Bad Bugs

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In much of life, change is a good thing. But a glaring exception exists — pathogens that continually mutate, creating resistance to the very pharmaceuticals designed to kill them. Their very nature is unfixed, mutable. Certain of these continually stand at the front of the line — resistant forms of tuberculosis, staphylococcus aureus, enterococcus, and others.

"Managing infections has been a "see-saw" battle pitting improved hygiene, preventive measures (especially immunization), and antimicrobial agents against microorganisms that can evolve into more virulent and antibiotic-resistant pathogens," says Hans Liu, MD, FACP, infectious disease specialist, Bryn Mawr Hospital, in Bryn Mawr, Pa. "During the 20th century, many of the major advances in controlling infection were based on better sanitation (sewage treatment, clean water), public health measures such as vaccination programs (smallpox and polio eradication), and improved nutrition. Individual patients benefited from increasingly potent and convenient antibiotics active against serious bacterial and mycobacterial infections. Unfortunately, this led to many patients expecting antibiotics for every illness, including self-limited viral infections and fevers. Physicians were prone to overuse antibiotics and some patients tended to miss doses or take too short a course of drug as they improved. This has led to the selection of multiply-antibiotic resistant microorganisms in virtually all classes (bacteria, fungi, mycobacteria, viruses, parasites). Advances in healthcare such as cancer chemotherapy, organ transplantation, and implantable prosthetic devices have also led to more difficult-to-treat and drug-resistant infections."

While some of these organisms are now prevalent in the community, the battle lines are most clearly drawn in the hospital. "With fewer antimicrobial agents currently in development, the emphasis is now on 'antibiotic stewardship' (using antibiotics more wisely to minimize development of resistance), controlling the spread of infections in the hospital and the community with programs emphasizing hygiene and appropriate isolation practices, and educating the public and healthcare workers that antibiotics are not always indicated," he adds.

There are notable efforts in the works to dramatically attack these pathogens, but, Liu says, "Many of these 'Star Wars' weapons won't be available for five to 10 years or more. A number of biotechnology approaches, such as finding new antimicrobial targets in pathogenic bacteria, developing advanced vaccines (against Staphylococcus aureus, Pseudomonas aeruginosa, and malaria, for example), and using immunologic or biochemical techniques to detect and inhibit pathogens before they cause infections are on the drawing boards."

The best short-term approach will be to work smarter, not harder, he stresses. "Emphasizing hospital infection control programs with more practitioners supported by computerized data management programs has been shown to decrease the number of hospital-acquired infections. So have programs encouraging appropriate patient isolation practices and rigorous handwashing. Taking a 'high dose, short course,' approach to antibiotic dosing may also eradicate pathogens and decrease the chance of surviving bacteria developing resistance. While not in themselves revolutionary, these measures can hold the line against some of the worst microbial threats giving us time to develop new prophylactic and therapeutic tools."

Of course, price is always a factor. "The cost of managing resistant pathogens is staggering, partially because treatment options are frequently limited to just a few available antimicrobial agents," says Peggy McKinnon, PharmD, clinical pharmacist, clinical research/infectious diseases at Barnes-Jewish Hospital. "Patients who develop resistant pathogens are often those with underlying comorbid conditions or those who are immunosuppressed, further compounding the risk of poor clinical outcomes.

Little profit stands to be made from managing acute infectious diseases, so more pharmaceutical companies are turning their backs on antibiotics and turning instead to research and development in areas of more chronic disease states. "The few companies that continue to pursue R&D efforts in the less-profitable antibiotic arena are to be commended," McKinnon adds.

Any of these risky pathogens require special treatment of patients. "In some institutions, positive patients are grouped together in a practice called 'cohort isolation.' TB also requires respiratory isolation, which is the most stringent form of isolation," says David Persing, MD, PhD, executive vice president and chief medical and technology officer for Cepheid.

Tuberculosis

Tuberculosis (TB) is back after relaxation of control due to decreased funding for public health led to increased rates, says Robert A. Weinstein, MD, BSc, chairman of the division of infectious diseases for Cook County Hospital and Rush University Medical Center in Chicago. "This disease is largely now a problem of those born in developing countries and in more vulnerable members of the U.S. population, such as HIV or AIDS patients."

"TB is spread through inhalation of dried droplet nuclei, microscopic particles of TB that are released into the air when someone with TB in their lungs or throat coughs, speaks, sneezes or sings," explains Marcia R. Patrick, RN, MSN, CIC, infection control director at MultiCare Health System in Tacoma, Wash.

