Coping with Updated CLSI Coping with Updated CLSI Antimicrobial Antimicrobial

Susceptibility Testing Susceptibility Testing (AST) Challenges(AST) Challenges

  Janet A. Hindler, MCLS MT(ASCP)Janet A. Hindler, MCLS MT(ASCP)Sr. Specialist, Clinical MicrobiologySr. Specialist, Clinical MicrobiologyUCLA Medical CenterUCLA Medical Centerjhindler@ucla.edujhindler@ucla.edu

““and a consultant with the Association of Public and a consultant with the Association of Public

Health Laboratories”Health Laboratories”

At the conclusion of this talk, At the conclusion of this talk, you will be able to……you will be able to…… Discuss some differences between Discuss some differences between

CLSI and FDA breakpointsCLSI and FDA breakpoints.. List criteria used by CLSI to List criteria used by CLSI to set or set or

revise breakpoints.revise breakpoints. Describe strategies for Describe strategies for verifying verifying

newly revised CLSI breakpointsnewly revised CLSI breakpoints on a on a commercial AST system.commercial AST system.

CLSI AST Standards CLSI AST Standards November 2010November 2010

M100-S20 M100-S20 Tables Tables (January 2010)(January 2010)– Lowered cephalosporin & aztreonam Lowered cephalosporin & aztreonam

breakpoints (Enterobacteriaceae)breakpoints (Enterobacteriaceae) M100-S20-UM100-S20-U (June 2010) (June 2010)

– Lowered carbapenem breakpoints Lowered carbapenem breakpoints (Enterobacteriaceae)(Enterobacteriaceae)

EUCASTEUCAST EMEAEMEACLSICLSI FDAFDA

Sets breakpointsSets breakpoints Sets breakpointsSets breakpoints Sets breakpointsSets breakpoints

Manufacturers of AST systems must use FDA breakpointsManufacturers of AST systems must use FDA breakpoints

• CLSI = Clinical and Laboratory Standards Institute (formerly NCCLS)CLSI = Clinical and Laboratory Standards Institute (formerly NCCLS) • EUCAST = European Committee on Antimicrobial Susceptibility TestingEUCAST = European Committee on Antimicrobial Susceptibility Testing• EMEA = European Medicines AgencyEMEA = European Medicines Agency

Standards Standards SettingSetting

EMEA sets breakpoints EMEA sets breakpoints through EUCASTthrough EUCAST

RegulatoryRegulatory

Reassesses Reassesses breakpointsbreakpoints

2010 - developing 2010 - developing mechanism to reassess mechanism to reassess

breakpointsbreakpoints

Standards Standards SettingSetting RegulatoryRegulatory

Ceftriaxone Prescribing Information - FDA BreakpointsCeftriaxone Prescribing Information - FDA Breakpointshttp://media.pfizer.com/files/products/uspi_ceftriaxone.pdfhttp://media.pfizer.com/files/products/uspi_ceftriaxone.pdf

CLSI and FDA and EUCAST breakpoints CLSI and FDA and EUCAST breakpoints may differ because .….may differ because .….

Different criteriaDifferent criteria used to set breakpoints used to set breakpoints Sometimes different Sometimes different dosingdosing regimens; different regimens; different

clinical indications clinical indications (USA vs. Europe)(USA vs. Europe) Some breakpoints set Some breakpoints set many years ago many years ago and not yet and not yet

reassessed by respective agencyreassessed by respective agency

Examples (Enterobacteriaceae): Examples (Enterobacteriaceae):

AgentAgent CLSICLSI FDAFDA EUCASTEUCASTCeftriaxone Ceftriaxone ≤≤1*1* ≤≤88 ≤≤11GentamicinGentamicin ≤≤44 ≤≤44 ≤≤22MeropenemMeropenem ≤≤1*1* ≤≤44 ≤≤22

