Show Me the Money! Antimicrobials vs. Rapid Diagnostics Melissa D. Johnson, PharmD, MHS, AAHIVP Associate Professor of Medicine Clinical Liaison Pharmacist Duke Antimicrobial Outreach Network Duke University Medical Center Durham, North Carolina Romney M. Humphries, PhD D(ABMM) Chief Science Officer, Accelerate Diagnostics Tucson, Arizona It s Friday at 4:00 48 Male h/o alcoholic cirrhosis S/p liver transplant, episode of VRE & E. coli bacteremia (susceptible only to aminoglycosides, carbapenems) ciprofloxacin, ertapenem, tigecycline, daptomycin Multiple hepatic abscesses Right sided hydropneumothorax, hypotension, ICU K. pneumoniae (x2) in hepatic abscesses & blood Resistant to everything tested: intermediate tigecycline & chloramphenicol Scr 3.5 mg/dl, wt= 88 lbs 1
Unmet Need: MDR Gram Negative Infections ESKAPE GN Pathogen Annual Number of Cases Annual Deaths CDC Hazard Level* Carbapenem-resistant Enterobacteriaceae MDR Acinetobacter baumannii MDR Pseudomonas aeruginosa Enterobacter species (ESBL-producing) 9,300 610 Urgent 7,300 500 Serious 6,700 440 Serious 26,000 1,700 Serious *CDC statement on antibiotic resistance threats in the US. http://www.cdc.gov/features/antibioticresistancethreats/index.html Major mechanisms of antimicrobial resistance Target site modification Decreased permeability Enzymic degradation X Efflux Bypass 2
Beta-Lactamases/ Carbapenemases Ambler Class Examples Activity Organisms Drugs impacted Class A serine serine - lactamase Class B metallo- beta lactamase (MBLs) Class C AmpC -lactamase, serine -lactamase Class D serine -lactamase KPC NMC/ IMISME TEM SHV CTX-M VEB IMP VIM SPM GIM SIM NDM CMY AmpC DHA OXA (OXA-23, 24, 58, 146) Hydrolyzes penicillins & narrow-spectrum cephalosporins Use a Zn 2+ cation for hydrolysis of beta-lactam ring Hydrolyzes broad & extended-spectrum cephalosporins Beta-lactamase production + membrane permeability or efflux Enterobacteriaceae Pseudomonas spp. Aeromonas Chryseobacterium Stenotrophomonas P. aeruginosa Acinetobacter K. pneumoniae Extended spectrum cephs & carbapenems, aztreonam Variable susceptibility to clavulanic acid (most susceptible except KPC) resistant to all β-lactam antibiotics except monobactams (aztreonam) resistant to clavulanic acid, tazobactam, & sulbactam May harbor additional resistance genes Enterobacteriaceae penicillins, cephalosporins/cephamycins, β- lactam/β-lactam inhibitors Cefepime & aztreonam/oxacillin/cloxacillin may retain activity A. baumanii Extended spectrum cephs & carbapenems http://microbiology.publish.csiro.au/paper/ma13014.htm Which antibiotic(s) would you recommend for CRE in this patient? A) Dual carbapenem B) Ceftazidime/avibactam + aztreonam C) Tigecycline + colistin D) Something else (kitchen sink?) 3
What s in the pipeline for these resistant infections? Number of Agents In Development 16 14 12 10 8 6 4 2 0 Phase 1 Phase II Phase III GN ESKAPE Activity No Activity Possibly Probably 41 antibiotics in development ~11-16 of these could potentially treat GN ESKAPE pathogens < 1/3 novel drug class or mechanism 2 recent drug approvals www.pewtrusts.org March 2017 Pipeline for GN ESKAPE pathogens Name Phase Company Class Target Comments Meropenem + vaborbactam Approved Rempex Carbapenem + BLI PBP; -lactamase Indication: cuti/pyelo Lacks activity vs. MBL & OXA carbapenemases Type II & IV GP + GN/ No indication Delafloxacin* Approved Melinta Fluoroquinolone *possible topoisomerase for resistant GNR Fosfomycin IV II/III Zavante Phosphonic antibiotic Cell wall synthesis inhibitor Approved in Europe Cefiderocol III Shinogi Siderophore -lactam PBP Eravacycline III Tetraphase Tetracycline 