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2013 Webinar Series
CLSI 2013 AST Update
2/7/2013
Speaker
Janet A. Hindler, MCLS MT(ASCP), Sr. Specialist, Clinical Microbiology, UCLA Medical Center, Los Angeles, CA
Ms. Hindler has worked as a clinical microbiologist for over 40 years, the past 35 at UCLA Medical Center, Los Angeles, CA. She
has written and taught extensively in the area of antimicrobial susceptibility testing. From 2000-2004 she held a contract with the
Centers for Disease Control and Prevention (CDC) where her focus was to develop and conduct training programs in antimicrobial
susceptibility testing. Ms. Hindler is now a consultant with the Association of Public Health Laboratories to continue in this role.
She is a fellow in the American Academy of Microbiology, member of the Clinical and Laboratory Standards Institute
Subcommittee on Antimicrobial Susceptibility testing, consultant to CAP’s Microbiology Resource Committee, Past Chair of ASM
Division C and Past President of the Southern California Branch of ASM. Ms. Hindler was the 2006 recipient of ASM’s bioMerieux
Sonnenwirth award for leadership in clinical microbiology and in 2007 she received an award from the Clinical and Laboratory
Standards Institute for Excellence in Standards Development. In 2011, she received the John V. Bergen award, one of CLSI’s
highest honors. And in 2012, she was awarded an honorary doctoral degree from Albright College, her alma mater. Ms. Hindler
has served as a consultant to the World Health Organization and assisted in teaching individuals in developing countries about
antimicrobial susceptibility testing and antimicrobial resistance. One of Ms. Hindler's primary professional goals is to provide
antimicrobial susceptibility testing information to clinical laboratory scientists and clinicians.
Objectives
At the conclusion of this program, participants will be able to:
 Identify the major changes found in the new CLSI M100-S23.
 Design a strategy for implementing the new practice guidelines into their laboratory practices.
 Develop a communication strategy for informing clinical staff of significant AST and reporting changes.
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has been approved for 1.0 contact hours for Florida Laboratory Licensees.
Evaluation/Printing CE Certificate
Continuing education credit is available to individuals who successfully complete the program and evaluation by 8/7/2013.
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Comments, opinions, and evaluations expressed in this program do not constitute endorsement by APHL/CLSI. The APHL/CLSI
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2/1/2013
Evaluation: www.surveymonkey.com/s/588-602-13
What’s New in the 2013 CLSI
Standards for Antimicrobial
Susceptibility Testing (AST) ?
Janet A. Hindler, MCLS MT(ASCP)
UCLA Health System
jhindler@ucla.edu
“and consultant with the Association of
Public Health Laboratories”
2
Objectives
List the major changes found in the
new M100-S23.
Describe a strategy for
implementation of the new practice
guidelines in your laboratory, as
appropriate.
3
jhindler clsi update 2013
1
2/1/2013
CLSI AST Standards
January 2013
M100-S23 Tables (2013)1
M02-A11 Disk Diffusion Method (2012)2
M07-A9 MIC Method (2012)2
M11-A7 Anaerobe MIC Testing (2007)
1
2
M100 updated at least yearly
M02, M07 updated every 3 years
4
Summary of
Changes
M100-S23 Page 15.
5
Major Changes 2013 (1)
Enterobacteriaceae
– Expanded recommendations for interpreting / reporting
fluoroquinolones on Salmonella spp.
Staphylococcus spp.
– Eliminated breakpoints (interpretive criteria) for all βlactams except oxacillin, cefoxitin, and penicillin; added
breakpoints for ceftaroline (cephalosporin with antiMRSA activity)
– Eliminated oxacillin disk diffusion test for
Staphylococcus aureus Group
6
2
2/1/2013
Neisseria gonorrhoeae
– Increased emphasis on susceptibility testing in select
settings to identify emerging cephalosporin resistance
Streptococcus pneumoniae
– Added test for inducible clindamycin resistance
– Added breakpoints for doxycycline; revised breakpoints
for tetracycline
Streptococcus spp. β-hemolytic Group
– Expanded testing / reporting recommendations for
inducible clindamycin resistance
7
Quality Control
– Quality control vs. verification
– New alternative recommendation for going from daily to
weekly QC testing schedule
– Revised “resistant” QC strain testing frequency for
screening tests
Additional Intrinsic Resistance Tables
– Non-Enterobacteriaceae
– Staphylococcus spp.
– Enterococcus spp.
8
CLSI Breakpoint
Additions / Revisions
Since 2010
“Newer” breakpoints
now referred to as
“current”!
“Previous breakpoints can be
found in the version of M100
that precedes the document
listed here, eg, previous
breakpoints for aztreonam are
listed in M100-S19 (January
2009).”
M100-S23. Page 23.
9
3
2/1/2013
Breakpoint Revision Reminders!
Both CLSI and FDA set breakpoints for USA
Criteria for establishing breakpoints differ
slightly between CLSI and FDA
Clinical laboratories can use either CLSI or
FDA breakpoints
– If using FDA-cleared commercial AST system, clinical
laboratory must perform verification for CLSI
breakpoints on that system
Manufacturers of commercial AST devices
must use FDA breakpoints!
10
What is the status of FDA breakpoint
revisions?
CLSI and FDA breakpoints now the same
for:
– Ceftriaxone – Enterobacteriaceae (2010)
– Ertapenem – Enterobacteriaceae (2012)
– Imipenem – Enterobacteriaceae and
Pseudomonas aeruginosa (2012)
Check with manufacturer of your
commercial AST system for status!