*new 2010*new 2010

Status of FDA Breakpoint RevisionsStatus of FDA Breakpoint Revisions

FDA Amendments Act (FDAAA)FDA Amendments Act (FDAAA) of 2007 of 2007 contains 200 provisions re: drug contains 200 provisions re: drug marketing/labelingmarketing/labeling– requires FDA to update drug labelsrequires FDA to update drug labels

FDA Guidance Documents (2009)FDA Guidance Documents (2009)– Will consider breakpoints of national or international Will consider breakpoints of national or international

standards organizationsstandards organizations– Describes approach for pharmaceutical companies to Describes approach for pharmaceutical companies to

update breakpoints in prescribing informationupdate breakpoints in prescribing information

CLSI leadership maintaining close watchCLSI leadership maintaining close watch

Why did CLSI lower cephalosporin, Why did CLSI lower cephalosporin, aztreonam, and carbapenem breakpoints aztreonam, and carbapenem breakpoints for Enterobacteriaceae? for Enterobacteriaceae? (1)(1)

Most of these breakpointsMost of these breakpoints were established over were established over 20 years ago (before ESBLs and when virtually all 20 years ago (before ESBLs and when virtually all Enterobacteriaceae were “S” to carbapenems)Enterobacteriaceae were “S” to carbapenems)

Newer tools / dataNewer tools / data to establish breakpoints (e.g., to establish breakpoints (e.g., PK/PD with Monte Carlo simulations) PK/PD with Monte Carlo simulations)

Increased knowledge of old and newer Increased knowledge of old and newer ββ-lactam -lactam resistance mechanismsresistance mechanisms

Revised breakpoints will better detect isolates Revised breakpoints will better detect isolates with awith a variety of resistance mechanisms variety of resistance mechanisms

Why did CLSI lower cephalosporin, Why did CLSI lower cephalosporin, aztreonam, and carbapenem breakpoints aztreonam, and carbapenem breakpoints for Enterobacteriaceae? for Enterobacteriaceae? (2)(2) Re: cephalosporin and aztreonam breakpointsRe: cephalosporin and aztreonam breakpoints

– CLSI ESBL test CLSI ESBL test only standardized for only standardized for E. coli, Klebsiella E. coli, Klebsiella spp. and Proteus mirabilis spp. and Proteus mirabilis (mid 1990s)(mid 1990s)

• ESBLs occur in other speciesESBLs occur in other species• ESBLs not always detected if multiple R mechanisms presentESBLs not always detected if multiple R mechanisms present

For ESBL positive isolates:For ESBL positive isolates:– Low MICsLow MICs to selected cephalosporins associated with to selected cephalosporins associated with

being poor substrates for specific ESBL being poor substrates for specific ESBL – Animal studies indicated Animal studies indicated % T > MIC% T > MIC did not differ for did not differ for

ESBL positive vs. ESBL negative ESBL positive vs. ESBL negative Enterobacteriaceae Enterobacteriaceae – Animal studies showed Animal studies showed no inoculum effectno inoculum effect w/ ESBL w/ ESBL

producersproducers

Why did CLSI lower cephalosporin, Why did CLSI lower cephalosporin, aztreonam, and carbapenem breakpoints aztreonam, and carbapenem breakpoints for Enterobacteriaceae? for Enterobacteriaceae? (3)(3)

Re: Carbapenem breakpointsRe: Carbapenem breakpoints– Carbapenem resistance Carbapenem resistance “issues” increasing “issues” increasing

rapidly rapidly – Phenotypic test for carbapenemasesPhenotypic test for carbapenemases [Modified [Modified

Hodge test (MHT)]Hodge test (MHT)]• Subjective interpretationSubjective interpretation• Does not detect all carbapenem “R” mechanismsDoes not detect all carbapenem “R” mechanisms

When applying revised cephalosporin, When applying revised cephalosporin, aztreonam and carbapenem breakpoints aztreonam and carbapenem breakpoints for….for…. Patient managementPatient management – no need to perform – no need to perform

testing (ESBL test, Modified Hodge test ) testing (ESBL test, Modified Hodge test ) to detect resistance mechanismto detect resistance mechanism

