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

2. 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

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

4. 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):

5. 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

6. Increasing antibiotic resistance

7. 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

8. Threat Report 2013
CDC

9. 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

10. 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

11. 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

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

14. Increasing carbapenem resistance in gram-negatives

15. Number of ESBL positive urine samples COCH 2008-2012

16. Antibiotic resistance (%) in ESBLs COCH 2012

17. 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

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

20. 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

21. 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

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

23. 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

24. 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

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

26. 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

27. 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

28. 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.

29. 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

30. 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

31. 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

32. 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

33. New guidelines, standards, recommendations

34. New guidelines, standards, recommendations

35. 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

36. 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

37. Local audits
Trust wide point prevalence antibiotic audits

41. Antibiotic review

42. 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

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

44. 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)

45. 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

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

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

48. 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

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

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

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

52. 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

54. 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