Danger is Brewing

The fight to keep America's patients safe and infection free continues to turn more volatile, and as the strength and resistance of bacteria evolves, our disarmament becomes more strenuous.

Even the healthy individuals who populate Capitol Hill can no longer turn their backs to the problem and are beginning to take notice realizing we are battling much more than terrorism on our home soil. In February, for example, Rep. Louise M. Slaughter (D-NY), chairwoman of the House Rules Committee, submitted proposed federal legislation to help in the fight of this ever-challenging battle.

"The Preservation of Antibiotics for Medical Treatment Act" (H.R. 962/S. 549) was designed to "preserve the effectiveness of antibiotics for the treatment of human diseases" by eliminating the use of antibiotics as animal feed additives. Healthcare organizations across the country are embracing this proposed legislation. The American Medical Association (AMA), the Infectious Diseases Society of America (IDSA), and the American Academy of Pediatrics (AAP) are just a few of the more than 350 health, agriculture and other groups nationwide that have endorsed the bill.

According to literature within the bill, it is estimated that 70 percent of all the antibiotics used in the U.S. are used as feed additives for livestock such as chicken, hogs, and beef cattle.1 "This indiscriminate use speeds the development of antibiotic resistant bacteria on farms and can result in potential outbreaks of foodborne illnesses for which treatment options would be limited," the materials read.

The Preservation of Antibiotics for Medical Treatment Act would phase out the non-therapeutic use in livestock of medically important antibiotics, unless their manufacturers can show that they pose no danger to the public health; requires this same tough standard of new applications for approval of animal antibiotics; provides for federal payments to farmers to defray their costs in switching to antibiotic-free husbandry practices, with a preference given to family farms; authorizes grants for research and demonstration programs on means to reduce the use of antibiotics in the raising of livestock; requires manufacturers to report on the amounts of antibiotics they supply for animal use, on the animals to which those drugs are given, and on the uses for which those drugs are supplied in addition to the legislation; the aforementioned medical organizations, as well as the American Public Health Association (APHA), have each sent letters to the U.S. Food and Drug Administration (FDA) requesting it not to approve an antibiotic for use in animals, according to a press release from the "Keep Antibiotics Working" a campaign designed to fight the overuse of antibiotics.2

This recent debate encircles that of the fourth-generation cephalosporin, cefquinome, which is used to treat serious, life-threatening infections in humans. The argument is that the use of the drug for the treatment of respiratory disease in cattle would erode its effectiveness in humans.

As our human antimicrobial armamentarium dwindles, it is essential that we preserve the remaining agents wrote Martin J. Blaser, MD, immediate past president of IDSA in its letter to FDA. A strong and compelling need is necessary to justify such a risk to human health ... he continued.

In the letter penned by the AMA, Michael D. Maves, MD, MBA, AMA's executive vice president, points out that data from the National Antimicrobial Resistance Monitoring System indicate that ceftriaxone (a third-generation cephalosporin)- resistant Salmonella and Escherichia coli (E. coli) have emerged and spread in the United States.

The FDA has approved the use of 14 other drugs in eight different drug classes to treat cattle respiratory diseases.2

The Latest and Greatest Guide

New guidelines developed by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) suggest all facilities develop an antimicrobial stewardship program. The program, say its founding fathers, are hosting impressive results. The guideline, featured in the January issue of Clinical Infectious Diseases, describes antimicrobial stewardship as an activity that includes appropriate selection, dosing, route, and duration of antimicrobial therapy.

The primary goal of antimicrobial stewardship, according to the authors of the guidelines, is to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms, and the emergence of resistance.3

The population targeted by these guidelines includes all patients in acute care hospitals, and the recommendations in the guidelines were drafted to be broadly applicable to all hospitalized patients.

Core members of such a program should be all-inclusive. The key players should be made up of a multidisciplinary team that includes an infectious diseases (ID) physician, a clinical pharmacist with ID training, a clinical microbiologist, an information systems specialist, an infection control professional (ICP), and a hospital epidemiologist. All medical staff within a facility, as well as administration, should be heavily involved in the program.

"The most important thing to get out of this guideline is that in order to have an effective program to improve the use of antimicrobials, the team really has to be multidisciplinary," asserts Neil Fishman, MD, co-author of the guideline and chair of the IDSA Antimicrobial Resistance Working Group, and the SHEA liaison for the guideline.