Surveillance, epidemiology, infection Surveillance, epidemiology, infection controlcontrol – ESBL and MHT tests (or other – ESBL and MHT tests (or other tests to detect resistance mechanism) tests to detect resistance mechanism) may be useful may be useful

www.eucast.orgwww.eucast.org

Setting / Revising BreakpointsSetting / Revising BreakpointsData Used by CLSI Data Used by CLSI

MIC distributions of MIC distributions of “wild type”“wild type” or normal or normal populations of bacteriapopulations of bacteria– Wild typeWild type = no acquired “R” mechanisms = no acquired “R” mechanisms

MICs associated withMICs associated with clinical outcome clinical outcome– Very Very limited “new” datalimited “new” data for older drugs for older drugs

Pharmacokinetic-pharmacodynamic Pharmacokinetic-pharmacodynamic (PK/PD) analysis(PK/PD) analysis

CLSI M23-A3 (2008) “Development of In Vitro Susceptibility CLSI M23-A3 (2008) “Development of In Vitro Susceptibility Testing Criteria and QC Parameters; Approved Guideline” Testing Criteria and QC Parameters; Approved Guideline” describes CLSI process for setting / revising breakpointsdescribes CLSI process for setting / revising breakpoints

www.eucast.orgwww.eucast.org

MEROPENEMMEROPENEM MIC distribution exampleMIC distribution exampleBlue = wild type isolatesRed = isolates w/ acquired “R” mechanism

What is PK/PD?What is PK/PD?

PK: pharmacokineticsPK: pharmacokinetics - the process by - the process by which a drug is absorbed, distributed, which a drug is absorbed, distributed, metabolized, and eliminated by the bodymetabolized, and eliminated by the body– Relates to drug concentration over timeRelates to drug concentration over time

PD: pharmacodynamicsPD: pharmacodynamics - the relationship - the relationship between concentration of drug and its between concentration of drug and its antimicrobial effects over time in vivoantimicrobial effects over time in vivo

PK/PDPK/PD can project potential efficacy of can project potential efficacy of antimicrobial agents in vivo antimicrobial agents in vivo

Key reference = Craig WA. 1998. CID. 26:1-10.Key reference = Craig WA. 1998. CID. 26:1-10.

Se

rum

Co

nce

ntr

ati

on

S

eru

m C

on

cen

tra

tio

n

(µg

/ml)

(µg

/ml)

Time (hours)

MIC MIC

Time above MICTime above MIC

dosedose dosedose

Cmax (peak concentration)Cmax (peak concentration)

PK/PD Goal (“Target”) for PK/PD Goal (“Target”) for ββ-lactams =-lactams =% of time during dosing interval that drug % of time during dosing interval that drug

levellevel in the patient exceeds MIC (%T > MIC)in the patient exceeds MIC (%T > MIC)

(hypothetical)(hypothetical)

What PK/PD target value is desired for What PK/PD target value is desired for ββ--lactams (e.g., “target attainment”)?lactams (e.g., “target attainment”)?

BacteriostaticBacteriostatic and and bactericidalbactericidal activity of activity of ββ-lactams -lactams depends on duration of time that free (unbound) drug depends on duration of time that free (unbound) drug levels exceed MIC (% T > MIC)levels exceed MIC (% T > MIC)

Drusano GL. 2004. Nat Rev Microbiol. 2:289.Drusano GL. 2004. Nat Rev Microbiol. 2:289.

