Options for Complicated Skin and Skin Structure Infections

Andrew F. Shorr, MD, MPH Washington Hospital Center Georgetown Univ. Disclosures

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

Currently Used Therapy for MRSA

FDA-approved Nosocomial cSSSI Evidence Evidence Bacteremia Evidence agent Pneumonia Ceftaroline (IV) ✔ AI 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. 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

http://www.fda.gov/Drugs/DrugSafety/ucm369580.htm Accessed 9/30/13. Dosing and Monitoring Vancomycin ASHP/IDSA/SIDP Recommendations

• Loading Dose: 25-30 mg/kg IV (actual body weight) over 2 hours in seriously ill patients with suspected MRSA infection may be considered (C-III).

• Maintenance Dose: 15-20 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 15-20 mg/L is recommended (B-II) Rybak et al. Am J Health-Syst Pharm 2009;66:82-98 Clinical Outcome: Vancomycin MIC

2.69 (1.60,4.51) 1.64 (1.14,2.37)

0.01 0.1 1 10 100 0.01 0.1 1 10 100 Low MIC failure High MIC failure Low MIC mortality High MIC mortality

Van Hal SJ et al. Clin Infect Dis 2012;54:755-71 Resistance: Prior Vancomycin Use Predicts High MICs

No prior vancomycin Prior vancomycin

80 74 Logistic Regression Analysis of Risk Factors Associated with Vancomycin MIC ≥ 1.5 mcg/ml

70 63 60 Variable AOR P P = 0.002 value 50 (95% CI)

40 35 Vancomycin last 9.4 0.04 30 days (1.1-80.7)

30 Percent Isolates of Percent 20 16 ICU-acquired 5.3 0.02 11 10 bacteremia (1.4-20.4) 2 0 0,5 1 2

Vancomycin MIC (mcg/ml)

Moise et al, J Antimicrob Chemo 2008;61:85–90 Lodise et al, J Antimicrob Chemo 2008;62:1138-41 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

• 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 Hawser et al. International Journal of Antimicrobial Agents. 2011;37(3):219-24. Sakoulas G et al. J Clin Microbiol. 2004;42:2398-2402

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

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 Linezolid 600 mg IV q12h P=NS Vancomycin 15 mg/kg IV q12h;

titrate per ClCr and trough levels Clinical Success (%) ClinicalSuccess

219/239 193/220 191/227 167/209

*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):804-816. 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 Linezolid 600 mg IV q12h P=.048

Vancomycin 15 mg/kg IV q12h;

titrate per ClCr and trough levels Clinical Success (%) Clinical

254/284 243/287 223/276 196/266

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. 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. Telavancin: Current Indications FDA-approved indications (2009 - 2011):

• 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 Ceftaroline Ceftaroline is a cephalosporin with in vitro activity against Gram-positive and Gram-negative bacteria1

• 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 PBP2a1 – Ceftaroline has the ability to bind to PBP2a, the mutant protein that produces methicillin resistance in S. aureus2 • Ceftaroline is bactericidal against S. pneumoniae due to its affinity for PBP2x1

1. TEFLARO (ceftaroline fosamil) [prescribing information]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2012. 2. Moisan H, Pruneau M, Malouin F. J Antimicrob Chemother. 2010;65:713-716. Ceftaroline Indications

CABP ABSSSI

• Gram-positive bacteria • Gram-positive bacteria – S. pneumoniae (including – S. aureus (including cases with concurrent methicillin-susceptible and bacteremia) -resistant isolates) – S. aureus (methicillin- – S. pyogenes susceptible isolates only) – S. agalactiae • Gram-negative bacteria • Gram-negative bacteria – H. influenzae – E. coli – K. pneumoniae – K. pneumoniae – K. oxytoca – K. oxytoca – E. coli

