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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
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
5-‐10 days of treatment
<
Li et al, AmJMed 2007
3-‐5 days of treatment
Rela0ve risk of clinical failure
5-‐10 days of treatment
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
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
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
DDDs/1000pt admissions in the OUH 2002-‐2012
Corresponding decrease in cefalosporin use
0.0
20.0
40.0
60.0
80.0
100.0
cefalosporins
co-‐amox
cipro
DDDs/1000pt admissions in the OUH 2002-‐2012
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
DDDs/1000pt admissions in the OUH 2002-‐2012
Amoxicillin
Co-‐amoxiclav
0.0
20.0
40.0
60.0
80.0
100.0
ce_riaxone
co-‐amox
carbapenems
tazocin
DDDs/1000pt admissions in the OUH 2002-‐2012
0.0
20.0
40.0
60.0
80.0
100.0
cefalosporins
co-‐amox
cipro
DDDs/1000pt admissions in the OUH 2002-‐2012
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
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