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Rapid Diagnostics for Use in Antimicrobial Stewardship

Rapid Diagnostics for Use in Antimicrobial Stewardship. Buddy Newton, MD FACP Director of Antimicrobial Stewardship Washington Regional Medical Center Fayetteville, AR jnewton@wregional.com. Disclosures. Speaker’s Bureau for Roche Diagnostics

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Rapid Diagnostics for Use in Antimicrobial Stewardship

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  1. Rapid Diagnostics for Use in Antimicrobial Stewardship Buddy Newton, MD FACP Director of Antimicrobial Stewardship Washington Regional Medical Center Fayetteville, AR jnewton@wregional.com

  2. Disclosures • Speaker’s Bureau for Roche Diagnostics • I have prescribed and occasionally taken antibiotics

  3. MALDI-TOF • Matrix Assisted Laser Desorption/Ionization-Time Of Flight

  4. MALDI TOF Analysis Matrix Assisted Laser Desorption/Ionization • Laser light pulses (Nitrogen Laser) • Matrix molecules readily absorb laser light (photon energy), creating an excited energy state • The matrix is acidic, and donates positive charge to the analytes

  5. MALDI-TOF Analysis Matrix Assisted Laser Desorption/Ionization • Localized heating causes micro-explosion of analyte • Collisions with neutral sample facilitate charge • transfer to/from excited matrix molecules • Ions “desorb” from the target surface Matrix Proteins

  6. Intensity m/z MALDI TOF Analysis: Time of Flight (TOF) Detector • Following acceleration, the charged ions are allowed to drift through a free field toward the detector • The speed of travel (time of flight) is proportional to the ion’s mass (smaller ions reach the detector first) Drift region

  7. 4 x10 5495.0 1.2 Intens. [a.u.] 1.0 5417.9 4470.0 0.8 6264.1 10835.4 0.6 7274.5 7122.5 4736.2 0.4 9589.7 7828.2 0.2 8021.2 8847.6 8369.5 10259.6 10051.3 0.0 5000 6000 7000 8000 9000 10000 m/z Creation of Spectra (Protein Fingerprint) for Unknown: y-axis for peak intensity (abundance), x-axis for mass/charge (size) The last step it to compare the collected spectra from the unknown to a “database ” that contains pre-identified spectra for comparison and identification…

  8. Bruker MALDI Biotyper - Product Workflow (3) Smear a Thin-Layer ontoa MALDI Target Plate (2) Select a Colony (1)Isolate organism using Primary culture (4) Add MALDI Matrix (6) MALDI Biotyper Data Interpretation (5) Generate MALDI-TOFProfile Spectrum Time To Result @ 5-8 minutes vs. hours or days for current biochemical methods. Research use only – not for use in diagnostic procedures

  9. Research Use Only Library Status of the MALDI Biotyper Microorganism database: > 5500 database entries > 2200 different species > 330 different genera Steadily growing

  10. “In our 1000-bed quaternary care hospital, we project a cost savings of ~$18 millionannually with the implementation of this strategy for the management of gram-negative BSIs”

  11. ”Within the first 36 hours after culture collection a 200% decrease in time to reporting could be observed when using BD EpiCenter™ and Sentinel™ compared to our current process of using hospital computer system.” 2008 ASM Poster Presentation

  12. Integrated System: Outcomes • Lab Efficiency • Increased effective & rapid communication • Pharmacy (antimicrobial stewardship) • Decreased vancomycin usage by 100 antibiotic days per 1,000 patient days • Infection prevention and control • Decreased time to intervention (by 17 hours) • Nursing/case management • 24% more patients AST results were known prior to discharge to decrease call-backs and increase effective discharge planning

  13. WRMC MALDI Case Report • 67 y/o male admitted to ICU with septic shock • Klebpneumo bacteremia ID’d within 9 hours • ABX de-escalated from 3 to 1 and vasopressors rapidly weaned off • Total ICU LOS=0.95 days • Total LOS =7.9 days

