Cover Story

 CONTINUING EDUCATION

To earn CEUs, see current test at www.mlo-online.com  under the CE Tests tab. The September test covers all articles in this section, except the product announcement.

LEARNING OBJECTIVES

Upon completion of this article, the reader will be able to:

1. Identify organisms that commonly cause HAIs and ARIs, including Clostridium difficile-associated infection (CDI).
2. Name mechanisms for the increases in HAIs, ARIs, and CDI.
3. Name trends in HAIs, ARIs, and CDI.
4. Name types of infections that put patients at greater risk of fatality from HAIs and ARIs.
5. Describe procedures to reduce the number of HAIs, ARIs, and CDI.
6. Understand testing methods for HAIs, ARIs, and CDI.

 

 

Reducing HAIs and ARIs: partnering with clinical labs

By Devendra Amin, MD, F(CCP)

Many of the most insidious of healthcare-associated (or hospital-acquired) infections (HAIs) — and antibiotic-resistant infections (ARIs) — are creatures of our own unintelligent design. Methicillin-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant enterococci (VRE), and a growing number of other pathogens developing resistance to many antibiotics are directly attributable to the overuse and misuse of these drugs. For example, 75% of antibiotics are prescribed for acute respiratory-tract infections, despite the fact that approximately 80% of them are of viral origin.

In just over a decade, S aureus, once described as a "controllable nuisance," has evolved into MRSA, one of the fastest-growing resistant infections that does not respond to most antibiotics. In the United States, current MRSA rates exceed 50%¹ of all S aureus infections and stand at nearly 90% in some Asian countries.² Lack of compliance with hand-disinfection procedures, inappropriate use of antimicrobials, and underlying diseases prior to hospitalization are some of the most common ways MRSA is spread. In the past five years, MRSA has exploded in the general community — an alarming and ominous trend.

In 1993, there were fewer than 2,000 MRSA infections in U.S. hospitals. By 2005, the figure had shot up to 368,000, according to the Agency for Healthcare Research and Quality. At Morton Plant Hospital, we now see HAIs almost every day. It is estimated that about 70% of bacteria that cause infections in hospitals are resistant to at least one of the drugs most commonly used to treat infections.

Those who track the genetic shift and drift that makes these pathogens so adaptable believe that VRE poses the next serious health threat. Unfortunately, these scientists believe that the organism has transferred a key antibiotic-resistance gene to Staphylococcus. We are also seeing more cases of Klebsiella pneumoniae Carbapenemase- (KPC-) producing organisms, such as Escherichia coli and Salmonella. KPC pathogens are virtually impervious to all penicillins, cephalosporins, carbapenems, and axteonam, which leaves us with no available treatment.

MRSA plus H1N1 influenza A a threat

At the Second World HAI Forum held in last month in the Les Pensières Conference Center in Veyrier-du-Lac, France, these supercharged microorganisms were discussed by experts from around the globe, gathered to anticipate what their next move will be. These experts focused on two looming threats.

In just over a decade, S aureus, once described as a “controllable nuisance,” has evolved into MRSA, one of the fastest-growing resistant infections that does not respond to most antibiotics.

The first is the convergence of MRSA and H1N1 influenza A. When combined with MRSA, even mild seasonal flu can become very dangerous. The virus distracts the immune system, which has a more difficult time battling the bacterial infection that can lead to severe pneumonia. A 50% mortality rate has been reported with community-acquired MRSA pneumonia.² This has already been seen in Australia, which is coming to the end of its flu season. Fortunately, these cases were not common; however, when they did occur, they were frequently fatal. The extent of the problem in the Northern Hemisphere will be determined by the severity of the H1N1 pandemic and the efficacy of the vaccine.

The second looming threat identified at the recent World HAI Forum are bacteria that produce extended spectrum beta-lactamase, or ESBL. This enzyme has evolved the ability to render many antibiotics useless. ESBLs are produced by E coli and K pneumoniae, which are becoming more pervasive and difficult to treat in the hospital setting. In fact, K pneumoniae Carbapenemase can inactivate nearly all antibiotics, including carbapenems, which had been the medical "weapon of last resort."

