HAIs: Early and Accurate Diagnosis

Michael Bell, MD CDC	Pete Bantock Accelerate Diagnostics	Douglas White OpGen Inc	Yemi Adesokan, PhD Pathogenica

 

 

Technologies go to the next level in diagnosing hospital-acquired infections

BY KAREN APPOLD

       Each year, two million Americans go to the hospital to be treated for a known condition. Ten percent of these patients will contract a hospital-acquired infection (HAI)—and 100,000 of these people will die—more than twice the number of people killed by breast and colon cancers combined. This makes HAIs the fourth leading cause of death in the United States.
       Unfortunately, this trend is steadily increasing because the pharmaceutical and laboratory diagnostics sectors have not been able to keep up with microbial evolution.
       “Antibiotics have been used so widely that the infectious organisms they are designed to kill have adapted to them, making the drugs less effective,” says Michael Bell, MD, acting director, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention (CDC), Atlanta. “People infected with antimicrobial-resistant organisms are more likely to have longer, more expensive hospital stays, and may be more likely to die as a result of the infection. In fact, some bacteria have no antibiotic options left.”
       Studies show that nearly 50% of antimicrobial use in hospitals is unnecessary or inappropriate. “Overusing antibiotics contributes to the growing challenges posed by Clostridium difficile (C. difficile) and the antibiotic-resistant bacteria in many hospitals,” Bell says. “However, studies also demonstrate that improving the use of antibiotics in hospitals can not only help reduce rates of C. difficile infection and antibiotic resistance, but can also improve individual patient outcomes, all while saving hundreds of thousands of dollars in healthcare costs.”

A dilemma

  Quidel’s Molecular Direct C. difficile assay is a real-time polymerase chain reaction (PCR) diagnostic test for the qualitative detection and identification of toxigenic C. difficile bacterial DNA.     A big part of the problem is that infections can’t be diagnosed quickly enough. Information garnered using standard pathogen culturing methods typically requires 2 to 3 days to process. Physicians, however, are required to initiate therapy within 2 hours of suspecting a serious infection. “Without adequate information being available from the laboratory, the physician typically is compelled to initiate a regimen of broad-spectrum antibiotics,” says Pete Bantock, chief commercial officer, Accelerate Diagnostics, Tucson, Ariz. “Because of increasingly complex drug resistance, these initial attempts fail to control the infection about 30% of the time. Increased use of broad-spectrum drugs only hastens the loss of efficacy of those very same compounds.”
       This situation occurs because extensive use of these drugs serves to promote the survival of new variant strains of bacteria that acquire resistance and thereafter have the liberty to spread their “successful” genes, Bantock says. The central issue, given the lack of major new antibiotic development, is the direct need for very rapid laboratory automation and assays that not only identify bacteria, but also rule in effective antibiotics before the physician initiates the second dose of antimicrobial therapy (in less than 8 hours after receiving a patient specimen).

The Quicker, the Better
Quidel Corp offers the AmpliVue C. difficile assay, a molecular diagnostic test for C. difficile detection.
       It is preferable when infections can be detected and treated as early as possible. “Not only does that save lives and allow patients to get well sooner, but it also can reduce the risk that the infection will spread to someone else,” Bell says.
       Very ill patients in the intensive care unit have depressed immune function. They are highly vulnerable to infections because of their underlying severe illness. “Studies have shown that switching antibiotics from an inactive drug to an effective drug makes little difference in outcome if delayed for even 24 hours,”¹ Bantock says. “Additional studies have shown that with the most severely ill patients, mortality risk climbs 7.6% per hour of delay in starting effective therapy.”²
       However, as important as early diagnosis is, accurate diagnosis is even more important. “Rapid tests for HAIs can lack sensitivity and are being replaced by more costly and complex molecular tests,” says Paul D. Olivo, MD, PhD, senior medical director, Quidel Corp, San Diego. “There is a need for molecular tests which are easier to perform and less expensive, but which retain a high degree of accuracy.”
       Facilities that run surveillance programs based on complete genetic profiling of HAIs can enable more informed and proactive infection control practices to ensure a safe environment and mitigate the financial risks associated with unit closures and decontamination, says Douglas White, CEO, OpGen Inc, Gaithersburg, Md.

