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Home , Brilacidin, Lipoglycopeptide, Relebactam

3/5/2015

Disclosure

Antibiotic Update • I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this Ashley Gustafson, Pharm.D., BCPS continuing education activity, or any affiliation PGY-2 Critical Care Pharmacy Resident with an organization whose philosophy could potentially bias my presentation Baptist Hospital of Miami

Pharmacist Objectives Technician Objectives

• Review resistance patterns • Recognize new antimicrobial agents and their appropriate use in infectious disease • Assess new antimicrobial agents and their appropriate indications • Discuss what is new in the antimicrobial pipeline • Discuss what is new in the antimicrobial pipeline • Explain why antimicrobial stewardship is • Explain why antimicrobial stewardship is important important

Antibiotic Resistance Threats Antibiotic Resistance

Variable Microbes Humans Factor

“The microbes are educated to resist ...… In such No. on earth 5 x 10 31 6 x 10 9 ~ 10 22 cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to Mass, metric ton 5 x 10 16 3 x 10 8 ~ 10 8 with the penicillin-resistant organism. I hope this evil 5 can be averted.” Generation time 30 min 30 years ~ 5 x 10 - Sir Alexander Fleming 1945 Time on earth, 3.5 x 10 9 4 x 10 6 ~ 10 3 years

Spellberg B et al. CID 2008;46:155-64

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Antibiotic Resistance Antibiotic Pressure

• Existed before • Caused by 4 general mechanisms – Inactivation/modification of antibiotic – Alteration of the target site – Modification of metabolic pathways to evade antibiotic effect – Reduced intracellular antibiotic accumulation by decreasing permeability and/or increasing efflux • Intrinsic in some species, acquired in others • So common that some organisms survive on antibiotics as their carbon source • Selected for by antibiotic pressure

Types of Resistance Antibiotic Approvals ESBL AmpC Carbapenemases MOA Hydrolyze , Hydrolyze narrow, broad Vary in the ability to , and expanded spectrum hydrolyze cephalosporins and and other B-lactams Common • CTX-M • CMY • Class A enzymes • SHV • FOX • KPC • TEM • DHA •Class B • NDM-1

• VIM Approvals • IMP • Class D • OXA Common • E. coli • Klebsiella spp. •Enterobacteriace bacteria • K. pneumoniae • Salmonella spp. • Pseudomonas spp. • K. oxytoca • C. freundii • Acinetobacter spp. • P. mirabilis • E. aerogenes • P. mirabilis • E. coli

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Government Takes Action New Antibiotics

• FDA Safety and Innovation Act Antibiotic FDA Approval Coverage – GAIN Act Generating Antibiotic Incentives Now Ceftaroline 2010 Gram positive • Extends by 5 years the exclusivity period during certain antibiotics can be 2011 difficile sold without generic competition Tedozolid June 2014 Gram positive – Qualified Infectious Disease Product (QIDP) August 2014 Gram positive • Provides incentives for the development of new antibiotics, including priority review and eligibility for the FDA’s fast track program, and a 5 year extension May 2014 Gram positive of exclusivity under the Hatch-Waxman Act Ceftolozane + December 2014 Gram negative

• Obama Administration Takes Actions to Combat + February 2015 Gram negative Antibiotic-Resistant Bacteria – Section 5. Improved Antibiotic Stewardship Phase 3 Trials Gram negative and gram positive

Ceftaroline (Teflaro ®) 2010 Ceftaroline Publications • Persistent Staphylococcal Bacteremia Class/MOA Broad-spectrum Spectrum Gram positive (MRSA) and gram negative associated with skin and skin – After failure, MRSA guidelines recommend structure and community acquired pneumonia combination therapy for bacteremia Does not cover Pseudomonas, Enterococcus, Acinetobacter or gram negative anaerobes Dose • 600mg IV q12h – Ceftaroline has synergistic activity with and • Renal dose adjustment when CrCl < 50mL/min, dose is decreased but may be a treatment option for resistant MRSA infections remains q12h dosing Safety In clinical trials, no adverse reactions in >5% of patients • Induces daptomycin binding to MSSA and MRSA to a Monitoring • Seroconversion from a negative to a positive direct Coombs’ test has comparable degree as studies with been reported • Hemolytic anemia was not reported • Sensitization to innate host defense cathelicidin Drug interactions • No clinical drug-drug interaction studies have been conducted LL37, which could attenuate virulence of the pathogen • May increase effects of vitamin K antagonists Special Pregnancy category B considerations

