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Treatment of Carbapenem Resistant Gram Negative Infections

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Treatment of Carbapenem Resistant Gram Negative Infections Treatment of Carbapenem Resistant Gram-Negative Infections STEPHANIE GIANCOLA, PHARMD, BCPS, BCIDP CLINICAL PHARMACIST, INFECTIOUS DISEASES BROOKE ARMY MEDICAL CENTER APRIL 11, 2021 Disclosures & Disclaimer Disclosure: ◦ No potential conflicts of interest in relation to this presentation Disclaimer: ◦ The view(s) expressed herein are those of the presenter and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force and Department of Defense or the U.S. Government Objectives 1. Describe the prevalence of carbapenem resistant Gram-negative infections 2. Explain the mechanisms of carbapenem resistance in Gram-negative bacteria 3. List the treatment options for carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii infections Antimicrobial Resistance CDC. Antibiotic Resistance Threats in the United States, 2019 Antimicrobial Resistance Threats Urgent threats • Carbapenem-resistant Acinetobacter • Carbapenem-resistant Enterobacterales (CRE) • Candida auris • Clostridioides difficile • Drug-resistant Neisseria gonorrhoeae Serious threats • Drug-resistant Campylobacter • Drug-resistant Candida • ESBL-producing Enterobacteriaceae • VRE • MDR Pseudomonas aeruginosa • Drug-resistant Non-typhoidal Salmonella Typhi • Drug-resistant Shigella • MRSA • Drug-resistant Streptococcus pneumoniae • Drug-resistant TB Concerning threats • Erythromycin-resistant Group A Streptococcus • Clindamycin-resistant Group B Streptococcus Watch list • Azole-resistant Aspergillus fumigatus • Drug-resistant Mycoplasma genitalium • Drug-resistant Bordetella pertussis CDC. Antibiotic Resistance Threats in the United States, 2019 Antibiotic Development Antibiotics approved since 2012: 2013: telavancin 2014: dalbavancin, oritavancin, tedizolid, ceftolozane-tazobactam 2015: ceftazidime-avibactam 2017: meropenem-vaborbactam, delafloxacin 2018: eravacycline, omadacycline, plazomicin 2019: cefiderocol, imipenem-relebactam, lefamulin Carbapenem-Resistant Enterobacterales Carbapenem-Resistant Enterobacterales (CRE) Definition: ◦ Resistant to at least one of the carbapenem antibiotics (ertapenem, meropenem, imipenem, doripenem) Prevalence: o 0.2-5% of Enterobacterales isolates in US hospitalized patients are CRE o Increase from 2012-2017: 3.36 to 3.79 cases per 10,000 hospitalizations Cai B, et al. Open Forum Infect Dis 2017;4(3): ofx176 Jernigan JA, et al. N Engl J Med 2020;382(14): 1309-1319 CRE Resistance Mechanisms Eichenberger EM, et al. Antibiotics 2019;8(2): 37 Carbapenemases Ambler Class β-lactamases Active Site Examples Substrates Serine PSE Penicillins A Penicillinases TEM, SHV, CTX-M Penicillins, 3rd generation cephalosporins KPC, IMI All β-lactams (including carbapenems) B Metallo-β-lactamases Zinc IMP, VIM, NDM All β-lactams, except monobactams Serine AmpC Cephamycins, 3rd generation C Cephalosporinases cephalosporins D Oxacillinases Serine OXA Variable, all β-lactams may be affected Eichenberger EM, et al. Antibiotics 2019;8(2): 37 Carbapenemases Klebsiella