Infectious disease specialist Brad Spellberg, MD, FACP, brought a report from the front lines of battle to Internal Medicine 2012 in April, and the news wasn't good.
“You'll often hear, ‘We're going to win the war against microbes.’ Really? We're going to win a war against organisms that outnumber us by 1022?” said Dr. Spellberg, who is an associate professor of medicine at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. “I don't think so.”
Not only do the bacteria have a numerical advantage, but they've also been applying themselves more diligently than we have in recent years, developing resistance to available antibiotics. This would happen with or without human involvement, Dr. Spellberg noted, describing a recent study that found bacteria resistant to synthetic antibiotics in the depths of a cave isolated from the world for four million years.
“But we sure are doing our best to help drive resistance,” he said. “What we do is simply select, by killing off the susceptible stuff and leaving behind the stuff that's already resistant so it can spread its resistance.”
The most problematic resistance is occurring among gram-negative drugs, although it's the gram-positives that get the most public attention, Dr. Spellberg said. “MRSA [methicillin-resistant Staphylococcus aureus] is the thing the press loves. It's the thing our patients come to us afraid of.”
There are a large number of MRSA cases, but there are also many drugs that can effectively treat the disease, including linezolid, which will likely become more affordable when it goes generic in 2015. “How many drugs in how many classes do we need to treat one bacterium?” asked Dr. Spellberg.
When treating gram-negative infections, physicians have many fewer drug choices. Several bacteria have strains that are resistant to almost all agents. Carbapenem-resistant Klebsiella has been spreading around the country in the past decade, and is associated with mortality rates of 30% to 45%, Dr. Spellberg reported.
Carbapenems are also increasingly ineffectual against Acinetobacter, with resistance increasing from 5% in the late 1990s to 70% to 80% last year. “That's a greater than an order of magnitude increase over the last decade,” he said. Pseudomonas strains are also showing resistance to almost all drugs.
“Aside from the problems of pan-resistance, we have the problem of increasing resistance to everything oral. I would guess that 10% of E. coli infections in the community in many parts of the U.S. are now quinolone-resistant,” said Dr. Spellberg. “This has changed my practice patterns. When I send people out on a quinolone, I get a urine culture and a phone number, and I not infrequently have to have my residents call the patient back to the hospital either to switch to a different therapy or potentially be admitted for carbapenem therapy.”
Because of increasing resistance, guidelines from the Infectious Diseases Society of America no longer call for fluoroquinolones as a first-line treatment for urinary tract infections, and recommend nitrofurantoin or fosfomycin instead. The latter is very new to the U.S. and only available as a powder, Dr. Spellberg said.
Enterobacter is another of the worrisome extended-spectrum beta-lactamase bacteria. What makes the gram-negative resistance situation worthy of particular concern is the lack of progress in fighting it. “It's been more than 40 years since the last time we had a new class of antibiotics approved to treat gram-negative bacilli,” he said.
In general, antimicrobial development has dramatically slowed. In the past five years, only two new systemic antibiotics were approved by the FDA and no new antifungals have come on the market, Dr. Spellberg reported. “Antibiotic development is dying,” he said.
The cause is a market failure with three components: science, economics and regulation. The problem with the science is that it's getting more difficult. “The easy-to-discover antibiotics have been discovered, and each subsequent generation it becomes harder and harder to find new ones,” said Dr. Spellberg.
Such research requires a lot of money, of course, and antibiotics are not a drug class that has offered great return on investment. “You take an antibiotic for seven days and then you stop. Companies make much more money selling a drug that you take every day for the rest of your life,” he said.
On the third front, regulation changes have made it increasingly difficult to conduct antibiotic research, according to Dr. Spellberg. “Over the last decade, the Food and Drug Administration has completely rewritten the rules for how antibiotic clinical trials should be conducted, in a manner that has essentially crushed innovation and development programs,” he said.
Requirements such as not providing patients, even very sick ones, with any antibiotics before randomization into a trial have scared drug manufacturers away from antibiotic research and development.
“There have been multiple companies that have stated publically, and many more privately, that yes, they are going to continue to develop their antibiotics. They're just not going to develop them for the U.S. market,” said Dr. Spellberg. “The European regulatory landscape is much friendlier and there are those that are projecting that the Chinese antibiotic market is going to be larger than the U.S. market in five years.”
There are, however, some potential solutions on the horizon for the U.S. system. The Generating Antibiotic Incentives Now (GAIN) Act would extend exclusivity for new antibiotics by five years and has attracted bipartisan support. “The bad news is that the incentives included may not be strong enough to lure industry back into antibiotic discovery,” Dr. Spellberg said.
The Infectious Diseases Society of America has also proposed legislation on the subject, the Limited Population Antibacterial Drug (LPAD) approval mechanism. This bill would create a new regulatory path to hasten and simplify approval for critically needed antibiotics.
“For a drug that's designed to treat pan-resistant infections that are life-threatening, it may mean a phase III trial as small as 30 patients could lead to approval,” Dr. Spellberg said.
The drugs would carry very narrow indications on their label, helping to limit prescriptions to the small group of patients for whom the benefits clearly outweigh the risks, so the drugs would not be widely used. “This is a win-win. It converges the need for us to develop new drugs for our unmet needs and our ability to protect those drugs once they're approved,” he said.
Protecting approved drugs is the primary assistance that practicing physicians can provide with the antibiotic problem, Dr. Spellberg added. Research has shown that prescribing of unnecessarily broad agents is common, for example, fluoroquinolones to treat community-acquired pneumonia. “These are oral gram-negative agents, folks. We have nothing to replace them with,” he said.
Antibiotics are also commonly prescribed for excessive durations. “We need to match the spectrum of the drug to the spectrum of the microbiology and shorten our therapy,” said Dr. Spellberg.
Better rapid diagnostic tests would assist with this matching, he added. “I cannot distinguish bacterial infections from viral infections based on my history and physical and X-ray; no one can,” Dr. Spellberg said, talking about upper respiratory infections. “Give me a printout that says this patient has enterovirus. I feel so much better.”
Such tests should be available in office practice within the next five to 10 years, he predicted. Until then, physicians will have to make do with the resources available.
“You cross your fingers, do a dance and hold your breath, because that's all you have left,” Dr. Spellberg said.