Personal ViewMinimising antibiotic resistance
Introduction
Growing resistance means that once good—and cheap—treatments for infection have been lost, including penicillin and, in hospitals, oxacillins for use against staphylococcal infections; sulphonamides and ampicillin against urinary tract infections; and penicillin and—increasingly—fluoroquinolones versus gonorrhoea.1 Mortality is increased among intensive care patients whose infections are resistant to first-line empirical therapy,2, 3 and the presence of bacteria resistant to antibiotics has been associated with increased rates of re-operation, surgical-site infection, and abscess formation in intra-abdominal infection.4 In the specific case of Staphylococcus aureus, outcomes are worse and costs higher for patients with infections due to meticillin-resistant S aureus (MRSA) strains,5, 6 although it is less clear to what extent this differential is due (1) to delay in appropriate therapy for MRSA infections, (2) anti-MRSA glycopeptides being inherently poorer drugs than penicillins, or (3) the traits of particular, locally dominant MRSA clones.
The evidence that antimicrobial prescribing is the main driver of resistance is overwhelming, with critical observations being that acquired resistance is absent from bacteria collected before the antibiotic era, although these may have plasmids resembling the elements that nowadays host resistance genes;7 resistance is most prevalent in those settings (eg, intensive care units8) and countries (figure 19) where antibiotic use is particularly heavy; resistant mutants are sometimes selected in individual patients during therapy, causing clinical failure;10 and new resistance has repeatedly emerged following introduction of new antibiotics, whether in the original target pathogens or via opportunistic species replacement in vulnerable patient groups.11
Since around 1998, concern about resistance has spread from specialist professionals to health-care bureaucrats, politicians, and the public, with numerous agency and governmental reports. These reports vary in emphasis, but can be summarised as advocating less antibiotic use, better use, improved infection control and—less prominently—continued antimicrobial innovation. The major single emphasis has been on reducing prescribing in the community, which accounts for at least 80% of all human antimicrobial use.12 This article reviews the lessons learnt, arguing that early hopes that resistance might be widely tractable to reduced prescribing have been proved optimistic and that we must, for the foreseeable future, depend on a multifaceted approach, discouraging unnecessary usage so as to minimise selection, but also making the best use of present agents and re-stimulating antimicrobial innovation. Infection control is largely outside the scope of this article but is also critical to the management of those resistance types—eg, MRSA—where new evolution is rare and where the major problem is the spread of a few resistant clones among many patients. However, infection control is not a panacea, and is less likely to achieve much useful effect where new resistance arises readily by mutation, or where the ultimately pathogenic organism has long previously colonised the bowel.
Section snippets
The effects of reduced antibiotic prescribing
If usage is the main driver of resistance it seems logical to reduce resistance by reducing usage, and there undoubtedly is scope for sizeable reductions, particularly outside northern Europe. According to data collected by the European Surveillance of Antimicrobial Consumption Group, the average southern European consumes two to four times more antibiotics per year than the average Briton, Dutchman, or Scandinavian,13 without obvious benefit to individual or public health. At least for
Better prescribing
Growing evidence argues against the likelihood of achieving major reductions in resistance by reducing prescribing, especially as other factors are pushing towards increased prescribing. These factors include a world population growing in numbers, wealth, and health-care expectations, and—most critically—growing numbers of vulnerable individuals with underlying medical problems who experience repeated infections. In addition, the lines between hospitals, care homes, and the community are
Selection differences between drug classes
In recent years the cephalosporins and fluoroquinolones have been used heavily, particularly in hospitals, which now live with the consequences of their particular selectivity.42 Second-generation and third-generation cephalosporins are associated with the selection of Enterobacteriaceae that are resistant via acquisition of extended-spectrum beta-lactamases (panel 1) and, in the case of Enterobacter spp, Citrobacter spp, Morganella spp, and Serratia spp, with selection of mutants that
Mutant selectivity within antibiotic classes
Selectivity varies within antibiotic classes, as well as between them. For example, streptomycin has only a single ribosomal binding site, and is compromised by high frequency mutations that alter this site; other aminoglycosides have multiple binding sites and are not compromised so easily. Fourth-generation cephalosporins (eg, cefepime and cefpirome) are more stable to AmpC beta-lactamases than third-generation analogues and so are less selective for AmpC-derepressed mutants.62
The wisest
Dose, duration, and emerging resistance
Unsurprisingly, the selection of mutational resistance is often promoted by prolonged therapy, by infection sites where it is difficult to achieve high drug concentrations, and by under-dosage. These points are well-exemplified by linezolid, a relatively new agent where resistance in target staphylococci and enterococci arises by mutations affecting genes encoding the 23S rRNA target. Staphylococci and enterococci have four to seven copies of these genes, and more than one copy must be altered
Do antibiotic combinations prevent resistance?
Antibiotic combinations are often proposed on the basis of preventing selection of resistance, as well as for potential synergy. Their value in preventing mutant overgrowth is well established for tuberculosis, leprosy, and HIV infection; elsewhere the evidence is less conclusive. Co-administration of an aminoglycoside (as a thrice-daily regimen) did not militate against the selection of AmpC-derepressed mutants during cephalosporin therapy of enterobacter bacteraemia, although it may have
Antibiotic cycling, or diverse usage as firebreaks?
Antibiotic cycling (rotation) is an old idea receiving renewed interest, more so in the USA than the UK.70 For 3 months, say, a unit might use a fluoroquinolone as its preferred empirical therapy, then a cephalosporin for 3 months, then a carbapenem and, last, a beta-lactamase inhibitor combination. Proponents argue that such strategies will militate against the establishment of a stable resistant flora;70 sceptics counter that the strategy will select bacteria with multiple resistances, a view
The role of guidelines in the control of resistance
Antibiotic prescribing, like that of other agents, is increasingly driven by guidelines, whether based on local epidemiology, learned-society advice, or (more or less overtly) on the diktat of insurers and health authorities. Any reasonable guidelines should discourage bad usage, including over-long or unnecessary prophylaxis or treatment, or the use of agents likely to be inactive against the pathogens. Antimicrobial guidelines (unlike those for other pharmaceuticals) must also contend with
The need for new agents
If—as seems likely—the best that can be expected from reduced and better prescribing is an amelioration of present resistance trends, the discovery and development of new antibiotics remains vital. Therefore, the fact that many pharmaceutical companies have quit the field is disturbing. This withdrawal is partly the result of companies merging into larger combines; as a result, the turnover that they seek per product has increased to around $1 billion per annum. For an injectible antibiotic,
Conclusions
The over-riding principle of medicine is “do no harm”, yet, in the case of antibiotics, harm is inevitable, for use (even appropriate usage) selects for resistance, complicating the treatment of future patients. Although reducing antibiotic prescribing seems the logical way to reduce selection pressure, the evidence that resistance can be reduced within the ambit of sustainable reductions in antibiotic prescribing is mixed at best. Moreover, withholding treatment may be associated with serious
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