The 1999 World Congress of Pharmacy and Pharmaceutical Sciences - the 59th international congress of the International Pharmaceutical Federation (FIP) - took place in Barcelona, Spain, from September 5 to 10. Our coverage continues
The world is rapidly running out of usable antibiotics, the congress heard on September 9, when Dr Richard Holliman (consultant medical microbiologist, St George's hospital, London) gave an update lecture to the FIP hospital pharmacists section.
Dr Holliman said that, as bacterial resistance continued to spread among currently used antibiotics, there was little in the way of new agents on the horizon. Within the next five years, only a few new antibiotics were likely to appear. They included streptogramins (such as quinupristin and dalfopristin), new oxazolidinones and second generation quinolones - all of which were active against Gram-positive bacteria. But for Gram-negative infections, there was not a single new drug on the horizon. "We have run out," Dr Holliman emphasised.
What the world was likely to see in the next five years, predicted Dr Holliman, was developments such as full-blown vancomycin-resistant Staphylococcus aureus. Some low-level resistance was already appearing. There would also probably be pneumococci that were resistant not just to penicillin but also to cephalosporins and macrolides. Totally antibiotic-resistant acinetobacter and enterococci had already just about arrived. Some hospitals were encountering strains that were not susceptible to anything they could offer. The only form of management was to "chop it off".
Dr Holliman said that world expenditure on antibiotics would probably exceed $20bn this year. Of all antibiotic use in human medicine, one fifth was in hospitals and four-fifths in the community. But human medicine accounted for only half of all consumption of antibiotics. The rest was used in animals - one-fifth for therapeutic reasons and four-fifths for growth promotion or prophylaxis. It was estimated that 20-50 per cent of antibiotic use in human medicine and 40-80 per cent of animal use was questionable.
Bacterial resistance to antibiotics was of five types: inactivation of the antibiotic; impermeability, through mutation of the cell wall; efflux mechanisms to pump the antibiotic out of the bacterial cell; bypass mechanisms to prevent the antibiotic reaching its target; and alterations to the target so that the antibiotic had no affinity for it. Any bacterium could use more than one of these methods simultaneously.
Looking at the genetics of resistance, Dr Holliman said that it could be either intrinsic or acquired. One means by which it was acquired was mutation, an example being multidrug-resistant tuberculosis (MDRTB). The mutation rate in bacteria was one in 107, which might not seem high. But bacteria could divide every 20 minutes, so that one bacterium could become 109 in 10 hours - and those 109 bacteria could therefore include 100 mutants.
Other means of acquiring resistance were through plasmids (eg, beta-lactamase production) by transposal (eg, the "jumping genes" of methicillin-resistant Staphylococcus aureus [MRSA]), by transformation (as with pneumococci that had acquired resistance to penicillin from commensal bacteria in the throat) or from phages (which were partly responsible for antibiotic resistance in staphylococci).
The main current problems were MRSA, vancomycin-resistant enterococci (VRE), MDRTB, penicillin-resistant pneumococci, and multiresistant enterobacter and klebsiella. Other problems included suprainfection by organisms such as Candida and Clostridium difficile growing in compromised hosts whose normal bacterial flora had been deranged by antibiotics.
Dr Holliman said that the incidence of resistance varied from country to country, and even countries with low levels could have "hot spots". For example, the incidence of pneumococcal resistance to penicillin in the United Kingdom was generally low (5 per cent) but it was much higher in Belfast. In other countries the figure could exceed 40 per cent. And in vast areas of the world, such as most of Africa, no one had any idea what the incidence of resistance was.
How was antibiotic resistance generated? Inadequate dosage was one problem, allowing resistance to develop because the bacteria were not killed quickly enough. Counterfeit drugs added to this problem. The World Health Organisation had estimated that most antibiotics used world-wide were sub-optimal formulations.
Resistance was also generated by the use of a treatment duration that was either too short, with the possibility of relapse, or too long, with the possibility of selection for resistance. A serious shortcoming of antibiotic therapy was that no one knew the optimal treatment period. Another factor was patient non-compliance. Antibiotics were often not prescribed and supplied in ways that encouraged good compliance.