*3 log reduction in colony-forming units*3 log reduction in colony-forming units

AntimicrobialsAntimicrobialsFree Drug % Time > MICFree Drug % Time > MIC

Bacteriostatic (%)Bacteriostatic (%) Bactericidal* (%)Bactericidal* (%)CephalosporinsCephalosporins 35-4035-40 60-7060-70PenicillinsPenicillins 3030 5050CarbapenemsCarbapenems 20-3020-30 30-4030-40

Factors that Affect PK/PD Factors that Affect PK/PD Target AttainmentTarget Attainment

Distribution of Distribution of pathogen MICspathogen MICs– (Species that would be treated with drug)(Species that would be treated with drug)

Drug Drug protein bindingprotein binding– (unbound drug is active)(unbound drug is active)

Drug Drug dosagesdosages– (various options for some drugs)(various options for some drugs)

Drug Drug administrationadministration – (e.g., frequency of dosing; length of infusion)(e.g., frequency of dosing; length of infusion)

Patient characteristicsPatient characteristics that affect drug distribution that affect drug distribution and clearance of drugand clearance of drug– (e.g., kidney function)(e.g., kidney function)

Monte Carlo SimulationMonte Carlo Simulation Used to answer question… Used to answer question… What percentage of What percentage of

patients are likely to attain the “target”?patients are likely to attain the “target”?– Target for Target for carbapenemscarbapenems = %T > MIC = %T > MIC

• 30-40% = bactericidal activity30-40% = bactericidal activity– Want Want ≥≥90% of patients to attain target90% of patients to attain target

Examine PK/PD data Examine PK/PD data by simulating dosing regimens by simulating dosing regimens and drug levelsand drug levels among a large sample of patients and among a large sample of patients and various MICsvarious MICs for pathogens that would be treated with for pathogens that would be treated with the drugthe drug– Plug in various MICs, dosing and drug levels that might be Plug in various MICs, dosing and drug levels that might be

encountered in many different patients (e.g., 1000 patients)encountered in many different patients (e.g., 1000 patients)

What PK/PD data were used to What PK/PD data were used to revise CLSI breakpoints?revise CLSI breakpoints?

Monte CarloMonte Carlo simulations simulations Studies in Studies in animal modelsanimal models and results and results

extrapolated to humansextrapolated to humans Limited clinical dataLimited clinical data

Goal - determine Goal - determine PK/PD MIC breakpointPK/PD MIC breakpoint that could predict the likelihood that a that could predict the likelihood that a specific drugspecific drug dose would be effective dose would be effective

against an organism with a specific MICagainst an organism with a specific MIC

Probability of Target Attainment Probability of Target Attainment Imipenem 1g every 8hImipenem 1g every 8h

S I R

42

Percent of patients Percent of patients likely to attain desired likely to attain desired

targettarget

1

Breakpoints (Breakpoints (µµg/ml):g/ml):Revised = Revised = ≤≤1 Old = ≤1 Old = ≤ 44

Sakka et al. 2007. AAC. 51:3304.Sakka et al. 2007. AAC. 51:3304.

AgentAgentCLSI 2010 (Old)CLSI 2010 (Old) CLSI June 2010 CLSI June 2010

(Revised)(Revised)

SuscSusc IntInt ResRes SuscSusc IntInt ResRes

DoripenemDoripenem -- -- -- ≤≤11 22 ≥≥44

ErtapenemErtapenem ≤≤22 44 ≥≥88 ≤≤0.250.25 0.50.5 ≥≥11

ImipenemImipenem ≤≤44 88 ≥≥1616 ≤≤11 22 ≥≥44

MeropenemMeropenem ≤≤44 88 ≥≥1616 ≤≤11 22 ≥≥44

Enterobacteriaceae - Carbapenems Enterobacteriaceae - Carbapenems Revised…Revised… Breakpoints (MIC Breakpoints (MIC µµg/ml)g/ml)

Corresponding disk diffusion breakpoints also revisedCorresponding disk diffusion breakpoints also revised

CLSI M100-S20-U

CLSI M100-S20-U CLSI M100-S20-U Revised Carbapenem Breakpoints and Dosing CorrelatesRevised Carbapenem Breakpoints and Dosing Correlates

S I RS I R S I RS I R

New CLSI Carbapenem Dosage New CLSI Carbapenem Dosage CommentComment

““Because of limited treatment options for Because of limited treatment options for infections caused by organisms with infections caused by organisms with carbapenem MICs or zone diameters in the carbapenem MICs or zone diameters in the intermediate rangeintermediate range, clinicians may wish to , clinicians may wish to design design carbapenem dosage regimens that carbapenem dosage regimens that use maximum recommended doses and use maximum recommended doses and possibly prolonged intravenous infusion possibly prolonged intravenous infusion regimensregimens as has been reported in the as has been reported in the literature.”literature.”

