are we over-rating the risk of low- dose drug exposure on the selection of resistant strains?...
TRANSCRIPT
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Are we over-rating the risk of low-dose drug exposure on the
selection of resistant strains?
Pierre-Louis ToutainNational veterinary School
ToulouseFrance
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The question: Are we over-rating the risk of low-dose drug exposure on the
selection of resistant strains
• But of what resistance are we speaking?
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Prevent emergence of resistance: but of what resistance?
Target pathogens Zoonotics Commensal flora
Drug efficacy in animal:
A vet issue
Drug efficacy in
man
Resistance genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
Target pathogens Zoonotics Commensal flora
Drug efficacy in animal:
A vet issue
Drug efficacy in
man
Resistance genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
Target pathogens Zoonotics Commensal flora
Drug efficacy in animal:
A vet issue
Drug efficacy in
man
Resistance genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
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The priorities of a sustainable veterinary antimicrobial therapy is
related to public health issues, not to animal health issues
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The question: Are we over-rating the risk of low-dose drug exposure on the
selection of resistant strains?• The public health issues being critical , we have
to investigate both:– The case of target pathogens– The case of non-target pathogens
• Zoonotic• Commensal flora
• And also acknowledge possible conflict of interest
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1-The case of target pathogens
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7
Selective pressure for antibiotic concentration lower than the MIC
CMI
Time
Concentration
Traditional hypothesis on emergence of AMR
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Current view for the emergence and selection of resistance for the
target pathogen:The selective window
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No antibiotics
Current view for the emergence and selection of resistance
With antibiotics
Mutation rate10-8
Mutation rate10-8
Mutation rate10-8
eradication
susceptible Mutants population résistant
Wild pop
Mutant pop
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Current view for the emergence and selection of resistance: with antibiotic
10
Eradication of all bacteria
Low inoculum size No mutants
Large inoculum with ABfew mutants
Wild population Usual MIC
Mutant MIC=MPC
Large inoculum MIC<[AB]<MPC i.e.within the selective window
Large inoculumAB>MPC
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Growth R
Growth S
Selective Window(SW)
S
R
Time in SW
Antibiotic concentration
Selection of R
Current view for the emergence and selection of resistance:
The selective window
MICWild population
MIC mutant=MPC
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MICs estimated with different inoculmum densities, relative to that MIC at 2x105
Ciprofloxacin
Gentamicin
Linezolid
Daptomycin
Oxacillin
Vancomycin
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MIC & MPC for the main veterinary quinolones for E. coli & S. aureus
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Comparative MIC and MPC values for 285 M. haemolytica strains collected from cattle
MIC50 MIC90 MPC50 MPC90 MPC/MIC
Ceftiofur 0.016 0.016 1 2 125Enrofloxacine 0.016 0.125 0.25 1 8Florfenicol 2 2 4 8 4Tilmicosine 2 8 16 >32 ≈8Tulathromycine 1 2 4 8 4
15
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Consequences of a selective window associated to an inoculum effect for a
rational treatment for veterinary medicine
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When to start a treatment?
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Disease health
TherapyMetaphylaxis
(Control)Prophylaxis(prevention)
Growth promotion
The different uses of antibiotics in veterinary medicine
HighHighPathogen loadPathogen load
SmallSmall NoNoNANA
Antibiotic consumptionAntibiotic consumption
Only a risk factor
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The inoculum effect and Very Early Treatment (VET)
• Tested hypothesis– Efficacious dosage regimen is different when the
pathogen load is large, low or null– Treatment should start as early as possible
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Inoculation of Pasteurella multocida
1500 CFU/lung
Model of pulmonary infection
Materials and methods
A strain of Pasteurella multocida isolated from the trachea of a pig with clinical symptoms of a bacterial lung infection
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Inoculation of Pasteurella multocida1500 CFU/lung
• Model of pulmonary infection
Materials and methods
Progression of infection
0 10 20 30 40 50
Time after infection (h)
Bacteria counts per lung (CFU/lung)
100
102
104
106
108
1010
18 control mice were used to assess the natural growth of Pasteurella multocida in the lungs.
