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Are we entering a post-antibiotic era?
Efforts to sustain the lifespan of current antibiotics are vital and must originate in primary care practices.
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Seventy years after widespread penicillin use revolutionized the way infections are treated, many infectious disease specialists worry that appropriate antibiotics will be unavailable to treat those who need them the most.
Experts agree that decades of antibiotic use and abuse have contributed to the emergence of antibiotic-resistant organisms in both hospital and community settings.
About 50% of pneumococci strains express some levels of penicillin resistance, 50% of hospital-associated S. aureus strains are methicillin-resistant and about 30% of enterococci are vancomycin resistant, according to data published in The New England Journal of Medicine.
“Prior to this era, there were several times when experts were concerned that antibiotic resistance would lead to the inability to treat patients,” said Thomas O’Brien, MD, vice president of the Alliance for the Prudent Use of Antibiotics. “Looking at the past, these concerns are often heightened in the years prior to the introduction of newer, stronger antibiotics.” However, currently there are no new classes of antibiotics entering late-stage clinical development — marking a breach between the past and present.
Michael Pichichero, MD, director of the Rochester General Hospital Research Institute in New York and Infectious Diseases in Children Editorial Board member, projects that it will be at least five to six years before any new antibiotics are approved for children.
Ron Dagan, MD, director of the pediatric infectious disease unit at Soroka Medical Center in Beer-Sheva, Israel, concurred.
“We now have a limited number of antibiotics we can give that are licensed for children and some of those bugs, such as Streptococcus pneumoniae 19A and methicillin-resistant Staphylococcus aureus, are basically resistant to almost anything you can give in the community setting,” Dagan told Infectious Diseases in Children. “Our only resources are drugs that are extremely expensive, toxic or otherwise not licensed for children.”
While MRSA and S. pneumoniae remain the most problematic pathogens, the Infectious Diseases Society of America has identified several bugs, called the “ESKAPE” pathogens, which cause the most U.S. hospital-associated infections and are resistant to many antibacterial drugs:
- Enterococcus faecium.
- Staphylococcus aureus.
- Klebsiella pneumoniae.
- Acinetobacter baumannii.
- Pseudomonas aeruginosa.
- Enterobacter species.
Furthermore, as therapies for conditions such as cancer, diabetes and HIV/AIDS improve, the proportion of patients who are susceptible to infection in the health care setting also increases. “There are a lot more immunosuppressant therapies coming to market, and we don’t know what kind of novel infections we’re going to see as a result of those treatments,” Steve Projan, PhD, global head of infectious diseases and vice president at Novartis Institutes for Biomedical Research in Cambridge, Mass., told Infectious Diseases in Children.
A dwindling pipeline
The push and pull between the economic driving forces of business and the regulatory committees designed to oversee drug development may be contributing to a stalemate for antibiotic development.
Bozena Korczack, PhD, vice president of drug development at PolyMedix, a company founded in 2002 to design novel product candidates, said that many pharmaceutical companies have been backing off of antibiotic development since the 1980s, leaving this work to smaller companies and startups.
“If you don’t have an investor that will support you during clinical stages of development, then the timing in developing something new and innovative is compromised,” Korczack said. While academic institutions are often successful at identifying novel genomic targets for therapy, the extensive resources needed to identify drug candidates for these targets and test them in clinical trials are expensive and often beyond the means of academia, she said.
High investment costs coupled with an 80% to 90% project failure rate makes anti-infective drug development less appealing to investors compared with other drug development endeavors.
“Antibiotics are used for a limited number of days in a limited number of individuals, so the return on investment of a company that dedicates itself to antibiotic development is going to be less than if they dedicate themselves to a cardiovascular drug or a neurological drug where the patient will have to take the medication every day of their life once they’re put on that drug,” Pichichero said.
Abbott, Merck and Roche are among key players that have either reduced efforts to develop antibiotics or abandoned them all together, according to reports in The Lancet. (See table list of antibiotics in phase-2 and phase-3 development.)
Investigational antimicrobials such as ceftobiprole, telavancin, and oritavancin — all with indications for complicated skin and soft tissue infections — are among the drugs the FDA has turned away in recent years.
“Unless we can demonstrate that our drugs actually have impact on unmet needs instead of presenting the next marginally-better MRSA drug, then we’re not going to get approval,” Projan said.
Heightened regulation
More pharmaceutical companies are finding work on investigational drug candidates delayed or halted in late stages of development due to increasing demands from the FDA for more stringent clinical documentation.
Projan said conservative estimates put the price tag for developing a new drug at around $300 million to $600 million, but these costs can easily surpass $1 billion when additional trials are required for approval and for post-marketing commitments.
In June 2008, the biopharmaceutical company Replidyne discontinued phase-3 trials of faropenem medoxomil, a broad spectrum beta-lactam oral antibiotic with initial indications sought for acute exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired pneumonia and uncomplicated skin and soft tissue infections.