30s ribosomal subunit Imipenem - relebactam III Merck & Co Carbapenem + BLI PBP; -lactamase Active vs. Acinetobacter & serine / MBLs Active vs. NDM, VIM, OXA CRE Lacks activity vs. MBL & OXA carbapenemases Omadacycline III Paratek Tetracycline 30s ribosomal subunit GP + GN activity Plazomicin III Achagoen Aminoglycoside 30s ribosomal subunit Aztreonam- Avibactam II Pfizer/Allergan Monobactam + BLI PBP; -lactamase GP + GN activity; potency vs CRE May have activity vs NDM CRE Finafloxacin II MerLion FQ Type II topoisomerase GP + GN activity Murepavidin II Polyphor peptide mimetic LptD Anti-pseudomonal 4
Targeting the Unmet Need Activity vs Critical Pathogen Novel Features Name Route(s) CRAB CRPA CRE OPP Class Target Mechanism No X-R Meropenem + vaborbactam IV + - - +/- Delafloxacin* IV + PO - - - - Cefiderocol IV - - - +/- Eravacycline IV + PO - - - - Imipenem - relebactam IV - - - - Omadacycline IV + PO - - - - Plazomicin IV - - - - Aztreonam- Avibactam IV - - - - Finafloxacin IV - - - - Murepavidin IV + + + + Adapted from: World Health Organization; 2017 (WHO/EMP/IAU/2017.11). Licence: CC BY-NC-SA 3.0 IGO Pipeline for Gram Negative ESKAPE pathogens- Phase I Name Co Class Target Cefepime + Wockhardt Cephalosporin + BLI PBP; -lactamase zidebactam ETX2514SUL Entasis Sulbactam + non - lactam BLI PBP; -lactamase (A,C,D beta-lactamases) TP-6076 Tetraphase Tetracycline 30s ribosomal subunit SPR741 Spero Polymixin B Cell wall Nacubactam Meiji Seika BLI -lactamase, PBP2 GSK-3342830 GSK PLC -lactam PBP KBP-7072 KPB Tetracycline 30s ribosomal subunit Biosciences TP-271 Tetraphase Tetracycline 30s ribosomal subunit 5
What s the impact on patient outcomes? Study Design Intervention & Infections Outcomes CRACKLE TANGO-1 TANGO-2 CARE EPIC Portsmouth et al. * Not statistically significant Prospective, multicenter observational Phase III doubleblind randomized Phase III open label randomized Phase III open label randomized Phase III doubleblind randomized Phase III doubleblind randomized ceftazidime-avibactam vs colistin, CRE infection meropenem-vaborbactam vs pip-tazo for cuti/pyelo meropenem-vaborbactam vs best available therapy plazomicin vs colistin (+ tige or meropenem) BSI or HAP/VAP due to CRE Plazomicin vs. meropenem cuti/pyelo cefiderocol vs. imi/cilastatin cuti +/- pyelo or acute uncomplicated pyelo All cause mortality (IPTW-adjusted): 9% vs 32% (difference 23% [95% CI: 9-35%]) 30-day outcome (IPTW adjusted): 64% probability [57-71%] better outcome w/ceftaz-avi Similar microbial eradication at TOC visit Shorter mean length of ICU stay: 9.3 vs 11.1 days* Clinical cure at test of cure visit, mortality, & renal toxicity better for meropenem-vaborbactam Lower 28-day all cause mortality/significant diseaserelated complications (23.5 vs 50%)* Lower 28-day all cause mortality (11.8 vs 40%) Superiority at TOC Microbiologic Success (87.4 vs 72.1%) Superiority for clinical/microbiologic response at TOC (72.6 vs. 54.6%) van Duin D. Clin Infect Dis 2017. https://doi.org/10.1093/cid/cix783; Stus V. ECCMID 2017. Abstract 1204; Shorr A. ASM Microbe 2017. Abstract 307; Kaye KS. IDWeek 2017. Abstract 1862; Connolly L. ECCMID 2017. Abstract OS042; Cloutier D. ECCMID 2017. Abstract 7648; Portsmouth S. ECCMID 2017. Abstract #7582. Diagnostics So... How (and when) do you find out it s a pan-resistant K. pneumoniae anyway? 6
Current Paradigm for Diagnosis of Blood Stream Infections We need data here! Blood drawn, sent to lab Cultured on automated system Flagged as positive Gram stain performed and called Sub-cultured to solid media Isolate ID and susceptibility Day 3-5 Approaches to Susceptibility Testing (to date) Phenotype What concentration of the drug inhibits growth of the bug? (e.g., MIC) Genotype Is there a gene that predicts the drug won t kill the bug? 14 7