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Materials and methods
Progression of infection
early (10h)Administration
Late (32h)Administration
Inoculation of Pasteurella multocida
1500 CFU/lung
0 10 20 30 40 50
Time (h) Bact
eria
cou
nts
per l
ung
(CFU
/lun
g)
100
102
104
106
108
1010no clinical
signs of infection
anorexia lethargy
dehydration
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Materials and methods
10 hours after the infection (n=14)
32 hours after the infection (n=14)
•A single administration of marbofloxacin
•Two doses tested for each group
1 mg/kg and 40 mg/kg
Inoculation of Pasteurella multocida1500 CFU/lung
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0
20
40
60
80
100 %
1 mg/kg
Marbofloxacin doses
40 mg/kg
early late
Marbofloxacin administrations Po
urce
ntag
es o
f mic
e al
ive
control
1-Clinical outcome (survival) A low early dose better than a late high dose
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2-Bacterial eradicationEarly low dose= late high dose
0
20
40
60
80
100 %
% o
f mic
e w
ith b
acte
rial
erad
icati
on
1 mg/kg
Marbofloxacin doses
40 mg/kg
Early Late
Marbofloxacin administrations
control
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3-Selection of resistant target bacteriaAn early 1 mg/kg marbofloxacin dose has no more impact
on resistance than a high late treatment while this low dose is selecting resistance when administered later
0
10
20
30
40
50 %
+38h
observation 16 hours after marbofloxacin administration= 48 hours after the infection = like early administration
1 mg/kg
Marbofloxacin doses
40 mg/kg
% o
f mic
e w
ith re
sist
ant
bact
eria
control
Early late
Marbofloxacin administrations
+38h1 mg/kg 40 mg/kg
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Metaphylaxis vs. curative
• Pulmonary infectious model by inhalation (P multocida)
• Amoxicillin & et cefquinome• Treatment during the prepatent
(incubation) period (24h) vs. when symptoms are present
28M V. Vasseur, A A. Ferran, M Z. Lacroix, PL Toutain and A Bousquet-Mélou,
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Effect of amoxicillin (clinical cure )metaphylaxis vs. curative
29Dose mg/kg
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Effect of amoxicillin (bacteriological cure)metaphylaxis vs. curative
30Dose mg/kg
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Effect of cefquinome (clinical cure )metaphylaxis vs. curative
31Dose mg/kg
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Effect of cefquinome (bacteriological cure)metaphylaxis vs. curative
32Dose mg/kg
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An early/low dose treatment is better for bacteriological cure than a late/high dose for three
antibiotics: marbofloxacin, amoxicillin & cefquinome
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Q:Are we over-rating the risk of low-dose drug exposure on the selection of
resistant strains?
• A: Apparently not for the target pathogen when an early treatment is initiated i.e when antibiotic only a low inoculum is exposed to an antibiotic
• But what about other non-targeted bacteria?
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The question: Are we over-rating the risk of low-dose drug exposure on the
selection of resistant strains?• The public health issues being critical , we have to
investigate both:– The case of target pathogens– The case of non-target pathogens
• Zoonotics• Commensal flora
• And acknowledge possible conflict of interest
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Example of conflict of interest
• the antimicrobial treatments should not only aim at curing the diseased animals but also at limiting the resistance on non target flora.
Optimal dosing for treatment ≠ optimal to prevent resistance!
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For AR, what are the critical veterinary ecosystems in
terms of public health (commensals)
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The critical animal ecosystems in terms of emergence and spreading of resistance
• Open and large ecosystems – Digestive tract– Skin
• Open but small ecosystem– Respiratory tract
• Closed and small ecosystem – Mammary gland
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Bacterial load exposed to antibiotics during a treatment
Infected Lungs
Digestive tract
1 mg Several Kg
Manurewaste
Food chain
Several tons
Soil, plant….
1µg
Test tube
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Duration of exposure of bacteria exposed to antibiotics
Infected Lungs
Digestive tract
Few days
ManureSludgewaste
Food chain
Several weeks/months
Soil, plant….