"The particles get breathed by someone else deep into their lungs, because they are so tiny, and get picked up by the alveolar macrophages of the immune system. From there, they get taken to lymph nodes, and the lymphatics dump back into the bloodstream. At that point, TB can go anywhere in the body -- the brain, bones, certain glands, etc., but 85 percent of the time in adults it goes right back to the upper lobes of the lungs. There it sets up housekeeping. People with a normal immune system will build a containment field around the little TB germ, and for most, that containment field will last for their entire life. An unlucky 5 percent to 10 percent will have their containment field fail, usually in the first two years after infection, often if they are elderly or become immunosuppressed with AIDS, cancer, treatment with chemotherapy, or suppressive therapy for organ transplants. A skin test can tell us whether there is TB in the body or not- infection or no infection. It takes two to 10 weeks for a TB test to 'convert' after an exposure if the person becomes infected. Treatment at that point can reduce the five percent to 10 percent lifetime risk of developing active TB disease to virtually zero."

Directly observed therapy is often used to ensure patient compliance with medications —outreach workers go into the community and observe TB patients taking their meds, usually either three or five days per week. "It is cheaper to do this than to have the patient take the meds for a month or two and stop," Patrick explains. "People who don't take the medications for the entire time are at risk of developing multi-drug-resistant TB. The first medications kill off the easy-to-kill TB germs, but leave the tough-to-kill ones. It's the final weeks of treatment that kills off all the TB bugs."

There are many other problems related to TB therapy, however. "Part of the problem is that therapy for tuberculosis in general has not been optimized," says Tawanda Gumbo, MD, assistant professor of medicine at the University of Texas Southwestern Medical Center. "We have been using paradigms that are dated to treat TB. In the fifties and sixties, we dealt with this by adding more drugs, and this seemed to work, but now we know that you get resistance.

"This has always been characterized as, 'If only patients took their medications, we would never have resistance.' I think we should take responsibility in developing treatment regimens that do not force patients to take so many pills for so long. Another approach would be using the new drugs and those that are experimental right now properly right away," he says.

"I think if you were to say one of the most important diseases of mankind has been TB, you would be right, because at present 1 in 3 human beings has been infected with TB. Most people don't get the reactivation disease, but we know that close to 3 percent of all human death is from TB, which for one disease is staggering. It's been around for at least 10,000 years. In the 1970s, there was an exuberance that TB was dying, and people patted themselves on the backs and everything looked fine. But it was still there and came back with a vengeance."

One of the most frightening of organisms is XDR-TB, a new strain of tuberculosis (TB) that has unsettled the World Health Organization (WHO) by creating mutations that are virulent and drug-resistant. XDR-TB leaves many patients — including those infected with human immunodeficiency virus (HIV) virtually untreatable with current anti-TB drugs.

In September 2006, the WHO joined with other TB experts to address the proper response to this drug resistance. Multi-drug resistant TB is resistant to at least the two first-line treatments for TB. The newest strain, extreme-drug-resistant TB, or XDR-TB, is resistant to not only the two main first-line TB drugs, but also three or more of the six classes of second-line drugs. The first-line treatments for TB include isoniazid and rifampicin.

Resistance to anti-TB drugs is often attributed to poorly managed TB care. The care can include problems due to incorrect drug prescribing practices, poor-quality drugs, an erratic supply of drugs, or patient non-adherence.

Recent findings from a survey conducted by WHO and CDC on data from 2000-2004 found that XDR-TB has been identified in all regions of the world but is most frequent in the countries of the former Soviet Union and in Asia.

In the United States, 4 percent of MDR-TB cases met the criteria for XDR-TB. In Latvia, a country with one of the highest rates of MDR-TB, 19 percent of MDR-TB cases met the XDR-TB criteria. Separate data on a recent outbreak of XDR-TB in an HIV-positive population in Kwazulu-Natal in South Africa was characterized by alarmingly high mortality rates. Of the 544 patients studied, 221 had MDR-TB. Of the 221 MDR-TB cases, 53 were defined as XDR-TB. Of those 53, 44 had been tested for HIV and all were HIV-positive. Fifty-two of 53 patients died, on average, within 25 days, including those benefiting from antiretroviral drugs.

WHO Guidelines for the Programmatic Management of Drug Resistant Tuberculosis include recommendations to strengthen basic TB care to prevent the emergence of drug-resistance; ensure prompt diagnosis and treatment of drug resistant cases, prevent further transmission, increase collaboration between HIV and TB control programs to provide necessary prevention and care to co-infected patients, and increase investment in laboratory infrastructures to enable better detection and management of resistant cases.

