2. About CLSI
• Clinical and Laboratory Standards Institute (
Previously NCCLS)
• International, voluntary, educational, not-for
–profit , interdisciplinary organization
• Accredited by American National Standards
Institute
• Guidelines are formulated to improve
diagnostic health care
4. CLSI Vs FDA
• CLSI tests investigational drugs
• FDA may/may not change after CLSI
changes
• Review is done by FDA if changes occur
• Industry people must follow FDA
5. EUCAST is organised by
European Society for Clinical Microbiology and Infectious
Diseases (ESCMID),
European Centre for Disease Prevention and Control
(ECDC),
Active national antimicrobial breakpoint committees in
Europe.
EUCAST was established by ESCMID in 1997,->
restructured in 2001-2002 and has been in operation in its
current form since 2002.
Financed by
- ESCMID
- National Breakpoint committees in Europe
6. Europe had a number of different breakpoints – setting
authorities….and therefore different breakpoints…..
Breakpoint committees 2016
7. Disc test from EUCAST and CLSI
EUCAST
• Mueller Hinton
• Inoculum 0.5 McF
• Incubation 16-20
+/_2h
• MH + 5% Horse blood
and 20 mg β – NAD
for fastidious
organism
• Disc strengths
• QC strains and
reference ranges
CLSI
• Mueller Hinton
• Incubation 18 +/_2h
• Disc strengths
• QC strains and reference
ranges
• Presence of
Intermediate and
susceptible dose
dependent category
• Recent introduction of
Epidemiological cut off
• New screening methods
for CRE
8. Staphylococcus species EUCAST vs. CLSI
(EUCAST 2017, CLSI 2017)
ANTIMICROBIAL
EUCAST(mg/L) CLSI
(mg/L)
S ≤ R> S I R
CEFTAROLINE 5μg
S.aureus only
≥20mm ≤20mm -
MIC ≤1 >1 -
Ceftobiprole 5 μg
S.aureus only
≥17mm ≤17mm -
MIC ≤2 >2 -
Ciprofloxacin 5μg ≥21mm ≤21mm ≥21 16-20 ≤15
24 24CONS
MIC ≤1 >1 ≤1 2 ≥4
levofloxacin5μg ≥22mm ≤22mm ≥17 14-16 ≤13
MIC ≤1 >1 ≤2 4 ≥8
Gentamycin10μg ≥18mm ≤18mm ≥15 13-14 ≤12
MIC ≤1 >1 ≤4 8 ≥16
Amikacin30μg ≥18mm ≤16mm ≥17 15-16 ≤14
MIC ≤8 >16 ≤16 32 ≥64
9. EUCAST and CLSI are different
EUCAST CLSI
Established 1997 1970
Membership Representatives of
national breakpoint
committtes &
medical profession
Medics, science,
industry, regulators
Relation to regulator Dialogue with
ECDC, EMEA
5-6 meetings per
year
2 meeting per yr
Relation to industry Consultation with
industry
Full members
Decisions Consensus Voting
(www.eucast.org, www.clsi.org)
10. EUCAST and CLSI are different
EUCAST CLSI
Work Sets breakpoints
for European
Medicines Agency,
Advices
ECDC,EFSA
US-FDA sets
breakpoints
Funding ECDC, ESCMID
National
committees
Industry and sales
Outputs ECOFF,
CBs,Resistance
Detection,Expert
rules
Gradually included
some this year
Rationales Published Not published
Documents Free download For
11. CLSI Vs FDA
• CLSI tests investigational drugs
• FDA may/may not change after CLSI
changes
• Review is done by FDA if changes occur
• Industry people must follow FDA
12. General points
• Group A – routine primary testing
• Group B- primary testing but selectively ( group A
resistant, polymicrobial infections, drug allergy,
intolerance)
• Group C- multidrug resistant drugs very common
• Group U- primarily urinary use only
• Group O- clinical indication but not routinely tested
in USA
• Group Inv. – not approved by FDA
13. General points
• Susceptible: ( S) resulting in likely clinical
efficacy
• Susceptible dose-dependent ( SDD):
Susceptibility is dependent on dosing
regimen
• Cefepime- Enterobacterales
• Cefaroline- Staphylococcus aureus
• Daptomycin- Enterococcus faecium
14. • Intermediate (I): response lower than
susceptible isolates
• Resistant: ( R) Isolates not inhibited by
usually achievable concentrations or
specific resistance mechanisms
• Nonsusceptible: (NS): absence or rare
occurrence of resistant strains
15. Definitions
• Routine test: tests for routine clinical testing
• Supplemental test: methods other than routine
disk diffusion and dilution
• Screening tests: presumptive tests and need
