I’m often asked why even older antimicrobials are still considered medically important to human medicine. The premise, right or wrong, is to preserve antibiotic effectiveness by reducing the risk of antimicrobial resistance attributed to wholesale use in animal agriculture. While debate still rages over the impact new legislation will have on preserving antimicrobial effectiveness in humans, we stand guilty by association. Statistics suggest 80 per cent of antimicrobials are used in agriculture to treat and control disease in animals. Even though modern agriculture is prudent in using critically important compounds, the future decrees change on our behalf.
Several recent articles on Medscape, a sponsored website providing access to medical information for clinicians and the general public (Four old antimicrobials that still work best, Medscape, Jan. 16) stand as a reminder that even “old-time” antimicrobials play an important role for the medical community today.
Physicians are reminded that although attention is often paid to newer and more expensive drugs, they should not forget older agents that have stood the test of time.
Here are four examples:
First synthesized in 1912, isoniazid’s activity against tuberculosis was identified in 1945. More than 100 years later, and despite growing drug resistance, isoniazid is still a standard component of multi-drug treatment regimens for both pulmonary disease and diseases affecting other areas of the body.
Alexander Fleming first discovered penicillin in 1928. It started with the observation that the mould Penicillium notatum destroyed colonies of Staphylococcus aureus. Use as an antibiotic began in the 1940s. Today, penicillin still has activity against many microbes and is recommended as first-line treatment for common upper respiratory diseases.
Resistance to penicillin varies substantially by region. It has been suggested that allergies to penicillin is over-diagnosed, particularly in children.
From January to May in 1942, 400 million units of pure penicillin were manufactured. By the end of the war, American pharmaceutical companies were producing 650 billion units a month.
According to British hematologist and biographer Gwyn Macfarlane, the discovery of penicillin was “a series of chance events of almost unbelievable improbability.” After just over 75 years of clinical use, it is clear that penicillin’s initial impact was immediate and profound. Its detection completely changed the process of drug discovery. Its large-scale production transformed the pharmaceutical industry, and its clinical use changed forever the therapy for infectious diseases.
In 1945, Fleming and his colleagues, Florey and Chain, were awarded the Nobel Prize in Physiology or Medicine. In his acceptance speech, Fleming presciently warned that the overuse of penicillin might lead to bacterial resistance.
Tetracycline, an antibiotic in the tetracycline family of drugs, is used to treat a number of human infections. It works by blocking the ability of bacteria to make proteins.
Tetracycline was originally made from bacteria of the Streptomyces type.
Tetracycline was patented in 1953 and came into commercial use in 1978. It is on the World Health Organization List of Essential Medicines, the most effective and safe medicines needed in a health system. It is a broad-spectrum antibiotic used to treat a variety of diseases like those caused by rickettsia (e.g. Rocky Mountain spotted fever, psittacosis); bacteria (e.g. chlamydia, Lyme disease, Q fever); and mycoplasma.
Resistance has greatly eroded the versatility of this group of antibiotics.
In 1932, a German pathologist found that prontosil, a chemical derivative from azo dyes, had antibacterial activity attributed to its metabolism to sulfanilamide. In the hands of the Nazi regime, experiments using sulfanilamide were carried out at the all-female Ravensbrück concentration camp, an ordeal chronicled in the novel Lilac Girls.
Sulfonamides are effective against many gram-positive and gram-negative bacteria and protozoa. Although sulfas remain a backbone of antimicrobial therapy, adverse effects, drug allergy, newer antibiotics, and resistance have reduced their utility.
Resistance to one sulfonamide means resistance to all.
We in the animal health arena and production agriculture have grown accustomed to using antibiotics as a part of food animal rations to prevent, control, and treat disease. They are being used diligently, and at times through the production cycle that eliminates any risk of residues. Several of the old-time antimicrobials are among those traditionally incorporated in rations for this purpose.
New regulations will strictly limit the use of these compounds. Veterinarians and producers need to get ready for the responsibilities inherent in the road ahead. We’ll be held accountable and must meet the challenge. All of these products will soon require a prescription when used in any capacity. Growth promotion claims on labels have already been eliminated.
The ability to measure success is still missing. The scientific community must address how we trace the origin and spread of resistant microbes — more fundamentally, the transmission and spread of specific resistance genes in microbial communities.
Finger pointing by the medical community will continue as long as animal health and the medical profession go to the same cupboard for antimicrobials. Meaningful surveillance systems are frequently missing and there seems to be no clear way of evaluating research findings and applying the knowledge in a way that we can collectively understand what’s happening.
A starting point: understanding what we both want from the cupboard, and knowing that a theory is simply a belief that guides behaviour.