24h
Test tube
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Biophases & antibiorésistance
G.I.TProximal Distal
Résistance = lack of efficacy
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
1-F%
F%
Target biophaseBug of vet interest
AB: oral route
Résistance = public health concern
Food chain Environmental exposure
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Bioavailability of oral tetracyclins• Chlortetracycline:
– Chickens:1% – Pigs Fasted or fed: 18 to 19% – Turkeys:6%
• Doxycycline:– Chickens:41.3% .– Pigs :23%
• Oxytetracycline:– Pigs:4.8%– Piglets, weaned, 10 weeks of age: by drench: 9%;in medicated feed for
3 days: 3.7% . – Turkeys: Fasted: 47.6% ;. Fed: 9.4%
• Tetracycline: – Pigs fasted:23% .
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Biophases & antibiorésistance
Gastrointestinal tractProximal Distal
Intestinal secretion Bile
Résistance = lack of efficacyRésistance =public health issue
BiophaseTarget pathogen
Blood
Food chain
Environment
Systemic Administration
QuinolonesMacrolidesTétracyclines
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
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Fluoroquinolone impact on E. coli in pig intestinal flora(From P. sanders, Anses, Fougères)
• Before treatment : E. coli R (0.01 to 0.1%)• After IV. :Decrease of total E coli , slight increase of E. coli R (4 to 8 %) • Back to initial level• After repeated IM (3d) : Decrease below LoD E. coli (2 days), fast growth (~ 3
106 ufc/g 1 d). E. coli R followed to a slow decrease back to initial level after 12 days
IVIM 3 days
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Genotypic evaluation of ampicillin resistance:copy of blaTEM genes per gram of feces
A significant effect of route of administration on blaTEM fecal elimination (p<0.001).
0 1 2 3 4 5 6 7days
cop
ies/
g o
f fe
ces
oral route fed
oral route fasted
intramuscular route
control group1 E+5
1 E+6
1 E+7
1 E+8
1 E+9
1 E+10
1 E+4
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• Performance-enhancing antibiotics (old antibiotics)– chlortetracycline, sulfamethazine, and penicillin
(known as ASP250)]
• phylogenetic, metagenomic, and quantitative PCR-based approaches to address the impact of antibiotics on the swine gut microbiota
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• It was shown that antibiotic resistance genes increased in abundance and diversity in the medicated swine microbiome despite a high background of resistance genes in nonmedicated swine.
• Some enriched genes, demonstrated the potential for indirect selection of resistance to classes of antibiotics not fed.
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Ecological consequences of the commensal flora
exposure by antibiotic
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Commensal floraZoonotic pathogensGene of resistance
one world, one health
Vet AB
Resistance is contagious!It will continue to spread even after infection has been cleared
Transmissible genetic elements allow antibiotic resistance genes to spread both to commensal bacteria and to strains that cause disease.
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One world, one health
EnvironmentEnvironment
Food chain
AMR should be viewed as a global ecological problem with commensal flora as the turntable of the system
Greening our AB
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Selectivity of antimicrobial drugs in veterinary medicine
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Innovation: PK selectivity of antibiotics
environment
ProximalDistal
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
BiophaseRésistance = public health concern
Food chain
1-F=90%
F=10%
Animal health
Efflux
Quinolones, macrolides
IM
Kidney
Oral
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Currently no veterinary antibiotic is selective of target pathogens and our hypothesis was that a low dose would be more selective than a high, regular,
dose
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In vitro assessment of the selectivity of antibiotics on the target pathogen
vs. commensal flora: eradication of a low vs. high inoculum size of P multocida
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Selectivity of amoxicillin & cefquinome
Using killing curves selectivity was tested using E.coli, as a commensal bacterium in condition for which the two tested antibiotics were able to eradicate a low or a large inoculum of P.multocida,
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Development of a selectivity index (SI)
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Selectivity of amoxicillin to eradicate a low a or a high inoculum size of P. multocida
SI=51 SI=5.54
Low: 105 CFU/mL High:107 CFU/mL
P. Multocida (105 or 107 CFU/ml)E coli (107 CFU/mL)
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Selectivity of cefquinome to eradicate a low a or a high inoculum size of P. multocida
SI=2.9 SI=0.66
Low:105 CFU/mL High:107 CFU/mL
P. Multocida (105 or 107 CFU/ml)E coli (107 CFU/mL)
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I there a selective window for the commensal flora
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• All macrolides are not equals• The normal flora is disturbed more or less
according to the pharmacokinetic profiles of the respective macrolides.• 85% of patients treated with
azithromycin were colonized by macrolide-resistant organisms 6 weeks after therapy, compared to 17% treated with clarithromycin
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ClarithromycinClarithromycin AzithromycinAzithromycin
Selective Window
MAC
MIC
10.00
1.00
0.1
0.01
0.001Con
cent
ratio
n (
ug/m
l )
0 1 2 3 4 5Weeks
Longer half-life antibiotics may create a greater windowof opportunity for the development of resistance
Guggenbichler JP, Kastner H Infect Med 14 Suppl C: 17-25 (1997)
Effect of Elimination Kineticson Bacterial Resistance
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Selective window can be longer and delayed in the GIT
Plasma/Lung
GIT/commensal
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A long half-life is desirable for convenience in vet medicine: two possible options
Macrolides/FQ Beta-lactams/sulfonamides
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Longer half-life antibiotics may create a greater window
of opportunity for the development of resistance
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One size does NOT fit all!