additional testing
• Surrogate agent testing: replaces drug of
interest
• Equivalent agent testing: predicts result of
closely related drugs of same class
23. Added azithromycin Disc diffusion and MIC breakpoint
for Shigella spp
Shigella
Salmonella
S= 16 or more 13 or more
I= 11 to 15
R= 10 or less 12 or less
S= 8 or less 16 or less
I= 16
R= 32 or more 32 or more
24. Treatment of Shigella
1. First line: Fluroquinolones
2. Second line: Beta lactams, Cephalosporins
Now azithromycin can be used as second line agent where
resistance to fluroquinolones high and among macrolides,
azithromycin preferred
25. Added azithromycin disc diffusion breakpoint for N.gonorrheae
S= more than 30
S= MIC 1 or less
Treatment:
1. Ceftriaxone 500 mg IM single dose
2. Gentamicin 240 mg IM single dose plus
azithromycin 2 gm orally single dose
26. Added Imipenem-relebactam disc diffusion and MIC
breakpoint for
Enterobacterales and Pseudomonas aeruginosa
MIC breakpoints for Anaerobes
Enterobacterales Pseudomonas aeruginosa
S= 25 or more S= 23 or more
I= 21-24 I= 20-22
R= 20 or less R= 19 or less
S= 1/4 S= 2/4
I= 2/4 S= 4/4
R= 4/4 or more S= 8/4
27. Beta Lactamase Inhibitors
• Protects beta lactam antibiotics from enzymatic
hydrolysis
• Current ones- active against Class A beta lactamases
• Poor activity against class C and D enzymes
• Newer agents – activity against class C and D enzymes,
with Carbapenems increase activity against MBLs
28. Relebactam
There are six betalactamse inhibitors:
Sulbactam, clavulanic acid, tazobactam, avibactam,
vaborbactam,
Relebactam
•Relebactam inhibits class A carbapenemases but
not class B or D Oxa
•Used for MDR Gram negative organisms
•Imipenem-relebactam used in cUTI, cIAI, VAP
29. Added ceftolozane-tazobactam MIC
breakpoints for H.influenzae
and H.parainfluenzae
S= 0.5/4 or less
Treatment : ceftriaxone or cefotaxime for
meningitis
azithromycin or quinolones for mild
infections
30. Ceftolozane/Tazobactam
• Novel oxyimino-aminothiazolyl cephalosporin
and betalastamse inhibitor combination
• MOA- novel cephalosporin and inhibitor
combination
• Organism profile – P. aeruginosa (
cephalosprin and carbapenem resistant ones)
• E.coli and Klebsiella
31. Ceftolozane/Tazobactam
• Clinical Uses- complicated intrabdominal
infections , complicated UTI
• Advantages : Good antipseudomonal activity
• Status- FDA approved ( 2014)
32. Added Lefamulin disc diffusion and MIC testing for
Staphylococcus spp, H.influenzae,
H.parainfluenzae and S.pneumoniae
H.Influenzae
H.parainfluenzae
S= 17 or more
S= MIC 2 or less
S. aureus
S= 23 or more
S= MIC 0.25 or less
S.pneumoniae
S= 17 or more
S= 0.5 or more
33. Pleuromitilin compounds
• Natural product antibiotic ( 1950s) first used in veterinary
infections
• Retapumilin: first human use ( topical)
• Organism profile: organisms infecting skin and respiratory
infections
• MOA: Inhibit bacterial protein synthesis
• Newer Compounds : Lefamulin( BC 3781)
34. Lefamulin
• Active against atypical organisms and Staphylococcus
aureus
• Also Enterococcus spp
• Used for CABP, skin and soft tissue infections
• No cross resistance between other antibiotics for
Gram positive bacteria
35. Separated breakpoints of oral and parenteral cefazolin
Oral cutoff ( Surrogate
test for other oral agents
like cefaclor, cefpodoxime
for UTI)
S= 15 or more
R= 14 or less
S= 16 or less
R= 32 or more
Parenteral
cutoff
S= 23 or more
I= 20 -22
R= 19 or less
S= 2 or less
I= 4
R = 8 or more
36. Revised oxacillin breakpoints for Staphylococcus
spp except S.aureus
And S.lugdunensis
Oxacillin S = 18 or more
Oxacillin R= 17 or less
Oxacillin MIC S= 0.5 or less
Oxacillin MIC R= 1 or more
Cefoxitin S= 25 or more
Cefoxitin R= 24 or less
38. Clarified the interpretative category of
intermediate
S: sensitive
I: Intermediate ( ˄ concentrates in urine): ampicillin,
ticarcillin, TZP, carbapenems, ceftaroline,
cefalosporins, aminoglycosides, fluoroquinolones
