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This article appears in the following Journal of Antimicrobial Chemotherapy issue: Daptomycin development and clinical experience [View the issue table of contents]
Articles |
Who's winning the war?
Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK
* Tel: +44-1224-554-954; Fax: +44-1224-550-632; E-mail: i.m.gould{at}abdn.ac.uk
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Abstract |
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 Top Abstract Methicillin-resistant...MRSA as an antibiotic...New antibiotics to treat...FundingTransparency declarationsReferences |
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Traditionally, methicillin-resistant Staphylococcus aureus (MRSA) has been seen as an infection control problem in healthcare communities. It is now clear that antibiotic use is also an important factor in the control of MRSA, both in the treatment of infection and also, paradoxically perhaps, as a cause of the MRSA problem, in the same way that antibiotic use causes Clostridium difficile disease. At both levels, major improvements in the quality of our antibiotic use are required, particularly antibiotic stewardship to reduce the selection, maintenance and transmission of MRSA strains. In addition, new agents are required to reduce our reliance on glycopeptides for the treatment of serious MRSA infections. Daptomycin has great promise in this regard as its rapid bactericidal activity makes it particularly suitable for the treatment of bacteraemia and endocarditis.
Keywords: MRSA , infection control , antibiotic resistance , stewardship
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Methicillin-resistant Staphylococcus aureus (MRSA) as an infection control (IC) problem |
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TopAbstractMethicillin-resistant...MRSA as an antibiotic...New antibiotics to treat...FundingTransparency declarationsReferences |
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It is now over a decade since the current MRSA epidemic struck hospitals around the world, and there are no consistent signs that it is declining. In the UK, for instance, despite much political and public concern and significant expenditure on IC, recent evidence suggests that the National Health Service (NHS) is not on course to achieve the (controversial) targets for its reduction (http://news.bbc.co.uk/1/hi/health/6249149.stm).1 Is MRSA controllable and if so, is it worth the effort and expense or should it just be seen as an inevitable consequence of ‘medical progress’ that can be countered by new antibiotics?
Certainly, the current high levels of MRSA should not be seen as inevitable. Scandinavia and Holland have managed to stay almost completely clear of such high levels of MRSA, by robust control measures,2 while France has had notable success with search and destroy policies in its public hospital network.3 Finally, the scientific literature has reports of many other studies, showing that variations on search and destroy do work and are highly cost-effective.4 Yet, in the UK, a recent Dr Foster report (http://www.drfoster.co.uk/library/reports/hospitalGuide2007.pdf) highlighted the dismal adherence to such measures with only 10 of the 167 hospital trusts surveyed able to demonstrate that they isolated >90% of the known MRSA cases, a small minority using rapid screening tests (levels of use of such tests lag significantly behind other countries) and most hospitals lacking the data to know just how many cases of MRSA are admitted and how many contracted during hospital stay. This is just the sort of data required to inform patients wishing to make a choice about the hazard of admission to a particular hospital.
With such data, it is not surprising that most countries seem to be losing the war. Is it too late now to turn the tide? What has gone wrong, where has all the resource gone and why has it so obviously failed? Clearly, the public is still anxious, with hospitals being seen as dirty, dangerous places—the ‘disease maker’ of Florence Nightingale's time. If sanctions are not imposed for failing to achieve targets, then other areas will be prioritized. Clinicians who do not see for themselves the awful price that MRSA can exact may find it difficult to understand the need for its control, and good IC needs to be a priority for all hospital employees. The IC community has also been too slow to see the need for MRSA-specific control measures such as rapid identification of carriers and their isolation, placing too much faith in universal (standard) precautions. There has also been too much concern about the loss of individual patient freedom at the expense of the public good. Hospital infrastructure is often poor with not enough isolation rooms and an unwillingness to resort to isolation wards, possibly as they are seen as not in keeping with modern health services. Overcrowding and staff shortages play their part too, and even in well-staffed areas, adherence to simple but important IC procedures such as handwashing is often poor. It has been mentioned that hygiene can be better in abattoirs than hospitals,5 and certainly, we need much more fail-safe procedures and redundant safety systems.6,7 We need more emphasis on outcome than process (which can lead to box ticking rather than proper patient care) and more action and prevention rather than description of events.8
The recent data demonstrating a 10% fall in MRSA bacteraemia in England in the past year may not all be good news if, as suggested, this is based on interventions at targeted risk areas and procedures. If nothing is done to control underlying MRSA colonization, then there will continue to be a large reservoir of MRSA at risk of infecting new patients and leading to the development of new strains, as seen by the predominance of MRSA in recent healthcare-acquired infection (HAI) and surgical morbidity audits and recent changes in MRSA epidemiology.9 Although the reduction in bacteraemia rates by targeted action is to be welcomed, it is only a short-term solution to the underlying problem. Recent emphasis on admission screening in both the USA10 and the UK,11 although expensive, is likely to prove cost-effective. MRSA, it should be remembered, is an additional epidemic burden to the NHS over and above existing staphylococcal infections.12 In 1956, Garrod13 wrote that there were few more disquieting features in hospital than the multiresistant Staphylococcus. Nothing has changed.
