Science Tribune - Article - November 1996
The antibiotic paradox
H.H. Humphrey Center for Experimental Medicine and Cancer Research, Hebrew University Hadassah Medical School, Jerusalem 91220, Israel
Website : http://www.md.huji.ac.il/special/cancer/home.html
E-mail : Gershom@md2.huji.ac.il.
Microbial resistance to antibiotics
Antibiotics are the most important medical discovery of our century, yet their widespread misuse gradually diminishes their potency. More and more bacteria are developing a resistance to antibiotics (1) conferred by randomly mutated genes. This alarming situation was documented recently in an important book, "The Antibiotic Paradox", by a well-known expert, Stuart B. Levy (2), but the danger was already recognized by Alexander Fleming, who discovered penicillin. Back in 1945, he warned that misuse of penicillin could lead to the selection and propagation of mutant forms of bacteria resistant to the drug. The first penicillin-resistant bacteria appeared several years later. Their mutant gene encoded for a penicillin-destroying enzyme, penicillinase. Penicillin treatment kills non-resistant, but leaves behind resistant, bacteria.
Plasmids and transposons
Bacteria may acquire resistance even if they are not exposed to antibiotics. Resistance is transferred between bacteria by plasmids which are accessory pieces of DNA that are separate from the chromosome. Plasmids are independent self-duplicating genetic elements which may fuse with other plasmids and thus acquire new genes. Up to a thousand plasmid copies may exist in a cell and each one may carry as many as 300 different genes. Plasmids are transferred from one bacterium to another by conjugation and continue to multiply once they have entered a new host. Some of their genes can even be transferred to the chromosome as transposons leading to the acquisition of functions not normally encoded in the chromosome. Resistance genes may also be transferred by bacteriophages or the bacterium may take in naked DNA fragments floating in its vicinity, a process known as transformation.
Transferable antibiotic resistance
Transferable antibiotic resistance was discovered in 1959 during a Shigella dysenteriae epidemic. The microbe was resistant to four antibiotics which were tetracycline, sulfonamide, streptomycin, and chloramphenicol. This resistance could not be explained by a simple mutation, as in the case of penicillin resistance, because the four drugs were unrelated; two are obtained by synthesis and two by extraction. In addition, non pathogenic E. coli found in the stools of these patients showed the same resistance profile. As stated by Levy, "transfer of resistance genes could occur among bacterial species more genetically and evolutionary distant than a horse is from a cow" (2, p. 74). Moreover, Levy specifies that "some data suggest that resistance genes evolved from genes found in the very microorganisms that produce antibiotics." The function of these genes would thus be to protect the antibiotic-producing microorganisms from their own lethal products. Clearly, "resistance genes existed before the development and clinical use of antibiotics" and antibiotic treatment has just selected resistant microbes and increased their abundance.
Treatment by a single antibiotic may induce multiple drug resistance
Different mechanisms account for drug resistance - e.g., decreased drug entry, drug inactivation, or alteration of the antibiotic target - and a single drug may induce multiple drug resistance. "For reasons beyond our present understanding, the continuous use of even a single antibiotic over a period of weeks to months will select bacteria with resistance to different kinds of antibiotics" (2, p. 99). An example is the treatment of women with chronic urinary tract infections by tetracycline. As therapy extends over weeks, these women excrete in their feces E. coli with an ever-broader resistance.
Low-level resistance precedes high-level resistance but the resistance level acquired is well beyond that needed to resist a normal therapeutic antibiotic dose. This results in an escalation which prompts Levy to write : "It is like taking a mallet to kill a fly".
Resistance may be an outcome or a by-product of an unspecified function of resistance genes in bacteria; it may be just accessorily that these genes also enable bacteria to resist antibiotics (2, p. 188). A given antibiotic can select for resistance to others and this resistance persists even after antibiotic use has diminished. Apparently there is no factor or agent that selects against resistant bacteria.
Transfer of resistance from animals to man
Most animals raised in the U.S. for human consumption receive some antibiotics during their short lifetimes for prophylactic reasons or for growth enhancement. Antibiotics are also used in the fish industry, and oxytetracycline is applied to bee-hives. Levy estimates that "30 times more animals are being given antibiotics yearly than are humans" (2, p.140). The animals grow resistant bacteria in their gut, seed them into the environment, and thus contaminate soil bacteria and humans. Levy et al. studied the effect of sub-therapeutic levels of tetracycline administered to chickens in a relatively remote farm. E. coli isolated from chicken feces became resistant to tetracycline within 24-36 hours of antibiotic feeding and acquired resistance to ampicillin, streptomycin, and sulfonamides over the ensuing months. After five to six months, the E. coli in the feces of farm-workers and their families also became resistant (2, p.145). Other studies have also shown that resistant genes selected in animals can enter human E. coli - and other - strains and cause human disease.
Antibiotics in plant diseases
Oxytetracycline and streptomycin are used to treat tree and plant diseases. In a study carried out in Boston, Levy et al. isolated 20,000 to 100,000 antibiotic-resistant bacteria per gram of vegetable. Of these, 10-20% could potentially colonize human intestines (2, p. 165). This led to the dramatic comment : "This situation raises the staggering possibility that a time will come when antibiotics as a mode of therapy will be only a fact of historic interest" (2, p. 183).
The Alliance for the Prudent Use of Antibiotics (APUA)
The World Health Organization has convened groups of experts to study microbial resistance and initiated an international cooperative effort. In January 1981, participants at a conference in Santo Domingo published an "Antibiotic Misuse Statement" declaring : "We are faced with a worldwide public health problem" (2, p. 249) and created an international study group of experts from 80 nations,"The Alliance for the Prudent Use of Antibiotics" (APUA). APUA, which acts outside political and economic pressures, promotes worldwide awareness of the resistance problem.
1. Zajicek G. How to diminish microbial resistance to antibiotics? The Cancer J 6, 52, 1993.
Microbial resistance to antibiotics and the wisdom of the body. The Cancer J 7, 168, 1994.
Antibiotic resistance and the intestinal flora. The Cancer J 9, 214, 1996.
2. Levy SB. The antibiotic paradox. How miracle drugs are destroying the miracle. Plenum Press, NY, 1992.