collateral(damage:(minimising(...

Collateral Damage: minimising an0bio0c use

Oxford University Hospitals NHS Trust & the University of Oxford Nuffield Department of Medicine, Grand

Round February 2014 Slides -‐ Dr Nicola FawceN

326 admissions (1 week) To Acute/General Medicine

299 Pa0ent records

56 pa0ents AdmiNed under

IDAP

243 pa0ents AdmiNed under Non-‐ID physician

27 notes unavailable for final review

An0bio0c use in Acute/General Medicine-‐ a benchmarking audit

0

0.5

1

1.5

2

2.5

3

3.5

IDAP Other

Days of an)bio)c therapy per pa)ent admi4ed

0 0.5 1

1.5 2

2.5 3

3.5 4

4.5 5

IDAP Other

DDDs per pa)ent admi4ed

Outcome IDAP Non-‐IDAP p

Pa0ent started on an0bio0c 11 (20%) 80 (33%) 0.06

An0bio0c days per pa0ent admiNed 0.88 1.7 0.06

DDDs per pa0ent admiNed 1.2 3.1 0.04

Composite clinical outcome 15 (27%) 72 (30%) 0.66

Mean length of stay/ days 5.2 4.4 0.07

326 admissions (1 week) To Acute/General Medicine

299 Pa0ent records

56 pa0ents AdmiNed under

IDAP

243 pa0ents AdmiNed under Non-‐ID physician

27 notes unavailable for final review

An0bio0c use in Acute/General Medicine-‐ a benchmarking audit

0 10 20 30 40 50 60

Amoxicillin Cefalexin

Ce_riaxone Ciprofloxacin

Clarithromycin Clindamycin

Co-‐Amoxiclav Doxycycline Flucloxacillin

Metronidazole Moxifloxacin

Nitrofurantoin Tazocin

Trimethoprim Vancomycin

Choice of an)bio)c

Decision Making in the Acute SeAng

RISKS POTENTIAL BENEFITS

?

?

Risk to the popula0on of drug-‐resistant infec0on ?

•  Risk of untreated or undertreated infec0on •  Risk of an0bio0c-‐related side effects •  Risk of future drug-‐resistant infec0on •  Impact on hospital and pa0ent experience

•  Asymptoma0c bacteruria is present in 20% of older adults

•  Urine dips0ck tes0ng relies heavily on pretest probability Trials of an0bio0cs have urinary symptoms in their diagnos0c criteria

An0bio0c or no an0bio0c Spectrum Dura0on

?INFECTION

<

Li et al, AmJMed 2007

3-‐5 days of treatment

Rela0ve risk of clinical failure


<

Li et al, AmJMed 2007


Rela0ve risk of clinical failure


Evidence for equivalence of outcome in shorter courses of therapy in: •  Uncomplicated CAP •  Uncomplicated UTIs •  Uncomplicated Skin/so_

0ssue •  Pyelonephri0s

0

5

10

15

20

25

Clindamycin -‐ 20.4

30, 184 pa0ents

prior exposure to an0bio0c and risk of C. diff

0

1

2

3

4

5

6

7

8

Quinolones Cephalosporins Penicillins Macrolides Sulphonamides Tetracyclines

5.65 4.47

3.25 2.55

1.84

0.91

prior exposure to an0bio0c and risk of C. diff

Do we care about class of an)bio)c used to treat CAP?

Deshpande et al 2013

30, 184 pa0ents

Decision Making in the Acute SeAng

RISKS POTENTIAL BENEFITS

?

?

•  Risk of untreated or undertreated infec0on •  Risk of an0bio0c-‐related side effects •  Risk of future drug-‐resistant infec0on •  Impact on hospital and pa0ent experience

•  Asymptoma0c bacteruria is present in 20% of older adults

•  Urine dips0ck tes0ng relies heavily on pretest probability (?)

•  Trials of an0bio0cs have urinary symptoms in their diagnos0c criteria

An0bio0c or no an0bio0c Spectrum Dura0on

?INFECTION

-‐  Altera0on in risk due to interven0on -‐  Factors which increase risk of drug-‐resistant

infec0on -‐  Prevalence of resistance in the popula0on

Costelloe et al, BMJ 2010

E.coli resistance and prior an0bio0c exposure

S0ll a weak associa0on even with an0bio0cs up to 12 months prior to infec0on

0-‐1 month

0-‐3 months

0-‐6 months

0-‐12 months

An0bio0c use associated with resistance

An0bio0c use associated with suscep0bility

Albrich et al, Emerg Infect Dis. 2004

Evidence for factors associated with reduced risk of resistance in isolates infec0on •  Low country-‐wide an0bio0c

use in humans •  Low an0bio0c use in animal

husbandry •  Robust healthcare systems

Europe data: 2008-‐2011 European An0microbial Surveillance System (EARSS)