CLSI M100-S20 (June 2010)

S

S

RI

RIImipenemImipenemProbability of Probability of

Target AttainmentTarget Attainment22 44

Revised Breakpoints (Revised Breakpoints (µµg/ml):g/ml): ≤≤1S 2I 1S 2I ≥≥4R 4R

11

22 4411Sakka et al. 2007. AAC. 51:3304.Sakka et al. 2007. AAC. 51:3304.

Carbapenem MIC - Reporting StrategyCarbapenem MIC - Reporting StrategyOld BPsOld BPs11 Revised BPsRevised BPs22

Meropenem MIC (Meropenem MIC (µµg/ml)g/ml) 88 44 22 88 44 22

Report if MHT Report if MHT not donenot done Int Int SuscSusc SuscSusc ResRes ResRes IntInt

Report if MHT Report if MHT negativenegative IntInt SuscSusc SuscSusc ResRes ResRes IntInt

Report if MHT Report if MHT positivepositive ResRes ResRes33 ResRes33 ResRes ResRes IntInt

11 Perform MHT if MIC 2-4 Perform MHT if MIC 2-4 µµg/ml and “R” to g/ml and “R” to ≥≥1 31 3rdrd gen cephalosporin gen cephalosporin22 MHT not needed for routine patient reporting; may perform for MHT not needed for routine patient reporting; may perform for

Infection Control but DO NOT change “S” or “I” to “R”Infection Control but DO NOT change “S” or “I” to “R”3 3 Change from CLSI M100-S20 January 2010Change from CLSI M100-S20 January 2010

SuscSusc IntInt ResRes

OldOld ≤≤44 88 ≥≥1616

Revised Revised ≤≤11 22 ≥≥44

MeropenemMeropenemBreakpoints (Breakpoints (µµg/ml)g/ml) CLSI M100-S20-U

Specimen: Nasal washSpecimen: Nasal washDiagnosis: Respiratory distressDiagnosis: Respiratory distressKlebsiella pneumoniaeKlebsiella pneumoniae

amikacinamikacin >32 R>32 Raztreonamaztreonam >32 R>32 Rcefepimecefepime >32 R>32 Rceftazidimeceftazidime >32 R>32 Rceftriaxoneceftriaxone >32 R >32 Rciprofloxacinciprofloxacin >2 R>2 Rcolistincolistin 1*1*ertapenemertapenem >8 R**>8 R**gentamicingentamicin >10 R>10 Rimipenemimipenem 4 R**4 R**meropenemmeropenem 8 R** 8 R** piper-tazobactampiper-tazobactam >128 R>128 Rtigecyclinetigecycline 1 S1 Stobramycintobramycin >10 R>10 Rtrimeth-sulfatrimeth-sulfa >>4/76 R4/76 R

MIC (MIC (µµg/ml)g/ml) Modified Hodge Test Modified Hodge Test

NegativeNegative

CDC subsequently CDC subsequently confirmed (by PCR) confirmed (by PCR)

NDM-1 NDM-1 carbapenemasecarbapenemase

UCLA September 2010UCLA September 2010

* no interpretive criteria* no interpretive criteria** interpreted with Revised CLSI Breakpoints** interpreted with Revised CLSI Breakpoints

Brief CLSI and FDA Brief CLSI and FDA Breakpoint (BP) StoryBreakpoint (BP) Story

• Might be delay in addition Might be delay in addition of new BPs to commercial of new BPs to commercial systemsystem

