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2014 Webinar Series
CLSI 2014 AST Update
February 6, 2014
Speaker
Janet A. Hindler, MCLS, MT(ASCP), Senior Specialist, Clinical Microbiology UCLA Medical Center Los Angeles, California, USA
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 20002004 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:
•
Provide additional guidelines for testing cefazolin as a surrogate for oral agents that might be used for treating uncomplicated
urinary tract infections and interpreting results for carbapenems and Acinetobacter spp.
•
Explain the revised breakpoints for cefepime and Enterobacteriaceae, including the new susceptible-dose dependent
interpretive category.
•
Discuss several other new recommendations found in M100-S24.
•
Offer an optional postprogram self-assessment that will allow individuals to assess their knowledge regarding the most
important AST and reporting issues for 2014, which can help to augment competency assessment requirements for their
laboratory staff.
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What’s New in the 2014 CLSI
Standards for Antimicrobial
Susceptibility Testing (AST) ?
Janet A. Hindler, MCLS MT(ASCP)
UCLA Health System
[email protected]
“and consultant with the Association of
Public Health Laboratories”
1
2
Objectives
 Identify the major changes found in CLSI
document M100-S24.
 Design a strategy for implementing the new
practice guidelines into your laboratory
practices.
 Develop a communication strategy for informing
clinical staff of significant AST and reporting
changes.
“President Obama acknowledged
need for innovation to address drugresistant bacteria”
3
CLSI AST Standards
January 2014
Please check supplemental
materials posted for this
webinar:
• Implementation Checklist
• Self study program
4
Summary of
Changes
M100-S24 Tables (2014)1
M02-A11 Disk Diffusion Method (2012)2
M07-A9 MIC Method (2012)2
M11-A8 Anaerobe MIC Testing (2012)
1
2
M100 updated at least yearly
M02, M07 updated every 3 years
M100-S24 Pages 13-17.
5
6
Major Changes 2014 (2)
Major Changes 2014 (1)
 General
 Acinetobacter spp.
– Rearranged tables - special tests for screening and
confirmatory tests in Section “3”
– Additional emphasis on “surrogate” drugs
– Added susceptible dose dependent (SDD) interpretive
category
– Added breakpoints for doripenem, revised
breakpoints for imipenem and meropenem
– “Relocated” minocycline
 Staphylococcus aureus
– Eliminated vancomycin disk diffusion screen for
vancomycin-resistant S. aureus (VRSA)
– Additional emphasis on potential for vancomycin-S
S. aureus to become vancomycin-I when prolonged
vancomycin therapy
 Enterobacteriaceae
– Cefepime – revised interpretive criteria (breakpoints)
and added “SDD”
– Cefazolin – added urine breakpoint
7
8
Major Changes 2014 (3)
 Quality Control
– Modified recommendations for use of “routine QC”
strains
– New colistin / polymyxin B QC ranges
– Describe use of retrospective data to convert from
daily to weekly QC
– Expanded recommendations for weekly QC out of
control
General Changes
10
9
Relocated and Consolidated “Screening and
Confirmatory” Tests…..
Note: QC tables
renumbered:
Disk = 4A - 4D
MIC = 5A - 5G
“Surrogate Drugs”
M100-S24. Page 38.
11
12
Table 2C –
Staphylococcus spp.
Breakpoints
M100-S23
2013
Table 2C
Suppl. Table 1
S. aureus
β-lactamase
Oxacillin agar screen
mecA using cefoxitin
Table 2C
Suppl. Table 2
S. aureus
Vancomycin screen
Inducible clindamycin
Mupirocin
Table 2C
Suppl. Table 3
CoNS
β-lactamase
mecA using cefoxitin
Inducible clindamycin
Example: single table for inducible clindamycin
resistance – Staphylococcus / Streptococcus
Table 3D β-lactamase in Staphylococcus spp.
M100-S24
2014
Table 3E
Methicillin Resistance in Staphylococcus spp.
Table 3F
Vancomycin MIC ≥8 µg/ml in S. aureus and
Enterococcus spp.
Table 3G Inducible clindamycin resistance in Staphylococcus
spp., S. pneumoniae and β-Streptococcus spp.
Table 3H Mupirocin
M100-S24. Pages 110-141.
M100-S24. Pages 134-136.
13
14
CLSI Breakpoint
Additions / Revisions
Since 2010
Interpretive Criteria (Breakpoint)
Update!
“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-S24. Pages 24-25.
15
16
FDA Same as CLSI (2014) Breakpoints (GNR)
Breakpoint Revision Reminders!
Antimicrobial Enterobacteriaceae P. aeruginosa Acinetobacter
 Both CLSI and FDA set / revise breakpoints in USA
 Criteria for establishing breakpoints differ slightly between
CLSI and FDA
 Several FDA breakpoints recently revised and now match
newer CLSI breakpoints
 Newer CLSI breakpoints may not be updated on commercial
systems
Aztreonam
Cefazolin
Cefepime
Cefotaxime
Ceftriaxone
Ceftazidime
Doripenem
Ertapenem
Imipenem
Meropenem
Piper –tazo
– A clinical laboratory must perform a verification for a commercial
system if using breakpoints other than those provided by the
manufacturer. References for verification:
• Clark et al. 2009. Cumitech 31A.
