Abstract
Antimicrobials are an extremely valuable resource across the spectrum of modern medicine. Their development has been associated with dramatic reductions in communicable disease mortality and has facilitated technological advances in cancer therapy, transplantation, and surgery. However, this resource is threatened by the dwindling supply of new antimicrobials and the global increase in antimicrobial resistance. There is an urgent need for antimicrobial stewardship (AMS) to protect our remaining antimicrobials for future generations. AMS emphasizes sensible, appropriate antimicrobial management for the benefit of the individual and society as a whole. Within the English National Health Service (NHS), a series of recent policy initiatives have focused on all aspects of AMS, including best practice guidelines for antimicrobial prescribing, enhanced surveillance mechanisms for monitoring antimicrobial use across primary and secondary care, and new prescribing competencies for doctors in training. Here we provide a concise summary to clarify the current position and importance of AMS within the NHS and review the evidence base for AMS recommendations. The evidence supports the impact of AMS strategies on modifying prescribing practice in hospitals, with beneficial effects on both antimicrobial resistance and the incidence of Clostridium difficile, and no evidence of increased sepsis-related mortality. There is also a promising role for novel diagnostic technologies in AMS, both in enhancing microbiological diagnosis and improving the specificity of sepsis diagnosis. More work is needed to establish an evidence base for interventions to improve public and patient education regarding the role of antibiotics in common clinical syndromes, such as respiratory tract infection. Future priorities include establishing novel approaches to antimicrobial management (eg, duration of therapy, combination regimens) to protect against resistance and working with the pharmaceutical industry to promote the development of new antimicrobials.
Introduction
Alongside vaccines and public health measures to control transmission of communicable diseases, antibiotics have helped to dramatically reduce mortality from infectious disease during the 20th century.Citation1 This success generated a sense of complacency among some figures in public health and academia in the 1960s and 1970s.Citation2 As Sir Frank Burnett, in accepting his Nobel prize for medicine in 1962, put it: “One can think of the middle of the twentieth century as the end of one of the most important social revolutions in history, the virtual elimination of the infectious diseases as a significant factor in social life.”Citation3 However, the enduring global challenge of pathogens such as influenza, tuberculosis, and malaria, as well as the emergence of human immunodeficiency virus, means that infectious disease remains an important problem.Citation4
The real value of antibiotics goes beyond simply preventing death and illness due to infection, in that antibiotics also permit the serious iatrogenic assault on the immune system occurring in cancer treatment or organ transplantation and have helped to keep surgical complication rates down.Citation5 Therefore, antibiotics are an extremely valuable resource across the spectrum of modern medicine.Citation6 However, the supply of new antibiotics has slowed dramatically, with only one or two agents targeting Gram-negative pathogens likely to be brought to market in the next decade.Citation7
Antimicrobial stewardship
There is an urgent need to protect our current antimicrobial drugs for future generations.Citation8 Antimicrobials can be conserved by judicious use to limit the development of antimicrobial resistance (AMR);Citation9 this is the core component of antimicrobial stewardship (AMS).Citation10 Additional benefits of AMS include preventing the selection of opportunistic pathogens such as Clostridium difficile,Citation11 limiting exposure to toxicities associated with misuse of antimicrobials,Citation10 and direct economic savings through reduced complication rates and antimicrobial consumption.Citation12 AMS emphasizes sensible, appropriate antimicrobial management for the benefit of the individual and society as a whole.Citation5,Citation13
Antimicrobial resistance
There is a clear role for AMS in controlling AMR. Microorganisms invariably develop resistance in response to the evolutionary pressure exerted upon them by exposure to antimicrobials.Citation14 This fact was recognized by Sir Alexander Fleming in his initial studies of the antibiotic properties of the Penicillium fungus. He cautioned, in his Nobel prize acceptance speech in 1945, that misuse of penicillin could contribute to development of AMR which could in turn compromise its usefulness. The history of treatment for Neisseria gonorrhoeae illustrates this point; the gonococcus has sequentially developed resistance against most antimicrobial agents to which it has been exposed, including sulfonamides, penicillin, quinolones, and now some cephalosporins,Citation13 leaving multidrug-resistant N. gonorrhoeae isolates for which there are very few therapeutic options.Citation15