Approaches to Susceptibility Testing (to date) Phenotype What concentration of the drug inhibits growth of the bug? (e.g., MIC) Genotype Is there a gene that predicts the drug won t kill the bug? Slow (but getting quicker!) Requires a large # of bacteria (but going down!) Mechanism does not matter Provides and MIC Quick! Requires few bacteria Mechanism matters you only find what you re looking for No MICs must assume R if gene detected. How to interpret no gene? 15 Problem with GNRs UCLA data, 2016 N=208 carbapenem-r Enterobacteriaceae 25% Not all are KPC! Plasmid AmpC Porin mutations + ESBL Other carbapenemases 3% 2% 70% KPC MBL OXA-48 None 8
Problem #2 with GNRs 1) Isolate harbors OXA-48 & other R genes/permeability defects 2) Isolate harbors OXA-48 & no other R genes / permeability defects Antimicrobial Antimicrobial Aminoglycosides R Aminoglycosides S R R R R R R Cephalosporins & Aztreonam Carbapenems Piperacillin-tazobactam Fluoroquinolones Tetracyclines Trimethoprimsulfamethoxazole Cephalosporins & Aztreonam Carbapenems Piperacillin-tazobactam Fluoroquinolones Tetracyclines Trimethoprimsulfamethoxazole S R S S S S Tigecycline R Tigecycline S Colistin R Colistin S 17 Final note on challenges Policies make development/improvement of new AST devices challenging 1) outdated reference method (but best we have!) 2) strict requirements for performance - more than possible by reference method in some cases 3) only clear tests if drug / bug combination listed in the drug labeling 4) no requirement for system re-evaluation if new R mechanisms 5) require new clinical trial data for device if breakpoint changes 18 9
Few AST Options Vitek 2 Phoenix MicroScan Etest Sensititre Disk #2 Disk #1 Ceftaroline Time to FDA- Clearance Note: time to market may be longer 0 10 20 30 40 50 Months Ceftazidime-avibactam testing options: - Disk (backordered) - Etest (research use only) - Sensititre MICs (few labs use) Data derived from FDA website clearance dates for ceftaroline Regulatory challenges: Example, Accelerate Pheno Acinetobacter baumannii Amp- Sulbactam Piperacillintazobactam Cefepime Ceftazidime Cefriaxone Meropenem Amikacin Gentamicin Tobramycin Ciprofloxaci n Colistin AxDx Panel Y Y Old systems Y Y Y Y Y Y Y Y Y Y N/Y (CLSI BP) Y, yes drug can be tested on system Why? No FDA BP for A. baumannii and the drugs! 10
What s coming? 1) 21 st Century Cures Act will help with AST regulatory dilemmas 2) Newer, rapid AST methods that are based on phenotype Accelerate Pheno System (FDA cleared) Rapid disk diffusion direct from blood (CLSI, EUCAST) Roche, MicrobeDx, LifeScale, BacterioScan, etc 3) Newer, more complete genotype methods DNAe, Qvella, GenMark, etc It s Friday at 4:15 55 yo female w/ history of diabetes mellitus, UTIs C. glabrata blood cultures x2, urine positive Receiving IV micafungin x 5 days, blood cultures have cleared Ophtho exam negative Ready for discharge? Susceptibility testing fluconazole MIC 64 mcg/ml 11
Invasive Fungal Infections-- Worldwide Infection Estimated lifethreatening infections/year Mortality rates in infected population Aspergillosis > 200,000 30% - 95% Candidiasis > 400,000 46% - 75% Cryptococcosis > 1,000,000 20% - 70% Mucormycosis > 10,000 30% - 90% Pneumocystis (PCP) > 400,000 20% - 80% Brown GD, et al. Sci Transl Med 2012;4(165):165rv13. Candida Bloodstream Isolates Showing Fluconazole, Echinocandin, or Multidrug Resistance Percent of resistant isolates 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 2008-2009 2009-2010 2010-2011 2011-2012 2012-2013 Year of Surveillance Fluconazole Echinocandins Multi-drug Percent of resistant isolates 35 30 25 20 15 10 5 0 Resistant C. glabrata BSI MDR 2001-2002 2003-2004 2005-2006 2007-2008 2009-2010 fluconazole anidulafungin caspofungin micafungin http://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html Alexander BD. Clin Infect Dis. 2013 Jun 15; 56(12): 1724 1732. 12
