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Difficult or Tricky Antibiotic
Resistance Phenotypes to
Recognize
Dr Koh Tse Hsien
Department of Pathology
Singapore General Hospital
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Contents
• Gram-positive
– Staphylococcus aureus with penicillinase production
– Vancomycin Resistant Enterococci (VRE)
– Staphylococcus aureus with reduced susceptibility to
glycopeptides (hVISA, VISA, VRSA)
• Gram-negative
– ampC Cephalosporinases ( AmpC and pAmpC)
– Carbapenemases (IMP, VIM, KPC, and OXA-48)
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Mechanisms of Resistance
Target modification
Antibiotic sequestration Enzymatic inactivation
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Penicillinase in S. aureus
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Penicillinase production
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Vancomycin susceptibility in S.
aureus
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Vancomycin-intermediate S.
aureus (VISA)
• First described in Japan in 1997
• Intermediate resistant (MIC 4-8 mg/L)
• Hetero-intermediate resistant (MIC <4 mg/L)
• Increased production of cell wall precursors and PBP 2’
• Reduced cross linking in cell wall (less target for vancomycin)
• Lower growth rates and thicker cell walls (vancomycin sequestration)
• Prolonged exposure to vancomycin
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MRSA VISA
Micky LEONG (Ms) :: Laboratory Technologist, Electron Microscopy Unit YLLSOM
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Vancomycin intermediate
Staphylococcus aureus
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Lab detection of VISA
• Not detected by routine disk or automated
methods
• Etest (consistently one twofold dilution
higher)
• Broth microdilution
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EUCAST MIC breakpoint (mg/L) Zone diameter breakpoint (mm)
S ≤ R > S ≥ R <
Vancomycin 2 2 - -
CLSI MIC breakpoint (mg/L) Zone diameter breakpoint (mm)
S ≤ I R ≥ S ≥ I R ≤
Vancomycin 2 4-8 16 - - -
1. Glycopeptide MICs are method dependent and should be determined by broth microdilution (reference ISO 20776). S. aureus with vancomycin MIC values of 2 mg/L are on the border of the wild type MIC distribution and there may be an impaired clinical response. The resistant breakpoint has been reduced to 2 mg/L to avoid reporting "GISA" isolates intermediate as serious infections with "GISA" isolates are not treatable with increased doses of vancomycin or teicoplanin.
18) MIC tests should be performed to determine the susceptibility of all isolates of staphylococci to vancomycin. The disk test does not differentiate vancomycin-susceptible isolates of S. aureus from vancomycin-intermediate isolates…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)…
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The clinical significance of vancomycin minimum inhibitory concentration in
Staphylococcus aureus infections: A systematic review and meta-analysis
van Hal et al. CID 2012; 54: 755-71
• High vancomycin MIC (≥1.5 mg/L by Etest) associated with higher mortality rate
• This was driven by BSI with vancomycin MIC of ≥ 2 mg/L by Etest
• Higher vancomycin MIC values (≥1.5 mg/L by Etest) predicted treatment failure
• Etest recommended for all MRSA BSI
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How does your lab measure the MIC?
• Etest 0.5-1 dilution higher than broth microdilution (gold standard)
• Automated MIC 1-2 dilutions lower than gold standard
• Most vancomycin outcome studies involved Etest
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Vitek versus Etest (92 isolates)
Vitek Etest
Dr Tan TY, Dept of Lab Medicine, Changi General Hospital
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(Hetero) hVISA
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Lab detection of hVISA
• Population analysis
• Macrodilution Etest (not true MIC)
• Etest GRD
• MHA5T screening plate (5 μg/ml teicoplanin)
• hVISA may predict potential failure of daptomycin therapy
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Howden, B. P. et al. 2010. Clin. Microbiol. Rev. 23(1):99-139
FIG. 8. Examples of Etest methodology used to detect hVISA
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Vancomycin-resistant S. aureus (VRSA)
• In-vitro transfer of VanA in 1992
• Michigan (June 2002), Pennsylvania (Sept 2002)
• MIC 1024 mg/L, 32 mg/L
• VanA positive
• Plasmid-mediated
• Detected by disk diffusion but may not be detected by automated methods
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Tenover, F. C. et al. 2004. Antimicrob. Agents Chemother. 48(1):275-280
FIG. 1. Disk diffusion and Etest analysis of the PA-VRSA isolate on Mueller-Hinton agar
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Vancomycin-resistant Enterococci
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Vancomycin-resistant Enterococcus
VanA VanB VanC
Vanc MIC
mg/L
64->1000
Resistant
4-1024
Resistant
2-32
Intermediate
Teic MIC
Mg/L
16-512
Resistant
0.5
Susceptible
0.5
Susceptible
Species E. Faecium
E. faecalis
E. Faecium
E. faecalis
E. Gallinarum
E. Casseiflavus
E. flavescens
Genetic
determinant
Acquired Acquired Intrinsic
Transferable Yes Yes No
