I. A SHORT HISTORY AND A SEQUENCE OF INSIGHTS
The scientific campaign against bacteria began in 1865 when Louis Pasteur identified microoganisms as the cause of infectious disease. Soon afterward, Joseph Lister reasoned that clean wounds wouldn't lead to blood sepsis (blood poisoning). With carbolic acid he inaugurated the era of 'antisepsis,' something we take for granted today.
Another pioneer, Robert Koch, developed methodology to identify the specific microbes responsible for disease such as anthrax and tuberculosis. It was Paul Ehrlich, reasoning from the specificity of staining tissues, who devised the idea a 'magic bullet,' and sought one for syphilis. His '606' was Salvarsan, a toxic brew based on arsenic that had many side effects. Then the field was quiet for a quarter century. In 1932, Gerhard Domagk developed the first sulfa drug; its initial success was with his own daughter who was dying of septicemia. Within 10 years, a whole assortment of sulfa drugs appeared. With them, side effects and microbial resistance appeared. The 'bugs' began to fight back.
A chance contamination of a petri dish led to the truly 'perfect' magic bullet, penicillin. A truly precious resource late in World War II, it was used primarily to fight venereal disease in soldiers. Streptomycin, Chloramphenicol, and the tetracyclines soon emerged. They too soon kindled drug resistance and their own side effects. Chloramphenicol killed hundreds of babies who suffered the 'gray baby syndrome.' Tetracycline stained teeth in their formative period and displayed other side effects.
Only one new family of antibiotics has appeared since the 1960s: the quinolones, which are a synthetic. Side effects caused by them include birth defects, shock, and an occasionally, death. In the meantime, antibiotic resistance by microbes has been increasing, especially in hospitals where some 60,000 hospital-based infections now appear annually. (My note: it is time now to learn an important term: iatrogenic diseases are 'doctor caused' diseases; unfortunate consequences of medical care.) The last and final antibiotic for many years has been Vancomycin. Two new 'last resort' antibiotics are described later in this article.
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II. MECHANISM OF DRUG RESISTANCE / PLASMIDS
Microorganisms have many resources in the struggle to survive. They occur in large numbers. A single infection may be caused by millions of individual organisms. Many reproduce in less than an hour. Of those, some will be mutations. If some happen to be drug resistant, then they multiply and can overwhelm the host by sheer numbers. You'd call it survival of the fittest, Darwinian fashion. It is natural selection at work.
Bacterial drug resistance goes far beyond traditional evolutionary mechanisms. Listen up: bacteria can pass on drug resistance one to another without having to inherit it. Furthermore, they can pass on drug resistance to an entirely different species of microorganisms. How they do it is a biochemical version of 'computer viruses.' You will find their strategy interesting.
We think of DNA as confined to the cell nucleus or mitochondria. Bacterial contain free floating rings of DNA called plasmids. Learn that term. These rings of DNA can pass between bacteria when they touch. They can also drift extracelluarly. Some bacteria are actually DNA scavengers. The pneumococci actually consume it and can genetically incorporate it to their benefit.
Bacteria also have 'jumping genes.' These are segments of DNA that can transpose themselves from one part of a chromosome to another--even to those in another cell. Thus, drug resistance can be multiplied and transferred from one bacteria to another.
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III. DRUG RESISTANCE
The mutability of bacteria coupled with their ability to exchange plasmids is steadily decreasing the effectiveness of antibiotics. In 1952, penicillin cured nearly all staphylococcus infections. By 1982, it could cure less than 10% of them. The rapid spread of drug resistance threatens to complicate the treatment of disease such as bacterial pneumonia, meningitis, bacteremia (a blood infection), sinusitis, and otitis media (ear infection in children).
The last line of defense against some infections has been Vancomycin©. Synercid©, a new Rhone-Poulenc Rorer antibiotic was announced in March, 1998. A Japanese infant infected with resistant Staph aureus was saved with Synercid.
In September, 1999, the FDA approved the use of Synercid to treat hospital-based antibiotic resistant infections. This was none too soon: by 1998, 20% of ICU and non-ICU enterococci bacteria had acquired resistance to Vancomycin. Zyvox© from Pharmacia & Upjohn has been announced but is awaiting FDA approval. Daptomycin© by Cubist Pharmaceuticals was in late stages of human testing as of September, 1998.
