PK/PD APPROACH AND ANTIMICROBIAL RESISTANCE

Pierre-Louis Toutain, Ecole Nationale Vétérinaire

INRA & National veterinary School of Toulouse, France

7th International Conference on antimicrobial agents in veterinary medicine Berlin September 16-19,2014

1

Introduction

• PK/PD concepts are now well established to determine the dosing regimen for antimicrobials (AM) in veterinary medicine. – the previous presentation by Stefan

• The main goal is to optimize clinical efficacy, but the risk of resistance development has

been generally ignored in these dose optimizations

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But of what resistance are we speaking?

3

4

Prevent emergence of resistance: but of what resistance?

Target pathogensTarget pathogens ZoonoticsZoonotics CommensalCommensal

Efficacy in animals Efficacy in man

Global ecological problem

Human Individual issue

Public health issueAnimal health issueAnimal health issue

Food chainFood chain EnvironmentEnvironment

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

6

The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal

health issues

A trade-off between these two objectives is difficult or even impossible to achieve due to the

non selectivity of most veterinary antibiotics.

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Outline of the presentation• The classical integrated PK/P indices and the

question of resistance: the MSW• The limits of the MSW• The mechanism-based models• Options to mitigate emergence and selection

of resistance– Early/low dose treatment– Duration of treatment– Dug combinations

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The mutant Selective Window(MSW)

Currently the MSW is the only PK/PD index that is use to mitigate the emergence of

resistance

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Selective pressure for antibiotic concentration lower than the MIC

MIC

Time

Concentration

Traditional hypothesis on emergence of AMR

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No antibiotics & low inoculum size

Current view for the emergence and selection of resistance : situation II

With antibiotics

Mutation rate10-8

eradication

susceptible résistant

Wild pop No Mutant pop

105 CFU105 CFU

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No antibiotics & high inoculum

Current view for the emergence and selection of resistance : situation II

With antibiotics

Mutation rate10-8

eradication

susceptible Mutants population

Wild pop

Mutant pop5-10xMIC=MPC

108 CFU108 CFU

Mutation rate10-8

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Nice buiatric 2006-13

The selection window hypothesis

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

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

MICSelective concentration (SC)to block wild-type bacteria

MICSelective concentration (SC)to block wild-type bacteria

Plas

ma

conc

entr

ation

s

All bacteria inhibited

Growth of only the most resistant subpopulation

Growth of all bacteria

Mutant Selection window

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MIC & MPC for the main veterinary quinolones for E. coli & S. aureus

The MSW

• The concept PK/PD of MSW was shown to be useful for quinolones for which resistance develops by mutational alterations of the drug target, but the concept is less clear for others mechanisms of resistance (e.g. plasmid mediated resistance) and for other classes of antibiotics even if the MIC/MPC ratio has been proposed for a variety of veterinary antibiotics (macrolides, cephalosporines, florfenicol)

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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

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Vet Microbiol 2012 Blondeau JM

MSW: target pathogen vs. commensal flora

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In the present study, we used fecal samples collected from these volunteers during and after ciprofloxacin treatment to analyze the

dynamics of the emergence of resistance in E. coli over time in each volunteer.

In the present study, we used fecal samples collected from these volunteers during and after ciprofloxacin treatment to analyze the

dynamics of the emergence of resistance in E. coli over time in each volunteer.

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Effect of ciprofloxacine on E coli• During antibiotic exposure (on days 8 and 14), no E.

coli could be detected in most volunteers. – This was explained by the high fecal concentrations of

ciprofloxacin, which was several thousand times greater than both the MIC and the mutant-prevention concentration against the dominant flora .

• Selection of resistance was unlikely during treatment.– The appearance of QREC strains 4 weeks after the end of

ciprofloxacin therapy was observed • explained by the pharmacokinetics of ciprofloxacin in stool,

because ciprofloxacin concentrations slowly decreased from day 14 to day 42, when they were undetectable, with ciprofloxacin concentrations passing through the mutant selection window between days 14 and 42, when emergence of resistance was eventually detected in the fecal microbiota.