• Patel, J et al. 2013. Clin Microbiol Nwslttr. 35:103.
• CAP Breakpoint Implementation Tool (BIT). 2012.
• Commercial AST manufacturers must use FDA breakpoints
• Clinical laboratories can use CLSI or FDA breakpoints
NA, not applicable
X
Not yet
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Not yet
Not yet
Not yet
X
X
X
NA
NA
X
X
Not yet
Not yet
NA
Not yet
Not yet
Not yet
X
NA
Not yet
1/22/14
Check with manufacturer of your commercial AST system for status!
17
18
.…labels (Prescribing Information) for these are
posted on the Drugs@FDA or Daily Med websites
FDA Breakpoint
Updates
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedic
alProductsandTobacco/CDER/ucm275763.htm
Google: “FDA Interpretive Criteria Updates”
19
…there may be several labels for a single drug
(different manufacturers of generic drug)
20
Breakpoints are located in Clinical
Pharmacology section
Links to meropenem labels
from 5 manufacturers
Clinical Pharmacology
21
22
CLSI Breakpoint Additions / Revisions
for 2014
Meropenem
Enterobacteriaceae Cefazolin
Cefepime
Acinetobacter spp.
Prescribing Information. AstraZeneca 12/2013
23
Doripenem
Imipenem
Meropenem
24
MIC and Disk Diffusion
Interpretive Categories
Before
Susceptible
Interpretive Criteria
Susceptible Dose Dependent (SDD)
Intermediate
Resistant
Nonsusceptible
Now
Susceptible
Susceptible Dose Dependent
Intermediate
Resistant
Nonsusceptible
M100-S24 Page 29-30.
25
26
“Intermediate” vs. “SDD” Categories
Definitions of
Interpretive Categories
 Intermediate
– Implies clinical efficacy in body sites where:
• drugs are physiologically concentrated (e.g.,
quinolones and -lactams in urine) or
• higher than normal dosage of a drug can be used
(eg, -lactams)
– Provides “buffer zone”
 Susceptible Dose Dependent (SDD)
…Intermediate
…Resistant
…Nonsusceptible
– Only applies when multiple approved dosing options
exist
– Expect same clinical response as “S” if higher or
more frequent dose used
M100-S24 Page 29.
28
27
What data are used to set / revise
breakpoints?
Why SDD and not Intermediate?
 Need to refine susceptibility reports to maximize
clinician’s use of available drugs.
 “Intermediate” poorly understood by clinicians –
generally considered “R”
 SDD provides specific doses and conveys:
 Microbiological - MIC distributions of
“wild type” or normal populations of
bacteria
 Pharmacokinetics-pharmacodynamics
(PK/PD) analysis
– higher dose may be effective if MIC in “SDD”
– (lower dose may be effective if MIC in “S” range)
 Clinical - MICs associated with clinical
outcome
 SDD in use for antifungals and accepted
 SDD consistent with antibiotic stewardship goals –
emphasize appropriate dosing and duration of
therapy options
29
30
Appendix E: “PK/PD”
“The evolving science of pharmacokineticspharmacodynamics has become increasingly
important in recent years in determining MIC
interpretive criteria….”
Pharmacokinetics (PK) - the process by which a drug is
absorbed, distributed, metabolized, and eliminated by the
body. Relates to drug concentration over time in vivo.
Cefepime
Pharmacodynamics (PD) - the relationship between drug
concentration and its antimicrobial effects over time in vivo
M100-S24
Page 206-207.
PK/PD projects potential efficacy of antimicrobial agents in
vivo
32
31
Appendix E (con’t): “Exposure”
What does PK/PD really tell us?
“……Proper application of interpretive criteria
requires drug exposure at the site of infection that
corresponds to or exceeds the expected systemic
drug exposure at the dose listed in adult patients
with normal renal function.”
It tells us about the relationship
between the amount of drug
available at the site of the
infection and the ability of the
drug to inhibit / kill the bacteria
at that site.
Exposure – “In biology, contact of an organism
with a harmful agent (for example, chemicals)”
More drug is required to inhibit
/kill bacteria with higher MICs.
sick
Wikipedia January 2014
34
33
“Drug Exposure”
(can vary among patients)
Lower dose
Less “exposure”
Enterobacteriaceae
Cefepime
Higher dose
More “exposure”
…for additional information please see June 2013 CLSI
AST Subcommittee Meeting Minutes / Presentations on
CLSI website (see last slide in this presentation for
access details)
sick
= antibiotic
= GNR
35
36
Enterobacteriaceae
Cefepime MIC (µg/ml) Breakpoints
Cefepime




Introduced 1996
IM, IV administration
Extended-spectrum (4th generation) cephalosporin
Active against gram-pos and gram-neg organisms
(including P. aeruginosa)
 More stable to AmpC β-lactamases than other
cephalosporins
 Indications for use include: (see Prescribing Information)
–
–
–
–
Old Breakpoints
Agent
Cefepime
New Breakpoints
Susc
Int
Res
Susc
SDD
Res
≤8
16
≥32
≤2
4-8
≥16
(13) The interpretive criterion for susceptible is based on a dosage
regimen of 1 g every 12 h.