• Use of CLSI or FDA BPs is Use of CLSI or FDA BPs is acceptable to acceptable to accrediting accrediting bodiesbodies; thus can use “Old” ; thus can use “Old” (same as FDA BPs) or (same as FDA BPs) or “New” CLSI BPs “New” CLSI BPs

• Labs can validate (verify) Labs can validate (verify) new BPs on commercial new BPs on commercial systemsystem

CLSI M100-S20

What criteria are used by FDA to determine if What criteria are used by FDA to determine if commercial AST systemcommercial AST system results are acceptable?* results are acceptable?*

CriteriaCriteria Defined as…Defined as… FDA Acceptable FDA Acceptable LimitsLimits

Essential Essential Agreement (EA)Agreement (EA)

TestTest MIC within +/- 1 MIC within +/- 1 doubling dilution of doubling dilution of

the the REFREF MIC MIC>89.9 %>89.9 %

Category Category Agreement (CA)Agreement (CA)

TestTest S, I, and R agree S, I, and R agree with with REFREF S, I, R S, I, R >89.9 %>89.9 %

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080564.htm

*must also meet criteria for very major, major and minor errors.must also meet criteria for very major, major and minor errors.

Manufacturers of commercial AST Manufacturers of commercial AST systems…systems… Cannot submit performance data for Cannot submit performance data for revised revised

CLSI breakpointsCLSI breakpoints until FDA revises until FDA revises breakpoints in each drug’s “Prescribing breakpoints in each drug’s “Prescribing Information”Information”

For Disk diffusionFor Disk diffusion– Manufacturer does not have to submit data to FDAManufacturer does not have to submit data to FDA– Cannot include Cannot include revised breakpointsrevised breakpoints in package in package

insert until FDA revises breakpoints in Prescribing insert until FDA revises breakpoints in Prescribing InformationInformation

Steps to Implementing Steps to Implementing Revised CLSI Cephalosporin, Aztreonam Revised CLSI Cephalosporin, Aztreonam

and Carbapenem Breakpointsand Carbapenem Breakpoints

1.1. Determine if Determine if low concentrationslow concentrations are are available on panelavailable on panel

2.2. Discuss with Discuss with stakeholdersstakeholders (lab director, (lab director, infectious diseases, pharmacy, infection infectious diseases, pharmacy, infection control, others)control, others)

3.3. Perform Perform “verification” “verification” ControversialControversial

4.4. Make Make computer / protocolcomputer / protocol changes changes

5.5. Inform stakeholdersInform stakeholders of changes of changes

Verification of Revised BreakpointsVerification of Revised BreakpointsPossible Isolate Selection Possible Isolate Selection

Revised Revised BreakpointsBreakpoints Isolates to Test for VerificationIsolates to Test for Verification

CarbapenemsCarbapenems • 5 carbapenemase (+) 5 carbapenemase (+) • 5 Modified Hodge Test (-) and elevated 5 Modified Hodge Test (-) and elevated

carbapenem MICscarbapenem MICs• 20 other Enterobacteriaceae20 other Enterobacteriaceae

Cephalosporins Cephalosporins and Aztreonamand Aztreonam

• 5 ESBL (+) 5 ESBL (+) • 5 ESBL (-) and ESBL screen positive5 ESBL (-) and ESBL screen positive• 20 other Enterobacteriaceae20 other Enterobacteriaceae (preferably with MICs within S range (preferably with MICs within S range

using old BPs)using old BPs)

S, I, RS, I, RTest MIC ASTTest MIC AST

(revised breakpoints)(revised breakpoints)

S, I, RS, I, RReference AST*Reference AST*

(revised breakpoints)(revised breakpoints)

* Disk diffusion, reference broth or agar dilution MIC, other MIC?

