Options for Complicated Skin and Skin Structure Infections. Andrew F. Shorr, MD, MPH Washington Hospital Center Georgetown Univ.

Transcription

1 Options for Complicated Skin and Skin Structure Infections Andrew F. Shorr, MD, MPH Washington Hospital Center Georgetown Univ.

2 Disclosures I have served as a consultant to, researcher/investigator for, or spoken for: Astra Zeneca Astellas Bayer Cubist Forest Pfizer Tetraphase Theravance

3 FDA-approved agent Currently Used Therapy for MRSA csssi Evidence Ceftaroline (IV) AI Nosocomial Pneumonia Evidence Bacteremia Evidence Daptomycin (IV) AI AI Linezolid (IV/PO) AI AII Telavancin (IV) AI Tigecycline (IV) Vancomycin (IV) AI AII AII Oral Generics (no FDA-approved indication) Tetracyclines - Doxycycline, minocycline Trimethoprim/sulfamethoxazole Clindamycin Liu C, et al. Clin Infect Dis. 2011;52(2):1-38.

4 Tigecycline Boxed Warning Issued 9/27/13: Health care professionals should reserve Tygacil for use in situations when alternative treatments are not suitable Additional analysis shows an increased risk of death when intravenous (IV) Tygacil (tigecycline) is used for FDA-approved uses as well as for non-approved uses In a 2010 Drug Safety Communication, the FDA informed the public that a meta-analysis of 13 Phase 3 and 4 trials showed a higher risk of death among patients receiving Tygacil compared to other antibacterial drugs (adjusted risk for death was 0.6% with 95% confidence interval) The increased risk was greatest in patients treated for ventilator-associated pneumonia, a use for which FDA has not approved the drug Since issuing the 2010 DSC, the FDA analyzed data from 10 clinical trials conducted only for FDA-approved uses (csssi, ciai, CABP), including trials conducted after the drug was approved (adjusted risk for death was 0.6% with 95% confidence interval) This analysis showed a higher risk of death among patients receiving Tygacil compared to other antibacterial drugs when used for FDA-approved uses as well as for non-approved uses In general, the deaths resulted from worsening infections, complications of infection, or other underlying medical conditions Accessed 9/30/13.

5 Dosing and Monitoring Vancomycin ASHP/IDSA/SIDP Recommendations Loading Dose: mg/kg IV (actual body weight) over 2 hours in seriously ill patients with suspected MRSA infection may be considered (C-III). Maintenance Dose: mg/kg (actual body weight) every 8-12 hours, not to exceed 2 g/dose in patients with normal renal function (B-III) Trough serum vancomycin concentrations should always be maintained above 10 mg/l to avoid the development of resistance (B-III) For complicated infections caused by S. aureus, total trough serum vancomycin concentration of mg/l is recommended (B-II) Rybak et al. Am J Health-Syst Pharm 2009;66:82-98

6 Clinical Outcome: Vancomycin MIC 2.69 (1.60,4.51) 1.64 (1.14,2.37) Low MIC failure High MIC failure Low MIC mortality High MIC mortality Van Hal SJ et al. Clin Infect Dis 2012;54:755-71

7 Percent of Isolates Resistance: Prior Vancomycin Use Predicts High MICs No prior vancomycin Prior vancomycin P = Logistic Regression Analysis of Risk Factors Associated with Vancomycin MIC 1.5 mcg/ml Variable AOR (95% CI) P value Vancomycin last 30 days 9.4 ( ) ICU-acquired bacteremia 5.3 ( ) ,5 1 2 Vancomycin MIC (mcg/ml) Moise et al, J Antimicrob Chemo 2008;61:85 90 Lodise et al, J Antimicrob Chemo 2008;62:

8 Vancomycin Increased doses of vancomycin does not necessarily improve outcomes The percentage of MRSA isolates with vancomycin MIC >2.0 μg/ml increased from 3% in 2005 to 11% in 2009 Vancomycin success rates at higher MICs are 5-fold lower Hawser et al. International Journal of Antimicrobial Agents. 2011;37(3): Sakoulas G et al. J Clin Microbiol. 2004;42: First case report of infection with VRSA reported in Europe from a patient in Portugal Genetic background similar to that of VRSA isolated in USA but no epidemiological link with the USA to the patient or healthcare providers

