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The Race Against Resistance Creates Urgency for theDevelopment of New Antimicrobials
By Tina Brooks
With the nations attention focused on bioterrorism countermeasures, a morepressing concern went unnoticed until recently the decline in newantimicrobials, particularly antibacterial drugs.
Current annual reports from 11 major pharmaceutical companies list four newantibacterials out of 290 agents in the drug development pipeline. Only sevennew 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 patientsacquire infections each year in U.S. hospitals, resulting in 90,000 deaths. Morethan 70 percent of bacteria that cause hospitalacquired infections are resistantto 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) andmethicillin-resistant Staphylococcus aureus (MRSA), which are no longerconfined to hospital environments, are causing outbreaks of infection incommunities nationwide.
Bacterial resistance problems are getting worse every year and there is alot of data to show this. If you interface this resistance problem with optionsto treat on the decline, a perfect storm is brewing. This is bad for everybody: patients, hospitals and doctors, says JosephDalovisio, MD, chairman of the infectious disease department at the OchsnerClinic Foundation in New Orleans.
Its these alarming trends that spurred the Infectious Disease Society ofAmerica (IDSA) to lobby Capitol Hill earlier this year, while lawmakers debatedPresident Bushs Project BioShield initiative against bioterrorism.
The decline of private investments into antimicrobial research anddevelopment and the increasing development of highly resistant infectiousstrains, coupled with the emergence of new infectious diseases, create a crisissituation that cries out for a similar immediate and longterm solution,testified John E. Edwards, MD, chair of IDSAs public policy committee, beforethe Committee on Government Reform of the U.S. House of Representatives. Thousands more Americans will succumb tonaturally occurring infections in the next 10 to 15 years than to agents ofbioterrorism. Yet, no plan is on the table to address this immediate publichealth crisis.
His testimony concluded, It is important to note that biodefense effortsalso can benefit from strengthening Bioshield to support the development of newpublic health tools. Experts believe it is highly likely that individuals areworking to develop drug resistant strains of common infections (e.g.,tuberculosis, etc.). Thus, expansion of Bioshields scope to includeincentives for development of new drugs to treat these common infections, andparticularly, drug resistant strains of common infections, will have favorableimplications in the bioterrorism context. IDSA and its expert members areavailable to assist you in any way that we can.
As a result of its work with the House Government Reform Committee and HouseEnergy and Commerce Committees on Project BioShield, IDSA secured stronglanguage in both committees reports related to antimicrobial resistance anddangerous viruses. Additionally, the General Accounting Office (GAO) now has begun studying thelack of new drug development and the discontinuance of previously FDA-approved drugs. 2
The Current State of Things
Even if Project BioShields incentives were expanded to include otherdrugs, major pharmaceutical manufacturers would most likely defer them tobiotechnology companies instead.
According to some estimates, a new drug costs more than $800 million todevelop, and while that exact number has been disputed, none have argued thefact 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 theFirst International Colloquium on Generic Medicine this year. And its anuncertain process. For every 5,000 to 10,000 compounds screened for development,250 proceed to preclinical testing, only five enter clinical testing, and onlyone results in an application to the FDA (Federal Drug Administration). Andfewer 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. Thats a costlybet with very long odds and the only payback to the product developer comesat the end, after all this money is spent, if the drug actually works. Currently, biotechnology companies are acquiring FDA approvals for newversions of older drugs. Cubist Pharmaceuticals in Lexington, Mass. recently wonapproval for Cubicin (daptomycin for injection), indicated for the treatment ofcomplicated skin and skin structure infections.
It is the first of a new class of drugs that does have activities againstStaphylococcus and Enterococcus, says Edward J. Septimus, MD, FACP, medicaldirector of Memorial Hermann Healthcare System in Houston, Texas. We may beable to use it, if in fact, vancomycin and linezolid become less active. Butthis drug has not been tested nearly as extensively as vancomycin and linezolidfor some of the more serious infections.
