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Breakpoints and epidemiological cutoff values (BPs and ECVs): Can they predict clinical response?

Breakpoints and epidemiological cutoff values (BPs and ECVs): Can they predict clinical response? Ana Espinel- Ingroff , MS,PHD VCU Medical Center, Richmond, VA, USA. Breakpoints and ECVS.

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Breakpoints and epidemiological cutoff values (BPs and ECVs): Can they predict clinical response?

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  1. Breakpoints and epidemiological cutoff values (BPs and ECVs): Can they predict clinical response? Ana Espinel-Ingroff, MS,PHD VCU Medical Center, Richmond, VA, USA

  2. Breakpoints and ECVS • EUCAST and CLSI BPs for Candida versus triazoles and echinocandins are the best predictors of patient outcome. • Until recently, we only had MIC/MEC distributions for mould species. The focus of the presentation will be: 1. To summarize criteria to define ECVs for CLSI methods as well as provided available CLSI ECVs for Aspergillus spp. 2. To summarize and contrast CLSI cutoffs with other endpoints proposed as either BPs or ECVs based on in vitro/in vivo data, including murine models (infection and PK/PD data models) and clinical data.

  3. Triazole Resistance and A. fumigatus • In 1997, Denning et al. reported two isolates with MICs >8 mcg/ml and no clinical response to treatment. (JAC 40: 401) • In 2001, Mellado et al. reported that cyp51A and cyp51B genes coded 14-α sterol demethylase in Aspergillus spp. (JCM 39: 2431) • Subsequently, specific point cyp51A mutations were identified as responsible for elevated triazole MICs: • Codon G54, M220 G138, L98 and others. Point mutations became associated with patient failure and azole resistance has increased among Apergillus spp. especially in Europe.

  4. Role of the ECV ECVs separate WT from non-WT isolates. • Non-WT isolates may harbor resistance mechanisms and usually correlate with high MICs or MECs. A categorization of an isolate as non-WT indicates decreased susceptibility to the agent evaluated or potential phenotypic resistance. Non-WT MIC/MEC values are >ECV.

  5. Triazole MICs (µg/ml) for A. fumigatus mutants Gregson et al. 2013; 57: 5778-578. Lepak et al. AAC. 2013; 57: 579-585 & 57: 6284. Kidd et al. 2015. doi.1111/myc.12324. Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001. CLSI M57, M59. 2016.

  6. Available ECVs for M38 method • ECVs have been defined for some Aspergillus spp. and: - Amphotericin B, caspofungin, and four triazoles(isavuconazole, itraconazole, posaconazole and voriconazole) • Mucorales and Fusarium spp.: - Amphotericin B and triazoles Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol. http://dx.doi.org/10.1016/j.riam.2016.04.001. CLSI M57 & M59. 2016.

  7. Criteria for the calculation of ECVs for CLSI methods

  8. Criteria for ECV calculation 1. MICs/MECs generated by specific methodology (CLSI M27, M38, commercial method) E.g., any method modifications and/or abnormal distributions are not acceptable 2. Distribution must be accompanied by within range QC isolate(s) data during the testing period. 3. MIC/MEC data must be generated by a minimum of 3 different laboratories (to allow interlaboratory variability evaluation) and 100 isolates/species/agent. 4. In the case of CLSI-ECVS, the raw data should be available to the CLSI Subcommittee for review and approval by a majority of voting members. • Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001.

  9. Abnormal distributions • Bimodal=“saddle” between two modes • Truncated= mode at highest or lowest drug concentration • Similar bars=Same or similar modes • Samples of abnormal distributions and modal variability in the next slide. Turnidge & Patterson. Clin. Microbiol. Rev. 2007; 20: 391-408

  10. ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Pool of the 14 single caspofungin MIC distributions received for the calculation of caspofungin ECV for C. albicans: Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001. • The examination of modes (bolded) in each participant laboratory indicated: • Interlaboratory variability (up to five dilutions) which precluded the calculation of caspofungin ECVs and Candida spp. for reference methods. • Abnormal distributions with aberrant modes: (i) truncated, mode at lowest conc. tested: lab 3 distribution (ii) and bimodal: lab 12 distribution. The total number of caspofungin MICs is 11,550. Espinel-Ingroff et al. AAC. 2013. 57: 5836-42.

  11. Analysis • Distributions from the different labs are screened for abnormal distributions and size, unusual modal variation, and percentage of data provided by each lab. • It is recommended that data should be normalized (weighting) when a lab. contributes >50 to the “pool” used for the analysis, but a decision has not been made regarding the ECV when values are different (see next slide). • The ECV is calculated by the iterative statistical method as described by Turnidge et al. (Microsoft Excel workbook [ECOFFinder]). • The MIC/MEC that captures at least 97.5% of the modeled WT population is the ECV for the particular species and agent. Turnidge et al. Clin. Microbiol. Infect. 2006; 12: 418-125; Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001.

  12. Posaconazole ECV of 0.25 mcg/ml (97.5% value) using the iterative statistical method (ECOFFinder) before normalizing (weighting [W]) the data, when one lab provided >50% of the data.