11
Ceftaroline
12
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2/1/2013
Ceftaroline (1)
 Broad-spectrum cephalosporin (with antiMRSA activity)
 IV only
 FDA clinical indications
– Acute bacterial skin and skin structure infections
(ABSSSIs)
– Community-acquired bacterial pneumonia (CABP)
– E. coli, Klebsiella pneumoniae, Klebsiella oxytoca
 Bactericidal against MRSA due to its affinity
for PBP2a and against penicillin-nonsusceptible Streptococcus pneumoniae due to
its affinity for PBP2x
13
Ceftaroline (2)
 Not active against ESBL, ampC (class C), or
carbapenemase (e.g., KPC) producing
Enterobacteriaceae
 No significant activity against Pseudomonas
aeruginosa
 Some activity against anaerobes (not
Bacteroides fragilis Group)
14
Ceftaroline Breakpoints (µg/ml) (1)
Organism
Enterobacteriaceae
CLSI1,2
FDA2,3
S
I
R
S
I
R
≤0.5
1
≥2
≤0.5
1
≥2
Clinical efficacy shown for
E. coli, K. pneumoniae,
and K. oxytoca
CABP and skin isolates
only
Staphylococcus aureus
≤1
2
≥4
S. aureus only, including
MRSA
1
2
3
≤1
M100-S23 Tables 2A and 2C
Corresponding disk diffusion breakpoints also defined
Ceftaroline Prescribing Information - see Drugs@FDA.gov
-
-
Includes MRSA
Skin isolates only
15
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2/1/2013
Ceftaroline Breakpoints (µg/ml) (2)
Organism
Haemophilus
influenzae
CLSI1,2
I
R
S
I
R
≤0.5
-
-
≤0.12
-
-
H. Influenzae only
Streptococcus
pneumoniae
≤0.5
≤0.54
Streptococcus
agalactiae
≤0.54
2
3
4
-
CABP isolates only
-
Nonmeningitis
Streptococcus
pyogenes
1
FDA2,3
S
-
≤0.25
-
-
CABP isolates only
-
≤0.015
-
-
Skin isolates only
-
-
≤0.03
-
-
Skin isolates only
M100-S23 Tables 2E, 2G, 2H-1
Corresponding disk diffusion breakpoints also defined
Ceftaroline Prescribing Information - see Drugs@FDA.gov
β-hemolytic streptococci (Table 2H-1); no species qualifier
16
Why do CLSI breakpoints differ slightly
from those of FDA?
 S. aureus
– CLSI added “I” and “R” because of strains with MICs of
2, 4, and 8 µg/ml reported outside the US
– “S” only breakpoint will not allow for testing variability
and create difficulties for labs when strains with MICs >
1 µg/ml are encountered
– Global surveillance - ceftaroline %S ( ≤1 µg/ml):
• MRSA (n=2849) 98.4%
• MSSA (n=5088) 100%
 S. pneumoniae, β-hemolytic streptococci,
Haemophilus spp.
– PK-PD data support breakpoint of ≤0.5 µg/ml and even
playing field for ceftaroline vs. other cephalosporins
17
MSSA
CLSI June 2012 Agenda Book
18
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2/1/2013
MRSA
CLSI June 2012 Agenda Book
19
Staphylococcus spp. Table 2C
Comment (17) not intended for patient reports;
discuss with infectious diseases, pharmacy, etc. when
developing / revising AST /reporting protocols
M100-S23. Page 75.
20
Ceftaroline vs. Other β-Lactams
%Susceptible
Organism
MSSA
186
N
Ceftaroline Ceftriaxone Imipenem
100
100
MRSA
215
100
0
0
E. coli
1075
93.6
94.8
99.9
Klebsiella
pneumoniae
596
86.1
86.7
94.6
Streptococcus
pneumoniae
894
100
90.8
NA
Haemophilus
influenzae
381
100
100
NA
100
NA, not available
Jones et al. 2011. J Antimicrob Chemother. 66 (Suppl 3):iii69–iii80.
21
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2/1/2013
Cetaroline Placement
in Tables 1A and 1B
And…Group C for
H. influenzae
S. pneumoniae
β-hemoltyic streptococci
Table 1A
Drugs to Test/Report
M100-S23. Page 34.
22
When should we test ceftaroline?
– When requested, for species with breakpoints
– Note: may be prescribed for MRSA and used
to “cover” other species in confirmed or
suspected mixed infection
How can we test ceftaroline
(FDA cleared as of 2/1/13)
– Disk diffusion
• Hardy Diagnostics
– MIC
• Sensititre TREK MIC panels
• Etest – FDA cleared for S. aureus only
23
Salmonella spp.
• Testing / reporting recommendations
• Fluoroquinolones
24
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2/1/2013
Salmonella – Current Taxonomy
 Two major species
– Salmonella bongori (uncommon in human infections)
– Salmonella enterica
• Six subspecies including Salmonella enterica subsp.
enterica
 >2500 serovars
Salmonella enterica subspecies enterica serovar Typhi
Salmonella enterica serovar Typhi
Salmonella ser. Typhi
Salmonella Typhi or S. Typhi
Typhoidal Salmonella = S. Typhi and S. Paratyphi A-C
WHO Collaborating Centre for Reference and Research on Salmonella
25
Salmonella Infections
 Typhoidal
– Require antimicrobial therapy from any source
– Usually ceftriaxone or fluoroquinolones in adults
 Non-typhoidal
– Systemic sources require antimicrobial therapy
– Gastroenteritis
• Usually self-limiting
• Therapy NOT recommended due to prolongation of carrier state
• Therapy often indicated for:
– Severe diarrhea
– Patients with underlying medical conditions (e.g.,
immunosuppression)
26
Salmonella spp.
