Antibiotic resistance: Global problem – local challenges Ildiko Kustos Medical Microbiology Consultant COCH 14 Oct 2016

Brief history Modern medical practice relies on the widespread availability of effective antimicrobials to prevent and treat infections in humans Penicillin 1928 Sir Alexander Fleming Antibiotics were first prescribed in 1940s 1970s: the battle of the bugs versus the drugs was over. 1967 William H Stewart US Surgeon General “it is time to close the book on infectious diseases” The Government de-emphasized bacterial research and the drug industry, sensing a saturated market, shifted resources elsewhere. Resistance has eventually been seen to all abx that have been developed Diverse mechanisms have been demonstrated

UK Prime Minister commissioned a review on antimicrobial resistance to address the growing global problem of drug- resistant infections. Report from 2014

Introduction Rapid emergence of resistant bacteria is occurring worldwide Bacterial infections are getting a threat again ‘Antibiotic crisis’ has been attributed to: Overuse and misuse of antimicrobials Lack of new drug development by the pharmaceutical industry CDC declared in 2013 that the human race is now in the ‘post-antibiotic era’ that could have ‘catastrophic consequences’ C. Lee Ventola MS: The Antibiotic Resistance Crisis P&T 2015; 40(4): 277-283

Why increasing antibiotic resistance is a problem? Significant threat to patient safety worse outcomes longer hospitalizations Significantly higher mortality rates greater healthcare expenditures Poor outcomes are multifactorial ?greater severity of underlying illness delays in initiation of effective therapy lack of effective antimicrobial therapy

Increasing antibiotic resistance

Annual Report of the Chief Medical Officer 2011 new infectious diseases have been discovered nearly every year over the past 30 years there have been very few new antibiotics developed encourage development of new drugs looking after the current supply of antibiotics is equally important. better hygiene measures to prevent infections prescribing fewer antibiotics making sure they are only prescribed when needed

Threat Report 2013 CDC

Threat Report 2013 CDC Each year in the US at least 2 million people become infected with multi-resistant bacteria at least 23,000 people die each year as a direct result of these infections. Many more people die from other conditions that were complicated by an antibiotic- resistant infection

Antibiotic resistant threats (CDC) The threats are ranked in categories: urgent, serious, and concerning assessed the threats according to seven factors (associated with resistant infections): health impact economic impact how common the infection is a 10-year projection of how common it could become how easily it spreads availability of effective antibiotics and barriers to prevention

Urgent threats (CDC US) Infections classified as urgent threats include: carbapenem-resistant Enterobacteriaceae (CRE) 9,000 infections/year in US, 600 deaths drug-resistant gonorrhea 820,000 gonococcal infection / year 246,000 drug resistant gonorrhoea infection 188,600 resistance to tetracycline 11,480 reduced susceptibility to cefixime 3,280 reduced susceptibility to ceftriaxone 2,460 redcued susceptibility to azithromycin Clostridium difficile 250,000 C. difficile infections/ year 14,000 deaths

Carbapenem resistant K. pneumoniae 2002 2012 North West England/London – higher prevalence

Increasing carbapenem resistance in gram-negatives

Number of ESBL positive urine samples COCH 2008-2012

Antibiotic resistance (%) in ESBLs COCH 2012

Microorganisms with a Threat Level of Serious (CDC US) Multidrug-resistant Acinetobacter Drug-resistant Campylobacter Fluconazole-resistant Candida Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs) Vancomycin-resistant Enterococcus (VRE) Multidrug-resistant Pseudomonas aeruginosa Drug-resistant non-typhoidal Salmonella Drug-resistant Salmonella Typhi Drug-resistant Shigella Methicillin-resistant Staphylococcus aureus (MRSA) Drug-resistant Streptococcus pneumoniae Drug-resistant tuberculosis

Microorganisms with a Threat Level of Concerning (CDC US) Vancomycin-resistant Staphylococcus aureus (VRSA) Erythromycin-resistant Group A Streptococcus Clindamycin-resistant Group B Streptococcus

Chief Medical Officer has warned that antibiotic resistance could bring a return to the hospital conditions of the 19th century It was said that the problem was a "ticking time-bomb" It should be added to the government's National Risk Register, alongside terrorist threats There are no new classes of antibiotics in the pipelines across the world (and there are very few in development) Drug resistance is growing in part because doctors are prescribing antibiotics in cases where they are not necessary