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MRSA as an antibiotic stewardship problem (antibiotics as a cause of MRSA) |
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TopAbstractMethicillin-resistant...MRSA as an antibiotic...New antibiotics to treat...FundingTransparency declarationsReferences |
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Antibiotics now need to be seen as much the villain of the piece as the solution: most of the unaddressed issues in HAI are down to antibiotic resistance (AR) caused and maintained by huge selective antibiotic pressure. Even the transmission of AR, up until now put down to poor IC, may be as much driven by antibiotic use (much of it inappropriate) increasing transmission, colonization and even virulence. How often do MRSA carriers receive a cephalosporin, quinolone, macrolide or other agent to which MRSA is usually resistant? This allows multiplication of MRSA in that patient at the expense of normal susceptible flora, increasing the chances both of MRSA infection in that patient and also transmission to others. Despite the emphasis on IC up until now, it seems evident that antibiotic stewardship has a lot to offer in the control of MRSA.14
Antibiotics can no longer be seen just as magic bullets. They have become an integral part of the problem of modern-day HAI. While we need to keep up the emphasis on stopping antibiotic prescribing for viral infections and non-infectious conditions, we should now be increasingly asking whether antibiotics should be prescribed for bacterial conditions where the benefits are likely to be minor. Much more public debate is required here. Furthermore, when it comes to more serious bacterial infections, we need to question guidelines that recommend very broad-spectrum or combination therapy with little evidence base.15,16 Such recommendations often seem to be based on the perceived benefit of covering as many potential pathogens as possible, but at what cost? If carbapenems are increasingly to be used as empirical therapy, then what is left to treat the inevitable carbapenem-resistant infections that will ultimately result?
We urgently need serious reconsideration of our standard therapies, taking account not only of patient needs but also of societal costs. It may be that the two are not mutually compatible and that some serious decisions need to be taken to protect key agents for genuinely life-threatening infections with proven resistant organisms. Value judgements and cost benefit for patients and society have to be debated professionally and with the public.
In the UK, for instance, where penicillin-resistant/intermediate pneumococci are rare, why have we moved away from penicillin as the mainstay for the treatment of serious community-acquired pneumonia (CAP) or even meningitis?17 Why is combination therapy the routine for CAP?15,18 Why are fluoroquinolones used so much in the community19 and co-amoxiclav20 (or any antibiotic for that matter) in upper respiratory tract infections? Why are cephalosporins still the mainstay of surgical prophylaxis with the advent of MRSA and methicillin-resistant Staphylococcus epidermidis?21
Clearly, a lot needs to be done in changing prescribing habits, but if this is to happen clinicians need to be protected from potential litigation by corporate responsibility for alternative policies. Maybe new diagnostics can help with more appropriate choice of empirical therapy. Rapid MRSA screening is an obvious recent development, MRSA carriage being a strong predictor of subsequent infection.22
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New antibiotics to treat MRSA (antibiotics as a solution to MRSA) |
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TopAbstractMethicillin-resistant...MRSA as an antibiotic...New antibiotics to treat...FundingTransparency declarationsReferences |
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In this context, we have great need for new antibiotics to treat the results of past poor practices. But do we need new agents to treat MRSA? Glycopeptide resistance still seems to be rare, and most MRSA are still susceptible to several other agents such as aminoglycosides, rifampicin, co-trimoxazole, tetracycline and fusidic acid. Moreover, there is still a high level of satisfaction with glycopeptides. There is, however, a large and increasing body of evidence questioning their efficacy, even against fully susceptible isolates of MRSA as defined by the new, lower breakpoints set by the CLSI (fully susceptible MIC
2 mg/L).23 Problems exist though with establishing accurate MICs, which makes the interpretation of the data difficult. It is possible that the Etest gives the best detection of isolates for which MICs are between 0.5 and 2 or 4 mg/L, levels defined as susceptible but often showing poor clinical response to treatment with glycopeptide. Broth microdilution, and automated methods based on it, require re-assessment for their ability to detect these strains.24 Clarification of these issues will establish the real degree to which clinical isolates are developing MIC creep, with more and more clinical isolates having borderline susceptibility than previously described. Worryingly, raising the glycopeptide dose does not seem to adequately compensate for reduced susceptibility and runs the risk of increased toxicity.25
The situation with other old agents such as tetracyclines and co-trimoxazole, which still retain high activity against most MRSA strains, is no clearer. The little robust data available suggest that these agents are no better than glycopeptides.26 As it is well established that glycopeptides give inferior outcome to β-lactams in serious methicillin-susceptible S. aureus (MSSA) infections such as S. aureus bacteraemia (SAB), options for the treatment of MRSA bacteraemia are clearly limited. This is confirmed by two meta-analyses27,28 and more recent studies,29 which demonstrate significantly poorer outcome in MRSA bacteraemia than MSSA bacteraemia.
