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New Antimicrobials Agents Michael J. Tan, MD, FACP, FIDSA Associate Professor of Internal Medicine, Northeast Ohio Medical University Summa Health System, Akron, OH
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Disclosures Speaker Bureaus Cubist Pfizer Actavis The Medicines Company Theravance Research Cubist Merck
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Which of the following is an approved indication for ceftolozane-tazobactam? A.Acute bacterial skin and skin structure infection B.Complicated intraabdominal infections C.Bacteremia due to methicillin-resistant Staphylococcus aureus D.Hospital acquired pneumonia due to resistant pseudomonas E.All of the above
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Objectives Review antimicrobials New antimicrobials
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Select New Antibacterial Agents Approved Since 1998 AntibacterialYearNovel Rifapentine1998No Quinupristin/dalfopristin1999No Moxifloxacin1999No Gatifloxacin*1999No Linezolid2000Yes Cefditoran pivoxil2001No Ertapenem2001No Gemifloxacin2003No Daptomycin2003Yes Telithromycin*2004No Tigecycline2005No Doripenem2007No Telavancin2009No Ceftaroline2010No Fidaxomicin2011Yes Tedizolid2014No Dalbavancin2014No Oritavancin2014No Ceftolozane/Tazobactam2014No Ceftazidime/Avibactam2015No Spellberg CID 2004, modified
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Pneumococcal conjugate vaccine (PCV13) CAPiTA trial Looking at difference with vaccine containing serotype pneumococcal pneumonia 1 st episode confirmed vaccine type-CAP, 49 vs 90 (PCV13 vs. placebo) 1 st episode confirmed NB/NI/VT-CAP, 33 vs. 60 1 st episode of VT-IPD, 7 vs 28. ACIP/CDC Over 65: Give PCV13, follow with PPSV 23 (8wk) Immunecompromised: Give PCV 13, follow with PPSV23. Previous PPSV23: Give PCV13 (at least 1y if known), follow with PPSV 23 (at least 5 yr after previous PPSV23 and 8 wks after PCV13) May have decreased efficacy with inactivated influenza vaccination Officially: PPSV23 should follow PCV 13 by 12 mos (based on reimbursement, immunecompromised, min 8 weeks) 6
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Pipeline Gram positive agents: Dalbavancin, oritavancin, tedizolid (all three approved 2014) CDI agents monoclonal antibody, non-toxigenic C diff, oxazolidinone with FQ moiety, Lipoglycopeptide HCV Multiple agents (new approvals 2014, 2015) Gram negative agents: Ceftolozane/tazobactam (CXA 201) (Approved December 2014) Ceftazidime/avibactam (NXL104) (Approved February 2015) Ceftaroline-avibactam Imipenem/MK-7655 Plazomicin (Aminoglycoside) Ervacycline (Fluorocycline) Brilacidin (Peptide defense protein mimetic) Novel
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Telavancin (Vibativ™) Approved September 2009 Lipoglycopeptide, built on vancomycin Cell wall and cell membrane active Indications: Complicated skin and skin structure infection due to certain Gram positives including MRSA NEW 6/13: HABP/VABP caused by susceptible isolates of S aureus (including MRSA) when alternative treatments are not suitable Dosing 10mg/kg IV q24h Renal dosing necessary Dialysis dosing not yet established
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AEs Teratogenic (but preg cat c!) in some animals Nephrotoxicity QTc prolongation (looks less than FQ) Interference with INR, PT, PTT, without bleeding risk Nausea/vomitting, taste disturbance, foamy urine No increase in Red Man Patients with pre-existing moderate-severe renal impairment (Crt Cl <=50), treated for HABP/VABP had higher mortality compared with vancomycin.
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Telavancin Unique aspects Based on vancomycin, but varied mechanism Cell Wall and Cell membrane active Another option for MRSA activity, some VRE IV only No need to check levels Looks to be more effective than vanc in skin, but results not statistically significant. Had issues with marketing and supply line Now has 2 year supply available
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Ceftaroline (Teflaro), Forest Pharmaceuticals Cephalosporin ? Generation Approved 10/29/2010 Indications: Acute bacterial skin and skin structure infections (ABSSSI) MRSA, MSSA, Strep, E coli, K pneumo, K oxy. Community-acquired bacterial pneumonia (CABP) MSSA, Pneumococcus (+/- bacteremia), H infl, K pneumo, K oxy, E coli Dosing 600mg IV q12h over 1hr Crt Cl >50 400mg IV q12h over 1hr Crt Cl >30-<=50 300mg IV q12h over 1hr Crt Cl >=15, <=30 200mg IV q12h over 1hr ESRD, including HD. Teflaro PI
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Ceftaroline Teflaro PI
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Ceftaroline Binds PBP2a, PBP2x AEs Well tolerated, no specific AE >5% Nausea, diarrhea, rash, most common No significant difference between ceftaroline and comparators, Vanc/Aztreonam, Ceftriaxone. Pregnancy B Minimal interactions with P450 drugs Excretion: Primarily kidneys, 64% in urine unchanged. Teflaro PI
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Ceftaroline-Unique Aspects IV Only No hepatic adjustment Dose have renal dosing recommendations Indicated for ABSSSI, CABP In vitro activity vs. MRSA Marginal at best for Enterococcus fecaelis, Minimal if any for E faecium.
