The Race Against Resistance Creates Urgency for the Development of New Antimicrobials

By Tina Brooks
From Infection Control Today
Posted December 2003

With the nation’s attention focused on bioterrorism countermeasures, a more pressing concern went unnoticed until recently — the decline in new antimicrobials, particularly antibacterial drugs.

Current annual reports from 11 major pharmaceutical companies list four new antibacterials out of 290 agents in the drug development pipeline. Only seven new antibacterials have been approved by the U.S. Food and Drug Administration (FDA) in the last five years. ¹

This is occurring at the same time that approximately 2 million patients acquire infections each year in U.S. hospitals, resulting in 90,000 deaths. More than 70 percent of bacteria that cause hospitalacquired infections are resistant to at least one of the drugs most commonly used to treat those infections, reports the Centers for Disease Control and Prevention (CDC).

Vancomycin-resistant Staphylococcus aureus (VRSA) and methicillin-resistant Staphylococcus aureus (MRSA), which are no longer confined to hospital environments, are causing outbreaks of infection in communities nationwide.

“Bacterial resistance problems are getting worse every year and there is a lot of data to show this. If you interface this resistance problem with options to treat on the decline, a perfect storm is brewing. This is bad for everybody: patients, hospitals and doctors, “says Joseph Dalovisio, MD, chairman of the infectious disease department at the Ochsner Clinic Foundation in New Orleans.

It’s these alarming trends that spurred the Infectious Disease Society of America (IDSA) to lobby Capitol Hill earlier this year, while lawmakers debated President Bush’s Project BioShield initiative against bioterrorism.

“The decline of private investments into antimicrobial research and development and the increasing development of highly resistant infectious strains, coupled with the emergence of new infectious diseases, create a crisis situation that cries out for a similar immediate and longterm solution,” testified John E. Edwards, MD, chair of IDSA’s public policy committee, before the Committee on Government Reform of the U.S. House of Representatives. “Thousands more Americans will succumb to naturally occurring infections in the next 10 to 15 years than to agents of bioterrorism. Yet, no plan is on the table to address this immediate public health crisis.”

His testimony concluded, “It is important to note that biodefense efforts also can benefit from strengthening Bioshield to support the development of new public health tools. Experts believe it is highly likely that individuals are working to develop drug resistant strains of common infections (e.g., tuberculosis, etc.). Thus, expansion of Bioshield’s scope to include incentives for development of new drugs to treat these common infections, and particularly, drug resistant strains of common infections, will have favorable implications in the bioterrorism context. IDSA and its expert members are available to assist you in any way that we can.”

As a result of its work with the House Government Reform Committee and House Energy and Commerce Committees on Project BioShield, IDSA secured strong language in both committees’ reports related to antimicrobial resistance and dangerous viruses. Additionally, the General Accounting Office (GAO) now has begun studying the lack of new drug development and the discontinuance of previously FDA-approved drugs. ²

The Current State of Things

Even if Project BioShield’s incentives were expanded to include other drugs, major pharmaceutical manufacturers would most likely defer them to biotechnology companies instead.

“According to some estimates, a new drug costs more than $800 million to develop, and while that exact number has been disputed, none have argued the fact that the cost of development is large and has doubled over the past decade,” said Mark B. McClellan, MD, PhD, commissioner of the FDA, in a speech before the First International Colloquium on Generic Medicine this year. “And it’s an uncertain process. For every 5,000 to 10,000 compounds screened for development, 250 proceed to preclinical testing, only five enter clinical testing, and only one results in an application to the FDA (Federal Drug Administration). And fewer than 1 in 2 that even enter the most expensive phase of clinical testing, so-called Phase 3, actually result in applications to the FDA. That’s a costly bet with very long odds — and the only payback to the product developer comes at the end, after all this money is spent, if the drug actually works.” Currently, biotechnology companies are acquiring FDA approvals for new versions of older drugs. Cubist Pharmaceuticals in Lexington, Mass. recently won approval for Cubicin (daptomycin for injection), indicated for the treatment of complicated skin and skin structure infections.

“It is the first of a new class of drugs that does have activities against Staphylococcus and Enterococcus,” says Edward J. Septimus, MD, FACP, medical director of Memorial Hermann Healthcare System in Houston, Texas. “We may be able to use it, if in fact, vancomycin and linezolid become less active. But this drug has not been tested nearly as extensively as vancomycin and linezolid for some of the more serious infections.”

Also under development is a range of new antibiotics called cationic antimicrobial peptides. Besides attracting increasing interest, these antibiotics are surrounded by controversy. They are based on antimicrobials that are naturally produced in all human, animal and plant life. Bacteria appear not to be able to develop resistance to them. Some experts, however, are concerned that bacteria will indeed develop resistance to them and learn to evade even the body’s normal defenses against disease, thus making recovery slower and many diseases more lethal.³

Edward Turos, PhD, professor of chemistry at the University of South Florida (USF) in Tampa, acknowledges that a dangerous situation could arise through the use of these antibitiocs, but stressed that we shouldn’t be scared off from exploring their possibilities. “If (resistance) does come along, then we have to deal with it and maybe discontinue the therapy that relies on that approach.”