Treating TB has historically had its own special issues. "Certainly oral therapy often is not feasible, and the parenteral options may be painful or have significant side effects. Most Americans and many healthcare providers are not aware of the extent and severity of the XDR-TB threat," points out Liu.

"There should be a return to management of all TB cases as a major public health threat. This includes educating healthcare practitioners and facilities about appropriate isolation for suspected TB cases, and using all public health tools (such as directly observed therapy) to cure existing cases."

For XDR-TB, reducing exposure by early case recognition is the best way to limit the spread, says Persing. "Molecular methods play a key role in this. A recent letter to the editor of Science stated this succinctly. Molecular methods also reduce the chances of the infection's spreading to lab personnel, since they do not have to grow the bug to make the diagnosis."

Molecular diagnostics technology can offer results in just a couple of hours as opposed to traditional culture-based tests that yield results in two to three days.

There are forces aligned against XDR-TB, including the Global Alliance for TB Drug Development, a not-for-profit, product development partnership accelerating the discovery and/or development of affordable new TB drugs that will shorten treatment, be effective against drug resistant strains, be appropriate for patients with HIV-TB co-infection, and improve treatment of latent infection. The alliance is working with public and private partners worldwide.

Methicillin-resistant Staphylococcus aureus (MRSA)

When battling MRSA and vancomycin-resistant enterococcus (VRE), of particular interest are improved environmental cleaning and cleansing patients with chlorhexidine, says Weinstein.

Researchers report that a patient infected with MRSA is five times more likely to die than other patients. MRSA infection rates, higher in the winter months, were linked to nearly 14,000 hospitalizations in Pennsylvania in 2004. But one hospital situated in southeastern Pennsylvania, an area with one of the highest MRSA infection rates in the state, has implemented a solution to improve infection control. The Chester County Hospital (CCH) of West Chester is a small, non-profit 234-bed facility that implemented a technology solution that made a quantifiable difference.

Before the program was implemented, identifying patients requiring isolation was not easy. Admission assessments were not done until after the patient was placed in a bed. If the assessment revealed that the patient was a carrier of a contagious infection, the patient had to be moved into isolation -- after exposing roommates and the staff. Contaminated beds and rooms required rapid disinfection. Isolation supplies sometimes ran out, and hospital workflow was significantly disrupted.

The new infection control solution uses state-of-the-art workflow technology from Siemens Medical Solutions. The fully automated management system integrates admissions, nursing and housekeeping, including all operational downstream work. When a patient enters with a history of a contagious infection, the system places an automated phone call to alert the nursing staff, directing them to perform a culture immediately to determine if the patient requires isolation. The system then guides the nursing staff to explain the situation to the patient’s family. The nursing staff now receives notification for 100 percent of all known MRSA patients. The solution has saved money by eliminating the unnecessary use of isolation rooms, shortening hospital stays, and saving thousands of healthcare dollars in the process.

The hospital was the 2006 Gold Winner of the North American Global Excellence in Business Process Management (BPM) and Workflow Award, acknowledging the positive impact on both clinical and business outcomes that it derived from its implementation of Soarian®, workflow management solution. The Bed Management and Infection Control workflows yielded positive outcomes by reducing the number of manual steps within the process of identification, notification and tracking.

"We realized that business process management was one of the keys to the survival of a healthcare system in the 21st century," stated Ray Hess, vice president, Information Management, TCCH. "The Chester County Hospital system upholds the fundamental principles of medicine – the desire to make people well, and to do so in the safest, most effective way possible."

Another unique program to combat the spread of MRSA has been kicked off by VHA Inc.. The accelerated improvement project is a national effort, with 125 hospitals participating around the country. The healthcare alliance is leveraging the collective strength of its membership to facilitate the rapid implementation of improvement methodologies and measurement. The initiative brings together industry-leading subject matter experts, data measurement tools, and a broad network of peer organizations to facilitate reduction of MRSA infections. It was launched in the fall of 2006 with a two and a half hour Web conference. The participating hospitals now network via listserv and on phone calls with VHA experts to obtain best practices and new concepts.

Marilyn Rudolph, RN, MBA, is the vice president of clinical performance improvement in the VHA Pennsylvania office, and is leading six regions in the Northeast in VHA’s national project.

"VHA started focusing on the reduction of MRSA back in May and the program came to fruition Oct. 25, 2006, when we kicked off a Web-based program," she says. "The intent is to provide the hospitals with information that is aligned with evidence-based practice or interventions that will help them to reduce MRSA infections."