Resistance enzymes that bypass extended spectrum cephalosporin and carbapenem antibiotics are known as carbapenemases. These molecules have versatile hydrolytic capacities that inactivate antibiotics in the penicillin, cephalosporin, monobactam, and carbapenem families.

Still, doctors perpetuate the problem by increasing the prescription of carbapenems due to the spread of pathogens armed with these resistance enzymes, thereby inadvertently creating carbapenemase-producing bacteria resistant to the antibiotic.

The cost of antibiotic-resistant infections

One of the central battlegrounds in the efforts to overcome antibiotic resistance is the human lung, which is the primary point of entry for many of these pathogens. Each year, 235 million doses of antibiotics are prescribed, but between 20% to 50% of these prescriptions are unnecessary.^3,4 Of the 41 million antibiotic prescriptions written in the United States each year for respiratory infections, as many 22.5 million (55%) are likely to have been prescribed for non-bacterial infections.⁵ One way to dramatically reduce overuse of antibiotics is to avoid treating viral infections and simple inflammation, as in the cases of asthma and chronic obstructive pulmonary diseases (COPD) with antibiotics that do no good.

C difficile is a Gram-positive anaerobic bacillus that exists in vegetative and spore forms, and is spread through the fecal-oral route.

Two recent studies demonstrate both the impact of this promiscuous use of antibiotics and the benefits that can be realized if we "kick this habit." Researchers at the Cook County Hospital in Chicago published research this month on the true cost of antibiotic-resistant infections.⁶ They concluded that the healthcare costs associated with ARIs in that hospital in 2000 ranged between $18,000 to $29,000 per patient, and these patients remained hospitalized for an additional 6.4 to 12.7 days in order to have these infections treated. These patients were more than twice as likely to die than comparable patients who did not become infected with antibiotic-resistant organisms. This study was one of the first to also look at the societal costs of ARIs — those costs borne by the patients and their families — resulting from lost wages or, in the fatal cases, lost income. The researchers calculated that this cost ranged between $10.7 and $15 million for the 188 ARI patient-study population.

Clearly, as healthcare professionals debate the best way to reform our healthcare system, taking steps to avoid ARIs and these monumental treatment and societal costs should be at the top of our list. In September, Schuetz, et al, published a study showing that antibiotic usage can be safely avoided or minimized using a new diagnostic tool to measure levels of procalcitonin, or PCT.⁷ Schuetz and his colleagues at six tertiary-care centers in Switzerland used PCT levels to determine the etiology of lower respiratory-tract infections (LRTIs) in more than 1,300 patients and used that information to guide antibiotic treatment, including if and when to start treatment and when to safely stop treatment. Prescription rates and overall antibiotic exposure were significantly reduced in the PCT group for the whole patient population as well as for each LRTI subgroup. The duration of antibiotic exposure was less in the PCT group, with the overall reduction in duration due to the PCT guidance ranging from 25.7% to 38.7% in the six study sites. The adverse effects associated with antibiotics such as nausea, diarrhea, and rash occurred less frequently in the PCT group.

The clinical lab is a vital partner in battling ARIs

Morton Plant Mease Health Care in Clearwater, FL, includes four hospitals and a free-standing emergency room. At the Morton Plant Mease critical-care department, personnel have worked closely with clinical lab staff to form a proactive approach to find and apply new technology and clinical practices with the goal of improving outcomes based on a overarching commitment to enhance antibiotic stewardship and reduce ARIs.

Physicians working closely with Morton Plant Mease’s laboratory director have developed a program to reduce the use of antibiotics based on the PCT test to help rule out LRTIs; suspected sepsis; asthma and COPD flare-ups that are not caused by bacterial infections — as well as using a sterile lavage protocol that helps rule out contamination in cases of suspected ventilator-associated pneumonias (VAPs).