Mechanisms of antifungal resistance Polyene Echinocandin Azole Target site modification Target abundance Target site overexpression Drug pump upregulation Biofilm formation Non-target effects Perlin DS. Lancet Infec Dis 2017. S1473-3099(17)30316-X Candida auris: fungal superbug Often multi-drug resistant Can be difficult to identify Cannot differentiate from other species on many commercial systems May be misidentified as Candida haemulonii Colonizes environmental surfaces Mortality 44-66% Tsay S, MMWR Morb Mortal Wkly Rep 2017;66:514 515. doi: http://dx.doi.org/10.15585/mmwr.mm6619a7 Lepak AJ, AAC 2017; 61(8): e00791-17. Azar MM, Clin Infect Dis 2017 doi: 10.1093/cid/cix460. 13
Resistance Among Cryptic Molds Amphotericin B Itraconazole Voriconazole Posaconazole Aspergillus calidoustus Aspergillus fumigatiaffinis Aspergillus lentulus Aspergillus hiratsukae Aspergillus pseudofischeri Aspergillus udagawae Aspergillus viridinutans Fusarium solani Fusarium spp Scedosporium apiospermum complex Lamentospora prolificans Mucorales Resistant, Susceptible, Intermediate/low MIC Perlin DS Lancet Infect Dis. 2017 Jul 31. pii: S1473-3099(17)30316-X. Limitations of available antifungal agents Spectrum of activity Polyenes Echinocandins Azoles (fluconazole) (voriconazole) Formulation challenges (e.g. IV only) Resistance Drug interactions Toxicity PK challenges (voriconazole) 14
Systemic Antifungal Agent Pipeline Posaconazole Anidulafungin Itraconazole Terbinafine Voriconazole ABLC L-AmB Micafungin Caspofungin Amphotericin B 5FC Fluconazole 1950 1960 1970 1980 1990 2000 2010 2020 Adapted from Ostrosky-Zeichner L. Nature Reviews Drug Discovery. 2010;9:719-727. Antifungals in Development (Phase II) Name Company Class Target Comments SCY078 Scynexis Triterpenoid glucan synthase inhibitor Cell wall / 1,3-β-Dglucan synthase VT1161 Viamet Tetrazole Ergosterol synthesis CYP51/ cell membrane Biafungin (CD101) Cidara Echinocandin Cell wall/ 1,3-β-Dglucan synthase MAT2203 Matinas Polyene- cohchleated amphotericin B Cell membrane F901318 F2G Orotomide Dihydroorotate dehydrogenase MGCD290 Mirati Therapeutics Histone deacetylase inhibitor Histone deacetylase 2 Candida; Aspergillus Candidiasis & onychomycosis Long t ½; once weekly dosing PO Aspergillus & Scedosporium spp. IV & PO Broad spectrum, synergy but did not add to fluconazole for VVC Perfect JR. nature Reviews 2017. 16: 603-616. Wiederhold NP. Int J Antimicrob Agents, 2017. in press. https://doi.org/10.1016/j.ijantimicag.2017.09.002 VVC= vulvovaginal candidiasis 15
So, again How do you find out that you re dealing with a resistant fungal infection? The (sorry) status of antifungal susceptibility testing CAP 2017 Survey: ~50% that do perform AFST only test: 2500 2000 90% of labs that do cultures Fluconazole Itraconazole Caspofungin # labs 1500 1000 500 39% of labs that do cultures ~30% use old breakpoints 0 Candida AST N testing Bacterial AST Source: CAP F and D Surveys,2017 16
