Articles |
The zeitgeist of resistance
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK
* Tel: +44-208-327-7223; Fax: +44-208-327-6264; E-mail: david.livermore{at}hpa.org.uk
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Abstract |
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 Top Abstract IntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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The accumulation of bacterial antibiotic resistance is a dramatic demonstration of Darwin's dictum of the survival of the fittest, with serious practical consequences for the treatment of infection. Patterns and mechanisms of resistance undergo continuous evolution and, while the prevalence of methicillin-resistant Staphylococcus aureus has stabilized in the UK, other resistances are proliferating rapidly, notably those to cephalosporins and quinolones among Gram-negative bacteria; carbapenem resistance is growing too, notably in Acinetobacter spp. In contrast, several much-feared resistances, for example to vancomycin in staphylococci, have failed to accumulate significantly, despite repeated emergence. For a resistance to ‘succeed’, it needs to have a mechanism that imposes little fitness burden, along with a biologically ‘fit’ host strain or strains. Once this combination arises, control is extremely difficult.
Keywords: extended-spectrum ß-lactamase , quinolone resistance , vancomycin-resistant Staphylococcus aureus , MRSA , epidemiology of resistance
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Introduction |
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TopAbstractIntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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Bacterial resistance arises randomly, either by mutation or by DNA exchange. Until man began to use antibiotics, this evolution did not matter, because there was no selection pressure. Subsequently, clinical and veterinary usage has selected for the accumulation of one resistance after another. No antibiotic has escaped resistance and few resistances have declined even when antibiotics have fallen into disuse, as, for example, with sulphonamides and streptomycin in the UK. The picture has worsened since 1997, when the UK's Standing Medical Advisory Committee first reported on the topic.1 Although the subsequent decade has seen a stabilization of the UK's methicillin-resistant Staphylococcus aureus (MRSA) problem,2 it has also witnessed a massive expansion in resistance to fluoroquinolones and cephalosporins among Gram-negative bacteria.
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Trends in resistance and multiresistance |
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TopAbstractIntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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The rise of fluoroquinolone resistance is perhaps the most dramatic shift. When fluoroquinolones were introduced in the 1980s, it was asserted that resistance among Enterobacteriaceae was unlikely because multiple mutations were required and that their simultaneous emergence was statistically improbable.3 Nevertheless, bacteraemia surveillance for England and Wales showed that resistance was slowly accumulating in Klebsiella and Enterobacter isolates by the mid-1990s, reaching 10% prevalence by 1999.4 Resistance rates among bacteraemic Escherichia coli then remained under 5%,4 but have since risen to 19% (Figure 1),5 narrowly exceeding the current rates for Klebsiella and Enterobacter spp. (Health Protection Agency, data on file). Cephalosporin resistance in E. coli is rising too, along with quinolone resistance, mostly owing to the spread of extended-spectrum ß-lactamases (ESBLs). These enzymes have been known since 1982 but their types, prevalence and distribution in Europe have changed remarkably since 2003,6 following similar but earlier shifts in South America and Asia. Before 2003, most ESBLs seen were mutants of the old TEM and SHV penicillinases, largely occurring in Klebsiella spp. from specialist units. The new and growing problem is of CTX-M ESBLs, not only in Klebsiella spp. but also in E. coli. Many infections with CTX-M-positive E. coli arise in the community, although occurring in patients with recent exposure to antibiotics or hospitals. From 2% in 1999, the proportion of bacteraemia E. coli resistant to oxyimino cephalosporins rose to 9% by 2005, with this rise largely due to the dissemination of CTX-M ESBLs.5 Over three-quarters of the isolates with CTX-M enzymes are multiresistant also to quinolones and aminoglycosides.6 This growth of multiresistance has practical consequences: E. coli is one of the two commonest agents of bacteraemia (S. aureus is the other),7 it is also the commonest agent of urinary infections, and is a component in mixed intra-abdominal infections—all settings where cephalosporins (particularly) and quinolones are standard therapies. Treatment failures associated with ESBLs in E. coli and Klebsiella spp. have been linked to increased mortality,8 and the spread of these resistances is driving wider use of carbapenems, which do remain active.9 Carbapenems previously were reserved agents, but now must be used more widely and, since early effective therapy is critical in severely-ill patients,10,11 even empirically for those at high risk of harbouring multiresistant strains.
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70% of all bacteraemias in England, Wales and Northern Ireland.A shift to greater carbapenem usage inevitably risks greater selection of carbapenem resistance and, to a limited extent—more in Klebsiella and Enterobacter than E. coli—this is happening already, associated with permeability mutations in strains already producing ESBLs or other potent ß-lactamases.12 Although doubts persist about their ‘fitness’, such strains are increasingly encountered. Carbapenem resistance is a clearer problem in Acinetobacter baumannii, an opportunistic pathogen frequently seen in ventilated patients, burns units and intensive care. In 2000, fewer than 3% of A. baumannii isolates were resistant to carbapenems13 and no resistant strain had disseminated among hospitals. By 2006, however, two carbapenemase-producing lineages, the ‘SE clone’ and the ‘OXA-23 clone 1’, had each spread to over 35 hospitals around London.14 OXA-23 clone 1 is consistently susceptible in vitro only to polymyxin, an agent with significant toxicity, and to tigecycline, a novel derivative with unproven efficacy in Acinetobacter infections.