Fidaxomicin (Dificid ®) 2011 Fidaxomicin Publications • Fidaxomicin Preserves the Intestinal Microbiome During and Class/MOA , protein synthesis inhibitor After Treatment of C.diff Spectrum Clostridium spp. Including all types of C. difficile – Preservation of the major microbiome components with fidaxomicin versus vancomycin Does not cover Gram negative organisms, bacteroides spp., staph aureus, coagulase-negative staph, enterococcus – Reappearance of toxin in fecal filtrates observed in 28% vanco treated patients vs 14% fidaxomicin Dose • 200mg tablet PO BID for 10 days, with or without food • No renal or hepatic dose adjustments – 23% vanco patients C.diff reoccurrence vs 11% fidaxocmicin reoccurrence Safety Most common adverse reactions: nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal • Fidaxomicin Inhibits Spore Production in C.Diff hemorrhage (4%), anemia (2%), and neutropenia (2%) – Possible mechanism of reducing recurrence Monitoring Acute sensitivity reactions have been reported – Compared to vanco, , Drug interactions Several tested, none noted – Fidaxomicin inhibited sporulation when added to early stationary phase Special Not approved in patients <18 years of age cells in C.diff strains, the comparator drugs did not considerations

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Tedizolid phosphate (SIVEXTRO™) 2014 vs

Class/MOA Oxazolidinone, protein synthesis inhibitor Studies Tedizolid Linezolid Spectrum MSSA, MRSA, Streptococcus spp., Enterococcus faecalis Dosage 200mg q24h IV or PO x6 days 600mg q12h IV or PO x10 days Approved for skin and skin structure infections, in phase 3 Dose adjustments No renal/hepatic adjustments No renal/hepatic adjustments clinical trials for hospital acquired pneumonia Kinetics T ½ = 12 h T ½ = 6 h Does not cover Gram negatives ESTABLISH-1 Early clinical improvement in Early clinical improvement in 266/335 ENDPOINT 264/332 (79.5%) (79.4%) Dose • 200mg once daily for 6 days (IV and PO formulations) • IV formulation given over 1 hour, reconstituted in NS, do not ESTABLISH-2 Early clinical improvement in Early clinical improvement in 276/334 mix with lactated ringers or divalent cations ENDPOINT 283/332 (85%) (83%) • No renal or hepatic dose adjustments Serotonin toxicity 0% mouse head twitch 4.5 x mouse head twitch at human equivalent dose, same with fluoxetine Safety Peripheral and optic neuropathy, dizziness, nausea MAOI 550mg needed with tyramine to Human equivalent dose+ tyramine Monitoring Neutropenia see > 30mmHg of BP observed >30mmHg of BP increase Drug interactions None, several tested, does NOT have the labeling warning for Myelosuppression Phase 1 study: Day 21 possible Observed with underlying MAOI or Serotonin toxicity dose and duration effect (seen at hematologic abnormalities and renal 400mg) insufficiency Pharmacokinetics • Oral bioavailability 91% Platelets <112k 2.3% patients Platelets <112k 4.9% patients • t ½:12h Peripheral/optic Not tested in patients over 6 days Seen in patients after 28 days of •70-90% protein binding neuropathy therapy

Oritavancin (Orbactiv™) 2014 Oritavancin Study Class/MOA antibacterial Spectrum MSSA, MRSA, Strepococcus spp. Enterococcus faecalis Approval for skin and skin structure infections • Primary endpoints Does not cover Gram negative • Early clinical improvement (FDA) Dose • 1200mg single dose IV infusion over 3 hours • Both cessation of spread of erythema associated with • Reconstitute ONLY in D5W for dilution, do NOT use NS • No renal or hepatic dose adjustments the infection and a temperature of 37.6 C or lower Safety Headache, nausea, vomiting, diarrhea, limb and • Post-therapy cure (EMA) subcutaneous abscess in ~3% of patients Monitoring Use of unfractionized heparin sodium is contraindicated for 48 hours after administration, activated aPTT test results may Primary End Point Oritavancin Vancomycin remain falsely elevated for ~48h Primary efficacy 391/475 (82.3%) 378/479 (78.9%) Drug interactions Nonspecific weak inducer of CYP3A4 and 2D6 Post-therapy 378/457 (79.9%) 383/479 (80%) Inhibitor of 1A2, 2B6, 2D6,2C9,2C19 and 3A4 Lesion reduction 413/475 (86.9%) 397/479 (82.9%) Caution with drugs that are metabolized through CYP450 enzymes MRSA success 84/104 (80.8%) 80/100 (80%) Pharmacokinetics •T ½ : 200 hours •85% protein binding