What s the big deal? CLSI has updated breakpoints (species-specific), FDA has not Breakpoints only for some drugs, some spp. Sometimes an ECV Commercial manufacturers cannot get devices cleared without FDA breakpoint (21 st Century cures?) Very few commercial AFST options! YeastOne, Vitek 2 TM Disks, Etest rarely used How about identifications? Only reliable way to identify C. auris is use of MALDI-TOF (or sequencing) Must be using most up-to-date databases Only 245/1060 (23%) of labs in CAP survey identifying yeast use MALDI or sequencing 17
What s Coming? disappointingly little Rapid ID of Candida spp., direct from blood Rapid ID of Candida spp., from positive blood cultures No rapid systems currently include C. auris Are species-specific identifications enough? Probably not (for long) What do we need? 1. More antifungal susceptibility test methods, that are reliable! Molecular approaches for echinocandins (fks mutations) 2. More reliable diagnostics for fungi Zhao et al 2016 AAC 18
It s Friday at 4:30 61 yo male with h/o NICM s/p LVAD HMI and bridge to OHT Feb 2017 (CMV D+/R-) Valganciclovir prophylaxis 450 mg QD (SCr ~1.7 mg/dl) 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 Ganciclovir induction WBC=1.7 3 months post transplant AKI, neutropenic, oral ulcers continued gan Clinical Course 3 5 7 9 CMV DNA persistent leukopenia, CMV genotype: L595S UL97 mutation Foscarnet SCr 1.6 AKI SCr 4.8 CMV Resistance Ganciclovir Valganciclovir Foscarnet Cidofovir UL97 X UL54 X X X 19
What s in the Pipeline for CMV? Maribavir Brincidofovir Letermovir Target/ Mechanism UL97 protein kinase inhibitor lipid-conjugated nucleotide analogue of cidofovir CMV terminase inhibitor Company Phase Comments Shire 3 vs best available therapy in transplant patients with resistant/refractory CMV; oral; resistance has been reported Chimerix 3 Prophylaxis HSCT (R+); prophylaxis renal transplant recipients [terminated]; other antiviral activity; UL54 may confer cross resistance Merck 3 ECCMID 2017- prophylaxis study allo- HST; oral or IV Schubert A BMC Infect Dis 2013. 13:330. https://doi.org/10.1186/1471-2334-13-330. El-Haddad D. Antiviral Research 2016; 134:58-62. How accurate is that CMV test, anyway? 20
CMV Viral Load Testing Reasons for CMV VL discrepancies: Genomic diversity of virus strains Input volumes Extraction method Detection chemistry & reagents Operator-induced variability Assay calibration WHO International Standard CMV calibrator developed in 2010 Goal: eliminate variability 6 labs, 10 assay permutations Tested WHO QS Panel, compared to expected Tested 40 CMV-positive clinical specimens WHO Standard 94% within +/- 0.5 log Clinical Samples 59% within +/- 0.5 log Intra-assay precision good Why is it poor inter-assay? (1.5 2.8 log) - Not genotype (trend for gb3) - Not quantity of virus in sample - Amplicon sizes inversely related to quant - Most CMV DNA is cell free & fragmented Bottom line: nope, not there yet. 21
How about CMV resistance testing? No commercial, FDA-cleared tests to date None in development Current standard: Sanger sequencing of PCR-amplified UL97 and UL54 genes Fails if VL is <1000 cp/ml Can only detect if mutation present in >20% of population Final thought on drugs vs. tests: where s the impact? New drugs Cost per day $250-$750 Per treatment course at least $3500-$10,500 Cost to institution depends on: - Clinical impact - Duration of therapy - Inpatient vs outpatient - Institutional guidelines/restrictions New tests $250 2000 per test Cost to institution depends on: - Screening vs. confirmatory test? - Population tested? - Inpatient vs outpatient - Institutional guidelines/restrictions Proven reductions in ICU stay, LOS, toxicities, & additional diagnostic work-up aid in overall cost Proven reductions in LOS, cost of antimicrobials Help reduce diagnostic uncertainty 22
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