CHICAGO — Nobody knows where Simon Sparrow picked up the bug that killed him.
One sunny April morning six years ago, the curly-haired toddler woke up with flulike symptoms; by afternoon he was struggling for breath. He went into septic shock. Doctors at the hospital gave him intravenous antibiotics, but the drugs failed.
By the next afternoon, Simon was dead at 18 months old, the victim of a highly drug-resistant bacterium, methicillin-resistant Staphylococcus aureus.
"I was insane for a year," said his mother, Everly Macario of Chicago. "You feel like you are in a dream. You feel like you will wake up sometime."
We have come to expect that modern medicine can cure just about any infection. But bacteria are finding ways to evade, one by one, the drugs in our arsenal, and that arsenal is not being replenished with new antibiotics.
Drug companies are abandoning the antibacterial business, citing high development costs, low return on investment and, increasingly, a nearly decade-long stalemate with the Food and Drug Administration over how to bring new antibiotics to market.
Soon, doctors fear, we could be defenseless against bacteria that can resist all existing antibiotics, which would mean more victims like Simon, dead from a staph infection that drugs used to conquer easily.
Brad Spellberg, an expert on antibiotic resistance, called the situation catastrophic.
At the core of the problem is a regulatory impasse over whether drug companies seeking FDA approval for antibiotics should be required to run much more stringent clinical trials.
The FDA says yes, citing advances in the science of clinical trial design and a series of humiliations involving trials for drugs the agency had approved, including the antibiotic Ketek.
"We don't want to approve products that don't work," Joshua Sharfstein, principal deputy commissioner of the FDA, told physicians and scientists gathered for a workshop on antibiotics and clinical trials in late July.
But the pharmaceutical industry and some infectious-disease doctors say the proposed rules will make it so difficult and expensive to gain approval for new antibiotics that the few remaining companies will abandon the field.
Clinical trial issues
The debate over setting new guidelines for antibiotic clinical trials has lasted almost a decade. In two years there have been at least nine meetings among the FDA, pharmaceutical industry scientists and physicians, academics, and infectious-disease doctors, but the group has agreed on little.
"I fear the conversation may be beyond all hope," said infectious-disease specialist Spellberg, who has been involved in the meetings. "We've hashed and re-hashed the same things over and over."
Edward Cox, director of the FDA's Office of Antimicrobial Products, said there has been some progress, pointing to recently issued draft rules for antibiotic trials involving sinus infections, ear infections, a type of bronchitis, skin infections and community-acquired pneumonia.
However, Spellberg said, "The end result is exactly the same: No drugs."
For years, new antibiotics often were approved based on clinical trials that didn't have to show the new drug was better than an old one. Instead it had to fall within an acceptable margin of efficacy, which meant it could test somewhat worse and still be considered a success.
Just how much worse is OK with the FDA lies at the heart of the debate. The FDA wants the margins for these "non-inferiority trials" to be scientifically justified, and that may result in margins much tighter than before.
This type of trial has pitfalls, the FDA has said. If the definition of success is too loose, you might not be measuring efficacy at all.
The FDA is now proposing that antibiotics used to treat non-lethal infections that often resolve on their own, such as sinusitis, ear infections and bronchitis, be tested under different methods: superiority trials or placebo-based trials.
But showing one antibiotic is superior to another is hard because many antibiotics work so well, Spellberg said.
Cox of the FDA said clinical trials that show an experimental drug is significantly better than a current drug would provide clear evidence that the experimental drug works. He also acknowledged it may be difficult to show that an experimental antibacterial drug is better than a current drug.
Placebo trials, in which the drug is tested against a look-alike but useless pill or injection, are also unrealistic, according to some experts. It's nearly impossible to persuade patients with a painful sinus infection to enroll in a study with a 50 percent chance of getting a sugar pill and not a drug, they said.
'Like proving gravity'
David Shlaes, who worked in pharmaceutical antibiotic development for decades and is now a consultant to the industry, said it is absurd to be, in effect, questioning if antibiotics work.
"This is like asking how do I know parachutes work?... Those of us in infectious disease, we are all scratching our heads wondering: What the hell they are talking about?" said Shlaes, whose book, "Antibiotics: The Perfect Storm," will be published this fall. "It is like proving gravity all over again."
In the case of life-threatening infections such as community-acquired pneumonia, the FDA is discussing whether to require much stricter non-inferiority trials.
That, several experts said, would create new obstacles in a field with few financial incentives to bring antibiotics to market.
In 1980, 36 U.S. and European companies were in the antibiotic business, said Karen Bush, an Indiana University professor who recently left antibacterial development at Johnson & Johnson. "Today there are somewhere between four and seven large companies, depending on how you count," she said.