Laboratory Medicine and Nosocomial Infections: Coping with Clostridium Difficile

difficile have received clearance from the U.S. Food and Drug Administration (FDA; Atlanta, GA, USA). These include products from Prodesse Inc. (Waukesha, WI, USA), BD Diagnostics, of Becton, Dickinson and Co (Franklin Lakes, NJ, USA), and Cepheid, (Sunnyvale, CA, USA).

The Health Protection Agency in the United Kingdom (HPA), which tracks deaths from C. difficile, reports that it is responsible for more deaths than the more widely known methicillin-resistant Staphylococcus aureus (MRSA), and that the death rate is increasing.

Many health care professionals maintain that the problem is compounded by the fact that more than 90% of US laboratories use immunoassay tests, which have been shown to be insensitive, with some testing below 50% compared to molecular testing.

"The previous lack of an accurate and rapid diagnostic test for C. difficile has greatly impeded our ability to halt the increasing rate of C. difficile, which has taken a severe turn in the past several years. Patients can have their first diarrhea symptoms on a Monday and be dead by Thursday," said Dale Gerding, MD, professor of medicine, division of infectious diseases, Loyola University Chicago Stritch School of Medicine (IL, USA).

"Toxigenic culture offers high sensitivity, but laboratories find it burdensome and far too slow for practical diagnostic use. Instead, many use less labor-intensive toxin EIA [enzyme immunoassay] and GDH [glutamate dehydrogenase] tests, which fail to detect 20 to 50 % of cases," he explained. "From a practical standpoint, this means many patients are not subjected to proper isolation procedures that can curtail transmission of C. difficile."

In April 2009, Prodesse received approval from the FDA to sell its diagnostic ProGastro Cd, which detects toxic strains of C. difficile. The tool uses real-time polymerase chain reaction (RT-PCR) technology to produce a sensitive result on a stool sample in about three hours. Simple to use and with low inhibition, ProGastro Cd runs on a standard molecular instrument and fits easily into existing workflow.

In trials at three clinics, ProGastro Cd detected 43% more positives than did the current gold standard. Genetic sequencing confirmed that more than 90% of the additional positives detected by ProGastro Cd were accurate. In addition, the three clinical sites reported no inhibited samples--an important aspect because stools usually contain many PCR inhibitors.

In January 2009, BD Diagnostics received the FDA go-ahead to market GeneOhm--a molecular assay for the rapid detection of the Toxin B gene found in C. difficile. The GeneOhm assay targets the Toxin B gene, discovered in 1978, to be the cause of antibiotic-associated diarrhea and colitis and found in virtually all toxigenic C. difficile strains, including the emerging BI/NAP1/027 epidemic strain. It combines high sensitivity and specificity, and provides definitive test results in less than 2 hours.

"From our assay, you do not have to do a culture confirmation," Tobi Karchmer M.D., medical affairs director, BD Diagnostics (Franklin Lakes, NJ, USA) said. "The hospital could start an infection control based on the assay."

Results can be obtained in 16 hours, a shorter time than the chromogenic incubation period of 18 to 24 hours and far shorter than the 48 hours required for a culture to give results.

Cepheid received FDA clearance in July 2009 for its Xpert C. difficile test, an on-demand molecular diagnostic test designed for 45-minute detection of the bacterium. Blue colonies on Cepheid's spectra plate represent a positive result for MRSA. The Xpert C. difficile test is Cepheid's seventh test to receive FDA clearance, and fourth in its expanding menu of on-demand HAI products. Cepheid will also continue to work closely with the FDA to deliver an additional product featuring simultaneous differentiation of the 027/NAP1/BI epidemic strain.

According to BD's Dr. Karchmer, before the advent of molecular testing, many physicians would ignore the results of the less sensitive tests if they did not confirm what the symptoms indicated.

"The clinicians would resend the test and order multiple tests," Karchmer says. "They didn't understand that ordering multiple tests using the same inaccurate method does not improve results. It doesn't help and is costly."

Related Links:
U.S. Food and Drug Administration
Prodesse Inc.
Becton, Dickinson and Co.
Cepheid
Health Protection Agency in the United Kingdom
University Chicago Stritch School of Medicine