Procalcitonin

PCT, the pro-hormone of calcitonin, was discovered to be a sensitive biomarker for systemic bacterial infections about 15 years ago.⁸ In response to bacterial infections, nearly all tissues in the body release PCT, especially the lungs.⁹ In Europe, PCT is commonly used to determine a bacterial-infection immune response from viral infections or an inflammatory response not linked to a pathogen.¹⁰ The "SEPSIS ALERT" protocol was started as a pilot study last year, and hospital staff is in the process of applying the protocol to all of the Morton Plant Mease facilities with the intent to measure the impact on patient care and antibiotic usage. In the Morton Plant Mease laboratory, the chart on page 14 indicates either the lack of or the level of bacterial infection.

Not only can the laboratory staff lead in the effort to mitigate HAIs by pushing new policies and protocols but also by educating its clinical colleagues.

PCT is used in the emergency department (ED) to test those admitted patients suspected of having a significant bacterial infection. ED protocol calls for an admitted patient with suspected pneumonia, LRTI, or sepsis, to have three PCT tests performed in the first 12 hours.

PCT typically spikes within the first 12 hours of systemic bacterial infection. If the patient starts improving, we perform the PCT test on that patient every other day. A PCT score on the decline indicates that we are treating the patient appropriately and that score often allows us to end antibiotic treatment once we know the patient is safe. When PCT continues to increase over a 24-hour to 48-hour period, this is a strong indication, according to our program, that we are not treating the patient appropriately.

Sterile lavage for suspected VAPs

The number of cases of hospital-associated pneumonia is overwhelming, in terms of incidence, mortalities, and treatment costs. A related area of critical concern is improving the accuracy of cultures in patients with suspected VAP. As with PCT, a proactive lab like that at Morton Plant Mease is vital to reducing antibiotic overuse. When we examine patients in our hospital’s intensive care unit (ICU) who are on ventilators and see early signs of VAP, our standard response would be to perform a bronchial washing and send it to the lab for culture. Invariably, these cultures were positive because contamination from the endotracheal, or ET, tube is almost unavoidable. The cultures show an organism that may or may not be the cause of the infection. In fact, there may be no infection at all. This then prompts antibiotic usage that may or may not be warranted. This problem is common in ICUs across the country.

If the washing is taken from the lung by sending an aliquot of saline down the endotracheal tube, then sucking it back and culturing the specimen, the specimen is often contaminated by the endotracheal tube colonizer.

At our hospital, we implemented sterile lavage to get a sterile sample by passing a catheter through the endotracheal tube within a protective catheter through the endotracheal tube within the proactive sleeve, which we push deep into the lung. By extracting a washing in that area under these conditions, contamination can be avoided.

The microbiology laboratory scientist then does a quantitative culture — a more accurate way to measure for an infection. If we see 10⁴ organisms per cubic centimeters per milliliter, this indicates a serious situation which is treated aggressively. If, however, the count is less than that, the urgency is significantly decreased since the organism may be a contaminant. Thus, we then have the time to monitor the patient in order to make sure that there is a true infection before we treat.^11,12

This change in the VAP protocol — designed by the laboratory staff who were essential to its implementation — has been successful, based on the results. Not only can the laboratory staff lead in the effort to mitigate HAIs by pushing new policies and protocols but also by educating its clinical colleagues. Laboratory personnel can remind doctors and pharmacists of this at every given opportunity. We are all partners in patient care.

By identifying resistance, the lab can help clinicians get clear actionable information, so they can begin effective antibiotic therapy as early as possible. The lab is critical to monitoring resistance with surveillance campaigns of antimicrobial resistance patterns within the hospital, and more broadly in the community. The lab can also play the pivotal role in tracking resistance by screening patients and healthcare workers for multidrug-resistant organisms.

Devendra Amin, MD, F(CCP), is the medical director of Critical Care Services at Morton Plant Hospital in Clearwater, FL.

Note: This article is followed by another article, "Real-time PCR testing for CDI," that is also part of the Continuing Education test.

