What’s specificity got to do with patient compliance?
Imagine you’re a microbiologist tasked with finding a way to kill a particular streptococcus. No problem. Just pour a little sodium hypochlorite (bleach) into your petri dish. It’ll be dead in seconds. Oh, it’s not in a petri dish? It’s in a human being? That’s going to be a problem. Sodium hypochlorite will still kill the strep in a human, but it’s going to kill every other living cell as well!
That’s the essential problem with killing pathological microbes. How does one simultaneously kill a specific pathogen without killing our own (somatic) cells at the same time? The solution lies in not killing whole cells at all, just specific parts, the parts that vary from species to species. All cells need some things — DNA, RNA, amino acids, proteins, and enzymes. DNA, of course, is the master program for everything a cell does. RNA copies segments of the DNA code for replication by ribosomes in the cytoplasm. Ribosomes manufacture proteins from the RNA templates by assembling amino acids with the help of thousands of enzymes.
The manufactured proteins form most of the cell structures and perform most of its functions. While all cells share these basic components, there’s an almost infinite variation in the types and numbers of proteins each species uses. Humans use over 75,000 enzymes to make an estimated two million different proteins. No one yet knows the exact numbers.
Another thing all cells have in common is some kind of an outer barrier to keep what’s inside a cell in and everything else out. The barriers simultaneously have to allow certain molecules like nutrients to pass through the barrier into the cell and other molecules like waste products to get out. How they do that is one of the major differences between bacterial and human cells. Both human and bacterial cells are bounded by a plasma membrane. Bacterial membranes are surrounded by an additional and thicker cell wall. Systemic antibiotics are only effective against bacterial cells because they only target components found exclusively in cell walls. Because there are variations in the way different groups of bacteria construct their cell walls, antibiotics can be designed to selectively target specific species.
The fundamental differences between somatic and bacterial cells is the key to selectively killing one and not the other. Killing is really a misnomer because most antibiotics don’t actually kill bacteria. They’re bacteriostatic, not bactericidal, which is why they have to be taken for long periods. Some antibiotics like rifamycin are narrow spectrum. It’s only effective against mycobacteria like Mycobacterium tuberculosis, the bacterium that causes tuberculosis.
Others such as penicillin and streptomycin are broad spectrum because they target components that are common in whole groups of bacteria. Penicillin is a broad spectrum antibiotic that used to be effective against almost all gram-positive bacteria. It inhibits an enzyme called transpeptidase that gram-positive bacteria use to cross-link the polysaccharides in their cell membranes. Without that enzyme, they can’t synthesize enough new cell membrane to grow and reproduce. Note that, because it only inhibits the cross-linking of new polysaccharide, it doesn’t kill existing cells. It only inhibits growth and reproduction. Unable to replicate, they eventually die.
Streptomycin is another broad spectrum antibiotic, but it only affects gram-negative bacteria. Unlike penicillin, it doesn’t target the cell membrane. Instead, it inhibits protein synthesis by the types of ribosomes specific to gram-negative bacteria. The mechanism may be entirely different, but the end result is the same. Without the ability to synthesize new proteins, the existing bacteria eventually die off.
The “eventually” part is why patient compliance is so crucially important. You’d think that over seven to 10 days, missing one dose wouldn’t make much of a difference. You’d be dead wrong. More importantly, the bacteria probably won’t be ... dead. That’s because once the level of the antibiotic in the blood (titer) drops below the inhibition point, the targeted enzymes and proteins start working again. The bacteria return to doing what they do best — reproducing. Because they reproduce so quickly, it takes them only a few hours to repopulate their numbers.
Think a few hours won’t matter much, one way or the other? Do the math. A typical penicillin VK dosage for a streptococcal infection is 250 mg three times a day for 10 days. It really should be written as 250 mg every 8 hours to keep the average concentration in the blood (titer) high enough to inhibit transpeptidase until all the streptococci die of old age. Some strep species can reproduce every 20 minutes. In eight hours they can double their numbers 24 times. What’s that in real numbers? If you started with just 10 streptococci, 24 generations later you’d have a total population of one billion trillion! You might as well start over from scratch.
Compliance is a massive problem. The vast majority of people taking antibiotics are noncompliant. Noncompliance is the number one reason bacteria develop resistance to antibiotics. According to the International Journal of Antimicrobial Agents, only one in 10 patients on a three-a-day regimen take the drug at the right intervals. That means 90% of prescription takers are breeding more resistant bacteria rather than killing them. No wonder we’re running out of effective antibiotics. RDH
Bill Landers has been president of OraTec Corp. since 1992. He is also a leading expert on chairside and laboratory periodontal risk assessment technologies, and his essays on periodontal disease have been published in several dental hygiene journals. Mr. Landers is a popular speaker and has presented hundreds of continuing education seminars on the microbiology of periodontal diseases.
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