Scientists at St. Jude Children’s Research Hospital have demonstrated a more effective treatment for bacterial pneumonia following influenza. They found that the antibiotics clindamycin and azithromycin, which kill bacteria by inhibiting their protein synthesis, are more effective than a standard first-line treatment with the beta-lactam antibiotic ampicillin, which causes the bacteria to lyse or burst.
The group, led by Jonathan McCullers, M.D., associate member of the St. Jude Infectious Diseases department, expect the new findings, currently demonstrated in mice, to be incorporated into standard clinical practice guidelines during the next few years.
The researchers based the new treatment on growing evidence that beta-lactams are relatively ineffective against secondary pneumonia because the drugs exacerbate inflammation caused by influenza.
‘With severe secondary pneumonia, it has seemed that physicians do almost everything they can, and it doesn’t work,’ McCullers said. ‘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 first-line therapy has been based on the belief that the bacteria are bad, so we have to get rid of them as quickly as possible,’ McCullers said. ‘But what we are finding is that maybe it is the inflammation we need to worry about first and the 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.’
In their experiments, the St. Jude researchers 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 researchers treated groups of the doubly infected mice with ampicillin, clindamycin, combined clindamycin and ampicillin, or azithromycin. They 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.
Ampicillin aggravated inflammation compared to clindamycin, the researchers confirmed in test tube studies. The investigators also found evidence of increased inflammation in lung cells of ampicillin-treated animals.
According to McCullers, lung tissue studies of ampicillin-treated animals also revealed the antibiotic’s deleterious 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,’ McCullers said. ‘The damage process was continuing.’
McCullers said he would like the new findings to influence treatment guidelines immediately for pneumonia secondary to influenza.
Release Date: January 9, 2009
Source: St. Jude Children’s Research Hospital
Filed Under: Drug Discovery