References

1. Centers for Disease Control and Prevention. S. aureus and MRSA Surveillance Summary 2007. http://www.cdc.gov/ncidod/dhqp/ar_mrsa_surveillanceFS.html . Accessed September 21, 2009.
2. Science Media Centre. Experts comment on new research regarding Community-Acquired MRSA and pneumonia, as published in The Lancet Infectious Diseases. http://www.sc iacentre.org/pages/press_releases/09-05-20_lancet_camrsa.htm . Published May 20, 2009. Accessed September 21, 2009.
3. Centers for Disease Control and Prevention, 2000, NEJM. December 28, 2000.
4. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Genday MM, et al. Effect of PCT-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised single-blinded intervention trial. Lancet. 2004;363:600-607.
5. Gonzales R, Malone DC, et al. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis. 2001; 33:757-762.
6. Roberts RR, Hota B, Ahmad I, Scott DS II, et al. Hospital and Societal Costs of Antimicrobial Resistant Infections in a Chicago Teaching Hospital: Implications for Antibiotic Stewardship. Clin Infect Dis. 2009;(10). http://www.journals.uchicago.edu/doi/abs/10.1086/605630?prevSearch=%2528Roberts%2529%2BAND%2B%255Bjournal%253A%2Bcid%255D&searchHistoryKey=. Accessed September 23, 2009.
7. Schuetz P, et al. Effect of Procalcitonin-Based Guidelines vs. Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections: The ProHOSP Randomized Controlled Trial. JAMA. 2009;302(10):1059-1066.
8. Assicot M, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341:515-518.
9. Muller B, et al. Ubiquitous expression of the calcitonin-I gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab. 2001;86:396-404.
10. Eberhard OK, et al. Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus or systemic anti-neutrophil cytoplasmic antibody-associated vasculitis) and invasive bacterial infection. Arthritis Rheum. 1997;40:1250-1256.
11. Zahar J-R, Cerf C, Maitre B, Brun-Buisson C, et al. Contribution of Blinded, Protected Quantitative Specimens to the Diagnostic and Therapeutic Management of Ventilator-Associated Pneumonia. Chest. 2005;128;533-544.
12. Guidelines for the Management of Adults with Hospital-acquired, Ventilator associated, and Healthcare-associated Pneumonia. This official statement of the American Thoracic Society and the Infectious Diseases Society of America was approved by the ATS Board of Directors, December 2004 and the IDSA Guideline Committee, October 2004. Am J Respir Crit Care Med. 2005;171:388-416.

Real-time PCR testing for CDI improves outcomes and reduces costs

By Brian Currie, MD, MPH

Enzyme immunoassay (EIA) testing for toxigenic Clostridium difficile has become standard in U.S. hospitals because of its rapid turnaround, but the assay’s low sensitivity and specificity make its use problematic. Since the consequences of not treating and isolating patients with C difficile-associated infection (CDI) can be dire, most physicians dismiss negative EIA results out of hand. As a consequence, patients are retested, treated, and isolated unnecessarily — at great cost to the healthcare system. Real-time polymerase chain reaction (RT-PCR) testing for CDI provides rapid turnaround and specificity/sensitivity that supports the elimination of most retesting and reduces the inappropriate use of scarce hospital resources.

Clostridium difficile has become a significant hospital-acquired pathogen, causing up to 25% of cases of antibiotic-associated diarrhea among inpatients.¹ Symptoms of CDI range from mild diarrhea to colitis, toxic megacolon, colon perforation, sepsis, and death.² CDI should not be confused with non-toxigenic or asymptomatic C difficile colonization.

C difficile produces two toxins: Toxin A, an enterotoxin, and Toxin B, a cytotoxin. Eighty percent of toxigenic C difficile isolates produce both toxins.³ Toxin B, produced by virtually all toxigenic C difficile strains, is approximately 1,000 times more potent than Toxin A and is essential for disease.⁴

The Association for Professionals in Infection Control and Epidemiology (APIC) estimates CDI incidence to be at least 13 per 1,000 inpatients, which is 20 times higher than previous estimates.⁵ According to APIC, approximately 109,000 patients die in U.S. hospitals every year from CDI, a figure 3.5 times higher than a nearly concurrent estimate of 28,000 deaths.⁶ Moreover, CDI adds between $2,454 and $7,179 per affected patient in additional, non-reimbursable costs and up to seven days to hospital length of stay. Estimates for costs related to CDI treatment and prevention in the United States are in the $1 billion range,⁷ but based on APIC’s figures for mortality and CDI hospital patient-days this figure is likely quite conservative.