Pneumonia
Intra abdominal infections
Urinary tract infections (complicated and uncomplicated)
Skin infections
The interpretive criterion for SDD is based on dosing regimens that
result in higher cefepime exposure, either higher doses or more
frequent doses or both, up to approved maximum dosing regimens.
 Multiple dosing options
New breakpoints – cover all dosage
ranges outside the urinary tract
M100-S24. Page 52.
37
Why were cefepime breakpoints
(BPs) changed?
38
Cefepime
Prescribing Information
Dosing Options
Sandoz, Inc. 10/2011
 Previous “S” BP ≤8 µg/ml based on higher dose
than often used for treatment
– Many patients given lower dose
 Some clinical failures with low dose when
cefepime MICs 4 and 8 µg/ml (previously “S”)
 Because of limited options for MDR GNR, need
to make most of drugs available
Plasma
Concentrations
With higher dose, higher
concentration or “exposure”
39
Enterobacteriaceae
Cefepime Disk Diffusion (mm) Breakpoints
Enterobacteriaceae
Cefepime MIC (µg/ml) Breakpoints
Susc
MIC (µg/ml)
≤2
Based on
dose of:
1 g every 12 h
Total Daily
Dose
2g
SDD
4
Res
8
1 g every 8 h or
2 g every 8 h
2 g every 12 h
3-4 g
6g
40
Zone (mm)
Agent
≥16
Cefepime
Susc
SDD
Int
Res
≥25
19-24
-
18
NA
NA
M100-S24. Page 52, 206.
“Because it is not possible to correlate specific zone diameters
with specific MICs, an isolate with a zone diameter in the SDD
range should be treated as if it might be an MIC of 8 µg/mL”
41
M100-S24. Pages 52, 206.
42
Enterobacteriaceae
Cefepime MIC (µg/ml) Breakpoints
CLSI vs FDA vs EUCAST
Breakpoints Susc SDD Int Res
≤2
4-8
-
FDA
≤8
-
16
EUCAST *
≤1
-
2-4
•Susc - 1 g every 12 h
(2 g/day)
•SDD MIC = 4 - 1 g every 8 h or
≥16
2 g every 12 h (3-4 g/day)
•SDD MIC = 8 - 2 g every 8 h
(6 g/day)
≥32
See Prescribing Information
≥8
1 g or 2 g every 8 h
(3-6 g/day)
ESBL + (n=142)
50
ESBL - (n=52)
40
30
20
10
10
1
1
<=0.5
4
1
24
2
4
4
8
MIC (µg/ml)
8
44
6
16
32
2
>32
Adapted from CLSI Agenda Book, June 2013.
Source: CDC Sept. ‘09 – Sept ‘12
44
Cefepime % Susceptible
65.5
70
66
43
Cefepime MIC Distribution
Enterobacteriaceae Carbapenemase + (n=637)
% of Isolates at MIC
69
60
0
*Kahlmeter G. 2008. Clin Microbiol Infect. 14 Suppl 1:169.
69
70
Dosage
% of Isolates at MIC
New CLSI
Cefepime MIC Distribution
Enterobacteriaceae ESBL + and ESBL -
Organism
60
N
MIC (µg/ml)
≤2 Susc 4 – 8 SDD ≥16 Res
50
E. cloacae 1
944
93.3
4.7
2.0
40
E. coli
K. pneumoniae 2
2705
557
95.6
93.2
2.2
1.0
2.2
5.8
2
30
11.6
20
10
0
0
<=0.5
0.3
1
0.2
2
0.9
3.4
4
8
MIC (µg/ml)
16
18.1
Isolates from all sources collected:
1 1/11 – 12/13
2 8/13 – 12/13
32
UCLA
>32
Adapted from CLSI Agenda Book, June 2013.
Source: CDC Sept. ‘09 – Sept ‘12
45
A few practical considerations for
implementing new cefepime BPs …..
46
Cefepime
ESBL Testing
 Only for Enterobacteriaceae
 FDA BPs not yet revised
ESBL testing is not needed for cefepime;
results can be interpreted using the new
breakpoints and reported
– Lab must “verify” new BPs if used on commercial
AST system
 SDD vs LIS or HIS reporting systems
ESBL testing may be useful for
epidemiology or infection control
– At least one electronic medical record vendor can
report SDD
• Report 1 character (e.g., “D”) in LIS, explodes to SDD in HIS
– If can’t report “SDD” , consider using new
breakpoints and report “I”
47
M100-S24. Page 51.
48
Specimen: Blood
Diagnosis: Bacteremia
Enterobacter cloacae
ampicillin
cefazolin
cefepime
ciprofloxacin
ertapenem
gentamicin
piperacillin-tazo
trimeth-sulfa
Specimen: Blood
Diagnosis: Bacteremia
Enterobacter cloacae
Final Report with
Optional Comment
As listed in CLSI M100-S24. Page 20.
MIC (µg/ml)
>32 R
>32 R
“The interpretive criterion for
0.5 S
“S” is based on a dosage
>2 R
regimen of 1 g every 12 h.”
