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The inflammatory response can be the key determinant in the survival of patients with bacterial pneumonia after influenza; yet standard treatment protocols can actually make the situation worse, according to findings from a recent study at St. Jude Children's Research Hospital. In an effort to prepare for the next possible influenza pandemic, the stockpiling of antivirals and more recently, antibiotics, has been suggested. However, most deaths during a pandemic are from secondary bacterial infections. In fact, secondary pneumonia is responsible for up to 95 percent of deaths during pandemics, therefore it becomes critical to identify which drugs are best for treating these infections.

That is why researchers at St. Jude are studying the effects of various antibiotics on inflammation, to determine if alternative drugs may have better outcomes.

In a recent article published in the Journal of Infectious Diseases, investigators found a more effective treatment using the antibiotics clindamycin and azithromycin. These drugs kill bacteria by inhibiting their protein synthesis and appear to be more effective than a standard first-line treatment with the "beta-lactam" antibiotic ampicillin, which causes the bacteria to lyse, or burst, thus exacerbating the inflammation.

"With severe secondary pneumonia, it has seemed that physicians do almost everything they can, and it doesn't work," said Jon McCullers, MD, associate member of the St. Jude Infectious Diseases Department. "People still die despite treatment with antibiotics that can kill the bacteria. Our research is showing that the intense inflammatory response that is already there from the virus is amplified by the bacterial infection. And, treatment with beta-lactams releases bacterial components into the bloodstream that the immune system recognizes, triggering an inflammatory burst that can be deadly."

Traditional therapy is essentially based upon the belief that bacteria are the ultimate enemy and must be destroyed as quickly as possible.

"But what we are finding is in some clinical scenarios the inflammatory response may be more important than the direct effects of the bacteria themselves," he explained, adding that perhaps inflammation should be considered first, and bacteria second. "Protein synthesis inhibitors shut down the bacterial protein-making factory, and they can avoid the inflammatory burst by killing them over days instead of quickly lysing them."

As explained by St. Jude literature, in their experiments, St. Jude investigators infected mice with a mild form of influenza that restricted itself to the lungs. After a week, the scientists infected the mice with pneumonia bacteria. This sequence mimics how humans with influenza would contract secondary pneumonia. The groups of doubly infected mice were treated with ampicillin, clindamycin, combined clindamycin and ampicillin, or azithromycin. Researchers found that 56 percent of the mice survived with ampicillin treatment, 82 percent survived with clindamycin, 80 percent with clindamycin and ampicillin, and 92 percent with azithromycin. Significantly, while clindamycin and azithromycin both inhibit protein synthesis, azithromycin also has anti-inflammatory properties.

Researchers confirmed in test tube studies that ampicillin, the standard beta-lactam therapy for pneumonia, aggravated inflammation compared to clindamycin. They also found evidence of increased inflammation in lung cells of ampicillin-treated animals.

In addition, lung tissue studies of ampicillin-treated animals revealed the antibiotic's harmful effects.

"We saw in those animals that, even though we were clearing their lungs of bacteria, the lungs looked just like those of animals in which the bacteria were continuing to multiply," he said. "The damage process was continuing."

Current guidelines still adhere to the theory that beta-lactams are the only drugs of choice, in order to kill bacteria rapidly, however, McCullers said, "Our findings represent the first data showing that inflammation is important, and that alternative therapies such as protein synthesis inhibitors should be considered and incorporated into revised guidelines."

McCullers said he hopes these new findings will influence treatment guidelines immediately for pneumonia secondary to influenza, as well as a revision of guidelines acknowledging that beta-lactam therapy should not be the first line for secondary bacterial pneumonia after influenza. These findings support a growing body of evidence that treating severe pneumonia in general should take into account the inflammatory response and not just the rapid demise of bacteria. He expects this study and the reaction to it will go a long way toward achieving that end.

The next step for McCullers and staff is to examine the mechanisms that underlie this problem from three main angles. Investigators will examine the cytotoxins from the virus and bacteria and how they contribute to the dysfunctional inflammatory response. They'll also look at the pathways and receptors that are active in generating inflammation. In addition, researchers will study the mechanisms by which azithromycin seems to give better outcomes to determine whether the improvement stems from its anti-bacterial effect or unrelated anti-inflammatory activity.

"We are also trying to get the message out that influenza pandemic planning needs to take into account secondary bacterial infections," added McCullers. "If stockpiling or boosting of production pipelines is considered, we need to look beyond standard beta-lactam drugs."

Tags:

influenza, pandemic, Pneumonia, pneumonia treatment, St. Jude Children's Research Hospital

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