9 Linezolid vs Vancomycin in Documented MRSA csstis The largest culture-confirmed MRSA cssti trial to date compared the efficacy and safety of ZYVOX with that of vancomycin Study Design Phase 4, prospective, randomized (1:1), open-label, multinational, multicenter, comparator-controlled trial Scope 1077 randomized patients from 102 centers in 12 countries Primary End Point Clinical efficacy at end of study (EOS) in per-protocol (PP) population Secondary End Points Clinical efficacy at end of treatment (EOT) in PP population Clinical efficacy at EOT and EOS in modified intent-to-treat population Microbiologic outcomes Safety

10 Clinical Success (%) Linezolid vs Vancomycin in Patients With Culture-Confirmed MRSA csstis: Clinical Success (Per-Protocol Subjects) Results of a prospective, randomized, open-label, multicenter study versus vancomycin in patients with culture-confirmed MRSA (intent-to-treat population=1052 patients) P=NS P=NS Linezolid 600 mg IV q12h Vancomycin 15 mg/kg IV q12h; titrate per Cl Cr and trough levels 219/ / / /209 *Primary analysis was a noninferiority comparison, with nested superiority hypothesis. Success rate was defined as the rate of patients assessed or classified as cured or improved. Itani KM, et al. Am J Surg. 2010;199(6):

11 Clinical Success (%) Linezolid vs Vancomycin in Patients With Culture-Confirmed MRSA csstis: Clinical Success (Modified Intent-to-Treat [mitt] Subjects) Results of a prospective, randomized, open-label, multicenter study versus vancomycin in patients with culture-confirmed MRSA (intent-to-treat population=1052 patients) P=NS P=.048 Linezolid 600 mg IV q12h Vancomycin 15 mg/kg IV q12h; titrate per Cl Cr and trough levels 254/ / / /266 Clinical success in mitt population at EOT and EOS are secondary end points. Success rate was defined as the rate of patients assessed or classified as cured or improved. Itani K et al. Clinical Microbiology and Infection 2008;14(suppl 7):S16. Abstract 080.

12 Daptomycin Outcomes with Higher Doses (1) CPK values 3 times the upper limit of normal (ULN) based on two serial measurements during therapy, and one of two levels 5 times the ULN or (2) CPK levels 5 times the ULNon two serial measurements if abnormal CPK levels at baseline [26]. he ULN of CPK value at NTUH is 160 IU/L.

13 Telavancin: Current Indications FDA-approved indications ( ): Treatment of adult patients with complicated skin and skin structure infections - Caused by susceptible Gram-positive bacteria - Including Staphylococcus aureus, both MRSA and MSSA Hospital-acquired and ventilator-associated bacterial pneumonia(habp/vabp) caused by susceptible isolates of Staphylococcus aureus, when alternative treatments are not suitable EMA-approved indication (2011): Treatment of adults with nosocomial pneumonia, including ventilator associated pneumonia - Known or suspected to be caused by MRSA; - Only in situations where it is known or suspected that other alternatives are not suitable

14 Ceftaroline Ceftaroline is a cephalosporin with in vitro activity against Gram-positive and Gram-negative bacteria 1 The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs) 1 Ceftaroline is bactericidal against S. aureus due to its affinity for PBP2a 1 Ceftaroline has the ability to bind to PBP2a, the mutant protein that produces methicillin resistance in S. aureus 2 Ceftaroline is bactericidal against S. pneumoniae due to its affinity for PBP2x 1 1. TEFLARO (ceftaroline fosamil) [prescribing information]. St. Louis, MO: Forest Pharmaceuticals, Inc; Moisan H, Pruneau M, Malouin F. J Antimicrob Chemother. 2010;65:

15 Ceftaroline Indications CABP Gram-positive bacteria S. pneumoniae (including cases with concurrent bacteremia) S. aureus (methicillinsusceptible isolates only) Gram-negative bacteria H. influenzae K. pneumoniae K. oxytoca E. coli ABSSSI Gram-positive bacteria S. aureus (including methicillin-susceptible and -resistant isolates) S. pyogenes S. agalactiae Gram-negative bacteria E. coli K. pneumoniae K. oxytoca