SDD: Susceptible dose dependent
R: Resistant
NS: Not susceptible
39. Statement for isolates for which there are not
current CLSI cut off
Only the microorganism listed in the table should be
reported. If FDA susceptibility test interpretative
criteria ( STIC) is there, it can be used
40. Warning of reporting of antibiotics for use in CSF isolate
Agents only given by oral route, 1st and 2nd generation
cephalosporins, cephamycins,
Doripenem, imipenem, ertapenem, lefamulin, clindamycin,
macrolides, tetracyclines,
Fluoroquinolones: should not be reported in CSF
41. Positive blood cultures as inoculum
Ampicillin, aztreonam, ceftazidime, ceftriaxone, tobramycin,
Trimethoprim-sulfamethoxazole: can be reported
42. Staphylococcus aureus testing for linezolid and tedizolid
Organisms that are susceptible to linezolid also
susceptible to tedizolid
But organisms that are resistant to linezolid may be
susceptible to tedizolid
43. Oxazolidinones
• New class of synthetic drug with 2-oxazolidine
ring
• Organism profile- multiple resistant Gram
positives
( VRE,MRSA)
• Act on ribosomal 50s subunit
• Good penetration and accumulation in tissue
• Linezolid- already used
44. Tedizolid phosphate
• After oral or IV administration rapidly
change to active form
• Organism profile: better activity than
Linezolid in Staphylococcus, Streptococcus,
Enterococcus
• Active against Linezolid and Daptomycin
reistant bacteria
• PK/PD: once daily administration
• Safety profile: no myelosuppression
45. Tedizolid phosphate
• No inhibition of Monoamine Oxidase
• Clinical Use: for SSTIs
• Status: FDA approved ( 2014)
46. Colistin test for Enterobacterales and Pseudomonas aeruginosa
For colistin = broth microdillution, colistin broth disc elution test ( CBDT), colistin agar
test
For polymyxin= only broth microdilution test
BSAC British Society for Antimicrobial Chemotherapy (UK)
CA-SFM Comité de l ́Antibiogramme de la Société Francaise de Microbiologie (France)
CRG Commissie Richtlijnen Gevoeligheidsbepalingen (Netherlands)
DIN Deutsches Institute for Normung eV. (Germany)
FESCI Federation of European Societies of Chemotherapy and Infection
NWGA (AFA) Norwegian Working Group for Antibiotics (Arbeidsgruppen for antibiotikaspørsmål) (Norway)
SRGA -The Swedish Reference Group of Antibiotics (SRGA)
SWAB Stichting Werkgroep Antibioticabeleid (Netherlands)
Structure
There were originally six National Breakpoint Committees: BSAC (UK), CA- SFM (France), CRG (The Netherlands), DIN (Germany), NWGA (Norway) and SRGA (Sweden).
The DIN breakpoint committee has been replaced by the German NAC and CRG is now incorporated into Stichting Werkgroep Antibioticabeleid (SWAB).
Each national breakpoint committee consists of 10-20 experts within the fields of clinical microbiology, infectious diseases and pharmacology. Some have additional experts from other medical specialties, from veterinary medicine and from the pharmaceutical and antimicrobial susceptibility testing industry.
No difference for susceptible isolates
• VISA reported resistant by EUCAST and intermediate
by CLSI
• No difference for VanA-mediated vancomycin
resistance
• hVISA no difference as not detected by either guidelines
EUCAST are generally more conservative with >50% of all breakpoints lower. when EUCAST is higher its mainly to avoid splitting the wild type and thereby reduce the test error .
Clsi uses the intermediate category to reduce test errors and prevent VME,ME
EFSA- FULL FORM-
EUCAST Susceptible less than equal to x mg/L Resistant > y mg/L.Intermediate is inferred.
CLSISusceptible- less than equal to < x μg/mL Resistant more than equal to y μg/mL .Intermediate and sdd spelt out.
EUCAST breakpoints lower than CLSI
- are updated as pharmacodynamic understanding advances
- CLSI has found changes more difficult , FDA more so
CLSI “I” as a buffer zone between S & R to minimize errors in MIC/zone correlation
