Emerging Antibiotics: Will We Have What We Need?
A Miracle of Medicine
The word "antibiotic" has always been to me a symbol of the miracles of modern medicine. Perhaps they're a bit ordinary these days compared with robotic surgery or capsule endoscopy, but in a different time, antibiotics literally changed the world. It began in 1928 when bacteriologist Alexander Fleming serendipitously realized that the growth of Streptococcus aureus was inhibited in a petri dish contaminated by mold. Within a few years we had sulfa drugs; rapidly followed by more effective beta-lactams, chloramphenicol, tetracycline, and by 1950, the aminoglycosides.
Unfortunately, while scientists were discovering new antimicrobial agents, we never developed the ability to swiftly identify an infectious agent, which might have permitted more targeted antibiotic therapy. Instead, broad-spectrum antibiotics became the vehicles of long-term innocent misuse of these live-saving drugs. But we underestimated the selective pressure that antibiotics were capable of exerting on bacteria. Within a few decades, it became clear that the overuse of antibiotics was fueling the natural evolution of the microbes we were trying to kill, encouraging them to develop resistance as rapidly as they were able.
Now, a vast and widening chasm divides the number of deadly antibiotic-resistant infections that we are seeing in healthcare and effective drugs to treat them. This situation is unlikely to change in the foreseeable future because too few of the right type of new antibiotics are making it through the drug development pipeline to match the pace of resistance.
How Did a Miracle Become a Crisis?
Paul Auwaerter, MD, MBA, Clinical Director, Division of Infectious Diseases at Johns Hopkins University School of Medicine, faces this problem on a daily basis. He recently described to me the convergence of events that has brought us to this point. "The patients are sicker than ever before, so we are using antibiotics more intensively, and the bacteria are changing in response. At the same time we have really lost ground in incentive mechanisms for creation and production of new antimicrobial compounds."
Few among the general public are losing sleep over antibiotic resistance or the absence of effective new antibiotics. People generally have faith or have been lulled into believing that medical scientists can develop effective new antibiotics whenever needed because they have always done so in the past.
By the time most people wake up to the realities of the situation, it will be too late. Antibiotic-resistant infections are becoming the next great equalizer, and this is not just a problem for the elderly or the immune-suppressed. Friends and family, rich and poor alike, will succumb to infections that should be curable but aren't, and everyone will be looking around for someone to blame.
And who should be blamed?
•Pushy patients who refuse to leave the office without their antibiotics, even when told they don't need them?
•Physicians who write antibiotic prescriptions for self-limiting viral illnesses out of fear of angering their patients or risking accusations of negligence?
•Farmers who treat their animals with antibiotics to keep them healthy?
•Pharmaceutical companies who won't invest in new antibiotic development?
•Or regulatory agencies that make it difficult or impossible to get a new antimicrobial through the approval process?
The many factors that have contributed to the current crisis have already been debated, but these sobering facts remain:
•More US patients die of MRSA infections than HIV/AIDS and tuberculosis combined.
•Only 2 new antibiotics — doripenem and telavancin — have been approved in the past 3 years.
•We have no drugs to treat infections with some strains of multi-drug-resistant gram-negative bacilli, like Pseudomonas aeruginosa and Actinobacter baumannii.
We may finally have arrived at the era of the untreatable bacterial infection.[1]
A (Brief) Review of Bacterial Resistance The outer structural matrix of the bacterium influences both susceptibility and resistance to antibiotics (Figure). All bacteria have cell membranes surrounding the cytoplasm, but gram-negative bacteria also have a thin layer of peptidoglycan and an additional outer lipopolysaccharide membrane. The cell membrane of a gram-positive bacterium is covered by a much thicker peptidoglycan cell wall. Bacteria are classified as gram-negative or gram-positive on the basis of how much color these structures retain when stained with a purple dye; the thicker peptidoglycan of the gram-positive bacteria holds more dye. Because these outer coverings control access to the antibiotic's target areas, changes in these structures can alter the ability of the antibiotic to reach its target and determine the intracellular drug concentration.