Dalbavancin (Dalvance™) 2014 Dalbavancin Studies

Class/MOA Lipoglycopeptide antibacterial • Primary end point: Early clinical improvement Spectrum MSSA, MRSA, Streptococcus spp including Strep. pyogenes, Strep. agalcatiae and Strep. Anginosus • Dalbavancin compared to intravenous vancomycin 1g or Approved for skin and skin structure infections 15mg/kg q12h for at least 3 days, with an option to switch to oral Does not cover Gram negatives linezolid 600mg q12h to complete 10 to 14 days of therapy Dose • Two dose regimen: • 1000mg followed one week later by 500mg. •CrCl<30mL/min dose 750mg followed by 375mg Primary End Point Dalbavancin Vanco/linezolid • Patients receiving regular hemodialysis receive full DISCOVER 1 240/288 (83.3%) 233/285 (81.8%) dose (administered without regard to HD time) DISCOVER 2 285/371 (76.8%) 288/368 (78.3%) Adverse Reaction Nausea, headache, diarrhea Pooled Analysis 525/659 (79.7%) 521/653 (79.8%) Monitoring Monitor ALT MRSA Success 72/74 (97.3%) 49/50 (98%) Drug interactions Does not interfere with CYP450 isoenzymes Pharmacokinetics • t ½ : ~8.5 days • 93-99% protein bound

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Ceftolozane/tazobactam Oritavancin vs Dalbavancin (Zerbaxa™) 2014 Oritavancin Dalbavancin Class/MOA Novel cephalosporin/established Beta-lactamase inhibitor combination Dosage 1200mg one time dose Two dose regimen 1000mg then one week later Spectrum • Activity against multidrug-resistant gram negative bacilli 500mg • Potent anti-pseudomonal activity • Tazobactam protects ceftolozane from many ESBLs and Dose Adjustment No renal/hepatic adjustments Renal adjustment required cephalosporinases Pharmacokinetic T ½ = 10.2 days T ½ = 8.5 days Does not cover MSSA, MRSA, enterococcus Protein binding 85% Protein binding 93-99% <5% of drug recovered in urine Renal excretion 33% Indications • complicated UTI, including pyelonephritis after 7 days • 1500mg q8H vs 750mg IV • complicated intra-abdominal infections Safety Headache, nausea, vomiting, limb Nausea, headache, diarrhea • 1000/500mg q8h + metronidazole vs mero and subcutaneous abscesses and • Hospital acquired and ventilator associated pneumonia diarrhea trials are ONGOING Monitoring ALT None noted • 3000mg q8h vs pipericillin/tazobactam Drug interactions Unfractionated heparin, drugs None noted Safety Headache, nausea, constipation, hypertension, diarrhea, predominately metabolized by fever, insomnia and vomiting CYP450 (Consistent with other cephalosporins)

Ceftolozane/tazobactam Ceftolozane/tazobactam

• Double-blind, active control study of ceftolozane/tazobactam • Double-blind, active control study of ceftolozane/tazobactam 1000/500mg IV q8h vs levaquin 750mg IV q24h for complicated UTI 1000/500mg IV q8h + metronidazole 500mg IV q8h vs • Non-inferiority with 10% margin 1g IV q8h for intra-abdominal infections • Primary endpoint: composite of microbiological eradication and • Non-inferiority with 10% margin in modified intention to treat clinical cure rate at 5-9 days after end of therapy (test of cure) population (MITT) and micro group Population Ceftolozane/ Levofloxacin Difference • Primary end point: clinical cure rate 26-30 days after initiation of tazobactam therapy Microbiological modified 306/398 (76.9%) 275/68.4 (68.4% 8.5% Population Ceftolozane/ Meropenem Difference intent to treat patients tazobactam + MTZ Microbiologically evaluable 284/341 (83.3%) 266/353 (75.4%) 8.0% Modified intention-to- treat 323/389 (83.0%) 364/417 (87.3%) -4.2% patient Clinically evaluable 259/275 (94.2%) 304/321 (94.7%) -1.0% E.Coli eradication rates 90.5% 79.6% 10.9% E. Coli n=426 96% 95% K. Pneumonia eradication 84% 61% 23.1% K. Pneumonia n=53 100% 88% rate P. Aeruginosa n=53 100% 100% P. Aeruginosa eradication 86% 58% 23.1% rate