  14. Cepheid Xpert • Integrated PCR-based rapid diagnostic system

  15. Xpert: Institution Wide Impact • Potential to Improve Patient Outcomes and Reduce Costs • Quicker turn around time • More efficient isolation protocols • fewer barrier precautions • Pre-surgical screening • Improved antibiotic stewardship, often with lower cost • Lower HAI rates • More efficient bed management

  16. Cepheid Xpert • No specialized training necessary • Universal preparation of specimen • <1 minute prep time with <1 hour for results

  17. Cepheid Xpert • Differentiates between FluA, FluB, and RSV • MTB identification with rifampin-R detection • N gonorrhorea, Chlamydia, Trichomonas • GBS screening and neonatal sepsis • MRSA screening and testing • 2 days faster than Chromagar or traditional micro • C diff testing • Sepsis-MSSA, MRSA, CoNS • Rapid CRE detection

  18. Cepheid Xpert • Rapid MRSA detection leads to: • 50%-80% reduction in MRSA infection • Significant reduction vancomycin use (empirically and therapeutically when MSSA ID’d) • 60% reduction in S aureus infection rate • 57% reduction in mortality rate • 14% reduction in LOS • 18% reduction in total cost of care (despite screening and decolonization)

  19. Cepheid Xpert • C diff testing: • Reduction in isolation days • Reduced empiric therapy • Targeted povancomycin use if 027/NAP1 gene ID’d • Decreased cost of stay

  20. Multiplex PCR (Film Array) • Direct specimen used • TAT about 1 hour • Detects common bacteria and many viruses • ABX can be streamlined or avoided on initial presentation • FDA-approved for CSF, sputum, blood, and stool

  21. FilmArray:The Fastest Way to Better Results Easy Fast Comprehensive • 2 minutes of hands-on time • Run time of about1 hour • Tests for a variety of pathogens that cause respiratory, blood, and gastrointestinal infections, as well antimicrobial resistance genes

  22. Challenges in Diagnosing Gastrointestinal Infections • Limited clinical guidelines for the diagnosis and treatment of patients with suspected infectious diarrhea1 • Challenges associated with currently available testing methods1-4: Time-consuming Limited coverage Labor-intensive Confounded by: Overlapping symptomology Technically complex/ require specific expertise Need to order multiple tests specific for suspected organisms Low yield Unavailability of tests for many organisms Lack sensitivity and specificity Guerrant RL et al. Clin Infect Dis. 2001;32:331-351. Hatchette TF, Farina D. CMAJ. 2011;183:339-344. Lalonde LF et al. Am J Trop Med Hyg. 2013;89:892-898. Lee SD, Surawicz CM. MedGenMed. 2001;3:1-5.

  23. Consequences of Misdiagnosis andMistreatment of GI Infections Potential outcomes of incorrect diagnosis and treatment Antibiotic resistance3,5 Worsened illness1 Postinfectious sequelae1,2 Unnecessary side effects3,4 Early diagnosis facilitates timely and appropriate therapeutic interventionsthat can alleviate symptoms and prevent secondary transmission1 Guerrant RL et al. Clin Infect Dis. 2001;32:331-351. Connor BA, Riddle MS. JTravel Med. 2013;20:303-312. CDC. Antibiotic Resistance Threats in the United States. www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed February 10, 2014. Owens RC, Ambrose PG. Clin Infect Dis. 2005;41:S144-S157. WHO. Antimicrobial Resistance Global Report on Surveillance. www.who.int/drugresistance/documents/surveillancereport/en. Accessed June 6, 2014.

  24. Gastrointestinal (GI) Panel Bacteria Campylobacter (jejuni, coli, andupsaliensis) Clostridium difficile(Toxin A/B) Plesiomonasshigelloides Salmonella Vibrio (parahaemolyticus, vulnificus, andcholerae) Vibrio cholerae Yersinia enterocolitica DiarrheagenicE. coli/Shigella EnteroaggregativeE. coli (EAEC) EnteropathogenicE. coli (EPEC) EnterotoxigenicE. coli (ETEC) Shiga-like toxin-producing E. coli (STEC) E. coli O157 Shigella/EnteroinvasiveE. coli (EIEC) Parasites Cryptosporidium Cyclosporacayetanensis Entamoebahistolytica Giardia lamblia Viruses Adenovirus F 40/41 Astrovirus Norovirus GI/GII Rotavirus A Sapovirus (I, II, IV, and V) FDA-cleared for the first time.