  13. Posaconazole ECV of 0.5 mcg/ml (97.5% value) using the iterative statistical method (ECOFFinder) after normalizing (weighting [W]) the data, when one lab provided >50% of the data.

  14. ECVs and other susceptibility endpoints for A. fumigatus and the triazoles

  15. ECVs for A. fumigatus complex (4 labs) CLSI mode EUCAST mode ECV: <1 mcg/mL Number of isolates Itraconazole 37 isolates >4 mcg/mL 7 mutants Rodrigez-Tudela et al. AAC. 2008; 52: 2648-2472 Espinel-Ingroff et al JCM. 2010; 48: 3251-3257 Meletiadis et al. AAA. 2012. 56: 2524-2529 MIC (mcg/mL)

  16. ECVsforA. fumigatuscomplex (4 labs) CLSI mode EUCAST mode Number of isolates ECV: < 1 mcg/mL Voriconazole Rodrigez-Tudela et al. AAC. 2008; 52: 2648-2472 Espinel-Ingroff et al JCM. 2010; 48: 3251-3257 Meletiadis et al. AAA. 2012. 56: 2524-2529 MIC (mcg/mL)

  17. S-BPs:Voriconazole and A. fumigatus 1JID 2012; 206: 642-652. 2JAC 2014. 3AAC 2013; 57: 1532-1534. 4Curr Fungal Infect Rep 2012; 5: 128-4. Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001

  18. ECVs for A. fumigatus complex (4 labs) CLSI mode EUCAST Mode *ECV: <0.12-0.25 mcg/ml CLSI ECV < 0.5 mcg/mL before normalization of the data Number of isolates Posaconazole *Rodrigez-Tudela et al. AAC. 2008; 52: 2648-2472 Espinel-Ingroff et al. JCM. 2010; 48: 3251-3257 *Meletiadis et al. AAA. 2012. 56: 2524-2529 MIC (mcg/mL)

  19. ECVs: Posaconazole and A. fumigatus complex tListed as EUCAST S-BP; Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001

  20. S-BPs: Posaconazole and A. fumigatus complex 1Drug Res Upgrades 2009; 12: 141-147. 2AAC. 2012; 56: 2524-2529. 3AAC. 2013; 57: 579-585. *Mavridou et al. AAC 2011; 860-865; Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001

  21. ECVs for A. fumigatus complex (8 labs) Mode 600 500 400 300 200 100 0 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4 >4 Isavuconazole Number of isolates EUC Mode/ECV: 1/2 mcg/mL CLSI ECV: < 1 mcg/mL Cyp51 TR/L98H &/or M220 MICs>4 mcg/ml MIC (mcg/mL) Chowdhary et al. JAC2012; 67: 362-366. Espinel-Ingroff et al. 2013; AAC 57: 3823-3828. Howard et al. 2013; AAC 57: 5426-5431

  22. S-BP: Isavuconazole and A. fumigatus complex Lepak et al. AAC. 2013; 57: 6284 ; Espinel-Ingroff & Turnidge. 2016. Rev IberoamMicol.http://dx.doi.org/10.1016/j.riam.2016.04.001

  23. S-BP: Isavuconazole and A. fumigatus complex Presented by L. Kovanda; CLSI meeting January 2015

  24. Azole resistance among A. fumigatus complex in Australia • Between 2000-2013, 13 A. fumigatus complex isolates with elevated MICs of itraconazole, posaconazole and/or voriconazole were collected at the National Mycology Reference Centre, Adelaide. • Molecular analysis confirmed that 4 isolates were Aspergillus lentulus, known to have reduced susceptibility to triazoles. • Among the A. fumigatus, the following cyp51A gene mutations (TR34/L98H, G54R, F46Y, Y431S and G448S) were observed) in 6 of the 9 isolates. MICs were >ECVs for all isolates with at least one of the agents. Kidd et al. 2015. doi.1111/myc.12324

  25. ECVs for A. terreus complex (5 labs) Mode ECV: < 1 mcg/mL Number of isolates Voriconazole Espinel-Ingroff et al. JCM. 2010; 48: 3251-3257 MIC (mcg/mL)

  26. ECV: Voriconazole and A. terreus complex Salas et al. AAC. 2013; 57: 1532-1543

  27. CLSI mode CLSI < 2 mcg/mL MIC distributions of amphotericin B against Aspergillus fumigatus complex (7 labs) BP: 1 mcg/mL EUC Mode: 0.25 mcg/mL (mcg/mL) Espinel-Ingroff et al 2011; AAC 55: 5150-5154: 330-43

  28. Amphotericin B and Aspergillus spp.

  29. ECV for A. fumigatus complex (5 labs) Mode < 0.5 mg/L Number of isolates Caspofungin Espinel-Ingroff et al. AAC 2011; 55: 2855-2859 MIC (mcg/mL)

  30. Caspofungin ECVs

  31. Conclusions for A. fumigatus Preliminary results support the potential clinical utility of triazole ECVs for A. fumigatus in detecting emerging resistance (non-WT MICs) due to cyp51A mutations.

  32. Conclusions • Similar data are needed for triazoles and other moulds as well for other antifungal agents. • ECVs have only been defined for Aspergillus spp., Fusarium spp. and the Mucorales

  33. Thank you

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