This fearsome prospect of untreatable infection also applies to several other organisms. The Infectious Diseases Society of America has termed the main culprits the “ESKAPE pathogens”Citation16 (), but the biggest global concern is AMR in Gram-negative bacteria. Enterobacteriaceae such as Escherichia coli or Klebsiella species that are resistant to all but one or two antimicrobials have evolved as a consequence of extremely high levels of antibiotic exposure in several parts of the world, including Asia and the Middle East.Citation17 Infections with these multidrug-resistant organisms are associated with approximately two-fold higher mortality rates and considerably prolonged hospital admissions.Citation17 In 2009, the European Centre for Disease Prevention and Control estimated that AMR costs the European Union €1.5 billion in health care expenses and lost productivity per year.Citation18 Nosocomial transmission has caused outbreaks in health care facilities, and international travel has facilitated global dissemination.Citation17 A history of hospitalization overseas has become a personal risk factor for acquisition of multidrug-resistant organisms.Citation19 In a recent survey, approximately one third of healthy travelers to Asia became asymptomatically colonized with multidrug-resistant Enterobacteriaceae despite low levels of health care contact.Citation20 Such asymptomatic carriage is also significantly higher in people in the UK from certain demographic groups with links to high incidence regions.Citation21
However, there is cause for optimism that this threat can be contained. Some European countries, such as Sweden, have pioneered stewardship programs that have successfully reduced antibiotic use and kept AMR rates low.Citation9 An AMS program in Scotland has had an important impact on antimicrobial consumption and C. difficile rates.Citation22 AMS programs also appear to have had a significant impact in the English hospital setting.Citation7 The incidences of both methicillin-resistant Staphylococcus aureus and C. difficile peaked in the mid 2000s, and it is believed that a combination of restrictive antimicrobial policies and better infection prevention and control practices (eg, source isolation and handwashing) were responsible for the decreasing incidence of both infections,Citation5 although it is not clear which of these interventions had the dominant role. At the global level, the problem of AMR in England is comparatively minor at present. However, with a relatively narrow focus on methicillin-resistant S. aureus and C. difficile, the growing problem of bacteremia due to other multidrug-resistant organisms has been largely ignored.Citation7
AMR is an emergent threat to health care delivery within the National Health Service (NHS) in England.Citation5 A multiplicity of government documents, recommendations, and position statements on AMS to address AMR in the English NHS have been produced over the last few years. Here we provide a timely summary of these publications to help clarify the current position and importance of AMS to the NHS in England. We outline the evidence base underpinning the AMS recommendations, and conclude with a discussion of future priorities.
Antimicrobial stewardship initiatives in the NHS
Concerns regarding the rise of AMR and the priority of AMS were recently highlighted by the Chief Medical Officer, Dame Sally Davies, in her annual report of 2011, published in March 2013.Citation5 This report received a lot of attention and provided much needed focus for AMS leadership.Citation7 The report addressed four broad areas of AMS:Citation13
Concerns about global AMR
The need to raise awareness and education about AMR among the public and within the NHS
The need for better surveillance systems for AMR
The need to improve diagnostics.
In parallel with the Chief Medical Officer’s report, a UK pan-governmental strategy and action plan for AMR has been recently published (see ).Citation23 However, awareness of AMR in the UK is not a recent development; a series of reports and policy initiatives has addressed AMR in the NHS over the last two decades, as summarized in . “The Path of Least Resistance” (1998)Citation24 first outlined the AMS imperatives for the NHS. Introducing several stewardship themes that are recognizable in subsequent reports, it highlighted the need for antimicrobial prescribing to be evidence-based and supported by national formularies, and emphasized the need for antimicrobial prescribing to take a more prominent place in medical education, to utilize the expertise of infection specialists, and for resources to be directed towards research into developing strategies to combat AMR.Citation24 Following this, the UK Department of Health produced several reports on AMR/AMS, starting with the first UK “Antimicrobial Resistance Strategy and Action Plan” in 2000.Citation25 The Health and Social Care Act 2008Citation26 provided a framework for the Care Quality Commission to objectively measure the quality of health care provision, and specifically included AMS outcomes. Criterion 9 states: “Procedures should be in place to ensure prudent prescribing and antimicrobial stewardship.”