  25. Overall 98.5% Sensitivity and 99.3% Specificity a C. difficileperformance is reported as positive percent agreement/negative percent agreement, and E. coli O157 performance is reported as sensitivity/specificity, in contrast to the headings of their respective sections. The performance measures of sensitivity and specificity only refer to those analytes for which the gold-standard bacterial culture was used as the reference method; Campylobacter, E. coli O157, Plesiomonasshigelloides, Salmonella, Vibrio, Vibrio cholerae, and Yersinia enterocolitica. Performance measures of positive percent agreement (PPA) and negative percent agreement (NPA) refer to all other analytes, for which PCR/sequencing assays were used as comparator methods. FilmArray GI [Instruction Booklet]. Salt Lake City, UT: BioFire Diagnostics, LLC.

  26. Unmet Needs in Treating Sepsis In 58%,therapy was delayed • A retrospective cohort analysis of 760 patients with severe sepsis1 31%received inappropriate antibiotic treatment 42%had resistance to the antibiotic administered Patients who progress to septic shock have a 7.6%increase in mortality every hour while not on appropriate therapy.2 ShorrAF et al. Crit Care Med. 2011;39(1):46-51. Kumar A et al. Crit Care Med. 2006;34(6):1589-1596.

  27. The FilmArray BCID Panel Provides Faster Results • For use on blood culture bottles that are: • Flagged as positive by a continuously monitoring blood culture instrument • Positive by Gram stain examination • 100 μL sample required The FilmArray Pathogen ID Blood Draw Blood Culture Gram Stain Approximately 1 h Positive AntimicrobialSusceptibility Testing Pathogen ID Standard Testing 12–72 h 24–72 h 5 min • In a clinical study, organisms covered by the BCID panel were detected 60% faster than organisms not included in the BCID panel (21.67 vs 53.92 hours, respectively)1 • BCID=blood culture identification; ID=identification. • AltunO et al. J ClinMicrobiol. 2013;51:4130-4136.

  28. Blood Culture Identification (BCID) Panel Gram+ Bacteria Enterococcus Listeria monocytogenes Staphylococcus S. aureus Streptococcus S. agalactiae S. pyogenes S. pneumoniae Antibiotic Resistance mecA – methicillin resistant van A/B – vancomycin resistant KPC – carbapenem resistant Gram- Bacteria Acinetobacterbaumannii Haemophilusinfluenzae Neisseria meningitidis Pseudomonas aeruginosa Enterobacteriaceae Enterobacter cloacae complex Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus Serratia marcescens Yeast Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida tropicalis FDA-cleared for the first time.

  29. Overall 97.5% Sensitivity and 99.8% Specificity a Data presented are from a combination of prospective and seeded blood cultures. See Instruction Booklet for detailed information. b Several apparent false-negative results occurred due to the limitations of traditional phenotypic identification methods in distinguishing closely-related organisms. c Some assays demonstrated a low frequency of cross-reactivity with closely-related organisms leading to false positive results,eg, Enterococcus assay with Staphylococcus spp. d Broad genus and family level assays detect the majority of commonly-occurring species in their respective groups, but may not detect all species in these groups. FilmArray BCID [Instruction Booklet]. Salt Lake City, UT: BioFire Diagnostics, LLC.

  30. Sensitivity and Specificity (cont’d) KPC=Klebsiellapneumoniaecarbapenemase. FilmArray BCID [Instruction Booklet]. Salt Lake City, UT: BioFire Diagnostics, LLC.