Anti Gram-positive Agents in the Pipeline

Class Company Drug Status (clinical) Timing

Fluoroquinolones III (ABSSSI) II First PIII for ABSSSI started in Rib-X delafloxacin 1H2013 (CAP) TaiGen nemonoxacin II (CAP/dfi) Furiex JNJ-Q2 III CAP/ABSSSI Entering PIII Lipogycopeptides (*) NDA late September/projected Durata dalbavancin III ABSSSI launch 2H14 PIII completed – projected filing The MedCo oritavancin III (ABSSSI) 4Q13 in US; 2014 European filing Ketolides Additional data requested by FDA / Adv. Life Sci. cethromycin III (CAP) / anthrax operations suspended Cempra solithromycin III (CAP) 4Q13 Initiation of PIII trial in CABP Oxazolidinones Two PIII trials completed; NDA Trius tedizolid III (ABSSSI) filing projected 2H13 Rib-X radezolid II ABSSSI/CAP) Pleuromotulin (*) Nabriva BC-3781 II (ABSSSI) Peptidomimetic (**) Polymedics PMX-30063 II (ABSSSI) Fab inhibitor (**) Affinium AFN-1252 II (ABSSSI) Deformylase inhibitor (**) GSK GSK1322322 II (ABSSSI/CAP)

* new target (not yet exploited) – dual site of action for oritavancin ** old target but not exploited in human systemic medicine Anti Gram-positive Agents in the Pipeline

Class Company Drug Status (clinical) Timing

Fluoroquinolones III (ABSSSI) II First PIII for ABSSSI started in 1H2013 Rib-X delafloxacin (CAP) TaiGen nemonoxacin II (CAP/dfi) Furiex JNJ-Q2 III CAP/ABSSSI Entering PIII Lipogycopeptides (*) NDA late September Durata dalbavancin III ABSSSI Projected launch 2H14 Near Term PIII completed – Projected filing The MedCo oritavancin III (ABSSSI) 4Q13 in US; 2014 European filing Ketolides Additional data requested by FDA / Adv. Life Sci. cethromycin III (CAP) / anthrax operations suspended Cempra solithromycin III (CAP) 4Q13 Initiation of PIII trial in CABP Oxazolidinones Two PIII trials completed; Trius tedizolid III (ABSSSI) NDA filing projected 2H13 Rib-X radezolid II ABSSSI/CAP) Pleuromotulin (*) Nabriva BC-3781 II (ABSSSI) Peptidomimetic (**) Polymedics PMX-30063 II (ABSSSI) Fab inhibitor (**) Affinium AFN-1252 II (ABSSSI) Deformylase inhibitor (**) GSK GSK1322322 II (ABSSSI/CAP)

* new target (not yet exploited) – dual site of action for oritavancin ** old target but not exploited in human systemic medicine Dalbavancin

First Phase 3 trial was conducted Two new Phase 3 clinical trials for Jan 2003 – May 2004 ABSSSI are completed

• Dalbavancin vs linezolid (2:1) • DISCOVER 1 and DISCOVER 2 trials • Primary outcome was clinical success in • Multicenter, double-blind, double- CE population at day 28 (TOC visit) dummy, randomized trials • Non-inferiority demonstrated – 57% • Two doses (1000 mg day 1; 500 mg MRSA day 8) of IV dalbavancin vs IV vancomycin (with option to switch to • Most patients who were early responders linezolid PO after 3 days) for 10 to 14 also demonstrated clinical success at days EOT • Both “traditional” end-of-treatment • When re-assessed, early response (EOT) and new early FDA-suggested endpoint may have limitions – specifically endpoints being assessed a low negative predictive value (34% in this study)

Jauregui LE, et al. Clin Infect Dis 2005; 41(10): 1407-15 Dalbavancin - Phase III ABSSSIs Trials

DISCOVER 1 DISCOVER 2

Vancomycin- Vancomycin- Efficacy Analysis Dalbavancin Linezolid Dalbavancin Linezolid (n=258) (n=285) (n=371) (n-368)

Primary Endpoint (48-72 hours) Clinical Success 83.3% 81.8% 76.8% 78.3% >20% Reduction in Lesion Size 89.9% 90.9% 87.6% 85.9%

Clinical Success (EOT - Day 14) CE population 87.0% 91.4% 93.5% 92.7% ITT population 81.9% 86.7% 88.7% 85.6%