Mechanisms of resistance. Resistance can be either inherent — as exemplified by the inability of vancomycin to penetrate the cell wall of gram-negative bacteria — or acquired. Acquired resistance is a change in the bacterium's genetic composition that permits clinical resistance to drugs that were once active against it. Acquired resistance can reduce the effectiveness of an antibiotic or render the antibiotic completely ineffective against the bacterium.[2]
Bacteria can also become resistant to other classes of antibiotics (cross-resistance) or transfer their resistance genes to other microbes and species (co-resistance). The strategies used by bacteria to resist the actions of antibiotics include [2]:
•Reduced outer membrane permeability
•Reduced cytoplasmic membrane transport
•Increased efflux/decreased influx of antibiotic
•Neutralization of antibiotic by enzymes
•Target modification
•Target elimination
Inactivating enzymes such as beta-lactamases (class 1 chromosomal beta-lactamases and extended-spectrum beta-lactamases) and carbapenemases are increasingly responsible for antibiotic failure. Target alteration involving modification of penicillin binding proteins is the primary mode of penicillin resistance of a number of serious pathogens, including Streptococcus pneumoniae, Neisseria meningitidis, and Enterococcus faecium.[2] Individual resistance mechanisms can act synergistically to strengthen antimicrobial resistance, a problem that has broadened the spectrum of resistance now seen in some gram-negative pathogens.[3] The evolutionary changes now conferring resistance to beta-lactam antibiotics and other emerging mechanisms of resistance among gram-negative bacteria are beyond serious — they are truly frightening.
Pathogens of Highest Concern
The most serious, life-threatening infections are caused by a group of drug-resistant bacteria that the Infectious Diseases Society of America (IDSA) has labeled the "ESKAPE" pathogens, because they effectively escape the effects of antibacterial drugs.[4] (Table) Table. The ESKAPE Pathogens E Enterococcus faecium Third most common cause of HCA BSI. Increasing resistance to vancomycin.
S Staphylococcus aureus (MRSA) Emerging resistance to current drugs and significant drug toxicities. Lack of oral agents for step-down therapy K Klebsiella Escherichia coli K pneumoniae ESBL-producing organisms increasing in frequency and severity; associated with increasing mortality. K pneumoniae carbapenemases causing severe infections in LTCF. Few active agents; nothing in development A Acinetobacter baumannii Increasing worldwide, recent surge reported in hospitals.[5] Very high mortality. Carbapenem-resistant.
P Pseudomonas aeruginosa Increasing P. aeruginosa infections in US and worldwide. Resistant to carbapenems, quinolones, aminoglycosides E Enterobacter speciesMDR HCA infections increasing; resistance via ESBLs, carbapenemases, and cephalosporinases HCA = healthcare associated; BSI = bloodstream infection; MRSA = methicillin resistant S aureus; ESBL = extended-spectrum beta-lactamase; LTCF = long-term care facility; MDR = multiple drug-resistant
Is the Pharmaceutical Cupboard Bare?
Brad Spellberg, MD, Associate Professor of Medicine, Geffen School of Medicine at UCLA, Division of General Internal Medicine, Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, is the author of a book about this issue called Rising Plague: The Global Threat from Deadly Bacteria and our Dwindling Arsenal to Fight Them. I recently asked Dr. Spellberg to comment on our nearly empty antibiotic pipeline.
"It needs to be recognized that antibiotics have a unique feature that distinguishes them from all other drugs," explained Dr. Spellberg. "And that is that antibiotics effective today will probably not be effective 15-20 years from now. That's something that is not true of any other class of drugs, and thus we have a critical public health need to continually develop new antibiotics.
"The economic and regulatory climates have changed so that the drug companies aren't making new antibiotics. We've been talking about antibiotic stewardship since the 1950s. It used to be 'new bug, new drug,' but not anymore. We are already seeing infections resistant to all of the antibiotics that we have now, and the number will increase at a geometric rate over the next 5 years."
It's not that there aren't any antibiotics in development. There are, but they won't solve our real problems. The antibiotics aimed at gram-negative infections that are currently in development have mechanisms of action similar to the drugs we already have available. Ceftobiprole and ceftaroline, for example, have both completed phase 3 trials, but they are essentially the same as cefepime, a drug already on the market. A gram-negative organism resistant to cefepime, then, will also be resistant to both ceftobiprole and ceftaroline. So, explains Dr. Spellberg, the real problem is that there are no gram-negative antibiotics in the pipeline that will work against bacteria already resistant to the drugs we have.
