The Need for Antimicrobial Stewardship

ANTIBIOTIC PRESCRIBING AND ANTIBIOTIC STEWARDSHIP

THE NEED FOR ANTIMICROBIAL STEWARDSHIP

In testimony to a US government committee in June 2010, the Infectious Diseases Society of America (IDSA) stated that Most commonly used antibiotics cost only a few dollars for a typical course of treatment… (and) a single course of antibiotics has the potential to protect and preserve many quality years of life for many people. No other type of medicine can claim such an achievement at such a price.

These statements were made as part of the argument presented by the IDSA to promote both antibiotic research and appropriate use (‘stewardship’) of antibiotics.

The wider point being made was that antibiotics have, since their discovery in the 1940s, revolutionized medicine, and many of the procedures that are taken for granted now —transplantation, cancer treatment, the care of premature babies and several forms of surgery—would be impossible without them. Yet, unfortunately, largely because they have been taken for granted, the antibiotics we already possess are becoming less effective as a result of bacterial resistance, and the prospects for producing new antibiotics currently look bleak. It was recognized right from the start of the antibiotic era that bacteria had the potential to develop resistance to antimicrobial drugs, but it was quite some time before the perception of antibiotic resistance changed from one in which it was regarded as unusual to one where it was expected; in other words, a recognition that long-term efficacy was the exception, and resistance was the rule.

As the 20th century drew to a close the emergence of the antibiotic-resistant pathogens brought with it both the spectre of untreatable infections where the organisms responsible were resistant to all available agents and a growing sense of urgency to take steps to preserve the usefulness of the antibiotics we currently have. The situation was exacerbated by a reduction in the number of new antibiotics coming into clinical use. Figure 15.1 shows that this number has continued to decline steadily for the last 20 years—a trend that would be difficult to reverse in the short term simply because several of the major international pharmaceutical companies are moving out of antimicrobials as a research and development area. Unfortunately, antibiotics have, in a sense, become victims of their own success: the more effective an antimicrobial is, the shorter the likely duration of treatment, so the lower the payback to the company that developed it. Many courses of antibiotic treatment last for a week or less, so the sales accruing from them are far inferior to those from drugs treating chronic conditions like diabetes and hypertension. This fact, together with (1) increasing pressure to use antibiotics sparingly anyway, (2) the expectation that the drug will ultimately become less effective due to resistance and (3) difficulties in establishing clinical trials for antibiotics that satisfy the US Food and Drugs Administration (FDA) criteria, all combined to create a climate in which antibiotics became an unattractive commercial proposition (except in the case of HIV/AIDS therapies that have to be taken throughout the patient’ s life).

Certainly the problem of growing antibiotic resistance had been recognized for some time before the end of the 20th century and policies designed to improve the quality of antibiotic prescribing and restrict resistance in hospitals became progressively more common in Europe and North America from the 1970s onwards. However, the increasing frequency in the new millennium of infections due to the so-called ‘ESKAPE’ pathogens( Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa and extended spectrum β-lactamase-producing strains of Escherichia coli and Enterobacter species) together with the drying up of the pipeline of new antibiotics from the pharmaceutical industry has further increased the tempo of measures to preserve what is increasingly being seen as a precious, and perhaps irreplaceable, resource that society has a duty to pass on to future generations rather than squander. These measures include the ‘10 × 20’ initiative to establish an international research effort to develop 10 new antibiotics by the year 2020, and the STAAR (Strategies to Address Antimicrobial Resistance) Act, which is, at the time of writing, being considered by the US Congress.

The cost of antibiotic resistance should, of course, be measured primarily in terms of the suffering that results from the failure of antibiotics to cure infections against which they were formerly effective. The antibiotic-resistant pathogens responsible for these infections can arise both in the home or the hospital environment, but it is in the latter that they are, by far, more common and problematic. Hospital-acquired infections account for a substantial number of deaths each year and the treatment of such infections is time-consuming, difficult and costly. In its testimony to Congress as part of the consultation process accompanying the STAAR Act, the IDSA stated that antibiotic-resistant infections acquired within hospitals were responsible for 90 000 deaths each year in the USA and cost the healthcare system between $21 and $34 billion annually. There are less obvious consequences of resistance too: when the first-line drugs cease to be effective it is sometimes necessary to revert to alternatives that are more toxic. Acinetobacter infections are a good example of this situation because the organism is naturally multidrug resistant and the incidence of isolates resistant to all first-line antibiotics has risen in the USA from 5% to 40% in 10 years, so now colistin, a drug that became virtually obsolete in the 1960s because of the significant risk of kidney damage is, for many patients, the most likely antibiotic choice.