  31. Clinical Benefits of Rapid and Accurate Diagnosis • The FilmArray RP provides rapid and accurate results with a turnaround time of ~1 hour • FDA cleared for use with nasopharyngeal swab samples (300 μL volume required) • Rapid identification of the causative agent of respiratory infections can improve patient management by: • Informing timely and effective antibiotic or antiviral therapy • Preventing secondary spread of infection • Shortening hospital stays • Reducing costs of unnecessary tests RP=respiratory panel. LoeffelholzMJ et al. J ClinMicrobiol. 2011;49(12):4083-4088.

  32. Respiratory Panel (RP) Viruses Adenovirus Coronavirus HKU1 Coronavirus NL63 Coronavirus 229E Coronavirus OC43 Human Metapneumovirus Human Rhinovirus/Enterovirus Influenza A Influenza A/H1 Influenza A/H3 Influenza A/H1-2009 Influenza B Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 Respiratory Syncytial Virus Bacteria Bordetella pertussis Chlamydophila pneumoniae Mycoplasma pneumoniae FDA-cleared for the first time.

  33. Overall 95% Sensitivity and 99% Specificity * Due to low prevalence in the prospective study, clinical sensitivity for these pathogens was based on less than10 positive samples. FilmArray Respiratory Panel [instruction booklet]. Salt Lake City, UT: BioFire Diagnostics LLC; 2012.

  34. Negative Results Do Not Always Equal No Infection • Administering empiric antibiotic therapy prior to CSF collection can confound traditional diagnoses and present therapeutic challenges1,2 PCR provides more rapid detection and enhanced sensitivity, guidingtimely and appropriate patient management5 • CSF=cerebrospinal fluid; ME=meningitis/encephalitis; PCR=polymerase chain reaction. • Kanegaye JT et al. Pediatrics. 2001;108;1169-1174. 2. Khoury NT et al. Mayo ClinProc. 2012;87:1181-1188. 3. Tunkel AR et al. Clin Infect Dis. 2004;39:1267-1284. 4. Hasbun R et al. J Infect. 2013;67:102-110. 5. Bryant PA et al. J ClinMicrobiol. 2004;42:2919-2925.

  35. Appropriate Management of Patients WithViral Meningitis • Patients with suspected viral meningitis should be treated as if they are infected with bacterial meningitis until a bacterial etiology has been excluded, at which point antibiotic therapy should be discontinued1 • Antiviral therapy is not available for the majority of viral agents causing meningitis, including enterovirus2,3 • Most patients recover completely within 7–10 days of disease onset; however complications such as seizures and coma occur in ~10% of cases2,4 • Supportive therapy should be provided to appropriately manage patients3 PCR=polymerase chain reaction. Nolte FS. Clin Infect Dis. 2006;43:1463-1467. CDC. Viral Meningitis. www.cdc.gov/meningitis/viral.html. Accessed December 29, 2014. Tunkel AR et al. Clin Infect Dis. 2008;47:303-327. March B et al. J Paediatr Child Health. 2014;50:216-220.

  36. Benefits of Early Detection of Viral Meningitis With Enteroviral PCR • Early detection of enteroviral meningitis with PCR can improve patient care and afford significant cost savings by reducing the duration of unnecessary hospitalizations and parenteral antibiotics • In a retrospective cohort study of children with meningitis, PCR decreased the time to enteroviral diagnosis from 53 hours to 12 hours For every hour saved, length of stay and duration of parenteral antibiotics decreased by 0.3 hours Median hospital stay decreased from 44 to 28 hours Median duration of parenteral antibiotics decreased from 48 to 36 hours 1:00 PCR=polymerase chain reaction. Lyons TW et al. J Hosp Med. 2012;7:517-520.

