May 11, Ceftriaxone for MSSA. Daptomycin Dosing Weight. Candidiasis Treatment

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1 Diagnostics and Debates: An Update on Rapid Diagnostic Testing and Current Controversies in Infectious Diseases Nicholas Torney, PharmD, BCPS Derek Vander Horst, PharmD Munson Medical Center WMSHP Annual Convention 2016 May 11 th, 2016 Disclosures Derek Vander Horst has no actual or potential conflict of interest in relation to this presentation Learning Objectives What Is a Controversy? Discuss several controversial topics in the realm of infectious diseases Images available from: Infectious Diseases Controversies Daptomycin Dosing Weight Candidiasis Treatment 1

2 Ceftriaxone: Third generation cephalosporin with both gram-positive and gram-negative activity, including MSSA Pros Cons Image available from: Treatment Outcomes for Osteoarticular Infections Caused By MSSA Wieland B et al. Clin Infect Dis. 5 Dec 2011;54(5): Treatment Success at 3-6 months follow-up Treatment Success > 6 months follow-up Oxacillin Ceftriaxone p-value Total: 32/37 (86%) Osteomyelitis: 15/17 (88%) Septic arthritis: 8/8 (100%) Total: 26/32 (81%) Osteomyelitis: 12/14 (86%) Septic arthritis: 7/8 (88%) Wieland B et al. Clin Infect Dis. 5 Dec 2011;54(5): Total: 50/60 (83%) Osteomyelitis: 26/30 (87%) Septic arthritis: 18/22 (82%) Total: 43/56 (77%) Osteomyelitis: 24/29 (83%) Septic arthritis: 15/20 (75%) Total: 0.7 Osteomyelitis: >0.99 Septic arthritis: 0.6 Total: 0.6 Osteomyelitis: >0.99 Septic arthritis: 0.6 Patel et al. Int J Clin Pharm. 2014;36: Patel et al. Int J Clin Pharm. 2014;36:

3 Patel et al. Int J Clin Pharm. 2014;36: Ceftriaxone-Resistant MSSA Ceftriaxone-Resistant MSSA Pickering A et al. Clin Infect Dis. 14 March (Retraction, 2014) Phe K et al. Antimicrob Agents Chemother. 17 Nov 2014;59:1730. Ceftriaxone-Resistant MSSA Phe K et al tested 17 isolates of MSSA and found 100% concordance between oxacillin and ceftriaxone Ceftriaxone MIC ranged from 1-8 µg/ml MRSA isolate was tested and shown to be resistant to ceftriaxone Ceftriaxone MIC = 32 µg/ml Ceftriaxone susceptibility for MSSA predicted by oxacillin*for and/or staphylococcal cefoxitin infections, sensitivity. a Clinical & daily Laboratory dose of 2-4 Standards grams daily Institute (CLSI) no longer should publishes be administered breakpoints to for ceftriaxone achieve > 90% target attainment and MSSA FDA breakpoints revised in 2011 FDA Breakpoints for MSSA Susceptible Intermediate Resistant MSSA* Adapted from: Ceftriaxone Reappraisal of Food and Drug Administration In Vitro Susceptibility Test Interpretive Criteria by Paul G. Ambrose, Pharm.D., FIDSA 3

4 Ceftriaxone Target Attainment Ceftriaxone Target Attainment Ceftriaxone 2g daily will attain ~25% free-drug time above MIC for a MIC 4 µg/ml with 90% probability Ceftriaxone 1g will attain this target at MIC 2 µg/ml Adapted from: Ceftriaxone Reappraisal of Food and Drug Administration In Vitro Susceptibility Test Interpretive Criteria by Paul G. Ambrose, Pharm.D., FIDSA Nguyen H et al. Clin Infect Dis. 2013;57: Ceftriaxone Using Oxacillin MIC Ceftriaxone Using Oxacillin MIC Probability of errors: Oxacillin-susceptible/ceftriaxone-resistant < 0.1% Oxacillin-susceptible/ceftriaxone-intermediate ~ 4.3% Probability of Ceftriaxone MIC 8 µg/ml in Oxacillin Susceptible MSSA Oxacillin MIC (µg/ml) Probability (%) Nguyen H et al. Clin Infect Dis. 2013;57: Nguyen H et al. Clin Infect Dis. 2013;57: The Bottom Line Ceftriaxone has been used with success for infections caused by MSSA Ceftriaxone MIC data is inferred from oxacillin and/or cefoxitin susceptibility Ceftriaxone gets adequate target attainment with a MIC 4 µg/ml with ~90% probability with daily doses 2g The Bottom Line Oxacillin MIC data may be used to predict ceftriaxone treatment success It has been suggested that success is optimized: Oxacillin MIC 0.5 µg/ml Ceftriaxone daily dose 2g/day Patients should be assessed on an individual basis until higher quality data exists 4

