how to establish a dosage regimen for a sustainable use of antibiotics in veterinary medicine

How to establish a dosage regimen for a sustainable use of antibiotics in

veterinary medicine

P.L. Toutain National Veterinary School ;

Toulouse, France

The workshop• A general presentation by PLT• Three questions to be discussed in subgroups

animated by team leaders:– Peter Lees:

• the needs of innovation

– Ted Whittem: • PKPD, pop kinetics & MCS in antibiotic development

– Marilyn Martinez: • regulatory hurdles to antibiotic development

"The design of appropriate dosage

regimens may be the single most

important contribution of clinical

pharmacology to the resistance

problem"Schentag et al. Annals of Pharmacotherapy, 30: 1029-1031

EMEA "Points to consider" July 2000

• Inadequate dosing of antibiotics is probably an important reason for misuse and subsequent risk of resistance

• A recommendation on proper dosing regimens for different infections would be an important part of comprehensive strategy

• The possibility to produce such a dose recommendation based on pharmacokinetic and pharmacodynamic considerations will be further investigated in one of the CPMP working parties...

Medical consequences of AMR

The antibiotic ecosystem: one world, one health

Treatment & prophylaxis

Human medicineCommunity

Veterinary medicine Animal feed additives

Environment

Hospital Agriculture

Plant protection

Industry

The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues,

not to animal health issues

The three (not 2) endpoints to consider in veterinary medicine

• Efficacy in animal• No promotion of resistance in

animal (target pathogen)• No promotion of resistance in

man

But of what resistance are we speaking?

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



A vet issue

Drug efficacy in

man




Natural eradication

Risk for permanent

colonisation




A vet issue

Drug efficacy in

man




Natural eradication

Risk for permanent

colonisation


What are the animal’s ecosystems potentially able to raise public health concerns in

terms of antimicrobial resistance?

The critical animal ecosystem's 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

Bacterial load exposed to antibiotics during a treatment

Infected Lungs

Digestive tract

1 mg 2-3Kg

Manurewaste

Food chain

Several tons

Soil, plant….

1µg

Test tube

Biophases & antimicrobial resistance

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

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% .

Biophases & antibiorésistance

Gastrointestinal tract

Proximal DistalIntestinal secretion

Bile

Résistance = lack of efficacyRésistance =public health issue

BiophaseTarget pathogen

Blood

Food chain

Environment

Systemic Administration

QuinolonesMacrolidesTétracyclines


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

18

Marbofloxacin 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

• 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

• 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.

The three (not 2) endpoints to consider in veterinary medicine

• Efficacy in animal

• No promotion of resistance in animal (target pathogen)

• No promotion of resistance in man???????

- 22

Innovation: PK selectivity of antibiotics

environment

ProximalDistal

Blood


BiophaseRésistance = public health concern

Food chain

1-F=90%

F=10%

Animal health

Efflux

Quinolones, macrolides

IM

Kidney

Oral

Question 1:Peter Lees

• Do we need new antibiotics to fit our expectation in terms of public health or rather to encourage the use of old antibiotics and the promotion of generics

The right dosage regimen

What are the elements of a dosage regimen

• The dose & The dosing interval

• The treatment duration–When to start

–When to finish

How to find and to confirm a dose (dosage regimen)

• Dose titration

– Animal infectious model

• PK/PD

Nice buiatric 2006-27

Dose titration

DoseResponseclinicalBlack box

PK/PD

Dose Response

PK PD

An exposure variable scaled by MIC

Body pathogen

ECVPT Toulouse 2009 - 28

The dose-titration

Only the parallel design for antibiotics: Statistical model

• The null hypothesis– placebo = D1 = D2 = D3

• The statistical linear model– Yj = wj + j

• Conclusion– D3 = D2 > D1 > Placebo

Placebo Dose

Response

1 2 3

*

*

NS

Selected dose

The parallel design

• Advantages– easy to execute– total study lasts over one period– approved by Authorities

• Disadvantages– "local information" (response at a given dose does not

provide any information about another dose)– no information about the distribution of the individual

patient's dose response.