A series of additional phone calls will occur monthly, and there will be Web-based interaction through March 2007. "All the improvement work is supported by a database VHA has created in alignment with the Centers for Disease Control and Prevention (CDC) to help capture the work being done, so as the hospitals apply the interventions, we are able to track their progress and give them baseline reports, as well as a report in early 2007, that will help them show their progress on work done at their organization and in comparison to other organizations."

In the northeast region of the U.S., there are six VHA regions working collaboratively, so in addition to the national project, Rudolph is supporting them with additional conference calls and data collection. "The intent is to determine where the opportunities are for making the biggest impact. Each hospital will prioritize which interventions they want to incorporate, using a self-assessment aligned with the SHEA guidelines," she adds.

The are four primary categories of interventions — hand hygiene, barrier precautions (placing patients in isolation and proper gowning and gloving), signage and flagging, to alert healthcare workers that they have a patient in isolation who needs those precautions. "If you are a known MRSA patient returning to an organization, you are flagged on admission so you can be appropriately placed and help prevent transmission. Step four is surveillance cultures. All of those interventions are optional. Nothing is mandated to participate in the program, but in active surveillance, we work to identify high-risk patients or units to start active surveillance."

The medical intensive care unit patients are considered high-risk. That entire population, then, might be selected for actives surveillance. All patients coming into unit would have their noses swabbed and a culture done to identify whether they are carrying MRSA or are free of the microorganism. Once the hospital has the results, they determine what precautions need to be taken to prevent further transmission.

"If they're coming into a hospital that is doing active surveillance, everybody would be cultured. If I returned as a patient, if I am not known to have MRSA, or if I am a high-risk population, then that hospital would be swabbing that patient," Rudolph clarifies. Long term care residents who have never been colonized with MRSA but who are coming back into the hospital for admission might be cultured, if the hospital identifies long-term care as high risk.

"Reducing and eliminating hospital acquired infections is a long term journey," she adds.

Rudolph recalls that when the program began, VHA anticipated only 30 to 50 hospitals wanting to participate, but the response was overwhelming, with, ultimately, 125 hospitals participating. "The awareness and desire to reduce MRSA has been demonstrated just through the enrollment," she says. "We think that part of it is the opportunity to participate via the Web and phone conferences, because anybody can dial in and listen in, so we can expose the initial knowledge to a broader audience than a seminar or educational session, which by necessity must limit attendance."

The company has engaged subject matter experts around the country with experience in applying all of these interventions. "We engage faculty who for the most part have done this type of work, who have experience and can directly relate to a hospital's wanting to apply these same interventions," she says.

Community-acquired MRSA (CA-MRSA) has become a widespread problem that may be more common than the hospital-acquired version.

"For several years, we've been looking at the community MRSA and have seen that most cases are of the community types of organisms," says Jane Siegel, MD, professor of pediatrics at University of Texas Southwestern Medical Center, and medical director for infection control at Children's Medical Center Dallas.

"Between 2001 and 2004, our rates just skyrocketed," she adds. "I think there is something about this organism that makes it readily transmissible. In certain environments we are seeing huge numbers of patients with it. Fortunately, most cases are relatively minor skin abscesses, but a small percentage of cases include serious invasive disease with bone infections, shock, pneumonia, and some deaths."

The hospital generally uses clindamycin for these cases, but there is approximately 8 percent to 10 percent resistance to that. "For the minor abscesses we do drainage, and the incision and drainage is often enough," Siegel says. "We do a lot of culturing, because we still see some susceptible staph, and those can be treated with other drugs. We really stress all of the hygienic techniques. For these teenagers on athletic teams, the Texas Department of Health has excellent information for school athletic departments on things to do in the locker rooms to prevent transmission, because it's been shown that when you follow these prudent practice hygienic things, such as separate towels for everybody, using appropriate cleaning and disinfection, and antimicrobial soaps, you stop the spread."

People can be colonized with MRSA and not know it. "There are certain practices in the football teams. Body shaving causes some breaks in the skin and is a risk factor, as is sharing razors and other personal items," adds Siegel. "Remarkably, if you observe all of the hygienic practices, you can control it. I think the other question that remains to be answered is, there is a huge amount of transmission of MRSA in jails and prisons, and I think people have raised the question whether that could be the reservoir for the community. We know the hygienic practices in jails and prisons are truly substandard, that people don't have their own materials and aren't able to do the things that we know work. It's important for those in charge of running the jails and prisons to see that this isn't just a jail problem, it's an overall community problem, and it's important to have an appropriate intervention in that setting."