Asia-‐Pacific: -‐2009 data Yen-‐Hsu Chen et al, Journal of Infec0on April 2011

USA – 2009 data

Bhusal et al, Chemotherapy, 2011

Percentage of ESBL-‐Producing E.coli Invasive Isolates

-‐ Worldwide data

5% 10%

23%

65%

3%

29%

Resistance of Klebsiella isolates in Neonatal ICU, Pakistan

Resistance to imipenem

Percentage Of isolates resistant

Year

Carbapenem-‐resistant enterobacter cases referred to HPA Colindale

Tradi)onal model of resistance acquisi)on and spread

Pathogen acquisi0on

An0bio0c treatment and selec0on pressure

Incomplete Treatment

Successful eradica0on

Persistence of resistant organism Transmission of resistant organism

Relevant in organisms where: •  Ver0cal transmission of

resistance is dominant •  Predominantly human

reservoir •  Eradica0on is possible •  Significant persistence of

infec0ng organism a_er treatment

•  M. tuberculosis •  S. aureus •  M. abscessus •  N. gonorrhoeae •  (Pseudomonas)

Acquired Resistance

meropenem

Nonpathogenic/environmental With endogenous an0bio0c resistance element

Co-‐existence under selec0on pressure

‘Capture event’ Under an0bio0c selec0on pressure Horizontal gene transfer

Integra0on into a highly transmissible vector

Epidemic Spread of mobile gene0c elements between strains and/or species

Global increase of resistance elements

Nonpathogenic/environmental With endogenous an0bio0c resistance element

Co-‐existence under selec0on pressure

‘Capture event’ Under an0bio0c selec0on pressure Horizontal gene transfer

Integra0on into a highly transmissible vector

Epidemic Spread of mobile gene0c elements between strains and/or species

Increased likelihood of acquiring resistant infec0on

"the spread of NDM-‐1(carbapenemase) is probably due to the high mobility of the NDM-‐1 plasmids as opposed to clonal dissemina0on" Sao Paulo “The spread of the KPC (carbapenemase) gene may be facilitated by its localisa0on on plasmids and transposons and also by efficient clones”

Mataseje et al 2014 Lopez-‐Camacho et al 2014

Global increase of resistance elements

•  Mobile-‐gene0c-‐element mediated resistance

•  Can be up/downregulated and easily shared

•  O]en li4le fitness cost of resistance

An0microbial resistance as a result of widespread anthropogenic altera)on and contamina)on of our biosphere with an)bio)cs

Where is it coming from? Community Reservoir: •  Prevalence of ESBL E.coli in Nursing Home in N. Ireland 40.5%

–  51% of carriers had no history of hospital admission Abroad: •  Travellers in Sweden-‐carriage of ESBLs:

–  Prior to travel 4% –  A_er travel 32% (Travel to India – 82%) –  Found in travellers without GI symptoms

Non-‐human sources: •  Retail meat –detected ESBL/CMY producing E.coli

–  Sevilla 67% -‐ PiNsburgh 85% Environment: •  Sewage from hospital waste water in Lebanon: mul0ple GNRs with different

resistance mechanisms •  Water sources in India-‐ high levels of NDM-‐carrying isolates… (Tim Walsh) •  Report of measured concentra0on of ciprofloxacin in factory efflux at near serum

therapeu0c range…

Rooney et al, JAmChem 2009, Ostholm Balkhed ECCMID abstract, Doi et al Clin Microb Infect 2010,

Penicillins

Daptomycin Tigecycline Colis0n

Carbapenems

3rd Gen Cephalosporins

Cephalosporins

We’re fine!

It’s been going on for years, why are we suddenly geyng so worked up about things?

Penicillins

Daptomycin Tigecycline Colis0n

Carbapenems

3rd Gen Cephalosporins

Cephalosporins

??

…

It’s been going on for years, why are we suddenly geyng so worked up about things?

The Human Microbiome Significant contributor to the an0bio0c-‐exposed biosphere -‐  Noneradicable -‐  Subject to high rela0ve levels of an0bio0c

exposure -‐  Co-‐existence of mul0ple species with

poten0al for horizontal gene transfer -‐  Direct source of poten0al pathogens -‐  Source of resistance elements for poten0al

pathogens

Carriage of resistant e.coli correlates with risk of resistant infec)on: Abundance of ESBL in faecal samples in pa0ents with ESBL u0 18-‐fold higher, with evidence of same clone found in both urine and gut

Ruppe et al An0microbial Agents and Chemotherapy 2013

Colonisa0on •  Prevalence of ESBL e.coli in healthy popula0on detected on faecal sample screening:

SeAng %ESBL Ref

Spain 1991 Outpa0ents 0.7% Valverde et al 2004

Spain 2003 Outpa0ents 5.5%

Spain 2003 Healthy Volunteers 3.7% (65% CTX-‐M)

Japan Healthy Volunteers 6.4% (92% CTX-‐M) Yamamoto et al 2011

Saudi Arabia Healthy volunteers 13.1% Kader et al 2007

Thailand Rural Community 58.2% CTX-‐M Sasaki et al 2010

(Although actual sensi0vity to low numbers of organisms unknown)

Long-‐term ecological impacts of an)bio)c administra)on on the human intes)nal microbiota

Jernberg et al 2007

Single course of Clindamycin administra0on

Number of bacteroides clones

Percentage with resistant phenotype

No clindamycin

Percentage with resistant phenotype

2 years later!

