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Virulence and Resistance in Staphylococcus Aureus: 2016 State of the Art Lyon, France Antimicrobial susceptibility tests for Staphylococcus aureus and EUCAST recommendations Virulence and Resistance in Staphylococcus aureus: 2016 State of the Art Lyon, France. 28 June – 1 July, 2016 © by author Dr. Rafael Cantón ESCMIDHospital Universitario Online Ramón y Cajal Lecture Library SERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA Departamento de Microbiología II Universidad Complutense. Madrid Antimicrobial susceptibility testing (AST) CLSI (NCCLS) EUCAST CLINICAL BREAKPOINTS CLINICAL BREAKPOINTS EPIDEMIOLOGYCAL CUT-OFF © by author ESCMID Online Lecture Library © by author www.eucast.org ESCMID Online Lecture Library MIC testing versus detection of resistance Susceptibility MIC Mechanism of resistance Mechanism© by author of resistance ESCMID Online Lecture Library Susceptibility MIC Clinical breakpoints: the philosophy . The aim of clinical breakpoints is to use MIC values … - to separate strains where there is a high likelihood of treatment success from those where treatment is more likely to fail - to adequately treat patients but not to detect resistance mechanisms from a microbiological point of view . Clinical breakpoints have not been created to detect resistance mechanisms . They are ultimately derived© by from author human clinical studies comparing outcomes with the MICs for the infecting pathogen . If clinical breakpoints are well established no actions (expert ESCMID rules) are needed Online beyond MIC Lecture interpretation Library (interpretive reading) .. but this has not been the case in the past! Interpretive reading of AST results . During more than twenty years interpretive reading of the antibiogram has been used to: - infer resistance mechanisms behind resistant phenotypes - identify resistant organisms for infection control purposes - apply expert rules* and modify (when needed!) previous clinical categorization Courvalin P. ASM News 19921992;58:368-75 Livermore et al. J Antimicrob Chemother 2001;48(Suppl 1):87-102 Cantón R. Enferm Infecc Microbiol Clin 2002; 20: 176-86 Cantón R. Enferm Infecc Microbiol Clin 2010; 28:375-85 © byLeclercq author et al. Clin Microbiol infect 2013; 19:141-60 This approach was partially needed ESCMID Online due to inadequate Lecture breakpoints! Library *Action to be taken (normally S or I to R), based on current clinical or microbiological evidence, in response to specific AST results Interpretive reading of AST results . Interpretative reading: the classical example ESBL positive isolate © by author expert rule ESCMID Online Lectureresistant toLibrary all cephalosporins and aztreonam (irrespective of MICs) Breakpoint definition (ISO 20776-1:2006) … beyond CLSI and EUCAST Values of parameters, such as MICs, on the basis of which bacteria can be assigned to the clinical categories “susceptible”, “intermediate” and “resistant” Susceptible bacterial strain inhibited in vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic success Intermediate bacterial© strain by inhibited author in vitro by a concentration of an antimicrobial agent that is associated with uncertain therapeutic effect ESCMID Online Lecture Library Resistant bacterial strain inhibited in vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic failure S R CLSI, 2014 S R EUCAST, 2016 ©ECOFF by author ESCMID Online Lecture Library Clin Microbiol Infect, 2013; 19:141-60 © by author ESCMID Online Lecture Library EUCAST: Detection of resistance mechanisms . EUCAST creates a subcommittee in 2012 to establish criteria for the detection of resistance mechanism of clinical and/or epidemiological importance © by author ESCMID Online Lecture Library www.eucast.org © by author ESCMID Online Lecture Library www.eucast.org EUCAST breakpoints, 2016 (version 6.0) © by author ESCMID Online Lecture Library EUCAST breakpoint tables MIC (mg/L) brpts* S≤ 2 R>2 mg/L Zone (mm) brpts* S≥ 22 R<22 mm Insufficient evidence IE (Literature: ”not enough evidence for a Can not be substituted. breakpoint” or ”no indication”) Can be supplemented with an MIC without interpretation. Inappropriate drug — (Literature: poor drug – don´t use!