0.5 S
2S
>128/4 R
>4/76 R
ampicillin
cefazolin
cefepime
ciprofloxacin
ertapenem
gentamicin
piperacillin-tazo
trimeth-sulfa
MIC (µg/ml)
>32 R
>32 R
4 SDD
>2 R
0.5 S
2S
>128/4 R
>4/76 R
Final Report with
Optional Comment
As listed in CLSI M100-S24. Page 20.
“The interpretive criterion for
“SDD” is based on dosing
regimens that result in higher
cefepime exposure, either
higher doses or more
frequent doses or both, up to
approved maximum dosing
regimens.”
If SDD, get Antibiotic
Stewardship
involved???
49
50
For what other drugs might SDD be
applied in the future?
 Only applies when multiple approved dosing
options exist
 Other β-lactam possibilities
–
–
–
–
–
–
SDD Q&A
Cefotaxime
Cefoxitin
Ceftriaxone
Ceftazidime
Ceftizoxime
Aztreonam
M100-S24
Pages 18-21.
 Other drug classes?
51
52
SDD Q&A
Labs should discuss potential utility of all new CLSI
recommendations that will impact reporting with
Antibiotic Stewardship team (or other clinicians)
prior to making changes…
Enterobacteriaceae
Cefazolin and Cephalothin
Need educational effort outside the lab to optimize
use of new recommendations!
M100-S24
Pages 18-21.
53
54
Cefazolin /
Cephalothin
 Cefazolin
Questions?
–
–
–
–
What do we do about testing
/reporting cefazolin?
What test best predicts activity of
oral cephalosporins that might be
used to treat uncomplicated urinary
tract infections (uUTIs)?
Introduced 1973
IM, IV administration
Multiple indications for use (see Prescribing Information)
Today, mostly used for:
• MSSA
• Prophylaxis for some surgical procedures
• If GNR known “S” (only E. coli, K. pneumoniae, P. mirabilis):
– Bacteremia
– Uncomplicated UTIs
 Cephalothin
–
–
–
–
Introduced 1964
IV administration
Discontinued for human use in USA
Historically tested as surrogate for oral cephalosporins
and Enterobacteriaceae
55
56
Enterobacteriaceae
Cefazolin
Test/
Report
Group
Agent
MIC Breakpoint
(µg/ml)
Susc
Int
Res
≤2
4
≥8
≤16
-
≥32
Comments
Cephems (Parenteral)
A
Cefazolin
based on dose of 2 g every 8 h
Cephems (Oral)
U
Cefazolin*
Footnote (20)
* “surrogate” agent
M100-S24. Page 38.
M100-S24. Pages 51, 53.
57
58
Enterobacteriaceae
Cefazolin Footnote
Enterobacteriaceae
Cephalothin
Test/
Report
Group
(20) Cefazolin - predicts results for the oral agents cefaclor, cefdinir, cefpodoxime, cefprozil, cefuroxime
axetil, cephalexin, and loracarbef when used for therapy
of uncomplicated UTIs due to E. coli, K. pneumoniae,
and P. mirabilis.
Cefpodoxime, cefdinir, and cefuroxime axetil may be
tested individually because some isolates may be
susceptible to these agents while testing resistant to
cefazolin.
Agent
MIC Breakpoint
(µg/ml)
Susc
Int
Res
≤8
16
≥32
Comments
Cephems (Oral)
U
Cephalothin
But does NOT
predict “R”
Footnote (11)
(11) Cephalothin - can be used only to predict
“susceptibility” to the oral agents - cefadroxil,
cefpodoxime, cephalexin, and loracarbef.
Testing cefazolin preferred over cephalothin to predict
activity of oral cephalosporins for uncomplicated UTIs
M100-S24. Page 53.
59
M100-S24. Page 52.
60
How well does cefazolin predict results for
oral cephalosporins that might be used for
uUTI?
Infectious Diseases Society of
America Practice Guideline re: βlactams for Acute uUTI in Women
http://www.idsociety.org
 If cefazolin “S”, ≥97% of results for the following are “S”:
–
–
–
–
–
–
–
 β-lactams including amox-clav, cefdinir, cefaclor, and
cefpodoxime are appropriate choices when other
recommended agents (e.g., nitrofurantoin, trimeth-sulfa,
fosfomycin, fluoroquinolone), cannot be used.
 Other β-lactams (e.g., cephalexin) are less well studied but
may also be appropriate in certain settings.
 β-lactams generally have inferior efficacy and more
adverse effects, compared with other UTI antimicrobials.
Cefaclor
Cefdinir
Cefpodoxime
Cefprozil
Cefuroxime axetil
Cephalexin
Loracarbef
Some isolates may be
“R” to cefazolin but “S”
to cefpodoxime, cefdinir
and / or cefuroxime.
 But, some cefazolin-”R” are “S” to:
– Cefpodoxime (10.7%)
– Cefdinir (8.8%)
– Cefuroxime (6.3%)
62
61
Cefazolin % Susceptible
UCLA 8/13 – 12/13 (urine isolates)
Cefazolin % Susceptible
SENTRY USA 2007-2010
% Susceptible
80
92
89
83
57
100
Susceptible at MIC:
≤16 µg/ml
≤2 µg/ml
60
40
20
0
80
5
E. coli
K.
