Antibiotic Update. Disclosure. Technician Objectives. Pharmacist Objectives. Antibiotic Resistance. Antibiotic Resistance Threats 3/5/2015

Transcription

1 Antibiotic Update Ashley Gustafson, Pharm.D., BCPS PGY-2 Critical Care Pharmacy Resident Baptist Hospital of Miami Disclosure I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation Pharmacist Objectives Review antimicrobial resistance patterns Assess new antimicrobial agents and their appropriate indications Discuss what is new in the antimicrobial pipeline Explain why antimicrobial stewardship is important Technician Objectives Recognize new antimicrobial agents and their appropriate use in infectious disease Discuss what is new in the antimicrobial pipeline Explain why antimicrobial stewardship is important Antibiotic Resistance Threats The microbes are educated to resist penicillin... In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted. - Sir Alexander Fleming 1945 Antibiotic Resistance Variable Microbes Humans Factor No. on earth 5 x x 10 9 ~10 22 Mass, metric ton 5 x x 10 8 ~ 10 8 Generation time 30 min 30 years ~ 5x 10 5 Time on earth, years 3.5 x x 10 6 ~ 10 3 Spellberg B et al. CID 2008;46:

2 Antibiotic Resistance Antibiotic Pressure Existed before antibiotics 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 MOA Common enzymes Common bacteria Types of Resistance ESBL AmpC Carbapenemases Hydrolyzepenicillins, cephalosporins, aztreonam CTX-M SHV TEM E.coli K. pneumoniae K. oxytoca P. mirabilis Hydrolyzenarrow, broad and expanded spectrum cephalosporins and cephamycins CMY FOX DHA Klebsiella spp. Salmonella spp. C. freundii E. aerogenes P. mirabilis E. coli Vary in the ability to hydrolyze carbapenems and other B-lactams ClassA KPC Class B NDM-1 VIM IMP Class D OXA Enterobacteriace Pseudomonas spp. Acinetobacter spp. Approvals Antibiotic Approvals 2

3 Government Takes Action FDA and Innovation Act GAIN Act Generating Antibiotic Incentives Now Extends by 5 years the exclusivity period during certain antibiotics can be sold without generic competition Qualified Infectious Disease Product (QIDP) 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 of exclusivity under the Hatch-Waxman Act Obama Administration Takes Actions to Combat Antibiotic-Resistant Bacteria Section 5. Improved Antibiotic Stewardship New Antibiotics Antibiotic FDA Approval Coverage Ceftaroline 2010 Grampositive Fidaxomicin 2011 Clostridium difficile Tedozolid June 2014 Gram positive Oritavancin August 2014 Gram positive Dalbavancin May 2014 Gram positive Ceftolozane + Tazobactam December 2014 Gram negative Ceftazidime + Avibactam February 2015 Gram negative Delafloxacin Phase 3 Trials Gram negative and gram positive Special considerations Ceftaroline(Teflaro ) 2010 Broad-spectrum cephalosporin Grampositive (MRSA) and gram negative associated with skin and skin structure infections and community acquired pneumonia Pseudomonas, Enterococcus, Acinetobacter or gram negative anaerobes 600mg IV q12h Renal dose adjustment when CrCl< 50mL/min, dose is decreased but remains q12h dosing In clinical trials, no adverse reactions in >5% of patients Seroconversion from a negative to apositive direct Coombs test has been reported Hemolytic anemia was not reported No clinical drug-drug interaction studies have been conducted May increase effects of vitamin K antagonists Pregnancy category B Ceftaroline Publications Persistent Staphylococcal Bacteremia After vancomycin failure, MRSA guidelines recommend combination therapy for bacteremia Ceftaroline has synergistic activity with daptomycin and may be a treatment option for resistant MRSA infections Induces daptomycin binding to MSSA and MRSA to a comparable degree as studies with nafcillin Sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen Fidaxomicin(Dificid ) 2011 Macrolide, protein synthesis inhibitor Clostridium spp. Including all types of C. difficile Gram negative organisms, bacteroides spp., staph aureus, coagulase-negative staph, enterococcus 200mg tablet PO BIDfor 10 days, with or without food No renal or hepatic dose adjustments Most commonadverse reactions: nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%) Special considerations Acute sensitivity reactions have been reported Several tested, none noted Not approved in patients <18 years of age Fidaxomicin Publications Fidaxomicin Preserves the Intestinal Microbiome During and After Treatment of C.diff Preservation of the major microbiome components with fidaxomicin versus vancomycin Reappearance of toxin in fecal filtrates observed in 28% vanco treated patients vs 14% fidaxomicin 23% vanco patients C.diff reoccurrence vs 11% fidaxocmicin reoccurrence Fidaxomicin Inhibits Spore Production in C.Diff Possible mechanism of reducing recurrence Compared to vanco, metronidazole, rifaximin Fidaxomicin inhibited sporulation when added to early stationary phase cells in C.diff strains, the comparator drugs did not 3