The Economic Burden of HAIs
      
       Time is of the essence in reducing HAIs, not only from a healthcare perspective, but also for financial reasons. According to the CDC, the annual estimated cost of HAIs ranges from $28.4 billion to $33.8 billion.³ Government regulations are already decreasing reimbursement to hospitals for HAIs and will continue to do so. As a result of the Deficit Reduction Act of 2005, which became effective on October 1, 2008, Medicare will not reimburse for certain types of HAIs.⁴
       The Affordable Care Act, which was also implemented in 2008, incentivizes hospitals to lower their readmission rates (which are often due to HAIs) and achieve better care on certain quality metrics. As of this year, hospitals get reduced reimbursement when their readmission rates exceed a certain amount.⁵ The program is funded by withholding payment from hospitals that perform poorly.

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Testing for HAIs

       In light of the impact of HAIs, laboratory technology manufacturers are stepping up to the plate to offer products that can quickly and accurately diagnose them. Here’s a sampling of what’s available now.

•        Quidel Corp has developed the AmpliVue C. difficile assay, a molecular diagnostic test for C. difficile detection. The assay is an in vitro diagnostic test for the direct, qualitative detection of the C. difficile toxin A gene (tcdA) in unformed stool specimens of patients suspected of having C. difficile infection. “The assay utilizes isothermal helicase-dependent amplification to magnify a highly conserved fragment of the tcdA sequence, and a self-contained disposable amplification detection device allows for visual evaluation of assay results,” Olivo says. The small handheld molecular device requires less than 10 minutes of hands-on time; results are available within 90 minutes.
•        Another offering from Quidel, the Molecular Direct C. difficile assay, is a real-time polymerase chain reaction (PCR) diagnostic test for the qualitative detection and identification of toxigenic C. difficile bacterial DNA. “The assay requires three steps for sample preparation and one step to set up reagents,” Olivo says. “No timed, heat, or vortexing steps are needed.” The simplified and uniform workflow with standard pipetting volumes takes less than 70 minutes. The assay can be stored refrigerated (2°C to 8°C) and set up at room temperature, eliminating the need for an ice or cooling block. The assay can be used on the Applied Biosystems 7500 Fast Dx, Life Technologies’ QuantStudioTM Dx Real-Time PCR instrument, and the Cepheid SmartCycler II.
•        OpGen’s C. difficile DNA complete test is a diagnostic test that also rapidly diagnoses the presence of C. difficile. “Unlike other available tests, it also predicts the severity of a patient’s illness based on the genetic analysis of the pathogen,” White says. “Understanding which patients are more likely to have severe cases allows faster responses with the appropriate therapy and proactive infection control measures.”
•        For outbreak surveillance and infection control, evidence shows that comparing ordered, genomic maps is the most accurate way to distinguish between outbreak isolates and sporadic infections. Unlike traditional microbial DNA fingerprinting methods, OpGen’s Whole Genome Mapping technology provides a rapid, comprehensive, highly discriminating method of strain typing, which also readily identifies and locates important genetic elements associated with virulence and drug resistance. “OpGen’s MapIt HAI Epi Services using Whole Genome Mapping will allow hospitals to better identify, analyze, and understand the genetic origins of microbial super bugs,” White says.
•        The VITEK 2 microbial identification system from bioMérieux, Durham, NC, provides microbial identification as well as state-of-the-art antibiotic susceptibility testing. “The VITEK 2 includes an expanded identification database, rapid test results, improved confidence, and minimal training time,” says Nedal Safwat, PhD, director of global marketing. It produces the information clinicians need to match the right drug to the infectious pathogen.
•        bioMérieux’s VIDAS and miniVIDAS instruments are multiparametric immunoassay systems designed to detect C. difficile and other pathogens. The VIDAS BRAHMS PCT assay measures the levels of procalcitonin in blood. This is a marker for bacterial infection and also serves as a predictive marker for sepsis.
  
