Antimicrobial Stewardship

PRIDA course week 8

John Ferguson Microbiology amp Infectious Diseases University of Newcastle NSW Australia

Joe Hessell Pharmacist DMDPorg Cambodia

Tw mdjkf httpaimednetau httpidmicnet

Overview

22420bull John Ferguson ndash overview of AMR and AMS bull Joe Hessell ndash practical approaches to LMIC implementation (1)

24420bull Joe Hessell ndash practical approaches to LMIC implementation (2)bull John Ferguson ndash therapeutic goals and the role of microbiology labs in AMS

Referencesbull ANTIMICROBIAL STEWARDSHIP PROGRAMMES IN HEALTH-CARE FACILITIES IN

LOW- AND MIDDLE-INCOME COUNTRIES A WHO PRACTICAL TOOLKIT 2019bull CDC The Core Elements of Human Antibiotic Stewardship Programs in Resource-

Limited Settings National and Hospital Levels 2018 bull Online course materials under consideration

Global AMR issues

bull Gram negative bacteriandash ESBL CPE Colistin resistancendash Multi (carbapenem)-resistant Acinetobacter

baumannii and Pseudomonas aeruginosa

bull Gram positivesndash MRSAndash VREndash DRTB

bull Fungibull Viruses See WHO AMR Information

resources

Purpose of antimicrobial stewardship

1 Optimise outcome for patient with infection - right diagnosis right antibiotic timing dose duration etc

2 Reduce antimicrobial resistance

3 Minimise individual and community unintended consequences of antimicrobials- adverse events added (super)infection

Clinicians as stewards

ldquoStewardship is an ethic that embodies the responsible planning and management of [scarce] resourcesrdquo Wikipedia

Leadership advocacy and collaboration amongst prescribers required to reduce AMR Everyonersquos business

We have the agency and scope to change patient management in ways that will reduce the impact of AMR on our patients and the community

Antibiotic usage drives resistance

UK Antibiotic use amp MRSA

httpswwwonsgovukpeoplepopulationandcommunitybirthsdeathsandmarriagesdeathsbulletinsdeathsinvolvingmrsaenglandandwales2012-08-22

Global AMR issues

bull Gram negative bacteriandash ESBL CPE Colistin resistancendash Multi (carbapenem)-resistant Acinetobacter

baumannii and Pseudomonas aeruginosa

bull Gram positivesndash MRSAndash VREndash DRTB

bull Fungibull Viruses See WHO AMR Information

resources

Purpose of antimicrobial stewardship

1 Optimise outcome for patient with infection - right diagnosis right antibiotic timing dose duration etc

2 Reduce antimicrobial resistance

3 Minimise individual and community unintended consequences of antimicrobials- adverse events added (super)infection

Clinicians as stewards

ldquoStewardship is an ethic that embodies the responsible planning and management of [scarce] resourcesrdquo Wikipedia

Leadership advocacy and collaboration amongst prescribers required to reduce AMR Everyonersquos business

We have the agency and scope to change patient management in ways that will reduce the impact of AMR on our patients and the community

Antibiotic usage drives resistance

UK Antibiotic use amp MRSA

httpswwwonsgovukpeoplepopulationandcommunitybirthsdeathsandmarriagesdeathsbulletinsdeathsinvolvingmrsaenglandandwales2012-08-22

Purpose of antimicrobial stewardship

1 Optimise outcome for patient with infection - right diagnosis right antibiotic timing dose duration etc

2 Reduce antimicrobial resistance

3 Minimise individual and community unintended consequences of antimicrobials- adverse events added (super)infection

Clinicians as stewards

ldquoStewardship is an ethic that embodies the responsible planning and management of [scarce] resourcesrdquo Wikipedia

Leadership advocacy and collaboration amongst prescribers required to reduce AMR Everyonersquos business

We have the agency and scope to change patient management in ways that will reduce the impact of AMR on our patients and the community

Antibiotic usage drives resistance

UK Antibiotic use amp MRSA

httpswwwonsgovukpeoplepopulationandcommunitybirthsdeathsandmarriagesdeathsbulletinsdeathsinvolvingmrsaenglandandwales2012-08-22