Causes of the antibiotic resistance crisis 1. Overuse As early as 1945 Sir A Fleming raised alarm regarding antibiotic overuse (New York Times 6/26/45) Misuse of penicillin could lead to propagation of mutant forms of bacteria that would resist the new miracle drug. Ca.14 % of Staph strains isolated in a London hospital had developed resistance to penicillin by 1946 Epidemiological studies: direct relationship between antibiotic consumption and emergence of resistant strains (Nature, 2013; 495(7440): 141 Selective pressure Over the counter antibiotic prescriptions Patient demands Not completing prescribed courses

Causes of the antibiotic resistance crisis 2. Inappropriate prescribing Studies have shown that indication, choice or duration of antibiotic treatment is incorrect in 30-50% of cases (Luyt et al, Crit Care 2014, 14(8): 480 Subinhibitory and subtherapeutic antibiotic concentrations can promote the development of antibiotic resistance

Causes of the antibiotic resistance crisis 3. Extensive agricultural usage Antibiotics used as growth supplements in livestock Estimated 80% of antibiotics used in animals in the US Improve animal health, produce larger yields, and higher quality products Abx used in livestock ingested by humans when consuming food

Causes of the antibiotic resistance crisis 4. environmental usage Agricultural use affect the environment as antibiotics are excreted in urine and stool by animals Tetracyclines and streptomycin used for spraying fruit trees

New antibiotics Number of new antibiotics has declined since 1980s Most of these drugs are in two classes (beta-lactams and quinolones)

Reasons of decreasing numbers of new antibiotics Technical difficulties – bacterial evolution is uncertain – development of resistance is unpredictable Antibiotics are used for short term treatment – ecomonically not good investment Withhold of new antibiotics in reserve for only the worst cases Complex regulatory procedures, changes in rules, absence of clarity, differences in clinical trial requirements among countries

Importance of AMR The importance of AMR has been recognised globally for many years. The first ‘World Health Assembly (WHA) AMR resolution’ was agreed in 1998 and urged Member States to take action to address AMR. The need to accelerate progress has been acknowledged by both the WHO and European Commission. The ‘2001 WHO Global Strategy for Containment of AMR’, the ‘2011 EU AMR Strategic Action Plan’ and the ‘2012 EU Council Conclusions’ have all helped to provide a renewed focus on the area

How to address the problem of increasing antibiotic resistance? WHO Antimicrobial resistance fact sheet 2016 Antimicrobial resistance is a complex problem Affects all of the society Driven by many interconnected factors Single, isolated interventions have limited impact Coordinated action is required All countries need national action plans on AMR Greater innovation and investment are required in research and development of new antimicrobial medicines, vaccines and diagnostic tools.

Includes 28 recommendations regarding implementation of AMS Program Published 2016 Includes 28 recommendations regarding implementation of AMS Program Preauthorisation of abx prescription Prospective audit and feedback Facility specific clinical practice guidelines Antibiotic stop orders on prescriptions Computerized clinical decision support Suggest against antibiotic cycling Monitoring and adjustment programs for aminoglycosides Implement programs to increase appropriate use of oral abx and timely transition from IV to oral abx Selective reporting of abx Development of anti biograms Rapid viral testing for respiratory pathogens PCT measurements on ICUs

UK Five Year Antimicrobial Resistance Strategy 2013 to 2018 sets out UK actions to address the key challenges to AMR The overarching goal of the Strategy is to slow the development and spread of AMR. It focusses activities around 3 strategic aims: improve the knowledge and understanding of AMR, conserve and steward the effectiveness of existing treatments, stimulate the development of new antibiotics, diagnostics and novel therapies

The 7 key areas for future action 1. improving infection prevention and control practices 2. optimising prescribing practice 3 improving professional education, training and public engagement 4 developing new drugs, treatments and diagnostics 5 better access to and use of surveillance data 6 better identification and prioritisation of AMR research needs 7 strengthened international collaboration