Ceftazidime/Avibactam(Avycaz™) Avibactam (NXL104) February 2015

• Novel beta-lactamase inhibitor Class/MOA Established ceftazidime/Novel beta- lactamase • Not based on beta-lactam structure inhibitor Spectrum • Gram negative infections including pseudomonas • ESBLs and KPCs Does not cover MSSA, MRSA, Enterococcus Pending approvals • Complicated UTI vs. -cilastatin • Complicated intra-abdominal infections vs. meropenem • Hospital acquired and ventilator associated Avibactam pneumonia trial is ONGOING • Active against KPC-type carbapenemases Dose 2000mg/500mg IV q8h given over 2 hours Safety /Monitoring Expected typical cephalosporin safety profile • Being studied with ceftazidime, ceftaroline (Phase II) and aztreonam (phase I)

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Ceftazidime/Avibactam Delafloxacin – Phase 3

• Intra-abdominal Infection – Phase II , n= 203 Class/MOA Fluoroquinolone – Ceftazidime/avibactam 2gm/500mg IV q8h given with metronidazole 500mg Spectrum Gram positive including MRSA, N. gonorrheae, IV q8h vs meropenem 1g IV q8h some GNR activity Population Ceftazidime/avibactam + Meropenem Difference Metronidazole Uses/Pending • Skin and Skin structure infections vs vancomycin and Microbiologically 62/68 (91.2%) 71/76 (93.4%) -2.2% Approvals linezolid evaluable patients • Uncomplicated gonorrhea vs mMITT 70/85 (82.4%) 79/89 (88.8%) -6.4% Dose • ABSSI: Delafloxacin 300mg IV q12h vs Vanco 15mg/kg • Complicated urinary tract infection, pyelonephritis IV q12h and linezolid 600mg IV q12h – Phase II clinical trial, n= 135 – Ceftazidime/avibactam 500mg/125mg IV q8h vs imipenem 500mg IV q6h • Gonorrhea: Delafloxacin 900mg PO x1 dose vs ceftriaxone 250mg IM x1 dose Population Ceftazidime/avibactam Imipenem-cilastatin Difference Safety Nausea (22%), diarrhea (15%), and vomiting (13%) Microbiologically 19/27 (70.4%) 25/35 (71.4%) -1.1% evaluable patients Clinically evaluable 24/28 (85.7%) 21/26 (80.6%) 5.1% patients

Delafloxacin Pipeline Agent Coverage Trial Phase Ceftaroline/Avibactam • Gram + (MRSA) Phase II • Enterobacteriaceae (ESBL and KPC) • NOT pseudomonas or Acinetobacter Aztreonam/Avibactam • Gram – coverage Phase I Imipenem/Cilastatin/ • Gram + similar to imipenem Phase II • Enterobacteriaceae (ESBL and KPC) Phase III planned for 2015 • Anaerobes Meropenem/RPX7009 • ESBL and KPC Phase III • Semisynthetic Phase II UTI • KPC and metallo-beta lactamases Phase III superiority study for • Moderate Pseudomonas activity CRE • Novel antibiotic Phase II • Gram + (MRSA, Enterococcus faecium) • Gram – (NDM-1) In a Phase 2 trial for skin and skin structure infections, the primary • Fluoroketolide antibiotic Phase III endpoint of Investigators' Global Assessment of Cure, delafloxacin was • Gram + (MRSA, S.pneumoniae) comparable to vancomycin (95% Confidence Interval -30.3%, -2.3%; • Atypicals and gonorrhea p=0.031) • , similar to Phase III • MRSA, VRE, CRE, Anaerobes

Fighting Back Against Antibiotic Resistance Antimicrobial Stewardship

Preventing infections, preventing spread • Pharmacist Role

– Ensure all orders have a Tracking resistance patterns • Dose • Duration • Indication Improving use of antibiotics – Obtain cultures before starting antibiotics – Take an “antibiotic timeout” reassessing antibiotics Developing new antibiotics and diagnostic tests after 48-72 hours