There should be an ongoing program of audit, revision, and update. In health care, this is usually monitored by the antimicrobial management team or local prescribing advisors. To provide practical guidance for NHS providers, the Antimicrobial Stewardship in Primary Care collaboration was formed in 2009. This multiagency collaboration produced a multifaceted AMS intervention for primary care that was launched in 2012. The Treat Antibiotics Responsibly, Guidance and Education Toolkit (TARGET)Citation27 contains evidence-based resources for clinician and patient education, as well as specific antimicrobial guidance and self-assessment and audit tools. Also in 2012, the Department of Health’s Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection produced the “Start Smart and Focus” guidanceCitation18 to provide a framework for best antimicrobial prescribing practice. Included within Start Smart and Focus is the Acute Hospital’s Assessment Tool,Citation28 an evidence-based checklist for AMS assessment and audit. Overall, these publications aim to standardize the practice of AMS across the NHS in England in both primary and secondary care settings.
Antimicrobial prescribing in the NHS
It is challenging to accurately assess current prescribing patterns across the NHS in England. Whilst the Health and Social Care Information Centre monitors antimicrobial dispensing data in primary care, there is no routine public reporting of antimicrobial use in hospitals.Citation29 For this, we must rely on intermittent antibiotic point prevalence surveys, such as that done in 2011 by the Health Protection Agency.Citation5 Within the NHS, most antimicrobial prescribing (up to 80%) happens in primary care. However, despite awareness of the problem of resistance and the raft of AMS reports discussed above (), there was a 16% increase in antimicrobial prescriptions in primary care between 2002 and 2012.Citation29 The “NHS Atlas of Variation in Health Care” also describes a three-fold variation in quinolone prescriptions and an 18-fold variation in cephalosporin prescriptions across primary care trusts in England in 2010.Citation18 Such regional variation also applies to inpatient antimicrobial prescriptions (which vary in the range of 29%–39.9% for inpatients) and seems not to be driven solely by demographic factors or regional variation in burden of disease.Citation5
Surveillance
More detailed understanding of patterns of antimicrobial use will be of central importance when directing and assessing the impact of AMS programs in England. As a result, Public Health England has developed the English Surveillance Programme for Antimicrobial Utilization and Resistance to monitor antimicrobial prescribing and resistance in primary and secondary care.Citation29 The English Surveillance Programme for Antimicrobial Utilization and Resistance also has the remit to develop quality measures and methods to monitor unintended outcomes of AMS and educational/behavioral interventions.Citation29
Education and training
The desire for more training in antimicrobial prescribing has been identified in surveys of both doctors in trainingCitation30 and medical students.Citation31 Trainee doctors generally view comprehensive antimicrobial prescribing guidelines positively,Citation30 although surveys continue to show that when prescriptions are noncompliant with guidelines, the antibiotic choice tends to be broader spectrum but not more appropriate to the organism,Citation32 suggesting that efforts to improve adherence with guidelines are warranted. Growing recognition that the principles of antimicrobial prescribing and stewardship are central to the practice of medicine in the UK has led to the development of specific antimicrobial prescribing competencies within a 2012 report entitled “A single competency framework for all prescribers”,Citation33 developed by the National Prescribing Centre on behalf of the National Institute for Clinical Excellence, which has been endorsed by the General Medical Council and the Academy of Medical Royal Colleges. To complement the National Prescribing Centre competency framework, five specific antimicrobial prescribing and stewardship competencies have been recently released by the Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection.Citation34 These cover infection prevention and control, AMR, antimicrobial prescribing, AMS, and monitoring and learning. The need for better education and training does not just apply to health care professionals. As consumers of antimicrobials, it is vital to engage patients and members of the public in AMS campaigns.
Public engagement
Public misconceptions about the role of antibiotics in viral infectionsCitation35 indicate a need for better education, and surveys have shown that among various reasons cited by practitioners for inappropriate antibiotic prescriptions, patient expectation was highly influential.Citation36,Citation37 Annual European Antibiotic Awareness Days (EAAD) aim to improve public understanding about the appropriate role for antibiotics in common clinical scenarios.Citation38 However, in a recent survey performed in conjunction with EAAD, approximately 35% of those surveyed in the UK were unaware that antibiotics have no effect in viral infection.Citation38 Some interventions such as the English 2008 poster-based EAAD educational program had a negligible impact on antimicrobial knowledge or consumption.Citation39 However, other simple practical measures such as an interactive booklet on respiratory infections in children supplied in primary care have been shown to significantly reduce antibiotic prescriptions without reducing parental satisfaction;Citation40 this booklet is included in the TARGET toolkit.Citation27 Whilst the need for better patient education about the role of antibiotics is widely acknowledged,Citation5,Citation12,Citation13 there is also a need for more evidence-based guidance about how best to achieve this. However, the main focus of AMS is on reducing antimicrobial prescribing by health care professionals, and we summarize evidence for such interventions below.