Clinicians as stewards

ldquoStewardship is an ethic that embodies the responsible planning and management of [scarce] resourcesrdquo Wikipedia

Leadership advocacy and collaboration amongst prescribers required to reduce AMR Everyonersquos business

We have the agency and scope to change patient management in ways that will reduce the impact of AMR on our patients and the community

Antibiotic usage drives resistance

UK Antibiotic use amp MRSA

httpswwwonsgovukpeoplepopulationandcommunitybirthsdeathsandmarriagesdeathsbulletinsdeathsinvolvingmrsaenglandandwales2012-08-22

Antibiotic usage drives resistance

UK Antibiotic use amp MRSA

httpswwwonsgovukpeoplepopulationandcommunitybirthsdeathsandmarriagesdeathsbulletinsdeathsinvolvingmrsaenglandandwales2012-08-22

UK Antibiotic use amp MRSA

httpswwwonsgovukpeoplepopulationandcommunitybirthsdeathsandmarriagesdeathsbulletinsdeathsinvolvingmrsaenglandandwales2012-08-22

UK falling Gram negative resistance

0

20

40

60

0 2 4 6 8

Community consumption

of macrolides and lincosamides

(DDD per 1000 inh-days 1997)

Ery

htr

om

ycin

-R S

p

neu

mo

nia

e

fro

m c

om

mu

nit

y-a

cq

uir

ed

RT

Is

( 1998)

Source Alexander Proj FINRES STRAMA

DANMAP and Cars O et al Lancet 2001

Correlation of resistance with Antimicrobial

Use in Community-Acquired Infections in

Europe 1997-2000

R2=076 Plt0001 R2=055 P=0002

Each dot represents a different European nation

A very tight relationship between overall community consumption and resistance (erythromycin is a macrolide)

Local story Piperacillintazobactam and vancomycin-resistant enterococci

MJA August 2019

Multi-resistant organism acquisitions and

infections- JHH study

Therapeutic factors promoting antibiotic resistance

1 Antibiotic selective pressure

ndash Number of patients exposed (volume of use)

ndash Breadth of spectrum

ndash Duration of use

2 Inadequate dosing

Unintended consequence mortality

Antibiotic class Mechanism Mortality risk

Chloramphenicol Aplastic anaemia 1 in 20-60000 courses

Betalactams Anaphylaxis 1 in 50-66000 courses

Trimethoprim Hyperkalaemia from reduced distal renal tubular tubular K secretion

In a population of patients gt 65 years on ACE inhibitors excess mortality of 1 in 350 courses

Macrolides(azithromycin)

Prolonged QT ndash sudden death

1 in 26000 courses (33 studies involving 20779963 participants)

Quinolones (ciprofloxacin and others)

Prolonged QT ndash sudden death

Similar level of risk for ciprofloxacin death in the trimethoprim study above Risk remains higher for 2 weeks following rx

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

0

20

40

60

0 2 4 6 8

Community consumption

of macrolides and lincosamides

(DDD per 1000 inh-days 1997)

Ery

htr

om

ycin

-R S

p

neu

mo

nia

e

fro

m c

om

mu

nit

y-a

cq

uir

ed

RT

Is

( 1998)

Source Alexander Proj FINRES STRAMA

DANMAP and Cars O et al Lancet 2001

Correlation of resistance with Antimicrobial

Use in Community-Acquired Infections in

Europe 1997-2000

R2=076 Plt0001 R2=055 P=0002

Each dot represents a different European nation

A very tight relationship between overall community consumption and resistance (erythromycin is a macrolide)

Local story Piperacillintazobactam and vancomycin-resistant enterococci

MJA August 2019

Multi-resistant organism acquisitions and

infections- JHH study

Therapeutic factors promoting antibiotic resistance

1 Antibiotic selective pressure

ndash Number of patients exposed (volume of use)

ndash Breadth of spectrum

ndash Duration of use

2 Inadequate dosing

Unintended consequence mortality

Antibiotic class Mechanism Mortality risk

Chloramphenicol Aplastic anaemia 1 in 20-60000 courses

Betalactams Anaphylaxis 1 in 50-66000 courses

Trimethoprim Hyperkalaemia from reduced distal renal tubular tubular K secretion

In a population of patients gt 65 years on ACE inhibitors excess mortality of 1 in 350 courses