  37. Meningitis/Encephalitis (ME) Panel: Bacteria Escherichia coli K1 Haemophilus influenzae Listeria monocytogenes Neisseria meningitidis Streptococcus agalactiae Streptococcus pneumoniae Fungi Cryptococcus neoformans/gattii Viruses Cytomegalovirus (CMV) Enterovirus Herpes simplex virus 1 (HSV-1) Herpes simplex virus 2 (HSV-2) Human herpesvirus 6 (HHV-6) Human parechovirus Varicella zoster virus (VZV)

  38. Overall 94.2% Sensitivity and 99.8% Specificity • The clinical performance of the ME panel was established in a multicenter study that evaluated 1560 eligible specimens collected and tested at 11 study sites across the United States between February 2014 and September 2014 • The performance of the FilmArray ME Panel was compared against appropriate comparator/reference methods (CSF bacterial culture or 2 PCR assays with bidirectional sequencing) CMV=cytomegalovirus; EV=enterovirus; HSV=herpes simplex virus; HHV=human herpesvirus; HpeV=human parechovirus; VZV=varicella zoster virus. FilmArray Meningitis/Encephalitis Panel [Instruction Booklet]. Salt Lake City, UT: BioFire Diagnostics, LLC.

  39. Procalcitonin Facts • Simple blood test specific for bacterial infection • In healthy people, PCT concentration are found <0.05ng/ml • Concentrations >0.5ng/ml can be interpreted as abnormal • During severe bacterial infections and sepsis, blood levels rise rapidly (up to x100K) – no elevation from viral infections • Standard of Care for much of Europe in the management of infection and sepsis

  40. Highly specific induction – Produced all tissue Healthy Sepsis In relevant bacterial infection, PCT is produced and released into circulation from the entire body Müller B. et al., JCEM 2001

  41. Induction and release of PCT due to bacterial infection Alternative synthesis of PCT Bacterial toxins (gram+/-) and cytokines stimulateproduction of PCT in all parenchymal tissues PCT is immediatelyreleased into bloodstream This process can be blocked during viral infections Adapted from Christ-Crain et al. 2005

  42. Induction and elimination of PCT • Three elements are required to the induction process • Stimulus – bacterial toxin or trauma • Differentiated parenchymal cells • Adhering monocytes • PCT plasma concentrations • Significant after 6 hours • Peak values – 12 to 24 hours • Half-life - about 24 hours • Not impaired by neutropenia or other immunocomprised states

  43. PCT values correlate directly with severity of bacterial load • In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection. Also excellent prognostic marker. • Integrating PCT in sepsis management has shown improved patient outcomes (ICU LOS and total length of ABX therapy) and lower mortality.

  44. Clinical Situations where PCT may be useful • Diagnosis of bacteremia/sepsis in adults and neonates (>72 hours old) • Differentiating bacterial vs nonbacterial pneumonia • Differentiating bacterial vs aseptic meningitis • Diagnosis of bacterial infection in febrile neutropenia • Diagnosis of septic arthritis

  45. PCT release in the absence of infection • Newborn <48hr-increased PCT values (physiological peak) • Primary inflammation syndrome following extensive trauma: extensive burns, major surgery (cardiac, transplant, abdominal) • Medullary C-cell cancers of the thyroid, pulmonary small-cell carcinoma • Prolonged circulatory failure (cardiogenic shock, hemorrhagic shock, thermal shock) • Malaria & some fungal infections

  46. Key Considerations when Interpreting PCT Levels • Consider the clinical context-(pts in septic shock should not have ABX withheld if PCT is normal) • Serial measurements are preferred and may be very helpful • Consider the dynamics of the disease-(PCT levels fall after trauma if no infection present. If PCT levels are rising after ABX, consider changing ABX or looking for drainable source of infection) • Keep in mind conditions that will cause PCT levels to rise

  47. PCT evidence-based use for various ID conditions Riedel S. Diagn Microbiol Infect Dis. 73 (2012); 221-7.

  48. Diagnostic accuracy of PCT compared to other biomarkers used in sepsis

  49. Algorithm-based or rule-guided decisions • May be general or disease specific • Simple or more involved • Assist in: • Should antibiotic therapy be initiated • Initial antibiotic intensity • Repeat PCT • Course adjustment • De-escalation of therapy • Discontinuation of therapy

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