By Dana Hinesly

dm01.jpg (17182 bytes)Antibiotic-resistant organisms are a growing threat; a quick online search produces thousands of articles and Web sites dedicated to the problem. While the predominant cause is often attributed to the overuse and misapplication of antibiotic therapies, many clinicians still feel compelled to prescribe broad-spectrum drugs, particularly for illnesses such as pneumonia where an accurate diagnosis is virtually impossible to make from symptoms alone.

“Without testing, you don’t know what the diagnosis is, so you end up treating for both pneumococcal pneumonia and Legionnaires’ Disease, though it may be only one of them,” says Victor L. Yu, MD, professor of medicine, University of Pittsburgh, and chief, Infectious Disease Section, VA Pittsburgh Healthcare System. “And the rule for antibiotics with subsequent emergence of resistant microorganisms is, you use it and you lose it.”

Compounding the issue is the fact that physicians continue to prescribe antibiotics for most instances of pneumonia, despite the fact that roughly half of all cases are caused by viruses.

 Will Weisburg

“If you treat a viral infection with an antibiotic, that doesn’t work, and what you’re really doing is contributing to the global problem of antibiotic resistance,” says Will Weisburg, executive director, Infectious Disease, Nanogen Inc.

Existing Tests Are Not Enough
Targeted treatment is rarely employed, however, because traditional testing can take as many as 5 days to provide the definitive results required for narrow-spectrum therapies. And even then, results are sometimes unreliable.

“There’s been controversy about whether the gram stain is useful, but we’ve learned that the gram stain is very useful,” says Yu. He adds that the test isn’t used as often as it should be. Blood cultures, another common method of identifying pneumococci, are accurate, but results can take 3 to 5 days. Currently, sputum culture is the most common specimen taken for diagnostic testing, but it has a low specificity and sensitivity due to upper-airway contamination and oropharyngeal colonization.

In the absence of an effective test, physicians are often left with no choice but to administer broad-spectrum antibiotics in the best interest of their patients, because there is often very little room for error. Failure to identify and treat the pneumonia-causing bacteria can have deadly consequences. More than 50 types of pneumonia have been identified; the most prevalent is pneumococcal pneumonia, which is caused by a bacterium called Streptococcus pneumoniae.1

The National Institute of Allergy and Infectious Diseases estimates that peumococcal pneumonia, or pneumococcus, accounts for 25% to 35% of all community-acquired pneumonia (CAP), resulting in about 500,000 cases annually in the United States alone. It is extremely common and one of the most fatal forms of the disease, killing more than 40,000 US citizens each year.2

“Pneumonia is certainly a significant problem,” says Norman Moore, PhD, director of new technologies, Binax, Inc (Scarborough, Me). “Right now, it is the sixth leading cause of infection and the major cause of death from infectious disease.”

Rapid Diagnostics Can Usher in Change
Even though it is justified, the pervasive use of antibiotics is contributing to increased antibiotic resistance, creating a cycle that can only be broken with fast, accurate clinical laboratory testing.

“We’ve been waiting for all these years for an accurate test so we can treat pneumococcus with penicillin, which has long been accepted as the drug of choice,” says Yu. “We finally have the test, and we should use it to provide safer, cheaper, and more targeted therapy,” he adds, referring to Binax’s NOW® Streptococcus pneumoniae antigen test, a rapid immunochromatographic assay that detects the S. pneumoniae antigen in urine.

The Binax urinary antigen test was the basis for a study conducted between 2001 and 2002 by Yu and local scientists at the Field Military Medical Unit in Russia. The study enrolled 219 soldiers who were diagnosed with CAP. It was designed as a proof of concept, assessing the “usefulness of a strategy of targeted antimicrobial therapy based on the results of a rapid urinary antigen test for S. pneumoniae.” Patients with positive urinary antigen test results were treated with amoxicillin, with a 90% success rate. Those who had negative results were treated with clarithromycin, with a 94% success rate.

Because the test identifies the most common cause of pneumonia, the pneumococcus arms the physician with the information required to accurately treat a large number of patients without resorting to broad-spectrum antibiotics.

“Close to a quarter of all individuals were effectively treated with penicillin,” says Yu. “The sensitivity and specificity of the Binax test are superior to those of sputum culture.” The test also proved to be more sensitive than blood culture. “Most importantly, results are available just 15 minutes after the urine sample is taken, not 3 days later, as is the case with existing tests,” he says.

Yu believes that widely accepted use of this test would play a pivotal role in the fight against antibiotic resistance by increasing targeted antibiotic therapy. Using narrow-spectrum treatments would allow physicians to give an efficient, safe, and affordable therapy without affecting mortality.

“This test means we don’t always have to use the broad-spectrum approach, so we can reduce quinolone-resistant and macrolide-resistant organisms, and those antibiotics could be held in reserve to fight against organisms that are resistant,” says Yu.

Curing Pneumonia, Thwarting Sepsis
According to the Society of Critical Care Medicine (SCCM), each year approximately 750,000 people in the United States are diagnosed with severe sepsis, a life-threatening infection that results when the body’s immune system is overwhelmed by bacteria in the bloodstream. Estimates are that almost 29 percent of them will die from the infection.3

An unexpected benefit of Yu’s study was identifying the urinary antigen test’s ability to single out the most severely ill patients, “raising the physician’s index of awareness that this may be a more invasive pneumonia,” Yu says. He emphasizes that this added attention can ensure patients receive targeted treatment before sepsis occurs.

