bousquet-melou metaphylaxis aavm 2010

8/9/2019 Bousquet-melou Metaphylaxis Aavm 2010

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AAVM-2010

Prophylaxis &

Metaphylaxis inVeterinary Antimicrobial

Therapy

Alain Bousquet-Mélou

National Veterinary School, Toulouse, France

Tel Aviv May 2010

ECOLE

NATIONALE

VETERINAIRE

T O U L O U S E


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Treatment & prop!la"is

#uman me$i%ine

Community

Veterinar!

me$i%ine

Animal ee$ a$$iti'es

En'ironment

Hospital A(ri%ulture

)lant prote%tion

In$ustr!

Ant m cro a res stance : rom an ma s tohumans


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AAVM-2010

• Antimicrobial resistance is an ineluctable adverse effect ofantibiotics use

• The association between the consumption of an

antimicrobial agent and the occurrence of antimicrobialresistance is well established

• The prudent use of antibiotics requires to reduce theoverall consumption

Ant m cro a res stance : rom an ma s tohumans


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AAVM-2010

Terapeuti%sMetap!la"isprop!la"is*ro+t

a%tor

)REVENTION*RO,T#

Ban in EU.

•To target the major uses contributing to antibiotics consumption

• Massive and collective administrations in food animals

• Oral routes

Prudent use in relation with antimicrobialresistance

T#ERA)/CONTROL


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AAVM-2010

Are prophylaxis and metaphylaxis thesame type of use ?

Prophylaxis

when antibiotics are administered to a herd or floc! of animals

at ris! of a disease outbrea!

A measure ta!en to maintain health and prevent disease

A measure to protect against infection


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AAVM-2010


• “… a form of prophylaxis called metaphylaxis …”

• “… the use of the term metaphylaxis is controversial …”– refers to situations where antimicrobials are used for both

therapeutic and prophylactic purposes

– refers to a particular form of prophylaxis in the presence of the

pathoen with a hih li!elihood of disease

Metaphylaxis

– when antimicrobials are administered to clinically healthy animalsbelonin to the same "oc! or pen as animals with clinical sins

– infections are treated before their clinical appearance


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• Phylaxis " P#OT$%T&O'

(rom phylax " guard) watchman

Arctophylaxis *+oote,

the - bear.driver /

*0rsus Minor) 0rsus Major,

• &n relation with the start of the aggression Pro . 1 before the aggression begins

Meta . 1 after the aggression begins



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No s!mptoms S!mptoms

#he time course of the bacterial disease

0isease#ealt

Bacterial contamination / Host defenses

Growth of the initial inoculum

Start

of the

infectious disease


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0isease#ealt


)REVENTIVE


Start

of the

infectious disease

)RO)#/LA1IS


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0isease#ealt



Start

of the

infectious disease

)REVENTIVE CURATIVE TREATMENT

%on'entional

e+ 2.

e+.

META)#/LA1IS

EARL/


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• Metaphylaxis

2Metaphylaxis is treatment given to animals experiencing any level of

*viral or, bacterial disease before overt disease occurs3 *4oung) 5667,

Metaphylaxis is an earl! %urati'e treatment launched after the start of

the disease *pathogen contamination) host defenses alteration, but

3eore %lini%al e"pression with the goal of the 3a%teriolo(i%al %ure o

te ine%te$ animals) which subsequently warrants the final protection

against infection outbrea!s

• Metaphylaxis should be compared to 2conventional3 *later,

curative treatments of sic! animals) not to prophylaxis



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• Ba%terial loa$ at the infection site and patop!siolo(i%al status

of the host are at the origin of differences in the responses to thedrugs) at both pharmacodynamic and pharmaco!inetic levels

• Pharmacodynamics 1 bug.drug interactions Ino%ulum si4e impacts both antimicrobial activity *bacteriological cure, and

resistant bacteria selection

$arly versus later %conventional& treatments


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'noculum si(e and antimicrobial activity

• &noculum effect on in vitro bacterial susceptibility assessment

=escription in the literature since more than >? years

@igher M&%s when using high density bacterial inocula compared to the standard 5?7 %(0 inocula *beta.lactams) fluoroquinolones , 2Antibiotics with inoculum effects administered empirically in clinical practice at a higher dose than the microbiological and

pharmaco!inetic data would indicate3 Boriano et al 8 CA% 566?