Fishman, who also serves as the director of the department of healthcare epidemiology and infection control and director of the antimicrobial management program at the University of Pennsylvania Medical Center, and associate professor of medicine for the division of infectious diseases at the University of Pennsylvania School of Medicine; advises an all-inclusive approach to the planning, implementation, and ongoing adherence of the program. People have a stake in the program when they contribute to the development," he adds.

A Glimpse of the Problem

"If you look at a physicians use of antibiotics, at least half the time that prescription is either unnecessary or inappropriate," Fishman contends. "Obviously that has some contribution to emergence of resistance."

The other crux of the problem, he says, is that we are losing antibiotics much faster than we are gaining antibiotics. Fishman says that the biggest problem is that the pharmaceutical industry, particularly large pharma, has gotten out of the antibiotic development business. Over the last two decades, there has been an 80 percent decrease in the number of new antimicrobials that are introduced to the market.

"As a personal story, I can tell you that the last time I rounded in the hospital, which was for a two-week period, I took care of five patients who had infections that I could not treat with antibiotics. The organisms that were causing the infections were totally resistant.

"My personal biggest concern has to do with the emergence of gram negative organisms that are resistant (E. coli, etc.). For instance, because there are no drugs zero no drugs in clinical development that are directed against resistant gram negative organisms, it will be 10 to 15 years, at a minimum, before we see any new drugs directed at those organisms. What that means is, we have to do everything we can to preserve our current antimicrobials.

Antimicrobial stewardship is one large piece of that puzzle. There are others that cant be ignored, but I like to think of antimicrobial stewardship as the main gear that ties the different pieces of the machine together."

Cost

Cost is always a key term. Cost in real American dollars speaks volumes, but the cost in human life screams for necessary change. In 1998, the Institute of Medicine (IOM) estimated that the annual cost of infections caused by antimicrobial-resistant bacteria was $4 billion to $5 billion.4

One example of the human toll of antimicrobial resistance is reflected in two guideline-cited research articles, one of which was a meta-analysis where it was found that compared with vancomycin-susceptible Enterococcus faecium infections, bloodstream infections due to vancomycin-resistant enterococcus (VRE) were associated with decreased survival (24 percent vs. 59 percent), an increased length of hospital stay (34.8 days vs. 16.7 days), and an astounding cost of $27,190 associated with each episode.5,6 Another meta-analysis of nine studies of VRE bloodstream infections found that 30 percent more patients died than those with a vancomycinsusceptible enterococcus bloodstream infection.7

It has been noted that a decrease of 22 percent to 36 percent in antimicrobial use can result in an annual savings of $200,000 to $900,000 in most acute care settings because, for example, antimicrobials account for upwards of 30 percent of hospital pharmacy budgets.3

"You do save money, theres a lot of low-hanging fruit. If you get rid of the unnecessary antibiotic use, you cant help but save money," but, Fishman adds, the source of those savings may be surprising. According to an in-house study conducted at the University of Pennsylvania, researchers projected an annual cost savings of $4 million.

But that savings, it turns out, was not due to the cost of drugs," Fishman explains. "It was because patients were spending less time in the intensive care unit. There is a misconception when talking about wanting to improve antibiotic therapy that we just want to do this to save money. While it is true that these stewardship programs usually do result in financial savings for the institution, the primary reasons for doing it are to improve patient care and clinical outcomes, and secondly, to decrease the emergence of resistance."

Going that Extra Mile

Education, education, education the term touted in response to most of the world's woes. Widespread educational programs must accompany any antimicrobial stewardship program. Education is indeed key, but this battle requires much, much more.

"Education alone, without incorporation of active intervention, is only marginally effective and has not demonstrated a sustained impact," the guideline authors note.3

Their answer: antimicrobial order forms.

These order forms can be massaged to read in any way seen fit by each individual facility. It can be incorporated into the standard and necessary protocol used by the facility's healthcare workers (HCWs) when ordering and using an antimicrobial for any and all patient treatment. It can require certain signatures or peer reviews to ensure proper use is being followed. It can be an effective component of antimicrobial stewardship. But most importantly, it will facilitate implementation of practice guidelines. In the end, it will enact change.

"Formulary restriction and preauthorization requirements can lead to immediate and significant reductions in antimicrobial use and cost," the guidelines point out. The authors do note however that the long term effects and overall effectiveness of preauthorization requirements for controlling antimicrobial resistance has not been solidly established.