“The urinary antigen sensitivity is up into the 90-plus percent for bacteremic patients, meaning it will almost surely be positive in patients on the verge of sepsis,” says Yu. “So when you need the test the most, it is at its best.”

A Burgeoning Interest
While the Binax test is currently the only one of its kind on the market, grants provided in response to an August 2004 request for application (RFA) from the National Institute of Allergy and Infectious Diseases (NIAID), a division of the US National Institutes of Health (NIH), are sure to change that. The RFA called for the development of diagnostics for early detection of the common causes of sepsis and bacteremia or candidemia, as well as pathogens that commonly cause CAP.4

Nanogen, in partnership with the Medical College of Wisconsin, was awarded one of the NIAID/NIH grants for $2.5 million to fund research of a fully integrated diagnostic system for clinical labs to identify infectious agents that cause sepsis and CAP.

“In previous government grant programs, Nanogen greatly reduced the size of its instrument and integrated essential biological sample-preparation, amplification, and detection technologies to design a sample-to-answer diagnostic system,” says Howard C. Birndorf, Nanogen’s chairman of the board and CEO. “This NIAID/NIH research program will further the design of a sophisticated prototype assay and instrument system, and sepsis- and pneumonia-detection panels, to help physicians expedite test results in the hospital lab and make better treatment decisions.”

Nanogen’s Infectious Disease Executive Director Weisburg explains that Nanogen’s focus will be on producing a test to correctly identify the specific organisms responsible for the patient’s illness. “Determining that someone has pneumonia is not a hard diagnosis, but knowing what organism is causing the disease is essential information in order to treat it,” he says. “What you need is the etiological agent in order to guide the direction of care.” Weisburg adds that because of the vague symptoms of sepsis, information required to manage the patient can often be more challenging.

“There are two key things. The first is determining that it is actually sepsis and not some underlying cause, and second, finding out what the organism is in order to most effectively treat the patient,” Weisburg says.

Nanogen’s partnership with the Medical College of Wisconsin has several tangible benefits. In addition to shared technology, the medical college will conduct the clinical studies required throughout the 5-year research program.

“Early on, there will be an important clinical study to determine how the Streptococcus pneumoniae normally present in many people’s throats will impact test accuracy,” says Weisburg. “They will also perform what is essentially an alpha-type clinical study toward the end of the grant.”

The vision is to produce a test to be used by physicians in concert with clinical laboratories to get accurate information much more quickly.

“We decided that for this to be useful for the clinical marketplace, we have to ultimately get this as close to the patient as possible,” says Weisburg. “You have to be able to get reasonable turnaround time between having a sample and getting a result the physician is able to act on.”

Moving Toward Rapid Diagnostics
For those hoping to contain the development of antibiotic-resistant bacteria, the advent of rapid diagnostic Streptococcus pneumoniae tests holds tremendous promise. To make that happen, however, physicians need to recondition themselves to order a laboratory test before writing a prescription.

 Graham P. Lidgard

“Identification of the organism, speed to diagnosis, and then speed to treatment is what is critical,” says Graham P. Lidgard, senior vice president, Research & Development, Nanogen. Without a fast, reliable test, a physician who suspects sepsis will begin treatment immediately with a broad spectrum, even when it isn’t the preferred therapy.

Another benefit to narrow-spectrum treatments is the potential for cost savings. Not only do broad-spectrum antibiotics increase the instances of antibiotic resistance, but they also tend to be expensive.

“It’s not unusual for those cocktails to cost about $1,000 a day,” says Weisburg. “That cost is in addition to all the other expenses associated with keeping a patient in the hospital.” Many in the industry feel that in an era of quinolone-resistant and macrolide-resistant pneumococci, cost shouldn’t be the ultimate determinant.

“I hear from a lot of people that the test costs a lot money,” says Yu. He points out that tests are relatively inexpensive when compared to the price of antibiotic therapies. “The cost of an antibiotic of the penicillin class—such as amoxicillin—is notably lower than that of broader-spectrum antibiotic therapy, for example, treatment with a quinolone or a macrolide. And, when resistance emerges, the physician often must use combination antibiotics.”

“There’s no question this test should revolutionize the management of pneumonia. Ironically, many clinicians think that if they have broad-spectrum antibiotics, there isn’t a need for another test,” says Yu. But the positive results of the urinary antigen test prove it is possible to successfully administer targeted therapy, he notes. “And if we can treat patients with a targeted drug, then everybody wins. The patient wins because correct and safer treatment is administered early, hospital administrators win because the antibiotic is cheaper, and the clinician wins because antibiotic resistance is minimized,” says Yu.

If widely adopted, tests focusing on delivering swift diagnoses of the specific illness-generating organisms provide one more way that doctors can provide superior care for their patients.

“These tests will not act alone, but will be utilized in combination with other things physicians are already looking at,” says Weisburg. “Providing that information means a doctor knows what they want to treat and they can treat it with the right thing, which is ultimately best for the patient.”

Dana Hinesly is a contributing writer for Clinical Lab Products.

1. Pneumonia. Available at: invoke.cfm?id=DS00135. Accessed September 15, 2005.
2. Pneumococcal pneumonia. Available at: Accessed September 15, 2005.
3. Press room: Sepsis statistics. Available at: Accessed September 15, 2005.
4. Sepsis and CAP: Partnership for diagnostic development. Available at: Accessed September 15, 2005.