Clostridium difficile

Another common bug is Clostridium difficile, or C. diff. "About 3 percent of the population has this organism in their bowel, living in peaceful coexistence with a host of other enteric bugs," Patrick explains. "When these people are given broad-spectrum antibiotics for an infection, it tends to kill off those other bacteria. C. diff is tough to kill, and without friendly competition from other organisms, it flourishes, and can coat the inside of the bowel with plaques called pseudomembranes. The patient can have severe diarrhea that can cause dehydration and other problems. Treatment for C. difficile is usually Flagyl or vancomycin. Linezolid can also be used. In severe cases, the colon can become very swollen, a condition called 'toxic megacolon,' and must be removed."

The problem with C. difficile is that it is highly contagious. It forms spores, which are the most difficult form of life to destroy. Usual hospital germicides do not have any effect on them. "Bleach may be of some value, but scrubbing to remove the spores is the most important part of cleaning — there's nothing like good old 'elbow grease!'" she says. Spores from C. diff can live in the environment for months and be infectious if someone touches a contaminated surface and puts a hand in their mouth. In the past several years, an extremely virulent strain of C. diff has been identified that is associated with severe disease and death."

Recently, there has been an increase in people presenting to their physicians with diarrhea caused by C. difficile — people who have not been in hospitals. "There is some evidence that this is associated with medication taken to prevent gastroesophageal reflux," Patrick adds.

"So what can the average person on the street do? First, wash your hands! It is amazing the number of people who walk out of a public restroom without washing their hands. Handwashing is the single most important action you can take to prevent the spread of infection. Use warm water to wet hands, apply soap and scrub hands for 20-30 seconds -- about two choruses of 'Happy Birthday' or 'Row, Row, Row Your Boat.' Rinse, pat dry with a paper towel, and use the towels to turn off the water and open the door to the restroom. That will keep you from putting back on your hands what you just washed off, or picking up what someone else left on the door handle when they didn't wash."


Pandemic Preparedness

According to the World Health Organization, an influenza pandemic occurs when a new influenza virus appears against which the human population has no immunity, resulting in several, simultaneous epidemics worldwide with enormous numbers of deaths and illness. With the increase in global transport and communications, as well as urbanization and overcrowded conditions, epidemics due the new influenza virus are likely to quickly take hold around the world. Annual outbreaks of influenza are due to minor changes in the surface proteins of the viruses that enable the viruses to evade the immunity humans have developed after previous infections with the viruses or in response to vaccinations. When a major change in either one or both of their surface proteins occurs spontaneously, no one will have partial or full immunity against infection because it is a completely new virus. If this new virus also has the capacity to spread from person-to-person, then a pandemic will occur.

In the past, new strains have generated pandemics causing high death rates and great social disruption. In the 20th century, the greatest influenza pandemic occurred in 1918 -1919 and caused an estimated 40–50 million deaths world wide. Although health care has improved in the last decades, epidemiological models from the Centers for Disease Control and Prevention, Atlanta, USA project that today a pandemic is likely to result in 2 to 7.4 million deaths globally. In high income countries alone, accounting for 15% of the worlds population, models project a demand for 134–233 million outpatient visits and 1.5–5.2 million hospital admissions. However, the impact of the next pandemic is likely to be the greatest in low income countries because of different population characteristics and the already strained health care resources.

If an influenza pandemic appears, expect the following, according to the WHO:

  • Given the high level of global traffic, the pandemic virus may spread rapidly, leaving little or no time to prepare.
  • Vaccines, antiviral agents and antibiotics to treat secondary infections will be in short supply and will be unequally distributed. It will take several months before any vaccine becomes available.
  • Medical facilities will be overwhelmed.
  • Widespread illness may result in sudden and potentially significant shortages of personnel to provide essential community services.
  • The effect of influenza on individual communities will be relatively prolonged when compared to other natural disasters, as it is expected that outbreaks will reoccur.
From an infection prevention and control point of view, there are a number of measures that can help curtail the spread of avian flu, including:

  • Follow proper infection control practices and principles in the healthcare environment
  • Consider the use of routine influenza vaccine during events with pandemic potential to decrease the chances of dual infection with the seasonal circulating influenza strain and the potential pandemic strain, if there is circulation of more than one influenza strain.
  • Ensure the availability of supplies of antiviral drugs for early treatment. In case of sufficient supplies, consider prophylactic use of these antiviral drugs.
  • Assess the need for additional infection control guidelines for non-medical settings, for instance for specific places where people gather or where there is a high risk of spread of infection
  • Engage in social distancing, isolation, and quarantine of individuals suspected of suffering from the flu, using proper containment mechanisms

To access the WHO Checklist for Influenza Pandemic Preparedness Planning, go to: http://www.who.int/csr/resources/publications/influenza/FluCheck6web.pdf

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