• &noculum effect on in vitro antibacterial activity @igher antibacterial activity against low versus high bacterial inoculum

MiDunaga et al. CA% :??7 E (erran et al. AA% :??F


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?G

:?G

>?G

H?G

I?G

5??G

?8??5 ?8?5 ?85%oncentrations *Jg;mK,

+ a c t e r i c i d a l e f f e c t * G

,

Kow

@igh

&nterm8

'noculum si(e and antimicrobial activity

• %iprofloxacin and imipenem against Staphylococcus aureus *MiDunaga et al8 CA% :??7,

• Marbofloxacin against Escherichia coli *(erran et al8 unpublished,

567

568


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58 %linical and microbiological cure 9

1. In vitro evidences of the effect of inoculum siDe on

antimicrobial activity

2. In vivo e'i$en%es

:8 #esistance selection;prevention at the infection site 9


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'noculum si(e and clinical or microbioloicalcure

• (luoroquinolones and beta.lactams against Staphylococcus

aureus and Pseudomonas aeruginosa *MiDunaga et al8 CA% :??7,

• &ntraperitoneal infection in mice

• =oses associated with survival

Lo+ Lo+#i( #i(


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• (luoroquinolone against Pseudomonas aeruginosa *Cumbe et al8 C%& :??


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(ractionated Bingle

Earl! treatment

lun( ine%tion

568 C=U > ? ater

5H mg;!g H> mg;!g 5?? mg;!g

(ractionated Bingle

Later treatment

lun( ine%tion

567 C=U > 9? ater

:

>

H

I

5?

L o ( 5 6

C = U ;

L u n (

• Marbofloxacin against klebsiella pneumoniae *Lesteman et al8 AA% :??6,



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58 %linical and microbiological cure 9

1. In vitro evidences of the effect of inoculum siDe on


2. In vivo evidences

9@ Resistan%e sele%tion;pre'ention at te ine%tion

site 2


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'noculum si(e and resistant mutantselection

• In vivo evidences1

Thigh infection in mice 1 marbofloxacin against Escherichia coli

*(erran et al8 AA% :??6,

Kung infection in rats 1 marbofloxacin against Klebsiella pneumoniae *Lesteman et al8 AA% :??6,

• In vitro evidence1

(or the same exposure) the li!elihood of resistant mutant selection islower with a small inoculum1 5?7 versus 5?6 %(0;mK

Marbofloxacin against Escherichia coli 1 (erran et al8 AA% :??F


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?G ?G

(ractionated Bingle

Earl! treatment

568 C=U > ? ater

5H mg;!g

?G

:?G

>?G

H?G

I?G

5??G

H> mg;!g 5?? mg;!g

77G

F?G

:FG

7?G

?G ?G

(ractionated Bingle

Later treatment

567 C=U > 9? ater

)er%enta(es o rats +it resistant K. pneumoniae in teir

lun(s 7 ater te start o mar3olo"a%in treatment

*ro+t in te presen%e o al M)C


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AAVM-2010

58 %linical and microbiological cure 91. In vitro evidences of the effect of inoculum siDe on





• The same dose provides much better results for items 5 :

when given early before clinical signs

• To reach 2optimal3 outcomes for items 5 and :) *much more 9,

lower doses are needed when given early to animals without

clinical signs compared to sic! animals

• #einforced by the wor! presented by A8 (erran


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AAVM-2010

58 %linical and microbiological cure 91. In vitro evidences of the effect of inoculum siDe on




@ Resistan%e sele%tion;pre'ention in te (ut lora 2


)ritical bacterial "ora for antimicrobial


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AAVM-2010

0i(esti'e tra%t0istal

Ine%tious site

)ato(ens o 'eterinar! interest

ANIMAL #EALT#

Bloo$

)ro"imal• Resistant 4oonoti% pato(ens salmonellaD

%amp!lo3a%ter spp.• Commensal lora resistan%e (enes.

