New Antimicrobials and Antifungal Agents
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New Antimicrobials and Antifungal Agents
Michael J. Tan, MD, FACP, FIDSAAssociate Professor of Internal Medicine,
NEOUCOM, Rootstown, OHInfectious Disease Service
Summa Health System, Akron, OH
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Objectives Review antimicrobials
New antimicrobials New indications
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Which of the following carbapenems appears to induce less resistance to Pseudomonas aeruginosa in vitro?
A. ertapenemB. Imipenem/cilastatinC. meropenemD. doripenemE. faropenem
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Which of the following is an approved indication for telavancin?A. Right-sided bacterial
endocarditisB. Complicated skin and
skin structure infections
C. Complicated intraabdominal infections
D. Infections due to vancomycin resistant enterococci
E. All of the above
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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
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Source: Centers for Disease Control and Prevention
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New Antibacterial Agents Approved Since 1998
ANTIBACTERIALRifapentine Quinupristin/dalfopristinMoxifloxacinGatifloxacinLinezolidCefditoren pivoxilErtapenemGemifloxacinDaptomycinTelithromycinTigecyclineDoripenem
YEAR199819991999199920002001200120032003200420052007
Spellberg CID 2004, modified
NovelNoNoNoNoYesNoNoNoYesNoNoNo
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Select New Antibacterial Agents Approved Since 1998Antibacterial Year NovelRifapentine 1998 NoQuinupristin/dalfopristin 1999 NoMoxifloxacin 1999 NoGatifloxacin* 1999 NoLinezolid 2000 YesCefditoran pivoxil 2001 NoErtapenem 2001 NoGemifloxacin 2003 NoDaptomycin 2003 YesTelithromycin* 2004 NoTigecycline 2005 NoDoripenem 2007 NoTelavancin 2009 No
Spellberg CID 2004, modified
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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
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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
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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
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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®)
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New Agents 2010 Ceftaroline
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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
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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
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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…
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Posaconazole (Noxafil) Oral administration only, q8h CYP3A4 inhibitor
Multiple interactions Unique aspects
PO Suspension only Consistent activity against zygomycetes
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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
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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 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 faceium.
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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.
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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
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A-telavancin B-vancomycin
Images are Public Domain
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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.
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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?
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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
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Coming Soon? CEM 102 – fusidic acid
Available outside US Good Gm Positive activity including MRSA Oral therapy Studies ongoing for skin and soft tissue