Antibiotic Stewardship

CME Infectious diseases Clinical Medicine 2013, Vol 13, No 5: 499–503

28 Department of Health Advisory Committee encompass initiatives that promote the on Antimicrobial Resistance and Healthcare Antibiotic responsible use of antibiotics, with the goal of Associated Infection. Antimicrobial steward- preserving their future effectiveness and safe- ship: ‘Start smart – then focus’. London: DH, stewardship 4–7 2011. www.gov.uk/government/uploads/ guarding public health. The physician may system/uploads/attachment_data/file/215308/ perceive the concept of stewardship as pat- dh_131181.pdf [Accessed 5 August 2013]. Kieran Hand, consultant pharmacist for ronising or insulting and a threat to clinical anti-infectives and post-doctoral clinical freedom; nonetheless, physicians in the USA academic fellow have recently called for mandatory imple- Address for correspondence: mentation of antibiotic stewardship backed Dr RA Seaton, Brownlee Centre for University Hospital Southampton NHS Foundation Trust by legislation.8 This article sets out the case Infectious Diseases, Gartnavel General for antibiotic stewardship and describes com- Hospital, 1053 Great Western Road, monly used stewardship strategies and the Glasgow G12 0YN. Introduction evidence supporting their effectiveness. Email: [email protected] Sir Frank MacFarlane Burnet, winner of the Nobel Prize for Medicine in 1960, wrote of the Misuse of antibiotics decline of infectious diseases in 1962: ‘One can Antibiotic misuse (Table 1) is common in the think of the middle of the twentieth century UK and throughout the world. In 2009, as the end of one of the most important social family doctors in Britain prescribed 50% and revolutions in history, the virtual elimination 25% more antibiotics per head of population of the infectious diseases’.1 Any clinician who than their contemporaries in the Netherlands has cared for a patient with severe sepsis due and Sweden, respectively.9 A cross-sectional to a multi-drug resistant (MDR) Klebsiella study of 8,057 general practices (GPs) in pneumoniae will recognise the significance of England revealed that antibiotic prescribing this misconception. Bacteraemias due to volumes varied fivefold between practices at MDR bacteria are estimated to have caused the extremes of the study sample and twofold more than 8,000 deaths and excess costs of between practices on the 10th and 90th per- €62 million in Europe in 2007, and prevailing centiles.10 Only one-sixth of this variability trends indicate that infections caused by MDR could be explained by patient characteristics. Gram-negative bacteria are rapidly increasing, A recent study of more than 1.5 million including in the UK.2 patient visits to GPs in the UK that resulted in Drug resistance is an inevitable conse- a diagnosis of acute respiratory infection quence of the evolution of microorganisms reported that the number needed to treat for under antibiotic selection pressure. This antibiotics to prevent one admission to hos- phenomenon mandates a perpetual quest to pital due to pneumonia was 12,255.11 Sixty- discover new agents that can circumvent five per cent of patient visits resulted in a emerging resistance mechanisms. Drug prescription, with prescribing rates varying discovery and development are expensive, and from 3% to 95% by practice. factors unique to antibiotics, such as relatively At any one time in hospitals in the UK, short treatment courses, have diverted invest- about one-third of inpatients are prescribed ment to more profitable areas, leaving an an antibiotic, with the main drivers being increasingly unmet clinical need.3 Although respiratory, urinary and skin and soft- resistance is inevitable, the pace and extent of tissue infections. Rates of antibiotic misuse propagation of resistant organisms is gov- in hospitals have remained unchanged at erned by human behaviour – most impor- about 50%.12,13 Overprescribing of broad- tantly antibiotic consumption by humans spectrum antibiotics is frequent, with such and animals, as well as hygiene, sanitation ‘defensive prescribing’ attributed to the and infection control. The profound conse- precedence of treatment success in current quences of antibiotic resistance for individual patients at the expense of loss of effective- patients and society create an ethical impera- ness due to resistance in the future.14 tive to protect public health by all available means, including antibiotic stewardship. Antibiotic prescribing and Stewardship is as an ethic that embodies resistance responsible planning and management of finite resources. The term antibiotic The relationship between antibiotic pre- stewardship has been adopted widely to scribing in the community and resistance is

