Transcript Enterobacteriaceae and 3rd generation cephalosporin

Enterobacteriaceae and 3rd generation
cephalosporin breakpoints
- European and US (CLSI) current and
pending breakpoints
Gunnar Kahlmeter
EUCAST
This presentation will deal with
European and US (CLSI) breakpoints for:
•
•
•
•
Cefuroxime
Cefotaxime
Ceftriaxone
Ceftazidime
• Cefepime
…it will not deal with ESBL detection or characterisation.
Breakpoint committees
Committee Country
AST system
BSAC
United Kingdom
Yes
CA-SFM
France
Yes
CLSI
USA
Yes
CRG
The Netherlands
No
DIN
Germany
No
NWGA
Norway
No
SRGA
Sweden
Yes
S/I-breakpoints
I/R-breakpoints
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
S/I-breakpoints
I/R-breakpoints
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
ESBL
To determine breakpoints has always
been part science and part art!
….the science is growing stronger….
…but so far we have had difficulties agreeing:
Cefotaxime
Committee
S< / R>
BSAC
1/1
CA-SFM
4 / 32
CLSI
8 / 32
CRG
4 / 16
DIN
2/8
NWGA
1/4
SRGA
0.5 / 1
Breakpoint committees must have procedures for
re-evaluating and revising breakpoints of existing
drugs.
• Initial breakpoints often overly optimistic,
- with few exceptions, revised breakpoints have been lowered
• New resistance mechanisms need to be assessed,
• Doses and indications may change,
• New drugs within the class provoke a need for reevaluation of breakpoints of existing drugs,
• The tools available for determining breakpoints have
improved and the older breakpoints need to be
”overhauled” with new tools!
EUCAST and CLSI
• EUCAST
- in concert with EMEA and the pharmaceutical
companies, EUCAST has devised procedures for setting
breakpoints for new drugs.
- has devised procedures for re-evaluating breakpoints
for existing drugs (can be initiated by the company,
EMEA or EUCAST).
• CLSI
- and FDA currently do not agree on the mandate of
CLSI to determine breakpoints for new drugs or to
revise breakpoints for existing drugs.
Why revise Enterobacteriaceae 3rd
generation cephalosporine breakpoints?
And why now?
Why?
1.
The multiflora of cephalosporine breakpoints in itself calls
for revision and hopefully harmonisation.
2.
Many of our current cephalosporine breakpoints are
- too high – do not in themselves correlate well with clinical outcome
- do not detect those enzymes that need to be identified for successful therapy
- are out of sync with modern pK/pD-concepts
3.
There is evidence that the clinical correlate is to the MIC
rather than to the presence of the enzyme.
4.
New techniques in breakpoint setting can improve on the
breakpoints determined 25 years ago.
Why?
5. It is becoming increasingly important to assure that
the breakpoints themselves correlate to clinical
outcome - the rapidly increasing multiflora of resistance mechanisms
and species with ESBLs makes screening more complicated
and increasingly unreliable,
- the screening for and identification of ESBLs often delay
the report (of an R) to the clinician,
- many laboratories do not employ adequate ESBL
screening across the board - they may screen isolates from
septicemia cases but not from UTI.
Both EUCAST and CLSI emphasise that the
new breakpoints are clinical breakpoints - not
breakpoints designed to detect every ESBL.
However, the clinical breakpoints will detect the
absolute majority of ESBLs
……and for anyone who wants to catch every
ESBL, irrespective of clinical significance, the
current detection methods (see next slide) have
not changed or EUCAST has made available
species specific epidemiological cut-off values
(see the slide after next and www.eucast.org).
ESBL detection tests
• Cefpodoxime
+ single substance which will detect all (?) ESBLs.
+ high sensitivity
- low specificity
- will screen for ESBL but when negative there is ”nothing to report”
- and, because of the low specificity, when positive you need to put
in more work (confirm and characterize) before you report to the
clinician
• Cefotaxime AND ceftazidime
- both needed to find all (?) ESBLs (many microbiologists hesitate to
”waste” space on two 3rd generation cephs)
+ high sensitivity
+ high specificity
+ will screen for ESBLs and give a plausible profile
+ cefotaxime and ceftazidime susceptibility to include in report
- these cephalosporines are not relevant for less serious infections
Comparison of EUCAST clinical breakpoints
and epidemiological cut-off values
EUCAST Epidemiological cut-off values
S≤
R>
E.coli
K.pne
K.oxy
P.mir
Cefuroxime
8Adj
8
8
8
8
4
Cefotaxime
1
2
0.25
0.12
0.12
0.06
Ceftriaxone
1
8
0.25
0.12
0.12
0.06
Ceftazidime
1
8
0.5
0.5
0.5
0.12
Cefepime
1
8
0.12
0.12
0.12
0.12
Adj
Adjusted from 4 to 8 to avoid dividing wild type Enterobacteriaceae
Should ESBL-detection and
characterization be abandoned?
• Yes – the new breakpoints shall predict
clinical outcome.
• No – ESBLs have implications for
infection control and the epidemiology of
antimicrobial resistance in hospitals.