The evidence backs up such assertions. In 2009, the IDSA published their latest assessment of the strength of the drug development pipeline for novel therapeutic agents to treat drug-resistant infections.[4] The findings were grim. Not only is the number of antibiotics in phase 2 or phase 3 clinical development disappointingly low, but this is clearly not a recent trend. The number of drugs that have made it through the developmental process and received FDA approval has plummeted in recent years. From 1983 through 2007, systemic antibacterial approvals declined by 75%. Fewer drug discovery efforts and drugs in early-phase trials prove that pharmaceutical companies have retreated from antibacterial research and development. Of grave concern is the lack of systemically administered antimicrobials in advanced development that have activity against gram-negative bacteria or bacteria that are already resistant to all drugs in our current armamentarium.[4]
Discovering new classes of antibiotics has become increasingly difficult.[3] Moreover, major pharmaceutical companies have simply lost interest in the antibiotics market because these drugs are not as profitable as drugs that treat chronic diseases and lifestyle factors.[6] Antibiotics are short-term drugs, taken only until the infection is gone, not daily for years and years by hundreds of thousands of people. It is extremely expensive to develop and establish safety and efficacy of a new antibiotic, especially because there is no guarantee that the drug will be approved even after a huge investment of time and money.
To understand why pharmaceutical companies have backed away from antibiotic development, it helps to understand the drug approval process, and in particular, some of the hurdles that must be overcome in getting regulatory approval for a new drug.
The Drug Approval Process
According to Dr. Spellberg, the few antibiotics that are trickling through the system are getting stopped by the FDA. "Most healthcare professionals do not completely understand the FDA process," says Dr. Spelling. "It is a huge impediment to getting a new antibiotic to market."
Imagine, he said, that a pharmaceutical company has developed a new antibiotic to treat community-acquired bacterial pneumonia, a major source of drug-resistance right now. The drug company is told by the FDA that their clinical trials need to prove that the new drug is not inferior to the old drug, with reduced all-cause mortality as the primary endpoint. No clinical endpoints will suffice; in other words, it doesn't matter if patients get better faster. That kind of trial, says Dr. Spellberg, is impossible. "You would need a sample size of 5000 patients to do a study like that. It can't be done." Unfortunately, this scenario isn't fantasy. It's really happening.
Statisticians argue that it should be easy to prove superiority of a new antibiotic because of all the drug resistance out there, "but they are missing a central concept," adds Dr. Spellberg. "To prove that a new drug is superior to the comparator, you would need to enroll patients whose infections are resistant to the comparator. But you can't do that. In a study, you would have to exclude the very patients in whom you would be able to demonstrate superiority. It's a conundrum that can't be solved."
It's also a conundrum that is perpetuated by the fact that statisticians (people who generally have never seen and certainly haven't treated a case of pneumonia or any other life-threatening infection) outnumber clinicians at the regulatory level, and it is the statisticians who are making the decisions.
Dr. Spellberg explains the IDSA's position. "We are advocating solely for patients. We understand the FDA's role, but it should not be so rigorous that it kills the production of new drugs. There has to be a middle ground. There is a saying: 'The perfect is the enemy of the good.' If you are going to demand perfect data, you are never gong to get it. You are going to have to accept imperfect data if it is robust enough to support efficacy."
A Global Commitment: 10 X '20
Dr. Auwaerter suggests that a new paradigm is needed for developing the drugs we need. "Historically, in this country, antibiotic development has been a for-profit enterprise. It's clear now that given the current regulatory climate, this is no longer tenable."
However, he does see a glimmer of hope, citing a precedent for a novel approach to refill the antibacterial pipeline. "For many years we had no new tuberculosis (TB) drugs. Then the TB Alliance (www.tballiance.org) was formed, including academics, pharmaceutical companies, philanthropic organizations, government agencies, and global health partnerships, who created a forum and a funding mechanism to develop the new antitubercular agents we needed. In an astoundingly short period of time, we had a pipeline for these drugs. We need a similar gathering of forces to solve the antibiotics problem. It's going to take an innovative approach — a new way to jump-start the developmental process, especially for gram-negative organisms."
The IDSA has taken a leadership role in generating awareness of the problem and suggesting legislative solutions. Noting that the time has come "to address the emerging disaster caused by the confluence of increasing bacterial resistance and a stagnant antibacterial drug pipeline," the IDSA has launched an initiative that it hopes will reinvigorate antibiotic development. On November 20, the IDSA sent a letter to President Barack Obama and to Prime Minister Fredrik Reinfeldt (representing the European Union [EU] Presidency) to request a commitment to develop 10 novel antibacterial drugs by the year 2020 (10 X '20).[7]
"It's a "John F. Kennedy-like call to action," says Dr. Spellberg.
The goal of 10 X '20 is to create a long-term, sustainable research and development infrastructure model that provides incentives across the spectrum of the antibacterial drug and related diagnostics research enterprises.
