Feb. 18, 2011 -- Harry L.T. Mobley has devoted the better part of 25 years to alleviating the "considerable human misery" created by bacteria that make themselves a little too at-home in millions of women's urinary tracts.
Working six days a week, Mobley and the dozen researchers in his University of Michigan lab are trying to develop a nasal spray vaccine for urinary tract infections, to keep these rugged invaders from sticking to the bladder, climbing into kidneys and inflicting a torrent of itching, burning, and frequent urination.
Despite the team's purposeful labors, a safe and effective vaccine for urinary tract infections remains at least a decade off, Mobley figures.
"It's painful to say that, because it's such an urgent need," Mobley, a bacteriologist who chairs the department of microbiology and immunology at Michigan, told ABC News in an interview this week. "Women that get repeated infections -- and I mean one after another and another -- represent about 2.6 percent of all women. These are the ones we get e-mails from that are totally miserable."
Urinary tract infection (UTI) is second only to respiratory infection as the most common contagious malady. It disproportionately plagues women, who can be stricken with the pain, pelvic pressure and associated symptoms at many stages of life: when they become sexually active, during pregnancy, around menopause, and in later years if they're hospitalized or in nursing homes.
Although few cases prove fatal, recurrent infections -- more than three a year -- of the bladder (cystitis) or kidneys (pyelonephritis) exact an enormous economic toll in medical costs and lost work days. There is a psychological cost too: sufferers feel debilitated and worried that something as enjoyable as sexual activity could lead to another infection.
The National Institute of Diabetes and Digestive and Kidney Diseases pegged the annual cost of evaluating and treating UTIs in 2000 at $3.5 billion (equivalent to the payout so far in BP's settlement of the Gulf oil spill). Women's cases accounted for $2.5 billion of the total. In the vast majority of cases, these infections arise in otherwise healthy women.
Mobley's top target, Escherichia coli bacteria, are responsible for 75 to 90 percent of UTIs, with smaller contributions from Staphylococcus saphrophyticus, Enterobacteriaceae, Proteus and Klebsiella. Many of these microbes, which form colonies in the delicate tissues lining the bladder, have grown increasingly resistant to antibiotics, forcing major changes in how and what doctors prescribe to knock them down.
Gone are the days of simply getting a prescription for penicillin.
Instead, patients undergo tests to determine which bugs are responsible and which drugs can be given for the shortest duration without promoting antibiotic resistance. In one interesting twist, doctors have turned back the clock by relying on a 50-year-old drug, nitrofurantoin (also called Macrodantin or Furodantin), which had fallen out of favor, but has become a mainstay because it doesn't promote resistance.
Many women become trapped in a vicious cycle as antibiotics rout the bacteria, but kill off good bacteria that keep yeast in check, setting the stage for yeast infections they then treat with antifungal pills or creams. They're then susceptible to additional UTIs because their bodies' defenses "are not up to par," said Dr. Ariana L. Smith, a urologic surgeon at the University of Pennsylvania.
Because the decrease in estrogen associated with menopause makes the vagina more alkaline, Smith prescribes vaginal estrogen to restore the formerly-acidic environment that's inhospitable to disease-causing bacteria.
Most UTI patients have experimented with self-help remedies, downing pitchers of cranberry juice or cranberry extract pills, although the largest and best-designed studies to date show cranberry doesn't help much.
Tired of spending months on continuous low-dose antibiotics as a preventive, chronic UTI sufferers increasingly try complementary and alternative approaches, such as acupuncture and probiotics, which have been shown in doctors' practices and some clinical trials to make them feel better.
Ultimately, vaccines may be the best way to reduce the incidence of UTIs, but in the meantime, researchers are studying UTIs from many angles. The biggest strides in UTI research have come in understanding the microbiology and genetics of the disease-causing bacteria; the biology and responses of the tissues they infect; and the response of the immune system to the bacterial invasion.
Scientists are trying to use that information to defeat those marauding microbes before they get the upper hand. They're devising ways of boosting the immune system so that if nasty bacteria reach the urinary tract, the immune system can defeat them. They're also designing vaccines to interfere with bacteria's ability to attach to urinary tract cells.
Why Women Are More Vulnerable to Recurrent UTIs
To appreciate the enormity of UTI infections, which have drawn attention and research funding from the National Institute of Digestive and Diabetes and Kidney Diseases, and the Office of Women's Health Research, it helps to understand the basic anatomy that makes women particularly vulnerable.
UTIs comprise infections of the urethra, the opening where urine leaves the body; the bladder, which holds urine; and the kidneys, which filter liquid wastes from the body.
Women's urethras are closer to the rectum than men's urethras, so they're more readily exposed to bacteria. Their urethras also are shorter than men's, so bacteria don't have to travel as far to enter the urinary tract. Other factors that contribute to women's susceptibility include use of contraceptives like diaphragms and spermicides containing nonoxynol-9, which eliminate normal protective vaginal bacteria.