Clinical Success (Day 28) CE population 93.8% 96.1% 96.3% 94.5% ITT population 83.7% 88.1% 88.1% 84.5%

Boucher HW, et al. Poster L-201. ICAAC 2013, Denver, CO Wilcox M, et al. Poster L-202. ICAAC 2013, Denver, CO 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

Oritavancin

Previous FDA submission resulted in Two new Phase 3 clinical trials for response letter from FDA in 2008 ABSSSI are completed

• Needed to conduct additional trials • SOLO I and SOLO II trials • Needed more MRSA patients • Multicenter, double-blind, randomized trials • Needed to assess impact on macrophage dysfunction (and possible • Single dose (1200 mg) of oritavancin subsequent infections) vs 7 to 10 days of IV vancomycin • Needed to further assess safety issues • Both “traditional” post treatment evaluation (PTE) and new early • This trial was conducted with 200 mg endpoints met 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)

Dunbar LM, et al. Antimicrob Agents Chemother 2011; 55: 3476–84 Billstein S, Eagle G. Eur Infect Dis 2011; 5(2): 98-101 Ambrose PG , et al. Clin Infect Dis 2012; 54(S3): S220–8 Oritavancin - Phase III ABSSSIs Trials

SOLO 1 SOLO 2

Efficacy Analysis Oritavancin Vancomycin Oritavancin Vancomycin (n=475) (n=476) (n=503) (n-502)

Primary Endpoint (48-72 hours) Clinical Success 82.3% 78.9% 80.1% 82.9% >20% Reduction in Lesion Size 86.9% 82.9% 85.9% 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 80.8% 80.0% 82.0% 81.2% >20% Reduction in Lesion Size 90.4% 84.0% 96.0% 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 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 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): S229–32 Billstein S, Eagle G. Eur Infect Dis 2011; 5(2): 98-101 Tice A. Clin Infect Dis 2012; 54(S3): S239–43 Tedizolid: Second Generation Oxazolidinone

Attribute Linezolid Tedizolid

Antimicrobial Activity Bacteriostatic Bactericidal

4- to 16-fold increased potency of TDZ Differences in Potency to ribosomal target binding pocket Activity Against cfr-Linezolid- No Yes Resistant Strains 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: 48–70 Prokocimer P, et al. JAMA 2013; 309: 559-69 Tedizolid – Integrated Phase III ABSSSIs Trials

Tedizolid Linezolid

100

90 87 87,9 86,7 86,8 81,6 79,4 80 70 60 50 40 30 20

10 Treatment Response (%) Response Treatment 0 48 - 72 hours EOT 7 - 14 Days Post-EOT (>20% Lesion Area (Programmatic (Investigator Reduction) Clinical Response) 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: 559-69 Tedizolid – Integrated Phase III AbnormalABSSSIs Laboratory Trials Values for Platelets (all patients) Laboratory: Tedizolid Linezolid (n=662) (n=662) P-value* Platelets (109/L) n (%) n (%)

Study Day 7-9 (N1) 554 551 Below LLN 18 (3.2) 31 (5.6) 0.0585 Below 75% of LLN 8 (1.4) 12 (2.2) 0.3778

Study day 11-13 (N1) 552 537 Below LLN 27 (4.9) 58 (10.8) 0.0003 Below 75% of LLN 7 (1.3) 20 (3.7) 0.0106

Last dose of active drug (N1) 546 520 Below LLN 20 (3.7) 56 (10.8) <0.0001 Below 75% of LLN 9 (1.6) 17 (3.3) 0.1114

Any post-baseline through last dose (N1) 627 626 Below LLN 27 (6.4) 54 (12.6) 0.0002 Below 75% of LLN 6 (2.1) 21 (4.5) 0.0175

De Anda C, et al. Poster L-203. ICAAC 2013. 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

Tedizolid – Integrated Phase III ABSSSIs Trials

Tedizolid Linezolid

60

50 42,7 43,2 40

30 23 18,9 20 16 13 Patients with TEAEs (%) TEAEs with Patients 10

0 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) 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), linezolid- resistant Staphylococcus aureus, and MRSA with reduced susceptibility to daptomycin