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A Brief History of Antibiotics, Antibiotic Resistance, and Antibiotic Alternatives

A Brief History of Antibiotics, Antibiotic Resistance, and Antibiotic Alternatives Antibiotic Resistance and Alternatives Antibiotics have been commonly, though mistakenly, thought of as the ultimate cure, for almost all illness, for over half a century now. However, the intended use of antibiotics is for the treatment of bacterial infections and diseases. Viruses or fungi-related illnesses will not be affected by antibiotics. This misunderstanding of the use of antibiotics has led to overuse, or the misuse, of antibiotics, in a wide range of countries worldwide.

As a result of overuse, misuse, and abuse, antibiotics, once hailed as the savior of mankind, are an increasing threat as bacteria grow ever stronger. (Bunyard) The development of antibiotic-resistant bacteria poses a looming threat to the medical industry and to society. A quick look into modern newspapers or journals would reveal startling reports about antibiotic-resistant bacteria, also known as superbugs, and how devastating their emergence could potentially be. (Ed. Bonomo and Ed. Tolmasky) Worldwide, hundreds of thousands die each year due to bacterial infections that can no longer be controlled.

These deaths are the ultimate consequence of over-the-counter sales of antibiotics, patient pressure on doctors always to prescribe and the indiscriminate use, especially in the U. S. , of antibiotics as growth factors in intensive farming, including the spraying of orchards with antibiotics. (Bunyard) Alternative antibacterial agents with fundamentally different modes of action than that of traditional antibiotics is desperately needed to stop bacteria from continuing to cause illnesses, once treatable, from becoming, once again, untreatable and deadly illnesses. Parisien, Allain and Mandeville) An antibiotic is a naturally produced agent that destroys bacteria, but has no effect on viruses, and that is used as a medication. (Encarta World Dictionary) Our most trusted antibiotic, penicillin, was discovered in 1928, and introduced in 1929 when Alexander Fleming published his seminal paper in the British Journal of Experimental Pathology on the “mold extract” from Penicillium as a germ-killing compound. (Ed. Bonomo and Ed.

Tolmasky) It was discovered by chance, when Fleming noticed that colonies of the common bacterial pathogen, Staphylococcus aureus, were destroyed in the region of penicillium mold that had contaminated a discarded petri dish. (Bunyard) Penicillin was further developed by Oxford University scientist Henry Florey, Ernst Chain, and Norman Heatley, in 1940. These scientists developed methods for growing, extracting, and purifying enough penicillin to demonstrate its power against bacterial infections. (Bunyard) Its success was so spectacular that penicillin was dubbed “the miracle drug. ” (Ed.

Bonomo and Ed. Tolmasky) In spite of over a half a century of tremendous commercial and scientific investment, bacterial infectious diseases were still not completely eradicated by the use of antibiotics. Bacteria’s ability to develop antibiotic-resistance genes enabled them to continue thriving and reproducing stronger, more resistant strains. (Ed. Bonomo and Ed. Tolmasky) Even though it had been reported by Ernst Chain and E. P. Abraham, in 1940, that there was in enzyme in the bacteria E. coli that was able to inactivate penicillin, the significance of this finding wasn’t immediately realized.

In fact, several diseases, thought to be extinct, have reemerged, and many of the known bacterial pathogens have become more and more resistant to antibiotics. (Ed. Bonomo and Ed. Tolmasky) The first highly publicized used of penicillin followed a devastating fire in the Cocoanut Grove nightclub in Boston, Massachusetts in November 1942, when some 400 people died and several hundred others were left with severe burns. Some of those survivors undoubtedly owe their lives to the new forms of treatment involving antibiotics.

The challenge for the medical staff, then as now, was to prevent Staphylococcus aureus from taking hold in the damaged tissue and killing the victims from septic shock. (Bunyard) Critical innovations in the successful treatment of burn victims were giving blood plasma, combined with administering antibiotics to control streptococcal blood infections, but it was the extraordinary results obtained with the liquid produced by cultures of the penicillium mold that really caught the imagination. (Bunyard) As it happened, at the instigation of Dr.

Henry Florey and Dr. Ernst Chain, the Merck pharmaceutical plant in New Jersey, had only just began manufacturing penicillin, and on the day following the fire, the company rushed 32 liters of the antibiotic liquor to the Massachusetts General Hospital in Boston. (Bunyard) The high mortality of infections due to wounds sustained in battle (gangrene) and the burgeoning problem of gonorrhea and syphilis in World War II veterans also enhanced interest in the curative powers of penicillin. (Ed. Bonomo and Ed. Tolmasky)

As a result of his continuing experiments with the antibiotic, Fleming discovered that by growing Staphylococcus aureus in increasing concentrations of penicillin, he could select mutated bacteria with cell walls that would keep out the antibiotic, therefore prevent its killing them. Fleming stressed the importance of patients receiving a full course of treatment, so as to minimize the opportunity for the bacteria to develop resistance. He was also perceptive enough to foresee the dangers of penicillin becoming available in an oral form such that anyone could take it, even without a special prescription. Bunyard) After penicillin had started being used to combat infections, S. aureus was one of the first publicized bacteria known to have become resistant to penicillin. (Ed. Bonomo and Ed. Tolmasky) In London, just a few years after the introduction of penicillin, strains of staphylococcus appeared that were resistant to penicillin, not simply by keeping it out, but by actually destroying it. (Bunyard) S. aureus caused serious illnesses, such as pneumonia, endocarditis, osteomylitis, and toxic shock syndrome. (Ed. Bonomo and Ed.