pneumoniae carbapenemase (KPC): Class A ◦ Most common carbapenemase in the US ◦ Most prevalent in the northeastern and upper Midwest regions of the US ◦ Inhibited by some beta-lactamase inhibitors: avibactam, vaborbactam, relebactam ◦ Not inhibited by clavulanate, sulbactam, tazobactam MBLs: Class B ◦ Not inhibited by available beta-lactamase inhibitors ◦ Rare in US, common in India OXA: Class D ◦ OXA-48-like are the most common, weakly hydrolyze carbapenems and spare the extended spectrum cephalosporins ◦ Uncommon in US, common in Turkey and parts of Europe ◦ Some are inhibited by avibactam and relebactam Eichenberger EM, et al. Antibiotics 2019;8(2): 37 Case #1 Chief complaint: 46-year-old male with fever (101.7), nausea, and flank pain PMH: ◦ HTN ◦ BPH ◦ Nephrolithiasis s/p bilateral percutaneous nephrostomy tubes ◦ Recurrent UTIs (with recent ESBL-producing Klebsiella pneumoniae) Allergies: None Recent antibiotics: ◦ Ertapenem x14 days 2 months ago for UTI ◦ Past UTIs have also been treated with levofloxacin, ceftriaxone, cefepime Labs: 12.1 138 100 16.2 16.1 250 106 1.5 37.3 3.7 26 Plan: Admit patient, obtain blood and urine cultures, and initiate meropenem 1g IV q8h Case #1 (continued) Blood and urine cultures return with Klebsiella pneumoniae with the following susceptibilities: Antibiotic MIC (mcg/ml) Interpretation Ampicillin/sulbactam ≥32 R Cefazolin ≥32 R Ceftriaxone ≥4 R Ciprofloxacin ≥4 R Ertapenem ≥2 R Meropenem ≥4 R Piperacillin-tazobactam ≥128 R TMP/SMX ≥ 320 R Tobramycin ≥16 R What do you do? What additional antimicrobial susceptibilities would you request? Carbapenem-Resistant Enterobacterales Potential treatment options ◦ Ceftazidime-avibactam ◦ Meropenem-vaborbactam ◦ Imipenem-relebactam ◦ Cefiderocol ◦ Ceftazidime-avibactam plus aztreonam ◦ Tigecycline ◦ Eravacycline ◦ Colistin Ceftazidime-Avibactam FDA-approved in 2015 • Complicated urinary tract infection • Complicated intra-abdominal infection • Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia Avibactam • Novel β-lactamase inhibitor • No antimicrobial activity by itself • Inhibits Class A (including KPC) and Class D (including OXA-48-like) carbapenemases • Does not inhibit Class B metallo-β-lacatamases Ceftazidime-Avibactam for CRE Ceftazidime-avibactam vs. other treatment regimens for carbapenem-resistant Klebsiella pneumoniae bacteremia Outcome, n (%) Ceftazidime- Carbapenem + Carbapenem + Other (n=41) P-value avibactam (n=13) aminoglycoside colistin (n=30) (n=25) Clinical success 11 (85) 12 (48) 12 (40) 15 (37) 0.02 30-day survival 12 (92) 17 (68) 21 (70) 28 (68) 0.37 90-day survival 12 (92) 14 (56) 19 (63) 20 (49) 0.04 Persistent 0 (0) 1 (4) 5 (17) 8 (20) 0.13 bacteremia Recurrent 2 (15) 5 (20) 3 (10) 9 (22) 0.60 bacteremia Shields RK, et al. Antimicrob Agents Chemother 2017;61(8): e0083-17 Ceftazidime-Avibactam for CRE Outcome Ceftazidime- Comparator Stats avibactam van Duin, 2018 n=38 n=99 Adjustment Adjusted difference (95% CI)/P-value Hospital death, n (%) 3 (8) 33 (33) 9% vs. 32% 23 (9-35)/ p=0.001 Tumbarello, 2019 n=104 n=104 P-value 30-day mortality, n (%) 38 (36.5) 58 (55.8) 0.005 Infection relapse, n (%) 10 (9.6) 9 (8.6) 0.81 van Duin D, et al. Clin Infect Dis 