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MSW: biophase vs Feces

Time

StoolsStools

MPCTarget pathogen

MIC

QRECFrom environment

QRECFrom environment

MSWMSW MSWMSW

1

10

100

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What is the better option :Collective vs. selective treatment

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The limit MSW and of PK/PD indices and of their breakpoint values regarding the resistance

issues

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The limit of MSW

• simulations with more advanced semi-mechanistic PK/PD models showed that the classical PK/PD indices, including the MSW, have several major limitations and there is a need to go beyond these summary PK/PD variables to efficiently combat resistance by designing appropriate dosage regimens.

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The three mains limits of classical PK/PD and MSW indices

• They ignore information on the time-course of the PK and PD.– The U shaped curve of the MSW

• They rely on the MIC that is not a PD parameter but a hybrid variable.

• They are established on 24 hours, a too short period to study the adaptation of the bacteria to antibiotic drug exposure and selection of resistant bacterial subpopulations

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T>MIC for 40-50% of the dosing interval:Daily dosing vs. long-acting drug

MIC

Both treatments ensure plasma concentrations above MIC for 50% of the dosing interval (1 or 14 days) but they are not equivalent

Daily formulationLong-acting drug/formulation

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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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What is a MIC?

• An hybrid variable• Its reflects:

– The drug potency– The drug efficacy – the bacterial growth rate,– the bacterial death rate – and many other factors associated to its in vitro

measurement (inoculum size, selected milieu, etc.).

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What is a MIC?An hybrid variable

From a mechanistic model point of viewAM Potency

Rate of growth(supply shortage)

Rate of deathDefense mechanisms

AM efficacy

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Effect of resistance on Kkill

• The observed killing rate is a function of the natural death rate(0) times a scalar given by the Emax function

Target site alterationReduced Emax=Kkillmax/Kdeath

Target site alterationReduced Emax=Kkillmax/Kdeath

Drug efflux pumps and enzymatic drug deactivation increase EC50

Can be surmounted by a higher dose

Drug efflux pumps and enzymatic drug deactivation increase EC50

Can be surmounted by a higher dose29

What is a MIC

• The MIC value is only a snaphot measure of the net effect of the antibiotic under well standardized conditions (18-24h, constant AM concentration).

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Clinical Pharmacokinetics 2005 44 201-210

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Investigation of resistance require more than 24h

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Impact on the total population of Staphylococcus aureus over time by two regimens of garenoxacin (in vitro model)

The less intense regimen ceases to be effective after a delay of 5 days.

the residual population to be eradicated by the immune systemThe less intense regimen ceases to be effective after a delay of 5 days.

the residual population to be eradicated by the immune system33

Impact on the less-susceptible population of S. aureus over time by two regimens of

garenoxacin.

If therapy had been ended at day 4 or 5, little or no resistant mutant amplification would have occurred

If therapy had been ended at day 4 or 5, little or no resistant mutant amplification would have occurred 34

Limits of the classical PK/PD indices to limit resistance

• Therefore, the classical PK/PD indices are not well suited to understand and predict the emergence of resistance.

• They are also unable to characterize the effect of drug combinations that are one of the best options to combat resistance

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Mechanism-based model of antimicrobials

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The value of mechanism-based models

• These models aim to give a better understanding of the PK/PD relationship when modeling the full time-course of bacterial growth and killing.

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A major review

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The mechanism-based models:4 submodels

• Models including equations to describe:– The microorganisms growth: microorganisms sub-

model,– the changing drug concentration: PK model– The effect of AM drug: PD sub-model

• to describe the interaction between the two preceding sub-models.

– They can also include a sub-model for the host defenses.

