In vitro infectious disease diagnostics: the frontline

First up, Duane Newton, Director of Microbiology and Virology Labs, and Betsy Foxman, Professor of Epidemiology and Director at the Center for Molecular and Clinical Epidemiology of Infectious Diseases at the University of Michigan’s Hospitals and Health Centers, provide us with an overview of how their institution is tracking and preventing infection.

Then, Andrew Onderdonk, Professor of Pathology at Harvard Medical School and Director of Clinical Microbiology Laboratory at Brigham and Women’s Hospital, give us an inside look at the techniques used in infectious disease diagnostics.

“Putting patients into precautions at admission is just too difficult to maintain and many hospitals don't have the luxury of that.”
-Duane Newton

Staying one step ahead of infection

Duane Newton plans a strategic offensive against the agents of infection in the healthcare setting.

The hospital setting is a double-edged sword when it comes to infectious diseases and infection control; the weak enter to leave healthy, yet what they bring with them in terms of bacteria and infective organisms can often introduce complications. Multiply that by the majority of patients within any given hospital, and what you're left with is a bubble of infection waiting to explode given the opportunity.

Fortunately for those in need of treatment, a team dedicated to controlling infections, diagnosing infectious diseases and preventing the spread of bacteria within the hospital setting is always on hand, relentlessly at battle to ensure the best possible environment for their patients. A hospital that takes just as much pride in its team as it does with its success record is the University of Michigan's Hospitals and Health Centers (UM).

Duane Newton, Director of Microbiology and Virology labs at UM Hospital, makes sure he has everything at his disposal to give patients entering the hospital the best possible chance of leaving without encountering anything infectious; and if they do, his presence allows the turnaround of results quick enough to minimize the risk of other patients becoming infected. Newton has a passion for what he does that is rarely appreciated by those outside the 'lab- world'- and it certainly shows in his track record.

"We have been doing active surveillance for MRSA for about two years now," says Newton. "It initially started in our neonatal intensive care unit (ICU) and later included our surgical ICU; then over the course of a summer we expanded that to include all of our ICUs and our bone marrow transplant unit as a high-risk patient population. There are probably seven or eight units in the hospital that are participating in this now, and it was based on all the information that's been going around and our recognition of the potential clinical and epidemiologic impact of carriage and infection."

Primary sites

"We weren't doing it broadly, and we expanded it to be more broad," Newton continues. "The practical desire is to eventually have nasal swabs collected upon admission to any of those units - weekly while the patient is on the unit and then upon discharge from that unit." The nasal cavity may seem like just another swab site, but it is in fact the primary anatomic site for colonization. Past studies have also concluded that if nasal swabs are used in conjunction with other body sites, a significant increase in detection rates is noticed. However, Newton is quick to point out that they haven't chosen any other sites to swab for MRSA.

And while published work has dedicated itself to the detection of colonization in other body sites, there has been very little clinical correlation with regard to the risk of infection based on the colonization of those body sites. On top of this, the probability of transmission to others is raised dramatically through nasal colonization. It then becomes clear why Newton notes the anterior nares as the primary site of choice.

The world of infection control is littered with challenges, of which swab site selection is the mere tip of the iceberg. "There are two things I see as most problematic," offers Newton. "The first is deciding who to include in the surveillance population and how wide a net to cast as it changes from institution to institution. The main thing to think about is how you're using this information. Are you putting patients into contact precautions at admission and then waiting until the test results are back to decide whether to keep the precautions or remove them? Alternatively, are you doing it the other way round; are you sampling them and only putting them under precautions once they are deemed to be positive? Both approaches have different logistical challenges associated with them.

"Putting patients into precautions at admission is just too difficult to maintain and many hospitals don't have the luxury of that. The challenge on the other hand is to provide the results in a timely enough fashion that you don't have positive patients sitting around the hospital needing to go into precautions, but it's taken you five days to get that information to the provider. That's the first thing that contributes to this process. The second, within our institution, is that we don't have 100 percent compliance with the sampling schedule that's required, so the data that we're collecting with regards to our colonization and acquisition rates is suboptimal.

"That's unfortunate because this is quality assurance; it's a patient care and patient safety issue in the context of a large quality assurance program that needs to have feedback, continuous monitoring, improvement and responses to. If your data stink because they are incomplete, then the conclusions that you're drawing up are going to be inappropriate. We know that we're not capturing all the samples, and it comes down to the patient's bedside standpoint and the inability of healthcare providers to[DWN1]  do this in the context of everything else that they're trying to do."