The decision came following the completion of 11 phase-3 efficacy trials and a safety database that included 5,000 patients. The FDA initially accepted Replidyne’s new drug application for faropenem in early 2006, but it issued a non-approvable letter for the drug in October of the same year, requiring further clinical studies for several of the indications and alternate dosing regimens.
In February 2007, Forest Laboratories dropped out of a partnership with Replidyne to commercialize the drug. After a second warning letter from the FDA in January of 2008 and unsuccessful attempts to secure a partner for the program, Replidyne could no longer afford to develop faropenem. Then in early 2009, Replidyne was dissolved in a merger with Cardiovascular Systems Incorporated, a catheter manufacturing company.
While he acknowledged the FDA should be focused primarily on safety and efficacy, Projan criticized the current regulatory process as “archaic.”
Pichichero agreed that after economics, inconsistencies in the regulatory process are the biggest problem facing new antibiotic development today.
Even when a new antibiotic is successfully approved, the process is often long and grueling. For example, 12 years passed from the time tigecycline was discovered in 1993 to the time it became commercially available. Between 2000 and 2005, Wyeth spent $12.5 million in research and development.
“Given the fact that we were told that there is a pressing need for new drugs against resistant strains, this process was far too long and far too time consuming,” Projan said.
IDSA voices concerns
In the August issue of Clinical Infectious Diseases, the IDSA took issue with several policies that it believes constitute “excessive regulatory oversight.”
In its report, IDSA identified several problem areas that it said are straining institutional review boards, confusing prospective study participants, perplexing scientists conducting pediatric research and unduly lengthening the research process.
Reducing redundant data review and increasing funding for the Office for Human Research Protection are two target areas that may help “restore the balance” between equal needs for research and oversight, according to the IDSA.
Clarifying regulatory terms used to classify pediatric research and streamlining the process by which regulatory panels provide guidance for pediatric trials are other steps, IDSA officials wrote.
Stimulating drug development
Efforts to refine clinical trial guidelines and improve intellectual property protection for researchers who develop antimicrobials are among options under discussion to resuscitate a suffocating industry.
Projan explained that the required design of clinical trials is often different from how a drug will actually be used in practice.
With so few antibiotics receiving approval, health care providers in the hospital setting are left with older antibiotics in some of the most difficult circumstances.
Another problem lies in establishing adequate safety profiles for rare, serious adverse event. Even a relatively large clinical trial will not be sufficiently powered to detect these. “We’re left in a position of generating lots of data that really don’t speak to the broader question of the absolute safety of a given product,” Projan said. Broader study populations are needed, which are often only available post-marketing.
Providing patent protection
Adjusting the standard 20-year patent life for new drugs or offering longer periods of market exclusivity may be a reasonable way to reinvigorate an industry with limited options.
Because of the long development process unique to the pharmaceutical industry, Projan feels that researchers who work to develop new antimicrobials do not have their intellectual property protected in the same way that inventors in other industries do. In the case of tigecycline, more than 50% of the patent-life had expired before the drug became commercially available.
“You get patents on things very often after you’ve actually begun selling them,” Projan said. “Isn’t it wonderful that the George Foreman Grill gets 20 years of intellectual property protection, but a life-saving antibiotic often gets less than five?”
Incentives for pediatric medications
In the meantime, Congress and the FDA have created several initiatives to foster dialogue with pharmaceutical companies and provide incentives to encourage new drug development for the pediatric population, a historically understudied subset of patients.
Before 1997, no standards existed to guide medication labeling for children, and pharmaceutical companies rarely pursued clinical trials in children due to difficulties enrolling patients and obtaining informed consent from parents and guardians.
Edward Cox, MD, MPH, director of the U.S. Office of Antimicrobial Products, noted the significance of growing drug resistance but also emphasized the time involved in drug development.
“To be prepared for infections currently or in years down the road, the investment into antibacterial drug development must be made in years prior so that new options are available,” he said.
Cox and Sumathi Nambair, MD, deputy director of safety in the Division of Antiinfectives and Ophthalmology at the FDA’s Center for Drug Evaluation and Research, spoke with Infectious Diseases in Children about some of the tools they hope will help not only make medications safer for children, but will also supply more effective antibiotics in greater abundance.
One of these tools is the Best Pharmaceuticals for Children Act (BPCA), passed in 2002, which enables the FDA to issue a written request to a given pharmaceutical company asking that pediatric studies be performed for medications in areas with the greatest need. Companies that choose to pursue pediatric indications for medications in response to FDA written requests are granted six months of market exclusivity.
Another is the Pediatric Research Equity Act (PREA), passed in 2003, which requires that a pharmaceutical company conduct pediatric clinical trials if a drug is likely to be used in children. “PREA provides requirements for developing drugs in the pediatric population, so there are regulations that are geared toward gathering data and promoting pediatric drug development,” Cox said.