Over the last decade, CDI epidemiology has trended toward higher incidence, increased severity, and greater mortality. Between 1999 and 2004, deaths attributed to CDI rose from 5.7 per million population to 23.7 per million,⁸ while the number of hospital discharges with CDI more than doubled between 2001 and 2005.⁶ Increased prevalence and disease severity is partly attributed to the emergence of BI/NAP1/027, the predominant strain of C difficile in the New York City metropolitan area. The rise of BI/NAP1/027 underscores the need to control C difficile and exposes the shortcomings of conventional diagnostic testing.

More than ever, rapid, accurate diagnosis of C difficile is imperative for timely and appropriate therapy and effective infection control.

Etiology and risk factors

C difficile is a Gram-positive anaerobic bacillus that exists in vegetative and spore forms, and is spread through the fecal-oral route. The spores are highly persistent and resistant to conventional disinfection and alcohol hand-gel sanitizers, which complicates isolation and containment strategies. When caring for CDI patients, healthcare workers should wash their hands with soap and water instead of alcohol-based cleansers. Soap and water does not kill spores effectively but provides physical removal and dilution. Diluted bleach solutions are required to disinfect patient environments.

Risk factors for CDI include antibiotic treatment, lengthy hospital stay, age over 65 years, and severe underlying disease.⁹ The APIC study reported that 79% of CDI patients received antibiotics before onset of CDI.⁵ Nearly all antimicrobials have been implicated in development of CDI but cephalosporins, clindamycin, and fluoroquinolones seem to carry higher risk.

The use of broad-spectrum antibiotics is a potentially long-term risk factor in the etiology of CDI through the elimination of beneficial microorganisms that compete with C difficile in the intestinal tract and because they select for strains of C difficile resistant to clindamycin and fluoroquinolones.

It has been generally assumed that risk for developing CDI diminishes in patients who discontinue antibiotic treatment. But a recent paper found that after six weeks, intestinal flora remained depleted in cefoperazone-treated mice, suggesting that risk may persist long after discontinuation of therapy.¹⁰

Another study noted that C difficile spores persist asymp-tomatically in the intestines of mice for many months with minimal shedding of spores.¹¹ Antibiotic treatment transformed such mice into highly contagious "super shedders" whose digestive tracts were depleted of beneficial bacteria. Lacking normal digestive flora, these mice experienced overgrowth of C difficile and excreted high levels of infectious spores.

These results hearken back to a small human study on patients with recurrent C difficile colitis who had received up to seven courses of systemic antibiotics. After normal intestinal flora were re-introduced, only one of 16 evaluable patients experienced a relapse of C difficile colitis.¹²

Diagnosis

A positive diagnosis of CDI requires that the patient be symptomatic and test positive for toxigenic C difficile, or have a pathologic colon specimen consistent with pseudomembraneous colitis, or show evidence of pseudomembraneous colitis on colonoscopy.¹³ When diarrhea is the primary symptom, three or more episodes per day over one to two days may be a reasonable trigger for ordering a diagnostic test for toxigenic C difficile.¹⁴ Following such rules could reduce unnecessary testing by up to 39%.¹⁵ Diarrhea can have many etiologies, however, and is not always easy to characterize clinically.

A good working definition of diarrhea is any stool that takes the shape of its container. C difficile testing, therefore, should be restricted to such samples. Simply asking about the frequency of loose stools they are experiencing can help screen patients at high risk for CDI and reduce unnecessary testing.¹⁴

Conventional diagnostic tests for CDI lack an acceptable combination of sensitivity, specificity, and timeliness. Stool culture, the most sensitive test, is labor-intensive, takes several days, and does not differentiate between toxigenic and non-toxigenic C difficile strains. Thus, confirmation of CDI requires an additional toxin-detection test which adds time and cost.