Evidence base for AMS interventions
Primary care
A variety of heterogeneous AMS interventions in the primary care setting have been evaluated.Citation41 The main objective is to reduce antimicrobial prescribing for various infections, particularly respiratory tract infection (which is most commonly viralCitation41) as well as uncomplicated urinary tract infection and otitis media, or reducing the prescription of specific agents. A previous Cochrane reviewCitation42 indicated that multifaceted interventions tailored to precise target populations were most likely to have significant effects on prescribing. Recent randomized controlled trials have evaluated multifaceted interventionsCitation43,Citation44 with positive effects on reducing antibiotic prescribing rates. However, few studies have been sufficiently powered, designed, or tested interventions with sufficient effect sizes to show an impact on AMR.Citation42
Secondary care
The effectiveness of AMS interventions on inpatient prescribing has been the subject of a recently updated Cochrane systematic review and meta-analysis.Citation45 Intervention studies have evaluated the effect of persuasive interventions (including circulation of educational material, educational meetings, and audit and feedback) and restrictive measures (including reporting selective antimicrobial sensitivities, formulary restrictions, and mandatory prior infection specialist approval for certain drugs) in reducing inappropriate antimicrobial prescriptions. The majority of interventions (in 84% of studies) focused on the antimicrobial prescribed, whereas the remainder addressed whether or not antibiotics should be prescribed at all. Both restrictive and persuasive interventions were effective in randomized controlled trials (median effect size 40.5% versus 24.7%, respectively). In a meta-analysis of 52 studies, restrictive interventions had significantly greater impact on prescribing outcomes at one month (32%, 95% confidence interval [CI] 2–61, P=0.03) and on microbial outcomes at 6 months (53%, 95% CI 31–75, P=0.001) but there were no significant differences at 12 or 24 months. Several beneficial outcomes were associated with reduced antimicrobial prescribing (regardless of how it was achieved), such as reduced C. difficile, methicillin-resistant S. aureus, and extended spectrum beta-lactamase Enterobacteriaceae rates. In addition, whilst there was no clinical evidence of increased mortality in nine studies aimed at reducing antibiotic exposure, four studies focusing on optimizing prescribing for community-acquired pneumonia showed a significant improvement in mortality (risk ratio 0.89, 95% CI 0.82–0.97). Overall, these data indicate that AMS interventions are effective and evidence-based, and support restrictive interventions when short-term improvements are required.
Diagnostics
Delay in administering effective antibiotics results in stepwise increases in mortality resulting from bacterial sepsis.Citation46 From the perspective of AMS this presents a paradox, given that as AMR becomes more prevalent the need for clinicians to use empirical broad spectrum antibiotics in patients with severe sepsis will become greater, driving selection of resistant microorganisms and exacerbating the problem. Strategies to improve the diagnosis of serious infection with multidrug-resistant organisms are a particular focus of AMS programs to guide the appropriate use of broad-spectrum therapy and avoid unnecessary antibiotic exposure. The role for novel diagnostic technologies lies in rapid identification of causative organisms (which permits targeted, narrow-spectrum therapy), as well as in improving the specificity of sepsis diagnosis (given that many patients with a systemic inflammatory response do not have serious bacterial infection and therefore do not require antibiotic therapy). Developments in this field are the subject of a recent review.Citation12
Biomarkers
The use of biomarkers has been shown to aid the clinical diagnosis of infection and to reduce unnecessary antibiotic prescriptions.Citation5 For example, the inclusion of the biomarker procalcitonin in an antibiotic management algorithm has been shown in randomized controlled trialsCitation47 and in pragmatic clinical trialsCitation48 to safely reduce the frequency and duration of antibiotic therapy for suspected lower respiratory tract infection, and to enhance de-escalation of broad-spectrum antibiotics in cancer patientsCitation49 and critical care patientsCitation50 with infection. In a recent meta-analysis, procalcitonin combined with careful clinical assessment had a sensitivity of 0.77 and specificity of 0.79 for the diagnosis of sepsis compared with systemic inflammatory response of noninfective etiology,Citation51 and preliminary studies suggest it can be used safely in NHS medical admission settings.Citation52 The use of C-reactive protein as a biomarker in primary care AMS initiatives has shown efficacy in reducing antimicrobial prescriptions (reviewed in MooreCitation41). Algorithms incorporating newer biomarkers, alone or in combination, are also under investigation,Citation12 but more data are required before their definitive role can be established.