ResistanceTherapeutic

failures

=oo$ %ain

En'ironment

)UBLIC #EALT#

#UMAN

Conta%t

genes flux

)ritical bacterial "ora for antimicrobialresistance

AB Oral route

AB )arenteral route

)ritical bacterial "ora for antimicrobial


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AAVM-2010

0i(esti'e tra%t0istal

Ine%tious site

)ato(ens o 'eterinar! interest

ANIMAL #EALT#

Bloo$

)ro"imal• Resistant 4oonoti% pato(ens salmonellaD

%amp!lo3a%ter spp.• Commensal lora resistan%e (enes.

)ritical bacterial "ora for antimicrobialresistance

AB Oral route

AB )arenteral route

$ffects of early vs later

treatments 9

• =ose levels 9

• Treatment duration 9


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AAVM-2010

• +acterial load at the infectious site and pathophysiological status of

the host are at the origin of differences in the responses to thedrugs) at both pharmacodynamics and pharmaco!inetics levels

• Pharmacodynamics 1 bug.drug interactions Ino%ulum si4e impacts both antimicrobial activity *bacteriological cure,

and resistant bacteria selection

• Pharmaco!inetics 1 drug exposure Te $isease impacts the relation between the dose and systemic

exposure and is a source of variability of exposure between animals


$* t f i f ti d


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AAVM-2010

• Kow versus high inoculum (erran et al. AA% :??6

E. coli thigh infection in mice

• @ealthy versus sic! animals

#eview by MartineD Modric CNPT :?5?

@igher inter.individual variability in sic! animals) increasing the

li!elihood of occurrence of under.exposure *Peyrou et al8 CNPT :??>,

$*ects of infection on dose+exposurerelation

Time *h,

M a r 3 o & l o " a % i n * J g ; m K ,

?8???5

?8??5

?8?5

?85

5

5?

? H 5: 5I :>

@igh inoculum

Kow inoculum

l d


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AAVM-2010

#o conclude

• (inally) whether metaphylactic setting *intervention at the group level, should

really benefit to the potential advantages of early curative treatment *at the

individual level, remains to be investigated) ideally in controlled clinical trials

with special attention for dose levels and duration of treatments

• &mportant questions to address when moving from early treatment tometaphylaxis

@eterogeneity of the treated group 1 effect of inter.individual variability 9

+acterial load 1 what is the ris! to under.expose high inocula 9

%ollective *oral, treatments 1 influence of inter.individual variability of drug inta!e

• (avorables features of early treatments at the individual level

@igher antimicrobial activity and prevention of resistance 1 different doses

Probably more predictable dose.exposure relationships

%urrently all regulatory PL) including for antibiotics) are obtained in healthy

animals) which is irrelevant for severe infections but probably not for early

treatments


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AAVM-2010

&n term of ris! communication it is probably

better to promote the concept of early

curative treatment in place of the

misleading word of metaphylaxis

,ast remar!


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AAVM-2010

' l i d i t t t t


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AAVM 2010

sus%epti3le

population

resistant mutants

population

The same

dosage regimen

#esistant mutants selection

Lo+ 3a%terial loa$si4e F mutation rate.

sus%epti3le

population

resistant mutants

population

#esistant mutants prevention

'noculum si(e and resistant mutantselection

#i( 3a%terial loa$si4e GG mutation rate.

bousquet-melou metaphylaxis aavm 2010

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