AST and Reporting (1)
“(2) When fecal isolates of Salmonella and Shigella spp. are
tested, only ampicillin, a fluoroquinolone, and
trimethoprim-sulfamethoxazole should be reported
routinely. In addition, for extraintestinal isolates of
Salmonella spp., a third-generation cephalosporin
should be tested and reported, and chloramphenicol
may be tested and reported if requested.”
M100-S23. Page 44.
Also reminder… WARNING: For Salmonella spp., first- and secondgeneration cephalosporins, cephamycins and aminoglycosides may
appear active in vitro, but are not effective clinically and should not
be reported as susceptible.
M100-S23. Page 30.
27
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2/1/2013
Salmonella spp.
AST and Reporting (2)
“(2) Susceptibility testing is indicated for typhoidal
Salmonella (S. Typhi and Salmonella Paratyphi
A–C) isolated from extraintestinal and
intestinal sources. Routine susceptibility
testing is not indicated for nontyphoidal
Salmonella spp. isolated from intestinal
sources.”
M100-S23. Page 44.
28
What is the issue for fluoroquinolones
(FQs) and Salmonella?
Clinical response rates to ciprofloxacin are
poorer for isolates with “decreased
ciprofloxacin susceptibility”
(MICs of 0.12 – 1.0 µg/ml)
Crump et al. 2008. Antimicrob Agents Chemother. 52:1278.
Parry et al. 2010. Antimicrob Agents Chemother. 54:5201.
MICs of 0.12 – 1.0 µg/ml are “S” with
standard “Enterobacteriaceae” breakpoints
29
Salmonella spp.
Fluoroquinolone AST and Reporting
CLSI Standard
Fluoroquinolone Breakpoints
M100-S21
(2011)
One set of breakpoints for all Enterobacteriaceae
including Salmonella spp.
Nalidixic acid screen for reduced ciprofloxacin
susceptibility in extraintestinal isolates of
Salmonella spp.
M100-S22
(2012)
Lower ciprofloxacin breakpoints for S. Typhi and
extraintestinal Salmonella spp.
M100-S23
(2013)
Lower ciprofloxacin, levofloxacin and ofloxacin
breakpoints for use with all Salmonella spp.
Details described in:
Humphries et al. 2012. CID 55:1107-13.
30
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Salmonella spp.
Fluoroquinolone Resistance
Phenotype
Genotype
Ciprofloxacin
MIC (µg/ml)
Nalidixic Acid
Wild type (No resistance)
0.008-0.06
Usually susceptible
Chromosomal gyrA (single mutation)
Chromosomal gyrB (single mutation)
0.12 - 2.0
0.12 – 0.5
Usually resistant
Usually susceptible
≥4.0
Resistant
0.12 - 2.0
Often susceptible
Chromosomal gyrA, gyrB (multiple
mutations)
PMQR (e.g. qnr or aac(6’)-lb-cr)
PMQR, plasmid-mediated quinolone resistance - newer mechanism and
less common than chromosomal gyrase mutations
31
Enterobacteriaceae (Table 2A)
Salmonella spp. and
Fluoroquinolones
M100-S23. Pages 48-49. 32
Enterobacteriaceae (Table 2A)
DD (mm)
Antimicrobial
Agent
Susc
Int
Res
MIC (µg/ml)
Susc
Int
Res
≥21
16-20
≤15
≤1
2
≥4
≥31
21-30
≤20
≤0.06
0.120.5
≥1
≥17
14-16
≤13
≤2
4
≥8
-
-
-
≤0.12 0.25-1
≥2
-
-
-
≤0.12 0.25-1
≥2
Ciprofloxacin
Levofloxacin
Ofloxacin
Comments
Enterobacteriaceae
other than
Salmonella spp.
Salmonella spp.
(including S. Typhi
and Paratyphi A-C)
Enterobacteriaceae
other than
Salmonella spp.
Salmonella spp.
(including S. Typhi
and Paratyphi A-C)
Salmonella spp.
(including S. Typhi
and Paratyphi A-C)
33
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2/1/2013
Salmonella spp. - Nalidixic Acid Test
DD (mm)
Antimicrobial
Agent
Susc
Int
Res
Nalidixic acid ≥31 21-30 ≤20
MIC (µg/ml)
Susc
Int
Res
≤0.06 0.12-0.5
≥1
“(37) Until laboratories can implement the current interpretive criteria for
ciprofloxacin, levofloxacin, and/or ofloxacin, nalidixic acid may be
used to test for reduced fluoroquinolone susceptibility in
Salmonella. Strains of Salmonella that test resistant to nalidixic acid
may be associated with clinical failure or delayed response in
fluoroquinolone-treated patients with salmonellosis.
Note that nalidixic acid may not detect all mechanisms of
fluoroquinolone resistance.”
M100-S23. Page 49.