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15 Table 1. Examples of inappropriate use of antibiotics.4,7 well characterised. Exposure to antibiotics in primary care is consistently associated Type Example with a subsequent twofold risk of antibiotic Overuse • Prescribing antibiotics for viral infections resistance in respiratory and urinary bac- • Prescribing antibiotics for non-infectious processes (eg febrile patient with pancreatitis) teria for up to 12 months after treatment.16 • Treating minor bacterial infections that do not require antibiotics (eg small skin Antibiotic prescribing in hospitals also abscesses that resolve with incision and drainage) selects for resistance at both the patient and • Treating bacterial colonisation (eg positive catheter urine culture from an institutional levels.17 The risk of acquiring asymptomatic older patient) methicillin-resistant Staphylococcus aureus • Prescribing prolonged treatment courses (eg >24 hours for low-risk surgical prophylaxis) (MRSA) was increased 1.8-fold in patients Misuse • Use of broad-spectrum antibiotics effective against multidrug-resistant organisms exposed to antibiotics.18 Prescribing of inef- in a patient with a community-acquired infection fective antibiotics for patients harbouring • Failure to de-escalate broad-spectrum antibiotics according to culture results resistant organisms was associated with a • Failure to adjust antibiotic prescription according to culture results when the 1.6-fold increased risk of mortality from isolated organism is resistant to initial therapy infection.19 Table 2 lists MDR organisms Underuse • Inadequate dosing of antibiotics that are currently problematic according to • Premature discontinuation of antibiotics the Infectious Diseases Society of America. • Delay to prompt treatment of severe sepsis • Failure to prescribe an antibiotic regimen with an adequate spectrum of activity in Knowledge and confidence a patient with a life-threatening infection among doctors Abuse • Prescribing antibiotics for financial incentive • Prescribing particular antibiotics as a result of pressure from a pharmaceutical A survey of doctors in a teaching hospital industry representative in the USA in 2004 reported that 90% of doctors wanted more education about antibiotics, with only 21% of doctors feeling Table 2. ESKAPE pathogens: resistant micro-organisms identified as particularly very confident that they were using antibi- 3 problematic by the Infectious Diseases Society of America. otics optimally.20 A more recent survey of Gram positive Gram negative junior doctors in Scotland suggested that • Enterococcus faecium • Klebsiella species 75% were confident about choosing the cor- rect antibiotic, but only 36% felt confident – Vancomycin resistant (VRE) – ESBL producer about planning the duration of treatment.21 • Staphylococcus aureus – Carbapenemase β-lactamase producer Of all antibiotic stewardship interventions, – Methicillin resistant (MRSA) • Acinetobacter baumannii junior doctors rated the availability of guide- – Vancomycin intermediate (VISA) – Carbapenem resistant lines most highly for promoting appropriate • Pseudomonas aeruginosa prescribing. A 2010 survey of more than – Carbapenem resistant 300 medical students in the USA reported • Enterobacter species and Escherichia coli that at least three-quarters of students – ESBL producers expressed a desire for more education about – Carbapenemase β-lactamase producers choice of antibiotic.22 ESBL = extended-spectrum β-lactamase. The impact of lack of knowledge of antibiotic pharmacology and pathogen epidemiology in practice is illustrated by a Key points recent study of guideline adherence for patients admitted to a Dutch university 1. Resistance to last-line antibiotics is emerging and spreading globally but few new hospital with sepsis.23 Off-guideline treat- antibiotic classes have been discovered or are close to market ment had a broader spectrum than on- 2. Antibiotic resistance increases morbidity and mortality for individual patients as guideline treatment in 87% of 108 off- well as posing a threat to public health guideline prescriptions, but the antibiotic 3. Doctors have a responsibility to prescribe antibiotics judiciously and participate susceptibility of isolated pathogens was actively in antibiotic stewardship similar for off- and on-guideline regimens 4. Antibiotic treatment must be prescribed only for patients with evidence of (or a (93% and 91% respectively). reasonable suspicion of) infection and administered promptly 5. Narrow-spectrum antibiotics should be selected where safe and effective, to Professional standards minimise collateral damage to normal flora and preserve the effectiveness of broad-spectrum agents The General Medical Council (GMC) and KEY WORDS: Antibiotic, antimicrobial, stewardship, resistance, prescribing Academy of Medical Royal Colleges have