5 Daptomycin Daptomycin: lipopeptide antibacterial agent with gram-positive activity, including vancomycin-resistant Enterococcus sp. (VRE) Image available from: Daptomycin Usage Pros Cons Daptomycin Generally dosed on mg/kg basis of actual body weight (ABW) Some institutions have decided to use a dosing weight (DW) Doses vary from 4-12 mg/kg One 500mg vial~$ Image available from: Dose (mg/kg) Calculated Dose of Daptomycin for Common Patient Weights Weight (kg) One vial ~$ Two vials ~$1, Three vials ~$1, Daptomycin Clearance in Obese All per dose! Dvorchik B et al. J Clin Pharmacol. 2005;45(8):

6 Daptomycin in the Obese Daptomycin Dosing Daptomycin levels: C min 24.3 mg/l correlated with increased probability for CPK elevation Obese patients have impaired clearance of daptomycin Higher doses and impaired clearance can lead to increases in C min and thus cause increased incidence of CPK elevations Bhavnani SM et al. Clin Infect Dis. 15 Jun 2010;50(12): Donovan B et al. Clin Infect Dis. 2010;51(8):989. Ng J et al. Antimicrob Agents Chemother. 21 Oct 2013;58(1): Daptomycin IBW vs ABW Outcomes Two Major Arms: ABW IBW Inclusion Criteria: 17 years of age Positive culture Daptomycin therapy 72 hours Exclusion Criteria: ABW < IBW Continuation of outside institution Renal impairment Preexisting rhabdomyolysis Ng J et al. Antimicrob Agents Chemother. 21 Oct 2013;58(1): Daptomycin IBW vs ABW Outcomes Daptomycin IBW vs ABW Ng J et al. Antimicrob Agents Chemother. 21 Oct 2013;58(1): Ng J et al. Antimicrob Agents Chemother. 21 Oct 2013;58(1):

7 The Bottom Line Overdosing on daptomycin doesn t seem to be a terrible safety concern in most patients, including the obese population Single study only included 4mg/kg and 6mg/kg regimens Study showed no significant differences between IBW or ABW The Bottom Line Most of the benefit of dosing on IBW appears to be cost related More data should likely exist before we dose all our patients on IBW Perhaps, the new generic daptomycin will help this problem as well Echinocandin Therapy Pros Cons Echinocandins vs Azoles Anidulafungin vs Fluconazole Reboli A et al. N Eng J Med. 2007;356: Reboli A et al. N Eng J Med. 2007;356:

8 The Bottom Line Candidiasis Guideline Update 2009 Guidelines 2016 Guidelines Empiric Therapy: Non-neutropenic Patients: Fluconazole Neutropenic Patients: Fluconazole Echinocandin recommended if patient has recent azole use Empiric Therapy: Non-neutropenic Patients: Echinocandin Neutropenic Patients: Echinocandin Pappas P et al. Clin Infect Dis. 15 Feb 2016;62(4): The Bottom Line Post-Assessment Question 1. Which of the following is a controversial topic discussed in today s lecture involving treatment of patients with daptomycin? a) Daptomycin dosing weight b) Treating infections caused by Klebsiella pneumoniae c) Potential creatinine kinase elevations d) Treating patients with pneumonia Pappas P et al. Clin Infect Dis. 15 Feb 2016;62(4): Post-Assessment Question Questions 1. Which of the following is NOT a potential benefit of using an echinocandin for therapy in patients with invasive candidiasis? a) Fewer drug interactions b) Cost c) Superior microbiologic response d) Empiric coverage for all Candida sp. 8

