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. B. Imipenem/cilastatin C. meropenem D. doripenem E. faropenem
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
Novel No
Yes
Spellberg CID 2004, modified

9. Select New Antibacterial Agents Approved Since 1998
Year
Novel
Rifapentine
1998 No
Quinupristin/dalfopristin
1999
Moxifloxacin
Gatifloxacin*
Linezolid
2000
Yes
Cefditoran pivoxil
2001
Ertapenem
Gemifloxacin
2003
Daptomycin
Telithromycin*
2004
Tigecycline
2005
Doripenem
2007
Telavancin
2009
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:

12. New Agents 2008 Antiretroviral Antibacterials
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 New Indication 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 Pregnancy B Minimal interactions with P450 drugs
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 Carbapenem
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 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?
PSA Activity
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 %
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 2009 Hotter: 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. L1-1306. CDI strain type in 2 P Fidaxomicin vs. Vanc. Gerding et al.
Combined data of 2 RCTS (003 and 004); Age 61.8; Inpatient 67%; UBMs/d=8; Prior ATB use 64%
BI grp in US 34%; Europe 5% (UK and Belgium)
Comment: Will be commercial success
CURE
Vanc
Fidax
P (V vs F
Total
BI grp
106/124 (85.4%)
105/120 (87.5) NS
211/244 (86.5)
Non-BI
220/236 (93.2)
225/236 (95.3)
445/472 (94.3)
p BI vs non BI
0.022
0.009
0.0006
RECURR BI
29/93 (31.2)
21/90 (23.3)
50/183 (27.3)
Non BI
49/194 (25.3)
17/203 (8.4)
66/397 (16.6)
0.001
0.003

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