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endorsed A single competency framework for Table 3. Examples of hospital antibiotic stewardship interventions.6,25 all prescribers, a report published in May 2012 by the National Prescribing Centre on Type of intervention Example behalf of the National Institute for Health Governance • Organisational strategy for antibiotic stewardship and Care Excellence (NICE).24 Competency structures • Antibiotic prescribing policy (statement of principles of responsible statements from this that are relevant for prescribing and expected quality standards), which may include: – 48-hour review antibiotic prescribing include: – intravenous-to-oral switch • Competency group 1: Knowledge – has – automatic stop orders (termination of prescriptions after a specified up-to-date clinical, pharmacological interval unless authorisation to continue obtained) – compulsory order forms (prescribers required to complete a form and pharmaceutical knowledge rele- with clinical details to justify use of restricted antibiotics) vant to own area of practice: – expert approval (prescriptions for restricted antibiotics authorised – Competency 11: Understands anti- by infection specialist or head of department) microbial resistance and the roles – dedicated antibiotic prescription chart of infection prevention, control – removal by restriction (restrictive policy imposed in target wards, units or operating theatres – eg by removing restricted antibiotics and antimicrobial stewardship from drug cupboards) measures – therapeutic substitution (pharmacists authorised to substitute • Competency group 7: Understands and alternative antibiotics) works within local and national poli- – antibiotic cycling and rotation policy cies, processes and systems that impact – mixing, diversity and heterogeneous prescribing policy • Antibiotic stewardship committee (including medical microbiologist or on prescribing practice; sees how own infectious diseases physician, specialist pharmacist and information analyst) prescribing impacts on the wider Operational delivery • Antibiotic formulary healthcare community: – may incorporate limited list of antibiotics subject to prescribing

– Competency 59: Understands and restrictions such as requirement for preauthorisation works within local frameworks for • Guidelines for initial treatment of common infections (evidence based, medicines use as appropriate (eg peer reviewed and informed by local resistance data where possible) local formularies, care pathways, • Guidelines for perioperative prophylaxis for common surgical procedures • Reminder systems (eg preprinted adhesive labels for medical case notes) protocols and guidelines). • Computerised physician order entry (electronic prescribing) – may incorporate computerised decision-support systems Aims of antibiotic stewardship • Mobile device software applications for point-of-care information and guidance Antibiotic stewardship has two primary 25 Risk management • Guidelines for management of infection in patients with allergy to goals: antibiotics • to ensure effective treatment for • Information on safe administration of intravenous antibiotics patients with bacterial infection • Guidelines for dosing and monitoring of serum levels of toxic antibiotics • to reduce unnecessary antibiotic use Clinical microbiology/ • Validation and interpretation of microscopy, culture and susceptibility and minimise collateral damage. infectious disease results for laboratory reporting specialist and • Surveillance and reporting of trends in antibiotic resistance Collateral damage is defined as the laboratory support • Telephone consultation for advice on infection management increased risk of colonisation and infec- • Bacteraemia follow-up service tion with antibiotic-resistant bacteria fol- • Antibiotic stewardship ward rounds lowing damage to the normal bacterial • Point-of-care rapid tests for