Antibiotic resistance: an increasing problem?BMJ 1998; 316 doi: https://doi.org/10.1136/bmj.316.7140.1255 (Published 25 April 1998) Cite this as: BMJ 1998;316:1255
It always has been, but there are things we can do
- C A Hart (), Professor of medical microbiology
- University of Liverpool, PO Box 147, Liverpool L69 3GA. CAH is a member of the Advisory Committee on Microbiological Safety of Food: Antibiotic Resistance.
News p 1261.
Although the “antibiotic era” dates from Fleming's discovery of the effects of the fungus Penicillium notatum in 1928, not until 1940 could penicillin be produced in a sufficiently pure form to treat humans.1 Ominously, a β lactamase (penicillinase) capable of inactivating penicillin was described in the previous year. Over the next few decades the production of new classes of antibiotics (derived from living organisms) and antimicrobials (synthesised chemicals) increased exponentially, and the burden of infection was lifted, especially in developed countries. In recent years concern has increased that the antibiotic era might be coming to an end—firstly, because the rate of production of new agents has diminished greatly and, secondly, because viruses, bacteria, fungi, protozoa, and parasites are showing great ingenuity in devising mechanisms for circumventing the killing activity of such agents.
So great is the concern that several committees both in the United Kingdom and elsewhere are examining different aspects of the problem. This week the House of Lords' Select Committee on Science and Technology has presented its conclusions (p 1261). 2 3 Its chairman, Lord Soulsby, an eminent veterinarian from Cambridge, said that the inquiry was an alarming experience and expressed concern that the misuse and overuse of antibiotics is undermining their effectiveness.
The report begs several questions. Firstly, is there a problem of antibiotic resistance? The answer is yes and no. Some bacteria still remain sensitive to long established treatments, including Chlamydia trachomatis to tetracyclines and macrolides, Streptococcus pyogenes to penicillin, and most anaerobes to metronidazole. (Treponema pallidium and penicillin used to be included in this list but the first resistant isolates have been encountered in Africa.) Against this, however, is the increasing array of resistance problems, including penicillin resistant pneumococci, multidrug resistant Salmonella typhi,4 multidrug resistant Mycobacteria,5 methicillin (and multidrug) resistant Staphylococcus aureus (MRSA), vancomycin insensitive MRSA (VISA),6 and vancomycin resistant enterococci (VRE).7 The problem is undoubtedly increasing: for example, penicillin resistant meningococci are emerging, and antiviral resistant HIV emerge even during treatment.8
The second question is, how does resistance arise? The first point to make is that resistance genes and mechanisms existed long before antibiotics were used. For example, antibiotic resistant bacteria have been isolated from deep within glaciers in Canada's high Arctic regions, estimated at 2000 years old.9 The micro-organisms used to produce antibiotics must, by definition, be resistant and are thus a source of antibiotic resistance genes. Antibiotics are given not for their direct effect on humans but to kill an infecting pathogen. Unfortunately they are not so narrowly targeted and will try to kill any bacterium they encounter. The adult human composes some 1014 cells, but only 10% of these are human. The remainder are the bacteria, fungi, protozoa, worms, and even insects that make up our normal flora. Each time an antibiotic is administered the normal flora are also exposed. In addition, many antibiotics are excreted in an active form and thus environmental bacteria are exposed. Under optimal conditions bacteria double in number every 20 minutes; Britons, with our 2.4 children, have a doubling time of 60 years.
Bacteria thus have infinitely expandable and mutable populations to throw in waves at the barrier of antibiotics. Thus in the presence of antibiotics, resistant mutants have a selective advantage. Not only can the resistance be passed vertically from generation to generation; methods of horizontal gene transfer—for example, plasmids—have also evolved, and resistance can be passed to other species and genera. Furthermore, large plasmids encoding multidrug resistance can be as assembled by sequential addition of other mobile genetic elements (integrons and transposons). Examples of resistance genes originating in commensal or environmental bacteria and transferring to pathogens include tetracycline resistance from enterococci to pneumococci and gonococci, and erythromycin resistance from Bacillus sphaericus to Bacteroides fragilis.10
The next question is, who's fault is it? The report recognises that antibiotics are overused and misused in human and veterinary medicine, farming (growth promoters), aquaculture, and plant culture. It is fruitless to apportion blame. A more productive route is for all to recognise the problem and agree strategies to slow down the loss of important drugs from our therapeutic armamentarium.
The final and most important question is, what can we do to achieve this aim? The report makes several recommendations. These include encouraging the prudent use of antimicrobials by educating the public, increasing the emphasis on infection and antimicrobials in undergraduate and postgraduate medical curriculums, developing surveillance systems for antimicrobial resistance, and developing and applying evidence based guidelines on antibiotic use and prescribing. In veterinary medicine the use of growth promoters such as virginiamycin, which belong to classes of antimicrobials likely to be used in human medicine, should be phased out. The veterinary use of antimicrobials such as fluoroquinolones, which are so important in treating human infection, should be used only in strictly defined circumstances. The report recognises that control of infection by proper hospital hygiene and vaccines will play a part in decreasing the use of antibiotics. It emphasises that we have insufficient information on the development, sources, mechanisms, and prevalence of resistance and recom-mends that this should be urgently addressed. It also recommends that the government should develop an overall strategy (and allocate the necessary resources) for safeguarding the effectiveness of antimicrobials.
Finally, we must not neglect international aspects. It is no use the United Kingdom or the European Union acting alone. Bacteria do not recognise international boundaries, and intercontinental spread of resistant bacteria is well described. 11 12
On 5 September the BMJ is having a theme issue on antimicrobial resistance, to coincide with a conference on the subject being organised by the chief medical officers of the European Union. Submissions of original articles should be sent to the editor by 30 June (s ee call for papers on www.bmj.com and opposite p 1317 (CR) and between pp 1274 and 1275 (GP edition).