  

A Close Look at the Worst Culprits        C. difficile infections affect the intestines of people who have received antibiotics. The infection not only causes diarrhea, but can also damage the colon so severely that it needs to be removed.        C. difficile infection is linked to 14,000 American deaths annually. Patients can be infected through contaminated surfaces or from contact with people’s unclean hands. Older adults are especially at risk when they take antibiotics and get medical care.6        An emerging threat that has been generated by the overuse of antibiotics is a family of germs called carbapenem-resistant Enterobacteriaceae (CRE). “CRE germs have become resistant to almost all of today’s antibiotics, and infections from these germs are on the rise among patients in medical facilities,” says Michael Bell, MD, acting director, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention (CDC). “Up to half of patients who get bloodstream infections from these germs will die.”        Although CRE germs are not very common at this time, they have increased from 1% to 4% in the past decade. One type of CRE has increased from 2% to 10%. “The United States is at a critical time in which CRE infections could be controlled if addressed in a rapid, coordinated, and consistent effort by physicians, nurses, lab staff, medical facility leadership, health departments/states, policy-makers, and the federal government,” Bell says.

 

Up and Coming        Although still under development, some technologies to detect hospital acquired infections (HAIs) are noteworthy.        To deliver same-shift, bacterial identification and antimicrobial susceptibility testing directly from patient specimens, the scientists at Accelerate Diagnostics, Tucson, Ariz, have adapted standard diagnostic test principles to take advantage of major advances in imaging technology, computing capability, and surface chemistry.        “We are eliminating the time-consuming steps of culturing and colony isolation, creating innovative methods to extract, concentrate, and immobilize live microbial cells directly from a patient specimen,” says Pete Bantock, chief commercial officer. “Using advanced fluorescent in situ hybridization technologies, coupled with sophisticated image analysis algorithms, we can identify and quantify a variety of pathogens that are associated with HAIs. In addition, using our automated time-lapse microscopy technology, we have devised a strategy of spatial clone isolation as well as high-resolution growth and phenotype analysis that enables antimicrobial susceptibility testing which can be completed in less than 8 hours.        “Through our clinical development program, we plan to demonstrate the system’s ability to rule in the drugs that remain effective against highly resistant organisms,” Bantock adds. “Our plan is to cover all significant species that are capable of expressing complex multidrug resistance.”        Pathogenica, Boston, is developing a kit that will quickly test and monitor environmental or patient samples for most known HAIs. Yemi Adesokan, PhD, CEO, says the technology is unique because it offers multiplex detection. “Many assays only focus on one or two specific pathogens,” Adesokan says. Pathogenica’s kit can detect the 17 most common HAI-causing bacteria, making it applicable for more than 95% of HAI cases worldwide, he says.        The technology also offers simultaneous resistance identification. “Users are informed of the presence of 10 of the most common drug-resistance genes (eg, mecA, vanA, KPC, and TEM), allowing hospitals to track their spread throughout their facilities,” he says.        Another advantage of the technology is that no cultures are required. “We can bypass this time-consuming step and work with patient samples directly [eg, urine, stool, and rectal swab],” Adesokan says. “This saves a great deal of time and returns results to physicians much more quickly than mass spectrometry or pulsed-field gel electrophoresis—the current standards in this field.”        Pathogenica has developed a software plug-in that automatically performs all of the bioinformatic analysis for end users, returning both species results and resistance gene information in a format that is simple and easy to understand.        The Pathogenica kit has been designed to run on almost any next-generation sequencing platform, and has already been validated to run on both the IonTorrent PGM and the Illumina MiSeq.        The kit is still marked as research use only in the United States and has not been FDA-approved. It has been CE-marked and approved for in vitro diagnostic use in the European Union.

References:
1. Niederman MS. Use of broad-spectrum antimicrobials for the treatment of pneumonia in seriously ill patients: maximizing clinical outcomes and minimizing selection of resistant organisms. Clin Infect Dis. (2006) 42 (Supp 2): S72-S81.
2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
3. The Direct Medical costs of Healthcare-Associated Infections in U.S. Hospitals and the Benefits of Prevention. Division of Healthcare Quality Promotion National Center for Preparedness, Detection, and Control of Infectious Diseases Coordinating Center for Infectious Diseases Centers for Disease Control and Prevention March 2009.
4. Hospital-Acquired Conditions (Present on Admission Indicator). Centers for Medicare & Medicaid Services.
5. Readmissions Reduction Program. Centers for Medicare & Medicaid Services.
6. Making health care safer: Stopping C. difficile infections. Centers for Disease Control and Prevention.

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Karen Appold is a contributing writer for CLP. For more information, contact Editor Judy O’Rourke, [email protected].