bacterial infection • Advanced sepsis biomarkers (eg procalcitonin) flora after antibiotic treatment. At the patient level, stewardship has been defined Controls and quality • Surveillance of antibiotic prescribing trends assurance • Public reporting and benchmarking of antibiotic consumption data as ‘the optimal selection, dosage and dura- (eg World Health Organisation-defined daily doses) tion of antimicrobial treatment that results • Audit and feedback of adherence to prescribing policy in the best clinical outcome for the treat- • Audit and feedback of adherence to guidelines ment or prevention of infection, with Education and • Induction training on antibiotic stewardship minimal toxicity to the patient and min- training • Revalidation training imal impact on subsequent resistance’.26 • Distribution of printed educational materials (eg pocket guidelines and The Royal College of Physicians issued patient information leaflet) • Educational meetings guidance on effective antibiotic pre- • Electronic learning 27 scribing in 2011 (Box 1). • Antibiotic prescribing competency assessment At the organisational level, stewardship • Academic detailing or educational outreach (one-on-one educational refers to evidence-based programmes intervention) and interventions to monitor and direct • Nominated clinical champions for antibiotic stewardship • Provision of patient information and counselling antimicrobial use.28 Table 3 summarises

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Table 4. Cochrane review of effectiveness of antibiotic stewardship interventions: Box 1. Royal College of Physicians’ insight antibiotic prescribing outcomes.25 into effective antibiotic prescribing – top ten tips.27 Type of Number Median effect size (%)∗ intervention of studies Antibiotics are essential to modern medicine ITS Controlled ITS CBA RCT CRCT and may be life saving, but their abuse leads Persuasive† 44 42.3 31.6 17.7 3.5 24.7 to resistance. All physicians who prescribe ∗∗ antibiotics have a responsibility to their Restrictive 24 34.7 – 17.1 – 40.5 patients and for public health to prescribe Structural‡ 8 – – – 13.3 23.6 optimally. ITS = interrupted time series; CBA = controlled before-and-after study; RCT = randomised controlled trial; 1 Institute antibiotic treatment CRCT = cluster-randomised controlled trial. immediately in patients with life - ∗ Meta-analysis by study design; results reported as a change in direction of intended effect. †Dissemination threatening infection of educational materials in printed form or via educational meetings, reminders, audit and feedback, and ∗∗ 2 Prescribe in accordance with local educational outreach. Compulsory order form, expert approval, restriction by removal, and review and policies and guidelines, avoiding change prescription. ‡Introduction of new technology for laboratory testing, changes to laboratory broad-spectrum agents turnaround time, and computerised decision support. 3 Document the indications for prescribing antibiotics in the clinical notes examples of antibiotic stewardship inter- The evidence for antibiotic 4 Send appropriate specimens to the ventions commonly deployed in hospi- stewardship microbiology laboratory, draining pus and removing foreign bodies if indicated tals. A primary focus of hospital steward- A recently-updated Cochrane review sum- 5 Use antimicrobial susceptibility data to ship programmes is prevention of the de-escalate, substitute and add agents, indiscriminate use of broad-spectrum marises the evidence for interventions to and to switch from intravenous to oral antibiotics. The rationale for this strategy improve antibiotic prescribing in hospital therapy 25 is twofold. Firstly, broad-spectrum anti- inpatients (Table 4). When comparable 6 Prescribe the shortest antibiotic course likely to be effective biotics, as well as being effective against a studies were analysed by meta-regression, restrictive interventions were found to have 7 Always select agents to minimise wide range of bacteria, are also frequently collateral damage (ie selection of multi- active against MDR bacteria and must be a greater impact on prescribing than resistant bacteria/Clostridium difficile) held in reserve for when they are genu- persuasive interventions at one month after 8 Monitor antibiotic drug levels, when inely needed (life-, limb- or sight-threat- implementation, but restrictive and per- relevant (eg for vancomycin) 9 Use single-dose antibiotic prophylaxis ening infections of unknown cause or suasive interventions