P. mirabilis
(n=3213) pneumoniae (n=477)
(n=2327)
93
92
89
91
64
% Susceptible
100
87
90
77
74
70
Cefazolin <=16
79
TMP-SMZ
Cipro
60
Nitrofurantoin
No nitrofurantoin data
available for K. pneumoniae
40
20
0
0
CLSI Agenda Book, June 2013.
Source: SENTRY (Ron Jones)
63
0
E. coli (n=2480)K. pneumoniae P. mirabilis
(n=419)
(n=227)
Specimen: Urine
Diagnosis: Recurrent Cystitis
E. coli
Cefazolin – UCLA Protocol
Only report on urine isolates of E. coli,
Klebsiella spp. and Proteus mirabilis
UCLA
64
Final Report with
Comment
MIC (µg/ml)
ampicillin
cefazolin
ciprofloxacin
nitrofurantoin
trimeth-sulfa
– Include report comment (on next slide)
Report on non-urine isolates by special
request - use breakpoints (µg/ml): ≤2 S, 4 I,
≥8 R
>32 R
8S
>2 R
≤16 S
>4/76 R
“Cefazolin results should only be used to predict potential
effectiveness of oral cephalosporins (e.g., cephalexin) for
treating uncomplicated urinary tract infections.”
UCLA
UCLA
65
66
Specimen: Urine
Diagnosis: Recurrent Cystitis
E. coli
Final Report with
Comment
MIC (µg/ml)
ampicillin
>32 R
oral cephalosporins
S
ciprofloxacin
>2 R
nitrofurantoin
≤16 S
trimeth-sulfa
>4/76 R
Acinetobacter spp.
Investigating this
reporting approach!
“Oral cephalosporins include
cephalexin, cefpodoxime, cefdinir.”
UCLA
67
68
Acinetobacter spp.
Breakpoints
Acinetobacter spp.
MIC (µg/ml) Breakpoints
Agent
Doripenem
Old Breakpoints
Susc
Int
Res
None (FDA ≤1 S)
New Breakpoints
Susc
Int
Res
≤2
4
≥8
Imipenem
≤4
8
≥16
≤2
4
≥8
Meropenem
≤4
8
≥16
≤2
4
≥8
M100-S24. Page 63.
M100-S24. Page 63.
69
70
Acinetobacter spp.
Carbapenem MIC (µg/ml) Breakpoints
CLSI vs FDA vs EUCAST
Agent
CLSI M100-S24. App. B2 Page 194. Intrinsic Resistance.
71
CLSI
FDA
EUCAST
Susc
Int
Res
Susc
Int
Res
Susc
Int
Res
Doripenem
≤2
4
≥8
≤1
-
-
≤1
2
≥4
Imipenem
≤2
4
≥8
≤4
8
≥16
≤2
4-8
≥16
Meropenem
≤2
4
≥8
≤4
8
≥16
≤2
4-8
≥16
72
Acinetobacter spp. (n=393)
SENTRY North America 2012
Acinetobacter spp. (n=393)
SENTRY North America 2012
45
70
40
60
35
30
% Susceptible
% of Isolates at MIC
50
Doripenem
Imipenem
Meropenem
25
20
15
10
5
0
53 52
58
54
52
53
Susceptible at MIC:
≤4 µg/ml
≤2 µg/ml
50
40
30
20
10
<=0.25
0.5
1
2
MIC (µg/ml)
4
8
0
>8
CLSI Agenda Book, June 2013.
Source: SENTRY (Ron Jones)
73
Acinetobacter baumannii
Carbapenem Resistance Mechanisms
Doripenem
Imipenem
Meropenem
CLSI Agenda Book, June 2013.
Source: SENTRY (Ron Jones)
74
Can’t extrapolate from
one carbapenem to
another – no “or” listed
with these drugs
 All A. baumannii produce naturally occurring oxacillinase
(e.g., OXA-51/69,) with carbapenemase activity
– Low expression – doesn’t confer carbapenem “R”
 Carbapenem hydrolyzing oxacillinases (Ambler Class D
enzymes)
Table 1A. Agents to Consider
for Testing and Reporting
– Low level hydrolytic activity compared to MBL, KPC
 Some metallo β-lactamases (IMP, VIM)
 Some KPCs
 Non-carbapenemase
Acinetobacter spp.
– Porin loss
– Efflux
Poirel & Nordmann. 2006. Clin Microbiol Infect. 12:826.
75
M100-S24. Page 39.
76
Acinetobacter spp.
Minocycline
Patient treated with
meropenem based on
imipenem-S result
Imip-S
 PO, IV formulation
 FDA approved for Acinetobacter infections
 Considerably more active than doxycycline and
tetracycline against A. baumannii
 Recent studies demonstrating clinical efficacy
Mero-R
– Bishburg et al. 2014. Infect Dis Clin Pract. 22:26.
– Jankowski et al. 2012. Infect Dis Clin Pract. 20:184.
 Option for multidrug resistant strains
Lesho et al. 2005. Fatal A. baumannii infection with discordant
carbapenem susceptibility. Clin Infect Dis. 41:758.
77
78
Acinetobacter spp.