Progressing technology

On top of this is the additional struggle of costs. Putting someone in precautions is far more expensive than the majority of people would like to believe, but when you trade off the issue of cost against another patient becoming infected, you begin to see where the struggle kicks in. To counteract this, UM and various other hospitals have begun employing specific tools and technologies to make the surveillance process more efficient.

"The traditional methods of culturing the organism have improved significantly," exclaims Newton. "In the old days, what we would do is get a nasal swab, set it up for culture, identify Staphylococcus aureus and then conduct tests to determine whether it was MRSA - that may take a couple of days to get to that endpoint. On the culture side, there are several vendors that have made media that are selective and differential for MRSA, so they allow you to specifically and selectively identify just MRSA from that sample.

"Those media are referred to as chromogenic because when you culture MRSA on the plate, it turns a specific color that's unique for whatever vendor's formulation. Companies like Bio-Rad, Becton-Dickinson, Thermo Fisher Remel and bioMérieux all have these types of selective media."

There are, perhaps unsurprisingly, more sophisticated methods that utilize molecular techniques such as PCR; Newton points out that there are also commercially available assays that are relatively simple and straightforward to use, whereby you take a swab, perform an amplification test and then potentially have a turnaround time to results of about two hours. There are assays from Cepheid that utilize the GeneXpert platform, in which the swab is put in a cartridge, then that cartridge is plugged into a machine. An hour-and-a-half later, the result is ready.

Besides these, there are other assays that remain slightly more manual and are considered 'real-time' PCR assays - but these require a fast extraction of the swab upfront. What some institutions have chosen to do, according to Newton, is utilize those types of technologies on a more rolling or potentially random access basis - allowing specimens to enter the lab and be tested to provide the results in real time. From this, the scenario that Newton describes of having everyone in precautions and only being taken out based on the results becomes more accessible - albeit from a testing standpoint.

Unfortunately, the reality of the situation always returns full circle to money; finding out how the information is being used and at what cost seems to underlie the majority of decisions in testing and infectious disease diagnostics, regardless of hospital facilities. Evanston Northwestern Hospital in Chicago, for example, tests multiple times a day, but the luxury of having single patient rooms allows them to accommodate infection control management with less difficulty than UM. The only way other hospitals can compete is by utilizing different detection methods to make up for the lack of single patient rooms.

Newton says that having evaluated several of the chromogenic media and one of the PCR assays, he found no analytical difference in the ability to detect MRSA from the swabs. When compared to molecular methods, he would also suggest a tie, but at higher price tag. "One reason we chose culture is that we're handling MRSA in the same way that we handle VRE - vancomycin-resistant enterococci - by conducting active surveillance for that organism, which is abnormal in the healthcare world. But patients that are MRSA or VRE colonized are put into precautions."

Precautions

Although UM isn't currently doing active surveillance for C. difficile, if patients are also found to be positive for that organism then they are put into contact precautions. In total, Newton hazards a turnaround time of about 24 hours to get these more comprehensive results. "It didn't make a whole lot of sense for us if we were going to handle all three of them in the same way," confirms Newton. "We could pay a lot of money for MRSA but we still had to wait for VRE and C. difficile. It didn't make a lot of sense managing those patients - so we decided we could do everything in 24 hours and that was adequate.

"Now the technology and assay availability is changing and we're seeing more molecular availability for other targets like VRE and C. difficile, so that's something that we could potentially readdress as an institution. But it's a challenge because MRSA is not the only drug resistant organism that we have to pay attention to. Undoubtedly, it's had the most attention, but especially in a large institution like ours, there are multi drug resistant organisms that are gram-positive and gram-negative that we are challenged to identify."

Inherent within this comes the simple truth: Infection control is the fundamental building block for hospital control levels. Washing hands, making sure equipment is sterile and that sterile techniques are employed should be standard - and there is no substitution for that. All the technology in the world will never replace the need for these disciplines. "It all goes back to what I was saying about the quality of our data," confirms Newton. "We're implementing multiple things at the same time, which include more robust contact precaution through programs, more attention to hand washing in addition to our active surveillance.

"It's really difficult to figure out what is having the most impact - or even if it's having any impact at all. From the lab point of view I recognize where the limitations are from the testing side and I want to make sure that all the resources we're putting into it are worthwhile. If testing doesn't have anything to do with it and it's actually hand washing, and that's all you need to focus on, then that's where you need to put your resources."