The cytotoxicity assay measures the production of Toxin B and the cytopathologic effect of a stool-sample preparation on cultured cells.¹⁶ Although it is sometimes considered the "gold standard" for detection of toxigenic C difficile and CDI diagnosis, it is less sensitive than toxigenic culture.¹⁷ In addition, cytoxicity assays are expensive, require extensive operator input, and take three to seven days.

Enzyme immunoassays use antibodies to one or both C difficile toxins. EIAs are inexpensive and take less than four hours, and have, therefore, become the default hospital-based test for CDI. Unfortunately, Toxin A/B EIAs have poor sensitivity (50% to 99%) and specificity (70% to 100%).¹⁸ Clinicians often treat regardless of the EIA result, which leads to over-treatment and unnecessary isolation.¹⁹

Another rapid assay, for glutamate dehydrogenase (GDH), a "common antigen," is based on EIA as well. Older versions of this test used latex agglutination, which is less sensitive. The GDH assay alone does not distinguish toxigenic from non-toxigenic strains of C difficile, and, thus, requires a second confirmatory test for the toxigenic pathogen. The GDH assay’s high sensitivity and negative predictive value (NPV) make it somewhat useful as a screening test for C difficile, but not for CDI.²⁰ GDH testing returns almost all true-positive results and some false-positives.¹⁶ But when coupled with cytotoxicity testing to differentiate false-positives from true-positives, the sensitivity of the two-step algorithm for detection of toxigenic C difficile fell to 77%.²¹ Thus, this two-step assay cannot be recommended for CDI testing.¹⁶

Real-time PCR

Polymerase chain reaction (PCR) assays represent the most significant recent development in CDI testing. Accurate, experimental PCR amplification methods for C difficile have existed since at least 1952 but are unsuitable for real-time testing because they require pre-test DNA purification steps which are hard to standardize and are not FDA certified.

At Monefiore Medical Center, we have had considerable experience with an assay which amplifies tcdB, the gene coding for C difficile Toxin B.⁴ The assay employs quantitative real-time PCR (qPCR), which simultaneously amplifies and detects the gene target thereby saving several hours compared conventional PCR. The test takes approximately one hour, involves 15 minutes of operator time, and runs on PCR equipment found in most labs. In addition, the assay has been optimized to allow direct stool swab sampling. The test’s sensitivity and specificity of more than 95%.²³ User groups have reported sensitivities for this assay ranging from 94% to 100%,^24,25 with NPVs of 99% and greater.^24,25 High NPVs permit clinicians to rule out a diagnosis of CDI from negative tests with confidence, a factor with great implications for patient health and hospital finances.

Comparison of methods

When using Toxin A/B EIA testing for C difficile, physicians often compensate by retesting patients with negative test results and by overtreating suspected cases. While national standards discourage retesting, few laboratories enforce these guidelines, and physicians generally ignore them.

Both positive and negative EIA results carry independent significance but only to the extent that the test result is accurate. Positive results prompt initiation of therapy and infection-control interventions; a negative result contraindicates treatment and isolation for CDI, while suggesting a workup for an alternative etiology.

False-positive and false-negative EIA test results also carry significant implications. Based on known statistics, EIA testing of symptomatic patients could be expected to return approximately 2% false-positives and 10% false-negatives.²⁶ Thus, for every 1,000 patients tested, approximately 20 will experience hospital stays prolonged by up to seven days, usually in isolation, and receive a 10-day course of antibiotics. Conversely, 100 patients who actually have CDI will not be isolated or treated.

Isolating patients is expensive. Personal protective equipment costs approximately $2 per patient visit, which adds up quickly when meals, examinations, and cleaning visits are considered. Accurate diagnostic testing could virtually eliminate inappropriate isolation, thus freeing hospital resources for more urgent caregiving.

