Antimicrobial Stewardship Implications for Primary Health Care, and how it can work

Basic acronyms
AMR – antimicrobial resistance
Resistance to drugs against microbes: bacteria, virus, protozoan, fungus
The most widely used antimicrobials are commonly called antibiotics, or sometimes antibacterials
ABR – antibiotic resistance or antibacterial resistance
ABS (AMS); antibiotic (antimicrobial) stewardship
Wider sense: ”any work to keep antibiotics working” (including e g WASH, IPC..)
Narrower sense: ”work for rational use of antibiotics”
Here: mostly use ABS, in the more narrow sense, focus on how we use AB:s

Outline
Why ABS?
AMR is an increasing problem
Antibiotics are a limited resource
We need to buy us time until new classes of antibiotics become available
And when they do, we must have learnt a way to work so that we do not quickly loose them also
One important way to achieve 3 and 4 is ABS
What is ABS?
To give todays patients optimal therapy;
while causing as little ”antibiotic resistance pressure” as possible
AB:s only when indicated – quantity comes down
AB choice – consider spectrum, thus minimizing ”collateral damage”
We call this ”rational therapy”
Ways to get there

Burden of AMR in Europe – a recent update
Cassini et al, The Lancet Infectious Diseases, January 2019
Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

Klein EY, Tseng KK, Pant S, et al
Tracking global trends in the effectiveness of
antibiotic therapy using the Drug Resistance Index
BMJ Global Health 2019;4:e001315.
There is an increasing problem with AMR – it is mostly measured in HIC:s, but burden is high also in LMIC:s

Hip replacement
Organ transplants
Cancer chemotherapy
Care of preterm babies
Some of the Blessings of Modern Medicine that would not be possible without Antibiotics

MAKMAX/IACMAC 2009, Feb 18-19, Omsk

Kaiser T, Finstermeier K, Häntzsch M, Faucheux S, Kaase M, Eckmanns T, et al. Stalking a lethal superbug by whole-genome sequencing and phylogenetics: Influence on unraveling a major hospital outbreak of carbapenem-resistant Klebsiella pneumoniae. Am J Infect Control. 2018;46(1):54-9.

3. We need to buy us time until new classes of antibiotics become available

Antibiotic consumption drives antibiotic resistance
H. Goossens Lancet 2005; 365: 579–87

…
Conclusions: Individuals prescribed an antibiotic in primary care for a respiratory or urinary infection develop bacterial resistance to that antibiotic. The effect is greatest in the month immediately after treatment but may persist for up to 12 months. This effect not only increases the population carriage of organisms resistant to first line antibiotics, but also creates the conditions for increased use of second line antibiotics in the community.
BMJ 2010;340:c2096
doi:10.1136/bmj.c2096
Antibiotic consumption drives antibiotic resistance, 2; at all levels: patient, community, country, regional and global

Where to work with ABS?
Infectious disease clinics – highly qualified, but small part of all antibiotic use
To achieve some impact on the resistance selection pressure, influence OTHER major clinics: general surgery, general internal medicine
AND – most antibiotics used are used by patients OUTSIDE hospitals, much prescribed at level of Primary Health Care
Raise awareness among public, especially if non-prescription use is common; then also work towards a prescription-only policy

Total antibiotic pressure
Agri/Vet side
Human health sector
Country X

Hospital/in-patient use
Community use

The paradox of seriousness of infection type versus
amount of antibiotic use it causes, and thus ”resistance drive”
Upper Resp Tract
Infection - URTI
Lower UTI
Pneumonia
Pyelonephritis
Sepsis
Bacterial meningitis
Seriousness of the infection for the patient
Antibiotics spent on the diagnosis in society as a whole
DIAGNOSIS:

The aim is effective treatment for the present patient with his/her present illness – with no or minimized collateral harm for the next patient; AND for the present patient on next occasion
Spectrum – narrow but effective
Optimally: know the causing agent and resistance patterns for each patient – not possible, so:
Empiric treatment – treat according to clinical treatment guidelines, based on:
Knowledge of common infections; what are the important causing bacteria?
Knowledge of local resistance pattern among important pathogens
Knowledge on ”ABR drive” of the various choices
Reduced amount in total
No antibiotics where damage outweighs benefit
No antibiotics for viral infections
No antibiotics for many self-limited bacterial infections

Total use – much to gain from stopping treatment of all viral respiratory infections
From wide to narrow spectrum – much to gain from switching from quinolones in lower UTI:s/uncomplicated cystitis (and to never start with quinolones for respiratory tract infections, at least outside hospitals..)

The TOTAL USE is easier to grasp and measure; but SPECTRUM is at least equally important
Antimicrobial consumption/pressure drives antimicrobial resistance; the SPECTRUM aspect
Swedish Public Health Agency
WHO EML AWaRe classification
Clin Microbiol Infect 2015; 21: 344.e1–344.e11
Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved http://dx.doi.org/10.1016/j.cmi.2014.11.016

Rational antibiotic use
The right antibiotic (for the disease, bacterium, patient condition..)
At the right time (not too late – pneumonia..)
In the right dose (patient characteristics – weight, renal function, interactions..)
For the right duration (for the disease to be cured..)
Obviously, the decisions on what is rational treatment should be taken on purely medical grounds, independent from pharma industry or other economic interests.

Antimicrobial stewardship programmes in health-care facilities in low- and middle-income countries. A practical toolkit. Geneva: World Health Organization; 2019.