2018;66(2): 163-71 Tumbarello M, et al. Clin Infect Dis 2019;68(3): 355-64 Meropenem-Vaborbactam FDA-approved in 2017 ◦ Complicated urinary tract infections Vaborbactam ◦ Novel β-lactamase inhibitor ◦ No antimicrobial activity by itself ◦ Inhibits Class A carbapenemases (including KPC) ◦ Does not inhibit Class B metallo-β-lacatamases or Class D carbapenemases Meropenem-Vaborbactam for CRE TANGO II: Phase 3 randomized, controlled trial of meropenem-vaborbactam vs. best available therapy for CRE infections Outcome, n (%) Meropenem-vaborbactam Best available therapy P-value (n=32) (n=15) Clinical cure at end of 21 (65.6) 5 (33.3) 0.03 therapy Microbiologic cure at 21 (65.6) 6 (40.0) 0.09 end of therapy 28-day mortality 5 (15.6) 5 (33.3) 0.20 Wunderink RG, et al. Infect Dis Ther 2018;7(4): 439-455 Meropenem-Vaborbactam for CRE Meropenem-vaborbactam vs. ceftazidime-avibactam Outcome, n (%) Ceftazidime-avibactam Ceftazidime-avibactam Meropenem-vaborbactam P-value monotherapy combination therapy monotherapy (n=41) (n=64) (n=22) Clinical success 26 (63.4) 39 (60.9) 15 (68.2) 0.83 90-day mortality 9 (22.0) 20 (31.2) 6 (27.3) 0.58 Recurrence (all) 9 (22.0) 6 (9.4) 3 (13.6) 0.20 Recurrence with 5 (12.2) 1 (1.6) 0 0.03 increase in MIC Adverse events 14 (34.2) 22 (34.4) 5 (22.7) 0.57 Ackley R, et al. Antimicrob Agents Chemother 2020;64(5): e02313-19 Imipenem-relebactam FDA-approved in 2019 • Complicated urinary tract infections • Complicated intra-abdominal infections • Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia Relebactam • Novel β-lactamase inhibitor • Inhibits Class A carbapenemases (including KPC) and some class D carbapenemases • Does not inhibit Class B metallo-β-lacatamases Imipenem-Relebactam for CRE RESTORE-IMI 1: Phase 3 randomized, controlled trial of imipenem-relebactam vs. colistin plus imipenem for imipenem-nonsusceptible infections Outcome, n (%) Imipenem-relebactam Colistin + imipenem Adjusted Difference (n=21) (n=10) (90% CI) Favorable overall response 15 (71.4) 7 (70) -7.9 (-27.5 to 21.4) Favorable clinical response 15 (71.4) 4 (40) 26.3 (1.3 to 51.5) 28-day all-cause mortality 2 (9.5) 3 (30) -17.3 (-46.4 to 6.7) Treatment-emergent nephrotoxicity 3/29 (10.3) 9/16 (56.3) -45.9 (-69.1 to -18.4) Enterobacterales outcomes: ◦ Favorable response: 2/5 (40%) treated with imipenem-relebactam vs. 2/2 (100%) treated with imipenem + colistin Motsch J, et al. Clin Infect Dis 2020;70(9): 1799-1808 Cefiderocol FDA-approved in 2019 for complicated urinary tract infections Mechanism of action: Shionogi, Inc. Antimicrobial Drugs Advisory Committee cefiderocol briefing document, NDA # 209445 Wu JY, et al. Infect Dis Ther 2020;9(1): 17-40 Cefiderocol for CRE CREDIBLE-CR: Phase 3, randomized, open-label trial of cefiderocol vs. best available therapy (BAT) for carbapenem-resistant gram-negative bacteria Outcome, n (%) Nosocomial pneumonia Bacteremia UTI Overall Cefiderocol BAT (n=19) Cefideroco BAT Cefiderocol BAT (n=5) Cefiderocol BAT (n=40) l (n=23) (n=14) (n=17) (n=80) (n=38) Clinical cure at end of 24 (60) 12 (63) 16 (70) 7 (50) 13 (77) 3 (60) 53 (66) 22 (58) treatment Clinical failure at end 13 (33)
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