1. New Antimicrobials Agents Michael J. Tan, MD, FACP, FIDSA Associate Professor of Internal Medicine, Northeast Ohio Medical University Summa Health System, Akron, OH

2. Disclosures  Speaker Bureaus  Cubist  Pfizer  Actavis  The Medicines Company  Theravance  Research  Cubist  Merck

3. 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

4. Objectives  Review antimicrobials  New antimicrobials

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

11. 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

12. Ceftaroline Teflaro PI

13. 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

14. 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.

15. 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

17. 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

18. 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

19. 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

20. ceftazidime avibactam

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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