Oct 11, 2012 - ... shows slides. Edwin Meese .... reporting the test result as susceptible may lead ... lactamase is detected (testing discouraged) THEN report.
EUCAST expert rules in AST: Gram positives BSAC User Day 11 October 2012 Trevor Winstanley
What is an expert? An expert is a man who has made all the mistakes that can be made, in a narrow field. Niels Bohr
An expert knows all the answers - if you ask the right questions. Levi Strauss
Make three correct guesses consecutively and you will establish a reputation as an expert. Laurence J. Peter
An expert is somebody who is more than 50 miles from home, has no responsibility for implementing the advice he gives, and shows slides. Edwin Meese
Expert rules
Describe an action to be taken
Assist clinical microbiologists
based on current clinical and/or microbiological evidence in response to AST results interpretation of AST results
Contribute to QA
highlight anomalous or unlikely results
www.eucast.org
EUCAST expert rules
The EUCAST expert rules in AST are divided into:
intrinsic resistances
exceptional phenotypes
interpretive rules
Intrinsic resistance
Opposed to acquired or mutational resistance Characteristic of all (or almost all) representatives of the species The drug is, in effect, clinically useless
AST is normally unnecessary
“Susceptible” results should be viewed with caution
an error in identification or susceptibility testing? if S is confirmed, the drug should preferably not be used
Intrinsic resistance
Intrinsic resistance
e.g.Enterococci
Rule 4 intrinsic resistance
Rule 4 intrinsic resistance (1)
Gram-positive bacteria
Staphylococci
fusidic acid, fosfomycin, novobiocin
S. cohnii, S. xylosus
ceftazidime
S. saprophyticus
aztreonam, temocillin, polymixin B / colistin, nalidixic acid
novobiocin
S. capitis
fosfomycin
Rule 4 intrinsic resistance (2)
Streptococci, enterococci
Enterococci
cephalosporins, erythromycin, sulphonamides
E. faecalis, E. gallinarum, E. casseliflavus
fusidic acid, aminoglycosides (low-level)
clindamycin, quinupristin-dalfopristin
E. gallinarum, E. casseliflavus
vancomycin
Rule 4 intrinsic resistance (3)
Corynebacterium spp.
Listeria monocytogenes
cephalosporins
Leuconostoc spp., Pediococcus spp., some Lactobacillus spp.
fosfomycin
vancomycin, teicoplanin
Clostridium ramosum, C. innocuum
vancomycin
Exceptional phenotypes
Not yet reported or very rare An error in identification or susceptibility testing?
further study reference laboratory
Resistance may develop and increase over time Local or national differences
very rare in one hospital, area or country, more common in another
Rules 6 & 7 exceptional phenotypes
Exceptional phenotypes (1)
Staphylococci, JK coryneforms, S. pneumoniae, ß-haemolytic streptococci
S. aureus, JK coryneforms, S. pneumoniae, ß-haemolytic streptococci
R to teicoplanin
S. pneumoniae
R to vancomycin, linezolid, quinupristin-dalfopristin, daptomycin, tigecycline
R to imipenem, meropenem, rifampicin
ß-haemolytic streptococci
R to penicillin, cephalosporins
Exceptional phenotypes (2)
Enterococci
E. faecalis, E. gallinarum, E. casseliflavus, E. avium
S to quinupristin-dalfopristin (+/- R to ampicillin)
E. faecium
R to linezolid, daptomycin, tigecycline; R teicoplanin but not vancomycin
R to quinupristin-dalfopristin (+/- S to ampicillin)
C. difficile
R to metronidazole or vancomycin
Interpretive reading of the antibiogram 1.
To establish the susceptibility phenotype
2.
To infer the potential resistance mechanism
3.
To predict a previously defined phenotype from the resistance mechanisms
Courvalin P, ASM News, 1992; Livermore DM et al. J Antimicrob Chemother 2001; 48 (Suppl 1): 87-102; Cantón R. Enferm Infecc Microbiol Clin 2010; 28:375-385
e.g. Staphylococci
Rule
12.3
TOB
KAN
GEN
GEN
TOB
KAN
AMI
STR ARB
R
R
R
R
R
S
APH(3’)1-3
ANT(4’)(4”)-1
APH(2’) AAC(6)
√
Grade
[B]
Evidence grades
A. Clinical evidence
B. Evidence is weak and based only on a few case reports or on experimental models
reporting the test result as susceptible leads to clinical failures
reporting the test result as susceptible may lead to clinical failures
C. Microbiological data
clinical use of the agent should be discouraged
Rule 8.2 interpretive rules ß-lactam agents
IF Staphylococcus spp. R to benzylpenicillin or IF ßlactamase is detected (testing discouraged) THEN report as R to all penicillins except isoxazolyl-penicillins and ß-lactamase inhibitor combinations [C]
Technically difficult and prevalence > 90% in most countries.
Rule 8.1 interpretive rules ß-lactam agents
IF Staphylococcus spp. R to isoxazolyl-penicillins (oxacillin, cefoxitin, mecA, PBP2a) THEN report as R to all ß-lactams except ceftaraline and ceftobiprole (low affinity for PBP2a) [A]
Rule 8.3 interpretive rules ß-lactam agents
IF ß-haemolytic streptococci (groups A, B, C, G) S to benzylpenicillin THEN report S to aminopenicillins, cephalosporins and carbapenems [C]
© Nathan Reading
Rare isolates of group B streptococci have benzylpenicillin MICs up to 1 mg/L.
