How they work and why they usually don’t
by Bill Landers
Dentistry is fortunate in having several highly effective systemic antibiotics for periodontal infections. About 85% of periodontal pathogens (Gram negative and positive anaerobic bacteria) are sensitive to metronidazole. The remainder are usually susceptible to amoxicillin. Very few species are resistant to both drugs. Nevertheless, they don’t seem to work nearly that well for patients, even in clinical studies. Why is that, since resistance is so rare?
To understand why, you need to know a little bit about how antibiotics work. Contrary to popular belief, antibiotics don’t kill bacteria on contact. If they did, you wouldn’t have to take them for a week. Antibiotics work slowly.
Most antibiotics are derived from natural compounds that microbes use in their fights for dominance. That’s a tricky proposition for bacteria. How do you make an enzyme that’s toxic enough to kill a neighbor but not yourself? The answer lies in subtlety rather than brute force. Instead of attacking the basic structures common to all bacterial cells, antibacterial toxins target minute variations in the thousands of different enzymes that different species use to build cell membranes, break down glucose, or copy their DNA.
Metronidazole, for instance, only reacts with an enzyme found exclusively in anaerobic species that helps them to uncoil their DNA prior to replication. Most anaerobic bacteria haven’t yet found a way to reproduce without that enzyme. That’s why resistance is so uncommon. It doesn’t kill them outright. By preventing reproduction, they slowly die out, but it takes about a week until they’re all dead … provided that the concentration stays high enough all seven days! And there’s the rub.
In order to inhibit anaerobic growth, metronidazole levels need to be at least 4.5 micrograms per milliliter (mg/mL). After taking the first dose, it takes 1-3 hours to reach an effective concentration in the blood, but it doesn’t stay that high for very long. The liver is constantly breaking it down, eliminating about half of it in eight hours. That’s why patient compliance is so important. In order to keep the level of metronidazole high enough to work, it has to be replaced every eight hours (if prescribing 250 mg) or 12 hours (if prescribing 500 mg).
If the level of antibiotic is not kept high, anaerobic bacteria will be back to their original populations very quickly because they can double their numbers every 4.8 hours when metronidazole drops below the critical threshold. In effect, miss a single dose and you might as well start over. They grow that fast.
That’s why metronidazole works almost perfectly in the lab but not in clinical practice. Most patients don’t take it properly and when I say most, I mean nearly all patients. According to a study in the International Journal of Antimicrobial Agents (Vol. 31, Issue 6, p. 531-536), for a typical “take three times a day” prescription, only one in 10 patients will be compliant, i.e., 9 out of 10 times, the antibiotic — even if it’s the right antibiotic — won’t be effective. That’s why, in hospitals, nurses bring you your pills in those little paper cups every few hours and watch to be sure you take it.
It’s also why you can’t just tell a patient, “Here, take this three times a day for a week.” You’ve got to be sure the patient understands why the antibiotic won’t work unless he or she takes it exactly as instructed. Every eight hours means every eight hours, not six or 10. It also means taking it without fail for an entire week. Miss one dose and the patient will need to start over.
By the way, instead of writing instructions as “tid” (three times daily), the American Pharmacists Association recommends writing “q8h” (every eight hours) and “q12h” (every 12 hours) instead of “bid” (twice daily). The 24-hour blood levels will be much more uniform than with the more vague instruction of “x times a day.”