4 Tedizolid phosphate (SIVEXTRO ) 2014 Tedizolid vs Linezolid Pharmacokinetics Oxazolidinone, protein synthesis inhibitor MSSA, MRSA, Streptococcus spp., Enterococcus faecalis Approved for skin and skin structure infections, in phase 3 clinical trials for hospital acquired pneumonia Gram negatives 200mgonce daily for 6 days (IV and PO formulations) IV formulation given over 1 hour, reconstituted in NS, do not mix with lactated ringers or divalent cations No renal or hepatic dose adjustments Peripheral and optic neuropathy, dizziness, nausea Neutropenia None,severaltested, does NOT have the labeling warning for MAOI or Serotonin toxicity Oral bioavailability91% t ½:12h 70-90% protein binding Studies Tedizolid Linezolid Dosage 200mg q24hiv or PO x6 days 600mg q12h IV or PO x10 days adjustments No renal/hepatic adjustments No renal/hepatic adjustments Kinetics T½ = 12 h T ½ = 6 h ESTABLISH-1 ENDPOINT ESTABLISH-2 ENDPOINT Early clinical improvement in 264/332 (79.5%) Early clinical improvement in 283/332 (85%) Early clinicalimprovement in 266/335 (79.4%) Early clinical improvement in 276/334 (83%) Serotonintoxicity 0% mousehead twitch 4.5 x mouse head twitch at human equivalent dose, same with fluoxetine MAOI Myelosuppression Peripheral/optic neuropathy 550mg needed with tyramineto see > 30mmHg of BP Phase1 study: Day 21 possible dose and duration effect (seen at 400mg) Platelets <112k 2.3% patients Human equivalent dose+ tyramine observed >30mmHg of BP increase Observed with underlying hematologic abnormalities and renal insufficiency Platelets <112k 4.9% patients Not testedin patients over 6 days Seen in patientsafter 28 days of therapy Pharmacokinetics Oritavancin(Orbactiv ) 2014 Lipoglycopeptide antibacterial MSSA, MRSA, Strepococcus spp. Enterococcus faecalis Approval for skin and skin structure infections Gram negative 1200mg single dose IV infusion over 3 hours Reconstitute ONLY in D5W for dilution, do NOT use NS No renal or hepatic dose adjustments Headache, nausea, vomiting, diarrhea, limb and subcutaneous abscess in ~3% of patients Use of unfractionized heparin sodium is contraindicated for 48 hours after administration, activated aptttest results may remain falsely elevated for ~48h Nonspecific weak inducer of CYP3A4 and 2D6 Inhibitor of 1A2, 2B6, 2D6,2C9,2C19 and 3A4 Caution with drugs that are metabolized through CYP450 enzymes T ½: 200 hours 85% protein binding OritavancinStudy Primary endpoints Early clinical improvement (FDA) Both cessation of spread of erythema associated with the infection and a temperature of 37.6 C or lower Post-therapy cure (EMA) Primary End Point Oritavancin Vancomycin Primary efficacy 391/475 (82.3%) 378/479 (78.9%) Post-therapy 378/457 (79.9%) 383/479 (80%) Lesion reduction 413/475 (86.9%) 397/479 (82.9%) MRSA success 84/104 (80.8%) 80/100 (80%) Dalbavancin(Dalvance ) 2014 Dalbavancin Studies Adverse Reaction Pharmacokinetics Lipoglycopeptide antibacterial MSSA, MRSA, Streptococcus spp including Strep. pyogenes, Strep. agalcatiae and Strep. Anginosus Approved for skin and skin structure infections Gram negatives Two dose regimen: 1000mg followed one week later by 500mg. CrCl<30mL/min dose 750mg followed by 375mg Patients receiving regular hemodialysisreceive full dose (administered without regard to HD time) Nausea, headache, diarrhea Monitor ALT Does not interfere with CYP450 isoenzymes t ½ : ~8.5 days 93-99% protein bound Primary end point: Early clinical improvement Dalbavancin compared to intravenous vancomycin 1g or 15mg/kg q12h for at least 3 days, with an option to switch to oral linezolid 600mg q12h to complete 10 to 14 days of therapy Primary End Point Dalbavancin Vanco/linezolid DISCOVER 1 240/288 (83.3%) 233/285 (81.8%) DISCOVER 2 285/371 (76.8%) 288/368 (78.3%) Pooled Analysis 525/659 (79.7%) 521/653 (79.8%) MRSA Success 72/74 (97.3%) 49/50 (98%) 4

