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Antibiotic Update 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 antimicrobial 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 penicillin ...… 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 infection 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 1 3/5/2015 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 Types of Resistance Antibiotic Approvals ESBL AmpC Carbapenemases MOA Hydrolyze penicillins, Hydrolyze narrow, broad Vary in the ability to cephalosporins, and expanded spectrum hydrolyze carbapenems aztreonam cephalosporins and and other B-lactams cephamycins 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 2 3/5/2015 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 Fidaxomicin 2011 Clostridium difficile sold without generic competition Tedozolid June 2014 Gram positive – Qualified Infectious Disease Product (QIDP) Oritavancin 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 Dalbavancin May 2014 Gram positive of exclusivity under the Hatch-Waxman Act Ceftolozane + Tazobactam December 2014 Gram negative • Obama Administration Takes Actions to Combat Ceftazidime + Avibactam February 2015 Gram negative Antibiotic-Resistant Bacteria – Section 5. Improved Antibiotic Stewardship Delafloxacin Phase 3 Trials Gram negative and gram positive Ceftaroline (Teflaro ®) 2010 Ceftaroline Publications • Persistent Staphylococcal Bacteremia Class/MOA Broad-spectrum cephalosporin Spectrum Gram positive (MRSA) and gram negative associated with skin and skin – After vancomycin failure, MRSA guidelines recommend structure infections 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 daptomycin 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 nafcillin been reported • Hemolytic anemia was not reported • Sensitization to innate host defense peptide 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 Macrolide, 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, metronidazole, rifaximin 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 3 3/5/2015 Tedizolid phosphate (SIVEXTRO™) 2014 Tedizolid vs Linezolid 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 Lipoglycopeptide 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
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