Of the 85% or so of patients with suspected CDI whose tests are negative by Toxin A/B EIA, 10% to 12% (about 100 patients) turn out to be false by cytotoxicity testing. Theoretically, false-negatives would not be treated. In reality, clinicians using Toxin A/B EIA testing treat most patients with a negative test anyway. In our hospital — Monefiore Medical Center in the north Bronx, NY — close to 40% of those patients undergo a full, 10-day CDI antibiotic course, which for vancomycin carries a price tag of $168. Direct costs associated with EIA retesting can also be significant. Most negatives with diarrhea are retested — some, numerous times — and nearly all are isolated.

A rapid, reliable assay like qPCR reduces false-positives by half. Even greater benefit accrues from the near-elimination of false-negatives, to about 1% of patients tested, from 10% to 12% for EIA. A near-zero rate of false-negatives introduces, for the first time in the management of CDI, a scientific basis for appropriate diagnosis, treatment, infection-control interventions, and the elimination of retesting.

Available studies suggest that qPCR assays for the Toxin B gene (tcdB) are the most sensitive, specific and appropriate tests for confirming a CDI diagnosis, but some experts have argued that qPCR are too sensitive and that false-positives would arise from its ability to detect colonizing C difficile, which does not cause disease.¹⁶ This argument should apply to all tests for toxigenic C difficile; but, in fact, no study has demonstrated that a more sensitive test is more likely to detect colonizing bacteria. The best solution to this concern is to restrict testing to patients who are likely to have CDI, that is those who meet the criterion of frequent episodes of diarrhea.¹⁶

Conclusion

q PCR provides both high sensitivity and rapid turnaround time, factors that could potentially revolutionize treatment of C difficile infection and transmission. While qPCR is more expensive than EIA (about $25 vs. $8), improved diagnostic testing provides significant opportunities to reduce CDI-related treatment and isolation costs. Therefore, qPCR should be considered as a cost-effective option.

The performance of qPCR supports laboratory policies that severely limit repeat testing. Realizing the cost-saving potential, however, will require significant caregiver education on the capabilities of qPCR to guide patient management. Monefiore Medical Center is in the process of linking qPCR results to an Antibiotic Stewardship Program to accomplish these goals and to achieve optimal savings.

Brian Currie, MD, MPH, is vice president and medical director for research at Monefiore Medical Center in the north Bronx, NY, which uses the BD GeneOhm Cdiff assay for testing for C difficille Toxin B. Dr. Currie is also assistant dean for clinical research at the Albert Einstein College of Medicine, a graduate school of Yeshiva University in Morris Park, also in the Bronx.

