Chapter 16 Antibiotics; past, present and future
Antibiotics are so familiar to us now that the thought of having to live without them is a very difficult one to contemplate. However, with increasing antibiotic resistance being shown by a variety of bacterial species it is a thought we have to treat seriously.
A century of use The antibacterial chemotherapy era began with the discovery of arsphenamine which was first synthesised by Alfred Bertheim and Paul Ehrlich in 1907 and used to treat syphilis. The first systemically active antibiotic, prontosil, was discovered in 1933 by Gerhard Domagk, for which he was awarded the 1939 Nobel Prize. Since the first pioneering efforts of Florey and Chain in the same year, the importance of antibiotics, including antibacterials, to medicine has led to intense research into producing them on a large scale. Following screening against a wide range of bacteria, production of the active compounds is carried out using fermentation, usually in strongly aerobic conditions. With advances in medicinal chemistry, most modern antibacterials are semisynthetic modifications of various natural compounds. The advance in antibiotic diversity and production has enabled medicine and surgery to develop to provide the modern techniques and standards with which we are so familiar. Without the suppression of infections many such procedures would have been impossible and the lurking fear is that they may once again become impossible if we cannot find either new antibiotics or alternative measures to quash infection.
Classification Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes. Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane (polymyxins), or interfere with essential bacterial enzymes (rifamycins, lipiarmycins, quinolones, and sulfonamides) have bactericidal activities. Those that target protein synthesis (macrolides, lincosamides and tetracyclines) are usually bacteriostatic (with the exception of bactericidal aminoglycosides).
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Further categorisation is based on their target specificity. ‘Narrow-spectrum’ antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria. Research and development in recent years has enabled the discovery of four new classes of antibacterial antibiotics that have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), oxazolidinones (such as linezolid), and lipiarmycins (such as fidaxomicin).
Resistance Although we think of the emergence of resistance of bacteria to antibiotics as a new phenomenon it reflects evolutionary processes that take place during antibiotic therapy and was demonstrated as early as 1943. Antibiotic treatment may cause the selection of bacterial strains with physiologically or genetically enhanced capacity to survive high doses of antibiotics. Under certain conditions, it may result in preferential growth of resistant bacteria, while growth of susceptible bacteria is inhibited by the drug. Antibiotics such as penicillin and erythromycin, which used to have a high efficacy against many bacterial species and strains, have become less effective, due to the increased resistance of many bacterial strains. UK dentistry is estimated to account for between 6-9% of total antibiotic prescribing in this country with dentists selecting from a small range of oral agents which are found on the British National Formulary (BNF) list. Various studies suggest that a significant proportion of cases in which antibiotics are prescribed could be treated more appropriately by surgical intervention. The urgency of addressing the situation has been emphasised by the World Health Organisation, European Commission and the UK Government and a ‘One Health’ approach is being promoted which recognises the intimate links between human and animal health and calls for concerted, international action on behalf of all stakeholders.
Antibiotics and daily practice But despite this awareness of the dangers of antibiotic overuse, figures suggest that around 10 million antibiotic prescriptions - out of the total of 42 million given each year - are inappropriate. Additionally, patients have been criticised for having an ‘addiction’ to them and doctors have been accused of being either too keen to prescribe them or too rapidly caving in to patient demand. An important part of the government’s programme is to now focus on patient education to try and explain when antibiotics are not the appropriate treatment.
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We can do more to ensure that we do not prescribe unnecessarily. In fact very few occasions arise in daily dental practice in which we need to reach for the metaphorical prescription pad. Generally, the vast majority of dental infections do not require the use of an antibiotic as treatment should focus on local surgical measures and provision of an analgesic, such as ibuprofen or paracetamol. Dentoalveolar abscess The first line of action should be drainage, established and maintained either through the opening up of a root canal and/or incision of the soft tissues which is easily achieved when there is an intra-oral swelling. If a good flow of pus can be established then antibiotic therapy is not required in an otherwise healthy individual. In the event that adequate drainage cannot be achieved, perhaps when an infection is spreading, or if the patient has a raised temperature then is it necessary to prescribe an antibiotic. In the UK, amoxicillin is generally regarded as the antibiotic of choice in the treatment of an acute dentoalveolar abscess. Although erythromycin has been used as a classic alternative for patients hypersensitive to the penicillins, metronidazole is now often used due to the recognised importance of strict anaerobes in this condition. Acute necrotising ulcerative gingivitis Thorough cleaning of the tissues affected by this this unpleasant and painful condition is best managed under local anaesthesia but, as above, there is no immediate need for antibiotics. Once again, if the condition is severe with systemic upset then metronidazole is the drug of choice, with amoxicillin being an alternative. Pericoronitis The same principles apply in the first line of treatment for pericoronitis which should be surgical and consist of irrigation under the operculum preferably using chlorhexidine. If indicated, the opposing upper molar should be removed. Antibiotic therapy, consisting of either amoxicillin or metronidazole, should only be prescribed if the patient has trismus or a raised temperature. Peri-implantitis The growing problem of peri-implantitis has been seen as a legitimate candidate for antibiotic therapy but the evidence suggests that this is not the case. Peri-impantitis responds to local mechanical and chemical reduction of the oral microflora immediately adjacent to the implant. Chlorhexidine irrigation has been shown to be beneficial and although the efficacy of systemic antimicrobial therapy has
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been investigated and needs further investigation the removal of organisms by conventional means seems to be the most successful course of action.