Rapid microbiological diagnosis
Current microbiological diagnosis is inefficient, with a minimum lag of 48 hours between the isolate reaching the laboratory and accurate organism identification. Molecular techniques have the potential to greatly speed up microbiological diagnosis and could also be used to detect genomic resistance, thus reducing exposure to unnecessary broad-spectrum antibiotics. With sufficient sensitivity, they could also play a part in determining whether antibiotics need to be prescribed or not. These techniques broadly involve either proteomic or genomic methods.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) detects the proteomic signature of an array of pathogens, and can yield diagnostic information in a matter of minutes.Citation53 The utility of MALDI-TOF in the AMS setting has been demonstrated in proof of concept studies.Citation54 However, technical issues currently preclude its more widespread application, such as difficulties in distinguishing certain bacterial species and problems identifying polymicrobial infections.Citation12
Additional molecular techniques, such as nucleic acid amplification or nucleic acid hybridization, are in clinical use for pathogen detection (eg, identifying N. gonorrhoeae, Chlamydia trachomatis, C. difficile, and several other pathogens). Rapid nucleic acid amplification kits can also identify resistance mutations, such as the mecA gene in methicillin-resistant S. aureus.Citation55 Next-generation whole genome sequencing has greater potential applicability to AMS, in view of its ability to simultaneously identify several pathogens as well as potential resistance mutations, as well as its ability to provide early indications of outbreaks through analysis of the relatedness of pathogen genomes in different patients.Citation56 However, much work remains before these technologies are available for cost-effective routine diagnostic applications.Citation56
Conclusion and outstanding challenges
In this review, we have outlined the current status of AMS in the English NHS, including national policies and guidance, the evidence base for intervention strategies, and issues of education, training, and improved diagnostic technologies. However, there are a number of outstanding challenges in the field of stewardship and AMR.
One important strategy to combat the potential threat of untreatable infection is to accelerate the development of novel antimicrobials, although this is unlikely to happen without extensive commercial and/or political incentives, such as tax breaks, government funding, financial rewards for specific outcomes, simplified regulatory requirements, or extended patents.Citation5 One such example is the 2012 US Generating Antibiotic Incentives Now (GAIN) Act. Clearly, AMS will remain of critical importance to protect any future antimicrobials developed through such effort.
Another priority for future work is to define the optimal duration of antimicrobial prescribing, for example, whether antibiotic conservation through short-duration regimens is safe and effective in limiting the development of resistance.Citation5 Additional strategies that have been suggested include the use of combinations of antibiotics from different classes (as is used in antiretroviral therapy for human immunodeficiency virus) or the cycling of first-choice antibiotics in empirical prescribing guidelines to avoid prolonged exposure.Citation5
Here we have summarized the current status and importance of AMS to the NHS in England, and outlined the evidence base for current and potential AMS programs. The ultimate success of AMS may well determine to a large degree the future scope, utility, and effectiveness of the English NHS.
Disclosure
The authors report no conflicts of interest in this work.