These "passive strategies" (i.e. education and order forms) should be followed by an active strategy with prospective audit and intervention.3 One case study of this type of program demonstrated decreased usage in antimicrobial consumption that resulted in a savings of $913,236 over an 18-month time period. During active intervention, 25 percent of antimicrobial orders were modified, and 86 percent of those resulted in less expensive therapy while 47 percent resulted in use of a drug with a narrower spectrum of activity. A significant increase was also noted in microbiologically-based prescribing 63 percent vs. 27 percent prior to implementation, the researchers add.

"Central to an effective program is a proactive strategy incorporating prospective audit with direct intervention and feedback to the provider and/or preauthorization requirements for antimicrobial use," the guideline authors write.

The whole program should be a work in progress forever evolutionary and it should change as treatment recommendations change and as new data becomes available, according to Fishman. "It is important to adapt to that and incorporate new concepts into your program as they become available," he says.

Doing Your Part

Too much is on the line to lose this battle against insidious bacterial enemies. Fishman realized this a decade-and-a-half ago when he developed an antimicrobial stewardship program at the University of Pennsylvania in 1992. Since, he has been tracking his progress and according to his research, the program has shown improvement in areas of appropriateness of antibiotic use, increased cure rates, decreased failure rates, and reduced healthcare- related costs.8 Fishman's data also suggests the program reduces the rates of Clostridium difficile-associated diarrhea, resistant gram negative bacilli, and VRE.

"These actions do tie into clinical outcomes," he offers. "We have shown this at our institution and others have shown this too. The appropriate use of antibiotics actually directly lead to improved clinical outcomes, improved patient outcomes.

"It is important that people understand the critical problem we are facing with respect to emergence of resistance," he warns. "Healthcare providers need to understand that their actions contribute to the emergence of resistance. Thats a difficult concept to get across when a doctor, a physicians assistant or a nurse is treating a patient.

It is very difficult to think beyond that person sitting in front of you, and to think globally."

IDSA and SHEA suggest a plethora of research and study ideas for those willing to yield some armor in this battle, and help to find a measurable outcome. A few such recommended topics include:3

Antimicrobial cycling at the patient, unit, and institutional level to determine whether cycling is effective and, if so, the optimal antimicrobials to be cycled, the optimal duration of the cycles, and the preferred order in which agents should be cycled.

Clinical validation of mathematical models suggesting that heterogeneous antimicrobial use slows the spread of resistance The long-term impact of formulary restriction and preauthorization requirements on antimicrobial use and resistance Evaluation of "bundled" approaches that incorporate many or all of the most effective strategies Examination of the effectiveness of these strategies in more detail in subpopulations of hospitalized patients, including neonates, infants, and children; elderly patients; and severely immunocompromised patients For a full list of research ideas, or to access the IDSA/SHEA guideline, visit www.journals.uchicago.edu/CID/journal/issues/v44n2/41270/41270.html?erFrom=6619466935396660965Guest.

References 

1. Slaughter L. M. Slaughter introduces bill to curb excessive use of antibiotics: new law will limit antibiotic use in livestock feed, help to combat growth of treatment-resistant bacteria. Feb. 9, 2007. www.louise.house.gov/index.php?option=com_content&task=view&id=765&Itemid. 

2. Keep Antibiotics Working: the campaign to end antibiotics overuse, press release. Four leading medical organizations tell FDA to reject animal drug used to treat life-threatening infections in humans; urge FDA to heed recommendation of scientific advisory committee. April 2007.

3. Dellit TH., et. al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clinical Infectious Diseases. 2007;44:159-177.

4. Institute of Medicine. Antimicrobial drug resistance: issues and options. Workshop report. Washington: National Academy Press, 1998.

5. Stosor V, et. al. Enterococcus faecium bacteremia: Does vancomycin resistance make a difference? Arch Intern Med 1998; 158:5227.

6. Diaz G. CA, et. al. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis 2005; 41:32733.

7. Salgado CD, Farr BM. Outcomes associated with vancomycin-resistant enterococci: a meta-analysis. Infect Control Hosp Epidemiol 2003; 24:6908.

8. Fishman N. Antimicrobial stewardship. Am J Infect Control. 2006 Jun;34(5 Suppl 1):S55-63; discussion S64-73.

Different as Night and Day Or Is It?