Macrolides(azithromycin)

Prolonged QT ndash sudden death

1 in 26000 courses (33 studies involving 20779963 participants)

Quinolones (ciprofloxacin and others)

Prolonged QT ndash sudden death

Similar level of risk for ciprofloxacin death in the trimethoprim study above Risk remains higher for 2 weeks following rx

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

Local story Piperacillintazobactam and vancomycin-resistant enterococci

MJA August 2019

Multi-resistant organism acquisitions and

infections- JHH study

Therapeutic factors promoting antibiotic resistance

1 Antibiotic selective pressure

ndash Number of patients exposed (volume of use)

ndash Breadth of spectrum

ndash Duration of use

2 Inadequate dosing

Unintended consequence mortality

Antibiotic class Mechanism Mortality risk

Chloramphenicol Aplastic anaemia 1 in 20-60000 courses

Betalactams Anaphylaxis 1 in 50-66000 courses

Trimethoprim Hyperkalaemia from reduced distal renal tubular tubular K secretion

In a population of patients gt 65 years on ACE inhibitors excess mortality of 1 in 350 courses

Macrolides(azithromycin)

Prolonged QT ndash sudden death

1 in 26000 courses (33 studies involving 20779963 participants)

Quinolones (ciprofloxacin and others)

Prolonged QT ndash sudden death

Similar level of risk for ciprofloxacin death in the trimethoprim study above Risk remains higher for 2 weeks following rx

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

Multi-resistant organism acquisitions and

infections- JHH study

Therapeutic factors promoting antibiotic resistance

1 Antibiotic selective pressure

ndash Number of patients exposed (volume of use)

ndash Breadth of spectrum

ndash Duration of use

2 Inadequate dosing

Unintended consequence mortality

Antibiotic class Mechanism Mortality risk

Chloramphenicol Aplastic anaemia 1 in 20-60000 courses

Betalactams Anaphylaxis 1 in 50-66000 courses

Trimethoprim Hyperkalaemia from reduced distal renal tubular tubular K secretion

In a population of patients gt 65 years on ACE inhibitors excess mortality of 1 in 350 courses

Macrolides(azithromycin)

Prolonged QT ndash sudden death

1 in 26000 courses (33 studies involving 20779963 participants)

Quinolones (ciprofloxacin and others)

Prolonged QT ndash sudden death

Similar level of risk for ciprofloxacin death in the trimethoprim study above Risk remains higher for 2 weeks following rx

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

Therapeutic factors promoting antibiotic resistance

1 Antibiotic selective pressure

ndash Number of patients exposed (volume of use)

ndash Breadth of spectrum

ndash Duration of use

2 Inadequate dosing

Unintended consequence mortality

Antibiotic class Mechanism Mortality risk

Chloramphenicol Aplastic anaemia 1 in 20-60000 courses

Betalactams Anaphylaxis 1 in 50-66000 courses

Trimethoprim Hyperkalaemia from reduced distal renal tubular tubular K secretion

In a population of patients gt 65 years on ACE inhibitors excess mortality of 1 in 350 courses

Macrolides(azithromycin)

Prolonged QT ndash sudden death

1 in 26000 courses (33 studies involving 20779963 participants)

Quinolones (ciprofloxacin and others)

Prolonged QT ndash sudden death

Similar level of risk for ciprofloxacin death in the trimethoprim study above Risk remains higher for 2 weeks following rx

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

Unintended consequence mortality

Antibiotic class Mechanism Mortality risk

Chloramphenicol Aplastic anaemia 1 in 20-60000 courses

Betalactams Anaphylaxis 1 in 50-66000 courses

Trimethoprim Hyperkalaemia from reduced distal renal tubular tubular K secretion

In a population of patients gt 65 years on ACE inhibitors excess mortality of 1 in 350 courses

Macrolides(azithromycin)