34
Salmonella spp. USA 2010
Distribution of Ciprofloxacin MICs
Wild Type
Decreased
Susc
Res
USA Data
*National Antimicrobial Resistance Monitoring System (NARMS)
http://www.cdc.gov/narms/
35
Salmonella spp. % Susceptible
USA 2010
Antimicrobial
Agent
Non-typhoidal
Breakpoint
Salmonella spp.
(µg/ml)
(n=2474)
S. Typhi
(n=444)
S. Paratyphi
A-C
(n=146)
Ampicillin
≤8.0
90.9
87.6
97.9
Ceftriaxone
≤1.0
97.2
100
100
Ciprofloxacin
≤0.06
97.3
31.1
9.6
Trimeth-sulfa
≤2/38
98.4
88.1
97.9
*National Antimicrobial Resistance Monitoring System (NARMS)
http://www.cdc.gov/narms/
36
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When should we test Salmonella spp.?
– Extraintestinal isolates
– Typhoidal Salmonella from all sources
– Other when requested (select patient
populations?)
How can we test Salmonella spp. and
fluoroquinolones?
– Of commercial AST systems, only Etest currently
encompasses new low MIC breakpoints
– Ciprofloxacin disk diffusion
– Nalidixic acid but doesn’t capture all isolates with
reduced fluoroquinolone susceptibility
37
Staphylococcus spp.
• Eliminate all β-lactam breakpoints except
oxacillin, cefoxitin, penicillin, ceftaroline
• Eliminate oxacillin disk test for S. aureus Group
38
Staphylococcus spp.
M100-S22. Table 2C.
Eliminate breakpoints for:
Penicillins
-lac inhibitor combos
Cephems (oral)
Cephems (parenteral)
Carbapenems
39
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Staphylococcus spp.
β-Lactam Breakpoints Remaining
Penicillin
– Represents penicillinase-labile penicillins
Oxacillin
– Represents penicillinase-stable penicillins
Cefoxitin
– Surrogate for oxacillin
Ceftaroline (added 2013)
– Cephem with anti-MRSA activity
40
Why did CLSI remove other β-lactam
breakpoints for Staphylococcus spp.?
 Can predict results for β-lactams with
established clinical efficacy for staphylococcal
infections by testing penicillin and oxacillin /
cefoxitin (CLSI recommendation since 1991)
 Need to distinguish new cephems with activity
against MRSA from cephems with MSSA
activity only (eg, ceftaroline)
 Breakpoints deleted had never been
extensively evaluated specifically for
Staphylococcus spp.
41
Staphylococcus spp. - β-Lactams
Test Results
Oxacillin
(cefoxitin)
Penicillin
S
S
R
S
R
R
Predicts
Susceptible to:
All penicillins
ß-lac / ß-lactamase inhibitor combos
Cephems
Carbapenems
Resistant to:
Penicillinase-labile penicillins
Susceptible to:
Penicillinase-stable penicillins
ß-lac / ß-lactamase inhibitor combos
Cephems
Carbapenems
Resistant to:
All ß-lactams (except cephems with antiMRSA activity, e.g., ceftaroline)
42
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2/1/2013
β-Lactams with
Antistaphylococcal Activity (1)
Penicillinase-labile
Penicillins
Amoxicillin
Ampicillin
Penicillinase-stable
Penicillins
Cloxacillin
Dicloxacillin
Carbenicillin
Flucloxacillin
Mezlocillin
Methicillin
Penicillin
Nafcillin
Piperacillin
Oxacillin
Ticarcillin
43
β-Lactams with
Antistaphylococcal Activity (2)
Cephems
Carbapenems
ß-lactam/ß-lactamase
Inhibitor Combinations
Amoxicillin-clavulanate
Ampicillin-sulbactam
Cefaclor
Cefamandole
Cefoxitin
Cefpodoxime
Doripenem
Ertapenem
Cephalexin
Cefprozil
Imipenem
Ticarcillin-clavulanate
Cefazolin
Ceftazidime
Meropenem
Piperacillin-tazobactam
Cefdinir
Ceftizoxime
Cefepime
Ceftriaxone
Cefmetazole
Cefonicid
Cefuroxime
Cephalothin
Cefoperazone
Loracarbef
Cefotaxime
Moxalactam
Cefotetan
44
Cefoxitin Disk Diffusion for S. aureus
and S. lugdunensis
Cefoxitin (R)
10 mm zone
Zone (mm)
R
I
S
Cefoxitin 21*
22**
Oxacillin 10 11-12 13
Drug
* Report as oxacillin resistant
** Report as oxacillin susceptible
• Cefoxitin detects mecAmediated MRSA better than
oxacillin
• Test cefoxitin as a surrogate
- Report OXACILLIN, not
cefoxitin
Eliminate oxacillin disk diffusion
test for S. aureus and S.
lugdunensis
45
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2/1/2013
Staphylococcus spp.
M100-S23. Page 75.
46
Staphylococcus spp.
“(24) For staphylococci that test susceptible, aminoglycosides
are used only in combination with other active agents that test
susceptible.”
•
Gentamicin – Test / Report Group “C” - Supplemental (report on special
request)
•
Not widely recommended to use gentamicin in combination therapy…see
Liu et al. 2011. Clin Infect Dis. 52:1
•
If gentamicin reported, consider adding comment to patient report re: not
to use gentamicin alone
M100-S23. Page 77. 47
What β-lactams should we test / report against
staphylococci?
– Oxacillin / cefoxitin
– Penicillin
• Test / report routinely?
• Report if “R”; suppress if “S” and add comment
“Contact laboratory if penicillin results needed”?
