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New Antibiotic Approvals 2017-2019 Joshua Garcia, Pharmd, BCPS Assistant Professor, Marshall B

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New Antibiotic Approvals 2017-2019 Joshua Garcia, Pharmd, BCPS Assistant Professor, Marshall B New Antibiotic Approvals 2017-2019 Joshua Garcia, PharmD, BCPS Assistant Professor, Marshall B. Ketchum University May 12th 2020 Conflicts of Interest No conflicts of interests to disclose Objectives Identify indications for new, recently approved antimicrobials Recognize pros and cons of using newly approved antimicrobials in a clinical situation Identify major adverse effect, monitoring parameters, and clinical pearls of newly approved antimicrobials Antimicrobial Resistance Problem Updated numbers: 2,800,000 illnesses and 35,000 deaths IDSA 10 x20 initiative CDC Antimicrobial Resistance Reports, 2013 and 2019 GAIN Act – 2012 Limited Population Antibacterial Drug (LPAD) pathway 2016 Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH) Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) The Antibiotic Resistance Problem: The General Idea Selective pressure (antibiotics) = Rise of resistant organisms Wild-type bacteria Bacteria with resistance gene The Antibiotic Resistance Problem: The Macroscale Selective pressures Inappropriate antibiotics In the US: CDC estimated 30-50% (47 million courses) of all prescribed antibiotics are inappropriate / unnecessary Increasing use of broad spectrum antibiotics Antibiotic use in livestock and environment Dearth of new antimicrobials in development 1. Dellit TH, et al. Clin Infect Dis. 2007 Jan 15;44(2):159-77. 2. Fridkin SK, et al. MMWR Morb Mortal Wkly Rep. 2014;63(9):194-200 3. Fleming-Dutra KE, et al. JAMA. 2016 May 3;315(17):1864-73. doi: 10.1001/jama.2016.4151. 4. Woolhouse M, et al. Philos Trans R Soc Lond B Biol Sci. 2015 Jun 5; 370(1670): 20140083. doi: 10.1098/rstb.2014.0083 The Antibiotic Resistance Problem: The Microscale Antibiotic Inactivation Active Efflux Ex. Beta-lacatamase production Ex. Tet(A) efflux pumps for tetracyclines Porin Channel Target Alteration Degradation Ex. OprD porin mutations in Pseudomonas aeruginosa Ex. mecA gene in MRSA Antibiotic Approval Timeline Antibiotic Deployment Antibiotic Resistance Clatworthy et al. Nat Chem Biol. 2007 Sep;3(9):541-8 Antibiotic Approval Timeline: Updated Antibiotic Deployment Dalbavancin Oritavancin Tedizolid Avycaz Zerbaxa 2010 2015 2020 Antibiotic Resistance Clatworthy et al. Nat Chem Biol. 2007 Sep;3(9):541-8 New Antibiotic Approvals: 2017-2019 Brand Name Generic Name Approval Date BaxdelaTM Delafloxacin 6/2017 VabormereTM Meropenem/vaborbactam 8/2017 ZemdriTM Plazomicin 7/2018 XeravaTM Eravacycline 8/2018 NuzyraTM Omadacycline 10/2018 RecarbrioTM Imipenem/cilastatin/relebactam 7/2019 XenletaTM Lefamulin 8/2019 Fetroja® Cefiderocol 11/2019 New Antibiotic Approvals by Intended Use / Indications Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Delafloxacin Resistant Gram Negative Bacilli Omadacycline Meropenem/vaborbactam Plazomicin Eravacycline Community Acquired Pneumonia (CAP) Imipenem/cilastatin/relebactam Omadacycline Cefiderocol Lefamulin Delafloxacin (BaxdelaTM) Delafloxacin (BaxdelaTM) Indication: Acute bacterial skin and skin structure infections (ABSSSI) Spectrum of activity: Activity against S. pyogenes, S. pneumoniae, enteric gram negative rods, M. cattharalis, H. influenzae, B. fragilis, atypical organisms, S. aureus (including MRSA), and P. aeruginosa Mechanism of action: Enhanced inhibition of DNA gyrase and topoisomerase IV due to addition of chlorine at C-8 and removal of basic group at C-7 Dosing: PO: 450mg twice daily IV: 300mg every 12 hours Renal impairment: PO: No adjustment IV: eGFR 15-29 – 200mg every 12 hours Not recommended in ESRD 1. Baxdela [package insert]. 2017 2. Mogle BT, et al. Journal of Antimicrobial Chemotherapy. 2018;73(6):1439-1451. doi:10.1093/jac/dkx543 Delafloxacin (BaxdelaTM) Metabolism Negligible Elimination IV: 65% urine, 28% feces PO: 50% urine, 48% feces Half-life 4.2 – 8.5 hours ADRs: Common: Nausea, diarrhea, vomiting, headache, transaminase elevations FQ Black boxed warnings: Tendon rupture, peripheral neuropathy, CNS effects, exacerbation of myasthenia gravis, hypoglycemia, AMS, aortic dissection Drug Interactions : Oral chelation with cations 1. Baxdela [package insert]. 2017 2. Mogle BT, et al. Journal of Antimicrobial Chemotherapy. 