Rule 8.4 interpretive rules ß-lactam agents
IF S. pneumoniae R by the oxacillin disk screening test THEN determine MIC of benzylpenicillin, aminopenicillins, cephalosporins and carbapenems [B]
Production of mosaic PBPs leads to various patterns of ß-lactam resistance. Report as interpreted by MIC. © Nathan Reading
Rule 8.5 interpretive rules ß-lactam agents
IF viridans group streptococci R to benzylpenicillin THEN determine MIC of aminopenicillins and cefotaxime / ceftriaxone and report as interpreted [C]
Production of mosaic PBPs leads to various patterns of ß-lactam resistance. Results cannot be inferred from benzylpenicillin results.
Rule 8.6 interpretive rules ß-lactam agents
IF Enterococcus spp. R to ampicillin THEN report as R to ureidopenicillins and carbapenems [C]
Alterations in PBP5 leads to decreased affinity for ß-lactams.
© Nathan Reading
Rare ß-lactamase-producing isolates have been reported in a few countries (not UK).
Rule 11.1 interpretive rules MLS antibiotics
Report azithromycin, clarithromycin and roxithromycin as per erythromycin result [C]
Erythromycin is the class representative for 14- and 15membered ring macrolides.
Production of an efflux pump. Ribosomal methylase encoded by erm genes (MLSB phenotype).
Interpretive rules MLS antibiotics Rule
Organisms
ERY
CLI
Inducible MLSB
CLI
Grade
11.2
Staphylococcus spp.
R
S
-
S
[B]
11.3
Streptococcus spp.
R
S
-
S
[C]
M phenotype. Probably expressing efflux pumps (msr, or mef(A) in streptococci) – clindamycin is not a substrate. Risk for selection of mutants resistant to clindamycin is no greater than that for erythromycin-susceptible isolates. © Nathan Reading
Interpretive rules MLS antibiotics Rule
Organisms
ERY
CLI
Inducible MLSB
CLI
11.2
Staphylococcus spp.
R
S
+
R
11.3
Streptococcus spp.
R
S
+
Peptostreptococcus spp.
>8
Bacteroides spp.
> 32
11.4
S
or
CLI
Grade
S + warning
[B]
S + warning
[C]
R
Ribosomal erm methylase genes confer inducible MLSB phenotype (iMLSB).
© Nathan Reading
“Clinical failure during treatment with clindamycin may occur by selection of constitutively resistant mutants. Use of clindamycin is probably best avoided in severe infections”.
[C]
iMLSB resistant isolates: clindamycin therapy failures in staphylococci No. of patients treated with clindamycin
No. of failures
No. of MLSB constitutive isolates selected
2
2
2/2
McGehee (1968)
3
2
1/3
Rao (2000)
2
2
1/2
Frank (2001)
3
1
1/3
Drinkovic (2002)
1
1
1/1
Siberry (2003)
1
1
1/1
Levin (2005)
12
9
7 / 12
Reference
Interpretive rules MLS antibiotics
Rule 11.5. IF Staphylococcus spp. R to clindamycin THEN report a warning than bactericidal activity of quinupristin-dalfopristin is reduced [C]
Constitutive MLSB resistance phenotype (cMLSB). Cross-resistance to streptogramin B-type factor. Conflicting data from experimental endocarditis models using Q-D vs. constitutive MLSB resistant isolates. © Nathan Reading
Rule 12 interpretive rules for aminoglycosides and staphylococci
Predicted loss of synergy with ß-lactams and glycopeptides in staphylococci Rule
TOB
12.3
GEN
GEN
TOB
KAN
AMI
R
R
R
R
R
R
R
R
>8
12.1 12.2
KAN
R R
R
STR ARB
S
APH(3’)1-3
ANT(4’)(4”)-1
APH(2’) AAC(6)
√
√
or
√
[C]
√
or
√
[C]
√
[B]
or
Grade
Rule 12 interpretive rules for aminoglycosides and enterococci /streptococci
Predicted loss of synergy with ß-lactams and glycopeptides in enterococcia and streptococcib Rule
GEN
KAN
GEN
TOB
KAN
AMI
R
> 512
12.4
R
> 512
12.5
12.6
STR
> 128
STR ARB
R
R
R
APH(3’)-1-3
S
APH(2’) AAC(6)
Grade
[A]a
√ or √
[C]b
√
R
R
ANT(6)
Other enzymes / ribosomal mutation
or
√ √
[B]a [C]b [A]a [C]b
Fluoroquinolone resistance
Selection and transmission of spontaneous chromosomal mutants
Increased levels bacterial membrane pumps
remove fluoroquinolones from the cell
Changes in target enzymes
reduce fluoroquinolone binding DNA gyrase; Topoisomerase IV
S. aureus (especially MRSA) S. pneumoniae (in community and in multidrug resistant clones)
DNA gyrase and topoisomerase IV Fluoroquinolones (Q) block DNA replication Resistance results from mutations in QRDR
separates interlocked DNA strands
ParC Ξ GrlA in staphylococci
alters DNA supercoiling
Rule 13 interpretive rules for fluoroquinolones
Risk of resistance development during fluoroquinolone therapy – first-step mutation Rule
13.1
13.3
Organisms
Staphylococcus spp.
Streptococcus pneumoniae
OFL
R
R
CIP
or
or
R
R
LEV
MOX
and S or
S
and or
S
S
Acquistion of
Grade
… at least one target mutation in grlA (Ξ parC)
[C]
… at least one target mutation in e.g. parC (parE) More reliably detected using norfloxacin
[C]
Complete / partial resistance to all fluoroquinolones – combined mutations Rule
Organisms
13.2
Staphylococcus spp.
13.4
Streptococcus pneumoniae
LEV MOX
Acquistion of
Grade
R
or
R
… combined mutations in grlA (Ξ parC) and gyrA
[C]
R
or
R
… combined mutations in e.g. parC and gyrA
[B]