Two current papers may open up new fronts in the fight against antibiotic resistance. A paper published online in Nature Biotechnology on March 25, 2007, reports on a peptide that can harness the innate immune system without activating inflammatory mechanisms, while the April 5, 2007, Nature shows how to mix and match antibiotics so that combination will select for nonresistant rather than resistant strains.

The discussion is appropriate because it's around the time of year when parents wonder whether they will ever have a household without at least one barfing member again. But Bob Hancock, co-founder of Inimex Therapeutics and a professor at the University of British Columbia in Vancouver, thinks it really could be worse. "When you think about all the days of your life, you really acquire infections quite rarely," despite being submitted to a barrage of bugs on a daily basis, he said.

And you can thank your innate immune system for that. The body's first line of defense, it basically kicks into gear the moment it detects an invader, while the more specific adaptive immune system takes three to five days to really get going.

That speed comes at a price, though. Innate immunity relies, among other mechanisms, on inflammation, which doesn't really care all that much whether it's shooting down invader or host cells.

Even that in itself is not so much of a problem as long as the inflammation stays localized. A little bit of swelling and redness is not too high a price to pay to avoid a staph infection. But "it's when it goes systemic or lasts too long that you get a problem," Hancock said. In the worst case scenario, that's septic shock.

Still, harnessing the innate immune system therapeutically is an attractive approach, especially since it might not suffer from the biggest problem facing classical antibiotics: resistance. Hancock believes that's because it activates many different mechanisms, rather than targeting one specific aspect of a bacterium's lifecycle, "you can't really get resistance" to a therapeutic that dials up the host immune system.

In their Nature Biotechnology paper, Hancock and his team describe a peptide that succeeds in activating the innate immune system, and without causing inflammation to boot.

The scientists presented data showing that in mice, a synthetic peptide known as Innate Defense Regulator, or IDR-1, was effective in fighting a number of bacterial infections, including vancomycin-resistant enterococcus and methicillin-resistant staph.

The peptide did not affect bacteria directly. Instead, it activated macrophages and monocytes, specifically increasing monocyte-produced chemokines.

Notably, the peptide also decreased the level of proinflammatory cytokines. Hancock believes this could be a significant advantage of the IDR peptide family in the clinic. "There's lots of focus on [targeting] toll-like receptor agonists" to harness the innate immune system, he said. But that approach is "the same route that pathogens themselves are activating," which increases the risk of inflammation as a side effect.

Inimex plans "to work under conditions where inflammation plays a significant role," Hancock said. The company currently is developing related peptides for use in hospital pneumonia, chemotherapy-induced neutropenia, surgical infections and inflammation.

With only 1 percent of drugs in advanced clinical trials being antibiotics, though, new drugs need all the help they can get. In Nature, researchers from Harvard report a counterintuitive finding: that there is a way to administer antibiotics that select for nonresistant, rather than resistant, strains.

The basic trick is to take two antibiotics that inhibit each other, rather than work in synergy. In assays using E. coli that were either sensitive or resistant to the antibiotic doxycycline, and treating them with varying concentrations of doxycycline and ciprofloxacin, the authors found that at certain concentration ranges, such a combination reversed the E. coli strains' resistance to doxycycline.

The authors note that there is no free lunch: "These findings point to an inherent tradeoff, where antagonistic combinations, which require a higher dosage and have therefore typically been shunned in clinical therapy, may have the benefit of reducing and even inverting selection for resistance," they wrote in their paper. They also noted that one should not try this at home. "We emphasize that our work is limited to sublethal drug concentrations, in a controlled environment in vitro and that any possible therapeutic implications from these findings are beyond its scope."

Nevertheless, they added, "we do hope that these findings may suggest avenues of research into new treatment strategies employing antimicrobial combinations with improved selection against resistance."