecessary treatment in many patients and drug-resistance in the bacteria that cause UTIs," says Dr. Joseph C. Liao, a urologist at the UCLA School of Medicine in Los Angeles and co-principal investigator for the electrochemical sensor research. "Older antibiotics such as penicillins and trimethoprim-sulfamethoxazole (Bactrim) are frequently ineffective. Ciprofloxacin is now commonly used, but resistance to it has been on the rise." Liao adds that since there is no oral antibiotic to replace Ciprofloxacin the need to change the current approach for UTI treatment is critical.
To rapidly identify bacteria, the detector has an array of 16 electrochemical sensors customized with a library of DNA probes that target the most common urinary bacteria. The detection process works at the molecular level: when the RNA target from the bacteria is recognized by the probes on the sensor, an electric signal is generated. The signal is transformed by a computer chip on the unit into a digital readout. The sensor is able to give quantitative results since the more bacteria that bind to the detector's probes the stronger the signal.
The biosensor performed well in a recent clinical study trial: In tests of actual clinical urine samples, it identified the most common bacterial species found in UTIs with 98% accuracy. "This pilot generation of probes can identify the five most common bacteria that cause UTIs. Additional probes are being developed but the most clinically relevant bacteria are already on the list," says Liao.
The new detector represents a collaboration between medical researchers led by Liao, and GeneFluidics, Inc., a company started by Vincent Gau, whose UCLA PhD is in biomedical engineering. Gau began work on his detector in 1998 - with an eye toward detecting airborne biowarfare agents - but changed over to a diagnostic instrument in 2000. "The UCLA Urology Department and GeneFluidics received a $5.6 million grant from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) to develop a prototype device and conduct a clinical study, and the Urology Department at UCLA is a top-notch partner to work with on this UTI application," Gau says.
In addition to the species-specific probes used in the clinical tests, Liao's team has also developed "universal" probes that can, in theory, detect bacterial RNA from any organism as well as dead bacteria, leading to more precise diagnoses. "[In current practice] if a patient were to have a negative urine culture the physician assumes that the patient does not have an infection," Liao says. "In reality the patient may harbor bacteria that does not grow well in an artificial laboratory setting for whatever reason. A rapid molecular approach such as ours that does not depend on the bacteria's ability to grow overcomes that problem."
In the months since the clinical study ended Genefluidics engineers have improved the biosensor so that, in preliminary tests, urinary bacteria can be identified in just 25 minutes, down from the 45 minutes it took during the clinical study.
Getting to Market
GeneFluidics is negotiating with several companies to commercialize the technology and expects to have a system ready for FDA approval in about 2 years. Gau expects the commercial design should be able to do much more than just find bacteria in urine: "It should be possible to develop detectors to analyze saliva, milk, serum, plasma and liquid culture media - and to detect bacteria, viruses and protein markers," he says. These results may be of interest to physicians studying infectious diseases in other organ systems or other non-infectious diseases processes.
Improved miniaturization and fabrication techniques will help create a "lab-on- a-chip" system that will permit all chemical analysis to occur within a single removable cartridge. "Eventually, though this will take several years, the design could lead to kits sold over the counter, for home use, like present-day pregnancy test kits," Gau says.
Liao JC, Mastali M, Gau V, Suchard MA, Møller AK, Bruckner DA, Babbitt JT, Li Y, Gornbein J, Landaw EM, McCabe ER, Churchill BM, Haake DA. Use of Electrochemical DNA Biosensors for Rapid Molecular Identification of Uropathogens in Clinical Urine Specimens, Journal of Clinical Microbiology 44: 561-570, 2006.
Burt CW, Schappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1999--2000. Vital Health Stat 13. 2004 Sep;(157):1-70. PubMed PMID: 15499797.