References
- GuyerBFreedmanMAStrobinoDMSondikEJAnnual summary of vital statistics: trends in the health of Americans during the 20th centuryPediatrics20001061307131711099582
- SpellbergBDrWilliamHStewart: mistaken or maligned?Clin Infect Dis20084729418564938
- PierGBOn the greatly exaggerated reports of the death of infectious diseasesClin Infect Dis2008471113111418800937
- FauciASMorensDMThe perpetual challenge of infectious diseasesN Engl J Med201236645446122296079
- Annual Report of the Chief Medical Officer 20112 Available from: https://www.gov.uk/government/publications/chief-medical-officer-annual-report-volume-2Accessed February 20, 2014
- SmithRCoastJThe true cost of antimicrobial resistanceBMJ2013346f149323479660
- KesselASSharlandMThe new UK antimicrobial resistance strategy and action planBMJ2013346f160123479662
- CarletJCollignonPGoldmannDSociety’s failure to protect a precious resource: antibioticsLancet201137836937121477855
- MolstadSErntellMHanbergerHSustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programmeLancet Infect Dis2008812513218222163
- DellitTHOwensRCMcGowanJEJrInfectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardshipClin Infect Dis20074415917717173212
- BarbutFJonesGEckertCEpidemiology and control of Clostridium difficile infections in healthcare settings: an updateCurr Opin Infect Dis20112437037621505332
- O’BrienDJGouldIMMaximizing the impact of antimicrobial stewardship: the role of diagnostics, national and international effortsCurr Opin Infect Dis20132635235823806898
- DaviesSCFowlerTWatsonJLivermoreDMWalkerDAnnual Report of the Chief Medical Officer: infection and the rise of antimicrobial resistanceLancet20133811606160923489756
- CostelloeCMetcalfeCLoveringAMantDHayADEffect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysisBMJ2010340c209620483949
- BolanGASparlingPFWasserheitJNThe emerging threat of untreatable gonococcal infectionN Engl J Med201236648548722316442
- BoucherHWTalbotGHBradleyJSBad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of AmericaClin Infect Dis20094811219035777
- Munoz-PriceLSPoirelLBonomoRAClinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemasesLancet Infect Dis20131378579623969216
- Ashiru-OredopeDSharlandMCharaniEMcNultyCCookeJImproving the quality of antibiotic prescribing in the NHS by developing a new Antimicrobial Stewardship Programme: Start Smart – Then FocusJ Antimicrob Chemother201267Suppl 1i51i6322855879
- NemethJLedergerberBPreiswerkBMultidrug-resistant bacteria in travellers hospitalized abroad: prevalence, characteristics, and influence on clinical outcomeJ Hosp Infect20128225425923103249
- PaltansingSVlotJAKraakmanMEExtended-spectrum beta-lactamase-producing Enterobacteriaceae among travelers from The NetherlandsEmerg Infect Dis2013191206121323885972
- WickramasingheNHXuLEustaceAShabirSSalujaTHawkeyPMHigh community faecal carriage rates of CTX-M ESBL-producing Escherichia coli in a specific population group in Birmingham, UKJ Antimicrob Chemother2012671108111322403261
- NathwaniDSneddonJPattonAMalcolmWAntimicrobial stewardship in Scotland: impact of a national programmeAntimicrob Resist Infect Control20121722958296
- Department of Health, Department for Environment, Food and Rural AffairsUK Five Year Antimicrobial Resistance Strategy 2013–2018 Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/244058/20130902_UK_5_year_AMR_strategy.pdfAccessed February 20, 2014
- United States National Library of Medicine and National Institutes of HealthThe path of least resistance1998 Available from: http://www.advisorybodies.doh.gov.uk/smac1.htmAccessed February 20, 2014
- Department of HealthUK antimicrobial resistance strategy and action plan2000 Available from: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4007783Accessed February 20, 2014
- Department of HealthThe Health and Social Care Act 2008: Code of Practice for health and adult social care on the prevention and control of infections and related guidance2008 Available from: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_110288Accessed February 20, 2014
- McNultyCAEuropean Antibiotic Awareness Day 2012: general practitioners encouraged to TARGET antibiotics through guidance, education and toolsJ Antimicrob Chemother2012672543254623014720
- CookeJAlexanderKCharaniEAntimicrobial stewardship: an evidence-based, antimicrobial self-assessment toolkit (ASAT) for acute hospitalsJ Antimicrob Chemother2010652669267320935301
- Ashiru-OredopeDHopkinsSAntimicrobial stewardship: English Surveillance Programme for Antimicrobial Utilization and Resistance (ESPAUR)J Antimicrob Chemother2013682421242324027247