Nambair said that the extent of required studies and the number of patients needed depend upon the specific drug, toxicities and the indication being sought.
“It is important to develop new antibacterial drugs that are safe and effective and to have information regarding appropriate use of these therapies in pediatric patients,” Cox said.
Waiting for new drug development
Limiting excessive and inappropriate antibiotic use remains the best way to prevent further drug resistance and to conserve existing therapies until a sustainable antibacterial research and development infrastructure is secured.
“Patients often ask their doctor for an antibiotic when they have a common cold,” George Pankey, MD, director of infectious disease research at Ochsner Clinic Foundation in New Orleans, said. “But 80% of patients who present with common colds have viruses and do not need an antibiotic.”
Pankey explained that many primary care physicians feel pressured to write prescriptions based on patient and parent expectations. Although most pediatricians are aware of the consequences, providing optimal care for the patient they see in front of them may often outweigh broader concerns about issues of antibiotic resistance.
“This area needs a lot of work,” according to Rosemary Johann-Liang, MD, chief medical officer at the U.S. Department of Health Resources and Services Administration. “Health care professionals need to learn to use these medical interventions not empirically but with appropriate diagnosis and only when we know the benefit outweighs the adverse reactions inherent to antibiotics.”
“One way to overcome antibiotic resistance would be to get more specific with treatment,” Pankey said. “As is the case today, when there are not always specific tests to determine what is infecting the patient, doctors — especially primary care physicians — are put in a tenuous position.”
Data suggest that very few physicians use rapid streptococcus tests when a patient presents with a sore throat even though it can reduce unnecessary antibiotic prescriptions by more than 50%.
A diagnostic technology that Pichichero regularly uses is a complete blood cell (CBC) count machine, which he said has reduced antibiotic use in his own practice by about 80%. Although this technology is not currently widely available, a point-of-care white blood cell count machine is currently before the FDA (HemoCue) and may receive a Clinical Laboratory Improvement Amendment waiver.
Making smart antibiotic choices
Becoming educated about which drugs create the most antibiotic pressure is another approach.
“Pediatricians are still using antibiotics much beyond what is needed, and they must remember that some are worse than others at driving resistance,” Dagan said.
Azithromycin is among the worst, according to Dagan. “This is a very popular drug because it is long acting. It can be given in three doses, sometimes maybe even one dose, to get rid of the susceptible organism, so a lot of pediatricians use it for almost everything.”
Cephalosporins are another offender, while amoxicillin and amoxicillin clavulanate have much less of an effect on antibiotic pressure.
However, many programs that aim to promote judicious antibiotic use depend on the cooperation between infectious disease specialists and practicing physicians. It is a relationship that Victor Yu, MD, professor of medicine at the University of Pittsburgh, said has grown further apart in recent years.
“In earlier eras, infectious disease specialists in medical schools and tertiary care centers saw more patients directly with prescribing physicians and spent more time on individual consults,” Yu said. “Today, those at the top of the academic pyramid are spending more time on grant writing and lab research with less teaching of junior physicians and minimal patient care.”
Fostering knowledge-based solutions with cooperation among different specialties should be an important strategy in the battle against drug-resistant organisms instead of the current administrative-based approach in which pharmacists and infectious disease specialists merely restrict antibiotic usage, according to Yu.
Investing in knowledge
Projan contends that improving the knowledge base regarding the physiology of bacteria and the components that affect drug resistance will help guide new innovation in pharmaceutical development.
“Appropriately and aggressively funding research in the academic setting is extremely important because if we don’t have good solid academic science to build on, we’re not going to be successful commercially and industrially,” Projan said.
But the solution will not be based entirely on new drugs, a fact acknowledged by IDSA in its “Bad Bugs, No Drugs” campaign. As part of the effort, IDSA officials have petitioned members of Congress to increase public funding for the CDC, FDA and NIAID, asked policymakers to increase funding for research that will stimulate drug development and educational campaigns aimed at improving infection control and immunization practices.
“Researchers should be working on various aspects simultaneously now because the answer is not going to come from just one place,” Pankey said. – by Nicole Blazek
Antibacterials in the pipeline: Drugs in phase-2 or later development |
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For more information:
- Boucher HW et al. Clin Infect Dis. 2009;48:1-12.
- The Infectious Disease Society of America. Clin Infect Dis. 2009;49:328-335.
- Norrby SR, Nord CE, Finch R. Lancet. 2005;doi:10.1016/S1473-3099(05)01283-1.
- PhRMA. 2007 Report: Medicines in development for infectious diseases.
- Pichichero ME, Casey JR. JAMA. 2007;298:1772-1778.
- Wentzel RP. N Engl J Med. 2004;351:523-526.
- Williamson I. Vaccine. 2008;doi:10.1016/j.vaccine.2008.11.007.