New Antimicrobials and Antifungal Agents

1. New Antimicrobials and Antifungal Agents Michael J. Tan, MD, FACP, FIDSA Associate Professor of Internal Medicine, NEOUCOM, Rootstown, OH Infectious Disease Service Summa Health System, Akron, OH

2. Objectives • Review antimicrobials • New antimicrobials • New indications

3. Which of the following carbapenems appears to induce less resistance to Pseudomonas aeruginosa in vitro? A. ertapenem B. Imipenem/cilastatin C. meropenem D. doripenem E. faropenem

4. Which of the following is an approved indication for telavancin? • Right-sided bacterial endocarditis • Complicated skin and skin structure infections • Complicated intraabdominal infections • Infections due to vancomycin resistant enterococci • All of the above

5. Where are all the new antibiotics? • IDSA 2004 White Paper “Bad Bugs, No Drugs” • Increasing microbial resistance • Challenges to Antimicrobial approvals • New drug development: $800,000,000 and 8 years • Antibiotics used for short duration • Science is difficult (e.g., gram negatives) • Lack of sufficient diagnostic tests • Regulatory uncertainty—FDA • Insufficient past research support—NIH • Antimicrobial resistance • Drugs in other markets (chronic disease, lifestyle) are more attractive

6. Source: Centers for Disease Control and Prevention

8. New Antibacterial Agents Approved Since 1998 ANTIBACTERIAL Rifapentine Quinupristin/dalfopristin Moxifloxacin Gatifloxacin Linezolid Cefditoren pivoxil Ertapenem Gemifloxacin Daptomycin Telithromycin Tigecycline Doripenem YEAR 1998 1999 1999 1999 2000 2001 2001 2003 2003 2004 2005 2007 Novel No No No No Yes No No No Yes No No No Spellberg CID 2004, modified

9. Select New Antibacterial Agents Approved Since 1998 Spellberg CID 2004, modified

10. New Antibacterial Classes??? • New drug development: $800,000,000 and 8 yrs • Other markets are better • Agency is indecisive • Expectations are unclear • Changes are common • Delays have become norm

11. Antibiotic Pipeline • Legislation 2007-STAAR Act • Evaluate susceptibility levels/concentrations • Determine diseases that qualify for grants for development • Clinical trial guidelines • Exclusivity provisions • Priority review for tropical disease • Nosocomial infections • Further proposals • More research on resistance, and hospital infections • Support development of new antimicrobials • Restrict antimicrobial use in food-producing animals • More information: www.idsociety.org/STAARact.htm

12. New Agents 2008 • Antiretroviral • NNRTI (second generation) • Intelence (etravirine) • Antibacterials • NONE!!! • NO APPROVALS 2008 • FDA Review 11/17/2008 • Oritavancin-Mixed response from FDA • Iclaprim-FDA wants more data

13. New Agents 2009 • New Agents • Telavancin (Vibative™) • Lipoglycopeptide • Artemisinin/lumefantrine (Coartem®) • Not really new, but first approval in US • Peramivir (investigational) • Compassionate Use • New Indication • Tigecycline (Tygacil®)

14. New Agents 2010 • Ceftaroline

15. On the Horizon • Dalbavancin (Zeven) – application pulled, going back to studies • Fusidic Acid (CEM-102) • CDAD Agents? (OPT-80/MDX-066/1388), Cubist agent? • Ceftibiprole • Need more data • FDA – data integrity issue • J&J has sent ceftibiprole back to Basilea • Ceftaroline, It’s Here! • NXL-104/B-lactamase inhibitor • Sulopenem • Fluoroketolide

16. Antifungals-Echinocandins • Anidulafungin, caspofungin, micafungin • Have gotten cheaper in last few years • All roughly equivalent in spectrum • Indications differ by agent (although similar activity) • Affects cell wall synthesis • Once daily IV dosing • in vitro spectrum • Yeasts, moulds, salvage for aspergillosis • NO Cryptococcal Coverage, weak C. parapsilosis

17. Posaconazole (Noxafil) • Triazole antifungal • Approved • prophylaxis of invasive Aspergillus and Candida infections • Treatment of oropharyngeal candidiasis • in vitro activity against moulds and yeasts similar to other broad spectrum azoles, sometimes more potent • Candida, Cryptococcus, Coccidioides, Aspergillus, Histoplasma, Zygomycetes…

18. Posaconazole (Noxafil) • Oral administration only, q8h • CYP3A4 inhibitor • Multiple interactions • Unique aspects • PO Suspension only • Consistent activity against zygomycetes

19. Peramivir • Neuraminidase inhibitor • Similar to oseltamivir, zanamivir • IM studied, IV, no oral formulation • 10/23/09 Compassionate use currently for confirmed or suspected pandemic H1N1 • Studies show it may be more effective than other neuraminidase inhibitors

20. 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

21. Ceftaroline Teflaro PI

22. ceftaroline • 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

23. 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 faceium.

24. Telavancin (Vibativ™) • Lipoglycopeptide • Approved September 2009 • Built on vancomycin • Cell wall and cell membrane active • Indication: • Complicated skin and skin structure infection due to certain Gm positives including MRSA • Pending Indication: • Pneumonia • Dosing • 10mg/kg IV q24h • Renal dosing necessary • Dialysis dosing not yet established.

25. 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

26. A-telavancin • B-vancomycin • Images are Public Domain

27. 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.