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Van A VRE
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VSE
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Van B VRE
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VRE
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VRE Lab Detection
• Disk diffusion-incubate full 24 h, view with transmitted light for hazy zones
• MIC methods
• Screening plates (vancomycin 6 mg/L)
• Multiplex PCR to detect vanA, vanB
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Identify all VRE to species level
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vanC motile E. gallinarum
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Mechanisms of Resistance
inner membrane
outer membrane
periplasmic space
Loss of membrane permeability
Efflux
Enzymatic inactivation
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EUCAST MIC breakpoint (mg/L) Zone diameter breakpoint (mm)
S ≤ R > S ≥ R <
Cefotaxime 1 2 20 17
Ceftriaxone 1 2 23 20
Ceftazidime 1 4 22 19
Cefepime 1 4 24 21
CLSI
MIC breakpoint (mg/L) Zone diameter breakpoint (mm)
S ≤ I R ≥ S ≥ I R ≤
Cefotaxime 1 2 4 26 23-25 22
Ceftriaxone 1 2 4 23 20-22 19
Ceftazidime 4 8 16 21 18-20 17
Cefepime 8 16 32 18 15-17 14
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EUCAST
1. The cephalosporin breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including ESBL and plasmid mediated AmpC). Some isolates that produce beta-lactamases are susceptible or intermediate to 3rd or 4th generation cephalosporins with these breakpoints and should be reported as tested, i.e. the presence or absence of an ESBL does not in itself influence the categorisation of susceptibility. In many areas, ESBL detection and characterisation is recommended or mandatory for infection control purposes.
CLSI
(7) Following evaluation of PK-PD properties, limited clinical data, and MIC distributions, revised interpretive criteria for cephalosporins (cefazolin, cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone) and aztreonam were first published in January 2010 (M100-S20) and are listed in this table. Cefazolin interpretive criteria were revised again in June 2010 and are listed below. Cefepime and cefuroxime (parenteral) were also evaluated; however, no change in interpretive criteria was required for the dosages indicated below. When using the current interpretive criteria, routine ESBL testing is no longer necessary before reporting results (ie, it is no longer necessary to edit results for cephalosporins, aztreonam, or penicillins from susceptible to resistant). However, ESBL testing may still be useful for epidemiological or infection control purposes. For laboratories that have not implemented the current interpretive criteria, ESBL testing should be performed as described in Table 2A Supplemental Table 1.
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Rationale for change
• PD modeling suggests cephalosporin breakpoints reduced to 1-4 mg/L, possible to obtain serum concentrations of cephalosporins above MIC for the required 40-50% of dosage interval
• Animal experiments show MIC better predictor of outcome than mechanism
• Reports of clinical failure correlated with higher MICs.
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AmpC in Gram-negative bacilli
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Class C beta-lactamases
• Gene normally found in most Gram negatives except
Klebsiella and Salmonella
• Cephalosporinases
• Not inhibited by clavulanate, tazobactam (except M.
morgannii)
• Resistant to cefoxitin
• Cefepime not generally affected
• Chromosomal
• Generally expressed at low level but are inducible
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ESCHAPPM
• Enterobacter cloacae/aerogenes
• Serratia marcescens
• Citrobacter freundii
• Hafnia alvei
• Aeromonas hydrophila/caviae
• Providencia stuartii/rettgeri
• Morganella morganii
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Induction vs Stable
Derepression • Induction
– transient switching on of -lactamase
synthesis in response to an inducer (cefoxitin,
imipenem)
• Stable Derepression
– permanent hyperproduction of the -
lactamase independent of an inducer
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Chromosomal AmpC in
Enterobacter spp.
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Ceftriaxone
Ceftoxitin
Ceftriaxone
Cefoxitin
Augmentin
Aztreonam
K. Pneumoniae
Would you treat this patient with
ceftriaxone?
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Ceftriaxone
Cefoxitin
De-repressed mutants
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De-repressed mutant
Original strain
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Original strain
De-repressed mutant
>32 mg/L-
-1.5 mg/L 1mg/L susceptible-
pAmpC DHA-1
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DHA in Klebsiella pneumoniae
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CLSI (8) Enterobacter, Citrobacter, and Serratia may develop resistance during prolonged therapy with third-generation cephalosporins as a result of derepression of AmpC β-lactamase. Therefore, isolates that are initially susceptible may become resistant within three to four days after initiation of therapy. Testing of repeat isolates may be warranted.