had similar effects at six months and beyond. wherever possible known MDR pathogens) to avoid 10 Consult your local infection experts selecting for extensively or pan-drug- resistant bacteria. Secondly, broad-spec- Clinical and microbiological outcomes trum agents cause extensive destruction of stewardship interventions arms (1.26 [1.02 to 1.57]), but the quality of of normal commensal flora, thereby com- Interventions intended to reduce antibiotic evidence was very low. Length of stay, reported promising host immune function and prescribing were found to be associated with in six studies, was comparable for the inter- rendering patients vulnerable to oppor- reductions in Clostridium difficile infections vention and control arms. tunist pathogens such as MRSA and and colonisation and infection with aminogly- Conversely, interventions intended to 18,29 Clostridium difficile. The importance coside- or cephalosporin-resistant Gram- increase effective prescribing can be associ- of this is increasingly recognised, as the negative pathogens, MRSA and vancomycin- ated with unintentional increases in unneces- presence of the human microbiota inter- resistant enterococci.25 Four interventions sary antibiotic prescribing and associated 25 feres with colonisation by potential path- intended to increase effective prescribing for collateral damage. Unintended conse- ogens by depletion of nutrients, produc- pneumonia were associated with a significant quences of prescribing restrictions, such as tion of enzymes and toxic metabolites, reduction in mortality (risk ratio 0.89 [95% compulsory order forms and pre- and modulation of the innate immune confidence interval (CI) 0.82 to 0.97]). authorisation restrictions, have been reported, response.29 including delays in starting restricted antibi- The use of broad-spectrum anti biotics Unintended consequences of otics and a pseudo-outbreak of nosocomial for patients with severe or life- threatening antibiotic stewardship infection caused by an altered threshold for sepsis is unquestionably justified. However, documentation of nosocomial infection evidence supports a more conservative A meta-analysis of interventions that aimed following implementation of an antibiotic approach for the vast majority of hospital- to decrease unnecessary prescribing in 11 management programme.25 Such problems ised patients, in whom a strategy that starts studies including 9,817 patients found no must be anticipated and managed. with narrow-spectrum antibiotics and detrimental impact compared with controls, escalates to broader-spectrum agents in with a trend towards lower mortality in inter- Conclusions the event of clinical failure or microbio- vention arms (0.92 [0.81 to 1.06]).25 A subset logical evidence of resistance is safe and of five studies reporting hospital readmission Antibiotic resistance, particularly in proportionate.30 suggested a higher risk in the intervention Gram-negative bacteria, is rapidly increasing,

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including in the UK, and few new antibiotics 10 Wang KY, Seed P, Schofield P et al. Which 21 Pulcini C, Williams F, Molinari N et al. are likely to be developed in the near future. practices are high antibiotic prescribers? A Junior doctors’ knowledge and perceptions cross-sectional analysis. Br J Gen Pract of antibiotic resistance and prescribing: a Acute and general physicians commonly 2009;59:e315–20. survey in France and Scotland. prescribe antibiotics and therefore have an 11 Meropol SB, Localio AR, Metlay JP. Risks Clin Microbiol Infect 2011;17:80–7. ethical obligation to understand, support and benefits associated with antibiotic use 22 Minen MT, Duquaine D, Marx MA, Weiss D. and adhere to the principles of antibiotic for acute respiratory infections: a cohort A survey of knowledge, attitudes, and stewardship. study. Ann Fam Med 2013;11:165–72. beliefs of medical students concerning 12 Cusini A, Rampini SK, Bansal V et al. Different antimicrobial use and resistance. Microb patterns of inappropriate antimicrobial use in Drug Resist 2010;16:285–9. References surgical and medical units at a tertiary care 23 van der Velden LB, Tromp M, Bleeker- hospital in Switzerland: a prevalence survey. Rovers CP et al. Non-adherence to 1 Pier GB. On the greatly exaggerated PLOS One 2010;5:e14011. antimicrobial treatment guidelines reports of the death of infectious diseases. 