• Perform β-lactamase test if penicillin “S” prior to
reporting penicillin result
– Ceftaroline – as requested
How can we test β-lactams against staphylococci?
– Oxacillin – MIC only
– Cefoxitin – disk diffusion; MIC (S. aureus only)
– Penicillin – disk diffusion or MIC
48
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Neisseria gonorrhoeae
• Emerging cephalosporin resistance
49
August 12, 2012
50
Antimicrobial Resistance
Therapeutic
Agent
Detection of
Resistance
Mechanism of
Resistance
1979
β – lactamase
1983
CMRNG
(chromosomallymediated resistant
N. gonorrhoeae);
altered PBP,
permeability
Fluoroquinolone
Early 1990’s
Mutations in gyrA
and parC
Cephalosporins
2009
Penicillin
penA mosaic
No Longer
Recommended
1987
2007
2012 (cefixime
alone)
51
17
2/1/2013
M100-S23. Page 38.
“i. Culture and susceptibility testing of N.
gonorrhoeae should be considered in
cases of treatment failure. Antimicrobial
agents recommended for testing
include, at a minimum, those agents
listed in Group A. The most recent CDC
guidelines for treatment and testing are
available at
http://www.cdc.gov/std/Gonorrhea/.”
† Routine
testing not necessary
52
Uncomplicated GC Treatment
Recommendations
Ceftriaxone 250 mg IM in a single dose
(or if not an option, cefixime 400 mg PO in
a single dose)
PLUS
Azithromycin 1 g PO in a single dose
Or Doxycycline 100 mg PO 2x daily for 7
days
Note: two drugs with different mechanisms of action may improve
treatment and delay emergence of ceftriaxone resistance.
MMWR August 10, 2012.
53
GC Treatment Failure
Test of cure is recommended for treatment
failure:
– Symptoms persisting after completing
recommended therapy
– Positive culture ≥ 72 hours after
recommended therapy
– Positive NAAT ≥ 7 days after recommended
therapy
Recent report of cefixime treatment
failures associated elevated cefixime MICs
– Allen et al. 2013. JAMA. 309:163.
54
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Ceftriaxone MIC Distributions
0.03 µg/ml
www.eucast.org
55
Percentage of urethral Neisseria gonorrhoeae isolates (n = 32,794) with
elevated cefixime MICs (≥0.25 µg/mL) and ceftriaxone MICs (≥0.125 µg/mL) Gonococcal Isolate Surveillance Project, United States, 2006–August 2011.
*cefixime not tested 2007-2008
†Jan – August 2011
MMWR August 10, 2012.
56
AST Methods
 CLSI Reference Methods
– Agar dilution MIC
– Disk diffusion
 Media & Incubation Conditions
– GC agar base + 1% defined growth supplement
– 36ºC (do not exceed 37ºC), 5% CO2, 20-24 h
 Interpret (see M100-S23 Table 2F for other drugs)
Antimicrobial
Agent
DD (mm)
MIC (µg/ml)
Susc
Int
Res
Susc
Int
Res
Cefixime
≥31
-
-
≤0.25
1
-
-
Ceftriaxone
≥35
-
-
≤0.25
1
-
-
1CDC
 Etest
uses ≥0.125 µg/mL for “non-susceptibility”
57
19
2/1/2013
What should we do about testing /
reporting for GC today?
– NAAT for routine diagnosis
– Maintain capability of performing C&S when
treatment failure suspected (reference lab
option?)
– Decreased susceptibility to cephalosporins
and/or cephalosporin therapeutic failures should
be reported to public health department
58
Inducible Clindamycin Resistance
•β-hemolytic Streptococcus spp.
•Streptococcus pneumoniae
59
Some Indications for Clindamycin
Therapy in 2013
 Penicillin-allergic patients
– E.g. dental infections, aspiration pneumonia, lung
abscess, head and neck infections, pelvic infections
– Intrapartum prophylaxis for highly penicillin-allergic
women colonized with Group B Streptococcus
 Strep throat – penicillin therapy failures
 Bone and joint infections
 Notes:
– Often more use in peds than adults
– Concern – Clostridium difficile
60
20
2/1/2013
 Staphylococcus aureus
– Known poor outcome with clindamycin therapy for
isolates with inducible clindamycin resistance
Lewis et al. 2005. Clin Infect Dis. 40:280.