If, as looks likely, daptomycin provides a much needed improvement for the treatment of MRSA bacteraemia and is as effective as β-lactams against MSSA bacteraemia, then we welcome a real step forward in our treatment options. The empirical use of glycopeptides in practices with high MRSA rates not only gives poor outcome in MRSA bacteraemia, but is also suboptimal treatment for MSSA bacteraemia.
In this welcome review of the most recent data available on daptomycin, Hawkey30 focuses on the in vitro data for daptomycin, highlighting its encouraging activity against enterococci and emphasizing, very importantly, that its rapidly cidal action against staphylococci and streptococci is maintained even against vancomycin-resistant enterococci. For anyone having to treat multiresistant enterococcal endocarditis, this is very encouraging.
Seaton31 concentrates on the wealth of data from the CORE registry and the translation of daptomycin rapid cidality into rapid clinical response and shortened treatment courses in skin and soft tissue infections. He also dwells very usefully on the reasons one might want to use increased doses of daptomycin.
Warren32 poses many intriguing questions about the potential for daptomycin in bacteraemia and endocarditis but calls for more studies, particularly in the pharmacoeconomic area. The problems of aminoglycoside resistance (particularly in enterococci) and aminoglycoside toxicity mean that a replacement therapy such as daptomycin, either as monotherapy or in combination with, e.g. rifampicin, is urgently required.
Levine33 focuses on translation of the in vitro data into efficacy in SAB and infective endocarditis, but sounds a cautionary note on the development of resistance to daptomycin in high inoculum infections, reminding us of the ever-relevant teaching, that pus should always be drained. The evidence suggests that finally we have a drug capable of giving results equal to the semi-synthetic penicillins in these difficult-to-treat infections, if dosed correctly.
In an intriguing paper, Livermore34 gives insight into the new clinical areas being investigated to make full use of daptomycin's promising qualities, including investigation in bone and joint infections and neutropenic patients. A cautionary note on the potential transfer of resistance from soil organisms such as Streptomyces, as has happened for macrolides and aminoglycosides, is rung.
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Funding |
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TopAbstractMethicillin-resistant...MRSA as an antibiotic...New antibiotics to treat...FundingTransparency declarationsReferences |
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I. M. G. received an honorarium from Novartis for the production of this article. The editorial support of MSC Ltd was funded by Novartis.
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Transparency declarations |
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TopAbstractMethicillin-resistant...MRSA as an antibiotic...New antibiotics to treat...FundingTransparency declarationsReferences |
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This article is part of a Supplement sponsored by Novartis.
I. M. G. is a consultant to various diagnostic and pharmaceutical companies including Novartis that market diagnostic tests and antibiotics for the treatment of MRSA-infected/colonized patients.
The editorial support of MSC Ltd in the preparation of this manuscript is acknowledged.
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References |
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1 Health Secretary Announces MRSA Target, and the Chief Nursing Officer Announces Infection Control Training for NHS Staff. CDR Weekly, 11 November 200414, no. 46http://www.hpa.org.uk/cdr/archives/2004/cdr4604.pdf (21 May 2008, date last accessed).
2 EARSS Annual Report. On-going Surveillance of S. pneumoniae, S. aureus, E. faecalis, E. faecium, E. coli, K. pneumoniae and P. aeruginosa (2005) ISBN-10: 90-6960-159-1, ISBN-13: 978-90-6960-159-5. http://www.mnp.nl/bibliotheek/rapporten/210624001.html (21 May 2008, date last accessed).
3 Carbonne A, Arnaud I, Coignard B, et al. Multidrug-resistant bacteria surveillance, France, 2002–2005. In: Abstracts of the Seventeenth European Congress of Clinical Microbiology and Infectious Diseases, Munich, Germany, 2007. Basel, Switzerland: European Society for Clinical Microbiology and Infectious Diseases. Abstract O364.
4 Gould IM. Control of methicillin-resistant Staphylococcus aureus in the UK. Eur J Clin Microbiol Infect Dis (2005) 24:789–93.[CrossRef][Web of Science][Medline]
5 Pennington H. Don't pick your nose. In: London Review of Books. 15 December 2005. http://www.lrb.co.uk/v27/n24/penn01_html (14 July 2008, date last accessed).
