Monday, September 3, 2012

Immunomodulators in the treatment of infectious disease

Hysterical infectious disease doctors will whine that "we are slowly sliding into the post-antibiotic era", which very well may be true. MRSA might be turning into VRSA and super duper totally drug resistant gonorrhea is popping up all over the world including France, Japan, Hawaii, and Ohio. Rather than developing more and more super expensive antibiotics that lose efficacy after 10-15 years of irresponsible use, it is time for us to reanalyze how we manage infections.  The common gestalt is to find the right drug for the right bug. This places all of the emphasis on killing bacteria, when it is actually the body's immune response to the bacteria which causes sickness symptoms. Our immune system evolved to react to infections briskly with the innate response just to keep the pathogen temporarily at bay and then in a more controlled fashion with the adaptive immune response. Our immune system is not equipped to handle the flood of antigen released when a bolus of antibiotic causes rapid bacteriolysis. This leads to massive immune activation, much more so than is "natural". This exaggerated response includes toll-like receptor activation, leukocyte chemotaxis, cytokine release, and immune cell degranulation. Sepsis is a prime example of our failure to address the immune response in infectious disease. You can kill as many bugs as you want in the septic patient, but that isn't going to raise their BP and neutralize the inflammation in the short term.

This article: Anti-inflammatory Drugs in CAP, Journal of Internal Medicine addresses some of the emerging therapies being studied in modulating the immune response in the setting of infection, in this case the focus is on community acquired pneumonia. The first modality is the use of corticosteroids. which seems to have mixed results in the studies they review here.

The two things that really interest me are statins and macrolide antibiotics. In retrospective studies, those who come into the hospital already taking a statin and treated for CAP have better outcomes. The idea is that besides lowering LDL cholesterol, statins somehow lower the basal inflammatory state decreasing atherosclerosis and allowing for a more controlled response to infection. There are no studies yet about whether statins are useful acutely or if they should be started as treatment for infection in those without dyslipidemia.

Macrolides are starting to look like something of a wonder-drug. Probably the next "add it to the water supply" type drug after statins, vitamin D, aspirin, and SSRIs. Besides their direct effect on bacteria, macrolides are anti-secretory for the bronchi, increase mucociliary function, decrease PMN degranulation, decrease inflammatory cytokines, and decrease reactive oxygen species. This is probably why we should be giving macrolides to everyone with CAP, not just to treat mycoplasma and chlamydia pneumonia. The ceftriaxone kills the bacteria and the macrolide modulates the immune response to the infection. Maybe this is why people with viral bronchitis and URIs tend to feel better when they convince their doctor to given them a Z-pack. And here we had finally convinced a generation of doctors to militantly deny our patients antibiotics for such viral infections, the effect may have actually be much more than placebo effect.

The last modality they look at is TLR antagonists, which sound really good in theory, but apparently doesn't have very good efficacy. On a side note, and possible fodder for a future post: it looks like TLR polymorphisms play a huge role in determining who dies from infection.

In conclusion, treat the infection and treat the inflammation.