Also under development is a range of new antibiotics called cationicantimicrobial peptides. Besides attracting increasing interest, theseantibiotics are surrounded by controversy. They are based on antimicrobials thatare naturally produced in all human, animal and plant life. Bacteria appear notto be able to develop resistance to them. Some experts, however, are concernedthat bacteria will indeed develop resistance to them and learn to evade even thebodys 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 theuse of these antibitiocs, but stressed that we shouldnt be scared off fromexploring their possibilities. If (resistance) does come along, then we haveto 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 classof antibiotics that selectively attack MRSA, but developed a vehicle to deliverthe drugs to a specific target. Using nanotechnology, the antibiotics can rideinto bacteria cells on nano-sized, plastic spheres that are one-millionth thesize of a pinhead. Once inside the bacterium, the drug is released. Turos, whosework is funded by the National Institutes of Health (NIH), says that the hopefor 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 ElizabethAlm, PhD, associate professor of microbiology at Central Michigan University inMount Pleasant. I think that they will always continue to evolve resistantmechanisms 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, Theyrecolonizing the world. Theyre getting out of hospitals and into the community.We dont even know what these bugs are necessarily capable of. There is someindication that the community-acquired MRSA may replicate faster than the othersdo, although I think that is still debatable.
Of course, the current overuse of antibiotics hasnt stemmed the tide ofthese resistant microorganisms. The U.S. Department of Health and HumanServices, however, unveiled an action plan to combat antimicrobial resistance in2001. The plan is a blueprint for coordinated effort by federal agencies toaddress this emerging public health threat domestically, and eventuallyinternationally.
Some of the more recent accomplishments of the plan included a final ruleissued from the FDA in March, requiring new warnings on antibiotic labels thatstress the proper use of antibiotics for infections with a strongly suspectedbacterial cause. The CDCs ongoing campaign, Prevent Antimicrobial Resistancein Healthcare Settings, has educated healthcare professionals about the issuethrough educational tools and materials, including 12 recommended action stepsto prevent antimicrobial resistance among specific patient populations.Similarly, the CDC, FDA and an alliance of major national health organizationsrecently launched a campaign targeted to the general public about the overuse ofantibiotics.
The fear is that we will be left with very few treatment options forinfectious 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.
Vaccines and related therapies are among the objectives of many new programsas a result of Sept. 11, 2001. President Bushs Project BioShield appears tobe moving forward for the procurement of vaccines. The National Institute ofAllergy and Infectious Diseases (NIAID) named five cooperative centers forresearch on human immunology and biodefense in September.
These new programs are warranted, however, they overlook one significantdetail. Recent attempts to vaccinate the countrys 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 healthcareworkers planned to receive the smallpox vaccine did so. The voluntary vaccineprogram has come to a grinding halt, not for lack of participation but due to aninordinate amount of time and finances, officials say.
The militarys mandatory vaccination program against anthrax faired better,but not without dissent. Several military personnel were court-martialed for refusing to take thevaccine, while hundreds of others resigned to avoid taking it because of thedrugs severe side effects.
Perceived risks of the vaccines and the fact that people do not view thethreat of bioterrorism to be urgent in this country, I think has driven down thenumbers 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 hospitals staff participated in a hepatitis Bvaccination program in New York City, while a hospitals influenza programs inGeneva, Switzerland regularly attracted 10 percent of its staff. 4,5
Although, It has been demonstrated multiple times that influenza vaccinesin healthcare workers and in people who need the vaccine prevents transmissionof influenza in the healthcare setting and also prevents bacterial infectionsthat can result from complications of influenza, we dont do a great jobvaccinating in our society, says Neil Fishman, MD, director of the Departmentof Healthcare Epidemiology and Infection Control and the director of theAntimicrobial Management Program at the University of Pennsylvania MedicalCenter in Philadelphia.
A survey of 999 healthcare workers revealed that the most common reason citedfor not receiving the influenza vaccine was that a previous inoculation wasineffective.6 Several studies have suggested that education and increasingawareness about a vaccination program was key to overcoming resistance inhealthcare workers.
Perhaps vaccination programs will never attract great numbers of healthcareworkers; however, one doctor summed up his reason for participating in one such program recently. My concern was if something happens, I dont want to take it home. So, what am I doing? Im 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. Tina Brooks