6 Shojania KJ, Duncan BW, McDonald KM, et al. Making health care safer: a critical analysis of patient safety practices. Evid Rep Technol Assess (Summ) (2001) 43:i–x. 1–668.[Medline]
7
Gosbee J. Human factors engineering and patient safety. Qual Saf Health Care (2002) 11:352–4.
8 Zell BL, Goldmann DA. Healthcare-associated infection and antimicrobial resistance: moving beyond description to prevention. Infect Control Hosp Epidemiol (2007) 28:261–4.[CrossRef][Web of Science][Medline]
9 Gould IM. Community-acquired MRSA: can we control it? Lancet (2006) 368:824–6.[Medline]
10 Jarvis WR. The United States approach to strategies in the battle against healthcare-associated infections, 2006: transitioning from benchmarking to zero tolerance and clinician accountability. J Hosp Infect (2007) 65:3–9.[CrossRef][Web of Science][Medline]
11 Ritchie K, Bradbury I, Craig J, et al. The clinical and cost effectiveness of screening for methicillin-resistant Staphylococcus aureus (MRSA). NHS Quality Improvement Scotland. Health Technology Assessment Report 9, October 2007.
12 Gould IM. Costs of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) and its control. Int J Antimicrob Agents (2006) 28:379–84.[CrossRef][Medline]
13
Garrod LP. Behaviour in vitro of some new antistaphylococcal antibiotics. Br Med J (1956) 2:61–5.
14
Gould IM. Antibiotic policies to control hospital-acquired infection. J Antimicrob Chemother (2008) 61:763–5.
15
British Thoracic Society Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults. Thorax (2001) 56(Suppl 4):iv1–64.
16
Anon. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med (2005) 171:388–416.
17 Begg N, Cartwright KA, Cohen J, et al. Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults. British Infection Society Working Party. J Infect (1999) 39:1–15.[CrossRef][Web of Science][Medline]
18 Kumarasamy Y, Cadwgan T, Gillanders IA, et al. Optimizing antibiotic therapy—the Aberdeen experience. Clin Microbiol Infect (2003) 9:406–11.[CrossRef][Web of Science][Medline]
19 Frippiat F, Chandrikakumari K, Moutschen M. Decline of antibiotic use in primary care. Lancet (2008) 8:272–3.[CrossRef][Web of Science]
20
Ferech M, Coenen S, Dvorakova K, et al, ESAC Project Group. European Surveillance of Antimicrobial Consumption (ESAC): outpatient penicillin use in Europe. J Antimicrob Chemother (2006) 58:408–12.
21 Antibiotic Prophyalxis in Surgery. SIGN Publication No. 104, ISBN 978 90581 334 6. http://www.sign.ac.uk/guidelines/fulltext/104/index.html (14 July 2008, date last accessed).
22
Robicsek A, Suseno M, Beaumont JL, et al. Prediction of methicillin-resistant Staphylococcus aureus involvement in disease sites by concomitant nasal sampling. J Clin Microbiol (2008) 46:588–92.
23 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Seventeenth International Supplement M100-S17 (2007) Wayne, PA, USA: CLSI.
24 Gould IM. MRSA bacteraemia. Int J Antimicrob Agents (2007) 30(Suppl 1):S66–70.[CrossRef][Web of Science][Medline]
25
Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med (2006) 166:2138–44.
26
Cenizal MJ, Skiest D, Luber S, et al. Prospective randomized trial of empiric therapy with trimethoprim–sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prevalence of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother (2007) 51:2628–30.
27 Whitby M, McLaws ML, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis. Med J Aust (2001) 175:264–7.[Web of Science][Medline]
28 Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis (2003) 36:53–9.[CrossRef][Web of Science][Medline]
29 Shorr AF. Epidemiology of staphylococcal resistance. Clin Infect Dis (2007) 45(Suppl 3):171–6.[CrossRef]
30
Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother (2008) 62(Suppl 3):iii7–14.
31
Seaton RA. Daptomycin: rationale and role in the management of skin and soft tissue infections. J Antimicrob Chemother (2008) 62(Suppl 3):iii15–23.
32
Warren RE. Daptomycin in endocarditis and bacteraemia: a British perspective. J Antimicrob Chemother (2008) 62(Suppl 3):iii25–33.
33
Levine DP. Clinical experience with daptomycin: bacteraemia and endocarditis. J Antimicrob Chemother (2008) 62(Suppl 3):iii35–9.
34
Livermore DM. Future directions with daptomycin. J Antimicrob Chemother (2008) 62(Suppl 3):iii41–9.
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