Tolmasky) The clinical impact of this resistance was staggering; this harmful pathogen had once again become untreatable. Since the 1940’s, antibiotic production has increased rapidly. By 1946, in one hospital, 14% of the strains isolated from patients had gained such resistance. In 1949, the U. S. produced penicillin and streptomycin at the rate of 6. 5 tons per month. (Bunyard) In the early 1950’s, nearly 60% of the strains isolated from patients had gained resistance. (Bunyard) By 1954, the rate of production of broad-spectrum antibiotics had tripled to 220 tons a year. Today, the quantity produced in the U.

S. alone is 18,000 tons a year, nearly half of which is used in the intensive rearing of animals as growth promoters and for controlling disease on the farm, which itself is largely a product of closely confined livestock. In the U. K. , the Swann Committee of 1969 warned of the dangers of antibiotic-resistance from farmers using antibiotic growth promoters, and recommended a ban specifically on the use of tetracycline and penicillin. All too little or no avail: by the end of the 1980’s, use of both these antibiotics as growth promoters had risen 16 and 7 times respectively.

Today, 95% of all Salmonella typhimurium, which causes debilitating, even deadly diarrhea in humans and young animals, such as calves, is tetracycline resistant. (Bunyard) Following the discovery of penicillin, the search was on to find more antibiotics in the natural environment. The microbiologist, Rene Dubos, in 1939, was the first to discover soil bacteria that produced antibiotics. He found that Bacillus brevis released a substance, which he then called gramicidin. Gramicidin was found to be extremely toxic when given intravenously and so its use was limited to topical applications against minor skin conditions. Bunyard) Dubos’ work inspired others to begin the search for natural antibiotics and, in 1943, Selman Waksman, discovered streptomycin which was released from a group of soul bacteria known as actinomycetes. Streptomycin proved to be the only means at the time of combating tuberculosis, although such treatments did have drawbacks, including kidney damage and temporary or even permanent deafness in some patients. A more serious drawback was the discovery that the T. B. mycobacteria became resistant to the antibiotic during drug therapy. Bunyard) Ever since Louis Pasteur and his demonstration that microscopic bacteria, such as the anthrax bacillum, were the causative agents of disease, we have tried to wage a war against bacteria. (Bunyard) The large quantity of products with antibacterial properties available to the public market, including soaps, detergents, antibiotic-impregnated fittings, simply for the purpose of turning our homes and our bodies into bacteria-free zones, expresses just how far our pathological fear of bacteria has taken us. Bunyard) The irony is that our world has become the “best of all possible worlds” only because of bacteria transforming our environment, from the air we breathe and the ground we walk on, to the water we drink. (Bunyard) Bacteria and life are parallel, and without bacteria having set the stage of an oxygen- and nitrogen-rich atmosphere, we would not be here today. (Bunyard) The central cause of the antibiotic-resistance problem is that the actual use of antibiotics has contributed to the inexorable rise of antibiotic resistant bacteria. (Ed. Bonomo and Ed.

Tolmasky) Several factors, including human and nonhuman use of antibiotics, have accelerated the emergence, acquisition, and spread of resistance. Some of these factors include the use of antibiotics in food-producing animals, which leads to the development of resistance in bacteria that find their way into the human food chain, the misuse and overuse of antibiotics in humans, the demand for antibiotics by patients when they are not appropriate, the noncompliance by patients who often fail to finish the antibiotic prescription, and the over-the-counter availability of antibiotics in a large number of countries. Ed. Bonomo and Ed. Tolmasky) In the U. S. , the Center for Disease Control and Prevention estimate that one-third of the 150 million outpatient prescription for antibiotics are unneeded. According to Stuart Levy, around 80% of the doctors he spoke to, admitted to having had written prescriptions on demand against their better judgment. (Bunyard) Hospitals, in particular, can become fertile grounds for the spread of drug-resistant bacteria, and not just those strains that caused the original infection that a patient had originally been treated for. Bunyard) The World Health Organization has estimated that bacterial resistance to antibiotics now accounts for 60% of nosocomial, or hospital derived, infections. They also estimate that out of 60,000 deaths caused by bacterial infections in the U. S. each year, 14,000 of them are due to antibiotic resistant bacteria. Antibiotic resistance is certainly not a recent occurrence. In the 1960’s, a search for antibiotic-resistance in the wild revealed that feces from Kalahari Bushmen and a range of animals in South Africa and Zimbabwe showed a smattering of antibiotic-resistant bacteria. Sometimes the resistance proved to be transferable.