- PulciniCWilliamsFMolinariNDaveyPNathwaniDJunior doctors’ knowledge and perceptions of antibiotic resistance and prescribing: a survey in France and ScotlandClin Microbiol Infect201117808720132254
- MinenMTDuquaineDMarxMAWeissDA survey of knowledge, attitudes, and beliefs of medical students concerning antimicrobial use and resistanceMicrob Drug Resist20101628528920624097
- van der VeldenLBTrompMBleeker-RoversCPNon-adherence to antimicrobial treatment guidelines results in more broad-spectrum but not more appropriate therapyEur J Clin Microbiol Infect Dis2012311561156822108843
- National Prescribing CentreA single competency framework for all prescribers Available from: http://www.npc.nhs.uk/improving_safety/improving_quality/Accessed February 20, 2014
- Department of Health and Public Health EnglandAntimicrobial prescribing and stewardship competencies Available from: https://www.gov.uk/government/publications/antimicrobial-prescribing-and-stewardship-competenciesAccessed February 20, 2014
- CalsJWBoumansDLardinoisRJPublic beliefs on antibiotics and respiratory tract infections: an Internet-based questionnaire studyBr J Gen Pract20075794294718252068
- AkkermanAEKuyvenhovenMMvan der WoudenJCVerheijTJDeterminants of antibiotic overprescribing in respiratory tract infections in general practiceJ Antimicrob Chemother20055693093616155062
- AkkermanAEKuyvenhovenMMvan der WoudenJCVerheijTJAnalysis of under- and overprescribing of antibiotics in acute otitis media in general practiceJ Antimicrob Chemother20055656957416033803
- StockleyJMEuropean Antibiotic Awareness Day 2012: getting smart about antibiotics, a public-professional partnershipJ Infect20126537737922960369
- McNultyCANicholsTBoylePJWoodheadMDaveyPThe English antibiotic awareness campaigns: did they change the public’s knowledge of and attitudes to antibiotic use?J Antimicrob Chemother2010651526123320488985
- FrancisNAButlerCCHoodKSimpsonSWoodFNuttallJEffect of using an interactive booklet about childhood respiratory tract infections in primary care consultations on reconsulting and antibiotic prescribing: a cluster randomised controlled trialBMJ2009339b288519640941
- MooreMAntibiotics: time to actBr J Gen Pract20136334034123834861
- ArnoldSRStrausSEInterventions to improve antibiotic prescribing practices in ambulatory careCochrane Database Syst Rev20054CD00353916235325
- GjelstadSHoyeSStraandJBrekkeMDalenILindbaekMImproving antibiotic prescribing in acute respiratory tract infections: cluster randomised trial from Norwegian general practice (prescription peer academic detailing (Rx-PAD) study)BMJ2013347f440323894178
- GerberJSPrasadPAFiksAGEffect of an outpatient antimicrobial stewardship intervention on broad-spectrum antibiotic prescribing by primary care pediatricians: a randomized trialJAMA20133092345235223757082
- DaveyPBrownECharaniEInterventions to improve antibiotic prescribing practices for hospital inpatientsCochrane Database Syst Rev20134CD00354323633313
- GaieskiDFMikkelsenMEBandRAImpact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency departmentCrit Care Med2010381045105320048677
- SchuetzPChrist-CrainMThomannREffect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trialJAMA20093021059106619738090
- AlbrichWCDusemundFBucherBEffectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter poststudy survey (ProREAL)Arch Intern Med201217271572222782201
- LiewYXLeeWCaiYYUtility and safety of procalcitonin in an antimicrobial stewardship program (ASP) in patients with malignanciesEur J Clin Microbiol Infect Dis2012313041304622678350
- HohnASchroederSGehrtAProcalcitonin-guided algorithm to reduce length of antibiotic therapy in patients with severe sepsis and septic shockBMC Infect Dis20131315823547790
- WackerCPrknoABrunkhorstFMSchlattmannPProcalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysisLancet Infect Dis20131342643523375419
- SaeedKDrydenMBourneSPagetCProudAReduction in antibiotic use through procalcitonin testing in patients in the medical admission unit or intensive care unit with suspicion of infectionJ Hosp Infect20117828929221636167
- SauerSKliemMMass spectrometry tools for the classification and identification of bacteriaNat Rev Microbiol20108748220010952
- PerezKKOlsenRJMusickWLIntegrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costsArch Pathol Lab Med20131371247125423216247
- GeigerKBrownJRapid testing for methicillin-resistant Staphylococcus aureus: implications for antimicrobial stewardshipAm J Health Syst Pharm20137033534223370140
- FrickeWFRaskoDABacterial genome sequencing in the clinic: bioinformatic challenges and solutionsNat Rev Genet2014151495524281148