The basic tools for diagnosing UTIs remain tests for blood, pus or bacteria in the urine, and urine cultures, which typically take 48 hours, to identify which bacteria are present and determine the medications to which they remain susceptible. Infections of the bladder and kidneys can be diagnosed with ultrasound, CT images or pyelograms that use dye to make certain features more readily visible.
Most laboratory-confirmed UTIs are treated with antibiotics and antimicrobials. Before urine culture results become available, symptomatic patients receive initial treatment based upon their doctors' best guesses about which bacteria are making them ill.
Doctors typically follow treatment guidelines that quickly become obsolete as bacterial resistance evolves, contends Dr. Anthony J. Schaeffer, chairman of urology at Northwestern University Feinberg School of Medicine in Chicago. He's using a tool called data-mining to improve the way doctors select the drugs for patients with UTIs.
In findings presented at the American Urological Association meeting in 2010, he and his colleagues showed that theoretical models based upon a database of 3,567 positive urine cultures from Northwestern urology clinic patients, which included their age, race, ZIP code, antibiotic susceptibilities and prior UTI history, produced 10 percent to 15 percent improvements in selecting the optimal therapy, Schaeffer said. Northwestern has patented the technique.
"It's pretty dramatic," Schaeffer said of how the data-mining better matched bacterial strains to one of three drugs most commonly prescribed for UTIs: ciprofloxacin (Cipro), nitrofurantoin (Macrodantin) and trimethoprim-sulfamethoxazole (Bactrim, Septra). "What's exciting about this is there's no added cost. You're not prescribing a more expensive drug, it's just picking the right drug."
For patients repeatedly infected by the same bacterial strain, Schaeffer prescribes one of three treatments:
Prophylactic nightly doses of medication to prevent, rather than suppress the bugs.
Single doses of antimicrobials taken "at the time of intercourse."
The "self-start therapy" he described in a 1999 paper, which allows patients to "do their own culture, start their own treatment and make a post-treatment follow-up." Although Northwestern frequently uses this approach because it facilitates prompt treatment, Schaeffer said it's not widely used because of difficulties with obtaining "devices for performing the cultures at home."
For her part, Penn's Smith said, "When women start taking antibiotics, you can start talking to them about things they can do to protect themselves" from the cycle of UTIs and yeast infections. That includes eating lactobacillus-rich yogurt or taking lactobacillus pills, which she uses "to treat patients who come in with these recurrent, cyclic problems – even though there isn't a lot of data to support it."
Smith is meticulous about seeing patients to document the cause of their infections, having them complete courses of antibiotics before she'll consider additional therapy, and turning to some less-studied, but anecdotally effective treatments, especially for her menopausal patients.
Those are what finally worked for Linda, 51, a Philadelphia attorney who began suffering the pain, disability and high fevers of recurrent UTIs only in the last five years, after menopause began. Linda, who asked that her full name not be used, said she tried virtually every over-the-counter, prescription and kitchen remedy, even taking her mother's advice to "drink gallons and gallons of fluid." All that drinking only gave her temporary relief.
"You'll try anything," she said. "I spent one vacation at the beach, rolled in a blanket for five or six days, and was on three antibiotics by the time I actually went home."
Debilitating, Recurrent Infections Can Interfere with Work, Relationships
Linda fell into a pattern familiar to many women: a urine test would confirm an infection, and she'd start taking an antibiotic while waiting for the urine culture that would identify the microorganism and antibiotics to which it was sensitive. The antibiotics wouldn't get rid of the infection, and once again she'd be racing to the bathroom.
She hit the wall about 18 months ago, when the UTIs were "so frequent and so intense… it was really affecting my life." The infections curbed her business travel, left her so incapacitated "I felt myself totally disintegrate in terms of high fever, losing all my strength" and limited romantic encounters with her husband, who "couldn't quite figure out what to do to help."
At that point, she began coming to Penn, where Smith's nurse-practitioner confirmed Linda's suspicion that menopause might be contributing to the problem. They put her on a twice-weekly dose of Estrace, a vaginal estrogen more typically prescribed for vaginal dryness and painful intercourse; and twice-daily doses of an older drug called mandelamine (Hiprex), thought to keep bacteria from clinging to the walls of the urinary tract. She also took Vitamin C with the Hiprex because "the drug works best with an acidic urine environment," Smith said.
Linda said the treatment worked so well for six months that Smith weaned her off the drug for a while, but the symptoms came roaring back. Linda went back on the Estrace, Hiprex and Vitamin C, which have kept her clear of infection for six months.
"I'll stay with them for a year. My hope is that once I get completely through menopause, my symptoms will abate and I won't need to do that anymore."