MIC (µg/ml) Breakpoints1
Tetracycline vs. Doxycycline vs
Minocycline
“Organisms that are susceptible to tetracycline are
also considered susceptible to doxycycline and
minocycline. However, some organisms that are
intermediate or resistant to tetracycline may be
susceptible to doxycycline, minocycline, or both.”
Agent
Susc
Int
Res
Minocycline
≤4
8
≥16
Doxycycline
≤4
8
≥16
Tetracycline
≤4
8
≥16
1
FDA breakpoints same as CLSI breakpoint
M100-S24. page 63.
M100-S24. Page 63.
79
Acinetobacter baumannii
Minocycline vs. Tetracycline (n=5478) 1
Acinetobacter baumannii
Minocycline vs. Tetracycline (n=5478) 1
Tetracycline
Resistant
(>8 µg/ml)
Intermediate
(8 µg/ml)
Intermediate
(8 µg/ml)
Tetracycline
Resistant
(>8 µg/ml)
Minocycline
Minocycline
Susceptible
(≤4 µg/ml)
0 (0%)
1 (<0.1%)
Susceptible
(≤4 µg/ml)
2000 (36.5%)
Resistant
(>8 µg/ml)
Susceptible
(≤4 µg/ml)
Intermediate
(8 µg/ml)
Resistant
(>8 µg/ml)
0 (0%)
3 (<0.1%)
497 (9.1%)
Intermediate
(8 µg/ml)
4 (<0.1%)
Susceptible
(≤4 µg/ml)
1650 (30.1%)
Tetracycline-S = 30.2%
Minocycline-S = 79.1%
1
80
SENTRY surveillance program 2007-2011
Jones et al. 2013. IDWeek. Abstract #256.
1
1 (<0.1%)
684 (12.5%)
633 (11.6%)
2000 (36.5%)
Doxycycline-S = 59.6%
(data not shown)
SENTRY surveillance program 2007-2011
Jones et al. 2013. IDWeek. Abstract #256.
81
82
Acinetobacter baumannii
% Susceptible (N=1660) 1
Table 1A. Agents to Consider
for Testing and Reporting
Acinetobacter spp.
2013
1
Mino
Cefepime
Amik
Levo
Mero
Piptazo
67.9
4.2
22.5
4.3
11.6
1.6
Multidrug-R isolates (R to ≥ 3 classes of drugs);
TEST surveillance program 2011-2012
2014
M100-S24. Page 39.
Hawser et al. 2013. ICAAC. Abstract #C2-1625.
83
84
Minocycline
In Vitro Testing Options
Disk diffusion (multiple suppliers)
Etest
Sensititre (Trek Diagnostics Systems)
Currently not on other test systems
(in progress)
Staphylococcus aureus
85
Staphylococcus aureus
Vancomycin
Staphylococcus aureus
Vancomycin Disk Diffusion
(19) Except for the following, disk
diffusion zone sizes do not correlate with
vancomycin MICs for staphylococci. The
vancomycin 30-μg disk test detects S.
aureus isolates containing the vanA
vancomycin resistance gene (VRSA).
Such isolates will show no zone of
inhibition around the disk (zone = 6 mm).
The identification of isolates showing no
zone of inhibition should be confirmed.
Isolates of staphylococci producing
vancomycin zones of ≥ 7 mm should not
be reported as susceptible without
performing a vancomycin MIC test.
(16) For S. aureus, vancomycin-susceptible
isolates may become vancomycin
intermediate during the course of prolonged
therapy.
No longer suggest
vancomycin disk test to
screen for VRSA. Why?
• Phenotype rare
• Potential for reporting
false R
• Only known to work for
vanA (other van R
mechanisms??)
• Must confirm with MIC
M100-S23. Page 76.
86
M100-S24 Page 72.
When should we perform AST on subsequent
isolates of MRSA from blood?
87
88
Persistent MRSA Bacteremia
Case 3
Vancomycin
MIC (µg/ml)
Day of
Hospitalization
on which Blood
Culture Drawn
Routine AST
Performed on
S. aureus
Isolated?
Fresh Isolate
Tested
6
yes
1S
7
no
1S
8
no
2S
9
no
40
yes
Isolate Tested
Retrospectively
Quality Control
4I
4I
Old policy – perform AST every 5 days
New policy – perform AST daily
Giltner et al. 2014. J Clin Microbiol. 52:357.
89
90
QC Changes / Additions (1)
QC Changes / Additions (2)
 3 x 5 day plan (vs. 20-30 day plan) for converting
from daily to weekly QC testing
–
–
–
–
 Colistin / polymyxin B QC ranges with / without
polysorbate 80
 Some QC range additions / revisions for
specific agents
First appeared in M100-S23 (2013)
Now acceptable to CAP
Pending CLIA approval
Other accrediting agencies?
– Televancin MIC – test in CAMHB with 0.002%
polysorbate 80; QC range change
– Several new drugs (QC ranges only; no breakpoints;
not yet FDA approved for patient use)
 Recommendations for QC strains to include for
“Routine” QC
– “Routine” QC strains are tested regularly (eg, daily,
weekly) to ensure the test system performs as expected
and produces results that fall within specified QC
ranges” M02-A11 Page 30; M07-A9 Page 36.