5 Oritavancin vs Dalbavancin Oritavancin Dalbavancin Dosage 1200mg one time dose Two dose regimen 1000mg then one week later 500mg Adjustment No renal/hepatic adjustments Renal adjustment required Pharmacokinetic T ½ = 10.2 days Protein binding 85% <5% of drug recovered in urine after 7 days Headache, nausea, vomiting, limb and subcutaneous abscesses and diarrhea T ½ = 8.5 days Protein binding 93-99% Renal excretion 33% ALT None noted Druginteractions Unfractionated heparin, drugs predominately metabolized by CYP450 Nausea, headache, diarrhea None noted Indications Ceftolozane/tazobactam (Zerbaxa ) 2014 Novelcephalosporin/established Beta-lactamase inhibitor combination Activity against multidrug-resistant gram negative bacilli Potent anti-pseudomonal activity Tazobactam protects ceftolozane from many ESBLs and cephalosporinases MSSA, MRSA, enterococcus complicated UTI, including pyelonephritis 1500mg q8h vs levofloxacin 750mg IV complicated intra-abdominal infections 1000/500mg q8h + metronidazole vs mero Hospital acquired and ventilator associated pneumonia trials are ONGOING 3000mg q8h vs pipericillin/tazobactam Headache, nausea,constipation, hypertension, diarrhea, fever, insomnia and vomiting (Consistent with other cephalosporins) Ceftolozane/tazobactam Ceftolozane/tazobactam Double-blind, active control study of ceftolozane/tazobactam 1000/500mg IV q8h vs levaquin 750mg IV q24h for complicated UTI Non-inferiority with 10% margin Primary endpoint: composite of microbiological eradication and clinical cure rate at 5-9 days after end of therapy (test of cure) Population Microbiological modified intent to treat patients Microbiologically evaluable patient Ceftolozane/ tazobactam Levofloxacin 306/398 (76.9%) 275/68.4 (68.4% 8.5% 284/341 (83.3%) 266/353 (75.4%) 8.0% Difference E.Coli eradication rates 90.5% 79.6% 10.9% K. Pneumonia eradication rate P. Aeruginosaeradication rate 84% 61% 23.1% 86% 58% 23.1% Double-blind, active control study of ceftolozane/tazobactam 1000/500mg IV q8h + metronidazole 500mg IV q8h vs meropenem 1g IV q8h for intra-abdominal infections Non-inferiority with 10% margin in modified intention to treat population (MITT) and micro group Primary end point: clinical cure rate days after initiation of therapy Population Ceftolozane/ tazobactam + MTZ Meropenem Difference Modified intention-to- treat 323/389 (83.0%) 364/417 (87.3%) -4.2% Clinically evaluable 259/275 (94.2%) 304/321 (94.7%) -1.0% E. Coli n=426 96% 95% K. Pneumonia n=53 100% 88% P. Aeruginosa n=53 100% 100% Avibactam(NXL104) Novel beta-lactamase inhibitor Not based on beta-lactam structure Avibactam Active against KPC-type carbapenemases Being studied with ceftazidime, ceftaroline (Phase II) and aztreonam (phase I) Ceftazidime/Avibactam(Avycaz ) February 2015 Pending approvals / Established ceftazidime/novel beta- lactamase inhibitor Gram negative infections including pseudomonas ESBLs and KPCs MSSA, MRSA, Enterococcus Complicated UTI vs. imipenem-cilastatin Complicated intra-abdominal infections vs. meropenem Hospital acquired and ventilator associated pneumonia trial is ONGOING 2000mg/500mg IV q8h given over 2 hours Expected typical cephalosporin safety profile 5