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True/False Questions References

• 1. Spellberg B, Guidos R, Gilbert D, et al. The Epidemic of Antibiotic-Resistant Infections: A Call to Action for the Medical Community from the • Ceftaroline covers the same bacteria as ceftriaxone Infectious Disease Society of America. CID 2008;46:155-64 • 2. Schmieder R, Edwards R. Insights into Antibiotic Resistance Through Metagenomic Approaches. Future Microbiol. 2012;7(1):73-89 • 3. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf but adds on coverage for MRSA • 4. Thomson KS. Extended-Spectrum-B-Lactamase, AmpC, and Carbapenemase Issues. J. Clin. Microbiol. Vol. 48, 2010, 1019-1025 • 5. Naas T, Cuzon G, Bogaerts P, et al. Evaluation of a DNA Microarray (Check-MDR CT102) for Rapid Detection of TEM, SHV, and CTX-M Extended- Spectrum B-lactamases and of KPC, OXA-48, VIM, IMP, and NDM-1 Carbapenemases. J. Clin. Microbiol. Vol. 49, No 4. 2011, 1608-1613 • 6. Boucher HW, Talbot GH, Bradley JS, et al. Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America. CID 2009:48:1-12 • 7. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda -gen/documents/document/ucm360058.pdf • Linezolid and tedizolid are both in the oxazolidinone • 8. TEFLARO () [prescribing information] St.Louis, MO. Forest Pharmaceuticals, Inc. 2011 • 9. Dhand A, Sakoulas G, et al. Daptomycin in Combination With Other Antibiotics for the Treatment of Complicated Methicllin-Resistant class and have contraindications for MAOI and Staphylcoccus aureus Bacteremia. Clinical Therapeutics. 2014;36:1303-1316 • 10. Sakoulas G, Moise P, Casapao A, et al. Antimicrobial Salvage Therapy for Persistent Staphylcoccal Bacteremia Using Daptomycin Plus Ceftaroline. Clinical Therapeutics.2014;36:1317-1333 serotonin toxicity • 11. Dificid (fidaxomicin) [prescribing information] Lexington, MA. Cubist Pharmaceuticals U.S. 2014 • 12. Louie TJ, Cannon K, Byrne B, et al. Fidaxomicin Preserves the Intestinal Microbiome During and After Treatment of Clostridium difficile Infection (CDI) and Reduces Both Toxin Reexpression and Recurrence of CDI. CID. 2012:55(suppl 2)S131-S142 • 13. Babakhani F, Bouillaut L, Gomez A, et al. Fidaxomicin Inhibits Spore Production in Clostridium difficle. CID 2012:55(Suppl2)S162-S169 • 14. Sivextro (tedizolid) [prescribing information] Lexington, MA. Cubist Pharmaceuticals U.S. 2014 • Delafloxacin is a new fluoroquinolone that has better • 15. Zyvox (linezolid) [prescribing information] New York, NY. Pfizer. 2008 • 16. Orbactiv (oritavancin) [prescribing information] Parsippany, NJ. The Medicines Company 2014 gram negative coverage than • 17. Dalvance (Dalbavancin) [prescribing information].Chicago, IL. Durata Therapeutics U.S. Limited 2014

References

• 18. Boucher H, et al. Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection. N ENG J MED 2014;370:2169-79 • 19. Safety and Efficacy Study of Ceftolozane/Tazobactam. Cubist Pharmaceuticals. http://clinicaltrials.gov • 20. Vazquez JA, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator blinded, randomized study. Curr Med Res Opin. 2012 Dec;28(12):1921-31 • 21. Lucasti C, et al. Comparative study of the efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double blind, Phase II trial. J Antimicrob Chemother 2013;68:1183-1192 • 22. Safety and Efficacy Study of Delafloxacin.. Melinta Therapeutics, Inc.. http://clinicaltrials.gov • 23. ceftaroline/avibactam http://clinicaltrials.gov • 24. aztreonam/avibactam http://clinicaltrials.gov • 25. Imipenem/cilastatin/relebactam http://clinicaltrials.gov • 26. Meropenem/RPX7009 http://clinicaltrials.gov • 27. Plazomicin http://clinicaltrials.gov • 28. Brilacidin http://clinicaltrials.gov • 29. Solithromycin http://clinicaltrials.gov • 30. Eravacycline http://clinicaltrials.gov

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