References

1. Blossom DB, McDonald LC, et al. The challenges posed by reemerging Clostridium difficile infections. Clin Inf Dis. 2007;45:222-227.
2. Centers for Disease Control and Prevention. Information for healthcare providers. http://www.cdc.gov/ncidod/dhqp/id_CdiffFAQ_HCP.html . Published July 22, 2005. Accessed June 27, 2008.
3. McFarland LV, Beneda HW, Clarridge JE, Raugi GJ. Implications of the changing face of Clostridium difficile disease for health care practitioners. Am J of Infect Control. 2007;35(4):237-253.
4. Lyras D, et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458(4):1176-1179.
5. Jarvis WR, Schlosser J, Jarvis AA, Chinn RY, et al. National point prevalence of Clostridium difficile in US health care facility inpatients. Am J Infect Control. 2009;37(4):263-270.
6. McDonald LC. The changing epidemiology of Clostridium difficile. Poster session presented at: June 2008 Annual Meeting of the Association for Professionals in Infection Control and Epidemiology, Denver, CO.
7. Dubberke ER, Reske KA, Butler AM, et al. Attributable outcomes of endemic Clostridium difficile-associated disease in non-surgical patients. Emerg Inf Dis. 2008;14:1031.
8. Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis. http://www.cdc.gov/EID/content/13/9/1417.htm . Published September 2007. Accessed September 14, 2009.
9. Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges from an established pathogen. Cleve Clin J Med. 2006;73:187-197.
10. Antonopoulos DA, Huse SM, Morrison HG, et al. Reproducible Community Dynamics of the Gastrointestinal Microbiota following Antibiotic Perturbation. Infection and Immunity. 2009;77(6):2367-2375.
11. Lawley TD,Clare S, Walker AW. Antibiotic Treatment of Clostridium difficile Carrier Mice Triggers a Supershedder State, Spore-Mediated Transmission, and Severe Disease in Immunocompromised Hosts. Infection and Immunity. 2009;77(9):3661-3669.
12. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36(5):580-585.
13. McDonald et al. Recommendations for Surveillance of Clostridium difficile-Associated Disease. Infect Control Hosp Epidemiol. 2007; 28:140-145.
14. Peterson LR, Robicsek A. Does My Patient Have Clostridium difficile Infection? Annals of Int Med. 2009;151:176-179.
15. Katz DA, Lynch ME, Littenberg B. Clinical prediction rules to optimize cytotoxin testing for Clostridium difficile in hospitalized patients with diarrhea. Am J Med. 1996; 100:487-495.
16. Alcalá L, Sánchez-Cambronero L., Catalán MP, et al. Comparison of Three Commercial Methods for Rapid Detection of Clostridium difficile Toxins A and B from Fecal Specimens. J Clin Microbiol. 2008;46(11): 3833-3835.
17. Peterson LR, Manson RU, Paule SM, et al. Detection of Toxigenic Clostridium difficile in Stool Samples by Real-Time Polymerase Chain Reaction for the Diagnosis of C difficile-Associated Diarrhea. Clin Infect Dis. 2007;45:1152.
18. Fedorko DP, Engler ED, O’Shaughnessy EM, et al. Evaluation of two rapid assays for detection of Clostridium difficile toxin A in stool specimens. J Clin Microbiol.1999;37:3044-3047.
19. Morelli MS, Rouster SD, Gianella RA, et al. Clinical Application of Polymerase Chain Reaction to Diagnose Clostridium difficile in Hospitalized Patients With Diarrhea. Clin Gastroenterol Hepatol. 2004;2:669–674.
20. Fenner L, et al. Rapid and Reliable Diagnostic Algorithm for Detection of Clostridium difficile. J Clin Microbiol. 2008;46(1):328–330.
21. Reller ME, Lema CA, Perl TN, et al. Yield of Stool Culture with Isolate Toxin Testing versus a Two-Step Algorithm Including Stool Toxin Testing for Detection of Toxigenic Clostridium difficile. J Clin Microbiol. 2007;45(11):3601-3605.
22. Arzese A., Trani G, Riul L, Botta GA. Rapid polymerase chain reaction method for specific detection of toxigenic Clostridium difficile. Eur J Clin Microbiol Infect Dis. 1995;14:716-719.
23. Metzger B. Comparison of BD GeneOhm Cdiff PCR Assay and the Meridian Premier Toxins A&B for Detection of C difficile from Clinical Specimens Poster session presented at: March 2009 Annual Meeting of the Society for Healthcare Epidemiologists of America, San Diego, CA.
24. Alcabasa R, Aird D, Wehrlin J, et al. Comparison of the BD GeneOhm Cdiff Assay (BD GeneOhm, San Diego, CA) to the Wampole Clostridium difficile Toxin B Test (TechLab, Blacksburg, VA). Poster session presented at: 2008 annual meeting of the American Society for Microbiology, Boston, MA.
25. Fuller D, Buckner R, Newcomer K, et al. Clinical Comparison of the Molecular-Based BD GeneOhm Cdiff Assay to the Cytotoxicity Tissue Culture Assay for the Direct Detection of Toxin B gene from Toxigenic Clostridium difficile Strains in Fecal Specimens. Poster session presented at: 2008 Annual Meeting of the Anaerobe Society of the Americas, Long Beach, CA.
26. Other data (Currie B. Unpublished data, 2009).