 β-hemolytic streptococci
– New data (J Jorgensen. June 2012. CLSI meeting presentation)
• Four human cases of infection (inducible clindamycin resistance)
did not resolve on clindamycin therapy
• 2 Streptococcus agalactiae, 1 Group A streptococcus,
1 Group C streptococcus
No isolate had constitutive clindamycin resistance
after failed clindamycin therapy
 β-hemolytic streptococci and S. pneumoniae
– Recent animal model data suggest inducible clindamycin
resistance is clinically significant
61
β-hemolytic Streptococci & S. pneumoniae
Resistance Mechanism
Efflux
Ribosome
modification1
Ribosome modification
1
2
Determinant
Erythro
Clinda
mef
R
S
erm
R
S2
erm
R
R
constitutive
known as MLSB resistance phenotype (M, macrolide; L, lincosamide; S,
streptogramin B)
requires induction to show resistance
mef = macrolide efflux
erm = erythromycin ribosome methylase
62
Neutropenic Murine Thigh Model
#1
GBS Isolate #1
Constitutive Clindamycin R
#2
GBS Isolate #2
Inducible Clindamycin R
(early killing then regrowth)
#3
GBS Isolate #3
Clindamycin Susceptible
CLSI Agenda book, June 2012 (WA Craig)
63
21
2/1/2013
Neutropenic Murine Thigh Model
#1
Spneu Isolate #1
Constitutive Clindamycin R
#2
Spneu Isolates #2 & #3
Inducible Clindamycin R
(early killing then regrowth)
#3
#4
Spneu Isolate #4
Clindamycin Susceptible
CLSI Agenda book, June 2012 (WA Craig)
64
β-hemolytic Streptococci & S. pneumoniae
Inducible Clindamycin Resistance Testing
Only if Erythromycin-R and Clindamycin-S
“D-Zone” Test:
• Routine disk diffusion method
• Place 2 g clindamycin disk 12
mm from edge of 15 g
erythromycin disk
12 mm
E
CC
No induction
Broth microdilution test – 1 well
• 1 µg/mL erythromycin and 0.5
µg/mL clindamycin in same well
E
CC
Induction
65
What should we do about testing /
reporting for inducible clindamycin
resistance?
1
2
Organism
Test1
Staphylococcus aureus
Coag-neg staphylococci
β-hemolytic streptococci
Streptococcus pneumoniae
Yes
If requested
If requested
If requested
Add
Comment 2
No
Optional
Optional
Optional
Report clindamycin “R” if inducible clindamycin test is positive
“This isolate is presumed to be clindamycin resistant based on
detection of inducible clindamycin resistance”
66
22
2/1/2013
β-hemolytic Streptococcus spp.
• Clindamycin & Group B Streptococcus from
Prenatal Screens
67
Many
footnotes!
† Routine
testing not necessary
M100-S23. Page 38.
68
Streptococcus spp. β-hemolytic Group
Table 1B
“p. …..When Group B Streptococcus is isolated
from a pregnant woman with severe penicillin
allergy (high risk for anaphylaxis), erythromycin
and clindamycin, (including inducible
clindamycin resistance) should be tested, and
only clindamycin should be reported.”
M100-S23. Page 40.
69
23
2/1/2013
http://www.cdc.gov/groupbstrep/about/prevention.html
70
Check for inducible
clindamycin R if
erythromycin-R and
clindamycin-S
71
More on GBS Prenatal Screen
(notes from bottom of algorithm)
 “….and testing for inducible clindamycin
resistance has been performed and is negative
(no inducible resistance), then clindamycin can
be used for GBS intrapartum prophylaxis
instead of vancomycin.”
72
24
2/1/2013
Table 2H-1 Supplemental
Table 1. Testing for Inducible
Clindamycin Resistance in βhemolytic Streptococci
• AST of β-hemolytic Streptococci
not needed routinely
• If clindamycin needed, must test for
inducible clindamycin resistance
• Test / report clindamycin on
prenatal screens (penicillin allergic)
M100-S23. Page 116.
73
When should we perform AST on βhemolytic Streptococci? What drugs
should we report?
Group A Streptococcus
– When requested (penicillin allergic patient)
• Report erythromycin, clindamycin
Group B Streptococcus
– Prenatal screen isolates from penicillin
allergic patients
• Report clindamycin
74
• Inducible clindamycin resistance
• Tetracycline and doxycycline
• Penicillin results and other β-lactams
75
25
2/1/2013
Table 2G Supplemental Table 1.
Testing for Inducible
Clindamycin Resistance in
• If clindamycin tested, should
screen for inducible clindamycin
resistance
M100-S23. Page 109.
76
Streptococcus pneumoniae (n=1021)
Phenotypic Tests vs. ermB PCR
ermB PCR
N
D-zone pos Broth pos2
positive
66
653,4
643,5
negative
36
0
0
erythromycin-R and clindamycin-S
1 µg/ml erythromycin and 0.5 µg/ml clindamycin
3 1 isolate ermB pos but negative in both phenotypic tests
4 Sensitivity: 98.5% Specificity: 100%
5 Sensitivity: 97% Specificity: 100%
1
2
Jorgensen et al. 2011. J Clin Microbiol. 49:3332.
77
Why add breakpoints for doxycycline
and S. pneumoniae?
 Doxycycline is an option for treating
community-acquired pneumonia
– Mandell et al. 2007. Clin Infect Dis. 44:S27
 Note: some isolates may be susceptible to
doxycycline but resistant to tetracycline
Antimicrobial
Agent
Susc
DD (mm)
Int
Res
MIC (µg/ml)
Susc
Int
Res
Doxycycline
≥28
25-27
≤24
≤0.25
0.5
≥1
New
Tetracycline
≥28
25-27
≤24
≤1
2
≥4
Revised
MIC data and PK/PD data used to set breakpoints
78
26
2/1/2013
CLSI Rationale Document
Doxycycline and
Tetracycline Breakpoints for
S. pneumoniae
http://www.clsi.org/wp-content/uploads/2013/01/Doxycyclineand-Tetracycline-Breakpoints-for-Streptococcus-pneumoniae.pdf
79
Doxycycline MIC (µg/ml) vs. tetM
CLSI Doxy-Tet Rationale Doc.
80
Tetracycline MIC (µg/ml) vs. tetM
CLSI Doxy-Tet Rationale Doc.