The Given that antibiotics are part and parcel of the natural flora and soils and are even synthesized in animals, it should not be surprising that antibiotic resistance is also a natural phenomenon. (Bunyard) Current multi-resistance to antibiotics among bacteria is, however, a new phenomenon, which indicates that somehow, resistance factors have found their way onto plasmids that existed before in the bacterial population, but which did not necessarily harbor these factors. Also, some of the mechanisms for extruding antibiotics possessed by bacteria may have previously served other functions, such as eliminating heavy metals from the cell. Bunyard) Research has shown that bacteria have formed quite a wealth of mechanism to resist antibiotics, as well as ways to transfer those mechanisms between cells of the same strain, or even between different strains, or even between different species, of bacteria. (Ed. Bonomo and Ed. Tolmasky) These resistance mechanisms include changes in the permeability of the bacteria that interfere with the penetration of the antibiotic into the cell, the presence or acquisition of efflux systems, which “flush” the ntibiotic out of the cell body, the modification, or substitution, of the target of antibiotic action, and the ability to chemically modify the actual antibiotic molecule. (Parisien, Allain and Mandeville) For pharmaceutical industry, the name of the game was not just to discover new antibiotics by scouring through the soil, but also to improve on those already in use, by altering parts of their chemistry and in some instances synthesizing new substances almost from scratch.

The important antibiotic, methicillin, was the outcome of the search for a penicillin-like antibiotic which would resist attack from the bacterial enzymes that degraded the natural penicillin. (Bunyard) Then, in 1968, doctors reported the first instances of MRSA, hospital-acquired methicillin-resistant S. aureus, in Northern Europe. (Bunyard)(Ed. Bonomo and Ed. Tolmasky) In 1978, the resistant form of Staphylococcus aureus had arrived in the U. S. , at the University of Virginia. By 1980, half of all S. ureus surgical site infections and about 40% of all blood infections from bacteria were the result of the MRSA strain. (Bunyard) Today, in the U. S. , MRSA and vanomycin-resistant enterococci cause the majority of antibiotic-resistant infections. They also cost significantly more to treat than infections resulting from antibiotic-susceptible strains of the same species. Duke University estimates the excess cost on average of a MRSA-induced blood infection as $27,083 compared to just over one-third the cost for a similar infection caused by antibiotic-sensitive strains.

Most of the deaths in the U. S. due to such infections were caused by MRSA. (Bunyard) The pharmaceutical industry has continued dealing with the resistance problem by modifying existing antibiotics or developing new ones, just as they had immediately after the discovery of antibiotic-resistance. However, only three new classes of antibiotics have been introduced into the medical market in the past four decades! (Parisien, Allain and Mandeville) Because bacteria have the capability of developing and transferring antibiotic resistance so rapidly, this method is becoming less and less effective.

The demand for new antibacterial agents with different fundamental modes of action than traditional antibiotics has triggered a worldwide effort in developing novel bacterial alternatives. (Parisien, Allain and Mandeville) The most promising candidates, at least as of yet, include bacteriophages, also called phages, bacterial cell wall hydrolyses, or BCWH’s, and antibacterial peptides, or AMP’s. The most common mode of action of phages is the causing of bacteriolysis, which occurs naturally at the end of the phage lytic cycle, by disruption of the cell wall.

Bacterial cell wall hydrolyses are enzymes that degrade peptidoglycan, the major component of the bacterial cell wall, and cause bacteriolysis. (Parisien, Allain and Mandeville) Antimicrobial peptides have a large variety of bactericidal activity, though very few are fully understood. AMP’s are promising candidates due to their broad spectrum of activity (antibacterial, antiviral, antifungal), rapid and potent bactericidal activity, low level of induced resistance, and the vast variety of AMP’s in terms of structures and antimicrobial functionalities, representing tremendous potential. Parisien, Allain and Mandeville) There are a multitude of potential antimicrobial alternatives including bacteriophages, bacterial cell wall hydrolyses, and antimicrobial peptides, that are under investigation to overcome the growing issue of bacterial resistance to antibiotics. (Parisien, Allain and Mandeville) Something needs to be done before all of our believed “extinct” diseases reemerge, before all of the “defeated” pathogens retaliate with a vengeance, and before it’s too late to save humanity from a range of unstoppable bacteria.

Works Cited Bunyard, Peter. “Breeding the Superbug. ” The Ecologist 32. 2 (2002): 33-37. Ed. Bonomo, Robert A. and Marcelo Ed. Tolmasky. Enzyme-Mediated Resistance to Antibiotics: Mechanisms, Dissemination, and Prospects for Inhibition. Washington, DC: ASM Press, 2007. Parisien, A. , et al. “Novel Alternatives to Antibiotics: Bacteriophages, Bacterial Cell Wall Hydrolyses, and Antimicrobial Peptides. ” Journal of Applied Microbiology 104 (2008):1-6.

Encarta World English Dictionary. Microsoft Corporation, 1998-2005. (From Microsoft Works Word Processor). Works Consulted Dean W, Boening and George J. Vascocelos. “Persistance and Antibiotic Immunity of Bacteria From a Wetland Used as a Medical Waste Landfill. ” Journal of Environmental Health 59. 6 (1997). Rossi, Lisa M. , et al. “Research Advances in the Development of Peptide Antibiotics. ” Journal of Pharmaceutical Sciences 97. 3 (2008).

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