Prescribing an antibiotic When all else fails, generally a prescription should be for five days, although the patient should be instructed to take the medication for as short a time as possible, the concept of a ‘complete course’ being no longer regarded as good practice. It is now considered that the longer an antibiotic is taken the greater the risk of developing bacterial resistance. Standard dosages, as outlined in the BNF, should be used for dental outpatients, although increased dosages may be used for severe infections where surgical drainage cannot be achieved. It is a good principle to provide antibacterial therapy comprising a single agent only.
Antibiotics – the future? The story of antibiotic resistance to date might be characterised as being a combination of complacency, misunderstanding and economic factors all of which have conspired to ensure that bacteria have had the opportunity to steal a march on the human race and defeat our hitherto cunning development and application of antimicrobials. While media focus can be fickle in so many ways there is no doubt that their attention to the growing awareness of the rise in antibiotic resistance has helped public, professional and now political immediacy on this literally life threatening eventuality. Indeed it is calculated that currently in the order of 25,000 people die each year in Europe alone from infections resistant to antibiotics. So, what can we do about it and can we develop new antimicrobials to help us in the battle against bacterial mutations that create resistance? The recent publication of NICE (National Institute of Clinical Excellence) guidelines (http://www.nice.org.uk/guidance/ng15) has helped to stimulate the debate on the sensible stewardship of this class of medicines. In essence the guidelines are aimed at health and social care practitioners (including dentists), organisations commissioning, providing or supporting the provision of care and people who are taking antimicrobials and their families and carers. The guidelines make recommendation on participation in antimicrobial stewardship programmes, antibiotic prescribing and introducing new antimicrobials.
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Barriers to development Factors surrounding the lack of development in recent decades include a reduction in the number of pharmaceutical companies due to take overs and mergers which have reduced the spur to competition and difficulties getting new antimicrobials through pre-clinical testing. But there are biological barriers too which mean that these agents are approximately five times less successful than other new drugs at successive stages of development. This is variously due to the mutability of the target, bacterial efflux mechanisms and the difficulty of reaching the appropriate body compartment of the host. Unfavourable costs also play a major part. It is estimated that it now costs £1.2billion over a 12 year period to bring a new drug successfully to market. However, the profitability of antibiotics is surprisingly weak due to their short courses, high dosages and low sale price. The consequence has been a dearth of investment in research. Suggested methods of redressing this include the easing of regulatory burdens or the introduction of earlier licencing but with suitably heightened post-market surveillance. Other factors might be incentives such as tax breaks, research and development grants and patent extensions. In the wider sense too stewardship is being promoted to improve awareness and education of health professionals and patients. European Antibiotic Awareness Day is now held every year on 18 November and includes joined up activities across government departments such as Health and DEFRA (Department for Environment, Food and Rural Affairs) since antibiotics are also widely used in animal husbandry.
Antibiotic guardians A further initiative is the setting up of a website (www.antibioticgaurdian.com) which encourages as many people as possible to sign up to increase public awareness of the immanent dangers of antibiotic resistance. Its three key messages are:
• Don’t ask for antibiotics. Treat your cold and flu symptoms with pharmacist
• Take antibiotics exactly as prescribed, never save them for later, never share
advice and over the counter medicines
them with others
• Spread the word, tell your friends and family about antibiotic resistance.
While these points do not specifically mention dentistry, given the influence of the media and of the universal availability of information on the internet it will become increasingly common for patients to question the need for antibiotics in any situation and ask whether alternatives are available. Which means that we too will have 128
pressure exerted to ensure that we undertake best practice in this field. Similarly, it is to be hoped that patient requests for antibiotics will also fall so that the insistence that toothache requires them will gradually, through education, become a thing of the past.
Will we all become things of the past as a result of these developments? The numbers are stacking up with over â‚Ź1.5billion spent each year EU wide for healthcare expenses and lost productivity due to antibiotic resistant bacteria. Not to mention the human cost. Part of all of us wishes not to consider a world without effective antibiotics. In which case an even bigger part in all of us needs to consider changing our habits in order to prevent the unthinkable.
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