81
27
2/1/2013
Extrapolating Other β-Lactams from Penicillin
“(5) For nonmeningitis isolates, a penicillin MIC of ≤0.06 µg/mL (or oxacillin
zone ≥20 mm) can predict susceptibility to the following β-lactams:
Ampicillin
Ampicillin-sulbactam
Amoxicillin
Amoxicillin-clavulanate
Cefaclor
Cefdinir
Cefditoren
Cefepime
Cefotaxime
Cefpodoxime
Cefprozil
Ceftaroline
Ceftizoxime
Ceftriaxone
Cefuroxime
Doripenem
Ertapenem
Imipenem
Loracarbef
Meropenem
Penicillin
Deleted: “Penicillin MICs ≤2 µg/mL indicate susceptibility to parenteral
penicillin, amoxicillin, amoxicillin-clavulanic acid, cefepime, cefotaxime,
ceftriaxone, and ertapenem.”
Only extrapolate if penicillin MIC is ≤0.06 µg/ml
or oxacillin zone is ≥20 mm
M100-S23. Page 105.
82
Penicillin vs. Cefotaxime or
Amoxicillin MICs
Strains with mosaic PBP genes can
have
– Low penicillin MICs (<1 µg/ml) and high
cefotaxime MICs (2-32 µg/ml)
– Low penicillin MICs (1-2 µg/ml) and higher
amoxicillin MICs (4-8 µg/ml)
McDougal et al. 1995. Antimicrob Agents Chemother. 39:2282.
Ruiz et al. 1998. Antimicrob Agents Chemother. 42:2768
Doit et al. 1999. Antimicrob Agents Chemother. 43:1480
83
When should we report doxycycline on S.
pneumoniae?
When AST is performed, if drug is on panel,
and stakeholders agree it should be reported
routinely; non-CSF isolates.
When can we extrapolate penicillin “S”
results to other -lactam agents?
For non-meningitis, if penicillin MIC is ≤0.06
µg/mL and drug of interest is listed in CLSI
M100-S23 Table 2G (5).
84
28
2/1/2013
Quality Control
•QC vs. verification
•Daily to Weekly QC
•QC for screening tests
85
M100-S23. Page 32.
QC
Verification
To ensure AST quality, lab must perform:
• QC - routine
• Verification – when new AST system introduced or
new drug added to existent AST system
• CLIA requirement per CLIA 42 CFR 493.1253[b]
• Reference - ASM Cumitech 31A (2009)
QC Recommendations
in Tables 2A-2G
86
Previously….
“Minimum” QC
now “Routine” QC
M100-S23. Page 44.
87
29
2/1/2013
Frequency of Routine QC Testing
Options
Each day test is performed
Weekly following documentation of
successful daily QC
– 20-30 day plan
– New 3 x 5 day plan
For weekly QC, documentation needed when:
• Add New AST system
• Add new drug
• Modify certain test variables – see M100-S23 Tables 3C & 4F
88
Routine AST QC – New Option
Convert from Daily to Weekly QC Schedule
(for each drug / organism combination)
 “3 x 5 day plan”
– Perform 3 tests each day for 5 days (15 results)
– Use 3 separate inoculum preparations for each
replicate / day
– Statistically comparable to current plan (20-30
day) for identifying problems
 Advantages
– Possibly identify problems quicker
– Complete QC testing quicker
– Utilize fewer resources
89
3 x 5 Day QC Plan – 2 Phases
 Phase 1 – test 3 replicates for 5 days (15 results)
– PASS if 0-1 of 15 results out of range
– FAIL if ≥4 of 15 results out of range
– Go to Phase 2 if 2-3 of 15 results out of range
 Phase 2 – test another 3 replicates for 5 days (15
more results)
– PASS if 2-3 of 30 results out of range
– FAIL if ≥4 of 30 results out of range
90
30
2/1/2013
3 x 5 Day
QC Plan
Pass
Fail
M100-S23. Pages
136 & 152.
Statistical summary here….
http://www.clsi.org/wp-content/uploads/2012/11/June-2012-Attachment-2.pdf
91
Have accrediting agencies acknowledged
the new 3 x 5 day QC plan?
Not at this time but CMS is considering
adoption of the plan. Other accrediting
agencies (e.g., CAP) could accept the new
plan following publication in CLIA
regulations.
92
AST “Screening Tests” 1
QC Frequency
QC Strain
OLD (M100-S22)
New (M100-S23)
Negative
(susceptible)
Test routinely
Test routinely
Positive
(resistant)
Test routinely
Test with each new
batch / lot / shipment of
testing materials
1
Applies to disks, or agar plates used for agar dilution, or
single wells or tubes used with broth dilution methods
93
31
2/1/2013
Staphylococcus aureus Group
Table 2C Supplemental Table 1
M100-S23.
Page 85.
Susceptible strain
QC – routine
Resistant strain
QC – Lot/shipment
94
Disk Diffusion QC Range Changes
Pseudomonas aeruginosa ATCC 27853
Antimicrobial Agent
Acceptable Range
(mm)
Gentamicin
17-23
Tobramycin
20-26
M100-S23. Pages 130-131.
95
Intrinsic Resistance Tables
•
•
•
•
Enterobacteriaceae – a few changes / additions
Non-Enterobacteriaceae – new
Staphylococcus spp. - new
Enterococcus spp. - new
M100-S23. Page 176-179.
96
32
2/1/2013
Check Q&A – more on:
• QC
• Verification
M100-S23. Page 196.