Inappropriate use was another factor. A common example was the use of antibiotics for sore throats, even though 85-90 per cent were of viral origin.
A further factor was the use of monotherapy in diseases such as tuberculosis, which required combination therapy. Monotherapy allowed mutations to occur.
The generation of resistance was also stimulated by the non-medicinal use of antibiotics — not only in animals but also on plants. It was not unusual for fruit trees to be sprayed with antibiotics to protect the fruit against bacterial infection.
One of the major factors in the development of resistance was cross-infection and colonisation arising from poor infection control after resistant bacteria had been allowed to become established in a hospital or community. Budget cuts were leading to reductions in infection control teams at a time when they were more important than ever.
The consequences of bacterial resistance included increased patient morbidity and mortality. Increased morbidity led to longer stays in hospital, the use of more expensive drugs to overcome the resistant bacteria, and the need for barrier nursing - all of which raised hospital costs.
Dr Holliman said that, as a medical student 29 years ago, he had been taught that if resistance to an antibiotic developed, the solution was to stop using that particular antibiotic and it would eventually disappear. The theory was that bacteria encumbered with redundant resistance would be at a disadvantage and would be supplanted by other strains. But that was not true. If an antibiotic was removed from use, resistance would fall but it never disappeared completely. And reintroduction of the antibiotic would result in a rapid rebound rise in resistance.
So what could be done to overcome resistant pathogens? The traditional approach of relying on novel agents was looking less and less attractive. The alternative was to change health care practice - to conserve the drugs that were still useful and concentrate on clinical and strategic reform.
The first important factor in changing health care practice was education. Health care workers needed to be educated in the appropriate diagnosis and management of infection. The public needed to be deterred from making inappropriate demands for antibiotics and educated to understand the need for rational use.
A second factor was evidence-based medicine, involving the introduction of antibiotic formularies and clinical guidelines. Practitioners who resisted such restrictions needed to be reminded that when other illnesses were treated inappropriately it was only the patient who suffered but when infection was treated inappropriately both the patient and the community suffered. Antibiotics were now too valuable to be left to the single decision of a clinician.
A third factor was infection control. Adequate resources were needed to implement effective control systems to prevent the spread of resistant strains.
The fourth major factor was surveillance to inform and direct local formularies and prescribing policies. Surveillance should include continual monitoring of resistance patterns and trends, and the identification of cross-infection. It should also include the identification of policy defects, so that policies could be revised as quickly as possible.
The constituents of a prescribing policy should include the initial empirical therapy, routes of administration, doses and dosage schedules, follow-on therapy, duration of therapy, and alternative agents in case a patient was intolerant. All these were essential, but current policies rarely covered them all.
There should also be a policy on ensuring optimal compliance, which should include verbal instruction backed by written reinforcement. It was important to seek the patient's own views - to negotiate with the patient about what he or she could achieve. It was estimated that in the UK 50 per cent of antibiotics went down the lavatory without the benefit of having passed through the patient first. Worse still, antibiotics remaining from uncompleted courses were stored for later use.
If bacterial infections were to be conquered in the future, there was a need to think laterally, because one could no longer rely on antibiotics. Supportive treatments might include vaccine programmes to avoid infection in the first place, debridants and drainage in surgery instead of antibiotics, astringents such as acetic acid and sugar paste to get rid of infection, disinfectants to reduce infection, immune support (such as immunoglobulins and colony-stimulating factors) to prop up the immune system, and novel approaches such as phage therapy (giving patients viruses that affected the bacterial strain) and quorum sensing (interrupting the message that bacteria sent one another).
Summarising, Dr Holliman said that the clinical consequences of antibiotic resistance were dire, and patients would suffer. He concluded: "If we carry on as we are, a lot of the surgery performed in many hospitals will become impossible because infections post-surgery will be non-treatable. The infection rate will be far too high. We have identified some control measures, but will they be effective? We do not know."