22 nd June 2015 Why we perform susceptibility testing Robin A Howe Antimicrobial use in Primary Care
Why do we perform AST? Clinical Clinical Prediction Prediction of of Efficacy Efficacy
Why do we perform AST? Clinical Clinical Prediction Prediction of of Efficacy Efficacy Epidemiological Tracking of Resistance
Why do we perform AST? Clinical Clinical Prediction Prediction of of Efficacy Efficacy Epidemiological Tracking of Resistance Selection of Empiric/Syndromic Therapy
Definitions of antimicrobial susceptibility and resistance in relation to clinical breakpoints Clinically Susceptible (S) a micro-organism is defined as susceptible by a level of antimicrobial activity associated with a high likelihood of therapeutic success Clinically Intermediate (I) a micro-organism is defined as intermediate by a level of antimicrobial activity associated with indeterminate therapeutic effect Clinically Resistant (R) a micro-organism is defined as resistant by a level of antimicrobial activity associated with a high likelihood of therapeutic failure. Micro-organism SIR is defined by applying the appropriate breakpoint in a defined phenotypic test system
Is susceptibility testing useful? Victor Lorian (1990) Journal of Antimicrobial Chemotherapy Vol 25, 175-181. Predictive value of susceptibility tests for the outcome of antimicrobial therapy
510 patients received antibiotics 382 (75%) had a specimen sent 298 (78%) had a positive culture 271 (91%) got appropriate antibiotics 27 (9%) got inappropriate antibiotics 219 (81%) improved 41 (15%) did not improve 1 (3%) improved 22 (82%) did not improve
Community-acquired bloodstream infections admitted to ITU 30 ITUs in Spain - 339 CA-BSI Inappropriate initial therapy in 14.5% patients Organism No. of patients S. pneumoniae 55 S. aureus 46 All Gram positives 148 E.coli 86 All Gram negatives 143 No. with Septic shock (%) 20 (36.4) 26 (56.5) 62 (41.9) 55 (64) 88 (61.5) No. with inappropriate therapy (%) 4 (7.3) 15 (32.6) 25 (16.9) 8 (9.3) 14 (9.8) No. died (%) 18 (33.3) 27 (58.6) 61 (41.5) 34 (39.5) 55 (38.5) Valles et al (2003) Chest 123: 1615
Overall Appropriate therapy Inappropriate therapy Mortality 43.1% 37% 69.4% Multivariate analysis: inappropriate therapy independently predicted mortality (OR, 4.11; 95% CI 2.03 8.32)
Predicting clinical efficacy Relationship between phenotypic measures of susceptibility and the amount of antibiotic exposure in the body Relationship between presence of a resistance mechanism and clinical efficacy
MIC (minimum inhibitory concentration) the gold standard for susceptibility testing Incubate for 18 hours
Pharmacodynamic parameters C max t
Pharmacodynamic parameters C max AUC t
Pharmacodynamic parameters C max AUC MIC t
Pharmacodynamic parameters C max AUC MIC T > MIC t
Pharmacodynamic parameters C max AUC MIC Cmax/MIC T>MIC AUC/MIC T > MIC t
PK/PD examples Antimicrobial class Dominant PD parameter Magnitude of dominant PD parameter Beta-lactams T>MIC >40-60% Aminoglycosides Cmax/MIC >10 Fluoroquinolones AUC/MIC >125 for Gram neg >33 for Gram pos
Breakpoint tables
MIC Distributions & Epidemiological Cut-Offs (ECOFFs) S/I/R results give abbreviated information and may not Identify presence of resistance mechanisms Allow dose optimisation MIC distribution Isolate MICs from different settings different countries human isolates veterinary isolates
ECO FF
Organism with MIC above ECOFF: -erroneous identification -erroneus MIC -resistance mechanism ECO FF
ECO FF
S. pneumoniae with reduced susceptibility to penicillin ECOFF 0.06 mg/l PK/PD & clinical data suggest higher BP for treatment of nonmeningitis Study Pallares et al. (1995) Winston et al. (1999) Ewig et al. (1999) Turett et al. (1999) Metlay et al. (2000) Feikin et al. (2000) Pneumococcal infection type Sample size PRSP PSP Pneumonia 145 359 Infection 65 411 Pneumonia 49 52 Bacteraemia 20 429 Bacteraemic pneumonia Invasive pneumonia 44 148 183 3452 RR of death PRSP vs. PSP 1.0 (95% CI 0.5 1.9) 1.25 (p=0.82) 2.8 (95% CI 0.8 10.1) 6.0 (p<0.02) 1.7 (95% CI 0.8 3.4) 7.1 (95% CI 1.7 30.0) MIC cut-off (mg/l) to define PRSP >0.1 >0.1 >0.1 >1.0 >0.1 >2.0
ECO FF
Continuous infusion ceftazidime Aim to maintain T>MIC 100% 2g 8 hourly vs 6g/day continuous infusion 100% cont inf patients maintained conc above 40mg/L 20-30% bolus patients maintained conc above 40mg/L
Meropenem vs E.coli ECO FF
Meropenem vs E.coli ECO FF
Meropenem vs E.coli ECO FF
Breakpoints set for clinical efficacy Specific phenotypic or genotypic screening tests needed for some resistance mechanisms Resistance mechanism may give MICs below breakpoint Phenotypic tests perform poorly
MRSA The presence of meca has been associated with clinical failure...although there were dissenters
MRSA Methicillin resistance is heterogeneously expressed by many strains When using methicillin to test need to optimise expression of resistance by addition of salt and/or incubation at 30 0C Ryffel et al (1994) AAC 38: 724
MRSA Even with optimisation, results with different beta-lactams are unreliable Jorgensen et al. (1988) JCM. 26: 1675
MRSA Screen with Cefoxitin or for PBP2a Expert rule: IF resistant to isoxazolyl-penicillins (as determined with oxacillin, cefoxitin, or by detection of mecagene or of PBP2a), THEN report as resistant to all b-lactams except those specifically licensed to treat infections caused by methicillin-resistant staphylococci owing to low affinity for PBP2a
Conclusions AST performed to Predict clinical efficacy Phenotypic tests correlated to outcome Optimise dosing Identify resistance Phenotypic or genotypic Presence of resistance mechanism does not always correlate with clinical failure caution for genomic approach