2018;73(6):1439-1451. doi:10.1093/jac/dkx543 Delafloxacin Clinical Trials Trial 1 (IV only) Trial 2 (IV to PO) Design Phase 3, multi-center, double-blind, randomized, non-inferiority Intervention • Delafloxacin 300mg IV BID • Delafloxacin 300mg IV BID for 3 • Vancomycin 15mg/kg + days, then switch to 450mg PO BID aztreonam 2g IV BID • Vancomycin 15mg/kg + aztreonam 2g IV BID Primary Efficacy Objective response at 48-72 hrs / clinical cure Outcome Exclusions Previous ABSSI antibiotic Pregnant or lactating Deeper tissue infection (bone, joint, etc.) or shock Immunocompromised ESRD or liver dysfunction > 10% body burns 1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 Trial 1 Delafloxacin Efficacy Results Trial 2 1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 S. Aureus Response Comparison Trial 1 Trial 2 1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 3. McCurdy S, Lawrence L, Quintas M, et al. Antimicrob Agents Chemother. 2017;61(9):e00772-17, e00772-17. doi:10.1128/AAC.00772-17 Trial 1 Delafloxacin Safety Results Trial 2 • No FQ related C. diff infections, tendon • 1 FQ related C. diff infection (delafloxacin), rupture, or peripheral neuropathy, tendon rupture, or peripheral neuropathy photosensitivity, or Qt prolongation • No tendon rupture, or peripheral neuropathy, • Equal delafloxacin hypo(hyper)glycemia photosensitivity, Qt prolongation or and vancomycin/aztreonam dysglycemia in either group 1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 A Deeper Look into Safety Photosensitivity Qtc Prolongation 1. Litwin JS, et al. Antimicrob Agents Chemother. 2015;59(6):3469-3473. doi:10.1128/AAC.04813-14 2. Dawe RS, et al. Photochem Photobiol Sci. 2018;17(6):773-780. doi:10.1039/C8PP00019K Delafloxacin Takeaways / Potential Places in Therapy Takeaways: Unique coverage of both Pseudomonas aeruginosa AND MRSA Less likely to use as routine ABSSSI No labeled warnings/adverse affects of Qt prolongation or photosensitivity Potential Places in Therapy: Step down oral therapy for polymicrobial diabetic foot infections Step down oral therapy for bloodstream infections Community Acquired Bacterial Pneumonia (DEFINE-CABP) Omadacycline (NuzyraTM) Omadacycline (NuzyraTM) Indication: Community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) Spectrum of activity: Streptococcus, E. faecalis, E. faecium, S. aureus (MSSA and MRSA), B. fragilis, atypical organisms, M. cattharalis, H. influenzae Potential coverage of vancomycin-resistant enterococci (VRE), Acinetobacter spp., and ESBL (extended-spectrum beta-lacatamase) producing organisms Mechanism of action: Aminomethyl group modification at C-9 allows for sustained protein synthesis inhibition in the presence of tetracycline efflux pumps Dosing: IV Load PO Load 1. Nuzyra [package insert]. 2018 2. Barber KE, et al. Pharmacotherapy. 2018;38(12):1194-1204. doi:10.1002/phar.2185 Omadacycline (NuzyraTM) Metabolism Negligible Elimination 27% urine, 73% feces Half-life ~16 hrs at steady state ADRs: Nausea, vomiting, diarrhea, transaminase elevations, hypertension Drug Interactions: Anticoagulants: Depression of prothrombin activity may require dose decrease of anticoagulants Oral chelation with cations 1. Nuzyra [package insert]. 2018 2. Barber KE, et al. Pharmacotherapy. 2018;38(12):1194-1204. doi:10.1002/phar.2185 Omadacycline Clinical Trials OPTIC Trial (PNA) OASIS-1 (ABSSSI, IV-PO) OASIS-2 (ABSSSI, PO Only) Design Phase 3, multi-center, double-blind, randomized, non-inferiority Intervention • Omadacycline 100mg IV BID x2 • Omadacycline 100mg IV BID x2 • Omadacycline 450mg PO doses, then 100mg IV daily doses, then 100mg IV daily BID for 2 days, then 300mg (optional transition to 300mg PO (optional transition to 300mg PO daily after 3 days) PO after 3 days) • Linezolid 600mg PO BID • Moxifloxacin 400mg IV daily • Linezolid 600mg IV BID (optional switch to 400mg PO (optional transition to 600mg after 3 days) PO BID after 3 days) Primary Efficacy • Early clinical response (72 – 120 Early clinical response (20% reduction in lesion size at 48 – 72 hours Outcome hours after first dose) after first dose) Exclusions • Previous antibiotic in last 72 hrs Previous antibiotic in last 72 hrs • Hospital acquired PNA Skin lesions < 75cm2 • PSI class V patients Anticipated treatment > 14 days • Renal or hepatic insufficiency Chronic wounds, bites, or diabetic foot infections • Immunocompromised Renal or hepatic insufficiency Immunocompromised 1. Stets R, et al. N Engl J Med. 2019;380(6):517-527. doi:10.1056/NEJMoa1800201 2. O’Riordan W, et al. N Engl J Med. 2019;380(6):528-538. doi:10.1056/NEJMoa1800170 3. O’Riordan W, et al. Lancet Infect Dis. 2019;19(10):1080-1090. doi:10.1016/S1473-3099(19)30275-0 Omadacycline Efficacy Results OPTIC Moxifloxacin better OASIS-1 OASIS-2
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