28. Tygacil (tigecycline) • Minocycline with attachment at 9 position • Broad Spectrum Gram Positive, Gram Negative, Anaerobic • NO Pseudomonas, Proteus, Providencia, Morganella • Approved • Complicated Skin and Skin structure infection • Complicated Intraabdominal Infection • NEW INDICATION • CABP due to H. influenzae, Pneumococcus +/- bacteremia, legionella, • NOT APPROVED • DM foot with osteomyelitis • Met endpoints for skin, but not osteo • Good in vitro killing of MRSA and VRE • Approved MSSA, MRSA , VSE (cSSSI) • Approved MSSA, VSE (cIAI)

29. Tygacil (tigecycline) • New Black Box on All Cause mortality • Unique Aspects • IV Only • Long Half-Life, still dosed twice daily • High tissue distribution, relatively low serum concentrations • May not be good for bacteremia • Broad Spectrum Non-Beta Lactam • May help consolidate therapy • Safe in Beta-Lactam allergic patients

30. Cubicin (daptomycin) • Cyclic lipopeptide • 8/03 Approved for Skin and Skin Structure (including MRSA) but only VSE • 5/06 S. aureus BSI including Right Sided endocarditis (MSSA/MRSA) • Daptomycin has NO lung penetration

31. Cubicin (daptomycin) • Another alternative for MRSA • Less renal dysfunction and better tolerance than vancomycin • No need to check levels • Vancomycin NOT always drug of choice for MRSA • Concern of Muscle toxicity, check CPK weekly

32. Doribax (doripenem) • Approved • Approved 10/07 • Complicated intra-abdominal • Complicated UTI • Carbapenem • More similar in spectrum to meropenem and imipenem than to ertapenem • Has anti-pseudomonal coverage • May have better susceptibility patterns vs other carbapenems for PSA • Renal adjustment

33. Doribax (doripenem) • Unique Aspects • IV Only • May have lower MICs and better PSA coverage than other carbapenems • Looks less likely to induce PSA resistance than other carbapenems • Like most of the carbapenems, covers acinetobacter • Not demonstrated to be any better vs. acinetobacter

34. Artemisinin/luxofantrine (Coartem) • Artesunate based antimalarial • Indication • Treatment of acute uncomplicated infections due toplasmodium falciparum • Effective >96% of chloroquine resistant malarias • First time available in US without going through CDC • QT, CYP 3A4 • Lots of AEs • Difficult to tell which are from malaria and which are from drug. Headache, dizziness, anorexia, nausea, vomitting

35. Coming Soon? • Zeven (Dalbavancin) • Lipoglycopeptide • Resistant Gram-Positive Pathogens • MRSA/VRE • Elimination T1/2 of 149-198 hours • Once-weekly dosing may be an option • Currently under review • Approval anticipated mid 2006 now maybe 2007, 2008, 2009, 2010,… • IND has been pulled pending more studies • Studies restarting now

36. Coming Soon…or we’re still waiting… • Cephalosporins • MRSA activity? • Ceftibiprole • Ceftaroline • Enterococcocus Activity? • Ceftibiprole • PSA Activity • Ceftibiprole • Under investigation for • Complicated Skin • Nosocomial and Community acquired pneumonia

37. MDX-066 (CDA-1) and MDX-1388 (CDB-1) • Phase II Completed • Human antibody-based monoclonal antibodies to neutralize CDTA/CDTB • 11/3/2008 • Standard of care (metro vs. vanco) + MAb vs. placebo one time infusion. • Placebo recurrence rate 20%, consistent with literature • MAb recurrence rate reduced 70% compared with placebo • Merck doing further development Medarex/Massachusetts Biologic Laboratories Press Release, 11/3/2008

38. OPT-80-fidaxomicin • One of Two Phase 3 trials completed • 10 days OPT-80 vs. vancomycin PO • Similar Cure rates compared with vancomycin 92.1% vs 89.9% • Lower recurrence rates compared with vancomycin, 13.3% vs 24% • Global Cure rates higher compared with vancomycin, 77.7% vs. 67.1% • Second Phase 3 trial just finished • Newest data-Second Phase 3 trial • As above, but recurrence rate similar to vancomycin when dealing with epidemic strain • Recurrence trends toward favoring fidaxomicin, but not statistically significant. Optimer Pharmaceuticals Press Release 11/10/2008

39. Horizon 2009Hotter: C. diff Infection • L1-1642: Gerding G et al. Phase 3 trial of Fidaxomicin vs Vanc-decreased cure rate for epidemic BI/NAP1/027 strain • Cure: Fidaxomicin-92%; Vanc-90%; • Cure if NAP1: Fidaxomicin: 86%; Vanc 85% • Recurrences overall: Fidaxomicin-13%; Vanc 24% (p=0.004) • Recurrences if NAP1: Fidaxomicin-24%; Vanc 24% • Cure rate for NAP1 was less than other strains; recurrence rate for NAP1 with Fidaxomicin therapy was not better than vanc • NAP1 strain is bad! OPT 80 has gained a name but lost some luster?

40. L1-1305. RCT Fidaxomicin vs Vanc for CDI. Cornely et al. • During 2 phase III RCTs, separate stratum of patients who had single prior CDI and recurred within 3 months • 128 patients ; FDX (66; 200 mg bid X 10), Vanc (62; 125 mg qid x 10); mean age 63; endpoint-recurrence in 4 weeks • Results: • Recurrences in 4 weeks • Vanc: 35.5% (22/62) • FDX: 19.7% (13/66); 45% reduction (p=0.045) • Recurrences in 2 weeks • Vanc 17 (27.4%); FDX 5 (7.6%) p = 0.003 • Risk of recurrence 2.7 fold greater in patients > 75 yrs compared to 55 years • FDX: negligible impact on fecal flora

41. Coming Soon? • CEM 102 – fusidic acid • Available outside US • Good Gm Positive activity including MRSA • Oral therapy • Studies ongoing for skin and soft tissue