97
Additional CLSI Changes and Topics
Under Evaluation (1)
 Continuing reevaluation of breakpoints
– Enterobacteriaceae – cefepime
– Acinetobacter and other non-Enterobacteriaceae carbapenems
– Fluoroquinolones
– …and others
 Colistin / Polymyxin B
– Reexamine best method for testing these difficult
agents (international collaboration)
98
Additional CLSI Changes and Topics
Under Evaluation (2)
 Improve QC recommendations
 Expand availability / user friendliness of concise
“Rationale Documents” behind new/modified
recommendations
 Reformat M100 booklet
CLSI AST Subcommittee welcomes new volunteers!
99
33
2/1/2013
An online interactive searchable version of
M100-S23 enables you to easily…
• Access M100-S23 – all you need is a web connection
• Dynamically filter by tables, organisms, and agents
• View only the information you want to see
• Customize for your institution’s formulary
• Easily find additional CLSI AST standards and
guidelines within the eM100 Resource Center
Available at www.CLSI.org
100
CLSI
Website
• Find information
from AST meetings
• Order CLSI AST
products
http://www.clsi.org/standardsdevelopment/microbiology/
subcommittee-on-ast/
101
The following summary slides will
not be discussed and are
presented for participant’s
review.
102
34
2/1/2013
Summary (1)
 CLSI updates AST tables (M100) each January.
 CLSI updates documents that describe how to perform
reference disk diffusion (M02) and reference MIC (M07)
tests every 3 years.
 Changes to CLSI documents are summarized in the front
of each document.
 Information listed in boldface type is new or modified
since the previous edition of M100.
 Recent breakpoint addition/revision dates are listed in the
front of M100-S23.
 Manufacturers of commercial AST systems, by law, MUST
use FDA breakpoints.
103
Summary (2)
 FDA breakpoints have recently been revised for ceftriaxone
and ertapenem (Enterobacteriaceae) and for imipenem
(Enterobacteriaceae and Pseudomonas aeruginosa).
 M100-S23 contains breakpoints for ceftaroline, a broadspectrum cephalosporin with anti-MRSA activity, for
several organism groups.
 Routine susceptibility testing is not indicated for
nontyphoidal Salmonella spp. isolated from intestinal
sources.
 M100-S23 includes unique breakpoints for ciprofloxacin,
levofloxacin and ofloxacin for use when testing any
Salmonella spp.
104
Summary (3)
 Reduced susceptibility to ciprofloxacin is most
commonly found in typhoidal strains of Salmonella spp.
 The only β-lactams with breakpoints for Staphylococcus
spp. in M100-S23 are penicillin, oxacillin, cefoxitin, and
ceftaroline.
 When testing Staphylococcus spp., results for antistaphylococcal β-lactams other than penicillin, oxacillin,
cefoxitin, and ceftaroline can be deduced from testing
penicillin and oxacillin (or cefoxitin).
 The oxacillin disk diffusion test is no longer considered
reliable for any Staphylococcus spp. Cefoxitin disks are
used to detect methicillin-resistant S. aureus and
coagulase-negative staphylococcus.
105
35
2/1/2013
Summary (4)
 Emerging resistance to cephalosporins in Neisseria
gonorrhoeae is a significant public health concern.
 Laboratories should maintain the ability to provide culture
and susceptibility testing of N. gonorrhoeae for patients
who are considered treatment failures. This might include
reference laboratory alignment as an alternative to in
house testing.
 Inducible clindamycin resistance has been reported to be
clinically significant for S. aureus.
 More recently, studies have shown inducible clindamycin
resistance can be clinically significant for Streptococcus
pneumoniae and β-hemolytic streptococci.
106
Summary (5)
 Testing for inducible clindamycin resistance in
erythromycin-R and clindamycin-S isolates of S. aureus,
S. pneumoniae and β-hemolytic streptococci should be
performed if clindamycin is reported.
 AST should be performed on isolates of Group B
streptococci from highly penicillin-allergic women. This
should include testing for inducible clindamycin
resistance, and only clindamycin (not erythromycin)
should be reported.
 Doxycycline can now be tested against S. pneumoniae,
when indicated.
 Results for β-lactams other than penicillin (nonmeningitis
isolates) can be deduced from S. pneumoniae that have
penicillin MICs ≤0.06 µg/ml or oxacillin zones ≥20 mm.
107
Summary (6)
 To ensure AST quality, laboratories must perform routine
QC testing. In addition, verification studies are required
when a new AST system is added, a new drug is added to
an existent AST system, or there is a change in certain
testing variables.
 Routine QC testing can be done daily or weekly; the latter
providing there is documentation that daily QC has been
satisfactorily performed.
 An alternative to documenting daily QC by use of the 2030 day QC plan is the new 3 x 5 day QC plan.
 For screening tests, QC of the susceptible strain must be
performed routinely but the resistant QC strain need only
be tested with each new lot/shipment of testing materials.
108
36
2/1/2013
Summary (7)
 M100-S23 now contains tables that define intrinsic
resistance profiles for Enterobacteriaceae and also nonEnterobacteriaceae, Staphylococcus spp. and
Enterococcus spp.
 Minutes of CLSI AST Subcommittee meetings and other
materials are available at www.clsi.org.
 CLSI and other groups welcome help with improving
susceptibility testing!
109
And thanks to:
APHL Staff
CLSI Staff
CLSI Subcommittee on AST especially:
Jean Patel
Jim Jorgensen
Susan Munro
110
37

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