So how to proceed?
For laboratories with other main interests than
”antimicrobial resistance”, the use of an appropriate
breakpoint will simplify everyday life.
A breakpoint which will guide therapy and where the SIRcategorisation is not delayed by the detection and
categorisation of every ESBL, will be beneficial to patient
care.
The clinical rationale for the new breakpoints are:
- When the breakpoint detects cephalosporine resistance you
immediately report the R or the I for the drug(s) you have tested.
- Then you perform ESBL confirmation and characterisation tests and
contact the appropriate infection control authorities.
New cephalosporine breakpoints in
Enterobacteriaceae from
EUCAST and CLSI
Old breakpoints in white.
New breakpoints in yellow.
Cefuroxime
Cefuroximeiv
Committee
S< / R>
WT
BSAC
8 / 16
S
CA-SFM
8 / 32
S
CRG
4 / 16
S and I
DIN
4/8
S and I
NWGA
1 / 16
I
SRGA
8/8
S
CLSI
8/16
S
CLSI pending
EUCAST*
*for dosage: 1.5 g x 3
4/8 (8adj/8 or
16)
8/8 (pKD 4/8)
S
S
Cefotaxime
Cefotaxime
Committee
S< / R>
WT
BSAC
1/1
S
CA-SFM
4 / 32
S
CRG
4 / 16
S
DIN
2/8
S
NWGA
1/4
S
SRGA
0.5 / 1
S
8/32
S
CLSI
CLSI pending
1/2
EUCAST*
1/2 (pKD 1/2)
*for dosage: 1 g x 3 and high dose 2 g x 3.
S
S
Ceftriaxone
Committee
S< / R>
BSAC
1/1
CA-SFM
4 / 32
CRG
4 / 16
DIN
4 / 16
NWGA
1 / 16
SRGA
0.5 / 1
CLSI
CLSI pending
EUCAST*
8/32
1/2
1/2 (pKD 1/2)
*for dosage: 1 g x 1 and high dose 2 g x 1.
Ceftazidime
Ceftazidime
Committee
S< / R>
WT
BSAC
2/2
S
CA-SFM
4 / 32
S
CRG
4 / 16
S
DIN
4 / 16
S
NWGA
1/4
S
SRGA
2/4
S
CLSI
8/16
S
4/8
1/8 (pKD 4/8)
S
S
CLSI pending
EUCAST*
*for dosage: 1 g x 3 and high dose 2 g x 3
The S/I-breakpoint was decreased from 4 to 1 to detect
clinically important ESBLs.
Cefepime
Cefepime
Committee
S< / R>
WT
BSAC
1/1
S
CA-SFM
4 / 32
S
CRG
NA
S
DIN
4 / 16
S
NWGA
NA
S
SRGA
0.5 / 1
S
8/16
S
8/16
1/8 (pKD 4/8)
S
S
CLSI
CLSI pending
EUCAST*
*for dosage: 2 g x 3
EUCAST clinical breakpoints and dosage
EUCAST
Adj
Dosage
S≤
R>
Low
High
Cefuroxime
8Adj
8
-
1.5 g x 3
Cefotaxime
1
2
1gx3
2gx3
Ceftriaxone
1
2
1gx1
2gx1
Ceftazidime
1
8
1gx3
2gx3
Cefepime
1
8
1gx3
2gx3
Adjusted from 4 to 8 to avoid dividing wild type Enterobacteriaceae
MIC distribution E.coli
CTX-M group 1 (n=29)
Courtesy Arnfinn Sundsfjord, Tromsö, Norway
30
Cefpodoxime
20
15
Ceftazidime
Cefotaxime
10
5
0
0,75
1
1,5
2
3
4
6
8
12
16
24
32
48
64
96
128
192
256
Number
25
MIC
MIC distribution
E.coli CTX-M group 9 (n=15)
Courtesy Arnfinn Sundsfjord, Tromsö, Norway
7
6
Ceftazidime
Cefpodoxime
4
3
2
1
0
0,06
0,09
0,13
0,19
0,25
0,38
0,5
0,75
1
1,5
2
3
4
6
8
12
16
24
32
48
64
96
128
192
256
Number
5
Cefotaxime
MIC
MIC distribution chromosomal AmpC
E.coli (n=13)
Courtesy Arnfinn Sundsfjord, Tromsö, Norway
7
Cefotaxime
Cefoxitin
Cefpodoxime
Ceftazidime
Cefepime
5
4
3
2
1
MIC
> 256
192
96
48
24
12
6
3
1,5
0,75
0,38
0
< 0,25
Number
6
MIC distribution plasmid mediated AmpC
E.coli (n=10)
Courtesy Arnfinn Sundsfjord, Tromsö, Norway
6
4
Cefepime
Ceftazidime
Cefoxitin
Cefpodoxime
3
2
1
0
< 0,25
0,25
0,38
0,5
0,75
1
1,5
2
3
4
6
8
12
16
24
32
48
64
96
128
192
256
> 256
Number
5
Cefotaxime
MIC
The end