Plan to pilot this technique as a measurement of an0bio0c selec0on pressure for resistance elements in enterobacteriaceae as an indicator of risk of future resistant infec0on

Pilot work: resistance elements in OUH faecal samples

Plan to pilot this technique as a measurement of an0bio0c selec0on pressure for resistance elements in enterobacteriaceae as an indicator of risk of future resistant infec0on

In Summary •  An0microbial resistance is likely to be a

result of widespread an0microbial use and contamina0on

•  Hospitals serve as a significant hub of resistance selec0on and spread

•  Reduced broad-‐spectrum use is probably protec0ve at a popula0on level

•  However blanket an0bio0c use is not a ‘risk free’ strategy

•  There is a need to be able to compare the rela0ve selec0on pressure of different an0bio0c strategies to inform clinical treatment

Addi0onal Informa0on

0.0

20.0

40.0

Major change in Cipro Use in 2006 Driven by c Diff outbreak and change to formulary

DDDs/1000pt admissions in the OUH 2002-‐2012

0.0

20.0

40.0

60.0

80.0

100.0

cefalosporins

cipro


Corresponding decrease in cefalosporin use

0.0

20.0

40.0

60.0

80.0

100.0

cefalosporins

co-‐amox

cipro


0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

co-‐amoxiclav

cefalosporins+ciprofloxacin

High volume broad spectrum an0bio0c use in the OUH – swapping one for the other…

0.0

20.0

40.0

60.0

80.0

100.0

co-‐amox

amoxcil


Amoxicillin

Co-‐amoxiclav

0.0

20.0

40.0

60.0

80.0

100.0

ce_riaxone

co-‐amox

carbapenems

tazocin


0.0

20.0

40.0

60.0

80.0

100.0

cefalosporins

co-‐amox

cipro


Significant lack of high quality studies Lack of standardised outcome measures meaning extremely difficult to compare

Effect

NJFawceN diagrama0c representa0on version because the figures are massively difficult to read properly

An0bio0c iv

An0bio0c po

Stool sampling at day 0 to day 15

Control 1 – not inoculated with resistant strain

Control 2 – inoculated with resistant enterococcus, (either tet or bla ) but not given an0bio0cs

separate experiments •  tet-‐inoculated mouse given Tetracycline high dose •  Tet-‐inoculated mouse given Tetracycline low dose •  Bla-‐inoculated mouse given Ampicillin

Plated and incubated to recover total cul0vatable microbiological popula0on

PCR

16srRNA – enterococcus primer Tet gene primer Bla-‐gene primer

Mice not inoculated with resistant bacteria Mice inoculated and given saline injec0on Mice given oral tetracycline high dose Mice given ivl tetracycline high dose

1)  Inocula)ng mice with tet enterococcus does not change total quan)ty of enterococcus as measured by 16srRNA copies

2)  Both iv and oral enterococcus had some impact on total cul)vatable enterococcus quan)ty (1 log)

Oral tetracycline has significantly higher peak of number of resistance copies and earlier (though persistence in iv longer?

Effect of high dose tetracycline po or iv On enterococcus numbers and resistance

Oral

iv

Tetracycline is excreted renally and via biliary tract -‐ iv tetracycline will s0ll impact on GI tract

Mice not inoculated with resistant bacteria Mice inoculated and given saline injec0on Mice given oral tetracycline low dose Mice given iv tetracycline low dose

Effect of low dose tetracycline po or iv On enterococcus numbers and resistance

Similarly – lower dose s)ll led to similar drop in total enterococcus -‐ 1 log

For comparison high dose oral tetracycline Low dose oral tetracycline

The lower dose s)ll had an effect on number of tetM gene pool copies, but not as much, with oral again having the larger effect

Oral

iv

Tetracycline is excreted renally and via biliary tract -‐ iv tetracycline will s0ll impact on GI tract

Mice not inoculated with resistant bacteria Mice inoculated and given saline injec0on Mice given oral ampicillin Mice given iv ampicillin

Effect of ampicillin po vs iv.

Iv ampicillin has no significant effect on number of copies of culturable enterococcus rRNA. ORAL ampicillin has a very significant effect

In mice inoculated with bla-‐gene carrying enterococcus you can detect significant levels – sugges0ng it colonises in decent numbers. When you give Ivs it doesn’t make a huge difference to numbers of detectable bla-‐enterococcus HOWEVER when you give orals you get a 5 log increase in resistance -‐ which isn’t seen with iv treatment.

Oral

iv

Oral

iv

Ampicillin is renally excreted only – iv will theore0cally not have significant GI levels

collateral(damage:(minimising(...

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