A further remarkable rise in fluoroquinolone resistance has occurred in Neisseria gonorrhoeae, whereas, previously, infection was standardly cured with a single 250 mg ciprofloxacin tablet.15 Until 2000, resistance occurred in fewer than 2% of UK gonococci, most of them from imported cases. Thereafter, the resistant proportion expanded, first in the heterosexual population and later—more extensively—among male homosexuals.16,17 By 2005, the overall rate was 21.7% and that among gay men was 42.4%. Long before then, in 2003, first-line ciprofloxacin treatment was abandoned in favour of cephalosporins.18
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Resistances that have remained rare |
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TopAbstractIntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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Perhaps as notable are those resistances—feared for a decade—that have not proliferated. Most obvious are vancomycin-intermediate and -resistant S. aureus, which remain extremely rare 10 years after their discovery,19 despite heavy vancomycin use. Moreover, although the VanA determinants of enterococci have finally reached MRSA, they have done so infrequently, only in the USA, and encoded by plasmids that are unstable in staphylococci.20 Linezolid resistance was reported almost as soon as this drug—representing the first new antibiotic class marketed in 30 years—was launched, but remains extremely uncommon,21 despite global sales of US $600 million (plus pirated material in India). Carbapenem-hydrolysing metallo-ß-lactamases of the VIM and IMP families were reported in the UK before CTX-M ESBLs, but remain extremely rare here, though there is evidence of spread in southern Europe.22
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Factors driving resistance |
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TopAbstractIntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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These data beg the question—why do some resistances proliferate, whereas others remain exotica for long periods? The answer lies partly in the extent of selection pressure, but this does not explain why CTX-M ESBLs have spread more than TEM and SHV ESBLs, which existed earlier, confer similar resistance and are often encoded by similarly promiscuous plasmids, nor why ciprofloxacin resistance continues to increase among gonococci despite being abandoned as therapy. What often appears critical is the coming together of easy-to-carry resistance, exerting little biological burden, and a fit strain. Many of the resistances discussed here—fluoroquinolone- and cephalosporin-resistant E. coli and Klebsiella spp., fluoroquinolone-resistant gonococci and carbapenem-resistant Acinetobacter spp.—are substantially clonal in the population structure of their host strains.14,23,24 Disseminated clones are also responsible for the resistance problems with MRSA,25 penicillin-resistant pneumococci26 and Clostridium difficile.27 The features that make some resistant clones particularly successful remain elusive, and it is likely that success arises through multiple favourable combinations of traits, perhaps controlled by global regulator genes, rather than single pathogenicity factors.28,29
Sometimes plasmids succeed, rather than strains: in Poland, those encoding CTX-M-3 ß-lactamase have disseminated hugely among hospitals and bacterial species.30 The features that make a successful plasmid include ‘cheapness to carry’, ‘useful’ resistances and addiction systems.31 Addiction systems encode a stable toxin and a complementary, but unstable, antitoxin; the result is that any cell that loses its plasmid is poisoned by a residual toxin. Such a system, which forces the bacterium to adapt to plasmid carriage, has recently been found in the predominant lineage of CTX-M-ß-lactamase-producing E. coli in the UK.32
In short, the initial evolution of resistance is a fluid process, forever generating random combinations of genes and strains. The subsequent accumulation of resistance reflects the degree of selection pressure and the fitness of the strains that have acquired resistance. It also reflects the new opportunities that arise for pathogens through social and demographic changes and as a result of advances elsewhere in medicine, which expand the pool of vulnerable patients. Resistances succeed in a time and place—they have the zeitgeist of the title—because such combinations of factors favour them. Although much can be done to slow the accumulation of resistance, the idea of mass reversal seems increasingly naive; most of all when resistant bacteria remain competitive even in the absence of continued selection. Rather, the battle is one of containment: minimizing selection and cross-infection, but also re-invigorating antibiotic and (especially) vaccine development as well as enabling faster laboratory recognition of pathogens and their resistances, allowing earlier tailoring of therapy.
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Transparency declarations |
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TopAbstractIntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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D. M. L. is employed within the UK public sector and is influenced by HPA and NHS policies and attitudes on prescribing; he has received grants and accepted lecture and conference invites from numerous pharmaceutical companies and holds shares in several, with these holdings amounting to less than 5% of a well-diversified portfolio. He does not believe that his comments in this paper have been materially influenced by these factors, nor that these interests will be materially influenced by his comments in this paper.
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References |
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TopAbstractIntroductionTrends in resistance and...Resistances that have remained...Factors driving resistanceTransparency declarationsReferences |
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