16 Anti Gram-positive Agents in the Pipeline Fluoroquinolones Class Company Drug Status (clinical) Timing Rib-X delafloxacin III (ABSSSI) II (CAP) TaiGen nemonoxacin II (CAP/dfi) Furiex JNJ-Q2 III CAP/ABSSSI Entering PIII Lipogycopeptides (*) Durata dalbavancin III ABSSSI The MedCo oritavancin III (ABSSSI) Ketolides Adv. Life Sci. cethromycin III (CAP) / anthrax First PIII for ABSSSI started in 1H2013 NDA late September/projected launch 2H14 PIII completed projected filing 4Q13 in US; 2014 European filing Additional data requested by FDA / operations suspended Cempra solithromycin III (CAP) 4Q13 Initiation of PIII trial in CABP Oxazolidinones Trius tedizolid III (ABSSSI) Rib-X radezolid II ABSSSI/CAP) Pleuromotulin (*) Nabriva BC-3781 II (ABSSSI) Peptidomimetic (**) Polymedics PMX II (ABSSSI) Fab inhibitor (**) Affinium AFN-1252 II (ABSSSI) Deformylase inhibitor (**) GSK GSK II (ABSSSI/CAP) * new target (not yet exploited) dual site of action for oritavancin ** old target but not exploited in human systemic medicine Two PIII trials completed; NDA filing projected 2H13

17 Anti Gram-positive Agents in the Pipeline Fluoroquinolones Class Company Drug Status (clinical) Timing Rib-X delafloxacin III (ABSSSI) II (CAP) TaiGen nemonoxacin II (CAP/dfi) Furiex JNJ-Q2 III CAP/ABSSSI Entering PIII Lipogycopeptides (*) Durata dalbavancin III ABSSSI Near Term The MedCo oritavancin III (ABSSSI) Ketolides Adv. Life Sci. cethromycin III (CAP) / anthrax First PIII for ABSSSI started in 1H2013 NDA late September Projected launch 2H14 PIII completed Projected filing 4Q13 in US; 2014 European filing Additional data requested by FDA / operations suspended Cempra solithromycin III (CAP) 4Q13 Initiation of PIII trial in CABP Oxazolidinones Trius tedizolid III (ABSSSI) Rib-X radezolid II ABSSSI/CAP) Pleuromotulin (*) Nabriva BC-3781 II (ABSSSI) Peptidomimetic (**) Polymedics PMX II (ABSSSI) Fab inhibitor (**) Affinium AFN-1252 II (ABSSSI) Deformylase inhibitor (**) GSK GSK II (ABSSSI/CAP) * new target (not yet exploited) dual site of action for oritavancin ** old target but not exploited in human systemic medicine Two PIII trials completed; NDA filing projected 2H13

18 Dalbavancin First Phase 3 trial was conducted Jan 2003 May 2004 Two new Phase 3 clinical trials for ABSSSI are completed Dalbavancin vs linezolid (2:1) Primary outcome was clinical success in CE population at day 28 (TOC visit) Non-inferiority demonstrated 57% MRSA Most patients who were early responders also demonstrated clinical success at EOT When re-assessed, early response endpoint may have limitions specifically a low negative predictive value (34% in this study) DISCOVER 1 and DISCOVER 2 trials Multicenter, double-blind, doubledummy, randomized trials Two doses (1000 mg day 1; 500 mg day 8) of IV dalbavancin vs IV vancomycin (with option to switch to linezolid PO after 3 days) for 10 to 14 days Both traditional end-of-treatment (EOT) and new early FDA-suggested endpoints being assessed Jauregui LE, et al. Clin Infect Dis 2005; 41(10):