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Ceftolozane/Tazobactam (Zerbaxa) Cubist, approved December 2014 Cephalosporin + B-lactamase inhibitor Extended gram negative, P aeruginosa, ESBL activity Indications (due to susceptible bacteria): Complicated intraabdominal infection (CIAI) + metronidazole E cloacae, E coli, K pneumo, K oxytoca, P mirabilis, P aeruginosa, B fragilis, S anginosus, S constellatus, S salivarius Complicated urinary tract infection E coli, K pneumo, P mirabilis, P aeruginosa Dosages Crt cl > 501.5g (1g/0.5) IV q8h Crt cl 30-50750mg (500mg/250mg) IV q8h Crt cl 15-29375mg (250mg/125mg) IV q8h Crt cl <15750mg (500mg/250mg) IV x1, 150mg (100/50) q8h
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Ceftolozane/Tazobactam (Zerbaxa) Unique aspects IV Only Similar AE profile to other cephalosporins Pregnancy Cat B *Anaerobic activity, but studies done with metro Increased ESBL activity No KPC or metallo beta-lactamase activity Retains activity against most resistant Pseudmonas Geriatrics, renal impairment In cIAI vs. meropenem, cure rate lower in 65 and older Not seen in cUTI In cIAI vs. meropenem, cure rate lower in crt cl 30-50 Similar trend seen in cUTI vs. levoflox in crt cl 30-50
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Ceftazidime/avibactam (Avycaz) Actavis (now Allergan), approved February 2015 Cephalosporin (3 rd gen) with new B-lactamase inhibitor Avibactam Inhibits AmpC, KPC, but NOT ESBL or NDM-1 Indications (due to susceptible bacteria), 18 and older Complicated intra-abdominal infection, in combination with metronidazole (E coli, K pneumo, P mirabilis, Providencia stuartii, E cloacae, K oxytoca, P aeruginosa) Complicated urinary tract infection, including pyelonephritis (E coli, K pneumo, Citrobacter koseri, Citrobacter, freundii, Proteus spp, E cloacae, E aerogenes, P aeruginosa Dosages 2.5g (2g/0.5g) over 2h q8h
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Ceftazidime/avibactam (Avycaz) Dosages >50mL/min2.5g (2g/0.5g) over 2h q8h 31-501.25g (1g/0.25g) over 2h q8h 16-300.94g (0.75g/0.19g) over 2h q12h 6-150.94g (0.75g/0.19g) over 2h q24h Contraindications Hypersensitivity to ceftaz/avi, ceftaz, cephs Warnings cIAI, cure rates lower in CrtCl 30-50 vs. >50. Dose in this subgroup was 33% less than what is recommended
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ceftazidime avibactam
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Ceftazidime/avibactam (Avycaz) Unique aspects IV Only Similar AE profile to other cephalosporins Pregnancy Cat B Minimal anaerobic activity, need metro Increased KPC/CRE activity No ESBL or metallo beta-lactamase activity Anti-Pseudmonal EXPENSIVE
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Tedizolid (Sivextro) Approval for Acute bacterial skin and skin structure infection caused by susceptible bacteria Gram positive and resistant GPC, including MRSA 2 nd of the oxazolidinone class Once daily option 200 mg IV/PO q24h x6 days HAP/VAP in development Cat C 22
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Tedizolid (Sivextro) Unique aspects and potential concerns Based on mouse studies, patients with neutropenia may have inadequate response to therapy AE profile similar to linezolid MIGHT: Have less hematologic side effects (duration dependent effect seen, but studies only for 6 days) Have similar peripheral and optic neuropathy issues Have less interaction with pressors Have less interaction with SSRI/MAO (SSRI/MAO patients excluded from study) Not be as good as linezolid for strep (by raw numbers) Cost currently on par with linezolid, but oral linezolid went generic early 2015. 23
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Dalbavancin (Dalvance) Indication for acute bacterial skin and skin structure infections caused susceptible strains of Gram positive microorganisms (including MRSA) Non-inf compared with vanc/linezolid Lipoglycopeptide Effective half life of 8.5d (204 hrs) 1000mg IV over 30min x1 followed by 500mg IV over 30min x1 (7d later) Renal impairment (<30mL/min not on scheduled HD) 750mg IV over 30 min x1 followed by 375mg IV over 30 min x1 (7d later) No recommendations for HD patients. May dialyze with high permeability membranes 24
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Dalbavancin (Dalvance) Unique aspects LONG half-life Two doses for ABSSSI, but will two doses get done? How do you deal with drug reactions and drug interaction issues? Redman can happen with rapid infusion Category C Currently one indication, potential for abuse? Quite expensive At least $1500/500mg vial May reduce cost by reducing hospitalization 25
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Oritavancin (Orbactiv) Indication for acute bacterial skin and skin structure infections caused susceptible strains of Gram positive microorganisms (including MRSA) Non-inf compared with vancomycin Lipoglycopeptide Terminal half life of 245h, clearance 0.445L/h 1200mg IV over 3h x1 (reconstitute from 400mg vials) Renal impairment >30mL/min, no dose adjustment required. <30mL/min no recommendation 26
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Oritavancin (Orbactiv) Unique aspects LONG half-life, SINGLE dose for ABSSSI How do you deal with drug reactions and drug interaction issues? Redman can happen with rapid infusion More cases of osteomyelitis reported in oritavancin arm as compared with vancomycin arm. Artificially prolonged aPTT for 48h and PT/INR for up to 24h. Category C Currently one indication, potential for abuse? Expected to be expensive May reduce cost by reducing hospitalization 27
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