Examples of actions taken in the UK to improve prescribing practice ‘European Antibiotic Awareness Day’ (since 2008) to raise awareness among health professionals and the public GP toolkit – ‘Treat Antibiotics Responsibly, Guidance and Education Tool’ (TARGET) (developed by HPA) ‘Start Smart then Focus’ launched in 2011to provide guidance on antibiotic stewardship in hospitals To improve prescribing, a number of measures relating to usage and choice of antibiotics were developed as part of the ‘Quality, Innovation, Productivity and Prevention’ (QIPP) programme in the NHS. Number of initiatives to promote the responsible use of antibiotics in the veterinary sector

New guidelines, standards, recommendations

New guidelines, standards, recommendations

Local actions Antimicrobial Stewardship: Definition AMS Committee had been set up in 2011 AMS Program had been initiated 2011 Antimicrobial Stewardship: Definition “optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection with minimal toxicity to the patient and minimal impact on subsequent resistance” A multi-faceted approach to influence antimicrobial prescribing, institution-wide to improve outcomes, prevent resistance and minimize excessive cost IDSA Guidelines. Clin Infect Dis 2007;44:159

Local actions Antibiotic guidelines Narrow-spectrum agents for empirical treatment (where appropriate) Minimize the use of 3rd gen cephalosporins, clindamycin, carbapenems, fluoroquinolones Give guidance on dosage, duration, for iv to oral switch. Daily review of drug prescriptions by ward Pharmacists Microbiology ward rounds / MDT Daily Critical care rounds Daily follow up of patients with positive blood cultures Weekly Haematology MDT Weekly CDT Ward Round Weekly Orthopaedic ward round

Local audits Trust wide point prevalence antibiotic audits

Antibiotic review

CQUIN 4b (72 hrs review) Q1 data 50 antibiotics per month Data collected by antibiotic Pharmacists Data obtained from Medical notes and MediTech As specified by PHE the review include documented evidence of: Stop IV to oral switch Change antibiotic Continue antibiotic OPAT This information can either be documented in the medical notes or electronically on EP system incl: Antibiotic stopped / changed / restarted / dose adjustment etc on EP Change in Stop / review date Change in plan for therapeutic drug monitoring plan e.g. change vancomycin level

CQUIN 4b (72 hrs review) Q1 data Month 2016 Documented review of antibiotic prescription (Medical notes OR EP) April 82% May 86% June 88%

CQUIN 4a Reduction in antibiotic consumption per 1,000 admissions There are three parts to this indicator: Total antibiotic consumption per 1,000 admissions - as measured by Defined Daily Dose (DDD) Total consumption of carbapenem per 1,000 admissions - as measured by Defined Daily Dose (DDD) Total consumption of piperacillin-tazobactam per 1,000 admissions - as measured by Defined Daily Dose (DDD) Baseline period/date 2013/14 (discussions regarding 2015/16 baseline figures)

CQUIN 4a Reduction of 1% or more in total antibiotic consumption against the baseline Reduction of 1% or more in carbapenem usage against the baseline Reduction of 1% or more in piperacillin-tazobactam usage against the baseline Each of the indicators is worth 25% of part 4a with an additional 25% to be paid for submission of consumption data to PHE for years: 2014/15 to 2016/17. Data will be collected quarterly Data will be reported to the commissioner annually

Total antibiotic consumption COCH 2013-2016 13% increase in 2014/15 10% increase in 2015/16

Tazocin consumption COCH 2013-2016 29% increase in 2014/15 7% increase in 2015/16

Carbapenem consumption COCH 2013-2016 meropenem ertapenem 15% increase in 2014/15 46% increase in 2015/16 5% increase in 2014/15 65% increase in 2015/16

Total antibiotic consumption Q1 + Q2 COCH 2015/16 vs 2016/17 2% increase compared to 2015/16 (Q1+Q2)

Quarter 1+ 2 carbapenem usage ERTAPENEM 19% increase compared to 2015/16 MEROPENEM 16.6% decrease compared to 2015/16

Quarter 1 + 2 Tazocin usage 5% decrease compared to 2015/16 (Q1+Q2)

AMS actions Microbiology input in patients positive blood cultures and other significant results Daily review of patients on Critical Care ?microbiology review of patients on meropenem ?microbiology review of patients on Tazocin >7 days Antibiotic reports Written consultation system for all doctors on Meditech

AMS actions for clinicians Review antibiotics on ward rounds Review antibiotics (and document) within 72 hrs Stop unnecessary antibiotics Review culture results Narrow the spectrum if possible Switch to oral antibiotics if clinically appropriate Contact microbiology if any concerns