Henry Trumbo, PharmD, CIC, clinical manager of infection control and antimicrobial pharmacy services at Mercy Hospital of Philadelphia, offers a unique spin to this multi-faceted problem. Trained and hired as a pharmacist, Trumbo now serves as the infection control practitioner (ICP) for Mercy Hospital. He shares with ICT his experience in both ends of the spectrum and how he has tied his experiences together to come up with an effective plan for his facility.

The No. 1 thing is that it is prospective; meaning there is a component where you have to look at these things every day as opposed to retrospectively analyzing things and making changes. You have to constantly be looking at it," he begins.

When I was in the pharmacy, we printed a list of patients on antibiotics and we went around chart by chart. We would look at those patients and ensure that their antibiotic regimen was appropriate. You dont always have cultures, so you make recommendations empirically as well. We did see results. We were able to make a significant amount of changes, and over a three-year span, we reduced antimicrobial expenditures by about $100,000.

In 2005, Trumbo switched over to infection control.

It was one of those deals where I was doing what I was doing in the pharmacy, and infection control was doing what infection control does, and I dont think either one of us realized that the other person held the key to really solving some of the antimicrobial usage. Certainly there is a big potential there to produce some good results.

"What I didnt know in pharmacy I now have the ability to pull electronic microbiology reports on patients. So now we pull patient charts that have had positive cultures. It is much easier to convince physicians to adjust the antibiotics when you actually have culture results in your hand because we know whats growing now. We have documented proof. The biggest problem I faced in the pharmacy is that I was looking at all of the patients on antibiotics. I didnt really have radar; everybody was on the radar. But now, with positive cultures, I have a way of seeing where the hot-spots are in the hospital and going and attacking it. Now I am not flying blind like I was in the pharmacy."

In May, Trumbo kicked off a new antimicrobial program. In 2006, we removed some of our antibiotic restrictions," he explains. "We used to be very restrictive and required infectious disease (ID) consults for half a dozen antibiotics and then there were other ones that they could not even start without an ID consult. Weve loosened those up because there is now data out there that shows if you start broader (with the antibiotics) and then streamline, you can reduce mortality specifically in critically ill patients."

He continues, "Obviously, when you remove the restrictions, on the tail end you have to have a way to bring them back in. We are now at the point where we are going to rein some of that back in."

Trumbo says the new program is a combination of allowing people to use the heavy-hitter drugs, but then streamlining the usage of those drugs on the backend.

" I think the most important thing is that it takes a multidisciplinary team of people. If pharmacy is just doing it themselves, you kind of chase your tail. You have to have physician approval to make the adjustments to some of these antibiotic regimens. It involves collaboration with your antimicrobial prescribers, which could be different at every hospital. We have to get together and agree on what our stance is on the antimicrobials that we have on formulary, how we are going to deal with certain infections, and how we are going to deal with certain resistant organisms.

"It is time consuming because someone has to be looking at this almost every day, and the resistant organisms you need to tackle bug by bug as they grow," he concludes.

Guidelines-at-a-Glance: "Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship"

1. Core members of a multidisciplinary antimicrobial stewardship team include an infectious diseases physician, a clinical pharmacist with infectious diseases training, a clinical microbiologist, an information system specialist, an infection control professional, and a hospital epidemiologist.

2. Collaboration between the antimicrobial stewardship team and the hospital infection control and pharmacy and therapeutics committees or their equivalents is vital.

3. The support and collaboration of hospital administration, medical staff leadership, and local providers in the development and maintenance of antimicrobial stewardship programs is vital.

4. The infectious diseases physician and the head of pharmacy, as appropriate, should negotiate with hospital administration to obtain adequate authority, compensation, and expected outcomes for the program.

5. Hospital administrative support for the necessary infrastructure to measure antimicrobial use and to track use on an ongoing basis is essential.

6. Two core strategies, that are not mutually exclusive, will provide the foundation for an antimicrobial stewardship program:
A: Prospective audit with intervention and feedback 
B. Formulary restriction and preauthorization 

7. The following elements may work as supplements to the core strategies: education, guidelines and clinical pathways, antimicrobial cycling, antimicrobial order forms, combination therapy, streamlining or de-escalation of therapy, dose optimization, parenteral to oral conversion.

8. Healthcare information technology (IT) in the form of electronic medical records, computer physician order entry, and clinical decision support can improve antimicrobial decisions through the incorporation of data on patient-specific microbiology cultures and susceptibilities, hepatic and renal function, drug/drug interactions, allergies, and cost.