19 Dalbavancin - Phase III ABSSSIs Trials DISCOVER 1 DISCOVER 2 Efficacy Analysis Dalbavancin (n=258) Vancomycin- Linezolid (n=285) Dalbavancin (n=371) Vancomycin- Linezolid (n-368) Primary Endpoint (48-72 hours) Clinical Success >20% Reduction in Lesion Size 83.3% 89.9% 81.8% 90.9% 76.8% 87.6% 78.3% 85.9% Clinical Success (EOT - Day 14) CE population ITT population 87.0% 81.9% 91.4% 86.7% 93.5% 88.7% 92.7% 85.6% Clinical Success (Day 28) CE population ITT population 93.8% 83.7% 96.1% 88.1% 96.3% 88.1% 94.5% 84.5% Boucher HW, et al. Poster L-201. ICAAC 2013, Denver, CO Wilcox M, et al. Poster L-202. ICAAC 2013, Denver, CO

20 Dalbavancin Once-a-week dosing with dalbavancin May obviate the need for the continued presence of IV lines in some patients, which could translate into fewer local infections and blood stream infections and which could facilitate transfer of the patients to skilled nursing facilities 30-minute infusion once-a-week for two doses Development of systems to monitor infection, underlying diseases and outcomes will be required Appropriate patient selection will be important Reimbursement questions outside of infusion center

21 Oritavancin Previous FDA submission resulted in response letter from FDA in 2008 Two new Phase 3 clinical trials for ABSSSI are completed Needed to conduct additional trials Needed more MRSA patients Needed to assess impact on macrophage dysfunction (and possible subsequent infections) Needed to further assess safety issues This trial was conducted with 200 mg doses given daily for 3 to 7 days vs 7 to 10 days of vancomycin (with possible step-down to cephalexin for cases not involving MRSA) SOLO I and SOLO II trials Multicenter, double-blind, randomized trials Single dose (1200 mg) of oritavancin vs 7 to 10 days of IV vancomycin Both traditional post treatment evaluation (PTE) and new early endpoints met Dunbar LM, et al. Antimicrob Agents Chemother 2011; 55: Billstein S, Eagle G. Eur Infect Dis 2011; 5(2): Ambrose PG, et al. Clin Infect Dis 2012; 54(S3): S220 8

22 Oritavancin - Phase III ABSSSIs Trials SOLO 1 SOLO 2 Efficacy Analysis Oritavancin (n=475) Vancomycin (n=476) Oritavancin (n=503) Vancomycin (n-502) Primary Endpoint (48-72 hours) Clinical Success >20% Reduction in Lesion Size 82.3% 86.9% 78.9% 82.9% 80.1% 85.9% 82.9% 85.3% Clinical Cure Rate (Day 7-14) ITT population 79.6% 80.0% 82.5% 80.5% Confirmed MRSA Infections Primary Endpoint (48-72 hours) Clinical Success >20% Reduction in Lesion Size 80.8% 90.4% 80.0% 84.0% 82.0% 96.0% 81.2% 90.1% Clinical Cure Rate (Day 7-14) 82.7% 83.0% 84.0% 85.1% Corey R, et al. Poster L-204. ICAAC 2013, Denver, CO Corey R, et al. Poster L-206c. ICAAC 2013, Denver, CO

23 Oritavancin - Phase III ABSSSIs Trials The rates of serious adverse events, adverse events (AEs) and study drug discontinuations were similar for each regimen The most common AEs for Oritavancin and Vancomycin were: SOLO 1: nausea (11.0% vs 8.9%), headache (7.2% vs 7.9%), pruritus (3.4% vs 9.1%), infusion site reaction (4.0% vs 7.1%), infusion site extravasation (3.8% vs 4.8%), vomiting (4.9% vs 3.7%), constipation (4.0% vs 4.4%), diarrhea (4.9% vs 3.5%), and cellulitis (4.2% vs 3.5%) SOLO 2: nausea (8.9% vs 12.0%), headache (7.0% vs 5.6%), vomiting (4.4% vs 5.6%), pruritus (2.6% vs 5.8%), cellulitis (3.4% vs 3.0%), constipation (2.8% vs 3.4%), and diarrhea (2.6% vs 3.0%) Corey R, et al. Poster L-204. ICAAC 2013, Denver, CO Corey R, et al. Poster L-206c. ICAAC 2013, Denver, CO