6 Ceftazidime/Avibactam Intra-abdominal Infection Phase II clinical trial, n= 203 Ceftazidime/avibactam 2gm/500mg IV q8h given with metronidazole 500mg IV q8h vs meropenem 1g IV q8h Population Ceftazidime/avibactam + Metronidazole Microbiologically evaluable patients Meropenem Difference 62/68 (91.2%) 71/76 (93.4%) -2.2% mmitt 70/85 (82.4%) 79/89 (88.8%) -6.4% Complicated urinary tract infection, pyelonephritis Phase II clinical trial, n= 135 Ceftazidime/avibactam 500mg/125mg IV q8h vs imipenem 500mg IV q6h Population Ceftazidime/avibactam Imipenem-cilastatin Difference Microbiologically evaluable patients Clinically evaluable patients 19/27 (70.4%) 25/35 (71.4%) -1.1% 24/28 (85.7%) 21/26 (80.6%) 5.1% Uses/Pending Approvals Delafloxacin Phase 3 Fluoroquinolone Gram positiveincluding MRSA, N. gonorrheae, some GNR activity Skin and Skin structure infections vsvancomycinand linezolid Uncomplicated gonorrhea vs ceftriaxone ABSSI: Delafloxacin 300mg IV q12h vsvanco15mg/kg IV q12h and linezolid 600mg IV q12h Gonorrhea: Delafloxacin 900mg PO x1 dose vs ceftriaxone250mg IM x1 dose Nausea (22%), diarrhea (15%), and vomiting (13%) Delafloxacin In a Phase 2 trial for skin and skin structure infections, the primary endpoint of Investigators' Global Assessment of Cure, delafloxacin was comparable to vancomycin (95% Confidence Interval -30.3%, -2.3%; p=0.031) Pipeline Antimicrobials Agent Coverage Trial Phase Ceftaroline/Avibactam Gram + (MRSA) Enterobacteriaceae(ESBL and KPC) NOT pseudomonas or Acinetobacter Phase II Aztreonam/Avibactam Gram coverage Phase I Imipenem/Cilastatin/ Relebactam Gram+ similar to imipenem Enterobacteriaceae(ESBL and KPC) Anaerobes Meropenem/RPX7009 ESBL and KPC Phase III Plazomicin Brilacidin Solithromycin Eravacycline Semisynthetic aminoglycoside KPC and metallo-beta lactamases Moderate Pseudomonas activity Novel antibiotic Gram + (MRSA, Enterococcus faecium) Gram (NDM-1) Fluoroketolideantibiotic Gram + (MRSA, S.pneumoniae) Atypicals and gonorrhea Tetracycline, similar to tigecycline MRSA, VRE, CRE, Anaerobes Phase II Phase III planned for 2015 Phase IIUTI Phase III superiority study for CRE Phase II PhaseIII Phase III Fighting Back Against Antibiotic Resistance Preventing infections, preventing spread Tracking resistance patterns Improving use of antibiotics Developing new antibiotics and diagnostic tests Antimicrobial Stewardship Pharmacist Role Ensure all orders have a Duration Indication Obtain cultures before starting antibiotics Take an antibiotic timeout reassessing antibiotics after hours 6

7 True/False Questions Ceftaroline covers the same bacteria as ceftriaxone but adds on coverage for MRSA Linezolid and tedizolid are both in the oxazolidinone class and have contraindications for MAOI and serotonin toxicity Delafloxacin is a new fluoroquinolone that has better gram negative coverage than ciprofloxacin 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 Infectious Disease Society of America. CID 2008;46: Schmieder R, Edwards R. Insights into Antibiotic Resistance Through Metagenomic Approaches. Future Microbiol. 2012;7(1): Thomson KS. Extended--B-Lactamase, AmpC, and Carbapenemase Issues. J. Clin. Microbiol. Vol. 48, 2010, 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- B-lactamases and of KPC, OXA-48, VIM, IMP, and NDM-1 Carbapenemases. J. Clin. Microbiol. Vol. 49, No , Boucher HW, Talbot GH, Bradley JS, et al. Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society ofamerica. CID 2009:48: gen/documents/document/ucm pdf 8. TEFLARO (ceftaroline fosamil) [prescribing information] St.Louis, MO. Forest Pharmaceuticals, Inc Dhand A, Sakoulas G, et al. Daptomycin in Combination With Other Antibiotics for the Treatment of Complicated Methicllin-Resistant Staphylcoccus aureus Bacteremia. Clinical Therapeutics. 2014;36: Sakoulas G, Moise P, Casapao A, et al. Antimicrobial Salvage Therapy for Persistent Staphylcoccal Bacteremia Using Daptomycin Plus Ceftaroline. Clinical Therapeutics.2014;36: Dificid (fidaxomicin)[prescribing information] Lexington, MA. Cubist Pharmaceuticals U.S 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-S Babakhani F, Bouillaut L, Gomez A, et al. Fidaxomicin Inhibits Spore Production in Clostridium difficle. CID 2012:55(Suppl2)S162-S Sivextro (tedizolid)[prescribing information] Lexington, MA. Cubist Pharmaceuticals U.S Zyvox (linezolid)[prescribing information] New York, NY. Pfizer Orbactiv (oritavancin)[prescribing information] Parsippany, NJ. The Medicines Company 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: and Efficacy Study of Ceftolozane/Tazobactam. Cubist Pharmaceuticals 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 Dec;28(12): Lucasti C, et al. Comparative study of the efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenemin the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double blind, Phase II trial. J Antimicrob Chemother 2013;68: and Efficacy Study of Delafloxacin.. Melinta Therapeutics, Inc ceftaroline/avibactam aztreonam/avibactam Imipenem/cilastatin/relebactam Meropenem/RPX Plazomicin Brilacidin Solithromycin Eravacycline 7