© by authorCan be substituted with an automatic ”R”. *whenESCMID numbers are the Online same = no intermediate Lecture category Library S. aureus: EUCAST susceptibility testing . Intrinsic resistance . Expert rules . Antimicrobial susceptibility and breakpoints © by author ESCMID Online Lecture Library Staphylococci: intrinsic resistance ac. Organisms Fusidic Ceftazidime Fosfomycin Novobiocin Staphylococcus saprophyticus R R R R Staphylococcus cohnii R R Staphylococcus xylosus R R Staphylococcus capitis R R Other CNS and Staphylococcus© by author aureus R Also R to aztreonam, temocillin, polymyxin B/colistin, nalidixic ac. R= intrinsic resitance ESCMID OnlineEUCAST Expert Lecture Rules Version 3.0Library (on consultation) Susceptibility testing is unnecessary and can be reported as R Staphylococci: expert rules Agent Agent Rule Exceptions, scientific basis, Evidence tested affected and comments grade Oxacillin, All IF R to isoxazolyl-penicillins (as Production of PBP2a (encoded A cefoxitin b-lactams determined with oxacillin, cefoxitin, by mecA) (disk diffusion) or by detection of mecA-gene or of leads to cross-resistance to b- or PBP2a) lactams detection of except ceftobiprole and THEN report as R to all b-lactams mecA gene ceftaroline except those specifically licensed or to treat infections caused by PBP2a methicillin-R staphylococci owing to low affinity for PBP2a Gentamcin All amino- IF resistant to gentamicin R to gentamicin is generally glycosides caused by the production THEN report© as by reisistant author to all production of ANT(4’)(4”)-I or aminoglycosides bifunctional APH(2’)-AAC(6) enzymes that determine loss of ESCMID Online Lecturesynergism Library of kanamycin, tobramycin and amikacin with b-lactams and glycopeptides irrespective of MIC values S. aureus: EUCAST susceptibility testing . MIC determination according with the International Standards Organisation (ISO) recommendations (identical to CLSI) ISO 20776-1, 2006 . Disk diffusion (EUCAST standardised disk diffusion method) - Medium: Mueller-Hinton agar - Inoculum: McFarland 0.5 - Incubation: Air, 35±1ºC, 18±2h - Reading: “Read zone edges as© the by point author showing no growth viewed from the back of the plate against a dark background illuminated with reflected light (except for benzylpenicillin and linezolid). ESCMID Online Lecture EUCAST breakpoint Library table v6, 2016 . Quality control: Staphylococcus aureus ATCC 29213 S. aureus ATCC 29213 QC Tables v6.1 (2016-03-01) © by author ESCMID Online Lecture Library http://www.eucast.org/ast_of_bacteria/qc_tables/ S. aureus and benzypenicillin MIC breakpoint (mg/L Zone diameter (mm) S ≤ R > S ≥ R < Benzylpenicillin 0.1251 0.1251 26A,B 26A,B 1/A. Most staphylococci are penicillinase producers, which are R to benzylpenicillin, phenoxy- methylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. Isolates negative for penicillinase and S to methicillin can be reported S to these agents. Isolates positive for penicillinase and methicillin-S are S to b-lactamase inhibitor combinations and isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin). Methicillin-R isolates are, with few exceptions, resistant to all b-lactam agents. B. Disk diffusion is more reliable© than by MIC determinationauthor for detection of penicillinase producers, provided the zone diameter is measured AND the zone edge closely inspected. If the zone diameter is <26 mm, then report R. ESCMID If the zone diameter Online is ≥26 mm AND Lecturethe zone edge is sharp, Library then report R. If not sharp, then report S and if uncertain, then report R Chromogenic cephalosporin-based b-lactamase tests do not reliably detect staphylococcal penicillinase S. aureus and benzypenicillin Examples of inhibition zones with benzylpenicillin © by author Fuzzy zone edge and Sharp zone edge and ESCMIDzone diameter ≥Online 26 mm Lecturezone diameter Library ≥ 26 mm Report susceptible Report resistant S. aureus and methicillin resistance MIC breakpoint (mg/L Zone diameter (mm) S ≤ R > S ≥ R < Oxacillin Note1,2 Note1,2 NoteA NoteA 1/A. Methicillin-R isolates are, with few exceptions, resistant to all b-lactam agents. 2. S. aureus, S. lugdunensis and S. saprophyticus with oxacillin MIC values >2 mg/L are mostly methicillin-R due to the presence of the mecA or mecC gene. The corresponding oxacillin MIC for coagulase-negative staphylococci other than S. saprophyticus and S. lugdunensis is >0.25 mg/L. © by author Cefoxitin is more reliable to detect ESCMID Online Lecturemethicillin resistance Library than oxacillin S. aureus and CNS and methicillin resistance MIC breakpoint (mg/L) Zone diameter (mm) S ≤ R > S ≥ R < Cefoxitin (screen) S. aureus, S. lugdunenesis, S. saprophyticus Note1 Note1 22A 22A Cefoxitin (screen) CNS other than S. lugdunenesis, S. saprophyticus Note2 Note2 25A 25A Cefoxitin (screen) S. pseudointermedius Note2 Note2 35A 35A A. Susceptibility of staphylococci to cephalosporins is inferred from the cefoxitin susceptibility except for cefixime, ceftazidime, ceftibuten and ceftolozane-tazobactam, which do not have breakpoints and should not be used for staphylococcal infections. Some methicillin- resistant S. aureus are susceptible© toby ceftaroline author and ceftobiprole 1. S. aureus and S. lugdunensis with cefoxitin MICs >4 mg/L and S. saprophyticus with cefoxitin MICs >8 mg/L are
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