9 Rapid Diagnostic Tests and Antimicrobial Stewardship Disclosures Nicholas Torney does not have any conflicts of interest as it pertains to this presentation. Nicholas Torney, Pharm.D., BCPS PGY-2 Infectious Diseases Pharmacy Resident Objective Introduction 1. Describe the available rapid molecular diagnostic tests and how they can be incorporated into an antimicrobial stewardship program. Conventional Microbiological Methods Rapid Molecular Diagnostic Tests Conventional Methods Utilizing Rapid Tests Day Blood Draw (+) Blood Culture Gram Stain Organism Identification Susceptibilities Day Blood Draw (+) Blood Culture Gram Stain Organism Identification Susceptibilities Empiric, Broad Spectrum therapy Targeted therapy Empiric, Broad Spectrum therapy Targeted therapy

10 What s the Big Deal? Mortality Depends on Appropriate Initial Therapy in Patients With Bacteremia Delay of Appropriate Antibiotic Therapy in Septic Shock Survival 7.6% for every 1 hour delay in antibiotics Leibovici L, et al. J Intern Med 1998 Nov;244(5): Micek ST, et al. J Hosp Med 2011 Sep;6(7): Kumar A,, et al. Crit Care Med 2006 Jun;34(6): Rapid Diagnostic Tests (RDT) Rapid Molecular Diagnostic Technologies Rapid Test MALDI-TOF FilmArray Verigene PNA FISH, Quick-FISH, Express-FISH T2-Candida Technology Mass spectrometry Nucleic acid amplification Nucleic acid amplification Nucleic acid hybridization Magnetic resonance imaging 57 Add-on systems 58 MALDI-TOF FilmArray vs. Verigene Need bacterial growth to run sample Sample takes ~1hr to run Reduced time to organism ID by hours Library contains MANY organisms High initial cost, low cost per test Cannot detect resistance mechanisms or susceptibilities Image available from : 59 Gram stain prior to processing FilmArray (BioFire) Unnecessary Verigene (Nanosphere) Necessary Hands on time 2 minutes < 5 minutes Run time 1 hour 2.5 hours Technology Rapid multiplex PCR Gold Nanoparticle Pathogens detected Resistance mechanisms detected 8 Gram (+) 11 Gram (-) 5 candida spp. 15 Gram (+) 14 Gram (-) Gram (+) Gram (-) Gram (+) Gram (-) meca vana, vanb KPC meca vana, vanb CTX-M KPC NMD OXA VIM 60 10

11 PNA-FISH, Quick-FISH, Xpress-FISH FISH = Fluorescent In Situ Hybridization Advantages: Strong evidence with clinical benefit Quick-FISH is really Quick Disadvantages: Current products only test up to 3 targets Limited ability to detect resistance organisms T2-Candida Magnetic resonance imaging Blood to bug detection Detects 5 candida spp. from whole blood in 3-5 hrs Albicans Glabrata Krusei Parapsilosis Tropicalis Sensitivity 91.1% Specificity 99.4% 61 Mylonakis E, et al. Clin Infect Dis. 2015;60(6): Impact on Mortality and Length of Stay RDT Incorporation into Antimicrobial Stewardship Study Forrest (2008) Bauer (2010) Perez (2013) Huang (2013) RDT [Pathogen(s)] PNA FISH [Enterococcus spp.] Rapid PCR [S. aureus] MALDI-TOF [GNRs] MALDI-TOF [All pathogens] Outcomes time to appropriate abx (3.1 vs. 1.3 days) 30 day mortality (45% vs. 26%) LOS (21.5 vs days)* LOS (11.9 vs. 9.3 days) 30 day mortality (10.7% vs. 5.6%)* LOS (14.2 vs days)* 30 day mortality (20.3 % vs. 12.7%) LOS = Length of stay *not statistically significant All study designs: Pre/Post Intervention, including antimicrobial stewardship intervention Impact of RDTs + ASPs Impact of RDTs + ASPs Impact on Gram-negative bacteremia using MALDI-TOF Passive notification via EMR Cost avoidance (avg): $3,411 (p = 0.04) Mortality: 9.4% vs. 4.9% (p=0.07) Active antimicrobial stewardship Adjust Therapy Pre: 71 (±41) hrs Int: 30 (±30) hrs p < After culture positivity Lockwood A, et al. Infect Control Hosp Epidemiol 2016 Jan 7;00(0): Lockwood A, et al. Infect Control Hosp Epidemiol 2016 Jan 7;00(0):

