Resistance testing challenges and solutions with emphasis on patient care

(1)

Pierrette

Pierrette MelinMelin

Medical microbiology, University hospital of Liege, Belgium

RESISTANCE TESTING CHALLENGES

AND SOLUTIONS

WITH EMPHASIS

ON PATIENT CARE

(2)

(3)

Clinical

Microbiology

_Microbiology

Laboratories

_Laboratories

Current

Challenges

Specimen Specimen Analysis : Analysis : Relevant Relevant Pathogens Pathogens Patient Patient’’s s optimized optimized management management

Identification

AST

Specimen collection Specimen collection

Cost effective & timely

Decreasing resources !

RESISTANCE:

• _{Detection / method-dependant} • _{Level of in vitro expression}

• _{Predictive value}

• _{Microbiological & therapeutic} interpretations

(4)

INCREASE

OF

FAILURES

Very

high

levels

of

Resistance

emergence

+

spread

+

escalation

A

(5)

Some

of

_of

the

_the

XXI

_XXI

st

_century

_-

-Challenges

Challenges

in

_in

infectious

_infectious

diseases

_diseases

Microorganisms

Increasing antimicrobial Resistance

Resistance determinant

«

Pathogens

»

evolution

Patients and medical improvements

Critical care

Immuno

-

compromised

(6)

The

challenging

_challenging

pathogens

_pathogens

In

hospital

S.aureus

(MRSA, (MRSA, GISA, VRSA)

GISA, VRSA)

Enterococci

(GRE)(GRE)

Enterobacteriaceae

(ESBL,

(ESBL, carbapenemasecarbapenemase, , FQ) FQ) MDRMDR--

P.aeruginosa

MDRMDR--

Acinobacter

baumanii

In

community

MDRMDR

-

S.pneumoniae

CACA--MRSAMRSA

Salmonella

(ESBL,(ESBL, FQ)FQ)

Campylobacter

(FQ, (FQ, macrolides)

macrolides)

HelicobacterHelicobacter pyloripylori

(7)

Appropriate

therapy

saves

lives

Early

inappropriate

therapy

Increase

of

mortality

in

severe

infection

Infection

with

antibiotic

-

R

bacteria

Increase

of

risk

of

inappropriate

therapy

Antibiotic

-

R

organisms

More

commonly

associated

with

inadequate

therapy

Streamlining

therapy

to

narrow

spectrum

drug

Saving

costs

Weinstein

Weinstein et et alal. Clin Infect Dis 1997:24:584. Clin Infect Dis 1997:24:584 Kollef

(8)

Appropriate

therapy

saves

lives

Target

empiric

therapy

to

likely

pathogens

,

basedbased on on hospitalhospital, , regionalregional, , specificspecific epidemiology

epidemiology

.

Target

definitive

therapy

to

known

pathogens

,

(9)

Who

/

_/

What

_What

do

_do

we

_we

treat

_treat

?

_?

Patient ?

Disease

?

Bug ?

(10)

Main goals

of

_of

anti

_anti

-

_-

infective

_infective

therapy

Clinical

cure

of

patients

Eradicating

the

pathogens

To

avoid

development

of

resistance

To

avoid

transmission

By

By givinggiving «« supposedlysupposedly »» oror provenproven effective effective antibioticantibiotic Choices

Choices oftenoften basedbased on on resultsresults in in termsterms ofof «« SS »» or or «

(11)

SIR,

bacteria

_bacteria

are

_are

not

_not

simply

_simply

«

S

»

or

«

Non S

»

S

Varies Varies overover a a widewide rangerange

May May bebe quantifiedquantified by MICby MIC

May May resultresult in in overdosingoverdosing or or underdosingunderdosing

RiskRisk ofof R R developmentdevelopment

UnnecessaryUnnecessary costscosts

IncreaseIncrease morbiditymorbidity//mortalitymortality

(12)

ACCURATE DETECTION

ACCURATE DETECTION ofof clinicallyclinically &

& epidemiologicallyepidemiologically significantsignificant R

R--determinantsdeterminants

COST

COST--EFFECTIVE EFFECTIVE to patient care to patient care & infection control

(13)

Are AST

results

clinically

relevant &

reliable

?