13 Hecker MT, Aron DC, Patel NP et al. results in more broad-spectrum but not Clin Infect Dis 2008;47:1113–4. Unnecessary use of antimicrobials in hospital- more appropriate therapy. Eur J Clin 2 de Kraker ME, Davey PG, Grundmann H. ized patients: current patterns of misuse with Microbiol Infect Dis 2012;31:1561–8. Mortality and hospital stay associated with an emphasis on the antianaerobic spectrum of 24 National Institute for Health and Care resistant Staphylococcus aureus and activity. Arch Intern Med 2003;163:972–8. Excellence. A single competency framework Escherichia coli bacteremia: estimating the 14 Mol PG, Denig P, Gans RO et al. Limited for all prescribers. London: National burden of antibiotic resistance in Europe. effect of patient and disease characteristics Prescribing Centre, 2012. www.npc.nhs.uk/ PLOS Med 2011;8:e1001104. on compliance with hospital antimicrobial improving_safety/improving_quality/ 3 Boucher HW, Talbot GH, Bradley JS et al. guidelines. Eur J Clin Pharmacol resources/single_comp_framework.pdf Bad bugs, no drugs: no ESKAPE! An update 2006;62:297–305. [Accessed 5 August 2013]. from the Infectious Diseases Society of 15 Bronzwaer SL, Cars O, Buchholz U et al. A 25 Davey P, Brown E, Charani E, Fenelon L, America. Clin Infect Dis 2009;48:1–12. European study on the relationship between Gould IM, Holmes A et al. Interventions to 4 Doron S, Davidson LE. Antimicrobial stew- antimicrobial use and antimicrobial resist- improve antibiotic prescribing practices for ardship. Mayo Clin Proc 2011;86:1113–23. ance. Emerg Infect Dis 2002;8:278–82. hospital inpatients. Cochrane Database Syst 5 McGowan JE. Antimicrobial stewardship – 16 Costelloe C, Metcalfe C, Lovering A et al. Rev 2013;(4):CD003543. the state of the art in 2011: focus on outcome Effect of antibiotic prescribing in primary 26 Gerding DN. The search for good antimi- and methods. Infect Control Hosp Epidemiol care on antimicrobial resistance in crobial stewardship. Jt Comm J Qual 2012;33:331–7. individual patients: systematic review Improv 2001;27:403–4. 6 Davies SC. Annual report of the Chief and meta-analysis. BMJ 2010;340:c2096. 27 Royal College of Physicians Healthcare Medical Officer, volume two, 2011: infec- 17 Tacconelli E, De AG, Cataldo MA et al. Associated Infection Working Group. tions and the rise of antimicrobial resistance. Antibiotic usage and risk of colonization and Effective antibiotic prescribing – top ten tips. London: Department of Health, 2013. infection with antibiotic-resistant bacteria: a London: RCP, 2011. 7 Dryden M, Johnson AP, Ashiru-Oredope D, hospital population-based study. Antimicrob 28 Tamma PD, Cosgrove SE. Antimicrobial Sharland M. Using antibiotics responsibly: Agents Chemother 2009;53:4264–9. stewardship. Infect Dis Clin North Am right drug, right time, right dose, right dura- 18 Tacconelli E, De AG, Cataldo MA et al. Does 2011;25:245–60. tion. J Antimicrob Chemother 2011;66:2441–3. antibiotic exposure increase the risk of 29 Lozupone CA, Stombaugh JI, Gordon JI 8 Society for Healthcare Epidemiology of methicillin-resistant Staphylococcus aureus et al. Diversity, stability and resilience of America, Infectious Diseases Society of (MRSA) isolation? A systematic review and the human gut microbiota. Nature America, Pediatric Infectious Diseases meta-analysis. J Antimicrob Chemother 2012;489:220–30. Society. Policy statement on antimicrobial 2008;61:26–38. 30 Corona A, Bertolini G, Lipman J et al. stewardship by the Society for Healthcare 19 Paul M, Shani V, Muchtar E et al. Systematic Antibiotic use and impact on outcome from Epidemiology of America (SHEA), the review and meta-analysis of the efficacy of bacteraemic critical illness: the BActeraemia Infectious Diseases Society of America appropriate empiric antibiotic therapy for Study in Intensive Care (BASIC). J (IDSA), and the Pediatric Infectious sepsis. Antimicrob Agents Chemother Antimicrob Chemother 2010;65:1276–85. Diseases Society (PIDS). Infect Control 2010;54:4851–63. Hosp Epidemiol 2012;33:322–27. 20 Srinivasan A, Song X, Richards A et al. Address for correspondence: Dr K Hand, 9 Adriaenssens N, Coenen S, Versporten A et al. A survey of knowledge, attitudes, and beliefs Pharmacy Department, Southampton European Surveillance of Antimicrobial of house staff physicians from various Consumption (ESAC): outpatient antibiotic specialties concerning antimicrobial use General Hospital, Tremona Road, use in Europe (1997–2009). J Antimicrob and resistance. Arch Intern Med Southampton SO16 6YD. Chemother 2011;66:vi3–12. 2004;164:1451–6. Email: [email protected]

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