91
92
Acceptable QC Ranges (µg/ml)
Carbapenems
E. coli
ATCC 25922
P. aeruginosa
ATCC 27853
Doripenem
0.015–0.06
0.12–0.5
Ertapenem
0.004–0.015
2–8
Imipenem
0.06–0.25
1–4
Meropenem
0.008–0.06
0.25–1
Agent
Rationale: P. aeruginosa 27853 more likely to detect
problems with carbapenems (on-scale endpoints)
M100-S24. Page 50.
M100-S24. Table 5A. Pages 154-155.
93
“Routine” QC Testing Changes
Table
Organism Group
Routine QC Change
94
QC Ranges (µg/ml)
Colistin / Polymyxin B
For use ONLY to QC:
2A
Enterobacteriaceae
Added P. aeruginosa
ATCC 27853
carbapenems
2B-1
Pseudomonas
aeruginosa
Deleted E. coli ATCC
25922
NA
2B-2
Acinetobacter spp.
E. coli ATCC 25922
tetracyclines
trimethoprim-sulfa
Colistin
2B-3
Burkholderia
cepacia
E. coli ATCC 25922
chloramphenicol
minocycline
trimethoprim-sulfa
Colistin
+ 0.002% polysorbate 80
2B-4
Stenotrophomonas
maltophilia
E. coli ATCC 25922
chloramphenicol
minocycline
trimethoprim-sulfa
Polymyxin B
2B-5
Other NonEnterobacteriaceae
E. coli ATCC 25922
chloramphenicol
tetracyclines
sulfonamides
trimethoprim-sulfa
Agent
Polymyxin B
+ 0.002% polysorbate 80
E. coli
ATCC 25922
P. aeruginosa
ATCC 27853
0.25–2
0.5–4
0.03–0.25
0.12–0.5
0.25–2
0.5–2
0.03–0.25
0.06–0.5
CLSI M100-S24 Table 4A.
95
96
Q&A
QC Ranges (µg/ml)
Colistin / Polymyxin B
E. coli
P. aeruginosa
Agent
ATCC 25922 ATCC 27853
Update January 2014:
CLSI
decision to eliminate polysorbate
Colistin
0.25–2 80 from media
0.5–4 for
colistin/polymyxin B reference MIC tests. Very recent data
Colistin
demonstrate
the presence of polysorbate
only prevents
0.03–0.25 80 not
0.12–0.5
+ 0.002%
polysorbate
80 but appears to enhance
drug
from sticking
to plastic
antibacterial
of colistin/polymyxin
B (synergism?).
Polymyxin activity
B
0.25–2
0.5–2
Polymyxin B
+ 0.002% polysorbate 80
0.03–0.25
CLSI acknowledges
now…. will be added to
next revision of M02 and
M07 (2015).
0.06–0.5
CLSI M100-S24 Table 4A.
97
Question 1
What should we do when a weekly QC
result is out of range?
Must determine if error is:
Question: Can we use retrospective QC data to
convert from daily to weekly QC using 20-30 day
QC plan?
Answer: Yes. You can use data from last 20
“consecutive test days” or “testing with each use”
– Random
• Corrects on repeat testing
– System (real)
• Persists on repeat testing
Random QC errors happen!
– Data must not be older than 2 years
– Test system used throughout must be the same
– QC ranges are established to include
≥95% results
If weekly QC out…
Retest (same day) and monitor
for 5 consecutive test days
Resume
weekly QC
testing
100
99
Weekly QC
out of range
All 5 results in range
98
Question 2
Drug A previously tested only on
special request and QC was done
same day as patient test. Now lab
wants to test drug A routinely.
M100-S24. Page 216.
M100-S24. Pages 216-217.
Option to use retrospective QC data
to document 5 “in range” QC results
Any result out of range
Corrective
Action
M100-S24. Page 216.
M02-A11 Page 40; M07-A9 Page 47.
101
102
Ampicillin E. coli ATCC 25922
Ampicillin E. coli ATCC 25922
Acceptable Range: 2-8 µg/ml
Acceptable Range: 2-8 µg/ml
MIC
Action
(µg/ml)
9661
4
9661
8
9661
16
Out of range. Repeat QC same day.
In range. 3 acceptable in range QC tests
9661
8
with lot 9661.
Repeat QC 2 more consecutive days.
9661
8
In range.
In range. 5 acceptable in range QC tests
9661
8
with lot 9661. Resume weekly QC.
Week Day Lot #
Week Day Lot #
1
2
3
4
5
1
1
1
1
1
3564
3564
3564
3564
3564
5
2
3564
MIC
Action
(µg/ml)
4
8
8
4
16
Out of range. Repeat QC same day.
In range. 5 acceptable in range QC tests
8
with lot 3564. Resume weekly QC.
If weekly “out” and have ≥5 “in” with
same lot, repeat QC ONE day
M100-S24. Page 217.
1
2
3
1
1
1
3
2
3
3
3
4
If weekly “out” and have <5 “in” with
same lot, repeat QC to get 5 “in”
M100-S24. Page 217.