As if that weren't enough, exchanges between hospitals and long-term care facilities in terms of introducing resistant bugs back and forth in those settings add further potential problems. To ensure this is regulated, UM monitors who - and more importantly what - comes into the hospital. The hospital staff concerns themselves with immediately finding out what a patient has been admitted for, not only so they can be treated and given more efficient individual care, but also to decrease the risk of infection to other patients in the hospital.

With home-care and long-term care facilities and hospitals all sharing a much closer space, the future of infectious disease diagnostics and the wider picture of infection control seems to be the cementing and progressing of present principles. "On the technical side," offers Newton, "the direction I see things heading in the short-term is the existence more platforms where you have integrated sample processing and target detection all in one box, so they're not separate entities. They're simplified to a level where you don't have to be a hardcore molecular biology technologist in order to understand how to run the system.

"Also, the footprints are getting smaller, so it doesn't take up as much room in the laboratory. The menus on those platforms are expanding, so they can do more than just one thing. All those factors, from a management and administrative standpoint, are important in deciding to bring a new technology into the lab because, we can't afford to have a lab full of one-trick ponies. We just don't have the space for that.

"What you're seeing when you go to the trade shows now is a greater awareness of this. Technology is moving in the same direction too. Some of them are amplification-based technologies and some of them are array-based. But the biggest challenge for them is to figure out how they want to make their panel. How many different tests or targets do you want to test for at the same time? You know when you get a room full of people like me and they ask us a question, we all have different answers, so it's very difficult from the vendors' perspective to come up with something that's going to be marketable."

And yet the world of in vitro infectious disease diagnostics finds itself being introduced to new technologies and methodologies that are being pushed to work in accordance with technologists and the greater laboratory mind. There will never be a true 'ground zero' in eliminating infectious diseases and hospital-acquired infections, but perhaps that isn't the point. With people like Newton continuing to identify and tackle increasingly resistant infectious bacteria, it won't be long before the human and technological elements collide to evolve the world of infection prevention to do precisely that - prevent.

Betsy Foxman

Betsy Foxman is Professor of Epidemiology and Director at the Center for Molecular and Clinical Epidemiology of Infectious Diseases at the University of Michigan Hospitals and Health Centers. She offers her take on MRSA prevention and infection control.

On swab sites

Even though MRSA and Staph aureus colonize in multiple body sites, the focus is on the nose. Nasal colonization is associated with auto-infection of other sites, leading to wound infections and medical device infections. I don't know how soon, but I can envision a day when we will have the technology so that someone with very little laboratory expertise can take a swab, put it in a machine and detect pathogens. That will be terrific, but what I want to emphasize is that detection methods cannot replace good infection control.

Betsy Foxman on hospital populations

There are two different sources of infection in the hospital: pathogens that the patient comes in with and pathogens circulating in the hospital. Screening patients on entry lowers their risk of getting a wound infection from a pathogen they are already carrying and prevents the introduction of new pathogens to the hospital. The rates of MRSA carriage in the community are increasing - the National Health and Examination Survey (NHANES)  found that about 32 percent of the general population carry Staph aureus in their nose and about one percent carry MRSA. Among those over 65 years of age, eight percent carry MRSA in their nose.

It's a different problem to keep pathogens from continuously circulating within the hospital, than preventing new ones from coming in. The hospital population is a very dynamic one. People go in and out rapidly. Virtually all patients are treated with antibiotics, which selects for resistant bacteria. The combination of a dynamic population and high antibiotic use selects for bacteria that are easily transmitted and are resistant to antibiotics. Hospital personnel have much higher carriage rates for Staph aureus than the general population: specifically, about 40 percent. MRSA rates are higher too, approaching 10 percent for some types of hospital personnel. Even clerical staff have higher rates than the general population.

Betsy Foxman on cost

Laboratory tests are just one piece of information and if you want a decrease in infections, testing has to be part of an overall system of infection control. The problem is that infection control costs are not going to go down. Procedures can be made more efficient; the use of checklists has been effective in reducing hospital-acquired infections.

You have to get everyone to buy in; they have to use the checklist and there has to be intervention and evaluation after break-downs are detected. The increasing use of electronic monitoring is exciting. Making electronic checklists facilitates rapid detection of breakdowns in the system; this can be linked to laboratory data. That's great, but someone has to analyze the data and implement appropriate interventions.

Good infection control saves money in the long term. Infection control procedures prevent all types of infections, not just those due to MRSA. If we want to decrease antibiotic resistance - and limit the emergence of those due to MRSA - we have to think about alternative strategies for treatment and prevention of bacterial infections so we don't find ourselves continuously chasing the next drug.