There is widespread agreement that greater use of antibiotics predisposes to the development of resistance. The strength of the link between use and resistance varies from one antibiotic to another, but for many antibiotics the connection is irrefutable. However, the situation is far from simple: there is substantial evidence, for example, that heavy use of one antibiotic may be a risk factor for the acquisition of infections by organisms resistant to other, unrelated antibiotics—heavy cephalosporin use has been shown to increase the risk of vancomycin resistant enterococci, and fluoroquinolone use has been associated with the prevalence of meticillin-resistant Staph. aureus (MRSA). The selective pressure created by the use of one antibiotic will often select for resistance in others because plasmids within the bacterial cell may carry resistance genes for multiple antibiotics from different chemical groups. If, for example, an organism possessed a plasmid with genes for both rifampicin and gentamicin resistance, constant exposure to gentamicin would represent a selective pressure that afforded an advantage to that organism so, not only would the incidence of isolates with gentamicin resistance be expected to rise, but so too would the incidence of rifampicin resistant isolates.

Arguments for curtailing antibiotic use in order to restrict resistance development have been supported by audits and surveys of antibiotic prescribing and costs. It has been estimated that up to 50% of antibiotic prescribing is either inappropriate (wrong drug, duration, dose, etc.) or unnecessary (not required at all). Antibiotic consumption varies widely throughout Europe: a 2005 survey showed that France, for example, used three times as much antibiotics per head of population as the Netherlands, but this difference was not justified by higher infection rates or better cure rates, so logic suggests that part of the antibiotic use in France was unnecessary. Inappropriate prescribing and consumption, together with the fact that antibiotics can represent up to 30% of a hospital pharmacy budget, have provided further impetus for measures designed to achieve more prudent prescribing. Such thinking is not new, however; it was the rationale for the introduction of antibiotic policies in the 1970s and 1980s which, in addition to setting out the general standards for safe and appropriate prescribing, advised on the selection of antibiotics for specific infections, for special situations like surgical prophylaxis and for the treatment of specific groups of patients, e.g. the newborn, those with poor kidney function and the immuno-compromised. What has changed since then is the recognition of the need for a much broader approach to the problem —in other words, the need for a comprehensive antimicrobial stewardship strategy that incorporates, but also extends, the policies formulated in the last century.

There is not a universally accepted definition of, or agreement upon, what constitutes an antimicrobial stewardship programme. For most people the term applies particularly, or even exclusively, to the manner in which antibiotics are used and distributed in hospitals. However, some see it in a much broader sense as a range of initiatives which, together, impact upon antibiotic resistance but are not necessarily even confined to antibiotic-related practices in the hospital or the home. The great majority of the annual global production of antibiotics is not used in the treatment of human or animal infection anyway. Most of the antibiotic output of the international pharmaceutical industry is used as a food additive to increase weight gain in cattle, pigs and poultry —some estimates put this proportion as high as 80%—and yet more is used in plant production, but this fraction is ill-defined. Although antibiotics that are used to treat human infections have been banned as growth promoters in Europe for many years it is still a common practice in many countries, and even the legitimate veterinary use of antibiotics is considerable: the total volume of antibiotics used in the UK for agricultural purposes in 2007 was 387 tonnes. Curtailment of the use of antibiotics for growth promotion—which many see as inappropriate and a likely contributor to resistance development—together with better-targeted and-promoted use of vaccines (that would reduce the need for antibiotics), better diagnostic agents which would more rapidly and accurately identify the infecting organism and so inform the selection of the best antibiotic, better epidemiological data and computer analysis to provide early warnings of resistance trends, and changes in other medical practices like the early removal of catheters and cannulas which are, themselves, a means by which pathogens can enter the body, might all be seen as part of a stewardship programme. But from the perspective of controlling the incidence and spread of antibiotic-resistant organisms within a hospital it cannot be over-emphasized that a comprehensive infection control programme is of paramount importance and the best results are achieved when data from antibiotic stewardship and infection control can be linked and analysed together.

It is generally accepted that the principal goals of a stewardship programme are to:

• Improve patient outcomes

• Lessen the risk of adverse effects

• Reduce resistance levels, or at least slow the rate of resistance development

• Improve cost-effectiveness.

Following the international financial crisis that began in 2007 it is likely, at least in many European countries, that the last of these goals will receive particular attention, so it is worth emphasizing that stewardship programmes can be self-financing. Although there is an initial start-up cost, there is substantial evidence that this is rapidly recovered by cost savings resulting from reductions in antimicrobial use that some reports have estimated to vary from 22 to 36%.