24 Oritavancin Concern regarding potential that accumulation of oritavancin in macrophage may cause dysfunction Macrophage killing in the presence or absence of oritavancin was tested and found that oritavancin accumulation does not prevent phagocytic killing of key pathogens Single dose yields similar cure rates as daily dosing in ABSSSI Shift in treatment paradigm but may match healthcare reimbursement and delivery changes? Extended infusion time Development of systems to monitor infection, underlying diseases and outcomes will be required Appropriate patient selection will be important Reimbursement questions Baquir B, et al. Clin Infect Dis 2012; 54(S3): S Billstein S, Eagle G. Eur Infect Dis 2011; 5(2): Tice A. Clin Infect Dis 2012; 54(S3): S239 43

25 Tedizolid: Second Generation Oxazolidinone Attribute Linezolid Tedizolid Antimicrobial Activity Bacteriostatic Bactericidal Differences in Potency 4- to 16-fold increased potency of TDZ to ribosomal target binding pocket Activity Against cfr-linezolid- Resistant Strains No Yes Dose per day 1200 mg 200 mg Dosing Frequency (IV/oral) Twice daily Once daily Treatment Duration 10 to 14 days 6 days Shaw KJ, Barbachyn MR. Ann NY Acad Sci 2011; 2041: Prokocimer P, et al. JAMA 2013; 309:

26 Treatment Response (%) Tedizolid Integrated Phase III ABSSSIs Trials ,6 79, hours (>20% Lesion Area Reduction) Tedizolid Linezolid 87 87,9 86,7 86,8 EOT (Programmatic Clinical Response) 7-14 Days Post-EOT (Investigator Assessed Response) De Anda C, et al. Poster L-203. ICAAC 2013, Denver, CO Results from ESTABLISH-1 (oral only) and ESTABLISH-2 (IV with option oral switch) Prokocimer P, et al. JAMA 2013; 309:

27 Tedizolid Integrated Phase III ABSSSIs Trials Abnormal Laboratory Values for Platelets (all patients) Study Day 7-9 (N1) Below LLN Below 75% of LLN Laboratory: Platelets (10 9 /L) Tedizolid (n=662) n (%) (3.2) 8 (1.4) Linezolid (n=662) n (%) (5.6) 12 (2.2) P-value* Study day (N1) Below LLN Below 75% of LLN (4.9) 7 (1.3) (10.8) 20 (3.7) Last dose of active drug (N1) Below LLN Below 75% of LLN (3.7) 9 (1.6) (10.8) 17 (3.3) < Any post-baseline through last dose (N1) Below LLN Below 75% of LLN (6.4) 6 (2.1) (12.6) 21 (4.5) De Anda C, et al. Poster L-203. ICAAC Includes all patients in safety analysis set; N1 is number of patients with non-missing data at summarized visit LLN = lower limit of normal; Substantially abnormal is <75% of LLN * Fisher s exact test

28 Patients with TEAEs (%) Tedizolid Integrated Phase III ABSSSIs Trials 60 Tedizolid Linezolid ,7 43, , Overall TEAEs Overall GI TEAEs GI TEAEs by Day 7 TEAEs - Treatment-emergent adverse events; GI gastrointestinal De Anda C, et al. Poster L-203. ICAAC 2013, Denver, CO Results from ESTABLISH-1 (oral only) and ESTABLISH-2 (IV with option oral switch)

29 How useful will these new anti-mrsa agents be in the future? Phase III ABSSSIs studies are promising and have identified new dosage regimens and/or shorter duration of therapy These agents should provide further opportunities for outpatient treatment of MRSA infections because of oral administration or 1 to 2 doses of IV therapy These advantages will need to be evaluated and compared to older and generic agents in regards to the use of healthcare resources and patient outcomes Impact of results from other clinical trials in severely ill patients and other types of MRSA infections such as pneumonia, bacteremia and/or endocarditis The need to further explore improved coverage against resistant pathogens such as vancomycin-intermediate Staphylococcus aureus (VISA), linezolidresistant Staphylococcus aureus, and MRSA with reduced susceptibility to daptomycin