Transcript New Antimicrobials What the Internist Needs to Know
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
Review antimicrobials New antimicrobials New indications
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
Which of the following is an approved indication for telavancin?
Right-sided bacterial endocarditis B.
Complicated skin and skin structure infections Complicated intraabdominal infections Infections due to vancomycin resistant enterococci All of the above
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
Source: Centers for Disease Control and Prevention
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 No No No Yes No No No Novel No No No No Yes
Select New Antibacterial Agents Approved Since 1998
Rifapentine Quinupristin/dalfopristin Moxifloxacin Gatifloxacin* Linezolid Cefditoran pivoxil Ertapenem Gemifloxacin Daptomycin Telithromycin* Tigecycline Doripenem Telavancin
1998 1999 1999 1999 2000 2001 2001 2003 2003 2004 2005 2007 2009 No Yes No No No No
No No No No Yes No No Spellberg
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
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
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
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®)
New Agents 2010
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
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
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…
Oral administration only, q8h CYP3A4 inhibitor Multiple interactions Unique aspects PO Suspension only Consistent activity against zygomycetes
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
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.
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.
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.
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.
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
A-telavancin B-vancomycin Images are Public Domain
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.
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)
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
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
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
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
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
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
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
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
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
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
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?
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
CEM 102 – fusidic acid Available outside US Good Gm Positive activity including MRSA Oral therapy Studies ongoing for skin and soft tissue