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Mechanism-based model of antimicrobials

• Equation with:– no replication inhibition– Time-invariant susceptibility to drug– Constant replication rate

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The microorganism sub-models

• The microorganism sub-models can consider simultaneously different bacterial subpopulations with different levels of susceptibility and they can differentiate different mechanisms of resistance (alteration of the mutation rate, adaptative resistance, persisters)

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PK/PD model for resistance and predicted bacterial time-kill curves

B1, compartment with drug sensitive bacteria; B2, compartment with less drug-sensitive bacteria;

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PKPD model for resistance (persisters) and predicted bacterial time-kill curves

B1, compartment with drug sensitive bacteria; B3, compartment with non growing, drug-insensitive bacteria

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The mechanism-based models

• The mechanism-based model can be used for many purposes to test mechanistic hypotheses, to predict untested doses and complicated dosing regimens (PK mimicking in vivo situations, drug combinations, duration of treatment, etc).

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Classical PK/PD indices vs. semi-mechanistic models

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Classical PK/PD indices vs. semi-mechanistic models

• These semi-mechanistic models are able to predict the classical PK/PD indices and their breakpoint values.

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Classical PK/PD indices vs. semi-mechanistic models

• However, they also predict that when the AM half-life is short, the best predictor is always T>MIC and when the half-life is long, the best predictor is always AUC/MIC whatever the antibiotic.

• For long-acting formulations AUC/MIC is likely an universal PK/PD index – This would greatly facilitate many tasks such as

finding an optimal dosage regimen and fixing sound clinical breakpoints for susceptibility testing.

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How to mitigate emergence of resistance: practical aspects

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How to combat resistance

• Early initiation of AM therapy• Short duration• Combination therapy with 2

antibiotics

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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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marbofloxacin, amoxicillin & cefquinome

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Low dose and gut microbiota

• In addition this strategy of an early low-dose treatment will be considered as the best in terms of public health to minimize the unselective impact of most AM used in veterinary medicine on the gut microbiota.

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Duration of therapy

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Reducing exposure by reducing the duration of therapy and prophylaxis

• With rare exceptions (e.g. bacteremia due to S. aureus, endocarditis, osteomyelitis), there is no evidence to support most of the traditional 10–14-day courses of antibiotics, which are based more on conventional wisdom than strong evidence.

• Short-course therapy for urinary tract infection, acute otitis media, tonsillopharyngitis, sinusitis and pneumonia is slowly gaining support (MASTIN study group, 2002; Lutters and Vogt, 2002).

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The one-shot therapy

• The so-called one-shot therapy is the veterinary option to minimize the treatment duration.

• Using PK/PD mechanistic models, it was shown that the killing rate of concentration dependent AM was dose-dependent and the goal of the one-shot high dose therapy is to kill as rapidly as possible the target pathogens or at least a sufficient fraction of the initial load to allow the host natural defenses to eradicate the remnant bacterial population.

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Increasing exposure trough combination therapy

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What is the clinical value of AM combination?

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Conclusion (1)

1. The optimization of dosing regimens should be accomplished by choosing the dose and schedule that results that will achieve the microbiological and clinical outcome desired while simultaneously suppressing emergence of resistance on both the target and commensal flora.

2. Early treatment and short duration are currently the two best options

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Conclusions (2)

3. To combat resistance and the public health impact, the best strategy is likely to be to develop new antibiotics that are selective for the target pathogens and not impacting the gut microbiota (green antibiotics).

4. While waiting for this new generation of veterinary antibiotics, we have to revisit the current dosage regimens of antibiotics (dose, dosing interval and treatment duration)

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Conclusion (3)5. This reevaluation should take into account the

different possible clinical conditions that are faced in veterinary medicine (curative, metaphylaxia and prophylaxia) and consider that a single regimen does not fit all.

6. As veterinary medicine is resources-limited and cannot test experimentally all possible situations and hypotheses, veterinary pharmacologists should explore more deeply the class of these so-called mechanism-based models and their regulatory acceptance should be rapidly considered.

•

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