COMMUNITY USE

2. COMMUNITY USE

This varies several fold in intensity between different countries, whether measured per capita or by population density (see Chapter 29 by Mölslad and Cars). Both have significance for the epidemiology of antibiotic resistance, with high relative use by both measurements being associated with more resistance (Bruinsma et al., 2003). Measurements of use are often open to questions over their accuracy because there is probably a significant amount of black market antibiotic available in many countries, much of it of dubious quality, with questionable amounts of active ingredients. Non-prescription, over-the-counter use is difficult to measure but is a significant problem, even in some European countries, where it is illegal. There are also difficulties in measuring the effects of all this antibiotic use—namely the levels of antibiotic resistance. Even in wealthy countries there are few unbiased data so that prob- lems of resistance may be overstated. Few studies are funded to go out and survey selected groups. Most data is taken from clinical samples submitted for analysis. These tend to be biased to those from more difficult or seriously ill patients who will probably have received prior antibiotic therapy. We know that previous antibiotic exposure, especially in the few months prior, increases the likelihood of carrying resistant organisms several fold (Steinke et al., 2001).

There is no doubt of the strong association between antibiotic use in the community and its inevitable consequence, namely antibiotic resistance. The relationship has been established at all levels from individual patients, through families to patient groups, towns, cities, regions, countries, and continents. Relationships are often complicated and not always clear cut. Even social class and deprivation have a relationship although this may be complicated by levels of access to and type of medical care (Howard et al., 2001). Penicillin resis- tance, for instance, has never developed in Streptococcus pyogenes, despite over 50 years of intense exposure. Clearly, the genetic make up of the organism and/or the mechanisms of resistance open to it do not suit the production of ␤-lactamase or a change in its penicillin binding proteins. And yet the same organism has become resistant to macrolides such as erythromycin and the closely related Streptococcus pneumoniae to both macrolides and pencillin (PRP), although it took 30 or 40 years of exposure for these resistance mecha- nisms to become well enough distributed to cause major clinical concern. While, it may largely be down to genetics of resistance mechanisms, other fac- tors also play a role such as clonal spread, intensity of antibiotic use, human behaviour, and pharmacodynamic/kinetic issues (see Chapter 21 by Mouton).

Clonal spread has clearly had a major role in the worldwide spread of peni- cillin (and multiresistant) pneumococci, with close links between resistance to ␤-lactams, macrolides, tetracyclines, chloramphenicol, co-trimoxazole, and now even quinolones. Use of any one drug can maintain selection pressure for

704 Ian M. Gould

Antibiotic Use—Ecological Issues and Actions 705 all linked resistances, so it is sometimes difficult to envisage antibiotic rotation

policies having much effect on such resistance. Restriction of key agents does seem to work in some situations, although the role of the natural evolution and decline and fall of epidemic clones has probably also played a role in the con- trol of some outbreaks. Even then, resistance often declines slowly in the com- munity and rarely declines to zero, such that levels can be anticipated to rise again quickly if antibiotic use increases. Up until now, plasmid-mediated resis- tance and its spread is not an issue in pneumococci, which are not tolerant of plasmids. The increased use of day-care centres for child care has played

a significant role in some outbreaks of multiresistant pneumococci, because of increased opportunity for spread and oropharyngeal colonisation of a very susceptible population. Carriage rates of up to 50% are not uncommon in such populations and often antibiotic use is very intensive.

Some antibiotics may be more likely to maintain outbreaks/cause resistance than others. In the extensive experience gained in Iceland, penicillin resistance seemed to be more related to high co-trimoxazole and macrolide use than actual penicillin use and others have described macrolide and cephalosporin use as more likely to select for penicillin resistance than penicillin use itself, by

a factor of up to 3 or 4 times (Kristinsson, 1999). This may be because these agents are less bactericidal than penicillin and its derivatives (such as amoxi- cillin) and thus less likely to eradicate the pathogen, allowing selection of resis- tant variants which might otherwise have been in a minority and suppressed because they were not at a selective advantage. Other issues to be considered in this context are the dose and duration of the antibiotic. For similar reasons, long term, low dose antibiotic treatment is more likely to select resistant strains in individual patients. Canet and Garau (2002), have calculated that for each day of pencillin use over 7 days in the preceding 6 months, the odds of a child carrying a PRP increased by 4%.

Macrolide use is of particular interest. The question has been raised that resistance only becomes a clinical problem where a threshold of use is exceeded in that community. Whether this threshold exists for other antibiotic groups or, indeed, what this threshold is for macrolides, remains to be estab- lished but it presumably varies depending upon the community’s epidemiol- ogy. For macrolides it has also been suggested that the newer, long-acting agents are more likely to select for resistance than the older, shorter half-life agents. This may be because of prolonged low residual tissue concentrations which select surviving resistant variants with, what are essentially, only bacte- riostatic agents (Lonks et al., 2002). Different mechanisms of resistance to the same antibiotic can also play their role in the epidemiology of resistance. There are two main mechanisms of resistance to macrolides—a mutation in the methylase gene (erm B) giving rise to high level resistance and cross resis- tance to lincosamides and streptogramins and a low level resistance due to

706 Ian M. Gould efflux (MefA) with no cross-resistance. While the clinical significance of the

latter has been questioned there is good evidence that it can cause treatment failures.