We need to broaden the concept of selection of resistance when devising optimal dosing strategies – both for guidelines for future and existing antibiotics
Conclusions
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When to finish a treatment?
• ASAP• Should be determined in clinics• Should be when clinical cure is actually
achieved• Should not be a hidden prophylactic
treatment for a possible next infectious episode
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• For a same dose of marbofloxacin, early treatments (10 hours after the infection) were associated to– more frequent clinical cure – more frequent bacteriological cure – less frequent selection of resistant bacteria
than late treatments (32 hours after the infection)
Conclusion
Early administrations were more favourable than late administrations
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• Treatment exerts selection on innocent bacteria
• Most of the harm done by use of a drug may be on species OTHER than the target of treatment
• Most of the exposure of a givenspecies to a given drug may be due to treatment of OTHER infections
Normal flora: Consequences
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One world, one health
EnvironmentEnvironment
Food chain
Vet ABHazard
AMR should be viewed as a global ecological problem with commensal flora as the turntable of the system
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New Eco-Evo drugs and strategies should be considered in vet
medicine
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- 72
Innovation: PK selectivity of antibiotics
environment
G.I.TProximal Distal
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
BiophaseRésistance = public health concern
Food chain
90%0%
Animal health
Trapping or destruction of the antibiotic
Efflux
Quinolones, macrolides
IM
Kidney
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73
My view of an ideal antibiotic for vet medicine
High plasma clearance Rapidly metabolized (in vivo, environment) to inactive metabolite(s)
High renal clearance Elimination by non-GIT route (not bile or enterocyte efflux)
volume of distribution not too high
Pathogens are extracellular; half-life rather short; not too short to compensate a relatively high clearance
High bioavailability by oral route
To avoid to expose distal GIT to active AB
Low binding to plasma protein Only free antibiotic is active; to reduce the possible nominal dosage regimen and environmental load
High binding to cellulosis To inactivate AB in large GIT
High potency To be able to select a low dose
High PK selectivity (biophase) To distribute only to target biophase
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Innovation pour une voie systémique
Tractus digestif
Proximal Distal
BiophasePathogène visé
sang
Chaîne alimentaire
EnvironmentAdministration
Elimination par efflux ou biliaire=0%
flore•Zoonotiques (salmonella, campylobacter )•commensaux ( enterococcus)
Elimination rénale=100%
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Renal clearance of different quinolones
Drugs % of total clearance
Ofloxacin 70
Levofloxacin 65
Ciprofloxacin 50
Sparfloxacin 13
Grepafloxacin 10
Trovafloxacin 5-10
Hooper DC CID 2000;30:243-254
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Conclusions
Appropriate use of antibiotics should not only include knowledge of the pathogen and its susceptibility, but also the spectrum and pharmacokinetic properties of the respective antimicrobial drug.
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S R
Sensitivepopulation
Resistantpopulation
Traditional pharmacokinetic/ pharmacodynamic models
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S R
Sensitivepopulation
Resistantpopulation
Incorporating the immune response
S
I
Sensitivepopulation
Immuneresponse
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Possible pathogen dynamics
Unregulated bacterial dynamics: Commensal bacteria that uses body as a habitat
Regulated bacterial dynamics: Bacteria and the immune response settles an equilibrium