12 Impact of RDTs + ASPs Impact of RDTs + ASPs Box M, et al. Pharmacotherapy 2015;35(3): Box M, et al. Pharmacotherapy 2015;35(3): Impact of RDTs + ASPs Time to Targeted Therapy Economic Impact RDT + Real-Time Culture Review $25,000 Cost Difference per Bacteremic Episode $20,000 $21,387 $19,583 $19,253 Unnecessary Duration of Antibiotic Therapy $15,000 $10,000 Box M, et al. Pharmacotherapy 2015;35(3): $5,000 Bauer (2010) Perez (2013) Huang (2013) Rapid PCR MALDI-TOF MALDI-TOF [S. aureus] [GNRs] [All Pathogens] 70 PCR without ASP Intervention PCR identification of Staphylococcal species from blood Compared to a historical control group PCR without ASP Intervention PCR identification of Staphylococcal species from blood Compared to a historical control group Time to Organism Identification hr hr Control Intervention Frye AM, et al. J Clin Microbiol 2012;50: hr difference (P < ) 71 Time to Optimal Therapy Unchanged in the post-intervention Group Difference 1.2 hours [95% CI : to 9.8 hrs] Demonstrates the necessity of prospective audit and feedback Frye AM, et al. J Clin Microbiol 2012;50:

13 PNA FISH CoNS Without ASP Intervention Blood Culture ID - Rapid Multiplex PCR Randomized Controlled Trial 3 groups 1. Control 2. Rapid Multiplex PCR 3. Rapid Multiplex PCR + Real-Time Stewardship Baseline Interventions (all groups) MALDI-TOF pathogen identification M-F antimicrobial stewardship interventions Prospective audit and feedback Restricted antimicrobial authorization Holtzman C, et al. J Clin Microbiol 2011;49(4); Banerjee R, et al. Clin Infect Dis 2015;61(7): Blood Culture ID - Rapid Multiplex PCR Randomized Controlled Trial Blood Culture ID - Rapid Multiplex PCR Randomized Controlled Trial Control (n=207) Standard Blood Culture Bottle processing rmpcr (n=198) Reported into EMR with templated comments rmpcr + Stewardship (n=212) Reported into EMR with templated comments Result paged to ID pharmacist (24/7) with real-time audit and feedback Gram Stain Result Banerjee R, et al. Clin Infect Dis 2015;61(7): Banerjee R, et al. Clin Infect Dis 2015;61(7): Blood Culture ID - Rapid Multiplex PCR Randomized Controlled Trial Most bang for your buck: Rapid molecular diagnostics coupled with real-time stewardship intervention Most interventions were made during the day may not need 24/7 coverage. Rapid Diagnostic Test Summary Common Theme rmpcr = Add-on test to baseline micro workflow Antimicrobial stewardship capabilities: Increased narrow-spectrum antibiotic use Less unnecessary vancomycin use Decreased treatment of blood culture contaminants Pharmacist Mortality LOS Cost Banerjee R, et al. Clin Infect Dis 2015;61(7):

14 Question #1 1. Which of the following rapid diagnostic testing technologies has the ability to detect pathogens from whole blood in 3-5 hours (i.e. without a blood culture incubation period)? a) PNA-FISH (Nucleic acid hybridization) b) Biofire Fimarray (Nucleic acid amplification) c) Nanosphere Verigene (Nucleic acid amplification) d) T2Candida - T2Biosystems (Nanoparticle- Magnetic Resonance Imaging) Question #2 2. Studies evaluating the use of rapid diagnostic tests have concluded all of the following except: a) Increased time to appropriate antibiotics b) Decreased length of stay c) Decreased mortality d) Decreased total hospital costs