Enterobacter spp., Citrobacter freundii, Serratia spp. and Morganella morganii. If susceptible in- vitro, the use of monotherapy of cefotaxime should be discouraged, owing to the risk of selection of resistance, or suppress the susceptibility testing result for this agent.
BSAC (EUCAST?)
Inducible plasmid AmpC (DHA) in K. pneumoniae?
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CDS method • E. cloacae, E. aerogenes, C. freundii, inducible pAmpC
– High frequency of derepressed mutants (10-5 to 10-6) – Report R to all cephalosporins – Test cefepime and carbapenems – Do not attempt to test other β-lactams
• S. marcescens – No derepressed mutants with ceftazidime, tazocin and
aztreonam – Derepressed mutants with other β-lactams including
cefotaxime.
• H. alvei, P. stuartii, P. rettgeri and M. morganii – Very low mutation rate (10-8) – Test and report accordingly
http://web.med.unsw.edu.au/cdstest/
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Carbapenemases in Gram-
negative bacilli
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Carbapenemases
• Class A
– KPC
• Class B
– IMP, VIM, NDM
• Class C
• Class D
– OXA-48
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EUCAST MIC breakpoint (mg/L) Zone diameter breakpoint (mm)
S ≤ R > S ≥ R <
Ertapenem 0.5 1 25 22
Imipenem 2 8 22 16
Meropenem 2 8 22 16
CLSI MIC breakpoint (mg/L) Zone diameter breakpoint (mm)
S ≤ I R ≥ S ≥ I R ≤
Ertapenem 0.5 1 2 22 19-21 18
Imipenem 1 2 4 23 20-22 19
Meropenem 1 2 4 23 20-22 19
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EUCAST
1. The carbapenem breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including the majority of carbapenemases). Some isolates that produce carbapenemase are categorised as susceptible with these breakpoints and should be reported as tested, i.e. the presence or absence of a carbapenemase does not in itself influence the categorisation of susceptibility. In many areas, carbapenemase detection and characterisation is recommended or mandatory for infection control purposes.
CLSI
24) Following evaluation of PK-PD properties, limited clinical data, and MIC distributions that include recently described carbapenemase-producing strains, revised interpretive criteria for carbapenems were
first published in June 2010 (M100-S20-U) and are listed below. Because of limited treatment options for
infections caused by organisms with carbapenem MICs or zone diameters in the intermediate range,
clinicians may wish to design carbapenem dosage regimens that use maximum recommended doses
and possibly prolonged intravenous infusion regimens, as has been reported in the literature.1 -4 Consultation with an infectious diseases practitioner is recommended for isolates for which the
carbapenem MICs or zone diameter results from disk diffusion testing are in the intermediate or resistant
ranges.
Until laboratories can implement the current interpretive criteria, the modified Hodge test (MHT) should
be performed as described in the updated Table 2A Supplemental Table 3. After implementation of the current interpretive criteria, the MHT does not need to be performed
other than for epidemiological or infection control purposes (refer to Table 2A Supplemental
Table 2).
The following information is provided as background on carbapenemases in Enterobacteriaceae that are
largely responsible for MICs and zone diameters in the new intermediate and resistant ranges, and thus the rationale for setting revised carbapenem breakpoints:
The clinical effectiveness of carbapenem treatment of infections produced by isolates for
which the carbapenem MIC or disk diffusion test results are within the new intermediate (I) range
is uncertain due to lack of controlled clinical studies.
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NDM-1
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DM23092 IMP+
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DM23092 IMP+
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Modified Hodge test
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pAmpC
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pAmpC
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pAmpC
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OXA-48
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Outcomes of infections caused by carbapenemase-
producing K. pneumoniae according to treatment regimen
A combination more than 1 active drug including carbapenem B combination more than 1 active drug excluding carbepenem
C monotherapy with aminoglycoside D monotherapy with carbapenem
E monotherapy with tigecycline
F monotherapy with colistin G inappropriate therapy Tzouvekelis et al. CMR 2012 25: 682-
707
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Carbapenemase-producing K.
pneumoniae: (when) might we still
consider treating with carbapenems?
• Carbapenem MIC ≤ 4 mg/L
• High-dose prolonged infusion
• Used in combination with another active
compound
Daikos and Markogiannakis CMID 2011; 17: 1135-1141
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My take
• Detection of mechanism may still have role for tertiary care hospitals with resistance problems and complicated patients
• Combination therapy usually including carbapenem for CP-CRE
• Should we be doing more MICs?
• Automated system may not be equivalent to MIC. Etest practical option for most labs