Therapeutic

predictive

values

Many

variables

affecting

results

Standardization

In

vitro

// in vivo ?

Current

breakpoints

S, I, R

(14)

Different

(15)

Are AST

results

_results

clinically

_clinically

relevant

-

reliable

?

Therapeutic

predictive

value

Many

variables

affecting

results

StandardizationStandardization / /

in vivo ?

Current

breakpoints

S, I, RS, I, R

NCCLS, BSAC, SFM, NCCLS, BSAC, SFM, JapaneseJapanese, , ……..

SafetySafety or or efficacyefficacy ??

EvolutionEvolution

//

pharmacology

-

pharmacodynamics

?

ββββββββ--lactamslactams, , aminoglycosidesaminoglycosides, FQ, FQ

Expression

of

resistance

?

Detection

?

ART

(16)

MIC

determinations

_{determinations}

and

_and

PK/PD

model

_model

Ser

Ser.. Conc

Conc PEAK PEAK CmaxCmax

MIC MIC AUC AUC TIME > MIC TIME > MIC

(17)

Practical

recommendations

for

PK/PD

-

optimized

therapy

Drug

Drug classclass RecommendationsRecommendations

B

B--lactamslactams --remainremain > MIC for > MIC for atat leastleast 50 % 50 % ofof thethe timetime

--FractionateFractionate thethe dosedose Aminoglycosides

Aminoglycosides --ObtainObtain CmaxCmax/MIC ratio /MIC ratio ofof atat leastleast 88

--AdministerAdminister once once dailydaily Fluoroquinolones

Fluoroquinolones --ObtainObtain a 24a 24--H AUC/MIC ratio > 125H AUC/MIC ratio > 125

--ObtainObtain CmaxCmax/MIC ratio /MIC ratio ofof atat leastleast 88

--Do Do notnot overfractionateoverfractionate thethe dailydaily dosedose

--ConsiderConsider loweringlowering breakpointsbreakpoints for for olderolder FQFQ Etc.

(18)

AST

methods

_methods

routinely

_routinely

used

_used

in Belgium

((E.faeciumE.faecium EQCEQC--ISP 2003) ISP 2003)

«

Disk

»

diffusion

PaperPaper discsdiscs 25 %25 %

RoscoRosco tabletstablets 50 %50 %

«

MIC

»

Automated

system

VitekVitek 1 1 7.5 %7.5 %

VitekVitek 22 17 %17 %

Real

MIC

Etest

(19)

AST

methods

_methods

routinely

_routinely

used

_used

Real

Real MICMIC Low

Low//veryvery highhigh ++

++

All

All kindskinds ofof organisms

organisms, , eveneven slow

slow growinggrowing Large range

Large range ofof MICs

MICs

Time

Time consumingconsuming «

« MICMIC »» High

High//highhigh

-Workload

Workload, , TAT,

TAT, qualityquality Reproducibility

Reproducibility

Sofware

Sofware expertexpert Not

Not for +/for +/- -fastidious fastidious, , …… Black box Black box R expression ? R expression ? Limited

Limited range range ofof MICs

MICs

S, I, R S, I, R Low

Low//LowLow ++

++

Not

Not for for fastidious fastidious, , …… False False SS // // BreakpointsBreakpoints Results Results Cost

Cost ((InvestInvest././fctfct)) Flexibility

Flexibility

Pro & Contra

E test

Vitek

Vitek/Phoenix/Phoenix D.Diffusion

(20)

To

prevent

_prevent

antimicrobial

_{antimicrobial}

R

_R

= to

treat

_treat

infections

_infections

effectively

_effectively

Detection

of

Resistance

Target optimal

therapy

ChoiceChoice ofof thethe mostmost potentpotent drugdrug in classin class

GivingGiving optimal optimal regimenregimen

To maximise To maximise effecteffect

To To enhanceenhance bacterialbacterial eradicationeradication

To minimise To minimise developmentdevelopment ofof RR

Strategies

using

PK/PD

parameters

Real

(21)

Improvement

expected

for

clinical

microbiology

_microbiology

lab.