Acceptable = ≥90% overall categoric agreement No very major errors (false “S”) ≤7% combined major (false “R”) and minor errors (I/R or I/S)

Verify Revised BreakpointsVerify Revised BreakpointsDetermine Determine Categoric AgreementCategoric Agreement

vsvs

JH Suggestion (not CLSI recommendation)JH Suggestion (not CLSI recommendation)

CeftriaxoneCeftriaxone MIC ( MIC (µµg/ml) vs. Zone Diameter (mm)g/ml) vs. Zone Diameter (mm)CLSI Previous (MIC CLSI Previous (MIC ≤≤8; zone 8; zone ≥21)≥21) vs. Revised (MIC vs. Revised (MIC ≤≤1; zone 1; zone ≥23)≥23)

Breakpoints for EnterobacteriaceaeBreakpoints for Enterobacteriaceae

Jones et al. 2005. Diagn Microbiol Infect Dis. 52:235-246.Jones et al. 2005. Diagn Microbiol Infect Dis. 52:235-246.

previousprevious

SuscSusc

ResRes

revisedrevised

Example: Categoric (S, I, R) Agreement Example: Categoric (S, I, R) Agreement Test MICTest MIC Panels vs. Reference Disk Diffusion Panels vs. Reference Disk Diffusion

Old vs. Revised Breakpoints - Old vs. Revised Breakpoints - CeftriaxoneCeftriaxone

StrainStrainTestTestMICMIC

((µµg/ml)g/ml)

RefRefDD DD

(mm)(mm)

OLD Breakpoints (S, I, R)OLD Breakpoints (S, I, R) Revised Breakpoints (S, I, R)Revised Breakpoints (S, I, R)

Test MICTest MIC Reference DDReference DD Test MICTest MIC Reference DDReference DD

≤≤8, 16-32, 8, 16-32, ≥≥6464 ≥ ≥21, 14-20, 21, 14-20, ≤≤1313 ≤≤1, 2, 1, 2, ≥≥44 ≥ ≥23, 20-22, 23, 20-22, ≤≤1919

11 11 2525 SS SS SS SS

22 44 2323 SS SS RR SS

33 44 2121 SS SS RR II

44 88 1919 SS I I RR RR

55 3232 1212 RR RR RR RROld Breakpoints:Old Breakpoints: 1 minor error 1 minor error Revised Breakpoints:Revised Breakpoints: 1 major errors (false R)1 major errors (false R)

1 minor1 minor errorerror

UCLA) Decisions re: Revised UCLA) Decisions re: Revised Enterobacteriaceae BreakpointsEnterobacteriaceae Breakpoints

Adopted revised Adopted revised carbapenemcarbapenem breakpoints breakpoints– Perform MHT on requestPerform MHT on request– (note: meropenem concentrations on urine panels not low enough; (note: meropenem concentrations on urine panels not low enough;

will test isolates “R” to ceftriaxone and piperacillin-tazobactam by will test isolates “R” to ceftriaxone and piperacillin-tazobactam by disk diffusion method)disk diffusion method)

Adopt revised Adopt revised cephalosporincephalosporin breakpoints breakpoints– Continue ESBL testing (Continue ESBL testing (E. coli, Klebsiella, P. mirabilisE. coli, Klebsiella, P. mirabilis))– Edit “S” results to “R”Edit “S” results to “R” for cephalosporins, penicillins, and for cephalosporins, penicillins, and

aztreonam for ESBL producersaztreonam for ESBL producers– Inform Infectious Diseases of ESBL-producing isolates that have Inform Infectious Diseases of ESBL-producing isolates that have

“S” MICs to one or more cephalosporins or aztreonam for follow up“S” MICs to one or more cephalosporins or aztreonam for follow up– CefazolinCefazolin

• Use old breakpoints (S, MIC Use old breakpoints (S, MIC ≤≤8 8 µµg/ml) for urine isolates (limitations g/ml) for urine isolates (limitations understood by medical staff) understood by medical staff)

• Use Use revised 2011 breakpoints (S, MIC revised 2011 breakpoints (S, MIC ≤≤2 2 µµg/ml)g/ml) for other isolates for other isolates

www.clsi.org