103
Some Additional Topics Under
Evaluation by CLSI AST Subcommittee
104
Carba NP Test for
Carbapenemase Production
 Examine additional drugs for possible SDD
 Isolated colonies (lyse /
centrifuge)
 Hydrolysis of imipenem
 Detected by change in pH of
indicator (red to yellow/orange)
 Rapid <3h
 Microdilution plate or microtube
method
 Explore new phenotypic test for carbapenemases
 Review anaerobe testing recommendations
 Update M45 (fastidious organism) guideline
– Add…Aerococcus, Gemella, Lactococcus, Micrococcus, Rothia
 Expand availability / user friendliness of material
on CLSI website (including rationale for new
recommendations)
105
“a” tubes – Solution A
“b” tubes Solution A + imipenem
Nordmann et al. 2012. Emerg Infect Dis. 18:1503.
Tijet et al. 2013. Antimicrob Agents Chemother. 57:4578.
Vasoo et al. 2013. J Clin Microbiol. 51:3092.
106
CLSI
Website
An online interactive searchable
version of M100-S24 enables you
to easily…
• Information from
AST meetings
• Order CLSI AST
products
• Access M100-S24 – all you need is a web connection
• Dynamically filter by tables, organisms, and agents
• View only the information you want to see
CLSI AST Subcommittee welcomes new volunteers!
• Customize for your institution’s formulary
• Easily find additional CLSI AST standards and guidelines within
the eM100 Resource Center
Available at www.CLSI.org
107
http://www.clsi.org/standardsdevelopment/microbiology/
subcommittee-on-ast/
108
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 interpretive criteria (breakpoint) addition/revision
dates are listed in the front of M100-S24 (pages 24-25).
 A surrogate drug can be tested to predict activity of
another drug(s).
The following summary slides will
not be discussed and are
presented for participant’s
review.
109
Summary (2)
110
Summary (3)
 Several FDA breakpoints were recently revised and now
match newer CLSI breakpoints.
 Newer CLSI breakpoints may not yet be updated on
commercial AST systems.
 Manufacturers of commercial AST systems, by law, MUST
use FDA breakpoints.
 Clinical laboratories can use CLSI or FDA breakpoints.
 A verification must be performed on commercial systems if
using breakpoints other than those provided by the
manufacturer.
 FDA breakpoints for a specific agent can be found by
accessing the drug label or Prescribing Information thru
“DailyMed” or “Drugs@FDA” websites.
 Breakpoints are based on specific dosing regimens and
CLSI is adding these to M100.
 A new interpretive category, “susceptible dose
dependent (SDD)” can be used for drugs where multiple
dosing options exist and PK/PD data support the
category’s definition.
 PK/PD tells us about the relationship between the
amount of drug available at the site of the infection and
the ability of the drug to inhibit / kill bacteria at that site.
 There are several approved dosing options and PK/PD
data to support an SDD (vs. intermediate) interpretive
category for cefepime and Enterobacteriaceae.
111
Summary (4)
112
Summary (5)
 Only a relatively small percentage of isolates of
Enterobacteriaceae are likely to have MICs in the
cefepime SDD category.
 ESBL testing is not necessary when testing cefepime.
 Cefazolin (IM or IV) occasionally might be used to treat
infections due to cefazolin-susceptible (MIC ≤2 µg/ml)
isolates of E. coli, Klebsiella pneumoniae, or Proteus
mirabilis.
 Oral cephalosporins (e.g., cephalexin, cefpodoxime, etc.)
might occasionally be used for therapy of uUTIs.
 Cefazolin can be tested to predict the activity of oral
cephalosporins that might be used for therapy of uUTIs
due to E. coli, Klebsiella pneumoniae, or Proteus
mirabilis.
– Testing cefazolin is preferred over cephalothin as a surrogate test
for oral cephalosporins.
 A breakpoint for doripenem was added and breakpoints
for imipenem and meropenem were revised for
Acinetobacter spp.
 Acinetobacter spp. are intrinsically resistant to
ertapenem.
 Results from testing Acinetobacter spp. with either
doripenem, imipenem or meropenem cannot be used to
extrapolate results for one of the other two carbapenems.
113
114
Summary (6)
Summary (7)
 Minocycline is considerably more active than doxycycline
or tetracycline against Acinetobacter spp.
 If susceptible, minocycline may represent a therapeutic
option for MDR Acinetobacter spp.
 The vancomycin disk diffusion screen is no longer
recommended for S. aureus.
 Isolates of S. aureus may become vancomycin
intermediate during prolonged vancomycin therapy;
subsequent isolates of MRSA (in particular) should be
considered for susceptibility testing.
 There are several new recommendations for QC of
specific agents with specific QC strains and these are
based on efforts to test QC strains with “on-scale”
endpoints.
 The reference method for colistin / polymyxin B MIC testing
(as of January 2014) utilizes media without
supplementation with polysorbate 80.
 20 days of retrospective QC results can be used to convert
from daily to weekly QC testing for an agent that was tested
“with each use” and is now tested routinely.
 When an out of range result is observed during weekly QC
testing, 5 days of in range QC results are needed with the
lot of materials in use to resolve random QC errors.
 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 and reporting!
115
And thanks to:
APHL Staff (especially Denise K.)
CLSI Staff
CLSI Subcommittee on AST, especially:
Romney Humphries
Linda Miller
Audrey Schuetz
Paul Schreckenberger
117
116