_lab.

Detection

of

resistance

Determination

of

true

MICs

To

be

cost

effective

To To definedefine clinicalclinical circumstancescircumstances requiringrequiring MICMIC

To To identifyidentify organismsorganisms requiringrequiring MICMIC

To To definedefine organismsorganisms, , phenotypesphenotypes or or clinicalclinical circumstances

circumstances requiringrequiring specificspecific methodmethod for for detection

(22)

Clinical

circumstances

_{circumstances}

worthy

_worthy

of

MICs

Patients

ICU or

other

high

risk

patients

Infections

Endocarditis

Meningitidis

Cystic

fibrosis

,

other

chronic

infections,

sterile

site infections

Serious

nosocomial infections

Versus

(23)

Treatment

of

_of

streptococcal

_{streptococcal}

endocarditis

MIC < 0.1 mg/L

Penicillin

G for 4

weeks

MIC 0.1

-

0.5 mg/L

Penicillin

+

gentamicin

2

2 weeks

weeks

;

penicillin

2

2 weeks

weeks

MIC > 0.5 mg/L

(24)

Organisms

or type

_{or type}

of

_of

R to

_{R to}

detect

worthy

_worthy

of

_of

Etest

_Etest

MICs

_MICs

R

proned

, invasive, virulent

S.pneumoniae

N.gonorrhoeae

FastidiousFastidious bacteriabacteria : NF GNB, GPB, : NF GNB, GPB, etcetc

AnaerobesAnaerobes

OpportunistOpportunist withwith nono defineddefined interpretativeinterpretative criteriacriteria

YeastsYeasts, , fungifungi

Confirmation / Confirmation / DetectionDetection ofof RR

PenicillinePenicilline (Pneumo)(Pneumo)

GlycopeptidesGlycopeptides ((staphylostaphylo, , enterococcienterococci))

(25)

Enterococci

AST

_AST

algorithm

_algorithm

Urine,

Urine, othersothers BloodBlood or or sterile sterile sitesite

Etest

Etest/MIC/MIC

Ampicillin Ampicillin Teicoplanin Teicoplanin Vancomycin Vancomycin HL HL GentamicinGentamicin HL HL StreptomycinStreptomycin Disc Disc Ampicillin Ampicillin Vancomycin Vancomycin FQ FQ Nitrofurantoin Nitrofurantoin Etest

Etest/MIC /MIC secondarysecondary

Rifampicin Rifampicin Chloramphenicol Chloramphenicol Minocycline Minocycline VA VA RR VA VA I orI or RR Etest primary Etest primary Ampicillin Ampicillin Vancomycin Vancomycin VA VA RR

(26)

Staphylococci

AST

_AST

algorithm

_algorithm

S.aureus

S.aureus CNS, urinesCNS, urines

Disc

Disc diffusiondiffusion Vitek Vitek Vancomycin Vancomycin I I or or MIC > 2 MIC > 2 Or Teico I / MIC > 4 ICU,

ICU, critical critical specimen specimen

MIC

Etest

Unusual Unusual results results

(27)

Gram positive

Bacilli

_Bacilli

AST

_AST

algorithm

_algorithm

Sterile

Sterile site, pure culturesite, pure culture Multiple positive

Multiple positive bloodblood culturescultures

Bacillus sp Bacillus sp Corynebacterium sp Corynebacterium sp Etest Etest Penicillin Penicillin Cefotaxime Cefotaxime Vancomycin Vancomycin FQ FQ Etest Etest Penicillin Penicillin Clindamycin Clindamycin Vancomycin Vancomycin FQ FQ