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How has all of the drug resistance come about? In the early days, it seemed about impossible to overdose with penicillin. Administered intravenously, saturations of penicillin are possible that cannot be achieved by the oral route. Patients came to demand them. Doctors would prescribe them for all manners of ailments, even non-bacterial ones. 'Just in case', surgeons would even spray them around operating rooms. They were even dispersed around hospital wards to keep pathogens at bay. (My note: one of my professors in dental school back in the early 60s told us about an antibiotic toothpaste briefly marketed. It contained penicillin!) In dentistry, if you have a history of rheumatic fever or a prolapsed heart valve defect, it is malpractice NOT to administer a large dose of antibiotic (penicillin or erythromycin) on the day a dental procedure is performed. The point is this: we are constantly exposed to them.
Humans aren't the only ones getting antibiotics. Cows, chickens, pigs, cattle, sheep, ducks and other livestock get them also. This adds to the global selective pressure upon bacterial populations. Salmonella infections are becoming more deadly due to antibiotic treatment of animals. Unregulated livestock antibiotic usage is altering their bacterial flora.
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As streptococcus A has receded, streptococcus B has stepped into its place in bacterial ecology. Strep A has mutated and multiplied in the background until it made headlines in the 1980s. It began striking people of all ages and all classes, almost at random. In 1989 it claimed its most famous victim--Jim Henson puppeteer and creator of the Muppets. Do you remember toxic shock syndrome associated with tampons? That's strep A, too.
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Many bacteria have another technique for dealing with threats to their livelihood: sporulation. When exposed to a toxic environment, they go dormant, toughening their cell walls to a nearly impermeable state, and wait it out until conditions improve. Historically, spore formation was a defense against drying out, high temperature, or some other change in their environment. As spores, microbes can drift about unharmed in 'antiseptic' solutions specifically designed to kill them. So-called 'cold sterilization' is no longer acceptable in dental offices. Dry heat or autoclaving is now virtually mandatory. (My note: when I took bacteriology in 1961, we were sent around the Northwestern Dental School to culture what we could out of cold sterilizing containers around the school. We grew all kinds of things. Then we went into the clinics and proceeded to use cold sterilization. Those days are gone. So is the school.)
By 1992, a number of strains of E coli (and others) have developed toleration of chlorine. Microbes can now survive in doses of chlorine that used to kill them. Chlorine has had a long use in treatment at municipal water treatment plants. There is catch-22 in using chlorine: if there are a lot of pollutants in the water, they can become carcinogens. If you decrease the chlorination level, more resistant E. coli can survive.
Do you recall the outbreak of cryptosporidium in Milwaukee a couple of years ago? It appears in the news from time to time. It is a one celled tiny parasite that is commonly found in the excreta of cows. As cities use water that comes from farmland runoff, the cryptosporidium can get into community water supplies--even those with current, state-of-the-art water treatment systems. The cryptosporidium oocysts are resistant to disinfection by chlorine. 400,000 fell ill in the Milwaukee outbreak due to that resistance.
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What can you do? Use antibiotics wisely. Exercise personal cleanliness like your Mom taught you. When you travel out of country, choose your food carefully and drink only bottled water. For most of us--most of the time, antibiotics DO work.
..... CJ '99
Resources
"Boy's illness fuels medical debate" Chicago Tribune February 25, 1998.
Brookesmith, P. Biohazard The Hot Zone and Beyond. New York: Barnes and Noble Books, 1997.
"Doctors want super antibiotic; Experts fear they'll ruin it too" Kankakee Daily Journal March 15, 1998.
"Drug-resistant bacteria worries health workers" Chicago Tribune August 20, 1999.
"Experts silence bacteria colonies" Chicago Tribune April 10, 1998.
Ewald, P. Evolution of Infectious Disease. New York: Oxford University Press, 1994.
Garrett, L. The Coming Plague. New York: Farrar, Straus and Giroux, 1994.
"Germ Fighter in Household Products is Found to Generate Resistant Strains" Wall Street Journal August 7, 1998.
Koktulak, R. "Potentially deadly supergerm is defeating best drug" Chicago Tribune. June 15, 1997.
"Resistant staph germ found in U.S." Chicago Tribune. Aug 22, 1997.
Tanouye, E. "Drug Makers Go All Out to Squash 'Superbugs' Wall Street Journal. June 25, 1996.
Tanouye, E. "How Bacteria Got Smart, Created Defenses Against Antibiotics" Wall Street Journal. June 25, 1996.
Waldhole, M. "As Bacteria Outsmart Old Antibiotics, Drug Makers Ready New Arsenal" Wall Street Journal September 27, 1999.