Now, the next one was Zithromax. That was fun because of the notion--not the notion--the philosophy. The actual dogma in medical school is that you have to have a high concentration of the drug in the blood to be successful. If you don't get a high concentration of drug in blood, you're probably not going to have any drug worthwhile in human medicine. Zithromax does not achieve high levels in the blood. So what we did, this was kind of a neat study I think. We took an infection model where we used Salmonella enteritidis as the infecting organism. By the way, this is a Gram negative bacterium. Zithromax is very unusual in that, unlike all the other macrolides, it does have some activity against Gram negatives. We dosed just one day, subcutaneously, three times with Zithromax at 50 mgs/kg. We didn't give any more drug. Two days after giving drug, we initiated the infection by giving the mice a suspension of S. enteritidis orally. At the time of infection, we found that the circulating blood level was 0.18 micrograms/ml. The inhibitory level determined in a test tube says we have to be as high as 1.56 µg/ml, almost 2 µg/ml to inhibit that organism. We were not at that level in the blood. In fact, the highest blood level achieved during the infection phase of the study was only one-tenth the MIC. Since we didn't give any further drug, the blood levels just kept on going down. At no time during the course of the infection did we achieved a blood level that should inhibit the organism.
However, Zithromax, being a drug that was distributed widely in tissues, we knew that the concentration achieved in the liver at the time of infection would be well above the MIC and continued to be at least 2X above the MIC for up to four days. The result after 14 days, even though we never were at the "MIC" in blood, was 100% survival with Zithromax therapy. We had 17% survival in the untreated infected control group. That was conclusive evidence that you do not have to have blood levels to be successful, particularly with this drug. You have to achieve some blood level because that's the way it gets distributed to these tissues. But otherwise, this is really a neat kind of a study. We had to show this. If we hadn't, the drug probably wouldn't have gone anywhere.
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