The dose-titration: experimental infectious model

• Severe• not representative of the real world

– Prophylaxis vs. metaphylaxis vs. curative

• power of the design generally low for large species

• influence of the endpoints

Antibiotic dosage regimen based on PK-PD and population PK

concepts

Measuring exposure and response in

PK/PD trial

It has been developed surrogates indices (predictors) of antibiotic

efficacy taking into account MIC (PD)

and exposure antibiotic metrics (PK)

Practically, 3 indices cover all situations:•AUC/MIC •Time>MIC• Cmax/MIC


PK/PD predictors of efficacy

MIC

Cmax

Co

nce

ntr

atio

ns

24hTime

Cmax/MIC

• Cmax/MIC : aminoglycosides

AUIC = AUCMIC

• AUC/MIC : quinolones, tetracyclines, azithromycins,

• T>MIC : penicillins, cephalosporins, macrolides,

T>CMI

Appropriate PK/PD indices for the different antibiotics according to their bactericidal properties

Bactericidal pattern Antibiotics Therapeutic goal PKPD

indices

Type IConcentration dependant & persistent effect

Aminoglycosides

Fluoroquinolones

To optimize plasma concentrations

Cmax/MIC

24h-AUC/MIC

Type IITime-dependent and no persistent effect

Penicillins

Céphalosporins

To optimize duration of exposure

T>MIC

Type IIITime-dependent and dose-dependent persistent effect

Macrolides

Tétracyclines

To optimize amount (doses)

24h-AUC/MIC

What is the appropriate magnitude of PK/PD indices

to guarantee efficacy i.e. how establish PK/PD breakpoint

values:

1. To optimize efficacy

2. To minimize resistance towards the target pathogen

Breakpoint values in veterinary medicine

• Starting values– From human medicine– From in vitro/ex vivo (tissue cage)

experiments

• In vivo experimental determination


First step of the PKPD approach

• To establish experimentaly the numerical value of the PKPD surrogate that garantee a Probability of cure (POC) or any other relevant endpoint (bacteriokogical cure…)– E. g what is the numerical value of the

AUC/MIC for a new quinolone to obtain more than 90% of clinical success in pigs treated metaphylactically for a lung condition?


A working example

Your development project

• You are developing a new antibiotic in pigs (e.g. a quinolone) to treat respiratory conditions and you wish to use this drug in for metaphylaxis (control)

• collective treatment & oral route

MonteCarlo-Orlando06 - 42

Questions for the developers

• What is the optimal dosage regimen for this new quinolone for metaphylaxis ings

• To answer this question, you have, first, to define what is an “optimal dosage regimen”

Step 1: Define what is an optimal dosage regimen

What is an optimal dosage regimen ?

1. Efficacy : – it is expected to cure at least 90% of pigs– “Probability of cure” = POC = 0.90

• We know that the appropriate PK/PD index for that drug (quinolone) is AUC/MIC

• We have only to determine (or to assume) its optimal breakpoint value for this new quinolone

What is an optimal dosage regimen ?

2. Emergence of resistance – The dosage regimen should avoid the

mutant selection window (MSW) in at least 90% of pigs

The selection window hypothesis

Mutant prevention concentration (MPC)(to inhibit growth of the least susceptible, single step mutant)

MICSelective concentration (SC)to block wild-type bacteria

Pla

sma

con

cen

trat

ion

s

All bacteria inhibited

Growth of only the most resistant subpopulation

Growth of all bacteria

Mutant Selection window

Two endpoints for an optimal dosing regimen

1. Probability of “cure” = POC = 0.90

2. Time out of the MSW should be higher than 12h (50% of the dosing interval) in 90% of pigs

Step 2: Determination of the AUC/MIC clinical breakpoint value for the new quinolone in pigs


Determination of the PK/PD clinical breakpoint value

• Dose titration in field trials : – 4 groups of 10 animals– Blood samples were obtained – MIC of the pathogen is known

Possible to establish the relationship between AUC/MIC and the clinical success

AUC/MIC vs. POC: Metaphylaxis

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 50 100 150 200

AUC/MIC

PO

C

Data points were derived by forming ranges with 6 groups of 5 individual AUC/MICs and calculating mean probability of cure

10 Control pigs (no drug)

AUC/MIC

PO

C

Probability of cure (POC)

• Logistic regression was used to link measures of drug exposure to the probability of a clinical success

Independent variable

MICAUCbfaePOC

1

1

Dependent variable

Placebo effect sensitivity

2 parameters: a (placebo effect) & b (slope of the exposure-effect curve)

MICAUCe 0325.0405.01

1

Metaphylaxis(collective treatment)

0

0.2

0.4

0.6

0.8

1

1.2

0 50 100 150 200

AUC/MIC

PO

C

Conclusion step 2

Step 3

What is the dose to be administrated to guarantee

that 90% of the pig population will actually

achieve an AUC/MIC of 80 for an empirical (MIC

unknown)

Determination of a dose for a quinolone

%

hours)(per

Ffu

MICMICAUC

ClearanceDose BP

Breakpoint value e.g. 80h PD

Free fractionBioavailability

Solving the structural model to compute the dose for my new quinolone

• With point estimates– (mean, median, best-guess value…)