Prolonged QT ndash sudden death

1 in 26000 courses (33 studies involving 20779963 participants)

Quinolones (ciprofloxacin and others)

Prolonged QT ndash sudden death

Similar level of risk for ciprofloxacin death in the trimethoprim study above Risk remains higher for 2 weeks following rx

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

Unintended consequence additive fraction

bull Antimicrobial resistant infections are more likely to occur in patients who are on antibiotics

bull MRO infections ADD rather than replace susceptible infections eg emergence of MRSA in UK hospitals in the 1980s

Barza M et al Clin Infect Dis 2002 Jun 134 Suppl 3S126-30 Excess infections due to antimicrobial resistance the Attributable Fraction

Q What class of antibiotic is vancomycin

1Betalactam

2Aminoglycoside

3Glycopeptide

4Tetracycline

5Not sure

What class of antibiotic is vancomycin

Why understand the class Differences in

ndash Pharmacodynamics and dosing

ndash Toxicity potential

ndash Antibacterial spectrum

ndash Mechanisms of resistance

httpsaimed99wordpresscom20170223q10-remembering-antibiotics-and-their-classes

httpsaimednetau20170201antibiotic-classes-why-so-important-to-know-about-them

What class of antibiotic is vancomycin

Why understand the class Differences in

ndash Pharmacodynamics and dosing

ndash Toxicity potential

ndash Antibacterial spectrum

ndash Mechanisms of resistance

httpsaimed99wordpresscom20170223q10-remembering-antibiotics-and-their-classes

httpsaimednetau20170201antibiotic-classes-why-so-important-to-know-about-them

httpsaimednetau20170201antibiotic-classes-why-so-important-to-know-about-them

PK and PD

bull Pharmacokinetics describes the time course of drug levels in body fluids as a result of absorption distribution and elimination of a drug after administration Parameters includendash Bioavailability and influence of food on absorptionndash Peak levelndash Vd- Volume of distribution (lipo versus hydrophilic drugs)ndash T12 - Half lifendash AUC ndash area under the concentration-time curve

bull Pharmacodynamics describes the rate and extent of bactericidal action and postantibiotic effects ndash used to provide a rational basis for determination of optimal dosing regimens in terms of the dose and the dosing interval

httpswwwncbinlmnihgovpmcarticlesPMC3675903

Maximising therapeutic effectDose in accord with PKPD understanding

1 Time-dependent kill ndash betalactams vancomycin ndash ensure drug concentration above organism MIC for gt 50 of the time ie more frequent dosing gives better efficacy than higher doses

2 Concentration-dependent kill ndash aminoglycosides quinolones metronidazole - ensure drug dose high enough to achieve adequate kill ndash target area under the curve ndashAUCMIC parameter used Concentration dependent Post antibiotic effect (PAE)

Other issues

AMS vs Infection Prevention programsbull Entirely complementarybull Both are critical for AMR control in all settingsOne Health focusbull AMR is an issue across animal production and human

healthbull Many resistance factors and bacteria are zoonotic ndash spread

via food (including vegetables) and water to humansbull AMS required ndash same principlesbull AMR surveillance required ndash quality representative

diagnostic samples quality lab practice quality antimicrobial susceptibility testing

httpsidmicnet20200229quality-microbiological-diagnostics-and-antimicrobial-susceptibility-testing-explained

Other issues

AMS vs Infection Prevention programsbull Entirely complementarybull Both are critical for AMR control in all settingsOne Health focusbull AMR is an issue across animal production and human

healthbull Many resistance factors and bacteria are zoonotic ndash spread

via food (including vegetables) and water to humansbull AMS required ndash same principlesbull AMR surveillance required ndash quality representative

diagnostic samples quality lab practice quality antimicrobial susceptibility testing

httpsidmicnet20200229quality-microbiological-diagnostics-and-antimicrobial-susceptibility-testing-explained

References

bull httpIdmicnet

bull httpaimednetau for discussions on antibiotic stewardship

bull WHO Information sheet on AMR ndash excellent overview -httpwwwwhointmediacentrefactsheetsfs194enindexhtml