Jointly, the US and Europe would establish a transatlantic task force to address antibiotic resistance. Under the US./EU agreement, the task force would focus on appropriate therapeutic use of antimicrobial drugs in the medical and veterinary arenas, prevention of both healthcare- and community-associated drug-resistant infections, and strategies for improving the pipeline of new antimicrobial drugs.
What the Rest of Us Can Do
We can't just focus on washing our hands and reducing the use of antibiotics, things that most healthcare professionals are already doing to the best of their abilities. We are, collectively, a huge group of healthcare professionals (and voters), and if we choose to, we could exert a lot of pressure on decision makers to force solutions to this crisis.
Dr. Auwaerter has 2 suggestions: First, education and awareness of this issue must increase among the medical community. Second, political, and scientific forces must work together to recognize the scope of the problem and develop solutions. "We learned a lesson from the H1N1 pandemic: the importance of being prepared. Right now, we are not close to being adequately prepared."
We need to realize that it isn't just our patients who are at risk, it's all of us. But nothing will change if we sit back and think this problem is too big, too complex, that it's someone else's problem, or that there is nothing we can do. There is something we must do, according to Dr. Spellberg. "Only when constituents start putting pressure on elected officials will things change."
"We need [physicians' and nurses'] voices because right now the FDA is dominated by statisticians and the clinicians are being shouted down. We have lost our voices. They are making drug approval decisions based on statistical results and have lost all sight of clinical reality."
Dr. Spellberg recommends writing letters to the editors of professional journals or other media, expressing concern — and yes, outrage — about the current situation. People can also inform regulatory officials and politicians that the current approach to approving drugs is unacceptable; that physicians are being excluded from these conversations, and that statisticians should not have the sole voice. Demand that the FDA stop insisting on perfection and demand that clinicians have a say in the approval process.
Pharmaceutical companies are not the enemy. We need to work with them. Write to your elected officials and other administrators, demanding that they take action to facilitate the drug development process and support the IDSA's initiative to develop 10 novel antimicrobials by the year 2020. Go to the IDSA's Policy & Advocacy Center. There, just by entering your zip code, you can send a letter to your congressional senators and representatives urging them to enact legislation to spur antibiotic discovery. It takes less than 5 minutes to deliver this important message.
Legislation already introduced in the current Congress is in need of support by individuals and groups. Representative Jim Matheson (D-Utah) introduced the Strategies to Address Antimicrobial Resistance (STAAR) Act (House Resolution 2400) on May 13, 2009, a bill that would require the Health and Human Services Department to establish an Antimicrobial Resistance Office. The STAAR Act will strengthen federal antimicrobial resistance surveillance, prevention and control, and research efforts, and it also will enhance the collection of critical information on the use of antibiotics in humans and animals. The STAAR Act currently has only 2 cosponsors, so an avenue of advocacy open to supporters is to write to their congresspersons and ask them to cosponsor this bill.
The Bottom Line
We are literally inches away from a crisis in public health that will severely hamper our ability to transplant organs, replace hips, provide cancer chemotherapy, perform dialysis, or keep premature babies alive. Then, it will only be a matter of time before otherwise healthy individuals will die because they contracted infections after routine surgery or were infected by pathogens that are common in the community but for which we no longer have a cure.
References
1.Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother. 2009;64(Suppl 1):29-36.
2.Chen LF, Chopra T, Kaye KS. Pathogens resistant to antibacterial agents. Infect Dis Clin N Am. 2009;23:817-845.
3.Chopra I, Schofield C, Everett M, et al. Treatment of health-care associated infections caused by gram-negative bacteria: a consensus statement. Lancet Infect Dis. 2008; 8:133-139. Abstract 4.Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs, no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1-12. Abstract 5.Hoffman MS, Eber MR, Laxminarayan R. Increasing resistance of acinetobacter species to imipenem in United States Hospitals, 1999-2006. Infect Control Hosp Epidemiol. 2009 Dec 23. [Epub ahead of print] 6.IDSA. Bad bugs, no drugs. As antibiotic discovery stagnates, a public health crisis quietly brews. July 2004. Available at: http://www.idsociety.org/badbugsnodrugs.htmlAccessed January 25, 2010.
7.IDSA. Letter to President Barack Obama and Prime Minister Fredrik Reinfeldt. November 20, 2009. Available at: http://www.cgdev.org/content/general/detail/1423276/Accessed January 25, 2010.