9. Computer-based surveillance can facilitate good stewardship by more efficient targeting of antimicrobial interventions, tracking of antimicrobial resistance patterns, and identification of nosocomial infections and adverse drug events.

10. The clinical microbiology laboratory plays a critical role in antimicrobial stewardship by providing patient-specific culture and susceptibility data to optimize individual antimicrobial management and by assisting infection control efforts in the surveillance of resistant organisms and in the molecular epidemiologic investigation of outbreaks.

11. Both process measures (ask yourself: 'Did the intervention result in the desired change in antimicrobial use?') and outcome measures (ask yourself: 'Did the process implemented reduce or prevent resistance or other unintended consequences of antimicrobial use?') are useful in determining the impact of antimicrobial stewardship on antimicrobial use and resistance patterns.

Source: Dellit, Timothy H., et. al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clinical Infectious Diseases. 2007;44:159-177.

IDSA Urges Congress to Support Hatch Amendment; Provisions Would Counter the Threat of Drug-Resistant Superbugs

The Infectious Diseases Society of America (IDSA) is calling on members of Congress to support the Antibiotic Safety and Innovation amendment introduced by Sen. Orrin Hatch (R-UT) to the Food and Drug Administration (FDA) Revitalization Act. Without innovative public policy, the IDSA says, the practice of medicine may return to the pre-antibiotic era when acquiring a bacterial infection was often a death sentence.

The FDA Revitalization Act offers an important opportunity to avert the public health crisis that antimicrobial resistance is creating in hospitals and communities across the nation and at the same time to strengthen patient safety. The Hatch amendment will:

• Expand incentives to spur the development of new, effective antibiotics 

• Spur research on new indications or uses for approved antibiotics 

• Require the FDA to establish and reassess antimicrobial breakpoints so that physicians have the information necessary to use antibiotics wisely and in a way that will not put patients safety or public health at greater risk 

The Centers for Disease Control and Prevention (CDC) reports that more than 63,000 patients in the United States die every year and many more suffer greatly from hospital-acquired bacterial infections that are resistant to at least one common antibioticmore deaths than from AIDS, traffic accidents or influenza. The actual number of deaths is likely much higher as many deaths attributed to other causes, particularly those of elderly patients suffering from multiple conditions, may in reality be due to drug-resistant infections.

Antibiotic-resistant bacterial infections kill tens of thousands of Americans every year and can strike anyone -- young or old, healthy or chronically ill. It is becoming quite common now for resistant bacterial infections to be acquired in the community-setting rather than in hospitals; methicillin-resistant Staphylococcus aureus (MRSA) is a good example of this recent phenomenon. MRSA is an aggressive, difficult to treat form of bacteria that has spread rapidly at an epidemic rate within communities. The FDA Revitalization Act can help to protect patient safety and the public health against antimicrobial resistance, the IDSA says.

As of press time in mid-May, it appears that the Senate has passed this piece of legislation. On May 9, Sen. Edward Kennedy, chairman of the Health, Education, Labor and Pensions Committee, released the following statement in response to the passage of the FDA Revitalization Act: This landmark legislation creates a stronger Food and Drug Administration and sets forth a new and better direction for the safety of drugs we take and the food we eat. Almost half of all Americans take at least one pill a day, so this legislation will make a difference in the life of every American family. From prescription drugs to pacemakers to chemotherapy to the food we eat, the FDA protects the health of hundreds of millions of Americans often in ways we barely realize. The FDA should be the gold standard for safety but its luster has been tarnished in recent years by failure to protect the American people from unsafe drugs. Congress has ample power to restore the luster that FDA has lost in recent years and the bill we just passed represents a bipartisan consensus on the best way to get the job done. Safety and better access are at the core of the bill. It greatly improves the way the FDA oversees the safety of the drugs. It recognizes that when patients are in danger, the FDA should not have to wait to get legal opinions to decide how to protect health. It should be able to act immediately, and our bill gives it that authority.

Kennedy continued, In this new era of the life sciences, medical advances will continue to bring immense benefits for our citizens. To fulfill the potential of that bright future, we need not only brilliant researchers to develop the drugs of tomorrow, but also strong and vigilant watchdogs for public health to guarantee that new drugs and medical devices are safe and beneficial, and that they actually reach the patients who urgently need them.