Turos and a team of chemists from USF not only recently patented a new class of antibiotics that selectively attack MRSA, but developed a vehicle to deliver the drugs to a specific target. Using nanotechnology, the antibiotics can ride into bacteria cells on nano-sized, plastic spheres that are one-millionth the size of a pinhead. Once inside the bacterium, the drug is released. Turos, whose work is funded by the National Institutes of Health (NIH), says that the hope for this new delivery system is that it can be applied eventually to other classes of drugs.

The Never-Ending Battle

“Bacteria have an amazing ability to adapt and evolve,” says Elizabeth Alm, PhD, associate professor of microbiology at Central Michigan University in Mount Pleasant. “I think that they will always continue to evolve resistant mechanisms to whatever drugs we put into the environment. We maybe able to slow the trend, but we will not be able to stop it.”

John F. Toney, MD, associate professor of medicine at USF, adds, “They’re colonizing the world. They’re getting out of hospitals and into the community. We don’t even know what these bugs are necessarily capable of. There is some indication that the community-acquired MRSA may replicate faster than the others do, although I think that is still debatable.”

Of course, the current overuse of antibiotics hasn’t stemmed the tide of these resistant microorganisms. The U.S. Department of Health and Human Services, however, unveiled an action plan to combat antimicrobial resistance in 2001. The plan is a blueprint for coordinated effort by federal agencies to address this emerging public health threat domestically, and eventually internationally.

Some of the more recent accomplishments of the plan included a final rule issued from the FDA in March, requiring new warnings on antibiotic labels that stress the proper use of antibiotics for infections with a strongly suspected bacterial cause. The CDC’s ongoing campaign, Prevent Antimicrobial Resistance in Healthcare Settings, has educated healthcare professionals about the issue through educational tools and materials, including 12 recommended action steps to prevent antimicrobial resistance among specific patient populations. Similarly, the CDC, FDA and an alliance of major national health organizations recently launched a campaign targeted to the general public about the overuse of antibiotics.

“The fear is that we will be left with very few treatment options for infectious diseases,” Alm says. “And, the hope is that our technology will be able to keep pace, we will be able to make new discoveries and bring new products on line.”

On the Home Front: Vaccination Programs

Vaccines and related therapies are among the objectives of many new programs as a result of Sept. 11, 2001. President Bush’s Project BioShield appears to be moving forward for the procurement of vaccines. The National Institute of Allergy and Infectious Diseases (NIAID) named five cooperative centers for research on human immunology and biodefense in September.

These new programs are warranted, however, they overlook one significant detail. Recent attempts to vaccinate the country’s first line of responders, healthcare workers and military personnel, were unsuccessful.

As of August 23, only 38,257 people of the nearly half a million healthcare workers planned to receive the smallpox vaccine did so. The voluntary vaccine program has come to a grinding halt, not for lack of participation but due to an inordinate amount of time and finances, officials say.

The military’s mandatory vaccination program against anthrax faired better, but not without dissent. Several military personnel were court-martialed for refusing to take the vaccine, while hundreds of others resigned to avoid taking it because of the drug’s severe side effects.

“Perceived risks of the vaccines and the fact that people do not view the threat of bioterrorism to be urgent in this country, I think has driven down the numbers that have participated in these programs,” says Edward Septimus, MD, medical director of Memorial Hermann Healthcare System in Houston, Texas.

Participation in vaccination programs, in general, has been traditionally low. Only 55 percent of a hospital’s staff participated in a hepatitis B vaccination program in New York City, while a hospital’s influenza programs in Geneva, Switzerland regularly attracted 10 percent of its staff. ^4,5

Although, “It has been demonstrated multiple times that influenza vaccines in healthcare workers and in people who need the vaccine prevents transmission of influenza in the healthcare setting and also prevents bacterial infections that can result from complications of influenza, we don’t do a great job vaccinating in our society,” says Neil Fishman, MD, director of the Department of Healthcare Epidemiology and Infection Control and the director of the Antimicrobial Management Program at the University of Pennsylvania Medical Center in Philadelphia.

A survey of 999 healthcare workers revealed that the most common reason cited for not receiving the influenza vaccine was that a previous inoculation was ineffective.6 Several studies have suggested that education and increasing awareness about a vaccination program was key to overcoming resistance in healthcare workers.

Perhaps vaccination programs will never attract great numbers of healthcare workers; however, one doctor summed up his reason for participating in one such program recently. “My concern was if something happens, I don’t want to take it home. So, what am I doing? I’m protecting myself and other healthcare providers with the smallpox vaccine,” says John F. Toney, MD, associate professor of medicine at the University of South Florida in Tampa.