Clinical trials have been exploring a variety of ways to combat UTIs:
PROBIOTIC SUPPOSITORIES: Dr. Ann E. Stapleton, a professor of medicine at the University of Washington in Seattle, has been studying the potential of a probiotic containing Lactobacillus crispatus, an organism in the vaginas of healthy women that protects against UTIs. In a series of studies, she and her colleagues have shown that L. crispatus produces hydrogen peroxide, suggesting "it's probably antiseptic," she said in an interview. They've followed UTI sufferers and proven that during an acute bladder or kidney infection, patients lose the protective lactobacilli, and that the lost lactobacilli don't return among women with recurrent UTIs. Stapleton and her colleagues are planning a Phase III trial of a lactobacillus vaginal suppository, called Lactin-V, to re-colonize patients' vaginas. They hope it will make it harder for E. coli to cause repeated infections. Scientists in Norway are studying a different vaginal probiotic, UREX-Cap-5, which contains two other Lactobacilli, L. rhamnosus and L. reuteri, and is sold in the United States as Fem-dophilus.
CRANBERRY COMPOUNDS: Most women with urinary tract infections have tried cranberry juice or cranberry extract. Although some small studies have found cranberry compounds helpful, large, well-designed studies haven't been positive. A University of Michigan study published last month in Clinical Infectious Diseases, and supported by the National Center for Complementary and Alternative Medicine, found that among otherwise healthy college-age women recovering from bladder infections, those who drank cranberry juice twice a day were no less prone to new infections than those drinking a look-alike placebo. Lab research presented at the Infectious Diseases Society of America meeting in 2004 found that cranberry compounds may inhibit the ability of E. coli to stick to the cells lining the bladder, but that hasn't translated into the treatment arena. Most doctors don't object to women trying cranberry. As Stapleton said: "We don't have any evidence that it's a bad thing to do."
ACUPUNCTURE: Smith at the University of Pennsylvania said a small pilot study of seven patients, in which participants had weekly acupuncture treatments for 12 weeks, found some evidence that it alleviated pain associated with interstitial cystitis, a painful bladder condition with discomfort but no clear evidence of infection. "Acupuncture is used a lot for stress reduction. A huge part of interstitial cystitis is exacerbations at the time of stress. When you think of it that way…a side effect of treating their stress would be less exacerbations of their cystitis," Smith said. However, she said, "this is really early. I don't think anyone is prescribing this for interstitial cystitis."
VACCINES: Mobley's vaccine aims to confer long-lasting immunity by targeting proteins that E. coli produces during an infection, including proteins the bacteria use to gather iron for energy. But his isn't the only vaccine approach to UTIs. Human studies of a promising vaccine developed at the University of Wisconsin stopped because of the $15 million price tag for a Phase III trial. "We tried to partner up with a pharmaceutical company. We thought they were going to be able to go ahead with it," said Walt Hopkins, a research professor in urology, who felt the vaccine had many acceptable aspects, notably that "there were almost no adverse effects seen in the women." He said the experimental vaccine contained heat-killed forms of "10 different types of bacteria that cause most UTIs," including six strains of E. coli, combined in a vaginal suppository. Hopkins explained that their approach, which would let a woman easily treat herself, took advantage of the body's mucosal immune system, which links mucus membranes of the vagina, bladder and other organs, and unleashes infection-fighting white cells that can intercept microbes before they can make someone ill. Phase II results with 75 women demonstrated that those women given an initial vaccination plus three boosters had fewer UTIs than women given a single dose, and fewer than women given a placebo. The effect of a single dose wore off in about six weeks; an initial dose plus boosters protected women for the six months of the trial, Hopkins said. He's still disappointed that the fruits of his labors never reached the 15 percent of women who have problems with recurrent bladder and kidney infections. "I'd say about every month or two, I get an e-mail from some woman looking for help with her infections. I have to say, 'I'm sorry, our trial is over and I can't offer you any additional options.'"
Many Women Experiment Until Finding Treatments That Work for Them
As they do with many other intractable health problems, patients often try a variety of treatments until they discover what works best for their bodies. For Lisa, 39, of Orlando, relief came when she ventured outside traditional infectious disease treatments.
A public relations professional, Lisa got her first UTI right after her divorce six years ago. "Every other month, I was on antibiotics," she said. At one point, she had discomfort in her bladder, but no detectable infection, and a urologist told her she had interstitial cystitis. He recommended limiting high-acid foods that could irritate her bladder, which she did; and a balloon-inflating procedure for her bladder, which she refused.
"That's when I reached out to alternative healing," she said. Lisa found a holistic practitioner who told her to eat simple foods like vegetables, chicken and fish, and give up sugars, alcohol and other foods thought to stimulate the growth of yeast. With the dietary changes and some probiotics, she felt immediate changes. But, she said, "it took me quite a few years before honestly I felt like I'd never get a UTI again."
She credits the acupuncture she began last year with finally eliminating her bladder problems, and believes a combination of alternative therapies have put them behind her. "It takes time; a lot more than taking drugs or surgery."