Tonsillopharyngitis: Strep A - 100 % sensitive to penicillin. We use pc V. Amoxicillin works as well
AOM, sinusitis, pneumonia: Pneumococci, to high degree S to penicillin. We use pc V. Amoxicillin works as well.
Erysipelas: Strep A. See tonsillitis.
Other skin infections, wound infections: Staph aureus.
We use cloxacillin/flucloxacillin.
E. coli, Klebsiella pn:
For lower UTI/cystitis, we use mecillinam or nitrofurantoin
For acute pyelonephritis we use ciprofloxacin
Of all the first choices above, only ciprofloxacin/f-quinolones have a significant impact on the gut flora. Amoxicillin some, but limited.

% survivors
Penicillin
Untreated
Days
Penicillin increased the chance of survival from 10% to 90%
Patients with
pneumonia
and bacteria
in blood

https://www.folkhalsomyndigheten.se/contentassets/e76b47c98f1a44058f22cfd4795a2c45/blod_ecoli_2017_nat.pdf
Swedish resistance surveillance build on
c:a 240 000 blood cultures/year
Swedish resistance surveillance in pneumococci c:a 1300 invasive isolates per year.

Clinical Treatment Guidelines/Treatment Protocols in infections
Generation I
Focus on infections dangerous to society
Examples: shigella, typhoid, salmonella, meningococcal infection
Based on already proven microbiological etiology or”nosologic form”
Therefore covering few pts..
Generation II
Generation II/AMR
Focus on infections dangerous to patient
Syndrome based rather than microbiological
Evidence based
Considering the normal etiology for a given syndrome – e g purulent meningitis, or bacterial pneumonia
Covering more patients..
Focus on infections responsible for largest flows of antibiotics
Syndrome based (e g URTI, tonsillitis, sinusitis, otitis media, pneumonia, lower UTI)
Clarifying which antibiotic to use for which syndrome
Also clarifying when NOT to treat with antibiotics

The process of developing Clinical Treatment Guidelines into a format useful in the clinical PHC setting; simplified example of Sweden
Challenge:
Finding the balance between depth and width; keeping in mind that a GP/PHC physician cannot allocate the same amount of time to for example an otitis media as a hospital specialist; and has to cover virtually ALL specialties..
Balance of experts in ”Guideline Boards”
Balanced, condensed versions of the full guidelines

Challenge: Local implementation!
Getting the CTG:s in place is not enough
Nothing changes until antibiotic use is changed on the ground
Distribute to each remote corner
Adaptability to local situation – ”culture eats strategy”..
Strama working lunch meeting:
Discuss PRESCRIPTION DATA; for PHC Centre, for County/Region, for nation
Distribute individual data; when possible diagnose related
Go through new guidelines
Discuss cases
Info in ”App” format

2000
2007
2008
2010
2013
2019
1995
Slide courtesy of dr Christer Norman, PHC ”Salem”, Sthlm, and PHA
Expedited antibiotic prescriptions per 1000 inhab. and year for various age groups in Sweden 1987 – 2018
Data source: Apoteket AB and the Swedish eHealth Authority

Time (days)
Disease
severity
0
≈5
≈10
To diagnose and treat a pediatric pneumonia (among many febrile/viral/flu patients) in time takes training, skill, and a very accessible Primary Health Care
Patient comes in late – easy
Patient comes in early – impossible; must be reassured, and given chance to return – if to withhold treatment more than a parent would
The more skilled the doctor, the better the chance
Standard course for many viral RTI
Possible trajectory for a patient with pneumonia

Strama-groups were formed, 1995 in every county (21 counties)
The County Medical Officers for Communicable Diseases Control took a leading role in these groups which include specialists from different medical fields
A main objective is to evaluate the use of antibiotics and antibacterial resistance in the region and to improve prescribing patterns
Sigvard Mölstad,
Professor and PHC clinician
”Champions”..
Gunnar Kahlmeter, Professor Clin. Microbiology
The local (regional) Strama groups (typically):
County medical officer
Pharmacist
Microbiologist
General practitioner
Infectious diseases specialist
Infection control
ENT, paediatrician, geriatrician, dentist…

Strama Advisory Council -
experts
Swedish
Medical
Association
National Board of Health and Welfare
Swedish
Veterinary
Institute
Swedish
Association of Local Authorities and Regions
Medical
Products Agency
The Dental and Pharmaceutical Benefits Agency
European Centre for Disease Prevention and Control
Network of local Strama groups
Swedish Institute for Communicable Disease Control, now Public Health Agency
Political level
Professional organizations
Strama
coordination and feedback
Exchange ideas - What works locally?
- Web page
- Larger yearly meetings
National coordination has always been there but the forms have shifted

Open benchmarking at all levels
(regions, municipalities, GP-station, hospital…)

Some LEAD WORDS – possible success factors in the implementation work of Strama
Local engagement
Network: bottoms-up, top-down, lateral sharing
Early and strong government support
Cooperation – multidisciplinary, multisectoral
Champions
Credibility
Adaptability
Long term perspective
Peace >200 years..

Useful resources
https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/antimicrobial-prescribing-guidelines
https://www.who.int/antimicrobial-resistance/ru/
http://www.euro.who.int/en/health-topics/disease-prevention/antimicrobial-resistance
https://www.who.int/medicines/publications/essentialmedicines/en/
https://openwho.org/courses/AMR-competency
https://www.folkhalsomyndigheten.se/pagefiles/17351/Swedish-work-on-containment-of-antibiotic-resistance.pdf
https://www.reactgroup.org/toolbox/rational-use/health-care/