• With range estimates– Typically calculate 2 scenarios: the best case & the

worst case (e.g. MIC90)

– Can show the range of outcomes

• By Monte Carlo Simulations– Based on probability distribution– Give the probability of outcomes

Computation of the dose with point estimates (mean clearance and F%, MIC90)

%

hours)(per

F

MICMICAUC

ClearanceDose BP

BP: 80 MIC50=1µg/mL

Bioavailability=50%

9mL/Kg/h

Dose: 1.44mg/kg


Computation of the dose with point estimates (worst case scenario for clearance and F%, MIC90)

%

hours)(per

F

MICMICAUC

Clearance

Dose BP

BP: 80MIC90=2µg/mL

Bioavailability= 30%

15mL/Kg/h

Dose: 8.0 (vs. 1.44) mg/kg


Computation of the dose using Monte Carlo simulation

(Point estimates are replaced by distributions)

%

80

F

MICClearanceDose

Dose to POC=0.9

BPmetaphylaxis

Log normal distribution: 9±2.07 mL/Kg/h

Uniform distribution: 0.3-0.70

Observed distribution

• An add-in design to help Excel spreadsheet modelers perform Monte Carlo simulations

• Others features– Search optimal solution (e.g.

dose) by finding the best combination of decision variables for the best possible results


Metaphylaxis: dose to achieve a POC of 90% i.e. an AUC/MIC of 80

(empirical antibiotherapy)

Dose distribution

Computation of the dose: metaphylaxis(dose=2mg/kg from the dose titration)

Sensitivity analysis

• Analyze the contribution of the different variables to the final result (predicted dose)

• Allow to detect the most important drivers of the model


Sensitivity analysisMetaphylaxis, empirical antibiotherapy

Contribution of the MIC distribution

The second criteria to determine the optimal dose:

the MSW & MPC

Kinetic disposition of the new quinolone for the selected metaphylactic dose (3.8 mg/kg)(monocompartmental model, oral route)

0

1

2

3

4

5

6

7

8

0 5 10 15 20 25 30

Time (min)

co

nc

en

tra

tio

ns

(µ

g/m

L)

Série1

Slope=Cl/Vc=0.09 per h (T1/2=7.7h)

Log normal distribution: 9±2.07 mL/kg/h

MPC

Uniform distribution: 0.3-0.70

F%

con

cen

trat

ion

s

MIC

MSW

Computation of the dose (mg/kg): for given target attainment rates (TAR) for efficacy and to

prevent selection of mutants

Monte Carlo curative

Efficacy 3.8

To guarantee T>MPC in 90% of pigs for 50% the dosage interval

5.9

Question 2Ted Whittem

• What is the place of PK/PD, population kinetic and Monte Carlo Simulations in the rational development of a new antibiotic: the pro & cons, limits….

4-The right duration

When to start a treatment?

Disease health

TherapyMetaphylaxis

(Control)Prophylaxis(prévention)

Growth promotion

The different usages of antibiotics

HighHighPathogen loadPathogen load

SmallSmallNoNo

NANA

Antibiotic consumptionAntibiotic consumption

Only a risk factor

MICs estimated with different inoculmum densities, relative to that MIC at 2x105

Ciprofloxacin

Gentamicin

Linezolid

Daptomycin

Oxacillin

Vancomycin

The inoculum effect and Very Early Treatment (VET)

• Efficacious dosage regimen is different when the pathogen load is large, low or null

• Treatment should start as early as possible

• 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)

What was demonstrated

Early administrations were more favourable than late administrations

Metaphylaxis and Very Early Treatment (VET)

• I suggest to replace metaphylaxis by VET because metaphylaxis convey negative values– Confusion with mass treatment,– Confusion with prophylaxis

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

Question 3Marilyn Martinez

• What are the hurdles to the development of a new antibiotic or to the revisit an old antibiotic– Possibility or not to have several dosage regimen

(curative vs. control VS prophylaxis)

– Protection of innovation

– Regulatory climate

– Acceptance or not of PK/PD, Pop, MCS….

– Validity of susceptibility testing and development of appropriate breakpoints

– Hypothesis to test for clinical trial: non inferiority or superiority?

– ….

Conclusion

• You have 25 minutes to discuss theses 3 questions

how to establish a dosage regimen for a sustainable use of antibiotics in veterinary medicine

Documents

emergence of resistance

resistance open

resistance problemschentag

public health issues

public health concerns

animal health issuesthe

veterinary medicinep

veterinary medicineefficacy